Ascaris pneumonia

Ascaris A.

Pneumonia*

P. GELPI, M.D. and A. MUSTA>;.&,M.D. Dhahran, Saudi Arabia

The clinical picture of Ascaris pneumonia is described, together with observations on the endemic occurrence of this condition among the Arab population of Eastern Saudi Arabia. The disease is an acute disorder of the lower respiratory tract presenting with cough and malaise, and in its severe form with chest pain, dyspnea and hemoptyses. Pulmonary infiltrations and a moderate eosinophilic leukocytosis identify the condition as a type of Loeffler’s syndrome. The outcome among Saudi Arabian patients invariably has been favorable with the application of symptomatic measures; however. in severe cases the use of adrenal corticosteroids and oxygen may be indicated because of the alarming degree of respiratory distress. The most reliable diagnostic criterion has been the finding of typical third-stage larvae in the sputum or gastric aspirate of suspect patients. Serologic tests) employing whole worm antigens, have not proved helpful in diagnosis under the conditions of the reported study. The pathogenesis of the condition is believed to be a response of hypersensitivity to highly allergenic components of Ascaris larvae. The pneumonia is analogous in its clinical features, and presumably pathogenesis, to the Loeffler’s syndrome which develops during treatment of Manson’s schistosomiasis with trivalent antimonials. The epidemiology of ascariasis under climatic conditions prevailing in temperate zones or arid areas in the tropics seems to determine the expression of the larval state of infection. Interruption of the infectious cycle by adverse climatic factors is likely to be associated with seasonal outbreaks of Loeffler’s syndrome.

T

HIS report is concerned with a syndrome which occurs with seasonal regularity in the coastal settlements of Eastern Saudi Arabia. Since 1962 a form of Loeffler’s syndrome has been observed annually in almost epidemic proportions among Saudi Arabian subjects residing in this area, with the peak incidence appearing during the months of March through May. A review of hospital records from the medical department of the Arabian American Oil Company (ARAMCO) indicates that this syndrome appeared with the same seasonal pattern as early as 1954. To date 108 subjects have had well documented illnesses which typify the picture of seasonal Loeffler’s syndrome, or transient pneumonitis with eosinophilia. In all instances there were significant respiratory symptoms, moderate to marked eosinophilic leukocytosis and pulmonary infiltration demonstrable on roentgenograms. Epidemiologic and parasitologic studies led to the conclusion that this syndrome was due to larval ascariasis, and

* From the Internal Medicine Service, Medical Arabia. Manuscript received April 17, 1967. VOL.

44,

MARCH

1968

this contention was supported by the findings of typical third stage larvae of Ascaris lumbricoides in sputum and/or gastric washings of four patients. Details of the epidemiologic investigations, the ecology of human ascariasis in Eastern Saudi Arabia and the serologic reactivity of patients with this syndrome to certain helminth antigens have been considered in a separate report [I]. It is our purpose to focus attention on the clinical aspects of Ascaris pneumonia, to offer a provisional hypothesis to explain certain features of this condition in terms of the pathophysiology of hypersensitivity reactions and to review certain historic material on Loeffler’s syndrome and its relevance to the problem of Ascaris pneumonia. A number of excellent recent reviews dealing with the more general aspects of eosinophilia are available [Z--7]. CLINICAL

MATERIAL

AND METHODS

The subjects of this study were all Saudi Arabian and mostly employees of the Arabian American Oil

Department,

377

Arabian

American

Oil Company,

Dhahran,

Saudi

Ascaris

378

Pneumonia-GeQi,

n

E3 Dirafilaria

PATIENTS

(14)

FIG. 1.

Seroreactivity (indirect hemagglutination) against whole worm antigens of Toxocara canis, Ascaris

lumbricoides and Dirofilaria immitis. Three patients with established Ascaris pneumonia and eleven patients with the presumptive diagnosis compared with a group of nineteen, healthy control subjects.

Company, or their dependents. All fulfilled the criteria for the diagnosis of Loeffler’s syndrome. All manifested the triad of acute respiratory symptoms, transient pulmonary infiltrates and an eosinophilic leukocytosis. Blood counts were performed with the standard counting chamber technic and included the examination of 200 leukocytes on a blood smear prepared with Wright’s stain. Stool specimens were concentrated and processed according to the method of Ritchie [S]. Beginning in 1963, sputum and gastric washings were obtained from all patients and processed as described by Proffitt and Walton [9] for the demonstration of helminth larvae. Serum specimens from patients seen during 1963 and 1964 and control subjects were tested against whole worm antigens of Ascaris lumbricoides, Toxocara canis and Dirofilaria immitis by indirect hemagglutination and bentonite flocculation procedures described by Kagan [ 701and Kagan et al. [ 7I]. Miscellaneous additional studies in selected patients included quantitation of serum proteins and serum protein electrophoresis, hepatic function tests and basic ventilation studies employing the Collins 9 L. respirometer. In the majority of patients two or more chest films were taken during the course of illness, and every effort was made to obtain late follow-up films to establish the transient nature of the pulmonary infiltrations. CLINICAL

AND

LABORATORY

FINDINGS

Symptomatology was consistent and characterized by an irritating, relatively nonproductive cough, and frequently substernal chest pain of a peculiar, burning quality, usually aggravated by coughing. In more severe cases hemoptysis and dyspnea were often present. Systemic symptoms were minimal, although a number of subjects felt feverish at the onset of respiratory symptoms.

