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Bilharzial asthma
25}1 TRANSACTIONS OF THE ROYALSOCIETY OF TROPICAL MEDICINE AND HYGIENE.
Vol. XXXII.
No. 2. August, 1938.
BILHARZIAL ASTHMA. BRONCHIAL ASTHMA IN SCHISTOSOMA INFECTION. BY
FRITZ MAINZER, M.D., Director, Department of Medicine, the Jewish Hospital, Alexandria, Egypt.
I.--INTRODUCTION. SUAREZ (1930) reported a case of infection with Schistosoma mansoni which showed the symptoms of bronchial asthma. He did not, however, consider the disease to be asthma in the proper sense, i.e., an allergic syndrome due to humoral action, but as a complex of manifestations brought about by pathological changes due to the presence of the parasite or its eggs in the lungs. This is indicated by the title of his paper: " Schistosomiasis of the lungs simulating bronchial asthma." Another case belonging to this category which could be definitely identified (MAINZER, 1935 and 1936) as bilharzial asthma from the description (with pulmonary involvement proved by X-ray) was published by BRUGSCH (1931) under the title, " Persistierende Eosinophilie mit Milzvergroesserung." The author, however, did not realise the nature of the disease. We ourselves have reported a third case of this kind (MAINZER, 1935 and 1936), when we were concerned with chronic isolated pulmonary bilharziasis, i.e., a form of bilharziasis not accompanied clinically by local manifestations of the disease in other organs. Being now in a position to add to these
9~54
BILHARZIAL ASTHMA.
observations two further cases, we propose to discuss bilharzial asthma in the present paper. I n contrast to SUAREZ' view bilharzial asthma has no connection with the a n a t o m i c a l p u l m o n a r y disease due to Schistosoma haematobium or mansoni to .which we have devoted four reports (MAINZER, 1935 and 1936; MAINZER & YALOUSSlS, 1936 ; and MAINZER, in the press) ; it is, however, as can be seen by the following observations a real allergic asthma induced by the products of metabolism of the parasites ortheir eggs whether these are present in the lungs or in any other organ. T h a t in such cases the X - r a y may reveal bilharzial involvement of the l u n g s - - a s in the cases reported by SUAREZ (1930) and BRUGSCH (1931); as well as in two of our three cases--does not contradict this view. I n cases of bilharzial asthma p u l m o n a r y involvement is naturally no less frequently met with than in other cases of schistosomiasis, in which, according to our roentgenological examinations (MAINZER, loc. cit.) it is the rule to find it even if there are no clinical s y m p t o m s of lung invasion. I n the asthmatic cases which we are discussing here the lungs are clinically the centre of interest and are examined by X - r a y more frequently than in other cases of bilharziasis where clinical s y m p t o m s do not direct attention to the respiratory tract. II.--CAsE HISTORIES.
Case 1.--G.A. 3608/34. Clinical observation : 3rd--15th November, 1934 (prior to that time he was an outpatient). The patient, a schoolboy, aged 10½, son of a police officer, had been suffering for 2 years from severe attacks of febrile asthma. The temperature used to rise to 40 ° C., there were severe paroxysms of difficult expiration, with loud and audible whistling. There was also much cough, but without expectoration. On occasions, these attacks were accompanied by urticarial rashes. Nine months previous to admission the patient had had an " attack of dysentery," but neither the microscopical examination nor the culture made in our laboratory revealed the presence of either amoebae or dysentery bacilli. Emetin treatment cured the disease within 3 months. In January, April and May, 1934, attacks of haematuria of short duration appeared the laboratory examinations, however, revealed only a few red blood corpuscles. No eggs of bilharzia were detected. In May, 1934, a rectal polypus which had drawn attention to itself by bleeding had to be removed ; its histological examination, however, was omitted. The parents who, on account of the frequent febrile attacks, suspected pulmonary tuberculosis, consulted a lung specialist who was able to dispel these suspicions as being unfounded. Nevertheless it was not possible to identify the disease or carry out any treatment. At that time the boy's condition was the same as when he was admitted to hospital (3rd November, 1934). He was in excellent general condition. There was no fever. The lungs showed the picture of an asthmatic attack: marked emphysema, the lung boundaries low in position with little movement, hypersonorous percussion note, the respiratory sound soft, expiration prolonged, abundant wheezing and whistling everywhere. There was a history of frequent urticarial rashes. The liver as well as the spleen were markedly enlarged and firm. The liver extended below the costal margin by a hand's breadth, the spleen by the width of three fingers. These findings had been already observed in X-ray examination performed previous to this. On rectal examination a new polypus was palpable.
FRITZ MAINZER.
255
TABLE I. BLOOD CELL COUNTSOF CASE I (G.A.). ~
m
i Haemo- ErythroDate. ; globin cytes. (Sahli) Millions. _ _ i Per cent__ _ _ _ _
Neutrophils. Leucocytes.
Lymphocytes. Per
Eosinophils.
! Monocytes. Per cent.
Batonnets. Per cent.
I 1,130
6
1
i' 6,810 25,400 12,350 10,140
--1 1
~
Per cent.
total.
cent.
Total.
cent.
7,500 22,700 34,800 19,600 15,600
12 28 13 8 14
900 6,360 4,520 1,570 2,180
66 42 14 28 17
4,950 9,530 4,870 5,490 2,650
15 30 73 63 65
17,600 17,000
13 11
2,290 1,870
36 37
6,340 6,290
49 48
8,620 8,160
2
17,100 11,500 17,000 10,100
14 13 13 23
2,390 1,500 2,210 2,320
35 34 45 35
5,990 3,910 7,650 3,540
49 49 40 38
8,380 5,640 6,800 3,840
1 4 2 4
2.2 9.2 16.2 23.2 2.3 9.3 16.3 23.3 13.4 20.4 27.4 4.5 11.5 18.5 25.5 1.6 8.6 17.6 25.6
10,500 6,500 6,900 5,000 4,800 7,500 6,500 7,400 6,200 5,800 6,800 8,300 9,100 16,900 12,900 15,990 12,200 20,000 15,700
23 24 24 23 30 28 22 37 32 20 27 27 15 11 8 11 13 13 14
2,410 1,560 1,160 1,150 1,140 2,080 1,430 2,740 1,980 1,700 1,840 2,240 1,370 1,860 1,030 1,720 1,590 2,600 2,200
52 57 52 64 42 51 62 31 47 49 42 38 38 46 38 30 47 23 31
5,460 3,710 3,590 3,200 2,020 3,830 4,030 2,290 2,910 4,180 2,860 3,150 3,460 7,780 4,900 4,680 5,740 4,600 4,870
23 18 20 ii 23 20 14 29 19 29 30 34 46 42 50 58 38 6~ 54
2,410 1,170 1,380 550 I,I00 1,500 910 2,150 1,180 2,670 2,040 2,820 4,280 7,090 6,450 9,050 4,640 12,800 8,480
2 1 3 o 4
29.6 6.7 13.7 20.7 27.7 3.8 17.8 31.8 7.9 14.9 21.9 5.10 19.10 29.10 25.11 11.12 14.12 1936. 30.1
14,200 12,000 15,700 9,500 6,500 6,100 5,700 5,400 8,300 5,200 5,800 5,100 5,700 5,200 5,600 7,000 5,500
10 18 2O 19 25 29 25 31 29 42 22 35 32 41 37 37 41
4,570 2,160 3,140 1,810 1,630 1,770 1,430 1,670 2,410 2,180 1,230 1,790 1,820 2,130 2,070 2,590 2,260
35 28 34 34 49 45 65 54 58 47 71 46 41 44 52 52 48
4,970 3,360 5,340 3,230 3,190 2,750 3,710 2,920 4,810 2,440 4,120 2,350 2,340 2,290 2,910 3,640 2,640
52 52 46 47 25 24 10 14 12 7 7 16 24 10 11 6 8
5,800
33
1,910
62
3,600
1934. 26.4 3.11 7.11 16.11 3.12
Total
Remarks.
i
77 83 81
15.12 27.12 1935. 2.1 10.1 18.1 26.1
4.3 4.1 4.2 -
-
-
-
--
--
----
--
--
-
! 81t :4,m o 6;1}34:
2
!~
-~1
J
--
]3.1.35 to 23.1.35 : ~" t r e a t m e n t with J fuadin (35 c.e.)
!
at
e t wit}
neostibosan
1 1
I
2 2 2 2 1 1 1 1 4 1 2 i
3 1
1
---
7,380 6,240 7,220 4,470 '~ 1,630 1,460 570 760 1,000 360 410 820 1,370 520 620 420 440
3 3 5 -5 3
------
120
3
--
1
1 2 1 1 4
] 1 3 to 25.6.35 :treat~ ment with fuadin J (35 c.c.)
