Postgrad Med J: first published as 10.1136/pgmj.56.657.506 on 1 July 1980. Downloaded from

Postgraduate Medical Journal (July 1980) 56, 506-508

The hypereosinophilic syndrome-a diagnostic enigma R. ELLUL-MICALLEF* D. EL-DIN MOHAMMEDt M.D.(Malta), Ph.D. M.B., M.D. F. F. FENECH* M.D.(Malta), F.R.C.P., F.R.C.P.E.

* Department of Medicine, University ofKuwait, and t Allergy Unit, Al-Sabah Hospital, Kuwait

Summary Full clinical, biochemical and radiological investiga- The hypereosinophilic syndrome groups together a tion at the surgical department had failed to reveal number of conditions in which eosinophilia occurs for a cause for his abdominal complaint. Clinical no apparently identifiable cause. Initial reports examination at the time of his first visit was thought indicated a uniformly grave prognosis but recent to be normal except for a barely palpable spleen. observations suggest a more favourable outcome in There was no family history of atopy. A complete certain cases. Two patients with hypereosinophilic biochemical investigation showed normal hepatic syndrome are described whose course of disease and and renal function. Repeated examinations of blood outcome have been completely different. and stools failed to detect any ova, cysts or parasites. A pre- and post-exercise ECG and chest X-raycopyright. Introduction were all normal. Echocardiography and a full A century ago Paul Ehrlich first used the term skeletal survey revealed nothing of note. A detailed eosinophil to describe this polymorphonuclear ophthalmological examination failed to detect any leucocyte. Its existence had first been hinted at by abnormality. Skin testing with a wide variety of Wharton Jones in 1846. The association of eosino- allergens was negative. There was no evidence of philia with metazoan parasitic infection has become drug hypersensitivity. Pulmonary function tests were well established since it was first recorded in ancylo- all within normal limits. Haematological investiga- stomiasis in 1891 by Muller and Rieder. Eosino- tion showed that the ESR was 3 mm in one hr; http://pmj.bmj.com/ philia occurring with allergies and atopic conditions haemoglobin concentration 15-3 g/dl; total leucocyte has been noted since the earliest identification of this count 19 x 109/l; absolute eosinophil count 8 17 x cell. Recently interest has become increasingly 101/1. A biopsy of the bone marrow showed hyper- focused on a number of disorders in which eosino- cellularity with large numbers of eosinophils. No philia occurs for no apparently identifiable cause primitive white cells were visible in either the marrow and which have been grouped together as the or in the peripheral blood. The patient refused to hypereosinophilic syndrome (Hardy and Anderson, undergo a liver biopsy. Regular haematological 1968). examinations have shown a persistent leucocytosis on October 2, 2021 by guest. Protected Two patients with this syndrome are described ranging from 15 x 109/l to 24 5 x 109/l with an eosino- whose outcomes have been totally different. philia of 38 to 66 %. Anaemia has never been present and the ESR continued to be normal. Serum immuno- Case reports globulin levels were normal. Repeated chest X-rays, Case I biochemical investigations and a further bone A 26-year-old policeman was first seen in 1976 marrow biopsy have failed to reveal any abnormali- with an 18-month history of sudden attacks of ties. An absolute eosinophil count performed in marked swelling of eyes and lips, unsuccessfully August 1979 showed an eosinophilia of 4 x 1O9/l; treated with various antihistaminic preparations. this has been the lowest count recorded. He has Other complaints included frequent episodes of dry continued to keep clinically well with occasional cough, at times severe enough to wake him up, attacks of peri-orbital oedema. The patient has not bouts of severe abdominal pain localized mainly received any treatment during these 3 years as there in the right iliac fossa, vague headaches and what has been no evidence of significant progressive he described as short periods of 'misty' vision. organ system involvement and dysfunction. 0032-5473/80/0700-0506 $02.00 © 1980 The Fellowship of Postgraduate Medicine Postgrad Med J: first published as 10.1136/pgmj.56.657.506 on 1 July 1980. Downloaded from

