THE ASSOCIATION OF PNEUMOCOCCI, HEMOPHILUS INFLUENZAE, AND STREPTOCOCCUS HEMOLYTICUS WITH CORYZA, PHARYNGITIS, AND SINUSITIS IN MAN B~ L. T. WEBSTER, M.D., AND A. D. CLOW (From the Laboratores of The Rockefeller Insttute for Medcal Research) (Receved for publcaton December 16, 1931) In a prevous paper (1) t was reported that persons harborng pneumococc n ther noses and throats were relatvely subject to coryza, pharyngts, and snusts, and conversely that persons not harborng these organsms were relatvely free of these dseases. Moreover, t was stated that the occurrence and degree of symptoms were assocated to some extent wth varatons n the numbers of pneumococc obtaned from the nose and throat cultures. These relatonshps are descrbed n more detal n the present paper. Technque The general scheme of study has been descrbed prevously (1). The group on whch the observatons were made comprsed adults workng at The Rockefeller Insttute and n some nstances ther chldren. Each ndvdual was questoned every 2 or 3 days to ascertan the presence of fever, chll, malase, headache, nasal dscharge, sore throat, sneezng, cough, etc., and was requested to report whenever such symptoms occurred. Cultures of the nasal passages and throat were usually made weekly; when symptoms were present, however, cultures were taken daly, f possble. Materal obtaned by means of a sterle swab was streaked over one or two freshly prepared 15 cm. rabbt blood agar plates. The resultant aerobc growth was classfed nto Gram-postve and negatve cocc and bacll. Pneumococc, S. kemolytcus, and tt. nfluenzae were dentfed wth care (1). RESULTS The present analyss s based on the protocols of the ndvduals studed most ntensvely. Snce consderable nformaton about each case s needed n order to judge the degree of assocaton of upper respratory tract symptoms and potental pathogens, the selected 445
446 CORYZA, PHARYNGITIS~ AND SINUSITIS IN MAN group consttutes less than 20 per cent of the entre number studed. Ths assocaton, moreover, became ncreasngly apparent wth the amount of care exercsed n obtanng full hstores, n takng frequent cultures, and examnng them mnutely. The protocols are dvded nto those of ndvduals not carrers of pneumococc, H. nfluenzae, and S. hemolytcus, and ndvduals who were transent, perodc, and chronc carrers of these organsms. Illustratve cases are descrbed n the followng paragraphs. Non-Carrers.--Two n number. Were free of symptoms 2½ years and 1 year respectvely. Transent Carrers.-- Case 1, free of upper respratory tract symptoms and pathogens on 25 tests from Sept. 4, 1928, to Nov. 27, 1928, suffered an nfluenzal attack from Nov. 26, 1928, to Dec. 10, 1928, durng the epdemc. At ths tme, 6 of 32 cultures contaned large amounts of H. nfluenzae and 2 contaned pneumococc of an unnumbered, specfc type. Subsequently, tests were negatve and remaned so durng a 9 day perod of sore throat from Feb. 1, 1929, to Feb. 10, 1929. Thereafter no symptoms were reported and 34 cultures contaned none of the above mentoned organsms. On Nov. 17, 1930, the ndvdual reported sore throat lastng 24 hours and yelded H. nfluemae on ths date and 1 week later. The succeedng 17 cultures were free of these organsms and no further symptoms were noted untl Apr. 20, 1931, at whch tme chlls, weakness, sneezng, nasal dscharge, and sore throat were experenced for 2 days and H. nfluenzae was recovered on Apr. 20, 1931. 