ATYPICAL PNEUMONIA AND

ATYPICAL PNEUMONIAANDPSITTACOSIS

By JOSEPHE. SMADEL(From the Hospital of The Rockefeller Institute for Medical Research, New York City)

(Received for publication July 24, 1942)

Attention has been focused in recent years onthe acute infectious pulmonary disease which, forwant of a better name, has been called "atypicalpneumonia." Many descriptions of this type ofmalady have appeared (1 to 10), and several dif-ferent non-bacterial infectious agents have beenincriminated or identified as the cause of certainof the outbreaks (3, 10 to 14). These findingsindicate that atypical pneumonia is a clinical-pathological entity which has a diverse etiology.One of the first approaches to the problem ofatypical pneumonia should be the establishment ofan etiological diagnosis whenever possible. Inthis way, certain types of cases can be removedfrom the general group and studied in a more in-telligent manner.

The fact that infection with psittacosis virus isresponsible for certain cases of non-bacterial pneu-monia is well recognized. For example, pulmo-nary consolidation is a characteristic feature ofclassical psittacosis in man, caused by psittacinestrains of the virus (15). Furthermore, Eatonand his co-workers (13) have demonstrated thata strain of psittacosis virus, which is practicallyindistinguishable (13, 16 to 18) from the agentdesignated meningopneumonitis by Francis andMagill (19), can cause pneumonia and death inhuman beings. Finally, Meyer and his associates(20 to 22) have emphasized the role of other mem-bers of the psittacosis group in producing broncho-pneumonia; recently, they have laid stress on thetransmission of certain strains of the virus to manfrom infected pigeons and chickens.

It is appropriate to discuss at once the confusionthat exists regarding the exact relationship of anumber of viruses, which have been isolated byseveral groups of workers from different sources,and which have many characteristics in commonwith one another and with classical psittacinestrains of the virus of psittacosis. Thus, Rake,Eaton and Shaffer (16) have demonstrated thatsera of patients convalescent from lymphogranu-loma venereum, from psittacosis of parrot or

pigeon origin, and from the pneumonitis studied byEaton, all possess an antibody which fixes comple-ment in the presence of antigen prepared from thevirus of lymphogranuloma venereum, of psitta-cosis, or of meningopneumonitis. Furthermore,these workers, as well as Pinkerton and Moragues(17), have noted similarities in the morphologicaland tinctorial qualities of these viruses, and in thecharacter of the lesions produced by them in ex-perimental animals. Although certain differencesin the morphological and antigenic properties ofthe viruses and in the disease they produce inexperimental animals have suggested that they arenot identical (16 to 18, 23, 24), these observeddifferences are less impressive than the similarities.Because of the obviously close relationship of theviruses and because of their tendency to producelatent infections with the persistence of immuno-logical phenomena, rigid diagnostic criteria mustbe fulfilled before one can state that a given acuteinfection is caused by a member of this group ofagents.

This report concerns itself primarily with theincidence of infections caused by strains of thepsittacosis virus among patients with atypicalpneumonia, who were encountered in a randomsampling of the disease in large eastern urbanareas.

MATERIALS AND METHODS

Serological studies. Samples of patients' sera werestudied for antibodies against the viruses of psittacosis,lymphocytic choriomeningitis, influenza A, and influenzaB. Titrations of influenza antibodies were made by Dr.F. L. Horsfall, Jr., of the Rockefeller Hospital as partof a cooperative investigation on the etiology of atypicalpneumonia.

Psittacosis. Psittacosis antigen for complement fixationtitrations with patients' serum was prepared from agarslant culture material (25), infected with the 6 BC strainof virus isolated from a parakeet by Dr. K. F. Meyer in1941. Our methods for the preparation of suspensions ofwashed inactiVe virus and our technique of complementfixation are modifications of those recommended by Meyerand Yanamura (26). Antigen is prepared as follows:Infected tissue is removed from the agar surface of one

