g^toijtw.i'.r'V-.-'.jR ;'.'-'..:«.:-.-r.-.::;.;.'-: v.. iV.. ttw '"»V -,v. Hi : J^ShV ■';•.■*/■:'- '• *i:'■>■■■ ■ 'i ;X' -'■'•'•"' '*' v&3? y\<: ,,t ,J>':Ci'w - .'/«►"" ^C • :{l-fK^; -'-2; •• .?*:• ^* 3: WC 202 061e 1921 NLM 051^715=1 1 NATIONAL LIBRARY OF MEDICINE v^y &'%. 74, T Af NLM051671591 . influenzae was still present in demonstrable numbers in the throat of only 25 cases or 30.5 per cent. Not only was there a material reduction in the number of patients in whom B. influenzae could be demonstrated by the throat culture method, but the contrast in the predominance of B. influenzae on the plates made early in the disease with those made during convalescence was often very striking. It is only fair to say, however, that some cases continued to carry B. influ- enzae in their throats in large numbers throughout the pe- riod of observation. Presence of Pneumococcus in Cases of Influenza.—It seemed of some importance to determine the prevalence of pneumococcus in cases of influenza, not because of any pos- sibility that pneumococci might bear an etiologic relation- ship to the disease, but more by way of comparison with the prevalence of B. influenza?, since both organisms are found in the mouths of normal individuals and are also frequently found together in the pneumonias that complicate influenza. The results obtained in cases of influenza early in the disease before the development of either a purulent bron- chitis or of pneumonia are presented. The presence of pneumococcus was determined by the intraperitoneal inocu- lation of white mice with the saliva or sputum. Twenty-four cases examined on September 27 and 28 gave th<« results shown in Table IV. These patients had been in the hospital from two to five days at the time the determinations were made. 34 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Table IV Pneumococcus in Cases of Influenza NUMBER PER CENT Pneumococcus, Type I 0 0 Pneumococcus, Type II 0 0 Pneumococcus, Atypical II 0 0 Pneumococcus, Type III 2 8.3 Pneumococcus, Group IV 15 62.5 No pneumococci found 7 29.2 From November 27 to December 1, the pneumococci pres- ent in 47 consecutive cases of influenza were determined. In this group specimens of sputum were collected shortly after admission of the patients to the receiving ward of the hospital. The results are shown in Table V. Table V Pneumococci in Cases of Influenza NUMBER PER CENT Pneumococcus, Type I 0 0 Pneumococcus, Type II 0 0 Pneumococcus, Atypical II 2 4.3 Pneumococcus, Type III 0 0 Pneumococcus, Group IV 25 53.2 No pneumococci found 20 42.5 The results obtained show that pneumococci found in early uncomplicated cases of influenza, both early and late in the course of the epidemic, differ in no respect from those found in the mouths of normal individuals at any time. Similar studies of the prevalence of S. hemolyticus as determined by throat cultures in early cases of influenza are shown in Table VI. The only point of interest in these observations is the in- creased prevalence of S. hemolyticus in cases examined late in the epidemic of influenza as compared with that found early in the epidemic. The significance of this will be dis- cussed in other parts of this report. Presence of Bacillus Influenzae in Normal Men.__For comparison with the results obtained in cases of influenza ETIOLOGY OF INFLUENZA 35 Table VI S. Hemolyticus in Cases of Influenza nAr__ number of s. hemolyti- s" hemolyti DATE PTTS 'Nrrvp CASES CULTURED CUS FOUND °l _____________FOUND Sept. 25-26 100 6 ~94 Nov. 27—Dec. 5 138 39 99 a fairly extensive study of the prevalence of B. influenzae in normal individuals has been made at various times prior to and throughout the course of the epidemic. This was deemed of special importance, since it was obvious that the results obtained by previous workers during interepidemic periods would not in all probability coincide with those ob- tained in the presence of a widespread epidemic of influ- enza where the opportunity for the dissemination of B. in- fluenzae was almost unlimited. From the results obtained in the multiple cultures in cases of influenza it is obvious that only like methods can be compared. The results obtained in normal individuals have, therefore, been tabulated in groups dependent upon the culture method employed. These groups have been subdivided according to the time and the place of the study, such explanatory notes as seem necessary being added. (See Tables VII-IX.) The most striking feature of the figures presented in Table VII is the wide variation in the incidence of B. influ- enzae in different groups varying all the way from 11.1 to 68 per cent. Analysis of these differences brings out cer- tain points of great interest. It is apparent that the per- centage of cases carrying B. influenzae depended in large part upon the prevalence of respiratory diseases in the group from which the data were obtained. In the studies made at Camp Funston prior to the fall outbreak of influ- enza in epidemic proportions, it is noteworthy that " bron- chitis" and pneumonia were prevalent throughout the sum- mer in those groups showing a relatively high incidence of B. influenzae. At the time these studies were made the pres- - PER CENT POSI- TIVE FOR S. HEMOLYTICUS 6 28.3 36 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Table VII Incidence of B. Influenzae in Normal Men as Determined by Intra- peritoneal Inoculation of White Mice with Saliva or Sputum S5 H 5 2; H H w > 2 71 « o 1—1 w p. a< CQ 1918 Aug. 13 Camp Funston, 22 Prov. 25 Kans. De- Colored tention Co. 164th Camp, No. 2 Depot Brigade Co. D. 3rd Dev. Bn. Aug. 18 Camp Funston, 25 Kans. De- tention Camp, No. 2 Aug. 20 Camp Funston, Kan. 70th Inf. 25 Aug. Ft. Rilev Quarters 32 22 Kan. 4M M.O.T.C. Aug. Camp 1210th Eng. 26 Funston, Kan. Nov. Hot Drafted 12 Springs, men Ark. assembled to entrain for camj) 27 50 Nov. 25 Camp Pike Miscella-Ark. neons Dec. 10 Camp Pike Ark. Miscella-neous Summary: Normals Cases of influenza (for com-parison1) 235 76 11 11 16 11 61 24 44 44 50 11.1 50 68 37.4 80.3 Bronchitis and pneumonia were prevalent in this or- ganization of recently drafted negroes during July and August, 1918 Recently drafted southern negroes not fit for full mili- tary duty. Bronchitis and pneumonia were prevalent in this organization during July and August, 1918 25 men presenting them- selves at sick call for vari- ous complaints; not strict- ly normal; respiratory dis- eases not prevalent Recently drafted white men oi 4 to 8 weeks' service. Pneumonia fairly prevalent in this organization About one mile distant from Camp Funston proper. No sickness in this organiza- tion 50 men selected from iso- lated farm communities; 12 gave a history of "influen- za '' within the preceding 8 weeks 12 of this group had influ- enza during the epidemic 12 of this group had influ- enza during the epidemic ETIOLOGY OF INFLUENZA 37 ence of influenza in these organizations was not recognized, but in view of knowledge gained throughout the course of the epidemic at Camp Pike, it seems not improbable that influenza in mild form was present throughout the summer in certain organizations at Camp Funston. This would seem more likely in view of the fact that this commission has clearly demonstrated that a considerable epidemic of influenza swept through Camp Funston in March, 1918, and was followed by recurring smaller epidemics in April and May.14 In contrast with these groups showing a high inci- dence of B. influenza} is that of the 210th Engineers, an or- ganization entirely free from respiratory diseases during the period of our study. On November 12 search was made for B. influenzae in 50 normal drafted men who had assembled at Hot Springs, Ark., on that date preparatory to entraining for Camp Pike. These men were all from isolated farming communi- ties where influenza was only moderately prevalent and where there was little opportunity for the wide dissemina- tion of B. influenzaa such as occurs when large bodies of men are assembled in camps. Twelve of the 50 gave a his- tory of influenza within the preceding eight weeks. The cultures were made by the same methods as those used at Camp Pike, the laboratory car "Lister" being taken to Hot Springs for that purpose. The incidence of B. influ- enzae was only 22 per cent. In striking contrast with this figure are the figures of 50 and 68 per cent obtained in the last two groups studied at Camp Pike after the epidemic had swept through the camp: 24 of the 51 men in these groups had influenza during the epidemic. It is of interest to record that the incidence of pneumo- coccus in these cases was approximately the same in all groups and bore no relation to the prevalence of influenza, bronchitis, or pneumonia. "Opie, Freeman, Blake, Small, and Rivers: Jour. Am. Med. Assn., 1919, lxxii, 108. 38 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Table VIII Incidence of B. Influenza in Normal Men as Determined by Throat Cultures on Blood Agar Plates < a < ►J a. < N 5 31 O ^ a* PER CENT POSITIVE FOR B. INFLUENZAE REMARKS Sept. 14— Oct. 5 Camp Pike, Ark. Med. De-tachment, Base Hos.; personnel on measles wards 82 14 17.1 82 throat cultures in 42 individuals Nov. 5-9 Camp Pike Ark. Miscella-neous 296 71 23.9 Number among this group ' who had had influenza not recorded Nov. 12 Hot Springs, Ark. Drafted men assem-bled to en-train for camp 64 0 0 Men, in large part from isolated farm communi-ties; 13 gave a history of "influenza" within the preceding 8 weeks Nov. 25 Camp Pike Miscella-neous 26 13 50 12 of this group had in-fluenza during the epi-demic Dec. 10 Camp Pike Miscella-neous 25 13 52 12 of this group had influ-enza during the epidemic Summary Normals ' 493 Cases of in-fluenza (for comparison) 166 111 109 22.5 65.7 The results obtained by throat culture are quite similar to those obtained by the mouse inoculation method. The entire absence of B. influenza* in the group of 64 throat cul- tures made in the draft men assembled at Hot Springs as compared with the relatively high incidence in the last two groups examined at Camp Pike is very striking. In consideration of the figures presented in Table IX it is important to remember that the group of 50 men from Hot Springs were all from isolated farm communities, had not previously been assembled and had not been in continu- ous contact with a widespread epidemic of influenza. On the other hand, the two groups of normal men at Camp Pike were studied immediately after the epidemic had ETIOLOGY OF INFLUENZA 39 Table IX Incidence of B. Influenza in Normal Men Contrasted With That in Early Casks of Influenza as Determined by Multiple Cultures from Nose, Throat, and Sputum PLACE Ph P o o a rv W 5 * s < S3 H PER CENT SHOWING B. INFLUENZAS w Eh a W o S3 Eh «: o M K Eh SPUTUM DIRECT CULTURE SPUTUM MOUSE INOCULATION J J3 EH P t* p Nov. Hot Normal 50 0 0 0 22 22 12 Springs, Ark. draft men assembled C4 cul-tures only) 38.6 (31 cul- to entrain tures for camp 26 only) Nov. Camp Pike i Normal 50 34.6 50 80.8 25 men; 12 had influ-enza dur-ing the epi-demic Dec. Camp Pike Normal 25 48 52 24 68 88 10 men; 12 had influ-enza dur-ing the epi-demic Patients Oct, Camp Pike 28 21.4 50 60.7 78.6 100 10 with influ- and enza in Nov. Base Hos. 19 swept through the camp and had been constantly in contact with epidemic influenza for a period of three months, 24 of the 51 actually having had the disease during this period. The fact that in the group of men from Hot Springs, B. influenzae was found only by the mouse inoculation method is noteworthy, since it indicates that the organism was pres- ent in relatively small numbers and could be detected only by a highly selective method. Summary of the results obtained in normal men shows that the incidence of B. influenzae in normal individuals from isolated communities or in groups free from respira- tory diseases prior to the occurrence of the fall epidemic 40 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT was relatively low, namely, 10 to 20 per cent; that in ob- servations made before the fall epidemic in groups in which ''bronchitis" and pneumonia were fairly prevalent, B. in- fluenzae was found much more frequently, namely, in 25 to 50 per cent of the cases; and that in groups studied at in- tervals during the epidemic the incidence of B. influenzae rapidly rose, reaching 85 per cent at the end of the epi- demic. In contrast with this, B. influenzae was found in 100 per cent of cases of influenza without reference to the time at which they occurred during the epidemic. It is obvious that the high percentage of normal men carrying B. influ- enzae found at the end of the epidemic can depend only on the wide dissemination of B. influenzae that must occur dur- ing epidemic times. Bacillus Influenzae in Measles.—Since the presence of B. influenzae in other diseases than influenza has been ad- vanced as an argument against its causal relationship to influenza, an extensive study of the incidence of B. influenzae in the throats of measles patients was made during the pe- riod of the epidemic of influenza at Camp Pike from Sep- tember 10 to October 20. In all a total of 830 throat cul- tures in 487 cases of measles were made, many cases being cultured repeatedly at weekly intervals. The results have been condensed as far as possible and are presented in Tables X, XI, XII. Table X Incidence of B. Influenza in 400 Consecutive Cases of Measles as De- termined by Throat Culture at Time of Admission to the Base Hospital DATE NUMBER OF CASES B. INFLUENZAE FOUND NUMBER PER CENT Sept. 16—Oct. 4 Oct. 4—Oct. 10 Oct. 10—Oct. 15 Oct. 15—Oct, 19 100 100 100 100 27 32 32 48 27 32 32 48 The prevalence of B. influenzae in cases of measles during the period of the influenza epidemic corresponded very closely with that found in normal individuals under similar ETIOLOGY OF INFLUENZA 41 Table XI Incidence of B. Influenzae in 8:>0 Throat Cultures in 487 Cases of Mea- sles; Cultures Eepeated at Weekly Intervals NUMBER OF B. INFLUENZAE FOUND CULTURES NUMBER PER CENT Sept. 10-15 47 15 31.9 Sept. 16-29 106 33 31.1 Sept. 30—Oct. 6 122 38 31.1 Oct. 7-13 235 96 40.8 Oct. 14-20 320 157 49.1 Total 830 339 40.8 circumstances. The increasing proportion of cases carry- ing B. influenzae as the epidemic of influenza advanced is further evidence of the wide dissemination of the organism during the epidemic. Table XII Total Number of B. Influenza Carriers Among 223 Cases of Measles as Determined by Repeated Throat Cultures at Weekly Intervals after Admission to Hospital TIMES CULTURED NUMBER OF CASES NUMBER OF CULTURES B. INFLUENZA FOUND TOTAL CARRIERS IN ONE OR MORE CULTURES NUMBER PER CENT NUMBER PER CENT 2 129 1st 2nd 37 63 28.7 48.8 82 63.6 3 69 1st 2nd 3rd 20 31 33 28.9 44.9 47.8 52 75.4 4 25 1st 2nd 3rd 4th 6 10 13 14 24 40 52 56 21 84.0 It is evident from the figures presented in Table XII that a large percentage of the measles cases studied were at one time or another carriers of B. influenzas. In consideration of this fact, it must be borne in mind that all these cases were cultured during the period when the influenza epi- demic was at its height and that many of these cases had in- fluenza while in the hospital for measles. Xo data are available as to the exact number, since a definite diagnosis of influenza could hardly be made during the acute stage of measles. It is probable that approximately 25 per cent 42 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT developed influenza, since that was the incidence of influ- enza in the total population of Camp Pike. The consistent increase in the percentage of influenza carriers clearly demonstrates that this was due to wide dissemination of B. influenzae with the progress of the epidemic. Another point of exceeding interest is that the percentage of meas- les cases carrying B. influenzae in the throat was lowest dur- ing the acute stage of the disease and increased during con- valescence. This is in direct contrast with the results found in cases of influenza where the number of cases carrying B. influenzae in the throat was highest during the acute stage and rapidly diminished in uncomplicated cases with the on- set of convalescence. Summary.—Multiple cultures made simultaneously from the nose, throat and lower respiratory tract showed that B. influenza* was invariably present in all cases of influenza from the onset of the disease. Xot only was B. influenzae present in all cases, but it was frequently present in pre- dominant numbers, sometimes in nearly pure culture. In the majority of cases that went on to rapid recovery with- out the development of an extensive bronchitis or compli- cating pneumonia, the predominance of B. influenzae over other organisms rapidly diminished coincident with onset of convalescence. Many cases, however, continued to carry B. influenzae in large numbers in the throat throughout con- valescence. Xo data on the possible duration of the carrier state have been obtained. By the culture methods em- ployed no other organism has been found that would sug- gest any etiologic relationship to the disease. The two organisms most frequently associated with B. influenza? in postinfluenzal pneumonias, pneumococcus and S. hemolyti- cus, have not differed in their incidence in early uncom- plicated cases of influenza from that found in normal in- dividuals. The incidence of B. influenzae in normal men, in different groups studied, has varied between 11.1 and 88 per cent. ETIOLOGY OF INFLUENZA 43 This wide variation has depended upon the prevalence of respiratory diseases, more particularly influenza, in the groups studied and the opportunity thereby offered for the wide dissemination of B. influenza. With the progress of the epidemic, the number of normal men carrying B. in- fluenzae has steadily increased until it reached its maximum at the end of the epidemic. The incidence of B. influenzae in cases of measles studied during the epidemic of influenza has been relatively high though never equaling that found in cases of influenza. As in normal men, the incidence in cases of measles has stead- ily increased during the period of the epidemic. Kepeated throat cultures at weekly intervals in cases of measles have shown that approximately 80 per cent became temporary carriers of B. influenzae at one time or another during the period of the epidemic. Many of these cases had influenza during the time that they were in the hospital. The carrier state in cases of measles was found to bear no relation to the acute stage of the disease since the number of carriers at the time of admission to the hospital was considerably lower than that found during convalescence as determined by repeated cultures in the same cases. Discussion The bacteriologic studies in cases of influenza described in this report fully support Pfeiffer's claim that B. influ- enzae is invariably present in the disease. It is particularly important to note that these results were obtained in early uncomplicated cases of influenza and are not dependent upon cultures made from oases complicated by pneumonia or obtained at autopsy. In view of this fact the tendency so apparent in much of the recent literature to relegate B. influenzae to a place of secondary or minor importance in the disease seems hardly justifiable. It would seem that this tendency is largely dependent upon three factors: first, the failure of many to find B. influenza? either during life or 44 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT at autopsy in any considerable proportion of cases; second. the frequent failure to draw a clear distinction between in- fluenza itself and the pneumonia to which it predisposes with a consequent overemphasis upon autopsy bacteriology where a considerable variety of secondary organisms have attracted particular attention; and third, an incorrect in- terpretation of the undoubtedly large number of B. influ- enzae carriers found among normal individuals and those with other diseases during the period of the epidemic and to less extent in interepidemic times. Since the majority of workers who are thoroughly fa- miliar with the technic of cultivating B. influenzae have en- countered little difficulty in finding it in a large majority of cases, it is felt that the considerable number of negative reports that have appeared can depend only upon the un- familiarity of those who have failed to find it with the proper bacteriologic methods. This is quite apparent in many of the reports that have been published, and is not surprising in the face of the excessive demand for well- trained bacteriologists occasioned by the war. One important feature in the successful isolation of B. influenzae from all cases that has been brought out in the course of the work hero reported, is the necessity of making simultaneous cultures from all portions of the respiratory tract, since by no single culture method was it found possi- ble to find the organism in all cases. It has been pointed out that one of the most characteristic local phenomena of the disease is the rapidly progressing attack upon the mu- cous membranes of the respiratory tract. It seems quite possible that B. influenza? in predominant numbers at least may be found in many cases only at the crest of the wave, if we may speak of it as such. By way of analogy is the well-recognized fact that the successful isolation of strep- tococcus from cases of erysipelas often depends upon tak- ing cultures from the margin of the advancing lesion. While definite proof is lacking for this opinion, it would seem to ETIOLOCV OF INFLUENZA 45 receive some support from the observation that B. influ- enza1 rapidly disappears from the throat with the onset of convalescence in a considerable proportion of cases. It is felt that these observations, establishing the predominance of B. influenza? in the early acute stages of the disease, are of considerable significance, especially when exactly the re- verse condition was found in studying the incidence of the organism in cases of measles. In consideration of the primary cause of influenza, atten- tion has often been focused upon the many different bacteria found in autopsy cultures. The most prominent of these are the ill-defined diplostreptococci of the European writ- ers, the various immunologic types of pneumococci, and S. hemolyticus. Other microorganisms less frequently found are staphylococci, M. catarrhalis, nonhemolytic strepto- cocci, and B. mucosus capsulatus. It is not within the scope of this paper to discuss their relation to the various types of pneumonia found at autopsy, but their very multiplicity would seem sufficient prima facie evidence that they bear no etiologic relationship to influenza and must be regarded only as secondary invaders. If any further support for this opinion were necessary, it may be found in the studies upon the incidence of pneumococcus and S. hemolyticus in early cases of influenza described in this report. Both were found to occur in the same proportions in which they may be found in normal individuals at any time. Although Pfeiffer maintained that B. influenzae was found only in true epidemic influenza, the incorrectness of this contention has been thoroughly established by many reliable investigators and it has been shown beyond ques- tion that influenza bacilli may always be found in a small proportion of normal individuals and are not infrequently found in other respiratory diseases. The fairly extensive study that has been made of the in- cidence of B. influenza? in normal men and in cases of mea- sles has clearly demonstrated that the proportion of car- 46 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT riers found in any group depends upon the prevalence of influenza in the group studied and that with the progress of the epidemic the percentage of carriers has steadily in- creased. When one considers that the opportunity for the dissemination of B. influenza* by contact infection is almost unlimited during an epidemic of the proportions of that which has swept over the country, this is not at all surpris- ing. That such a large number of normal individuals be- came carriers of B. influenza? during the epidemic would seem to be sufficient evidence that actual dissemination does occur and to controvert the theory that in actual cases of influenza, conditions are established in the respiratory tract whereby B. influenza?, always present in small numbers, is enabled to "grow out" and become the predominant or- ganism. From a consideration of all the observations made as to the incidence of B. influenzae in various conditions it would appear that the carrier condition is quite analogous to that found with many other bacteria, and may be divided into three groups: (a) acute carriers, those having influ- enza, (b) contact carriers, those who during epidemic times become temporary carriers of the organism without con- tracting the disease, and (c) chronic carriers, the relatively small number of normal individuals or those with chronic respiratory conditions who carry B. influenzae over long periods of time. From the facts at hand this would seem to be the most probable explanation of the conditions found. It is certainly true that the established presence of pneu- mococcus, B. diphtheria?, meningococcus and many other organisms in a varying proportion of normal individuals is not regarded as sufficient evidence to exclude them as the etiologic agents of the diseases which they cause. It is quite obvious that if B. influenza? is to be regarded as the cause of epidemic influenza, it must change quite rapidly under certain circumstances from a relatively sap- rophytic organism to a relatively virulent pathogenic or- ganism, and conversely return to its avirulent state follow- ETIOLOGY OF IXI'LUENZA 47 ing the passage of an epidemic. Animal experimentation has taught us that virulence is acquired by the rapid pas- sage of an organism from host to host. That an oppor- tunity for the rapid transference of B. influenza? from man to man was provided by the assembling of large groups of individuals relatively susceptible to respiratory diseases in our camps and cantonments is by no means impossible. It has been clearly shown by Vaughn and Palmer15 that men from rural districts are very susceptible to respiratory diseases and that the camps in which such men were as- sembled suffered most heavily in this respect during the winter of 1917-18. This Commission has clearly demon- strated that an epidemic of influenza swept through Camp Funston14 in the spring of 1918 and that a similar epidemic occurred at Camp Pike. Accumulating evidence will un- doubtedly show that like epidemics existed in many of our southern camps (Vaughn and Palmer,15 Soper16). It is of considerable interest that B. influenza? was found in almost one-half of the cases of bronchopneumonia studied by Cole and MacCallum17 at Fort Sam Houston in February and March, 1918. This relation is especially noteworthy, since an epidemic of influenza was seen by one of us (Blake) among the troops at Kelly Field and Fort Sam Houston during these months. That similar conditions existed in European armies as early as 1916-17 is suggested by the reports of Hammond, Holland, and Shore18 and of Abra- hams, Hallows, Eyre, and French19 on epidemics of "pur- ulent bronchitis" with bronchopneumonia in the British army. B. influenzae was found abundantly in these cases. Theoretically, under the conditions outlined above, ideal opportunities have been provided for B. influenzae to build up sufficient virulence to enable it to produce the pandemic of 1918-19. While it is thoroughly recognized that these 15Vaughn and Palmer: Jour. Lab. and Clin. Med., 1918, iii, 635. 36Soper: Jour. Am. Med. Assn., 1918, lxxi, 1899. 17Cole and MacCallum: Jour. Am. Med. Assn., 1918, lxx, 1146. "Hammond, Rolland, and Shore: Lancet, London, 1917, ii, 41. "Abrahams, Hallows, Lyre, and French: Lancet, London, 1917, ii, 377. 48 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT considerations are in the main hypothetical, it is felt that they are by no means beyond the bounds of possibility, and for that reason are offered as suggestions worthy of fur- ther investigation. It is, of course, perfectly possible on the basis of the ob- servations presented still to regard B. influenza? as a sec- ondary invader which makes its appearance in all cases of influenza simultaneously with the onset of clinical symp- toms. Final proof of its causal relationship to the disease must depend upon the production of influenza by experi- mental inoculation. Kesults hitherto obtained in attempts to produce the disease experimentally have been contra- dictory. Pfeiffer1 claimed to have produced a disease in monkeys in some respects resembling influenza by the in- tratracheal injection of freshly isolated cultures of B. in- fluenzae. Wollstein,12 in studies upon the pathogenicity of various strains, has shown that B. influenzae is generally pathogenic for mice and guinea-pigs without respect to source or virulence for man. Pathogenicity for rabbits and monkeys, on the other hand, was possessed only by strains that were highly virulent for man. She further- more pointed out that for successful animal experimenta- tion, it is imperative that inoculations be carried out im- mediately after the isolation of the bacilli because they rap- idly lose virulence by subculture on artificial media. It is felt that failure to appreciate these facts has been respon- sible for the often repeated statement that B. influenzae is not pathogenic for animals. In a series of animal experiments carried out by this com- mission recorded in an appendix to this report, sixteen- hour cultures of B. influenzae freshly isolated from early cases of influenza were demonstrated to be pathogenic for monkeys, both by inoculation of the nasal and pharyngeal mucosa and by intratracheal injection. Monkeys so inocu- lated developed coryza, epistaxis, tracheitis, bronchitis, and extreme prostration. Experiments with forty-eight-hour ETIOLOGY OF INFLUENZA 49 cultures of strains preserved by subculture during from ten to fifteen days failed to demonstrate pathogenicity for mon keys. Proof that these monkeys had influenza can depend only upon the demonstration that they suffered with a dis- ease having the clinical character and pathologic lesions of influenza. The reported failure to produce influenza in man by di- rect inoculation with freshly isolated cultures of B. influ- enza? in experiments conducted on volunteers by the United States Public Health Service20 at Gallops Island, Boston, is interesting, but would seem to lack definite significance since attempts to transmit the disease from man to man by direct contact also failed. Since all the subjects of these experiments had been previously exposed to influenza dur- ing the epidemic, 30 per cent actually having contracted the disease, it would seem probable that the remaining 70 per cent were only very slightly if at all susceptible. It is note- worthy that the attack rate of influenza in most army groups was approximately 20 to 30 per cent during the epi- demic, the remaining 70 to 80 per cent failing to contract the disease though equally exposed. No other explanation presents itself except that influenza is no longer transmis- sible when clinical symptoms have appeared. Conclusions 1. Consideration of all the evidence available makes it seem highly probable that B. influenzae is the specific etio- logic agent of epidemic influenza, because (a) it is always present in early uncomplicated cases of influenza; (b) it is predominantly so during the acute stage of the disease in cases going on to rapid recovery without development of complications; (c) its presence in varying numbers in nor- mal individuals and in other diseases of the respiratory tract is not valid evidence against its etiologic relationship to influenza, but on the contrary is quite in harmony with =°Public Health Reports, U.S.P.H. Service, 1919, xxxiv, 33. 50 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT what should be expected from our knowledge of other bac- teria known to be the etiologic agents of various respira- tory diseases; (d) its rapidly increasing prevalence in nor- mal individuals simultaneously with the progress of the epidemic indicates that actual dissemination of B. influenzae readily occurs and is very widespread during pandemic times; (e) cultures of B. influenzae freshly isolated from early acute cases of influenza are pathogenic for animals, and may produce in monkeys a disease closely resembling influenza. 2. Final proof of the exact relationship of B. influenzae to influenza must depend upon (a) more definite knowledge of the immunology both of the organism and of the disease, and (b) knowledge of the pathologic lesions of influenza and the production of these lesions in animals by inocula- tion with B. influenzae. CHAPTER II CLINICAL FEATURES AND BACTERIOLOGY OF IN- FLUENZA AND ITS ASSOCIATED PURULENT BRONCHITIS AND PNEUMONIA Francis G. Blake, M.D., and Thomas M. Rivers, M.D. The material presented in this section of the report con- sists of clinical and bacteriologic observations made dur- ing the course of an investigation of influenza and its asso- ciated bronchitis and pneumonia at Camp Pike, Ark., be- tween September 6 and December 15, 1918, comprising part of a correlated study of the epidemiology, bacteriology, pathology, and clinical features of these diseases. The bac- teriologic studies are in the main limited to those made dur- ing life, those made at necroivsv being reported in another section of this report. Methods.—All cases upon which the clinical and bacte- riologic data presented are based, were examined by the authors and our own clinical histories and physical exam- inations were recorded. This was considered of special im- portance, since in studying a group of diseases in which secondary infection of the respiratory tract might super- vene at any time, it was essential to determine as far as possible the exact clinical condition of the patient at the time when bacteriologic examinations were made. The bac- teriologic methods employed were the direct culture of nose and throat swabbings and of selected and washed specimens of sputum on the surface of 5 per cent defibri- nated horse blood agar plates, the intraperitoneal inocula- tion of white mice with specimens of sputum according to the method described by Blake1 for the determination of ^lake: Jour. Exper. Med., 1917, xxvi, 67. 51 52 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT pneumococcus types, and in some cases the method of Avery.2 B. influenza? pneumococci and hemolytic strep- tococci were identified by the methods described elsewhere. Note was made in most instances of the presence of other organisms such as members of the Gram-negative diplo- coccus group, staphylococci, diphtheroids, and members of the streptococcus viridans group, but no attempt was made to further isolate or identify them since they played no sig- nificant part in the cases studied except in rare instances. Influenza The fall epidemic of influenza at Camp Pike began about September 1, 1918, and reached epidemic proportions on September 23 when 214 cases were admitted to the base hospital. The epidemic was at its height from September 27 to October 3, during which period there were in the neighborhood of 1,000 new cases daily. From this date un- til October 31 the number of new cases occurring daily steadily decreased and by the latter date the epidemic was over. Scattered cases continued to occur, however, through- out November, and during the last week of this month and the first week of December a second epidemic wave of rela- tively mild character occurred. From September 1 to Octo- ber 31 the total number of cases of influenza reporting sick was 12,393. During the same period there were 1,499 cases of pneumonia with 466 deaths. Influenza as observed at Camp Pike differed in no es- sential respects from that occurring elsewhere. In brief, it presented itself as a highly contagious, self-limited infec- tious disease of relatively short duration in most instances, the principal manifestations of which were sudden onset with high fever, profound prostration, severe aching pains in back and extremities, conjunctival injection, flushing of the face, neck, and upper thorax often amounting to a true erythema, and a rapidly progressing attack upon the mu- 2Avery: Jour. Am. Med. Assn., 1918, lxx, 17. CLINICAL FEATURES AND BACTERIOLOGY OF INFLUENZA 53 cous membranes of the respiratory tract as manifested by coryza, pharyngitis, tracheitis and bronchitis with a marked tendency to hemorrhage; in itself it is rarely se- rious, but in reality serious because of the large number of individuals attacked and temporarily incapacitated and be- cause it predisposed to widespread and highly fatal sec- ondary infection of the lungs. Clinical Features.—A clinical study of 100 consecutive cases of influenza admitted during the height of the epi- demic was made. The onset was sudden, in most instances being initiated with marked sensations of chilliness in 82 cases. Although a severe chill was probably relatively uncommon, 44 of these patients considered the symptom of sufficient severity to describe it as such. This was accompanied by extreme gen- eral malaise with severe aching pains throughout the whole body. Intense backache was complained of in 40 cases, headache in 54 cases. A varying degree of prostration, sometimes leading to complete collapse, was almost uni- versal; 5 patients complained of extreme asthenia and 2 of marked dizziness. At time of admission to the hospital the face, neck and upper chest exhibited a uniform eryth- ematous flush, never macular in appearance. The conjunc- tivae were deeply injected, but lacrimation was not notice- able and a true exudative conjunctivitis was not encoun- tered. Onset was accompanied by a sharp elevation of tem- perature ranging from 100°F. to 106° F., in most cases be- ing between 102° F. and 105° F., at the time of admission. No constant type of temperature curve was maintained. Excluding the 15 cases in this group that developed pneu- monia, the temperature was well sustained throughout the course of the disease in 46, irregular in 33, and definitely remittent in 6. The duration of the fever varied between one and seven days, the temperature having returned to normal in all but 19 of the 85 cases by the end of four days. The duration of fever was one day in 18 cases, two days in 54 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT 12, three days in 19, four days in 17, five days in 10, six days in 4, and seven days in 5. Of the 4 cases with fever for six days, 2 had a fairly extensive bronchitis, 1 a laryn- gitis. Of the 5 cases with fever of seven days' duration, 3 had signs of an extensive bronchitis, 2 of only a mild bron- chitis. The pulse was relatively slow in rate as compared with the degree of temperature elevation, running between 90 and 100 beats per minute in the large majority of cases. At the height of the disease it was full and easily com- pressed. No irregularities were noticed. With recovery it fell promptly to normal. The respiratory rate showed only moderate elevation, being between 20 and 26 in most cases. In a few instances a rate as high as 32 was recorded at time of admission to the hospital, but this promptly fell with rest in bed. A respiratory rate rising above 26 after the third or fourth day of the disease nearly always indi- cated a beginning pneumonia. "With recovery the rate promptly fell to normal. Cyanosis did not occur in the absence of pneumonia. Aside from the manifestations of a profound toxemia, influenza was preeminently characterized by symptoms of respiratory tract infection. The appearance of respiratory symptoms occurred at varying intervals after the onset of the disease, being well developed by the end of twenty-four hours in most cases. A progressive attack upon the mu- cous membranes of the respiratory tract was universal, be- ginning with coryza and pharyngitis and progressing to tracheitis or vice versa. Further extension of the infection to the bronchi, however, was by no means universal, 49 cases in the group studied recovering without developing evidence of bronchitis. Sore throat was rarely complained of, and laryngitis, possibly due to secondary infection, oc- curred only once. The progress of the infection was marked subjectively by sensations of irritation, stinging, and a feel- ing of tightness. A profuse, thin, mucoid exudate appeared; CLINICAL FEATURES AND BACTERIOLOGY OF INFLUENZA 55 the pharyngeal walls and the soft palate showed a charac- teristic deep red granular appearance. The onset of tra- cheitis began with a sense of burning and tightness beneath the sternum accompanied by a harassing cough, at first non- productive, later with the outpouring of an exudate becom- ing productive. The sputum varied in character between a scanty, thin, mucoid sputum and a profuse, frankly puru- lent -sputum in cases subsequently developing an extensive bronchitis. Hemorrhage from the mucous membranes was common. Epistaxis occurred in 12 per cent of the cases and was often profuse. The sputum contained fresh blood in varying amounts in 24 per cent of the cases; 51 per cent of the cases developed signs of bronchitis. In 15 of these the bronchitis was mild, probably limited to the larger bronchi, physical examination showing only inconstant sibi- lant and musical rales. The sputum in these cases was neither profuse nor frankly purulent; 36 cases developed a fairly extensive purulent bronchitis as manifested by more or less diffusely scattered moist rales and by moderately copious mucopurulent or frankly purulent sputum. This bronchitis was not accompanied by an increase in the re- spiratory rate or by cyanosis unless pneumonia subse- quently developed. Gastrointestinal symptoms were insignificant: 8 patients complained of nausea early in the disease and 6 of them vomited. Diarrhea occurred in only 1 case, constipation being the rule. The spleen was palpable in 21 cases, but this is of doubtful significance, since nearly all the patients came from malarial regions. Jaundice was not noted. Aside from the profound depression, sometimes amounting to stupor, mental symptoms were not noted except in 1 case which showed a mild delirium. Influenza, although per se a self-limited disease of short duration, frequently leads to the development of serious complications, the most important of which are pneumonia and purulent bronchitis with a varying degree of bronchi- 56 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT ectasis. In the group of 100 cases of influenza studied, pur- ulent bronchitis developed in 36 instances, pneumonia in 15; in 3 eases there was lobar pneumonia, in 12 broncho- pneumonia. Further discussion of these complications is reserved for the sections dealing with them in detail. Other complications were relatively rare. Otitis media occurred in one case and frontal sinusitis in one. No fatalities were observed among cases of uncomplicated influenza, the deaths that occurred being invariably associated with a secondary pneumonia due in nearly all instances to sec- ondary infection with pneumococci or hemolytic strepto- cocci. Purulent Bronchitis It has been stated that a considerable number of cases of influenza developed a more or less extensive purulent bronchitis. This term is used as descriptive of a group of cases showing clinically evidence of a diffuse bronchitis as manifested by numerous medium and fine moist rales scat- tered throughout the chest and evidence of a definitely pu- rulent inflammatory reaction as indicated by the expectora- tion of fairly copious amounts of mucopurulent or frankly purulent sputum. This condition is regarded as quite dis- tinct, on the one hand, from the common type of mucoid bronchitis frequently associated with "common colds" and a fairly common feature of uncomplicated cases of influ- enza, in which physical examination of the chest reveals only transient sibilant and musical rales without evidence of extension to finer bronchi, and, on the other hand, from bronchopneumonia. Bacteriology.—Thirteen cases of purulent bronchitis fol- lowing influenza in none of which was there any evidence of pneumonia at the time cultures of the sputum were made nor later were subjected to careful bacteriologic study. Specimens of bronchial sputum were collected in sterile Petri dishes and selected portions thoroughly washed to remove surface contaminations before bacteriologic ex- CLINICAL FEATURES AND BACTERIOLOGY OF INFLUENZA 57 aminations were made. The results are shown in Table XIII. Table XIII Bacteriology of the Sputum in Cases of Purulent Bronchitis Follow- ing Influenza CASE stained film of SPUTUM DIRECT CULTURE ON BLOOD AGAR PLATE MOUSE INOCULATION GJ B. influenza^ + + + B. influenza? 4-4-4-4- B. influenza? Gram 4- diplococci 4- Pneumococcus 4- Pneumococcus (type undetermined) WAL B. influenzae + 4- B. influenza? 4-4-4- — Gram -1- diplococci 4-4- Pneumococcus IV 4-4- TH B. influenza? + + + B. influenza? 4-4-4-4- — Gram + diplococci + + + Pneumococcus IV 4-4- LH B. influenza? 4- B. influenza? 4- 4- — Gram 4- diplococci 4- Pneumococcus IV 4-4- FBD Gram 4- diplococci 4-4-4-4 Pneumococcus IV 4-4-4- Pneumococcus IV B. influenza? 4- B. influenza? Wa B. influenza? 4-4- B. influenza? 4-4- — Gram + diplococci + 4- Pneumococcus IV 4- 4- Sh B. influenza? + + + B. influenza? 4-4- — Gram + diplococci 4-4- Pneumococcus IV 4- 4- + Wal Gram 4- diplostrep 4 4-4- S. viridans 4-4- — B. influenza; 4- B. influenza? + 4- CLF B. influenza? 4-4-4-4-4- — B. influenza? Gram 4- diplococci 4- Pneumococcus IV NCC B. influenza? 4-4- B. influenza? 4-4-4- B. influenza? Gram - micrococcus 4- M. catarrhalis 4-4- M. catarrhalis Gram 4- diplostrep. 4- S. viridans 4-4- JCM B. influenza? 4-4-4- B. influenza? 4-4-4-4- B. influenza? Gram 4- streptococcus 4- S. hemolyticus 4- S. hemolyticus Gram - micrococcus + M. catarrhalis 4- Pneumococcus IV Gram + diplococcus 4- Bl B. influenza? 4- — B. influenza? Gram 4- diplococcus 4 Pneumococcus Ila Bu B. influenza? 4-4-4-4- B. influenza? 4-4-4- B. influenza? Gram 4- diplococcus 4-4-4-4 Pneumococcus IV 4-4-4- Pneumococcus IV From the data presented in Table XIII it is evident that a mixed infection existed in all cases. The results obtained by stained sputum films and by direct culture on blood agar plates are of special significance. B. influenza? was present in all cases, being the predominant organism in 6 cases, abundantly present in others, and few in number in 2. Of other organisms the pneumococcus was most frequently found, occurring in 11 of the 13 cases, in all but 2 instances being present in considerable numbers. S. viridans was en- countered twice, once in association with a Gram-negative 5S PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT micrococcus resembling M. catarrhalis culturally. S. hem- olyticus was found once, together with M. catarrhalis and a few pneumococci, Type IV, coming through in the mouse only and of doubtful significance. The stained sputum films and direct cultures always showed these organisms present in sufficient abundance to indicate that they were present in the bronchial sputum and were not merely con- taminants from the buccal mucosa. It seems quite probable from these results that purulent bronchitis following influenza is, in most cases at least, due to mixed infection of the bronchi and should be looked upon as a complication of influenza. Whether the condition may be caused by infection with B. influenzEe alone is difficult to say. No evidence that it may be caused by B. influenzae alone was obtained in the cases studied. It is not intended to enter here into a discussion as to whether B. influenzae should be regarded as a secondary invader or not; the other organisms encountered certainly are. It would seem most probable that purulent bronchitis is caused by the mixed infection of B. influenzse and various other organisms, com- monly the pneumococcus, but that the condition is initiated by the invasion of the bronchi by these other organisms in the presence of a preceding infection with B. influenzse. Clinical Features.—Purulent bronchitis following in- fluenza began insidiously without any prominent symptoms to mark its onset. About the third or fourth day of in- fluenza, when recovery from the primary disease might be looked for, the patient would begin to cough more fre- quently, raising increasing amounts of mucopurulent sputum. This sputum was yellowish green in color, copious in amount, and often somewhat nummular in character, sometimes streaked with blood. These symptoms were ac- companied by the appearance of coarse, medium and fine moist rales more or less diffusely scattered throughout the chest and usually most numerous over the lower lobes. The percussion note, breath and voice sounds, and vocal CLINICAL FEATURES AND BACTERIOLOGY OF INFLUENZA 59 and tactile fremitus remained normal. There was no increase in the respiratory rate or pulse rate, and cya- nosis did not develop in the absence of a beginning pneu- monia. Many such cases, of course, developed broncho- pneumonia; in this event areas showing diminished reso- nance, suppressed breath sounds, and fine crepitant rales with the "close to the ear" quality would appear, the res- piratory rate would become increased and cyanosis would become evident. In those cases of purulent bronchitis not developing pneumonia, a moderate elevation of tem- perature, rarely above 101° F., and irregular in character usually occurred and persisted for a few days or a week. Many cases maintained a persistent cough, raising con- siderable amounts of sputum throughout the period of their convalescence in the hospital, which was often considerably prolonged when this complication of influenza occurred. Although no clinical data are available on such cases over a prolonged period of observation, it seems probable that some of them, at least, had developed some degree of bron- chiectasis. This would seem all the more probable, 'since many cases of pneumonia following influenza showed at autopsy extensive purulent bronchitis with well-developed bronchiectasis. Bronchiectasis will be discussed in greater detail in another section of this report. It is this group of cases with more or less permanent damage to the bron- chial tree that makes this type of bronchitis following in- fluenza a serious complication of the disease. PNEUMONIA The opportunity presented for a correlated study of the clinical features, bacteriology, and pathology of pneumonia following influenza throughout the period of the epidemic at Camp Pike from September 6, 1918, to December 15, 1918, made it evident that this pneumonia could be regarded as an entity in only one respect, namely, that influenza was the predisposing cause. Clinically, bacteriologically, and 60 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT pathologically it presented a very diversified picture rang- ing all the way from pneumococcus lobar pneumonia to hemolytic streptococcus interstitial and suppurative pneu- monia with the picture modified to a varying extent by the preceding or concomitant influenzal infection. One hundred and eleven consecutive cases in which care- ful clinical and bacteriologic studies were made form the basis of the material presented. Of these cases, 38 came to necropsy so that ample opportunity was presented to cor- relate the clinical and bacteriologic studies made during life with the pathology and bacteriology at necropsy. It has seemed advisable to group the cases primarily on an etiologic basis with secondary division according to clinical features in so far as this can be done. Bacteriologic studies showed that at the time of onset these pneumonias were either pneumococcus pneumonias or mixed pneumococcus and influenza bacillus pneumonias in nearly all instances. Certain of these cases later became complicated by a super- imposed hemolytic streptococcus or a staphylococcus in- fection. In a few instances hemolytic streptococcus pneumonia directly followed influenza without an interven- ing pneumococcus infection. B. influenzse was present in varying numbers in nearly all cases. In only 2 instances however, was it found unassociated with pneumococci or hemolytic streptococci, once alone and once with S. viridans. Clinically the cases fell into four main groups: (1) Lobar pneumonia; (2) lobar pneumonia with purulent bronchitis; (3) bronchopneumonia (pneumococcus); (4) bronchopneu- monia (streptococcus). It should be borne in mind, how- ever, that the picture was a complex one and that cor- rect clinical interpretation was not always possible, since many cases did not conform sharply to any one type and superimposed infections during the course of the disease often modified the picture. Pneumococcus Pneumonia Following Influenza.—Bacte- riologic examination of selected and washed specimens of CLINICAL FEATURES AND BACTERIOLOGY OF INFLUENZA 61 sputum coughed from the lungs at time of onset of pneu- monia showed the various immunologic types of pneumo- coccus to be present in 105 cases. The incidence of the different types is shown in Table XIV. Table XIV Types of Pneumococcus in 105 Cases of Pneumococcus Pneumonia Fol- lowing Influenza LOBAR PNEUMONIA BRONCHO-PNEUMONIA TOTAL PER CENT Pneumococcus, Type I 8 0 8 7.6 Pneumococcus, Type II 3 1 4 3.8 Pneumococcus, II atyp. 12 7 9 18.1 Pneumococcus, Type III 3 3 6 5.7 Pneumococcus, Group IV 32 36 68 64.S The most noteworthy feature of the figures in Table XIV is the high proportion of pneumonias due to types of pneu- mococci found in the mouths of normal individuals, 93 cases or 88.6 per cent, being caused by Pneumococcus Types II atypical, III, and IV. This is in harmony with the results generally reported and is in all probability due to the fact that in patients with influenza pneumococci, which under normal conditions would fail to cause pneumonia, readily gain access to the respiratory tract and produce the disease. It is also of interest that with one exception the highly parasitic pneumococci of Types I and II were associated with pneumonias clinically lobar in type. Superimposed infection of the lungs with other types of pneumococci than those primarily responsible for the de- velopment of pneumonia occurred not infrequently in this group of cases either during the course of the disease or shortly after recovery from the first attack of pneumonia. Pneumococcus Type II infection was superimposed upon or shortly followed pneumonia caused by Group IV pneu- mococci in 4 instances, by Pneumococcus II atypical m 1 instance. In 1 case pneumonia due to Pneumococcus II atypical occurred three days after recovery from a Pneu- mococcus Type I pneumonia, in another case Pneumococcus 62 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Type III infection was superimposed upon a pneumonia or- iginally due to a pneumococcus of Group IV. These cases are presented in detail in another section of this report, and in several instances were shown to be directly due to contact infection from patients in neighboring beds. In a similar manner, superimposed infection with S. hemolyticus at some time during the course of the pneu- monia occurred in 13 cases in this group, with fatal result in all but one. Streptococcus infection occurred in pneu- monia due to Pneumococcus II atypical once, to Pneumo- coccus Type III once, and to pneumococci of Group IV eleven times. Nine of these cases were free from hemo- lytic streptococci at the time of onset of the pneumonia, 4 showed a very few colonies of hemolytic streptococci in the first sputum culture made. B. influenzEe was found in the sputum coughed from the deeper air passages in the majority of cases, being present in 80, or 76.2 per cent, of the 105 cases. In the 58 cases of lobar pneumonia it was found 41 times, or 70.7 per cent, in the 47 cases of bronchopneumonia 39 times, or 82.9 per cent. The abundance of B. influenzae in the sputum varied greatly in different cases. Microscopic examination of stained sputum films and direct culture of the sputum on blood agar plates showed that in general it was more abun- dant in the mucopurulent sputum from cases of broncho- pneumonia than in the mucoid rusty sputum from cases of lobar pneumonia. This was by no means an invariable rule, however, since in the former the bacilli were some- times very few in number, in the latter quite abundant. Whether B. influenza? shared in the production of the actual pneumonia in these cases is difficult to decide and cannot be stated on the basis of the bacteriologic and clinical ob- servations which have been made. Clinical Features.—One of the most striking aspects of pneumococcus pneumonia following influenza was the diversity of clinical pictures presented. These varied all CLINICAL FEATURES AND BACTERIOLOGY OF INFLUENZA 63 the way from the classical picture of lobar pneumonia to that of bronchopneumonia of all grades of severity from the rapidly fatal coalescing type to that of very mild char- acter with very slight signs of consolidation. For this reason it is questioned whether there is any real justifica- tion for speaking of a typical influenzal pneumonia, an opinion that seems well supported by the diversified picture found at the necropsy table. For purposes of presentation, pneumococcus pneumonia following influenza may be divided into three clinical groups: (1) Lobar pneumonia; (2) lobar pneumonia with purulent bronchitis; (3) bronchopneumonia. No accurate data are available as to the relative frequency with which these three types occurred at Camp Pike. In the group of 105 cases studied there were 58 cases of lobar pneumonia, 11 of which had purulent bronchitis, and 47 cases of broncho- pneumonia. The majority of these cases, however, oc- curred during the early days of the epidemic of influenza and probably show a considerably higher proportion of lobar pneumonias than actually occurred in the total num- ber of pneumonias throughout the epidemic. This is indi- cated by the fact that of 100 consecutive cases of influenza selected for observation at the height of the epidemic, 3 de- veloped clinical evidence of lobar pneumonia and 12 of bronchopneumonia. (1) Lobar pneumonia presenting the typical clinical pic- ture with sudden onset, tenacious rusty sputum, sustained temperature, and physical signs of complete consolidation of one or more lobes occurred in 47 cases; 36 cases in this group definitely followed influenza. In 11 cases no certain clinical evidence of a preceding influenza was obtained, and it is probable that some of these represent cases of pneu- monia occurring independently of the epidemic of influenza. The onset of pneumonia in this group of cases occurred from four to nine da}^s after the onset of influenza and with few exceptions was ushered in by a chill and pain in the 64 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT chest. In several instances the patient had apparently re- covered from influenza as evidenced by fall of temperature to normal. After twenty-four to seventy-two hours of nor- mal temperature the patient would have a chill and develop lobar pneumonia. In the majority of cases, however, lobar pneumonia developed while the patient was still sick with influenza. The course of the disease, symptomatology and physical signs were quite characteristic of lobar pneu- monia and require no special comment. Recovery by crisis occurred in 21 cases, by lysis in 8. Pneumococcus empyema developed in 3 cases, fibrinopurulent pericarditis in 3 and all but 1 of these 6 cases terminating fatally. In Table XV 5 fatal cases of lobar pneumonia, which illustrate some of the unusual features of the disease when it follows influenza, have been summarized. The first 2 cases represent examples of recurring attacks of pneu- monia which developed shortly after recovery from the first attack, in both instances being due to types of pneu- mococci different from those causing the first attack. The third case represents an example of superimposed infection of the lungs with hemolytic streptococci and staphylococci during the course of a pneumonia due to Pneumococcus IV and disappearance of the latter organism from the tissues so that it was not found at time of necropsy. The last 2 cases are examples of fulminating rapidly fatal cases of lobar pneumonia associated with mixed infections of pneu- mococci and hemolytic streptococci, the streptococci prob- ably being secondary in both cases. Cases like the few examples cited above, which occurred not infrequently throughout the epidemic of influenza, serve to illustrate the difficulties which may be met in attempting to corre- late the clinical, bacteriologic and pathologic features of pneumonia following influenza unless careful bacteriologic examinations are made both during life and at the necropsy table in the same group of cases. Table XV Cases of Lobar Pneumonia Following Influenza ONSET OF 1 INFLUENZA ONSET OF PNEUMONIA SPUTUM EXAMINATION COURSE OF PNEUMONIA NECROPSY CASE DATE BACTERIOLOGY DIAGNOSIS BACTERIOLOGY Ful Sept. 7 Sept. 9 Sept. 10 Pn. IV + + + + Becovery by crisis on Lobar pneumonia. H.B. Pn. II 1st attack B. inf. + + + Sept. 14. On Sept. 21 Gray hepatiza- Br. Pn. II + + + + bronchopn. developed lobar pneu-monia. Died Sept. 30 tion L.L, L.U, R.L. R.L. B. inf. Pn. II + + + + + Lew Sept. 16 Sept. 20 Sept, 22 Pn. I + + -I Lobar pn., recovery by Lobar pneumonia. H.B. Pn. II atyp. chill H. inf. + crisis Sept. 29. De-veloped 2nd attack lo-bar pn. on Oct. 2. Died Oct. 8 Gray hepatiza- Br. tion R.U. Fibrino purulent pleurisy 1 R.U. B. inf. Pn. Ila S. hem. Staph. Pn. Ila + + + + + + + + T 4- + + + Col Sept. 20 Sept. 24 Sept. 27 Pn. IV ++. Severe lobar pneumonia. Died on Sept. 30 Lobar pneumonia. H.B. Red hepatiza- Br. tion all lobes. Sero-fibrinous L.L. pi., rt. 125 c.c. S. hem. S. hem. Staph. S. hem. Staph. 4- 4-4- 4-4- 4-4-4-4-4- Gar Sept. 23 Sept. 28 Sept. 30 Pn. IV + + . Fulminating rapidly fa Lobar pneumonia. H.B. S. hem. S. hem. + tal lobar pneumonia. Engorgement Br. S. hem. + + + + B. inf. 4- Died Sept. 30 and red hepati-zation L.U., R.U. L.U. Lobar pneumonia. H.B. B. inf. S. hem. sterile 4- 4-4- 4-4- 4-4- Hoi Sept. 25 Sept. 30 Sept. 30 Pn. Ill 4-4- Fulminating rapidly fa B. inf. 4-4- tal lobar pneumonia. Died Oct. 1. Engorgement all lobes Br. R.L. B. inf. Pn. Ill S. hem. Pn. Ill 4-4-4-4-4- + 4-4- 4-4- 4- B. inf. + + S. hem. + Iv.L,. R.L,., etc., indicates lobes involved. H. B. = Heart's blood. Br. = bronchus. 66 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT (2) There were 11 cases of lobar pneumonia with puru- lent bronchitis in the group studied. Clinically, they closely resembled the cases in the preceding group except in so far as the picture was modified by the presence of the purulent bronchitis. All directly followed influenza. The sputum, instead of being rusty and tenacious, was profuse and mucopurulent, usually streaked with blood. Stained films and direct culture on blood agar plates showed pneu- mococci in abundance and B. influenzae in varying numbers, in only two instances the predominant organism. The physical signs were those of lobar pneumonia with, in addi- tion, those of a diffuse bronchitis as manifested by medium and coarse moist rales throughout both chests. Five cases recovered by crisis; 6 terminated fatally and in all of them the clinical diagnosis of lobar pneumonia with purulent bronchitis was confirmed at necropsy. (3) Forty-seven cases in the group studied presented the clinical picture of bronchopneumonia. The onset of pneu- monia in these cases was in most instances insidious and appeared to occur as a continuation of the preceding in- fluenza. The temperature, instead of falling to normal after from three to four days, remained elevated or rose higher, the respiratory rate began to rise, a moderate cya- nosis appeared, the cough increased, and the sputum became more profuse, usually being mucopurulent and blood streaked, sometimes mucoid with fresh blood. The pulse showed little change at first, being only moderately accelerated. Pleural pain, so characteristic of the onset of lobar pneumonia, was rarely complained of, but a certain amount of substernal pain was common, probably due to the severe tracheobronchitis. Physical examination at this time revealed small areas showing relative dullness, di- minished or nearly absent breath sounds, and fine crepitant rales. These areas usually appeared first posteriorly over the lower lobes. CLINICAL FEATURES AND BACTERIOLOGY OF INFLUENZA 67 The subsequent course of the disease showed the widest variation from mild cases with limited pulmonary involve- ment going on to prompt recovery in four or five days with defervescence by lysis or crisis to those presenting the pic- ture of a rapidly progressive and coalescing pneumonia with fatal outcome. In the milder cases the diagnosis of pneumonia depended in considerable part upon the general symptoms of continued fever, increased respiratory rate, and slight cyanosis. Definite pulmonary signs were always present if carefully looked for, though sometimes not out- spoken. Areas of bronchial breathing and bronchophony often appeared late, sometimes not until the patient was apparently recovering. In the severe cases cyanosis be- came intense and an extreme toxemia dominated the pic- ture. In certain of these cases there was an intense pul- monary edema. The respiratory rate showed wide varia- tion, the breathing in some cases being rapid and gasping, in others comparatively quiet. Progressive involvement of the lungs occurred with the development of marked dul- ness, loud bronchial breathing and bronchophony. Abun- dant medium and coarse moist rales were heard throughout the chest, probably due in considerable part to the exten- sive bronchitis almost universally present. An active de- lirium was not uncommon. Signs of pleural involvement, even in the most severe and extensive cases, rarely occurred,' except in those cases in which a hemolytic streptococcus infection supervened. Of the 47 cases in this group, 29 recovered; 14 by crisis, 15 by lysis. The average duration of illness from the onset of influenza until recovery from the pneumonia was ten days, the majority of these cases being relatively mild in character with pneumonia of three to six days' duration. Empyema with ultimate recovery occurred in 1 of these cases, Pneumococcus Type II being the causative organism. There were 18 fatal cases in the group. Nine of these are summarized in Table XVI as illustrative of the fre- 68 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT quently complex character of bronchopneumonia following influenza and because of the interest attaching to the bac- teriologic examinations made during life and at necropsy. Case 70 is a typical instance of the rapidly progressive type of confluent lobular pneumonia with extensive puru- lent bronchitis, intense cyanosis, and appearance of suf- focation, with which pneumococci, in this case Pneumococ- cus IV, and B. influenza? are commonly associated. Case 59 is illustrative of the small group of bronchopneumonias following influenza which die, often unexpectedly, after a long drawn out course, in this instance three weeks after onset. Examination of the sputum at the time the pneu- monia began, showed Pneumococcus Type IV and B. in- fluenzae. At necropsy there was a lobular pneumonia with clustered small abscesses, probably due to a superimposed infection with S. aureus. There was a well-developed bron- chiectasis in the left lower lobe. Cultures taken at autopsy showed a sterile heart's blood, which is not infrequently the case in cases of pneumococcus lobular pneumonia after influenza. Cultures from the consolidated portions of the lung showed no growth, the pneumococcus having disap- peared as might be expected from the duration of the case. B. influenzae together with staphylococci were found in the bronchi. In Cases 50 and 56 a second attack of pneumonia caused by a different type of pneumococcus from that re- sponsible for the first attack occurred, the second attack in both instances being due to contact infection with Pneumo- coccus Type II from a patient in a neighboring bed suffer- ing with Pneumococcus Type II pneumonia. Both cases showed at necropsy the type of confluent lobular pneumonia so commonly found in pneumococcus pneumonias following influenza. Case 107 illustrates well the extent to which mixed infections may occur, especially when cases are treated in crowded hospital wards. The sputum at time of onset showed Pneumococcus IV in abundance and a few staphylococci. At necropsy there was a confluent lobular Table XVI Cases of Bronchopneumonia Following Influenza CASE ONSET of influenza onset of pneumonia SPUTUM EXAMINATION COURSE of pneumonia NECROPSY DATE BACTERIOLOGY B. inf. ++++ Pn. IV ++ DIAGNOSIS BACTERIOLOGY 70 Sept. 18 Sept. 21 Sept. 22 Diffuse bronchitis with rapidly progressive con-fluent bronchopneumonia Died Sept. 24 Nodular and diffuse con-fluent lobular pneu-monia. Purulent bron-chitis. Bronchiectasis 11. P.. sterile Br. B inf.++++ Pn. IV 44-Lun. B.inf. 444-Pn. IV +++ 59 Sept. 13 Sept. 18 Sept. 19 Pn. IV+++ B. inf. + Bronchopneumonia with long drawn out course. Died Oct. 4 Lobular pneumonia, with clustered abscesses. Bronchiectasis H.B. sterile Br. B.inf. +++ Staph. ++ R.L. no growth. 50 Sept. 14 Sept. 17 Sept. 18 Pn. IV +++ Mild bronchopneumonia improving on Sept. 24. On Sept. 26 became sud-denly worse and died on Sept. 30 Nodular and confluent lobular pneumonia. Pu rulent bronchitis 1 L B. sterile Br. B.inf. +++ Staph + R.L Pn. II +++ B.inf. + L.l\ Pn. 11+44- 56 Sept. 10 Sept. 17 Sept. 18 Pn. Ila +++ Bronchopneumonia with recovery by crisis on Sept. 19. Developed a second attack of pneu-monia and died Sept. 29 Confluent lobular pneu-monia H.B. Pn. II Br. Pn. 11+44-B.inf. 44-L.L. Pn. II++4 B.inf. + 107 Sept. 27 Sept. 29 Oct. 1 Pn. IV +++ B. inf. + Staph. + Diffuse bronchitis and se-vere bronchopneumonia Died Oct. 5 Confluent lobular pneu-monia with clustered ab-scesses. Pur. bronchitis and bronchiectasis Lobular pneumonia. Em-pyema. Purulent bron-chitis H.B. sterile R.L. Pn. III++ Staph. 4+ L.L. Staph. ++ 92 Sept. 23 Sept. 28 Oct. 1 B. inf. +++++ Pn. IV 444-S. hem. 2 col. Severe bronchopneumo-nia with empyema. Died Oct. 5 H.B. S.hem. Br. B.inf. +44-S.hem. +++ R.L. S.hem. +++ B.inf. ++ Emp. S.hem. 99 Sept. 24 Sept. 29 Oct. 1 B. inf. ++++ Pn. IV ++ S. vir. + Diffuse purulent bron-chitis with broncho-pneumonia. Died Oct. 7 Severe bronchopneumo-nia with empyema. Died Oct. 4 Bronchopneumonia. Pu-rulent bronchitis H.B. S.hem. Br. B.inf. +++ Lun. S.hem. +++ S.hem. ++ B. inf. + 102 Sept. 24 Sept. 28 Oct. 1 Pn. Ila +++ B. inf. 4 + Lobular pneumonia with interstitial suppuration. Pur. bronchitis. Empy-ema H.B. S.hem. Br. B.inf. +++ S.hem. +++ R.L. S hem.+44- 104 Sept. 26 Oct. 1 Oct. 1 B. inf. ++4+ Pn. IV +++ Diffuse purulent bron-chitis with severe bron-chopneumonia. Develop-ed streptococcus empy-ema. Died Oct. 11 Nodular bronchopneu-monia with interstitial suppuration. Pur. bron-chitis and bronchiecta-sis. Empyema H.B. S.hem. R.L. S.hem. ++++ Em]). S.hem. 70 PNEUMONIAS AXI) INFECTIONS OF RESPIRATORY TRACT pneumonia with clustered abscesses, purulent bronchitis, and bronchiectasis in the left lower lobe. The heart's blood was sterile, the lungs showed Pneumococcus Type III and staphylococci. B. influenzEe was not found, but through oversight no cultures were taken from the bronchi. Cases 92, 99,102, and 104 are all examples of superimposed hemo- lytic streptococcus infection occurring in the presence of a Pneumococcus Type IV pneumonia, with the picture of in- terstitial suppuration, abscess formation, " and empyema clue to S. hemolyticus on the background of a pneumococcus lobular pneumonia found at necropsy. All showed abun- dant pneumococci and B. influenzas in the sputum and were free from hemolytic streptococci at time of onset of pneu- monia, except Case 92 which showed 2 colonies of S. hemo- lyticus in the first sputum culture made. At time of death the pneumococci had disappeared in all cases and were re- placed by hemolytic streptococci. The cases cited in the preceding paragraph are illustra- tive examples from a series of over 250 necropsies which are described in another section of this report. They serve to indicate clearly the extent to which mixed and superim- posed infections of the lungs may occur in pneumonia following influenza and leave little doubt that a considerable proportion of the deaths from influenzal pneumonia are due to this circumstance. Hemolytic Streptococcus Pneumonia Following Influenza But 4 cases of hemolytic streptococcus pneumonia di- rectly following influenza without an intervening pneumo- coccus infection of the lungs occurred in the group of cases studied clinically. Superimposed infection with S. hemo- lyticus, however, occurred not infrequently during the course of pneumococcus pneumonia following influenza, as has been stated above. This occurred 3 times in lobar pneumonia and 10 times in bronchopneumonia, with fatal outcome in all but 1 case. CLINICAL FEATURES AND BACTERIOLOGY OF INFLUENZA 71 Bacteriology.—Bacteriologic examination of the sputum in the 4 cases of streptococcus pneumonia directly follow- ing influenza showed S. hemolyticus present in abundance. B. influenzas was also present in large numbers in 3 cases, but was not found in the fourth. In 1 case a Gram-nega- tive micrococcus resembling M. catarrhalis was also pres- ent in large numbers in the sputum. Pneumococci were not found either by direct culture on blood agar plates or by inoculation of the sputum intraperitoneally in white mice. In the 13 cases of superimposed hemolytic streptococcus infection occurring during the course of pneumococcus pneumonia, bacteriologic examination of the sputum by di- rect culture and by mouse inoculation shortly after onset of the pneumonia showed Pneumococci (atypical IT once, Typo III once, Group IV eleven times) B. influenzae present in large numbers, and no hemolytic streptococci ex- cept in 4 instances in which a very few organisms were pres- ent. Subsequent invasion of the lower respiratory tract by S. hemolyticus was shown to occur by means of cultures of empyema fluids or by cultures made at necropsy. Clinical Features.—The 4 cases of hemolytic streptococ- cus pneumonia following influenza that occurred in this series resembled in all respects the secondary streptococcus pneumonias of the winter and spring of 1918 and presented no features requiring special comment. The onset re- sembled that of pneumococcus bronchopneumonia, the disease appearing to develop as a continuation of the pre- ceding influenza. The sputum was profuse and muco- purulent in 3 cases, mucoid and bloody in the other. Two cases ran a severe and rapid course with the development of empyema early in the disease and fatal outcome. The other 2 cases ran only moderately severe courses without developing empyema and recovered by lysis in twenty and fifteen days, respectively, after the onset of influenza. Clinical differentiation between streptococcus and pneumo- 72 PNEUMONIAS AND INFECTIONS OF KESIMILYTORY TKACT coccus bronchopneumonia following influenza did not seem possible without bacteriologic examination of the sputum except in those cases of the streptococcus group which de- veloped an extensive pleural effusion early in the disease. The advent of superimposed hemolytic streptococcus in- fection of the lower respiratory tract during the course of pneumococcus pneumonia following influenza presented no clinical features that made diagnosis certain without bac- teriologic examination. The sudden occurrence of a pleu- ral exudate during the course of the disease seemed of par- ticular significance, especially since empyema in the bron- chopneumonias following influenza was exceedingly rare in the absence of hemolytic streptococcus infection. Other suggestive symptoms were a chill during the course of the disease, a sudden turn for the worse in cases apparently doing well, or the development of a cherry red cyanosis. None of these features, however, was sufficiently constant or distinctive of streptococcus invasion to be depended upon and when they occurred, were merely indications for fur- ther bacteriologic examination. Bacillus Influenzae Pneumonia Following Influenza Bacteriologic evidence that cases of pneumonia following influenza might be due to B. influenzae alone was very meager in the group of cases studied clinically at Camp Pike; in fact, no convincing evidence was obtained that such cases occurred. In one case B. influenzas alone was found in the sputum coughed from the deeper air passages, and in another case B. influenzas with a few colonies of S. viridans was found. Both were cases of bronchopneu- monia, mild in character, and recovered promptly. They presented no clinical features by which they could be dis- tinguished from cases of pneumococcus bronchopneumonia. It has been previously stated that B. influenzas was found in all early uncomplicated cases of influenza somewhere in the respiratory tract; that it was present together with CLINICAL FEATURES AND BACTERIOLOGY OF INFLUENZA 73 other organisms, notably pneumococcus in the sputum from cases of purulent bronchitis following influenza; and that it was found in the sputum coughed from the lung in ap- proximately 80 per cent of cases of pneumonia compli- cating influenza. In 35 cases it was very abundant, often being the predominating organism. In all these cases, however, pneumococci or hemolytic streptococci were also present in considerable numbers at the time of onset of the pneumonia. It is impossible to say merely from the clin- ical and bacteriologic data under consideration what part B. influenzae played in the development of the actual pneu- monia in these cases. Discussion of this subject is there- fore reserved for the section of this report dealing with the pathology and bacteriology of pneumonia following in- fluenza. Summary Influenza as observed at Camp Pike presented itself as a highly contagious infectious disease, the principal clinical manifestations of which were, sudden onset with high fever, profound prostration with severe aching pains in the head, back and extremities, erythema of the face, neck and upper chest with injection of the conjunctiva*, and a rapidly progressive attack upon the mucous mem- branes of the respiratory tract as evidenced by coryza, pharyngitis, tracheitis and bronchitis with their accom- panying symptoms. In the majority of cases it ran a short self-limited course, rarely of more than four days' dura- tion, and was never fatal in the absence of a complicating pneumonia. Bacteriologic examination in early uncomplicated cases of the disease showed the B. influenzas of Pfeiffer to be present in all cases, often in predominating numbers. It was found more abundantly present during the acute stage of the disease than during convalescence in uncomplicated cases. No other organisms of significance were encountered by the methods employed. 