Mustafa

Approximately 15 per cent of the patients complained of a transient, intensely pruritic, generalized eruption which appeared within the first four or five days after the onset of respiratory symptoms. The majority of subjects were febrile, and oral temperatures ranged from 99 to 101 “F. during the early phase of illness. Temperatures exceeding 102’F. were exceptional and occurred only in patients with other evidence of severe illness. Examination of the chest usually revealed scattered musical rales and wheezing respiration which persisted for several days. Physical findings suggestive of pulmonary consolidation, such as dullness to percussion and bronchial breathing, were rarely encountered. Cutaneous eruptions varied from scattered, discrete, erythematous papular lesions to extensive, confluent urticarial patterns. Enanthems were not observed, lymphadenopathy was never encountered, and splenomegaly, which was noted in several patients, appeared to be an incidental finding related to previous experience with malaria or associated with hemoglobinopathy and accompanying chronic, hemolytic anemia. Hepatomegaly of a minimal degree was noted on occasion, but the significance of this finding was not apparent. The most impressive laboratory feature was an eosinophilic leukocytosis which almost invariably reached its peak when the symptoms were subsiding, physical signs were minimal and the x-ray picture of pulmonary infiltrations was well developed. In many cases the eosinophilic leukocytosis was minimal or inapparent at the time the patient presented with symptoms of brief duration. Inevitably there was a progressive increase in the leukocyte count, with a concommitant rise in the percentage of eosinophils. In many patients the total leukocyte count rose from 20,000 to 25,000 per cu. mm., with 30 to 70 per cent eosinophils. The highest recorded count among this group of patients was 40,100 per cu. mm., with 56 per cent eosinophils. The eosinophilia was the last abnormality to disappear during convalescence, and in subjects who could be followed for a month or more after the acute phase an eosinophilia of 10 per cent or more was sustained for several weeks. Marrow aspirates from several patients showed a reactive granulocytic hyperplasia with a marked shift toward immature eosinophils. Approximately one-third of the patients were studied for seroreactivity against a panel of worm antigens, using the indirect hemagglutination

Ascaris

Pneumonia--G+,

and flocc ulation tests. nlost of the patients showed ~~loder-ate reacti\+ty with at least one worm antigen, there was no evidence of selective scrorcactl\ity with Ascaris, and, in general, there was considerable cross reactivity between Ascaris, ‘l‘oxocara and Dirofilaria. The highest hemagglutination titers were obtained with Toxocara. Control subjects showed comparable patterns of srroreactivity; thus there was no distinctive serologic response of aid in the diagnosis of Ascaris pneumonia. Figure 1 illustrates the comparative patterns of seroreactivity for fourteen of the patients whose diagnosis was established or presumptive on the basis of parasitologic findings, and a group of nineteen Saudi PIrabian control subjects, nine of whom were known to have intestinal ascariasis. It is apparent that the distribution of seropositive reactions at variol~s titers is almost identical in the two groups. A majority of patients tested had minor alterations ill thrir serum protein electrophoretic patterns consisting of a relative increase in the beta and gamma globulin fractions. Stool examinations for ova and parasites were carried out in 103 patients, forty-three had Ascaris ova in one or more stool samples. This moderately high frequency of intestinal ascariasis (42 per cent) does not differ significantly from that in a random sample of a similar population group of Saudi Arabians living under the same conditions, but without a history of Loeffler’s syndrome. Follow-up stool examinations during late convalescence, or within a period of two to three months following illness, were exceedingly difficult to obtain because of the logistic problem in contacting patients residing at some distance from ARAMCO medical facilities. However, in 1963 it was possible to follow thirteen patients without evidence of intestinal ascariasis at the time of illness or during early convalescence. Within a six month period, stool samples from all contained Ascaris ova. Among the larger group of patients (log), stools positive for ova of Schistosoma mansoni, S. hematobium or Ancylostoma were found in nine; none were positive for lar\lae of S. stercoralis. The vector for transmission of schistosomiasis is not present in the Eastern Province of Saudi Arabia, but Saudi Arabian immigrants from the Western portion of the country frequently have asymptomatic Ancylostomiasis and strongyschistosomiasis. loidiasis are not indigenous to the Eastern Province, but occur not infrequently among immigrants to this area from the Trucial coast and from Oman. Trichuriasis is very common among VOL.

4.4,

MARCH

1968

Saudi Arabialls, afflictillS an estirnatc,tl 011 ~IJ ~0 per cent of the local inhabitants. Howc:\~r, this infection has IIO significance in tvrlils of ~~~IiIllonary conlplications. Filariasis is not klloM.,-l to occur in Eastern Saudi Arabia, hut is oc.casionally found among immigrants from the t )r:ent. The frequency of Toxocara infection ar~long cloys of Eastern Saudi Arabia has not brekr dt*tcrmined. However, religious tradition alld prrsonal taste interdict intimate contact with these animals; thus incrimination of the caninca ascarid as the etiologic agent of seasonal Locfller’s syndrome seems unwarranted. In slullrllary? the only helminth parasite with the propensitv for pulmonary larval migration, and which is known to infect a significant proportion of the .ocal Saudi Arabian population is A. lrunbricoides. A study of sputum samples from patients with seasonal Loeffler’s syndrome, using standard bacteriologic technics, has yielded an array of microflora, most of which could he considered nonpathogcnic. Prior to 1962 man)- patients were subjected to rigorous study for pulmonary tuberculosis. However, in no instance were typical mycobacteria seen on sputurll smear or isolated on culture of sputum or gastric washings. In a number of instances appropriately stained sputum smears have shown a high percrntagr of eosinophils. Four subjects were found to have typical third-stage larvae of Ascaris in sputum samples and/or gastric aspirates. For screcaning purposes a dissecting microscope is used to survey sputum and gastric aspirates. Structural detail of the larvae is best seen with thr low power objective of the regular laboratorv nlicroscope (Fig. 2).

380

Ascaris

Pneumonia-Gelpi,

Mustafa

TABLE I CLINICALSPIROMETRYIN ASCARISPNEUMONIA Vital Capacity

(L.)

FEVI

X 100

FEV,* Patient

Date

Observed

Predicted

(L.1

21

M.H. 23012

2/25/64 3/3/64

1.63 2.81

3.73 3.73

1.13 2.39

69.5 85.1

M.B. D-55514

415164 4/16/64

0.70 2.43

3.15 3.15

0.64 2.07

90.0 85.0

M.A. 9990

4/25/64 5/2/64

1.22 2.80

3.84 3.84

1.01 2.02

83.0 73.0

* One-second

forced expiratory volume,

Two patients have been subjected to thoracotomy and lung biopsy during early convalescence. At operation a small amount of fibrinous exudate was noted in the pleural cavities, and the affected lungs showed multiple areas of dusky, hyperemic discoloration. On microscopic section of biopsy specimens from the abnormal appearing areas, pathology was minimal. Some interstitial edema was observed, with scattered perivascular accumulation of eosinophils. There was no obvious alveolar exudate, and no granulomas or parasites were found. In Saudi Arabian patients with frank Ascaris pneumonia the chest roentgenogram invariably shows bilateral involvement, with considerable variation in the extent and location of the pulmonary infiltrations. In cases of moderate severity there are usually scattered soft densities several centimeters in size which tend to be discrete and more concentrated in the perihilar regions. In the most severe cases the densities are confluent, and a lobular pattern of infiltration is evident. In the early years of experience with this syndrome a number of patients with an alarming degree of pulmonary infiltration were suspected initially of having acute pyogenic or tuberculous bronchopneumonia, and accordingly were treated with a variety of antibiotics. With the appearance of the striking eosinophilia, prompt subsidence of signs and symptoms, and the day to day variation in the extent and location of pulmonary infiltrates as evidenced by serial roentgenograms, the benign nature of the condition was appreciated and symptomatic measures were substituted for antibiotic therapy. In general it was possible to correlate the magnitude of pulmonary involvement determined by roentgenograms with the severity of symptoms, and in several instances, with the degree of pulmonary functional impairment as determined by clinical