57

JOSEPH E. SMADEL

Kolle flask, which had been inoculated 5 days previouslywith minced chicken embryo tissue and culture virus, andtriturated with 50 cc. of buffered water, i.e., Sorensen'sphosphate buffer, pH 7.6, diluted 1: 50. The tissue sus-pension is centrifuged in 25 cc. amounts in 50 cc. centri-fuge tubes, at 3000 r.p.m., for 10 minutes in the Inter-national machine. The supernatant fluid is saved for highspeed centrifugation and the sediment is thoroughly re-suspended in 40 cc. of buffered water and recentrifuged;again the supernatant fluid is saved. The fluid obtainedfrom the first centrifugation is placed in capped lusteroidtubes and spun at 12,400 r.p.m., in the angle centrifugeof Pickels (27), for 30 minutes in the cold room. Thesupernatant fluid is discarded and the sediment materialis resuspended, by means of a capillary pipette, in thefluid saved from the second preliminary run in the Inter-national machine. This suspension is again spun at 12,400r.p.m. for 30 minutes, and the resultant sediment is re-suspended in 50 cc. of physiological saline solution, buf-fered at pH 7.6. This preparation of washed virus isfreed of large aggregates by a final centrifugation at 2000r.p.m. for 10 minutes. A portion of the material is savedfor a titration of its infectivity; such material, wheninoculated into mice by the intracerebral route, generallyhas a titration endpoint of 10' to 10'. The suspensionof virus is rendered non-infectious by heating in a steambath at 100 C. for 30 minutes. Only non-infectious anti-gens are used in the complement-fixation tests.

The complement-fixation test is performed as follows:0.2 cc. amounts of antigen, 2 units, are mixed with 0.2cc. volumes of serial two-fold dilutions, beginning at 1: 8,of the serum to be tested, and then 0.5 cc. of diluted com-plement, 2 units titered in the presence of antigen, areadded. After the mixture has been incubated for 2VAhours at 37 C., the hemolytic system is added; this con-sists of 0.2 cc. of hemolysin appropriately diluted to coh-tain 2 units and 0.5 cc. of a 2 per cent suspension ofwashed sheep erythrocytes. The test materials are incu-bated at 370 C. for one-half hour when final readings aremade. Titration end points are estimated on the basis ofthe last tube showing complete or three plus fixation, andthe titer represents the dilution of serum originally addedto that tube. In addition to the controls usually employedin complement fixation tests, each serum is titered againsta control antigen which is prepared in exactly the sameway as the test antigen, except that the culture flask isnot infected with virus.

Lymphocytic choriomeningitis. Soluble antigen oflymphocytic choriomeningitis was employed in the com-plement fixation tests for antibodies against this virusinfection. Instead of our usual technique (28) for dem-onstrating fixation with choriomeningitis materials, amodification of the procedure described for the psittacosistest was adopted in order to simplify the work. The twomethods gave equally satisfactory results with chorio-meningitis, but the former was less desirable for psitta-cosis. Samples of serum from each patient were titeredfor antibodies against the soluble antigen of choriomenin-gitis over the range of dilutions from 1: 2 to 1: 32. Pre-

vious work had demonstrated that these immune sub-stances are detectable in human sera during only a fewweeks in convalescence, i.e., usually between the third andsixth weeks (28). Therefore, results were recorded asnegative only for those patients whose sera taken duringthis period failed to fix complement in the presence ofsoluble antigen.

Influenza A and B. Samples of serum were titeredfor antibodies against influenza A and B by means of theagglutination-inhibition technique of Hirst (29). Serialtwo-fold dilutions of the serum to be tested were prepared,and to 0.5 cc. amounts of each dilution were added 0.5cc. volumes of suspensions of A and B virus, obtainedfrom allantoic fluid of infected eggs; the PR-8 and Leestrains, respectively, were employed. Suspensions ofvirus for the test were known to contain 4 units of activematerial, i.e., 4 times the concentration which causedclumping of 50 per cent of the chicken erythrocytes in atest suspension (29). One cc. amounts of a 1.5 per centsuspension of washed chicken red cells were then addedto the serum-virus mixtures, and readings were madeafter the tests had stood for an hour at room temperature.The titer of antibody was taken as the highest dilutionof serum which was capable of inhibiting the agglutinationreaction sufficiently to prevent the aggregation of halfthe red cells.

The diagnostic importance of demonstrating a rise intiter of antibodies of influenza viruses in the sera ofpatients during convalescence has been emphasized (30);therefore, whenever possible, a sample of serum takenduring the first few days of illness and one taken laterwere tested. When this was not feasible, the antibodylevels in single convalescent sera were determined. Whiletoo great diagnostic significance cannot be attached to theresults obtained with a single serum, certain ranges ofantibody levels have been reported for apparently normalindividuals (31). Therefore, one can say that the titersare within the normal limits and that the patient probablyhad not had a recent infection, or that the antibody levelfor one of the viruses is distinctly elevated and that thepatient may have had contact with this virus within thelast few months.

