A CLINICAL REPORTON CASESOF PRIMARYATYPICALPNEUMONIACAUSEDBY A NEWVIRUS1

By GORDONMEIKLEJOHN, MONROED. EATON,'2 AND WILLIAM VAN HERICK

(From the Research Laboratory of the California State Department of Public Health, Berkeley, and theDepartment of Medicine, University of California Medical School, San Francisco)

(Received for publication August 16, 1944)

During the 10 years which have passed sincethe disease now designated as primary atypicalpneumonia began to take form as a definiteclinical entity, considerable progress has beenmade in studies of its clinical and epidemio-logical aspects (1). Progress in etiological stud-ies, however, has been comparatively slow. Theisolation of a number of infectious agents fromsingle patients or small groups of patients (2 to10) has made it clear that the clinical syndromeunder discussion is of diverse etiology and thatthe human organism, like a variety of experi-mental animals, may show a somewhat similarclinical and pathological response when any oneof a number of unrelated nonbacterial infectiousagents is introduced into the lower respiratorytract. At the same time, there is no convincingevidence that the great majority of cases re-ported have been due to any of the viruses orrickettsiae isolated up to the present.

The discovery that an infectious agent in thesputum or lungs of patients with primary atyp-ical pneumonia produced a pneumonic infiltra-tion when inoculated intranasally into cottonrats (11) opened a new line of approach. In-vestigation was further facilitated by the sub-sequent demonstration that this agent, pre-sumably a virus, multiplied when introducedfrom human material into the amniotic sac ofthe chick embryo and that suspensions of in-fected chick embryo tissues produced a similarpneumonic response in cotton rats and hamsters.The properties of this virus, which is apparently

1 The studies and observations on which this paper isbased were supported by the International Health Divisionof The Rockefeller Foundation.

2Representing the Commission on Influenza, Board forthe Investigation and Control of Influenza and OtherEpidemic Diseases in the Army, Preventive MedicineService, Office of the Surgeon General of the UnitedStates Army.

not related to influenza virus (type A or B),psittacosis-like viruses, or the rickettsia ofQ-fever, have been described elsewhere (12).It was found that serum taken early in thecourse of the disease failed to neutralize thevirus, but that convalescent serum consistentlyprotected the test animals. On the basis of thisneutralization test, it has been possible toclassify a group of cases of primary atypicalpneumonia of a type which has, up to the presenttime, fallen into the category of unknownetiology.

The correlation of the clinical and pathologicalfindings in the various types of primary atypicalpneumonia with the responsible etiological agentconstitutes an important problem at the presenttime. In a previous report (13), clinical, labora-tory, and pathological data have been presentedon a group of 10 patients with atypical pneu-monia from whom psittacosis-like viruses wereisolated. It was emphasized that infectionsdue to those agents were comparatively rare anddiffered in certain important respects from thosenot due to psittacosis-like viruses. The purposeof this paper is to present similar data on anothergroup of cases of primary atypical pneumonia,together with evidence that they were causedby this new atypical pneumonia virus. Criteriaof proof of such an etiological relationship are(1) demonstration of virus in lung or sputumduring the course of illness by animal inoculationor by adaptation to chick embryos, (2) demon-stration of an increase in neutralizing antibodyduring or after recovery from the illness, orpreferably (3) both.

The 16 cases presented represent that formof primary atypical pneumonia which has oc-curred frequently in this area during the past4 years, either as an epidemic or endemic disease.The group is somewhat weighted in favor of themore severe cases because these are more readily

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investigated. It is of considerable interest thatmost of the patients in the group developed sig-nificant titers of cold agglutinins (14).

MATERIAL AND METHODS

Clinical material. The cases studied, with one excep-

tion, were selected from a larger group of approximately100 cases which occurred in students at the University ofCalifornia in Berkeley and at the University of CaliforniaMedical Center in San Francisco during the period fromJuly 1942 to March 1944. All the patients were between19 and 27 years of age. Ten of them were males. Thesingle fatal case occurred at Letterman General Hospital.

Isolation of virus. Specimens of sputum or lung were

ground with alundum, diluted with broth to 10 or 20 per

cent suspensions, lightly centrifuged, and inoculated intra-nasally in 0.4 ml. amounts into cotton rats under etheranesthesia. Animals were sacrificed 7 to 14 days later,and the result was interpreted as positive when a definitearea of pulmonary consolidation was present. Attemptsto produce similar consolidation consistently by passageof lungs'have, to date, failed or have been masked by theacquisition of other viruses, presumably of animal origin.