spirometry. Significantly, ventilation studies revealed essentially a restrictive defect with a minor obstructive component, suggesting that bronchitis or bronchospasm was not a major determinant in the production of dyspnea or ventilatory impairment (Table I). The administration of antibiotics had no significant beneficial effect on the course of illness. Symptomatic measures directed toward amelioration of bronchospasm or bronchial mucosal edema, which in many instances included the use of aminophyllin (intravenously and in suppository form) the parenteral administration of epinephrine, the inhalation of nebulized isoproterenol and the oral administration of ephedrine, were without noticeable effect either on the severity or duration of symptoms. Codeine was helpful for control of the irritating, nonproductive cough. In selected cases of unusual severity the use of ACTH as a continuous intravenous drip, or moderate doses of adrenal corticosteroids for several days, produced a dramatic diminution in symptoms, a decrease in temperature and a sharp drop in the eosinophilia, without definite alteration in the x-ray picture. Regardless of management, the majority of patients were asymptomatic within seven to ten days after the institution of outpatient or hospital surveillance, or within two weeks from the onset of illness. An interesting clinical counterpart to Ascaris pneumonia which has been regularly observed among patients with severe, chronic intestinal schistosomiasis treated in ARAMCO medical facilities is a Loeffler’s syndrome appearing during treatment with trivalent antimonials. Within a few days following the initiation of therapy, mild respiratory symptoms consisting of cough and wheezing develop and coincide with a sharp, transient febrile reaction, roentgenoAMERICAN

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MEDIClNE

i&ark

Pneumonia--Gel$,

graphic Gdence of widespread pulmonary infiltratioli and an increasing eosinophilia. The severity of sy~nptoms rarely precludes continuation of treatment, but in many subjects the degree of puhllonar); involvement observed in serial roentzcllograms Inlay be spectacular. CASE

REPORTS

The following cases illustrate variations in severity, x-ray findings, eosinophilic responses, serologic changes and ventilatory impairment among patients with Ascaris pneumonia. These cases can be di\-ided into two groups: those in which the diagnosis was established by the demonstration of L%scaris larvae in sputum and/or gastric washillgs, and a larger number in which a presun1ptk.e diagnosis was based on the observation of a characteristic illness and recently acquired intestinal ascariasis as determined by follow-up stool examinations. The first two cases were selected frown a group of thirteen studied during 1963 and an additional case observed in 1964 in which the patients were apparently free fro111 intestinal ascariasis during the period of pneurllonia and were found to have Ascaris ova in the stool within a two to three month period following illness. CASE 1. This twenty-five year old Saudi Arabian employcac (A.A.. No. 53265) was hospitalized on April IO, 196.5, with a three day history of low grade fever, srvrre cough and anterior chest pain aggravated by cou$ing. The temperature was %3.4’~., pulse 70 prr minute, respiration 18 per minute and blood pressure 120;‘80 mm. Hg. Examination of the chest was negative. ‘l%e white blood cell count was 9,750 per cu. mm.. with 1 per cent eosinophils and

28 per cent lymphocytes. The stool was negative for ova and parasites, and the sputum was negative for bacterial pathogens and fungi. On admission a chest film showed soft. bilateral densities and clouding of the right costophrenic recess suggestive of fluid. Treatment was limited to analgesic and cough suppressant medication. The temperature rose to 1oo.8°F. on the first hospital day. but thereafter the patient remained afebrile. By April 19, 1963, he was completely free of symptoms, and serial chest roentgenograms showed rapid clearing of the pulmonary infiltrates, although one parahilar density still remained at the time of discharge on April 21. 1963, and the white blood cell count Ilad risen to 12,900 per cu. mm., with 56 per cent cosinophils. _A follow-up stool examination on July il, 1963. revealed Ascaris ova. CASI‘. 2. This forty-eight year old Saudi Arabian man (M.A., No. 9990) was hospitalized on April 24, 1964, \vith a two day history of cough, dyspnea and

opprc~ve VOL.