7 tests thereafter were negatve; 1 on Aug. 27, 1931, contaned H. nfluenzae; 5 tests then proved negatve. On Oct. 19, 1931, chlls, fever, malase, and sore throat developed, lastng 5 days. Durng ths tme and thereafter to Nov. 1, 1931, 5 cultures were taken, all negatve for the organsms. Case 55 was a carrer of pneumococc Type XIII on 14 tests from Oct. 11, 1929, to Feb. 7, 1930. Durng ths tme one 6 day perod of nasal dscharge preceded by malase, nasal obstructon, and sore throat was noted. Tests were negatve from Feb. 7 to Apr. 15, 1930. From Apr. 11 to Apr. 22, 1930, the ndvdual suffered a relatvely severe attack of prostraton, rrtablty, and general achng sensatons, accompaned by sneezng, nasal obstructon, and slght dscharge. On Apr. 15 and 16, S. hemolytcus was recovered from the throat. Subsequent tests were negatve. On Oct. 14, 1931, malase and nasal congeston were reported, but 5 tests from Sept. 24 to Oct. 27, 1931, were negatve. Commencng Oct. 30, 1931, a moderately severe attack of coryza, lastng 8 days, was experenced, and 2 weeks later, a second attack, lastng 10 days, was reported. 7 of 9 cultures taken durng ths perod contaned S. kemolytcus. Shortly after the symptoms dsappeared, the tests became negatve and remaned so for 2½ months, durng whch tme a 48 hour perod of nasal dscharge and sore throat
L. T. WEBSTER AND A. D. CLOW 447 occurred. On Feb. 13, sore throat and nasal dscharge were reported, lastng 5 days, and on Feb. 14 and 16 H. nfluen~.ae was obtaned. No further symptoms were reported and subsequent tests were negatve for these organsmst (Textfg. 1). These cases are examples of ndvduals who, on bref and nfrequent occasons, carry a few pneumococc, H. nfluenzae, or S. hemolytcus. Ther appearance s usually assocated wth the presence of upper respratory tract symptoms, although symptoms may occur durng a perod of negatve cultures. The organsms usually decrease n numbers or dsappear at varyng ntervals after the symptoms have subsded. Perodc Carrers.-- Case 17, free of pneumococc on 34 tests, from January, 1929, to Jan. 17, 1931, and free of upper respratory symptoms, save for one 6 day attack of coryza and cough whch was not studed, developed on Jan. 16, 1931, chll, nasal dscharge, sore throat, and cough whch perssted 11 days. Cultures taken the day after the onset of symptoms were negatve; those taken daly thereafter, to Jan. 30 and Feb'. 4 and 9, contaned abundant pneumococc of a sngle, unnamed type, together wth tt. nfluenzae and S. hemolytcus. A second smlar attack was reported from Feb. 20, 1931, to Feb. 24, 1931, but only 1 test was made and ths proved to be negatve. Thereafter, no further symptoms were noted and 21 tests were negatve (Text-fg. 2). Case 50, free of the organsms on 8 cultures over a 5 months' perod, developed on Mar. 3, 1931, chlls, malase, headache, and sore throat, lastng 72 hours. Tests Mar. 30, 1931, Apr. 1, Apr. 7, and Apr. 14 revealed pneumococc Types VIII and XXlI and H. nfluenzae. 10 subsequent cultures were free of these organsms and no further symptoms have been reported. Case 51, sufferng a severe attack of fever, chlls, malase, nasal obstructon and dscharge, sore throat, and cough from Jan. 3, 1931, to Jan. 13, 1931, was frst cultured Jan. 8 and 9. Pneumococcus Type V and H. nfluenzae were present. A second attack, wth nasal dscharge and sore throat, lasted from Feb. 16, 1931, to Mar. 8, 1931, durng whch tme 6 cultures were taken, and was accompaned by the presence of Pneumococcus Type X, It. nfluenzae, and occasonal S. hemolytcus. Durng a thrd 7 day perod of coryza, 11 cultures were taken whch contaned these same organsms. 4 subsequent tests were negatve, wth the excepton of 1 nstance, when pneumococc Type X appeared n the culture from 1 Durng the past 17 weeks, Oct. 15, 1931, to tme of wrtng, typcal menngococc Type I[ have been recovered n large numbers and t s not known how long these organsms had been present but unrecognzed.