74 PXEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Purulent bronchitis of varying extent developed in ap- proximately 35 per cent of the cases and often prolonged the course of the illness to a considerable extent. Bacte- riologic studies showed that it was invariably associated with a mixed infection of the bronchi with B. influenzas and other bacteria, in most instances the pneumococcus, and in- dicated that it should be regarded as a complication rather than as an essential part of influenza. Its clinical features consisted of a mild febrile reaction, frequent cough with the raising of considerable amounts of purulent sputum, and the physical signs of a more or less diffuse bronchitis. It led to a varying degree of bronchiectasis in at least some instances. Pneumonia complicating influenza presented a very di- versified picture and appeared to have only one constant character, namely, that influenza was the predisposing cause. It may be best classified on an etiologic basis since the clinical features to some extent and the pathology to a much greater extent depended upon the infecting bacteria in a given case. Bacteriologic examination showed that a very large pro- portion of the cases was due to infection with the different immunologic types of pneumococci or to a mixed infection with B. influenzas and pneumococci. The types of pneumo- cocci commonly found in normal mouths, namely, II atypi- cal, III, and IV, comprised approximately 88 per cent of these, the highly parasitic Pneumococci Types I and II, but 12 per cent. A small number of cases were due to hemolytic streptococci or to mixed infection with B. influ- enzas and S. hemolyticus. No certain evidence was obtained that pneumonia was due to B. influenzas alone. This or- ganism was present in varying numbers, however, in approximately 80 per cent of the sputums examined, and it seems fairly certain that it must have played at least a part in the development of the pneumonia in many of the cases in which it was found. Superimposed infections CLINICAL FEATURES AND BACTERIOLOGY OF INFLUENZA 75 with other types of pneumococci than those primarily re- sponsible for the development of pneumonia, with hemo- lytic streptococci and with Staphylococcus aureus occurred frequently in cases of pneumococcus or mixed pneumococcus and B. influenzas pneumonia and undoubtedly contributed to a considerable extent in increasing the number of deaths. Three clinical types of pneumococcus pneumonia follow- ing influenza occurred: lobar pneumonia, lobar pneumonia with purulent bronchitis, and bronchopneumonia. Lobar pneumonia was usually sudden in onset and ran the char- acteristic course of the primary disease. Lobar pneumonia with purulent bronchitis similarly ran the characteristic course of the primary disease but presented the unusual picture of lobar pneumonia with mucopurulent rather than rusty, tenacious sputum and numerous moist rales through- out the unconsolidated portions of the lungs. The cases of bronchopneumonia ran a very variable course from mild cases of a few days' duration and meager signs of consoli- dation to rapidly progressive cases with signs of extensive pulmonary involvement. Purulent bronchitis was very frequently associated with bronchopneumonia. Hemolytic streptococcus pneumonia following influenza presented the clinical picture of bronchopneumonia and was not readily distinguished on clinical grounds from pneu- mococcus bronchopneumonia except in those cases which developed a pleural exudate early in the disease. The ad- vent of tertiary infection of the lower respiratory tract with hemolytic streptococci in cases of secondary pneumococcus pneumonia presented no symptoms sufficiently constant or certain to make clinical diagnosis easy. The development of empyema in pneumococcus bronchopneumonia usually meant streptococcus infection. Pure B. influenzas pneumonia, if such cases existed, pre- sented no diagnostic features by which it could be distin- guished from pneumococcus bronchopneumonia following influenza. It was impossible to determine on clinical and 76 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT bacteriologic grounds alone what part the prevalent in- fluenza bacilli played in the causation of the actual pneu- monia. Discussion That wide variations in the conception of influenza have arisen during the recent pandemic, even a hasty review of the literature makes clear. In its essence this divergence of opinion seems to depend upon whether pneumonia is considered an essential part of influenza or a complica- tion due either to the primary cause of influenza or to secondary infection. One extreme is expressed by Dunn3 who says "the so-called complication is the disease," the other by Fantus4 who finds influenza a relatively mild disease with pneumonia a relatively infrequent and largely preventable complication. A similar divergence of opinion prevails with respect to the bacteriology of influenza. There is fairly general agreement that the members of the pneumococcus and streptococcus groups and to a less extent other organisms are responsible for a large proportion of the secondary pneumonias, and but few observers hold that they possess any etiologic relationship to influenza. Xo such uniform- ity of opinion exists, however, with respect to the relation of B. influenza^ to influenza and to the complicating pneu- monia. By some it is considered the primary cause of influenza, by others it is regarded as a secondary invader responsible for a certain proportion of the secondary pneumonias, and by still others it is not considered to bear any relation either to influenza or its complications. A limited number of references to the extensive litera- ture of the recent pandemic will amply serve to illustrate the various points of view that have developed. Keegan5 regards pneumonia as a complication and con- siders that B. influenzas, the probable cause of influenza, is 3Dunn: Jour. Am. Med. Assn., 1918, lxxi, 2128. 'Fantus: Jour. Am. Med. Assn., 1918, lxxi, 1736. BKeegan: Jour. Am. Med. Assn., 1918, lxxi, 1051. CL1XICAL FEATURES AND BACTERIOLOGY OF INFLUENZA 77 the primary cause of the pneumonia which may or may not be still further complicated by pneumococcus or streptococ- cus infection as a terminal event. Christian6 states that epidemic influenza causes a clinically demonstrable bron- chitis and bronchopneumonia in the larger proportion of cases, and lays particular emphasis upon the fact that it is quite incorrect to consider fatalities in the epidemic as due to influenza uncomplicated by bronchopneumonia. Blanton and Irons7 speak of influenza as an "antecedent respiratory infection'' of undetermined etiology, and be- lieve that pneumonia when it occurs is due to autogenous infection by a variety of secondary invaders, principally of the pneumococcus and streptococcus groups. Hall, Stone, and Simpson8 regard pneumonia strictly as a com- plication and quite distinct from influenza itself. Synnott and Clark9 believe that the infection is characterized by a progressive intense exudative inflammation of the respira- tory tract often terminating in an aspiration pneumonia with a variety of conditions found at autopsy and a mul- tiplicity of secondary organisms responsible for the fatal termination. B. influenzas was usually found but always with other organisms. Friedlander and his collaborators10 speak of a fulminating fatal type of influenza with acute inflammatory pulmonary edema, but regard true broncho- pneumonia as secondary, due to infection with pneumococ- cus or S. hemolyticus. B. influenzas was not found more frequently than under normal conditions. Brenl11 and his collaborators present a clear cut clinical picture both of influenza and the secondary pneumonia to which it predis- poses, regarding the latter as definitely clue to secondary infection with pneumococcus, streptococcus or B. influenzae, the virus of influenza being unknown. Ely12 and his col- "Christian: Jour. Am. Med. Assn., 1918, lxxi, 1565. 'Blanton and Irons: Jour. Am. Med. Assn., 1918, lxxi. 1988. "Hall, Stone and Simpson., Jour. Am. Med. Assn., 1918, lxxi, 1986. "Svnnott and Clark: Jour. Am. Med. Assn., 1918, lxxi, 1816. "Friedlander, McCord, Sladen and Wheeler: Jour. Am. Med. Assn., 1918, lxxi, 1652. "Brem, Boiling and Casper: Jour. Am. Med., Assn., 1918, lxxi, 2138. ,2EIy, Lloyd, Hitchcock, and Nickson: Jour. Am. Med. Assn., 1919, lxxii, 24. 78 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT laborators make no distinction between influenza and pneu- monia, and apparently consider the epidemic due to a hemo- lytic streptococcus of indefinite and inconstant characters. The Camp Lewis Pneumonia Unit13 states "the process [influenza], whether mild or severe, is etiologically and pathologically the same; * * *." B. influenzas was not found. In a report of The American Public Health Asso- ciation14 it is stated that deaths resulting from influenza are commonly due to pneumonias resulting from an in- vasion of the lungs by one or more forms of streptococci, by one or more forms of pneumococci, or by the so-called influenza bacillus. This invasion is apparently secondary to the initial attack. AVolbach15 found B. influenzas in a high proportion of cases, not infrequently in pure culture in the lung, and believes that there is a true influenzal pneu- monia whether B. influenzas is the cause of the primary dis- ease or not. Spooner, Scott and Heath16 isolated B. in- fluenzas in a high percentage of cases and consider it reasonable to suppose that it was the prime factor in the epidemic. Kinsella17 found B. influenzas infrequently and regards it as a secondary invader. MacCallum18 regards B. influenzas as a secondary invader and believes that it is responsible for a form of purulent bronchitis and broncho- pneumonia following certain cases of influenza. Pritchett and Stillman19 found B. influenza1 in 93 per cent of cases of influenza and bronchopneumonia. Hirsch and McKinney211 state that B. influenzas played no role in the epidemic at Camp Grant and apparently consider it due to a specially virulent pneumococcus. No further references to the extensive literature of the recent pandemic seem necessary, since those cited above serve to illustrate the various points of view that exist. 13Camp Lewis Pneumonia Unit: Jour. Am. Med. Assn., 1919 lxxii 268 14Jour. Am. Med. Assn., 1918, lxxi, 2068. ir'Wolbach: Bull. Johns Hopkins Hosp., 1919, xxx, 104. "Spooner, Scott and Heath: Jour. Am. Med. Assn., 1919, lxxii, 155 17Kinsella: Jour. Am. Med. Assn., 1919, lxxii, 717. lsMacCallum: Jour. Am. Med. Assn., 1919, lxxii, 720. "Pritchett and Stillman: Jour. Exper. Med., 1919, xxix, 259. 20Hirsch and McKinney: Jour. Am. Med. Assn., 1918, lxxi, 1735. CLINICAL FEATURES AND BACTERIOLOGY OF INFLUENZA 79 A similar diversity of opinion may be found in the reports from foreign sources. It would appear that much of the divergence of opinion that has been formed has depended to a considerable ex- tent upon the conditions under which cases have been ob- served. This is clearly brought out by contrasting the experience of Fantus4 dealing with private cases in civilian practice, where pneumonia was relatively uncommon, with that of others dealing only with cases in large hospitals, where those admitted have been in large part selected se- riously ill patients with a high incidence of pneumonia, the milder cases comprising from 60 to 90 per cent of those attacked by influenza never reaching the hospital. Varia- tions in opinion with respect to the bacteriology of the epidemic, especially in regard to B. influenzas, would appear to be due for the most part to differences in bacteriologic technic, in some degree to differences in interpretation. Accumulating evidence can leave little doubt that B. in- fluenzas was at least extraordinarily and universally preva- lent throughout the period of the epidemic and thereafter, and that earlier reports of failure to find it were due to the use of methods unsuitable for its detection and isolation. The opportunity afforded the commission at Camp Pike to devote their full time to a systematic and correlated group study of the epidemic simultaneously from many aspects throughout its whole course made it apparent that influenza*per se is in the large majority of instances, in spite of the initial picture of profound prostration, a rela- tively mild disease which tends to rapid spontaneous re- covery. This opinion is supported by the fact that the disease during the first waves of the epidemic in this coun- try, which it is now recognized occurred pretty generally in the army camps during the spring of 1918, was so mild that it attracted only passing attention, since the disease at that time was not sufficiently virulent to predispose to any alarming amount of pneumonia. With the return of 80 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT the epidemic in the late summer and early fall, however, the disease had attained such a high degree of virulence that it predisposed to an appalling amount of severe and often rapidly fatal pneumonia, which often detracted at- tention from the real nature of the preceding disease. Yet even during the fall epidemic from 60 to 90 per cent of the cases of influenza proceeded to rapid recovery with- out developing complications. On this ground alone it would seem only logical to regard pneumonia strictly as a complication of influenza rather than as an essential part of the disease, irrespeetive of whether the pneumonia may be caused by the primary cause of influenza or not. The complexity of the clinical features, the bacteriology and pathology of the pneumonias following influenza lend fur- ther support to this opinion. It seems better, therefore, to consider influenza first as a disease by itself and subsequently to take up the question of pneumonia and the relation of influenza to it. The most striking clinical features of influenza are its epidemic character, its involvement of the respiratory tract, its extremely prostrating effect, and the often sur- prising rapidity with which the individual cures himself. These features strongly suggest that the etiologic agent of the disease is an organism subject to rapid changes in vir- ulence ; that it is confined to the respiratory tract where it produces a superficial inflammatory reaction giving rise to the characteristic symptoms of coryza, pharyngitis and tracheitis; that it elaborates a poison, possibly a true toxin, readily absorbed by the lymphatics, the effect of which is manifested in the profound prostration, severe aching pains, erythema, and leucopenia; and that it may either disappear promptly from the respiratory mucous mem- brane at time of recovery or may persist, leading a rela- tively saprophytic existence for an indefinite period of time, being no longer harmful to the individual, at least more than locally, because of an acquired immunity. Fur- CLINICAL FEATURES AND BACTERIOLOGY OF INFLUENZA 81 thermore, in our opinion, the very brief incubation period suggests that the disease is bacterial in origin, rather than that it is analogous to the exanthemata, the majority of which present a comparatively long, fairly constant, incu- bation period. B. influenzas has characteristics in accord with the clinical features of influenza. It is an organism of very labile viru- lence; it is always present in our experience on the mucous membranes of the respiratory tract in early uncomplicated cases of influenza, often in overwhelming numbers; in only very exceptional instances, in adults at least, does it invade the body producing a general infection, as the numerous reports of negative blood cultures testify; recent investiga- tions by Parker'1 and others indicate that it is capable of producing a toxin quickly fatal for rabbits; it is predomi- nantly present in the respiratory tract during the active stage of the disease and disappears in a considerable pro- portion of cases at time of recovery, while in others, more particularly those that develop an extensive secondary bronchitis and bronchiectasis it may persist for an in- definite period of time. It is, of course, fully appreciated that the foregoing is in the main merely argumentative reasoning and it is put forth only to suggest that B. influenza* merits a much closer scrutiny with respect to its etiologic relationship to influ- enza than the trend of present opinion has awarded it. Although there remains some difference of opinion as to the relation of influenza to pneumonia, the majority of ob- servers concur in regarding pneumonia as a complication and this would seem to be the only logical interpretation of the facts available. The same may be said with respect to purulent bronchitis and bronchiectasis. It is of consider- able significance in this connection that pneumonia follow- ing influenza presents no uniform clinical picture, no uni- form bacteriology and no uniform pathology. Whether the "Parker: Jour. Am. Med. Assn., 1919, lxxii, 476. 82 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT predisposition of patients with influenza to contract pneu- monia is preponderantly due to lowering of general resist- ance to infection by the extremely prostrating effect of the disease and the inhibition of leukocytic defense, or to a de- struction of local resistance against bacterial invasion by reason of profound injury to the bronchial mucosa, or to a combination of both factors, is difficult to say. It seems most probable that both are concerned. At any rate it seems clear that in the presence of influenza a considerable variety of organisms which under ordinary conditions do not find lodgement in the lungs are able to gain access to the lower respiratory tract and produce pneumonia. CHAPTER III SECONDARY-INFECTION IN THE WARD TREAT- MENT OF INFLUENZA AND PNEUMONIA Eugene L. Opie, M.D.; Francis G. Blake, M.D.; James C. Small, M.D.; and Thomas M. Rivers, M.D. One of the most pressing problems that presented itself in the care of influenza and pneumonia patients in the army cantonments during the recent epidemic was the clanger of secondary contact infection because of the overcrowding of the base hospitals, nearly all of which were taxed far be- yond the limits of their capacity. That this danger was very real was fully demonstrated by certain studies in ward infection that this commission was able to make at Camp Pike1. It is the purpose of the present section of the re- port to present these studies and to discuss the means whereby this danger may be most successfully met. It is perhaps well, first to define exactly what is meant by secondary contact infection in influenza and pneumonia. In our experience at Camp Pike it was found that a very large percentage of the pneumonias following influenza were accompanied by secondary infection with pneumococ- cus, some few being caused by hemolytic streptococcus. The types of pneumococcus encountered were almost en- tirely those that are found normally in the mouths of healthy men, approximately 85 per cent being Types II atypical, III, and IV. It has been generally accepted that infection with these types of pneumococci is usually autog- enous—that is, that under the proper conditions of low- ered resistance an individual becomes infected with the pneumococcus that he carries in his own mouth. Many ob- 'Opie, Freeman, Blake, Small and Rivers: Jour. Am. Med. Assn., 1919, lxxii, 556. 83 84 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT servations made during the course of the present work have suggested that this is probably not so in many in- stances and that the influenza patient may not be so much in danger from the pneumococcus that he normally carries in his own mouth as he is from that carried by his neighbor, in other words, he is in danger from contact infection. The same considerations hold true with respect to hemolytic streptococcus infection. Secondary contact infection in cases of already existing pneumonia following influenza were found to occur frequently. These were for the most part caused by hemolytic streptococcus infection superim- posed upon a pneumococcus pneumonia. Many instances of double pneumococcus infection, however, either coinci- dent with or following one another were encountered. Secondary Infection with S. Hemolyticus in Pneumonia Pneumonia caused by streptococci was repeatedly ob- served2 during the pandemic of influenza which occurred in 1889-90. With clearer recognition of the characters which distinguish varieties of streptococci several observers have shown that secondary infection with hemolytic streptococci may occur during the course of pneumonia and though defi- nite evidence has been lacking have suggested that it may be acquired within hospital wards. That a similar second- ary infection with S. hemolyticus in pneumococcus pneu- monias following influenza occurred not infrequently at Camp Pike during the epidemic was shown by bacteriologic studies made during life and at autopsy in a considerable series of cases. During the early days of the epidemic of influenza, secondary streptococcus infection was almost entirely limited to certain wards which were opened for the care of the rapidly increasing number of patients with pneumonia. During this period these wards were overcrowded, organization was incompletes and the op- portunities for transfer of infection from patient to pa- 2See discussion on pages 115 to 118. SECONDARY INFECTION IN WARD TREATMENT 8.1 tient were almost unlimited. The spread of streptococcus contagion and its fatal effect may be clearly brought out by comparison of these wards with wards that had long been organized for the care of patients with pneumonia. Ward 3 had been in use for the care of patients with pneumonia for some time prior to the outbreak of influenza. It was provided with sheet cubicles and conducted by medi- cal officers, nurses and enlisted men accustomed to the care of patients with pneumonia, ordinary precautions being taken against transfer of infection from one patient to an- other. The data in Table XVIT show the average number of patients in the ward, the number of new cases of pneu- monia admitted, and the number of deaths among patients admitted during the corresponding period, for three periods of ten clays each from September 6 to October 5. The types of infection in fatal cases as determined by cultures taken at autopsy are also shown. Table XVII Pneumonia in Ward 3 TOTAL DEATHS I CULTURES AT AUTOPSY o en q a bj ha ~ W z <-< « w > fe AMONG PATIENTS ° oa Q , ADMITTED DURING m Z g i THE CORRESPOND-ED S tl ING PERIOD <5 Ch - 6 03 DETER-INED opsy) > ^ < £ < z &. 2 £ ^ 3 NUMBER PER CENT Sept. 6-15 18.6 Sept. 16-25, 46.1 Sept. 26— 58.6 Oct. 5 11 3 1 27.2 52 16 30.7 23 i 8 34.7 3 13 5 0 1 1 0 2 2 During the period from September 6 to lo, just prior to the outbreak of influenza in epidemic proportions, the ward had an average population of 18.6 patients. The total number of new patients admitted was 11, of whom 3 died, a mortality of 27.2 per cent. All these cases were pneu- mococcus pneumonias as determined by bacteriologic ex- amination of the sputum at time of admission. The 3 fatal cases showed pneumococcus infection at autopsy. During the second period, from September 16 to 25, with the out- 86 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT break of the epidemic of influenza, the ward rapidly filled with new cases of pneumonia, attaining an average popula- tion of 46.1 patients. Of the 52 new cases admitted 16 died, a mortality of 30.7 per cent. Again all the cases ad- mitted during this period in which bacteriologic examina- tion of the sputum was made, were found to be pneumococ- cus pneumonias with one exception. This case, admitted on September 21 and dying two days later, had a hemolytic streptococcus pneumonia. Fortunately, though quite by ac- cident, he was placed in a bed at one end of the porch and no transmission of streptococcus infection to other cases in the ward took place. At autopsy 13 cases showed pneu- mococcus infection; the foregoing case, hemolytic strepto- coccus. During the third period from September 26 to October 5 the ward became even more crowded, having an average of 58.6 patients; 23 new cases were admitted, 8 of whom died, a mortality of 34.7 per cent. Autopsy showed that 5 of these were pneumococcus pneumonias and 1 was caused by hemolytic streptococcus infection. It is note- worthy that the death rate from pneumonia gradually in- creased as the ward became more and more crowded. This may possibly be attributed in part to the increasing severity of the pneumonia during the early days of the influenza epidemic. That it was in part directly due to secondary contact infection with pneumococcus will be shown when the transmission of pneumococcus infection is discussed. In spite of the overcrowding of the ward the introduction of 2 cases of streptococcus pneumonia did not cause an out- break of streptococcus infection. AVhether this was due to precautions taken against the transfer of infection or was merely a matter of good luck is difficult to say, in view of the fact that a considerable amount of transfer of pneu- mococcus infection from one patient to another did occur. AVard 8 had long been used for the care of colored pa- tients with pneumonia. As in AVard 3 cubicles were in use SECONDARY INFECTION IN WARD TREATMENT 87 and ordinary precautions against the transfer of infection were used. The data are presented in Table XVIII. Table XVIII Pneumonia in Ward 8 AVERAGE NUMBER OF PATIENTS IN WARD NUMBER OF PATIENTS ADMITTED TOTAL DEATHS CULTURES AT AUTOPSY AMONG PATIENTS ADMITTED DURING THE CORRESPOND-ING PERIOD 6 w § u Ph S. HEMO-LYTICUS UNDETER-MINED (NO AU-TOPSY) NUMBER PER CENT Sept. 6-20 Sept. 21 —Oct. 5 25.5 46.1 18 59 2 20 11.1 33.9 2 10 0 1 0 9 During the period from September 6 to 20, prior to the outbreak of influenza in epidemic proportions among the colored troops, the ward had an average population of 25.5 patients; 18 new cases of pneumonia were admitted during this period, all of whom were pneumococcus pneumonias as determined by bacteriologic examination of the sputum at time of admission to the ward. Only 2 died, a mortality of 11.1 per cent, autopsy cultures showing pneumococcus in both cases. All these patients were treated on the porch of the ward while they were acutely sick. During the sec- ond period from September 21 to October 5, when the in- fluenza epidemic was at its height, the ward rapidly filled with active cases of pneumonia and became distinctly crowded. It contained an average of 46.1 patients, but had actually reached a population of 64 patients at the end of the period. Of the 59 new cases admitted, 20 died, a mortality of 33.9 per cent, 10 with pneumococcus pneu- monia, one with hemolytic streptococcus pneumonia. In 9 there was no autopsy. The conditions in AVard 8 were quite analogous to those in AVard 3. In spite of the over- crowding during the second period no outbreak of second- ary infection with S. hemolyticus occurred, but secondary pneumococcus infection did occur as will be shown below. 88 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT In contrast with these two wards are AY aids 1 and 2 in which widespread secondary contact infection with S. hemolyticus took place. AVard 2 was opened September 26, at the beginning of the period when 20 new wards for pneumonia were organized. From September 26 to Octo- ber 1 the cubicle system was not in use, the ward was crowded, organization was imperfect, and few precautions were taken to prevent transfer of infection from one pa- tient to another. On October 2 the cubicle system was installed and precautions against transfer of infection were instituted. The data are shown in Table XIX. Table XIX Pneumonia in Ward 2 Ph o CO Q TOTAL DEATHS CULTURES AT AUTOPSY AMONG PATIENTS CO a ADMITTED DURING , CO J * • NUMBER g PATIENT IN WAR « H fe S * R « g s S EH 3 £ < a Z, CU < 101 THE CORRESPOND-ING PERIOD P o Ph rDETEI [INED NO AU OPSY; NUMBER PER CENT p Sept. 26 Sept. 27 27 17 HO 27 67.5 0 23 4 Sept. 28 40 13J Sept. 29 51 121 Sept. 30 49 1 H7 6 35.3 2 2' 0 Oct. 1 43 4J Oct. 2 47 61 Oct. 3 42 0 MO 4 40.0 2 1 1 Oct. 4 41 4J During the first three days 40 patients with pneumonia were admitted to the Yard. Of these 40 patients, 27 died, a mortality of 67.5 per cent. Cultures at autopsy showed that 23 of these died with hemolytic streptococcus infection, none of pneumococcus infection. In four there was no au- topsy. To appreciate the full significance of these figures it must be emphasized that these, patients at time of ad- mission to the ward in no way differed from those admitted to AVard 3 during the corresponding period and were not in any sense selected cases. The type of infection in 9 of these patients had been determined by bacteriologic exami- SECONDARY INFECTION IN WARD TREATMENT 89 nation of the sputum just prior to or immediately after ad- mission to the ward before opportunity for secondary con- tact infection in this ward had occurred. All 9 were shown to have pneumococcus pneumonia free from hemolytic strep- tococci at that time. All 9 died, 7 with secondary strepto- coccus infection as shown by cultures taken at autopsy, 1 with a secondarily acquired Pneumococcus Type III infec- tion—sputum showed a Pneumococcus Type IV on admis- sion—and in 1 there was no autopsy. In view of the fact that bacteriologic examination of the sputum in cases of pneumonia following influenza had shown that the large majority of them were due to pneumococcus infection, it is probable that most of the other cases of pneumonia ad- mitted to this ward were pneumococcus pneumonias at time of admission, and that they acquired the streptococcus in- fection after admission. During the next three days 17 new patients were admit- ted, of whom 6 died, a mortality of 35.3 per cent. Cultures at autopsy showed pneumococcus infection in 2, strepto- coccus in 2. It is noteworthy that the porch was first put into use on September 29. Of the 12 patients admitted on this date, 8 were treated throughout the acute stage of their illness on the porch. Of these 8 patients but one died, of a Pneumococcus Type IV infection and none became in- fected with S. hemolyticus. From October 4 to October 6, 10 patients were admitted, of whom 4 died. Cultures at autopsy showed pneumococcus infection in 2, hemolytic streptococcus in 1. The widespread prevalence of hemolytic streptococcus infection in this ward as compared with its almost entire absence in AVards 3 and 8 is very striking. Cultures made during life and at autopsy have shown clearly that it was clue to rapid spread of contagion throughout the ward. The almost unlimited opportunities for transfer of infection from patient to patient, during the first six days the ward was in use, undoubtedly greatly facilitated this spread. 90 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT From the data available it is impossible to state exactly when and by which patients hemolytic streptococcus in- fection was introduced into the ward, but it must have been very early since the death rate was very high from the be- ginning, and the first 23 cases coming to autopsy died with streptococcus infection. AVard 1 was opened on September 24. From that date until October 2 no cubicles were in use and few precautions were taken against transfer of infection. On October 2 cubicles were installed and ordinary precautions to prevent transfer of infection were instituted. On October 6 the ward was closed to further admissions. The data pre- sented in Table XX are divided into two periods, because on September 29 and 30, 4 patients with streptococcus pneu- monia were admitted to the Yard. TABLE XX Pneumonia in Ward 1 average number of patients IN WARD NUMBER of PATIENTS ADMITTED TOTAL DEATHS CULTURES AT AUTOPSY AMONG PATIENTS ADMITTED DURING THE CORRESPOND-ING PERIOD O M Z o Ph » o CO ^ UNDETER-MINED (NO AU-TOPSY) NUMBER PER CENT Sept. 24-29 Sept. 30 —Oet. 5 35.8 55.3 34 40 11 24 32.3 60.0 5 6 3 14 3 4 During the first period from September 24 to 29 the ward contained an average of 35.8 patients, being only mod- erately crowTded; 34 cases of pneumonia were admitted, of whom 11 died, a mortality of 32.3 per cent. It is note- worthy that deaths among this group which occurred prior to September 30 were due to pneumococcus infection with one exception, a patient entering the ward on September 26 and dying the following day. Of the other 2 patients in this group who died with hemolytic streptococcus pneu- monia, 1 was admitted to the ward on September 25, was SECONDARY INFECTION IN WARD TREATMENT 91 shown to be free from S. hemolyticus on September 30, and died on October 12 with a secondarily acquired streptococ- cus pneumonia and empyema; the other was admitted on September 29 with streptococcus pneumonia and died the following day. During the second period from September 30 to October 5 the ward contained an average of 55.3 patients, being very overcrowded; 40 new cases of pneumonia were ad- mitted of whom 24 died, a mortality of 60 per cent. Cul- tures taken at autopsy showed that 6 died of pneumococcus pneumonia, 14 with hemolytic streptococcus infection. As in AVard 2, patients admitted to this Yard were in no way selected and were probably, as experience has shown, in large part pneumococcus pneumonias at time of admission. The widespread dissemination of hemolytic streptococcus and its fatal effect following the introduction of the organ- ism on September 29 and 30 is only too evident. Secondary Infection with Pneumococcus in Pneumonia The foregoing studies have shown that hemolytic strep- tococcus infection may spread by contagion throughout an entire ward with great rapidity. Other observations have demonstrated that pneumococcus infection may be trans- mitted in the same way. Only three instances of this nature will be cited. The first occurred in AVard 3 (Table XXI). Between September 6 and 16 no cases of pneumonia caused Table XXI Secondary Infection with Pneumococcus Type II secondary infection NAME Pvt. Wolfe Pvt. Pullam Pvt. Swain BED OCCU- PIED No. (5 No. 5 No. 3 ADMITTED Sept. 17 Sept. 9 Sept. 16 PNEUMO- COCCUS IN SPUTUM ON ADMISSION IV IV II DATE Sept 23 Sept. 24 PNEUMO- COCCUS AT AUTOPSY II* II *Isolated by blood culture on Sept. 23. Patient recovered. 92 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TKACT by Pneumococcus Type II had been admitted to the ward. On September 16 Pvt. Swain was admitted to the ward and placed in Bed 3. Bacteriologic examination of his sputum showed that his pneumonia was caused by Pneumococcus Type II. At this time Pvt. Pullam, who had been ad- mitted to the ward on September 9 with a pneumococcus Type IV pneumonia, occupied Bed 5 separated from Bed 3 by one intervening bed. He had had his crisis on Septem- ber 14 and was doing well, his temperature being normal. On September 24 he developed a second attack of pneu- monia and died on September 30. Cultures at autopsy showed Pneumococcus Type II in heart's blood and lung, Pneumococcus Type II and B. influenza? in the right bron- chus. Pvt. AVolfe was admitted to the ward Avith broncho- pneumonia on September 17 and placed in Bed 6 next to Pvt. Pullam. Pneumococcus Type IAT and B. influenzae were found in his sputum. His temperature had fallen to normal by lysis on September 21 and he was doing well. On September 23 his temperature suddenly rose and he developed a second attack of pneumonia. Pneumococcus Type II was isolated by blood culture on this date. He recovered. In both instances Pneumococcus Type II was acquired after the admission of a patient with a Pneumo- coccus Type II pneumonia, the opportunity for contact in- fection having been favored by the association of these patients in adjoining beds. The second instance is almost identical and occurred on the opposite side of AVard 3 at about the same time (Table XXII). Pvt. Linehan was admitted on September 16 and placed in Bed 30. Pneumococcus Typo IV was found in his sputum. Pvt. Thompson was admitted the following day with a Pneumococcus II atypical pneumonia and placed in Bed 28. The next day Pvt. Smith was admitted and placed in Bed 26. Pneumococcus Type II was found in his sputum. On September 19 Pvt. Thompson recovered by crisis and was doing well. On September 21 he had a SECONDARY INFECTION IN WARD TREATMENT 93 Table XXII Secondary Infection with Pneumococcus Type II BED occu-pied ADMITTED pneumo-coccus in sputum ON ADMIS-SION SECONDARY INFECTION NAME \ DATE PNEUMO-COCCUS AT AUTOPSY Pvt. Smith Pvt. Thompson Pvt. Linehan No. 26 No. 28 No. 30 Sept. 18 Sept. 17 Sept. 16 II Atyp. II IV Sept. 21 Sept. 26 II II II chill, his temperature rose to 104.4° F. and he developed a second attack of pneumonia. He died on September 29; cultures at autopsy showing Pneumococcus Type II in heart's blood and left pleural cavity, Pneumococcus Type II and B. influenzas in bronchus and lung. Pvt. Linehan had begun to improve on September 24 and his temperature was falling by lysis. On September 26 he became worse, developed signs of pericarditis and died on September 30. Cultures from lungs and bronchus at autopsy showed Pneu- mococcus Type II and B. influenzae. In both instances the fatal secondary infection with Pneumococcus Type II was undoubtedly acquired from Pvt. Smith in the nearby bed. The third instance occurred in AVard 8 (Table XXIII). Pvts. Lewis and Scott were admitted on September 21 and were placed in adjoining beds, 50 and 51. Lewis showed Pneumococcus Type I in his sputum, Scott Pneumococcus II atypical. The following day Pvts. Pighee, Jones, and Columbus were admitted and given Beds 48, 49 and 53 re- spectively. All showed Pneumococcus II atypical in the sputum. Pvt. Lewis with Pneumococcus Type I pneu- monia recovered by crisis on September 29. His tempera- ture remained normal until October 2 when it suddenly rose to 104.2° F. He developed a second attack of pneu- monia and died on October 8. Cultures at autopsy from heart's blood and lung showed Pneumococcus II atypical, from the bronchus Pneumococcus II atypical and B. influ- 94 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Table XXIII Secondary Infection with Pneumococcus II Atypical BED OCCU-PIED admitted PNEUMO-COCCUS IN SPUTUM ON ADMIS-SION SECONDARY INFECTION name DATE PNEUMO-COCCUS AT AUTOPSY Pvt. Pighee Pvt. Jones Pvt. Lewis Pvt. Scott Pvt. Columbus No. 48 No. 49 No. 50 No. 51 No. 53 Sept. 22 Sept. 22 Sept. 21 Sept. 21 Sept. 22 Atyp. II Atyp. II I Atyp. II Atyp. II Oct. 2 Atyp. II enzas. It is, of course, impossible to say from which one of his neighbors Pvt. Lewis acquired his second pneumo- coccus infection. It is noteworthy that these instances of secondary con- tact infection with pneumococci occurred in wards where every precaution was supposedly taken to prevent trans- fer of infection from one patient to another. It is true however that the wards were greatly overcrowded at the time. Many other instances of secondary pneumococcus infection in cases of pneumonia following influenza were encountered in which it was impossible to trace the source of infection, many combinations of different types of pneu- mococcus being found. There were two instances in which Pneumococcus Type IV was found in the sputum by inocu- lation of white mice shortly after onset of pneumonia, whereas secondary infection with other types was found at autopsy, one with Pneumococcus Type II, one with Pneu- mococcus Type III. In 2 cases by inoculation of white mice, two types of pneumococcus were found simultaneously in the sputum coughed from the lung, in one Pneumococ- cus Types III and IV, in the other Pneumococcus Types I and IV. There were 5 cases in which two types of pneu- mococcus were found in cultures at autopsy as shown in Table XXIV. Combined pneumococcus infections of this nature are almost never encountered in pneumonia occur- SECONDARY INFECTION IN WARD TREATMENT 95 Table XXIV Mixed Pneumococcus Infections in Pneumonia NAME CULTURES AT AUTOPSY heart's blood BRONCHUS LUNGS Pvt. Gal. Pn. Type III S. hemolyticus Pn. Type III B. influenzae Staphylococcus Pn. Type III Pn. Type IV B. influenzae Staphylococcus Pn. Type III Pn. Type IV B. influenzae Pvt. Sug. Pn. Type III Pn. Type IV B. influenzas Pvt. Hig. Pn. Type II Pn. Type IV S. hemolyticus Staph, aureus Pvt. Can. I'n. Type I —■ Pn. Type III S. hemolyticus Pvt. Fer. Sterile Pn. Type IV B. influenzas Staphylococcus Pn. Type I Pn. Type IV B. influenzas ring under normal conditions in the absence of epidemic in- fluenza. The foregoing data show that infection with one type of pneumococcus may readily be superimposed upon or closely follow infection with another type. Cases have been cited in which it was clearly demonstrated that this was due to contact infection. It is furthermore evident that pneumo- nia caused by one type of pneumococcus affords no relia- ble immunity against pneumonia caused by another type. The same conditions that favored the spread of hemolytic streptococcus infection also favored the transfer of pneu- mococcus infection from patient to patient. Secondary Contact Infection in Influenza The material so far presented has dealt with contact in- fection in cases of pneumonia following influenza. That a similar contact infection in cases of influenza treated in crowded hospital wards is responsible in considerable de- gree for the development of pneumonia in cases of influ- enza seems quite probable. It has already been stated that this pneumonia was found in large part to be caused by 96 TXEUMOXTAS AXD INFECTIONS OF RESPIRATORY TRACT infection with types of pneumococcus that are found in the mouths of normal individuals. It has been fairly definitely established by Stillman3 that lobar pneumonia caused by pneumococcus Types I and II is in all probability due to contact infection, and definite instances of such infection by Pneumococcus Type II have been reported above. In a recent communication Stillman4 has furthermore shown that of the various groups of Pneumococcus II atypical those most frequently associated with pneumonia are rarely found in normal mouths, while those infrequently associated with pneumonia are more commonly found. AVhether similar considerations will hold true for pneu- mococci of Group IA" can only be determined by further investigation. It has been stated that certain observations made during the course of this work have suggested that cases of pneumonia which complicate influenza may be due to contact rather than to autogenous infection. The data available are far too limited to establish this fact and it would require a very extensive study to furnish conclusive evidence. Certain general observations have suggested this point of view. It is well recognized that the incidence of pneu- monia in patients with influenza has been much higher where overcrowding has existed. It would seem probable that this has been in large part due to the greater oppor- tunity for the dissemination of organisms capable of pro- ducing pneumonia and the consequently increased oppor- tunity for secondary contact infection among patients treated under such conditions. The not infrequent occur- rence of influenzal pneumonia due to combined infections of the different types of pneumococci, hemolytic strepto- cocci, staphylococci, and other bacteria, instances of which have been cited, is in harmony with this view, especially since pneumonia under ordinary conditions is rarely found to be associated with mixed infections of this nature. It 3Stillman: Jour. Exper. Med., 1916, xxiv, 651. 4Stillman: Jour. Exper. Med., 1919, xxix, 251. SECONDARY INFECTION IN WARD TREATMENT 97 is true that healthy individuals occasionally carry more than one type of pneumococcus simultaneously in the mouth, though this is very infrequent, and autogenous in- fection occurring in such individuals might account in some instances for the mixed pneumococcus infections en- countered. By way of analogy it has been clearly shown in other studies by the Commission on the relation of hem- olytic streptococcus carriers to the complications of mea- sles, that secondary infection of the respiratory tract with S. hemolyticus is in very large part clue to contact infec- tion, the chronic carrier rarely developing complications due to this organism. To obtain further light on this question the type of pneu- mococcus present in the mouths of 46 consecutive cases of early uncomplicated influenza was determined by the mouse inoculation method at time of admission to the receiving ward of the hospital before the patients had been associ- ated, with the purpose of determining if cases among this group which subsequently developed pneumonia might be shown to have acquired a pneumococcus which they did not carry at time of admission. This group of patients was treated in a special ward set apart for the purpose. The patients were assigned to beds in rotation and confined in bed until thoroughly convalescent. Beds were well separ- ated and cubicles, masks and gowns were in use. Cultures were made from the ward personnel. By these procedures an accurate record was kept of all sources of pneumococcus infection. The types of pneumococcus found in the mouths of these patients at time of admission are shown in Table XXV. Only 1 patient in this group developed pneumonia. At time of admission he had no pneumococcus in his mouth as determined by inoculation of a white mouse with his spu- tum. Examination of the sputum by the same method at time of onset of pneumonia three days after admission showed Pneumococcus Type III. The only ascertainable PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Table XXV Types of Pneumococci in the Mouths of Influenza Patients pneumococcus number per cent Pneumococcus, Type I 0 0 Pneumococcus, Type II 0 0 Pneumococcus, II atypical 1 2 2 Pneumococcus, Type III 0 0 Pneumococcus, Group IV 25 54.3 No pneumococci found 20 43.5 source of infection in this case was one of the ward attend- ants who carried Pneumococcus Type III in his throat in sufficiently large numbers to be demonstrable by direct cul- ture and who frequently came in contact with the patient. In this instance the development of pneumonia was prob- ably due to contact infection. An extensive study of this nature would be necessary to determine in what proportion of cases pneumonia following influenza is caused by second- ary contact infection and in what proportion to autogenous infection. It is at least evident that contact infection with a type of pneumococcus found in the mouth of normal indi- viduals may occur in influenza and be responsible for the development of pneumonia. Therefore every precaution should be taken to prevent it. Methods for the Prevention of Secondary Contact Infection in Influenza and Pneumonia The methods at present in vogue for preventing the spread of contagion in wards devoted to the care of patients with influenza and pneumonia may be briefly enumerated: The separation of patients by means of sheet or screen cubicles, the wearing of masks and gowns by the ward per- sonnel and to some extent by convalescent patients who are up and about the ward, and in some hospitals the separa- tion of streptococcus carriers from noncarriers as deter- mined by throat culture at time of admission. That these methods are of some value in preventing spread of infec- tion cannot be denied, and it is probable that they are fairlv SECONDARY INFECTION IN WARD TREATMENT 99 effective under ordinary conditions when conscientiously carried out. That they inevitably break down in the pres- ence of an overwhelming epidemic when hospital wards become overcrowded is only too evident. Under such con- ditions the sheets hung between the beds are constantly be- ing displaced and are slight proof against a patient's curi- osity as to the identity and condition of the man in the ad- joining bed; masks cannot be worn by patients seriously ill with pneumonia, during the very time when they are most dangerous and in greatest danger and those worn by the Yard personnel are very rarely sufficiently well made to prevent spread of contagion by droplet infection as the studies of Haller and Colwell5 and Doust and Lyon6 have shown; the separation of streptococcus carriers from non- carriers as at present carried out cannot keep pace with the ever increasing influx of patients nor with the rapidity of the spread of the hemolytic streptococcus, in part because of the time required to make the bacteriologic diagnosis, in part because the amount of work involved cannot be accomv" plished by the laboratory personnel available. That this is f% so will be shown in data presented below. Not only doJ,%,3 these methods break down in the face of an epidemic, but , they often provide a false sense of security. In searching for a solution of the problem it is essential to have the following considerations clearly in mind. Ev- ery patient with influenza must be considered a potential source of pneumococcus or hemolytic streptococcus infec- tion for his neighbor until he is proved otherwise by bac- teriologic examination. Every person engaged in the care of patients with respiratory diseases must also be regarded as a potential source of danger. Pneumonia cannot be re- garded as one disease but must be looked upon as a group of different diseases, with more or less similar physical signs and symptoms, it is true, but caused by a considerable variety of bacteria, infection with any one of which not 5Haller and Colwell: Jour. Am. Med. Assn., 1918, lxxi, 1213. 8Doust and Lyon: Jour. Am. Med. Assn., 1918, lxxi, 1216. 100 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT only provides no protection against infection with another, but may even render the individual more susceptible to secondary infection. Therefore, every patient with pneu- monia must be regarded as an actual source of danger to his neighbor, at least until it is established that he has the same type of infection. All these considerations are espe- cially true in the presence of influenza, for it has become evident that many organisms readily gain access to the lung and produce pneumonia in patients with influenza which under ordinary circumstances fail to cause disease of the respiratory organs. Since secondary infection in respiratory disease is un- doubtedly spread in large part by droplet and contact in- fection, the prevention of secondary infection must depend upon the elimination of these methods of transmission. Three solutions present themselves: (1) AVard treatment with absolute elimination of overcrowding and much wider „,, separation of patients than has hitherto been deemed nec- essary; (2) segregation of patients according to type of '/'..bacterial infection; (3) effective individual isolation of .;' ';•, every patient. . cct.' It has been clearlv shown that treatment of influenza and °c'»*" pneumonia in overcrowded wards even with the use of such precautions to prevent transfer of infection as cubicles, masking of attendants and patients, etc., is attended by se- rious danger of contact infection and that such infection will almost inevitably occur. This is not at all surprising when it is remembered that we are treating in the same Yard, in the case of pneumonia, a group of what are in real- ity entirely different diseases, all of which may be trans- mitted from one patient to another, and in the case of in- fluenza a group of individuals who carry a variety of potentially pathogenic bacteria. No one would expect to treat cases of scarlet fever, measles, and diphtheria to- gether in a hospital ward without having contact infection result. Among patients ill with influenza and postinflu- SI-X'OXDARY INFECTION IN WARD TREATMENT 101 enzal pneumonia, certainly streptococcus pneumonia and to some extent pneumococcus pneumonia may be transmit- ted quite as readily as any of these diseases. In view of these considerations it must be apparent if Yard treatment of these diseases is to be continued without respect to type of bacterial infection, not only that overcrowding is abso- lutely contraindieated but also that much wider separation of patients than has hitherto been regarded as necessary is imperative. Furthermore, beds should be separated by permanent cubicles that cannot readily be displaced. Pa- tients should be confined to their cubicles until thoroughly convalescent and when up and about should not be allowed to enter cubicles occupied by patients still sick. Medical officers, nurses and attendants yt1io come into contact with the patients should use the same rigid precautions that are used in the care of patients with typhoid or erysipelas or meningitis with the additional use of means to prevent droplet infection of the patients, always bearing in mind that the respiratory tract in patients with influenza or postinfluenzal pneumonia is as susceptible to secondary infection as the postpartum uterus or an open surgical wound. In other words, the most rigid aseptic technic should be maintained. The recognition of a case of strep- tococcus pneumonia in a ward should be an indication for immediate quarantine of the ward until it has been shown by bacteriologic examination that there is no longer danger of spread of streptococcus contagion. This is clone in the case of meningitis or diphtheria, neither of which diseases is comparable with streptococcus pneumonia in rapidity of spread or in resulting fatality. Segregation of patients in wards according to type of bacterial infection while theoretically an improvement over the indiscriminate mixing of patients with many different types of infection presents many practical difficulties which make it impossible to carry out in the presence of an over- whelming epidemic. It is quite obvious that grouping of 102 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT influenzal patients on the basis of the types of pneumococci that they carry in their mouths is impossible since the great majority of mouth pneumococci belong to Group IA" and comprise a heterologous immunologic group. The separa- tion of influenza patients YTho carry S. hemolyticus from those who do not would appear to offer a more hopeful field. Since YTe cannot make an immediate distinction between streptococcus carriers and noncarriers by inspection of the patient, this procedure requires the taking of throat cul- tures at time of admission to the hospital, the holding of patients for eighteen to twenty-four hours in receiving Yards until the bacteriologic diagnosis has been made, and their subsequent distribution to streptococcus and non- streptococcus wards. This is feasible when the admission rate is low and the number of streptococcus carriers found at time of admission is small. In the presence of an influ- enza epidemic it immediately becomes impossible to carry out in base hospitals as now constituted, since the demand for beds under such conditions at once converts a large part of the hospital into a group of receiving wards with little room remaining for subsequent separation of patients. The amount of bacteriologic work involved at once be- comes prohibitive and the time required to make the bac- teriologic diagnosis defeats its purpose since it allows the spread of hemolytic streptococcus to occur in the receiving wards during the interval. The foregoing statements are based on results obtained in an attempt to separate streptococcus carriers from non- carriers in a limited group of cases of influenza at Camp Pike, the investigation being conducted during a secondary wave of influenza between November 27 and December 5. A special group of five wards consisting of one receiving ward and four distributing wards were set aside for the study. Cubicles, masks and gowns were in use and the wards were not crowded. The personnel on these wards did not carry S. hemolyticus in their throats. Patients entering SECONDARY INFECTION IN YTARD TREATMENT 103 the receiving ward were assigned to beds in rotation. Throat cultures were made on blood agar plates at time of admission. The plates were examined promptly the next morning, the diagnosis of S. hemolyticus being made by the characteristic hemolytic colonies and microscopic examina- tion of stained smears. By this method a report reached the receiving ward at 9:30 a.m. and patients were promptly evacuated to the streptococcus and nonstreptococcus wards, where they were again assigned to beds in rotation, re- maining confined in bed until convalescent. Confirmation of all strains of hemolytic streptococcus was subsequently carried out by isolation in pure culture, bile solubility test, and hemolytic test with washed sheep corpuscles. All cases free from hemolytic streptococci at time of admission who were sent to the "clean" Yards were recultured daily throughout the period of study, those acquiring a hemo- lytic streptococcus being transferred to a streptococcus ward as soon as the bacteriologic diagnosis was made. The results are shown in Table XXArI. Table XXVI S. Hemolyticus in Cases of Influenza THROAT '' CLEAN ' 'CASES ACQUIR- DATE PATIENTS ADMITTED TO RECEIV-ING WARD ON ADMIS-SION. S. HEMOLY-TICUS : ING S. HEMOLYTICUS IN THE HOSPITAL WHILE IN REC. WARD WHILE IN ''CLEAN '' WARD TOTAL + - Nov. 27 12 4 8 0 2 2 Nov. 28 8 2 6 0 1 1 Nov. 29 17* 8 9 1 2 3 Nov. 30 11 2 9 3 0 3 Dec. 1 10 5 5 0 0 0 Dec. 2 37 16 21 1 1 2 Dec. 3 21 8 13 0 2 2 Dec. 4 32* 11 21 4 2 6 Dec. 5 17 10 7 5 0 5 Totals 165 66 99 14 10 24 *Held in receiving ward 40 hours because of admission of case of meningococcus meningitis to ward by mistake. One hundred and sixty-five cases were admitted to the receiving ward during the period of study as cases of influ- 104 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT enza. Of these, 137 had influenza; 4 of those with influenza had pneumonia at time of admission, 23 had acute follicular tonsillitis, 3 epidemic cerebrospinal meningitis, 1 scarlet fever, and 1 A incent's angina. Sixty-six cases (40 per cent) showed hemolytic streptococcus in the throat at time of admission and were sent to the streptococcus Yards; 99 cases (60 pen- cent) were negative for hemolytic streptococ- cus on admission, and of these 91 vTere sent to the "clean" influenza wards. Tventy-four of these clean cases subse- quently became positive for S. hemolyticus. It is especially noteworthy that 14 of them acquired a hemolytic strepto- coccus during the short period that they were held in the receiving ward awaiting the report of the culture taken at time of admission, the first culture taken shortly after ad- mission to the "clean" wards being positive. This result was undoubtedly due to the fact that these cases were un- avoidably associated in the receiving Yard with many car- riers of hemolytic streptococcus. It is evident that cases which vere supposedly free from streptococci but which in reality had picked up the organism in the receiving ward were constantly being sent to the "clean" wards. It is furthermore evident that if the precaution had not been taken of reculturing all clean cases on clay of admission to the "clean" Yards and daily thereafter these wards would soon have become saturated with hemolytic strep- tococci. Even under these conditions, 10 cases, after vary- ing periods in the "clean" wards, acquired the organism in their throats. AVhen it is stated that it required the full time of two men under very special conditions to carry out this work in a very limited number of cases and that it failed to keep "clean" wards free from hemolytic strepto- cocci, it is only too apparent that the efficient separation of carriers from noncarriers in the presence of an epidemic of influenza is an impossible task. The segregation of pneumococcus pneumonias following influenza according to type of infection is obviously impos- SECOXDARY INFECTION IN WARD TREATMENT 105 sible, since they are caused by an almost unlimited variety of immunologic types as far as present knowledge goes. Even the efficient separation of streptococcus pneumo- nias from pneumococcus pneumonias would require a con- siderable team of workers and the closest cooperation be- hveen laboratory and ward staffs, so that no case of pneu- monia would be sent to a pneumonia ward until the bacte- riologic diagnosis had been made. In our experience this is rarely considered feasible even under ordinary conditions, and in the presence of an epidemic is nearly impossible be- cause of the volume of work involved and the delay neces- sitated by bacteriologic methods. It is, nevertheless, abso- lutely essential if highly fatal ward epidemics of strepto- coccus pneumonia are to be prevented. In vioAv of the considerations discussed above, it is be- lieved that the clear and most fundamental indication for the management of epidemic respiratory diseases in the army is to scatter patients as widely as possible instead of following the time-honored custom of concentrating them. In brief, abandon open ward treatment and adopt effective individual isolation of every case, maintaining as strict a quarantine as is demanded in other highly contagious and infectious diseases. The adoption of a strict aseptic tech- nic in the handling of these patients is an evident corollary. Only by this means can the serious and highly fatal second- ary hospital infections, which occur in influenza and pneu- monia when these diseases are present in epidemic form, be prevented. The prevention of secondary infection, prior to admis- sion to the hospital, is another and more difficult problem. That opportunity for secondary contact infection in cases of influenza before patients reach the hospital is great seems unquestionable, since many cases have already de- veloped these infections at time of admission. During the epidemic patients were crowded in regimental infirmaries, in ambulances, and in the receiving office of the hospital 106 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT with every opportunity for droplet infection present. No study has been made of this question, but it seems reason- able that the same methods of prevention should apply, namely, effective separation of patients. It is not YTithin the scope of this paper to discuss details of method, but anything that is possible becomes feasible as soon as sufficient evidence can be brought to bear that it is a necessity. In the present instance it would seem that any means that can be used to reduce materially the ter- rific toll taken by respiratory diseases is an absolute neces- sity. Summary 1. Secondary contact infection with pneumococci not in- frequently occurs in patients with pneumonia following in- fluenza when they are treated in hospital wards. 2. Secondary contact infection vTith S. hemolyticus read- ily occurs in patients vith pneumonia and may spread rapidly throughout an entire ward vith highly fatal results. 3. Secondary contact infection may be responsible for the development of pneumonia in patients with influenza. 4. AVard treatment of these diseases is fraught with se- rious danger which is greatly increased by overcrowding, by imperfect separation of patients by cubicles, and by imperfect aseptic technic of medical officers, nurses, and attendants. 5. It is probable that secondary contact infection can be effectively prevented only by individual isolation and strict quarantine of every patient. CHAPTER IV THE PATHOLOGY AND BACTERIOLOGY OP PNEU- MONIA FOLLOAVIXG INFLUENZA E. L. Opie, M.D.; F. G. Blake, M.D.; and T.M. Rivers, M.D. Alany observers have described isolated phases of the recent epidemic and of past epidemics of influenza. Few have had an opportunity to follow the pathology of influ- enza from the onset of an epidemic through a period of sev- eral months and to observe the succession of acute and chronic changes which occur in the lungs. Our commission arrived on September 5, 1918, at Camp Pike two weeks be- fore the outbreak of influenza. The commission had pre- viously made a careful study of the clinical course, the bac- teriology and to a limited extent the pathology of pneu- monia occurring at Camp Funston where there was little if any influenza. Study of the records preserved at the base hospital at Camp Funston had convinced us that this camp had passed through an epidemic of influenza dur- ing the spring of 1918, this epidemic being followed by a very severe outbreak of pneumonia. Our investigation at Camp Funston had brought to our attention those phases of pneumonia which with the facilities of a base hospital laboratory could be most profitably studied with a view to determining the causation, the epidemiology and the prevention of the pneumonias prevalent in the Amer- ican army. Study of pneumonia after death offers the only oppor- tunity of determining the relation of pulmonary lesions to the considerable variety of microorganism associated with them. Clinical diagnosis furnishes no certain crite- rion for distinguishing lobar and bronchopneumonia; sup- 107 108 PNEUMONIAS AND INFECTIONS OF INSPIRATORY TKACT purative pneumonia is rarely recognizable during life. The relation of pneumococci, streptococci, staphylococci or B. influenza? to one or other typo of pneumonia can be deter- mined Avith accuracy only after death; for the demonstra- tion of one or more of these microorganisms in material obtained from the upper respiratory passages in life, though of value, furnishes us no definite evidence that the organism which has been identified has entered the lung and passed from the bronchi to produce pneumonia. Study of autopsies following examination of the sputum during life has shown that an individual primarily attacked by influenza may suffer with a succession of pneumonias, one microorganism having prepared the way for another. The complexity of the subject is much increased by the truth that pyogenic microorganisms, like the tubercle bacilli, are capable of producing a considerable variety of pulmonary lesions. Examination of the lungs of a large number of individuals who have died as the result of pneumonia following in- fluenza has disclosed a succession of acute and chronic dis- eases. Immediately succeeding the height of the epidemic of influenza, death occurred with acute lobar pneumonia or YTith diffusely distributed hemorrhagic bronchopneumo- nia caused in the majority of instances by Pneumococcus IV in association with B. influenzas. Superimposed infec- tion with hemolytic streptococci increased in frequency and in individuals vho had occupied certain wards was almost invariable. At a later period, from one to two months fol- lowing the maximum incidence of influenza chronic lesions, namely, bronchiectasis, unresolved pneumonia, and chronic empyema were common and often occurred as the result of influenza which had had its Onset at the height of the epi- demic. AVhen influenza attacked the encampment, about 50,000 troops were quartered in it, and for a considerable period no more troops were brought into the camp and none left PATHOLOGY AND RACTFRIOLOGY FOLLOYTING INFLUENZA 109 it. All cases of pneumonia occurring among these troops were brought to the base hospital so that the autopsies which were studied were representative of all the pneu- monias following influenza in this limited group of men. It is noteworthy that autopsy disclosed no instance of fatal influenza unaccompanied by pneumonia. Pneumonia of Influenza.—Knowledge concerning the bac- teriology of the pneumonia of influenza dates from the study of the epidemic of 1889-90. The frequency with which Diplococcus lanceolatus occurred in association with influenzal pneumonia was well recognized, although several observers, notably Finkler1 and Ribbert,2 found Streptococ- cus pyogenes so often that they attributed the pneumonia of influenza to this microorganism. During a subsidiary outbreak of influenza occurring in 1891-92 Pfeiffer3 discovered the microorganism which he believed was the cause of the disease. Pneumonia, he be- lieved, was caused by the invasion of this microorganism into the lung, and the pneumonia of influenza, if death oc- curred at the height of the disease, was characterized not only by the presence of the bacillus of influenza, but YTas recognizable by its anatomic peculiarities. He described lobular patches of consolidation which were separated from one another by air containing tissue or were confluent, so that, although the lobular character was still recognizable, whole lobes might be affected. The consolidated tissue was dark red and within each lobular area wore small, yel- lowish gray spots varying in size from that of a pinhead to a pea. In the mucus of the larynx and trachea were nu- merous microorganisms, including diplococci and strepto- cocci, among which influenza bacilli were predominant; in the larger bronchi, bacteria other than influenza bacilli were less abundant, whereas in the finer bronchi filled with 'Finkler, D.: Infectionen der Lunge durch Streptococcen und Influenza Bacillen, Bonn, 1895. 2Ribbert: Anatomische und bacteriologische Beobachtungen uber Influenza, Deutsch. med. Wchnschr., 1890, xvi, 61, 301. 3Pfeiffer: Die Aetiologie der Influenza, Ztschr. f. Hyg. 1893, xiii, 357. 110 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT purulent fluid and in the lung tissue influenza bacilli had undivided sway. Pfeiffer stated that the changes de- scribed were found when death occurred at the height of the disease, whereas other pulmonary lesions might be sequelae of this typical influenzal pneumonia. Observations upon the pathology of influenzal pneumonia made during the epidemic of 1889-92 have been collected in the monograph of Leichtenstern4 published in 1896. He combats the opinion held by some observers that pneumonia with influenza is always catarrhal and cites many writers to prove that lobar pneumonia not infrequently accom- panies the disease. Indeed, some have found "croupous" pneumonia more often than "catarrhal." Krannhals5 at Riga found typical fibrinous pneumonia in 53 instances, doubtful forms in 22 and bronchopneumonia in 37. Cruick- shank0 in England found croupous forms predominant. Among 43 autopsies performed upon individuals dead with influenza Birch-Hirschfeld7 found 11 instances of croupous lobar pneumonia, 8 instances of croupous lobular pneumo- nia and 24 instances of catarrhal pneumonia. Leichten- stern thinks that the atypical symptomatology of lobar pneumonia with influenza—for example, the purulent char- acter of the sputum—has led many physicians to believe that lobar pneumonia rarely occurs. It is equally true that many instances of confluent lobular pneumonia are mis- taken for lobar. There appears to be no comprehensive description of the pneumonias of influenza based upon the epidemics of 1889- 92. Descriptions dating from this period are much ob- scured by attempts to separate croupous or fibrinous from catarrhal pneumonias. Croupous lobular pneumonia has been recognized, for example, by Birch-Hirschfeld. Leicht- enstern describes a form of pneumonia which he regards as leichtenstern, O.: Influenza, Nothnagel's Specielle Pathologie und Therapie Wien 1896, vol. ii, pt. 2. ' ' sKrannhals: Quoted by L,eichtenstern. "Cruickshank: Brit. Med. Jour., 1895, i, 360. 7Birch-Hirschfeld: Schmidt's Jahrbucher, 1890, ccxxvi, 110. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 111 neither lobar nor lobular although it implicates whole lobes; the consolidated tissue is homogeneous and varies in color from fleshy red to bluish red; it is tough and elastic in consistency. The author thinks that it is an error to regard this lesion as a confluent lobular pneumonia. Kuskow8, who has discussed the pathology of influenza in considerable detail, has seldom seen lobar pneumonia but has almost invariably found, even when there is lobar dis- tribution of the lesion, lobular patches of consolidation in- volving groups of lobules, single lobules or only parts of lobules; the lung tissue has been hyperemic and in places edematous. Opinions concerning the pathology and bacteriology of the pneumonias of influenza, published since the recent epidemic, have varied almost as much as those just cited. Few observers have had the opportunity of making a con- siderable number of observations under conditions Y-hich determine the relation of the pulmonary lesions to the pri- mary disease. Keegan9 has found with influenza a massive and conflu- ent bronchopneumonia, frequently resembling lobar pneu- monia but distinguishable particularly in its early stages when the cut section of the consolidated lung has a finely granular character and each bronchiole stands out as a grayish area with intervening dark red alveolar tissue. Symmers10 states that the pneumonia of influenza is a confluent lobular exudative and hemorrhagic pneumonia which bears a close resemblance to the pneumonic variety of bubonic plague. Our commission11 published a preliminary report on pneumonia following influenza observed at Camp Pike. The occurrence of purulent bronchitis, distention of lungs, sKuskow, N.: Zur pathologischen Anatomie der Grippe, Yirchow's Archiv., 1895, cxxxix, 406. 9Keegan, J. J : The Prevailing Fpidemic of Influenza, Jour. Am. Med. Assn., 1918, lxxi, 1051. 10Svmmers, D.: Pathologic Similarity between Pneumonia of Bubonic Plague and of Pandemic Influenza, Jour. Am. Med. Assn., 1918, lxxi, 1482. "Opie, E. L, Freeman, A. W., Blake, F. G., Small, J. C, Rivers, T. M.: Pneumonia Following Influenza, Jour. Am. Med. Assn., 1919, lxxii, 556. 112 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT peribronchial hemorrhage and bronchiectasis were de- scribed. B. influenzas was isolated from the bronchi in ap- proximately 85 per cent of instances of influenzal pneu- monia but from the consolidated lung in less than half this number of autopsies. Lobar pneumonia YTas present in a large proportion of autopsies but was less frequent than bronchopneumonia. Bronchopneumonic consolidation is in part red, lobular and confluent, in part nodular; pneumo- cocci have a predominant part in the production of these lesions. Three types of suppurative pneumonia are de- scribed: (a) Abscess caused by hemolytic streptococci usually in contact with the pleura and accompanied by em- pyema; (b) Suppuration of interstitial tissue of the lung caused by hemolytic streptococci and accompanied by em- pyema; (c) multiple foci of suppuration clustered about a bronchus of medium size and caused by staphylococci. AVe have expressed the opinion that B. influenzae descends into the bronchi; pneumococci, usually Type TV, may enter the lung and produce either lobar or bronchopneumonia. Hemolytic streptococci may descend and infect the pneu- monic lung causing death often before suppuration has oc- curred. Epidemics of such superimposed streptococcus pneumonia in Y'ards of the hospital were described. LeCount12 says: "The pneumonia of influenza is com- monly referred to as bronchopneumonia. It may be so des- ignated, but it differs from other bronchopneumonias in its predilection for the periphery of the lungs and in the extent to vdiich the inflammation is hemorrhagic." MacCallum13 states that the following types of pneumo- nia following influenza may be recognized. 1. Pneumococcus pneumonia. The lobular character of the consolidation is in these cases well marked, although it tends to lose its definiteness through the confluence of adjacent areas. The cut surface of the lung shoves in the more acute cases a 12IveCount, E. R.: The Pathological Anatomy of Influenzal Bronchopneumonia Tour Am. Med. Assn., 1919, lxxii, 650. "MacCallum, W. G.: Pathology of the Pneumonia Following Influenza Tour Am Med Assn., 1919, lxxii, 720. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 113 peculiar lobular or confluent consolidation which corre- sponds YTell with what is commonly written of the stage of engorgement in the description of lobar pneumonia. Later stages in the pneumonia show within these areas patches of rough gray consolidated tissue from which def- inite plugs of exudate project. 2. Staphylococcal pneumo- nia. 3. Streptococcal pneumonia. There is lobular pneu- monia, the interlobular septa arc edematous and, micro- scopically, bronchi and alveoli are loaded with streptococci. Whole areas of lung, though retaining their form, are en- tirely necrotic. Lymphatics are distended with exudate containing streptococci in great numbers, but in none of these cases is interstitial bronchopneumonia found. 4. Pneumonia produced by B. influenzae of Pfeiffer. The lung is studded with palpable shot-like grayish yellow nodules; the bronchi exude thick yellow pus, which contains in- fluenza bacilli. Microscopically, the walls of the bronchi are found to be thickened by mononuclear infiltration and new formation of connective tissue. The walls of the al- veoli are thickened and indurated and the alveoli often con- tain fibrin in process of organization. Absence of conspic- uous changes in lymphatics, absence of intense pleural in- fection and relatively scant numbers of polynuclear leuco- cytes in the exudate within the alveoli and bronchial vails are, MaeCalluni states, all that distinguish this pulmonary change from the interstitial bronchopneumonia caused by the hemolytic streptococcus and described by him in previous papers. Lyon14 designates the pulmonary lesion following in- fluenza, hemmorrhagic pneumonitis, the lung tissue con- taining serous fluid loaded with red blood corpuscles; in many instances there was such scant consolidation that the process could not be regarded as a true pneumonia. In 35 instances the lesion was lobular in distribution and in 16 14Lyon, M. W.: Gross Pathology of Epidemic Influenza at Walter Reed Hospital, Jour. Am. Med. Assn., 1919, lxxii, 924. 114 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT instances was sufficiently extensive to be designated lobar, but it vTas not typical lobar pneumonia, and, often asso- ciated with lobular patches of consolidation, appeared to be a confluent lobular pneumonia. Goodpasture and Burnett15 say: "The difficulties of ana- lyzing the pulmonary lesions in any group of influenza pneumonias as they have appeared in this epidemic, are very apparent to anyone who has had an opportunity to ob- serve the bacteriology and pathology of this accompani- ment of the disease." There is an acute outflow of the fluid elements of the blood and of hemorrhage into the lung tissue filling the alveoli in lobular areas and not infre- quently in an entire lobe. By a special method of staining these authors have studied the distribution of Gram-nega- tive bacilli with the morphology of B. influenzae. The fact that in certain very early cases demonstrable bacteria of any kind are scarce or not found at all, has lead them to believe "notwithstanding the demonstration of influenza bacilli in pure culture in the lung in all but one instance, that at this stage organisms are comparatively fevr within the alveoli, and the primary injury is due to a very potent toxic agent elaborated in and disseminated through the larger air passages. In the later stages or from the be- ginning, if the injury be slight, the infection focalizes about the bronchi or their terminations, so that the bronchial and lobular distribution becomes very conspicuous." Typical lobar pneumonia with "croupous" exudate within the al- veoli occurs in cases complicated by secondary pneumo- coccus infection. AVolbach16 has found that tvTo types of pneumonia are characteristic of influenza. In cases in which death has occurred within a few days after onset of pulmonary signs, the lung tissue is dark red and "meaty in consistency" and contains abundant blood-tinged serous fluid which drips ir'Goodpasture, E. W. and Burnett, F. 1,.: The Pathology of Pneumonia Accompanying Influenza, U. S. Naval Medical Bull., 1919, xiii, No. 2. "Wolbach: Comments on the Pathology and Bacteriology of Fatal Influenza Cases as Observed at Camp Devens, Mass., Bull. Johns Hopkins IIosp. 1919, xxx, 104. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 115 from the cut surface. The other type of lesion is found in patients who have lived for ten clays or more after onset of the disease: there is extensive bronchitis, bronchopneu- monia, discrete or confluent, and peribronchitis. The lungs are voluminous and the smaller bronchi are distended. Microscopically, there is peribronchitis with extensive in- filtration of the interlobular septa and organization in al- veoli and bronchioles. This lesion is that designated by AlacCallum as "interstitial bronchopneumonia." AVolbach thinks that the tvTo types of lesion represent different stages of the same process. He regards as distinctive of the pneumonias of influenza the presence of hyalin fibrin lining distended air spaces. AVith the two types of lesion which have been described, B. influenzae was the only or- ganism which could be cultivated, and the author associates these distinctive conditions with that microorganism. Streptococcus Pneumonia.—Finkler emphasized the im- portance of streptococcus pneumonia as a complication of influenza. In 1888 he described instances of acute primary streptococcus pneumonia observed in 1887 and 1889. This form of pneumonia, Finkler thought, occurred in Bonn in epidemic form before the influenza epidemic of 1889-90 and, he states, exhibited an astonishing similarity to the pneumonia of influenza. Tie thought that later there was in Bonn a mixed infection of influenza and primary strepto- coccus pneumonia. In one type of streptococcus pneumo- nia, described by Finkler, there was lobular consolidation which in multiple patches produced "pseudolobar" con- solidation; the consolidated lung was smooth and red, and similar to spleen, rather than hepatized. In another group of instances the lesion merited the name "erysipelas of the lung." The lesion was an acute interstitial pneumonia in some places, a cellular or occasionally fibrinous pneumo- nia with involvement of the interstitial tissue in other places. There was edematous sv7elling and accumulation of leucocytes in the interstices between the alveoli and about 116 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT the blood vessels and bronchi. Finkler stated that the sim- ilarity to erysipelas might suggest that the lymphatics con- tain streptococci, but this relation did not exist although large lymphatic channels vere occasionally filled with coag- ulum. He asserted that the disease was contagious and cited cases which he believed had their origin in hospital wards. The widespread occurrence of streptococcus pneumonia in the army camps in this country attracted attention dur- ing the first months of 1918. Cummings, Spruit and Lynch17 at Fort Sam Houston, Texas, recognized the prev- alence of streptococcus pneumonia, both as a complication of measles and in association with lobar pneumonia, and showed that the microorganism concerned was a hemolytic streptococcus. In 7 autopsies upon individuals with lobar pneumonia, they found pneumococcus alone in 2 instances and pneumococcus and hemolytic streptococcus or hemo- lytic streptococcus alone in 5 instances. Hemolytic strep- tococcus was found in all of 24 instances of bronchopneumo- nia, three-fourths of which followed measles. They rec- ommend the bacteriologic examination of the throat of patients with measles and the segregation of those who harbor hemolytic streptococci. Cole and MacCallum18 have published almost simul- taneously, with that just cited, a report upon the pneumonia which has occurred at Fort Sam Houston and have shown the importance of hemolytic streptococci in its causation. They have found two varieties of pneumonia, namely, acute lobar pneumonia vhich does not differ essentially from that which occurs elsewhere and bronchopneumonia which in most cases has followed measles and is caused by S. hemo- lyticus. They think this infection is usually acquired in the hospital. They believe that the pulmonary lesions are characteristic. In this publication and elsewhere Mac- 17Cummings, J. G., Spruit, C B, and Evnch, C: The Pneumonias: Streptococcus and Pneumococcus Groups, Jour. Am. Med. Assn., 1918, lxx, 1066. lsCole, R. and MacCallum, W. G.: Pneumonia at a Base Hospital, Jour Am Med Assn., 1918, lxx, 1146. