; amy, SG REPORT OF THE DIRECTOR OF THE HOSPITAL October 1919 $s. LI92S REPORT OF THE DIRECTOR OF THE HOSPITAL otober 1919. To the Corporation of The Rockefeller Institute for Medical Research Gentlemen; = One year ago the Hospital was practically a military hospital. ‘the chief activities concerned the care of sick soldiers, the instruction of army medical officers and assistance to the government in the solution of immediate practical problems. Practically all the men~ bers of the staff of the Hospital had entered the ary, many of them were in France, and research, " the diligent inquiry and laborious, persistant search of truth", was at the lowest level since the Hospital was opened, Today the Hospital is again an institution for investigation, Some of the men have returned to their old activities. Some have gone elsewhere, but their places have been filled by capable, wall«trained nen, Enthusiasm for obtaining new knowledge about disease is in the air; many of the men have already entered diligently upon the solution of new problems, . A year &go it seemed doubtful whether at the end of the war any spirit of Anvestigation would remain, or students to do the investigating. “foday it socus Certain that. this spirit is alive, and that men, a few years older it is. true, are still ready to quietly undertake the study of disease, eo Dm, ° It is hoped and believed that the reorganization of the Hospital) is in progress and that the Coming year will be the best we have ever had. Hospital Staff, During a large part of the past year the staff has consisted of a few regular members of the staff who did not onter the army or were assigned to duty here, in addition to the medical officers who were ordered here for special training, Pollowing the signing of the armistice and the release of men from military service, some of the old mombers of the staff returned, but it was impossible to satisfactorily reorganize the staff before the beginning of the summer vacation, During the past monthe numerous additions and changes in the staff have been made. the most important loss has been that of Dr. Doches, who goes to Johne Hopkins University, where he and Dr. Palmer, also a former member of the ‘staff, become Associate Professors of Medicine. Dr, Dochez has been associated with the Hospital since its - opening and he should share very largely in any credit for the ‘Fesults of the Hospital activition, His departure is a distinot loss to the Insti- tute, entirely apart trom the personal loss to all the workers, | “Among the new ‘appointments on “the staff of the . Hospital are ‘the following; most of these men are only now undertaking _ their new duties: | Dr. Robert Levy has been appointed Resident Physician, Dr. Levy has had a large elinical experience ag Assistant. Resident Physician at Johns Hopkins Hospita. Dr. Homer Swift has been appointed an Associate o> in Medicine, It will be remembered that Dr. Swift was formerly a mem- ber of our staff and made important contributions to the subject of the treatment of tabes and corebro-spinal syphilis. He left us to become Associate Professor of Medicine at Columbia University and later was appointed Professor of Medicine at Cornell University, but before taking up his duties there, entered the army and was sent overseas. Here he did important and distinguished medica) Work, taking an important share in the investigations which resulted in showing that trench fever ie transmitted by body lice. Dr. Swirt will undertake the investigation of acute artic- ular rheumatism, Dr. Francis Blake has been appointed Associate in Medicine, Dr. Blake was also formerly a momber of the staff. A graduate of Harvard Medical School and interne at Peter Bent Brigham Hos- pital, he worked one winter in this Hospital under a Harvard Traveling | Fellowship. While here he carried on interesting studies concerning Pneumonia. He was later made Associate Professor of Medicine at the University of Minnesota, and after a year entered the army. While here he has done extrenely important work on. pneumonia, Collaborating with Dr. Cecil, he has Misceoded in inciting ie Production of ‘Pneumonia in monkeys by injecting Ante the trachea very minute anounte of pneumecocei or strep- ‘tococes or influenza. bacilli. ‘The pneumonia developing in each case has greatly resembled the type pneumonia in man which has been considered to be due to the same respective organisms. Dr. Blake is to share in the studies concerning acute respiratory disease and in collaboration with others may- undertake the etudy of measles. Dr. Binger of the University of Harvard and * et Sa Massachusetts General Hospital becsmes an Assistant Resident Physician. He has had considerable experience in the laboratories of Dr. Folin at Harvard and of Dr. Able at Baltimore, and has already made a number of scientific publications. Dr. Austin of the University