THE OCCURRENCE OF CARRIERS OF DISEASE-PRO- DUCING TYPES ,OF PNEUMOCOCCUS. BY A. R. DOCHEZ, M.D., AND 0. T. AVERY, M.D. (From the Hospital of The Rockefeller Institute for Medical Research.) (Received for publication, May 20, 1915.) In previous papers1 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- matelv 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, lxi, 727. Dochez, -4. R., and Avery, 0. T., Jour. Exper. Med., 1915, xxi, 114. 103 106 Ga,rriers 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-producin, 1 p u t 7 es 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 idly 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 durin g 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 iact that the recovered dase also may carry the pneu- n~ococcus responsible for his disease during a relatively long period of time. A. R. Dochex and 0. T. Avery. 107 In the present paper are presented the s&dies 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 unesposed individuals, and of the period of time during which convalescents harbor the disease-producing organisms. For TABLE I. Itzcidmcc of Carrier Condition in Healthy Individuals in Contact z&h Lobar Pneunzofria. 2309 2314 2333 Type II Type II Type II 2326 Type II 2330 Type II 2343 Type II I835 Type II 2174 Type II 217.5 Type II 2202 Type II 2199 Type II 2298 Type II 2226 Type II 224s Type II z230 Type II 2247 Type II 2266 2270 2265 Type II Type II Type II _I Type I Type 1 Type 1 Type I Type I Type I Type II Wiie Husband Wiie Mother Nurse Wife Wife Daughter Wife Mother Father Sister Type II Type II Type II ~ Wife Wife Mother Wife Mother Sister Wife Daughter Sister Wife son Mother Sister Nurse Relationship of 1 Type found in associates. associates. Type 1 Type I Type IV Type IV Type 1 Type IV No pneumococcus Mother Husband Sister Wife Mother Brother Wife Daughter Wife son Wife Brother-in-law Mother Sister Physician = .- I] I LTndetermined. - Tj$e IV No pneumocokus No pneumococcus No pneumococcus Type IV Type II No pneumococcus No pneumococcus No pneumococcus Type II No pneumococcus Type II Type IV Type II No pneumococcus Type II Type II Type IV Type IV Type IV Type IV Type II No pneumococcus Type II No pneumococcus Type IV No pneumococcus No pneumococcus Type II Duration of period of carrying. co days+ a4 days. Undetermined Undetermined. P days + 27 days+ Developed pneumonia. Type II. 45 days. 7 days+ No pneumococcus Type II , 21 days. 39 days -I- Undetermined. 108 Carriers of Disease-Produiing Types of Pneurnococcus. TABLE I.-Concluded. Type of pneumococcus. No. of cases. ; Positive contacts. Per cent. / Type I. . . . . . . .' 8 3 37.5 Type II. . . . . 24 IO 41.7 Total. 32 I3 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 IV. Groups I, II, and III are found only in association with disease and are distinctly parasitic in type. Members of Groups I, II, and III 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 P~~cu~~~ococcus Isolated from Sputum of Norntal Indizliduals. Fneumococcus. Incidence. Per cell*. Contacts Type I Tyl~e II 2.6 7.0 Type IV 55 48.6 So pneumococcus 47 41.6 Total 113 Pneumococcus present 66 58.4 Pneumococcus absent 47 41.6 TABLE III. Type of P~c~~wococcus Isolated from Individuals asith Lobar P?icumonia. Pneumococcus. x0. OS CIses. Per cent. Type I 78 34.97 Type II 75 33.63 Type III 22 9.86 Type IV 48 21.52 Total No. of cases 223 A. R. Dockex alld 0. T. Avery. 108 TABLE IV. Pcrsistcllcc of Disease-Produrirlg Type of Pneumococcus durirrg Corwalescence. Case pie. 1654 Type of pneumococcus during height of disease. Type 1 1751 TYPO 1 1775 Type I 1867 Type I 1828 Type I 1792 Type I 2167 Type 1 2168 Type I 2191 Type 1 2195 Type I 2203 Type 1 2237 Type 1 W Type I B Type 1 2250 Type I 2269 Type 1 2284 Type 1 2267 Type 1 2276 Type 1 1679 Type II I753 1763 Type II Type II 1761 Type II 1825 Type II 1786 Type II 1820 Type II 1827 Type II 1880 Type II 1950 Type II 1969 Type II 2174 Type II 2175 Type II 2212 Type II Type of pneumococcus after recovery. 