For this reason, isolation and passage in the amnioticsac of chick embryos has been used for most purposes.

One strain was adapted to eggs from a sterile specimen ofhuman lung without filtration. Two other strains were

derived from sputum specimens which had been filteredthrough collodion membranes of 600 mjs average pore

diameter. Passage has been made in 11- or 12-day-oldembryos at 5-day intervals, amniotic membrane, trachea,and lungs being ground together for passage material.Presence of virus was detected by inoculating suspensionsof these tissues intranasally into hamsters or cotton rats.Pulmonary consolidation like that following sputum inocu-lation was observed if virus was present in sufficientamounts.

Neutralization tests. Suspensions of chick embryotissues, previously tested for ability to produce pulmonaryconsolidation in test animals, were mixed with an equalvolume of serum. Acute and convalescent sera were

inactivated and diluted with an equal volume of horseserum before mixing with the virus suspension, the testserum dilution being 1:4. After 20 minutes' incubationat room temperature, these suspensions were inoculatedintranasally into hamsters or cotton rats. Four animalswere tested with each suspension. Hamsters were sacri-ficed at 7 days and cotton rats at 12 to 14 days. Theresults were expressed as a fraction, the numerator indi-cating the number of animals showing pulmonary con-

solidation, and the denominator, the total number tested.A mixture of the original virus suspension with an equalamount of horse serum served as virus control, while a

suspension of normal amniotic membrane, trachea, andlungs and an equal amount of horse serum served as

animal control. Because the virus is labile, animalsreceiving the convalescent serum suspension were alwaysinoculated before those receiving the acute serum suspen-sion. Results of neutralization tests, together with certainclinical and laboratory findings, are presented in Table I.

BLE I

Summary of certain clinical and laboratory findings, cold agglutination tests, results of inoculation of sputuminto cotton rats, and neutralization tests in 16 cases of primary atypical pneumonia

Cold agglutinin titers Result Neutralizationof in- tests

High- Dura_________ ocula -______Case est tion White blood Lobes tion of

temp. of cell range involved sputum Con-. fever Day bled Titer into Acute vales,-Daybled Titer ~~~cotton serum centrats serum

° F. daysIr 104 9 5,800 to 9,600 RLL 5*, 37t 2/2 3/4 0/4Ki 103.6 14 8,800 to 9,550 RML, RLL 7*, 43t 2/4 2/8 0/8Pa 101 12 9,300 RML 7$, 13, 27t 10, 80, 40 1/2 6/7 0/7Gi 103.6 9 8,450 RLL, LLL 3*, 11 37t <10, 40, 40 4/6 2/4 0/4Yo 104 9 5,500 to 12,400 RUL, RLL 4*, 16, 26, 80t <10, 2,560,640,320 7/12 3/8 0/8Sn 104 10 4,950 RLL 6*, 9, 16t <10, 80, 320 2/2 2/4 0/4tMu 104 14 5,100 to 8,300 RUL 4*, 12, 18t <10, 40, 1,280 6/9 6/7 0/7Bu 104.8 24 7,750 to 37,600 RLL, RUL, LLL, 4*, 12, 25t, 46t <10, 80, 160, 20 5/9 6/11 0/11$

LULSo 102 8 8,200 to 13,200 LLL 7*, 12, 19, 27t 20, 320, 160, 80 3/3 0/34Do 101.8 16 10,000 to 7,900 LLL, RLL 8*, 14, 21, 28t 5, 40, 160, 160 4/4 0/41Hu 104.8 19 7,650 to 11,600 RLL, LLL 7*, 14, 21, 28t <10, 320, 160, 80 6/10 1/4 0/4Kr 101.4 7 6,600 to 10,700 LLL 7*, 16t, 76 < 10, 160, 10 3/8 0/8tMur 101.8 8 9,100 to 8,900 RLL 6*, 15t, 60 < 10, 80, 10 3/4 1/4Ta 103.4 16 8,200 to 13,100 RLL 4*, 10, 19, 31t <10, 10, 80, 80 1/4 4/4§ 0/4Pg 101 8 8,200 RML 5*, 11, 21, 50t <10, 80, 80, 40 3/4§ 0/4Dell 105.4 12 8,000 to 22,000 LLL, LUL, RLL, 8/27

RML, RUL

* Acute serum. t Convalescent serum specimen used in neutralization tests. t Serum shown by subsequent test toneutralize at dilution of 1: 16 or more. §Neutralization test done in chick embryos. II Died.

In the last three columns numerator indicates number of positive animals; denominator the total number tested.