of Pannsylvania becomes an Assistant Resident Physician. He has had an extensive clin- ical training in the University Hospital and has worked for several years with Dr. Pearce and has made a number of important publications relating to nephritis and blood diseases. Other assistant resident physicians will be Dr. James Trask, coming to us from Cornell University; Dr. Arthur Lyon, from Harvard Medical School, and Dr. Ralph Boots, from the University of Pitts- burgh, We are therefore starting the new year with a Well-trained, enthusiastic and Capable staff. Training Courses Given to Army Medical Officers. Up to the ‘time of signing the armistice the following training courses were given in whole or in part by the Hospital staff: ae Le ; . I. A course in bacteriological methods given for medical offi- cers in the Institute laboratories. . » Thé instruction of the men in the . methods of studying the bacteriology. of acute infections has been given | by Dr. Avery and Dr. Dochez, assisted by Dr. Stillman, and this has required a considerable amount of their time. It, A.course in chemical methods for membere of the Sanitary Corps has been given in the chemical laboratory of the Hospital, III. 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SOC Notwithstanding this fact and also that the staff was greatly depleted, an effort was made to do What wag possible in the study of the disease and in investigating the cause of the epidemic, Clinical Features of Influenza. Although an enormous literature hag developed concerning the symptoms and Cause of influenza, there ig etill much differ. ence of opinion as to the essential features of the disease, - indeed, there is stil) doubdt in the minds of some whether influenza ig a single Specific infectious disease. During the epidemic of the past winter pneumonia occurred with very great frequency, In exactly how many patients suffering from influensa, changes in the lungs sufficient to justify the diagnosie of pneumonia occurred, will probably never be known, Even ina hospital like this One where facilities for diagnosis are very good, it was impossible under the conditions prevailing last winter to be certain that no cases of pneumonia were overlooked, or that no influensal broncho-pneumonia cases were included among the lobar pneumonia Cases and vice verea. Of the 213 | patients suffering trom acute infections of the respiratory tract that were treated, 41 were considered to have had typical lobar pheumonia. : Of these 1a, or 29 per cent, died. ‘there ‘wore 168 casee © which were sonsidered ‘to de » Anfluensa, and of these pationte, 32, or a3 per cent, died. Wasty-one, or Sonsiderably over half of the influenza cases, were, believed to have sufficient inflammatory reaction in the lungs, as indicated by dulness, tubular breathing etc., to justify the diagnosis of broncho-pneunonia, and of these, 32, or 35 per cent, died. Of the 77 cases of influensa without denonst rable Pneumonia not one died. of these 77 cases diagnosed ag influensa and which were not thought to have pneumonia, ore TSO ay 29 had rales or other signs which indicated some degree of pulmonary involvement. The experience here indicates that influenza is a disease of the respiratory tract, though in some cases the infection of the lung ie of a mild grade and in some possibly, the infection never reaches below the larger bronchi, In the recent epidemic the lungs became involved in many cases, and it was among these cases that the mortality was ao high.. It is true that after the height of the epidemic had been passed it was preferred to admit to this Hospital only those patients having pulmonary involvement. Por thie reason it 1s probable that a larger percentage of our cases had Pneumonia than wag the case in the general hospital or in civilian practice, Nevertheless our experience indicates that pneumonia was much more common in the epidemic than was gon= erally assumed, An effort was made to determine the bacteria pras- ent in the lungs in our cases. This was done by making a careful bacteri- ological study of the sputum a by making cultures from material removed from the lung by puncture either during life: or immediately after. death, and by making cultures’ from’ the lungs at autopsy. - - The ‘results of those cultures indicated: that a number: of! pathogenic organione were. ‘concerned in’ the Process.