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 117 Galium has designated the lesion "interstitial bronchopneu- monia. '' The epidemic of streptococcus pneumonia and empyema occurring at Camp Dodge, Iowa, from March 20 to May 10 is described by Miller and Lusk1". During this period there were 400 cases of pneumonia, whereas from September 20, 1917, to March 20 there had been only 276 instances of lobar pneumonia. The type of pneumonia changed, there was more severe intoxication and empyema became very fre- quent; in 85 of 95 exudates streptococci were found. The outbreak of pneumonia bore no relation to measles. The authors state that a mild tracheitis was prevalent in the cantonment during March, and whenever a large group of soldiers congregated coughing was noticeable. MacCaHum20 studied the pneumonia at Camp Dodge dur- ing May and found 17 instances of the lesion which he had designated interstitial bronchopneumonia; of these, 9 fol- lowed measles, although in the earlier part of the epidemic there appear to have been, he states, few such cases. Cul- tures made at autopsy, except in a few fatal cases of un- complicated lobar pneumonia caused by the pneumococcus, showed the hemolytic streptococcus in every situation throughout the respiratory tract and pleura. The pneumonia which occurred at Camp Funston is of special interest to our commission because wo vere for a time stationed at this camp and had the opportunity of following in the excellent records of the hospital the history of the occurrence of pneumonia during the year following the establishment of the camp in September, 1917. Stone, Phillips and Bliss21 have described the outbreak of pneu- monia which occurred in March, 1918. At this time there was, the authors state, severe pneumonia with frequent empyemas due to hemolytic streptococci. This condition 19Miller, J. L,., and Lusk, F. B.: Epidemic of Streptococcus Pneumonia and Empyema at Camp Dodge, Iowa, Jour. Am. Med. Assn., 1918, lxxi, 702. 20MacCallum, W. G.: Pathology of the Epidemic of Streptococcus Bronchopneumonia in the Army Camps, Jour. Am. Med. Assn., 1919, lxxii, 720. "Stone, W. J., Phillips, B. G, and Bliss, W. P.: A Clinical Study of Pneumonia Based on 871 Cases, Arch. Int. Med., 1918, xxii, 409. 118 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT which did not follovT measles was responsible for the greatly increased death rate in March; 9 deaths occurred in February, 45 in March, 25 in April and 14 in May. They found during March 26 instances of multiple pulmonary abscess. In 29 autopsies they found a pleural lesion which they designate "subcostosternal pus pockets"; it occurs only in association with empyema caused by hemolytic streptococci. Our commission22 has shown that an epidemic of in- fluenza, well characterized by its epidemiology and symp- toms, preceded and accompanied the outbreak of pneumo- nia just described. Between March 4 and 29 1,127 men from Camp Funston, which then contained 29,000 men, were sent to the base hospital with influenza and many more were treated in the infirmaries of the camp; on March 11 107 patients with influenza were admitted to the hospital. The greatest incidence of pneumonia in the history of the encampment up to this time occurred between A larch 9 and 29, immediately following the outbreak of influenza, the maximum incidence of pneumonia occurring five days after the maximum for influenza. The foregoing observations are cited to prove that strep- tococcus pneumonia, which occurred during the spring of 1918 at Camp Funston and doubtless at other camps, had its origin in influenza and did not differ in character from that which occurred on a much larger scale in the fall of 1918. Table of Autopsies.—In order to present as briefly as possible the data upon which the present study has been based, autopsies have been assembled in tabular form in the order of their performance (Table XX\TI [). During the early period of the epidemic autopsies were performed on all who died with pneumonia, but later, with increase in the number of deaths, this became impossible and autopsies were performed on all those who died in certain wards. --Opie, E. L., Freeman. A. W., Blake, F. 0,.. Small, J. C. and Rivers, T. M.: Pneu- monia at Camp Funston, Jour. Am.'Med. Assn., 1919, lxxii, 108. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 119 Comparison of charts representing incidence of influenza and of deaths from pneumonia furnishes evidence that fa- tal pneumonia during the period of investigation was with few exceptions referable to influenza. During two weeks, namely, from September 1 to 14, before the presence of the epidemic was evident, there were only 2 fatal cases of pneumonia. In most instances the relation of pneumonia to influenza is established by a definite history of influenza having its onset during the epidemic. Bronchopneumonia usually develops gradually as a sequence of influenza in which purulent bronchitis has occurred. Lobar pneumonia may develop in cases of influenza complicated by purulent bronchitis. In some instances there is apparent recovery from influenza indicated by return of temperature to nor- mal ; after from one to three days of normal temperature there is typical lobar pneumonia with rusty sputum. In many instances of pneumonia having their onset at the height of the epidemic of influenza, the history indicates that pneumonia was present immediately after the onset of symptoms, so that the onset resembled that of pneu- monia rather than of influenza. Cases of pneumonia following measles have been ex- cluded from the table in order that they may be studied separately and compared with the pneumonias of influenza. It is noteworthy that the lesions of pneumonia following measles have shown a very close resemblance to the pneu- monias of influenza, with regard both to pathologic char- acters and to bacteriology. Five instances of pneumonia following typhoid fever (Autopsies 245 and 329), scarlet fever (Autopsy 311) or mumps (Autopsies 403 and 417) have been excluded from the table. These secondary pneumonias are grouped as an appendix to the section on pneumonia following measles. It is not improbable that individuals with the diseases named are just as susceptible as others to influenza. 1 '^1 to to to NS| tOi tOl io W CO M IO 1—1 i ° ^o ce -j cm w! to £ o NO. OF AUTOPSY n RACE Oil cc DURATION OF ILLNESS w 01 * OT £* Ol W1 10 + to On i^ to + DURATION OF PNEUMONIA "_ c i --- < L", L L —j — ( >- CLINICAL DIAGNOSIS ^ \ | *o| TJ PURULENT BRONCHITIS +| +| +| +| | +1 | +| | +| LOBAR PNEUMONIA >> + 21 | |>| l l l PERIBRONCHIOLAR CONSOLI-DATION - . ■ -.- . , •• 11 1 HEMORRHAGIC PER1BRONL.H1-| +1 | | 1 +1 1 1 1 1 > OLAR CONSOLIDATION +| +| | +| | +| | +| | +| | LOBULAR CONSOLIDATION [ PERIBRONCHIAL CONSOLIDATION z| | ABSCESS ------:----i----i--i----i----i--i----, 1 I | 1 INTERSTITIAL SUPI'UHAllVJi || | || I II | 1 | 1 PNEUMONIA l . 1 Cii i II ! | 1 1 1 MULTIPLE ABSCESSES IN II II II CLUSTERS | H | EMPYEMA +| II BRONCHIECTASIS | l 1 1 i 1 | || 1 UNRESOLVED II II 1 II | 1 1 1 1 BRONCHOPNEUMONIA | ] | j | | ||| I ORGANIZING BRONCHITIS < a 5'^ "1 < X 'f -v 5" OS a b 5" BACTERIA IN SPUTUM a n" BACTERIA IN BRONCHUS r*5 i— ►d 3 CfltC 3 3 >-* ? BACTERIA IN LUNG *3 3 ►d 3 3 3 3W V3 tJ 3W ;_. ►—i HH HH 3- O 3 5 O <; as nT.Stapli ~~iF St.h.Pn. 7St.h7" St7h7 Ila.Staph. Pn.Staph7 Pn.IIa. Pn7lla^ B.infStapli Pn.I. Pn.IV. B.inf.Pn. [V. St.h. B.inf. St.h. Staph. St. h. Staph.B. inf. St.h.Pn. IV. B.inf. St.h.Pn. " Ill.Staph. St.h. St.h.B. inf.Staph. St.h. Staph. Pn.IV. B.inf. St.h. St.h. St. h. St.h.Staph. St.h. St.h. 10. to 01 1 *- rsj -*■ 10 to I to I to - 1 -1 -1 -1 :!,,§;; NO. OF AUTOPSY RACE i—l -1 cl a. I LENGTH OF MILITARY SERVICE \C, \C\ CO -J £. Ui >H M tn w W' DURATION OF PNEUMONIA r r1 r; r H C3i r~ CLINICAL DIAGNOSIS PURULENT BRONCHITIS LOBAR PNEUMONIA PERIBRONCHIOLAR CONSOLI- DATION .1 HEMORRHAGIC PERIBRONCHI- + l OLAR CONSOLIDATION LOBULAB CONSOLIDATION PERIBRONCHIAL CONSOLIDATION 2^2 ABSCESS INTERSTITIAL SUPPURATIVE PNEUMONIA I I MULTIPLE ARSCESSES IN CLUSTERS EMPYEMA BRONCHIECTASIS UNRESOLVED BRONCHOPN EUMONIA 2,Z-|XrX _ _™ ^ _. T* • ;/> 3 i—i 3 i—i 7* —' —i _ Cd Fi *■* 3'x i—i -/-, 3* i_ — ^d —i O N3 *0 o co -1 t0> 3\ NO. OF AUTOPSY 2! ^ n| -a o ^! o ^'^ RACE *l i* 01, *-j| to Nil to] i-j| !—i LENGTH OF MILITARY SERVICE 1-1 ~j © ON -j 3s V© CO Oil —1 ,cc DURATION OF ILLNESS w| 00 + 0"i| I—i to + 00 © ■« CO DURATION OF PNEUMONIA ^; tc r ^ w| M F CLINICAL DIAGNOSIS 1 1 1 w| "C ^ >d •d PURULENT RRONCHITIS +1 1 +1 +1 + + + LOBAR PNEUMONIA 1 £ i .1 PERIBRONCHIOLAR CONSOLI-| DATION |||[ ! | HEMORRHAGIC PERIBRONCHI-1 ' II 1 1 1 1 OLAR CONSOLIDATION 1 +1 1 1" | +| | LOBULAR CONSOLIDATION cr PERIBRONCHIAL CONSOLIDA-TION | + ABSCESS | i INTERSTITIAL SUPPURATIVE II 1 1 1 | PNEUMONIA III || 1 1 1 1 MULTIPLE ABSCESSES IN CLUS-II 1 1 TERS a EMPYEMA +| BRONCHIECTASIS I | i 1 | UNRESOLVED I 1 1 RRONCIIOPNEUMONIA | i i OBGANIZING BRONCHITIS 3W F 3'hh ■ jb F.55 2td 3-is "^ "■/? F 5" M) 3-F 3' BACTEBIA IN SPUTUM 2?l_x idgi r>i 7>p -.. ^ 1 "^ 3" ^\7 0 BACTEBIA IN BBONCHUS X F 3 be 3 *0 a i—1 B > a H H 3J O 7 O a o 7 7 O Ow | IsO I--M O Sh1 S Sg NO. OF AUTOPSY RACE 3 '?\ LENGTH OF MILIIAUY SERVICE —1 in I—1 On -j to ~ 00 h on 4 | to ce 1" DURATION OF ILLNESS 1 -f w 00 ~t-+ Cs DURATION OF PNEUMONIA F r 7- k- 1 «»v 1 vv 53 CLINICAL DIAGNOSIS ^d'i ^cl 1 ^ 1 1 ^i x + j PURULENT BRONCHITIS 4 4 4 +| LOBAR PNEUMONIA +* ^! '^1 | j > | PERIBBONCIIIOLAR CONSOLI-I DATION | I I 1 i| | i 1 HEMORRHAGIC PERIBRONCH1-1 1 1 1 II 1 1 1 'iOLAR CONSOLIDATION +| +| | LOBULAR CONSOLIDATION ! ! II" 2 PERIRRONCIIIAL CONSOLIDATION z izi ABSCESS +! + i , , | INTERSTITIAL SUPPURATIVt-, II +l 1 PNEUMONIA i +1 i l 1 1 MULTII'LE ABSCESSES IN 1 1 CLUSTERS - | ™ ' EMPYEMA - +j | +| | BBONCHIECTASIS 1 | UNRESOLVED 1 I' 1 1 1 1 1 1 BRONCHOPNEUMONIA ! | ORGANIZING BBONCIIITIS '' BACTEBIA IN SPUTUM X 7\ ! i— z- P*5 3* ZJ Z xC x£. — ^,"3 F T3 3 F BACTEBIA IN BRONCHUS X X 3" F^ X w 1 •"*5 X 0 BACTEBIA IN LUNG X- X © < _l X X. 3- r BACTERIA IN BLOOD OF HEART r. xjvux AiioxvHRisaii a:o sxoix.xuxi axv svixoKnaNd: 93T PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 127 1 > CO X 3 j . C 3 — o -3 -3 -*. HH C Ph -3 H -a c X) X X 3 X 3 63 X Ph Uh "~ Ph ' 1 =>lr r« = > X £ —i *j -3 ~X2 Li 'T lc/2 .32 1 uj = L: P2"& 65 X) Ph T2 ^ cc 1—1 3 »:x X G Ph I B.inf.Pn. St.h.B.inL Staph. StXB.inf. Pn.IV. Staph. u 1 1 1 w I I I I 1+ I + I I + + + + + + + + -.» I 1 '*r 1^; 1 '' I _ ~q jj \zz, '_j '25 '.j '— Im |j Jpc ci t-. ,1—1 ci •I — — -h CI I-- CI |CI |— |CI O I- X ^ 13 -IC1 M —'It i'o lit I.C W •c ci 7 o ,m — ,'7' — joir- ,— |rt oc :v£ ci |co|— ^ | j CO |2 or- lec Oi ~1 OT ' ■ n ^ ^lirliflSfiyicoiooiooiWiooi^iio © o co ~j on oa; ,-! oo to P^ c o NO. OF AUTOPSY .,--, RACE tol oi —! -J —' CM .£• —'i -1 -ii + ON I 00 | ~| 00 P- 3 3 3 LENGTH OF MILITARY SERVICE DURATION OF ILLNESS -^1 + + oo ts3 DURATION OF PNEUMONIA - ^c r~ — td ic id H^-1 t~ F ~1 ~i | | I _M I. I +1+1 +1 +! I +1 +l + CLINICAL DIAGNOSIS PURULENT BBONCHITIS LOBAR PNEUMONIA PERIBRONCHIOLAR CONSOLI- DATION "Hemorrhagic peribronchi- olar consolidation_____ LORULAR CONSOLIDATION PERIBBONCHIAL CONSOLIDATION ^ ABSCESS INTEBSTITIAL SUPPURATIVE PNEUMONIA. ________ I 1 1 1 1 1 MULTIPLE ABSCESSES IN CLUS-1 TERS EMPYEMA | +| BRONCHIECTASIS | i i UNRESOLVED 1 1 1 1 1 1 1 BRONCHOPNEUMONIA ||| ORGANIZING BRONCHITIS 1 1 5*1 c ! x BACTERIA IN SPUTUM ' td3 BACTERIA IN BRONCHUS X-'| _ < BACTERIA IN LUNG !7 x X _ "d 3 ■d'^d 3 l3 X 7 X 3 *d 3 i—I B" O " 'm'h H h~ ir l-H ""^ Lh *^ . ' < <'< -< < <; - ^ BACTERIA IN BLOOD OF HEART xovax Aaoxvaidsaa jo snoixoimxi qnv sviNownaNa ggT. Table XXVII—Continued 376 YV ~\V~ \Y "VY" \V \V vr YY \Y \Y W YV AY ^vV~ Vv W vv lm 10 28 Tf 13 9 9 T3 12 11 17 ;» 19 11 15 13 "iY 20 ;t 19 12 7+ B B B B P P P + 4- 4-+ + M M M 4-+ + + + 4- M + E \E~ \E~ + 4- -- [No.St h.] lSt.h.li.inf.1 St.h. Staph.aur.| St.h. "TnTvT 1*11.1 la. PYTlaY Pn.III. St.h. hi 377 1 m lm > h3 378 — + -- -- -- St.h.I5.inf. St.h.B.inf. Pn.IIa. Pn.IIa. B.inf. + ? T1 c t-l 379 11 in 3m 2ld lm 2m lm 3\v 2m 2 Id lm 1 9? "6+_ o "6? 1 + c c K| 380 B P + + 4-+ -- -- E Pn.III. Y St.lKPn. II.Pn.IV. Staph.aur. 381 L L P P - + -- — 382 0 Pn.III. Pn.IV. St.h. PndV. St.h. Pn.III. td > 383 L l7 P7 p --- B.inf.Pn. IILSt.h. St.h. 381 E C 385a 4- + + 4-4-4- + -- --- - 385h L p c 385c 10 "5 B 4-+ + + + 4- — W M" "E" E St.h.B.inf. k; 386 L IT p "p^ p + ~+ Pn.III.B. inf.Staph. anr. C r c 387 3w 9 St.h.B.inf. Staph.alb Staph. Pn.II.B. aur.Pn. inf. St.h. £ 388 3m lm 25d lm lm 7 15 13 8+ 1 T~ up 3? L Pn.IV. St. Ik PiiIY. Pn.Il. 'Pn.IV. - 389 L P L P + St.h. 391 h + 4- -- -- Pn.IV. 7 392 L P 4-4- B 393 w L L L B "p" p is 39 1 w vv 21d lm 4- + 4- h St.h. YYhV " Pn.IIa. 0 > 395a iSt.h.B.inf. _i 395b w 3m p 4- 4- h Pn.IIa. IC 396 w 2m 1 + B . 0 S § o CO *> O ON o on <3 to c 1—1 o 00 00 co oo NO. OF AUTOPSY ^ "" n Y ■""' *- "' ** ^ ^i^'^i RACE g 00 OoY =r to lo Y^1^ I—< 1 h-1 3J3 t\3 p. LENGTH OF MILITARY SERVICE h-1 on £ + h-1 tsS 1—I 1—' 00 CO h-' 00 H- j 00 4 Ol l-H co on to to DURATION OF ILLNESS i—' to! w + 4- YY1 cc •v; oi t— Y + vv -4 -1^1- DURATION OF PNEUMONIA r uT L 1 L j ^ i ^ ^ r ri id cd clinical diagnosis ! ^ ^ ^ ^c 'd | *d *d "d 'd PURULENT BRONCHITIS +1 +j 4 + 1 + +| LOBAR PNEUMONIA 1 4- 1 — + >• 4 % PERIBRONCHIOLAR CONSOLI-DATION + + + | + | ! | HEMORRHAGIC PERIBRONCHI-1 1 OLAR CONSOLIDATION + 4- 4- + | 1 +1 LOBULAR CONSOLIDATION Y o> — — £ 4- 3" | PERIBRONCHIAL CONSOLIDATION l H 1 + | | | ABSCESS | S ■ ; i 1 INTERSTITIAL SUPPURATIVE | + PNEUMONIA i 1 i l MULTIPLE ABSCESSES IN CLUSTERS h| SI tr]| EMPYEMA + 4- 1 Tl Tl | +| BRONCHIECTASIS 1 | | + | 1 1 UNRESOLVED | +| | BRONCHOPNEUMONIA |- | 4- | | ORGANIZING BRONCHITIS BACTERIA IN SPUTUM ►d F ___ BACTERIA IN BRONCHUS J F rtd 3 5" F BACTERIA IN LUNG ►d 3 J—i ►d 3 O O *d 3 <1 ►d 3 'd <-" ►d 3 3 o GO r* 3" BACTERIA IN BLOOD OF HEART xovax Auoxvaidsaa jo snoixohlini axv svixoi\rnaxa Qgx Table XXVII- -Continned 413 C °in 13 8+ 4 L 17 L L B P ~P~ P P + 4-4-4- 4- + + 4-4-4-4- + Pn.lILB. inf. Pn.III. HI C YY c YY YY 7d 16d 7d 2m Ynt 18 -- 4 4-4- -- -- ---- — Pn.IIa.B. inf. St.h. Pn.IIa. 115 8 YY" 0 116 11 6? 4- Pn.IV. Pn.IV. Pn.IIa.St, v.B.inf. Pn.IV. 418 19 1 4-4 + ~r 4- Pn.IIa. 419 20 ;> L P B lr M M ' M Pn.II.B. inf. Pn.II.B. inf. 0 420 YY lm 11 3 1 J<: St.h.B.inf. Staph.aur. St.h. 421 W vr V\ YY YY Yv "\V 21d 19 YT+ 15? B P -- ~E 4 + 4- + Pn.IV. St.h. St.h. 422 3in lm 5\ Ym lm~ lm 3w 2m 2m 11+ B B L P P P + + M Pn.IIa.B. | inf. ' 0 423 16 i2;>~ M St.h.B.inf. Pn.IV. St.h.B.inf. Staph.alb. St.h. 421 11 29 6 -- 4- 4- 4- — 4- 4- 425 11 B T P + M St.h. 426 20 16 13 -- Pn.IIa.B. ' inf. Pn.IIa. 427 L P M +■ 4- 4-4- St.h. St.h. 428 YY c Yy YY w YY 25 21 L P — 4- -- E 4- St.h.B.inf. St.h.B.inf. St.h. 429 7+ 5 L P 4 -- -- B.inf. Staph.alb St.h.B.inf. Staph.aur. 0 0 130 16+ 7 L P 4- 4 4 IN -- St.h. 431 21d l2d 23 18 19 12+? L P + E" E" 4- 4- 0 4.32 L P -- M 4- —T" -- Binf.Pn. Ila. Pn.IIa. 433 lm 19 17 B P M St.h.B.inf. Staph.aur. 0 -i td H NO. OF AUTOPSY r to -4 O P- CO CO £ b's - Ins -4 ~1 O w to -0 NO £ NO t-" 00 4 — 4 IO t> I—' ON to ^1 n On + IO • O RACE r LENGTH OF MILITARY SERVICE Ot DURATION OF ILLNESS oo + DURATION OF PNEUMONIA f H _. ^ _ CLINICAL DIAGNOSIS ~ 'd hd id 'dl 'di d PURULENT BRONCHITIS LOBAR PNEUMONIA PERIBRONCHIOLAR CONSOLI- DATION HEMORRHAGIC PERIBRONCHI- OLAR CONSOLIDATION 4 4 4 + LOBULAR CONSOLIDATION 3" S PERIBBONCHIAL CONSOLIDATION ABSCESS INTERSTITIAL SUPPURATIVE PNEUMONIA MULTIPLE ABSCESSES IN CLUSTERS H EMPYEMA BRONCHIECTASIS UNRESOLVED BRONCHOPNEUMONIA ORGANIZING BRONCHITIS BACTERIA IN SPUTUM COl CO X r+ co 03 "d as •S F 3- o cr cr ?"3- 33 » 83 "5 cu c 1-1 ' ji 1 3'5|CO| £ ^ ■1 c; 3; I ww. ."" vv BACTERIA IN BRONCHUS aTtd 03 K 3 • X X 1 X r+ _ c+ HTJB3 -§ « -^ ov .5 ^ o F3" 03 !-*> 3 " !— 3 33 ' + Fb-03 • 3 >-! ►1 ;-> BACTEBIA IN LUNG X h- ro co f* r+ 0— o o _ cr 3" r" BACTEBIA IN BLOOD OF HEART xovux Auoxvaidsaa ao sxoixoaaxi axv svixoi\rnaNh. St.h.B.inf. Staph. St.v. 0 B.inf.Pn. I. 0 St.h. YYVlaY 0 St.h. Pn.IIa. St.h.B.inf. Staph.aur, B.inf.St.v. Pn.IIa. St.h. B.inf.St.v. 0 Pn.lV.B. inf.Staph. aur. Pn.I.Pn. IV.B.inf. 0 B.coli. St.h.B. coli. St.h. CO CO CO on CO to CO O co •~t as —1 00 NO OF AUTOPSY 3 3 «*" O 3 A- RACE 00 P- to ►u co to On P- ^1 Q. £- to 3 LENGTH OF MILITARY SERVICE ^O 4 h-' h-1 00 4 to ^0 \o VO ON 00 OS tO) CO 4 DURATION OF ILLNESS 00 on + 4 to 1—1 on 00 On to 00 + to DURATION OF PNEUMONIA Cr 6a 65 - r ba ta t-1! ta CLINICAL DIAGNOSIS ►d| n: ^ M 1 ^ PURULENT BRONCHITIS 1 +l 1 1 LOBAR PNEUMONIA ■ s| * £ § 4 PERIBBONCHIOLAR CONSOLI-DATION 1 1 HEMORRHAGIC PERIBBONCHI-| +| I I +l | | OLAR CONSOLIDATION + | + 1 + + 4- LOBULAR CONSOLIDATION 4-1 Y PERIBRONCHIAL CONSOLIDA-TION. 4! 2 J 2 1 4 | ABSCESS 4i ■ i 4 1 INTERSTITIAL SUPPURATIVE I PNEUMONIA III 1 1 1 1 1 MULTIPLE ABSCESSES IN CLUS-1 TERS H H B h| EMPYEMA | +| | | | + BRONCHIECTASIS III 1 | 1 ,1 UNRESOLVED +| BRONCHOPNEUMONIA ' + 1 ORGANIZING RRONCHITIS 1 1 BACTERIA IN SPUTUM St.h.B.inf. Staph.aur. B.coli. ■< 0.. x 5, CY CO •' 03 3 53 o-r- Vw X ^ h-H S3 ca 2-pa 5^3* 3, 3. ->s BACTERIA IN BRONCHUS St.h. W •d 3 pa co r>cr < 6 CO is ^ 93 • 3 ►1 X cr ' pa CO cr X < BACTERIA IN LUNG St.h. pa 0 0 3. CO X fcr X X br O H-.X 3 r r>cr pa J BACTERIA. IN BLOOD OF HEART 1 xovax Aaoxvaiasaa ao sxoixoaaxi axv svixownaxa fg[ Table XXVII—Continued 487 \Y VV C YV YV IT W YV 21d 55 16 11 10 B P P P~ P~ + 4-M M 4- 4-4-4- + _ E + 4 488 Id 8 4 ~B~ 4- E , + 489 8d M ■ — 4 E" 491 2m ly 11 6 3 h 4-N" 498 1? 499 5m 3m 36 6 7+ .) B 504 •3 B 4 506 8ni 2? B i B. inf.St.h. St.h.Pn. Ila. B.inf. St.h. B.inf.Pn. IV. Pn. IV. B. inf. St.h.B.inf. " St.v. St.h.B.inf. St.v. Staph.aur. Staph.alb, St.h.B.inf. St.h.B.inf. Staph. 0 St.h. Pn.lV.B. inf.Staph aur.M.cat Pn.IV. Staph.aur. St.h. St.h. St. St.v. St.h. St.h. Pn.IV 136 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Included in the table is an instance (Autopsy 487) in which a definite attack of influenza preceded scarlet fever. In successive columns the table gives the autopsy num- ber, race, and length of military service. These factors have had an important influence upon the incidence of in- fluenza and pneumonia and have been discussed in a pre- liminary report.23 The duration of illness (4th column of table), counted from the date of onset of symptoms of influenza or in some instances, when the earliest symptoms were those of pneumonia, from onset of pneumonia, can usually be determined accurately. The duration of pneu- monia (5th column of table) is much more uncertain, be- cause its determination dates from the first recognition of the physical signs of pneumonia. Clinical Diagnosis.—The clinical diagnosis recorded upon the clinical history of the patient is given in column 6. Many clinicians have been impressed with the difficulty of determining during life the type of pneumonia associated with influenza. The occurrence of purulent bronchitis, the frequent coexistence of lobar and bronchopneumonia and an atypical onset often make the recognition of lobar pneumonia more difficult than usual. The diffuse consoli- dation of confluent lobular pneumonia increases the diffi- culty of recognizing bronchopneumonia. In the table (col- umn 6) lobar pneumonia is indicated by L., bronchopneu- monia by B. Among 227 autopsies the clinical diagnosis agreed with the condition found at autopsy in 109 instances (48 per cent) ; in 35 instances (15.4 per cent) both lobar and bronchopneumonia were found at autopsy and a diagnosis of one or other was made during life. In 83 instances (36.6 per cent) the diagnosis made during life was incor- rect. Cases admitted to the base hospital at Camp Pike were as carefully studied as the conditions in a base hos- pital during an epidemic permitted and diagnosis of pneu- monia was doubtless as accurate as in other base hospitals. ^Jour. Am. Med. Assn., 1919, lxxii, 5S6, PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 137 Statistics from military and other hospitals based upon clinical diagnosis of the pneumonias of influenza are prob- ably subject to an error of at least 1 in 3 cases, and conclu- sions based upon them are almost valueless. The inaccuracy of clinical diagnosis of the pneumonia of influenza is further illustrated by a consideration of lobar pneumonia. This diagnosis on the one hand was made 136 times and was correct (57 times and incorrect 69 times; on the other hand, lobar pneumonia was found at autopsy 98 times and had been diagnosed in only 67 of these cases (68.4 per cent). Classification of the Pulmonary Lesions of Influenza.— Influenzal pneumonia exhibits the following noteworthy characters: 1. Acute bronchitis with injury or destruction of lining epithelium and accumulation of inflammatory exudate within the lumen. 2. Hemorrhagic pneumonia with accumulation of blood within the alveoli and within and about the bronchi. 3. Susceptibility of bronchi and pulmonary tissue to sec- ondary pyogenic infection with necrosis and suppuration. 4. Bronchiectasis. 5. Tendency to the occurrence of chronic pneumonia fol- lowing failure of pneumonia to undergo resolution. All these changes are doubtless referable to the severity of the primary injury to the lower air passages. In the presence of destructive changes in the bronchi many bacterial species, including B. influenzae, pneumococci of various types, streptococci (notably hemolytic strepto- cocci) and staphylococci may invade the lungs and produce acute inflammation. The anatomic characters of the pneu- monic lesions following influenza are equally varied. In order to obtain insight into the pathogenesis of these lesions, it is desirable to imitate the historical development of knowledge concerning the characters and causes of dis- ease, namely, first to define accurately the lesions concerned 138 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT and later to determine with what microorganisms these lesions are associated. The difficulties of this undertaking are increased by the multiplicity of the microorganisms concerned and by the well-known truth that the same mi- croorganism, e. g., the tubercle bacillus, may produce widely different anatomic lesions. In the table of autopsies the following lesions are listed: Column 7. Purulent bronchitis.—"P" indicates that the small bronchi contain mucopurulent fluid. Column 8. Lobar pneumonia.—The occurrence of the lesion is indi- cated by the plus sign (+). Column 9. Peribronchiolar consolidation.—The presence of nodular patches of consolidation about respiratory bronchioles is indicated by the plus sign (+) when the lesion has been recognized at the time of autopsy. When the lesion has been first recognized by microscopic examination the letter "M" is used. Column 10. Hemorrhagic peribronchiolar consolidation.—The occur- rence of this lesion which represents the preceding on a background of hemorrhage is indicated by the plus sign (+). Column 11. Lobular consolidation.—The presence of the lesion is in- dicated by the plus sign (+). Column 12. Peribronchial consolidation.—Peribronchial pneumonia recognized at the time of autopsy is indicated by the plus sign (+). Peri- bronchial pneumonia recognized microscopically is indicated by "M.'' The presence of peribronchial hemorrhage without consolidation is indicated by "h." Column 13. Abscess formation with pneumonia.—Suppuration with ab- scess formation almost invariably just below the pleura is indicated by the plus sign (+). Necrosis of lung tissue recognized microscopically and un- accompanied by suppuration is indicated by "N." Column 14. Suppurative interstitial pneumonia.—This lesion invaria- bly associated with suppurative lymphangitis is indicated by the plus sign (+)• Column 15. Multiple abscess in clusters.—Abscesses in clusters about a bronchus of medium size are indicated by the plus sign (+). Column 16. Empyema.—The presence of the lesion is indicated by "E." Column 17. Bronchiectasis.—"P>" indicates the lesion. Column 18. Unresolved bronchopneumonia.—Presence of the lesion is indicated by the plus sign (+). Column 19. Organizing bronchitis and bronchiolitis.—"O" indicates the lesion. The lesions of columns 7 to 12 are acute inflammatory processes, columns 9 to 12 represent different types PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 139 of bronchopneumonia. Columns 13 to 15 represent sup- purative lesions. Columns 17 to 19 represent chronic lesions. A survey of the table shows the predominance of acute lesions in the early period of the study and the gradual increase of chronic lesions. The last four columns of the table of autopsies give the bacteriology of the sputum during life and the bacteria found in the bronchi, in the lungs, and in the blood of the heart after death. Mortality of Pneumonia Following Influenza.—From September 6 to December 15, 250 autopsies were performed on patients who had died with pneumonia at the base hos- pital at Camp Pike, and with few exceptions bacteriologic cultures were made from them. Although it was not pos- sible to perform autopsies on all who died, those which were performed afford a fair index of all deaths, for throughout the epidemic of influenza and its outbreak of pneumonia approximately one half of all who died were examined after death. The relation of autopsies to deaths is shown by a comparison by weeks of the number of deaths and number of autopsies during the months of September and October. WEEK DEATHS AUTOPSIES Sept. 1- 7 Sept. 8-14 Sept. 15-21 Sept. 22-28 Sept. 29—Oct. 5 Oct. 6-12 1 1 4 15 121 191 1 1 3 14 67 78 Oct. 13-19 78 43 Oct. 20-27 22 15 Oct. 28-31 8 441 6 228 For most of these autopsies there is a record of the date of onset of the illness, namely, influenza, which finally resulted in pneumonia and death. Comparison of the num- ber.of cases of influenza which developed on any day with the number of fatal cases which had their onset on the same 140 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT day will determine the mortality of influenza at different periods of the epidemic. Chart 1 shows the number of cases of influenza which had their onset on each day from September 1 to October 31 and the number of fatal cases with autopsy which had their origin on corresponding days. The comparison by weeks between autopsies and total number of deaths shows that the autopsies represent with considerable accuracy the deaths. If there is any error it occurs at the height of the outbreak of pneumonia from September 29th to October 5th and not at its beginning, or end. The chart shows that the highest mortality occur- red among cases of influenza which had their origin at the beginning of the epidemic from September 21 to October 1, whereas after October 1, though the maximum number of cases of influenza occurred on October 3, very few developed fatal pneumonia. Mortality from Pneumococcus and Streptococcus Pneu- monias.—By referring fatal cases of streptococcus pneu- monia back to their date of origin it is possible to determine what proportion of the cases of influenza, which developed on any day, died with infection by hemolytic streptococcus. The accompanying chart (Chart 1) shows that infection with hemolytic streptococci has been very frequent at the beginning of the epidemic of influenza (shown by area with double hatch in chart) that is, from September 20 to 30 and subsequently has gradually diminished so that few cases have had their onset in the second half of the epi- demic from September 30 to October 15. Pneumococcus pneumonia uncomplicated by streptococ- cus infection (shown by area with single hatch in chart) pursued a course which more closely conformed to the curve representing influenza. The cases of influenza which re- sulted fatally bore a fairly constant ratio to the total num- ber of cases of influenza from the onset of the epidemic until October 1, but subsequently few cases of influenza de- veloped fatal pneumococcus pneumonia, PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 141 These charts arranged with reference to the onset of fatal pneumonias dissociate very clearly the outbreak of strep- tococcus pneumonia, which reached its height at the begin- ning of the influenza epidemic, from the uncomplicated pneumococcus pneumonia which reached its maximum at the midpart of the influenza epidemic and then abruptly abated. Chart 1 —Showing the relation of (a) onset of cases of pneumonia shown by autopsy to be uncomplicated by secondary infection with hemolytic streptococcus, indicated by upper continuous line with single hatch, and of (b) onset of fatal cases of streptococcus pneumonia, indicated by the lower continuous line with double hatch, to (c) the occur- rence of influenza, indicated by the broken line. The onset of each case of fatal pneu- monia is represented by a single square. Our study of ward infection in pneumonia furnishes an explanation of the outbreak of fatal streptococcus pneu- monia coincident with the initial stage of the influenza epi- demic. This oubreak is a true epidemic of streptococcus infection superimposed, in many instances at least, upon preexisting pneumococcus pneumonia, but in some in- 142 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT stances, doubtless, a primary streptococcus pneumonia, following the bronchitis of influenza. In the absence of secondary streptococcus infection a very large proportion of these individuals would have recovered. This epidemic of streptococcus pneumonia, it has been shown, was the re- sult of unfavorable conditions produced by great over- crowding of the hospital and in the early part of the epi- demic by inadequate separation of those with streptococcus infection from those with none. With control of these con- ditions, streptococcus pneumonia rapidly diminished. Greater susceptibility to pneumococcus pneumonia in the early than in the late period of the epidemic is perhaps explained by differences in the severity of influenza; the more susceptible individuals were attacked by influenza in the early period, whereas the less susceptible did not acquire the disease until they had been exposed to an im- mensely increased number of infected individuals. A bet- ter explanation is furnished by the greater opportunity at the beginning of the epidemic for the transmission of mi- croorganisms causing pneumonia, for at this time patients with influenza were crowded together and methods to pre- vent the transmission of infection were little used. Bronchitis Clinical study has shown that purulent bronchitis (see Fig. 2) occurs in about one-third of the cases of influenza. In a large proportion of cases of bronchitis there is no clin- ical evidence of pneumonia. The bronchial lesions found in association with the pneumonia of influenza are an index of the ability of the agent, which causes influenza, to injure the bronchi. In those who have died with pneumonia following influ- enza the large bronchi (with cartilage) are intensely in- jected, so that the mucosa has a deep red color which on cross section contrasts very sharply with the pearly white of the cartilage. Superficial injury to the bronchi is PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 143 not infrequently evident in the larger bronchial branches; superficial loss of epithelium is indicated by erosion of the surface, whereas somewhat deeper destructive changes are occasionally evident. Microscopic examination accurately determines the degree of destructive change. Purulent bronchitis was noted in 134 autopsies (55.6 per cent of autopsies). From the small bronchi, in many in- stances, purulent fluid welled up upon the cut surface of the lung, whereas in other instances tenacious mucopuru- lent fluid could be squeezed from small, cut bronchi by pres- sure upon lung tissue. The consistency of the material within the bronchi varied greatly, ranging from a viscid and tenacious mucus of creamy, yellow color to a thin, tur- bid, gray fluid. The coexistence of local inflammatory or of general edema of the lungs modifies the character of the material found in the bronchi at autopsy; with edema the purulent exudate is in some instances diluted so that a thin cloudy fluid flows from the small bronchi. In the presence of advanced edema of the lungs the bronchi rarely if ever contain purulent exudate. The underlying changes in the bronchi are more significant than the character of the exu- date found at autopsy. Nevertheless, the group of cases in which the diagnosis of purulent bronchitis has been made, because small and medium sized bronchi have con- tained purulent or mucopurulent exudate, represents in- stances of readily recognizable bronchitis of considerable severity. With few exceptions, purulent bronchitis was diffusely distributed in the lungs; occasionally it was observed in one lung alone, and in several instances was limited to the bronchi at the base of a lung, usually of the left lung. In a considerable proportion of instances of purulent bronchitis abnormal distention of the lungs was noted. On removal from the chest the lungs fail to collapse and retain the size and shape of the thorax. Even after section is made through the organ, parts of the lung fail to collapse 144 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT and have a resistant cushion-like consistency. This condi- tion is present where the lung tissue is air containing and dry, and occurs when very small bronchi contain tenacious mucous exudate which becomes apparent upon the cut sur- face after the sectioned lung is squeezed. Microscopic ex- amination shows that the alveolar ducts and infundibula are distended with air, though the respiratory bronchioles contain inflammatory exudate. Complete obstruction of the bronchi is followed by absorption of air from the tribu- tary pulmonary tissue with atelectasis. It is not improb- able that partial obstruction, permitting the penetration of air with inspiration, produces distention of air containing tissue. It is furthermore probable that cyanosis, which is a con- spicuous feature of many instances of pneumonia following influenza, is referable, in part at least, to obstruction of the bronchi by mucopurulent exudate. The term pneumonia will refer to those inflammatory changes in the lung which are found within the alveoli; it will include inflammatory changes in the alveoli surround- ing the respiratory bronchioles, in the alveolar ducts and infundibula and in their tributary alveoli. Bronchitis will be described by defining the changes which occur (a) in the small bronchi with no cartilage or mucous glands, and {b) in the large bronchi including the primary branches of the trachea. For convenience of description those bronchi may be designated small, which have no cartilaginous plates in their wall. Larger bronchi have cartilage and mucous glands, the latter situated in considerable part outside the cartilaginous plates. These bronchi, of which the largest are the right and left bronchi formed by bifurcation of the trachea, diminish with repeated branching to a caliber of about 1 mm. Small bronchi are lined by columnar ciliated epithelium; their wall consists of very vascular connective PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 145 tissue containing a layer of smooth muscle and their cali- ber varies approximately from 1 to 0.5 mm. It is con- venient to designate as respiratory bronchioles24 the ter- minal ramifications of the bronchi; they are lined by a single layer of columnar ciliated cells passing over into cuboidal nonciliated epithelium and are beset with small air sacs lined by flat cells or epithelial plates similar to those of the alveoli elsewhere. Not infrequently these alveoli oc- cur along only one side of the bronchiole, the remainder of the circumference being covered by a continuous layer of cubical epithelium. The respiratory bronchiole by branch- ing along its course or at its end is continued into several alveolar ducts which unlike the respiratory bronchioles have no cubical or columnar epithelium but are closely be- set by alveoli lined by flat epithelial plates. The alveolar duct is recognized by the absence of cubical epithelium and the presence of bundles of smooth muscle which occur in the wall. The infundibula or alveolar sacs arise as branches from the alveolar ducts and like them are beset with alveoli, but smooth muscle does not occur in their walls. The base of the infundibulum is wider than its ori- fice, which Miller states is surrounded by a sphincter-like bundle of smooth muscle. Changes in the main bronchi and their primary branches are usually less severe than those in bronchi of smaller size. The epithelium is often intact, the superficial cells being columnar and ciliated, but not infrequently des- quamation of superficial cells has occurred and the lower layers alone remain. Occasionally (Autopsy 471) there is necrosis of epithelium with which, although the architec- ture of cells is preserved, nuclei have disappeared. Accu- mulation of blood or serum may separate epithelium from the underlying basement membrane (Fig. 1). Complete loss of epithelium occurs, usually in small patches. "Miller, W. S.: Am. Rev. Tuberc, 1919, iii, 65. 146 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Polynuclear leucocytes are numerous upon the surface of the epithelium and are sometimes fixed in process of migration through epithelium and basement membrane. The blood vessels of the mucosa are engorged. There is sometimes edema or hemorrhage, and in the superficial part of the mucosa polynuclear leucocytes are often fairly abundant. When superficial epithelium has been lost, poly- nuclears are numerous immediately below the surface of of epithelium by serum and blood. Autopsy 352. the exposed tissue. Fibrin is often present upon the de- nuded surface and extends for a short distance into the tissue below. In the deeper part of the mucosa, about the muscularis and especially about and between the acini of the mucous glands, the tissue is infiltrated with lymphoid and plasma cells. Changes in the mucous glands are invariably present. These changes are distention of ducts and acini with mu- PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 147 cous, degenerative changes occasionally ending in necrosis of cells, disappearance of acini, dense infiltration of inter- stitial tissue with lymphoid and plasma cells and finally proliferation of this interstitial tissue. The duct of a mu- cous gland, dilated and filled with mucus, may be sur- rounded by lymphoid and plasma cells in great number. Acini, similarly dilated, contain mucus and are composed of cubical cells which have discharged their mucous content. In some instances (e. g., Autopsy 257) the cells of the acini have undergone necrosis; the cytoplasm stains homogen- eously and the nuclei have disappeared. Where necrosis has occurred, polynuclear leucocytes may penetrate into the dead cells. In association with degenerative changes in the acini there is abundant infiltration of the interstitial tissue within and about the glands with lymphoid and plasma cells. When the acini have1 disappeared there is proliferation of fibroblasts and new formation of fibrous tissue, and mucous glands are found in which a few atrophied acini are separated by newly formed fibrous tissue. With the bronchitis of influenza the small bronchi (with no cartilage or mucous glands) show every stage of transi- tion from early acute inflammation characterized by accu- mulation of polynuclear leucocytes within the lumen, en- gorgement of blood vessels, and infiltration of the wall with polynuclear leucocytes, through various stages of destruc- tive changes to complete disappearance of the bronchial wall and formation of an abscess cavity at the site of the bronchus. In the early stages of acute bronchitis, hemor- rhage is frequently associated with the lesion. Blood may be abundant within the lumen of the bronchus, and in the mucosa red blood corpuscles often infiltrate the tissue around greatly distended blood vessels, or accumulating below the epithelium, separate it from its basement mem- brane. Hemorrhage is not limited to the wall of the bron- chus, but frequently occurs into the alveoli in a zone en- circling the bronchus. 148 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT With acute bronchitis there may be desquamation of epithelial cells with partial or complete loss of epithelial lining. In the smallest bronchi the single layer of colum- nar cells may be separated in places from the underlying tissue, so that intact rows of cells are found within the lumen. In somewhat larger bronchi, lined by epithelium in multiple layers, superficial columnar ciliated cells may be lost. In some instances superficial epithelial cells ap- s pear to have lost their cohesion and are separated by nar- row spaces; in these instances, polynuclear leucocytes are often numerous between epithelial cells. Epithelium is oc- casionally separated from its basement membrane by small accumulations of serum or blood. Occasionally necrosis of epithelial cells with disappearance of nuclei is seen and is doubtless caused by the action of bacteria; the affected cells may be raised from the underlying tissue by accu- mulated serum (Autopsy 253). The changes which have been described bring about partial or complete loss of the ciliated lining of the bronchial tube. The severity of changes in the bronchial wall is in direct relation to the extent of destruction of the lining epi- thelium: when the epithelium remains intact polynuclear leucocytes may be found in considerable number imme- diately below it, but as the lesion progresses, cells in great part mononuclear, namely, lymphoid and plasma cells, ac- cumulate in large number throughout the wall of the bron- chus. There is often abundant cellular infiltration within and about the bundles of the muscular coat. The changes assume the character of chronic inflammation. When the lining epithelium of the bronchus is lost, fibrin tends to accumulate over the surface of the defect, to which it is firmly attached. It remains separated by a conspicu- ous space from adjacent intact epithelium over which it may project. This superficial network of fibrin merges with a similar network, extending to a variable depth within the tissue. What may well be described as coagulative PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 149 necrosis has often occurred, and structures, such as white fibrous bundles or wall of blood vessels, are marked out by hyaline material which merges with fibrin. When the walls of the blood vessels which are invariably engorged are involved, the lumen is plugged by a fibrinous thrombus. Little patches of fibrin adherent to the inner surface of the bronchus may occur in spots where epithelium has been lost; with uniform loss of epithelium the entire circumfer- ence may be lined with fibrin forming a circular zone occasionally quite uniform in thickness. Accumulations of polynuclear leucocytes doubtless bring about conditions which cause solution of fibrin or prevent its formation (when disintegration of leucocytes sets free leucoprotease in abundance). The activity of the infecting microorganisms, usually hemolytic streptococci or staphylo- cocci, may cause complete necrosis of a part or all of the bronchial wall. The cavity which is formed may penetrate into lung tissue that has previously undergone pneumonic consolidation. Further changes caused by the bronchitis of influenza will be considered under peribronchial hemorrhage and edema, peribronchial pneumonia and bronchiogenic ab- scess. Purulent bronchitis is almost invariably associated with dilatation of the bronchi, the affected bronchi being distended with pus. With increasing dilatation bronchiec- tasis becomes evident upon gross examination of the tissue, and is much more advanced in the small bronchi than in the larger cartilaginous passages. This subject will be further considered under bronchiectasis. In association with the acute bronchitis of influenza the epithelium of bronchi not infrequently looses its superficial columnar ciliated cells and assumes some of the characters of a squamous epithelium being covered by polygonal or flat cells (Figs. 17 and 18). The condition is often de- scribed a "squamous metaplasia," although it doubtless represents a stage of regeneration following injury rather 150 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT than a true metaplasia. The basal cells of the epithelium have a cubical or columnar form; above them the cells be- come polygonal and as the surface is approached, cells are flat and even scale-like. The nuclei of these superficial cells are often lost. There is no close resemblance to the squamous epithelium of the skin, for intercellular bridges are not seen. This change may occur within six days after onset of influenza, though in most instances the duration of illness has been two weeks or more. It may affect either large or small bronchi, but it is more frequently found in the latter. Whenever ciliated columnar cells are lost, super- ficial cells tend to become flat. Epithelium on one side of a bronchus may have a squamous character, whereas that elsewhere is columnar and ciliated. The flat epithelium may undergo thickening so that it is 0.1 mm. or more in thick- ness. It is noteworthy that regenerating epithelium grow- ing over a denuded surface has the squamous character which has been described (Plate XIV, Fig. 22). Bacteriology of the Bronchitis of Influenza.—With the pneumonia of influenza, bronchitis is invariably present. Cultures have been made from the right or left main bron- chus or from the very small bronchi which contained puru- lent exudate. A routine method of making the culture has been adopted. The right main bronchus, exposed by draw- ing the right lung out of the chest and toward the midline, was widely seared with a hot knife; the bronchus was par- tially cut across through the seared surface with a heated knife ami a platinum needle inserted into the lumen. The bacteria obtained named in the approximate order of their relative frequency have been: B. influenza1, pneumococci, hemolytic streptococci, staphylococci (aureus and albus), B. coli, S. viridans, M. catarrhalis, and diphthoid bacilli which have not been identified. Mixed infections occurred in most instances. The following list arranged by grouping PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 151 bacteria in the order cited above, shows how varied have been the combinations which occur: B. influenzae......................................................... 3 Pneumococci ........................................................ 5 S. hemolyticus ...................................................... 3 Staphylococci ....................................................... 3 B. coli.............................................................. 3 S. viridans .........................................................,. 1 B. influenzae, pneumococci ............................................17 B. influenzae, S. hemolyticus .........................................18 B. influenzae, staphylococci............................................ 4 Pneumococci, S. hemolyticus .......................................... 1 Pneumococci, staphylococci ........................................... 3 S. hemolyticus, staphylococci.......................................... 4 S. hemolyticus, B. coli................................................ 2 Staphylococci, S. viridans............................................. 1 B. influenzae, pneumococci, S. hemolyticus .............................. 6 B. influenzae, pneumococci, staphylococci................................15 B. influenzae, pneumococci, S. viridans.................................. 2 B. influenzae, S. hemolyticus, staphylococci..............................16 B. influenzae, S. hemolyticus, M. catarrhalis............................. 1 B. influenzae, staphylococci, S. viridans................................. 1 Pneumococci, S. hemolyticus, staphylococci.............................. 3 Staphylococci, B. coli, S. viridans ..................................... 1 B. influenzae, pneumococci, S. hemolyticus, staphylococci.................. 7 B. influenza?, pneumococci, staphylococci, M. catarrhalis................... 1 B. influenzae, S. hemolyticus, staphylococci, B. coli....................... 1 B. influenzae, S. hemolyticus, staphylococci, S. viridans.................... 1 B influenzae, S. hemolyticus, staphylococci, M. catarrhalis................. 1 B. influenzae, staphylococci, S. viridans, M. catarrhalis.................... 1 B. influenzae has been present in the bronchi in 79.3 per cent of instances of pneumonia referable to influenza. Com- binations which have been found most frequently are B. influenzae and pneumococci (17 instances), B. influenzae and hemolytic streptococci (18 instances), or the same combina- tions with staphylococci, namely, B. influenzae, pneumococci and staphylococci (15 instances), and B. influenzae, hemo- lytic streptococci and staphylococci (16' instances). There is little doubt that B. influenzae was not identified in some instances in which it was present; when other microorgan- isms are very numerous its inconspicuous colonies may be overgrown even though the presence of pneumococci, strep- 152 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT tococci or staphylococci tends to increase the size of its col- onies. Moreover, it is not improbable that the microorgan- ism may disappear from the bronchi. Comparison with observations made upon influenza suggests that multiple methods of examination might have demonstrated a much higher incidence of B. influenzae. Throat cultures alone made during life demonstrated the presence of B. influenzae in only 65.7 per cent of patients with acute influenza, whereas when cultures were made from the nose, throat and sputum, and a mouse was inoculated with sputum from each patient, B. influenzae was found in every instance. After the acute stage of the disease had passed, the num- ber of microorganisms diminished, and in many instances B. influenzae disappeared from the upper air passages. In some of our autopsies B. influenzae doubtless present dur- ing life has similarly disappeared before death due to pneumonia caused by pneumococci or streptococci. In view of these considerations it is not improbable that B. influ- enzae demonstrated by a single culture in 80 per cent of instances has been constantly present. Table XXVIII represents the incidence of pneumococci, hemolytic streptococci, staphylococci, and B. influenzae in the bronchi, lungs and blood of those individuals with pneu- monia in whom bacteriologic examination has been made at autopsy. The number of cultures made from the bronchi, lungs or blood of the heart is given in the second column of the table and in other columns are given the incidence in number and percentage of the microorganisms which have been mentioned. Table XXVIII CO ° £ PNEUMOCOCCI HEMOLYTIC STREPTOCOCCI STAPHYLO-COCCI B. INFLU-ENZAE > Eh ^ 53 Jz; a, ° & « 53 w o ft. a. > Eh -; 53 £ ft. PS X w o ft. ft. > Eh ° s a 53 w o Ph ft. 50.4 24.2 0.5 > EH ^ 53 8 ° A Ph U Eh PS W H O Ph Ph Bronchus Lung Blood 121 153 218 56 68 87 46.3 44.4 39.9 58 77 85 47.9 50.3 39.0 61 37 1 96 70 1 79.3 45.7 0.5 PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 153 Cultures from the bronchus represent the bacteriology of the bronchitis of influenza. Infection of the lung fol- lowing influenza doubtless occurs by way of the bronchi, so that the bacteria which cause pneumonia are present in the bronchi before they enter the lung tissue. The figures in Table XXVIII, similar to those previously cited, show the high incidence of B. influenzae, and the occurrence of pneumococci, hemolytic streptococci and staphylococci each present in approximately half of all autopsies. The figures in Table XXVllf are an index of the capacity of the microorganisms which enter the bronchi to invade the lungs and finally the blood. Pneumococci were pres- ent in the bronchi in 46.3 per cent of instances, in the lungs in only slightly less, and in approximately 40 per cent of autopsies they had penetrated into the blood. Hemolytic streptococci enter the bronchi with the same frequency and exhibit an equal ability to penetrate into the lungs and blood. Staphylococci enter the bronchi in half of these in- dividuals, but penetrate into the lungs in only a fourth of the instances. They have entered the blood only once (Au- topsy 263) in this instance in association with hemolytic streptococci. B. influenzae has been present in the bronchi in approximately 80 per cent of autopsies. It is notewor- thy that it has been found in the lung in little more than half this percentage of instances and has entered the blood only once (Autopsy 474), in this instance in association with hemolytic streptococci. In a limited number of autopsies there was purulent bronchitis recognized by the presence of mucopurulent ex- udate in small bronchi. It has been stated that this group of cases is not sharply separable from other instances of bronchitis, because in some cases death has occurred before a purulent exudate has accumulated or in other instances a purulent exudate has been displaced by edema. Table XXIX shows the bacteriology of instances of purulent bronchitis: 154 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TKACT Table XXIX CO r Oh Si PNEUMOCOCCI HEMOLYTIC STREPTOCOCCI STAPHYLO-COCCI B. INFLU-ENZAE & Eh a 53 s ° A ft, O Eh « 53 H O Ph Ph > Eh 8 ° 2; Ph 32 a « w & O Eh OS 53 w o Ph Ph > hH Eh a 53 8 ° A Ph ps 53 w o Oh Ph > 8 o A Ph 1 w w & O Eh 03 53 W O Ph Ph Bronchus 66 33 50.0 48.5 36 54.5 53 80.3 The percentages of various bacteria with purulent bron- chitis do not differ essentially from those obtained from all autopsies with pneumonia. B. influenza1 is found in ap- proximately 80 per cent of autopsies. In 16 instances cul- tures wore made from the purulent fluid contained in a small bronchus and the incidence of B. influenzae (namely, 81.4 per cent) has not differed from that in the main bron- chus. In 7 of 8 instances in which cultures were made, both from the right main bronchus and from the purulent fluid in a small bronchus, B. influenzae was found in one or other in all but one autopsy (87.5 per cent) ; in this instance (Au- topsy 472) respiratory disease began thirty-seven days be- fore death and cultures from large and small bronchi at autopsy were overgrown by B. coli. Since observations upon influenza made during life have shown that B. influ- enzae is constantly demonstrable when multiple methods are employed for its detection, the figures just cited give sup- port to the suggestion that B. influenzae is constantly pres- ent in the bronchi with the bronchitis of influenza. Lobar Pneumonia The frequency with which the confluent lobular consol- idation of bronchopneumonia involving whole lobes or parts of lobes follows influenza has emphasized the desira- bility of distinguishing carefully between lobar and conflu- ent lobular pneumonia. The pulmonary lesion has been designated lobar pneumonia when it exhibited the well- known characters of this lesion, namely, firm consolidation of large parts of lobes, coarse granulation of the cut sur- PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 155 face, fibrinous plugs in the bronchi and, on microscopic ex- amination, homogeneous consolidation and fibrinous plugs within the alveoli. AVith confluent lobular consolidation of bronchopneumonia the consolidated area is in most cases obviously limited by lobule boundaries, and well-defined lobules of consolidation occur elsewhere in the lungs. Lobar pneumonia occurred in 98 among 241 instances of pneumonia following influenza, namely, in 40.7 per cent of autopsies. The difficulty of separating lobar and bronchopneumonia following influenza has been increased by the frequent com- bination of the two lesions in the same individual. There were 34 instances in which lobar and bronchopneumonia occurred together. The anatomic diagnosis of lobar pneu- monia was made only when lobes or parts of lobes were firmly consolidated and exhibited the characters of the le- sion enumerated above; in several instances, in which there was some doubt concerning the nature of the lesion, micro- scopic examination was decisive. The associated broncho- pneumonic lesions represented all the types which have been associated with influenza. In the group of 34 cases of coexisting lobar and bronchopneumonia, lobular consolida- tion occurred 10 times, peribronchiolar consolidation 14 times (recognized in all but 4 instances by microscopic ex- amination), hemorrhagic peribronchiolar consolidation 9 times, peribronchial pneumonia 4 times. The intimate re- lation of these lesions to changes in the bronchi is well shown by the frequent presence of purulent bronchitis. The associated lesions of the bronchi in these cases were as follows: purulent bronchitis in 23 instances; peribronchial hemorrhage in 6; bronchiectasis in 11. The frequency of purulent bronchitis and other bronchial lesions in associa- tion with coexisting lobar and bronchopneumonia is in sharp contrast with the occurrence of these lesions in asso- ciation with lobar pneumonia alone; with 69 instances of 156 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT lobar pneumonia alone purulent bronchitis occurred 17 times and bronchiectasis once. Lobar pneumonia following influenza passes through the usual stages of red and gray hepatization. Red hepatiza- tion was found 16 times, combined red and gray hepatiza- tion 28 times, and gray hepatization 20 times. The average duration of pneumonia with red hepatization was 3.7 days, with combined red and gray hepatization 5.1 days and with gray hepatization 7.5 days. These figures, it will be shown later, have some importance in relation to the stage at which hemolytic streptococcus infects lungs the site of lobar pneumonia. Bacteriology of Lobar Pneumonia.—Table XXX is com- piled with the purpose of determining the bacteriology of the bronchi, lungs and heart's blood in autopsies performed on individuals with lobar pneumonia. In some instances bacteriologic examination of one or other of these organs was omitted; the percentage incidence is an index of the presence of pneumococci, hemolytic streptococci, staphylococci or B. influenzae in the bronchi, lungs or heart's blood and measures the invasive power of these mi- croorganisms during the course of lobar pneumonia fol- lowing influenza. Table XXX ° E O f A O PNEUMOCOCCI HEMOLYTIC STREPTOCOCCI STAPHYLO-COCCI B. INFLU-ENZAE Eh Eh -; 53 8 o A £L O Eh 03 53 H O ft. ft. £ Eh 14 13 11 03 53 w o Ph ft. Eh x 53 8 ° A Ph Be ° Eh 03 53 w o Ph Ph & Eh a 53 8 ° A Cm ° £ 03 53 w o Ph Bh Bronchus Lung Blood 44 53 87 29 41 57 56.9 77.3 65.5 31.8 24.5 12.6 8 50.0 15.1 37 26 84.1 49.1 Pneumococci, the recognized cause of lobar pneumonia, were found in the lungs in 73.3 per cent of autopsies; fail- ure to find the microorganism in all instances is doubtless the result of its disappearance from the lung, which, it is well known, occurs not infrequently particularly during PATTTOLOOY AND BACTERIOLOGY FOLLOWING INFLUENZA 157 the later stages of the disease. In 65.5 per cent of instances of fatal lobar pneumonia pneumococci have entered the heart's blood. Hemolytic streptococci unlike pneumococci were found more frequently in the bronchi than in the lungs; this mi- croorganism which exhibits little tendency to disappear, once it has established itself within the body, found en- trance into the bronchi in 31=8 per cent of instances of lobar pneumonia and in 24.5 per cent entered the lungs. Its inva- sive power is further illustrated by its penetration into the heart's blood approximately in half this proportion of au- topsies. Staphylococci enter the bronchi in many instances (50 per cent), but relatively seldom (15.1 per cent) invade the lung and rarely if ever penetrate into the blood. The high incidence, namely, 84.1 per cent, of B. influenzae in the bronchi is particularly noteworthy; it exceeds that of pneumococci, the well-recognized cause of lobar pneu- monia, within the lung. It is found much less frequently within consolidated lung tissue and shows no tendency to invade the heart's blood. B. influenzae finds the most fa- vorable conditions for its multiplication within the bronchi. In view of the frequent occurrence of coexisting lobar and bronchopneumonia it has appeared desirable to de- termine how far the existence of obvious bronchopneumonia modifies the bacteriology of lobar pneumonia. In Table XXXI the incidence of pneumococci, hemolytic streptococci, staphylococci and B. influenzae after death with lobar pneu- monia on the one hand is compared with their incidence after combined lobar and bronchopneumonia on the other. Pneumococci are found in the lung more frequently with lobar than with combined lobar and bronchopneumonia. The incidence of hemolytic streptococci and of staphylo- cocci in the lung is on the contrary higher when broncho- pneumonia is associated with lobar pneumonia. It is not improbable that these microorganisms have a part in the 158 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TIIACT Table XXXI With Lobar Pneumonia Alone w . I-H 8 i3 PNEUMOCOCCI HEMOLYTIC STREPTOCOCCI 1 STAPHYLO-COCCI B. INFLU-ENZA £ Ph 20 29 36 P- ft, !> o g £ p. O fH 03 5: sq o a. ft, Eh 8 ° A ft. w « U E-03 5: W O Ph ft. > ,-; 53 §2 U Eh m 55 H O ft, Ph Bronelius Lung Blood 30 34 54 66.6 8.3.2 66.7 | 9 7 7 30 20.6 13 1-3 3 50 8.8 26 18 86.7 52.9 With Combined Lobar and Bronchopneumonia , Oh pneumococci hemolytic streptococci staphylo-cocci B. INFLU-ENZA fc ft. O E-Oh X w o Ph ft, > Eh ^ 53 8 ° A ft, O Eh 03 W W O ft, ft. (3 > Eh ii O Eh 03 5c w p 2, ft, y. r-« r. w c Ph C- Bronchus Lung Blood 14 19 33 9 12 21 64.3 63.2 63.1 5 6 4 34.3 31.6 12.1 7 5 50 26.3 11 8 78.6 42.1 production of associated bronchopneumonia. The fre- quency with which microorganisms invade the blood is al- most identical in the two groups. The relative frequency with which different types of pneumococci produce lobar pneumonia under the conditions existing when Camp Pike was attacked by an epidemic of influenza is indicated by Table XXXII in which in- stances of lobar pneumonia alone and of combined lobar and bronchopneumonia are listed separately. Pneumococcus I and II, which are found approximately in two-thirds of instances of lobar pneumonia occurring in cities, have an insignificant part in the production of these lesions. Pneumococcus IV and atypical Pneumococcus II, which are commonly found in the mouth, are the predom- inant cause of these lesions, and with Pneumococcus III, also an inhabitant of the mouths of normal individuals, have been the cause of two-thirds of all instances of lobar pneumonia observed in this camp. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 159 Table XXXII With Lobar Pneumonia A J p PNEUMO-COCCUS I PNEUMO-COCCUS II PNEUMO-COCCUS II (Atyp.) Eh t- ■ ° H -; X a X ■ 9 ^ ? PNEUMO-COCCUS III Eh W ! A W > 1 w > • 35 m «: p o wo 2 ft. ft. ft. PNEUMO-COCCUS IV NO. POSITIVE PER CENT POSITIVE > Ej • xn p o A Oh Eh A W 03 55 w o ft. ft. NO. POSITIVE PER CENT POSITIVE Bron-chus Lung Blood 30 34 54 1 1 2 3.3 2.9 3.7 1 2 o 3.3 5.9 3.7 4 | 13.3 9 ' 26.5 12 22.2 4 13.3 6 17.6 3 5.6 10 33.3 11 32.4 17 31.5 With Combined Lobar and Bronchopneumonia Bron- chus Lung Blood PNEUMO- COCCUS I a a w PNEUMO- COCCUS II PNEUMO- COCCUS II (Atyp.-) PNEUMO- COCCUS III PNEUMO- COCCUS IV K K o 6 A W ft. Oh w %i 'A W H p o 14 19 33 14.3 5.3 6.1 7.1 9.1 21.4 26.3 12.1 A g os 35 H O ft, ft, 21.4 31.6 36.4 There is no noteworthy difference in the occurrence of these types of pneumococci among instances of lobar pneu- monia, on the one hand, and of combined lobar and broncho- pneumonia, on the other. Different types exhibit no note- worthy differences in their ability to penetrate into lungs and blood. Hemolytic Streptococcus with Lobar Pneumonia.—There can be no doubt that the concurrent infection with microorganisms other than pneumococcus modifies the progress of lobar pneumonia. With lobar pneumonia alone hemolytic streptococci have entered the bronchi in 30 per cent of instances and have penetrated into the lungs in 20.6 per cent; with associated lobar and bronchopneumonia the same microorganism has entered the bronchi in 34.3 per cent of instances and invaded the lung in 31.6 per cent. Hemolytic streptococci are the only microorganisms other than pneumococci which, in association with lobar pneu- 160 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT monia, have found their way from the lungs to the blood stream; more than one-third of all instances of lobar pneu- monia in which hemolytic streptococci find entrance into the bronchi die with streptococcus septicemia. Separation of instances of lobar pneumonia into groups on the basis of the occurrence of red or gray hepatization shows that infection with hemolytic streptococcus is more likely to occur during the early stages of the disease. The average duration of lobar pneumonia with red hepatization has been 3.7 days, with red and gray hepatization, 5.1 days, and with gray hepatization, 7.5 days. Infection with hemo- lytic streptococcus has occurred in association with red or gray hepatization as shown in Table XXXIII. Table XXXIII no. or NO. WITH HEMO- PER CENT WITH autop- LYTIC STREPTO- HEMOLYTIC sies COCCUS STREPTOCOCCUS Lobar pneumonia with red hepatization 16 6 37.5 Lobar pneumonia with red and gray hepatization 28 6 21.4 Lobar pneumonia with gray hepatization 20 1 5.0 Notwithstanding the longer duration of the disease and consequent prolongation of exposure to infection, lobar pneumonia, which has reached the stage of gray hepatiza- tion, has shown the smallest incidence of infection with hemolytic streptococci. In the stage of gray hepatization there is diminished susceptibility to secondary infection with this microorganism. Characterstic histologic changes have been found in the lungs of those who have died with lobar pneumonia fol- lowed by invasion of lungs and blood by hemolytic strepto- cocci {e.g., Autopsies 273, 430), but with no evidence of suppuration found at autopsy. Within the pneumonic lung occur patches of necrosis implicating both exuded cells and alveolar walls; in some places nuclei have disappeared; elsewhere nuclear fragments are abundant. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 161 In these patches of necrosis Gram-positive streptococci in short chains occur in immense number. In some instances {e.g., Autopsies 273, 34(5, 479) interlobular septa are very edematous and often contain a network of fibrin; lymphat- ics are dilated and contain polynuclear leucocytes in abun- dance. Streptococci are found within these lymphatics. The histologic changes which have been described repre- sent the earliest stages of abscess formation and interstitial suppuration, lesions almost invariably caused by hemolytic streptococci. Relation of Lobar Pneumonia to Influenza.—Some writ- ers have suggested that lobar pneumonia, heretofore ob- served during the course of epidemics of influenza, is an Chart 2.—Showing the relation of (a) date of onset of cases in which autopsy dem- onstrated lobar pneumonia, indicated by upper continuous line with single hatch, and of (6) date of death of these cases, indicated by lower continuous line with double hatch to (<-) the occurrence of influenza, indicated by the broken line, and to (d) the total num- ber of fatal cases of pneumonia, indicated by the broken dotted line. Each case of fatal pneumonia is indicated by one division of the scale as numbered on the left of the chart; cases of influenza are indicated by the numbers on the right of the chart. 162 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT independent disease with no relation to influenza, both dis- eases being referable perhaps to similar meterologic or other conditions. Chart 2, which shows by weeks from September 1 to October 31 the relation of deaths from lobar pneumonia (indicated by double hatch) to deaths from all forms of pneumonia, disproves this suggestion. The two curves follow parallel courses; that representing lobar pneumonia reaches a maximum approximately one week after the outbreak of influenza had reached its height. Lo- bar pneumonia, like other forms of pneumonia, was second- ary to influenza. When a chart is plotted to represent the dates of onset of fatal cases of lobar pneumonia (indicated by single hatch in Chart 2), it becomes evident that the greatest number of these cases of pneumonia had their on- set at the beginning of the influenza epidemic, approxi- mately one week before it reached its height. Fatal lobar pneumonia developed less frequently in the latter part of the epidemic; to obtain an explanation of this relation it is necessary to chart separately cases of lobar pneumonia with secondary streptococcus infection, for Ave have already learned that streptococcus infection was the predominant cause of death in the early period of the influenza epidemic. Exclusion of these instances of secondary streptococcus in- fection makes no noteworthy change in the character of the chart. Fatal lobar pneumonia, like all forms of fatal pneumonia (p. 140), was more frequent in the first half than in the second half of the epidemic. This differ- ence is referable either to greater virulence of the virus of influenza or to the greater susceptibility of those first se- lected by the disease or, as more probable, to conditions such as crowding together of patients with influenza, favor- ing the transmission of microorganisms which cause pneu- monia. Bronchopneumonia For the purpose of the present study it is convenient to group together instances of bronchopneumonia which have PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 163 been unaccompanied, on the one hand, by lobar pneumonia (p. 155) or, on the other hand, by suppuration, which with few exceptions is caused by hemolytic streptococci or by staphylococci. A group of cases in which lobar and bron- chopneumonia have occurred in the same individual have already been considered. In many instances, bronchopneu- monia is accompanied by abscess formation or by some other form of suppuration; these lesions will be discussed elsewhere. Bronchopneumonia unaccompanied by lobar pneumonia or by suppuration occurred in 80 autopsies. Pneumonic consolidation distributed with relation to the bronchi exhibits considerable variety, and an attempt to define a type of bronchopneumonia characteristic of influ- enza would be futile. Nevertheless, the bronchopneumonia of influenza has in many instances distinctive characters. Lesions of bronchopneumonia which are frequently found in the autopsies under consideration may be con- veniently designated by descriptive terms, indicative of their location in the lung tissue. These lesions, of which two or more often occur in the same lung, are: 1. Peribronchiolar consolidation with which the inflam- matory exudate is limited to the alveoli in the immediate neighborhood of the bronchioles. 2. Hemorrhagic peribronchiolar consolidation in which gray patches of peribronchiolar pneumonia occur upon a deep red background produced by hemorrhage into alveoli. Pfeiffer believed that this lesion was characteristic of in- fluenza. 3. Lobular consolidation with which consolidation is lim- ited to lobules or groups of lobules. 4. Peribronchial pneumonia with which small bronchi are encircled by pneumonic consolidation. Each one of these lesions will be discussed separately. Following is a list of the bacteria which have been iso- lated from the consolidated lung of individuals with bron- 164 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT chopneumonia unaccompanied by lobar pneumonia or by suppuration: B. influenzae ......................................................... 1 Pneumococci ........................................................ 5 S. hemolyticus .......................:.............................. 5 S. viridans .......................................................... 1 B. influenza?, pneumococci ............................................ 9 B. influenzae, S. hemolyticus........................................... 4 B. influenzae, staphylococci ............................................ 4 Pneumococci, S. hemolyticus .......................................... 1 Pneumococci, staphylococci ........................................... 2 S. hemolyticus, staphylococci .......................................... 1 S. hemolyticus, B. coli ............................................... 1 Staphylococci, S. viridans ............................................. 1 Staphylococci, B. coli ................................................ 1 B. influenzas, pneumococci, staphylococci ............................... 1 B. influenzas, pneumococci, S. viridans ................................. 1 B. influenzae, S. hemolyticus, staphylococci ............................. 2 B. influenzas, pneumococci, staphylococci, S. viridans ..................... 1 No microorganisms found ............................................ 6 47 The similarity of this list to that representing the bac- teriology of bronchitis is evident; there is the same multi- plicity of microorganisms and the frequent occurrence of mixed infections. B. influenzae is much less frequently found in the lung. The relative pathogenicity of the large group of. microorganisms enumerated above is better indi- cated by the following list which shows what microorgan- isms have penetrated into the blood in autopsies performed on individuals with bronchopneumonia: Pneumococci ...............................................20 S. hemolyticus ..............................................23 S. viridans ................................................. 1 Pneumococci, S. hemolyticus .................................. 2 No bacteria found ..........................................25 Total..................................71 Table XXXIV shows the percentage incidence of pneu- mococcus, hemolytic streptococcus, staphylococcus and PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 165 B. influenzae in the bronchi, lungs and blood and is in- serted for comparison with the similar table (Table XXX) showing the incidence of these bacteria in lobar pneumonia. Table XXXIV PNEUMO- HEMOLYTIC STAPHYLO- B. INFLU- O w Eh O t£ A ti COCCI STREPTOCOCCI COCCI ENZAE K A 0- E-i A, K os 55 w o > Eh A % 2 ° 13 Eh A W ° e w o Oh Ph Eh A W 2 ° E Oh 22 Eh A W W > ° a as 55 w o Oh Oh > Eh O o *4 Oh PER CENT POSITIVE Bronchus 37 19 4S.fi 35.1 59.5 28 75.7 Lung 47 20 42.6 14 29.8 13 27.7 23 48.9 Blood 70 22 31.4 24 34.3 Table XXXIY shows that pneumococci have a less impor- tant part in the production of broncho than of lobar pneu- monia; with lobar pneumonia this microorganism was found in the lungs in 77.3 per cent of instances and in the blood, in 65.5 per cent, whereas with bronchopneumonia it was found in the lungs in 42.6 per cent and in the blood in 31.4 per cent. Hemolytic streptococci (in lungs and blood) and staphylo- cocci (in lungs), on the contrary, were more common with bronchopneumonia, and doubtless have a part in the pro- duction of the lesion. Streptococcus viridans, B. coli and M. catarrhalis, which are not infrequently found in the bronchi (p. 151), occasionally enter the lungs with bron- chopneumonia but are rarely found with lobar pneumonia. B. influenza3 has been found in less than 80 per cent of instances in the bronchi and in about half of the lungs, maintaining an incidence approximately the same as that with lobar pneumonia. Table XXXV shows the types of pneumococci found in association with bronchopneumonia and is inserted for comparison with the similar table (Table XXXII) show- ing types of pneumococci with lobar pneumonia. With broncho as with lobar pneumonia pneumococci com- monly found in the mouth, namely, atypical II, and Types III and IV, have a more important part in production of the 166 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Table XXXV w w « O Eh 2 p PNEUMO-COCCUS I PNEUMO-COCCUS II PNEUMO- PNEUMO-COCCUS COCCUS (Atyp.) Ill III PNEUMO-COCCUS IV > EH 2 ° A Oh O Eh S3 W W O Oh Oh 2 ° A Oh O Eh « W H O Oh Oh F i A § g Eh , o Eh Eh _r 55 , a 55 x 55 g O I w o o o £ Oh Oh Oh j Z p. Ph W W O Oh Oh H A ™ 2 ° A Oh O Eh « 55 w o Oh Oh Bron-chus Lung Blood 37 47 70 1 2 1 2.7 4.3 1.4 3 2 1 8.1 4.3 1.4 2 4.3 2 5 i 7.1 4 14 37.8 4.3 j 12 25.2 5.7 11 | 15.9 lesion than the so-called fixed types, I and II. Atypical Pneumococcus II has been less frequently encountered with broncho than with lobar pneumonia. Peribronchiolar Consolidation.—In many instances of bronchopneumonia, usually in association with lobular or confluent consolidation, small firm nodules of consolidation are clustered about the bronchioles (Fig. 2). These nodu- lar foci of consolidation are usually 1.5 to 2 mm. in diam- eter, being sometimes slightly smaller or slightly larger. They are usually gray and occasionally surrounded by a red halo; sometimes they are yellowish gray. They are clustered about the smallest bronchial tubes to form groups which are from 0.5 to 1 cm. across. A group of nodular foci of consolidation occupies the central part of a lobule of lung tissue. When pneumonia has been of short duration these foci are fairly soft and not sharply defined, and in many instances this form of bronchopneumonia is first rec- ognized by microscopic examination. When the disease has lasted from ten days to two weeks, the consolidated nodules are very firm and sharply circumscribed, closely resem- bling tubercles. When they have assumed this character, microscopic examination shows that chronic changes indi- cated by new formation of interstitial tissue have occurred. The lesion may be designated peribronchiolar consolida- tion. It has occurred usually in association with other types of pneumonic lesion in 61 instances, being recognized at autopsy in 18 and by microscopic examination in 43. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 167 Fig. 2.—Acute bronchopneumonia with nodules of peribronchiolar consolidation and puru lent bronchitis. Autopsy 429. 168 PNEUMONIAS AND INFECTIONS OF RESPIRATORY' TRACT In association with this lesion there are almost invari- ably severe lesions of the bronchi. Purulent bronchitis was noted in 47 of the (il instances, in which this nodular bron- chopneumonia was found at autopsy. An index of the se- verity of the bronchial injury is the frequency with which bronchiectasis has occurred; dilatation of small bronchi was observed in 24 instances. In 10 instances the bronchi were encircled by conspicuous zones of hemorrhage. In association with this peribronchiolar lesion the lung is often voluminous and fails to collapse on removal from the chest. Pressure upon the lung squeezes from the smallest bronchi, both in the neighborhood of the nodular consolida- tion and elsewhere, a droplet of viscid, semifluid mucopuru- lent material. The presence of this tenacious material throughout the small bronchi doubtless explains the failure of the lung tissue to collapse. Interstitial emphysema has been present in some of these lungs. A red zone of hemorrhage has occasionally been observed about the foci of peribronchiolar pneumonia. A further stage in the same process is represented by hemorrhage into all of the alveoli separating these patches of consolida- tion. This hemorrhagic lesion, which will be described in more detail later, has been found repeatedly in the same lung with peribronchiolar pneumonia, being present in 8 among the 61 autopsies cited. Lobular bronchopneumonia accompanied the peribronchiolar lesion 27 times and lobar pneumonia accompanied it 20 times. When an abscess caused by hemolytic streptococcus is associated with peribronchiolar pneumonia, empyema is present, but otherwise pleurisy is absent or limited to a scant fibrinous exudate. Histologic examination demonstrates very clearly the re- lation of this lesion to the bronchioles (Fig. 3). These passages are filled and distended with an inflammatory ex- udate consisting almost entirely of polynuclear leucocytes. The respiratory bronchioles are beset with alveoli often PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 169 limited to one side of the tubule and these alveoli are filled with leucocytes. The alveolar ducts, distinguishable from the bronchioles by the absence of columnar or cubical epi- thelium and by possession of smooth muscle, are similarly filled with leucocytes; the numerous alveoli which form the walls of the alveolar ducts are distended by an inflamma- tory exudate. In sections which pass through an alveolar Fig. 3.—Acute bronchopneumonia with peribronchiolar consolidation; a respiratory bronchiole partially lined by columnar epithelium passes into alveolar duct and the adja- cent alveoli are filled by polynuclear leucocytes. Autopsy 333. duct and one or more of its infundibula, the further exten- sion of the lesion may be determined (Fig. 4). The infun- dibulum in proximity with the alveolar duct contains poly- nuclear leucocytes and the same cells are seen in the alveoli which here form its wall, but the intensity of the inflamma- tory reaction diminishes toward the periphery, so that the distal part of the infundibulum, which is much distended 170 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT and in consequence more readily definable than usual, is free from inflammatory exudate. Occasionally there is irregularly distributed hemorrhage and perhaps some edema in the alveoli immediately adja- cent to those which form the peribronchiolar focus of in- flammation. In such instances small bronchi, that is, air passages, lined by columnar epithelium and devoid of trib- Fig. 4.—Acute bronchopneumonia with peribronchiolar consolidation; a respiratory bronchiole is in continuity with an alveolar duct and two distended infundibula; alveoli about bronchiole, alveolar duct and proximal part of infundibula contain polynuclear leu- cocytes, the distal part of the infundibula showing no evidence of inflammation. Autopsy utary alveoli, may be surrounded by a zone of hemorrhage; immediately surrounding the bronchus, the wall of which shows intense inflammation, alveoli, in a zone of which the radius represents several alveoli, are filled with blood. This hemorrhagic zone is continued from the bronchus over the focus of inflammation which surrounds the bronchiole. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 171 Another variation in the character of the lesion is doubt- less referable to variation in the severity of primary bron- chial injury. Alveoli immediately surrounding small bron- chi are filled with dense plugs of fibrin. The alveoli which beset the Avails of the bronchioles contain fibrin, but the alveolar duct and its tributary alveoli are filled with poly- nuclear leucocytes. The bacteria which have been cultivated from the lung in autopsies with peribronchiolar pneumonia are as follows: Pneumococcus ....................................................... 5 S. hemolyticus ...................................................... 