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ATYPICAL PNEUMONIADUE TO A NEWVIRUS

CLINICAL PICTURE

The onset of the disease was, in most instances,gradual. Presenting symptoms most frequentlynoted were malaise, cough, feverishness, head-ache, and moderate aching. Chilly sensationswere common, but true chills infrequent. Sorethroat, if present, was not severe (15). Pleuriticpain was not noted, though chest pain, eitherretrosternal in location or felt along the costalmargin, was present in several instances. Coughwas often troublesome and persistent. Sputumwas scanty, usually tenacious, greenish in color,and occasionally streaked with bright red blood.On physical examination, the patient did notappear severely ill unless considerable areas oflung were involved. Slight dulness and scat-tered moist rales were often the only findings onexamination of the chest. Later in the courseof the disease coarse rales were heard and signs ofconsolidation sometimes appeared.

Admission white blood cell counts ranged from4,950 to 10,000. As the illness progressed, par-ticularly when it was severe, the white blood cellcount tended to rise. Thus, in the single fatalcase (De) it rose to 22,000 before death, and inanother extremely severe case (Bu) a count of37,500 was recorded at the height of the disease.Sputum cultures revealed only the usual pharyn-geal organisms. Stained smears showed fewbacteria and a relatively sparse cellular exudatein which mononuclear cells were common.X-rays of the lungs showed small or extensiveinfiltrations. Lateral films were often of valuein disclosing minimal lesions. Not infrequently,the areas of pneumonia continued to spread forseveral days or new areas were noted, but themigratory type of pneumonia was uncommon.

The temperature curve was either very irregu-lar or fairly sustained, and usually fell by lysis.Most patients began to show clinical improve-ment and clearing of x-ray findings within 10days of onset. At no time did they appear veryill. In others, however, the pneumonic processcontinued to spread and the patients becamedesperately ill and showed intense dyspnea andcyanosis. The one fatal case was remarkablein that within 11 days the pneumonia had in-volved most of one lung and more than halfof the other. Herpes labialis was noted in

patients with high fever. The spleen was pal-pable in one patient (Yo) during the first weekof illness. Disturbance of cerebral functions wasinfrequent even in those patients who were mostseriously ill. Convalescence was slow, manypatients complaining of weakness, dyspnea onexertion, and persistent cough. No other se-quelae have been observed.

CASE SUMMARIES

Three cases are presented in detail. Thefirst, a comparatively mild one, was selected as anexample of the type of case most frequentlyseen. The second case, which was extremelysevere, and the third, which terminated fatally,represent less commontypes, but present a num-ber of points of unusual interest. Clinical dataon these 3 and 13 other cases are presented inTable I.

Case 1. Gi, a male, aged 22, awoke on March 21, 1943,with a tickling sensation in his throat. That evening hefelt feverish and complained of generalized aching andmalaise. Next day these symptoms were more pronouncedand a troublesome cough had developed which producedsmall amounts of tenacious greenish sputum. It is ofinterest that the patient's brother, with whom he wasliving, had previously suffered a similar attack of primaryatypical pneumonia, beginning on March 1, 1943, and hadshown a rise in cold agglutination titer from less than 10during the acute phase to 40 during convalescence. The2 brothers were in contact with each other until March 9.

Onadmission to the University of California Hospital onMarch 22, the patient's temperature was 103.60 F., pulse100, respirations 20, and blood pressure 108/80. He didnot appear acutely ill, but complained of severe generalizedheadache, retro-orbital soreness, and occasional pain inhis right ear. His skin was hot and dry, his nose moder-ately congested; but no other symptoms were noted.

Course: On March 24, slight dulness and a few cracklingrales were noted at the base of the right lung. Thesebecame more prominent during the following days. Thetemperature remained elevated until March 29, with dailypeaks of 102.20 or more, and fell by lysis. Throughout thisperiod, the patient felt and looked comfortable and con-tinued to eat well. Headache and cough were the mosttroublesome symptoms. Recovery was fairly rapid.

Laboratory findings: On March 23, the blood countshowed 5,000,000 red blood cells (hemoglobin 14 grams)and 8,450 white blood cells with 70 per cent polymorpho-nuclears (F./N.F. 34/36). Sputurn examination was nega-tive for pneumococci and acid-fast bacilli. Chest x-rayon March 23 showed a small patch of pneumonitis in theright lower lung in the cardiohepatic angle. On March 29,this area had spread and involved a good deal of the rightlower lobe and there was evidence of minimal spread to the

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G. MEIKLEJOHN, M. D. EATON, AND W. VAN HERICK

middle of the left lung. On April 22, the lungs appearednormal.