‘ In: the cultires made in’ the various ways mentioned Paouno- 3 coccus, chiefly pneumococous” ‘eroup ‘iv; “Streptococcus hasiolyticus, in” a: small number of Cases, and Staphylococcus aureus, ina few cases, were found, Influenza bacilli‘were present in 85 per cent of the cases, as demonstrated by cultures made from the throat, from the sputum, or by cul-- tures at autopsy. - It is an interesting fact that influensa bacilli were cultivated from 20 of the 32 fatal cases of broncho-pneumonia in such numbers and under such conditions that it seemed likely that they played at least a 4 part in the pathologic process. The very frequent presence of B. influenzae in cases of the disease made it seem important that our chisf attention at the Hospital should be directed to learning more concerning this organism and its relation to the disease and the epidemic. As is well known there are two chief opinions concerning the etiology of the disease and the epidemic: first, that B. influenzae plays an etiologic role, and second, that this organiem is a secondary invader,, analogous to S. haemolyticus, Staphylococcus, Pneumococcua etc., and that the primary organism ig unknown, probably a filterable virus. As the staff of the Hospital was too much disorganized to permit any special investigations starting from the second of these two premises, it seemed better to confine our studies largely to the influensa bacillus, In order to Carry out these studies it was first necessary to find improved methods of cultivating this organiem so that we could be reasonably sure that it was not being overlooked when it Was actu- ally present. Dr. Avery undertook this problem and succeeded in devising a new method, employing a medium containing sodium oleata, In thie medium the growth of certain common bacteria ig inhibited, while influenza bacilli grow with very great luxuriance, | Since influenza bacilli were found to be almost constantly presont in the throats of persons suffering from influenza or. other acute respiratory disease during the epidemic, it seemed important to learn more concerning their distribution in the throats of healthy - persons or in persone who had recovered from influenza, Consequently, several surveys were made under the direction of Dr. Ernest Stillman of all the persons associated with the Institute. In the first survey made during 399 the September-Decembar quarter, it was possible to cultivate influenza bacilli from the throats of 42 per.cent of all individuals associated with the Institute, In January only 11 per cent of the individuals | were found to be carrying influenza bacilli,but this low percentage may probably be accounted for by certain defects in the medium employed. In February influenza bacilli Were cultivated from 30 per cent of the person- nel, in March from 50 per cent in April from 36 per cent and in May from 41 per cent. The results show that a large number of the individuals in the Inatitute during the past year have been chronic carriers of this organism. From some individuals all of the cultures made have been pose itive; from others the cultures have been poreistently negative; while still other individuals, who at first were negative, later became carriers, and vice versa, Investigations were made to show whether the cultivation of the organism from the throat might depend upon some incidental factor; for instance, whether cultures might be positive and cultures made a& few hours later might be negative, . The evidence 80 sal obtained indicates that this is not the case, but indicates that the technique employed may be relied — upon to show whether or not a person is a carrier of influensa bacilli, : — Investigations Were also made to determine from what part of the naso-pharynx the organisms © Were most readily isolated, oe most frequently encountered, In a series of about 90 individuals three cultures were made from the throat - one culture from each tonsil and one from the posterior wall ot the pharynx. In five individuals positive cul- tures were obtained on plates from all three sources. In five individuals the cultures from the pharynx,and from one or the other tonsil, were positive. In 13 individuals only the culture from the pharynx showed a growth of influ- enza bacilli. In no case were the organiems isolated from the tonsil and not i 360 TH from the pharynx, In these 90 individuals, therefore, positive cultures were obtained from 23 or 26 per cent, and the resulte show that the organ- iems were most likely to be encountered on the posterior wall of the pharynx. Consequently in most of our cultures since these observations were made, and in most of the cultures before, the cultures were made by touching the posterior wall of the pharynx alone. In tabulating the results, the. persons who gave a history of having had influenza during the present epidemic were separated from those persons from whom no such history could be obtained. The per- centage of carriers of influensa bacilli did not differ in these two groups of individuals, The results of cultures from the sick and the well, as mentioned above, indicate that during the epidemic of acute respiratory disease of the past winter, influensa bacilli could be cultivated from a much larger proportion of the pereons suffering from influensa or acute respiratory disease than from the healthy. Doubt might be thrown on this statement 1f we