8 B. influenzas, pneumococcus .......................................... 5 B influenzas, S. hemolyticus .......................................... 7 B. influenzas, staphylococcus .......................................... 1 Fneumococcus, staphylococcus ........................................ 2 S. hemolyticus, staphylococcus ........................................ 2 B, influenzas, pneumococcus, S. hemolyticus ............................ 2 B. influenzas, pneumococcus, staphylococcus ............................. 1 B. influenzas, S. hemolyticus, staphylococcus.............................. 2 Pneumococcus, S. hemolyticus, staphylococcus........................... 3 No organism ........................................................ 3 Total .............................................................41 The following list which shows the bacteria found in the blood is an index to the pathogenicity of pneumococci and hemolytic streptococci: Pneumococcus ...................................................... 22 S. hemolyticus...................................................... 20 Pneumococcus, S. hemolyticus ....................................... 1 No organism ....................................................... I ^ Total ............................................................ 57 The percentage incidence of pneumococcus, hemolytic streptococcus, staphylococcus and B. influenzae in bronchus, lung and blood, given in Table XXXV1, is inserted to indicate with what readiness each one of these microorgan- isms passes from the bronchus through the lung into the circulating blood, 172 PNEUMONIAS AND INFECTIONS OF INSPIRATORY TRACT Table XXXVI PNEUMOCOCCUS HEMOLYTIC STREPTOCOCCUS STAPHYLO-COCCUS B. INFLUENZA Bronchus Lung Blood 39.4% 43.9% 40.3% 57.7% 61.(»7r 36.8% 60.6% 21.9% 0. % 84.8% 43.9% 0. % B. influenzae is present in the bronchi in a very large pro- portion (84.8 per cent) of those in whom this type of bron- chopneumonia has been found at autopsy; it is much less frequently recovered from the lungs. Staphylococci, in part S. albus and in part S. aureus, are less frequently found in the bronchi and are recovered from the lungs in a relatively small proportion of autopsies. The percentage incidence of pneumococci and streptococci in lungs and blood demonstrates the pathogenicity of these microorgan- isms, for whereas pneumococci and hemolytic streptococci are found in the consolidated lungs in 43.9 and 61.0 per cent of instances of the lesion respectively, they make their way into the blood in 40.3 and 36.8 per cent of instances. Coexisting infection with pneumococci and hemolytic streptococci has been not uncommon e. g., Autopsy 275 in which both were in the blood; in 2 instances (Autopsies 333 and 378) in which pneumococci were obtained from the blood, hemolytic streptococci were found in the lungs and bronchi; in 3 instances (Autopsies 258, 273 and 445) in which hemolytic streptococci were present in the blood, pneumococci were obtained from the lungs. In the group of autopsies under consideration, examina- tion of the sputum was made during life and after onset of pneumonia in 11 instances. The microorganisms found in the sputum and at autopsy were as follows: SPUTUM Autopsy 240 Pneum. IV 246 Pneum. atyp. II, B. inf. 247 Pneum. IV, B. inf. 250 Pneum. atyp. II, B. inf. 253 Pneum. atyp. II 285 Pneum. atyp. II, B. Inf. 288 S. hem., B. inf. IN BLOOD, Ll'NGS OR BRONCHUS AT AUTOPSY Pneum. IV II Pneum. IV Pneum. ntyj; Pneum. II S. hem., B. inf. S. hem., B. inf. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 173 IN BLOOD, LUNGS OR BRONCHUS SPUTUM AT AUTOPSY Autopsy 291 Pneum. IV, B. inf. Staph., B. inf. 300 Pneum. atyp. II, B. inf. Pneum. atyp. II, B. inf. 312 Pneum. IV, S. hem., B. inf. S. hem., B. inf. 346 Pneum. IV, B. inf. S. hem., B. inf! In 2 instances (Autopsies 285 and 346) among this small group of cases, pneumococci but no hemolytic streptococci were found in the sputum several days before death, whereas death occurred as the result of secondary invasion with hemolytic streptococci and no pneumococci were found at autopsy. It is probable that this sequence of events is not uncommon. B. influenzae iinds its way into the bronchi and pneumococci follow it; pneumonia limited to peribron- chiolar alveoli may occur in consequence of this invasion. Later hemolytic streptococci may follow the same path and cause death with bacteremia. Hemorrhagic Peribronchiolar Consolidation.—Peribron- chiolar pneumonia accompanied by diffuse accumulation of blood within the alveoli is one of the most frequent com- plications of influenza. The lung tissue is laxly consoli- dated, and on section there is a homogeneous dull deep red background upon which are seen small gray spots (1.5 to 2 mm. in diameter) grouped in clusters about the smallest bronchi (Fig. 5). Wide areas of lung tissue are implicated and the lesion is more common in the dependent parts of the lung than elsewhere. In common with other forms of bronchopneumonia the lesion is in most instances associ- ated with changes in the bronchi; in 55 instances of hemor- rhagic bronchiolar pneumonia purulent bronchitis was found in 43 instances; it is noteworthy that purulent bron- chitis often is not evident in the presence of pulmonary edema and edema is not infrequent with this pneumonic lesion. Microscopic examination demonstrates the presence of acute bronchitis; the lumina of the small bronchi contain polynuclear leucocytes and red blood corpuscles. Accumu- lation of blood may separate the epithelium from the base- 174 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT ment membrane. The mucosa immediately below the epi- thelium contains polynuclear leucocytes in fair abundance and the blood vessels of the bronchial wall are much en- gorged. Respiratory bronchioles are distended with poly- nuclear leucocytes and red blood corpuscles. In a zone about each bronchiole, in areas corresponding to the small gray spots seen upon the cut surface of the lung, the alveoli are filled with polynuclear leucocytes. In the lung tissue intervening between these spots of leucocytic pneumonia the alveoli are distended with red blood corpuscles. Fig. 5.—Bronchopneumonia with hemorrhagic peribronchiolar consolidation. In favorable sections it is occasionally possible to follow the bronchiole and alveolar duct, both filled with leuco- cytes, into an infundibulum. The proximal part of the in- fundibulum contains polynuclear leucocytes, whereas the distal part and its tributary alveoli are filled with serum and red blood corpuscles. When the lesion has persisted for a short time there is evidence of beginning migration of polynuclear leucocytes from the blood vessels into the alveoli which are filled with Pathology and bacteriology Following influenza 175 blood. The alveolar walls contain numerous polynuclear leucocytes and leucocytes which have entered the intraal- veolar blood are numerous in contact with the Avail but occur in scant number in the center of the alveolar lumen. Alveolar epithelium in contact with the blood in the lu- men is usually swollen and often uniformly nucleated. The inflammatory process is evidently transmitted from the bronchioles and to a less degree from the small bronchi to the adjacent alveoli. Polynuclear leucocytes fill the lu- men of the bronchiole and the alveoli immediately adja- cent; at the periphery of the focus of pneumonia, the alve- oli may contain fibrin. In such instances small bronchi (lined by a continuous layer of columnar epithelial cells) may be surrounded by alveoli containing fibrin. In sections from one part of the lung, the alveoli between the peribronchiolar foci of pneumonia may be uniformly filled with red blood corpuscles, whereas in sections from iinother part pneumonic foci may be surrounded by a zone of intraalveolar hemorrhage or of hemorrhage and edema outside of which some air-containing tissue occurs. There are transitions between this halo of intraalveolar hemor- rhage and edema surrounding each bronchiolar focus and complete hemorrhagic infiltration of all intervening alveoli. Large mononuclear cells are occasionally fairly numer- ous within the alveoli containing blood. These colls act as phagocytes ingesting red corpuscles, so that at times they are filled with corpuscles. Disintegration of red corpuscles occurs and brown pigment remains within the cell. It is not uncommon to find numerous mononuclear pigment con- taining cells which resemble those found with chronic pas- sive congestion of the lungs. Lungs, the site of hemorrhagic peribronchiolar pneumo- nia, may undergo chronic changes which will be described elsewhere. The lesion which has been designated hemorrhagic peri- bronchiolar pneumonia is that which Pfeiffer regarded as 176 PNELMONIAS AND INFECTIONS OF RESPIRATORY TRACT the characteristic type of influenzal pneumonia. In the small bronchi containing pus and in lung tissue, Pfeiffer states, influenza bacilli are predominant and present in as- tonishing number in smear preparations. The demonstra- tion of B. influenzae by cultures from pneumonic lung is mentioned by him but its association with other microor- ganisms in such cultures is not discussed. Microorganisms which we have isolated from the lungs of individuals with hemorrhagic peribronchiolar pneumo- nia are as follows: B. influenzae ............................ 1 Pneumococcus ......................... 0 S. hemolyticus ................................. -. ~ B. influenzas, pneumococcus .......................... 7 B. influenzae, S. hemolyticus.............................. 3 B. influenzae, staphylococcus .............................. 2 S. hemolyticus, B. coli ........................... o B. influenzas, pneumococcus, staphylococcus ...................... _ 2 B. influenzae, S. hemolyticus, staphylococcus............................ 5 Pneumococcus, S. hemolyticus, staphylococcus ................ 1 No organisms......................... <, Total.............................................................38 With this type of pneumonia B. influenzae has not been isolated in pure culture; B. influenza? alone is recorded onlv once (Autopsy 435), but in this instance the culture has been so obscured by contamination that the occurrence of pneumococci or streptococci cannot be excluded; S. hemo- lyticus has doubtless been present in this lung, for it has been found in the heart \s blood, in the bronchus, and in the peritoneal exudate of the same individual. The incidence of pneumococci and hemolytic streptococci m this list does not differ materially from that with peri- bronchiolar pneumonia unaccompanied bv extensive intra- alveolar hemorrhage, though hemolytic' streptococci are somewhat more frequent with the hemorrhagic lesion The following table shows the frequency with which pneumo- cocci and hemolytic streptococci have penetrated into the blood: PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 177 Pneumococcus .......................................................11 S. hemolyticus ......................................................24 Pneumococcus, S. hemolyticus ........................................ 1 No organism ........................................................12 Total Table XXXYII showing the percentage incidence of pneumococci, hemolytic streptococci, staphylococci and B. influenza^ further emphasizes the similarity between the bacteriology of peribronchiolar pneumonia (Table XXXVI) and the closely related hemorrhagic lesion: Table XXXVII PNEUMOCOCCUS HEMOLYTIC STREPTOCOCCUS STAPHYLO-COCCUS B. INFLUENZAE Bronchus Lung Blood of heart 44.0% 31.6% 2.1.0% 64.0% 57.9%, 52.1% 44.09; 26.8%. 0% 72.07; .12.6% <>7r Pneumococci have been found in the lungs (31.6 per cent) and blood (25 per cent), somewhat less frequently than with peribronchiolar pneumonia (43.9 and 40.3 per cent respectively), and hemolytic streptococci have been found in the blood more frequently (52.1 per cent) than with the latter (36.8 per cent) but otherwise the bacteriol- ogy of the two lesions corresponds closely. The low inci- dence of B. influenza? in the bronchi (72 per cent) with hem- orrhagic peribronchiolar pneumonia is perhaps incorrect as the result of the relatively small number of bacteriologic examinations (namely, 25), but the incidence of the same microorganism in the lung has been higher (52.6 per cent) than with nonhemorrhagic peribronchiolar lesion (43.9 per cent). In some instances infection with hemolytic streptococci has occurred after the onset of pneumonia. The following list compares the results of bacteriologic examination of the sputum made after the onset of pneumonia with that of blood, lungs or bronchus after death: 178 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT SPUTUM IN BLOOD, LUNGS OR BRONCHUS AT AUTOPSY Autopsy 237 S. hem. S. hem. 242 Pneum. atyp. II, B. inf. Pneum. atyp. II 247 Pneum. IV, B. inf. Pneum. IV 266 S. hem. S. hem., B. inf. 346 Pneum. IV, B. inf. S. hem., B. inf. 376 (No. S. hem.) S. hem., staph., B. inf. Instances of secondary infection with hemolytic strepto- coccus occur in the list, namely, Autopsies 346 and 376. From the foregoing studies of the bacteriology of peri- bronchiolar and hemorrhagic peribronchiolar pneumonia the following conclusions may be drawn: {a) B. influenza1 is found in most instances of these lesions in the bronchi and in about half of all instances in the lungs, but does not occur unaccompanied by other microorganisms, {b) In a considerable number of autopsies pneumococcus is the only microorganism that accompanies B. influenzae: from the lungs it penetrates into the blood from which it is obtained in pure culture, (c) In a considerable number of instances S. hemolyticus accompanies B. influenza^, and in some of these instances (representing a large proportion of the rel- atiyely small number of cases examined during life), exam- ination of the sputum has demonstrated that infection has been secondary to a pneumonia with which no hemolytic streptococci have been found in the sputum. Lobular Consolidation.—Consolidation of scattered lob- ules or groups of lobules has occurred in nearly all in- stances, namely, 71 of 80 autopsies with bronchopneumonia unaccompanied by lobar pneumonia or by suppuration. "When death follows shortly after the onset of pneumonia, patches of consolidation have a dull deep red color; blood- tinged fluid escapes from the cut surface which is almost homogeneous or finely granular. The consolidated tissue seen through the pleura, which is raised above the general level, has a bluish red color. Isolated lobules or groups of lobules which have undergone consolidation may be scat- tered throughout the lungs, but not infrequently there is confluent consolidation of the greater part of lobes, of PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 179 whole lobes or of almost an entire lung. Such lungs are very heavy and may weigh 1,400 or 1,500 grams; bloody serous fluid exudes from the cut surface. The lesion resem- bles the red hepatization of lobar pneumonia, but confluent patches of pneumonia are usually well defined by lobule boundaries. The tissue is soft and the granulation of lobar pneumonia is absent. In many instances the lobular or con- fluent areas of consolidation are reddish gray; in some in- stances consolidated tissue is in places red and elsewhere gray, and in a smaller group of autopsies there is gray consolidation only (Fig. 6). Ked lobular consolidation is often seen in those who have died within the first four days following the onset of pneumonia, but is almost equally fre- quent after from five to ten days; the average duration of pneumonia in these cases was 5.5 days. Combined red and gray consolidation was more frequently found when pneu- monia had lasted more than five days, the average duration of pneumonia being 7.3 days. The greater number of in- stances of gray consolidation were found after seven days of pneumonia, the average duration of the disease being 10.0 days. These figures are cited to show that lobular, like lobar, consolidation passes gradually from a stage of red to gray hepatization, but the change occurs more slowly and is often long delayed. Lobular pneumonia, which occurred 71 times among 80 cases classified as bronchopneumonia, may be regarded as an almost constant lesion of the disease. It is found not only in association with other lesions of bronchopneumo- nia, but with lobar pneumonia of influenza as well. The bacteriology of this lesion shows no deviation from that of the slightly larger group of bronchopneumonia (p. 163). All typos of pneumococcus have been found in association with the lesion, Pneumococcus I in 2 instances, Pneumococcus II in 1 instance; atypical Pneumococcus II and Pneumococcus IV have been found much more fre- quently. Pneumococci have been found in more than a 180 PXEU.MONIAS AND IXFECTIOXS OF RESPIRATORY TRACT Fig. 6.—Acute bronchopneumonia with confluent gray lobular consolidation in lower part of upper lobe and hemorrhagic peribronchiolar pneumonia in lower lobe; purulent bronchitis. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 181 third of these autopsies (42.9 per cent in the lungs, 33.3 per cent in the blood) ; hemolytic streptococci in less than one- third (28.5 per cent in the lungs, 30.2 per cent in the blood). The following list shows the bacteriology of a small group of autopsies in which the sputum was examined after onset of pneumonia: SPUTUM BLOOD, LUNGS OR BRONCHUS AT AUTOPSY °33 Pneum. atyp. II Pneum. 237 S. hem. S. hem. 242 Pneum. atyp. II, B. inf. Pneum. atyp. II 250 Pneum. atyp. II, B. inf. Pneum. atyp. II °.13 Pneum. atyp. II Pneum. atyp. II, staph., B. inf. 266 S. hem. S. hem., B. inf. 274 Pneum. IV S. hem. 291 Pneum. IV, B. inf. Staph., B. inf. 312 Pneum. IV, S hem., B. inf. S. hem., staph., P>. inf. Ill one instance of streptococcus pneumonia (Autopsy 274) infection with streptococci occurred subsequent to the examination of the sputum made five days before death; pneumococcus was found in the washed sputum. With lobar pneumonia there was evidence that superim- posed infection occurred more frequently during the stage of red than of gray hepatization. With the lobular con- solidation of bronchopneumonia this relation has not been found. Among 27 instances of red lobular consolidation, hemolytic streptococcus has occurred 6 times, namely in 22.2 per cent; among 26 instances of red and gray consol- idation, 8 times, namely, in 30.7 per cent; among 13 in- stances of gray consolidation, 5 times, namely, in 38.5 per cent. Infection with hemolytic streptococci is more fre- quent when the lesion has persisted to the stage of gray hepatization. This difference between lobar and broncho- pneumonia is probably dependent in part at least upon the more severe and persistent lesions of the bronchi with bronchopneumonia. The histology of consolidation which is definitely limited to secondary lobules or groups of lobules varies consider- ably. When death occurs in the earlv stage of the lesion, 182 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT consolidated patches are deep red and somewhat edema- tous, so that bloody serous fluid escapes from the cut sur- face of the lung and red blood corpuscles are present in the alveoli in great abundance together with polynuclear leu- cocytes, fibrin and serum in varying quantity. It is not uncommon to find evidence that the lesion has had its or- igin in the bronchioles and extended from them to other parts of the lobule. Polynuclear leucocytes may be rela- tively abundant within and immediately about the bronchi- oles and alveolar ducts, whereas the intervening alveoli and infundibula are filled with red blood corpuscles among which are polynuclear leucocytes and perhaps some fibrin. It ma)r be evident that bronchiolar pneumonia with hemor- rhage into intervening alveoli is in process of transforma- tion into a more diffuse leucocytic pneumonia, for polynu- clear leucocytes are making their way from the alveolar wall into the blood-filled lumen and, as the result of the presence of blood, remain for a time close to the lining of the alveolus. When the consolidated lobules have assumed a gray or reddish gray color, polynuclear leucocytes are more abun- dant and often almost homogeneously pack every alveolus within the boundaries of the lobule. In some instances there is fibrin partially obscured by the presence of leuco- cytes in great number. Although fibrin is less abundant with bronchopneumonia than with lobar pneumonia, nevertheless in a considerable proportion of instances it is a very conspicuous element of the inflammatory exudate within the bronchioles, alve- olar ducts and alveoli. It is unusual to find the alveolar ducts and alveoli uniformly plugged with fibrin containing leucocytes; there is a variegated distribution of exudate which has little resemblance to that of lobar pneumonia. Occasionally (Autopsies 242 and 247) polynuclear leuco- cytes fill the bronchioles, alveolar ducts and infundibula, whereas the surrounding tributary alveoli contain fibrin PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 183 and polynuclear leucocytes in moderate number; red blood corpuscles may be present in sufficient number to give a homogeneously red color to the lobular consolidation. In association with lobular pneumonia, fibrin within the lung tissue undergoes certain changes which outline very sharply the alveolar ducts and the other structures usually ill defined in preparations of the lung. A remarkable ap- pearance is produced by the deposit of hyalin fibrin upon the surface of the alveolar ducts and infundibula. This lesion has been described by LeCount. Within the alveolar tissue of the lung, spaces are seen lined by a layer of fibrin which stains homogeneously and very brightly with eosin. They are recognized as alveolar ducts by the presence of scattered bundles of smooth muscle in their Avail. The layer of hyaline fibrin overlying the surface of the alveolar duct usually forms a continuous lining and covers over the orifices of the alveoli which sur- round the alveolar duct. These ducts are rendered still more conspicuous by the character of their contents which exhibits a sharp contrast with that of the surrounding alveoli. The alveoli duct occasionally contains a bubble of air, but more frequently it is filled with serum in which red blood corpuscles are sometimes numerous. Thei^; is within the lumen scant fibrin and very few cells, among which poly- nuclear leucocytes are predominant. In the surrounding alveoli on the contrary leucocytes and fibrin are abundant. A similar change is found in the infundibula very clearly defined by their conical form, which is especially well out- lined below the pleura or in contact with interlobular septa. The infundibulum is outlined by hyaline fibrin which passes over the orifices of the tributary alveoli and separates the serous contents of the infundibulum from tin1 cellular fibrin- ous contents of the alveoli about. The lesion which has been described is often associated with acute bronchitis and bronchiolitis, and the alveoli im- mediately about the respiratory bronchioles may be filled 184 PNEUMONIAS AND INFECTIONS OF INSPIRATORY TRACT with polynuclear leucocytes. It is very common to find large bubbles of air sharply defined within the purulent contents of the bronchiole. In some lobules the alve- olar ducts, infundibula and alveoli intervening between these foci of leucocytic pneumonia are almost uniformly filled with fibrin and polynuclear leucocyte's, but in other places the formation of complete layers of hyaline fibrin is in process. Bubbles of air are often seen within the al- veolar ducts, and about them is an irregular layer of fibrin formed by the penetration of air into a channel previously filled with a loose network of fibrin containing serum in its meshes. The fibrin compressed against the walls of alve- olar duct and infundibulum remains as a compact layer sep- arating these structures from the alveoli which project from their walls. The bubble of air is doubtless later ab- sorbed and replaced by serum, so that many alveolar ducts are filled with serum almost wholly free from cells, whereas alveoli outside the fibrinous membrane contain a network of fibrin with leucocytes in greater or less abundance. In association with this fibrinous pneumonia, which has been described, hyaline thrombosis of the Capillaries is not uncommon. This hyalin material within the capillaries gives reactions of fibrin, and in sections stained by the Gram-Weigert method for demonstration of fibrin, these thrombosed vessels have the appearance of capillaries ir- regularly injected with a blue material. The interstitial tissue surrounding consolidated lobules is often edematous; the lymphatics are distended with serum and contain a moderate number of lymphocytes and polynuclear leucocytes. Among the lungs which have been studied histologically, pneumococcus has been almost invariably associated with the lobular lesions which have just been described, whether hemorrhagic, leucocytic or fibrinous; the histologic changes accompanying infection of the lung with streptococcus will be described later. Pneumococcus has been cultivated from Table NXNVIII NO. OF AUTOPSY 242 244 247 249 303 314 336 39.1 464 476 498 506 character of lob- ular CONSOLIDATION Red Red Red and gray Red and gray Red and gray Red and gray Red Red Red and gray Red Red Red and gray Bed predominant type op inflammatory exudate Fibrinous Leucocytic and hemorrhagic Fibrinous Fibrinous Fibrinous Leucocytic Fibrinous Fibrinous Fibrinous Leucocytic Leucocytic and hemorrhagic Leucocytic and hemorrhagic Fibrinous Fibrinous CULTURE FROM HEART'S BLOOD Pneum. atyp. II CULTURE FROM LUNG CULTURE FROM BRONCHUS Pneum. IV B. inf. Pneum, IV, B. inf. Pneum. IV Pneum. III Pneum. II B. inf. Pneum. II, B. inf., S. vir. Pneum . I Pneum. IV B. inf. B. inf., staph. rneum. IV, B. inf., staph. Pneum. IV Pneum. IV rneum. IAT, B. inf., staph. Pneum. at yp- ii Pneum. atyp. P'ncum. I B. inf. S. aur. II Pneum. I, B. inf., staph. Pneum. IV Pneum. IV S. aur. Pneum. IV, B. inf., S. aur., M. catarrh 186 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT the consolidated lung and is found in section of the lung. B. influenzae is found in cultures made from the bronchi. Table XXXVIII includes those instances in which the histology of the consolidated lung accords with the descrip- tion given above. Pneumococcus was found in all but 2 instances, and in one of these (Autopsy 336) the only culture was from the, heart's blood and in the other (Autopsy 498) cultures were unsatisfactory because proper media were not obtainable. Pneumococci of Types I, II, II atypical, III and IV are rep- resented in the list. B. influenzae has been found in a con- siderable number of instances in which cultures have been made from the lung and in every instance in which cultures have been made from the bronchi. Staphylococci are often found in the bronchi, but in most instances they do not penetrate into the lung. Another group of cases of lobular pneumonia are im- portant because in association with necrosis of lung tissue recognized by the microscope hemolytic streptococci have been found in the lungs. In such instances serum is abun- dant and polynuclear leucocytes are relatively scant though their distribution varies considerably; in some places leucocytes are fairly abundant though elsewhere al- most absent, but this distribution bears no obvious relation to the bronchioles. In some instances (Autopsies 274 and 487) red blood corpuscles are numerous but in others (Au- topsies 27o and 312) they are inconspicuous. The char- acteristic feature of the lesion is the occurrence of patches of necrosis within which the nuclei both of exudate and of alveolar walls have partially or completely disappeared. In these areas of necrosis short chains of streptococci are found in immense number whereas in living tissue they are present in moderate number. There has been a relatively inactive inflammatory reaction, great proliferation of streptococci and necrosis of invaded tissue. The bacte- riology of instances of lobular pneumonia with necrosis is shown in Table XXXTX, GO O o !* o o H H O < c A < C •J o X H Table XXXIX NO. OF AUTOPSY 274 275 312 478 CHARACTER OF LOB- ULAR CONSOLIDATION Red Red and gray Red and gray Red PREDOMINANT TYPE OF INFLAMMATORY EXUDATE Leucocytic and hemorrhagic Leucocytic Leucocytic Leucocytic and hemorrhagic CULTURE FROM HEART'S BLOOD S. hem, Pneum. IV S. hem. S. hem. S. hem. CULTURE FROM LUNG S. hem. S. hem., B. inf., staph. S. hem., B. inf., S. hem. CULTURE FROM BRONCHUS S. hem., staph. S. hem., B. inf., staph. S. hem., B. inf., staph. 188 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Lobular pneumonia, in some of these instances at least, has been caused primarily by pneumococci; necrosis has been the result of secondary invasion by streptococci. In Autopsy 275 Pneumococcus IV has been obtained from the blood, but in the presence of streptococci has presumably disappeared from the lung and bronchus. In the case rep- resented by Autopsy 274, Pneumococcus IV has been found in the sputum five days before death at the onset of pneu- monia, but at this time no hemolytic streptococci have been found. In the case represented by Autopsy 312, Pneumo- coccus TV, B. influenzae and a few colonies of hemolytic streptococci have been obtained from the sputum two days after recognition of pneumonia and five days before death. The hemorrhagic and edematous consolidation of the early pulmonary lesions of influenzal pneumonia is their most distinctive feature. Ked confluent lobular pneumonia is frequently found in those who have died within the first week following the onset of influenza. The lungs are vol- uminous and heavy and may weigh as much as 1,500 grams; the pleura which overlies the consolidated area is blue or plum colored and usually shows scant if any evidence of pleurisy. Scattered patches of consolidation are accu- rately limited to lobules, but in addition there are large areas often involving the greater part of the lobes and not infrequently situated in the lowermost part of the lower lobes. This confluent consolidation may be obviously lim- ited by lobule boundaries. The consolidated tissue is deep red and laxly consolidated; red serous fluid escapes from the cut surface. The lesion not infrequently occurs in as- sociation with hemorrhagic peribronchiolar pneumonia. The histology of this confluent lesion has been studied in Autopsies 242, 244, 303, 336, 464, 474 and 506. The his- tology varies, because, in some instances, leucocytes, in other instances, fibrin, is abundant, but the presence of red blood corpuscles in large number within the alveoli gives a red color to the consolidated tissue. In these cases pneu- PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 189 niococci, associated in the lungs or in the bronchi with B. influenzae, have been the cause of pneumonia. In two au- topsies studied histologically (Autopsies 274 and 478) there was red lobular and confluent pneumonia and the blood and lungs contain hemolytic streptococci demonstrated by cul- tures ; microscopic examination showed the presence of a widespread necrosis of the lung tissue. In the group of autopsies in Table XL there4 was red con- fluent lobular pneumonia. These autopsies are separated from those just cited because there was no histologic ex- amination of the tissue. TABLE XL BACTERIOLOGY OF BACTERIOLOGY OF BACTERIOLOGY OF HEART S BLOOD LUNGS BRONCHUS TOPSY 289 Pneum. IV Pneum. IV Pneum. IV, B. inf., staph. 297 Pneum. IV, B. inf. Pneum. IV, B. inf., S. hem. (a few) 306 339 Pneum. IV 364 S. hem. 418 Pneum. atvp. II Pneum. atyp. II, B. inf., S. vir. 424 Pneum. IV. This group of autopsies confirms the view that the red confluent lobular pneumonia is caused by pneumococci in association with B. influenzae. Hemolytic streptococci may invade secondarily. In Autopsy 297 a few hemolytic strep- tococci were found in the bronchus but apparently had not entered the lungs. In the absence of histologic examina- tion it is not possible to determine if the invasion of hemo- lytic streptococcus (in Autopsy 364) has caused necrosis of the pneumonic tissue. Peribronchial Hemorrhage and Pneumonia In a considerable number of instances, namely, in 19 au- topsies, hemorrhage about the small bronchi has been rec- ognizable upon gross examination of the lung. A conspicu- ous zone of hemorrhage 2 or 3 mm. in thickness surrounds 190 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT small (with no cartilage) often dilated bronchi and on lon- gitudinal section may be tracted for a considerable distance along the bronchus (Fig. 7). In many additional instances peribronchial hemorrhage has been found by microscopic examination. In some instances the peribronchial zone of hemorrhage is firmer than the tissue elsewhere and it is occasionally difficult to determine whether the lesion is hemorrhage or pneumonia. In 7 instances frank red con- Fig. 7.—Bronchopneumonia with purulent bronchitis and peribronchial hemorrhage. solidation of peribronchial tissue was recognized at au- topsy; this lesion will be considered later under peribron- chial pneumonia. Hemorrhage about bronchi, like other evidences of severe injury to bronchi following influenza, is more frequently found in the lowermost parts of the lungs than elsewhere. It is invariably associated with severe bronchitis; the bronchi have contained purulent PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 191 fluid in 15 of 19 instances of peribronchial hemorrhage and in 10 instances the lesion has been associated with dilata- tion of the bronchi. Microscopic examination furnishes further evidence of the severity of the bronchial changes which have brought about hemorrhage into the surrounding alveoli. The lumen of the bronchus contains blood and leucocytes; the epithe- lium is sometimes raised in places from the underlying basement membrane by blood; blood vessels of the bron- chial wall are engorged, and there is hemorrhage into the tissue of the bronchus. More frequently the bronchial epi- thelium is completely lost and the denuded surface is often covered by a layer of fibrin intimately adherent to the in- flamed mucosa. Transitions between simple hemorrhage and pneumonia are found, polynuclear leucocytes being mingled with red blood corpuscles. In several instances the alveoli in immediate contact with the bronchial wall have contained fibrin, whereas those in the surrounding zone have contained blood. Bacteria found in the bronchi in 10 instances of peri- bronchial hemorrhage have been as follows: Staphylococci ...................................................... 1 B. influenzae, pneumococci ........................................... 1 '' S. hemolyticus ......................................... 2 " pneumococci, staphylococci ............................. 1 '' S. hemolyticus, staphylococci ............................ 4 No organism found.................................................. 1 The high incidence of B. influenza? and the frequent as- sociation of B. influenzas and hemolytic streptococci are noteworthy. The instance in which no organisms were found is probably due to a defect in media and should per- haps be excluded from the list. The percentage incidence of pneumococci, hemolytic streptococci, staphylococci and B. influenzas in the bronchus, lungs and blood of the heart is an index of the facility with which these microorganisms penetrate internal organs when the bronchi are the site of this hemorrhagic lesion. 192 PNEUMONIAS AND INFECTIONS OF RKSP1RATORV TRACT Table XLI in w « o I 6 £ A O PNEUMOCOCCI HEMOLYTIC STREPTOCOCCI STAPHYLO-COCCI B. INFLUENZA Eh X A ^ Eh (-£ b o £ Oh ^ ~20.0 30.8 23.;! Pn Eh ° ? Eh fe 2 ° Pn b . to ° ? Eh Pn fc b P^ Ph O 5 W ? Oh " Pn b Eh . to ° ? Eh W 121 b 03 g Bronchus Lung-Blood 10 13 17 2 4 4 6 7 9 60.0 53.8 52.9 6 3 60.0 23.1 8 5 80.0 38.5 When these figures are compared with those for all forms of bronchitis no very noteworthy differences are found; the incidence of pneumococci here is less and that of hemo- lytic streptococci greater. In association with the severe changes present in the bronchi, hemolytic streptococci which enter the lungs almost invariably find their way into the blood. In 6 instances there has been frank pneumonic consolida- tion limited to a zone encircling small and medium-sized bronchi which have often been obviously dilated. On cross section these patches of pneumonia are circular, from 1 to 2 cm. in diameter and each contains a bronchus at its center. When the bronchus is cut longitudinally it is evident that pneumonic consolidation forms a cylindrical sheath about the tube. The consolidation varies in color from red to grayish red. In one instance (Autopsy 25l>) the consoli- dated tissue has formed a gray zone in contact with the bronchus and is red in a peripheral zone; microscopic ex- amination shows that the alveoli about the bronchus con- tain fibrin, whereas those at a greater distance contain red blood corpuscles. In this instance, the associated pneu- monia in another part of the lung has been somewhat anomalous and has had characters both of lobar and bron- chopneumonia, for scattered in the left lung there have been patches of firm consolidation not more than 2 cm. across. The smaller of these patches are dee]) red, but the larger are coarsely granular and gray in the center. The patchy PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 193 character of the lesion has suggested bronchopneumonia, but the coarse granulation on section and the presence of fibrinous plugs within the small bronchi have presented a close resemblance to lobar pneumonia. This autopsy is one of the few instances in which Pneumococcus II has been found, Pneumococcus II being present in blood and lungs, B. influenzae, in lungs and bronchi. In 2 additional in- stances (Autopsies 374 and 392) peribronchial pneumonia, recognizable at autopsy, has been associated with consoli- dation having the characters of lobar pneumonia. In one instance, Autopsy 371, the right lung has contained two patches of firm, mottled red and pinkish red coarsely gran- ular consolidation each about 6 cm. across, one situated in the upper lobe and the other in the lower lobe. Elsewhere in the lung, in definite relation to dilated bronchi, occur patches of firm, red, coarsely granular consolidation from 1 to 1.5 cm. in diameter when cut transversely. The bron- chus in the center has contained purulent fluid. In the op- posite lung similar consolidation has been limited to zones about dilated bronchi which contain purulent fluid. Pneu- mococcus IV has been obtained from the blood of the heart. The peribronchial pneumonia which has been described occurs in association with evidence of profound injury to the bronchial wall. In 5 of 6 instances purulent bronchitis has been found at autopsy; in half of these instances bron- chiectasis has been noted. The epithelium of the bronchus has been found separated from the underlying tissue by se- rous exudate, blood and leucocytes; epithelial cells undergo necrosis and disappear, the denuded surface being covered by fibrin. Necrosis extends a varying depth into the wall of the bronchus; blood vessels are engorged, and there is in some instances hemorrhage throughout the wall of the bronchus. The character of the exudate in the alveoli surrounding the bronchus differs considerably in different instances. In some instances (Autopsies 374 and 392) red blood cor- 194 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT puscles are predominant in the alveoli in contact with the bronchial wall, whereas in a peripheral zone polynuclear leucocytes are more abundant. In other instances (Autop- sies 253 and 402) alveoli next the bronchial wall contain abundant fibrin and these are surrounded by a zone in which the alveoli are filled with blood. Peribronchial pneumonia is the result of the direct ex- tension of the inflammatory process through the wall of the bronchus; it occurs when the epithelium of the bronchus is destroyed and the underlying tissues are injured, but may be present in a wide encircling zone even when the lesion has not penetrated the bronchial wall. The dis- tribution of the pneumonia demonstrates very clearly that the inflammatory process does not reach the affected peri- bronchial alveoli by way of the bronchioles tributary to the bronchus. The bacteriology of these instances of peribronchial pneumonia is noteworthy. (Table XLII.) Table XLII AUTOPSY BLOOD LUNG BRONCHUS 253 Pneum. II Pneum. II, B. inf. Staph., B. inf. 374 Pneum. IV 387 Pneum. II, S. hem. Pneum. II, staph., Pneum. II, S. hem., B. inf. staph., B. inf., 392 Pneum. II 402 Pneum. IV, S. hem. 424 ? Pneum. IV Pneumococcus has been found in every instance either in the lungs or blood. Pneumococcus II, which has been un- common with the pneumonia following influenza at Camp Pike and has occurred only ten times in more than 200 autopsies, has been present in one-half of these cases. The constant association of the lesion with pneumococcus is particularly significant when a comparison is made between the incidence of pneumococcus with peribronchial hemor- rhage, on the one hand, and peribronchial pneumonia on the other; pneumococcus has been present in less than a third PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 195 of the instances of hemorrhage but in all instances of pneu- monia. In addition to the instances in which gross peribronchial consolidation has been noted at autopsy, microscopic ex- amination has demonstrated the presence of fibrinous pneu- monia surrounding bronchi in a considerable number of autopsies. In a zone encircling small bronchi (with no cartilage) alveoli are filled by plugs of dense fibrin (Fig. 20) containing in variable number polynuclear leucocytes and mononuclear cells. The width of the zone is often equal or greater than the diameter of the bronchus. Alve- oli outside the zone of fibrinous inflammation may contain red blood corpuscles or serum, and desquamated epithelial cells are often abundant. Of 21 instances of peribronchial fibrinous pneumonia 20 were associated with purulent bronchitis. Further evi- dence of the relation of the lesion to profound injury to the bronchi is its association with bronchiectasis in 17 in- stances. Peribronchial fibrinous pneumonia, like other lesions en- circling the small bronchi, bears a direct relation to the severity of microscopic changes in the bronchus. The epi- thelium of the bronchus is either partially or completely lost. Occasionally epithelium is raised by hemorrhage or leucocytes from the underlying tissue but more frequently it is wholly lost and the surface is covered by a layer of fibrin. In the early stages of the lesion, polynuclear leuco- cytes may be numerous throughout the bronchial wall, in- dicating that the inflammatory irritant within the lumen is affecting the entire wall and extending its influence to the surrounding pulmonary tissue. Later lymphoid and plas- ma cells are more abundant than polynuclear leucocytes. Coagulative necrosis and disintegration of the bronchial wall, proceeding from the inner surface outward, may ex- tend more or less deeply, and fibrinous inflammation of adjacent alveoli is often more extensive about that segment 196 PNEUMONIAS AND INF1XTIONS OF RESPIRATORY TRACT of the bronchus which shows the greatest change. In some instances segments of the bronchial wall or even the entire wall has disappeared, so that alveoli containing fibrin form part of the wall of the cavity thus formed. When bron- chiectasis has occurred, there are often fissures from the lumen through the entire wall extending into the surround- ing lung tissue: here fibrinous pneumonia is particularly conspicuous, occurring in a zone about the edges of the defect. This deposition of fibrin within the alveoli adja- cent to the injury doubtless has a part in limiting the dis- tribution of bacterial infection. Xevertheless breaks in the continuity of the bronchial vail are not essential to the production of the lesion and the irritant, which is respon- sible for the lesion, may penetrate through the bronchial wall to surrounding alveoli and from alveoli to other al- veoli immediately adjacent. With this peribronchial pneumonia the smallest bronchi are distended with pus and their walls are infiltrated with polynuclear leucocytes, lymphoid and plasma cells. In a broad zone encircling the bronchus the alveoli are filled with plugs of fibrin. Bronchioles are similarly distended with polynuclear leucocytes; the alveoli which occur upon the wall of the bronchiole are often limited to one side of the wall and are filled with fibrin. This fibrin occasionally projects into the lumen of the bronchiole and forms a con- tinuous layer in contact with the wall on the same side. The alveolar duct and infundibulum are distended with polynuclear leucocytes. The alveoli upon the wall of the alveolar duct and upon the proximal part of the infundib- ulum are filled with fibrin. The bronchus, bronchiole, alveolar duct and part of the infundibulum are thus sur- rounded by a continuous zone of alveoli containing fibrin. The alveoli about the distal part of the infundibulum may be filled with polynuclear leucocytes. Lung tissue between adjacent zones of fibrinous pneumonia may contain serum and desquamated epithelial cells. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 197 Organization of peribronchial fibrin was found in 10 of the 22 autopsies in which peribronchial fibrinous pneu- monia had been found. Fibroblasts have invaded the fibrin and newly formed capillaries have penetrated into it. In some instances the interalveolar septa are thickened and infiltrated with lymphoid and plasma cells, and in 7 in- stances there was chronic pneumonia with thickening and mononuclear infiltration of the interstitial tissue about the bronchi and blood vessels, and elsewhere. The duration of the fatal illness in 12 instances with no organization was usually from ten days to two weeks, though in 3 instances there was no organization although the respiratory disease had lasted from seventeen to nineteen days (average dura- tion with no organization, 13.5 days). The duration of illness in 10 instances with organization of fibrin was slightly less than three weeks (average 18.9 days). These figures do not accurately represent the duration of pneu- monia which usually develops after a period of several days following onset of influenza. This group of instances of peribronchial fibrinous pneu- monia has offered an opportunity to study the bacteriology of pneumonia with organization and to determine if it pre- sents any unusual characters. The bacteriology of autop- sies with peribronchial fibrinous pneumonia with no or- ganization is shown in Table XLIII: Table XLIII AUTOPSY BLOOD LUNG BRONCHUS 289 Pneum. IV P neum. I V Pneum. IV, B. inf., staph. 372 370 S. hem. 8. hem. S. hem., B. inf., S. aur. 409 0 410 »S. hem., B. inf. S. aur. 412 Pneum. II Pneum. II, B. inf. 420 S. hem. S. hem., B. inf. S. aur. 423 S. hem. S. hem., B. inf. 440 0 B. inf., S. aur. B. inf., S. aur. 448 0 0 0 482 0 B. inf., Pneum. IV B. inf., Pneum. IV, S. hem. 489 0 Pneum. IV, B. inf. Pneum. IV, B. inf. 198 PNEUMONIAS AND INFECTIONS OF RESPIRATORY' TRACT The bacteriology of instances of peribronchial fibrinous pneumonia with organization of the intraalveolar fibrin is shown in Table XLIV: Table XLIV AUTOPSY BLOOD LUNG BRONCHUS 283 Pneum. IV Staph., B. inf. B. inf., Pneum. IV, staph, 291 0 0 B. inf., staph. 398 0 419 0 Pneum. II, B. inf. Pneum. II, B. inf. 421 S. hem. Pneum. IV, S. hem. 422 0 Pneum. II atyp., B. inf. 425 S. hem. S. hem., B. inf., S. alb. 433 0 S. hem., B. inf., S. aur. 460 S. hem. S. hem., B. inf. S. hem., B. inf., staph. 463 0 B. inf., staph. B. inf., staph., Pneum. TV B. influenza? has been present in the bronchi in every in- stance save one in which cultures have been made, and it is probable that in this exceptional instance cultures have remained sterile because the media employed have been de- fective. The incidence of B. influenzae in the lung has been unusually high both with and without organization (66.7 per cent with no organization; 77.8 per cent with organ- ization). Streptococci and staphylococci have been found in a considerable proportion of all instances of peribron- chial fibrinous pneumonia, but there has been no notable preponderance of these microorganisms when organiza- tion has occurred. Organization has been present in in- stances in which pneumonia is referable to pneumococcus associated with B. influenza* and unaccompanied by either streptococci or staphylococci (Autopsies 419 and 422). Wadsworth1 found no organization after inoculation of the lungs of dogs with pneumococcus or with staphylococcus alone, but produced organization when he inoculated an- imals Yvith both microorganisms. Injury to bronchi produced in part at least by B. in- fluenzas exposes the bronchi and lung tissue to repeated infection with a variety of microorganisms; absorption of 'Wadsworth, A. B.: A Study of Organizating Pneumonia. Jour. Med. Research, 1918 xxxix, 147. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 199 fibrin and regeneration of alveolar epithelium are pre- vented, resolution fails to occur and organization of fibrin follows. Suppurative Pneumonia With Necrosis and Abscess Formation Three varieties of suppurative pneumonia have occurred in association with influenza. A. Necrosis and suppuration with formation of one or several abscesses usually below the pleura and almost in- variably caused by hemolytic streptococci. B. Interstitial suppurative pneumonia caused by hemo- lytic streptococcus. 0. Multiple abscesses in clusters caused by staphylococci. Suppurative pneumonia with necrosis and abscess for- mation will be discussed in this section. Pulmonary ab- scesses which occurred in 43 autopsies may be included in this group; in 4 of these autopsies abscess and interstitial suppurative pneumonia occurred in the same individual. These abscesses wore much more frequently situated in the lower than in the upper lobes and more often in the right than in the left lung. In most instances there was one or several abscesses situated below the pleura of one lobe; occasionally abscesses occurred in two lobes of the same lung or in both lungs. The distribution Yvas as follows: Abscess in only one lung occurred in right upper lobe in 6 autopsies; middle lobe, 3; lower lobe, 15; left upper lobe, 2; lower lobe, 16. Abscesses occurred in both right and left lower lobes, twice. The usual situation was at the lower and posterior part of the lower lobe at or near the basal edge, less frequently below the posterior border or upon the basal surface of the lobe. These abscesses in almost every instance were found immediately below the pleural surface, so that they appeared upon the pleura as opaque yellow spots usually surrounded by narrow zones of hemorrhage. In one instance (Autopsy 376) the 200 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT abscess cavity was separated from the pleural cavity by remains of the pleura which was as thin as tissue paper and in other instances perforation had occurred (Fig. 9). In Autopsy 480 the abscess cavity which had perforated the pleura was in free communication with a bronchus of me- dium size. In most instances of suppurative pneumonia there have been associated lesions of bronchopneumonia which have been peribronchiolar, hemorrhagic or lobular and have ex- hibited no unusual characters. The abscess or abscesses are situated within an area of pneumonic consolidation which is not limited by lobule boundaries and has not the characters of bronchopneumonic consolidation. In some instances this consolidation is limited to a zone immediately about the abscess, but often it involves the greater part of a lobe. The tissue is laxly consolidated and flabby; on sec- tion it has a dull, conspicuously cloudy appearance and is grayish red, pinkish gray or gray; it is homogeneous or very finely granular. Turbid gray fluid, which sometimes resembles thin pus, oozes from the cut surface. Widespread necrosis of tissue is not infrequently a con- spicuous feature of this pyogenic pneumonia (Fig. 8). Upon a cloudy gray background of consolidation are nu- merous opaque yellowish gray or yellow patches, occasion- ally 2 or 3 cm. across, giving a mottled character to the cut surface. Upon the pleura these necrotic patches ap- pear as dull opaque yellow spots. They may be sur- rounded by a zone of hemorrhage. The opaque material is at first firm but may undergo softening, becoming semi- solid and finally purulent. Necrotic patches may be scat- tered throughout a lobe, but fully formed abscesses are with few exceptions immediately below the pleura (Fig. 9). The duration of illness in cases of pneumonia with ab- scess varied from a week or less (11 instances) to more than four weeks. The duration of the greater number of cases (17 instances) was between one and two weeks. In PATHOLOGY AXTD BACTERIOLOGY FOLLOWING INFLUENZA 201 Fig. 8.—Streptococcus pneumonia with massive necrosis. Autopsy 354. 202 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Fig. 9.—Abscess below pleura with perforation caused by hemolytic streptococci. Heal- oLarTnfa'It h«erStf|al pne,Ton,aA indicated by yellowish gray lines marking inter- lobular septa at base of lower lobe. Autopsy 474; right lung. (See left lung, Fig. 10.) PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 203 one instance onset occurred with symptoms of influenza, pneumonia was recognized two days later, and death oc- curred only four days after the onset of illness. When the duration of the illness was less than a week the symptoms of onset were in some instances those of pneumonia. Table XLY shows the incidence of pneumococcus, S. hem- olyticus, staphylococcus and B. influenza? in instances of suppurative pneumonia with abscess formation, 4 instances of abscess with interstitial suppurative pneumonia being excluded: Table XLV « O H i 1 PNEUMOCOCCI HEMOLYTIC STREPTOCOCCI STAPHYLO-COCCI B. INFLUENZAE > EH d 1 A P- A « A > 5 Eh 63 W w o 3h Ph > EH A ^ 9 ° A Ph 6-1 w A > O H 63 W H O Ph Ph > EH A to 2 ° A Ph 63 W H O Ph Ph > EH 2 ° £ Ph £ IS O £-g to Ph p. Bronchus Lung Blood 24 36 37 5 9 6 20.8 25.0 16.2 22 30 31 91.6 83.3 83.8 12 14 50.0 35.6 18 8 75.0 22.2 In over 80 per cent of instances of pulmonary abscess hemolytic streptococcus has been found in blood, lungs and bronchus and, when cultures have been made, in the in- flamed pleural cavity as well. Streptococci have been found in immense number in sections from the necrotic lung tissue and the abscesses which have been formed. It is evident that hemolytic streptococci have caused suppura- tive pneumonia and death, being found in the blood of the heart just as frequently as in the lungs (83 per cent). The relative unimportance of pneumococci is indicated by their low incidence in the blood (16.2 per cent) when compared with that of lobar pneumonia {67)7) per cent) or of broncho- pneumonia (31.4 per cent). B. influenza? has been found in three-fourths of these autopsies in the bronchus, but its incidence in the lungs has been much smaller. In 3 instances of suppurative pneumonia with abscess formation no hemolytic streptococci were found; they are as follows: 204 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Autopsy 380.—Bronchopneumonia with gray and red lobular consolida- tion in right upper and lower lobes; peribronchiolar nodules of consoli- dation in left lower lobe; abscess, 1.5 cm. across, below the pleura of the posterior border of the left lower lobe near its base; fibrinopurulent pleu- risy (300 c.c.) on right side: serous pleurisy (200 c.c.) on left. Pneumo- coccus III was found in cultures from the blood of the heart from the right lung and with B. influenza; from the right pleural cavity. No culture was made from the left lung which contained the abscess. In sections of the abscess gram-positive streptococci in chains of 4 to 8 cocci were numerous. Autopsy 406.—Acute lobar pneumonia with red hepatization of greater part of right lung; patch of consolidation in lower lobe of left lung con- taining an abscess cavity 2.5 x 1.5 em.; localized seropurulent pleurisy (375 c.c.) on left side. Pneumococcus IV was obtained from the blood of the heart; a culture from the lung was contaminated. Tissue from the abscess was not saved for histologic examination. Autopsy 416.—Suppurative pneumonia with necrosis and abscess forma- tion in right lower lobe; fibrinous pleurisy on right side. Pneumococcus IV was obtained from the blood, right lung and right main bronchus. No streptococci were found in sections from the abscess in the right lung. The foregoing observations demonstrate that suppura- tive pneumonia with abscess formation following influenza is with few exceptions caused by S. hemolyticus. The autopsies (Table XLY1) in which pneumococci have been found in association with hemolytic streptococci in the blood or lungs indicate that pneumococci have had a part in the production of fatal pneumonia. Table XLVI CULTURE FROM AUTOPSY CULTURE FROM BLOOD CULTURE FROM LUNGS BRONCHUS 25 S S. hem. S. hem., Pneum. IV B. inf. 282 S. hem., Pneum. II S. hem., Pneum. II S. hem., B. inf. Pneum. II, staph. 345 S. hem., Pneum. II. staph. 378 Pneum. atyp. II S. hem., Pneum. atyp. S. hem., B. inf., II Pneum. atyp. II 381 S. hem. S. hem., Pneum. II Pneum. TV, staph. 383 Pneum. Ill S. hem.. Pneum. Ill B. inf. 387 S. hem. Pneum. II, staph., S. hem., pneum., B. inf. staph., B. inf. These autopsies, notably those in which pneumococci have been found in the blood, suggest that infection with PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 205 pneumococci has preceded suppurative pneumonia caused by hemolytic streptococci. In a small number of instances the sputum was examined in li fe after onset of pneumonia. Table XLYII AUTOPSY SPUTUM CULTURES FROM BLOOD, LUNHiS AND BRONCHUS 282 288 376 Pneum. IV. B. inf. S. hem., B. inf. (No S. hem., Oct. 8) S. hem., Pneum. II, staph., B. inf. S. hem., B. inf. S. hem., staph., B. inf. (Oct. 11) In 2 of these 3 cases infection with hemolytic streptococ- cus occurred subsequent to the onset of pneumonia. Several observations help to explain the occurrence of abscess in association with the pneumonia of influenza. The fissures which will be described in association with bronchiectasis represent traumatic ruptures of the bron- chial wall consequent upon weakening by necrosis and over distention. They expose the injured bronchial wall and the alveolar tissue adjacent to it to infection by the micro- organisms contained within the lumen of the inflamed bronelius. Occasionally a favorable microscopic section demonstrates the relation of pulmonary necrosis and con- sequent suppuration to injuries of the bronchial wall. Peribronchial fibrinous pneumonia occurs about the bron- chi of which the epithelial lining has been destroyed, and when a fissure penetrates the bronchial wall fibrinous pneu- monia is almost invariably found in a zone about the tear; it doubtless tends to limit the extension of the process. Occasionally, wide areas of necrosis occur within consoli- dated tissue near the site of the fissure (Autopsy 312 with S. hemolyticus and B. influenzas p. 254). Accumulation of polynuclear leucocytes between living and dead tissue may form a line of demarcation (Autopsy 387) ; finally, fairly large, irregularly formed, abscess cavities are found. Necrosis and beginning suppuration in contact with the lumen of the bronchus will be described in association with bronchiectasis (Autopsies 312, Fig. 24, and 423, p. 250). In 206 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT the following autopsies upon individuals who have died with pulmonary abscesses, favorable microscopic sections have demonstrated abscess formation in contact with lesions which have penetrated the Avails of small bronchi. They help to explain the pathogenesis of abscess in association with influenza. Autopsy 376.—H. M., white, aged twenty-four, a fireman, resident of Oklahoma, had been in military service one month. Onset of illness oc- curred October 1, ten days before his death; he was admitted to the base hospital on the fourth day of his illness with the diagnosis of broncho- pneumonia. Anatomic Diagnosis.—Acute bronchopneumonia with patches of lobular and confluent lobular consolidation in both lungs and hemorrhagic peri- bronchiolar consolidation in right upper lobe; abscess in right upper lobe below pleura; fibrinopurulent pleurisy on right side; purulent bronchitis; bronchiectasis at base of left lobe. An irregular abscess, 2x1 cm., filled with creamy purulent fluid is separated from the interlobular surface of the right upper lobe by a thin membrane representing the pleura. The right pleural cavity contains 200 c.c. of turbid yellow fluid in which is soft fibrin. The bronchi contain purulent fluid in great abundance. The bronchi at the base of the left lower lobe are widely dilated, so that many small bronchi with no car- tilage in their wall measure from 3 to 5 mm. in diameter. Cultures show the presence of hemolytic streptococci in the blood of the heart and in three plates from the lung; B. influenza? and S. aureus were found in the left bronchus. The bronchi have wholly or partially lost their epithelium and there is deep erosion of the walls. Cavities containing polynuclear leucocytes occur within the alveolar tissue; in some instances pus containing cav- ities are surrounded by alveolar tissue, but in other places it is evident that they have had their origin in bronchi. In a short segment of the circumference the wall of the preexisting bronchus is preserved and consists of squamous epithelium, vascular connective tissue and smooth muscle. The remainder of the bronchus has disappeared and a cavity is produced. The very irregular wall of the cavity is formed by partially destroyed alveoli filled with fibrin and leucocytes. Autopsy 387.—('. M., white, aged twenty-one, laborer, resident of Miss- issippi, had been in military service twenty-one days. Illness began on September 22, nineteen days before death, and the patient was admitted to the hospital on the same day with a diagnosis of bronchitis; a diagnosis of bronchopneumonia was made on October 2, nine days before death. The leucocytes on October 3 numbered 8000 (small mononuclear, 36 per cent; large mononuclear, 5 per cent; polynuclear, 59 per cent). PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 207 Anatomic Diagnosis.—Acute bronchopneumonia with consolidation in right upper lobe and hemorrhagic peribronchiolar consolidation in left lower lobe; abscess below pleura in left lower lobe; purulent pleurisy on both sides; edema of mediastinum; purulent bronchitis; bronchiectasis. There is advanced bronchiectasis, and bronchi with no visible cartilage are dilated to from 4 to 8 mm. in diameter; they contain purulent fluid which wells up from the cut surface. About dilated bronchi there is in places dull red or grayish red consolidation forming an encircling zone. Situated below the pleural surface within an area of consolidation at the posterior border of the left lower lobe there is a spot 3 cm. across where the tissue is yellow and has in places undergone purulent softening. Sev- eral smaller abscesses occur nearby. Cultures from the blood of the heart and from the edematous medias- tinum contain hemolytic streptococci. From the abscess are grown S. albus, Pneumococcus II and B. influenzae. The purulent contents of a small bronchus contains S. hemolyticus, B. influenza1, S. aurens and a few pneumo- cocci. Microscopic examination shows that the epithelium of dilated bronchi has disappeared and the denuded surface is covered by fibrin and polynuclear leucocytes; fissures extend from the lumen through the bronchial wall into the surrounding alveolar tissue. A zone of fibrinous pneumonia surrounds these bronchi and fissures in the bronchial wall penetrate into this zone. One dilated bronchus 2.4 mm. in diameter with no cartilage in its wall has vascular connective tissue covered by epithelium on one side, whereas the remainder of the circumference is formed by exposed alveoli filled with fibrin, the bronchial wall having disappeared. A section through a part of the abscess which has been mentioned shows a very irregularly formed cavity approximately 1 x 0.7 cm. Remains of bronchial wall, consisting of very vascular tissue covered by flat epithelium in several layers, indicate the origin of the cavity. Between these remnants of bronchi deep pockets extend into the pulmonary tissue which in the margin of the cavity is the site of fibrinous pneumonia. In one place, in contact with the cavity, a wide area of consolidated tissue has undergone necrosis and both alveolar walls and their contents have lost their nuclei. Leucocytes which are accumulating at the margin of the necrotic patch form a line of demarca- tion between living and dead tissue. Abscess may be the result of the profound changes which occur in the bronchi as the result of influenza. Necrosis caused by bacteria within the bronchi weakens and in places destroys the wall. Bacteria penetrate into the sur- rounding tissue and hemolytic streptococci (or staphylo- cocci) may produce localized abscesses. These abscesses are usually situated near the pleural surface of the lung, be- cause destructive changes causing rupture of the bronchial 208 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT wall occur more frequently in the smaller peripheral bron- chi than in the larger bronchi containing cartilage. Ab- scesses occur more frequently at the bases of the lungs, because the most severe changes in the bronchi occur in the dependent part. (See "Bronchiectasis," p. 240.) Healing of Abscess.—The following autopsy is of interest in relation to the treatment of pulmonary abscess and as- sociated empyema. Autopsy 467.—P. (\, white, aged twenty-five, a farmer from Missouri, had been in military service three months. Illness began September 27, thirty days before death, and the patient was admitted the day following onset with headache, backache and cough. Pneumonia with consolidation in the right lower lobe was recognized on the sixth day of illness. On the ninth day 500 c.c. of fluid were withdrawn from the right pleural cavity; there were cyanosis and dyspnea. On the eleventh day 700 c.c. of fluid were withdrawn. On the twelfth day thoracotomy was performed and 100 c.c. of greenish fluid were removed. The patient's condition improved for a time, but on the twenty-sixth day 1,000 c.c. of straw colored fluid were aspirated from the left pleural cavity and on the twenty-eighth day the same amount of seropurulent fluid was withdrawn. Anatomic Diagnosis.—Healing abscess of right lower lobe communicating with the pleural cavity; acute purulent pleurisy with closed thoracotomy tvound on the right side; purulent pleurisy on the left side; acute broncho- pneumonia with lobular consolidation in the left lung; purulent bronchitis; bronchiectasis with formation of spherical bronchiectatic cavities; acute splenic tumor. At the base of the right chest is a closed thoracotomy wound 2 cm. in length; the right pleural cavity contains 200 c.c. of thick creamy pus nnd the cavity is lined by a thick tough membrane. The left pleural cav- ity contains 800 c.c. of white purulent fluid thinner than that on the right side. The right lung is compressed into the posterior and inner part of the chest. The upper lobe is pink and air containing; the posterior and lower part of the lower lobe is red and atelectatic, and fibrous septa are more conspicuous than elsewhere. The pleura of the external surface near the basal edge, in an area 2 cm. across, is depressed and yellowish gray in color. In the center of this area is a small opening communicating with a pocket 0.5 cm. across within the substance of the lung. In the lower lobe beneath the interlobular surface are two spherical bronchiectatic cavities, each about 1.5 cm. across, with smooth lining in continuity with two branches of the same bronchus of medium size. Bacteriologic examination showed the presence of S. hemolyticus in the blood of the heart. No growth was obtained from the left lung; the left pleural cavity contained hemolytic streptococci and S. aureus, the latter in PATHOLOGY AXTD BACTERIOLOGY FOLLOWING INFLUENZA 209 small number. S. hemolyticus and B. influenzae were grown from the left main bronchus. A microscopic section through the abscess and its communication with the pleura shows that its cavity contains polynuclear leucocytes and the wall is formed by granulation tissue covered by fibrin. Some alveoli out- side the abscess contain compact balls of fibrin containing a few fibroblasts; this fibrin stains deeply with hematoxylin as if it contained calcium. The surface of the lung is covered by fibrin in process of organization. In the foregoing instance a pulmonary abscess on the right side has ruptured into the pleura and, completely separated from the adjacent lung by a Avail of newly formed tissue, is in process of healing. It shows that these pul- monary abscesses below the pleura may heal provided drainage is established by rupture into the pleural cavity and subsequent evacuation of pleural exudate. It is note- worthy that in this instance empyema extended from the right to the left pleural cavity, both S. hemolyticus and S. aureus were found at autopsy. The thoracotomy wound on the right side was closed at autopsy. Interstitial Suppurative Pneumonia A second type of suppurative pneumonia is characterized by acute inflammation of interstitial tissue between the sec- ondary lobules of the lung and by acute lymphangitis; sup- puration involves the interstitial septa and the walls of the lymphatics. The lesion is designated by Kaufmann,1 Beitzke2 and others acute interstitial pneumonia. Pneu- monia dissecans in which solution of interstitial tissue iso- lates sections of lung tissue is said to be a consequence of the lesion. Many text books of pathology, overlooking the occurrence of this lesion, limit the consideration of in- terstitial pneumonia to chronic processes in which the in- terlobular and interalveolar fibrous tissue is increased. Acute inflammation and edema of the interlobular septa of the lung with no suppuration is often found with both lobar and bronchopneumonia and is occasionally so far ad- 1Kaufmann: Srezielle Pathologische Anatomic 1909, ed. 5, p. 260. 2Beitzke: Respirations Organe. Aschoff's Path. Anat., 1913 ed. 3, Vol. II, p. 308. 210 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT vanced that it can be recognized on gross examination of the lungs. In a small area interlobular septa are conspicu- ous as yellowish lines of edematous appearance which may lie 1 to 1.5 mm. in thickness and sometimes form a network with rectangular or polygonal meshes. The gelatinous ap- pearance of the edematous fibrous tissue does not suggest suppuration. Microscopic examination shows that the tissue is distended by edema and contains fibrin and poly- nuclear leucocytes; the lymphatics are distended and con- tain a network of fibrin within which leucocytes are nu- merous. Inflammatory edema of the interstitial tissue has been recognized at autopsy four times in association with bronchopneumonia (Autopsy 253 with Pneumococcus II; Autopsy 335, with Pneumococcus TV and S. viridans; Au- topsy 477 with S. hemolyticus and Autopsy 498 with S. viridans); twice with lobar pneumonia (Autopsy 343 with Pneumococcus IV and Autopsy 353 with atypical Pneu- mococcus II) ; twice with combined lobar and broncopneu- monia (Autopsy 273 with S. hemolyticus and Pneumococcus IV and Autopsy 357 with Pneumococcus IV). Edema of interstitial septa was recognized at autopsy in the imme- diate neighborhood of an abscess three times (Autopsies 277 and 278 with hemolytic streptococci and Autopsy 282 with hemolytic streptococci and Pneumococcus II). In these instances of inflammation and edema the lymphatics are found distended by fibrinous thrombi, and it is probable that occlusion of lymphatics determines the occurrence of inflammatory edema within the surrounding tissue. In- flammation has not proceeded to suppuration. With interstitial suppurative pneumonia, interlobular connective tissue is marked by conspicuous yellow lines, 1 to 3 or even 5 mm. in thickness, forming a network with polygonal meshes which represent secondary lobules (Figs. 10 and 11). The distended septa, not infrequently have bead-like enlargements at intervals and from the cut sur- face it is often possible to scrape away creamy yellow pus. PATHOLOGY AND BACTERIOLOGY FOLLOWING INTLLEXZA 211 Fig. 10.—Interstitial suppurative pneumonia; interstitial septa are the site of suppura- tion and lymphatics are distended with purulent fluid; empyema. Autopsy 474, left lung. i,Sce right lung; Fig. 9. 212 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT „,,i£rgm LT.^iT* J" erstlt.lal pneumonia; the left lower lobe is the site of almost umform consolidation and here interstitial septa and their lymphatics are distended with frZ'in,, ur»h«,pnIn0Ti.eXtV1S'Te mterstltlaI suppuration in the upper lobe where consol- opsy 452 " y appearance of the consolidated lung is well shown. Au PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 213 These lines of suppuration invariably extend up to the pleura and are often broadest immediately below it. Adja- cent septa which have not undergone suppuration are much thickened and have the yellowish gray appearance produced by edema. Suppurative interstitial pneumonia frequently occurs in association with bronchopneumonic consolidation which may be peribronchiolar, hemorrhagic or lobular, but there is in addition consolidation of the pulmonary tissue between the inflamed septa which may affect part of a lobe, an en- tire lobe, or parts of several lobes; it does not exhibit the characters of confluent lobular pneumonia. In approximately half of the cases consolidation, asso- ciated with interstitial suppuration, has been lobar in dis- tribution (Fig. 11). The tissue is laxly consolidated, finely granular, and has a cloudy red or gray appearance. The coarsely granular surface of lobar pneumonia is absent. The affected lung may weigh 1,500 or 1,650 grams. Oc- casionally, interstitial septa of air containing lung tissue is the site of suppurative inflammation or edema. In Autopsy 452 the lower lobe, save a small part at the base, is laxly consolidated; interstitial septa in the consolidated area are yellow, 1.5 to 2 mm. in thickness, beaded and ex- ude purulent fluid on pressure. In the adjacent part of the upper lobe there is a patch of consolidation, and a net- work of yellow thickened septa extends from it far into the surrounding air containing tissue. The weight of the right lung is 635 grams; of the left, 1,650 grams. The distribution of interstitial suppuration in 21 in- stances, including 4 in which the lesion has occurred in the same lungs with abscess formation, has been as follows: right upper lobe, 9 instances; middle lobe, 4; lower lobe, 5; left upper lobe, 7; left lower lobe, 6. In 6 of these autop- sies more than one lobe of the same lung has been affected by the lesion; in 2 autopsies parts of both lungs have been affected. Localized abscess of the lung is more common in 214 PNEUMONIAS AND INFKA'TIONS OF RESPIRATORY TRACT the lower than in the upper lobes, but suppuration of the interstitial tissue is more often found in the upper lobes. The duration of illness with interstitial suppurative pneumonia has varied from six days to five weeks. In over half of the cases death has occurred during the second week of illness. The bacteriology of these cases is shown in Table XLVIII. Table XLVIII HEMOLYTIC STAPHYLO- PNEUMOCOCCI B. INFLUE m STREPTOCOCCI COCCI w Eh W W Eh H K Eh K W Eh K fe p > A > A > £ > > ^ > O E- Eh Eh Eh o 5 H 5 £3 O p 03 * § . w « O . c/". « g 03 »3 $2 A o <=> ? o ? o o o ? A ^ £ ^ £ Ph £ ^ A £■ Oh -1 A ^ £ p- Bronchus 10 9 90.0 5 50.0 10 100.0 Lung 20 1 5.0 17 85.0 5 25.0 7 35.0 Blood 21 2 9.5 17 81.0 S. hemolyticus has been almost invariably present in lungs, heart's blood and bronchi. In 16 of 21 autopsies hemolytic streptococci have been obtained from the blood in pure cultures, in one instance associated with pneumo- coccus. "With associated empyema, pericarditis or peri- tonitis, the same microorganism has been found in the pleural cavities, pericardium or peritoneum. Further- more, microscopic examination has demonstrated the pres- ence of chains of streptococci in the affected interlobular tissue and in much greater abundance in the distended lymphatics. Nevertheless in 2 instances no streptococci have been found. These cases are as follows: Autopsy 330.—Illness began with symptoms of influenza ten days before death; signs of pneumonia were recognized three days before death. There is firm, gray red consolidation of the entire left upper lobe; the interlobular septa are here indicated by yellow lines of obvious suppuration and thick pus- like fluid exudes from the cut surface of the consolidated tissue. The upper half of the left lower lobe has undergone gray hepatization, but here there is no distention of the interlobular septa. There is fibrinopurulcnt pleurisy on the left side with accumulation of 400 c.c. of fluid. Pneumococcus IV is PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 215 obtained from the blood of the heart and from the lung. In the suppurating tissue diplococci which stain by Gram's method are present in large number; there are a few short chains. Autopsy 379.—Illness began seven days before death with influenza; signs of pneumonia were first recognized the day before death. The middle lobe of the right lung is firmly consolidated; on section there is mottling of deep red and pinkish red and the cut surface is coarsely granular. The inter- stitial septa are distended by fluid and are grayish yellow. There is fibrino- purulent pleurisy on the right side with accumulation of 600 c.c. of fluid. Pneumococcus atypical II is obtained from the blood of the heart. A large bacillus unstained by Gram \s method is obtained from the right lung and from the right main bronchus. In the bronchus are a few influenza bacilli. In the suppurating and necrotic tissue of the interstitial septa are found diplococci and chains of 4 to 6 cocci in great number; a few large Gram-negative bacilli are found. Ill both these autopsies consolidation had the characters of lobar pneumonia, and pneumococci were obtained from the blood of the heart. It is possible that streptococci failed to grow or while present elsewhere were absent at the spot where cultures were made. It is noteworthy that B. influenzae was found in the bron- chi in every instance (10) in which cultures were made, but was obtained much less frequently from the lung. In one instance (Autopsy 471) this microorganism was found in the blood in association with hemolytic streptococci. There was suppurative interstitial pneumonia in the left lung and abscess in the right lower lobe with rupture into the cavity and empyema. Hemolytic streptococci and B. influenzae were1 found in the bronchus, right pleural cavity and blood of the heart. In 4 instances (Autopsies 251, 25!), 295 and 474) inter- stitial suppurative pneumonia has been associated with abscess formation. In one instance (Autopsy 251) the right middle lobe has been the site of interstitial suppura- tion and abscess formation; in another (Autopsy 295) the left lower lobe has been the site of both lesions, but in the other 2 instances suppurative interstitial pneumonia and abscess formation have occurred in opposite lungs. In all 216 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT 4 autopsies hemolytic streptococci have been found in the blood of the heart and in lungs or bronchi. Empyema has been present in all but 3 of 21 instances of interstitial suppurative pneumonia. Histologic examination of lungs with interstitial sup- puration shows that the interlobular septa are distended by serum and contain a conspicuous network of fibrin. Poly- pi?:. 12.—Suppurative interstitial pneumonia, showing an immensely dilated lymphatic containing purulent exudate, a short distance below the pleura. Autopsy 474. nuclear leucocytes are present in varying number, and at times densely infiltrate the distended tissue; it is not un- common to find a zone of densely crowded polynuclear leu- cocytes along each edge of the septum, whereas the central part contains comparatively few. Occasionally, there is hemorrhage into the distended connective tissue. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 217 Within the distended septa occur greatly dilated lym- phatics filled with polynuclear leucocytes (Figs. 12 and 13). Thrombosis of the distended lymphatics has usually oc- curred, and a conspicuous network of fibrin in which are polynuclear leucocytes plugs the- lumen. Streptococci in chains of variable length are found in the inflamed inter- stitial tissue, but are present in far greater number within the distended lymphatics. Fig. 13.