FIG. 1
FIG. 2. Fro. l.--Case 1. Radiograph of Lungs Oct. 22nd, 1934 (before admission to hospital). FIG. 2.--Case 2. Radiograph of Lungs Nov. 2nd, 1937. To face p.
254.
FIO. 3. FIG. 3,--Case 8.
Radiograph of Lungs.
Dec. 1st, 1937.
356
BILHARZIAL ASTHMA.
The blood picture showed--in agreement with a previous count (26th April, 1934, cf. Table I)--a leucocytosis of 22,700 leucocytes, 30 per cent. of which were mature eosinophilie cells. A few days later 34,800 leucocytes were counted, 73 per cent. of which were eosinophils. On microscopic and cultural examination of the blood, urine and stools, no suggestion of a parasitic disease was found. In the sputum a large number of eosinophilic cells was detected, but neither pathogenic bacteria nor eggs of parasites. The radiograph of the lungs taken before admission (22nd October, 1934 ; Plate Fig. 1) showed nothing particular except some increase of striations and emphysema. Later radiographs (26th January and 22nd May, 1935) showed further retrogression of the emphysema. The assumption that this kind of asthma was caused by anaphylactogenic substances of bilharzial origin was made evident by the presence of many of the classical phenomena of bilharziasis of the bladder in spite of the failure to detect eggs in the urine or faeces. There was the pathognomic haematuria, and the dysentery which was favourably influenced by emetin in spite of absence of amoebae. There was, moreover, eosinophilia and urticaria (as have been described as typical of the initial stage of schistosomiasis), enlargement of liver and spleen (which occurs, as a rule, in the type of infection occurring in the Far ]East), as well as repeated formation of intestinal polypi characteristic of intestinal bilharziasis. In view of these facts antimony was given, neostibosan (8th November to 6th December, 1934) and later on fuadin (two series, 3rd to 23rd January and 13th to 25th June, 1935) the latter being an incomplete series of injections. The asthmatic attacks definitely disappeared from the beginning of the first series of injections. Urticaria occurred several times between the first and second series, but not again afterwards. The liver and spleen regained their normal size, the blood picture approached the normal (as shown by Table I), a somewhat increased number of eosinophilic cells persisting, as usual, while the total leucocyte count became normal.
Summary.--The case considered here is one of bilharziasis of the bladder and intestine accompanied b y m a r k e d enlargement of liver and spleen and a high degree of eosinophilia. Eggs of parasites could not be detected either in the urine or in the stools. Adequate a n t i m o n y t r e a t m e n t effected complete cure. T h e disappearance of the asthmatic attacks effected b y the a n t i m o n y t h e r a p y proves that these were a consequence of the bilharzia infection. T h a t they were not due to p u l m o n a r y i n v o l v e m e n t b y the parasite, i.e., a local disease of the lungs (as according to SUAREZ) is s h o w n b y two facts : - (1) T h e X - r a y (Fig. 1) reveals the lungs to be free f r o m bilharzia f o c i ; (2) I n addition to, and mostly simultaneous with, the bronchial asthma there was, as a second allergic p h e n o m e n o n , urticaria which also disappeared u n d e r specific bilharzia therapy.
Case 2.--A. ~. Private patient. Ambulatory observation : 1st November, 1937, to 10th Febnlary, 1938. The patient was a boy, aged 14, without any peculiarities in the family history and without important previous diseases. He had been suffering for 5 years from periodically recurring severe asthmatic attacks. In spite of thorough questioning no information could be obtained concerning a bilharzia infection of the bladder or intestine. The boy was markedly backward in growth, of a pale coffee-brown colour, in poor nutritional condition (height : 151 cm. ; weight : 38-5 kg.). He visited my surgery while
FRITZ MAINZER.
257
having a severe asthmatic paroxysm with high degree of emphysema and marked expiratory dyspnoea. Over the whole area of both lungs intense wheezing and whistling was heard, becoming even perceptible to the touch. The liver extended three finger breaths below the costal margin and its consistence was increased ; the spleen was firm and pushed hard against the hand on inspiration. On account of the combination of asthma and enlargement of liver and spleen it was possible to make a clinical diagnosis of " bilharzial asthma." Eggs of parasites could not be found either in the stools or in the urine. The X-ray picture of the lungs (Fig. 2) showed, in addition to a high degree of emphysema, increased striations and especially, on the right near the hilum in the inferior lobe a number of irregularly outlined foci varying in size from that of a pea to a bean. Some of these foci were confluent or joined together by the striations, thus casting a very soft shadow. The blood cell count (Table II) showed a leucocytosis of 14,900, of which 64 per cent. was due to eosinophilic cells. The intradermal reaction with liver extract of infected snail (Fairley reaction) was positive. The first course of antimony was given from the 4th to the 22nd of November (fuadin, 30 c.c.). After no more than three injections (7th November) the status asthmatieus which had lasted for 20 days improved progressively. A week later all subjective difficulty in breathing had disappeared. During this period, as has been our invariable experience, the blood count showed at the beginning of the treatment (MAINZER, 1935, 1936 and in press) a further increase both of the total leucocyte count and of the proportion of eosinophilie cells (18th November, 19,400 leucocytes, 61 per cent. of which were eosinophilic cells ; Table II). The liver and spleen regained their normal size. On 22nd November, percussion as well as auscultation revealed no pulmonary abnormality. From 7th December to 22nd, a further course of antimony was given (30 c.c. fuadin). During this period occasionally some musical rMes (wheezing and humming) were to be heard. Subjectively the patient felt well and respiration was normal. He was able to take part in gymnastic lessons at school. At that time the general condition improved greatly. The body weight increased from 38.5 kg. (2nd November) to 41 kg. (28th December). During December the blood picture developed in a normal direction. The total leucocyte count became normal, the number of eosinophilic cells also decreased but remained stationary at a level of 30 to 40 per cent. In spite of the disappearance of the asthmatic manifestations a second radiograph showed that the condition of the lungs was quite unchanged (8th January). During the first half of January and more so in the second half, the blood began to deteriorate, the figures obtained approaching those found at the beginning (Table II). Early in February the liver and spleen were once more enlarged. During the last week of January the subjective troubles of bronchial asthma reappeared. Pulmonary emphysema as well as wheezing and humming increased, but the symptoms both subjective and objective did not reach the degree of severity seen at the beginning of November. After an adequate interval a new course of antimony was borne in mind.
Summary.--In view of the absence of eggs of parasites the bilharzial nature of the disease was accepted from the presence of enlargement of liver and spleen accompanied by high eosinophilia, positive Fairley reaction and the good therapeutic effect of antimony u p o n the clinical manifestations as well as on the b l o o d ' picture. P u l m o n a r y involvement was clearly demonstrated by X - r a y examination. T h e p r o m p t effect of the antimony therapy upon the severe status asthmaticus showed that the bronchial asthma was closely connected with the bilharziasis. T h e fact that the X - r a y findings remained completely unchanged indicated that we Were not dealing with an effect b r o u g h t about by the p u l m o n a r y disease (recognizable in the X - r a y photograph) ; it proved, however, the allergic nature of this type of asthma.
258
BILHARZIAL ASTHMA. TABLE II. BLOOD-CELLCOUlqTSOF eASE 2 (A.I~.).
Date.
1937. 2.11 9.11 18.11
Haemo- ErythroNeutrophils. globin cytes. Leuco(Sahli). Millions. eytes. Per Per cent. cent. Total. -93 93
26.11 3.12 17.12 24.12
90 --
31.12 1938. 7.1 14.1 22.1 28.1. 4.2
--
-4.6 4.6 M
Lymphocytes.
Eosinophils.
Per cent. Total.
Per cent. Total.
Monoeytes, Per cent.
9,540 8,360 11,830
Batonnets. Per cent.
14,900 15,200 19,400
11 17 17
1,640 2,580 3,300
25 27 22
3,720 4,100 4,270
64 55 61
16,700 18,500 7,200 6,900
21 18 23 24
3,510 8,330 1,660 1,660
10 19 40 43
1,670 3,520 2,880 2,970
69 11,520 62 !11,470 36 2,590 30 2,170
10,900
39
4,250
27
2,940
32
3,490
1
1
14,400 8,500 8,000 13,100 13,600
21 27 11 19 85
3,020 2,290 880 2,490 4,760
51) 35 46 39 20
7,201) 2,970 3,680 5,110 2,720
28 4,030 37 3,140 40 i 3,200 39 5,110 41 i 5,580
1 1 3 3
-----
1
} 4.11.37 to 22.11.87 : treatment with fuadin (35 c.c.)