depended entirely upon the observations of the physicians in the wards, since in these cases a very great effort was made to isolate . influenza bacilli in every case, while cultures from the healthy persons Were made in a more or less routine manner. However, Miss Winchell, who made the routine cultures from the normal individuals, also made studies in a series of patients, ‘making the cultures in exactly the same way as they were made from the healthy. Whereas among a well persons influenza bacilli were cultivated only from 30 to 40 per cent of individuals, they were obtained by exactly the same technique from over: 85 per cent of the - cases in the wards. There can be no doubt, therefore, that during the epidemic of influensa of. the past winter influensa bacilli have been fre~ quently present in the mouths of healthy persons living in New York, and almost invariably present in patients suffering from acute respiratory Ht disease. Further than this we cannot go at the present time. Whether during the previous winter, or whether during subsequent winters when no epidemic is present, similar conditions exieted or will exist, cannot be stated, However, another survey has just been made, September 1919, and it has been possible to cultivate influenza bacilli from only 13 per cent of the Institute personnel. This is of some interest but gives us little real information, for it 1s possi- ble that exactly the same conditions may have been present in previous years, namely, that when persone return from their vacations during the period when respiratory infections are not prevalent, few persons may be found carrying influenza bacilli, but later when these infections become more common, @ larger percentage of persons carry these organisms. | Dr. Stillman and Miss Winchell aleo during the past winter made observations concerning the prevalence of influenza bacilli in two institutions near New York. At the New York State Training School for Girls at Rudeon, N. Y., influensa prevailed to a considerable extent during January and early in February. On February léth cultures were made from the throats of 52 patients still in the hospital, but convalescent, From these 52 patients influenza bacilli were cultivated from 20, or 38 per cent. One of the cottages at this institution had been under close quarantine since October 1918 on account of trachoma. No case of influensa had developed in this cottage. Cultures were made from 20 inmates of this cottage and of these 5, or 25 per cent, showed B. influenzae. Cultures were also made from a number of children at Mt. Loretta, a Catholic institution for children on Staten Island, This inetitution was said to have been under strict quarantine during the influensa epidemic, but investigation showed that the quarantine had been quite lax. TH, ‘yE%s . WU 3 The employees went to tow from time to time and the doctor and priest were frequent visitors to the institution, and the population was more or less shifting. No definite history was obtained, however, of the occurrence of influenza. Cultures were made from 190 of the children, and from 74, or 39 per cent, influenza bacilli were cultivated. The results of all thsse studies indicate that it will be very difficult by this line of investigation to demonstrate any etiologic relation of influenza batillus to this type of infection, unless it can be shown that influenza bacilli are not all identical, but that different types or varieties exist, A study to determine if possible by immunologic methods whether all influensa bacilli are or are not of the same type has been undertaken by Dr. Lyon. He has immunized a considerable number of rabbits to B. influenzae and now also has a sheep in process of immunisa- tion. By paying attention to certain factors,such as salt concentration of the medium, it has been possible to devise a method by which agglutina- tion reactions of influensa bacilli can be readily distinguished. Sera have been obtained which cause characteristic agglutination, but in our experience all races of influenza bacilli agglutinate equally well, This” reaction, however, has not been found to be absolutely specific, This study is still in progress but so far no definite evidence of differentia- tion of influensa bacilli into types has been obtained. | During the studies of influensa bacilli in normal throats a haemoglobinophilic bacterium has been frequently encountered which differe from B. influenzae in being hemolytic for red blood corpuscles. It is usually slightly larger than B. influenzae but otherwise resembles it very closely. It haa been tentatively called B. X. It haa not been found ae gil MER oe Oye rey JUD under ciroumstances in which it seems to have pathological significance. In summarizing our studies concerning influenza we may say that considerable knowledge has been obtained concerning the clinical features of the