Arch Dis Child: first published as 10.1136/adc.62.6.601 on 1 June 1987. Downloaded from

Archives of Disease in Childhood, 1987, 62, 601-613

The idiopathic hypereosinophilic syndrome

M A ALFAHAM, S D FERGUSON, B SIHRA, AND J DAVIES Departments of Paediatrics and Cardiology, Royal Gwent Hospital, Newport, Gwent, Wales

SUMMARY A 14 year old girl with idiopathic hypereosinophilic syndrome is described. In addition to weight loss, anaemia, amenorrhoea, general lethargy, anorexia, mouth ulcers, blisters of hands and feet, and petechial skin rash, she had features of involvement of the cardiovascular system as the major complication. She responded well to treatment. After a comprehensive search of the published reports 18 cases of this syndrome were identified in children under 16 years. Fifteen of these children had involvement of the cardiovascular system as the major source of their morbidity and mortality. Summary of the clinical details and laboratory, biopsy, and necropsy findings of the involvement of the various organ systems of the 18 children is presented.

Hypereosinophilia of over 1 5x109/1 accompanies of her fingertips were tender on palpation. She was various diseases. In some cases no cause can be in congestive heart failure, with clinical evidence of found and the hypereosinophilia may be accompa- a pericardial effusion. A grade 2/4 pansystolic nied by multiple organ involvement, especially of murmur radiated from the apex to the axilla. There copyright. the cardiovascular system, with high morbidity and was no lymphadenopathy or , but the mortality. The idiopathic hypereosinophilic syn- liver was enlarged, 2 cm below the costal margin at drome is primarily a disease of middle age, but an the mid-clavicular line, and tender. occasional case has been encountered in children. Investigations. Her haemoglobin concentration was Case report 9.3 g/dl, mean corpuscular volume 78-7 fl, mean

corpuscular haemoglobin 26-7 pg, platelets 315 http://adc.bmj.com/ A 14 year old white girl presented six weeks after an x109/1, white blood cells 13*4x109/l (neutrophils illness that lasted 10 days, in which she had 45%, lymphocytes 15%, 1%, and eosi- developed mouth ulcers and blisters of the hands nophils 39% (5 2x109/l), showing partial degranula- and feet. These had settled spontaneously, but the tion), and erythrocyte sedimentation rate 66 mm in lethargy, nausea, and anorexia had persisted, and the first hour. The prothrombin and kaolin cephalin she had complained of aching limbs. She had clotting times were normal. Bone marrow biopsy described symptoms of increasing dyspnoea on and trephine examination showed a hypercellular minimal exertion and orthopnoea and developed a marrow with pronounced but no evi- on September 29, 2021 by guest. Protected fine petechial rash two days before presentation. dence of malignancy. Chest x ray film showed Her menses, which had started a year earlier, had considerable cardiac enlargement, with a globular stopped during the illness. shaped heart, pulmonary oedema with vascular She had had asthma for two years, which was redistribution, and a small right sided pleural controlled with regular inhalations of beclometha- effusion. M mode and 2D echocardiography showed sone and occasional inhalations of salbutamol. She a large pericardial effusion and areas of increased was allergic to feathers. There was no recent echodensity in the region of the apex of the left infectious or relevant travel history. ventricle and the posterior leaflet of the mitral On examination she was unwell, with a tempera- valve, suggesting endocardial thickening. An elec- ture of 38°C, pulse rate 128 beats/minute, regular, trocardiogram (ECG) showed sinus tachycardia. respiratory rate of 28/minute, blood pressure 130/ The serum electrolytes, glucose, and liver func- 100, weight 46 kg (25th centile), and height 163 cm tion tests yielded normal results except for a low (60th centile). There was a sparse petechial rash on albumin concentration (32 g/l) and slightly raised the upper trunk and upper arms, with splinter lactate dehydrogenase activity (351 IU/l (normal haemorrhages under her fingernails, and the pulps 100-300 IU/l)). Serum concentrations of vitamin B12 601 Arch Dis Child: first published as 10.1136/adc.62.6.601 on 1 June 1987. Downloaded from