I
- -
1
1 1
i
-2
i
81 75 --
4.0 3"9
Remarks.
4
i
i
t
7.12.37 to 22.12.37 : treatment with fuadin (35 c.c.)
--
Case 3 . - - W . A . Private p a t i e n t . A m b u l a t o r y o b s e r v a t i o n f r o m 3 0 t h N o v e m b e r , 1937, to 10th February, 1938. T h e p a t i e n t , aged 40, a m e r c h a n t , was t h e u n c l e of t h e p a t i e n t A . J . (Case 2). H i s o w n h i s t o r y , before t h e o n s e t of t h e p r e s e n t illness a n d t h a t of his family revealed n o t h i n g of importance. A y e a r a n d a half p r e v i o u s l y he h a d h a d a d y s e n t e r y - l i k e attack of 3 to 4 days' d u r a t i o n . T h e r e h a d b e e n t e n e s m u s as well as f r e q u e n t stools a p p a r e n t l y w i t h o u t a d m i x t u r e of blood. F o r 1 y e a r h e h a d suffered f r o m c o u g h w i t h e x p e c t o r a t i o n ; t h e r e w e r e also a s t h m a t i c p a r o x y s m s i n c r e a s i n g i n f r e q u e n c y a n d severity. T h e s e lasted 2 to 3 h o u r s a n d e n d e d w i t h t h e e x p e c t o r a t i o n of a glassy s p u t u m . I n t h e ~course of 9 m o n t h s h e lost 27 kg. I n M a y a n d J u n e , 1937, h e was u n d e r m e d i c a l o b s e r v a t i o n for these t r o u b l e s d u r i n g w h i c h e n l a r g e m e n t of t h e liver was. d i a g n o s e d a n d s y m p t o m a t i c a l l y treated w i t h n o success. Since t h e a s t h m a t i c d y s p n o e a increased m o r e a n d m o r e , u n t i l finally t h e p a t i e n t Was u n a b l e to m o v e a b o u t freely, h e u n d e r w e n t t r e a t m e n t i n a hospital of a E u r o p e a n capital.* T h e r e h e c o m p l a i n e d of dyspnoea, t e m p o r a r y " a s t h m a - l i k e crises," c o u g h w i t h e x p e c t o r a t i o n a n d severe attacks of p a i n i n t h e u p p e r a b d o m e n . H e looked wasted, his w e i g h t b e i n g 67"5 kg. T h e pulse rate was 104 p e r m i n u t e a n d t h e b l o o d p r e s s u r e , 115/75 r a m . H g . B r o n c h i t i c rMes c o u l d b e h e a r d all over t h e e m p h y s e m a t o u s lungs. T h e liver e x t e n d e d b e l o w t h e costal arch b y a h a n d ' s b r e a d t h , it was m a r k e d l y firm a n d sensitive tO pressure, particularly i n t h e v i c i n i t y of t h e gall-bladder. T h e r i g h t rectus w a s rigid. T h e r e was n o fever. I n t h e u r i n e t h e r e was a l b u m i n , red b l o o d corpuscles w h i c h occasionally w e r e p r e s e n t i n large q u a n t i t i e s , a n d f r o m t i m e to t i m e n u m e r o u s hyaline a n d g r a n u l a r c a s t s . T h e b l o o d p i c t u r e s h o w e d leucocytosis of 23,000 leucocytes, of w h i c h 70 p e r cent. Were • eosinophilic cells ( T a b l e I I I ) . T h e s e d i m e n t a t i o n rate was n o r m a l : 4-6 r a m . p e r hour (Linzenmayer). ' " .... *I a m greatly iridebted to Prof. D r . KALK i n Berlin for t h e i n f o r m a t i o n a b o u t t h e course of t h e disease a n d t h e findings w h i c h were o b t a i n e d t h e r e . •
FRITZ MAINZER,
'
259
T h e X - r a y showed e m p h y s e m a t o u s lungs with increased striations especially in b o t h l o w e r fields. T h e s t o m a c h was p u s h e d to the left by the liver w h i c h apparently reached the true pelvis. :. . . . . . . . . . . : O n the 26th of July, 1937i laparotomy w a s p e r f o r m e d since a hepatic abscess was suspected. T h e liver was f o u n d to be riddled w i t h small, glassy, white nodules t h e size of a millet seed (as in miliary tuberculosis) ; two of t h e m w e r e excised. O n histological examination, a nodule-like granulation tissue was found, already partly transformed into fibrous tissue, around the p i g m e n t e d remainders of decayed eggs, It could not be d e t e r m i n e d w h e t h e r they. were eggs of Schistosoma haematobium or S . mansoni. T h e granulation tissue showed an i m m e n s e n u m b e r of eosinophilic cells w i t h , s o m e giantcells. O n the days following the operation some asthma paroxysms occurred. I n the s p u t u m the eggs of S . haematobium were detected on one occasion. I n the urine no eggs could be found. T h e patient received a course of fuadin (50 c.c.) and left the hospital on the 3 0 t h of August. A t his next visit (24th N o v e m b e r ) he felt quite well, looked well and had gained 8 kg. I n the urine there were no longer any pathological substances. O n the 20th of S e p t e m b e r another course of fuadin was started, b u t this c o u l d not be c o m p l e t e d (35 c.c.). T h e changes o f the blood count during the treatment can be seen in T a b l e I I I . O n the 25th of S e p t e m b e r , 60 per cent. of eosinophilic cells were still present, w i t h a total leucocyte count of 6,000. • TABLEIiL BLOOD CELL COUNTS OF CASE 3 (W,A.).
ophils. M0no- Batoncytes, nets. Per Per Total. cent. ' cent
Remarks.
--7-7 15,100 15,210 3,510 7,790 8,500 8,470
3 1 3 4 2
7,~00 8,400 •8,580 7,640 7,840 9,980 3,600
3 3 3 5 3 1
9,240 13,900
1
3 9 1 4 4
1 5
11.8.37 to 20.8.37: "~- treatment with J fuadin (50 c,c.)
4 3 3 3 3 2
8,~80 2,270 2,800 4,300 i2,320
[
]15.9.37 to 1.10.87 : "~ treatment with ) fuadin (35 cm.) /30.11.37 to 15.12.37: ~ treatment with ) fuadin(45 c,c.)
C~60
BILHARZIALASTHMA.
When on 29th November, 1937, the patient came under our observation, wheezing and humming was to be heard all over the emphysematous lungs and expiration was very difficult. The liver was only slightly, if at all, enlarged, but its consistency was increased. The spleen was not palpable. The blood picture showed that the leucocytes had once more increased to 13,200 with 70 per cent. eosinophilic cells. The general condition was, however, satisfactory ; weight 73.7 kg. while the height was 170 cm. The urine was free from pathological substances and from eggs. In the stools, however, the concentration method revealed the presence of eggs of S. haematobium. The X-ray photograph of the lungs showed the typical multiform picture of bilharziasis associated with emphysema (Plate Fig. 3). The diaphragm was low, the position of the ribs almost horizontal. The striations were markedly increased. There were on both sides dense striae radiating fr6~aa the enlarged and intensified hilum to the superior lobes. The whole of both lungs was riddled by miliary opacities. On the left they were not so close together and were connected with one another by fine threads giving the appearance of a fine network which we have repeatedly described. On the right the foci were nearer to one another and coalesced particularly in the inferior lobe. There was thus produced a diffuse cloudy opacity which varied in density in different regions. Further upward the small loci looked like berries suspended on the dense striations. From 30th November to 15th December, 1937, a course of fuadin was given (45 c.c.). The asthmatic manifestations rapidly abated. From the end of the treatment up to the middle of January, 1938, the clinical condition of the lungs, was absolutely normal. Similarly the blood picture showed progressive improvement to the middle of January, though at the beginning of the treatment there had been the usual increase of pathological phenomena---on the 9th of December, 1937, there had been 18,400 leucocytes with 75 per cent. eosinophilic cells. On the 17th of January, 1938, there were 8,500 leucocytes with 33 per cent. eosinophilic cells. (Table III.) A radiograph taken on the 17th of January, 1938, revealed no change. Towards the end of January the blood picture began again to deteriorate (24th January, 1938 ; cf. Table III), while the asthmatic manifestations reappeared--at first only noticeable to the ear of the physician without the patient having subjective troubles. From the beginning of February, the patient suffered every evening from severe asthmatic paroxysms which were successfully combated b y a mixture of adrenalin:.atrbpin-hypophysin, given subcutaneously. The attacks became so severe that in the middle o f February further antimony treatment was considered.