44,

antrrior chest discomfort. His oral temMARCH

1968

M~.\iq/a

3x1

perature was 98.6”r., pulse 100 per minute. rcsp~rations 26 per minute and blood pressure 150 90 mm Hg. Coarse rhonchiZ Ivheezing and inconstant moist rales were heard over both lung fields. ‘1‘11~,\L,lhite blood cell count was 11.400 per cu. mm.. \vit!l 53 per cent segmented neutrophils, 10 per cent eoiinophils and 28 per cent lymphocytes. 1%~ urinalysis M;IS normal and the stool was negative t’or ova and Clarasites. Two successive sputum samples and gastric aspirates were negative for helminth larvae. On April 25, 1964, spirometry revealed marked rc.strictivr ventilatory impairment (Table I) whiclr improved considerably over the follolving week. ‘I‘rcarment \~as limited to analgesic and antihistamine medication. On April 26. 1964, the temperature spiked to ~C)?‘F., but by April 30. 1964, the patient \VL~afrtjrile and his subsequent hospital course was uneventful. Serial chrsr roentgenograrns showed soft, discrete. bilateral pulmonary infiltrates, with progressive clearing which paralleled clinical improvement, The film taken on May 4, 1964, the day of discharge, showed c,omplete resolution of the pulmonary infiltrates. .\ iolloc~-up stool examination on June 27, 1964, revealed Aicaris ova. CASE 3. This thirty-five year old Saudi 12ral,ian man (M.H.. No. 23012) appeared in the outl)atient department on February 17, 1964, with a one da! history of fever, chills and a pruritic urticarial eruption. Temperature at that time was 9!).8°~.. and there were several small wheals on both arms l‘he patient was treated with antihistamines, and over the next five days the eruption recurred togetller with cough and dyspnea of such severity as to require hospitalization. Examination on admission revealed an acutely ill, dyspneic young man. with an oral temperature of 101.8”P., pulse 112 per minute, respirations 40 per minute and I)lood pr’rs’cure ut 118/‘60 mm. Hg. Thrrc was a generalizFt1 <%rytllematous, papular eruption and the pharynx 1~3s markedly injected. There was dullness to percussion at tllc hasr of the right lung and scattered musical ralr\ were heard over both lung fields. The ~1bitt l)lood cell count was 14,200 per cu. mm., \vith 15 per c CI~I band forms, 46 per cent neutrophilic granuloc!-tcs, :!5 IJVI cent eosinophils, 13 per cent lympllocyteh Jnd I per cent monocytes. The hematocrit \vas 40 pt.1 (‘ent and corrected sedimentation rate 6 mm. pt~ iiurlr ‘l‘he urine showed a trace of albumin and a stool specirncn showed ova of ‘l’richuris. Ascaris larvae \vc~reidrntificd in sputum samples and gastric asl)iratc.; suOmitted on P’ebruary 23, 1964, and lTel)ruar\ 14. 1964. A chest roentgenogram showed extrnsivr. bilateral, confluent pulmonary infiltrations. On I:cl)ruary 25, 1964, spirometry showed a marked, primarily ~t.h~rictive, ventilatory defect, with definite improvement over the following week (Table I). Additional ldi)oratory investigations included a negative ~rolop ic test for syphilis. serum total proteins of 6.05 qul. per cent and a serum electrophoretic pattern silo\\ ins an iI1 Ir.ar.tic>ns crease in tile alpha? and gamma qloi)ulili

382

Ascaris Pneumonia-Gelpi,

Mustafa

3A

,3B

FIG. 3. Case 3. A, routine posteroanterior chest film taken on February 3, 1964, approximately eleven days prior to onset of illness. B, chest film taken on day of admission, February 22, 1964. White blood cells 14,200 per cu. mm. with 25 per cent eosinophils. C, convalescent chest film taken on February 29, 1964, showing marked clearing of left lung field. White blood cells 18,500 per cu. mm. with 65 per cent

Treatment was supportive only, with cough suppressants, bronchodilators and antihistamines. By February 25, 1964, the urticarial eruption had cleared, cough had subsided, dyspnea was minimal and the temperature was normal. Resolution of the pulmonary infiltration was evident on February 23, 1964, and progressed rapidly over the next ten days (Fig. 3). The patient was discharged asymptomatic on March 6, 1964. On June 20, 1964, he was readmitted to the hospital with symptoms and signs of an acute intestinal obstruction. At laparotomy, the entire small bowel from the ligament of Treitz to the ileocecal valve contained adult Ascaris worms. Masses of worms had apparently impacted just above the ileocecal valve, and were readily evacuated through two incisions in the ileum. There was prompt decompression of the small bowel above this region, and following enterostomy repair and abdominal wall closure the patient returned from surgery in excellent condition. His postoperative course was entirely uneventful.

CASE 4. This thirty year old Saudi Arabian woman (M.B., No. D-55514).was admitted to the hospital on April 4, 1964, with a three day history of fever, cough, dyspnea and substernal chest pain. The oral temperature was ~OO’F., and there were scattered wheezes and musical rales over both lung fields. The white blood cell count was 16,650 per cu. mm., with 14 per cent eosinophils. The stool was positive for Asearis ova, and the sputum showed typical third-stage Ascaris larvae. Serum protein electrophoresis disclosed a reversal of the albumin-globulin ratio with a moderate increase in the gamma globulin fraction. Two days after admission an intensely pruritic generalized urticarial eruption developed. Microscopic examination of a punch biopsy specimen of a typical lesion disclosed prominent dermal edema, dilated lymphatics and perivenular eosinophilic infiltration. A chest roentgenogram taken on the day before admission showed an extensive pattern of confluent infiltrates in the right lower lung field, with similar although less dense infiltrates scattered over AMERICAN

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OF

MEDICINB

Ascaris the whole left lung,

and a pleural

reaction

Pneumonia--Gel& showed

at the left

TABLE LABORATORY

Maximal Eosinophilia -___Case No.

P.,tirnt

Age (yr.l ;rnd Srx

hIonth Ol Onsrt

\%BCt

% Eosinophils

DATA

Asraris

Larvae

SplIturn

Gastric

A.A. 53265

25, hl

April

12,900

56

. ..

. ..

2

MA. 9090

48, hl

April

16,500

37

Neg.

Neg.

3

M.H. 23012

35, M

Feh.

20,100

70

POU.

4

M.B. D-55514

30, F

April

14,750

44

42, hl

.kpril

15,100

25, F

Feb.

10,850

6

S.H. 1783 F.H. D-12370

* Lakocytcs, VOL.

44,

MARCH

1968

and

in-

L‘S WI L‘tI ASCAKIS

PN?,I,MOW,.\

Date

4/20/63 4/21/63 7j3lj63

Trichlrix Trichuris Ascaris

4/25/64 4/28/64 5/2/64 6127164

Negalivc Trichuris Trichuris Ascaris

4/25/64 5/Z/64 10/24/64

Pas 1: 50 Nrg. Pas. 1

POS.

2/18/64 6/20/64

Trichuris Ascarirt

3/X/64 3/9,‘64

Pos. I: Pas. 1 : 50

1:5 Pos. 1 20

PO%

Neg.

4/j/64

Asrnns

4/R/64 4/16/64

Pas. 1:50 Pas. 1:50

Pas. 1:to PCS. 1:lO

28

Pas.

Neg.

4/5/64 5/la/64

‘Trichilris Ascaris

4/8/64 4/10/64

Pas. 1 :50 Pas. 1

Pas.I:5

23

Neg.

Pos.