448 CORYZA~ PHARYNGITIS~ AND SINUSITIS IN MAN F~g 1 Thr'~t ~ -"-f,. d -~" C~ner,al 1. II!'Px IT T[ II II 111 li II II L]lI II IIIIL II II II 1 15 l Ib 1 15 I lb 0c~ 1930 ~ov 1)e Jan 1931 1 " '[~' " I... 13 "I " 13 Feb tl~p Ape ly~g 2 Throat 18 1 15 1 15 1 13 1 I~ t 1~ 1 I~ 1 Jan 1931 Feb H~r A W ~y &me July Aug _,m- Nose Throat Gener.~l 1 a h a.k,. Ftg 8 1. Hem. zn[luemae 5" ~ l;emolyt*cas L-te B naem R - Rtght. 7opn = PeP cent pne~nococct on plate ~_j I1 I I Ib 1 Jan 1931 Feb I 21 I1 1,,.-,,n, ~....... ~,,!,~ IIIIIII II II Illl-"....,...,. lb 1 1,5 1 18 [ k5 1"[~" Apt, tt~ TExT-FIGS. 1, 2, and 3
L. T. WEBSTER AND A. D. CLOW 449 Nos~ Throat ~n e*aneeed I I I I I ~Cdtl l, ~,I I llllm''. l I. II II It H III~ LIH II II 1 15 1 15 1 15 1... 15'" Oct 1~30 Nov DeC Jan 1931 ~eb 1,5 1 15 Hae Nose Throat L.,m, Genees1 -. ~,,,,... m,,,, ~...,...,, ~r...,... I..., 1 15 1 15 l 1`5 1 13 Ocl 1930 Nov Dec Jan 1931 1 15 1 I~ Feb Hem Throt~t eaeneral I ]tpcedt Jlll II tl II II II] II II II I... 1 15 1 Oct 19~0 Nov... L,,, 1 15 1 15! 15 1 15 De~ Jan 1931 Feb lq'~t, TExT-FIG. 4
450 CORYZA, PHARYNGITIS~ AND SINUSITIS IN MAN the rght nars. From Apr. 17, 1931, to Apr. 25, nasal congeston and dscharge were reported; on Apr. 25 and 27 and May 11, Pneumococcus Type X was recovered. 1 culture taken May 23, 1931, contaned none of these organsms (Text-fg. 3). Cases 33, 34, 35, and 36 are members of a famly. The father, No. 36, has been free of pneumococcus wth the excepton of 1 bref perod, and free of upper respratory tract symptoms for 3 years. The mother, No. 35, has been a transent carrer of pneumococc on 3 occasons, durng the past 3 years, assocated wth the appearance of upper respratory tract symptoms. The 2 chldren, Nos. 33 and 34, have carred the same type of pneumococc durng 3 wnter perods and have experenced 2 or 3 mld attacks of coryza and cough. The present study was made durng the wnter of 1930-1931. One chld, No. 33, after 2 negatve cultures n September, became a carrer of pneumococc of a specfc, unnumbered type on Oct. 10, 1930. The other chld, No. 34, after 3 negatve cultures, suffered a mld 3 day attack of coryza, durng whch pneumococc of the same type appeared on culture. Subsequently, both chldren contnued to carry ths organsm on 21 cultures for the remander of the wnter. They experenced smultaneous attacks of coryza and cough for 2 to 10 days on 3 separate occasons. Durng the most severe attack, the mother, No. 35, came down wth malase and sore throat, and yelded pneumococc of the same type as found n the chldren. Thereafter, tests became negatve and no symptoms were noted untl October, 1931 (Text-fg. 4). In ths group of ndvduals, the organsms appeared durng llness and dsappeared at varyng ntervals after the symptoms ceased. Chronc Carrers.-- Case 15 has been a carrer of Pneumococcus Type XIII for at least 4 years and Case 52 a carrer of an unnumbered specfc type of pneumococcus for at least 1 year. Each has experenced durng the wnter months 4 to 6 attacks of frontal headache, malase, nasal dscharge, and sore throat. On these occasons, roentgenographs have shown extensve cloudng of the antra, cultures from the throat show a great ncrease n numbers of organsms, and cultures from the nares, prevously free, show the organsms present often n nearly pure culture. Moreover, n nstances when the ndvdual's pan was localzed to one antrum, ths localzaton corresponded to the localzaton of cloudng n the roentgenogram and to the localzaton of the organsms n rght or left nares. When symptoms subsded, the nasal cultures became free of pneumococc, the throat cultures contaned them n fewer numbers, and the roentgenographs showed some clearng of the antra (Text-fgs. 5 and 6). In bref, chronc carrers of pneumococc proved subject to respratory tract symptoms and antrum dsease. There appeared, more- over, a drect relaton between the degree of symptoms, amount of