Summary.--A m o s t severe case of bilharziasis (S. haematobium) of the liver identified afterwards b y ihistological examination was laparotomized on the grounds of a mistaken diagnosis, T h e disease involved to an equal extent the lungs (X-ray, eggs of parasites in the sputum), the bladder (haematuria, no eggs) and the intestines (presence of eggs). T h e blood picture showed a high degree of eosinophilia. T h e r e was bronchial a s t h m a with m o s t severe paroxysms. T h e asthma p r o m p t l y reacted to a n t i m o n y therapy , as was proved b y the response to three courses of fuadin which established its relation to the S. haematobium infection. But it was the X - r a y appearance of the lungs which d e m o n strated that the case was one of humoral allergy not one resulting directly f r o m the p u l m o n a r y involvement and the anatomical changes this h a d b r o u g h t a b o u t ; the X - r a y appearance of the lungs remained u n c h a n g e d during the whole period of observation and was quite unaffected b y the treatment.
FRITZ MAINZER.
261
III.--DlscussloN. The three cases of bilharziasis described above were severe, and of the chronic type. It was not possible to discover how infection Occurred, as all three patients resided in large towns. Neither for professional nor any other reason known to them had they been exposed to the possibility of infection. Neither could the duration of the schistosomiasis be determined in any of the cases (except, perhaps, in the third: ? a year and a half), for none of the patients had observed any symptoms which would enable him to fix the moment of infection. In every case, however, the disease could be traced back over many months and it was possible to decide that all the patients were in the chronic tertian stage of bilharziasis. In one of the patients the parasite was identified as S. haematobium by eggs found in the stools and sputum. In the two other patients eggs could not be detected but the involvement of the bladder suggested S. haemotobium infection without, however, enabling a definite diagnosis to be established. In all three cases the liver (and the spleen) were severely affected. That the bladder and the intestines were involved in Cases 1 and 3, and the lungs in Cases 2 and 3, was proved by the clinical signs. All patients showed high eosinophilia (up to 23,400 leucocytes, of which 70 per cent. were eosinophilic cells); this finding is quite unusual for the chronic tertian stage of ordinary bilharziasis of the bladder (S. haematobium) and of the intestine (S. mansoni), but is typical, however, of the cases of isolated pulmonary bilharziasis which have been described by us. In none of the cases was there fever as a sign of infection. As shown in our previous reports (MAINZER,loc. cit.) this group of cases, (i.e., those in which the clinical signs of involvement of liver and lungs are the outstanding features as well as general symptoms such as fever and emaciation) exhibit special features from the therapeutic standpoint. I n contrast to the results obtained in uncomplicated bilharziasis of the bladder (KHALIL, 1931), the ordinary course of antimony treatment with fuadin is insufficient to eradicate the infection, just as it fails to do in the Japanese forms of schistosomiasis (LEE, 1932). As a rule, relapses occur after treatment has been terminated. In our cases it had to be repeated once or several times (in one of the cases as many as five times) before complete cure was achieved. During the treatment and during the following 1 to 3 weeks, all pathological phenomena subsided ; enlargement of liver and spleen as well as cough, fever, fatigue, and the symptoms of bladder and rectum infection if there had been any. The leucocyte count returned to normal, the eosinophils decreasing in number but remaining, however, at a high level (20 to 40 per cent.). If a complete cure has been effected the number of eosinophils decreases still further
~69,:
BILHARZIAL ASTHMA.
during the course of the following weeks. T h e first indication of a relapse is seen in the blood count, both th e proportion of eosinophilic cells and the total number of leucocytes start increasing once more, a fortnight up to 6 weeks after termination of the treatment. T h e clinical phenomena of the disease immediately follow these first signs. T h e retrogression of the pulmonary process due to s~iccessful treatment as revealed by X-ray inspection takes much longer than that o f t h e ab6ve Clinicalmanifestations ; at least 2 months bu:t often considerably more. T h u s the radi0graphmay not show ahy changes w h e n there is an ehl?Iy relapse which occurs before the treatment could have effected the X:ray picture of the lungs.. This isso in Cases 2 and3. It may be assumed that in the cases which relapse, the antimony has killed only some of the Worms, the remaining ones being temporarily poisoned or inhibited, especially as regards egg-laying capacity. It is not the presence of the mature parasites in the blood Vessels but the deposition of eggs in the tissues that gives rise to the local and general manifestations of the disease (feVer, allergy). This hypothesis is in absolute agreement with all other experience of schistosome infection. For these reasons it is possible to understand the complete parallelism which exists between the course of bilharziasis in its strictest sense and the course of bilharzial asthma under the influence of therapy, to which we shall refer below. T h e importance of this clinical parallelism from the point of view of affording an explanation of bilharzial asthma makes it necessary to discuss more fully the treatment of the cases, and any questions which arise in connection with this. In all three patients there were typical asthmatic paroxysms while a rise in temperature was only present in Case 1 (febrile asthma). T h e instantaneous effect exerted by specific antimony treatment upon the asthmatic manifestations demonstrates that this type of asthma is the direct result of the bilharzia infection and not a rare concurrence of two different diseases. From the point of view of their duration and intensity there is an absolute parallelism between the response to treatment of the main disease and the accompanying syndrome, quite apart from whether there has been only a transitory improvement (Cases 2 and 3) or complete cure (Case 1). The following observations appear to prove that this asthma is not brought about by the presence of the parasite in the lungs or by the changes induced by such an invasion. (1) In Case 1, pulmonary involvement cannot be definitely proVed. In this case the asthma crises, as a rule, were accompanied by urticarial rashes, an unmistakably allergicphenomenon. (2) In Cases 2 and 3 the administration of antimony which impedes the activity of the parasites, caused the asthmatic paroxysms to disappear although, according to X-ray, the pulmonary involvement remained unchanged.
FRITZ MAINZER.
268
The improvement is absolutely parallel to the changes in the blood count which, according to previous observations (I~/[AINZER, 1935, 1936 and in the press) is a decisive test of therapeutic success. In cases in which complete cure, i.e., destruction of all parasites which were present in the organism, could not be achieved by means of antimony treatment a relapse occurred when the damaged parasites recovered. This relapse was characterized by an increase in the number of the eosinophilic cells i f f t h e blood and the recurrence of the asthmatic attacks, These observations demonstrate unmistakably that the bronchial asthma associated with the bilharzia infection is of an allergic nature and should be included in this group as a new type of allergic asthma. As in the case with every allergic phenomenon bilharzial asthma, in contrast to the pulmonary lesions caused by Schistosoma, is an exceptional reaction due to constitutional factors. In spite of the enormous number of people suffering from schistosome infections--in Egypt alone the number must be about ten millions--only five of these cases have been reported in the literature (including those described here). The constitutional nature of the affection is particularly revealed by the fact that the patients (Cases 2 and 3) are consanguineous, being uncle and nephew. We are inclined to believe, however, that attention once drawn to this syndrome the number of observations will rapidly increase.
IV.--SUMMARY.
Three cases of bitharzial asthma are described as a type of allergic reaction dependent on constitutional factors and substances liberated by Schistosoma (haematobium or mansoni). One of these cases showed febrile asthma with simultaneous urticarial rashes. The two other observations concerned blood relations (uncle and nephew). It was possible to prove that the asthmatic paroxysms had no relation to lesions of the lungs brought about by the parasite, the pulmonary bilharziasis. In all kinds of infections with S. haematobium and mansoni X-ray examination constantly reveals pulmonary involvement. The causal relationship between bilharzia infection and asthma is demonstrated by the complete parallelism in the course of both diseases subsequent to specific therapy. The allergic nature of this kind of asthma has been proved by its association with urticaria and the constitutional and hereditary character of this allergy, which is very infrequently encountered, by its occurrence in relatives. The resistance of the atypical bilharziasis of the liver and lungs to fuadin treatment is noted.
~64
BILHARZIALASTHMA. REFERENCES.
BRUGSCH,H. (1931). Dtsch. Arch. klin. Med., 170, 537. KHALrL, M. (1931). The treatment of schistosomiasis. Arch. Schiffs- u. Tropen-Hyg., 35, Beih. 2. LEE, S.W. (1932). Chin. reed. ft., 46, 1169. MAINZER, F. (1935). Acta reed. scand., 85, 538. .. (1936). Fortschr. R6ntgenstr., 54, 154. . ( ). Ueber latente Lungenerkrankung (im Roentgenbild) bei Darmbilharziosis (S. mansoni). In press. - & YALOUSSlS. (1936). Fortschr. Rantgenstr., 54, 373. Su,~mEz, R . M . (1930). Bol. Asoc. todd. P. Rico., 9.1, 40.