disease and the pneumonia associated with it. The bacteria present have been carefully determined in a series of cases. It has been shown that B. influenzae was almost constantly present in cases of the disease, and during the past winter was very frequently pres- ent in the mouths of normal persons. Whether this organism bears any etiologic relationship to the disease has not been determined, but this possibility has not been excluded. Some new knowledge concerning the characteristics of this organism has been obtained. Streptococcus hgemolyticus. In view of the severe epidemic of pneumonia during the winter of 1917-18 which was apparently demonstrated to be due to infec- tion with S, haemolyticus, it seemed most important that the study of this organism should be continued during the past winter, especially as we were in possession of a very large number of strains collected from cases of pneumonia occurring during the previous epidemic, This work has been carried on by Dr. Doches and Dr.’ Avery and has involved a very large amount of work, and has necessitated the employment of a large number of smaller animals. The work has resulted in the demonstration of certain principles which apply to the development of pathogenicity in organisms belonging to other groupe of bacteria,as well as to the bacteria of this group. | As regards streptococci it has been possible to show that: He (364 I. Immunological differences exist between strains of &. haemo- lyticus of the human type. II. Four biological types have been identified by means of the reactions of agglutination and protection. III. At least two other types have been encountered and the indications are that more exist. Much of our knowledge concerning the epidemiology of atreptococcus pneumonia has been obtained by means of throat cultures. The question arose as to whether wrong conclusions might not be drawn, owing to the cultivation from the throat of haemolytic streptococci of the bovine type derived from milk and cheese which had been previously eaten. Dr. Stillman has thoroughly studied this question and has shown that error is not likely to occur from the cultivation of milk streptococci, owing to the slight degree of haemolysis which these organisma cause when they are grown on the surface of blood agar plates. Cheese streptococci are more likely to cause confusion, but it has been shown that by employing proper methods in any case where doubt exiete,the origin of the streptococci may be determined without great difficulty. Acute Lobar Pneumonia. _Authough during the ‘past two years many more cases. . of acute. ‘respiratory disease, were treated dn the Hospital. than. over vetore, the number. of cases. of ‘typical lobar pneunonta has been comparatively ual. All cases of type I infection have been treated with ifmune serum and the 7 results have: continued to be as a good as thoee previously reported. This experience has also been repeated in certain army camps where it was possi- ble to carry out the method properly. Unfortunately this was possible in only a few places owing to the prevalence of the epidemics of streptococcus MZ 360 pneumonia and of influenza. In the autumn of 1918 Dr. Stillman made a further study of a large number of strains of so-called atypical type II pneumococci, It was found that organisms belonging to certain groups were encountered very frequently in cases of disease and probably are quite pathogenic for man, while other organiame belonging in other groups are frequently present in normal mouths, but are seldom found in patients with pneumonia, Dr. Avery and Dr. Cullen have carried on extensive studies with pneumococci to determine the {inal hydrogen ion concentration of pneumococcue cultures and also the optimum hydrogen ion concentration for growth of these organisms. The results obtained have a practical bearing on the best methods for cultivating these bacteria,as well as on the more ready and certain identification of them. Dr. Barber has studied further the question of ; so-called antiblastic immunity, employing for this problem the method which he has devised for isolating and cultivating single bacterial cells. He has not been able to demonstrate that ant i-pneumococcus serum has any power to inhibit the growth of these organisms, either in artificial culture medium or in the body of the animal. _ We are compelled therefore to believe that the action of the serum le chiefly dependent upon some activity of the protected animal, probably in part at least upon phagocytosia. Dr. Barber's study, which was carried out with great care and attention to detail, is of much theoretical importance. Treatment of Syphilis with A 189. The study of the therapeutic effect of the drug A 189 was commenced in January 1918 and continued until January 1919. “ys 4 566 As the toxic dose for man was entirely unknown the work had to proceed at first