THE OCCURRENCE OF CARRIERS OF DISEASE-PRO-— DUCING TYPES OF PNEUMOCOCCUS. By A. R. DOCHEZ, M.D., anv O. T. AVERY, M.D. (From the Hospital of The Rockefeller Institute for Medical Research.) (Received for publication, May 20, 1915.) In previous papers! we have discussed the varieties of pneumo- coccus responsible for the production of lobar pneumonia and the differences that exist between such organisms and those found in the mouths of healthy individuals. The pneumococci obtained from persons suffering from lobar pneumonia have been divided into four groups. We have pointed out that the first three groups are comprised of disease-producing races, and are responsible for about 75 per cent of all cases of lobar pneumonia. Approxi- mately 25 per cent of cases of pneumonia are due to the fourth group. The pneumococci of this group cannot readily be distin- guished from those dwelling in the normal human mouth. Disease caused by the highly parasitic types is usually much more severe than that occasioned by the strains which are indistinguishable from the sputum pneumococci. Inasmuch as the highly virulent forms are always associated with disease, and only occur in the mouths of healthy individuals under the special conditions which are reported in this paper, the evidence is strong that in the spread of lobar pneumonia the disease in a majority of instances is transmitted from one individual to another. Infectious dis- eases usually spread by immediate contact, through the interme- diation of a temporary host, or by the agency of a healthy car- rier. The importance of these modes of transmission varies with different diseases and in many instances more than one of these mechanisms may be involved. In all likelihood the healthy carrier may be a greater menace to-the health of the community than the 1 Dochez, A. R., and Gillespie, L. J., Jour. Am. Med. Assn., 1913, 1xi, 727. Dochez, A. R., and Avery, O. T., Jour. Exper. Med., 1915, xxi, 114. 105 106 Carriers of Disease-Producing Types of Pneumococcus, infected individual, largely because of failure to recognize the car- , rier condition. In the epidemiology of certain diseases, notably typhoid and epidemic cerebrospinal meningitis, the importance of the carrier state is well known because of the definite tracing of foci of disease to such a condition. The more readily a disease is transmitted from one individual to another, the greater becomes the number of instances at any one time, and consequently the more vigorous the search for the source of infection. The spo- radic occurrence of lobar pneumonia, combined with the inability to distinguish disease-producing types of pneumococcus from those habitually living in normal mouths, has probably been responsible for the failure to establish a well defined epidemiology for this disease. It is not our purpose in this paper to discuss the importance of immediate contact as a cause of the spread of pneumonia, for, although instances have occurred in which two closely associated individuals, such as husband and wife, have been infected within a short period with the same type of pneumococcus, cases of pneu- monia usually develop at such wide intervals of space and time that direct contact relationships are obscured. Inasmuch as fully 75 per cent of all cases of lobar pneumonia are caused by peculiarly distinct races of pneumococci, not occurring in the normal mouth, then, as we have previously assumed, these instances of the disease must be due to contact infection, either direct or indirect, and some mechanism must exist by means of which the etiological agent is transmitted from one individual to another, In the pres- ent study we shall show that persons closely associated with indi- viduals suffering from pneumonia in a large percentage of instances harbor in their mouths pneumococci of the same type as those causing the disease, that such organisms are not found in the mouths of normal individuals not exposed to pneumonia, and that the considerable period of time during which these organisms are carried may in part account for the sporadic occurrence of indi- vidual cases of pneumonia. An additional means of transmission exists in the fact that the recovered case also may carry the pneu- mococcus responsible for his disease during a relatively long period of time. A. R. Dochez and O. T. Avery. 107 In the present paper are presented the studies of the pneumococci obtained from the mouths of persons associated with cases of pneu- monia, of the type of pneumococcus encountered in the mouths of normal unexposed individuals, and of the period of time during which convalescents harbor the disease-producing organisms. For TABLE f. Incidence of Carrier Condition in Healthy Individuals in Contact with Lobar Pneumonia, | ee epee) BGSocrates” | Aeoctaues. Duration of period of carrying. 2276 Type I Wife | Type I to days+ 2195 Type I Husband | Type I 24 days. 2203 Type I Wife | Type IV Mother | Type IV 2237 Type I Nurse : Type I Undetermined. Ww Type I Wife Type IV B Type I Wife No pneumococcus Daughter Type IV 2269 Type I _ Wife Type IV 2286 Type IT Mother Type IV Father Type IV 2299 Type IT Sister No pneumococcus 2301 Type II Wife No pneumococcus 2294 Type II Wife No pneumococcus 2309 ° Type II Mother Type IV 2314! Type Il Wife Type II Undetermined. 