Suspensions of sputum collected on the fourth day ofdisease produced pulmonary lesions in 4 of 6 cotton rats.Cold agglutination titers (as shown in Table I) of serumspecimens taken on the third, eleventh, and thirty-seventhdays of disease were less than 10, 40, and 40, respectively.

Case 2. Bu, a female, aged 20, noted aching andmalaise on April 26, 1943. During the following 2 days,these symptoms became more troublesome, and in additionshe complained of cough, feverishness, restlessness, andanorexia. Slight wheezing with respiration was noticed.She was admitted to Cowell Memorial Hospital on April 29.

Physical examination: The patient's temperature was100.20 F., pulse 84, respirations 22. She did not appearacutely ill. Cough was frequent and produced moderateamounts of tenacious, yellowish sputum. Conjunctivaeand pharynx were injected. Fine and coarse rales wereheard over the right lower lobe as far anteriorly as theaxillary line.

Course: The high, spiking temperature curve is repro-duced in Figure 1. On May 1, bronchial breathing washeard over the right lower lobe and the patient was placedin an oxygen tent. On May 5, dulness was noted overthe right lower lobe and bronchial breathing was heardover most of the right lung and over the upper half of theleft lung. On May 6, respirations were wheezing incharacter. By May 7, respirations had risen to 38,cyanosis was marked, and the patient appeared seriouslyill. On May 9, 200 ml. of pooled plasma from 3 patientsrecently convalescent from primary atypical pneumonia,who had shown significant cold agglutinin titers, weregiven intravenously. On the next day, the patientappeared somewhat more alert and 300 ml. more of thesame pool of plasma were given. One hour later, her pulsehad risen to 140 and she was apprehensive and sweating

profusely. That evening, the respiratory rate was 50,pulse 156, and the patient appeared moribund. Sheremained in an extremely critical state throughout thenext day, and then slowly improved. Her temperaturemeanwhile had fallen and subsequently did not exceed1010, though another 10 days passed before it returned tonormal. Convalescence was slow, but at last reportthere were no sequelae. Sulfadiazine was given fromMay 3 to May 10, the blood level on May 4 being 7.1 mgm.per cent. No effect on the course of the illness was seen.

Laboratory findings: Admission white blood cell countwas 7,750. As the illness progressed, the count rosesteadily. On May 9, it was 17,200, with polymorpho-nuclears constituting 86 per cent (F./N.F. 56/30). OnMay 12, it was 37,600. It dropped to 24,400 on May 15,to 19,700 on May 20, and to 9,200 on May 30. Sputumcultures showed a growth of Staphylococcus aureus andalpha streptococci, but were negative for pneumococci,beta streptococci, and acid-fast bacilli.

Chest x-ray on April 29 showed a fairly extensivepneumonic area at the base of the right lung, lobar incharacter, and mottling near the left hilum. On May 6,films showed an extensive pneumonia involving much ofthe right lung and the middle portion of the left lung.On June 3, there was much clearing, but slight residualinfiltration on both sides. On June 11, clearing was morecomplete, but an area of increased density, which suggestedfibrosis, remained at the left apex.

Sputum collected on April 29 and May 6 was tested incotton rats. The results with both specimens were posi-tive, 5 out of 9 animals showing pulmonary consolidation.Later, this material was passed through a collodionmembrane of 600 m, pore diameter, and the virus wasadapted to chick embryos. This strain has been carriedthrough 25 passages and is neutralizable by the convales-cent sera of this and other patients with atypical pneu-

20 22 24 26 28 30

FIG. 1. TEmPERATURERECORDOF PATIENT (Bu) WHOSEILLNESSWASUNUSUALLYSEVERE

B F-I IOIeI IBlu. F- 20 Onnet - Aps. 26,1943

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ATYPICAL PNEUMONIADUE TO A NEWVIRUS 2

monia. The acute serum does not neutralize the virus.The results of serial cold agglutination tests are recordedin Table I.

Case 3.3 De, a male, aged 26, was admitted to Letter-man General Hospital on November 11, 1942, with ahistory of an illness of 4 days' duration. Complaintsduring this period were coryza, sore throat, cough, fever-ishness, malaise, generalized muscular pains, and anorexia.Symptoms had become markedly worse on the day ofadmission.

Physical examination: The patient's skin was hot anddry. The right nostril was obstructed and the pharynxinjected. Respiratory movements were equal and shallowbecause deeper respiration incited cough and pain in chest.Slight dulness to percussion was noted at the bases of bothlungs, and many fine moist rales were heard throughoutthe lungs, particularly at the bases. Blood pressure was118/50. Examination of the heart showed it to be normal.