Isolation of psittacosis virus. Isolation of virus fromhuman material was attempted in only a few instances;this was due in part to the scarcity of proper specimens.For example, only one of the 2 patients who contractedpsittacosis from infected pigeons of the G. flock coughedup sputum and this individual produced only 2 specimens;yet both patients presented x-ray evidence of extensivepulmonary consolidation. Specimens for virus studies, i.e.,sputum, throat washings, and lung tissue, were storedat -70 C., generally until the results of serological testswere available. Only materials from the patients whomwe suspected of having psittacosis were examined in ourlaboratory. Specimens from patients with atypical pneu-monia unassociated with psittacosis were investigated byDr. F. L. Horsfall, Jr.

A study of the characteristics of the strains of virusof- the psittacosis group which were isolated from the 2

58

ATYPICAL PNEUMONIAAND PSITTACOSIS

patients A. G. and B. T., and from the pigeons of theG. flock, is in progress. It need only be stated at thistime that strains isolated from these sources have manyproperties in common with the strains of psittacosis virusisolated from psittacine birds (32) and from pigeons (21),and with the virus of meningopneumonitis (16).

RESULTS

Previous experimental studies on the etiology ofatypical pneumonia have generally dealt with smalloutbreaks of the disease (10 to 14) or with indi-vidual cases in whoma history of contact with sickbirds suggested the possibility of psittacosis (22).A somewhat different approach to the problem wasmade in the present investigation. Cases of atypi-cal pneumonia sporadically distributed in severallarge eastern cities were selected at random andinvestigated with the object of determining theincidence of infection with certain of the viruseswhich might be expected to cause pulmonary in-volvement. Wewere interested primarily in dis-ease produced by members of the psittacosis groupof viruses, but also investigated the possible roleof the viruses of lymphocytic choriomeningitis andof influenza A and B as etiological agents of theatypical pneumonia present in our patients. Wehave been impressed by the high incidence of psit-tacosis in such patients and by the frequency withwhich some sort of association can be demon-strated between the patients and non-psittacinebirds, infected with one of the psittacosis groupof viruses.

Atypical pneumonia caused by the virusof psittacosis

The clinical picture observed in patients withpsittacosis infection varied considerably; more-over, no distinguishing features were encounteredin this group which permitted a clean cut separa-tion of these patients from the group of indi-viduals who had atypical pneumonia due to someother cause. In a like manner, histopathologicalexamination of human lung tissue failed to revealsignificant differences between the pulmonary le-sions seen in the one specimen from which psitta-cosis virus was isolated and in the two specimensfrom which the virus was not obtained. The le-sions in all three instances were like those de-scribed by McCordock and Muckenfuss as charac-teristic of the response of lung tissue to infection

with a number of viruses (33). In brief, theclinical and pathological findings in our group ofsporadic cases of atypical pneumonia of knownand unknown etiology were similar. Further-more, our patients resembled in most repectsthose observed by Kneeland and Smetana (6)and by Longcope (7).

Emphasis has already been laid on the difficul-ties encountered in establishing proof of recentinfection with a virus of the psittacosis group.Formerly, the demonstration, in a single sampleof convalescent serum, of complement fixing anti-bodies which reacted with psittacosis antigen wasconsidered adequate for diagnosis. Evidence ofthis nature is no longer conclusive in view of theubiquity of agents capable of eliciting such anti-bodies, and of the long interval of time that theseantibodies may persist. Therefore, certain mini-mal criteria have been selected arbitrarily as essen-tial for the proof that a given illness is caused by astrain of psittacosis virus. These are (1) isola-tion of virus during the acute phase of the disease,or (2) the demonstration of the appearance ofcomplement fixing antibodies during convalescenceor of a significant rise in titer of these antibodiesduring the period of recovery. In other words,it is now imperative to adopt the same type ofcriteria for the diagnosis of psittacosis that previ-ously has been found necessary for lymphocyticchoriomeningitis (34) and influenza (30).