—Suppurative interstitial pneumonia showing a dilated lymphatic. Autopsy 428 Xecrosis of the cells which fill the lymphatics occurs in spots, usually in the center of the thrombus, and occasion- ally affects the entire contents of the lymphatic; polynu- clear leucocytes have lost their nuclei or in some the nu- cleus has undergone fragmentation. In these spots the net- work of fibrin has disappeared. Xot infrequently the wall of the lymphatic in a small sector or throughout the cir- 218 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT cumference has undergone necrosis, and spots of necrosis may occur in the interlobular septa distended by inflam- matory exudate. AVherever necrosis has occurred, chains of streptococci are present in immense number. Accumulation of polynuclear leucocytes, necrosis of these cells, solution of fibrin at first in the centers of the lym- phatic thrombus and later throughout, occasionally with necrosis of the wall of the vessel, result in the formation of an abscess at the site of the distended lymphatic. These lymphatics, dilated by purulent fluid, may have a diameter from 2 to 3 mm. and may cause considerable compression and collapse of immediately adjacent alveoli. Lymphan- gitis, distention of lymphatics, thrombosis and finally sup- puration may occur in the lymphatic vessels encircling the blood vessels and in those situated in the adventitia of the bronchi of medium size. The alveoli adjacent to the distended septa are filled by inflammatory products; edema is almost invariably pres- ent and the alveoli may contain serum and desquamated epithelial cells; fibrin is often present, but more frequently polynuclear leucocytes are predominant. Xot infrequently, abscess formation, recognized microscopically, has oc- curred in contact with septa most often immediately below the pleura. Polynuclear leucocytes are present in immense number and alveolar septa have disappeared; occasionally, with abscess formation there is more or less widespread necrosis of tissue, cells both of the exudate and of the alve- olar walls having lost their nuclei. Lymphatics in many places are distended and plugged by fibrinous thrombi, whereas elsewhere softening of the thrombus has been brought about by suppuration. Sup- puration, both within the lymphatic and in adjacent alve- oli, appears to be secondary to lymphatic obstruction. In some instances the lymphatic appears to have undergone distention after the thrombus has formed, for between the PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 219 thrombus and the wall of the lymphatic a channel is occa- sionally found containing nncoagulated lymph. Acute endophlebitis has been repeatedly observed in as- sociation with interstitial suppurative pneumonia (Fig. 14). The lesion usually occurs in veins situated within the septa which are the site of intensely acute inflammation associated with necrosis. The wall of the vein appears to be so injured by the surrounding changes that polynuclear Fig. 14.—Endophlebitis occurring in association with suppurative pneumonia; the intim'a contains lymphoid cells in great number; at one spot there is a small thrombus adherent to the intima. Autopsy 325. leucocytes and small mononuclear cells accumulate below the endothelium. Throughout the circumference of the veins, often 0.5 to 1 mm. in diameter, the endothelium is separated from the underlying media by polynuclear leu- cocytes which form a conspicuous zone encircling the lu- men. Some cells of lymphoid type are usually present among the polynuclear leucocytes. Polynuclear leucocytes 220 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT are often adherent to the endothelial lining of the vessel and are not infrequently fixed in the process of passing through the endothelium. The lesion may be more severe (Autopsy 325), so that the endothelium has disappeared, and upon the exposed surface fibrin is deposited; within this fibrin polynuclear leucocytes are numerous and nu- clear fragmentation has occurred. The middle coat of the vessel usually contains few cells; some polynuclear leuco- cytes within it may be stretched out as if in process of wan- dering through the wall. In other instances the accumulation of cells below the endothelium is almost wholly mononuclear. Cells of the type of lymphocytes occur, but more abundant are slightly larger cells with more abundant cytoplasm. These cells may form a thick zone below the intima throughout the en- tire circumference of the lesion. It seems probable that these cells, like the polynuclear leucocytes, are derived from circulating blood within the lumen of the vessel, for small cells of the type of lymphocytes are not infrequently found adherent to the lumen and occasionally one is fixed in process of passing through the endothelium. This endophlebitis appears to be the result of changes outside the vessel; there is usually necrosis of the adjacent tissue and the production of the lesion is favored by lymph stasis; as the result of injury to the vessel wall, polynuclear leucocytes in response to chemotaxis, or with milder irrita- tion, mononuclear cells, wander through the endothelium and accumulate below it perhaps on account of the greater impermeability of the middle coat to the passage of cells. The lesion described does not occur exclusively with in- terstitial suppurative pneumonia caused by hemolytic streptococci, but has been found in association with abscess formation (Autopsies 354 and 383) caused by hemolytic streptococci or (Autopsy 322) caused by staphylococci. In 1 instance it has been found with lobar pneumonia (Au- topsy 320) caused by atypical Pneumococcus II and in 2 PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 221 instances with combined lobar and bronchopneumonia (Autopsy 357 with Pneumococcus IV; Autopsy 392 with Pneumococcus II). In these 3 instances there has been in- terstitial inflammation, edema and lymphangitis without suppuration. Interstitial suppurative pneumonia of long standing may occasionally be accompanied by chronic changes which bring about thickening of the interlobular tissue. In the following autopsy acute suppurative inflammation in the left lung has been associated with conspicuous thickening of interlobular septa in the right lung. Autopsy -174.—I. H., white, aged twenty-one, was a native of Oklahoma and had been in military service one month. His illness began with influenza thirty-six days before death; he was admitted to the base hospital thirty-one days before his death with signs of pneumonic consolidation of the right lower lobe. Evidence of fluid in the right pleural cavity was obtained two weeks before death, and from 100 to 700 c.c. of thick purulent fluid were as- pirated on five occasions. Hemolytic streptococci were found in the aspirated fluid. Anatomic Diagnosis.—Interstitial suppurative pneumonia in left lung; abscess of right lower lobe with rupture into pleural cavity; thickening of interlobular septa of right lower lobe; double purulent pleurisy with thorac- otomy on right side; serofibrinous pericarditis. The right pleural cavity contains 85 c.c. of thick purulent fluid; the right lung (Fig. 9) is collapsed and pushed to the median line, being bound by firm adhesions to the pericar- dium. Over the external and basal surfaces is a localized cavity walled off by adhesions. An abscess cavity in the lower part of the lower lobe communicates through a per- foration in the basal surface of the lung with the pleural cavity and is in free communication with a small bronchus. About the abscess the lung is red and laxly consolidated, but elsewhere air containing; throughout the lower half of the lower lobe, the interlobular septa are marked by con- spicuous yellowish gray lines about 1 mm. in thickness. Between these thickened septa the lung tissue contains air. The lung weighs 600 grams. The left lung (Fig. 10) is vo- luminous and heavy, weighing 1,320 grams. The surface is 222 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT everywhere covered by thickened pleura and fibrin, the pleural cavity containing 150 c.c. of thick purulent fluid. The lung is consolidated varying in color from a fleshy red to yellowish gray. The surface is very conspicuously marked by 3^ellow lines 2 or 3 mm. thick, corresponding to the interlobular septa which have undergone suppuration. The septa have bead-like swellings along their course, and when pus escapes from the cut surface small cavities re- main at the site of these swellings. Bacteriologic examination has shown hemolytic strepto- cocci in the blood, left lung, right and left pleural cavities, and right bronchus. B. influenza* has been found in the bronchus, in the right pleura and in the heart's blood. A few colonies of S. aureus have been found on the plate from the right pleural cavity (site of thoracotomy). Microscopic examination of the right lower lobe shows that the interstitial septa are much thickened by young fibrous tissue infiltrated with lymphoid and a few plasma cells. Large mononuclear cells with granular cytoplasm are very numerous. A lymphatic is much distended and con- tains a few polynuclear leucocytes and many lymphoid and large mononuclear cells. There is no suppuration. Sec- tions from the right lung show suppurative lymphangitis with suppurative inflammation of interstitial tissue. The right lung is the site of a healing lesion of the inter- stitial tissue which has developed simultaneously with acute interstitial suppurative pneumonia in the left lung. Both lesions are doubtless caused by S. hemolyticus. This healing lesion exhibits little similarity to the interstitial bronchopneumonia described by several observers with both measles and influenza. The following autopsy furnishes further evidence that interstitial suppurative pneumonia exhibits a tendency to heal. Proliferation of endothelial cells lining the inflamed lymphatics gives rise to phagocytic cells which aid in re- moving the accumulated leucocytes. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 223 Autopsy 397.—N. P., white, aged twenty-one, farmer, a native of Okla- homa, had been in military service twenty-one days. Illness began twenty-two days before death, the patient being admitted on the day following onset with influenza, pharyngitis and bronchitis. A diagnosis of lobar pneumonia was made fourteen days before death. The left pleural cavity was aspirated twelve days later and S00 c.c. of thick yellow pus were withdrawn. Hemolytic streptococci were found in the sputum five days before death. Anatomic Diagnosis.—Interstitial suppurative pneumonia in left upper lobe; acute bronchopneumonia with lobular consolidation in right upper lobe; localized purulent pleurisy on left side with compression and atelectasis of left lung; compensatory emphysema of right lung; purulent bronchitis; be- ginning serofibrinous pericarditis; chronic passive congestion of liver, spleen and kidneys. The right lung is very voluminous, free from coal pigment and bright pink save over lobular patches of consolidation which have a bluish red color; the bronchi contain mucopurulent material. The anterior surface of the left lung is bound to the chest wall by firm adhesions, but over the external and posterior surfaces of the lung there is a localized cavity containing 1,100 c.c. of turbid fluid. The left lung is collapsed and airless with deep fleshy red color. In the upper lobe there are scattered patches of consolidation 1.5 to 2.5 cm. across where the tissue is grayish red and coarsely granular. In the adjacent tissue interstitial septa are thickened to 1 or 2 mm. and are con- spicuous as gray bands. Along their course occur bead-like swellings from which purulent fluid can be scraped. These septa at one point reach the anterior surface of the lung where the pleural cavity is in large part obliter- ated by adhesions; here there is an encapsulated pocket 4 x 1.5 em. con- taining thick creamy pus. Bacteriologic examination of the blood shows the presence of hemolytic streptococci; cultures from the lungs contain hemolytic streptococci and B. influenzae. Microscopic examination shows that interlobular septa are thickened and infiltrated with plasma cells in large number. Leucocytes in the center of much dilated lymphatics have undergone necrosis and have lost their nuclear stain. About the periphery of the lumen and evidently derived from the swollen endothelial cells which surround it, are numerous large mononuclear cells. They act as phagocytes and ingest polynuclear leucocytes. Multinu- cleated giant cells, derived from these cells, occur. In several places throm- bosed lymphatics in process of organization occur; the lumen is filled with compact fibrin which is invaded by fibroblasts and newly formed capillaries. The process just described is analogous to that which oc- curs whenever an unopened abscess heals; mononuclear cells accumulate and act as phagocytes ingesting polynu- clear leucocytes. 224 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT The following instance of streptococcus empyema is note- worthy because no suppurative pneumonia has been found in association with it. Nevertheless the character of the changes present in the lung indicate that the organ has been the site of an interlobular inflammation which has healed. Autopsy 499.—J. H. M., white, aged twenty-four, a farmer from Arkan- sas, had been in military service five months. Onset of illness began two weeks before his admission to the hospital on November 15 with cough, fever, headache and malaise; on admission there was acute bronchitis. Thirteen days after admission the patient developed parotitis (mumps?) ; five days later and five days before death pleurisy was recognized on the right side and pneumonia was suspected. Death occurred thirty-six days after onset. The temperature on admission was 103.2° F. and remained elevated during one week falling by lysis; from this time until the pleurisy was recognized it was normal and later it remained approximately 103° F. Anatomic Diagnosis.—Fibrinopurulent pleurisy on right side; fibrinous pleurisy on left side; fibrinopurulent pericarditis; chronic interstitial (inter- lobular) pneumonia in process of healing; purulent bronchitis; acute splenic tumor; parenchymatous degeneration of kidneys. The right pleural cavity contains 1,650 c.c. of grayish yellow fluid con- taining an abundant sediment of softened fibrin. Part of this fluid, more opaque than the remainder is confined in a localized pocket between the inner surface of the lung and the pericardium. The apex and anterior surface of the right upper lobe, over an area about 7 cm. across, is held by fibrinous adhesions to the chest wall; when this adhesion is broken a pocket is exposed (1.5 x 2.5 cm. containing fibrin and fluid. The pericardial cavity is distended by 350 c.c. of turbid yellow seropurulent fluid. The pericardial surfaces are covered by shaggy, tough gray fibrin. The right lung is collapsed; the lower and posterior part of the upper lobe is deep red and atelectatic. Throughout the upper lobe the interlobular septa are thickened, often 1 mm. across and very conspicuous; in the lower and anterior tip of the lobe is an area where tissue is firm grayish red and heavier than water. The lower and posterior half of the right lower lobe is firm and airless, and the tissue is reddish gray or gray and in places finely granular on section; interlobular septa are conspicuous. Although the lung is cut into thin sections, no abscesses are found. Bronchi throughout the lung contain mucopurulent fluid. The left lung over its lower half is covered by a thin layer of fibrin. The tissue is crepitant throughout and moderately edematous. Bronchi contain mucopurulent fluid. Hemolytic streptococci in pure culture are obtained from the blood of the heart, right pleural cavity and pericardium. No growth is obtained on a plate inoculated with material from the right lower lobe. The right bronchus contains hemolytic streptococci and B. influenzas. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 225 The pleural surface of the right lung is covered by a thick layer of fibrin which has undergone advanced organization. Fibrous septa within the lung are much thickened by the presence of newly formed fibrous tissue; the in- terstices of the tissue are distended and contain fibrin into which fibroblasts and new blood vessels have penetrated. Some lymphatics are plugged with fibrin and contain polynuclear leucocytes, lymphoid and large mononuclear cells. In several places organization of these thrombi is beginning. About the blood vessels are thrombosed lymphatics in which polynuclear leucocytes and mononuclear cells, are equally abundant. Alveoli immediately adjacent to blood vessels and to fibrous septa often contain fibrin, and alveoli elsewhere contain desquamated cells in abundance. Iii association with hemolytic streptococci in the blood, pleura and pericardium, there has been inflammation of the interlobular septa of the lungs with acute lymphangitis; there has been no suppuration and the lesion is in process of healing with new formation of fibrous tissue. It is evi- dent that this lesion, as well as pleurisy with advanced or- ganization, preceded the exacerbation of the patient's ill- ness which occurred five days before death. The advanced chronic changes found at autopsy indicate that the pul- monary and pleural lesions had their origin during the illness which was present at the time of admission to the hospital. Interstitial pneumonia caused by hemolytic streptococci was of mild character and did not produce suppuration within the lung; nevertheless, hemolytic strep- tococci which reached the pleura caused empyema. Suppurative Pneumonia with Multiple Clustered Abscesses Caused by Staphylococci In the preliminary report of this commission published in The Journal of the America)) Medical Association, loc. cit., pg. Ill, we described suppurative pneumonia with mul- tiple abscesses caused by staphylococci and cited 4 instances of the lesion which followed influenza. Chickering and Park4 published in a subsequent number of the same journal 4Chickering, H. T. and Park, J. IP: Staphylococcus Aureus Pneumonia, Jour. Am. Med. Assn. 1919, lxxii, 617. 22G PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT an account of staphylococcus pneumonia, a lesion which has heretofore attracted very little attention. In a small group of cases abscesses in the lungs have had characters which serve to distinguish them from the ab- scesses previously described. Small, sharply circumscribed yellow nodules, which in their centers have undergone sup- purative softening, form a cluster upon a red, airless back- ground (Figs. 15 and 16). One or more of these groups several centimeters across, occur in the lungs. It is usually evident that the abscesses are clustered about a medium- sized bronchus, but occasionally with increase in the size of the small cavities the lung tissue assumes a honey-combed appearance. These clustered abscesses occur in association with bron- chopneumonia and have been in all instances associated with purulent bronchitis. The mucosa of the small bronchi may be destroyed so that the surface is eroded. These small clustered abscesses are seen as conspicuous yellow spots immediately below the pleura, but there has been no associated empyema. In 2 instances these abscesses were accompanied by fibrinous pleurisy, but in the remaining au- topsies the pleura has been normal. The infrequency of empyema is in contrast with its almost invariable presence when a streptococcus abscess is found below the pleura. Autopsy 280.—Onset of illness with malaise, headache, cough and fever was on September 24, eight days before death. At autopsy there were hem- orrhagic peribronchiolar and lobular bronchopneumonia, clustered foci of sup- puration in right lung, purulent bronchitis and fibrinous pleurisy. Hemo- lytic streptococci were obtained from the consolidated lung and from a bronchus. A culture from the right lung was contaminated. In the bronchus were found B. influenzae and a few staphylococci. Microscopic examination of the abscesses shows that they contain Gram-staining cocci grouped into staphylococeus-like colonies. Autopsy 286.—Duration of illness, which began September 25 with symptoms of influenza, was nine days. At autopsy there were lobular and confluent patches of bronchopneumonia, clustered abscesses in the right lung below the pleura, purulent bronchitis, and serofibrinous pleurisy localized in the neighborhood of the abscesses. Pneumococcus IV was obtained from the blood of the heart, and Pneumococcus IV, staphylococci and B. influenzas from the right main bronchus; growth failed to occur on plates from right PATHOLOGY AND BACTEltlOLOGY FOLLOWING INFLUENZA 227 Fig. IS.—Abscesses in two clusters caused by S. aureus in upper part of right upper lobe; confluent lobular consolidation in lower part of lobe. Autopsy 333. 22S PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT and left lungs. Microscopic examination shows the presence of clumps of cocci with staphylococcus grouping in the centers of the small abscesses. Section through one abscess shows its continuity with the wall of a bronchus; along one side of the abscess is epithelium composed of flattened epithelial cells in multiple layers continuous with that of the bronchus; the remainder of the abscess wall is formed by disintegrated lung tissue. Autopsy 322.—The patient was admitted with influenza eight days be- fore death; signs of pneumonia appeared two days later, and on the follow- ing day Pneumococcus IV was obtained from the sputum. At autopsy Fig. 16.—Abscesses in cluster caused by S. aureus at apex of right upper lobe. Autopsy 322. there were bronchopneumonia with lobar consolidation, abscesses clustered about a bronchus in the right upper lobe and purulent bronchitis. The blood was sterile; S. aureus was obtained from the consolidated part of the left lung; S. aureus and Pneumococcus III from the abscesses of the right lung. Microscopic examination of sections of abscesses showed the pres- ence of Gram-staining cocci in staphylococcus-like colonies, surrounded by necrotic material and polynuclear leucocytes; Gram-negative bacilli re- sembling B. influenzae were seen. (See Fig. 16.) PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 229 Autopsy 333.—The onset of influenza was fifteen days before death; a diagnosis of pneumonia was made seven days before death. At autopsy there were confluent bronchopneumonia, clustered abscesses in the right lung and purulent bronchitis (no pleurisy). The blood contained Pneumococcus II atypical. S. aureus and Pneumococcus II atypical were obtained from the abscesses; S. hemolyticus, from the consolidated left lung; S. aureus, B. in- fluenzae and a few hemolytic streptococci, from the bronchus. (See Fig. 15.) Autopsy 370.—The patient was admitted seventeen days before death and signs of pneumonia were noted three days after admission. At autopsy there were lobular and confluent bronchopneumonia and small abscesses clus- tered about bronchi and situated within the gray consolidated lung; purulent bronchitis and patches of atelectasis, with' distention of the lungs, so that they failed to collapse on removal. No growth was obtained from the heart's blood; S. aureus in pure culture was obtained from the abscesses of the right lung; S. aureus, Pneumococcus IV and B. influenzas were obtained from a small bronchus on the left side. Autopsy 425.—Illness began with influenza twenty-nine days before death; a diagnosis of pneumonia was made fourteen days before death. At autopsy there were chronic bronchopneumonia with tubercle-like nodules of consolidation with some large patches of consolidation, multiple small ab- scesses giving a honey-combed appearance to part of the right middle lobe, purulent bronchitis and bronchiectasis. S. hemolyticus was grown from the heart's blood; S. hemolyticus, B. influenzae and S. albus from the lung. Sec- tions of an abscess contain clumps of cocci. An abscess cavity has along one side remains of a bronchial wall covered by squamous epithelium; a dilated bronchus, cut longitudinally, terminates in this irregular abscess cavity. Table XLIX shows the incidence of pneumococci, hemolytic streptococci, staphylococci and B. influenzae in the foregoing autopsies with abscesses clustered about bronchi: Table NLIX X H ° t -" ^ 'A Q PNEUMOCOCCI HEMOLYTIC STREPTOCOCCI STAPHYLO-COCCI B. INFLUENZA > E-i •f. o o A " A > * x ° ? A ^ Eh W Z £ o 5 .*. CO 3 ° > CO ° ? A ^ Eh H & £ > . CO ° P A ^ Eh H A > « S3 Bronchus Lung Blood 4 6 6 2 2 2 50.0 33.3 33.3 2 3 2 50.0 50.0 33.3 4 4 100.0 66.7 4 2 100. 33.3 Staphylococcus shows in the lung the same tendency to produce localized abscesses which it exhibits in other tis- sues of the body; it invades the lung by way of the bronchi, 230 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT but shows no ability to invade lymphatics, and in the cases we have examined rarely enters the pleura or the blood. In all of these cases B. influenzae has been found in the bron- chi and perhaps precedes the staphylococcus as an invader of the lower respiratory passages. Pneumococci atypical II, Types III and IV have been found in over half of these cases. The significance of this organism is emphasized by the 2 cases in which it has been found in the heart's blood at autopsy. It appears not improbable that S. aureus has invaded the lung already the site of bronchopneumonia caused by pneumococci. Notwithstanding the small number of autopsies, the fig- ures in Table XLIX, showing the incidence of pneumococci, streptococci, staphylococci and B. influenzae, are cited so that they may be compared with the corresponding figures for the usual type of streptococcus abscess (p. 203). The incidence of hemolytic streptococci is relatively low, whereas that of staphylococci approximates 100 per cent. S. aureus was present in great number in the lung of Au- topsies 322 and 333 and in pure culture in the abscess of Autopsy 370. Microscopic examination of sections from the abscesses which have been described, demonstrated the presence of Gram-staining cocci in characteristic staphylo- coceus-like clumps within the exudate of the abscesses; scat- tered chains of streptococci were not found. In those in- stances (Autopsies 280 and 280) in which cultures failed to demonstrate staphylococci, microscopic examination dem- onstrated staphyloeoceus-like clumps of bacteria within the abscess cavity. Cultures were usually made from the con- solidated lung near the abscess where the pleural surface could be seared, rather than from the pus, so that in some instances the microorganism has doubtless escaped detec- tion although present. In association with the multiple abscesses which have been described, injury to the bronchi and bronchopneu- monia have been invariably present. Purulent bronchitis PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 231 has been present in all instances of this lesion; in 2 in- stances there has been dilatation of the bronchi, and in 1 instance in which the onset of influenza was twenty-nine days before death, there has been advanced bronchiectasis. Microscopic examination shows that the epithelium of the bronchi is partially or completely destroyed and that de- struction of the underlying tissue, with acute suppurative inflammation, penetrates to a greater or less depth into the wall. "When the epithelium of the bronchus is wholly destroyed and the lumen is filled and distended with poly- nuclear leucocytes, a cross section of the tube has the ap- pearance of a small abscess; but more careful examination often shows that the engorged mucosa is still intact. Occasionally, a network of fibrin forms a layer covering the denuded mucosa. Disintegration of the superficial tissue may extend to the muscularis or through it, and may pene- trate the wall of the bronchus. The tissue in contact with the exposed surface contains many polynuclear leucocytes and blood vessels plugged with fibrinous thrombi, but deeper in the tissue lymphoid and plasma cells are more numerous. In 2 instances (Autopsies 280 and 425) favor- able sections have demonstrated that the wall of an abscess on one side consists of tin1 remains of a bronchus, covered by epithelium composed of squamous cells, whereas the remainder of the wall, here very irregular, is formed Im- partially destroyed alveoli plugged with fibrin. The sup- purative process has penetrated the Avail of the bronchus on one side and extended into the surrounding alveolar tissue. In other instances, abscess cavities occur within the alveolar tissue of the lung and their relationship to bronchi is not evident. In the mass of polynuclear leuco- cytes which fill the abscess cavity, are clumps of staphy- lococci in great abundance, usually forming characteristic colonies which are conspicuous with the low power of the microscope. 232 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Empyema, Pericarditis and Peritonitis No sharp line can be drawn between nonpurulent and purulent pleurisy. A diagnosis of empyema has been made when the fluid in the chest has become opaque and fibrin has undergone softening or solution. The lesion has been designated seropurulent when there has been abundant thin, opaque, gray fluid. Pleurisy has been designated fibrinopurulent when the cavity has contained opaque fluid and ragged soft white or yellowish fibrin ad- herent to the chest wall; this fibrin is evidently in process of disintegration and there may be numerous shreds and flakes of fibrin which subside to the bottom of the fluid. The amount of fluid in the cavity may occasionally exceed 1,700 c.c.; that in both pleural cavities may exceed 2,500 c.c. The lesion has been designated purulent when fibrin has almost wholly disappeared and the cavity contains thick yellowish white fluid. In 4 of 5 instances in which tho- racotomy had been performed, empyema has assumed this otherwise uncommon type. Some inflammation of the pleura is almost constantly found in association with all forms of pneumonia, but in many instances is so slight that it has no noteworthy sig- nificance. Table L shows the incidence of various types of pleurisy. Table L SUPPURA- INTERSTI- LOBAR BRONCHO- TIVE PNEU- TIAL SUPPU- PNEUMONIA PNEUMONIA MONIA WITH RATIVE ABSCESS PNEUMONIA No. % No. % No. % No. , % No pleurisy noted 30 46.9 44 55 1 2.6 1 5.9 Serous pleurisv 5 7.8 9 11.2 Fibrinous pleurisy 10 15.6 5 6.2 1 2.6 Serofibrinous pleurisy 12 18.2 14 17.5 3 7.7 Seropurulent pleurisy 9 23.1 1 5.9 Fibrinopurulent pleurisy 7 10.9 5 6.2 17 43.6 12 70.6 Purulent pleurisy 3 3.7 8 20.5 3 17.6 Total 61 80 39 17 PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 233 Empyema has occurred, on the one hand, in 12.4 per cent of instances of lobar pneumonia and in 9.9 per cent of in- stances of bronchopneumonia alone. It has occurred, on the other hand, in 87.2 per cent of instances of suppura- tive pneumonia with abscess formation and in 94.1 per cent instances of interstitial suppurative pneumonia. These suppurative lesions are caused by hemolytic streptococci, and when cultures are made from the pleural exudate this microorganism is isolated. Of 16 instances in which empyema has occurred in asso- ciation with lobar pneumonia or bronchopneumonia unac- companied by suppuration in 6 there has been infection with hemolytic streptococci. Empyema has occurred in the absence of hemolytic streptococci only 10 times. Empyema Caused by Hemolytic Streptococci.—"When necrosis preceding abscess formation has occurred in the lung, streptococci are found in immense numbers in the dead tissue. The pleura overlying the abscess undergoes necrosis and occasionally streptococci are particularly nu- merous upon the pleural surface of the necrotic tissue. In Autopsy 376 a membrane thin as tissue paper, representing the pleura, separated an abscess containing thick pus from the pleural cavity which was the site of empyema. The abscess may rupture into the pleural cavity and at the same time may be in free communication with a bronchus (Au- topsy 480). In one (Autopsy 467) instance an abscess which had ruptured into the pleural cavity had completely discharged its contents and was in process of healing, newly formed fibrous tissue being abundant in its Avail. With few exceptions empyema has accompanied sub- pleural abscess caused by hemolytic streptococci, being found on the side corresponding to the abscess. Among 39 instances of pulmonary abscess, empyema has been limited to the side of the abscess in 23; it has been present on the opposite side as well in 10 instances. In 2 instances there have been abscesses in both lungs; in one (Autopsy 234 PNEUMONIAS AND INFECTION'S OF RESPIRATORY TRACT 385 A) there has been double empyema, and in the other (Autopsy 487) empyema only on the left side. In one in- stance abscess has been recognized by microscopic exami- nation and its location is not recorded. In 5 instances of abscess formation there has been no empyema. In Autopsy 383 there has been no pleurisy noted; in Autopsy 416 there has been fibrinous pleurisy and in Autopsies 277, 290 and 380, serofibrinous pleurisy. Empyema has been almost invariably found in associa- tion with interstitial suppurative pneumonia. This lesion extends by way of the lymphatics up to the pleural surface and is often more conspicuous just below the pleura than elsewhere. Empyema has been absent in only 3 of 21 ex- amples of the lesion and in one of these there has been serous effusion. In 12 instances interstitial suppuration has occurred only on one side and empyema has been lim- ited to this side; in 5 instances with interstitial suppura- tion on one side there has been empyema on both sides; in 2 instances with interstitial suppuration in both lungs there has been double empyema. The amount of fluid in the pleural cavity has varied from less than 100 to 1,500 c.c. The fluid has occasionally been seropurulent or yellow, thick and purulent, but in most instances the exudate is. best described as fibrinopurulent. There is yellow or yellowish gray purulent fluid contain- ing flakes of soft ragged fibrin. The foregoing study has shown, on the one hand, that empyema is a frequent complication of streptococcus pneu- monia and, on the other hand, that empyema following in- fluenza with relatively few exceptions is caused by hemo- lytic streptococci. Empyema caused by this microorgan- ism exhibits in some instances characters not seen with other varieties of pleural inflammation. The tissue be- tween sternum and pericardium is often edematous and the adjacent fat has a firm brawny consistence. In some in- stances the exudate contains blood, and hemolysis has oc- PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 235 curred so that the fluid has a diffuse red color. The occur- rence of multiple pocketed collections of purulent fluid within the pleural cavity is peculiar to streptococcus empy- ema. These pockets have been found 6 times in association with abscess and 5 times with interstitial suppurative pneu- monia. In the presence of an exudate within the pleural cavity, some part of the lung, usually the anterior surface behind the sternum and costal cartilages, is glued by fibrin- ous adhesions to the parietal pleura. Here occur pockets containing thin purulent fluid and softened fibrin or thicker creamy pus walled off by fibrin about the edges of the pocket. At the site of the lesion the lung, after it is sepa- rated from the chest wall, is marked by a shallow depres- sion surrounded by the fibrin which has walled in the pocket. The little cavity thus formed, varying much in size, is usually oval, the long diameter being from 1 to 3 cm. These pleural pockets may occur over the external sur- face of the lung (Autopsies 452, 455, and 472) or between the internal surface and pericardium (Autopsy 452). Oc- casionally with partial fibrinous adhesion between the pleu- ral surfaces there are both scattered pockets containing purulent fluid and a larger encapsulated collection of fluid; in Autopsy 455 the pleural surfaces were adherent and there was 100 c.c. of purulent fluid encapsulated in a space over the external surface of the lung, 12x8 cm. In Autopsy 452 the lower part of the pleural cavity was encapsulated and contained 650 c.c. of fluid. This tendency of empyema caused by S. hemolyticus to form encapsulated pockets is doubtless of considerable importance in the treatment of the condition. Stone, Bliss and Phillips5 have described these encap- sulated pockets as "subcostosternal pus pockets" and have maintained that they are formed about the sternal lym- phatic nodes. "We have found them so widely scattered that this relation seems improbable. °Stone, W. T., Phillips, P». G., and Bliss, W. P.: A Clinical Study of Pneumonia Based on 871 Cases. Arch. Int. Med., 1918, xxii, 409. 236 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Pneumococcus Empyema.—Empyema occurred in asso- ciation with pneumonia referable to pneumococci 10 times, once with Pneumococcus II; 6 times with Pneumococcus atypical II; once with Pneumococcus III and twice with Pneumococcus IV. The lesion was seropurulent once; fibrinopurulent 8 times and purulent once. Fibrin in sev- eral instances was somewhat voluminous. In the following instance voluminous masses of fibrin had an important in- fluence upon the attempted treatment. Autopsy 473.—A. D. P., white, aged twenty-one, a student from Mis- souri, had been in military service two weeks. He was admitted to the hospital with influenza twenty-eight days before his death, and four days after admission there were signs of pneumonia. Paracentesis was per- formed on the right side on the eleventh day after admission; 4 c.c. of cloudy fluid which contained Pneumococcus III were obtained at this time and later in the day 800 c.c. were withdrawn. On the thirteenth day at- tempted withdrawal of fluid from both pleural cavities failed. On the eighteenth day aspiration of the right pleural cavity yielded only 30 c.c. of fluid. On the nineteenth day 400 c.c. of purulent fluid were withdrawn from the right pleural cavity. On the twenty-fifth day there was cyanosis and delirium. Shortly before death aspiration of the right pleural cavity was attempted, but only 4 c.c. of fluid were obtained. Anatomic Diagnosis.—Chronic bronchopneumonia with lobular and peri- bronchiolar consolidation in left lung; fibrinopurulent pleurisy on both sides; purulent bronchitis and bronchiectasis. On removal of the sternum, encysted purulent pleurisy is found be- tween the inner surface of the right lung and the pericardium; there is here 450 c.c. of very thick creamy, greenish yellow pus entirely separated from the remainder of pleural cavity. The external part of the cavity contains 1,450 c.c. of fluid and voluminous masses of firm fibrin which placed in a measuring cylinder occupy 450 c.c. The left pleural cavity con- tains 400 c.c. of seropurulent fluid in which there is abundant sediment of fibrinous particles. The right lung is compressed; the bronchi exude purulent fluid. The left lung is voluminous; in the upper and lower lobes there are small yel- lowish gray nodules of consolidation, grouped in clusters, and gray patches of lobular consolidation occur. Bronchi are dilated and filled with puru- lent fluid. Bacteriologic examination shows the presence of Pneumococcus III ob- tained in pure culture from the blood of the heart and from the right pleural cavity. S. viridans is grown from the left lung; a plate from the right bronchus contained B. influenzae, S. viridans and a few colonies of staphylococcus and M. catarrhalis. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 237 The foregoing case is particularly noteworthy because aspiration failed repeatedly to yield more than a few cubic centimeters of fluid, doubtless because the voluminous masses of fibrin present in the cavity prevented escape of fluid. Aspiration was attempted shortly before death, but only 4 c. c. of fluid were obtained; nevertheless, at autopsy the right pleural cavity contained 2,350 c.c. of exudate. An- other factor of much importance in relation to treatment is the encapsulation of 450 c.c. of purulent fluid between the inner surface of the right lung and the pericardium. It is possible that free drainage might have emptied the main cavity and perhaps even freed the encapsulated fluid. Pericarditis.—Among 241 autopsies on individuals with pneumonia following influenza, pericarditis occurred 23 times; these lesions were classified as follows: Serous peri- carditis, 1; serofibrinous pericarditis, 9; seropurulent peri- carditis, 1; fibrinopurulent pericarditis, 10; purulent peri- carditis, 2. It is noteworthy that in 12 of 23 instances of pericarditis the lesion was associated with S. hemolyticus infection of the lung and whenever in these instances cultures were made (Autopsies 434, 485, 499 and 504) hemolytic strepto- cocci were obtained from the pericardial exudate in pure culture. The tendency of interstitial suppurative pneumonia to produce pericarditis is especially evident. Among 21 in- stances of interstitial suppurative pneumonia pericarditis occurred 6 times (28.6 per cent); among 39 instances of sup- purative pneumonia with abscess formation, pericarditis occurred twice (5.1 per cent); whereas among all other autopsies, namely, 181, the lesion occurred 15 times (8.3 per cent). Pericarditis occurred in association with pneumonia re- ferable to Pneumococcus I, once, (Pneumococcus I isolated from the pericardium); to Pneumococcus II, once; to atypi- cal Pneumococcus II, 5 times (twice isolated from the peri- 238 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT cardium); and to Pneumococcus IV, twice (once isolated from the pericardium). Peritonitis.—Purulent peritonitis occurred only twice, in both instances in association with pneumonia caused by hemolytic streptococci. Purulent peritonitis was part of a general serositis involving both pleural cavities, peri- cardium and peritoneum in 2 noteworthy instances: Autopsy 465.—J. K., white, aged twenty-two, farmer from Oklahoma, had been in military service one month. He was admitted to the hospital with influenza, sore throat and bronchitis twenty-four days before his death. Signs of pneumonia were recognized thirteen days later and at the same time there was otitis media on the right side. Empyema and peri- carditis were found three days before death and two days later 1000 c.c. of cloudy fluid were withdrawn from the chest. Anatomic Diagnosis.—Suppurative pneumonia with consolidation and abscess in right lower lobe below pleura; purulent pleurisy on right, sero- purulent pleurisy on left side; beginning serofibrinous pericarditis; fibrino- purulent peritonitis; purulent bronchitis. The body is emaciated. The right pleural cavity contains 350 c.c. of thick, creamy yellow pus in which are flakes of fibrin; the right lung is collapsed and lies at the back and inner side of the cavity. The left pleural cavity contains 500 c.c. of turbid, yellow, seropurulent fluid in which is soft fibrin. The lower lobe of the right lung is consolidated throughout, flabby, gray red and finely granular on section. Below the pleura of the posterior border is a wedge-shaped cavity with its base 1.5 cm. across, in contact with the pleural surface. About the cavity consolidated tissue has an opaque, yellow color. Bronchi in both lungs contain mucopurulent fluid. The pericardial cavity contains 20 c.c. of turbid fluid; the left auricular appendage is bound by a. thin layer of fibrin to the parietal pericardium. The peritoneal cavity contains 100 c.c. of thick, creamy, yellow, purulent fluid. Between the diaphragm and liver is a layer of fibrin, in places 1.5 cm. in thickness; fibrin is present upon the peritoneum overlying the kidneys and base of mesentery. Bacteriologic examination shows the presence of hemolytic streptococci, obtained in pure culture from the blood of the heart, right pleural cavity and peritoneum. From the right bronchus are grown S. hemolyticus, B. influenzae and a few colonies of S. viridans and staphylococcus. Autopsy 504.—G. E. C, white, aged twenty-eight, farmer from Alabama, had been in military service three months. Onset of illness occurred six days before death, and two clays later he entered the hospital with fever (103.4° F.), pains in the abdomen and vomiting. Consolidation at the bases of the lung was recognized on the day following admission and on the day before death 900 c.c. of greenish brown fluid were aspirated from the left pleural cavity. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 239 Anatomic Diagnosis.—Interstitial suppurative pneumonia with consoli- dation in left lower lobe; purulent pleurisy on both sides; purulent peri- carditis; purulent peritonitis; parenchymatous degeneration of kidneys; acute splenic tumor. The body is that of a large well-nourished man. The left pleural cavity contains 975 c.c. of creamy, yellow fluid; right pleural cavity contains 425 c.c. of purulent fluid thinner than that on the left side. The left lung is collapsed; the posterior and lower half of the lower lobe is consolidated, flabby, deep red and fleshy in appearance. The interstitial septa are yel- low, thickened with bead-like enlargements and contains creamy purulent fluid which flows away and leaves small cavities. This interstitial sup- puration is more advanced below the outer surface of the lobe than else- where. The pericardial cavity contains 25 c.c. of creamy, yellow, purulent, fluid; the epicardium is dull, covered in a few places by a small amount of fibrin and below it are ecchymoses. The peritoneal cavity contains 100 c.c. of thick, yellow pus; the peri- toneal surfaces are injected and between the liver and diaphragm is fibrin. Bacteriologic examination shows the presence of S. hemolyticus in pure culture from the blood of the heart, the lower lobe of the left lung, peri- cardium and peritoneum. The right main bronchus contains the same microorganism, B. influenzae and a few staphylococci. General serositis has been caused by hemolytic strep- tococci which in one instance have entered the pleura from a subpleural abscess, and in the other from the suppurating interstitial tissue of the lung. In one of these cases the patient entered the hospital with symptoms suggestive of acute peritonitis. Bronchiectasis Acute dilatation of the bronchi is a common result of the bronchitis of influenza, and its frequent occurrence is an index of the severity of the changes in the bronchial wall. In some instances the smaller bronchi in well-local- ized areas are uniformly dilated; in other instances, large cavities, several centimeters in diameter, are formed and all transitions between the two extremes occur. The occurrence of bronchiectasis following influenza is mentioned by Leichtenstern6. He states that evidence of «Loc. cit., p. 110. 240 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT bronchiectasis can persist for weeks or months and never- theless end with complete restitution of the lungs to normal. Lord7 has described instances of bronchiectasis occurring in association with infection by B. influenza? and Boggs8 has recorded similar observations. We have had abundant opportunity to observe early stages in the production of bronchiectasis and to study the much discussed pathogenesis of the condition. The following figures show the predilection of bronchiec- tasis for the left lung and for the lower lobes: Bronchiec- tasis occurred 30 times in the left lung alone, 9 times in the right lung alone and 13 times in both lungs, the total being 52. Among 30 instances in which the lesion occurred only in the left lung, in 24 it was limited to the lower lobe, and in 15 of these 24 instances to the base of the lower lobe. Among 9 instances in which dilatation of bronchi occurred only in the right lung, it was limited to the lower lobe in 4 instances and to the base of the lower lobe in 2 of these 4 instances. When the lesion is limited to the base of the lower lobes small bronchi with no recognizable cartilage in their wall are dilated to a diameter of from 3 to 6 cm. and are dis- tended with thick mucopurulent fluid. The tenacious char- acter of the bronchial contents and the action of gravity doubtless have a part in the production of the dilatation. In several instances dilatation of the bronchi was limited to the basal parts of both upper and lower lobes. When bronchiectasis occurs throughout a whole lung, usually the left, or in both lungs, the lesion is more ad- vanced and conspicuous (Fig. 26). There is diffuse dila- tation of small and medium-sized bronchi. Dilated bronchi with deeply injected mucosa and filled with yellow muco- purulent fluid, are seen throughout the sectioned lung. A bronchus cut longitudinally may have a nearly uniform TLord, F. T.: Infections of the Respiratory Tract with Influenza Bacilli, Boston Med. and Surg. Jour., 190S, clii, 537, 574. sBoggs, T. R.: Influenza Bacillus in Bronchiectasis, Am. Jour. Med. Sc, 1905, cxxx, 902. PATHOLOGY AND BACTERIOLOGY FOLLOWING 1XTFLUENZA 241 diameter of from 5 to 9 mm. for a distance of 5 or 6 cm., maintaining this diameter to within 1 cm. of the pleural surface, where normally only small bronchi occur. More advanced bronchiectasis is represented by the oc- currence of spherical bronchiectatic cavities, having a diameter from 1 to 2.5 cm. In some instances there have been two or three of these cavities but occasionally there may be many. Cylindrical dilatation of the bronchi usu- ally occurs widely distributed in the lungs. In Autopsy 440 a small bronchus, cut longitudinally, was dilated to a diameter of 5 mm. for a distance of 5 cm. and terminated in a spherical cavity 2 cm. in diameter; there was another smaller spherical cavity nearby and dilated bronchi oc- curred elsewhere. In Autopsy 467, in the upper part of the lower lobe, two spherical cavities 1 and 1.5 cm. in diame- ter communicated with a bronchus of medium size. Autopsies with bronchiectasis are listed in the order of the duration of illness to show the parallel increase in the severity of the lesion (Table LI). In 2 instances (Autopsies 244 and 314) bronchiectatic cavities surrounded by firm fibrous tissue have evidently existed before the onset of the fatal illness, which has lasted in one instance approximately four and in the other six days; these autopsies have been omitted from the table. The table shows that bronchiectasis observed within twelve days after onset of illness with symptoms of influ- enza is moderately advanced and almost invariably limited to the left lower lobe and usually to the base of the lobe. Advanced dilatation, indicated by the formation of spheri- cal or cylindrical cavities, occurs with increasing frequency as the duration of the respiratory disease increases. Bronchiectasis has been almost invariably associated with purulent bronchitis. The dilated bronchi contain mu- copurulent material and throughout the lungs the same con- dition is usually widespread. Among 137 instances of pur- ulent bronchitis bronchiectasis consequent upon influenza has been present in 50. 242 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Table LI DURATION LOCATION CHARACTER OF TYPE OF OF BRON- OF BRON- BACTERIA IN NO. OF ILLNESS PNEUMONIA CHIECTASIS CHIECTASIS BRONCHUS AUTOPSY IN DAYS 394 5 1 Broncho Rt. base Dilatation 359 7 + Lobar and broncho Lt. lower lobe Dilatation 322 8 Abscess (staph.) Lt. base Dilatation 325 8 Interst. sup-puration Lt. base Dilatation S. hem., B. inf., staph. 352 8 Lobar and broncho Lt. lower lobe Advanced dilatation 429 8 % Broncho Rt. base Dilatation 288 10 Abscess Lt. base Dilatation S. hem., B. inf. 374 10 Lobar and Rt. and It. A dvanced broncho lungs dilatation 376 10 Abscess Lt. base Dilatation S. hem. 437 11 Lobar Rt. lower lobe Advanced dilatation 482 11 Broncho Lt. base Dilatation B. inf., Pneum. IV, S. hem. 489 11 Lobar and broncho Lt. lung Dilatation B. inf., Pneum. IV. 287 12 Lobar and Lt. lower lobe Advanced Pneum. IV., broncho dilatation B. inf., staph. 289 12 Broncho Lt. lower lobe Advanced Pneum. IV., B. inf. staph. 29.1 12 Interst. sup. Rt. lung Advanced S. hem., and abscess dilatation B. inf. 336 12 Broncho Lt. base Dilatation 375 12 Broncho Rt, and It. bases Dilatation 422 12 ? Lobar and broncho Lt. base Dilatation 381 13 Abscess Lt. base Spherical 391 13 Lobar and broncho Lt. lung Dilatation 401 14 ? Lobar and broncho Rt. and It. lungs Spherical 402 14 Chronic broncho Rt. lower lobe Dilatation 410 14 1 Abscess Rt, upper lobe Dilatation 333 15 Abscess (staph.) Lt. upper lobe Dilatation S. aur., B. inf. S. hem. 389 15 Interst. sup-puration Lt. lung Advanced dilatation 412 15 Lobar and broncho Lt. lower lobe Cylindrical 398 16 Broncho Rt. and lt. lungs Advanced dilatation 423 16 Broncho Lt. base Dilatation PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 243 Table LI—Cont'd DURATION LOCATION . CHARACTER NO. OF OF TYPE OF OF BRON- OF BRON- BACTERIA IN AUTOPSY ILLNESS IN DAYS PNEUMONIA CHIECTASIS CHIECTASIS BRONCHUS 488 16 Abscess Lt. lower lobe Dilatation S. hem., Pneum. atyp. II., 312 17 Broncho Rt. and It. lungs Dilatation S. hem., B. inf. staph. 372 17 Broncho Rt. lung Dilatation 385 C 17 Interst. sup-puration Lt. base Dilatation 448 17 Broncho Lt. lung Dilatation 460 17 Abscess Lt. lower lobe Spherical S. hem., B. inf., staph. 291 18 Broncho Lt. base Advanced dilatation B. inf., staph. 296 18 Abscess Lt. base Dilatation S. hem., B. inf., 387 19 Abscess Rt. and It. Advanced S. hem., B. lungs dilatation inf., S. a^r. Pneum. II. 421 19 Chronic broncho Rt. lung Advanced dilatation 440 19 Chronic Rt, and lt. Spherical B. inf., S. broncho lungs aur. 419 20 Broncho Rt. lung Dilatation Pneum. II, B. inf. 463 20 Chronic Rt. and It, Spherical B. inf., broncho lungs staph., Pneum. IV 431 23 Chronic broncho Lt. base Dilatation 468 23 ? Lobar and broncho Lt. lung Dilatation S. aur., B. inf., S. vir. 465 25 ? Broncho Lt. base Dilatation S. hem., B. inf., staph., S. vir. 445 27 Broncho Lt. lower lobe Spherical S. aur. 449 27 Abscess Rt. and lt. lungs Spherical S. hem., P. coli. 378 28 Abscess Lt. base Cylindrical S. hem., B. inf., Pneum. atyp. II. 473 28 Chronic Lt. lung Advanced B. inf., S. broncho dilatation vir., staph., M. catarr. 425 29 Abscess (staph.) Rt. and It. lungs Cylindrical 467 30 Abscess Rt. lower lobe Spherical S. hem., B. inf. 472 37 Chronic Rt. and lt. Advanced B. coli broncho lungs dilatation 487 55 Abscess Rt. and lt. lungs Cylindrical B. inf. S. hem. 244 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT The bacteriology of autopsies with bronchiectasis is shown in Table LIT. Table LII NO. EXAMINED PNEU-MOCOCCUS S. HEMOLY-TICUS STAPHY-LOCOCCUS B. INFLUENZAE > EH A to 2 ° A P* Eh W ^ £ > Eh A to 2 ° A A, PER CENT POSITIVE > s ° A P* W Ph O 5 S 9 > Eh A to 2 ° A CU 23 19 « o 0. ^ Bronchus Lung Blood 29 37 50 9 16 12 31,0 43.2 24.0 15 18 22 51.7 48.6 44.0 16 10 55.2 27.0 79.3 51.4 Comparison of the percentage incidence of the organisms which have to be found associated with bronchiectasis and with purulent bronchitis unaccompanied by bronchiectasis shows that there is no noteworthy difference in the occur- rence of pneumococci, hemolytic streptocccci or B. influ- enza? within the bronchi. "When allowance is made for the difficulty of demonstrating B. influenzae in the presence of a large number of other microorganisms, it is not improb- able that this organism has been constantly present in the purulent contents of the bronchi with purulent bronchitis, with and without bronchiectasis. Pneumococci, strepto- cocci and staphylococci are each present in the bronchi in about one-half of the instances of bronchiectasis and mixed infections are very common, S. viridans, B. coli and M. catarrhalis being occasionally found in the bronchi. The table shows that pneumococci, streptococci and staphyl- ococci show no greater tendency to enter the lungs and blood when bronchiectasis and purulent bronchitis coexist than with purulent bronchitis alone. Moderate dilatation of the small bronchi at the base of the left lung was found in several instances eight days after onset of symptoms referable to the respiratory pass- ages. Advanced, diffuse dilatation of the bronchi was seldom seen before the lapse of two weeks, and bronchiec- tasis with formation of spherical or cylindrical cavities PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 245 was found with few exceptions three weeks after onset of the fatal illness. Long continued, purulent bronchitis does not necessarily produce dilatation of the bronchi. It is noteworthy that the average duration of the fatal illness in 137 instances of pneumonia and purulent bronchitis with no bronchiectasis was 12.5 days, whereas the average dura- tion of 49 instances of pneumonia with purulent bronchitis and bronchiectasis was only 16.5 days. Bronchiectasis is almost invariably associated with pur- ulent bronchitis in which tenacious mucopurulent fluid ac- cumulates in the bronchi. It begins at the bases of the lower lobes and is usually more advanced here than else- where. Mechanical distention of the small bronchi by viscid fluid, expelled with difficulty, brings about their dila- tation and gravity appears to have a part in accentuat- ing the process. Histologic examination of the changes accompanying bronchitis show that lesions which penetrate into the muscular layer and presumably weaken the bron- chial Avail are not uncommon and partial or complete de- struction of the Avail may result. To what extent infiltra- tion of the muscular Avail by polynuclear leucocytes or by lymphoid and plasma cells is accompanied by changes which weaken the Avail may be questioned. When the epithelial lining of the bronchus is destroyed coagulative necrosis of the underlying tissue occurs and may extend a variable distance into the bronchial Avail, not infrequently pene- trating into or entirely through the muscular layer. These changes furnish an explanation of the occurrence of bron- chiectasis following influenza. Acute bronchiectasis may be found following influenza after the illness has lasted eight or ten days. There is no increase of fibrous tissue. Small bronchi with no cartilage, which in normal lungs have a diameter approximating 1 mm., are dilated to 3 mm. or more. The surface epithelium is wholly or partially lost. Necrosis occurs in places and extends deep into the tissue, destroying muscle and often 246 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT penetrating the entire thickness of the Avail Avhich in these small bronchi consists in large part of fibrous tissue con- taining greatly engorged blood A'essels. In this necrotic material nuclei are absent and the tissue containing fibrin stains deeply Avith eosin. In it occur fissures or tears Avhich extend from the lumen a ATariable distance, very frequently penetrating the entire thickness of the Avail and entering adjacent alveoli (Figs. 17 and 19). Alveoli thus exposed Fig. 17.—Acute bronchiectasis showing fissures penetrating into bronchial wall and at one place entering surrounding alveolar tissue; the surrounding alveoli are filled with fibrin. Autopsy 425. almost invariably contain plugs of dense fibrin. Where these rents have occurred, adjacent edges of the bronchial wall, held together by underlying lung tissue, have sepa- rated from one another, so that the circumference of the bronchus has been increased (Fig. 18). These breaks in the continuity of the Avail may occur in several places, so that a fourth or a third of the circumference mav be formed PATHOLOGY AND BACTERIOLOGY FOLLOAVING INFLUENZA 247 by exposed alveolar tissue which has become the site of fibrinous pneumonia (Fig. 20). During life, though the in- flamed bronchus is filled by mucopurulent exudate, disten- tion of loose alveolar tissue, uniting the interrupted bron- chial Avail, is doubtless greater than it appears in the lung fixed by hardening fluids. Recently dilated bronchi have an irregularly stellate lu- men as the result of clefts penetrating at intervals into or Fig. 18.—Acute bronchiectasis showing fissures in the bronchial wall extending into neighboring alveoli which in zone about are filled with fibrin; one fissure has separated widely; peribronchial fibrinous pneumonia (fibrin is black). Autopsy 425. through the bronchial Avail (Fig. 26). Longitudinal fissures mark the lining of these dilated bronchial tubes. When the fatal illness has lasted more than two Aveeks, abundant neAv formation of fibrous tissue occurs in a zone surrounding the dilated bronchus. Adjacent alveolar AA^alls are thickened by young fibrous tissue. Alveoli, much di- minished in size, are filled by hyaline fibrin into Avhich fibro- 248 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT blasts and newly formed blood vessels have penetrated. These changes are limited to a Avide zone in immediate con- tact Avith the dilated bronchus, Avhereas at a greater dis- tance ahToolar Avails have undergone no thickening and alveoli contain no fibrin. Fig. 19.—Acute bronchiectasis; the bronchial wall indicated by engorged mucosa shows a varying degree of destruction, fissures extending into and through the bronchial wall. Autopsy 352. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 249 This stage is well represented by Autopsy 421 after an illness of nineteen days. Bronchiectatic cavities, from 3 to 6 mm. in diameter, are numerous in sections of the lung; their lumina are irregular in outline and often irregularly stellate. Microscopic examination shows the presence of f«\*v » *%0*rd Fig. 20.—Acute bronchiectasis; with destruction of bronchial wall exposing alveoli filled with fibrin; peribronchial fibrinous pneumonia is seen about several bronchi present in the section; Gram-Weigert fibrin stain. Autopsy 425. 250 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT clefts which interrupt the bronchial Avail at intervals throughout its entire circumference. The original Avail is well indicated by the very richly vascularized connective tissue containing scattered muscle bundles and is infil- trated with lymphoid and plasma cells in great number. Where fissures haA'e occurred the adjacent edges of the in- terrupted Avail have separated from one another, leaAung a Avide interval where underlying alveolar tissue is exposed. Two changes tend eventually to render the fissures incon- spicuous, namely, regeneration of epithelium and hcav for- mation of fibrous tissue. Exposed ahTeoli filled Avith fibrin are in process of organization and epithelium Avhich has as- sumed a squamous type has groAvn doAvn 0ATer the exposed surfaces of the interrupted bronchial Avail. It has begun to cover or in some instances lias completely coA^ered the sur- face of rents entering alveoli plugged Avith fibrin (Fig. 21). In the periphery of the bronchus areolar Avails are thick- ened and infiltrated Avith lymphoid and plasma cells. The same changes affect bronchi, containing cartilage Avhich is undergoing atrophy. The reinforcement of the fissured bronchial Avail by iicav formation of fibrous tissue, by thickening of the interalve- olar Avails and by organization of fibrin Avithin the alveoli is well shown after four weeks (Autopsy 425; Fig. 28). There are spherical bronchiectatic caA~ities more than a cen- timeter in diameter surrounded by a dense fibrous Avail in which are atrophied alveoli lined by epithelium of cubical form. Occasionally, the fibrous Avail is interrupted and al- veoli, plugged Avith organizing fibrin, are in immediate con- tact Avith the lumen. When these plugs of fibrin Avhich are slowly absorbed disappear, evidence of preexisting rents in the bronchial Avail are lost, and there are in this lung bron- chiectatic ca\Tities of Avhich the Avail is a continuous circle of dense fibrous tissue. Epithelium lining the dilated bronchi is at times com- pletely destroyed (Fig. 28), but more frequently it persists PATHOLOGY AND BACTERIOLOGY FOLLOW I N(J INFLUENZA 251 in part. That which remains has almost constantly the character of squamous epithelium (Figs. 22 and 23). The loAvermost cells are cubical; those above them are poly- gonal, tending to become flatter as the surface is ap- proached; upon the surface are cells often much flattened and occasionally they have lost their nuclei and stain deeply FiR 21.—Bronchiectasis with fissures extending through the bronchial wall into alve- olar tissue which is the site of fibrinous pneumonia; epithelium has grown down into these fissures and has covered the exposed surfaces. Autopsy 463. 252 PNEUMONIAS AND INFECTIONS OF RESPIRATORY' TRACT Avith eosin as the result of superficial necrosis. The change should not be regarded as metaplasia, for the epithelium assumes this squamous type Avhen the superficial columnar cells haATe been lost. Actual necrosis of superficial ciliated columnar cells is occasionally seen (Autopsy 352); injured cells have separated from one another and desquamated Fig 22.—-Regeneration of epithelium over fissures which have been formed in the wall of a bronchus; the epithelium in the neighborhood of and within the fissure is squamous. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 253 into the lumen of the bronchus. The epithelium which re- mains after the superiicial cells are lost consists of cells which become flatter from base to surface, but the intercel- lular bridges characteristic of the epithelium of the skin are not found. When epithelium is in process of regenera- tion, a layer gradually diminishing in thickness extends epithelium below. 254 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT over the denuded surface, the advancing edge being formed by very flat cells in a single layer. The epithelium grow- ing into fissures Avhich have penetrated the bronchial Avail may completely cover the exposed alveolar tissue. The neAvly formed epithelium may follow a fissure into an alve- olus Avhich has been opened and come into contact Avith the fibrin which fills the alveolus. Bronchiectasis usually affects the small bronchi Avith no cartilage. It is not uncommon to find greatly dilated bron- chi Avith no cartilage in close proximity to cartilage con- taining bronchi of smaller caliber. In one instance (Au- topsy 421) a bronchus of medium size Avith cartilage meas- ured 3 mm. in diameter, Avhereas tAvo bronchi Avith no car- tilage Avere dilated to 4 and 6 mm., respectively. Neverthe- less, larger bronchi are occasionally the site of superficial loss of epithelium, necrosis extending into the bronchial Avail, formation of fissures and stretching of the Avail at the spot Avhich is Aveakened. In association Avith these changes atrophy of the cartilage may occur (Autopsies 421, 425, 440, 463). Plates of cartilage in process of atrophy are readily recognized by their irregularly indented outline and often by their small size. The fibrous tissue surround- ing the cartilage is the site of chronic inflammation and is densely infiltrated with lymphoid and plasma cells among which polynuclear leucocytes are scant. Nevertheless, polynuclear leucocytes are abundant in immediate contact Avith the cartilage and appear to have an important part in the solution of its matrix, for about them occur indenta- tions of the edge. Leucocytes penetrate into the cartilage. The necrosis and tears which occur in the Avail of the bronchus are not always limited to the bronchus, but may extend deeply into the surrounding tissue. In Autopsies 312 (Fig. 21) and 423 wide areas of necrosis have pene- trated deeply into the tissue about the bronchi. Autopsy 312.—Illness began with influenza on September 2(1, seventeen days before death; a diagnosis of lobar pneumonia with consolidation of PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 255 the right lower lobe was made ten days after onset and Pneumococcus IV, B. influenziE and S. hemolyticus were found in the sputum. At autopsy there Avas bronchopneumonia with red and gray lobular and confluent lobular patches of consolidation and right and left serofibrinous pleurisy; there was purulent bronchitis; no abscesses were seen. Small bronchi throughout both lungs were dilated and often surrounded by a zone of hem- orrhage. Hemolytic streptococci were found in the heart's blood, in the pleural exudate, consolidated lung and bronchus; B. influenzae was found in the lung and in a small bronchus, and staphylococci in the contents of a small bronchus. Fig. 24.—Acute bronchiectasis with fissures extending through bronchial wall which is marked by great engorgement of blood vessels; at one point a fissure has penetrated deep into the alveolar tissue and formed a small cavity containing purulent exudate and surrounded by fibrinous pneumonia. Autopsy 312. Bronchi which are the site of acute inflammation have lost their epi- thelium wholly or in part, and deep fissures penetrate the entire thickness of the bronchial wall, extending into the surrounding lung tissue which is the site of fibrinous pneumonia. In some instances plugs of fibrin within the alveoli are bisected by these tears. There is some superficial necrosis along the edge of each fissure, in several places extending outward from defects in the walls of small bronchi dilated to approximately 1.5 mm. There are wide patches of necrosis affecting both alveolar walls and con- 256 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TItACT tents of alveoli and extending 2 mm. into the lung tissue. When a fissure has penetrated from the lumen of the bronchus into necrotic tissue {Fig. 21), polynuclear leucocytes have accumulated within the necrotic tissue, disintegration of tissue occurs, and a small cavity communicating with the bronchus is formed. Autopsy 423.—C. H., white, aged twenty-five, resident of Oklahoma, had been in military service one month. Death occurred sixteen days after onset of influenza. Anatomical Diagnosis.—Chronic bronchopneumonia with peribronchiolar consolidation throughout right lung and in left lower lot>e; right purulent pleurisy; purulent bronchitis; bronchiectasis at base of left king. The right lung weighs l,-!60 grams; in the upper lobe are yellowish gray nodules having the appearance of tubercles clustered about small bronchi; in places similar nodules occur upon a background of pinkish gray consolidation occupying the greater part of the lower lobe. Bron- chi contain purulent fluid. The left lung weighs 760 grams; it is edema- tous and small, yellowish gray nodules of consolidation in the lower lobe are clustered about terminal bronchi. Bronchi at the base of the lower lobe are dilated. Bacteriologic examination showTs the presence of hemolytic streptococci in the blood of the heart; hemolytic streptococci and B>. influenzae in the lung. Microscopic examination shows that the walls of the bronchi are in- filtrated with lymphoid and plasma cells; these cells are very numerous in peribronchiolar patches of consolidation. A small bronchus 1 mm. in diameter has squamous epithelium along one side; on the opposite side, the wall is completely absent and there is superficial necrosis of exposed al- veoli filled with fibrin. A deep fissure passes from the bronchus into the consolidated tissue; its edges are necrotic and it is filled with polynuclear leucocytes. A small cavity in contact with the bronchus has been formed. In another part of the lung a distended bronchus has lost its epithelium on one side, and here alveoli filled with fibrin form the wall of the bronchus which is filled with leucocytes. Extending outward from the eroded wall is a focus of necrosis where both alveolar walls and contained exudate have lost their nuclei. The necrosis which has had its origin in the bronchi is soon folloAved by accumulation of polynuclear leucocytes, softening and disintegration of tissue. Discharge of the disintegrated tissue through the bronchi results in the for- mation of a small cavity continuous with the bronchus. These changes are Avell illustrated by the bronchiogenic abscesses which have been described elsewhere (Autopsies 376, p. 206, and 387, p. 206). \Vhen disintegrated tissue PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 257 is discharged by Avay of the bronchi no accumulation of pus occurs, but caATities Avill be formed, in part by dilation of bronchi, in part by erosion of the adjacent lung tissue. His- tologic examination sIioavs that these changes have pro- duced the advanced bronchiectasis found in Autopsy 445 (Fig. 25). Autopsy 445.—AV. F., white, aged twenty-three, from Mississippi, had been in military service one month. His illness began September 22, twenty- seven days before death, with severe coryza, weakness, nausea and vomit- ing; great pain in bones, cough and sore throat. He was admitted to the base hospital one week later with diagnosis of influenza and bronchitis. On October 3, sixteen days before death, signs of consolidation were found on the left side over the back and a diagnosis of lobar pneumonia was made. On October IS there was severe headache, pupils were dilated, and there wTas rigidity of neck; lumbar puncture was made and pneumococci were found in the fluid obtained. Death occurred on the following day. Anatomic Diagnosis.—Bronchiectasis with unresolved pneumonia limited to the left lower lobe; acute bronchopneumonia with peribronchiolar con- solidation '■:in. right lung; purulent bronchitis, peribronchial hemorrhage and organizing bronchiolitis in right lung; adherent pleura on left side; purulent meningitis. The left upper lobe is crepitant throughout. The outer and posterior two-thirds of the left lower lobe is riddled with cavities often rounded and varying in diameter from 0.3 to 3 cm. but not infrequently irregular in shape and in communication with adjacent cavities (Fig.. 25). In places cavities pass in a tortuous course from pleura to the midpart of lung. The lining of these cavities is usually smooth, but in places is covered by gray necrotic material. Communication between the cavities and me- dium-sized bronchi is occasionally found. The lung tissue between the cavities is in part grayish red and consolidated, in part pink and air con- taining. The right lung is edematous throughout; the bronchi in the lower part of the right lung contain purulent fluid and are in places surrounded by zones of hemorrhage. The spleen is very large (14 x 11 x 5 cm.) and firm. The spinal fluid is cloudy and blood vessels over the lumbar enlargement and lower thoracic region are congested; in the upper thoracic region the cord is covered by purulent exudate. Bacteriologic examination demonstrates the presence of hemolytic strep- tococci in the blood of the heart; plates from the left lung contain a few colonies of S. aureus and Pneumococcus IV; plates from the right main bronchus contain S. aureus and a large bacillus which does not stain by Gram's method. Three plates from the spinal meninges contain Pneu- mococcus IV. Microscopic examination shows that the cavities which have been de- scribed are lined by very vascular connective tissue containing many cells; 258 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Fig. 25.—Advanced bronchiectasis throughout lower left lobe. Autopsy 4-45. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 259 there is no epithelial lining and the surface is in places covered by fibrin. On the surface polynuclear leucocytes are numerous, but immediately be- low, large mononuclear cells occur and frequently contain one or several ingested polynuclear leucocytes. None of the structures peculiar to the bronchi can be identified in the wall of these cavities, and in many places it is evident that lung tissue has undergone destruction, for in places the lining of vascular connective tissue is interrupted and an extension of the cavity penetrating into the lung substance is surrounded by alveoli filled with fibrin; in contact with the cavity there is some necrosis. The cavities communicate with the bronchi and are lined in part by vascular connective tissue which may in part represent preexisting bronchial Avails, but no epithe- lium is present and the relation to the bronchi cannot be es- tablished with certainty. These cavities have extended by necrosis Avhich has broken the vascular connective tissue of their Avail and penetrated into adjacent lung tissue. Death has been the result of purulent meningitis caused by pneu- mococcus, and the histologic changes in the Avails of the cavities suggest that the activity of the inflammatory reac- tion here is subsiding, for large mononuclear cells are nu- merous and are ingesting polynuclear leucocytes. The changes described would, if continued, result in the forma- tion of caAuties lined by fibrous tissue and resembling many of those formed as the result of dilatation of the bronchi. A study of the progress of the changes Avhich result in the formation of bronchiectatic cavities has shoAvn how the inflammatory irritant within the bronchus destroys the epi- thelium of the bronchus, penetrates into the deeper tissues and produces fissures which extend through the entire thickness of the bronchial Avail at one or usually several places. These longitudinal fissures, which at first often give a stellate outline in cross section to the cavity of the affected bronchus, permit the separation of the edges of the fissure, so that an increase in the circumference occurs. The base of the fissure is formed by surrounding alveolar tissue and its edges are the site of necrosis. Tears may extend into the surrounding alveolar tissue, thus permit- ting further stretching of the bronchial wall. The conse- 260 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT quences of rupture of the small bronchi into the adjacent alveoli are to some extent overcome by the inflammatory reaction which plugs the adjacent alveoli with fibrin. Compression of the lungs by forced expiration, even though the glottis were closed as in coughing, Avould not dilate the bronchi, because pressure outside and Avithin the bronchi would be equally elevated (Thornton and Pratt9). The pressure within the bronchi does not differ greatly from atmospheric pressure, Avhereas the negative pressure within the pleural cavity may vary from approximately 6 mm. of mercury during quiet inspiration to 30 mm. with forced inspiration. Excess of pressure upon the inner sur- face of the bronchial Avails Avill vary with coughing and other respiratory efforts, between these limits depending upon the readiness Avith Avliich pressure is equalized Avithin and Avithout the bronchi by penetration of air into the alve- oli. The presence of viscid mucopurulent fluid Avithin bron- chioles Avill obstruct these tubules and retard the entrance of air into ah7eoli. Weakening of the bronchial Avail by the changes which haATe been described Avill cause lasting dilatation of the bronchi. "Whatever increases pressure Avithin the bronchi Avill increase the tendency to dilatation; the bronchi being filled Avith mucopurulent exudate dilatation usually ap- pears first at the bases of the lung, since gravity increases intrabronchial pressure here. NeAV formation of fibrous tissue Avithin the Avail of the bronchus, thickening of adja- cent alveolar Avails, and organization of fibrin reinforce the weakened bronchial Avail and limit the dilatation Avhich fol- lows injury to the wall. Regeneration of epithelium cov- ering the dilated tube Avill further obscure the early changes Avhich have made dilatation possible. The changes Avhich weaken the bronchial Avail permit dilatation at a time Avhen there is no new formation of fibrous tissue. When the bronchial lesion has persisted seATeral Aveeks, "Thornton and Pratt: Bull. Johns Hopkins Hosp., 1908, xix, 230. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 261 chronic pneumonia is associated Avith it. It has been sug- gested that the contraction of neAvly formed fibrous tissue within the substance of the lung might cause bronchi to be enlarged by traction upon their walls. Newly formed con- nectiATe tissue is most abundant in the Avail of the bronchi- ectatic caATity, and here contraction would tend to diminish the size of the cavity. Unresolved Bronchopneumonia Chronic bronchopneumonia is characterized by changes similar to those associated Avith chronic inflammation in other parts of the body, namely, by thickening of the inter- stitial tissue of the lung, by accumulation of mononuclear cells, by proliferation of fibrous tissue and by organization of exuded fibrin. In a feAv instances these changes have be- gun at the end of two Aveeks after onset of influenza, but they haA'e been little advanced until three weeks has elapsed; adATanced chronic inflammation has occurred after from four to eight Aveeks. Chronic inflammation primarily affects those structures which are most severely injured by the acute lesion and is most conspicuous in immediate prox- imity to the small bronchi and bronchioles; the perivascu- lar and interlobular connective tissue are secondarily involved. Corresponding to each of the lesions of the alve- olar tissue which have been found with bronchopneumonia, namely, peribronchiolar, hemorrhagic peribronchiolar, lob- ular and peribronchial consolidation, there is a chronic le- sion Avhich develops Avhen pneumonia has failed to resolve. The term interstitial bronchopneumonia has been used by MacCallum to designate a lesion which he has found in association with measles at Fort Sam Houston. This name lie states does not describe accurately the early stage of the lesion, for its interstitial character is not evident at first. Tn his monograph on "Epidemic Pneumonia in the Army Camp," published in 1919, MacCallum describes and pic- 262 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT tures instances of the lesion Avhich Ave Inne designated in- terstitial suppuratiATe pneumonia and classifies them as in- terstitial bronchopneumonia. We have sIioavii that this le- sion, which is the result of infection of the lymphatics with S. hemolyticus, bears no necessary relation to the lesion which is characterized in its early stage by peribronchiolar pneumonia and in its later stages by chronic inflammation with mononuclear infiltration and proliferation of the peri- bronchial, perivascular and interalveolar tissue. At Fort Sam Houston, nearly every patient Avith measles Avas in- fected Avith hemolytic streptococci; Ave obseiwed, folloAving influenza, similar prevalence of hemolytic streptococci in certain wards in the base hospital at Camp Pike. Among the cases at Fort Sam Houston there were doubtless instances both of interstitial suppurative pneumonia caused by hemo- lytic streptococcus and of chronic bronchopneumonia not referable to this microorganism. Studying pneumonia folloAving influenza at Camp Lee, Va., and later at Camp Dix, N. J., during the fall of 1918, MacCallum reached the conclusion that "interstitial bron- chopneumonia" folloAving influenza Avas caused by B. influ- enzae of Pfeiffer. This lesion attributed to B. influenzas differed from that previously referred to hemolytic strep- tococcus in the folloAving characters: the lymphatic chan- nels in the bronchial Avails and Avidened interlobular septa are inconspicuous and none are found distended Avith exu- date ; there is no intense infection of the pleura, and poly- nuclear leucocytes are inconspicuous in the alveolar exu- date and in the Avails of the bronchi. It seems probable these differences are explained by the absence of hemolytic streptococci which tend to invade lymphatics and produce severe inflammatory changes in the pleura. Chronic Bronchitis.