602 Alfaham, Ferguson, Sihra, and Davies were 501-3 ng/l (normal 180-710 ng/l), of folate were restarted on inhaled beclomethasone. Within two 2-2 [sg/l (normal >2 5 [g/l), and of ferritin were 70 weeks of stopping oral steroids her eosinophil count ng/ml (normal 10-64 ng/ml). Protein electrophoresis increased to 1-5 x 109/l, and her total white blood cell (in g/l) showed total protein 62, albumin 25, count was 8 Ox 109/l. She was restarted on predniso- globulins 37, (alpha, 4 (normal 2-4), alpha2 10 lone at a dose of 10 mg on alternate days, after (5-8 5), beta 7 (7-11), and gamma 16 (18-16)), IgG which the eosinophil count returned to normal. She 19-22 (7-19), IgM 1 (0.50-2.2), and IgA 0-93 (0.9- remains anticoagulated with warfarin. 4.5). Serum total IgE concentration was 154 KU/l (normal <70*3 KU/l), functional CH50 3-25 min Discussion (1-82-3-62), C3 209 mg/dl (70-160), C4 29 mg/dl (10-30) properdin factor B 58-1 mg/dl (20-50). and Eosinophilia. Eosinophilia is the term applied to an C reactive protein 0-61 mg/dl (<0.6). Rheumatoid increase in the total blood eosinophil concentra- factor was 240 IU/ml (<15). Antibodies for nuclear, tions. In normal individuals living in the United mitochondrial, smooth muscle, parietal, canalicular, Kingdom the blood eosinophil count is less than glomerular, and reticulin were negative. Anti- 0-55x109/l. The practice of referring to eosinophil double stranded deoxyribonucleic acid (DNA) bind- concentrations as 'percentages' may be misleading ing capacity was 0-9 mg/l (normal <5 mg/I). and absolute figures (x 109/l) should be used. Serial blood cultures and faeces examination, Usually, the presence of eosinophilia has no det- throat swab, Paul-Bunnell test, and tests for viral rimental effect on the body and there is evidence titres, hepatitis B surface antigen, and hepatitis A that it may have a role in the body defence IgM yielded negative results. Antistreptolysin 0 was mechanisms. It accompanies many disease states, <100 Todd Units and antistreptococcal deoxyribo- mainly allergic and parasitic (Table 1), or it can be nuclease B 1/75 (upper limit 1/200). Antibodies to an incidental finding, but occasionally patients with cysticerci, filaria, fasciola, hydatid disease, tox- eosinophilia are found to have one of the more ocara, toxoplasma, Aspergillus fumigatus, Micro- serious and rarer causes, such as Hodgkin's disease.' polyspora faeni, and Thermoactinomyces vulgaris Treatment of the primary disease will usually copyright. were negative. Tests on urine samples showed resolve the eosinophilia. protein 3+, white blood cells <1/HPF, few granular casts and large number of epithelial cells and mucus, Hypereosinophilia. Hypereosinophilia is the term no growth, and a 24 hour protein excretion of 0-3 g. applied empirically when the blood eosinophil count Her karyotype was normal. On the basis of the clinical syndrome, eosinophilia

without a recognisable cause, and the echocardio- http://adc.bmj.com/ gram findings, a diagnosis of idiopathic hypereosi- Table 1 Some recognised causes ofeosinophilia. All nophilic syndrome was made. She was begun on disorders mentioned might cause hypereosinophilia. Those treatment with prednisolone 2 mg/kg/day, frusemide. that might be associated with a very high eosinophil count and folic acid, and was anticoagulated with warfarin. are underlined The signs of congestive heart failure improved 1 Allergic disorders: asthma, hay fever, allergic rhinitis, urticaria. eczema, appreciably within two days and the petechial rash pulmonary aspergillosis disappeared within three days. The eosinophil count 2 Drug reactions