Technical difficulties involved in work with un-diluted human sera in the test used for psittacosishave now led us to begin our titrations for psitta-cosis antibodies with a 1:8 dilution of serum.For a given specimen to be considered positive inour laboratory, it must give complete fixation in adilution of serum of 1: 16 or greater. Signifi-cance is attached to a rise in antibody titer duringconvalescence only if the increase is fourfold ormore. Furthermore, for a mere fourfold increaseto be considered valid, the early and late samplesof serum must be tested in the same experiment.

Ten persons, among the 45 from eastern citieswho had atypical pneumonia, suffered from psitta-cosis. Stated another way, on the basis of thecriteria enumerated in the preceding paragraph,infection with a strain of psittacosis virus wasproved to have been associated with the illness ofalmost one-fourth of the members of the group of

59

8 .24.)X

r (D

4i 004-J 4J 4-) 4J 4i 4i 4i 4i 4i 4i 4i 4J 4J 4J

g) Cd gL gL cd cd Cd 9L a ce Cd Cd Cd Cd 9Lblo blo bic bic blo blo blo blo ba NO NO blo

zzzzzzz z z zzz zzzz zzz

4i -4 ...44i 4i 4i 4J 4J 4-# 4.) 4i 4iCd cd cd - - cd cd co g) Cd

blo blo to ba blo lbdO blo

z zz zz z zz zz zz

W-4 -4 W-4 V-4 V-4 C4 V-4 (M v-4

4) (L) 4) 4) (DI la 1.4 00 it4i 4i 4i 4i 4i 14-il C4 IZ 4i 4i 4-J 4J 4J 4J

9L 9-4 bldlo bldlo Id

W CD 4) r (D 4) 4) 4) (L) ezzzz Z. z z z zzz Z'ZZZ

,i X

.~~~~~~~~~4 E:9 :004

¢ OOOM0ooue oSuoNo+N+mo+o CoooS~~~~~~~~o 00 00.

.) ZZZZ-Zzz¢mmuostoe::n - Ozzzz zzzzz >=>dxa_o23xddH _S Xua=_umduSx Oc~9-

a4i

roV.

.2Cd

I 1.:5 4i

93v

I s

Uh la.u C-4.1 08 u

ad

la

co

.8

.1

A %C oob PrO aooLft-% o to in uw "o %O In CDP r 0s 0 'o co co

g

0

0J

IIRII.aIRI

1)II

5

4) (L)r. 9:

00 0 0 010"azzzz 4i 4i

0 0zz

00000000 000000 000Z>.ZZZZZZ zzzzzz zzz

0 0 0 0lzzzzzoI

9 4) (D0 00 00 0 0 1010

zzzz 4J 4-J0 0zz

t0 00 00z

za aA4* -f

C)0of)46i

har.0

E06.0.6

9r.Lldw:30w00wi

6

mm0L)edwwrALi°.al

G09

* - 4-l 4-) +J4-i 4J 4J 4J 0 0

bio bi biD bbaObO .a 9Mboa uW4u t Co o 0 -u (LW 4w@@ (L 4) 4) 4) 4) 0 0

Z;Z;Z;Z;Z;Z;;Z; z ;W Z;zZ; CZ;Z'Z; Z;zZ;Z ;Z;Z

4) 4) (D 4).-4 ..A,4J 4J .0tv. . 4-i tzzzzz

ev d4i.- n4i

1200

.1.8 00000000tOt t000,00z p00,0to

uU)r

xoZ

^. uo -

_a 0 V

JOSEPH E. SMADEL

sporadic cases of atypical pneumonia. A virusof the psittacosis family was isolated from sputumof one patient and from lung tissue of another.The diagnosis of psittacosis which was made onthe remaining 7 persons depended entirely onresults of serological studies. A summary of per-tinent data on the 10 cases of proved psittacosisis included in Table I, together with informationon the findings in the remaining 35 members ofthe group with atypical pneumonia.

Psittacosis virus may have been of etiologicalimportance in 5 additional patients with atypicalpneumonia but this remains unproved. Only theresults of serological investigations implicate thevirus in the disease of these 5 individuals, and,although each person had significant amounts ofcomplement fixing antibodies in his convalescentserum, none developed a fourfold increase in titerof these substances during the period of study. Itis not unlikely that we have been too drastic inour choice of minimal standards for the diagnosisof psittacosis infections in human beings, and thatsome or all of these 5 patients should be includedas cases of psittacosis. Indeed, Meyer (20) didnot hesitate to make the diagnosis of psittacosis in2 women (O. W. and E. W., patients of Dr.George S. Mirick of the Rockefeller Hospital) onthe basis of his serological studies, although theevidence in these 2 instances was no more im-pressive than that obtained on C. M. and F. S.(Table I). Nevertheless, until increased experi-ence is gained in this field where serological re-actions are so involved, it seems preferable tomaintain a conservative viewpoint.