Vol. XXXII.
No. 2. August, 1938.
BILHARZIAL ASTHMA. BRONCHIAL ASTHMA IN SCHISTOSOMA INFECTION. BY
FRITZ MAINZER, M.D., Director, Department of Medicine, the Jewish Hospital, Alexandria, Egypt.
I.--INTRODUCTION. SUAREZ (1930) reported a case of infection with Schistosoma mansoni which showed the symptoms of bronchial asthma. He did not, however, consider the disease to be asthma in the proper sense, i.e., an allergic syndrome due to humoral action, but as a complex of manifestations brought about by pathological changes due to the presence of the parasite or its eggs in the lungs. This is indicated by the title of his paper: " Schistosomiasis of the lungs simulating bronchial asthma." Another case belonging to this category which could be definitely identified (MAINZER, 1935 and 1936) as bilharzial asthma from the description (with pulmonary involvement proved by X-ray) was published by BRUGSCH (1931) under the title, " Persistierende Eosinophilie mit Milzvergroesserung." The author, however, did not realise the nature of the disease. We ourselves have reported a third case of this kind (MAINZER, 1935 and 1936), when we were concerned with chronic isolated pulmonary bilharziasis, i.e., a form of bilharziasis not accompanied clinically by local manifestations of the disease in other organs. Being now in a position to add to these
9~54
BILHARZIAL ASTHMA.
observations two further cases, we propose to discuss bilharzial asthma in the present paper. I n contrast to SUAREZ' view bilharzial asthma has no connection with the a n a t o m i c a l p u l m o n a r y disease due to Schistosoma haematobium or mansoni to .which we have devoted four reports (MAINZER, 1935 and 1936; MAINZER & YALOUSSlS, 1936 ; and MAINZER, in the press) ; it is, however, as can be seen by the following observations a real allergic asthma induced by the products of metabolism of the parasites ortheir eggs whether these are present in the lungs or in any other organ. T h a t in such cases the X - r a y may reveal bilharzial involvement of the l u n g s - - a s in the cases reported by SUAREZ (1930) and BRUGSCH (1931); as well as in two of our three cases--does not contradict this view. I n cases of bilharzial asthma p u l m o n a r y involvement is naturally no less frequently met with than in other cases of schistosomiasis, in which, according to our roentgenological examinations (MAINZER, loc. cit.) it is the rule to find it even if there are no clinical s y m p t o m s of lung invasion. I n the asthmatic cases which we are discussing here the lungs are clinically the centre of interest and are examined by X - r a y more frequently than in other cases of bilharziasis where clinical s y m p t o m s do not direct attention to the respiratory tract. II.--CAsE HISTORIES.
Case 1.--G.A. 3608/34. Clinical observation : 3rd--15th November, 1934 (prior to that time he was an outpatient). The patient, a schoolboy, aged 10½, son of a police officer, had been suffering for 2 years from severe attacks of febrile asthma. The temperature used to rise to 40 ° C., there were severe paroxysms of difficult expiration, with loud and audible whistling. There was also much cough, but without expectoration. On occasions, these attacks were accompanied by urticarial rashes. Nine months previous to admission the patient had had an " attack of dysentery," but neither the microscopical examination nor the culture made in our laboratory revealed the presence of either amoebae or dysentery bacilli. Emetin treatment cured the disease within 3 months. In January, April and May, 1934, attacks of haematuria of short duration appeared the laboratory examinations, however, revealed only a few red blood corpuscles. No eggs of bilharzia were detected. In May, 1934, a rectal polypus which had drawn attention to itself by bleeding had to be removed ; its histological examination, however, was omitted. The parents who, on account of the frequent febrile attacks, suspected pulmonary tuberculosis, consulted a lung specialist who was able to dispel these suspicions as being unfounded. Nevertheless it was not possible to identify the disease or carry out any treatment. At that time the boy's condition was the same as when he was admitted to hospital (3rd November, 1934). He was in excellent general condition. There was no fever. The lungs showed the picture of an asthmatic attack: marked emphysema, the lung boundaries low in position with little movement, hypersonorous percussion note, the respiratory sound soft, expiration prolonged, abundant wheezing and whistling everywhere. There was a history of frequent urticarial rashes. The liver as well as the spleen were markedly enlarged and firm. The liver extended below the costal margin by a hand's breadth, the spleen by the width of three fingers. These findings had been already observed in X-ray examination performed previous to this. On rectal examination a new polypus was palpable.
FRITZ MAINZER.
255
TABLE I. BLOOD CELL COUNTSOF CASE I (G.A.). ~
m
i Haemo- ErythroDate. ; globin cytes. (Sahli) Millions. _ _ i Per cent__ _ _ _ _
Neutrophils. Leucocytes.
Lymphocytes. Per
Eosinophils.
! Monocytes. Per cent.
Batonnets. Per cent.
I 1,130
6
1
i' 6,810 25,400 12,350 10,140
--1 1
~
Per cent.
total.
cent.
Total.
cent.
7,500 22,700 34,800 19,600 15,600
12 28 13 8 14
900 6,360 4,520 1,570 2,180
66 42 14 28 17
4,950 9,530 4,870 5,490 2,650
15 30 73 63 65
17,600 17,000
13 11
2,290 1,870
36 37
6,340 6,290
49 48
8,620 8,160
2
17,100 11,500 17,000 10,100
14 13 13 23
2,390 1,500 2,210 2,320
35 34 45 35
5,990 3,910 7,650 3,540
49 49 40 38
8,380 5,640 6,800 3,840
1 4 2 4
2.2 9.2 16.2 23.2 2.3 9.3 16.3 23.3 13.4 20.4 27.4 4.5 11.5 18.5 25.5 1.6 8.6 17.6 25.6
10,500 6,500 6,900 5,000 4,800 7,500 6,500 7,400 6,200 5,800 6,800 8,300 9,100 16,900 12,900 15,990 12,200 20,000 15,700
23 24 24 23 30 28 22 37 32 20 27 27 15 11 8 11 13 13 14
2,410 1,560 1,160 1,150 1,140 2,080 1,430 2,740 1,980 1,700 1,840 2,240 1,370 1,860 1,030 1,720 1,590 2,600 2,200
52 57 52 64 42 51 62 31 47 49 42 38 38 46 38 30 47 23 31
5,460 3,710 3,590 3,200 2,020 3,830 4,030 2,290 2,910 4,180 2,860 3,150 3,460 7,780 4,900 4,680 5,740 4,600 4,870
23 18 20 ii 23 20 14 29 19 29 30 34 46 42 50 58 38 6~ 54
2,410 1,170 1,380 550 I,I00 1,500 910 2,150 1,180 2,670 2,040 2,820 4,280 7,090 6,450 9,050 4,640 12,800 8,480
2 1 3 o 4
29.6 6.7 13.7 20.7 27.7 3.8 17.8 31.8 7.9 14.9 21.9 5.10 19.10 29.10 25.11 11.12 14.12 1936. 30.1
14,200 12,000 15,700 9,500 6,500 6,100 5,700 5,400 8,300 5,200 5,800 5,100 5,700 5,200 5,600 7,000 5,500
10 18 2O 19 25 29 25 31 29 42 22 35 32 41 37 37 41
4,570 2,160 3,140 1,810 1,630 1,770 1,430 1,670 2,410 2,180 1,230 1,790 1,820 2,130 2,070 2,590 2,260
35 28 34 34 49 45 65 54 58 47 71 46 41 44 52 52 48
4,970 3,360 5,340 3,230 3,190 2,750 3,710 2,920 4,810 2,440 4,120 2,350 2,340 2,290 2,910 3,640 2,640
52 52 46 47 25 24 10 14 12 7 7 16 24 10 11 6 8
5,800
33
1,910
62
3,600
1934. 26.4 3.11 7.11 16.11 3.12
Total
Remarks.
i
77 83 81
15.12 27.12 1935. 2.1 10.1 18.1 26.1
4.3 4.1 4.2 -
-
-
-
--
--
----
--
--
-
! 81t :4,m o 6;1}34:
2
!~
-~1
J
--
]3.1.35 to 23.1.35 : ~" t r e a t m e n t with J fuadin (35 c.e.)
!
at
e t wit}
neostibosan
1 1
I
2 2 2 2 1 1 1 1 4 1 2 i
3 1
1
---
7,380 6,240 7,220 4,470 '~ 1,630 1,460 570 760 1,000 360 410 820 1,370 520 620 420 440
3 3 5 -5 3
------
120
3
--
1
1 2 1 1 4
] 1 3 to 25.6.35 :treat~ ment with fuadin J (35 c.c.)