returned to normal within two days. The erythrocyte 3 Parasitic infestations: visceral larva migrans (toxocariasis). trichinosis, on September 29, 2021 by guest. Protected ascariasis, hookworm disease, stronglyloidiasis, filariasis (tropical sedimentation rate, lactate dehydrogenase activity, eosinophilia), schistosomiasis, hydatid disease, malaria rheumatoid factor, and serum IgE and folate con- 4 Skin disorders: eczema, dermatitis herpetiformis, exfoliative dermatitis, psoriasis. pemphigus centrations returned to normal. The endocardial 5 Infections: brucellosis, scarlet fever, acute infectious lymphocytosis, echoes and pericardial effusion decreased within a infections due to mycobacteria, chlamydia, cytomegalovirus. and Pneumocvtis carinii few days of beginning treatment and had completely 6 Haematological: Fanconi's anaemia, thrombocytopenia with absent radii. disappeared within three months. Signs of mild post-splenectomy mitral regurgitation confirmed by Doppler ultra- 7 Neoplastic disorders: Hodgkin's disease, lymphosarcoma, leukaemia, carcinoma of lung and gut sound persisted. 8 Connective tissue/vasculitis/granulomatous disorders, especially those After her dramatic clinical improvement the involving the lungs: polyarteritis nodosa, Churg-Strauss syndrome, rheumatoid arthritis, systemic lupus erythematosis, scleroderma, steroids were gradually withdrawn and were stopped cryptogenic pulmonary eosinophilia after six weeks. She then developed mild broncho- 9 Immune deficiency disorders: congenital immune deficiency syndromes, on hyper-IgE with infections spasm excitement, which responded to inhaled 111 Miscellaneous: liver cirrhosis, radiation treatment, Crohn's disease, salbutamol with concomitant improvement in the ulcerative colitis, peritoneal dialysis, congenital heart disease, familial peak flow rate and forced expiratory volume in one eosinophilia (? autosomal dominant), idiopathic hypereosinophilic syndrome (including eosinophilic leukaemia) second/forced vital capacity percentage, and was Arch Dis Child: first published as 10.1136/adc.62.6.601 on 1 June 1987. Downloaded from