Course: Fever remained high, with peaks reaching105° F. The patient soon became markedly dyspneic andcyanotic and was placed in an oxygen tent. Signs ofpneumonia became more prominent over the right upperlobe and the whole left side. The cough was troublesome,but virtually no sputum was raised. Sulfadiazine wasgiven throughout hospitalization in doses of 1 gram every4 hours and an adequate blood level was obtained, but noeffect was apparent. Dyspnea became progressivelyworse, and the patient died on November 17.

Laboratory findings: Admission blood count showed3,770,000 red blood cells and 8,000 white blood cells, withnormal distribution. Subsequently, the white blood cellsrose to 11,000, to 16,000, and finally to 22,000 on November16. Urinalysis showed albumin (+ +). Throat swabsand a single sputum examination failed to show pneumo-cocci. Chest x-ray taken on November 11 revealed anextensive bronchopneumonia in the left lower lobe. OnNovember 15, x-ray showed an extremely extensivebronchopneumonia involving both lobes on the left andparts of all three right lobes.

Autopsy findings: Post-mortem examination was madewithin 1 hour after death. Intestines were markedlydistended. A slight excess of blood-tinged fluid was founddeep in the peritoneal cavity. Both pleural cavitiescontained about 200 ml. of slightly blood-tinged fluid.The pericardial cavities contained about 200 ml. of palestraw-colored fluid.

The right lung weighed 1,085 grams, the left 945 grams.The lungs were similar. On palpation, from apex to base,there were noted innumerable distinct and confluent softand firm nodules, which varied from about 1 to 4 cm. indiameter. Lymph nodes at the hilum were somewhatenlarged, soft, and greyish between the areas of pigmenta-tion. Bronchi were distended with yellow, purulent,frothy exudate. Beneath the pleura the nodular fociappeared as lighter or darker areas against the slate-grey

3This case is reported through the courtesy of theMedical. and Laboratory Branches, Letterman GeneralHospital, from whomthe clinical and pathological findingswere obtained.

background. Except for a number of areas over the leftlung, where dull and granular areas were covered with apinkish-red exudate, the pleura was smooth and showedno exudate. On cut surface, the nodular areas could beseen as distinct or confluent, frequently poorly circum-scribed, dry granular foci of irregular size and shape,which stood above the cut surface of the lung. Thenodules were sometimes pink and duller than the sur-rounding tissue. Some were grey and many had ayellowish cast, as though slightly broken down. Thispneumonic process extended from apex to base, involvingall lobes.

The heart weighed 430 grams. The right auricle andventricle were markedly dilated. The coronary arterieswere smooth, and the lumens were patent. The myo-cardium was red and of good tone. The spleen weighed250 grams. The cut surface showed a soft grumous redpulp, and the follicles were not observed. The brainweighed 1,640 grams. Cerebral vessels were markedlycongested, particularly the pial vessels. Other organsshowed nothing noteworthy.

Microscopic examination: All sections (Figure 2) takenfrom different portions of the two lungs showed a pneu-monic reaction which might be classified as an atypicalbronchopneumonia. Practically all combinations of cellu-lar, fibrinous, and serous exudate could be found in thevarious alveoli, the exudate in some appearing fresh, whilein others it seemed to be undergoing resolution. In somesections, the character of the pneumonia was that of adiscrete bronchopneumonia. In other areas, the pneu-monia was of the confluent bronchopneumonic type.

Certain features in the inflammatory reaction were ofinterest. In the first place, there was a good deal of fibrinpresent, much of which was distributed peripherally andappeared tightly adherent to the inner wall of the alveolus.In the second place, there were certain areas in which itseemed that the exudate was breaking down and abscesseswere forming. In these areas, the exudate was cellular,often consisting predominantly of polymorphonuclearleukocytes. Necrosis of the alveolar walls had apparentlyoccurred and the center of the pneumonic focus seemed tobe undergoing liquefaction. A third point of interest wasthat in certain areas the exudate appeared to be undergoingorganization, the process consisting almost exclusively ofinvasion by young fibroblasts with no proliferating capil-laries observable. A fourth point of interest was themarked morphological change which had taken place inthe epithelial lining of a few of the bronchi. Here theepithelial lining had changed wholly or in part to a stratifiedsquamous type. The appearance of the epithelial liningof these bronchi was that of a pavement type of epitheliumwith loss of cilia, squamous cells on the surface, and pricklecells interspersed in the deeper layers. Mitotic figureswere extremely numerous. In several sections showingstrips of pleura, the pleura was practically always free ofexudate.