60 days, Type I. 65 days, Type IV. jQ days, StreptOCOCCIIS. 73 days, streptococcus. 30 days, Type IV. 90 days, Type I. 33 days, Type IV. 30 days, Type IV. 12 days, Type IV. 45 days, Type I. 15 days, Type IV. 28 days, Type I. 4g days, no pneumococcus. 12 days, no pneumococcus. 13 days, Type I. 15 days, Type I: 23 days, Type IV. 14 days, no pneumococcus. IO days, Type I. 13 days, no pneumococcus. 15 days, Type I. 29 days, no pneumococcus. 15 days, no pneumococcus. 15 days, Type I. 30 days, streptococcus. 48 days, Type IV. 108 days, Type IV. 60 days, Type IV. 34 days, streptococcus. 40 days, Type IV. 47 days, streptococcus. 78 days, Type IV. 53 days, Type II. zo days, Type IV. 25 days, Type IV. 30 days, Type II. 14 days, Type IV. 63 days, Type II. 21 days, Type IV. 24 days, Type IV. 15 days, streptococcus. 17 days, no pneumococcus. 12 days, Type II. 17 days, no pneumococcus. 110 Carriers of Disease-Producing Types of Pneumococcus. Case No. 2202 2199 Type II 2226 Type II 2245 Type II 2266 Type II 2270 Type II 2286 Type II 2292 Type II 2296 Type II I743 Type III 2185 2249 TABLE IV.-Corlcluded. Type of pnemococcus during height of disease. Type II Type III Type III Type of pneumococcus after recovery. 37 days, Type II. 43 days, Type IV. 32 days, no pneumococcus. zg days, Type II. 16 days, Type IV. 15 days, Type II. 37 days, Type II. IO days, Type II. 25 days, no pneumococcus. 29 days, Type IV. Ig days, no pneumococcus. 13 days, Type III. 73 days, Type IV. 16 days, Type III. 34 days, no pneumococcus. 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 lvith 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, 30.6 per cent. Types I and II show approsimately the same percentage incidence of the carrier con- dition. and in eT.ery instance the pneumococcus isolated corresponds in type \vith that of the infected individual. The approximate duration of the carrier state has been twenty-three days, which is probabl>- 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 awl 0. T. Avery. 111 flora. Study of Table I shows that positive carriers are more con~n~only observed amon, rr 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, III, and IV develop somewhat further, points brought out in a previous communication. In Table II 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 ha\-e 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, Pnez~- IIzocucclfs ~?llfCOSZIS, presents certain difficulties. Only recently ha\-e we been able to obtain an immune serum effective against organisms of this group. Further development of the study of the I~COLIS group is showing that certain organisms resembling in their cultural reactions Pmmmococcus 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 Pneunzo- COCCUS I~ZZ~COSZ~S, 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 II, which illus- trates the prevalence of the mouth type of pneumococcus in normal indil-iduals, 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 sllutum type of pneumococcus in the mouth flora of normal individuals. Table IV shows the length of time during which reco\.ered 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 dl;ease-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 betn-een ob- servations, the average duration of this condition can onI!, be approsimately 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 e.xamples of the carrier state is difficult, but even the small amount of effort that has so far been de\-oted 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 t!-pes of pneumococci possessed of a high degree of pathogenicity. A1ltllough pneumococci occur in the mouths of 60 per cent of nor- mal indi\-iduals, such organisms are readily distinguishable from the highly parasitic types of pneumococcus responsibIe 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 \\.itll A. R. Dockez and 0. T. Avery. 113 cases of lobar pneumonia 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 iron `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.