—The earliest changes in the bron- chial Avail with bronchitis of influenza are hyperemia, leu- cocytic infiltration and hemorrhage, and they may occur even though the lining epithelium remains intact. Epithe- PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 263 Hum frequently undergoes partial or complete destruction, and Avith this severe injury the influence of the inflamma- tory irritant may extend directly through the Avail of the bronchus, for in some instances there is hemorrhage into all the alveoli in a zone encircling the bronchus. Since these alveoli have only indirect communication with the affected bronchus through alveolar tissue not involved in the in- flammatory process, it is evident that the surrounding hemorrhage is secondary to the lesion of the bronchus. Fibrinous inflammation in other instances, similarly local- ized in a zone of alveoli encircling a bronchus, is doubtless the result of direct extension of the inflammatory process through the bronchial Avail. After the disease has existed during tAvo or three Aveeks inflammation is still active im- mediately beloAv the inner surface of the bronchus; here polynuclear leucocytes are numerous Avhereas in the deeper parts of the mucosa and about the muscularis leucocytes are scant but lymphoid and plasma cells are \Tcry numerous. The severity of the inflammatory reaction may be judged by the abundance and extent of this cellular reaction and is in close relation to the intensity of the changes affecting the mucous membrane of the bronchus. Infiltration of the entire bronchial Avail Avith lymphoid and plasma cells is almost invariable Avhen the primary injury to the bronchus has destroyed the epithelial lining, and this infiltration is not limited to the bronchial Avail but extends outward into the contiguous alveolar septa Avhich are thickened by it. The sheath of the pulmonary artery which accompanies the bronchus exhibits a similar change, and the alveolar septa, as a fringe about it, are thickened and infiltrated with mon- onuclear cells. Interlobular septa continuous with the bron- chus often show some infiltration. A later phase in this series of changes is represented by neAV formation of fibrous tissue. The bronchial Avails and interalveolar septa are thickened by proliferating fibrous tissue, young fibroblasts and neAvly formed collagen fibrils 264 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TKACT being abundant (Fig. 28; also Fig. 30). This increase of fibrous tissue is especially noteworthy immediately sur- rounding the Avails of the small bronchi, which are often considerably dilated, and about the smaller of those bron- chi which have cartilage; with thickening of alveolar Avails immediately adjacent to the bronchus every stage in the obliteration of the alveoli may be found. Their Avails are thickened and their lumina are diminished in size and often flattened in a direction concentric with the bronchus. Such atrophied alveoli lined by cubical epithelial cells occurring within the thickened peribronchial fibrous tissue give evi- dence that this tissue has replaced alveoli. Alveoli sur- rounding and within the new fibrous tissue are fre- quently filled with fibrin, and organization indicated by penetration of fibroblasts and capillaries into the fibrin may be far advanced. There is some increase of perivascu- lar and interlobular tissue. The bronchiectasis which is almost invariably found with unresolved bronchopneumo- nia has been described. Squamous transformation of epi- thelium (page 2.)1) is frequently found in association with the chronic bronchitis of unresolved pneumonia. Organizing Bronchitis and Bronchiolitis.—When the bronchial epithelium is destroyed, fibrin is deposited upon the denuded surface and may partly or completely fill the lumen of the bronchial tube. The plug of fibrin is adherent to the underlying tissue Avherever epithelium is lost but is separated from the bronchial Avail by a well-defined space where epithelial lining is still intact. Fibroblasts promptly migrate from the wall of the bronchiole into this fibrin, and fibroblasts, fixed during ameboid movement, are irregularly elongated in a direction toAvard the fibrin. . Organization of fibrin occurs Avithin the smallest bronchi (diameter 0.3 to O.fj mm.) or within respiratory bronchioles. It has been found in 8 autopsies. In one instance it has been present eleven days after the onset of influenza, but usually it is seen three or four Aveeks after onset of symp- PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 26-1 toms of respiratory disease. In the early stages of the lesion a plug of fibrin Avithin the lumen of the bronchus or bronchiole is nwadod by fibroblasts, plasma cells and neAvly formed capillaries. These capillaries have their origin in the Avail of the tube and enter the fibrin at points where in consequence of loss of epithelium fibrin is continuous with the connective tissue. When the bronchiole is cut longitudinally, partially or completely organized fibrin may be found adherent at several places with intact epithelium, sometimes beautifully ciliated, between the sites of attach- ment. The fibrin is finally replaced completely and the lumen of the bronchiole contains a mass of organized fibrous tissue in which young fibroblasts and plasma cells are numerous. The lesion has been associated Avith chronic bronchopneu- monia in 6 of 8 instances. In Autopsy 44.1, p. 2.17, organ- izing bronchitis and bronchiolitis occurred in the right lung unassociated with other chronic lesion, although there Avas advanced bronchiectasis Avith fibrous induration in the left lung. In Autopsy 499 (p. 224) organizing bronchiolitis occurred in association Avith chronic changes which appear to have followed interstitial suppurative pneumonia caused by S. hemolyticus. Other severe lesions of the bronchi have accompanied organizing bronchitis and bronchiolitis. Purulent bronchitis has been present in 7 of 8 instances; bronchiectasis in .1 of 8 instances. The bacteriology of autopsies with organizing bronchitis and bronchiolitis is shown in Table LIII. The bacteriology of these cases presents no constant feature. Invasion of the blood by S. hemolyticus has been present in a large proportion of cultures, namely, in 5 of 7 (71.4 per cent). In one of the 2 instances in which hemo- lytic streptococci have been found, neither in the blood nor lungs, Pneumococcus III has been found in the blood and S. viridans in the lungs and bronchus; in the other, S. aureus has been found in the lung and bronchus. Staphylococci 266 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Table LIII AUTOPSY DURATION OF ILLNESS BLOOD LUNGS BRONCHUS 420 11 days S. hem. S. hem., B. inf., S aur. 402 14 " Pneum. IV, . hem. S. 370 17 " S. aur. S. aur., Pneum. IV, B. inf. 4.17 17+ " Pneum. IV, B. inf. 421 19 " S. hem. Pneum. IV, S. hem. 445 27 " S. hem. Pneum. IV, S. aur. S. aur. 473 28+ " Pneum. Ill S. vir. B. inf., S. vir., staph., M. catarr. 499 36 " S. hem. S. hem. B. inf. haA^e been found frequently in the bronchi (60 per cent) and in the lungs (.10 per cent). B. influenzae has been pres- ent in the bronchi in the usual proportion of instances (80 per cent). The lesion has occurred in the presence of B. influenzae combined Avith streptococci or staphylococci. Thrombosis of lymphatics in the Avail of bronchi adjacent to blood vessels and in interlobular septa occurs, and occa- sionally organization of the fibrinous plug Avithin the lym- phatic is in progress (Autopsies 283, 42,1 and 463). Fibro- blasts and capillaries penetrate from the Avail of the lym- phatic into a mass of hyaline fibrin Avhich fills the lumen. Unresolved Bronchopneumonia.—The most common type of pneumonic lesion folloAving influenza is characterized by acute inflammation of the alveoli immediately adjacent to the bronchioles and the lesion is associated in many in- stances Avith hemorrhage or edema. If this lesion persists unresolved during several Aveeks, evidences of chronic in- flammation are found. Peribronchial, perivascular and in- terlobular connective tissue is thickened and richly infil- trated with lymphoid and plasma cells, large mononuclear cells and many young fibroblasts. Interalveolar septa ad- jacent to the Avails of bronchi and between alveoli surround- ing inflamed bronchioles are implicated in the process. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 267 Interstitial changes characterize the lesion only in its late stage. It appears undesirable to give the name "interstitial pneumonia" to the early stage of a lesion which begins and in most instances terminates as an acute relatively super- ficial inflammation of the bronchi, bronchioles and peri- bronchiolar alveoli. Chronic bronchopneumonia is often overlooked at au- topsy because newly formed connective tissue is not present in sufficient quantity to attract attention (Fig. 26). When the lesion is advanced conspicuous gray Avhite patches of fibrous tissue may be seen about the bronchi (Autopsy 487; Fig. 27) and interlobular septa may be obviously thickened (Autopsy 472). The most distinctive feature of the lungs is the presence of small, firm, gray or yellowish gray nod- ules of consolidation Avhich resemble miliary tubercles. They represent the peribronchiolar patches of broncho- pneumonia present during the acute stage and have assumed the Avell-defined outline and firm consistence of tubercles because polynuclear leucocytes and red blood cor- puscles haA'e in large part disappeared, interstitial tissue is increased, and exudate is in process of organization. These nodules are grouped in clusters about the small bronchi. With unresolved bronchopneumonia the lungs are very voluminous and fail to collapse after they are removed from the chest and in some instances even after incision. The air containing tissue is usually dry. In our autopsies the lungs haATe been pink in color and often free from coal pig- ment, because those suffering Avith pneumonia haAre been in considerable part men from rural districts. Thick muco- purulent material exudes from the small bronchi which haATe been cut across; purulent bronchitis has been present in 20 of 21 instances of chronic bronchopneumonia. Bron- chiectasis has been present in 13 instances; dilatation is often advanced, so that throughout the lungs are found bronchi Avith no cartilage distended to a diameter of 0.5 cm. 268 PXEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT •ig. 26.—Unresolved bronchopneumonia with tuberclelike nodules of peribronchiolar consolidation best seen in lower lobe; bronchiectasis. Autopsy 425. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 269 In addition to the firm peribronchiolar tubercle-like nod- ules of consolidation there are scattered patches of gray lobular or confluent lobular consolidation. Yellowish nod- ules, grouped about bronchi and resembling those found elseAvhere in air containing tissue, are occasionally seen scattered upon the cut surface of a patch of gray, confluent lobular consolidation (Autopsies 421, 423, 431). Microscopic examination demonstrates the presence of those changes Avhich have been described in association with chronic bronchitis and bronchiectasis. There is abun- dant new formation of fibrous tissue about the bronchi of small and medium size, thickening of adjacent interalveolar walls and incorporation of alveoli into the thickened bron- chial Avail (Figs. 27, 28,. 30, and 31). In half of the in- stances of chronic bronchopneumonia there has been peri- bronchial fibrinous pneumonia, and organization of fibrin within the alveoli is usually well advanced. In one instance (Autopsy 487; Figs. 27 and 28) after an illness of fifty-five days this process has resulted in the formation of conspic- uous patches of firm, grayish white.fibrous tissue surround- ing dilated bronchi. Organization of fibrinous exudate within the lung has not been limited to the alveoli but has occurred in the bronchioles as well. Organizing bronchio- litis has been present in .1 instances (Autopsies 370, 402, 4,17 and 473). Increase of fibrous tissue occurs about the blood atcssc1s and in the septa between the lobules, which are infiltrated with mononuclear wandering cells and fibroblasts. Dila- tation and thrombosis of the lymphatic vessels have oc- curred in both situations, and in 3 instances (Autopsies 283, 425 and 463) organization of these fibrinous thrombi has occurred. Thickening, cellular infiltration and fibrosis of the bron- chial Avails with interstitial inflammation and fibrosis of im- mediately adjacent alveolar septa are found about the ramifications of the bronchial tree and may be followed 270 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT ig- 27.—Unresolved pneumonia with peribronchial formation of fibrous tissue; b: chiectasis. Autopsy 487. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 271 to the smallest bronchi. When the respiratory bronchioles are reached it Avill be found that the alveoli Avhich stud their Avails are implicated in the change. The fibrin Avhich they contain is infiltrated Avith lymphoid and plasma cells, and with progress of the lesion is invaded by fibroblasts and capillaries. Infiltration and fibroid thickening extends from the bronchiolar Avail to the alveolar septa continuous with it (Fig. 31 Avith measles). Similar changes occur about Fig. 28.—Unresolved pneumonia with bronchiectasis showing new formation of fibrous tissue about a greatly dilated bronchus of which the epithelial lining has been lost. Autopsy 487. the alveolar ducts, and about the orihees of the tributary infundibula (Kig. 32), peribronchiolar foci of acute inflam- mation having assumed the characters of a chronic inflam- matory process. Fibrin Avithin the alveoli contains round cells and fibroblasts. With thickening of alveolar Avails the alveolar lumina may be much diminished in size and often persist as spaces lined by cubical cells. Polynuclear leu- cocytes are usually numerous Avithin the alveolar duct and 272 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT in a feAV alveoli immediately adjacent to it, but elscAvhere throughout the focus of inflammation round cells are pre- dominant. The changes which have been described corre- spond with the transformation of ill-defined, gray or red- dish gray spots of consolidation grouped about the termi- nal bronchi into firm sharply defined grayish Avhite nodules having the consistence and appearance of miliary tubercles. One of the most constant characters of pneumonia fol- lowing influenza is its hemorrhagic character. In the earlier stages of pneumonia phagocytosis of red blood cor- puscles by large mononuclear cells is frequently seen. In association Avith the chronic changes which haA^e been de- scribed, large mononuclear cells filled with brown pigment, doubtless formed from red corpuscles, are often found within the alveoli. These pigment containing cells are sim- ilar to those commonly associated with chronic passive con- gestion of the lungs. In one instanee (Autopsy 4.17) hemorrhagic peribron- chiolar pneumonia has been found in process of organiza- tion. The bronchioles and alveoli adjacent to them contain polynuclear leucocytes, but intervening alveoli almost uni- formly contain blood and are the site of neAV formation of connective tissue. Interalveolar septa are thickened and alveoli Avliich are lined by cubical epithelium are often di- minished in size. In many places fibroblasts have pene- trated in considerable number into the blood Avithin the al- veoli and occasionally neAvly formed capillaries are found Avithin them. Lobular patches of pneumonia are often found in process of organization (Autopsies 370, 421, 423, 433, 463, 472 and 473). Microscopic examination shows that whole lobules well defined by thickened septa are the site of chronic in- teralveolar inflammation and intraalveolar organization of exudate, Avhereas adjacent lobules are air containing and relatively normal. In the earlier stages of the process fibrin present within the alveoli is invaded by fibroblasts, PATHOLOGY AND BACTETUOLOGV FOLLOWING INFLUENZA 273 mononuclear wandering cells and blood A'essels but in the later stages fibrin has disappeared; the lumina of the alve- oli are occupied by cellular fibrous tissue and in places the thickened alveolar Avails and intraalveolar fibrous tissue have been fused to form Avide patches of new tissue. With chronic bronchopneumonia confluent lobular con- solidation occasionally has a gray ground upon which are scattered small yelloAv spots clustered about the small bronchi (Autopsies 421, 423 and 431). Microscopic exam- ination has shown that the yelloAvish spots correspond to dilated bronchioles filled Avith purulent exudate and sur- rounded with alveoli containing many polynuclear leuco- cytes. In the interstitial tissue about the bronchiole and between adjacent alveoli plasma cells are often present in great number. Between these spots of subacute bronchio- lar inflammation lung tissue is the site of interalveolar pro- liferation of fibrous tissue and intraalveolar organization of exudate. In all instances of chronic bronchopneumonia there has been peribronchial pneumonia in a zone encircling small bronchi with no cartilage and the smallest of the bronchi which have cartilage in their Avail; thickening of interal- veolar septa, organization of peribronchial fibrinous pneu- monia and partial disappearance of alveoli have been de- scribed. In the following autopsy peribronchial fibroid pneumonia has been so advanced that conspicuous patches of gray white tissue surrounding bronchi have replaced in some parts of the lung a considerable part of the lung sub- stance. Autopsy 487.—W. C, white, aged twenty-seven years, a farmer from Mississippi had been in military service twenty-one days. Illness began on September 17, fifty-five days before death, with chill, fever, cough, back- ache, pain in the chest and coryza. The patient was admitted two weeks after onset with the diagnosis of influenza. Eight days later his sputum was blood tinged and there were signs of bronchopneumonia. One month after admission the patient developed a rash and a diagnosis of scarlet fever was made. 274 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Anatomic Diagnosis.—Chronic bronchopneumonia with peribronchial fibroid induration; bronchiectasis; purulent bronchitis; abscesses at the bases of both lungs; seropurulent pleurisy on the left side. The body is much emaciated. The left pleural cavity contains 650 c.c. of opaque, dull yellow, thin, purulent fluid. The surface of the left lung is covered in spots by white partially organized fibrin. On section of the right lung (Fig. 27) the tissue is found in great part air containing but there are numerous firm, gray patches, irregular in shape and from 1 to 2 cm. across. In these spots the tissue is tough and resembles fibrous tissue; within them are much dilated bronchi. In the central part of the upper lobe is a group of cavities with smooth wall, the largest of these cavities being 12 mm. in diameter; immediately adjacent are di- lated bronchi. Between and surrounding these cavities is gray tissue, like that described above. Below the outer surface of the upper lobe is an extensive area 7 cm. from above downward, thickly studded with bron- chiectatic cavities, in the walls of which there is tough fibrous tissue. In the middle lobe are several dilated bronchi, the largest of which is 7 mm. in diameter, and elsewhere occur dilated bronchi with thickened walls. At the base of the lung below the pleura are two abscesses, which are yellow in the center and surrounded by hemorrhagic tissue. At the posterior part of the lower lobe there are numerous firm, nodular, yellowish spots grouped in clusters upon a background of red, air containing tissue. The bronchi throughout the lung contain mucopurulent fluid. In the left lung patches of fibrous tissue are more numerous than on the right side and are irregular in shape, from 1 to 2 cm. across and most abun- dant in the center of the upper lobe. This fibrous tissue is in great part gray but in places it has a yellowish tinge. The bronchi everywhere are moderately dilated. At the base of the lung below the pleura is an abscess. The other organs show no noteworthy change. Bacteriologic Examination.—The fluid in the left pleura and right main bronchus contain S. hemolyticus. B. influenzae is found in the right lung and right main bronchus. Microscopic examination shows that the patches of dense fibrous tissue seen at autopsy almost invariably surround dilated bronchi Avith no cartilage in their walls (Fig. 28) and with a diameter of from 1 to 2 or more milli- meters. These bronchi have lost their epithelial lining; they1 contain poly- nuclear leucocytes, and their wall in contact with the lumen is infiltrated to a varying distance with the same cells. Their inner surface is very irregular, and superficial necrosis occurs. The limits of the preexisting bronchial wall is no longer recognizable in the dense surrounding fibrous tissue richly infil- trated with lymphoid and plasma cells. In contact with the bronchus, often in a wide zone, all traces of alveoli have been destroyed, but further outward alveoli are represented by spaces lined by cubical epithelium. At the peri- phery of the zone of fibroid induration alveolar walls are much thickened and richly infiltrated with mononuclear wandering cells; the lumina of the alveoli contain plugs of organized fibrous tissue often covered by flat or cubical epithelium. In the surrounding tissue a few small bronchi are lined by col- PATHOLOGY AND BACTERIOLOGY FOLLOAVING INFLUENZA 275 umnar epithelium; there is scant new formation of fibrous tissue but the alveolar walls are thickened and infiltrated with cells. Epithelium of the larger bronchi with cartilage in their walls is usually intact and there is about them little peribronchial inflammation. Advanced induration about the bronchioles represents a late stage of chronic peribronchiolar pneumonia. A bron- chiole cut transversely is found in the center of a focus of induration situated within relatively normal air containing lung tissue. Next the bronchiole which in some instances has wholly or partly lost its epithelium there is very cellu- lar fibrous tissue; further from the bronchiole alveoli are much diminished in size, lined by flat or cubical epithelium and separated by thick cellular Avails. Plugs of cellular fibrous tissue sometimes fill the alveolar duct. In favorable sections, cut in a plane Avhich sIioavs the alveolar duct open- ing out into infundibula, it is found that newly formed fi- brous tissue surrounds the alveolar duct and extends into the Avails of its tributary alveoli; alveoli may be obliterated by this fibrous tissue. Induration of alveolar Avails is evi- dent along the proximal part of the infundibula Avhich are readily demonstrable because they are much dilated. (See Fig. 32.) The distal parts of the infundibula are sur- rounded by ahTeoli Avith delicate Avails. One bronchus retains along one side part of its epithe- lium which has assumed a squamous form. In other places the Avail has undergone necrosis Avhich at one spot extends deeply into the surrounding tissue. Necrotic tissue in an- other part of the circumference is infiltrated Avith polynu- clear leucocytes and separated from the surrounding tissue by a space filled Avith leucocytes. An abscess communicat- ing with the bronchus is thus formed. The foregoing instance is an example of the chronic fi- broid pneumonias Avith bronchiectasis Avhich occur as se- quela1 of the epidemic of influenza. It is not improbable that a considerable number of those A\ho suffer Avith chronic bronchitis and bronchiectasis folloAving influenza have less extensive lesions similar to those Avhich have been described. 276 PNEUMONIAS AND INFECTIONS OF RFSPIRATORY TRACT Bacteriology of Unresolved Bronchopneumonia.—Bacte- ria found in the bronchi in 10 instances of chronic broncho- pneumonia have been as follows: Bacteria in Bronchi avith Chronic Bronchopneumonia B. coli............................................................. 1 B. influenzae and pneumococcus ....................................... 1 B. influenza} and S. hemolyticus ..................................... 2 B. influenza? and staphylococcus ...................................... 1 S. hemolyticus and B. coli ........................................... 1 B. influenza?, pneumococcus and staphylococcus ........................ 3 B. influenzas, S. viridans and M. catarrhalis ........................... 1 Bacteria found in the lungs in 17 instances of chronic bronchopneumonia ay ere as folloAvs: Bacteria in Lungs with Chronic Bronchopneumonia B. influenzas ........................................................ 1 Staphylococcus...................................................... 1 S. viridans......................................................... 1 B. influenza; and pneumococcus....................................... 1 B. influenzas and S. hemolyticus ...................................... 3 B. influenza? and staphylococcus ...................................... 3 Pneumococcus and S. hemolyticus .................................... 1 S. hemolyticus and B. coli........................................... 2 B. influenza?, S. hemolyticus and staphylococcus ........................ 3 No organism found................................................. 1 A noteAvorthy feature of these lists is the multiplicity of microorganism found, namely, B. influenza1, S. hemolyticus, pneumococcus, staphylococcus, S. viridans, B. coli, and M. catarrhalis. More than one microorganism is usually found in both bronchus and lung. In the one instance (Autopsy 472) in Avhich B. coli alone has been found in the bronchus, B. coli and S. hemolyticus haATo been found in the lung and hemolytic streptococcus in the blood; it is eA7ident that B. coli alone has not been responsible for the lesion. In one instance (Autopsy 487) B. influenzae alone has been found in the lung but hemolytic streptococci have been found in the bronchus, pleura and blood of heart; Avith S. aureus alone in the lung (Autopsy 370), S. aureus, Pneu- mococcus IV and B. influenza? haA'e been found in the bron- chus. "With S. viridans alone in the lung (Autopsy 473), PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 277 Pneumococcus III has been found in the pleura and in the blood of the heart and has doubtless had an important part in the production of pneumonia; S. viridans, M. catarrhalis and B. influenza? have been found in the bronchus in this in- stance. No single microorganism is associated with the lesions but combinations of B. influenza? Avith hemolytic strepto- cocci or staphylococci are common (over 50 per cent). In Autopsy 422 B. influenza1 and Pneumococcus atypical II have been present in the lungs. Among 10 instances in Avhich cultures have been obtained from the bronchus B. influenza? is found 8 times, and in the 2 instances in Avhich it has not been identified B. coli has been present. B. in- fluenza1 has seldom been found (Table XXVII) in the pres- ence of B. coli, and it is not improbable that B. coli out- groAvs and obscures the presence of B. influenza?. Table LIV sIioavs the per cent incidence of pneumo- cocci, hemolytic streptococci, staphylococci and B. in- fluenza' in the bronchus, lung and heart's blood Avith chronic bronchopneumonia and serves as an index of the readiness Avith Avhich each of these microorganisms passes from bron- chus to lung and from lung to the blood in this disease. Table LIV hemolytic pneumococcus streptococcus per cent per cent positive : positive STAPHYLO-COCCUS PER CENT POSITIVE B. INFLUENZAE PER CENT POSITIVE Bronchus 1 40.0 30.0 Lung 12.5 i 56.2 Blood 16.6 11.6 50.0 37.5 0 80.0 68.7 0 Comparison of Table LIV with the analogous figures for acute bronchopneumonia sIioavs little noteworthy dif- ference. Pneumococci are less frequently found in the lung (12.0 per cent) and in the blood (16.6 per cent) with chronic bronchopneumonia than Avith acute bronchopneu- monia (lung 43.9 per cent; blood, 40.3 per cent). Hemolytic streptococci and staphylococci are not more frequently 278 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT found Avith unresolved than Avith acute bronchopneumonia and failure to resolve cannot be referred to either or to both microorganisms, for bronchopneumonia not infrequently re- mains unresolved in their absence. B. influenza? is present in the bronchi in at least 80 per cent of instances and per- haps in all; it is usually combined both in the lungs and in the bronchi with one of the pyogenic cocci. The severity of the injury to the Avails of bronchi result- ing in continued infection with a variety of bacteria, appears to be the factor determining failure of resolution and the persistence of bronchopneumonia. The Relation of Unresolved Bronchopneumonia to Inter- stitial Suppurative Pneumonia Caused by Hemolytic Strep- tococci.—Hemolytic streptococci have been present in a considerable proportion of those Avho have had unresolved bronchopneumonia and its occurrence in the bronchi, lung and blood of the heart indicates that it has had an impor- tant part in causing death. Unresolved bronchopneumo- nia, folloAving measles, designated by MacCallum "inter- stitial bronchopneumonia" in a series of autopsies at Fort Sam Houston in the spring of 1918, was constantly asso- ciated Avith hemolytic streptococci. Among the lesions de- scribed as interstitial bronchopneumonia Avas at least one Avhich Avas evidently Avhat Ave haATe designated interstitial suppurative pneumonia. Lymphangitis Avas not infre- quently found A\*ith "interstitial bronchopneumonia" fol- loAving measles. At Camp Lee and Camp Dix, folloAving the epidemic of influenza, MacCallum found "interstitial bronchopneumonia" Avith no hemolytic streptococci and noted that lymphatics in the interstitial septa Avere incon- spicuous and that none was found distended with exudate; empyema Avas not present. WTe have shown that interstitial suppurative pneumonia is an acute lesion caused by hemolytic streptococci. Unre- solved bronchopneumonia is accompanied by chronic pneu- monia and has no necessary relation to this microorganism. PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 279 In a foregoing section Ave have described instances of in- terstitial suppurative pneumonia unaccompanied by chronic changes, and in the present section we have described in- stances of unresolved bronchopneumonia with no infection by hemolytic streptococci. "We have pointed out that the incidence of streptococcus infection with unresolved bron- chopneumonia does not materially differ from that with acute bronchopneumonia even though the greater duration of the disease gives more opportunity for infection. In some of the autopsies made by MacCallum at Fort Sam Houston, lesions of streptococcus infection doubtless coex- isted with unresolved bronchopneumonia. In the 3 autopsies described below, interstitial suppura- tive pneumonia with empyema caused by hemolytic strepto- coccus occurs in association with unresolved broncho- pneumonia. Autopsy 420.—J. E. S., white, aged thirty-two years, born in England and resident of Los Angeles, Cal., had been in military service one month. Onset of illness began on October 3, eleven days before his death. He was admitted to the hospital on the following day writh the diagnosis of influenza and acute bronchitis. Pneumonia believed to be lobar was recognized eight days after admission. Anatomic Diagnosis.—Unresolved bronchopneumonia with hemorrhagic peribronchiolar consolidation in right lung; interstitial suppurative pneumonia with consolidation in left upper lobe; fibrinopurulent pleurisy; purulent bron- chitis. The left pleural cavity contains 200 c.c. of turbid yellow fluid in which are flakes of fibrin. In the inner and upper part of th£ left upper lobe there is an area of consolidation where the tissue has a cloudy, pinkish gray color and is finely granular on section. Here the interstitial septa are distended by edema, so that they are in places 0.5 c.c. across; in some spots they have a bright yellow color. In the posterior parts of the middle and lower lobes there is flabby consolidation where the tissue has a cloudy, red color with scattered ill-defined yellow spots. Bacteriologic examination shows the presence of hemolytic streptococci in the blood of the heart; hemolytic streptococci with B. influenzas and S. aureus in the left lung and S. hemolyticus with S. aureus in the right lung. Microscopic examination shows that bronchi, bronchioles, alveolar ducts and the greater part of the infundibula are filled with polynuclear leucocytes, whereas the alveoli surrounding these structures contain fibrin. The walls of the small bronchi are thickened and contain mononuclear cells; the adjacent 280 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT alveolar walls are similarly infiltrated and thickened and the fibrin within them is undergoing organization, being invaded by plasma cells, fibroblasts and newly formed blood vessels. In some sections interstitial septa are dis- tended by edema and contain fibrin in abundance; in places the tissue contains polynuclear leucocytes closely packed together. There are lymphatics greatly distended by polynuclear leucocytes with some fibrin, lymphocytes and red blood corpuscles. Autopsy 428.—D. B., white, aged twenty-five, a farmer from Oklahoma, had been in military service three weeks. Onset of illness was on September 21, twenty-five days before death, with fever, cough and mucopurulent ex- pectoration. The patient was admitted with the diagnosis of acute bilateral bronchitis. Four days later bronchopneumonia was recognized, and subse- quently there was otitis media and empyema; 600 c.c. of thin, purulent fluid were aspirated from the right chest three days before death. Anatomic Diagnosis.—Unresolved bronchopneumonia; suppuration of in- terstitial tissue of upper right and lower left lobes; purulent bronchitis; fibrinopurulent pleurisy; thoracotomy wound at the base of the right chest; collapse of both lungs; serofibrinous pericarditis. The left pleural cavity contains 550 c.c. of turbid seropurulent fluid in which are numerous flakes of soft fibrin. The right pleural cavity contains 150 c.c. of similar fluid. The mediastinum is edematous. The pericardial cavity contains 50 c.c. of yellow fluid. The right lung is moderately collapsed. In the upper and lower lobes are small patches of red, lobular consolidation. The upper third of the upper lobe is laxly consolidated and near its inner surface the interstitial septa are thickened to from 1 to 1.5 mm. in width, and at intervals occur bead-like swellings from which creamy purulent fluid exudes upon the cut surface. In the left lung small patches of gray consolidation occur throughout the lower lobe and here the interstitial septa arc thickened, beaded and contain puru- lent fluid. Bacteriologic examination shows that the blood contains S. hemolyticus; from the right lung and from the right main bronchus hemolytic streptococci and B. influenza? are grown. Microscopic examination shows that the epithelium of the bronchi has undergone hypertrophy; the wall is infiltrated with lymphoid and plasma cells and thickened by new formation of fibrous tissue; there is similar thicken- ing of adjacent alveolar septa and alveoli, often lined by cubical cells, are diminished in size. Connective tissue about the blood vessels and the inter- stitial septa are thickened and infiltrated with mononuclear cells. In parts of the lung the interstitial septa are edematous and contain polynuclear leu- cocytes, in some places in great number. Lymphatics are greatly dilated and filled with polynuclear leucocytes which in the center of some lymphatics have undergone necrosis. In one place a small abscess is in contact with a dis- tended lymphatic. Lymphatics contain Gram-staining cocci in pairs and short chains, present in immense number where necrosis has occurred. Autopsy 433.—B. -L, white, aged twenty-seven, from Arkansas, has been in military service one month. Onset of illness was on September 28, nine- PATHOLOGY AND BACTERIOLOGY FOLLOWING INFLUENZA 281 teen days before death, with cough and expectoration. Pneumonic consolida- tion was recognized two days later and 20 c.c. of cloudy fluid were aspirated from the left chest on the same day. Hemolytic streptococci were found in a culture from the throat nine days before death. Anatomic Diagnosis.—Unresolved bronchopneumonia with peribronchiolar and confluent lobular consolidation; interstitial suppuration of the right lower lobe; purulent bronchitis; fibrinopurulent pleurisy. The right pleural cavity contains 700 c.c. of yellowish gray purulent fluid containing flakes of fibrin. The left pleural cavity contains seropurulent fluid localized over the external part of the lung. The right lung is voluminous and free from consolidation save at the lower and posterior part of the lower lobe where the tissue is deep red and studded with firmer spots of yellow color clustered about the bronchi. In places the interstitial septa are thickened and yellow. Surrounding some of the bronchi near the apex of the left lung are red patches of consolidation. Culture from heart's blood remained sterile. S. hemolyticus was grown from right pleural cavity, and S. hemolyticus and B. influenza? were grown from the right lung. Culture from the left lung contained S. aureus and contaminating microorganisms. Microscopic examination shows the presence of peribronchiolar patches of pneumonia in which there are few polynuclear leucocytes and many lymphoid and plasma cells; the alveolar walls are thickened and infiltrated with mono- nuclear cells. In some sections the tissue is wholly consolidated and the site of advanced organizing pneumonia. Interlobular septa and connective tissue about blood vessels are thickened and cellular. Small bronchi have lost their epithelial lining, their walls are thickened and there is peribronchial organ- izing pneumonia. In some sections the lymphatics are immensely dilated and distended with polynuclear leucocytes. There is necrosis of the walls of the lymphatics and of the polynuclear leucocytes within the lumen. In the discussion of acute bronchopneumonia it has been shown that S. hemolyticus is not infrequently a secondary invader of a pneumonic lesion perhaps caused by pneumo- cocci. With progress of the disease hemolytic strepto- cocci persist. In the autopsies with unresolved pneumo- nia just described, hemolytic streptococci have found their way into the lymphatics and produced suppurative lym- phangitis with inflammation of the interstitial septa of the lung. CHAPTER V SECONDARY INFECTION IX THE WARD TREATMEXT OF MEASLES James C. Small, M.D. A study of 979 cases of measles Avas made in the base hospitals of Camps Funston and Pike from July to Decem- ber, 1918, Avith the purpose of establishing any existing re- lation between the prevalence of the hemolytic streptococci and the incidence of the graATer complications of measles, especially the pneumonia folloAving measles. The greater number of these cases occurred at Camp Pike coincidentlv Avith the influenza epidemic, so that the picture is modified during this period by a summation of the after effects of the tAvo diseases. The Avork undertaken includes : (a) Routine throat cultures on admission of all patients with measles. (b) Separation and treatment in separate Avards of the patients harboring hemolytic streptococci and those free from such streptococci. (c) Investigation of the bacteriology of all cases under treatment, by weekly throat cultures during the period in the hospital. (d) Bacteriologic study of the complications of measles during life and at autopsy. (e) Study of the throat bacteriology of men on duty in the camp, to establish the prevalence of hemolytic strep- tococci and of B. influenza1 in normal individuals. The work is further divided into that done at Camp Funston during the latter part of July and throughout August, and that done at Camp Pike during September, October, November and December, 1918. SECONDARY INFECTION IN WARD TREATMENT OF MEASLES 283 Studies at Camp Funston.—The work done at Camp Funston is limited strictly to the identification of hemo- lytic streptococci in the throats of all patients with measles coining into the base hospital at Ft. Riley and to the same study of a group of normal men on duty. During the period of study hemolytic streptococci Avere identified by throat culture in about 1 in 5 of all the normal men ex- amined. Two instances of otitis media represent the only complications diweloping in the 112 cases of measles. Cul- tures from both patients showed staphylococci. The entire absence of streptococcus complications appears the more surprising in Anew of the fact that the prevalence of hemo- lytic streptococci among patients under treatment in the ward Avas for a time as great as that among the normal men. No special hospital management Avas instituted on the basis of the findings in throat culture. S. hemolyticus carriers remained in the wards and Avere treated alongside the "clean" cases. The sheet cubicle system Avas used for bed patients. Face masks Avere not worn. Convalescent patients Avere not segregated, and they assisted in the care of the bed patients and in the ward kitchen. After the initial throat culture on admission, the throats were gargled Avith argyrol and afterwards sprayed Avith the same solution three times a day. This solution Avas also em- ployed to relieve the discomfort caused by the conjunctivitis during the acute stage of the disease. Throat Culture and Identification of Hemolytic Strep- tococci.—In general the methods for the isolation and identification of hemolytic streptococci as adopted by the Medical Department of the Army Avere used. All organ- isms Ave re isolated in pure culture, groAvn in broth, exam- ined microscopically and subjected to tests for hemolysis, (a 5 per cent suspension of sheep corpuscles being em- ployed), and for bile solubility. Beef infusion broth and beef infusion agar constituted the two basic media used. They were prepared so that the 284 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT finished product titrated about 0.3 per cent acid to phe- nolphthalein. Broth tubes ay ere carried to the bedside. In swabbing, the attempt Avas made to produce gagging. This causes the tonsils to protrude from behind the anterior pharyn- geal pillars and places a slight tension on the capsule which tends to squeeze material from the crypts. The surfaces of the tonsils thus protruding toAvard the midline were brushed quickly Avith a small cotton sAvab Avhich Avas lastly touched to the posterior pharyngeal Avail and withdrawn so as to avoid touching any other parts. The swab was im- mediately introduced into a tube of broth, tAvirled freely under the surface of the liquid and discarded. The ma- terial thus Avashed into the broth Avas carried to the labo- ratory and kept in the ice box until plating, which Avas ac- complished Avith as little delay as possible. Tubes of melted agar containing 12 c.c. cooled below 45° C, after receiving 0.6 c.c. of sterile defibrinated horse blood, were inoculated Avith a loopful of this broth. Thor- ough mixing and pouring into Petri dishes (10 cm. diam- eter) followed. After cooling, a second loopful Avas streaked over the surface of one half of the plate. Deep and superficial planting were thus effected on the same plate. This method was found to be very useful. It can be used with advantage provided one is not called upon to make a great number of cultures when its time consuming factor is a great inconvenience. Another disadvantage is the dif- ficulty of picking single colonies for subculture. In spite of the most careful selection and fishing of a deep colony, subcultures are less likely to lie pure than when surface colonies are chosen. By careful regulation of the amount of agar in the tubes, the addition of a measured amount of blood to each enabled one to pour standard blood agar plates. Uniform thorough mixing of the blood is essential so that the plate may present the desired "silkv" rather SECONDARY INFECTION TN AVARD TREATMENT OF MEASLES 285 than a "curdled" appearance when viewed by transmitted light. The plates were incubated eighteen to twenty-four hours when subcultures in broth were made from the hemolytic colonies. After growing these for a similar period the additional tests were carried out as indicated above. Hemolytic Streptococci with Measles.—The incidence of hemolytic streptococci in the throats of patients Avitli measles admitted to the base hospital at Ft. Riley was found to lie remarkably small. Table LY Hemolytic Streptococci "with Measles in all Patients Admitted to the Wards at Camp Fcxston DAYS IN HOSPITAL APPROX-IMATE DAY OF DISEASE NO. OF PATIENTS CULTURED NO. WITH HEMOLYTIC STREPTO-COCCI PER CENT WITH HEMO-LYTIC STREPTO-COCCI First Culture Second Culture Third Culture 0 to 1 3 to 10 S to 23 1 to 8 4 to 16 12 to 26 112 86 58 3 11 14 2.67 12.79 24.14 The first culture represents the findings on admission, in a series of 112 cases; SO patients being cultured twice; 58 patients three times. Of the 112 cases examined on admission only 3, or 2.67 per cent aycic found to carry hemolytic streptococci. Those patients avIio Ave re recultured after from three to ten days in the hospital shoAved an incidence of 12.S per cent. A third culture including patients from eight to tAventy-three days in the hospital, shoAved an incidence of 24.1 per cent. Hemolytic Streptococci in the Throats of Normal Men.— A total of 274 throat cultures from normal men on duty at Camp Funston (Table LVI) sIioavs that 21.9 per cent car- ried hemolytic streptococci at a time Avhen there Avere foAv upper respiratory infections in the camp. A small group of men resident in the hospital sIioavs a slightly higher prevalence of hemolytic streptococci (29.3 per cent). The figures in Table TjVI are in sharp contrast Avith those for measles patients on admission to the hospital. 286 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Table LVI Incidence of Hemolytic Streptococci, Camp Funston. M 3 & 8 Rg &2§ W z 5 En A ENT LYT TOC s a o &< w n W VI o o « fc> < *. ±_-------^^^="^*!!SlN5: = = = r-S-" "S--------- SEPT 4 ii (8 15 OCIZ 16 21 30 NOV* 13 f0 27 DEC 4 II Chart 3.—Shows the relation of the epidemic of measles to that of influenza at Camp Pike, and the relations of the pneumonia following measles to both measles and influenza. The large incomplete curve represents influenza; the intermediate curve, measles; the small curve, pneumonia following measles. 294 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT It aa ill be noted from the overlapping of the Iavo curves in Chart 3 that a considerable portion of the measles cases appeared before the influenza had subsided in Cam]) Pike. This occurrence of the iavo epidemics at the same time makes it impossible to separate the parts played by each disease in producing the pneumonias and other complica- tions folloAving measles. Analysis of the chart, hoAvever, sIioavs that the pneumonia Avith measles occurred in large part during the first half of the measles epidemic. This is of particular significance since it Avas during this period that the effects of the influenza avra'c were felt most se- verely. In Table LIX the cases of measles are grouped into fifteen day periods according to their dates of onset and the pneumonias arising from each group are tabulated. This tabulation shows very clearly that the pneumonia complications (hwelopod in large part in patients Avith measles entering the hospital during the influenza period, that is, late in September and during the first half of October. Table LIX Patients with Measles and with Subsequent Pneumonia DATES TOTAL CASES OF MEASLES DURING INTERVALS OF 15 DAYS TOTAL CASES OF PNEUMONIA FROM SAME PER CENT INCIDENCE OF PNEUMONIAS Sept. 11 to 30 86] 14 1 16.28 1 U33 42 \ 9.1% Oct. 1 to 15 347 ) 28 J 8.07 J Oct. 16 to 31 270 ' 8^ 2.96 " Nov. 1 to 15 91 •434 2 •14 2.2 ■ 3.2% Nov. 16 to 30 56 4 7.15 j Dec. 1 to 15 17. 0 The high incidence of pneumonia among measles patients coming into the hospital prior to, with, or immediately fol- loAving the height of the influenza epidemic is very striking. It so happens that half of the total number of measles cases SECONDARY INFECTION IN AVARD TREATMENT OF MEASLES 295 considered, date their onsets prior to October 15. From the 433 cases included in this first half, 42 cases of pneumonia arose, while from the 434 cases arising during the two months following October 15, only 14 or one-third as many cases of pneumonia developed. These figures very strongly suggest that influenza played a large part in the production of the pneumonia Avith measles in this group of cases. Again the 9.7 per cent incidence of pneumonia in the first half of cases considered, approaches the 12 per cent inci- dence of pneumonia folloAving influenza observed in the epi- demic at Camp Pike, while the incidence of 3.2 per cent in the second half of the cases conforms more nearly to figures for pneumonia folloAving measles in the army prior to the pandemic of influenza. It has been shoAvn that the prevalence of B. influenzae at Camp Pike increased Avith the passing of the AvaATe of in- fluenza (p. 40) and that this increase applied to the measles admissions. For a time the separation of measles patients carrying B. influenza* as identified by throat cul- ture on admission, from those free from it, ay as practiced. All cases Avere then folloAved up by Aveekly throat cultures, and cases in negative AYards on being identified as positives Ave re transferred. This practice Avas discontinued as impractical Avhen it became apparent that about 80 per cent of patients Avith measles Avould be found positive for B. influenzae Avhen re- peated throat cultures Avere made during their hospital treatment. The dissemination of B. influenza* through the AYards from Avhich ayc Ave re attempting to exclude it took place much faster than Ave could loIIoav its spread by cul- tural methods. "When this became evident, the practice of separating the tAvo groups of patients Avith reference to B. influenza? Avas discontinued and the great incoiwonieiiee of repeated transfer of patients Avas largely eliminated. Table LX ^ives the findings in 426 cases of measles cultured for B. influenza? during the period A\7hen the prac- Results of Repeated Throat Cultures to Oct. Table LX for B. Influenza on 426 Cases of Measles, Camp Pike, Sept. IS 20, 1918. p o a z ? " Z H .J 3 $% o s fcH O n ft? • fe /I 'A - yj sg* o u. o RESULTS OF CULTURES TO DATE > 5 E " O fcH. ■ fc §2 o a cj p GROUP OF POSITIVES DEVELOPING TO DATE IN CASES NEGATIVE FOR B. INF. ON ADMISSION S2 o o H fc, OS o g fH £>£ km" woo a, a. H GROUP PER CENT OF POSITIVES TO DATE AMONG CASES NEGATIVE FOR B. INF. ON ADMISSION GROUPS 1st CULTURE 2nd culture 3rd culture 4th culture no. in each class I 1st culture on admis-sion 426 __ 274 + 152 152 35.6 II 1st and 2nd culture, after one week in hospital 201 143 - - 75 - + 68 + + 29 + - 29 126 08 62.7 47.5 III 1st, 2nd and 3rd cul-tures after two weeks in hospital 94 C9 - - - 22 - - + 18 - + - 13 - + 4 16 + + + 8 + - + 6 + + - 4 4- - - 7 72 47 77,7 68.1 IV 1st, 2nd, 3rd and 4th cultures after three weeks in hospital 25 19 - - _ - 4 - - - + 3 - - + + 3 - - + - 2 - + + + 2 - + - + 2 - + + - 2 - + - - 1 + + + + 2 + - - + 1 + - + + 1 4- + + - 1 + - - - 1 21 15 84 79. co OS •-d SECONDARY INFECTION IN AVARD TREATMENT OF MEASLES 297 tice of separating measles patients carrying B. influenzae from those not carrying the organisms Avas folloAved. On admission 35.(1 per cent of the patients Avere found positive for B. influenza}. Repeated throat cultures Avere not confined to those appearing negative on this initial cul- ture, but were made on all patients Avitliout regard to their being previously positiA^e or negative. By a summation of the results of the weekly cultures of all patients, the per- centage of patients carrying B. influenzae rises from 35.6 per cent on admission, to 62.7 per cent after one Aveek; to 77.7 per cent after tAvo AA^eeks; to 84 per cent after three weeks ill the hospital. To gain some idea of the rate of spread of B. influenzae in Avards receiving only patients Avhose throat cultures Avere negative for B. influenzae on admission, a similar summa- tion of the results of repeated throat cultures on patients in negatiA^e Avards sIioavs Aveekly increases from 47.5 per cent after one Aveek, to 68.1 per cent after two Aveeks; to 79 per cent at the end of three Aveeks. These results demonstrate quite clearly that the measles Avards Avere saturated Avith B. influenzae during the period of the influenza epidemic. Conditions Avithin the measles wards Avith regard to B. influenzae ayc re not at all dif- ferent from those in the camp community during this pe- riod. While no clinical methods could be relied upon to diagnose influenza in the presence of an acute attack of measles, there is every reason to believe that the occurrence of clinical influenza Avith measles Avas no less frequent than Avas its incidence in the camp at large, that is, about 20 to 25 per cent. That influenza played a large part in deter- mining predisposition to the complications of measles in this series seems evident. Hemolytic Streptococci Avith Measles at Camp Pike Between September 15 and December 15, 1918, 867 cases of measles, admitted to the AATards of the base hospital, Avere 298 PNEUMONIAS AND INFECTIONS OK RESPIRATORY TRACT studied and handled according to the system outlined above. About one half of these cases appeared during the first month of the study. During this month hemolytic streptococci played a very insignificant role. This micro- organism did not appear Avith alarming prevalence until after the wards had been thoroughly overcroAvded. After the emergency, when better Avard conditions Avere provided, S. hemolyticus carriers continued to develop in the AYards and Avere removed Avhen identified. The first S. hemolyti- cus carriers to develop in the Avards were identified on Oc- tober 8. The first case of streptococcus pneumonia de- veloped on October 17, while streptococcus otitis as a com- plication of measles did not begin until a little later. Dur- ing the latter tAvo months of the study, S. hemolyticus be- came rampant in the AYards. The streptococcus compli- cations date their onset at some time during these tAvo months. Table LX! sIioavs the number of admissions to the measles AYards by Aveeks and the patients among them found to be carrying hemolytic streptococci. It also sIioavs the num- ber of S. hemolyticus carriers deA7eloping each Aveek among patients under treatment in the "clean" AYards, as identi- fied by throat cultures repeated at Aveekly intoiwals. For purposes of orientation, the number of cases deA7eloping streptococcus pneumonia and otitis media AATith its subse- quent mastoiditis are given for each week during the period of observation. An admission to the measles Avard can generally be re- garded as an acute case of measles. There are a few ex- ceptions to this statement and these are cases of measles treated in barracks and aftei'Avards transferred to the base hospital. A relatively small number of such cases fur- nished 16 of the cases positive for hemolytic streptococci on admission to the measles Avard. An admission to the measles ward does not indicate ad- mission to the hospital, because a considerable number of Table LXI S. Hemolyticus Carriers Identified by Throat Culture Among Admissions; Those Developing Among Patients Un- der Treatment in the Streptococci's "Clean" Measles AYards; S. Hemolyticus Com- plications According to Their Dates of Onset ADMISSION CASES HEMOLYTIC STREPTOCOCCI HOSPITAL CASES DEVELOPING PRINCIPAL COMPLICATIONS DUE TO HEM. STREP. GROUPING OF CASES BY WEEKS NO. CASES CULTURED NO. POS. HEM. STREP. PER CENT POS. HEM. STREP. NO. CASES CULTURED NO. POS. HEM. STREP. PER CENT POS. HEM. STREP. PNEUM. OTITIS MASTOID-ITIS Sept, 15 to Sept. 21 23' 1 0 0 0 0 0 0 Sept. 22 to Sept. 29 25 ,252 1 y 3 1.2 23 0 0 0 . 0 0 Sept. 30 to Oct. 6 95 0 24 0 0 *1 0 0 Oct. 7 to Oct. 13 . 109 1 121 4 3.3 0 0 0 Oct . 14 to Oct. 20 223 7 175 8 4.6 1 0 0 Oct. 21 to Oct. 27 156 494 5 1.19 3.8 451 35 7.7 2 3 0 Oct. 28 to Nov. 3 71 6 333 29 S.7 1 12 1 Nov. 4 to Nov. 10 44 1 263 45 17.1 3 8 11 Nov. 11 to Nov. 17 3r 4" 149 46 30.8 0 5 5 Nov. 18 to Nov. 24 41 >117 4 .13 11.1 93 7 7.5 0 2 2 Nov. 25 to Dec. 1 19 0 48 7 14.6 0 3 2 Dec. 2 to Dec. 8 26 5 52 12 23.1 0 3 0 Dec. 9 to Dec. 15 4 2 47 12 25.5 1 0 0 fS. hemolyticus infection implanted upon a pneumococcus pneumonia. Place in Table indicates onset of pneumonia and not appearance of streptococcus complication. 300 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT cases of measles dcweloped from time to time among pa- tients under treatment in the hospital for other conditions. Since these patients remained in other Avards not subject to the same Avard management and Avith no distinction be- t Ave en those positive and those negative for hemolytic streptococci, they cannot be included in figures to shoAV the incidence of hemolytic streptococci in patients Avith measles at the time of admission to hospital from the camp. Tavo classifications of the 37 cases, positiATe Avhen first obseiwed, are necessary. 1. DiAnsion of cases according to days in the hospital before first culture Avas taken: Days in Hospital Xo. of cases 0-1 (admission) 15 (2 not acute) 2-7 10 More than 7 12 2. Classification according to stage of the disease: During acute stage 21 cases After acute stage 16 cases The first classification sIioavs only 13 cases positive when cultured on admission to the hospital and also during the acute stage of the disease; the incidence of S. hemolyti- cus in patients on admission is very Ioav (1.76 per cent). The second classification shows a slightly higher in- cidence for cases during the acute stage of the disease, re- gardless of Avhether they Avere admitted to the measles ser- vice from camp or from another service of the hospital (2.4 per cent). These findings conform with those at Fort Riley in a smaller series of cases and support the opinion that the hemolytic streptococci temporarily disappear from the throat during the acute onset of measles. Unfortu- nately controls among normal men in Camp Pike were not taken at intervals throughout the period of three months represented by this study of measles, but all controls taken show a higher incidence than that found among measles SECONDARY INEKCTIOX IN AVARD TREATMENT OF MEASLES 301 patients on admissions over a period of time comparable to that of the control series. The gradual increase in the percentage of patients de- veloping hemolytic streptococci in their throats in Avards receiving only streptococcus free cases demonstrates that the admission culture and the subsequent Aveekly cultures, Avith the separation of all patients indentified as carriers, did not suffice to control the spread of streptococcus in this group of cases. It is interesting to note that the greatest incidence of streptococcus carriers among these patients occurred three Aveeks after the height of the measles epi- demic, Avhen it became about four times that observed at tin1 height of the measles epidemic. When Ave consider the time relations of the strepto- coccus complications, it is notoAvorthy that they begin to appear someAvhat after the appearance of streptococcus carriers and then increase parallel Avith the increase in the numbers of carriers. The relative number of complications developing among the first carriers Avhich Avere identified is less than that among the carriers appearing later. This suggests an increase in virulence of hemolytic streptococci attending their Avider dissemination. Tables LXII and LX111 are introduced for the purpose of shoAving to Avhat extent duration of stay in the hospital increases the indiATidual's chances of acquiring hemolytic streptococci. Table LXII includes all cases admitted to and treated in the measles Avards. On repeated cultures, prev- ious positiAT's and negatives ay ere cultured alike and the total positiATos reported for each Aveek. Table LXTII includes only those cases treated in the "clean" Avards and knoAvn to be negatiATe on preA7ious cul- ture. A comparison of Tables LXII and LXIII gives some indi- cation of Avhat might haATe been expected if the carriers had not been removed from the treatment Avards at Aveekly in- toivals. "With the carriers remoAred from the "clean" 302 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Table LXII Incidence of Hemolytic Streptococci in Throats of Measles Cases with Eeference to Period in Hospital (All cases treated in the wards) period in measles ward NO. CASES CULTURED NO. POSITIVE FOR PER CENT POSITIVE HEMOLYTIC STREPTOCOCCI FOR HEMOLYTIC STREPTOCOCCI (Admission) 867 37 4.2 1 week 768 84 10.9 2 weeks 479 109 22.8 3 weeks 240 63 26.2 4 weeks 133 44 33.1 5 weeks 82 26 31.7 6 weeks 53 14 26.4 7 weeks 25 8 32.0 8 weeks 13 1 7.7 9 weeks 9 1 11.1 10 weeks 6 0 0 11 weeks 5 0 0 Table LXHI Weekly Development of Hemolytic Streptococci in Throats of Patients Treated in PERIOD IN NO. CASES MEASLES WARD CULTURED 1 week 738 2 weeks 424 3 weeks 195 4 weeks 92 5 weeks 46 6 weeks 26 7 weeks 14 8 weeks 8 9 weeks 5 10 weeks 4 11 weeks 3 NO. POSITIVE PER CENT POSITIVE FOR HEMOLYTIC FOR HEMOLYTIC STREPTOCOCCI STREPTOCOCCI 67 9.1 74 17.4 34 17.4 16 17.4 7 15.2 4 15.4 3 21.4 0 --- 0 --- 0 --- 0 --- cases and segregated in a separate Avard so as to be re- moved effectively as sources of spread of the S. hemolyti- cus infection to clean cases, the percentage incidence Avith all cases considered rose to a point nearly twice as high as that ever reached in the wards where clean cases alone were allowed to remain. Had these carriers not been sep- arated, and remained in contact with cases free from hemo- lytic streptococci, they would have served as just so many more sources of infection, and an incidence of at least twice SECONDARY INFECTION IN WARD TREATMENT OF MEASLES 303 that recorded for all cases combined, or four times that of the treatment wards, might have been expected. These results indicate that the Aveekly separation of carriers from clean cases did, to a considerable extent, loAver the indi- vidual's danger of acquiring S. hemolyticus infection while in the hospital. Complications of Measles In Table LX1V the complications developing in the mea- sles patients under observation at Camp Pike are tabulated. In the division of the complications developing in "carri- ers" and "noncarriers" of the hemolytic streptococci, ref- erence is made only to the records of the throat cultures. The division is therefore not dependent upon the bacteriol- ogy of the complications. For example, only 9 of the 12 cases of pneumonia deATeloping in "carriers" Avere streptococcus pneumonias. On the other hand, the cases of mastoiditis folloAving otitis media Avere almost invariably due to hemo- lytic streptococci. Of the 10 otitis cases occurring in "non- carriers," -1 developed mastoiditis and 3 of these shoAved hemolytic streptococci on culture from the mastoid cells at operation. Missed cases of identification of S. hemo- lyticus by throat culture in cases Avhich develop S. hemo- lyticus complications may arise from a number of causes. It is desired here only to direct attention to these dis- crepancies. Pneumonia Following Measles.—Fifty-six cases of pneu- monia following measles occurred during the period of ob- servation in this group of 867 cases of measles. Of these, 9 Avere streptococcus pneumonias. This gives an incidence for streptococcus pneumonias of 1.04 per cent, Avhile that for all the pneumonia is 6.4 per cent. There were 8 cases of lobar and 48 cases of bronchopneumonia. Seventeen fatal cases occurred giving a mortality rate of 30.4 per cent for the group. Five of these fatal cases occurred among 304 PNEUMONIAS AND INFECTIONS OF RESPIRATOR Y Til ACT Table LXIV Complications Developing in 867 Cases of Measles at Camp Pike. Distribution of Complications Between 242 "Carriers" and 625 "Noncarriers" of Hemolytic Streptococci from September 15 to December 15, 1918 NUMBER OCCURRINC IN X MBER PER CENT IN name of complication s" STREP. RIEUS STREP. c A X X W to 2 &H M « . H aq O K « « « . ai X A W X rn O A J Eh W W 5 6 « % X o W a W « ? •** o a o z X j a h s ° 21 r „ ft , E-< ^ =- o r^ &■ - o , o ly H "I a - .. o Pneumonia 12 44 0 56 1 6.4 5.0 7.0 Otitis media 31 11 6 48 5.5 12.8 1.8 Mastoiditis (follow- ing otitis media) 15 4 4 23 2.6 6.2 0.6 Local meningitis (ex tension from mas toid) 2 0 0 2 Frontal sinusitis 1 0 0 1 Ethmoidal sinusitis 0 1 0 1 Suppurative arthritis 1 0 0 1 Cervical adenitis 1 0 0 1 Acute bronchitis 4 o 0 6 Acute tonsillitis 4 1 0 5 Acute laryngitis and aphonia 1 0 0 1 Acute pleurisy 2 1 0 3 Erysipelas of face 0 1 0 1 Epidemic meningitis 0 1 0 1 Note.—The percentages of incidence of pneumonia and otitis media in the "carrier" and "noncarrier" groups are at direct variance. It would appear from these findings that streptococci very readily invade the middle ear from the throat and set up grave disorders. The invasion of the lung from the throat occurs with less frequency. Hemolytic streptococci perhaps never initiate the pneumonic processes and can be regarded as more or less accidental secondary invaders. the 9 streptococcus pneumonias. The mortality rate for the streptococcus pneumonia thus Avas 55.5 per cent; that for the nonstreptococcus group was 25.5 per cent. All 9 cases of streptococcus pneumonia developed empyema. In 7 cases it Avas diagnosed clinically; in 2 at autopsy only. Xo cases of empyema developed in the group of nonstrepto- coccus pneumonias. SECONDARY INFECTION IN AVARD TREATMENT OF MEASLES 305 The relation of these pneumonias folloAving measles, to the influenza epidemic has been discussed. The time rela- tions between the onsets of measles and that of the sub- sequent pneumonia ATiry Avidely. There appears to be nothing constant in the length of time between the onset of measles and that of the pneumonia. In 30 of the cases this period is less than ten clays; in the remaining 26 cases, it ranges from ten to thirty-two days (Chart 4). In the ward treatment of these cases of pneumonia, they Avere divided into three groups according to their clinical characters and according to the results of throat and sputum cultures. {a) Streptococcus pneumonias 9 cases (o) Pneumonia Avith hemolytic streptococci in the throat Avithout symptoms referable to the streptococcus 13 cases (c) Pneumococcus pneumonias not carrying hemolytic streptococci 34 cases The streptococcus-free cases Avere treated in a separate Avard. Cases Avere admitted to this ward directly from the "clean" measles Avards, but only after a throat culture taken prior to their transfer had been negatiATe for the hemolytic streptococcus. The other two groups Avere treated together in another ward, but in strictly separate compartments of it. This precaution was carried out on the assumption that patients Avith an acute streptococcus pneumonia Avere real sources of danger in the ward because of a heightened virulence of the organism causing the grave symptoms. The pneumo- nias subsequently developing hemolytic streptococci in their throats, without their presence modifying the course of the pneumonia, came to be regarded as being in the same class with uncomplicated cases of measles carrying hemo- lytic streptococci, in so far as their being potential sources of clanger in a Avard is concerned. 5 10 15 20 25 50 Chart 4.—Shows the time interval between the onset of measles and the onset of the subsequent pneumonia in the 56 cases of pneumonia following measles at Camp Pike. Each case is represented by one of the small blocks measured along the ordinate. The onset of measles in all cases is represented by the line at the extreme left of the chart. The onset of pneumonia in each case is indicated by the limit of the block marked off in days to the right of this line. SECONDARY INFECTION IN AVARD TREATMENT OF MEASLES 307 (a) Streptococcus Pneumonias.—Nine cases of strepto- coccus pneumonia deATeloped. Of the 867 cases of measles studied, 242 shoAved throat cultures positive for the hemo- lytic streptococci at some period of their stay in the hos- pital. It appears then that 3.7 per cent of the patients carrying hemolytic streptococci in their throats developed streptococcus pneumonia. Thirty-seven cases had positiATe throat cultures Avhen first observed on admission to the measles Avards. It is significant to note that not a single case of pneumonia of any kind developed among these cases. MEASLES PNEUMONIA; STREPTOCOCCUS GROUP Case OS, O. McN. Onset of measles, Sep. 19; admitted to hospital Sep. 21; onset of bronchopneumonia, Oct. 21; of empyema, Oct. 23- Recovered from pneumonia; convalescent in empyema ward. Bacteriology.—1. Throat culture for: (a) S. hem.: Sep. 21, -; 28, -; Oct. 9, -; 20, -; 23, +; Nov. 2, -; 9, -; 15, -; (b) B. influenza): Sep. 21, +; 28, -; Oct. 9, +. 2. Pleural fluid (culture) S. hem- Oct. 2:5, +. Case 141, J. G. G. Autopsy No. 438. Onset of measles, Sep. 28; admitted to hospital, Oct. 1; onset of bronchopneumonia, Oct. 6; of otitis media (bilat- eral), Oct. 12; died, Oct. IS. Bacteriology.—1. Throat culture for: (rt) S. hem., Oct. 2, -; 6, -; 8, -; (6) B. influenza), Oct. 2, -; 6, +; S, +. 2. Autopsy cultures: Heart blood, neg- ative ; left lung, Pneumococcus II atypical, B. influenzae and S. viridans; right lung, S. hem. and B. influenzae; right bronchus, S. hem. and B. influenza?. Case 147, S. AV. Autopsy No. 442. Onset of measles, Oct. 1; admitted to hospital, Oct. 2; onset of bronchopneumonia, Oct. 17, with chill and rapid development; died, Oct. 18. Bacteriology.—1. Throat culture for: (a) S. hem., Oct 2, -; 9, -; 15, -; 18, +; (6) B. influenza), Oct. 2, -; 9, -; 15, -; 18,-. 2. Autopsy cultures: Heart blood, S. hem.; right main bronchus, S. hem. and B. influenza?. Case 281, T. M. Onset of measles, Oct. 6; admitted to hospital Oct. 9; on- set of bronchopneumonia, Oct. 21; of empyema, Oct. 23; recovered from pneu- monia; convalescent in empyema ward. Bacteriology.—!. Throat culture for: (a) S. hem., Oct. 10, -; 20, -; 24, +; Nov. 2, +; 9, +; 15, +; (6) B. influenza?, Oct. 10, -; 20, +. 2. Culture from pleural fluid, Oct. 23, S. hem. Case 285, J. H. Onset of measles, Oct. 4; admitted to hospital, Oct 9; onset of lobar pneumonia, Oct. 29; of empyema, Nov. 9; convalescent in em- pyema ward. Bacteriology.—1. Throat cultures for: (a) S. hem., Oct. 11, -; 20, -; 24, + ; 29, -; Nov. 2, -; 9, -; (b) B. influenzae, Oct. 11, -. 2. Cultures from pleu- ral fluid, Nov. 9 and 13, S. hem. 308 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Case 714, AV. H. Onset of measles, Oct. 26; admitted to hospital, Oct. 28; otitis media, Nov. 8; onset of bronchopneumonia, Nov. 9; of empyema, Nov. 17; convalescent in pneumonia ward. Bacteriology.—1. Throat cultures for: S. hem., Oct. 28, -; Nov. 4, -; 12, +; 23, +; 30, +; Dec, 7, +; 12, -. 2. Sputum: Nov. 10, Pneumococcus II atypical, S. hem. and B. influenza?. Case 730, W. S. Autopsy No. 491. Onset of measles, Oct. 26; admitted to hospital, Oct. 29; onset of bronchopneumonia, Nov. 10; of empyema, Nov. 11; of cervical adenitis, Nov. 5; died, Nov. 15. Bacteriology.—1. Throat culture for: S. hem., Oct. 30, -; Nov. 4, +. 2. Sputum: Nov. 10, S. hem. 3. Pleural fluid: Nov. 11, S. hem. Autopsy bac- teriology: Heart blood, S. hem.; right main bronchus, B. influenza?, B. coli; right lung, S. hem. and B. influenza?; right pleura, S. hem.; peritoneum, S. hem. Case 751, P. B. Autopsy No. 492. Entered hospital, Oct. 19; onset of measles, Oct. 30; of bronchopneumonia, Nov. 5; of right empyema, Nov. 12; died, Nov. 16. Bacteriology.—1. Throat cultures for: S. hem., Nov. 1, -; 4, +; 15, +. 2. Sputum: Nov. 13, B. influenza? and S. hem. 3. Autopsy cultures: Heart blood, S. hem.; right lung, S. hem., Pneumococcus I A", B. influenza?, B. coli; pericardium, negative; right pleura, S. hem.; peritoneum, S. hem. Case 880, B. McN. Autopsy No. 507. Onset of measles, Nov. 30; entered hospital, Dec. 3; onset of bronchopneumonia, Dec. 11; of empyema, Dec. 14; died, Dec. 14. Bacteriology.—1. Throat cultures for: S. hem., Dee. 3, -; 5, -; 12, +. 2. Cultures from pleural fluid, Dec. 14, S. hem. 3. Autopsy cultures: Heart blood, S. hem.; right main bronchus, S. hem., B. influenza?, staphylococcus (a few); left lung, S. hem.; left pleura, S. hem. The average period in the hospital before the develop- ment of the streptococcus pneumonia is about two Aveeks. Cases 98 and 28o Avere in the hospital thirty and tAventy days respectively before the onset of pneumonia. There is a record of from one to four negative throat cultures on each case before streptococcus was found in the throat. This enables us to fix the onset of the pneumonia Avith reference to the appearance of the streptococcus in the throat. Case 141 stands alone as representing a class in Avhich S. hemolyticus was implanted upon a pneumococcus pneu- monia during its course. In this instance tAvo throat cul- tures on alternate days after the onset of the pneumonia Avere negative for hemolytic streptococci. Unfortunately SECONDARY INFECTION IN AVARD TREATMENT OF MEASLES 309 the last record of a throat culture is for one taken ten days before the fatal termination of the case, and it can only be stated that the S. hemolyticus infection Avas implanted Avithin the last ten days of the course of the pneumonia, perhaps on or about October 12 Avhen bilateral otitis media deA7eloped. In Cases 285 and 730 hemolytic streptococci Avere found in the throats five and six days respectively before the onset of pneumonia. They represent the 2 cases of pneumonia Avhich deAToloped in patients isolated in the streptococcus "carrier" Avard. Case 285 is of particular interest for seATeral reasons. It is the only case of lobar pneumonia in the group and happens also to be the only case from which B. influenza* Avas not obtained. S. hemolyticus was found only once on throat culture, ?'. c, five days before the onset of the pneumonia. Three throat cultures after the onset of the pneumonia Avere negative. The case ran the course of a lobar pneumonia. KleA^en days after the onset (November 9) a small amount of pleural fluid Avas diag- nosed. Aspirated fluid on this date and again four days later shoAved many streptococci in smears and pure cultures of S. hemolyticus. The remaining 6 cases belong to a group in which hemo- lytic streptococci were first identified in the throats after the cases had been reported to the laboratory as pneumonia sus- pects to be examined by culture before transfer from the measles ward. In all these cases the culture taken at this time Avas positive while all cultures taken before Avere nega- tive. In some cases, e. g., Cases 98, 147, and 281, throat cultures taken only one or two days before the onset of the pneumonia were negative. In these cases the onset of the pneumonia and the appearance of the streptococcus in the throats appear to be simultaneous. It should be noted that the period between the appearance of the hemolytic streptococci in the throat and the develop- ment of the pneumonia is very short in all cases. In this 310 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT small group of cases S. hemolyticus infection Avhich has complicated pneumonia has been acquired at or near the time of onset of the pneumonia. {b) Pneumonia with Hemolytic Streptococci in the Throat without Symptoms Referable to the Streptococcus. -—Thirteen cases of pneumonia associated Avith measles de- veloped into S. hemolyticus "carriers" Avithout haAung the course of the disease affected by the presence of the organ- ism in the throat. Cases 705, 872, and 188 are of interest in that hemolytic streptococci Avere identified in the throats from one to six days prior to the onset of the pneumonia. In spite of their presence, the symptoms, course and out- come of the pneumonia were apparently unaffected. One of these cases (Case 872) died. Autopsy shoAved lobar pneumonia with no signs of invasion of the lung by hemo- lytic streptococci. Cultures at autopsy showed that pneu- monia Avas due to a pneumococcus, Type II atypical. A feAv hemolytic streptococci were found in culture from the right main bronchus. Of the remaining 10 cases 1 developed S. hemolyticus in a throat culture at the end of the first week of the pneu- monia ; 3 during the second Aveek; 1 during the third Aveek, and 5 further along in the convalescent period. In 8 cases hemolytic streptococci appeared in the throat, at a time Avhen iiiATasion of the loAver respiratory tract by the strep- tococcus might be expected, and yet none of them doATeloped eATidence of streptococcus pneumonia. The 9 cases Avith hemolytic streptococci appearing late in coiwalescenco are not of particular interest, since the dangers of loAver res- piratory invasion are much reduced after the acute stage of the pneumonia has passed. Three of these cases (Cases 678, 725 and 398) did howeATer develop ear complications directly referable to the streptococcus invasion of the throat. Two of them terminated in mastoiditis Avith op- eration. These cases emphasize the greater tendency of S. hemolyticus to inATade the middle ear rather than the lung. SECONDARY INFECTION IN AVARD TREATMENT OF MEASLES 311 Iii 3 fatal cases of pneumococcus pneumonia in which dur- ing life no hemolytic streptococci were found by throat cul- ture, a feAv hemolytic streptococci Avere found at autopsy in culture from the main bronchi, along with predominating groAvths of pneumococci and 1>. influenza*. In 2 instances there Avas frank lobar pneumonia and in the third broncho- pneumonia; there Avas no evidence to sIioav that hemolytic streptococci had any relation to the pneumonia Avhich Avas found. MEASLES PNEUMONIAS; GROUP CARRYING HEMOLYTIC STREPTOCOCCI Case 705. Onset of measles, Oct. 25; admitted to hospital, Oct. 27; onset of bronchopneumonia, Nov. 10; acute pleurisy, Nov. 16; convalescent in pneu- monia ward. Bacteriology.—1. Throat cultures for: S. hem., Oct. 27, -; Nov. 4, -; 11, -f; 15, +; 23, -; 30, -; Dec. 7, -; 12, -. 2. Sputum: Nov. 10, Pneumococcus II atypical, S. hem. and B. influenzae. Case 872. Autopsy No. 508. Onset of measles, Nov. 29; admitted to hos- pital, Nov. 30; onset of lobar pneumonia, Dec. 10; died, Dec. 14. Bacteriology.—1. Throat cultures for: S. hem., Nov. 30, -; Dec. 5, +; 10, +; 12, +; 14, +. 2. Autopsy culture: Heart blood, Pneumococcus II atyp- ical; right main bronchus, Pneumococcus II atypical, B. influenza?, S. hem. (a few); left lung, Pneumococcus II atypical; left pleura, Pneumococcus II atypical. Case 188. Onset of measles, Oct. 3; admitted to hospital, Oct. 4; onset of bronchopneumonia, Oct. 14; recovered and discharged from hospital, Nov. 24. Bacteriology.—1. Throat cultures for: (a) S. hem., Oct. 5, -; 8, +; 12, +; 19? +. 20, +; 27, -; Nov. 2, -; 9, +-; 15, -; (b) B. influenzae, Oct. 5, -; 8, -; 12, +; 19, +. Case 678. Onset of measles, Oct. 23; admitted to hospital, Oct. 2.j ; onset of bronchopneumonia, Nov. 2; of otitis media, Nov. 9; of mastoiditis, Nov. 13; mastoid operation, Nov. 20; still under treatment. Bacteriology.—1. Throat cultures for: S. hem., Oct. 25, -; Nov. 4, -; 5, -; 12, +. 2. Sputum: Nov. 3, Pneumococcus Type IAr, and B. influenza?. 3. Cul- ture from mastoid bone at operation, Nov. 20, S. hem. Case 389. Admitted to hospital, Oct. 2, with diagnosis of influenza; onset of bronchopneumonia, Oct. 7; onset of measles, Oct. 13; phlebitis (right leg), Oct. 22; otitis media, Oct. 31; recovered. Bacteriology.—1. Throat cultures for: (a) S. hem., Oct. 16 -; 20, -; 27, +; Nov. 2, +; 9, +; 15, -; 2:5, -; 30, -; Dec. 7, -; 12, -; (b) B. influenzae, Oct. 16, -. ' Case 725. Onset of measles, Oct. 18; one week in measles barracks; ad- mitted to hospital, Oct. 27; onset of lobar pneumonia, Oct, 23; otitis media, Nov. 7; mastoid operation, Nov. 20; still under treatment. 312 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Bacteriology.—1. Throat cultures for: (a) S. hem., Oct. 29, -; Nov. 1, -; 5, -; 12, +; (6) B. influenza?, Oct. 29, +. 2. Sputum: Nov. 2, Pneumococcus II atypical. B. influenza?. 3. Culture from mastoid at operation, Nov. 20, S. hem. (c) Pneumococcus Pneumonias not Carrying Hemolytic Streptococci.—Thirty-four cases of pneumonia folloAving measles Avent through their entire course in the hospital Avith no throat culture positive for hemolytic streptococci. In some of these cases there are records of twehTe negative throat cultures. Eleven fatal cases occurred in this group. Autopsy findings and bacteriology shoAved in each instance that S. hemolyticus Avas not the cause of the pneumonia. Measles During the Course of Pneumonia.—Eleven cases of pneumonia Avhich deATeloped measles during the course of the pneumonia came under observation. Hemolytic streptococci appeared in the throats of 3 of these patients during convalescence, but there Avas no eA'idence that it in- vaded the lung. In one fatal case autopsy shoAAred that there Avas no streptococcus pneumonia; pneumonia folloAved influenza and the onset of measles occurred three days after the onset of bronchopneumonia. Bacteriology of Pneumonia Following Measles.