The coronary arteries were normal. Sections of myo-cardium revealed sporadic degenerated and necrotic musclefibres, some being lumpy and pale, and in certain instances

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G. MEIKLEJOHN, M. D. EATON, AND W. VAN HERICK

PLATE 1. Section from edge of a small discrete pneumonic focus, showing densecellular exudate in alveoli in upper portion and comparatively sparse cellular exudatewith numerous macrophages in lower portion. X 120.

PLATE 2. High magnification of same section, showing composition of alveolarexudate. Small mononuclear and polymorphonuclear cells predominate and occasionalmacrophages are seen. The alveolar septa are not markedly thickened. X400.

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ATYPICAL PNEUMONIADUE TO A NIEW VIRUS

PLATE 3. Section from another area, showing fibrin distributed peripherally alongsome of the alveolar walls. The exudate in this area is less cellular. X 120.

PLATE 4. Section showing metaplasia of the bronchial epithelium. The ciliatedcolumnar epithelium has changed to an irregular stratified squamous type. X400.

FIG. 2. SECTIONS FROMLUNGSOF PATIENT (DE) WITH FATAL CASE OF PRIMARY ATYPICAL PNEUMONIA. SECTIONSSTAINED WITH HEMATOXYLINAND EOSIN

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G. MEIKLEJOHN, M. D. EATON, AND W. VAN HERICK

showing loss of striation. Tl he small capillaries of themyocardium were markedly congested, and some containednumerous leukocytes. In one or two sections, leukocyteswere present in the somewhat edematous interstitial tissueoutside the capillary walls. There were, however, nodefinite areas of infarction and no specific rheumaticnodules. Sections from other organs showed nothingnoteworthy.

Etiological studies: Cultures of lung tissues remainedsterile after 72 hours. Impression smears showed nobacteria or elementary bodies. Suspensions tested intra-nasally in cotton rats produced pulmonary lesions in 8 of27 animals. WNithout filtration, the virus in the humanlung suspension was adapted to the amniotic sac of chickembryos and has been carried through 45 passages. Thisprocedure was subsequently repeated. Suspensions ofamniotic membrane, lungs, and trachea retain theirinfectivity for cotton rats and hamsters and are neutralizedby convalescent serum from other persons who have hadprimary atypical pneumonia. The properties of the virusisolated from this patient have been described in detail ina separate publication (12). A cold agglutination testrun with serum pipetted from the lung specimen showed atiter of less than 10.

DIFFERENTIAL DIAGNOSIS

An attempt to differentiate primary atypicalpneumonia from other diseases is rendered diffi-cult by the fact that several diseases of differentetiology have been included under this heading.The observations which follow will therefore berestricted to the type of the disease prevalent inthe area which the cases described in this reportrepresent. WA"hile these cases present a fairlycharacteristic picture, the number of the diseaseswhich may cause difficulty in diagnosis is verylarge. Thus, mild cases with slight or, perhaps,no pulmonary involvement may closely resemblecertain nonbacterial upper respiratory infections,particularly influenza and other influenza-likediseases.

The more familiar form of the disease, withslight or extensive pulmonary involvement, mustbe distinguished on the one hand from bacterialand mycotic pneumonias, and on the other frompneumonias due to other viruses and rickettsiae.Pneumococcal lobar pneumonia presents severalfeatures ver- uncommon in primary atypicalpneumonia, notably pleuritic pain, rust) sputum,and leukocytosis early in the disease. Broncho-pneumonias due to pneumococci, streptococci,staphylococci, and other bacteria may causemore difficulty. Those primary atypical pneu-monias restricted to upper lobes or presenting a

very diffuse pneumonia may closely resemblepulmonary or miliary tuberculosis. The pictureof primary coccidioidal pneumonia may be vervsimilar, and isolation of Coccidioides immitis andserological tests may be necessary for differentialdiagnosis (16). It is possible that the coldagglutination test may prove extremely usefulin separating out the primary atypical pneu-monias, but further substantiation of this pointis needed.

The clinical differences between primaryatvpical pneumonia and pneumonias due topsittacosis-like viruses or Q-fever are sometimestoo slight to permit differentiation, but suspicionmav be directed toward the psittacosis groupwhen a severely ill patient shows marked im-pairment of cerebral function and prominentgastro-intestinal symptoms, and appears gravelyill despite the fact that the area of lung involvedis comparatively limited. A history of aviancontact should be sought. Laboratory proce-dures, including isolation of virus and demonstra-tion of an increase in antibody to the agent inquestion are usually required.