Atypical pneumonia unassociated with psittacosisThirty of the 45 persons with atypical pneu-

monia presented no evidence of recent infectionwith a virus of the psittacosis group (Table I).Several samples of serum, taken at intervals afteronset of pneumonia, were available from 23 of the30 patients; none of these sera contained appre-ciable amounts of antibodies which reacted withpsittacosis antigen. Lung tissue obtained at post-mortem examination from 2 of the 30 persons, andthroat washings and sputum from another patientwho recovered, all failed to yield a virus of thepsittacosis group despite persistent efforts of thetype which had proved successful with material

from other patients. Single specimens of serum,drawn during the second month of convalescence,were available from 5 patients; these also gavenegative results in our test for antibodies ofpsittacosis.

It is axiomatic in virus research that a negativeresult, i.e., the failure to isolate a viral agent or todemonstrate an immune response in a host, is lesssignificant than a positive result. Therefore, onecan only say that it is highly unlikely that 25 pa-tients (23 from whom several samples of serumwere obtained and 2 who died) of the group hadan infection with the virus in question. Discus-sion might arise concerning the validity of theassumption that psittacosis was unrelated to theillness of those 5 individuals whose serum wasexamined only between the 4th and 8th weeks. Itis our experience, as well as that of others (35),that complement fixing antibodies generally per-sist in high titer for many weeks after infectionwith the virus of psittacosis. Therefore, we feeljustified in our opinion that a negative result inthe psittacosis test on serum taken rather late inconvalescence is of considerable value in rulingout the diagnosis of psittacosis. This is in con-trast to the diagnostic value that may be assignedto the demonstration of psittacosis antibodies in asingle sample of blood, drawn during this sameperiod of recovery.

Serological investigations, undertaken to deter-mine the incidence of influenza A and B and oflymphocytic choriomeningitis in the entire groupof patients with atypical pneumonia, gave essen-tially negative results in all except 2 instances.None of the 37 patients on whomadequate mate-rial was available possessed demonstrable anti-bodies against antigen of choriomeningitis. Bothof the persons who showed deviations from thenormal levels of influenza antibodies were encoun-tered in the group of patients in whose diseasepsittacosis was not a factor. Serum of one ofthese, M. B., had a high titer of antibodies forinfluenza B virus ( 1: 768) as early as the -9th day,and this level did not change materially during the10 weeks of observation. Serum from the otherpatient, T. L., showed an influenza A antibodylevel of 1: 364 on the 6th day, and 1: 64, fourweeks later. It is possible that these 2 indi-viduals had recent infections with the viruses of

62


influenza B and A respectively, but the data areinsufficient to prove that such infections were re-sponsible for the pulmonary disease.

Epidemiological observationsThe source of infection was clearly evident in 2

of the patients with psittacosis. Both A. G. andE. G. handled acutely ill pigeons during the courseof an epizo6tic disease in their flock, which wascaused by a virus of the psittacosis group. Theincubation period of the disease in both patientswas approximately 3 weeks; a more detailed de-scription of the human and avian infection will bereported (36). Similarly, patient J. M. in allprobability derived his psittacosis from pigeons.Two of 6 birds in J. M.'s flock had complementfixing antibodies that reacted with psittacosis anti-gen. Therefore, a latent infection was undoubt-edly present among the pigeons even though noneof the birds was obviously sick. The occasionalexposure of patient R. L. to pigeons occurredwhen he visited a friend while the latter "flew"his birds; this may have been the source of hisinfection but none of the pigeons was availablefor examination.