FIG. 1
FIG. 2. Fro. l.--Case 1. Radiograph of Lungs Oct. 22nd, 1934 (before admission to hospital). FIG. 2.--Case 2. Radiograph of Lungs Nov. 2nd, 1937. To face p.
254.
FIO. 3. FIG. 3,--Case 8.
Radiograph of Lungs.
Dec. 1st, 1937.
356
BILHARZIAL ASTHMA.
The blood picture showed--in agreement with a previous count (26th April, 1934, cf. Table I)--a leucocytosis of 22,700 leucocytes, 30 per cent. of which were mature eosinophilie cells. A few days later 34,800 leucocytes were counted, 73 per cent. of which were eosinophils. On microscopic and cultural examination of the blood, urine and stools, no suggestion of a parasitic disease was found. In the sputum a large number of eosinophilic cells was detected, but neither pathogenic bacteria nor eggs of parasites. The radiograph of the lungs taken before admission (22nd October, 1934 ; Plate Fig. 1) showed nothing particular except some increase of striations and emphysema. Later radiographs (26th January and 22nd May, 1935) showed further retrogression of the emphysema. The assumption that this kind of asthma was caused by anaphylactogenic substances of bilharzial origin was made evident by the presence of many of the classical phenomena of bilharziasis of the bladder in spite of the failure to detect eggs in the urine or faeces. There was the pathognomic haematuria, and the dysentery which was favourably influenced by emetin in spite of absence of amoebae. There was, moreover, eosinophilia and urticaria (as have been described as typical of the initial stage of schistosomiasis), enlargement of liver and spleen (which occurs, as a rule, in the type of infection occurring in the Far ]East), as well as repeated formation of intestinal polypi characteristic of intestinal bilharziasis. In view of these facts antimony was given, neostibosan (8th November to 6th December, 1934) and later on fuadin (two series, 3rd to 23rd January and 13th to 25th June, 1935) the latter being an incomplete series of injections. The asthmatic attacks definitely disappeared from the beginning of the first series of injections. Urticaria occurred several times between the first and second series, but not again afterwards. The liver and spleen regained their normal size, the blood picture approached the normal (as shown by Table I), a somewhat increased number of eosinophilic cells persisting, as usual, while the total leucocyte count became normal.
Summary.--The case considered here is one of bilharziasis of the bladder and intestine accompanied b y m a r k e d enlargement of liver and spleen and a high degree of eosinophilia. Eggs of parasites could not be detected either in the urine or in the stools. Adequate a n t i m o n y t r e a t m e n t effected complete cure. T h e disappearance of the asthmatic attacks effected b y the a n t i m o n y t h e r a p y proves that these were a consequence of the bilharzia infection. T h a t they were not due to p u l m o n a r y i n v o l v e m e n t b y the parasite, i.e., a local disease of the lungs (as according to SUAREZ) is s h o w n b y two facts : - (1) T h e X - r a y (Fig. 1) reveals the lungs to be free f r o m bilharzia f o c i ; (2) I n addition to, and mostly simultaneous with, the bronchial asthma there was, as a second allergic p h e n o m e n o n , urticaria which also disappeared u n d e r specific bilharzia therapy.
Case 2.--A. ~. Private patient. Ambulatory observation : 1st November, 1937, to 10th Febnlary, 1938. The patient was a boy, aged 14, without any peculiarities in the family history and without important previous diseases. He had been suffering for 5 years from periodically recurring severe asthmatic attacks. In spite of thorough questioning no information could be obtained concerning a bilharzia infection of the bladder or intestine. The boy was markedly backward in growth, of a pale coffee-brown colour, in poor nutritional condition (height : 151 cm. ; weight : 38-5 kg.). He visited my surgery while
FRITZ MAINZER.
257
having a severe asthmatic paroxysm with high degree of emphysema and marked expiratory dyspnoea. Over the whole area of both lungs intense wheezing and whistling was heard, becoming even perceptible to the touch. The liver extended three finger breaths below the costal margin and its consistence was increased ; the spleen was firm and pushed hard against the hand on inspiration. On account of the combination of asthma and enlargement of liver and spleen it was possible to make a clinical diagnosis of " bilharzial asthma." Eggs of parasites could not be found either in the stools or in the urine. The X-ray picture of the lungs (Fig. 2) showed, in addition to a high degree of emphysema, increased striations and especially, on the right near the hilum in the inferior lobe a number of irregularly outlined foci varying in size from that of a pea to a bean. Some of these foci were confluent or joined together by the striations, thus casting a very soft shadow. The blood cell count (Table II) showed a leucocytosis of 14,900, of which 64 per cent. was due to eosinophilic cells. The intradermal reaction with liver extract of infected snail (Fairley reaction) was positive. The first course of antimony was given from the 4th to the 22nd of November (fuadin, 30 c.c.). After no more than three injections (7th November) the status asthmatieus which had lasted for 20 days improved progressively. A week later all subjective difficulty in breathing had disappeared. During this period, as has been our invariable experience, the blood count showed at the beginning of the treatment (MAINZER, 1935, 1936 and in press) a further increase both of the total leucocyte count and of the proportion of eosinophilie cells (18th November, 19,400 leucocytes, 61 per cent. of which were eosinophilic cells ; Table II). The liver and spleen regained their normal size. On 22nd November, percussion as well as auscultation revealed no pulmonary abnormality. From 7th December to 22nd, a further course of antimony was given (30 c.c. fuadin). During this period occasionally some musical rMes (wheezing and humming) were to be heard. Subjectively the patient felt well and respiration was normal. He was able to take part in gymnastic lessons at school. At that time the general condition improved greatly. The body weight increased from 38.5 kg. (2nd November) to 41 kg. (28th December). During December the blood picture developed in a normal direction. The total leucocyte count became normal, the number of eosinophilic cells also decreased but remained stationary at a level of 30 to 40 per cent. In spite of the disappearance of the asthmatic manifestations a second radiograph showed that the condition of the lungs was quite unchanged (8th January). During the first half of January and more so in the second half, the blood began to deteriorate, the figures obtained approaching those found at the beginning (Table II). Early in February the liver and spleen were once more enlarged. During the last week of January the subjective troubles of bronchial asthma reappeared. Pulmonary emphysema as well as wheezing and humming increased, but the symptoms both subjective and objective did not reach the degree of severity seen at the beginning of November. After an adequate interval a new course of antimony was borne in mind.
Summary.--In view of the absence of eggs of parasites the bilharzial nature of the disease was accepted from the presence of enlargement of liver and spleen accompanied by high eosinophilia, positive Fairley reaction and the good therapeutic effect of antimony u p o n the clinical manifestations as well as on the b l o o d ' picture. P u l m o n a r y involvement was clearly demonstrated by X - r a y examination. T h e p r o m p t effect of the antimony therapy upon the severe status asthmaticus showed that the bronchial asthma was closely connected with the bilharziasis. T h e fact that the X - r a y findings remained completely unchanged indicated that we Were not dealing with an effect b r o u g h t about by the p u l m o n a r y disease (recognizable in the X - r a y photograph) ; it proved, however, the allergic nature of this type of asthma.
258
BILHARZIAL ASTHMA. TABLE II. BLOOD-CELLCOUlqTSOF eASE 2 (A.I~.).
Date.
1937. 2.11 9.11 18.11
Haemo- ErythroNeutrophils. globin cytes. Leuco(Sahli). Millions. eytes. Per Per cent. cent. Total. -93 93
26.11 3.12 17.12 24.12
90 --
31.12 1938. 7.1 14.1 22.1 28.1. 4.2
--
-4.6 4.6 M
Lymphocytes.
Eosinophils.
Per cent. Total.
Per cent. Total.
Monoeytes, Per cent.
9,540 8,360 11,830
Batonnets. Per cent.
14,900 15,200 19,400
11 17 17
1,640 2,580 3,300
25 27 22
3,720 4,100 4,270
64 55 61
16,700 18,500 7,200 6,900
21 18 23 24
3,510 8,330 1,660 1,660
10 19 40 43
1,670 3,520 2,880 2,970
69 11,520 62 !11,470 36 2,590 30 2,170
10,900
39
4,250
27
2,940
32
3,490
1
1
14,400 8,500 8,000 13,100 13,600
21 27 11 19 85
3,020 2,290 880 2,490 4,760
51) 35 46 39 20
7,201) 2,970 3,680 5,110 2,720
28 4,030 37 3,140 40 i 3,200 39 5,110 41 i 5,580
1 1 3 3
-----
1
} 4.11.37 to 22.11.87 : treatment with fuadin (35 c.c.)