—"When observations made during life are combined Avith the results of postmortem cultures, the bacteriology of 35 of the 56 cases is aA^ailable and is as folloAvs: Pneumococcus Type II atypical in 36 per cent, Type IV in 22.9 per cent, Type I in 2.8 per cent, Type III in 2.8 per cent, hemolytic streptococci in 22.4 per cent, and B. influenza* in 88.6 per cent of these cases. Otitis Media and Mastoiditis Complicating Measles.—The occurrence of otitis media and mastoiditis complicating measles in patients harboring hemolytic streptococci in their throats has already been presented (Table LXIV). The bacteriology of these complications Avas not studied by this commission. The records of the base hospital lab- oratory at Camp Pike contain reports of twenty-nine cul- tures made at operation from pus in the middle ear and SECONDARY INFECTION IN AVARD TREATMENT OF MEASLES 313 the mastoid bone. Hemolytic streptococci were found in 22 of these cases. Throat cultures were in accord with these positive findings in all except a few instances. The throat culture seiwes as a fairly reliable index of the bac- terial nature of these complications. l>y combining our records of throat cultures Avith the results of the cultures from the lesions, hemolytic streptococci were obtained from 37 of the 48 cases of otitis media. In 23 cases of mastoditis following the otitis media, hemolytic streptococci were dem- onstrated in all except 2. It is evident that the great ma- jority of these complications Avere due to hemolytic strep- tococci. The relation betAveen the appearance of hemolytic strep- tococci in the throat and the onset of the otitis is recorded in all except 4 of the 31 instances of otitis media occurring in patients Avith throat cultures positive for hemolytic streptococci. These four patients had positive throat cul- tures Avhen first observed and represent the only patients avIio carried hemolytic streptococci Avhen admitted to measles AA^ards and deATeloped complications. The first of these patients had been under treatment in an otologic AA~ard during a month before measles chwelopecl. Measles caused a recurrence of disease of the ear Avith double mastoiditis requiring bilateral operation. Taa^o other patients had been in the hospital ten and eloATen days respectively before they Avere admitted to the measles ward; on admission to the Avard otitis media Avas present in one patient and in the other it developed six days later. The fourth patient Avas admitted to the measles Avards di- rectly from the camp, and culture from the throat on the day of admission shoAved the presence of S. hemolyticus. Tavo Aveeks later at the time of onset of otitis media, culture from the throat contained no hemolytic streptococci. Re- peated cultures during the next three Aveeks Avere negative. Xo complications of otitis media developed and no direct cultures from the ear are recorded. 30 30 ZO 10 0 10 20 30 20 10 &±$ it: % Ifl ~ a 6 o k a. w EH « fc « Eh H > «3 Ph (h W complications associated with hem. strep, with dates of onset REMARKS Ward 57 11-3 11-10 11-17 35 13 16 1 2 6 2.8 15.5 37.5 None Ward 58 11-3 11-10 11-17 38 11 6 7 4 2 18.4 36.4 33.0 Otitis media: 11-8 1 case 11-7 1 case Wards 57 and 58 served by same ward staff. Members of staff cul-tured on 11-5, 11-12 and 11-19. No positives Ward 49 10-25 11-1 11-8 11-15 11-22 37 31 35 32 16 29 43 32 20« 11 7 3 9 18 7 18.9 9.7 25.7 56.3 43.8 Otitis media: 10-25 2 cases 10-26 1 case 10-28 1 case 11-15 1 case 11-18 1 case 11-27 1 case Ward 50 10-25 11-1 11-8 11-15 11-22 2 2 3 11 0 3.4 4.6 9.4 55.0 0.0 Otitis media: 11-8 1 case 11-13 1 case 11-22 1 case Wards 49 and 50 served by same AA-ard staff. Ward staff cultured: 11-5 1 positive 11-12 1 positive 11-26 2 positives Ward 41 10-28 11-4 11-11 Ward 11-21 11-28 12-5 12-12 45 34 12 closed 13 8 12 4 4 9 8 —No 0 4 4 3 8.9 26.5 66.6 patients. 0.0 50.0 33.3 75.0 Streptococcus pneu-monia : (11-9 1 case) 11-10 1 case Otitis media: 10-29 1 case 11-4 1 case 11-5 1 case 11-11 1 case 11-27 1 case 12-3 1 case Case of pneumonia developing on 11-9 was transferred to the "clean" pneu-monia ward without a throat culture to warrant its trans-fer ; last culture 11-4 negative; cul-ture 11-12 in pneu-monia Avard posi-tive Ward 42 10-28 11-4 AVard 10-21 11-28 12-5 12-12 32 43 closed 16 12 20 14 0 7 —No 4 1 10 7 0 16.3 patients. 25.0 12.5 50.0 50.0 Streptococcus pneumonia: 11-10 1 case 12-11 1 case Otitis media: 10-29 1 case 12-3 1 case 12-6 1 case Wards 41 and 42 served by same Avard staff. Ward staff cultured: 11-5 2 positive 11-12 2 positive 11-26 2 positive 12-2 1 positive SECONDARY INFECTION IN AVARD TREATxAIENT OF MEASLES 317 Table LXV—'(Concluded) Ward 59 Streptococcus pneumonia: The 3 cases of strep-tococcus pneumonia acquired S. hemoly- 10-24 37 6 16.2 10-17 1 case ticus infection Avhile 10-31 27 5 IS.5 10-21 1 case patients in the 16 11-7 9 3 33.3 10-29 1 caso bed south section 11-12 7 1 14.3 Otitis media: 11-1 1 case of this ward Case developing 10-29 was removed from section a few days before onset of pneumonia Ward 60 AVards 59 and 60 Streptococcus served by same pneumonia: ward staff. 10-24 1 4.5 10-21 1 case Ward staff cultured: 10-31 17 2 11.7 Otitis media : 11-5 0 positive 11-7 8 1 12.5 10-31 1 case 11-12 1 positive 11-12 6 1 16.6 11-19 0 positive "When the streptococcus complications are traced back to the Avards in Avhich the streptococcus infection of the throat Avas acquired, it is found that Avith the exception of Case 141 (already cited) all the streptococcus pneumonias arose from tAvo double Avards. Wards 41 and 42 furnished 4 cases at times Avhen streptococcus Avas rampant in them and 3 of these cases arose within a period of a feAv days. Wards 59 and 60 furnished 4 cases, very closely associated. In 3 cases the streptococcus infection Avas acquired in a section of Ward 59 containing 16 beds. These patients were in beds, of Avhich the positions are represented by num- bers 2, 5, and 7, along one side of the ward. The fourth instance of pneumonia appeared at the same time in Ward 60, which was attended by the same ward personnel, but no other connection can be established between this case and the other three. The otitis media appeared in patients scattered through- out those wards for measles in- which the weekly incidence of "carriers" Avas rising rapidly. This relation is illus- trated by Wards 58, 50, and 41. The same observation ap- plies to streptococcus pneumonia arising in Wards 41 and 42. In Ward 41 the weekly percentage of carriers are October 28, 8.9, November 4, 26.5 and November 11, 66.6. 318 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT On November 9 and 10 the first 2 cases of streptococcus pneumonia arising from this Avard developed. At the same time, November 10, a third case appeared in another part of this same ward unit (AVard 42) Avhere the spread of hemolytic streptococci had been ATory active. These ob- servations suggest that hemolytic streptococci may build up its Aurulence as the result of rapid dissemination to such a degree that it is capable of causing graATe compli- cations. The relation of complications to "carriers" in Wards 59 and 60 is different from that in the wards just cited. Wards 59 and 60 Avere opened on October 9 and before Oc- tober 17; Avhen the first case of fulminating streptococcus pneumonia occurred, only three "carriers" had been found in them. From October 17 to 24 Avhen the record in Table LXV begins eight "carriers" were removed. The appear- ance of a case of severe streptococcus pneumonia in an unusually clean ward Avas followed by the rapid develop- ment of "carriers," and the appearance Avithin tAvelve days of 3 other cases of streptococcus pneumonia, 2 of which Avere in beds close to the first case. This sequence suggests focal dissemination of a streptococcus from a case in Avhich it had suddenly assumed high A'irulence. An outbreak of infection Avith S. hemolyticus Avas recog- nized on November 12 in a measles-pneumonia Avard Avhich had been opened for several Aveeks and had continued free from streptococcus. In three patients hemolytic strepto- cocci Ave re found by throat cultures. Inquiry repealed that a nurse in this Avard, recognized as a streptococcus "car- rier" the week before, had been retained on duty. Tavo patients well advanced in the course of their pneumonias, had acquired S. hemolyticus demonstrated by throat ex- amination. Both patients developed otitis media Avith mas- toid extension requiring operations. Cultures from both at operation shoAved hemolytic streptococci. SECONDARY INFECTION IN AVARD TREATMENT OF MEASLES 319 The third patient, with acute pneumonia, had been sent into the Avard on November 11 from Ward 42, which at the time Avas a highly infected Avard; no culture of the throat was made before transfer. This patient developed strepto- coccus pneumonia Avith empyema requiring subsequent op- eration. Discussion.—At Camp Funston, whore the prevalence of S. hemolyticus in the measles wards did not rise above that among normal men in the camp at large, 112 consecutive cases of measles were treated without a single complication due to hemolytic streptococci. At Camp Pike, the investigation began at the onset of a small epidemic of measles at a time when hemolytic strep- tococci Avere an almost neglible factor. The epidemic of measles Avas folloAved throughout its course; and, Avith the passing of the epidemic, there Avas an increase in the prev- alence of hemolytic streptococci Avhich assumed alarming importance in the production of complications. The epidemic of measles Avas in part superimposed upon the epidemic of influenza, so that deductions concerning complications strictly due to measles became impossible. It is evident that influenza played a considerable part in producing the complications of measles at Camp Pike. The dissemination of hemolytic streptococci through measles wards Avas controlled only in part by the methods used. This partial control may haA'e seiwed to limit the incidence of streptococcus pneumonia, nine instances oc- curring among S67 cases of measles. In the AArard treatment of measles effort should be di- rected to preA'ont the exposure of patients free from hemo- lytic streptococci to S. hemolyticus "carriers." By this means the rate of development of S. hemolyticus "car- riers" may be reduced. Measures Avhich should lie adopted are as f oIIoavs : 1. Adequate Avards should be prepared in advance for the treatment of measles. The rather gradual onset of epidemics of measles makes this proAusion possible. 320 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT 2. The separation of S. hemolyticus "carriers" from other patients should be enforced. Observation wards, where strict technic to prevent transfer of infection is practiced and Avhere throat cultures are made on admission, are essential. Those Avards should be promptly evacuated to Avards for the care of S. hemolytic "carriers" on the one hand and for "noncarriers" on the other. As far as pos- sible patients should be admitted to a ward until it is filled and then another Avard should receive consecutive cases in the same manner. It is desirable to haATe all cases in each treatment ward in the same stage of the disease. With this system of Avard rotation convalescent Avards are neces- sary, so that cases requiring a period of hospitalization longer than the aATerage may be segregated, thus rendering treatment AYards available for another levy of acute cases. 3. Strict Avard technic elaborated to preA^ent transfer of bacterial infection from one patient to another must be employed. 4. Throat culture for identification of "carriers" is la- borious but essential. An accurate method for identifying and reporting "carriers" as speedily as possible must lie employed. A competent bacteriologist is essential. A twenty-four hour interval betAveen culture and its report is desirable. The following scheme is recommended: (a) A culture from the throat made on admission to the observation ward (first day in hospital). {b) A culture made on the first day in the treatment ward (third day in hospital). (c) A culture made one week later (tenth day in hos- pital). If the ward incidence of hemolytic streptococci reaches 10 per cent, especially in a filled ward, the cultures should be repeated on the thirteenth day in the hospital. If the incidence of "carriers" of hemolytic streptococci increase rapidly, cultures on alternate days should be made so that "carriers" may be removed from the ward. Wherever SECONDARY INFECTION IN AVARD TREATMENT OF MEASLES 321 possible, culturing of the treatment wards as units should be practiced. 5. Patients developing acute symptoms in any Avay sug- gestive of infection with S. hemolyticus should be imme- diately isolated; culture from the throat should be made at once and final disposal of the patient should depend upon its result. Carriers of Hemolytic Streptococci During the winter of 1917-18, with the establishment of the army camps, it very soon became evident that in many of the serious and fatal complications of measles and other respiratory diseases, hemolytic streptococci Avere playing a very important role. The epidemic prevalence of hemo- lytic streptococci among hospital cases, and later among men on duty in the camps, Avas established by bacteriologic studies. Prior to this time in civil life, hemolytic strep- tococci under epidemic conditions had been studied in milk- borne epidemics of septic sore throat, such as are reported from Chicago in 1911-131; from Boston in 19112; and from Baltimore in 1911-123. Contact air-borne infection has not been emphasized in considering the dissemination of hemo- lytic streptococci. Smillie4 reports a feAv cases of hemo- lytic streptococcus throat infections which he attributes to contact infection. Conditions Avithin the army camps were such as to suggest the dissemination of hemolytic streptococci by contact air-borne infection. Some knowl- edge of the percentage of individuals showing positive throat cultures became desirable at the very beginning of studies of contact dissemination of hemolytic streptococci. Smillie found that only one of 100 normal throats har- bored the Beta hemolytic streptococci of Smith and BroAvn. Levy and Alexander' report the presence of hemolytic iCapps, J. A., and Davis, D. J.: Arch. Int. Med., 1914, xiv, 650; Illinois Med. Jour., November, 1912. 2Windsor, C-E. A.: Jour. Infect. Dis., 1912, x. 73. 'Hamburger, L. P.: Jour. Am. Med. Assn., April 13, 1912, lviii, 1109. 4Smillie, W. S.: Jour. Infect. Dis., 1917, xx, 45. BLevy and Alexander: Jour. Am. Med. Assn., 1918, lxx, 1827. 322 PNEUMONIAS AND INFECTIONS OK RESPIRATORY TRACT streptococci in 83.2 per cent of healthy men at Camp Tay- lor, and hemolytic organisms (not definitely identified as streptococci) in 14.8 per cent of recruits arriving at Camp Taylor. Irons and Marine6 found hemolytic streptococci among 70 per cent of healthy men at Camp Custer. Among measles patients on admission to the hospital at Fort Sam Houston, Cole and MacCallum7 report 11.4 per cent and Cummings, Spruit and Lynch,8 35 per cent of throat cultures positive for hemolytic streptococci. At Camp Taylor, Levy and Alexander report 77.1 per cent positive among 388 cases of measles on admission to the hospital. The spread of hemolytic streptococci in measles Avards was shoAvn by Cole and MacCallum when on admission 11.4 per cent of cases had positive throat cultures, 38.6 per cent after from three to five days, and 56.8 per cent after from eight to sixteen days in the Avard. In our study of hemo- lytic streptococci Avith measles at Camp Funston, 2.6 per cent of the cases had positiA^e throat cultures on admission, 12.8 per cent after three to ten days, and 24.1 per cent after eight to^ tAventy-three days in the hospital. In a similar study at Camp Pike Ave found 1.7 per cent positive on ad- mission; 10.9 per cent after one Aveek; 22.8 per cent after two Aveeks; 26.2 per cent after three Aveeks; and, 33.1 per cent after four Aveeks in the hospital. Hemolytic Streptococci in the Throats of Normal Men.— The percentage of normal individuals harboring hemolytic streptococci in their throats Avas investigated in three dis- tinct classes of men, classified according to the degree of exposure to contact infection. The first group includes men largely from country dis- tricts, cultured ayithin an hour after being assembled by their local draft board. The laboratory car "Lister" Avas sent to Hot Springs, Ark. to meet the November draft of 6Irons and Marine: Jour. Am. Med. Assn., 1918, lxx, 687. 7Cole and MacCallum: Jour. Am. Med. Assn., 1918, lxx, 1146. 8Cummings, Spruit and Lynch: Jour. Am. Med. Assn., 1918, lxx, 1066. SECONDARY INFECTION IN AVARD TREATMENT OF MEASLES 323 men to be sent to Camp Pike. These men Ave re returned to their homes when the armistice Avas signed, so that there Avas no opportunity to study them after they had lived un- der camp conditions. The second group includes men on duty in Camps Funs- ton and Pike. These men, while largely from country dis- tricts, had been living crowded together in the camp for a period varying from a few weeks to several months. The third group includes normal men resident in the base hospitals at Ft. Riley and Camp Pike. This group includes at Camp Pike the medical personnel of the measles and measles pneumonia wards and represents individuals most exposed to contact infection Avith hemolytic strep- tococci. On the other hand, the group includes doctors, nurses and seasoned medical detachment men who are per- haps less susceptible to respiratory infections than are raw recruits. The results of studies of these groups are presented in Tables LNVI and LXVIT. Table LXVI Hemolytic Streptococci in Throats of Normal Men Not Resident in the Base Hospital Ph H PLACE OF STUDY £ w 9 H EH fe « En uh- DATE fc .r to s 2 W EH H £ m REMARKS O to ° H w ■ X _• A y multiplying the chances of identifying hemolytic streptococci by making parallel cultures from the saliva, and from the peritoneal exudates of mice in- oculated with saliva, hemolytic streptococci were found, in small numbers, in 3 instances. The findings in this group Avere only three throats lightly infected with hemo- lytic streptococci. They are in direct contrast with the findings among individuals living in camps under croAvded conditions and are in accord with the findings among re- cruits arriving in camp as recorded by Levy and Alexander. In the second group, men living for a time in camp, the findings at Camp Funston and at Camp Pike shoAv rather SECONDARY INFECTION IN AVARD TREATMENT OF MEASLES 325 striking differences. The loAver percentage incidence at Camp Pike is the more remarkable since the studies Avere made soon after the influenza epidemic had SAvept the camp and made necessary the hospitalization of about 20 to 25 per cent of the camp population. In the third group, namely, individuals resident in the hospital, percentage rates at Camp Funston are slightly higher than for men resident in camp. This difference disappears for the entire group at Camp Pike if Ave con- sider a single throat culture, as Ave must for the sake of comparison. The majority of these individuals at Camp Pike seiwed in measles Avards from Avhich patients carry- ing hemolytic streptococci Avere removed at Aveekly inter- vals. Seven and one-half per cent of the Avard personnel avcre positives Avhen first cultured. An additional 7.5 per cent acquired the streptococcus AAmile under observation. Duration of the "Carrier" State.—Unfortunately there are ATery feAV observations Avith regard to the duration of the "carrier'' state Avhich can be determined only by re- peated cultures at short intervals. "We haATo made no ob- servations of the duration of the "carrier" state in healthy men. Two hundred and forty-tAvo individuals carrying hemolytic streptococci ayc re identified in the Avard treat- ment of measles. All except 37 of these cases were "non- carriers" Avhen first observed. The remaining 205 include 166 contact "carriers" and 39 patients with acute symp- toms of infection by hemolytic streptococci. The complete record of throat cultures on these cases is presented in Table LXVIII. Group I includes 37 cases positive for hemolytic strep- tococci on admission. {a) Twenty-two of these remained positive throughout the period of observation. Four patients became negative after one or two weeks and later shoAved positive findings, leaving the hospital as positives. These are classified as "irregular." The results of culture were as follows: Cul- 326 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Table LXVIII Results of Throat Cultures in 242 Hospital Patients Identified as "Carriers" of Hemolytic Streptococci; (Yetukes Taken at Weekly Intervals CD m 0> 33 in £ Sh ■ I* „ , - 3 ' 3 3 3 3.3 3 ' £ ■^ •— , a : -^ , a a x i — 3 ' 3 3 3 3 3 , 3 i 3 u^lo^ o O ' u ', c *j ifl. O'fll J3 X'h31X II 67|Cases III !7j Cases + 1 1 + | + | + 1+7+ + 1 + 1 + +1±TI +1 -1 + + + + - + + -i+ + - + - + + + + -i + i^ 74lCases -l-T-F -M+_ -1-1 + -1-1 + -1-1 + 1 + 1 + -1-1 + -1-1 + -1-1 + o - e c X c« 3 ^ o u **£ £ o O P= a 0) o - - — — — IIIA IIIA llA 1 1 T i 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ** i i i + i i i + i i i + i i T + i II 1 1 1 1 r- GROUP 1 1 ' W 1 ! 1 1 -I-I 1 1 ' 1 i 9 i i i 7 ! i i; i ^5 S3* 1 1 1 1 1 1 1 1 M O S3 CO '-D CO 1 1 1 + i i i + col 4- 1st Culture 2nd Culture i i 5 i + + 1 J. 1 1 Ml CO 1 + ' 1 i 3rd Culture — i i i i + + + + i i i + i i i i i M + 1 1 + + 1 4th Culture — 1 + 1 1 M 1 + 1 io 1 + + to 1 + — + + 1 1 1 + + + i + + 1 + + + 1 M + 1 1 1 1 1 M + 1 1 1 O INS + 1 to h-' + + —' 1—' + _ M M — + 1 1 r i i i i + + + + i + i i i i + + + — 5th Culture 6th Culture 7th Culture —il 8th Culture 9th Culture 10th Culture 11th Culture 12th Culture h-» to J r-> |_l —' to =' p—■ i—^ i—>! s—> W. 4- No. of Con-tact "Carriers." — -------- ~ ~ — — — —' ! — - 1-1 — No. with Acute Hem. Strep. Complications E a c A > 3d r> —I A H O H t-3 C 5 ^ H ^ A < M ^ O 3: 328 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT tured once only, 7; positive after one Aveek, 7 ; positive after two weeks, 6; positive after three Aveeks, 2; irregular, 4. {b) Eleven of the patients entering as positives became negate, 10 after one Aveek and 1 after tAvo Aveeks. This group of cases furnishes no data concerning the duration of the "carrier" state, since all cases Avere posi- tive Avlien first observed. In 30 per cent of instances hemo- lytic streptococci disappeared Avithin the first iavo Aveeks of observation. Groups II to VIII include 205 patients avIio became pos- itive at some time during their stay in the hospital The arrangement in groups depends upon the length of time the patients remained in the hospital before acquiring S. hemolyticus. Ninety-five of these patients had no further cultures after the initial positive culture. Fourteen appear as "irregular," as defined above. These iavo classes of cases are omitted in the f olloAving summary of these groups. The initial positiATe culture is arbitrarily considered the day of infection and subsequent cultures mark off Aveekly intervals. {a) Thirty-nine patients had acute infections due to hemolytic streptococci. Thirteen of these patients passed from observation after their initial positive culture. The cases Avith repeated cultures after initial positive may be summarized as in Table LXIX. Table LXIX NO. patients cultured NO. BECOMING NEGATIVE PER CENT BECOMING NEGATIVE Recultured after one week Recultured after two weeks Recultured after three weeks Recultured after four weeks 26 14 7 2 7 8 4 2 26.9 57.1 57.1 100.0 The records Avithin this small group of cases indicate that hemolytic streptococci tend to disappear Avith the pass- ing of the acute infection. SECONDARY INFECTION IN AVARD TREATMENT OF MEASLES 329 {b) One hundred and sixty-six contact "carriers" are included in (1 roups II to VIII. Eighty-two of these passed from observation after their initial positive culture and 14 appear as "irregular." The cases with repeated throat cultures after the initial positive are summarized in Table LXX. Table LXX NO. PATIENTS CULTURED NO. BECOMING NEGATIVE PER CENT BECOMING NEGATIVE Recultured after one week Recultured after two weeks Recultured after three weeks Recultured after four weeks 70 22 5 4 26 9 5 4 37.1 40.9 100.0 100.0 These records indicate that contact carriers in great part harbor hemolytic streptococci during short intervals. A longer period of obsoiwation after the disappearance of hemolytic streptococci Avoulcl have been desirable in many instances. Some patients Avere folloAved Avith consistently negative cultures during three, four and free Aveeks after hemolytic streptococci had disappeared. It is difficult to explain those instances in Avhich nega- tivo cultures are interposed between positives. "Where one negative interrupts positive cultures, it is possible that the throat culture failed to demonstrate hemolytic streptococci Avhich were present. Such cases in this series fall Avithin the limits of the percentage error of throat culture iden- tification. Where tAvo or three, or eA^on four negative cul- tures intei'ATene, reinfection is not impossible. Relation of S. Hemolyticus "Carriers" to the Compli- cations of Acute Respiratory Diseases.—In the present study of measles it has been shown that pneumonia fol- loAving measles has been no more common in "carriers" than in "noncarriers." Nevertheless, pneumonia occur- ring in badly infected wards has been modified by strep- tococcus complications. More cases of otitis media have appeared in "carriers" than in "noncarriers." The possibility that mild otitis 330 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT media, Avhich Avould ordinarily pass unnoticed, might be- come evident as the result of streptococcus invasion must be considered. Levy and Alexander have made an impor- tant contribution to our knowledge of the role of hemolytic streptococci in measles. They find that "carriers" of hemolytic streptococci among measles patients are espe- cially predisposed to complications folloAving measles. Their cases Ave re draAvn from a camp population highly saturated Avith S. hemolyticus "carriers." In the organ- ization from Avhich 89 per cent of their patients with measles came, there Avere 83 per cent hemolyticus "car- riers" among men on duty. Among patients Avith measles, throat cultures Avere positiATo for hemolytic streptococci on admission in 77 per cent. It is (widont that all patients with measles have been exposed to hemolytic streptococci during the first day or Iavo after admission. Failure to carry streptococcus Avould appear to lie dependent upon ability to resist it rather than upon lack of opportunity for acquiring it. Of 388 cases observed by Levy and Alexander only 79 Avere "noncarriers" of hemolytic streptococci on admission, and of these, 27 became positive while under observation; only 52 remain as "noncarriers" of hemolytic streptococci. This small group must be regarded as a highly selected one, composed of individuals more than or- dinarily resistant to hemolytic streptococci and perhaps to all complications of measles. The chances are that these 52 cases placed under any circumstances might very Avell have been among the large number of measles cases in which no complications develop. Furthermore, it is not unlikely that any complication of measles may be modified by a streptococcus secondarily when about So per cent of the cases show S. hemolyticus in the throat, The complications in the cases of Alexander and Levy appear to have been caused in large part by streptococcus, but a complete bacteriologic study of them is not recorded. Complications among streptococcus "car- SECONDARY INFECTION IN WARD TREATMENT OE MEASLES 331 riers" are not identical Avith complications due to the streptococcus, and it is desirable to knoAY Avhat percentage of complications actually due to hemolytic streptococci oc- curred among the 85 per cent of patients with measles Avho carried hemolytic streptococci. Summary.—No hemolytic streptococcus complications occurred in 112 cases of measles observed at Ft. Riley, among which streptococcus "carriers" rose from 2.6 per cent on admission to 24.1 per cent before discharge from the hospital. The percentage of "carriers" of hemolytic streptococci among normal men in the camp supplying these cases Avas about 25.5 per cent. The influenza epidemic and a small epidemic of measles occurred in part simultaneously at Camp Pike during Sep- tember and October, 1918. The complications following measles at Camp Pike were to a considerable extent de- pendent upon the combined effects of influenza and measles. Thirty-five per cent of the measles patients showed throat cultures positive for B. influenzae on admission to the hospital. ()n repeated cultures, this rose to 84 per cent be- fore discharge. Ward separation of cases of measles carrying hemolytic streptococci in their throats and cases not carrying these organisms were practiced in handling this epidemic. Of 867 cases of measles treated in this manner, 37 ayc re posi- tive for hemolytic streptococci on admission, and 205 de- veloped positive throat cultures for these organisms dur- ing their period of observation in the hospital. At Camp Pike, the percentage incidence of S. hemolyti- cus "carriers," on admission to the measles wards, was 4.2 per cent. In cases recultured offer one Aveek, it was 10.9 per cent; after two Aveeks 22.8 pen- cent: after three Aveeks 26.2 per cent; and after four weeks 33.1 per cent. The weekly development of "carriers" in the "clean" treatment wards Avas during the first week 9.1 per cent; during the second Aveek 17.4 per cent; during the third 332 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT week 17.4 per cent; and during the fourth week 17.4 per cent. The principal complications of these 867 cases of measles at Camp Pike Avere; pneumonia, 56 cases; otitis media, 48 cases, Avith subsequent mastoiditis in 23 cases, 2 of Avhich had extensions to the meninges and brain. The greater part of the pneumonia occurred early in the period of ob- seiwation, Avhile most of the otitis media occurred later. Incidence of hemolytic streptococci Avas Ioav during the pneumonia period and high during the prevalence of otitis media. Hemolytic streptococci complicated 9 of these pneumo- nias; caused a large percentage of otitis (bacteriology in- complete), and 21 of the 23 cases of mastoiditis. The bacteriology of 35 of the 56 pneumonias shoAved: Pneumococcus Type II atypical, in 36 per cent, Type IV in 22.9 per cent, Type I in 2.8 per cent and Type III in 2.8 per cent; hemolytic streptococci in 22.4 per cent; and B. influ- enzas in 88.6 per cent. The culturing of wards as units revealed widespread con- tact dissemination of hemolytic streptococci, at times 25 to 50 per cent of the patients in a A\-ard becoming "car- riers" Avithin the period of a week. Streptococcus pneu- monias, otitis media and its complications were furnished in large part by wards in which active dissemination occurred. Streptococcus complications did not occur among 37 pa- tients who Avere "carriers" of hemolytic streptococci when admitted to the hospital. The epidemic dissemination of hemolytic streptococci oc- curs in measles wards, and is a serious danger. Many pa- tients Avhose throats become infected, develop no symptoms. In some instances streptococcus invades, and renders much more serious lesions caused by other microorganisms. Methods to prevent transfer of infection Avithin the Avard and separation of "carriers" from "noncarriers" in dif■■ SECONDARY INFECTION IN WARD TREATMENT OF MEASLES 333 ferent AYards are efficient in keeping epidemic dissemina- tion of hemolytic streptococci under control. Frequent throat cultures and prompt report of the results of cul- tures are essential. The dissemination of B. influenza? in patients with meas- les was not controlled by segregation of "carriers" and "noncarriers" of this organism as identified by throat cul- tures in separate AYards. CHAPTER VI THE PATHOLOGY AND BACTERIOLOGY OF PNEUMONIA FOLLOWHNC MEASLES Eugene L. Opie, M.D.; Francis 0. Blake, M.D.; James C. Small, M.D.; and Thomas M. Rivers, M.D. Among 18 autopsies upon men ayIio haAe died Avith pneu- monia folloAving measles there are pulmonary lesions rep- resenting almost every type of pneumonia Avhich has been found in association Avith influenza. In most instances pneumonia made its appearance during the second week of measles and death occurred during the third Aveek. Of 16 instances in Avhich the record is definite, pneumonia had its onset during the first Aveek of measles in 4 instances, during the second Aveek in 11 instances, and in one instance (Au- topsy 390) perhaps not referable to measles in the fifth Aveek. The duration of pneumonia ATaried from three to thirty-two days; in 10 instances it did not exceed one Aveek, in 5 instances it Avas betAveen one and two Aveeks and in one instance, thirty-tAvo days. When the duration of pneu- monia exceeded ten days some evidence of chronic pul- monary disease Avas found at autopsy. The same lack of correspondence between clinical diag- nosis and pulmonary lesions noted with influenza Avas found folloAving measles. In accordance AATith the prcwailiiig opinion concerning the character of pneumonia folloAving measles, the diagnosis of bronchopneumonia Avas made in 13 instances and in all of these cases bronchopneumonia Avas found at autopsy. The diagnosis of lobar pneumonia A\'as made 5 times and Avas correct only once. Ne\Tertheless, lobar pneumonia was present 4 times, but Avas recognized only once (Autopsy 486.) Failure to recognize lobar pneu- 334 Table LXXI > X s, 0 H D < fa c 0 z w u < > a. < §g p S w Z 7) w J C/l a z -1 J to 0 Z 0 < X D Q < Z C 3 D a z a. to C Z 0 H < a! 0 ir. z z t/1 a (/> w w u pa Bi W H a. (/: ^3 § s w a. S (/! on < H u w 3 u z c a! PC 0 X u z o tt n < gz > 2 J s o -IS* ee <■ Z ~ P X H 5 z 0 s: PC 0 Z z < c a: 0 7. Z < 2 a H U < 03 i/i D X f~J 7. O a. pq z < 2 a H U < a z j z < 5 w H U < O Q O 0 J a Z «H a, a, w < H H UX m 390 438 439 441 W W w w vv w vv vv vv vv w c w w w c c c lm. 2m. lOd. lm. lm. 21d. lm. 29d. 36 d. 54 d. 42 d. 6d. 2m. 49 d. lm. 4m. 5m. 2m. 35 22 14 16 17 23 9 19 13 4+ 20 17 19 20? 43 16 14 16 6 12? 11? 11 2 + 14 3 5 6 3? 7 8 5 11? 32 6 3 5 L B B B L B B B B B B L B L L B B B P P P P P P P P P P "+ ' + M + M + M + M M + + + + + + + + + + + + + E + + + + B. inf............ Pneum. 11, S. vir. B. inf., S. hem.... Pneum. Ila.S,aur B. inf., S. aur . . 0 No S. hem....... No S. hem....... B. inf........... B.inf.,No. S.hem. B coli.................... 0 M 'm' B. inf., S. aur............. 0 N + E 443 444 450 453 481 484 486 491 492 496 505 507 508 + + B. inf., B. coli............ Pneum. Ila, B. inf....... B. inf.. Staph............. B. coli........... 0 Pneum. Ila,B.inf. B. inf........... Pneum. 1........ B. inf........... Pneum. II a. Pneum. IV. + + + M + + + + + No S. hem....... Pneum. IV, B. inf. B. infl., Pneum. Ila, S.hem. 0 M 0 B. inf., Pneum. II a, S. hem., Staph............ B. inf., B. coli............ B. inf........... + + + E E 0 P P P "+' M + + + M + + + + + + B. inf., no S. hem B. inf................... B. coli.. B. inf___ 0 S. hem., S. aur. . . 0 Pneum. 11 a, S. hem....... N + E + M M Pneum. 11 a, B. inf., S. hem. 336 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT monia, Avas doubtless due in part at least to its association Avith purulent bronchitis and peribronchiolar pneumonia (Table LXXI). Changes in Bronchi.—The changes in the bronchi do not differ in character from those associated Avith pneumonia following influenza. Purulent bronchitis recognized at au- topsy by the presence of mucopurulent material in the small bronchi Avas found in a much larger proportion of instances in this group of autopsies occurring in 13 of 18 instances (72.2 per cent), Avhereas it Avas present in only 55.6 per cent of autopsies on individuals Avith pneumonia folloAving influenza. There Avas peribronchial hemorrhage recognizable on gross examination in 3 autopsies and mi- croscopically in 3 additional instances. Bronchiectasis Avas present in a considerable proportion of these autopsies, dilatation of bronchi being noted in 7. but it Avas usually moderately adATanced and at times limited to the bases of the lungs. The short duration of respira- tory disease perhaps explains the infrequency of adATanced bronchiectasis. The incidence of the lesion is greater Avith measles (43.7 per cent) than Avith influenza (22.4 per cent). Microscopic changes in the bronchi do not differ from those found after influenza. Evidence of acute inflamma- tion, often hemorrhagic in character, is found Avithin the lumen of the bronchus and in the tissues immediately in contact Avith the lumen. Not infrequently the epithelium is lost; there is superficial necrosis and deposition of fibrin upon the surface and Avithin the tissue. In the deeper tis- sues of the bronchial Avail there is infiltration with lymphoid and plasma cells, which in the larger bronchi is particularly advanced about the mucous glands of which the acini ex- hibit degenerative changes. With the onset of chronic changes new formation of fibrous tissue occurs in the Avail of the bronchus and in the contiguous interalveolar Avails. The lining epithelium often loses its columnar cells and assumes a squamous type. PATHOLOGY AND BACTERIOLOGY FOLLOWING MEASLES 337 Changes in the bronchi with bronchiectasis have been similar to those following influenza. Weakening of the Avail permitting dilatation is brought about by necrosis ex- tending outward from the lumen a varying distance into the bronchial Avail and permitting the formation tears which diminish resistance to intrabronchial pressure. Lobar Pneumonia.—Lobar pneumonia following measles occurred in 4 instances. Onset in these cases was on ap- proximately the 9th, 10th, 11th or 14th day of measles; the onset of bronchopneumonia bore a similar time relation to the onset of measles, the aA'erage inteiwal being nine days. Hepatization Avith lobar pneumonia Avas in 1 instance red, in 3 instances gray, and in all sa\Te 1 instance the consolidation was firm and coarsely granular on section. In the excep- tional instance the greater part of the right upper lobe Avas laxly consolidated and rather finely granular but the mi- croscopic appearance Avas in all instances that of lobar pneumonia. Lobar pneumonia in 2 of these cases Avas as- sociated Avith purulent bronchitis present in parts of the lung that had not undergone consolidation, Avhereas in the other 2 instances there Avere acute bronchitis and peri- bronchiolar pneumonia recognized by microscopic exam- ination. In one instance hepatization of the lung presented some noteAvorthy features. Autopsy 450.—G. D., white, aged twenty-one, a farmer, resident of Arkan- sas, had been in military service twenty-nine days. Onset of illness began on October 2, nineteen days before death, and on admission on the same day the diagnosis of measles was made. Signs of pneumonia, regarded as bron- chopneumonia, were recognized five days before death. Three days later there was otitis media and paracentesis was performed. On October 3 and 10 neither S. hemolyticus nor B. influenzae was found in the sputum; on Octo- ber 17 and 20 S. hemolyticus was not found but B. influenzas was present. Anatomic Diagnosis.—Acute lobar pneumonia with gray and red hepati- zation in right upper and lower lobes; edema and peribronchial hemor- rhage in left lung. The entire lower lobe of the right lung (Fig 29) with the exception of a narrow air-containing zone in contact with basal surface is firmly con- solidated. The greater part of the consolidated tissue is yellowish gray, 338 PNEUMONIAS AND INFECTIOXS OF RESPIRATORY TRACT Fig. 29.—Isobar pneumonia following measles, showing extension of gray hepatiza- tion from lower to upper lobe through a defect in the septum separating the two lobes. Autopsy 450. PATHOLOGY AND RACTERTOLOGY FOLLOWING MEASLES 339 firm and coarsely granular. The uppermost part of the consolidated tissue is softer than elsewhere as if it has undergone autolysis. The lowermost part of the consolidated tissue in a zone from 2.5 to 3.5 em. in breadth is firmly consolidated but deep red. The bronchi contain stiff plugs of fibrin. In the upper lobe continuous with the consolidated part of the lower is a semicircular patch of yellowish gray consolidation. It overlies the line of the interlobular cleft at the site of a break in its continuity. Consolidation appears to have spread from the lower lobe into the upper at the site where the alveolar tissue of the two lobes is continuous but is absent from that part of the upper lobe separated from the lower by the interlobular cleft. This semicircular patch of yellowish gray consolidation is separated from air containing tissue of the upper lobe by a zone of red hepatization, about 1 cm. in thickness. Bacteriologic examination showed the presence of Pneumococcus IV in the blood of the heart; B. influenzae alone was obtained from the right lower lobe and B. influenzas and staphylococcus from the left main bron- chus. The distribution of lobar pneumonia in the foregoing autopsy indicates that it has spread like a AvaA'e from the upper part of the loAver lobe (Fig. 32) penetrating into the upper Avhere the alveolar tissue of the two lobes is in con- tact ; gray hepatization is everywhere separated from air containing tissue by an adATaucing zone of red hepatiza- tion. It ma}T be assumed that lobar pneumonia Avas caused by Pneumococcus II atypical in 3 instances although it was recoATered from the lungs only tAvice, for in the third in- stance (Autopsy 486) it Avas found in the bronchus and in the inflamed pleural cavity; pneumococci were doubtless previously present in the lung, but had disappeared at least from that part from which the culture Avas made. Pneu- niococcus IV Avas evidently the cause of pneumonia in 1 instance (Autopsy 450), for it was found in the blood of the heart although it Avas absent in the culture from the lung. Little significance can be attributed to the observation that B. influenza was present in pure culture in the lungs from Autopsies 450 and 486, for the presence of Pneumo- cocci IV in the blood of the heart in Autopsy 450 and of 340 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Pneumococcus II atypical in the pleura in Autopsy 486 fur- nishes evidence in aucay of the occurrence of lobar pneu- monia that pneumococci had disappeared from the lungs. B. influenzae Avas found both in the lungs and bronchus or in the bronchus alone in 3 of these 4 cases. The relation of hemolytic streptococci to the lesion is of interest. In 3 of 4 instances of lobar pneumonia this mi- croorganism had entered the bronchi but Avas not found in the lungs or in the heart's blood; and gross and histologic examination shoAved none of the lesions Avhich are usually caused by it. In 1 instance (Autopsy 508) hemolytic strep- tococci, absent from the throat Avhen the patient Avas ad- mitted to the hospital Avith measles sixteen days before death, appeared in a culture made five days later and Avas subsequently found three times; it had penetrated into the bronchus but failed to reach the lung. Observations made upon lobar pneumonia f ollowing influenza haATo sIioaaui the relative insusceptibility of lobar pneumonia Avith gray hepatization to secondary infection Avith hemolytic strepto- cocci (p.160). Autopsy 508 demonstrates that occurrence of hemolytic streptococci in the sputum of a patient Avith pneu- monia does not furnish conclusiA'o proof of the existence of streptococcus pneumonia. Bronchopneumonia.—Bronchopneumonia has been found in every instance of pneumonia folloAving measles saATe 3, namely in Autopsy 486, Autopsy 505 with lobar pneumonia and Autopsy 507 with interstitial suppurative pneumonia. It is not improbable that further histologic study might have demonstrated small patches of peribronchiolar pneu- monia, for purulent bronchitis was present in the two autop- sies with lobar pneumonia. This small group of cases has re- produced all of the important features of bronchopneumo- nia folloAving influenza. Hemorrhagic peribronchiolar con- solidation characterized by the inesence of small gray spots clustered about terminal bronchi upon a homogeneously red background has been found in 5 of 18 instances of pneu- PATHOLOGY AND BACTERIOLOGY FOLLOWING MEASLES 341 monia Avith measles. Pfeiffer regarded this lesion as char- acteristic of the pneumonia of influenza. Peribronchiolar patches of consolidation Avith no surrounding hemorrhage were found in 14 instances, being recognized first by mi- croscopic examination in half of this number. Lobular consolidation occurred in 11 autopsies and peribronchial fibrinous pneumonia Avas present in a third of the autopsies on patients with pneumonia of measles. Bronchial, peribronchial and intraalveolar hemorrhage is much more commonly associated Avith the pneumonias of influenza than Avith the more familiar types of acute bron- chopneumonia. Exuded blood may undergo absorption; and Avith bronchopneumonia Avhich, persisting unresolved, has assumed the characters of a chronic lesion, it is com- mon to find mononuclear cells often in great abundance filled with brown pigment derived from the hemoglobin of red blood corpuscles. Autopsy 439 is an example of acute hemorrhagic broncho- pneumonia ; there are red lobular and confluent lobular patches of consolidation Avhich upon the pleural surface haATe a blue or purplish color. In the dependent part of the left lung occupying a large part of the lower lobe there is lax, red consolidation marked by gray or yelloAvish gray spots of peribronchiolar pneumonia and in this lobe bronchi are encircled by zones of hemorrhage. Pneumococcus II atypical was obtained from the lung. In Autopsy 444 the lesion has the same hemorrhagic character although lob- ular patches are in a stage of grayish red hepatization. Pneumococcus II atypical has been found in the heart's blood, and with B. influenza? in lungs and bronchus. Au- topsy 441 is an example of the occurrence of conspicuous nodules of peribronchiolar consolidation in some parts of the lungs with the same lesion in other parts on a back- ground of hemorrhage. B. influenza} and S. aureus have been found in both lungs and bronchi. 342 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Steinhaus1 states that the pneumonia of measles is never lobular inflammation but occurs in small patches several of Avhich may lie found in a single lobule. Chronic fibroid pneumonia folloAving measles character- ized by cellular infiltration and proliferation of the intersti- tial tissue of the lung has been described by Bartels,- Stein- haus,3 Hart,4 MacCallum3 and others. Fig. 30.—Unresolved bronchopneumonia with measles showing new formation of fibrous tissue about a bronchus and in immediately adjacent alveolar walls; partially obliterated alveoli occur in the peribronchial fibrous tissue. Autopsy 481. The incidence of unresolved bronchopneumonia among instances of bronchopneumonia folloAving measles is higher than that among bronchopneumonias folloAving influenza. There have been 6 instances of chronic or unresolved bron- chopneumonia among 18 pneumonias following measles, 'Steinhaus: Ziegler's Beitr. 1901, xxix, 524. 2I!artels: Yirchows Arch. f. path. Anat.; xxi. 3Loc. cit., p. 116. 4Hart: Deutsch. Arch. f. Klin. Med., 1904, lxxix, 108. PATHOLOGY AND BACTERIOLOGY FOLLOWING MEASLES 343 namely 33.3 per cent, The incidence of unresolved broncho- pneumonia among 241 autopsies on pneumonia following in- fluenza has been 21, namely 8.7 per cent. The essential fea- tures of this chronic lesion have been as follows: (a) chronic peribronchiolar pneumonia indicated by the presence of firm nodules of peribronchiolar consolidation which have considerable resemblance to miliary tubercles. Induration of Fig. 31.—Unresolved bronchopneumonia with measles showing a nodule of chronic fibrous pneumonia surrounding a respiratory bronchiole. Autopsy 481. the nodule occurs because the walls of alveoli surrounding and adjacent to a respiratory bronchiole (Fig. 31) become thickened and infiltrated Avith cells and there is organiza- tion of exudate Avithin the alveoli. New formation of fibrous tissue (Fig. 32) occurs where the acute inflamma- tory reaction of peribronchiolar consolidation is most ad- A^anced (p. 169 and compare Avith Figs. 3 and 4), namely, about the respirator)' bronchiole, alveolar duct and the 344 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT proximal parts of the infundibula, disappearing as the dis- tal half of the infundibulum is approached. Distention of the alveoli explaining the distention of the lung and its fail- ure to collapse on section is a noteAvortlry feature of the lesion, {b) Chronic peribronchial inflammation (Fig. 30) Avith neAv formation of fibrous tissue about the smaller and medium-sized bronchi extending into immediately adjacent alveolar Avails and often associated Avith organization of peribronchial fibrinous pneumonia. (c) Chronic lobular inflammation with changes similar to those just cited, dis- tributed throughout entire lobules, (d) Moderate thicken- ing of interlobular septa. Bronchiectasis may be associ- ated with the chronic lesion (Autopsies 443, 481, 484, 492 and 496) but with one exception (Autopsy 443) has been PATHOLOGY AND BACTERIOLOGY FOLLOWING MEASLES 345 only moderately advanced. Suppurative pneumonia Avith abscess formation has occurred twice (Autopsies 438 and 492). With acute bronchopneumonia following measles the av- erage duration of pneumonia, determined by the date upon Avhich physical signs of pneumonia were first recognized and in consequence subject to some error, was seven days; in instances of chronic bronchopneumonia the average duration of pneumonia has been fifteen days. The bacteriology of acute bronchopneumonia following measles is sIioavu in Table LXXII. Table LXXII WITH NO SPUTUM BACTERIA IN BACTERIA IN BACTERIA IN SUPPURATION IN LIFE BLOOD OF HEART LUNGS BRONCHI Autopsy 390 Pneum. II atvp. 439 0 Pneum. II atyp. S. aur. B. coli 441 0 B. inf., S. aur. B. inf., S. aur. 444 B. inf. Pneum. II atyp. Pneum. II atyp. B. inf. Pneum. II atyp. B. inf. 453 Pneum. I Pneum. I Pneum. I, B. inf. AVith suppuration: 442 S. hem. S. hem. B. inf., S. hem. 491 S. hem. S. hem. S. hem., B. coli B. inf., B. coli 507 S. hem. S. hem. S. hem., S. aur. S. hem., B. inf., S. aur. It is noteAvorthy that pneumococci haATe been recovered from the heart's blood or lung in all but 1 (Autopsy 441) of 5 instances of acute bronchopneumonia Avith no suppuration and is doubtless the cause of this pneumonia. Pneumococ- cus II atypical has been found in 3 of 4 instances of lobar pneumonia following measles and is present in 3 of these 5 instances of bronchopneumonia. "Where suppuration has been found, hemolytic strepto- cocci have been present in the sputum, in the heart's blood and either in the lungs (Autopsy 491) or in the bronchi (Au- topsy 442) or in both (Autopsy 507). In these instances pneumococci have not been found, though in view of the readiness Avith which pneumococci disappear from the lungs 346 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT it is possible that they have been the primary cause of bronchopneumonia. The bacteriology of 6 instances of unresolved broncho- pneumonia folloAving measles is given in Table LXXII!. Table LXXIII WITH NO SPUTUM BACTERIA IN BACTERIA IN BACTERIA IN SUPPURATION IN LIFE BLOOD OF HEART LUNGS BRONCHUS Autopsy 443 0 B. coli B. inf., B.coli 481 0 B. inf. B. inf., Pneum. II, atyp., S. hem. 484 Pneum. IV., B. inf. 0 0 B. inf., diph-theroids 496 Pneum. IV. B. inf. 0 0 B. inf. With Suppuration: Autopsy 43S B. inf. 0 Pneum. II atyp., S. vir. B. inf. S. hem. S. hem., B. inf. 492 St. hem., B. inf. S. hem. S. hem., Pneum. IV, B. coli, B. inf. Whereas Avith acute bronchopneumonia death has been accompanied and perhaps caused by bacterial invasion of the blood by pneumococci or streptococci in 5 of 7 instances, with unresolved or chronic bronchopneumonia bacteriemia has been present only once, namely, in Autopsy 492 in Avhich Avith suppurative pneumonia hemolytic streptococci haAxe entered the blood. It is probable that pneumococci have likewise had an important part in the causation in these instances of bronchopneumonia Avhich have run a chronic course but in all save 2 cases (Autopsies 438 and 492) have disappeared from the lungs. Pneumococcus II atypical has been found twice. B. influenza? has been found in association Avith acute bronchopneumonia in the lungs in 1 of 6 examinations and in the bronchi in 5 of 6 examinations. These figures indi- cate that it is present in small numbers if at all in the con- solidated lung tissue but is relatively abundant in the bron- chi. With chronic bronchopneumonia B. influenzae has been PATHOLOGY AND BACTERIOLOGY FOLLOAVING MEASLES 347 found in every instance, in half of the examinations of lungs and in all of the examinations of bronchi. In 1 instance (Autopsy 481) B. influenza has been found in pure culture in the lung; Pneumococcus II atypical has been found in the bronchus and has perhaps disappeared from the pneu- monic lung, since this microorganism is often destroyed in the late stages of pneumonia so that its demonstration at autopsy is no longer possible. In 1 instance B. influenza found in the bronchus has been the only microorganism isolated at autopsy, although the sputum during life con- tained B. influenza? and Pneumococcus IV. Suppurative Pneumonia.—Suppurative pneumonia with formation of abscesses has occurred in 2 autopsies Avith pneumonia folloAving measles (Autopsies 438 and 492), both instances of chronic bronchopneumonia. In Autopsy 438 the loAver and posterior part of the left loAver lobe has been consolidated and has had on section a cloudy, grayish red color; Avithin this area of consolidation and immediately be- low the pleural surface there haATe been opaque, yellow- spots where the tissue has been softer than elsewhere. Mi- croscopic examination shows that the tissue has here under- gone Avidepread necrosis so that all nuclear stain has disap- peared; at the edges of the necrotic tissue polynuclear leucocytes are often present in large numbers, but necrosis is much more conspicuous than suppuration. In the necrotic tissue and at its edges streptococci are present in vast num- bers. Hemolytic streptococci have been grown both from the lung and from the bronchus, but these have not been the only microorganisms present, for Pneumococcus II atyp- ical and S. viridans have been obtained from the lungs and B. influenza from lungs and bronchus. In Autopsy 492 with chronic bronchopneumonia the pos- terior half of the right lower lobe is laxly consolidated, dee]) red in color and with the cloudy appearance often asso- ciated with streptococcus pneumonia; upon this background are peribronchiolar spots of yellow color, in places well 348 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT seen beloAv the pleura; in the corresponding part of the left loAver lobe similar nodules have been converted into small abscesses by central suppuration. There is empyema on the right side, fibrinopurulent pericarditis, and purulent peritonitis. Hemolytic streptococci had been found in the sputum three times, the first examination being thirteen days before death. This microorganism is found in pure culture in the blood of the heart and Avith Pneumococci IV, B. coli and B. influenza? in the lung. Hemolytic strepto- cocci Ave re found in the right pleural exudate and perito- neum. The pneumonias folloAving measles giAe opportunity to consider the relationship of suppuratiATe interstitial pneu- monia to unresolved or chronic bronchopneumonia, Avhich is characterized by infiltration and proliferation of the fibrous tissue of the lungs. A number of those ayIio haATe studied the pneumonia of measles have recognized that this chronic interstitial lesion is a common sequela of measles. MacCallum has designated the lesion "interstitial broncho- pneumonia," and has included under this name its acute stage in Avhich the interstitial character of the lesion is not more cwident than Avith other forms of acute bronchopneu- monia. He has regarded S. hemolyticus as the cause of '"interstitial bronchopneumonia" folloAving measles. A revieAv of the autopsies which he has described sIioavs that he has included under the same designation typical in- stances of interstitial suppurative pneumonia associated with suppurative lymphangitis. Instances of unresolved, chronic or "interstitial" bronchopneumonia and of inter- stitial suppurative pneumonia AAdiich Ave have observed after measles, demonstrate that the two lesions are distinguish- able both by their anatomic characters and by their etiology. Three instances of suppurative interstitial pneumonia occurred among the pneumonias following measles (Au- topsies 442, 491 and 507). The lesion is characterized by suppuration of the interlobular septa and particularly note- worthy is the occurrence of suppurative lymphangitis, PATHOLOGY AND BACTERIOLOGY FOLLOWING MEASLES 349 lymphatics being immensely dilated and distended with purulent fluid so that their irregularly dilated, beaded ap- pearance is recognizable upon the section of the lung. In the group of pneumonias f olloAving measles this lesion has not been associated Avith unresolved or chronic broncho- pneumonia ; no nodular tubercle-like foci of bronchopneu- monia have been found at autopsy, and there has been no thickening of the interstitial tissue. The lesion has accom- panied confluent lobular pneumonia in 2 instances (Autop- sies 442 and 491). In the third instance (Autopsy 507) there Avas in the neighborhood of the suppuratiATe lesions diffuse consolidation Avhich had the cloudy, gray red color of streptococcus pneumonia, but this consolidation Avas not lobular in distribution. The etiology of interstitial suppurate pneumonia es- tablished by study of instances folloA\7ing influenza is con- firmed by Table LXXII (p. 345) shoAving the bacteriology of instances of acute bronchopneumonia f olloAAung measles. Pneumococci are almost invariably found in uncomplicated instances of bronchopneumonia and hemolytic streptococci haA^e been absent, Avhereas in 3 instances of suppurative interstitial pneumonia hemolytic streptococci have been found in the sputum during life, in pure culture in the blood of the heart and in the lungs and bronchus (missed in the bronchus in one instance, Autopsy 507). In the 3 instances of the disease B. influenza has been found in the bronchi. Table LXXIII shoAvs that suppuration has accompanied unresolved bronchopneumonia ("interstitial bronchopneu- monia") in 2 instances (Autopsies 438 and 492), but in these instances the interlobular tissue of the lung has not been the site of suppuration and there has been no suppura- tive lymphangitis. Localized abscesses have been formed; hemolytic streptococci, as Avith abscesses folloAving influ- enza, have been found. Empyema has occurred only 5 times in association Avith pneumonia folloAving measles and in these 5 instances has 350 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT been associated Avith suppuratiATe pneumonia caused by hemolytic streptococci. In Autopsy 492 there Avas fibrino- purulent pleurisy on both sides. Aspiration had been per- formed 3 times and at autopsy the right pleural caATity con- tained 150 c.c. of purulent fluid. In small pockets, corre- sponding to shalloAv oval depressions upon the anterior surface of the lung, fluid Avas Availed off from the general caArity. The pericardial cavity contained 25 c.c. of turbid yelloAv fluid containing yelloAv flakes of fibrin and the peri- toneal cavity contained thick purulent fluid. Hemolytic streptococci present in the heart's blood and lung Avere re- coA^ered from the right pleural caATity and from the peri- toneum. Among 3 instances of empyema accompanying interstitial suppuratiATe pneumonia, in 1 (Autopsy 491) there1 Avere Availed off pockets of fluid similar to those just described. Aspiration of the right pleural caA'ity had been performed 3 times; at autopsy 100 c.c. of fibrinopurulent fluid Avas found on the right side and 450 c.c. on the left. There Avas general purulent peritonitis and the peritoneal caATity contained 350 c.c. of thick yelloAv pus. Hemolytic streptococci Avere obtained from the heart's blood, right lung, right pleural cavity and peritoneum. Among 4 instances of lobar pneumonia following measles there Avas serofibrinous pleurisy 3 times; in 1 instance there is no record of pleural change. In 1 instance of lobar pneumonia (Autopsy 505) the right pleural cavity con- tained 800 c.c. of serofibrinous exudate and the pericardial cavity contained 510 c.c. of opaque, yellow seropurulent fluid; Pneumococcus II atypical in pure culture was ob- tained from the blood, lung and pleural and pericardial exudates. Among 9 instances of bronchopneumonia follow- ing measles there was fibrinous pleurisy 3 times, serofibrin- ous 3 times, and no recorded lesion of the pleura 3 times. Empyema, like suppurative pneumonia following measles, is in most instances, but not constantly, caused by invasion of hemolytic streptococci. PATHOLOGY AND BACTERIOLOGY FOLLOWING MEASLES 351 The foregoing study has shown that pneumonia which has followed measles has reproduced all of the lesions usually found after influenza. There is no pulmonary lesion peculiar to measles. Lobar- pneumonia follows the disease in some instances, but bronchopneumonia with purulent bronchitis is more common. The same tendency to hemorrhagic inflammation found Avitli the pneumonia of influenza is seen after measles. Unresolved pneumonia with chronic inflammatory changes in the interstitial tissue of the lung has all of the characters of the similar lesion folloAving influenza but has been found in a larger propor- tion of the pneumonias of measles. B. influenza has been found in the bronchi in 14 of 16 examinations, namely in 87.5 per cent of fatal instances of pneumonia. In 1 instance in which B. influenza? has not been found at autopsy, it has been isolated from the sputum during life. It is not improbable that B. influenza? has been constantly present in the inflamed bronchi both after influenza and measles. It is noteAvorthy that the outbreak of pneumonia folloAving measles has been in part coincident Avith, in part slightly subsequent to, an epidemic of influ- enza AAdiich has exposed every individual in the camp to in- fection Avith this disease. B. influenza? has been found in the lung Avith the pneumo- nia of measles in 7 of 17 examinations, namely, in 41.2 per cent of instances. The microorganism with measles, as with influenza, is found in the inflamed lung only half as frequently as in the bronchi. It appears to be peculiarly adapted for multiplication Avithin the bronchial tubes, and its isolation from the inflamed lung in less than half of the cases of pneumonia is perhaps referable to its presence in the small bronchi and bronchioles. The presence of B. in- fluenza? in the lungs in pure culture in 3 instances at first sight suggests that the microorganism produces pneumo- nia, but a more intimate survey of these cases gives little support to this view. In Autopsy 450 B. influenza has been 352 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT found in pure culture in the lung, but Pneumococcus IV has been isolated from the blood of the heart and has been with little doubt the cause of typical lobar pneumonia present in this instance. In Autopsy 486 the condition is almost iden- tical, for in the presence of lobar pneumonia B. influenzr has been found in the lung in pure culture, but Pneumococ- cus II atypical has been isolated from the pleural cavity and from the bronchus; in both autopsies the pneumococci Avhich have caused lobar pneumonia have disappeared from that part of the consolidated lung from Avhich a culture has been made; and here doubtless its invasion has been effec- tively resisted although it is still present in other organs. In Autopsy 481 in Avhich B. influenza? has been isolated from the lung in pure culture, the part of pneumococci in the production of the fatal disease is less eATident; in this in- stance, Pneumococcus II atypical, S. hemolyticus and B. in- fluenzae have been isolated from the bronchus. The presence of microorganisms Avhich haA*c a Avell-es- tablished etiologic relation to pneumonia explains the occur- rence of pneumonia and makes unnecessary the assumption that B. influenza?, Avhich is present in the lungs in less than half of the instances examined, is essential to the production of the pneumonic consolidation. In aucav of the Avell-recog- nized etiology of lobar pneumonia Ave may conclude that this lesion is referable to the pneumococci (Pneumococcus II atypical in 3 instances and Pneumococcus IV in 1 in- stance) isolated from the autopsies in Avhich this lesion oc- curred. Pneumococcus (Pneumococcus II atypical in 3 in- stances and Pneumococcus I in 1 instance) has been isolated from the lungs or heart's blood in 4 of 5 instances of acute bronchopneumonia unaccompanied by suppuration. AVith unresolved bronchopneumonia with no suppuration, pneu- mococci have been in no instance found in the lungs or blood though their presence in the Avashed sputum during life or in the bronchus at autopsy suggests the possibility that they may have disappeared from the lungs. PATHOLOGY AND BACTERIOLOGY FOLLOWING MEASLES 353 In all instances in Avhich suppuration has occurred hemolytic streptococci haAre been found in the lungs or blood, or in both. The occurrence of pneumococci in the lungs in 2 of 5 instances of suppurative pneumonia indi- cates that infection with S. hemolyticus is in some instances at least superimposed upon acute bronchopneumonia caused by pneumococci. Bronchopneumonia in 3 instances has the character of that caused by pneumococci. It is probable that the sequence of infection frequently observed after in- fluenza, namely, bronchial infection by B. influenza?, fol- loAved by pneumonia caused by pneumococci, followed in turn by infection by hemolytic streptococci Avith necrosis or suppuration, is not uncommon after measles. Pneumonia Associated with Acute Infectious Diseases Other than Influenza and Measles.—A small group of au- topsies have been excluded from the list of those Avhich accompanied the epidemic of influenza, because pneumonia has been associated with an acute infectious disease to Avhich it is perhaps secondary. These few instances of pneumonia, like those following measles reproduce char- acters of the pneumonia following influenza and may lie in part referable to influenza which has attacked an individual suffering with typhoid fever, mumps or scarlet fever. In 2 instances pneumonia followed typhoid fever and ap- peared on September 23 and 26 shortly after the epidemic of influenza had become evident. In the following autopsy there was acute lobar pneumonia which appeared ten days after onset of typhoid fever. Autopsy 245.—O. H., white, aged twenty-one, a farmer, resident of Okla- homa, had been in military service twenty-one days. Onset of illness was on September 13 with chill, headache, cough and nausea. The patient was admitted two davs later with the diagnosis of acute bronchitis. On Sep- tember 20 the abdomen was tense, the spleen was enlarged and rose spots were present. Signs of lobar pneumonia were found September 23. Death occurred September 25, twelve days after onset of typhoid fever and two clays after recognition of pneumonia. Anatomic Diagnosis.—Typhoid fever with necrotic ulcers in lower ileum and in colon; hyperplasia of ileocecal lymphatic nodes; acute splenic tumor; 354 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT parenchymatous degeneration of liver and kidneys; acute lobar pneumonia with gray hepatization in left lower lobe and red hepatization and edema in left upper lobe and in right lung; serofibrinous pleurisy on left side. The left pleural cavity contains 75 c.c. of yellowish gray turbid fluid. Over the left lower lobe there is a layer of fibrin. The upper half of the lobe is firmly consolidated, pinkish gray and coarsely granular; the bronchi contain plugs of fibrin. The lower and posterior part of the lower lobe is consolidated deep red and edematous. The left upper lobe is edematous and a layer in the lowermost part in contact with the lower lobe is deep red and consolidated. The left lung weighs 1,490 grms. The lower half of the right upper lobe and the posterior border of the lower is consolidated deep red and edematous; the lung weighs 970 grms. Bacteriologic examination shows that the blood of the heart contains Pneumococcus II atypical. The foregoing autopsy is of interest because typical lobar pneumonia appears to have spread from the left loAver lobe, Avhere consolidation is firm and gray, to the adjacent part of the upper lobe Avhere consolidation is red and edematous. The second instance of pneumonia folloAving typhoid fever is an instance of suppurate pneumonia caused by S. aureus. Autopsy 329.—J. B., white, aged twenty-two, laborer, resident of Okla- homa, had been in military service two days before onset of symptoms of typhoid fever. He was admitted to the hospital on August 27 and B. typhosus was found in cultures from the blood on September 2 and 3. Acute bronchitis appeared on September 26 when the epidemic of influ- enza had almost reached its height. A diagnosis of bronchopneumonia was made on the day preceding death, which occurred forty-one days after onset of typhoid fever and eleven days after onset of bronchitis. Anatomic Diagnosis.—Typhoid ulcers of ileum; acute splenic tumor; acute bronchopneumonia with red hemorrhagic peribronchiolar and lobular consolidation in right lung; multiple abscesses forming a circumscribed group in left upper lobe; purulent bronchitis. The pleural cavities contain no excess of fluid. The lungs are voluminous and there is interstitial emphysema. Below the pleura are bluish red spots of lobular consolidation; in the right upper lobe is a large patch of red consolidation marked by yellowish gray spots in clusters. In the external and upper part of the left upper lobe is a patch of gray consolidation within which, beneath the pleura, there are small abscesses grouped to form a cluster 1.5 cm, across. Bacteriologic examination demonstrates no microorganisms in the blood of the heart; of two cultures from the left lung one contains S. aureus in pure culture, the other S. aureus and a few colonies of Pneumococcus IV. PATHOLOGY AND BACTERIOLOGY FOLLOAVING MEASLES 355 Cultures from the left main bronchus and from the mucopurulent exudate in a small bronchus both contain B. influenzae, S. aureus and Pneumococcus IV. Ill the foregoing case bronchitis has appeared thirty days after onset of typhoid fever on September 2(5, imme- diately preceding the height of the epidemic of influenza. In association with hemorrhagic bronchopneumonia there is suppurative pneumonia Avith small abscesses forming a circumscribed group beloAV the pleura; there is no em- pyema. The lesion has the characters of the staphylococ- cus abscesses folloAving influenza, and S. aureus is found in association Avith the lesion; B. influenza is identified in tAvo cultures from the bronchi. In 2 instances pneumonia Avas associated Avith parotitis AArhich aatis diagnosed mumps. Autopsy 403.—C. T., colored, aged twenty-live, a laborer, resident of Ar- kansas, had been in military service one month. Illness began September 27 with swelling of face behind jaw and difficult mastication; the patient was admitted to the hospital on the same day with the diagnosis of mumps. Pneumonic consolidation was recognized on October 8. Death occurred Octo- ber 13, sixteen days after onset of illness and six days after recognition of pneumonia. Anatomic Diagnosis.—Acute lobar pneumonia with red and beginning gray hepatization of lower and parts of upper and middle right lobes; acute bronchopneumonia with lobular consolidation in left lung; purulent bron- chitis; bronchiectasis in left lung. The lower lobe of the right lung with the exception of the anterior and basal edge is firmly consolidated; the posterior part of the middle lobe and a small corner at the posterior and lower part of the upper lobe is similarly consolidated. The consolidated tissue is gray and coarsely granular on section. The remainder of the lung is dry and voluminous, and the bronchi contain purulent fluid. The left lung contains red and gray patches of consolidation, from 0.2 to 3 cm. across. Bronchi contain purulent fluid and in the lowermost parts of both upper and lower lobes are moderately dilated. Bacteriologic examination shows that the blood of the heart contains Pneumococcus III. It is noteworthy that there was in this case, as in many instances of influenza, both lobar and bronchopneumonia. Purulent bronchitis was present and there was bronchiec- tasis throughout one lung. 356 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT In the folloAving case the diagnosis of mumps may be questioned since the lesion of the parotid has characters of terminal suppurative parotitis. Autopsy 417.—H.W.D., white, aged twenty-four, a farmer, resident of Oklahoma, had been in military service one month. He said that he had had pneumonia four times. He was admitted to the hospital delirious and the diagnosis of lobar pneumonia was made. Parotitis regarded as mumps appeared five days before death and suppuration occurred on the right side of the face. Death of the patient occurred thirteen days after admis- sion to the hospital. Anatomic Diagnosis.—Acute bronchopneumonia with lobular consolida- tion in both lungs; suppurative pneumonia with necrosis and beginning ab- scess formation in left lung; purulent pleurisy in left side; purulent bron- chitis; bronchiectasis; acute parotitis. The left pleural cavity contains 100 c.c. of purulent fluid of creamy con- sistence. The left lung is voluminous and bound to the chest wall in places. There are numerous patches of lobular consolidation. At the apex of the lung there is a large area of consolidation, 7 cm. across, where the tissue is cloudy gray and soft in consistence. In the upper lobe is a well-defined patch of grayish yellow color, 6 by 2 cm., with opaque yellow edges; puru- lent fluid escapes from the cut surface. Bronchi throughout the lung are widely dilated and contain purulent fluid. The right lung is voluminous and contains lobular patches of consolidation; bronchi of this lung are widely dilated. Bacteriologic examination shows the presence of hemolytic streptococci in the blood of the heart; hemolytic streptococci and B. influenzae in the lung, and hemolytic streptococci, B. influenzae and S. aureus in a main bronchus. In association Avith bronchopneumonia there have been necrosis and beginning abscess formation Avith empyema, the suppurative lesions being caused by hemolytic strep- tococci which had finally entered the blood stream. There was purulent bronchitis, and the lungs had the voluminous character often associated with this lesion; there was be- ginning bronchiectasis. B. influenza? was obtained both from the lung and from the bronchus. In 2 instances (Autopsies 323 and 335) the diagnosis of scarlet fever was made in patients suffering with pneu- monia following influenza. These lesions have been in- cluded in the list of influenzal pneumonias. In the follow- ing instance the patient was admitted with scarlet fever, PATHOLOGY AND BACTERIOLOGY FOLLOWING MEASLES 357 later developed acute follicular tonsillitis, and finally sup- purative pneumonia caused by hemolytic streptococcus. Autopsy 311.—E. J., white, aged twenty-two, a tinsmith and automobile repairer, resident of Arkansas, had been in military service three months. Onset of illness was on September IS with headache and sore throat. The patient was admitted September 24 with the diagnosis of scarlet fever; two days later there was acute follicular tonsillitis. Pneumonic consolidation on the right side was recognized October 2, three days before death. Anatomic Diagnosis.—Acute suppurative pneumonia with three small ab- scesses below pleura of right lower lobe; acute fibrinopurulent pleurisy on both sides; serous pericarditis. The right pleural cavity contains 1500 c.c. of turbid, dirty yellow fluid containing masses of fibrin; the left cavity has 500 c.c. of similar contents. The pericardium contains 30 c.c. of turbid fluid containing a small quantity of fibrin; there are ecchymoses below the epicardium. The right lung is col- lapsed and in the lower lobe contains three small subpleural abscesses, the largest of which is 1.5 cm. across. Bacteriologic examination shows the presence of hemolytic streptococci in pure culture in the blood of the heart and in the right lung. From the right main bronchus are obtained hemolytic streptococci, B. influenzas, Pneumococcus IV and a few staphylococci. In this instance there has been infection Avith strepto- coccus Avhieh is a common sequela of scarlet fever. In the absence of eAndence of bronchopneumonia there has been abscess formation beloAv the pleura Avith empyema and pericarditis. B. influenza? has been found in the bronchus. The pneumonias found in association with measles re- produce the characters of the pneumonias described in as- sociation with influenza. Particularly noteworthy is the occurrence of lobar pneumonia, hemorrhagic peribronchio- lar pneumonia, interstitial suppurative pneumonia, severe bronchitis with bronchiectasis and unresolved bronchopneu- monia. In the presence of an epidemic of influenza at- tacking more than one fourth of the population of a camp, those suffering with diseases, such as measles, typhoid fever, mumps, etc., are unlikely to escape entirely, and it is probable that the tendency to the occurrence of pneu- monia present in association with these diseases will be increased. The close resemblance between the pneumonias 358 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT Avhich Ave haATe found Avith the diseases mentioned, on the one hand, and the pneumonias of influenza on the other, both being characterized by the occurrence of hemorrhagic, suppurative and chronic pulmonary lesions, indicates that influenza has had a part in the production of the pneumonia found Avith measles and some other infectious diseases dur- ing the progress of the epidemic of influenza. CHAPTER VII SUMMARY OF THE INVESTIGATION AND CON- CLUSIONS REACHED Eugene L. Opie, M.D. There is no reason for believing that the influenza which prevailed in this country differed in any essential feature from that of previous epidemics and particularly of the pandemic of 1889-90. Our studies have shown that an or- ganism with the morphologic and cultural characters of B. influenza? of Pfeiffer has been constantly found in associa- tion Avith the disease, and so frequently demonstrated in association Avith its pulmonary complications that there is little doubt of its constant presence. The bronchial and pulmonary complications of influenza present characters which, Avhile A'aried, are not usually observed in the absence of epidemic influenza, and in this pandemic agree Avith those of the former pandemic so far as it is possible to determine from the descriptions aATailable. Especially noteAvorthy is the severity of the changes within the bronchial passages. Clinical studies have shoAvn that purulent bronchitis has occurred in 36 per cent of in- stances of influenza. The sputum Avith this condition has contained B. influenza? in all instances, but although there Avere no signs of pneumonia it has been constantly associ- ated with other microorganisms, namely, pneumococci (in 11 of 13 instances), S. hemolyticus, S. viridans, M. catar- rhalis, etc. Identification of the bacteria which have been present in the bronchi of those dead with pneumonia folloAving in- fluenza have determined what microorganisms have pene- trated into the lower respiratory passages. B. influenza? 