2335: Type Il Mother No pneumococcus Sister No pneumococcus 2326 Type II Wife No pneumococcus | 2330 Type IT Daughter Type II ‘Undetermined. 2344 Type II Sister No pneumococcus 1835 Type II Wife Type II 9 days+ 2174 Type IT Son Type IV 2175 Type II Mother Type II 27 days+ | Sister No pneumococcus Nurse Type II Developed pneumonia, Type II. 2202 Type II Mother Type II 45 days. 2199 Type II Husband Type IV 2298 Type II Sister Type IV 2226 Type IT Wife Type IV 2245 Type II Mother Type IV Brother Type II ‘39 days+ 2230 Type II Wife No pneumococcus 2247 Type II Daughter Type II Undetermined. Wife No pneumococcus Son Type IV 2266 Type II Wife No pneumococcus Brother-in-law | No pneumococcus 2270 Type II Mother Type IT 7 days+ Sister No pneumococcus 2265 Type IT Physician — Type II .2I days. 108 Carriers of Disease-Producing Types of Pnewmococcus. Summary. TABLE I—Concluded. Type of pneumococcus, No. of cases. Positive contacts. Per cent. Type lI... .... ee eee ee 8 3 37-5 Type IT.............-. 24 : 10 4l.7 Total... 2... 22 eee. 32 13 40.6 Approximate duration of carrier state 23 days. the sake of clearness, an explanation of our classification of pneu- mococci is given. The organisms have been placed into four groups, numbered from I to ITV. Groups I, IJ, and IIT are found only in association with disease and are distinctly parasitic in type. Members of Groups I, II, and ITI are recognized by their immune reactions which are identical within the respective group. Group IV consists of a heterogeneous series of strains which are not re- lated antigenically, and which cause a minority of cases of pneu- monia, and from which the pneumococcus occurring in the normal mouth is indistinguishable. In the Tables I to IV the pneumococci studied are classified according to this numerical grouping. TABLE II. Type of Pneumococcus Isolated from Sputum of Normal Individuals. Pneumococcus. Incidence. Per cent. Type I 3 2.6 Contacts Type II a) 7.0 Type IV 55 48.6 No pneumococcus 47 41.6 Total 113 Pneumococcus present 66 58.4 Pneumococcus absent 47 41.6 TABLE IIL Type of Pnewmococcus Isolated from Individuals with Lobar Pneumonia. Pneumococcus. No, of cases. : Per cent, Type I 78 34.97 Type I 75 33-63 Type III 22 9.86 Type IV 48 21.52 Total No. of cases 223 A, R. Dochez and O. T. Avery. TABLE IV. 109 Persistence of Disease-Producing Type of Preumococcus during Convalescence. Case No. 1654 1775 1867 1828 1792 2167 2168 2191 2195 2203 2237 2250 2269 2284 2267 2276 1679 1753 1763 1761 1825 1786 1820 1827 1880 1950 1969 2174 2175 2212 Type of pneumococcus during height of disease. Type I Type I Type I Type I Type I Type I Type I Type I Type I Type I Type Type Type I eR Type Type Type Type Mee eS ol Type Type I Type Ii Type II Type II Type II Type I Type II Type II Type II Type II Type II Type II Type II Type II Type I 60 days, 65 days, 59 days, 73 days, 30 days, go days, 33 days, 30 days, 12 days, 45 days, 15 days, 28 days, 49 days, 12 days, 13 days, 15 days, 23 days, 14 days, 10 days, 13 days, 15 days, 29 days, 15 days, 15 days, 30 days, 48 days, 108 days, 60 days, 34 days, 4o days, 47 days, 78 days, 53 days, 20 days, 25 days, 30 days, 14 days, 63 days, 21 days, 24 days, 15 days, 17 days, 12 days, 17 days, Type of pneumococcus after recovery. Type I. Type IV. streptococcus. streptococcus. Type IV. Type I. Type IV. Type IV. Type IV. Type I. Type IV. Type I. no pnheumococcus, no pneumococcus. Type I. Type I. Type IV. no pneumococcus. Type L. no pneumococcus. Type I. no pneumococcus. no pneumococcus. Type L streptococcus. Type IV. Type IV. Type IV. streptococcus. Type IV. streptococcus. Type IV. Type II. Type IV. Type IV. Type IT. Type IV. Type II. Type IV. Type IV. streptococcus. no pneumococcus. Type II. no pneumococcus. 110 Carriers of Disease-Producing Types of Pneuwmococcus, TABLE IV.—Concluded. Type of pnemococcus Type of pneumococcus Case No. during height of disease. after recovery. 2202 Type II 37 days, Type II. 43 days, Type IV. 2199 : Type II 32 days, no pneumococcus. 2226 Type II 29 days, Type II. 2245 Type II 16 days, Type IV. 2266 Type II 15 days, Type II. 2270 Type II 37 days, Type II. 2286 Type II 10 days, Type II. 25 days, no pneumococcus. 2292 Type II 29 days, Type IV. 2296 Type II ig days, no pneumococcus. 1743 Type III 13 days, Type III. 73 days, Type IV. 2185 Type III 16 days, Type III. 34 days, no pneumococcus. 2240 Type III 14 days, Type III. In the above four tables are given the main facts upon which we base our assumption that in the majority of cases lobar pneumonia is a disease the continued wide-spread incidence of which is de- pendent upon communication of infection from one individual to another. Table I establishes beyond doubt the existence of healthy carriers of the disease-producing types of pneumococcus. The study of the carrier state was limited to the investigation of infection with pneumococcus Types I and II because of the relative ease with which these organisms can be distinguished from other types of pneumococcus. Out of a total of thirty-two cases studied, at least one carrier of infection among the patient’s associates was found in thirteen instances, 40.6 per cent. Types I and II show approximately the same percentage incidence of the carrier con- dition, and in every instance the pneumococcus isolated corresponds in type with that of the infected individual. The approximate duration of the carrier state has been twenty-three days, which is probably somewhat shorter than would be found had it been pos- sible to retain under observation all carriers until the disease-pro- ducing type of pneumococcus had disappeared from the mouth A, R. Dochez and O. T. Avery. 