I
- -
1
1 1
i
-2
i
81 75 --
4.0 3"9
Remarks.
4
i
i
t
7.12.37 to 22.12.37 : treatment with fuadin (35 c.c.)
--
Case 3 . - - W . A . Private p a t i e n t . A m b u l a t o r y o b s e r v a t i o n f r o m 3 0 t h N o v e m b e r , 1937, to 10th February, 1938. T h e p a t i e n t , aged 40, a m e r c h a n t , was t h e u n c l e of t h e p a t i e n t A . J . (Case 2). H i s o w n h i s t o r y , before t h e o n s e t of t h e p r e s e n t illness a n d t h a t of his family revealed n o t h i n g of importance. A y e a r a n d a half p r e v i o u s l y he h a d h a d a d y s e n t e r y - l i k e attack of 3 to 4 days' d u r a t i o n . T h e r e h a d b e e n t e n e s m u s as well as f r e q u e n t stools a p p a r e n t l y w i t h o u t a d m i x t u r e of blood. F o r 1 y e a r h e h a d suffered f r o m c o u g h w i t h e x p e c t o r a t i o n ; t h e r e w e r e also a s t h m a t i c p a r o x y s m s i n c r e a s i n g i n f r e q u e n c y a n d severity. T h e s e lasted 2 to 3 h o u r s a n d e n d e d w i t h t h e e x p e c t o r a t i o n of a glassy s p u t u m . I n t h e ~course of 9 m o n t h s h e lost 27 kg. I n M a y a n d J u n e , 1937, h e was u n d e r m e d i c a l o b s e r v a t i o n for these t r o u b l e s d u r i n g w h i c h e n l a r g e m e n t of t h e liver was. d i a g n o s e d a n d s y m p t o m a t i c a l l y treated w i t h n o success. Since t h e a s t h m a t i c d y s p n o e a increased m o r e a n d m o r e , u n t i l finally t h e p a t i e n t Was u n a b l e to m o v e a b o u t freely, h e u n d e r w e n t t r e a t m e n t i n a hospital of a E u r o p e a n capital.* T h e r e h e c o m p l a i n e d of dyspnoea, t e m p o r a r y " a s t h m a - l i k e crises," c o u g h w i t h e x p e c t o r a t i o n a n d severe attacks of p a i n i n t h e u p p e r a b d o m e n . H e looked wasted, his w e i g h t b e i n g 67"5 kg. T h e pulse rate was 104 p e r m i n u t e a n d t h e b l o o d p r e s s u r e , 115/75 r a m . H g . B r o n c h i t i c rMes c o u l d b e h e a r d all over t h e e m p h y s e m a t o u s lungs. T h e liver e x t e n d e d b e l o w t h e costal arch b y a h a n d ' s b r e a d t h , it was m a r k e d l y firm a n d sensitive tO pressure, particularly i n t h e v i c i n i t y of t h e gall-bladder. T h e r i g h t rectus w a s rigid. T h e r e was n o fever. I n t h e u r i n e t h e r e was a l b u m i n , red b l o o d corpuscles w h i c h occasionally w e r e p r e s e n t i n large q u a n t i t i e s , a n d f r o m t i m e to t i m e n u m e r o u s hyaline a n d g r a n u l a r c a s t s . T h e b l o o d p i c t u r e s h o w e d leucocytosis of 23,000 leucocytes, of w h i c h 70 p e r cent. Were • eosinophilic cells ( T a b l e I I I ) . T h e s e d i m e n t a t i o n rate was n o r m a l : 4-6 r a m . p e r hour (Linzenmayer). ' " .... *I a m greatly iridebted to Prof. D r . KALK i n Berlin for t h e i n f o r m a t i o n a b o u t t h e course of t h e disease a n d t h e findings w h i c h were o b t a i n e d t h e r e . •
FRITZ MAINZER,
'
259
T h e X - r a y showed e m p h y s e m a t o u s lungs with increased striations especially in b o t h l o w e r fields. T h e s t o m a c h was p u s h e d to the left by the liver w h i c h apparently reached the true pelvis. :. . . . . . . . . . . : O n the 26th of July, 1937i laparotomy w a s p e r f o r m e d since a hepatic abscess was suspected. T h e liver was f o u n d to be riddled w i t h small, glassy, white nodules t h e size of a millet seed (as in miliary tuberculosis) ; two of t h e m w e r e excised. O n histological examination, a nodule-like granulation tissue was found, already partly transformed into fibrous tissue, around the p i g m e n t e d remainders of decayed eggs, It could not be d e t e r m i n e d w h e t h e r they. were eggs of Schistosoma haematobium or S . mansoni. T h e granulation tissue showed an i m m e n s e n u m b e r of eosinophilic cells w i t h , s o m e giantcells. O n the days following the operation some asthma paroxysms occurred. I n the s p u t u m the eggs of S . haematobium were detected on one occasion. I n the urine no eggs could be found. T h e patient received a course of fuadin (50 c.c.) and left the hospital on the 3 0 t h of August. A t his next visit (24th N o v e m b e r ) he felt quite well, looked well and had gained 8 kg. I n the urine there were no longer any pathological substances. O n the 20th of S e p t e m b e r another course of fuadin was started, b u t this c o u l d not be c o m p l e t e d (35 c.c.). T h e changes o f the blood count during the treatment can be seen in T a b l e I I I . O n the 25th of S e p t e m b e r , 60 per cent. of eosinophilic cells were still present, w i t h a total leucocyte count of 6,000. • TABLEIiL BLOOD CELL COUNTS OF CASE 3 (W,A.).
ophils. M0no- Batoncytes, nets. Per Per Total. cent. ' cent
Remarks.
--7-7 15,100 15,210 3,510 7,790 8,500 8,470
3 1 3 4 2
7,~00 8,400 •8,580 7,640 7,840 9,980 3,600
3 3 3 5 3 1
9,240 13,900
1
3 9 1 4 4
1 5
11.8.37 to 20.8.37: "~- treatment with J fuadin (50 c,c.)
4 3 3 3 3 2
8,~80 2,270 2,800 4,300 i2,320
[
]15.9.37 to 1.10.87 : "~ treatment with ) fuadin (35 cm.) /30.11.37 to 15.12.37: ~ treatment with ) fuadin(45 c,c.)
C~60
BILHARZIALASTHMA.
When on 29th November, 1937, the patient came under our observation, wheezing and humming was to be heard all over the emphysematous lungs and expiration was very difficult. The liver was only slightly, if at all, enlarged, but its consistency was increased. The spleen was not palpable. The blood picture showed that the leucocytes had once more increased to 13,200 with 70 per cent. eosinophilic cells. The general condition was, however, satisfactory ; weight 73.7 kg. while the height was 170 cm. The urine was free from pathological substances and from eggs. In the stools, however, the concentration method revealed the presence of eggs of S. haematobium. The X-ray photograph of the lungs showed the typical multiform picture of bilharziasis associated with emphysema (Plate Fig. 3). The diaphragm was low, the position of the ribs almost horizontal. The striations were markedly increased. There were on both sides dense striae radiating fr6~aa the enlarged and intensified hilum to the superior lobes. The whole of both lungs was riddled by miliary opacities. On the left they were not so close together and were connected with one another by fine threads giving the appearance of a fine network which we have repeatedly described. On the right the foci were nearer to one another and coalesced particularly in the inferior lobe. There was thus produced a diffuse cloudy opacity which varied in density in different regions. Further upward the small loci looked like berries suspended on the dense striations. From 30th November to 15th December, 1937, a course of fuadin was given (45 c.c.). The asthmatic manifestations rapidly abated. From the end of the treatment up to the middle of January, 1938, the clinical condition of the lungs, was absolutely normal. Similarly the blood picture showed progressive improvement to the middle of January, though at the beginning of the treatment there had been the usual increase of pathological phenomena---on the 9th of December, 1937, there had been 18,400 leucocytes with 75 per cent. eosinophilic cells. On the 17th of January, 1938, there were 8,500 leucocytes with 33 per cent. eosinophilic cells. (Table III.) A radiograph taken on the 17th of January, 1938, revealed no change. Towards the end of January the blood picture began again to deteriorate (24th January, 1938 ; cf. Table III), while the asthmatic manifestations reappeared--at first only noticeable to the ear of the physician without the patient having subjective troubles. From the beginning of February, the patient suffered every evening from severe asthmatic paroxysms which were successfully combated b y a mixture of adrenalin:.atrbpin-hypophysin, given subcutaneously. The attacks became so severe that in the middle o f February further antimony treatment was considered.