359 360 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT has been found so frequently (80 per cent) that there is good reason to believe that it has been constantly present and has not been isolated in every instance because it has been OATergroAvn by other microorganisms on the plates or after long continued illness has disappeared from the bron- chi. Mixed infections of B. influenzae and other microor- ganisms are constantly found in the inflamed bronchi; com- binations of B. influenza? and pneumococci, B. influenza? and hemolytic streptococci or these combinations Avith staphylo- cocci or the four organisms together are common. Other microorganisms such as B. coli, S. viridans, M. catarrhalis and diphtheroid bacilli are not infrequently associated Avith those which haAre been mentioned. Purulent bronchitis has been found in 137 of 241 autop- sies; its bacteriology differs in no respect from that Avhich has just been described and indeed no line can be drawn betAveen this condition and the bronchitis invariably pres- ent Avith the pneumonias of influenza. Other eAudence of profound injury to the bronchi is the frequent occurrence of hemorrhage in a zone ensheathing the smaller bronchi, and the common occurrence of bronchiectasis Avhen the fatal disease has lasted more than tAvo or three Aveeks. Microscopic study demonstrates that the changes in the bronchial Avails are such as destroy the defences against invasion by microorganisms. The bronchial epithelium undergoes destruction which is not infrequently limited to the superficial ciliated cells, but often complete loss of epi- thelium occurs. The mucous glands of the larger bronchi exhibit a special susceptibility to injury, and in the early stages of the lesion profound degenerative changes are found in the secreting cells, Avhereas at a later stage chronic inflammatory changes are almost invariably present. Pneumonia following influenza is in most instances bron- chopneumonia, but typical lobar pneumonia has been found in autopsies representing 40.7 per cent of pneumonias of in- fluenza. Lobar pneumonia is frequently accompanied by SUMMARY OF INA^ESTIGATION AND CONCLUSIONS 361 purulent bronchitis, and in a considerable number of au- topsies (34 of 98 Avith lobar pneumonia) lobar and broncho- pneumonia have occurred in the same individual. Statistics based upon the clinical diagnosis of lobar and bronchopneumonia folloAving influenza are so inaccurate that they haATe little if any value. NotAvithstanding care- ful study of the symptomatology of the disease, lobar and bronchopneumonia folloAving influenza are not ac- curately distinguishable by the means usually employed, and an erroneous diagnosis has been recorded on the pa- tient's history in 36.6 per cent of 227 fatal cases Avith au- topsy. A diagnosis of suppurative pneumonia is rarely if ever made. The difficulties of diagnosis are in part ex- plained by the frequent association of lobar pneumonia Avith purulent bronchitis, with bronchopneumonia or Avith both, and by the occurrence of bronchopneumonia Avith con- fluent lobular consolidation iirvohung a large part of a lobe or Avhole lobes. There are many defects in the present knowledge of the symptomatology of the pneumonias under considera- tion. The symptoms of suppurative pneumonia are not clearly defined. Many of these deficiencies might be sup- plied by further application of the time-honored method of comparing the clinical course of the disease with the changes found at autopsies, supplemented by bacteriologic studies made during life and confirmed after death. With peribronchial pneumonia bronchi of medium size, on the cut surface of the lung, are surrounded by sharply defined zones of pneumonic consolidation perhaps 0.5 cm. in radius, and this lesion furnishes conclusive proof that the inflammatory process can extend directly through the bronchial Avail reaching all alveoli within a limited dis- tance for these alveoli bear no relation to the distribution of the terminal bronchi of the affected bronchus. This peribronchial pneumonia is usually characterized by fibrin- ous exudate, and pneumococcus has been found either in 362 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT the blood of the heart or in the lung in all of 6 instances in which peribronchial consolidation has been recognized at autopsy; in half of these autopsies Pneumococcus Type II has been isolated and this relationship is especially note- Avorthy because Type II has been uncommonly associated with the pneumonias of influenza. Lobar Pneumonia.—The distribution of lobar pneumonia has repeatedly furnished evidence that the process spreads like the peribronchial lesion directly through the tissue of the lung and is not necessarily disseminated by Avay of the bronchial tree. Pneumococci doubtless enter the lung by way of the bronchi; the occurrence of lobar pneumonia in frequent association Avith influenza Avhich exhibits a pecu- liar capacity to destroy the defences of the loAver respira- tory passages is in harmony Avith this vieAv. The presence of pneumococci in the blood furnishes no evidence that infection is hematogenous, for bacterial infections, par- ticularly at their onset, are frequently accompanied by bac- teriemia. The Avave-like spread of lobar pneumonia may be indicated by a narroAv zone of red hepatization separating a large patch of firm, gray consolidation from engorged but air containing lung tissue. A semicircular patch of con- solidation not infrequently extends from the left loAver lobe into the upper lobe at the site where the interlobular cleft is absent. This patch may be firm and gray in continuity Avith similar consolidation in the Ioavci* lobe but surrounded 0ATer its convex surface by a zone of red hepatization. There is no reason to doubt that the lobar pneumonia which Ave have found Avith influenza has been constantly caused by pneumococci. We have encountered no instance of lobar pneumonia caused by the capsnlated bacillus of Friedlander. The incidence of different types of pneumo- cocci in the lung with lobar pneumonia has been as folloAvs: Type IV, 32.4 per cent; Type II, atypical, 26.5 per cent; Type III, 17.6 per cent; Type II, 5.9 per cent; Type I, 2.9 per cent; no pneumococci found 14.7 per cent. It is note- SUMMARY OF INVESTIGATION AND CONCLUSIONS 363 worthy that this distribution of types is in sharp contrast with the lobar pneumonia of civil life Avith which Typos I and II constitute the cause of two-thirds of all instances, and is in agreement with the etiology of the pneumonias found in an army camp (Funston) in the absence of in- fluenza in epidemic proportion. Bronchopneumonia.—Bronchopneumonia is associated with intense bronchitis penetrating to the finest bronchioles and is characterized by consolidation distributed in such definite relation to the bronchial tree that dissemination of the inflammatory irritant by way of the bronchi is evi- dent. Consolidation occurs (a) in foci affecting alveoli in immediate proximity to the respiratory bronchioles and in consequence clustered about the terminal bronchi, the intervening alveolar tissue containing air; (b) in foci of the same character surrounded by intraalveolar hemor- rhage Avhch occupies all alveolar tissue between adjacent foci; (c) throughout whole lobules or groups of lobules, intervening lobules being unaffected ; {d) surrounding bron- chi of medium size like a sheath. The lobar pneumonia of influenza is characterized by frequent association Avith purulent bronchitis and broncho- pneumonia. The bronchopneumonia of influenza exhibits characters which serve to distinguish it from other forms of bronchopneumonia; (a) The associated lesions of the bronchi are unusually severe; purulent exudate accumulates Avithin the lumen and the lining membrane is destroyed. (b) Pneumonia is frequently hemorrhagic with accumula- tion of blood within the alveoli and within and surrounding the bronchi, (c) There is unusual susceptibility of the in- jured bronchi and of the pulmonary tissue to secondary in- vasion by streptococci and staphylococci Avith consequent necrosis and suppuration, (d) Bronchiectasis frequently accompanies bronchitis, (c) Bronchopneumonia frequently fails to resolve and the lesion assumes the character of a chronic pneumonia. 364 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT With bronchopneumonia pneumococci are found with B. influenza? in the bronchi and lungs in nearly half and in the blood in approximately one-third of instances of the disease, but hemolytic streptococci, staphylococci, S. viri- dans, B. coli, M. catarrhalis and other microorganisms are very frequently found in various combinations: they un- doubtedly have a part in the production of the lesion. Mixed infection of the lung and even of the blood Avith pneu- mococci and hemolytic streptococci is often found, and study of the sputum during life has repeatedly shown that pneumococci alone are present shortly after the onset of the disease, Avhereas hemolytic streptococci appear later or are first discovered at autopsy. In such instances pneu- mococci have not infrequently disappeared from the lung and at autopsy hemolytic streptococci alone are demon- strable. The part which B. influenza? has in the production of bronchopneumonia is of great interest. This microorgan- ism is demonstrable by cultures in at least three-fourths of all instances of bronchopneumonia but is obtained from the inflamed lung tissue in less than half. In no instance of pneumonia have Ave found B. influenza? unassociated with other microorganisms, Avhereas repeatedly pneumococci have been the only microorganism demonstrable in the lung and very frequently the only organism present in the blood. In view of the difficulty of demonstrating the mi- croorganism in plates overgrown by other bacteria, it is probable that its incidence in the bronchi is much higher, if it is not constantly present, whereas its isolation from the lung is in part referable to its presence in the small bronchi where it can be readily demonstrated by cultures or by microscopic preparations. We have been almost uni- formly unsuccessful in demonstrating the microorganism in thejdveoli of the lung. Goodpasture and Burnett,1 who in/ln&^^ P—ia Accomp,„y- SUMMARY OF INVESTIGATION AND CONCLUSIONS 365 have devised a special method for the demonstration of B. influenza in tissues, have found feAV of these microorgan- isms in the ahTeoli of the lungs. Pneumonia characterized by the occurrence of small (peribronchiolar) spots of leucocytic pneumonia upon an almost homogeneous background of intraalveolar hemor- rhage, was regarded by Pfeiffer as the characteristic lesion produced by his microorganism. B. influenza? in our autop- sies has borne the same relation to this lesion which it has exhibited to other forms of bronchopneumonia; pneumo- cocci haATe been present Avith approximately the same fre- quency and hemolytic streptococci have often been found. Streptococcus Pneumonia.—The occurrence of strepto- coccus pneumonia Avith suppuration occurring in the trail of influenza Avas frequently observed during the pandemic of 1889-90. It is now well recognized that the streptococcus concerned is one capable of causing hemolysis. Suppura- tive pneumonia referable to hemolytic streptococci is of two types which are readily separable by their anatomic characters: {a) One or several abscesses are situated below the pleura and accompanied by empyema. Their relation to severe lesions of the bronchi is not infrequently demon- strable, for a destructive lesion of the bronchial Avail has penetrated into the surrounding alveolar tissue so that ne- crosis of tissue and subsequent abscess formation occur r continuity with the bronchial lumen. The localization of the abscess below the pleura is referable to the greater severity of the lesions of the small bronchi which are most numerous at the periphery, to the greater severity of these bronchial lesions at the bases of the lung, and to the rela- tion of lymphatics within the interior of the lung to those of the pleura. It is not improbable that stasis of lymph caused bv thrombosis of the lymphatics has a part in the production of abscess. Preceding or accompanying ab- scess formation, the lung tissue undergoes consolidation and in a wide area about the abscess has a homogeneous gray 366 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT cloudy appearance occasionally mottled by opaque patches of necrosis, {b) Interstitial suppurative pneumonia is a lesion not infrequently found in association with influenza (21 times among 241 autopsies) and rarely, if ever, seen in its absence. There are few references to this lesion in the pathologic literature of the English language and those of German origin in great part refer to the period of the pan- demic of 1889-90. The lesion is essentially suppurative lymphangitis, and both thrombosis and suppuration of the lymphatics are Avidespread throughout the affected lung. In proximity to the inflamed lymphatics and the surrounding interstitial septa, lung tissue throughout parts of the lobes or even throughout a Avhole (lower) lobe has undergone consolidation and has the gray, cloudy appearance of strep- tococcus pneumonia. Staphylococcus Pneumonia.—Abscesses produced by staphylococci differ in anatomic characters and sequela from those caused by hemolytic streptococci. Small ab- scesses occur in one or several localized clusters; these ab- scesses are grouped about a bronchus and have their origin in its terminal branches. This relation may be readily dem- onstrated in microscopic sections. The lesion tends to re- main localized and pneumonic consolidation is limited to the immediate neighborhood of the group of abscesses. There is no lymphangitis and the lesion is not accompanied by empyema. Empyema.—Empyema is almost invariably associated with suppurative pneumonia caused by hemolytic strep- tococci. Among our autopsies purulent fluid has been found in the pleural cavity 55 times; it occurred 15 times among 178 instances of lobar or bronchopneumonia and 50 times among 60 instances of suppurative pneumonia re- ferable to S. hemolyticus. In our experience hemolytic streptococci and pneumococci are the only microorganisms which exhibit a noteworthy capacity to penetrate from the lung to the pleural cavity. We have not found nonhemo- SUMMARY OF INVESTIGATION AND CONCLUSIONS 367 lytic streptococci {e.g., S. viridans) in association Avith em- pyema. Staphylococcus has failed to invade the pleural cavity even when a pulmonary abscess has been present below the pleura, and in the only instances in which staphylococci have been isolated from the pleural cavity thoracotomy had been performed for empyema caused by hemolytic strep- tococci (2 instances) or an abscess communicating with both bronchus and pleura. B. influenza? has been found in the pleural cavity with empyema only once and in this instance cannot be regarded as the cause of the lesion, for it has accompanied hemolytic streptococci. Bronchiectasis.—Bronchiectasis has been frequently found as a sequela of the severe bronchitis of influenza and there has been abundant opportunity to study the lesion in process of development. These observations have fur- nished a satisfactory explanation of its etiology and patho- genesis. Infection of the bronchi by B. influenza?, accom- panied by a variety of other microorganisms, notably hem- olytic streptococci and staphylococci, has caused profound changes in the bronchial Avail beginning with destruction of the epithelial surface, and followed by necrosis pene- trating partially or completely through the Avail and oc- casionally extending into the surrounding alveolar tissue. The difference between the atmospheric pressure within the bronchi and the loAver inspiratory pressure Avithin the surrounding ah'eoli, accentuated by forced inspiration at intervals and by occlusion of the bronchioles Avith mucopur- ulent exudate, ruptures the necrotic tissue and produces longitudinal fissures Avhich are recognizable both macro- scopically and microscopically. In consequence of the sep- aration of the edges of these fissures by intrabronchial pres- sure the circumference is increased. These rents in the wall are limited and partially healed by fibrinous pneu- monia about them, by hcav formation of fibrous tissue from the bronchial Avail, and adjacent interalveolar septa, by 368 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT organization of fibrin within adjacent alveoli and finally by growth of epithelium over the denuded surfaces. Bronchitis caused by B. influenza? and pyogenic micro- cocci with necrosis of the bronchi Avail is the essential fac- tor in the production of bronchiectasis, but advanced bron- chiectasis is found only in those individuals ayIio have sur- ATived the onset of illness during several Aveeks, for dila- tation under the influence of positive intrabronchial and negative extrabronehial pressure occurs sIoayIv. Unresolved Bronchopneumonia.—Unresolved lobar pneu- monia has not been recognized among instances of pneu- monia folloAving influenza, but unresolved bronchopneu- monia is of frequent occurrence and has Avell definable gross and microscopic characters. There are purulent bronchitis, bronchiectasis and distention of the lung tissue, so that it fails to collapse; particularly characteristic are the indur- ated foci of peribronchiolar pneumonia, which being firm and sharply defined, have the appearance of miliary tu- bercles. When the process is sufficiently long continued there are recognizable patches of fibroid pneumonia. Mi- croscopic examination shows that the lesion is characterized by organization of fibrinous exudate not only within the alveoli but within bronchioles as well, and by thickening of the alveolar Avails, thickening of fibrous tissue about the bronchi and blood vessels, and thickening of interstitial septa. These changes may occur as peribronchiolar patches of consolidation, producing tubercle-like nodules, or may in- volve areas of hemorrhagic peribronchiolar or of lobular consolidation, or may be limited to the immediate neigh- borhood of bronchi (peribronchial). No peculiarity of the bacterial flora of the bronchi or of the lung offers a satisfactory explanation of the failure of pneumonic exudate to resolve. Mixed infections have been common and S. hemolyticus, staphylococci, pneumococci, S. viridans, B. coli, etc., have been found in association with B. influenza? but the incidence of these microorganisms has SUMMARY OF I XVFSTKIATIOX AND COXCLCSIOXS 36!) not been greater than Avith bronchitis. The lesion has oc- curred in association Avith B. influenza' and pneumococci unassociated Avith other microorganisms. It seems prob- able that the severity of injury to the bronchial and al- veolar Avails accompanied by recurring bacterial invasion or by continued infection Avith 1>. influenza1 and one or sev- eral cocci, is the factor concerned in the inhibition of reso- lution and the production of chronic pneumonia. If the disease does not result in early death, chronic pneumonia has an opportunity to manifest itself. In this investigation of the bacteriology and pathology of influenza and its complications, certain microorganisms lnwe been found so frequently that it is desirable to discuss the pathogenicity of each and to define the character of the lesions Avhich it causes. Bacillus Influenzae.—The microorganism has been con- stantly found in association Avith influenza Avhen cultures and animal inoculations luwe been made from various parts of the respiratory tract within from one to five days after the onset of the disease1 at a time Avhen there have been acute symptoms of the disease. It is often identified with difficulty in the presence of other microorganisms and may be overlooked when a single culture is made. Repeated cultures from the throat alone made from the fourth to the eighth day after admission to the hospital, at a time when temperature had fallen to nor- mal, have demonstrated the presence of B. influenza- in 30.5 per cent, Avhereas the incidence of the microorganism in similar cultures on admission had been 63.4 per cent. The incidence of B. influenza in the present epidemic of influenza is not less than that found by Pfeiffer in the epi- demic which he studied in 1892. Nevertheless Ave have found that B. influenza1 is fre- quently an inhabitant of the mouth and throat of normal in- dividuals. By inoculation of mice Avith the saliva or sputum of 76 patients with influenza, the microorganism 370 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT has been found in 80.3 per cent; by inoculation of mice with the saliva of 185 normal men at army cantonments, it Avas found in 41.6 per cent; by inoculation of mice with saliva from 50 recruits immediately after they Avere as- sembled from isolated farming communities where only a feAv cases of influenza had occurred, it was found in 22 per cent. Figures for the same groups examined by a single throat culture were as follows: 65.7 per cent, 25.9 per cent and 0 per cent. Experiments which Ave have performed on monkeys sIioav that inoculation of the nasopharynx with B. influenza1 ob- tained from patients Avith influenza is folloAved by ill- defined symptoms associated with the presence of B. in- fluenza? within the throat. After from Iavo to eleven days the symptoms and the microorganism disappear. Injection of B. influenza? into the trachea causes bronchitis and the microorganism may be recoArered from the inflamed bronchi two or three days after inoculation. The constant association of B. influenza? Avith influenza suggests that it is the cause of the disease. Its Avidespread occurrence in the throats of normal individuals does not contradict this Anew, since pneumococci long indistinguish- able from those Avhich usually cause lobar pneumonia are commonly found in the throats of healthy men. It is pos- sible that B. influenza? is a secondary invader, entering the respiratory tract Avhen susceptibility is increased by an un- known virus causing influenza; but there is no convincing evidence in favor of this vieAv. It is desirable to determine if microorganisms having the characters of B. influenza found Avith influenza differ in typo from those found in the throats of healthy men and if the invasion of the respiratory tract by B. influenza? is followed by the appearance of im- munity reactions in the serum of the patient. Experiments on monkeys demonstrate the pathogenicity of the micro- organism. SUMMARY OF INVESTIGATION AND CONCLUSIONS 371 The relation of B. influenza1 to the bronchitis of influenza indicates that it has a part in the production of the pul- monary sequela? of influenza. The microorganism has been found by a single culture from the bronchial passages in 80 per cent of instances of bronchitis with fatal pneu- monia following influenza and is probably constantly pres- ent, usually in immense number, in the bronchial mucus. It is obtained from the pneumonic lung in only about 40 per cent of instances, and microscopic examination of pre- pared tissue shows that a bacillus with the morphology of B. influenza- is often demonstrable in the bronchial pas- sages but seldom in the alveoli of the lung. The microor- ganism is Avell adapted to multiply under conditions present in the bronchi but doubtless readily disappears from the alveoli which are the site of an inflammatory reaction. The microorganism has an important part in the production of the associated mucopurulent and hemorrhagic inflammation of the bronchi, but it is rarely if ever found in pure cul- ture, being associated Avith a considerable ATariety of pyo- genic cocci and occasionally bacilli. Infection of the bron- chi Avith B. influenza in immense numbers offers an ex- planation of the severity of the inflammatory process Avithin the bronchi, and of the subsequent dilatation and other chronic changes which occur in them. The presence of the microorganism and the accompanying injury to the cil- iated epithelium and mucous glands are important factors in lowering the resistance of the bronchial passages to secondary bacterial infection. We have obtained no evidence that B. influenza1 alone is capable of causing pneumonia. Its occurrence in less than half of all pneumonic lungs is explainable, in part at least, by its presence in the terminal bronchi which are cut across whenever the lung is punctured for culture. B. in- fluenza? alone has been found only once among 153 pneu- monic lungs from which cultures Avere made, and in this instance (Autopsy 487) S. hemolyticus present in the blood 372 PNEUMOXIAS AX1) INFECTIONS OF UESPI HATOlt Y TRACT of the heart, pleural cavity and bronchus doubtless had a part in the production of the associated pneumonia. Pfeif- fer maintained that the lesion ayc have designated hemor- rhagic peribronchiolar consolidation was characteristic of infection Avith his microorganisms. With this lesion B. influenza1 has been found in the lungs in slightly more than half of our autopsies but never alone, pneumococci being found in a third, hemolytic streptococci in more than a half and staphylococci in a fourth of the lungs examined. B. influenza has relatively little capacity to penetrate from the bronchi into the lung tissue and rarely penetrates into the pleural cavitAT (once Avith Pneumococcus III, once Avith S. hemolyticus and once in pure culture), and only once has it been found in the blood of the heart, in this instance in company Avith S. hemolyticus. Capacity of the microorganism to penetrate from the bronchi into other tissues, both in man and as our experiments hnxo sIioayii in the monkey, is increased by association Avith pyogenic cocci. Pneumococcus.—Lobar pneumonia folloAving influenza, like lobar pneumonia in civil life unassociated Avith in- fluenza, has been caused by pneumococci, but there is tin1 notable difference that the pneumococci usually found are those typos Avhich are commonly present in the mouths of healthy men, namely, Types IV, III and atypical II and not the so-called fixed types, namely, Types I and IT, Avhich represent the usual cause of lobar pneumonia unassociated with influenza. It appears that influenza increases suscep- tibility to lobar pneumonia, so that it is frequently caused by microorganisms which under other conditions are less capable of producing this lesion. The association of the pneumococci usually found in the mouth with the lobar pneumonia of influenza does not exclude the possibility that pneumococci transmitted from one individual to another, when newly recruited troops are brought together, have an important part in the production of pneumonia. SUMMARY OF INVESTIGATION AND CONCLUSIONS olo Bronchopneumonia is frequently caused by pneumococci and tin1 types Avhich are recovered from the lung and blood do not differ from those found with lobar pneumonia, those usually present in the mouth being predominant, but the incidence of pneumococci Avith bronchopneumonia has been much less than with lobar pneumonia. Both lobar and bronchopneumonia caused by pneumococci have1 undergone secondary infection Avith hemolytic streptococci in a large proportion of instances and both pneumococci and strep- tococci are often recovered at autopsy. Nevertheless, the bacterial flora of the bronchi and lungs is much more varied Avith broncho than Avith lobar pneumonia, and it is evident that microorganisms other than pneumococci are capable of causing bronchopneumonia. In instances of bronchopneumonia associated Avith pneu- mococci, fibrin has been abundant in the alveolar exudate. The pneumococcus exhibits a notable tendency to pro- duce an inflammatory process Avhich extends through the bronchial Avails and from one alveolus through the alveolar Avails to those adjacent, for in 6 instances in which the bronchi Avere surrounded by pneumonic consolidation rec- ognizable at autopsy, pneumococci were uniformly the causative agent, Pneumococcus Type II, otherwise rarely found, being present in half of these cases. Pneumonia caused by one type of pneumococcus does not necessarily confer immunity from other types of pneu- mococci, and with somewhat limited opportunity we have observed a number of instances in which, following recov- ery from pneumonia caused by one type of pneumococcus, a second attack of pneumonia, usually fatal, has been as- sociated with pneumococci of a different type. This re- curring pneumonia in a considerable proportion of the rela- tively small number of instances observed has been pro- duced bv Pneumococcus Type II which otherwise has been seldom found among the cases which we have studied. The 374 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT virulence of this microorganism doubtless explains its abil- ity to cause recurrent pneumonia. Streptococcus Hemolyticus.—Secondary infection with S. hemolyticus is a common event during the course of lobar pneumonia following influenza. It is noteworthy that this streptococcus infection of the lung has almost invariably occurred in the stage of red hepatization, whereas with gray hepatization, when the alveoli are filled Avith polynuclear leucocytes, S. hemolyticus rarely invades the lung. It is possible that infection Avith S. hemolyticus tends to prolong the stage of red hepatization. The most significant change produced in the pneumonic lung by streptococci is necrosis. When after death Avith lobar pneumonia hemolytic streptococci, usually associated with pneumococci, are found both in the lungs and blood of the heart, the lung contains patches of necrosis recog- nized microscopically, in which the alveolar Avails and ex- uded cells have uniformly lost their nuclei. Microscopic examination demonstrates the presence of chains of strep- tococci in immense number in these necrotic foci; elscAvhere chains of streptococci occur but are much less abundant. In some instances streptococci exhibit a tendency to enter lymphatics and to cause acute lymphangitis Avith lymphatic thrombosis and edema of the adjacent interstitial tissue1. Hemolytic strex>tococci haATe been more frequently found in association Avith broncho- than Avith lobar pneumonia. In 24.5 per cent of instances of lobar pneumonia, doubtless in all instances caused by pneumococci, hemolytic strep- tococci have invaded the lungs and in 12.6 per cent of in- stances haATe found their Avay into the blood With bron- chopneumonia hemolytic streptococci have been obtained from the lungs in 29.8 per cent of instances and from the blood of the heart in 34.3 per cent. With lobar pneumonia there is little doubt that pneu- mococcus has been the primary cause of pneumonia, but with bronchopneumonia pneumococci have been less fre- SUMMARY OF INVESTIGATION AND CONCLUSIONS 375 quently found. It is difficult to determine Iioav often hem- olytic streptococci haATe invaded a bronchopneumonic lesion, caused by pneumococci because pneumococci tend to disap- pear. In numerous instances in which the sputum had been studied during life, it was evident that pneumonia Avas pri- marily referable to pneumococci, and hemolytic streptococci made their appearance in the sputum late in the disease or Avere first recognized at autopsy. When hemolytic streptococci occur in association with bronchopneumonia, foci of pulmonary necrosis similar to those found under the same conditions with lobar pneu- monia have been repeatedly found by microscopic exam- ination. In the patches of necrosis, cocci in chains are much more abundant than in the tissue elscAvhere. In some instances of pneumonia, caused by hemolytic streptococci, opaque gray or yellowish gray patches of necrosis occur upon a background of flaccid homogeneous consolidation which has a peculiar cloudy, gray color. This mottled consolidation may implicate an entire loAver lobe and has the characteristic features neither of lobar nor of bronchopneumonia. More frequently the lesion is less widespread and necrosis occurs in one or several spots Avhich undergo softening so that finally a small abscess caA'ity may be formed; it is surrounded by pneumonic con- solidation which is soft and has the cloudy appearance de- scribed above. These pulmonary abscesses are almost in- variably situated below the pleural surface; the adjacent pleural cavity is infected by streptococci and there is puru- lent inflammation of the pleura. Streptococcus infection, which has been described, doubt- less has its origin in the bronchi, for in favorable sections it is not infrequently possible to demonstrate that necrosis extends through the bronchial Avails into the surrounding alveolar tissue and is followed by suppuration with abscess formation. Localization of abscesses below the pleura is 11(6 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT in part at least referable to transmission of streptococci by way of the lymphatics. Streptococci in the lung, as in other tissues, often invade lymphatics and produce an acute inflammatory reaction Avithin and about these vessels. The peculiar lesion which may be designated suppurative interstitial pneumonia is a suppurative lymphangitis associated with inflammation and edema of the interstitial tissue. Lymphatics invaded by streptococci are the site of acute lymphangitis; occlusion by fibrinous thrombi occurs and finally the immensely dis- tended lymphatics, filled with purulent fluid, take a char- acteristic nodular or beaded form and pus flows from them Avhen they are cut. Streptococci are present in vast num- bers. Suppurative inflammation may extend to the sur- rounding interstitial tissue which is distended by inflam- matory edema. This interstitial suppurative pneumonia extends up to the pleural surface and empyema is almost invariably associated with it. The lesion is seldom seen in the absence of influenza. One of the most significant characters of S. hemolyticus is its ability not only to enter the bronchi and penetrate into the tissue of the lung, but to find its way into more distant structures, namely, the pleural cavity, pericardial sac and peritoneal cavity and to penetrate into the blood. Among 121 examinations, hemolytic streptococci wore found in the bronchi in 47.9 per cent; among 153 examina- tions of the lung it Avas present in approximately the same proportion, namely, 50.3 per cent; among 218 examina- tions of the blood it was found in 39 per cent. In 4 of 5 fatal pneumonias in which the organism has penetrated into the bronchi it has ultimately found its way into the blood. Nonhemolytic Streptococci.—In contrast with S. hemo- lyticus nonhemolytic types have rarely been encountered in association with the pneumonias of influenza. S. viri- dans has been found only 5 times among 153 autopsies in which cultures have been made from the lung and has been SUMMARY OF INVESTIGATION AXD CONCLUSIONS 377 invariably associated Avith other microorganisms. In no instances have nonhemolytic streptococci been found Avith empyema. In one autopsy Avith lobular bronchopneumonia S. viridans has been isolated from the blood of the heart and in this instance it has boon found in the bronchus and lung as Avell. This type of streptococcus is 0ATidently little adapted to invade the bronchi and produce lesions of the lung and adjacent tissues. Staphylococci.— Staphylococci have been very frequently isolated from the bronchi in association with the pneu- monias of influenza, being found in approximately half of our autopsies. Their isolation in cultures from the lung in a fourth of the autopsies examined is in part perhaps referable to their presence in the small bronchi cut across Avhen the lung is punctured for cultures. S. aureus sIioavs little ability to invade the pleura, being found in associa- tion Avith empyema only 3 times; in these autopsies there has been opportunity for entrance from the exterior through thoracotomy wounds in 2 instances and from a bronchus in free communication with an abscess which had ruptured into the pleural cavity in 1 instance. Abscesses of the lung caused by staphylococci have been found in a small number of autopsies and have1 exhibited characters which differ from those1 ordinarily seen in as- sociation with S. hemolyticus. Small, sharply defined ab- scesses are grouped about terminal bronchi, so that they occur in one or several isolated clusters. Microscopic ex- amination demonstrates that these abscesses have arisen by destruction of the bronchial Avails and extension of sup- puration into the surrounding alveolar tissue; clumps of staphvlococci are found in sections through the abscess, and cultures made1 from the pus within the abscess cavity demonstrate the presence of S. aureus or albus, but the microorganism mav be missed if the culture is made from the adjacent lung tissue. It is noteworthy that there1 is little tendencv for the staphylococcus to mlect the1 pleura 378 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT for even though these clusters of abscesses have been situ- ated just beloAv the pleura, there has been no associated em- pyema. Staphylococci luwe scant tendency to enter the blood and have been obtained from the blood of the heart only once, in this instance with hemolytic streptococci. Pneumonia of Measles.—Pneumonia following measles has been responsible for a considerable part of the1 deaths occurring in the United States Army during the period of the Avar. The importance of measles as a factor in the production of pneumonia is illustrated by the history of pneumonia at Camp Funston from the establishment of the camp in September, 1917, until September, 1918. Pneu- monia folloAving measles occurred throughout the year; but in association Avith the high incidence of measles dur- ing the1 second half of November and the first half of De- cember, 1917, there1 Avas an outbreak of related pneumonia characterized by frequent empyema and a mortality of 45.3 per cent. During the period of our investigation at Camp Funston there Ave re 112 cases of measles, but no pneumonia occurred among them. At Camp Pike, during the period of observa- tion, there Avas an outbreak of measles almost coincident Avith the epidemic of influenza, and among 867 cases pneu- monia occurred in 56, otitis media in 48, and mastoiditis in 23. Pneumonia following measles Avas almost coincident Avith that of influenza, and it is not improbable that the epi- demic of influenza had an important part in the production of pneumonia in individuals suffering Avith measles. In 9 of 56 instances of pneumonia following measles at Camp Pike, S. hemolyticus had invaded tholung and caused pneumonia; among 48 instances of otitis media following measles a very large1 proportion were caused by hemolytic streptococci, and 21 of 23) instances of mastoiditis were caused by the same microorganism. No complication SUMMARY OF INVESTIGATION AND CONCLUSIONS 379 caused by S. hemolyticus occurred among 37 patients who carried this microorganism when admitted to the hospital. A special study has been made to determine' if those' pa- tients with measles who carry S. hemolyticus in their throats are especially susceptible to complications during the course of measles. The low incidence of streptococcus "carriers" among those admitted to the hospitals with measles was noteworthy both at Camp Funston (2.(57 per cent) and at Camp Pike (4.2 per cent). Indeed, it Avas found at both places that the incidence of hemolytic strep- tococci in the throats of normal men in the camp was higher (Camp Funston 21.9 per cent; Camp Pike 7.4 per cent) than that in the throats of those admitted Avith measles. While in the hospital there was a gradual increase of the incidence of S. hemolyticus, so that in three weeks it had risen to 19 per cent at Camp Funston and to 26.2 per cent at Camp Pike. It seems not improbable that hemolytic streptococci disappear from the1 throat in the early stages of measles, so that they are1 not demonstrable by cultural methods. During the course of the disease in the hospital ward the number of those Avith S. henmlytious has increased in some Avards Avith great rapidity, infection being appar- ently transmitted from one individual to those adjacent. At Camp Funston the incidence of S. hemolyticus in the throats of those convalescent with measles was almost identical with that among normal men in organizations from Avhich the patients had come, but at Camp Funston the percentage of hemolytic "carriers" among convalescents was much higher than that obtained among normal men in the camp. The demonstration of S. hemolyticus in the throat of a patient suffering with pneumonia is not conclusive proof that the lungs have been invaded by this microorganism. Pneumonia in indivduals carrying S. hemolyticus in the throat may pursue1 a favorable course and exhibit no evi- dence that the1 microorganism has found its Avay into the 380 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT lung. In some instance's hemolytic streptococci lurve been found in the bronchi at autopsy yet none have entered the lung or blood and the lung exhibits none of the lesions which are referable to hemolytic streptococci. Nevertheless, the occurrence' of S. hemolyticus in cultures from the throat of a patient with pneumonia suggests the probability that he is suffering Avith streptoe-occus pneumonia. Pneumonia folloAving measles studied in 18 autopsies upon patients Avho died during or shortly after the epi- demic of influenza, exhibited all the characters exhibited by the pneumonias of influenza. In 4 instances there Avas typ- ical lobar pneumonia; bronchopneumonia Avas found in all but 3 instance's, being associateel with lobar pneumonia twice. All the noteworthy features of the bronchopneu- monia of influenza have been reproduced among these in- stances of pneumonia Avith meash's; there is severe1 injury to the bronchi, and purulent bronchitis has been present in 13 instance's; pneumonia has freepiently had a hemorrhagic characten1, hemorrhagic peribronchiolar pmnimonia occur- ring in 5 instances; secondary infection of the pneumonic lungs Avith hemolytic streptocexri has been common; bron- chiectasis has been associated Avith bronchitis (in 8 in- stances) Avhen purulent bronchitis has persistent so\-eral weeks: and unresolved bronchopneumonia has been more1 froejuent (6 instances or one-third of the autopsies) than with influenza. The bacteriology of pneumonia folloAving measles has been the same as that of influenzal pneumonia. B. influ- enza? is found Avith few exceptions in the bronchi and much less frequently in the pneumonic lungs. Pncumex'occi have1 been obtained from the blood or lungs in 5 of 13 instance's of lobar or bronchopneumonia unac- companieel by suppuration; Avhen suppuration has been ab- sent no hemolytic streptococci have1 boon found. Pneumo- cocci concerned in the production of pneumonia of measles, as Avith influenzal pneumonia, have been types usually SUMMARY OF 1 XVESTIGATION AXD CONCLUSIOXS 381 fenind in the mouth; Pneumococcus II atypical has been found 6 time's, Type IV once, Typo I once. Hemolytic stroptoe-oe'ci have1 iiuvaded the1 pnenimonic lung in 5 instances. They have produce1*! subpleural abscesses accompanied by empyema in 2 instances. Interstitial sup- purative pneumonia, a lesion repeatedly found in conse- quence of secondary infection with S. hemolyticus ToIIoav- ing influenza and rarely found in this country, at least in the1 absence of an epidemic of influenza, has occurred 3 times among 18 instances of pneumonia following measles. The foregoing observations show that the pneumonia fol- lowing measles, which has occurred almost coincielentally with pneumonia accompanying epidemic influenza has re- produced the lesions found with influenzal pneumonia. They indicate that influenza attacking patients with measles has had a part in the production of this pneumonia. The Transmission of Streptococcus Pneumonia.—The im- portance of streptococcus as a cause1 of pneumonia follow- ing influenza was recognized during the pandemic of 1889- 90. Patients suffering with pneumonia following influenza or measles are suse-eptible to infection by S. hemolyticus and this streptococcus pneumonia may be transmitted from one patient to another throughout a ward in which patients with pneumonia are1 assembled. There is no evidence that primarv pneumonia caused by S. hemolyticus has prevailed as an epidemic in the army or elsewhere in the absence of preceding infection with influenza or measles. Our autopsies demonstrate that at least half of all deaths which have occurred at Camp Pike have been cause,! by hemolvtic streptococci which have' invaded the lung and entered the blood. It is significant that this mortality had its origin in the1 first half of the1 epidemic of influenza^at a lime when the military and medical organization of the eamp was confronted with an ^^n^ency^ overwhelmed all agencies for the care of dise ^ C > - prepare,! bv roforring cases ot pneumonia m Arinch an- I'82 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT topsy demonstrated the nature of the fatal infection back to the date of the onset of influenza, demonstrate that fatal streptococcus pneumonia was frequently acquired during the early period of the epidemic, the1 maximum number of case's occurring September 23 and 24 and became grad- ually less common as a sequela of the influenza which be- gan at a later period. Fatal pneumococcus pneumonia had its origin with increasing frequency at a later period, the maximum incidence following influenza which had its onset September 29 and 30. Overcrowding of influenza patients in infirmaries, ambulances and hospital had an important part in the1 dissemination of streptococcus pneumonia among influenza patients Avhose1 disease might otheiAvise have pursued a benign course1. The most important factor in the high incidence of strep- tococcus pneumonia has been the spread e>f the disease in the hospital wards. On September 24 the base hospital contained 2,789 patients, although it had been planned to care1 for only 2,009. AVith the progress of the epidemic the number of admissions increased A'ery rapidly, so that on September 30 the hospital contained 3,587 patients and on October 5, 4,233. Aften September 24 the mildeu* cases of influenza Avere1 treated in barracks. The pressing need of diminishing the ovororoAvding of the hospital Avas fully rec- ognized and adjacent barracks Avere transformed into hos- pital Avards; between October 3 and 6, 1,362 patients Avere transferred from the hospital to these quarters. In the main hospital, during the period of oA'eu'croAvding 20 Awards for patients Avith pneumonia ay ore added to the two which already existeel. These hastily organized and o\Ter- crowdcel Avards haA'e been attacked by outbreaks of strep- tococcus pneumonia, Avhich during certain periods have been fatal to metre1 than tAvo-thirels of those avIio have been admitted with pneumonia, Avhereas in the two long estab- lished Avards for pneumonia isolated cases of streptococcus infection, which have appeared, have failed to spread to SUMMARY OF INVESTIGATION AND CONCLUSIONS 383 other patients and pneumococcus pneumonia with few ex- ceptions has been found in those who have died. In one newly established ward 67.5 per cent of those1 admitte'd within a period of three days have died, and in all of the 23 autopsies which have been performed, streptococcus pneumonia has been found. In another ward 50 per cent of all who have been admitted during a period of on*1 week have1 died, and among the autopsies performed on these individuals pneumococcus pneumonia has been found in 6 and streptococcus pneumonia in 14. The sputum of 9 patients in this Avard has been examined on admission, and pneumococci, but no streptococci, have been found. All these patients lnave died, and infection Avith S. hemolyticus has been found at autopsy in 7. Transmission of Pneumococcus Pneumonia.—Our study of secondary Avard infection has not only sIioavh that pa- tie'iits with pneumococcus pneumonia following influenza are susceptible to infection by S. hemolytie'iis, but that patients suffering Avith pneumonia caused by one type of pneumococcus may be infected Avith another type1 during the course of the disease or after convalescence has begun, the second infection being acquire el from patients in ad- jacent beds. Pneumonia caused by Typo IV has ended in crisis and has been followed by a period of normal tem- perature; recurrent pneumonia has been fatal and Pneu- mococcus Type II has been found in the organs at autopsy. Pneumonia caused by Type I has been followed by recur- rent pneumonia caused by Pneumococcus II atypical ac- quired from a patient in the next bed. These secondary pneumococcus infections acquired within the hospital are apparently not uncommon. Prevention of the Transmission of Pneumonia.—The es- sential factor in the management of influenza and pneu- monia is such isolation of each patient that microorganisms cannot be transmitted from one to another or from attend- ants or others to patients. This condition may be fulfilled 384 PXEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT by the separation of patients in rooms or isolated compart- ments especially constructed for the treatment of pneu- monia and by the1 employment of all possible means to pre- vent the transmission of infection from one patient to an- other by physicians, nurses and orderlies. It is elesirabh' to examine1 attendants te> determine if they carry hemolytic streptococci in their mouths and to exclude those avIio are found to be "carriers." Influenza is a self-limited disease Avhich, in the absence of complications implicating the loAver respiratory tract, is of relatively mild character. When death en-curs as the result of influenza it is with A'ery rare, if any, exceptions referable to pneumonia; Ave have hrvariably found pneu- monia in those who have died in consequence1 of influenza. The individual attacked by influenza may carry Avithin his upper respiratory passages pneumococci or hemolytic streptococci capable1 of invading the bronchi and causing pneumonia, but in most instances the microorganism which produces serious pulmonary complications is dorhTed from others Avith Avhom the influenza patient has come into con- tact. The greatest source of danger to one with influenza is contact Avith patients who haATe acquired pneumonia, and this danger is immensely increased Avhen infection Avith S. hemolyticus makes its appearance among pneumonic pa- tients. Hospital epidemics of streptococcus pneumonia Avill be1 preATented Avhen the disease is dreaded as much as puerperal fever or the hospital gangrene of former years, and Avidespread knoAvledge of the suppurative pneumonias of influenza Avill bring a clear recognition of the fatal char- acter of streptococcus infection in patients suffering with pneumococcus pneumonia. Overcrowding of barracks has been an important fac- tor in the1 propagation of acute1 respiratory disease and in the transformation of othenvise trivial influenza into fatal pneumonia. Crowded troop trains have doubtless had a part in disseminating infection among hoavIv as- SUMMARY OF INVESTIGATION AND CONCLUSIONS 385 sembled recruits. Should these dangers be recognized they may be avoided by appropriate measures which -will pro- mote rather than retard those military aims which must be placed foremost in time of Avar. It may be possible by ade- quate expenditure to avoid the death of thousands of re- cruits Avithin one month of their entrance into military soiwice. A second factor in the increase of death rate from pneu- monia is the overcrowding and confusion of hospital facil- ities in the presence of an epidemic disease. "When troops are maintained in camps precautions should be taken to pro- vide effective safeguards against the overcrowding of the base hospital. Isolation of each patient with pneumonia is the most ef- fective way of protecting him from infection and of pre- venting him from becoming a possible source of danger to others. The effectiveness of this isolation will depend upon the separation of patients by some means more effective than the cubicles composed of sheets heretofore employed, upon an aseptic technic sufficiently rigid to prevent the transfer of pyogenic infection to pneumonia patients, and upon the exclusion from the Avarel of those who harbor S. hemolyticus. EATen should each patient be completely isolated from his neighbors, no effort should be neglected to determine, as far as possible, the nature of the infection with which he suffers. In the presence of an overwhelming epidemic such as that which attacked our army camps, the bacter- iologic work which is required may be far beyond the facil- ities which are available and in many instances it may be wholly impossible. Nevertheless effective control of strep- tococcus pneumonia will depend upon its recognition as soon as it appears, and bacteriologic examination of the sputum offers the1 readiest means for its identification. The routine performance of autopsies will furnish an index of the success of the measures in force, and the discovery 386 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT of suppurative pneumonia Avill suggest the presence of im- minent danger. HoAvever perfect the organization of pneumonia wards and hoAvever accurate the aseptic technic in force, it is elesirable to separate as far as possible those infected Avith streptococcus from those avIio are' free from this infection, so that the accuracy of the technic in force may not be put to too severe a test. When streptococcus pneumonia has appeared in a Avard it should be closed to further admissions. Those Avho are concerned in the planning and construc- tion of military and other similar hospitals might well give special attention to the possibility of epidemics such as those Avhich avc have experienced, and special provision might be made to aAToid OAT'rcroAvding in the presence of a demand far in excess of the routine need for hospital facil- ities. In the construction of these hospitals appropriate provision should be made for the care of patients with pneumonia. Medical officers should receive detailed in- struction in the organization and conduct of Avards designed for the treatment of pneumonia. APPENDIX EXPERIMENTAL INOCULATION OF MONKEYS WITH BACILLUS INFLUENZA AND MICRO- ORGANISMS ISOLATED FROM THE PNEL MONIAS ()F INFLUENZA Eugene L. Opie, M.D.; Allen W. Freeaian, M.D.; Francis (J. Blake, M.D.; James C. Small, M.D.; and Thomas M. Rivers, M.D. Experiments were undertaken at Camp Pike in Decem- ber, 1918, to determine Avhether bacteria freshly isolated from patients suffering Avith influenza and pneumonia dur- ing the outbreak of influenza and its associated pneumo- nias A\Tere capable of producing similar diseases Avhen in- troduced into the1 respiratory passages of monkeys. The number of animals aATiilable for the study Avas limited. The attempt Avas made (a) to determine if B. influenza? produces in monkeys a disease comparable' to influenza of human beings, and (b) to determine so far as possible, with the limited opportunity, the character of the lesions produced by combinations of pneumococcus or S. hemo- lyticus Avith B. influenza? and to compare these lesions Avith lesions produced by pneumococcus or by hemolytic strep- tococcus alone. Pfeiffer1 found monkeys alone susceptible to invasion by B. influenza? and obtained no evidence of multiplication of the microorganism within the body of any other animal. A suspension containing mucus from the sputum of a pa- tient with influenza was injected into a monkey. There was elevation of temperature and the animal died after seven davs. Lobular patches of atelectasis occurred along the sharp edges of the lungs and the adjacent bronchial ipfeiffer: Ztschr. f. Hyg., 1893, xiii, 357. 387 388 pneumonias and infections of respiratory tract branches contained mucus. Cultures on agar from the bronchi remained sterile1. Microscopic examination showed the presence of bacilli resembling B. influenza. Death Avas caused, the author states, by an abscess at the site of in- oculation and not by the process in the lungs. Three mon- keys received each 0.5 c.c. of bouillon containing a blood agar culture injected into the lung through the chest Avail. There Avas elevation of temperature lasting from three to five days Avith return to normal eATcry morning. There Avas cough but little evidence of illness. B. influenza Avas introduced by a platinum loop into the nose of a monkey. Febrile reaction is recorded lasting four or five days. Pfeiffer found that guinea pigs and mice Avere resistant to the microorganism. Large doses injected intnwenously cause1*I in rabbits intoxication Avith •dyspnea and eAuelence of profound muscular Aveakness. Kameir used a culture of B. influenza? which Avas nonpath- ogenic for mice1, but when it was inoculated into the peri- toneal cavity with streptococcus both influenza bacilli and streptococci appeared in the blood. Jacobson3 found that B. influenzas appeared in the blood and viscera of mice killed by intraperitoneal inoculation of B. influenza? mixed with cultures of streptococcus either living or killed by heat. B. influenza? which had successively passed through mice, simultaneously inoculated Avith killed streptococci, acquired such virulence that it was capable of producing septicemia when inoculated alone. Richie4 introduced by lumbar puncture a suspension of two blood agar cultures of B. influenza? obtained from the meninges of a patient with influenzal meningitis into the' subdural space of a rhesus monkey. Death occurred in eighteen hours and there Avas beginning meningitis. B. in- fluenza^ was present in the exudate in abundance. :Kamen, L : Centralbl. f. Bakteriol., 1901, xxix, Krste Abt. 339. 3Jacobson, G.: Arch, de med. exper. et d'anat. path., 1901, xiii, 425. "Richie, J.: Journal Path, and Bacterid., 1910, xiv, 615. APPENDIX 389 In tAvo species of monkeys Wollstein5 produced fatal meningitis by injecting suspensions of B. influenza? into the subdural space by lumbar puncture1. During the course of our investigation of pneumonia and influenza, sputum of approximately 400 normal individuals or patients Avith influenza Avas injected into the peritoneal cavity of mice. B. influenza aa^is found in approximately 150 instances. In only 4 instances Avas B. influenza? found in pure culture in the blood; in all other mice in Avhich B. influenza? appeared in the blood it accompanied pneumo- coccus or S. hemolyticus. Before experiments Avere performed cultures Avere made from the throats of all monkeys in order to exclude the presence of B. influenza. Blood agar plates inoculated with a SAvab applied to the nasopharjmx failed to sIioav in any instance B. influenza, pneumococci, or hemolytic strep- tococci. Streptococci causing green discoloration of blood agar were usually found. Inoculation of the Nose and Pharynx with B. Influenzae.— B. influenza? was introduced into the nose and pharynx of two healthy monkeys. An actively growing culture of the microorganism made on alkaline blood agar and sixteen hours old Avas used. The culture was the first subculture from a groAvth obtained from the nose and throat of a patient with influenza. A cotton swab moistened with broth was applied to the surface of the culture. It was introduced into the nostrils and smeared over the pharynx of the animals. A swab moistened with sterile broth was applied to the nose and pharynx of a third monkey as a control; cultures from this animal kept in a cage removed from those inoculated failed to sIioav B. influenza?. Experiment 1 November 21, 1918.—Small female monkey; throat culture: negative. No- v mber 23—10-20 A.M.—White blood corpuscles, 16,700; polynuclear leuco- Iy™s,%S per cent; small lymphocytes, 17.5 per cent; large lymphocytes, 8 per ^^— M.: Am. lour. Dis. Child., 1911, i, 42. 390 PNEUMONIAS and infections of respiratory tract cent; large mononuclears, 1 per cent; eosinophils, 2.5 per cent; basinophiles, 0.5 per cent. 10:30 A.M.—Mucous membranes of nose and throat were inoc- ulated with B. influenzae as described above. November 25.—The animal ap- pears sick and is huddled in back of its cage; the nose is running. AVhite blood corpuscles, 13,500; polynuclear leucocytes, 44 per cent; small lymphocytes, 30 per cent; large lymphocytes, 22 per cent; large mononuclears, 3 per cent; eosin- ophiles, 1 per cent. 3 :40 P.M.—Free epistaxis occurred after culturing of nose; the swab was discolored with old brownish blood indicating previous epistaxis. Nose culture: B. influenza? present in abundance; Gram-positive cocci present. Throat culture: negative for B. influenzae. November 28.—Monkey is more active and appears to be fairly well. Nose and throat cultures: negative for B. influenzas. December 4.—Monkey is apparently well. Experiment 2 November 21( 1918.—Small male monkey. Throat culture: negative. No- vember 23.—10:10 A.M.—White blood corpuscles, 10,900; polynuclear leuco- cytes, 52 per cent; small lymphocytes, 18 per cent; large lymphocytes, 25 per cent; large mononuclears, 3 per cent; eosinophiles, 2 per cent. 10:15 A.M.— Mucous membranes of nose and throat were inoculated by means of moist swab with 4 strains of B. influenzae recently isolated from acute cases of in- fluenza. November 24.—Monkey is quiet and takes no interest in surroundings. November 25.—Animal appears sick and remains huddled at back of its cage. Nose culture: B.. influenzae present. Throat culture: B. influenzas present. Swab applied to nose is stained brown with old blood indicating previous epistaxis. November 26.—Animal is still sick; nose is running. White blood corpuscles, 14,400; polynuclear leucocytes, 61 per cent; small lymphocytes, 23 per cent; large lymphocytes, 15 per cent; large mononuclears, 1 per cent. No- vember 27.—White blood corpuscles, 11,300. November 28.—Nose culture: negative for B. influenzas. Throat culture: B. influenzas present. November 29-—Animal is active, but still appears sick. White blood corpuscles, 19,300. December 4.—Monkey appears well. Throat culture: B. influenzas present. These animals were sick two and six days following in- oculation. There was discharge from the nose. In both in- stances there was epistaxis. The temperature of the ani- mals was subject to such wide variation in relation to ex- ternal temperature that it could not be used as an index of the progress of the disease. There was no leucocytosis, but in one animal there was some increase in the numbers of leucocytes during recovery. In one animal B. influenzae present in the nose after Iavo days was absent after four days. In the other animal the organism was repeatedly found in the nose and throat and was still present in the throat eleven days after inoculation. The two animals suf- APPENDIX 391 fered Avith a self-limited disease resembling many cases of influenza. Introduction of Bacillus Influenzae into the Trachea.—In the attempt to reproduce the bronchitis Avhich occurs in a considerable proportion of all cases of influenza and is al- most invariably associated with B. influenza?, this organism Avas introduced into the trachea of monkeys. In Experi- ment 3 a suspension containing young cultures of freshly isolated B. influenzae was introduced into the trachea by a silver catheter passed through the glottis and larynx into the trachea. Young cultures of B. influenza, subcultured only once after isolation from early cases of influenza, Avere used. The microorganism Avas recovered in abundance by throat SAvab tAvo days later and again from the bronchus at autopsy three days after inoculation. Tuberculosis of mesenteric lymph nodes, of intestine and of liver and several small tuberculous nodules in the lung were found at autopsy. A secondary invasion of the lung by staphylococci had oc- curred. There A\Tas bronchitis with an inflammatory infil- tration of the subepithelial tissue of the bronchi by lym- phoid and plasma cells. Bronchopneumonia was present, and the bronchi and many of the alveoli contained blood. These changes do not differ essentially from the changes found in many instances of pneumonia following influenza. In three instances cultures of B. influenza? were injected into the trachea by means of a hypodermic syringe. In one of these experiments (Experiment 4) intratra- cheal injection of 2 c.c. salt solution suspension of B. in- fluenzae (isolated at autopsy from bronchus of the monkey used in Experiment 3), representing growth on V/2 blood agar plates, was made with a needle inserted into trachea just above the suprasternal notch. On the following day a throat culture contained B. influenzae in abundance. Three davs after inoculation the monkey appeared to be very sick and there was profuse nasal discharge. The animal 392 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT coughed and sibilant rales were heard over the chest. There was no leukocytosis. A throat culture contained B. influenzae. Four days after inoculation the monkey was still sick and weak, but appeared much improved and was killed. The trachea and large bronchi contained thick vis- cid mucus. In the middle lobe of the right lung was a patch of grayish reel, airless tissue, firmer than the lung substance elsewhere. Cultures from the trachea, bronchus and lung contained a variety of microorganisms, but B. influenza? was not recovered. In two additional experiments (Experiments 6 and 7) cultures of B. influenzae forty-eight hours old were injected into the trachea of monkeys. The microorganism was re- covered in cultures made from the pharynx two days later. These animals Avere only slightly sick. Introduction of B. Influenzas and S. Hemolyticus into the Trachea.—In view of the frequent association of B. influen- za? and S. hemolyticus in the sputum of patients with strep- tococcus pneumonia folloAving influenza and in the bronchi and lungs of those avIio have died with this disease, the tAvo microorganisms Avere injected simultaneously into the tra- chea of monkeys. B. influenza? and S. hemolyticus in Experiment 7 pro- duced bronchitis and bronchopneumonia. There was acute inflammation of the interstitial tissue of the lung, and acute lymphangitis with numerous polynuclear leucocytes within the lumen of the lymphatics was present. B. influenza? and S. hemolyticus were present in the trachea at autopsy four days after inoculation. It is probable that part of the in- jected culture entered the tissue outside the trachea, for an abscess was formed in this situation. It is noteworthy that acute pericarditis occurred and both S. hemolyticus and B. influenza? were found in the pericardial exudate. B. influ- enza? not infrequently exhibits this tendency to penetrate in association with other bacteria localities which it does not invade independently. APPENDIX 393 In a second experiment (Experiment 8) in which B. influ- enza? and S. hemolyticus Avere injected into the trachea, both microorganisms were recovered from the throat on the clay following inoculation; on the fifth clay S. hemo- lyticus alone was recovered and on the sixth day a throat culture was negative both for S. hemolyticus and B. influ- enza?. Introduction of B. influenzae and of Pneumococcus or of Pneumococcus Alone into the Trachea.—In Iavo experi- ments B. influenza and Pneumococcus Type III Avere simul- taneously injected into the trachea. In Experiment 9 a large male monkey Avas used and intra- tracheal injection made Avith syringe and needle of 5 c.c. salt solution suspension of Pneumococcus Type III and B. influenza? (growth on 5 blood agar plates of mixed cultures of Pneumococcus III and B. influenza). On the folloAving day the animal was very sick, lying on the floor of its cage, and Avas dead two days after inoculation. The dosage of bacteria in this experimemt Avas large. The lesions in gross appearance and microscopically resembled those seen in many instances of pneumonia following influ- enza. In the trachea there Avas loss of ciliated epithelium, congestion of the subepithelial tissue, hemorrhage and infil- tration with plasma cells. The lungs Avere consolidated and red and there Avere hemorrhage and edema. B. influenza?, as in human cases, was abundant in the bronchi, less abun- dant in the consolidated lung, being present though scant in the left lung, and absent in cultures from the right. B. influenza? as in Experiment 8 with streptococcus had en- tered the left pericardial cavity in company in this experi- ment with Pneumococcus III. In Experiment 10 a very large monkey received by intra- tracheal injection, made with syringe and needle, 5 c.c. salt solution suspension of Pneumococcus III and 3 strains of B. influenzae, (2 recently isolated from cases of influenza 394 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT and 1 from autopsy in a case of postinfluenzal pneumonia). The animal died tAventy-f our hours later. This simultaneous introduction of B. influenzae and Pneu- mococcus III in large quantity has produced rapidly fatal pneumonia Avith lobar distribution. Hepatization Avas homogeneous and red, and outside the consolidated parts of the lung there Avas hemorrhage and edema. The lesion resembled that found A\iien death has occurred Avithin a feAv days after the onset of pneumonia folloAving influenza, but had no distinctive characters establishing its relation to pneumonia f olloAving influenza. In Experiment 11 Pneumococcus III alone in small amount Avas introduced into the trachea of a small monkey. The animal Avas ATery sick, but its condition improATecl and recovery seemed probable. The animal was killed seven clays after inoculation, and typical lobar pneumonia with gray hepatization Avas found at autopsy. Experiment 11 November 20, 1918.—Small monkey; throat culture: negative for B. influ- enzas, pneumococcus and S. hemolyticus. November 28 and December 6.— Nose and throat cultures again negative for B. influenzas. December 9.— 4:30 P.M.—Intratracheal injection with syringe and needle of 0.33 c.c. of an eighteen hour broth culture of Pneumococcus Type III. December 10.—The animal is sick, huddled up in his cage with head down; there is rapid respi- ration with expiratory grunt and the mucous membranes are moderately cya- notic. There is frequent cough. Throat culture: Pneumococcus III present in abundance. December 15.—The animal appears to be better. Respirations are still rapid but less labored. December 16.—The animal is improving but very weak and emaciated. Autopsy.—The pleural cavities contain no fluid. On the right side are sev- eral strands of fibrin. The right lower lobe with the exception of a small patch at the summit and the lower part of the middle lobe are voluminous, have a dull gray surface covered by a scant layer of fibrin and are firmly con- solidated. On section the consolidated tissue has a gray color and is con- spicuously granular, the granulation resembling, on a slightly smaller scale, that seen in human lobar pneumonia. The bronchi contain a small amount of viscid fluid. Bacteriology.—Direct smears from the trachea and the lower lobe of the left lung contain Gram-positive diplococci. Cultures from the trachea and from the blood of the heart contain Pneumococcus III. Cultures from the left lower lobe, from the liver and from the spleen remain sterile. APPENDIX 395 Microscopical Examination.—There is abundant infiltration of the subepi- thelial tissue of the trachea with plasma cells. Superficial ciliated epithelium is in places lost. At one point is a small focus of hemorrhage. Alveoli in the consolidated part of the lungs contain polynuclear leucocytes and fibrin and exhibit the appearance seen in lobar pneumonia in man. In Experiment 12 B. influenza) was injected into the tra- chea and two days later identified in a culture made from Fig. 33.—Experimental lobar pneumonia in the stage of gray hepatization produced by injection of Pneumococcus III into the trachea of a monkey (Experiment 11). The alveoli are uniformly filled with plugs of fibrinous exudate. the pharynx; four days after inoculation Pneumococcus IV was injected into the trachea. The animal Avas killed seven days after the first inoculation, and three days after inocu- lation with pneumococcus. The lower half of the upper lobe of the right lung and the greater part of the loAver and 396 PNEUMONIAS AND INFECTIONS OF RESPIRATOI1Y TRACT middle lobes were consolidated. The pleural surface of the consolidated areas was dull red and covered by a small amount of fibrin. The Ioayop lobe, with the exception of a small part at the summit, was very firmly consolidated, on section pinkish gray in the anterior part and deep red in a small zone at the posterior border. The cut section was conspicuously granular. The trachea and bronchi con- tained mucus. Cultures from the trachea, the right lung and the right pleural cavity contained Pneumococcus IV in pure culture. Alveoli in the consolidated part of the lung were filled with polynuclear leucocytes and fibrin. Lobar pneumonia has been produced by the introduction of Pneumococcus IV into the trachea. It is doubtful if pre- ceding inoculation of B. influenza? has influenced the course of the disease. The foregoing experiments have shoAvn that B. influenza? introduced into the* nasopharynx or into the trachea of monkeys is capable of causing lesions of the mucosa of these structures; the microorganism persists Avithin the nasopharynx or trachea and is reecwerable during a Avail- able period of from tAvo to eleA^en days after inoculation. Spontaneous infection of monkeys Avith B. influenza? has not been observed. The animals infected AAuth the microor- ganism are ill during several clays, but the experimental disease like most instances of human influenza is self lim- ited. FolloAving inoculation of the nose and throat of mon- keys Avith B. influenzae there is discharge from the nose, tendency to epistaxis and absence of leucocytosis. Bronchitis Avas produced by the introduction of B. influ- enza? into the trachea of monkeys, and the microorganism Avas recovered from the nasopharynx two and three days folloAving inoculation. There Avas no leucocytosis. In tAvo experiments death occurred folloAving inoculation, and in both instances it Avas found that the animal suffered Avith tuberculosis Avhich had produced only trivial lesions of the APPENDIX 397 lungs. In both animals staphylococci Avere obtained from the internal organs. There Avas bronchitis Avith changes in the bronchi Avhich, although not characteristic, resembled those found in association with B. influenza? in man. It is noteworthy that B. influenza? is usually found mixed with other bacteria in the bronchi of those ayIio have died Avith bronchitis and pneumonia following influenza. In the ex- perimental animals there Avas in places superficial loss of ciliated epithelium, exudation of polynuclear leucocytes, in- filtration of the subepithelial tissue Avith plasma cells and hemorrhage into this tissue. In one instance simultaneous injection of B. influenza? and S. hemolyticus, freshly obtained from autopsy upon a man dying with pneumonia folloAving influenza, caused bronchi- tis and bronchopneumonia; there Avere acute lymphangitis and infiltration of the interstitial tissue of the lung Avith polynuclear leucocytes such as occurs in human cases, but the lesion had not proceeded to suppuration. In man B. influenzae is usually found in greatest abun- dance upon the mucosa of the respiratory passages, less frequently it invades the alveoli of the lungs and is almost invariably found in association with other microorganisms. In company AATith other microorganisms B. influenza? pene- trates into tissues outside the lungs. In Experiment 7 it has entered the pericardium, with streptococcus, and in Experiment 9 with pneumococcus. AVhen B. influenzae and streptococcus are injected into the peritoneal cavity of a mouse both organisms appear in the blood, Avhereas in the absence of streptococcus, B. influenza? seldom leaves the peritoneal cavity. Typical lobar pneumonia has been produced for the first time in monkeys by injecting pneumococci (in quantity as small as 0.33 c.c. of suspension) into the trachea. With the animals available it has not been possible to adjust the dos- age of the tAvo microorganisms so that the influence of one 398 PNEUMONIAS AND INFECTIONS OF RESPIRATORY TRACT upon the other might be determined. Pneumococcus III, in small quantity, introduced into the trachea has produced typical acute lobar pneumonia in the stage of gray hepati- zation. A similar lesion has been produced Avith Pneumo- coccus IV obtained from the lung of a man dead Avith pneu- monia. INDEX Abscess of lung, bacteriology of, 203 empyema with, 233 healing of, 208 measles with, 347 parotitis with, 356 pathogenesis of, 205, 375 scarlet fever with, 357 staphylococcus causing, 199, 225, 366, 377 S. hemolyticus causing, 199, 365 Autopsies, table of, US, 120, 335 Autopsy protocols, No. 280, 226; No. 28(5, 220; No. 312, 254; No. 322, 228; No. 330, 214; No. 333, 229; No. 370, 229; No. 376, 206; No. 379, 215; No. 380, 204; No. 387, 206; No. 397, 223; No. 406, 204; No. 416, 204; No. 420, 279; No. 425, 229; No. 428, 2S0; No. 433, 28ii; No. 445, 257; No. 465, 238; No. 467, 208; No. 47.1, 236; No. 474, 221; No. 487, 273; No. 499, 224; No. 504, 238 B Bacillus influenza?, 369 bronchi and, 178, 215, 346 bronchitis and, 153, 371 experimental inoculation with, 389 history of, 25 influenza and, 30, 42, 43, 46, 49, 76, 370 isolation of, 30, 32, 38, 44. measles with, 26, 40, 43, 295, 351 meningitis and, 26 normal men carrying, 34, 42, 45, 369 pathogenicity of, 26, 48, 370, 387, 396 pneumococcus pneumonia with, 62. 178 Bacillus influenza—Cont'd pneumonia with, 72, 75, 76, 173, 364, 371 Bronchi, inflammation of mucous glands of, 146 Bronchiectasis, 239, 269, 355, 367 abscess with, 254 bacteriology of, 244 bronchitis with, 245 measles with, 336 pathogenesis of, 245, 259 Bronchiolitis, organizing, 264 Bronchitis, 40, 142, 195, 359 bacteriology of, 56, 150, 164, 359, 371 bronchiectasis with, 245 chronic, 262 clinical course of, 58 measles with, 336 organizing, 264 purulent, 47, 56, 60, 63, 74, 143, 149, 153, 360 Bronchopneumonia, 60, 63, 66, 162, 360, 363 bacteriology of, 68, 163, 171, 176, 181, 184, 189, 194, 197, 345, 364 fibrin with, 182 lobar pneumonia with, 155, 157 measles with, 340 secondary infection by S. hemolyti- cus with, 172, 177, 181, 374 C Carriers of B. Influenza?, 46, 101, 369 of S. hemolyticus, 99, 285, 287, 298, 303, 309, 310, 315, 319, 321, 332, 379 Cartilage, atrophy with bronchiectasis of, 254 Contact infection in influenza, pre- vention of, 98 in measles, 289 in pneumonia, prevention of, 98 Cubicles to prevent contact infection, 98, 290 Cyanosis, 144 399 400 INDEX E Empyema, 64, 67, 224, 226, 233, 304, 366 abscess of lung and, 233 encapsulated, 235 interstitial suppurative pneumonia with, 216, 234 measles with, 349 pneumococcus, 236, 350 streptococcus, 233, 350 Endophlebitis, 219 H Hemorrhagic and edematous consolida- tion with bronchopneu- monia, 188 peribronchiolar consolidation with b r o n c hopneumonia, 163, 173, 272, 340 Hepatization with bronchopneumonia, 179, 181 with lobar pneumonia, 160 Influenza, B. influenza? with, 30, 73 bronchitis with, 55, 56 clinical course of, 28, 53, 73, 80 coryza with, 54 cyanosis with, 54 epidemic in fall of 1918, 52, 108, 359 epidemic in spring of 1918, 47 fever with, 53 gastrointestinal symptoms with, 55 laryngitis with, 54 lobar pneumonia and, 161 measles and, 292, 319, 331, 351, 357, 380 pandemic of 1889-90, 109, 115 pandemic of 1918-19, 27, 359 pharyngitis with, 54 pneumococcus with, 33 pneumonia with, 55, 59, 74, 81, 139 pulmonary lesions of, 137 pulse with, 54 secondary infection with, 28, 45, 57, 95 sputum with, 55 S. hemolyticus with, 103 Interstitial bronchopneumonia, 261, 278, 348 suppurative pneumonia, 199, 209, 366, 376 bacteriology of, 214 interstitial suppurative pneumonia— Cont'd chronic inflammation with, 221 empyema with. 216, 234 healing of, 222, 224 measles with, 348 pericarditis with, 237 Lobar pneumonia, 60, 63, 154, 360, 362 bacteriology of, 64, 156, 164, 339, 362 bronchopneumonia with, 155, 157 experimental production in mon- keys of, 394, 397 influenza and, 161 measles with, 337 purulent bronchitis with, 60, 63, 66 secondary infection by hemolytic streptococci with, 64, 159, 340, 374 spread in lung of, 339, 354 typhoid fever with, 353 Lobular consolidation, confluent, 188, 341 with bronchopneumonia, 163, 178, 272, 341 Lymphatics, suppurative inflammation of, 217, 218, 376 thrombosis of, 217, 218 Lymphangitis, experimental produc- tion with S. hemolyticus of, 392 M Masks to prevent contact infection. 98, 290 Mastoiditis, 303, 312, 332 Measles, 119, 288 B. influenza? with, 26, 40, 43, 295 bronchiectasis with, 336 bronchitis with, 336 bronchopneumonia with, 340 complications of, 303, 378 empyema with, 349 influenza and, 292, 319, 331, 351, 357, 380 interstitial suppurative pneumonia with, 348 lobar pneumonia with, 337 pneumococcus pneumonia with, 312 pneumonia and, 292, 303, 312, 332, 334, 378 secondary infection with, 282 INDEX 401 Measles—Cont 'd S. hemolvticus with, 285, 287, 297, 319, 330, 331, 353, 378 suppurative pneumonia with, 345, 347 unresolved bronchopneumonia with, 342 Methods, 29, 51, 283, 291 Mortality of pneumococcus pneu- monia, 140 of pneumonia following influenza, 139 of streptococcus pneumonia, 140 Mumps, 119, 355 N Necrosis with bronchopneumonia caused by S. hemolyticus, ISO, 375 ' with lobar pneumonia caused by S. hemolyticus, 160, 374 with S. hemolyticus, 199, 200 0 Oedema, interstitial, 209 Organization of pneumonic exudate, 197 Otitis media, 289, 303, 312, 317, 329, 332 Peribronchiolar consolidation with b r o n c hopneumonia, 163, 166, 267, 340 Pericarditis, 64, 237 . Peribronchial consolidation with b r o n e hopneumonia, 163, 192, 361 hemorrhage, 189 Peritonitis, 238 Phagocytosis of red blood corpuscles, 272 Pneumococcus, 372 bronchitis and, 153 bronchopneumonia with, 165, 184, 373 empyema, 236 experimental lobar pneumonia with, 393 influenza with, 33 lobar pneumonia with, 158, 372 pneumonia, 60, 75, 104 clinical course of, 62 measles and, 312, 332 Pneumococcus, pneumonia—Cont 'd mortality of, 140 secondary pneumococcus infection with, 61 secondary streptococcus infection with, 62 transmission of, 91, 383 secondary infection in pneumonia with, 91 Pneumonia, B. influenza? causing, 72, 76, 371 bacteriology of influenza and, 60, 74, 107 bacteriology of measles and, 351 chronic fibroid, 273 clinical course of influenza with, 62 diagnosis of, 136, 334, 361 dissecans, 209 immunity following, 373 influenza with, 59, 76, 81, 109, 360 measles and, 119, 292, 303, 312, 332, 334, 378 mumps and, 119 pneumococcus, see Pneumococcus pneumonia prevention of, 98, 319, 383 scarlet fever and, 119 secondary infection with, 83, 106 spread through lungs of, 194, 373 staphylococcus, see Staphylococcus pneumonia streptococcus, see Streptococcus pneumonia S. hemolyticus in throat with, 310, 329, 379 Pseudomfluenza bacilli, 26 S Scarlet fever, 119, 356 Squamous transformation of bron- chial epithelium, 149, 251, 275, 336 Staphylococcus, 153, 377 pneumonia, 112, 225, 354, 366 pneumonia, pathogenesis of, 230 Streptococcus empyema, 233 hemolyticus, 374 bronchitis with, 153 dissemination in wards of, 315 experimental production of acute lymphangitis with, 392 identification of, 283 influenza with, 103 lobar pneumonia with, 64, 159 measles with, 285, 287, 297, 330, 331, 345, 353, 378 402 INDEX Streptococcus hemolyticus—Cont 'd normal men with, 285, 322 secondary infection in pneumonia with, 84, 106, 178, 204, 374 nonhemolytic, 376 peritonitis, 238 pneumonia, 60, 70, 75, 115, 307, 365 bacteriology of, 71 clinical features of, 71 measles with, 303, 305, 307, 318 mortality of, 140 transmission of, 84, 381 viridans, 377 Suppurative pneumonia, 199, 347 with measles, 345, 347 T Thrombosis of capillaries with bron- chopneumonia, 184 Typhoid fever, lobar pneumonia with, 353 staphylococcus pneumonia with, 354 U Unresolved bronchopneumonia, 261, 266, 342, 368 bacteriology of, 276 interstitial suppurative pneu- monia with 278 'o. r^:?nw;'*^ NLM051671591