Case reports 507

Case 2 showed this to be hypercellular with moderate A 16-year-old boy was first seen at the Allergy eosinophilia but there was no evidence of a neo- Clinic in April 1976 with one year's history of plastic process. In spite of high doses of oral cortico- episodic attacks of wheezing and breathlessness. steroids (80 mg/day) his condition failed to improve. Clinical examination at the time revealed marked On 15 February 1979 he developed an itchy maculo- scattered bilateral expiratory rhonchi but was other- papular, bluish-red, tender rash over the flexor wise normal. Pulmonary function studies showed a aspect of both lower limbs and over the palms. This moderate degree of airway obstruction. His leucocyte diffuse involvement of the skin later evolved into a count was 11 -6 x 109/l with an eosinophilia of 14o%. petechial eruption over the legs. Biopsy of skin and Skin testing with a wide variety of allergens was underlying muscle of one of these areas showed no negative, as was repeated examination of blood and evidence of periarteritis nodosa. Over the next 2 faeces for ova, cysts or parasites. A chest X-ray was weeks there was slow deterioration of the patient's normal. There was no family history of atopic condition with clinical evidence of a multiplex disease and no evidence of drug hypersensitivity. mononeuropathy. The patient first complained of He attended the Allergy Clinic irregularly for a numbness and later complete anaesthesia of the period of about 2 years where his condition, diag- left foot, weakness of both upper and lower limbs nosed as bronchial asthma, was fairly well controlled and loss of sensation in his hands. Clinical examina- with salbutamol and beclomethasone diproprionate tion confirmed the loss of sensation; the wrist and inhalers and aminophylline suppositories. During ankle jerks were also completely absent. Repeated this time, various short courses of oral corticosteroids ESR estimations and eosinophil counts showed these had to be added to his therapeutic regimen because to be consistently elevated in spite of high oral and of attacks of acute breathlessness. The patient parenteral corticosteroid therapy. A series of ECGs underwent an appendectomy at another hospital taken at this time showed widening of the QRS in May 1978. Nine months later he was admitted complex and slurring of the downstroke of the R as a medical emergency to Al Sabah Hospital with a wave mainly in leads I, II and AVF, changes which