Summary.--A m o s t severe case of bilharziasis (S. haematobium) of the liver identified afterwards b y ihistological examination was laparotomized on the grounds of a mistaken diagnosis, T h e disease involved to an equal extent the lungs (X-ray, eggs of parasites in the sputum), the bladder (haematuria, no eggs) and the intestines (presence of eggs). T h e blood picture showed a high degree of eosinophilia. T h e r e was bronchial a s t h m a with m o s t severe paroxysms. T h e asthma p r o m p t l y reacted to a n t i m o n y therapy , as was proved b y the response to three courses of fuadin which established its relation to the S. haematobium infection. But it was the X - r a y appearance of the lungs which d e m o n strated that the case was one of humoral allergy not one resulting directly f r o m the p u l m o n a r y involvement and the anatomical changes this h a d b r o u g h t a b o u t ; the X - r a y appearance of the lungs remained u n c h a n g e d during the whole period of observation and was quite unaffected b y the treatment.
FRITZ MAINZER.
261
III.--DlscussloN. The three cases of bilharziasis described above were severe, and of the chronic type. It was not possible to discover how infection Occurred, as all three patients resided in large towns. Neither for professional nor any other reason known to them had they been exposed to the possibility of infection. Neither could the duration of the schistosomiasis be determined in any of the cases (except, perhaps, in the third: ? a year and a half), for none of the patients had observed any symptoms which would enable him to fix the moment of infection. In every case, however, the disease could be traced back over many months and it was possible to decide that all the patients were in the chronic tertian stage of bilharziasis. In one of the patients the parasite was identified as S. haematobium by eggs found in the stools and sputum. In the two other patients eggs could not be detected but the involvement of the bladder suggested S. haemotobium infection without, however, enabling a definite diagnosis to be established. In all three cases the liver (and the spleen) were severely affected. That the bladder and the intestines were involved in Cases 1 and 3, and the lungs in Cases 2 and 3, was proved by the clinical signs. All patients showed high eosinophilia (up to 23,400 leucocytes, of which 70 per cent. were eosinophilic cells); this finding is quite unusual for the chronic tertian stage of ordinary bilharziasis of the bladder (S. haematobium) and of the intestine (S. mansoni), but is typical, however, of the cases of isolated pulmonary bilharziasis which have been described by us. In none of the cases was there fever as a sign of infection. As shown in our previous reports (MAINZER,loc. cit.) this group of cases, (i.e., those in which the clinical signs of involvement of liver and lungs are the outstanding features as well as general symptoms such as fever and emaciation) exhibit special features from the therapeutic standpoint. I n contrast to the results obtained in uncomplicated bilharziasis of the bladder (KHALIL, 1931), the ordinary course of antimony treatment with fuadin is insufficient to eradicate the infection, just as it fails to do in the Japanese forms of schistosomiasis (LEE, 1932). As a rule, relapses occur after treatment has been terminated. In our cases it had to be repeated once or several times (in one of the cases as many as five times) before complete cure was achieved. During the treatment and during the following 1 to 3 weeks, all pathological phenomena subsided ; enlargement of liver and spleen as well as cough, fever, fatigue, and the symptoms of bladder and rectum infection if there had been any. The leucocyte count returned to normal, the eosinophils decreasing in number but remaining, however, at a high level (20 to 40 per cent.). If a complete cure has been effected the number of eosinophils decreases still further
~69,:
BILHARZIAL ASTHMA.
during the course of the following weeks. T h e first indication of a relapse is seen in the blood count, both th e proportion of eosinophilic cells and the total number of leucocytes start increasing once more, a fortnight up to 6 weeks after termination of the treatment. T h e clinical phenomena of the disease immediately follow these first signs. T h e retrogression of the pulmonary process due to s~iccessful treatment as revealed by X-ray inspection takes much longer than that o f t h e ab6ve Clinicalmanifestations ; at least 2 months bu:t often considerably more. T h u s the radi0graphmay not show ahy changes w h e n there is an ehl?Iy relapse which occurs before the treatment could have effected the X:ray picture of the lungs.. This isso in Cases 2 and3. It may be assumed that in the cases which relapse, the antimony has killed only some of the Worms, the remaining ones being temporarily poisoned or inhibited, especially as regards egg-laying capacity. It is not the presence of the mature parasites in the blood Vessels but the deposition of eggs in the tissues that gives rise to the local and general manifestations of the disease (feVer, allergy). This hypothesis is in absolute agreement with all other experience of schistosome infection. For these reasons it is possible to understand the complete parallelism which exists between the course of bilharziasis in its strictest sense and the course of bilharzial asthma under the influence of therapy, to which we shall refer below. T h e importance of this clinical parallelism from the point of view of affording an explanation of bilharzial asthma makes it necessary to discuss more fully the treatment of the cases, and any questions which arise in connection with this. In all three patients there were typical asthmatic paroxysms while a rise in temperature was only present in Case 1 (febrile asthma). T h e instantaneous effect exerted by specific antimony treatment upon the asthmatic manifestations demonstrates that this type of asthma is the direct result of the bilharzia infection and not a rare concurrence of two different diseases. From the point of view of their duration and intensity there is an absolute parallelism between the response to treatment of the main disease and the accompanying syndrome, quite apart from whether there has been only a transitory improvement (Cases 2 and 3) or complete cure (Case 1). The following observations appear to prove that this asthma is not brought about by the presence of the parasite in the lungs or by the changes induced by such an invasion. (1) In Case 1, pulmonary involvement cannot be definitely proVed. In this case the asthma crises, as a rule, were accompanied by urticarial rashes, an unmistakably allergicphenomenon. (2) In Cases 2 and 3 the administration of antimony which impedes the activity of the parasites, caused the asthmatic paroxysms to disappear although, according to X-ray, the pulmonary involvement remained unchanged.
FRITZ MAINZER.
268
The improvement is absolutely parallel to the changes in the blood count which, according to previous observations (I~/[AINZER, 1935, 1936 and in the press) is a decisive test of therapeutic success. In cases in which complete cure, i.e., destruction of all parasites which were present in the organism, could not be achieved by means of antimony treatment a relapse occurred when the damaged parasites recovered. This relapse was characterized by an increase in the number of the eosinophilic cells i f f t h e blood and the recurrence of the asthmatic attacks, These observations demonstrate unmistakably that the bronchial asthma associated with the bilharzia infection is of an allergic nature and should be included in this group as a new type of allergic asthma. As in the case with every allergic phenomenon bilharzial asthma, in contrast to the pulmonary lesions caused by Schistosoma, is an exceptional reaction due to constitutional factors. In spite of the enormous number of people suffering from schistosome infections--in Egypt alone the number must be about ten millions--only five of these cases have been reported in the literature (including those described here). The constitutional nature of the affection is particularly revealed by the fact that the patients (Cases 2 and 3) are consanguineous, being uncle and nephew. We are inclined to believe, however, that attention once drawn to this syndrome the number of observations will rapidly increase.
IV.--SUMMARY.
Three cases of bitharzial asthma are described as a type of allergic reaction dependent on constitutional factors and substances liberated by Schistosoma (haematobium or mansoni). One of these cases showed febrile asthma with simultaneous urticarial rashes. The two other observations concerned blood relations (uncle and nephew). It was possible to prove that the asthmatic paroxysms had no relation to lesions of the lungs brought about by the parasite, the pulmonary bilharziasis. In all kinds of infections with S. haematobium and mansoni X-ray examination constantly reveals pulmonary involvement. The causal relationship between bilharzia infection and asthma is demonstrated by the complete parallelism in the course of both diseases subsequent to specific therapy. The allergic nature of this kind of asthma has been proved by its association with urticaria and the constitutional and hereditary character of this allergy, which is very infrequently encountered, by its occurrence in relatives. The resistance of the atypical bilharziasis of the liver and lungs to fuadin treatment is noted.
~64
BILHARZIALASTHMA. REFERENCES.
BRUGSCH,H. (1931). Dtsch. Arch. klin. Med., 170, 537. KHALrL, M. (1931). The treatment of schistosomiasis. Arch. Schiffs- u. Tropen-Hyg., 35, Beih. 2. LEE, S.W. (1932). Chin. reed. ft., 46, 1169. MAINZER, F. (1935). Acta reed. scand., 85, 538. .. (1936). Fortschr. R6ntgenstr., 54, 154. . ( ). Ueber latente Lungenerkrankung (im Roentgenbild) bei Darmbilharziosis (S. mansoni). In press. - & YALOUSSlS. (1936). Fortschr. Rantgenstr., 54, 373. Su,~mEz, R . M . (1930). Bol. Asoc. todd. P. Rico., 9.1, 40.