It seems worthwhile to record certain observa-tions on the direct and indirect exposure of pa-tients with atypical pneumonia, to birds, some ofwhich had latent psittacosis. These data are pre-sented only to emphasize the need for furtherstudy, since no conclusions may be drawn at thistime. Three additional patients among the 10who had psittacosis, and one patient in the groupof 5 who may have had this disease, were eitherin direct contact with birds or had a remote con-nection with them, preceding the onset of atypicalpneumonia. Mention need hardly be made of pa-tients B. T. and C. M., see Table I, who were ex-posed to apparently healthy canaries. This avianspecies has been known to transmit infection toman; moreover, B. T. visited bird stores to pur-chase food for her canaries and may have beenexposed to classical psittacine strains of the virus.The epidemiological importance of indirect expo-sure over long periods of time to pigeons withlatent psittacosis must be considered. For ex-ample, E. Gu. and J. W. lived nearby flocks ofpigeons but neither person handled the birds oreven visited the lofts. It must be borne in mind

that not all patients who are associated with birdshave atypical pneumonia and psittacosis, viz., G. E.and M. M. in Table I.

Finally, the question arises concerning the sourceof infection of 3 proved cases of psittacosis andof 4 cases of atypical pneumonia who may havehad psittacosis, since none of these individuals hadany known contact with birds. Of course, nu-merous flocks of pigeons are present in all metro-politan areas and previous observations (21, 24),as well as present ones, indicate a high degree ofparasitism of such birds with strains of the virusof psittacosis. Therefore, it is possible, as Meyer,Eddie, and Yanamura suggest (21), that theseindividuals were infected by inhaling contaminatedmaterial during transient indirect exposure toacutely ill or latently infected pigeons. On theother hand, it appears desirable to search for ahumanized strain of virus of this general groupwhich is moderately contagious for man and whichis transmitted from man to man by way of theupper respiratory route. A family of viruses, aswidely disseminated throughout the avian, mam-malian, and human species as is the psittacosis-lymphogranuloma venereum group of agents,might be expected to possess a member with po-tentialities of this type.

Differences were noted in the age and sex dis-tribution of our cases with psittacosis and withatypical pneumonia of unknown etiology. Theaverage age of the patients with proved or sus-pected psittacosis was 49 years, and 9 of the 15individuals were females. In contrast, the aver-age for the patients with atypical pneumonia un-associated with psittacosis was 31 years, and only11 of the 30 persons were females. In this smallseries of cases of atypical pneumonia, the inci-dence of psittacosis among pigeon fanciers, mostof whomare men, and among middle aged women,many of whom are fond of pets, is impressivelyhigh.

DISCUSSION

The present work indicates that an appreciablenumber, approximately one-fourth, of the sporadiccases of atypical pneumonia are caused by infec-tion with strains of the virus of psittacosis. Italso indicates that about two-thirds of the patientspresent no evidence of infection with members of

63

JOSEPH E. SMADEL

the psittacosis group of viruses. Diagnostic dif-ficulties are encountered among the patients whoearly in the course of their disease possess anti-bodies that fix complement in the presence of psit-tacosis antigen, but who develop no notable in-crease in the titer of these antibodiesduring con-valescence. At the present time, one is not justi-fied in assuming that infection with strains of thevirus of psittacosis is responsible for the pneu-monic disease in this group of patients. Our ob-servations on sera of patients with lymphogranu-loma venereum are in agreement with those ofRake, Eaton and Shaffer (16), vAz., antibody inthe sera of such individuals fixes complement withpsittacosis antigen. Accordingly, rigid criteriahave been established which must be fulfilled foreach patient before we are willing to say that psit-tacosis virus is of etiological importance in thatperson's illness.

In this paper, the term "psittacosis" has beenapplied to the disease of the patients with atypicalpneumonia caused by a psittacosis-like virus.Furthermore, reference has been made repeatedlyto infection with strains of the virus of psitta-cosis. These expressions have been used becausewe think that the viruses isolated in our labora-tory from human beings and from pigeons haveso much in commonwith classical psittacosis virusthat they are merely strains of this agent. Simi-larly, we would designate the viruses describedby others as meningopneumonitis (19), pneu-monitis (13, 16), and ornithosis (21) as strainsof the virus of psittacosis. Certainly, the differ-ences between the agents just mentioned are nogreater than those found among the strains of anumber of viruses. As an example, one needonly mention the virus of vaccinia with its nu-merous strains, some of which differ strikinglyfrom the classical agent isolated from lesions ofcowpox. If only the strains of virus discussedabove constituted a specific group, then there mightbe justification for dividing the human diseasewhich they cause into psittacosis and ornithosis,as Meyer has done (21, 22). However, we mustreckon with the viruses of lymphogranuloma ve-nereum and of mouse pneumonitis (37) (and un-doubtedly others yet to be discovered), for theytoo belong in the family. Therefore, until suf-ficient data have accumulated to warrant a reason-