2/22/65

Trichuris Ascaris

t Adult

per cu. lnm.

infiltration,

II

IN PATIEN

1

5

pcril)ronclrial

CASE 6. ‘l‘his twenty-five year old Saudi Arabian housewife (F.H., No. D-12370) was seen in the clinic on February 20, 1965, with a one day history of anterior chest pain, a dry cough and a generalized cutaneous eruption. The oral temperature was 99"~.. pulse 120 per minute and blood pressure 110 ‘80 mm. Hg. There were scattered urticarial lesions over the trunk and extremities. There were no ahnormal chest findings. The white blood cell count was 10,850 per cu. mm., with 23 per cent eosinophils. A rocntgenogram of the chest showed increased t)ronchovascular markings, and a stool examination revealed _4scaris and Trichuris ova. The patient ~\ar treated symptomatically with salicylates and antihistamines, and followed closely I\-ith successive clinic visits. Chest pain and cough continued, and by February 3, 1965, she was moderately dyspneic. On this date the oral temperature was 99’F., pulse 120 per minute, respirations 36 per minute and blood pressure 130; 70 mm. Hg. There were loud expiratory- wheezes over both lung fields. An injection of 0.5 ml. of epinephrine (1: 1000) provided some relief from respiratory clistress. Over the following two days she experienced recurrent urticaria, her cough continued and dyspnca subsided. On February 28, 1065, a gastric astrirate revealed typical third-stage Ascaris larvae. Late follow-up on March 10, 1965, indicated ttrat sire was

CASE i. This forty-two year old Saudi Arabian employee (S.H., No. 1783) was admitted to the hospital on April 3, 1964, with a five day history of nonproductive cough, malaise and generalized myalgia. For three days preceding admission he noted substernal pain, mild dyspnea and feverishness. Physical examination revealed an acutely ill middle-aged man with a paroxysmal, uncontrollable cough. The oral temperature was loooF., pulse 95 per minute, respirations 24 per minute and blood pressure 130/80 mm. Hg. ‘[‘he tongue was coated and there was intense injection of the nasal and pharyngeal mucosa. Breath sounds were decreased over the bases of both lungs, and there were scattered inspiratory wheezes over both lung fields. The white blood cell count was 10.400 per cu. mm., with 2 per cent band forms, 71 per cent segmented neutrophils, 9 per cent eosinophils and 18 per cent lymphocytes. The urinalysis was normal and the stool showed ova of Trichuris only. A sputum sample taken on April 4, 1964. showed one larva of .\scaris> but on the following day numerous larvae were observed in the sputum. Gastric aspirates on three successive days were negative for larvae. Successive stool examinations were negative for Ascaris. .\ chest roentgenogram taken on admission

AND

patchy

creased bronchial markings. The patient r**craivtbd supportive treatment only, and follo\ving a temp~:r+ ture elevation to 100.6”~., on the tlrird hospital tlav, he experienced a rapid subsidence in Iris i>nrptoms and an uneventful lrospital course. A MO\\-rtp stool examination on hfay 18, 1964, revealed A>c.aris IW~.

costophrenic angle. Spirometry on April 5, 1964, demonstrated marked ventilatory impairment of the restrictive type (,‘l‘able I) which improved markedly over the next eleven days. Serial chest roentgenograms showed rapid clearing, the cutaneous eruption subsided in one da>-, the remainder of the hospital course was uneventful, and the patient was completely asymptom&: at the time of discharge on April 13, 1964.

EPIDEhIIOLOGIC

?iHi

A44u.s/aJ~~

worms.

:200 50

:50

1’0s. 1:lO Pas. 1 : 5

1’0s. :

Pos. 1:lO

384

Ascaris Pneumonia-Gelpi,

schistosomiasis have been observed with repeated episodes of Loeffler’s syndrome, during successive, widely spaced courses of treatment with trivalent antimonials. Symptoms and physical signs have tended generally to be less severe than those found among the patients with Ascaris pneumonia.

5ofi

Jan.

Feb. Mar

Apr

May

June July

Aug.

Sept. Oct.

Nov. Dec.

Fro. 4. Seasonal incidence of Ascaris pneumonia, 19541965. 108 cases. completely cough.

Mustafa

without

symptoms except

for a mild

All but one patient had an illness of such severity as to warrant hospitalization. Three patients exhibited cutaneous reactions during the course of illness and were found to have Ascaris larvae in sputum or gastric washings. Three patients with proved larval ascariasis failed to show a hemagglutination titer for Ascaris of greater than 1: 50 during illness. Pertinent data relating to hematologic changes, parasitology, serology and epidemiology for this group of six patients are summarized in Table II. This group of patients is quite representative of the larger number of subjects with seasonal Loeffler’s syndrome. Most of the patients had an illness of mild to moderate severity and were managed on an outpatient basis. The height of the eosinophil response did not correlate well with the severity of the illness; the first two patients (Cases 1 and 2), in whom the illness was moderately severe, had maximal eosinophilic leukocytosis comparable to that exhibited by the succeeding three patients (Case 3, 4 and 5) in whom the illness was severe. These six patients illustrate particularly well the characteristic seasonality of Ascaris pneumonia. All subjects were seen within a two and a half month period, from mid-February to late April. This seasonal incidence can be more readily appreciated by reference to Figure 4, which shows the seasonal incidence pattern for the larger group of 108 subjects. The following case report is an excellent example of Loeffler’s syndrome observed during treatment of Manson’s schistosomiasis, and demonstrates a close clinical parallel with the usual course of Ascaris pneumonia. Patients with

CASE 7. This fourteen year old Saudi Arabian boy (A.S., No. D-40908) was admitted to the hospital on September 6, 1966, with a two week history of upper abdominal pain. He had been treated as an outpatient in 1962 for intestinal schistosomiasis, and subsequently had returned to an area (Najran) in Southwest Arabia endemic for Manson’s schistosomiasis. Physical examination revealed a frail, prepuberal boy of short stature, weighing 61 pounds. There was slight pallor of the skin and the mucosa, but essential abnormalities were confined to the abdomen. There was moderate abdominal distention, a rounded liver edge was palpable 8 cm. below the right costal margin and the tip of the spleen was readily palpable during quiet respiration. Hemoglobin was 11 .l gm. per cent, hematocrit 34 per cent, corrected erythrocyte sedimentation rate 30 mm. per hour, and the white blood cell count was 6,400 per cu. mm., with 2 per cent band forms, 46 per cent segmented neutrophils, 6 per cent eosinophils, 45 per cent lymphocytes and 1 per cent monocytes. The urinalysis was normal and the urine sediment negative for schistosome ova. The stool was repeatedly positive for ova of S. mansoni. The serum glutamic oxalacetic transaminase was 720 units and the serum total bilirubin was 0.72 mg. per cent. A chest roentgenogram showed increased bronchovascular markings but was otherwise within normal limits. The baseline electrocardiogram was normal with occasional atria1 premature beats. A needle biopsy specimen of the liver showed sections with prominent interlobular fibrosis and focal granulomas containing schistosome ova. Treatment with Stibophen@ on alternate days was initiated on September 17, 1966, and followed by development of a transient cough and febrile response, widespread pulmonary infiltrations and a progressive rise in the eosinophil count (Fig. 5). Minor changes in the ST-T waves were observed on serial electrocardiograms. The patient was discharged essentially asymptomatic on October 20, 1966, after a dose of Stibophen equal to 540 mg. of trivalent antimony had been given over a period of thirty-one days. COMMENTS It has long been suspected that larval ascariasis is one of the most common causes of Loeffler’s syndrome, and this association has been emphasized in a number of European publications over the past thirty years [YZ-ZO]. Interestingly, exAMERICAN