111 flora. Study of Table I shows that positive carriers are more commonly observed among females than among males, a fact that is probably accounted for by the more frequent service of the for- mer in a nursing capacity, thus entailing more intimate association with the sick. Tables II, IIJ, and IV develop somewhat further, points brought out in a previous communication. In Table IT is shown the inci- dence of pneumococcus in the mouth flora of normal individuals and the classification of such pneumococci. All normal individuals studied are given in this table, whether in contact with cases of lobar pneumonia or not. Pneumococcus was found in 58.4 per cent of all instances and was absent in 41.6 per cent. Of the cases in which pneumococcus has been found, 48.6 per cent of the organ- isms have been of the sputum type and 9.6 per cent have been of the disease-producing type. All the latter have occurred in indi- viduals intimately associated with cases of lobar pneumonia, and their presence is dependent upon this association. Determination of contact carriers of pneumococci belonging to Group III, Pneu- mococcus mucosus, presents certain difficulties. Only recently have we been able to obtain an immune serum effective against organisms of this group. Further development of the study of the mucous group is showing that certain organisms resembling in their cultural reactions Pnewmococcus mucosus, are, in reality, mucous types of streptococcus. The latter varieties are frequently found in normal sputum, and have led to some confusion. With the working out of the serological reactions of the true Pneumo- coccus mucosus, evidence is accumulating that this organism is as strictly pathogenic in type, and has quite as specific immunological characteristics as pneumococci belonging to Groups I and II. For comparison with the statistics given in Table I], which illus- trates the prevalence of the mouth type of pneumococcus in normal individuals, Table III is added to show the percentage incidence of the fixed types of pneumococci observed in individuals suffering from lobar pneumonia. In this table the highly pathogenic types are dominant, being responsible for 77.2 per cent of all infections studied. This fact is convincing evidence that specific types of 112 Carriers of Disease-Producing Types of Pneumococcus. pneumococci are mainly responsible for the production of lobar pneumonia. The dominance of these organisms in disease is in striking contrast to the high percentage incidence of the sputum type of pneumococcus in the mouth flora of normal individuals. Table IV shows the length of time during which recovered cases of pneumonia harbor the organism responsible for their disease. The period of carrying is measured from the date of onset of the pneumonia. The shortest time in which the disease-producing pneumococcus has disappeared from the mouth has been twelve days, and the longest duration of carrying has been ninety days. These results show that pathogenic types of pneumococcus persist in the mouths of individuals recovering from lobar pneumonia for a variable period of time. Because of wide intervals between ob- servations, the average duration of this condition can only be approximately determined, and has been found to be about twenty- eight days. The studies detailed in this paper show that there are two sources of danger in the spread of pneumococcus infection. One lies in the occurrence of healthy carriers of disease-producing pneumococci among individuals associated with cases of pneumonia, and the other in the fact that patients recovering from the disease harbor the responsible organism for a considerable length of time. The actual tracing of cases of pneumonia to examples of the carrier state is difficult, but even the small amount of effort that has so far been devoted to this side of the study has brought to light an occa- sional suggestive fact. SUMMARY. Lobar pneumonia in 75 per cent of instances is due to specific types of pneumococci possessed of a high degree of pathogenicity. Although pneumococci oecur in the mouths of 60 per cent of nor- inal individuals, such organisms are readily distinguishable from the highly parasitic types of pneumococcus responsible for the severe forms of lobar pneumonia, a convincing proof that infec- tion in this disease is, in the majority of instances, not autogenic in nature, but is derived from some extraneous source. In a high percentage of instances healthy persons intimately associated with al. R. Dochez and O. T, Avery. 113 cases of lobar pnettmonia harbor the disease-producing types of pneumococcus. In every such instance the pneumococcus isolated has corresponded ir type with that of the infected individual. Convalescents fron ‘pneumonia carry for a considerable length of ° time the type of pneumococcus with which they have been infected. The existence of the carrier state among healthy persons and among those recently recovered from pneumonia establishes a basis for understanding the mechanism by means of which lobar pneu- monia spreads and maintains its high incidence from year to year.