able taxonomic approach to this confusing prob-lem, it seems preferable to employ the termpsittacosis-lymphogranuloma virus for this entiregroup, just as the expression vaccinia-variola virusis applied to that group of agents. Furthermore,until the situation is clarified, it appears reasonableto speak of the members of the family as strainsof the viruses of psittacosis and of lymphogranu-loma venereum, depending upon which one ofthese the agent in question resembles more closely.

SUMMARY

Ten of the 45 sporadic cases of atypical pneu-monia encountered among large eastern urbarpopulations were caused by infection with strainsof the virus of psittacosis. Five additional casesin the series may have had psittacosis but the diag-nosis was indefinite because of the failure todemonstrate a significant rise in antibody titer inthe convalescent sera of these patients. In noinstance was the virus of lymphocytic choriomenin-gitis associated with the illness of individuals inthe group, and in only two instances was influenzavirus even suspected as a possible etiological agent.

The importance of establishing an etiologicaldiagnosis in cases of atypical pneumonia is empha-sized and the essential laboratory data necessaryfor such a diagnosis are discussed.

The author wishes to thank Miss Margaret J. Walland Miss Elizabeth M. Rolb for their valuable assistance.

BIBLIOGRAPHY

1. Allen, W. H., Acute pneumonitis. Ann. Int. Med.,1936, 10, 441.

2. Scadding, J. G., Disseminated focal pneumonia. Brit.M. J., 1937, 2, 956.

3. Reimann, H. A., An acute infection of the respiratorytract with atypical pneumonia. A disease entityprobably caused by a filterable virus. J. A. M. A.,1938, 111, 2377.

4. Smiley, D. F., Showacre, E. C., Lee, W. F., andFerris, H. W., Acute interstitial pneumonitis: anew disease entity. J. A. M. A., 1939, 112, 1901.

5. Reimann, H. A., and Havens, W. P., An epidemic dis-ease of the respiratory tract. Arch. Int. Med.,1940, 65, 138.

6. Kneeland, Y., Jr., and Smetana, H. F., Currentbronchopneumonia of unusual character and unde-termined etiology. Bull. Johns Hopkins Hosp.,1940, 67, 229.

64


7. Longcope, W. T., Bronchopneumonia of unknown eti-ology (variety X). A report of 32 cases with 2deaths. Bull. of Johns Hopkins Hosp., 1940, 67,268.

8. Hornibrook, J. W., and Nelson, K. R., An institutionaloutbreak of pneumonitis. I. Epidemiological andclinical studies. Pub. Health Rep., 1940, 55, 1936.

9. Gallagher, J. R., Acute pneumonitis. A report of 87cases among adolescents. Yale J. Biol. and Med.,1941, 13, 663.

10. Adams, J. M., Primary virus pneumonitis with cyto-plasmic inclusion bodies. Study of an epidemic in-volving 32 infants, with 9 deaths. J. A. M. A.,1941, 116, 925.

11. Dyer, R. E., Topping, N. H., and Bengtson, I. A., Aninstitutional outbreak of pneumonitis. II. Isolationand identification of causative agent. Pub. HealthRep., 1940, 55, 1945.

12. Weir, J. M., and Horsfall, F. L., Jr., The recoveryfrom patients with acute pneumonitis of a viruscausing pneumonia in the mongoose. J. Exper.Med., 1940, 72, 595.

13. Eaton, M. D., Beck, M. D., and Pearson, H. E., Avirus from cases of atypical pneumonia. Relationto the viruses of meningopneumonitis and psitta-cosis. J. Exper. Med., 1941, 73, 641.

14. Stokes, J., Jr., Kenney, A. S., and Shaw, D. R., Anew filtrable agent associated' with respiratory in-fections. Tr. Coll. Phys. Phila., 1938-1939, 6,329.

15. Cecil, R. L., editor, A Textbook of Medicine. W. B.Saunders, Philadelphia, 1940, 5th edition, pp. 66-67(Rivers, T. M., on Psittacosis).