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ITrc. 5. CLse 7. .\ posteroanterior c:lv\l 1111l, taken on Scptembcr 4, 1966, two days prior- IO hospitalization, showing a slight increase nil bronchovascular markings. B, chest tilm t.+h<,n on September 23, 1966, after cumulati\,e dose of 112 mg. trivalent antimony. \\Fhitc blood cells 6,800 per cu. mm. with 13 per cent eosinlophils. C, chest film taken on October 1, 1964, after cumulative dose of190 mg. trivalent antimony. Scattered, confluent, soft densities throughout both lungs, particulariy dcnw o\ or left mid-lung field. White blood cells lCl.iiK~ cu. mm. with 21 per cellt eosinophils.

pcrilllt,ntal ascariasis ii1 t’nc guinea pig [21] sho\\s :I close parallel with the clinical pattern descriI)cd in a ~lrunbcr of reports of isolated cases of larval ascariasis in 1nan, and to the clinical pictur;, cyhibited by Saudi Arabs with the seasonal l,o~tRer’s syndrome. The delayed eosinophilic response in Ascaris pneumonia has been noted by European workers [78,22,23], and Locfflc~r has pointed out the characteristic seasonal illcidrnce [22]. In Europe the maximum numb(~r of cases occurred during the summer and rarly alltlnnn. Ascaris pneumonia is thought to be rather freclrlent in certain districts of Bavaria and Northt,rn Switzerland brcallse of the practicr of usi!?q “night soil” for- fertilization

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of small vegetable gardens [24], and institutional and family “micro-epidemics” have been reported from these areas [25,26]. Interesting reports of a seasonal Loeffler’s syndrome appearing among foreign residents in Shanghai [27,28], and thought to be due to sensitivity to Privet pollen, show close clinical similarity to the Ascaris pneumonia described by European workers, and to that believed to occur among Saudi Arabs. Moreover, “privet cough” has a short seasonal incidence. The majority of the cases develop during the months of June and July. In 1948 an epidemic of Loeffler’s syndrome, which affected seventy-four peoplr. appeared

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among a group of Israeli workers excavating a subterranean canal in Jerusalem [29]. Helminth parasites could not definitely be incriminated as a cause for this outbreak, and epidemiologic studies were inconclusive. However, the clinical course was identical with that encountered in Saudi Arabian patients, including the observation of transient skin eruptions in four of the Israeli patients. Since this report there have been additional well defined outbreaks of respiratory illness conforming to the criteria for Loeffler’s syndrome, and in which a strong case could be made for Ascaris etiology. Thus Patz [30] described a small epidemic of Loeffler’s syndrome which involved twelve adult Bantu patients and began six to eight days after a “beer party” which all attended. In this group, wheezing was a prominent feature of the acute illness, and the x-ray evidence of pulmonary involvement tended to be much more extensive than the physical signs would suggest. Eight patients had Ascaris ova in stool samples during the acute illness, and three patients with negative stool examination were found to have intestinal ascariasis eight to sixteen weeks later. Barlow et al. [31] reported another beer party epidemic in which thirteen subjects had symptoms five to seven days after consuming home-made beer from the same source. Interestingly, all these patients had transient skin eruptions and ten subjects had Ascaris ova in the stool during their illness or within a period of one to four months after their illness. The counterpart to Ascaris pneumonia which fulfills all the clinical criteria, and which serves as an experimental model for Loeffler’s syndrome in man, can readily be produced in many patients with chronic Manson’s schistosomiasis during treatment with trivalent antimonials. Low and Newham [32] were perhaps the first to report the eosinophilic response in schistosomal infections during treatment with tartar emetic. Mainzer [33] suggested that a brisk eosinophilic response during a therapeutic trial of antimonial drug may be equivalent to the Herxheimer reaction, and that it probably occurs regularly in patients with intestinal schistosomiasis treated with tartar emetic. The phenomenon of widespread, transient pulmonary infiltrations with eosinophilia during treatment with antimonial drugs is ignored in textbooks of tropical medicine, but is familiar to many physicians practicing in areas endemic for schistosomiasis. Mohr [34] believes

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that the height of the eosinophilic response during treatment of intestinal schistosomiasis may be a rough indicator of the severity of infection in terms of the number of viable adult parasites, and that the reaction probably results from liberation of antigenic materials from dead and dying parasites. Although deposition of Schistosome ova in the lung occurs regularly at certain stages of infection [35], and incites an intense granulomatous reaction with local eosinophilic infiltration, the effect of antimonial drugs is on the adult worm. This raises the question of whether certain patients with advanced schistosomiasis may have aberrant localization of some adult parasites in the lungs; lung shifts of adult schistosomes have been demonstrated in experimentally induced infections [36], but this phenomenon is believed to occur rarely if at all in natural infection of man. In summary, the striking similarity between Ascaris pneumonia and Loeffler’s syndrome observed during the treatment of schistosomiasis may be an indication of hypersensitivity to the particulate antigens in pulmonary ascariasis and to soluble or microparticulate antigens in schistosomiasis. The mechanical effects of migrating larvae are likely to account for the hemoptysis and a proportion of the bronchial irritation which is often noted during Ascaris pneumonia, but can hardly explain the extensive pulmonary involvement which is often seen in these cases. The limited biopsy material available from the reported study, the disproportion between the physical findings and x-ray signs, and the rapidly changing picture of the pulmonary infiltrates all suggest that the pulmonary reaction is that of intense congestion and/or edema, and that cellular reaction and alveolar exudate is minimal. This is consistent with a hypersensitivity reaction. Unquestionably, Ascaris antigens are extremely potent sensitizing agents and will cause urticarial reactions and asthmatic symptoms in nonatopic subjects working in laboratories in which Ascaris worms are dissected and processed [37,38]. In a limited number of cases of ascariasis in man, at the stage of larval migration, a circulating antigen reacting with high titer antiserum to a polysaccharide-rich component of adult whole worm extract has been isolated by agar gel precipitation [39]. Such a finding may have considerable significance explaining certain clinical features of Ascaris pneumonia, in particular, bronchospasm and transient urticarial AMERICAN