with great care in order that no harm might be done. Various modes of administration had to be tried out in order to learn the most effective one. Without going into details, it may be said that it was demonstrated that this drug ie effective in curing syphilis. It was decided from our studies that probably the most effective method of treatment would consist in the administration of 7 mg. of the drug per kilogram body weight every ten days, combined with treatment with mercury. If the drug were given in larger doses or more frequently, toxic effects might result; if smaller doses were employed,the therapeutic results were not aatisfactory. Having obtained this information, it seemed advisable to. discontinue the studies here and have the drug tested on a larger scale elsewhere. Chemical Laboratory. During the early part i the year research activ- ities in the chemical laboratory were very greatly diminished owing to Dr. Van Slyke! 8 illness and the ‘employment: of Dr. cullen ia the War Demon- The laboratory space and ‘equipment wore largely stration Hospital. “Bagot tar beditis Pe ae “he employed for ‘the. cours in clinical ‘laboratory methods given te the men of an ‘ines feet he abiieed “le Ghat ugha hb the Sanitary ‘orpet Sines the signing: of. the arhistice and ‘the. return ° of Dr. van siyke ‘and Dre Guiien, ‘the laboratory has deen gradually reor- - ganized and new problens have been undertaken. In apite of all the a difficulties and disorganization during the war, a considerable number of studies were made and results of importance obtained. A brief survey of this work follows: Dr. Van Slyke,with the assistance of Lt. Donleavy, has devised an improved method for estimation of blood chlorides. He LAr ease has aleo devised a method for titration of the organic acids in the urine. oper eat ee ea “ 3 Pe os ane * as ce pipet me With Dr. Stillman and Dr. Cullen he has improved the method for determining ee plasma bicarbonates. Miss Hiller has continued her work assisting Dr. Van Slyke in the study of proteins. She has brought about certain improvements in the methods employed in the hydrolysis of proteins and has been studying a new method for the determination of histidine. “Dr. Stadie, in connection with the study of A 189, has investigated the question of the distribution of arsenic in the body after intravenous injection of A 189, and the mode and rate of its excre- tion, Dr. Salvesen, of Christiania, who since April has worked in the laboratory as a voluntary assistant, has devised an improved mothod for measuring the carbon dioxide content of the blood. This work is an extension of the study of methods for estimation of blood gases so successfully undertaken by Dr. Van Slyke. The possession of an accurate and simple method for determining carbon monoxide has permitted a further . development of the Haldane method for determining blood volume. In employing this nethod, the subject ie allowed to absorb into his blood a og measured amount of carbon monoxide ,and the amount present: per cc. of blood is then determined. Dr. Salvesen has employed this method both in animals and in man, and with the improvements in technique which he has devised, the method seems both reliable and comparatively simple. C sis in Pneumonia. Dr. Stadie has demonstrated that the withdrawal of small amounts of arterial . »,od from man isa perfectly safe and nara less procedure, and for the first time determinations of the blood gases in arterial blood in a series of patients have been made. These studies have led to much increase in knowledge concerning cyanosis, about which there had been a great deal of difference of opinion. It has now been demonstrated that cyanosis in pneumonia is due to incomplete oxygenation of arterial blood and that a low oxygen saturation is of bad prognostic importance. This method has already been applied by others to the study of cyanosis in heart disease and it is planned to extend the investigation along this line here during the coming year. Dr. Stadie has also devised a gasonet ric method for the determination of methaemoglobin. This will permit a more accurate study of the question of methaemoglobin formation in vivo and in vitro by pneumococci. Circulatory Disturbances. Dr. ‘Cohn was absent with the American Expedition- ary Forces until February. Since his return he has made an extensive study of the size and functional capacity of the heart in 206 returned soldiers. He is also ongaged with Dr. Peabody in writ ing a took concern~ ing the cardiac disability which occurs go often in soldiers,’ and concerning which he has had except tonal opportunity to gain information. | . Dr. Levy has been studying, both in animals and in man ,the mods of action and dosage of strophanthin. It is hoped that this information will permit a@ much more accurats and rational therapy with thia drug of the digitalis series.