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452 CORYZA, PHARYNGITIS, AND SINUSITIS IN MAN cloudng of antra n roentgenographs, and numbers of organsms contaned on throat and nose cultures. A relatonshp between the presence of these pathogens and symptoms, although demonstrated n all cases of ths specal seres, may not nvarably exst. Indeed, n three cases studed wth less care durng 1928 and 1929, no such organsms were found durng attacks of upper respratory tract dsease. The lmts of ths relatonshp therefore must be decded by panstakng study. DISCUSSION AND CONCLUSIONS Pneumococc, 1t. nfluenzae, and S. hemolytcus are known to be frequent nhabtants of the upper respratory tract, but most workers have not recognzed any defnte relatonshps between ther presence and coryza, sore throat, nfluenzal, and snusts attacks (2-5). Dochez, Shbley, and Mlls, however, n ther expermental studes of common cold, state that n both the spontaneous and expermentally nduced "colds" n anthropod apes, the "most sgnfcant change observed has been the ncrease of actvty on the part of the potental pathogens habtually present n the throat flora. Concdent wth the appearance of symptoms, pneumococc, S. hemolytcus, and B. pfeffer have developed n greatly.ncreased numbers and have spread over a wde area of the nasopharyngeal mucous membranes. These organsms became at ths tme conspcuous even n the nose, where they are seldom or never present under normal condtons. The same phenomena have not been observed n human bengs" (6, 7). The essental facts of the present observatons are that persons free of pneumococc, H. nfluenzae, and S. hemolytcus are n general free of coryza, sore throat, nfluenzal and snus attacks; that persons who are occasonal or perodc carrers of these organsms may be negatve on tests over long healthy perods, but generally become postve durng or followng attacks and subsequently become negatve agan; fnally, that persons who are chronc carrers show durng these llnesses ncreasng numbers of organsms n the throat and extenson of the organsms to the nose. That these organsms may be the actual nctants has been clamed by Park (8); that they are secondary nvaders s the vew of Shbley,
L. T. WEBSTER AND A. D. CLOW 453 Mlls, and Dochez who state as a result of ther expermental work on ths subject that "the most mportant sgnfcance of vruses of ths type [common cold] seems to le n ther capacty to ncte actvty on the part of the more dangerous pathogenc organsms that nfect the upper respratory tract" (7). The present observatons brng out the ntmate relatonshp between these pathogens and upper respratory tract symptoms, but do not dsclose the nature of ths relatonshp. Fnally, an addton has been made to the knowledge of the mode of spread Of these organsms. A focus of growth and dssemnaton has been determned n the nasal passages and throat of ndvduals wth chronc upper respratory tract dsease and ncreases n numbers of the organsms at the focus and ther spread to contacts have been related to the wnter season and to the occurrence of symptoms n the carrer. The observatons suggest that the dosage of these organsms n a communty s controlled by the resstance of the carrer and of the contacts. Ths vew s n agreement wth the facts derved from studes of natve anmal nfectons (9). REFERENCES 1. Webster, L. T., and Hughes, T. P., J. Exp. Med., 1931, 53, 535. 2. Bloomfeld, A. L., Bull. Johns Hopkns Hosp., 1921, 32, 121. 3. Jordan, E. O., Norton, J. F., and Sharp, W. B., J. Infect. Ds., 1923, 33, 416. 4. Skbley, G. S., Hanger, F. M., and Dochez, A. R., J. Exp. Med., 1926, 43, 415. 5. Noble, W. C., Fsher, E. A., and Branard, D. H., J. Prey. IVed., 1928, 2, 105. 6. Dochez, A. R., Shbley, G. S., and Mlls, K. C., Proc. Soc. Exp. Bol. and Med., 1929, 27~ 59. 7. Dochez, A. R., Shbley, G. S., and Mlls, K. C., J. Am. IVed. Assn., 1930, 95, 1553. 8. Park, W. H., Am. J. Pub. Health, 1930, 20, 403. 9. Webster, L. T., J. Exp. Med., 1930, 52,901.