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Ascaris Pneumonia-Gelpi, eruptions. These phenomena are characteristic of atopic reactivity and imply the presence of reapill type antibody. It is also possible that the preserice of circulating antigen may modify the serologic reactivity of the patient, resulting in low titer reactions to Ascaris antigen, as employed in the indirect hemagglutination and bentonite flocculation tests. Thus the ambiguous pattern of low or moderate titer cross reactivity to Ascaria, Toxocara and Dirofilaria observed in the reported study could result from in uivo selective adsorption by circulating Ascaris antigens. However, serum frorn the control group showed comparable reactivity to the same panel of antigens, which could be interpreted variously as an indication of almost universal and repeated Ascaris infection in the population of controls, lack of serologic specificity of the test antigens or a loss of circulating antibody to Ascaris associated with a hypersensitivity response in the patients. The absence of an apparent convalescent antibody increase in the few patients from whom it was possible to obtain additional serum samples is of uncertain significance, but because of the timing in respect to duration of illness this finding could still be consistent with the concept of antibody depletion following a hypersensitivity reaction. With the possible exceptions of the latex slide flocculation test in the diagnosis of trichinosis, the indirect hemagglutination test using an extract of Dirofilaria immitis for the diagnosis of tropical eosinophilia [@I, and the complement fixation test and indirect hemagglutination test in the diagnosis of hydatid disease [41], no truly sensitive or specific serologic tests have been developed for clinical application. Until dependable serologic procedures are generally available, the clinician must depend upon meticulous parasitologic studies in the diagnosis of Ascaris pneumonia. The demonstration of typical third stage larvae in sputum specimens and/or gastric washings affords diagnostic confirmation in the suspected case. On the basis of experience in our laboratory, few patients are likely to provide this diagnostic certainty. In a highly sensitized subject, a few larvae may be capable of inciting a rather intense and widespread pulmonary reaction, and the local inflammatory response may serve to inhibit or prevent larval migration. Under these circumstances the emergence of several larvae into the bronchial tree could readily be overlooked despite repeated studies of sputum and gastric VOL.

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aspirates. ‘l’he appearance of ,-iscaris o\ a in the stool several weeks after a ty pica1 illness ui 2 slrbject with negative stool examinations tiltring the acute phase and early- convalescence. IS strong presumptive evidence of Ascaris pne!anionia. Of interest, and possible practical application in the retrospective diagnosis of Ascaris pncumoina, is the fact that the development of the foltrth stage larva to the adult form occurs within a few weeks in the small bowel of the human host. Interruption of this stage by administration of a vermifuge may prov-ide evidence of recent infcctioll by the appearance of iminature adult forins of the parasite in the stool. Ascaris pneumonia is not likely to be confused clinically with tropical eosinophilia. In the latter condition the course is typically chronic, the pulmonary infiltrates tend to be small, discrete and of a miliary distribution, the response to the administration of arsenicals or diethylcarbamazine is dramatic, and there is usually strong seroreactivity to extracts of Dirofilaria imrnitis /3.!--~31. In areas in which ankylostomiasis and ‘or strongyloidiasis as well as ascariasis are prevalent, Loeffler’s syndrome may ob\.iously, result from larval migration of diverse etiology. ‘I‘oxocara infection, producing the visceral larva migrans syndrome, may be associated with a spectacular eosinophilic leukocytosis and occasional pulmonary involvement [45,46]. However, this condition is rarely seen in adults, and the essential clinical feature of adenopathy, hepatomcqaly and rather marked hyperglobulinemiS~ are notably lacking in Ascaris pneumonia. In certain endemic areas paragonimiasis, clonorchiasis and fascioliasis conceivably could be confused with larval ascariasis. However, in the former conditions the course is protracted, and in the case of infections with Fasciola hepatica and Clonorchis sinensis hepatobiliary involvement is a distinguishing feature. A number of drugs have been incrirnilratrd in the etiology of Loeffler’s syndrome, notably antituberculous medications [47-&l, but also penicillin [50,51], sulfonamides [52], nitrofurantoin [53] and mephanesin [54]. In the isolated instance of Loeffler’s syndrome superimposed on another illness, drug sensitivity- must be considered. In asthmatic patients moderate eosinophilia may develop coinciding with exacerbations in symptoms, but the previous medical history and the absence of pulmonary infiltrations serve to

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separate these patients from those with Loeffler’s syndrome. There is a small group of patients with so-called intrinsic or maturity-onset asthma who tend to have an inexorable and complicated downhill course characterized by frequent febrile episodes, recurrent pulmonary infiltrations, sustained eosinophilic leukocytqsis and evidence of polysystemic involvement, including cardiac and renal disease [55-581. At the outset, some of these patients may present with a clinical picture indistinguishable from that in classic Loeffler’s syndrome. However, the multiple recurrences, chronic eosinophilia and poor general health of the patients indicate a more sinister problem and suggest the possibility of a disseminated vasculitis. A few epidemiologic considerations with respect to Ascaris pneumonia and intestinal ascariasis merit comment. All the patients whose case histories were included in this communication were adults, and the larger group from which this series was collected were all adults with two exceptions. Children should have possibly even a greater potential for infection with Ascaris than adults, but it may be that the expression of Loeffler’s syndrome from a relatively small inoculum of Ascaris ova requires repeated previous infections, and the development of the hypersensitive state. A stepwise increase in hypersensitivity could be enhanced by climatic factors which favor cyclic infections with Ascaris. The climatic situation which prevails in Eastern Saudi Arabia is such that the cycle of infection is probably completely interrupted from May through October because of high temperatures, lack of shade and sandy soils, all of which preclude the survival and/or embryonation of Ascaris ova. This hypothesis can be supported by data reported elsewhere [I] which clearly show cyclic fluctuations in the parasitic indices for Ascaris infection among Saudi Arabs. The peak incidence of intestinal ascariasis follows the sharp seasonal increase in Loeffler’s syndrome by one to two months. It is tempting to speculate that in areas in which conditions are optimal for year-round survival of Ascaris ova, the population may be desensitized by repetitive infections. Conversely, it might be predicted that in relatively unhygienic settlements, where the infectious cycle is interrupted by inclement winters or torrid summers, Ascaria pneumonia is prevalent. Acknowledgment: We are indebted to Dr. Irving G. Kagan, Chief of the Parasitology Unit, Com-

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municable Disease Center, special serologic studies.