diagnosis of status asthmaticus. On this occasion were absent before and consistent with cardiac copyright. he also complained of a 3-week history of recurring involvement. A number of chest X-rays taken during bouts of low grade pyrexia and multiple flitting his last stay in hospital showed flitting soft shadows joint pains involving mainly wrists, fingers and appearing first in the right upper zone, then in the ankles. Clinical examination showed marked bi- left lower zone and again in the right lower and left lateral inspiratory and expiratory wheezing and middle and lower zones. These shadows had tender and swollen wrists and ankle joints but was disappeared by the time chest X-rays were taken on otherwise normal. His temperature was 37°C, 24 February and 6 March 1979. These showed BP 120/80 mmHg, pulse 120/min regular. Haemato- clear lung fields and a heart shadow which was not logical examination showed an ESR of 50 mm/hr enlarged. There was never any evidence of renal or http://pmj.bmj.com/ (Westergren); a leucocyte count of 17 1 x 109/l hepatic dysfunction. His blood pressure remained with an eosinophilia of 48 %. His serum immuno- normal throughout. His leucocyte count on 6 March globulin levels were normal. A chest X-ray and an 1979 was 36 x 109/l with an eosinophilia of 41 %; ECG were both normal. A full laboratory investiga- his ESR was 66 mm/hr. The following day he tion of his joint pains was carried out but no developed fast atrial fibrillation with multiple identifiable cause could be found. His wrist and ventricular ectopic beats and died suddenly. Per- ankle joints remained tender and swollen and, after mission to perform a post-mortem was refused. one week, in spite of corticosteroid treatment, his on October 2, 2021 by guest. Protected knees were similarly affected. Treatment with intra- Discussion venous hydrocortisone, high doses of oral predniso- The hypereosinophilic syndrome affects pre- lone, salbutamol and aminophylline had in the dominantly young adults and middle-aged men meantime relieved his acute breathlessness but the (20-45 years). As is the case with other syndromes of patient still had some impairment of his pulmonary undetermined aetiology, the hypereosinophilic syn- function and audible wheezing. At this time he drome has boundaries which are still blurred and started to complain of diffuse, vague abdominal largely indistinct. Owing to its apparent heterogenous pain which he claimed to be of similar nature to that nature involving a number of different organs and present before his appendectomy. No cause could systems, the syndrome had previously been given be found to explain his abdominal symptoms in spite various names, each indicating a specific characteris- of repeated laboratory and radiological investiga- tic of the condition. When the term was first tions. His ESR remained high (42 mm/hr) and so introduced by Hardy and Anderson in 1968 it did his eosinophil count (WBC 15-7 x 109/l with an included a whole list of diseases ranging from the eosinophilia of 38 %). Biopsy of his bone marrow benign self-limiting Loffler syndrome to conditions Postgrad Med J: first published as 10.1136/pgmj.56.657.506 on 1 July 1980. Downloaded from 508 Case reports of longer duration, more widespread involvement achieved good results in treating patients unrespon- and more serious prognosis including Loffler's sive to corticosteroid (Parillo et al., 1978). The pre- endomyocarditis, disseminated eosinophilic collagen sent authors had no opportunity to try using disease and eosinophilic leukaemia. Subsequently hydroxyurea in their second case. Dramatic Loffler's syndrome has been omitted by various improvement has also been reported in a single authors. It has been suggested that one should look case by using a continuous-flow cell separator to upon the hypereosinophilic syndrome as some form remove circulating eosinophils (Ellmann, Miller of 'diagnostic catchall' (Beeson and Bass, 1977). and Rappeport, 1974). In 1975 Chusid and his colleagues established It appears that the hypereosinophilic syndrome criteria in an attempt to define this syndrome. embraces a spectrum of disease entities. It is perhaps These criteria include a persistent eosinophilia of best regarded as a clinical and pathological con- 1-5 x 109/ for longer than 6 months, or death tinuum of conditions reflecting a hypersensitivity before 6 months associated with signs and symptoms or autoimmune process and which seem to range from of hypereosinophilic disease, lack of evidence of the benign to the rapidly fatal forms, having as known causes of eosinophilia, and multiple organ their common denominator infiltrative eosinophilia involvement. Both the present patients satisfied these (Parillo et al., 1979). The causative mechanisms criteria. The heart and bone marrow are most underlying this syndrome, in particular the role frequently involved but the CNS, skin and muscle, of the eosinophil and the nature of the cause or the gastrointestinal tract including liver, lungs, effect relationships of this cell, are still largely kidneys and the lymphatic system have all been unknown and remain to be determined. commonly reported to be affected. Initial observa- tions indicated a uniformly grave prognosis References (Benvenisti and Ultmann, 1969; Roberts, Liegler BEESON, P.B. & BASS, D.A. (1977) The Eosinophil, p. 180. and Carbone, 1969; Chusid et al., Recent W. B. Saunders Co., Philadelphia. 1975). BENVENISTI, D.S. & ULTMANN, J.E. (1969) Eosinophilic reports however suggest a more variable course, leukaemia. of five cases and review of literature. with a more favourable outcome in certain cases Report Annals of Internal Medicine, 71, 731. copyright. (Resnick and Myerson, 1971; Parillo, Fauci and BUSH, R.K., GELLER, M., BUSSE, W.W., FLAHERTY, D.K. & Wolff, 1978; Bush et al., 1978). Grave DICKIE, H.A. (1978) Response to corticosteroids in the prognostic hypereosinophilic syndrome. Archives ofInternal Medicine, signs are said to include a total white cell count 138, 1244. greater than 100 x 109/, eosinophil myeloblasts in CHUSID, M.J., DALE, D.C., WEST, B.C. & WOLFF, S.M. (1975) the peripheral blood, the presence of leukaemic The hypereosinophilic syndrome, Medicine, 54, 1. markers and the appearance of congestive heart EHRLICH, P. (1879) Uber die spezifischen Granulationen des Bliites. Archiv fur Anatomie und Physiologie (Leipzig), failure (Parillo et al., 1978). Cardiac disease has 3, 571. been implicated as the major cause of death in ELLMANN, L., MILLER, L. & RAPPEPORT, J. (1974) Leuko- this syndrome. phoresis therapy of a hypereosinophilic disorder. Journal of http://pmj.bmj.com/ The first patient seems to fit in the small group of the American Medical Association, 230, 1004. who have been as a HARDY, W.R. & ANDERSON, R.E. (1968) The hypereosino- patients reported having relatively philic syndromes. Annals of Internal Medicine, 68, 1220. benign form of the disease compatible with a mild MULLER, H.F. & RIEDER, H. (1891) Ueber Vorkommen prolonged course. As he had no evidence of signific- und klinische Bedeutung der Eosinophilen Zellen, Ehrlich, ant progressive organ involvement he received no in circulirenden Bliite der Menschen. Deutsches Archiv but is and fur klinische Medizin, 48, 96. treatment, being carefully regularly PARILLO, J.E., FAUNCI, A.S. & WOLFF, S.M. (1978) Therapy followed-up. Parillo has reported following-up 5 of the hypereosinophilic syndrome. Annals of Internal similar cases, for a period of 1-9 years, who all did Medicin, 89, 167. on October 2, 2021 by guest. Protected well clinically without being treated. High doses of PARILLO, J.E., LAWLEY, T.J., FRANK, M.M., KAPLAN, A.P. corticosteroids have been used to treat cases with & FAUCI, A.S. (1979) Immunologic reactivity in the hypereosinophilic syndrome. Journal of Allergy and severe multi-organ involvement, resulting in variable Clinical Immunology, 64, 113. responses. In general, the following characteristics RESNICK, N. & MYERSON, R.M. (1971) Hypereosinophilic have been found useful in predictinggoodresponses to syndrome. Report of two cases, with prolonged courses. corticosteroid the of American Journal of Medicine, 51, 560. therapy: presence angioedema; ROBERTS, W.C., LIEGLER, D.C. & CARBONE, P.O. (1969) elevated serum IgE levels; and a prolonged eosino- Endomyocardial disease and eosinophilia. A clinical penic response to single-dose challenge with pred- pathological spectrum. American Journal of Medicine, nisolone (Parillo et al., 1978). Busulphan, chlor- 46, 28. and methotrexate have WHARTON JONES, T. (1846) The blood corpuscle considered ambucil, 6-mercaptopurine in its different phases of development in the animal all been tried and found to have no significant series. Memoir l-Vertebrata. Philosophical Transactions of effect. It has been claimed that hydroxyurea has the Royal Society, 1, 63.