TREATMENT

Symptomatic therapy, directed chiefly towardrelieving headache and cough, was used in allcases. Only in the most severe cases weresulfonamides employed, and in no instance wasany response observed. Oxygen was adminis-tered to 6 patients and appeared to have abeneficial effect. One patient (Bu) received apool of convalescent plasma from patients w-hohad previously shown high cold agglutinin titers.Her temperature fell after the second transfusion,but her condition never appeared xvorse thanduring the following day. X-ray therapy wasnot tried.

DISCUSSION

The cases of primary atypical pneumoniastudied at this laboratory can be divided intotwo main groups: (1) a large group presentingthe same general characteristics as the casesdescribed above, and (2) single cases or smallgroups of cases due to a variety of agents, in someinstances psittacosis-like viruses, in others un-known agents. While the occurrence of clear-cutepidemics of the former type suggests a single

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ATYPICAL PNEUMONIADUE TO A NEWVIRUS

etiology, it is by no means certain that the groupis homogeneous with. respect to its etiology. Thedata presented in this paper and in a previouspublication indicate that a substantial propor-tion of the cases of this type on which neutraliza-tion tests have been done are due to this newatypical pneumonia virus. It has already beenshown that the virus can cause an illness whichvaries in severity from a comparatively mild oneto an extremely severe or, in rare instances, afatal one. The number of cases studied is small,however, and no definite statement can be madeat the present time concerning the frequency ofinfection with the virus in this and other areas.

The occurrence of cold agglutinins in the seraof most of those patients whose illness was shownto be due to the new virus raises the questionwhether a significant increase in cold agglutinintiter following a respiratory disease represents aspecific response to a single etiological agent or arelatively nonspecific response to any one of anumber of agents. The cold agglutination testsdone in this laboratory on a large number ofsera from patients in the first group have shownthat more than half of the persons studied de-veloped significant (40 or more) titers duringthe latter part of their illness or during convales-cence. Certain other patients with clinicallysimilar cases did not. Further combined coldagglutination tests and etiological studies mustbe made before it is possible to state in whatproportion of pneumonias due to this virus coldagglutinin titers rise. The frequency of highcold agglutinin titers in pneumonias and upperrespiratory infections due to other agents like-wise remains to be determined. Even in ourpresent state of knowledge, however, the test hasproved very useful, possessing the great ad-vantage of simplicity of performance. Its chiefdisadvantage lies in the fact that titers returnto within normal limits in a relatively shorttime, thus curtailing its usefulness in epidemio-logical investigation.

The comparatively infrequent cases compris-ing the second group in which the etiology hasbeen determined represent, for the most part,infections with viruses or rickettsiae present in avariety of species of birds, mammals, or arthro-pods, or occur as laboratory infections. As agroup, they tend to be more severe and not in-

frequently terminate fatally. The largest num-ber is caused by viruses in the psittacosis group,3 of which have been isolated from human pa-tients, namely psittacosis, the pigeon ornithosisvirus, and the S-F strain (13, 17). Because ofcertain similarities in the clinical picture, incu-bation period, and pathological findings ob-served in psittacosis-like infections and in theprevalent type of primary atypical pneumonia, ithas been suggested that these or related agentsplay an important part in the etiology of primaryatypical pneumonia (17, 18). Evidence to sup-port such a hypothesis is at present lacking.In this laboratory, less than 10 per cent of morethan 250 cases studied have been shown to bedue to viruses in the psittacosis group. Wehave not observed pneumonias due to therickettsia of Q-fever or infections with thelymphocytic choriomeningitis virus in whichpulmonary consolidation occurred.

Specimens of lung tissue from a considerablenumber of persons, in which a bacterial etiologyhas been definitely excluded, have failed to yieldany of the viruses mentioned in this paper.This fact, together with certain observations,such as that (19) of a pneumonia of infantscharacterized by eosinophilic inclusion bodies,makes it seem probable that a number of non-bacterial infectious agents capable of causingpneumonia remain to be discovered.

SUMMARY

1. Clinical and laboratory data have beenpresented on 16 cases of primary atypical pneu-monia assumed to be due to a recently isolatedvirus.

2. This atypical pneumonia virus is transmis-sible to chick embryos, cotton rats, and hamstersand is apparently not related to previously de-scribed viruses isolated from cases of atypicalpneumonia.