Atlanta,

Georgia,

for

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20. ~:HI..RI. Il. Lurch .\skaridrnbcfall verursachtes llllchtigcs rosinophiles I,ungeninfiltrat bei mehr<‘rrn Familirn mit Gliedcrn. %/.rrhr. A~rztf. Forthi/d., 48: 442. 1954. 2-. L~(:I,L.. D. Ocdrma pulmonia allergicurn vernale. .\ ww discasr of the lungs. C:hinrs~ ILf. ./., 49: 1162, l’i35. 28. ENW .I.. I). epidemic of ‘acute eosinophilic pneumonia’ following ‘becAr drinking’ and probably dllr to infestation with Ascaris lumbricoides. South .*l/rican .If. .J., 35: 390, 1961. 32. I.cw. G. (1. and NEWHAM, II. B. G. A series of cases of bilharziasis treated by intravenous injections of alltimonium tartratum. Lam&, 2: 633, 1919. 33. MAINY.ER. F. Keactional increase of the eosinophil proportion of the blood in schistosomiasis subsequent to antimony trcatmt’nt: A phenomenon in support of the recognition of latent infection. ./. 7‘rq. .Wrd., 42: 86, 1939. 34. MOHR. \Y. Etioloe;ic drs hypcreosinophilies des pays chauds. Hull. SOC.path. mot., 55: 546, 1962. 35. I:.ARID. 1.. GREEK. .J. \I:., ISIIAK,K. G., EL NAGAH, .\. MM.. LE GOLVAN. P. C. and MOUSA, A. H. ( Chronic pulmonary schistosomiasis. Am. Rea. 7‘ub~~rr. e Pull?l. Dis.. 79: 119, 1959. 36. I leu~r r, R. and GILL, E. The “lung shift” of .)ihz~fo.~nrarr~~nmniin mice following therapy with tartar cxxtic or Miracil I>. ilm. .I. ?;@I. Med., 9: 402, 1960. 37. GIKGES, li. Pathogenic factors in ascariasis. J. Tro,b. .\lPd.. 37: 209, 1934. 38. .\NDRLWX .I. M. Parasitism and allergy. J. Parasitol., 48: 3, 1962. 30. K1N.x. X. H. Seminar on immunity to parasitic tl~lminths. v. .\ntigrns. l%,bcr. Parasitol., 13: 45, 1963.

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42. (:01.1 INHO. .\.Tropical cosiilophilia: (:lilli( ~1. tlL(.r‘tpcutic. and cstiologic considcratioils. I,s1x~rirn~~nt;rI work. I&I. Znt.Med., 44: 88, 1950. 43. H!ZXLIN(XK, 1-I. Pulmonary changrs 111 tropical cosinophilia. Hrit. ./. Radial.. 36: 889. 1063. 44. DoNOHI.OH, I>. L. Tropic,al cosinophili;i. .\n vtioloyic inquiry. .\‘rzc,l?ngland .1. .\lcd.. 209: 13s;. 1003. 45. BEAVER. P. C. Parasitological rr\it.w;. I AXa n11gram. Eupo. ~ara~z/cil.,5: 58’. 1056. 46. SNYDER. C. H. Viscrral larva migrates. I~rrr y~rs rxpcricncc. Prdiatrics, 28 : 85, 190 1. 47. U’AKRI~C:, F. C. and HOWLI’.I.I. K. S. .\llrrgic rcxtion to para-aminosalicylic acid. Krport of SCWII CRSCS, including one case of I,otffIPr‘s ~yndromc. ..l,,i. IiW. 7‘uherc., 65: 235, 1952. 48. Cu 1HR~RT,K. J. LorIfler‘s syndromr occurrinK durirlg streptomycin alld P..\.S. therapy. HlY/,.W. ./.. 2: 398. 1954. 49. \Vor.n. 11. E. and ZAHN, D. \V. .\llergic I I,ocfflrr’s) pneumonitis occurring during arlti-tnberculous chemotherapy. Am. Kw. Tubrrc.. 74: 445; 1956. 50. FALR, M. S. and NEWCOMER, 1’. I_). Locfflc:r svndromr ; occurrence in two patients trcatc.d with penicillin in oil and wax. ./.:g..\f.;l.. 141: 21. 1940. 51. KEICHLIN, s., LOVCLESS, M. I I. and LhXF., 15.c;. I,ocftlrr syndrome following pl-rricillitl tllcrapy. Atrri. Inl. Mrd., 38: 113, 1953. 52. KLINGHOE.FER, J. F. Loeffler syndrome following usf‘ of vae;inal cream. Ann. Znt. &fed., 40: 343, 1954. 53. MUIR, I). C. F. and SL.AN.~ON,.I..\..\llcrgic pulmonary infiltration due to nitrofurantoin. /&i/.,W. .J.. 1: 1072, 1963. 54. KODMAN, T., FRAIMOW, L2:. and ~~WXSON. I<. I,ocfflrr’s syndrornc. Report of a case associatrd with administration of mephancsin carbamate (Tolscram). Ann. Inf. Mrd., 48: 668. 1058. 55. HAKKAVY, J. Vascular allergy. Pathog-enesis of bronchial asthma with recurrent pulmonary infiltrations and eosinophilic polyserositic. Arch. 17~. ‘Med.. 67: 709, 1941. 56. BEKCXRAND, H. Morphological eyuival~nts in polyarthritis rheumatica, periartrritis nodosa, transient caosinophitic infiltrations of the lung and other allergic syndromes. J. Path. 2 Rnc/., 5%: 399. 1946. 57. INCAPR~RA, F. P. Pulmonary cosinophilia. ,4n,. Kw. Resl,. IIis., 84: 730, 1961. 58. hVDHOLM, B. and THULESTUS, 0. Blood cosinophilia and transitory pulmonary infiltrations assoriatcd with cardiac involvement. .1. .-lllrr<1. 32: 483, 1061.