16. Rake, G., Eaton, M. D., and Shaffer, M. F., Similari-ties and possible relationships among viruses ofpsittacosis, meningopneumonitis, and lymphogranu-loma venereum. Proc. Soc. Exper. Biol. and Med.,1941, 48, 528.

17. Pinkerton, H., and Moragues, V., Comparative studyof meningopneumonitis virus, psittacosis of pigeonorigin, and psittacosis of parrot origin. J. Exper.Med., 1942, 75, 575..

18. Eaton, M. D.' Martin, W. P., and Beck, M. D., Theantigenic relationship of the viruses of meningo-pneumonitis and lymphogranuloma venereum. J.Exper. Med., 1942, 75, 21.

19. Francis, T., Jr., and Magill, T. P., An unidentifiedvirus producing acute meningitis and pneumonitisin experimental animals. J. Exper. Med., 1938, 68,147.

20. Meyer, K. F., Pigeons and barn yard fowls as pos-sible sources of human psittacosis or ornithosis.Schweiz. med. Wchnschr., 1941, 71, 1377.

21. Meyer, K. F., Eddie, B., and Yanamura, H. Y.,Ornithosis (psittacosis) in pigeons and its relationto human pneumonitis. Proc. Soc. Exper. Biol. andMed., 1942, 49, 609.

22. Meyer, K. F., The ecology of psittacosis and ornitho-sis. Medicine, 1942, 21, 175.

23. Rake, G., Jones, H. P., and Nigg, C., Sulfonamidechemotherapy of mouse pneumonitis, meningo-pneumonitis, and lymphogranuloma venereum.Proc. Soc. Exper. Biol. and Med., 1942, 49, 449.

24. Eddie, B., and Francis, T., Jr., Occurrence of psitta-cosis-like infection in domestic and game birds ofMichigan. Proc. Soc. Exper. Biol. and Med., 1942,50, 291.

25. Yanamura, H. Y., and Meyer, K. F., Studies on thevirus of psittacosis cultivated in vitro. J. Infect.Dis., 1941, 68, 1.

26. Meyer, K. F., and Yanamura, H. Y., Personalcommuniation.

27. Pickels, E. G., An improved type of electrically drivenhigh speed laboratory centrifuge. Rev. Scient. In-struments, 1942, 13, 93.

28. Smadel, J. E., and Wall, M. J., A soluble antigen oflymphocytic choriomeningitis. III. Independenceof anti-soluble substance antibodies and neutralizingantibodies, and the role of soluble antigen and in-active virus in immunity to infection. J. Exper.Med., 1940, 72, 389.

29. Hirst, G. K., The quantitative determination of in-fluenza virus and antibodies by means of red cellagglutination. J. Exper. Med., 1942, 75, 49.

30. Francis, T., Jr., Magill, T. P., Rickard, E. R., andBeck, M. D., Etiological and serological studies inepidemic influenza. Am. J. Pub. Health, 1937, 27,1141.

31. Hirst, G. K., Rickard, E. R., Whitman, L., and Hors-fall, F. L., Jr., Antibody response of human beingsfollowing vaccination with influenza viruses. J.Exper. Med., 1942, 75, 495.

32. Rivers, T. M., and Berry, G. P., Psittacosis. II. Ex-perimentally induced infections in mice. J. Exper.Med., 1931, 54, 105; III. Experimentally inducedinfections in rabbits and guinea pigs. Ibid., 1931,54, 119; IV. Experimentally induced infections inmonkeys. Ibid., 1931,'54, 129.

33. McCordock, H. A., and Muckenfuss, R. S., The simi-larity of virus pneumonia in animals to epidemic in-fluenza and interstitial bronchopneumonia in man.Am. J. Path., 1933, 9, 221.

34. Scott, T. F. McN., and Rivers, T. M., Meningitis inman caused by a filterable virus. I. Two cases andthe method of obtaining a virus from their spinalfluids. J. Exper. Med., 1936, 63, 397.

35. Meyer, K. F., and Eddie, B., The value of the com-plement fixation test in the diagnosis of psittacosis.J. Infect. Dis., 1939, 65, 225.

36. Smadel, J. E., Wall, M. J., and Gregg, A., To bepublished.

37. Nigg, C., An unidentified virus which produces pneu-monia and systemic infection in mice. Science,1942, 95, 49.

65

Documents

ATYPICAL PNEUMONIA AND