3. The clinical picture did not differ in signifi-cant respects from that presented in other reportsof epidemics of primary atypical pneumonia.

4. The pathological findings in a fatal casefrom which virus was isolated have been de-scribed.

5. Significant titers of cold agglutinins weredemonstrated in the convalescent serum speci-

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G. MEIKLEJOHN, M. D. EATON, AND W. VAN HERICK

mens of all 13 patients in whom this test wasperformed.

The authors wish to acknowledge the cooperation ofDrs. W. G. Donald, R. T. Sutherland, M. G. Zeff, andA. H. Schaeffer, and Mrs. Elva May, of Cowell MemorialHospital; and of Drs. W. J. Kerr, Saxton J. Pope, andEllen Brown, of the University of California MedicalSchool. Valuable technical assistance was provided byMiss M. Corey and Miss V. L. Hanford.

BIBLIOGRAPHY

1. For review of literature and detailed bibliography, seeDingle, J. H., and Finland, M., Medical progress;virus pneumonias; primary atypical pneumonias ofunknown etiology. New England J. Med., 1942,227, 378.

2. Stokes, J., Jr., Kenney, A. S., and Shaw, D. R., Newfiltrable agent associated with respiratory infections.Tr. and Stud., Coll. Physicians, Philadelphia, 1939,6, 329.

3. Weir, J. M., and Horsfall, F. L., Jr., Recovery frpmpatients with acute pneumonitis of virus causingpneumonia in the mongoose. J. Exper. Med., 1940,72, 595.

4. Dyer, R. E., Topping, N. H., and Bengtson, I. A.,Institutional outbreak of pneumonitis; isolationand identification of causative agent. Pub. HealthRep., 1940, 55, 1945.

5. Eaton, M. D., Beck, M. D., and Pearson, H. E.,Virus from cases of atypical pneumonia. J. Exper.Med., 1941, 73, 641.

6. Meyer, K. F., Pigeons and barnyard fowls as possiblesources of human psittacosis or ornithosis. Schweiz.med. Wchnschr., 1941, 71, 1377.

7. Smadel, J. E., Green, R. H., Paltauf, R. M., andGonzales, T. A., Lymphocytic choriomeningitis;2 human fatalities following unusual febrile illness.Proc. Soc. Exper. Biol. and Med., 1942, 49, 683.

8. Johnson, H. N., quoted by Dingle, J. H., and others.Primary atypical pneumonia, etiology unknown.War Med., 1943, 3, 223. Also personal communi-cation to M. D. Eaton.

9. Horsfall, F. L., Jr., Curnen, E. C., Mirick, G. S.,Thomas, L., and Zeigler, J. E., A virus recoveredfrom patients with primary atypical pneumonia.Science, 1943, 97, 289.

10. Smadel, J. E., Atypical pneumonia and psittacosis.J. Clin. Invest., 1943, 22, 57.

11. Eaton, M. D., Meiklejohn, G., van Herick, W., andTalbot, J. C., Infectious agent from cases of atypicalpneumonia apparently transmissible to cotton rats.Science, 1942, 98, 518.

12. Eaton, M. D., Meiklejohn, G., and van Herick, W.,Studies on the etiology of primary atypical pneu-monia; a filterable agent transmissible to cottonrats, hamsters, and chick embryos. J. Exper.Med., 1944, 79, 649.

13. Meiklejohn, G., Beck, M. D., and Eaton, M. D.,Atypical pneumonia caused by psittacosis-likeviruses. J. Clini. Invest., 1944, 23, 167.

14. Meiklejohn, G., Cold agglutination test in diagnosis ofprimary atypical pneumonia. Proc. Soc. Exper.Biol. and Med., 1943, 54, 181.

15. Young, L. E., Storey, M., and Redmond, A. J.,Clinical and epidemiological features of outbreakof primary atypical pneumonia of unknown etiologyamong hospital and medical school personnel.Am. J. M. Sc., 1943, 206, 756.

16. Smith, C. E., Coccidioidomycosis. Med. Clin. NorthAmerica, 1943, 27, 790.

17. Meyer, K. F., Ecology of psittacosis and ornithosis.Medicine, 1942, 21, 175.

18. Favour, C. B., Ornithosis (psittacosis); report of 3cases and historical, clinical, and laboratory com-parison with human atypical (virus) pneumonia.Am. J. M. Sc., 1943, 205, 162.

19. Adams, J. M., Green, R. G., Evans, C. A., and Beach,N., Primary virus pneumonitis; comparative studyof two epidemics. J. Pediat., 1942, 20, 405.

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