The idiopathic hypereosinophilic syndrome 603 is 1-5 x109/l or higher. Some disorders usually give tures of a leukaemic disease, characterised as rise to counts above 1 5 x 109/l, '-for example, drug eosinophilic leukaemia. Occasionally, the second reactions, intrinsic asthma (a surprising fact com- form terminates as a blast cell leukaemia.6 Hyper- pared with patients with extrinsic asthma, in whom eosinophilia as an isolated finding is not considered the eosinophil count is usually below 1x 109/l), to be a subgroup of this syndrome and probably has parasitic diseases, vasculitis and granulomatous no special clinical relevance, although the patient diseases, and neoplasms. Certain other diseases are will require regular reviews to exclude an occult associated with striking eosinophilia: leucocyte underlying disease process. counts of 30x 109/-1-00x 109/l or higher may be seen where 50-90% of the blood leucocytes may be Aetiology eosinophils. Diseases that are more commonly Several theories have been put forward to explain associated with such high counts are underlined2 in the idiopathic hypereosinophilic syndrome. Some Table 1, but in general any of the disease processes authors have claimed that it is an autoimmune mentioned in the Table-that is, any cause of disease.7 It is also possibly of a neoplastic nature.8 eosinophilia-may be associated with hypereosi- Parrillo et al showed a variety of immunological nophilia of whatever degree. abnormalities in the patients they studied.9 In most Hypereosinophilia can be primary. This may be of the cases described by Spry et al the findings an isolated finding. On the other hand, it might be suggested that a parasitic or allergic disease had associated with organ system dysfunction of varying preceded the onset of hypereosinophilia, and some extent and severity, the cardiovascular and nervous had high serum IgE concentrations.'0 These findings system and skin being most commonly involved- raised the possibility that an initial eosinopoietic the idiopathic hypereosinophilic syndrome. stimulus may lead to a late and exaggerated re- sponse, which persists. Carey et al reported a case of The idiopathic hypereosinophilic syndrome. In 1968 transient hypereosinophilia in an infant of a mother Hardy and Anderson drew attention to the fact that with this syndrome and suggested that the infant's persistent hypereosinophilia of any type could be hypereosinophilia could be a response to an eosi- copyright. associated with a range of similar complications and nophilia producing factor by the mother, with they grouped these together as the hypereosinophi- transplacental transfer.' l lic syndrome.3 Chusid et al confirmed this in 1975 A definitive cause for this syndrome, however, but restricted the diagnosis of hypereosinophilic has not been identified, but perhaps understanding syndrome to patients in whom no underlying cause the factors that influence the production and for the hypereosinophilia could be shown,4 so that distribution of the eosinophil and the mechanisms of the term idiopathic hypereosinophilic syndrome is tissue damage might give some insight into its http://adc.bmj.com/ applied when the following criteria are fulfilled: aetiology. (1) Eosinophilia >,1 5x109/l; (2) Persists for at least six months or fatal in a Factors that influence blood and tissue eosinophil shorter time; concentration. Eosinophils normally constitute a (3) Results in organ system dysfunction; small proportion of the circulating leucocytes. A (4) Absence of a recognised cause for the eosi- diurnal variaton that is the converse of the variation nophilia. in plasma corticosteroid concentrations occurs, with The term encompasses various diagnostic terms blood eosinophilia peaking at night. The production on September 29, 2021 by guest. Protected applied previously to a range of cases with almost of the eosinophil in the bone marrow is under the similar natural history, physical findings, laboratory control of the T lymphocytes. Lymphocytes also data, and autopsy findings, including eosinophilic produce factors that are chemotactic for eosinophils. leukaemia, disseminated eosinophilic collagen dis- Once eosinophils are released from the marrow they ease, and Loeffler's fibroplastic endocarditis with circulate in the blood only briefly, with a half life of eosinophilia. The condition called eosinophilic gas- six to 12 hours. They leave the blood stream and are troenteritis is probably part of the wide range of this distributed in tissues where they persist for at least syndrome.5 several days, being a tissue dwelling cell. They are The idiopathic hypereosinophilic syndrome has a most abundant in those tissues with epithelial wide range of severity with at least three different surfaces exposed to the environment, including the forms. Some patients only have hypereosinophilia gastrointestinal tract, the skin, and the upper with lung involvement and angio-oedema. Others respiratory tract.'2 present with (or develop) severe cardiac and central Apart from the lymphocytes, several other factors nervous system complications. A third group have may influence eosinophil concentrations in blood eosinophil cytogenic abnormalities and other fea- and tissue. On triggering and degranulating the mast Arch Dis Child: first published as 10.1136/adc.62.6.601 on 1 June 1987. Downloaded from

604 Alfaham, Ferguson, Sihra, and Davies Table 2 Summary ofclinical, biopsy, and necropsyfindings of19 children with the idiopathic hypereosinophilic syndrome

Author (years) Ageat Sex Presentingsymptono Cardiovascular Nervoussystem Skinlmusclejoints Renal Pulmonary Gastrointestinaltract Hepatic onset system (years) Bentley (1961)15 5 M Fever, macularrash, Postmortemexanona- Coma,decorticate, Macularand petec- Postmortemex- Drycough. Chestx Postmortemex- Hepatomegaly. Post- pctcchial rash, coma tion: Myocardial posturc. Cerebrospi- hial rash. Sub- amination: Petechiae ray: Lung infiltratcs. amination: Stomach mortem examination: petechiac and scar- nalfluidt No abnor- cutaneous nodulcs in both kidncys. Postmortem ex- dilatation. Peteehiae Blast cclls infiltration ring, mural thrombus mality. Postmortem ovcr parietal boncs. Blast cells infiltration amination: Hacmor- all over gastrointes- in left ventricic examination: Myclo- Biopsy: Lymphoid of kidncys and rhagic areas. Pul- tinal tract blastic infiltratc of and eosinophil infil- bladder monary oedema and meninges and brain tration mycloblast infiltra- tion Chusid (1975)4 5.5 M Pcriodic attacks of None Abnormal cice- Rash, angio-oedema. Mild to moderate in- Transient infiltration None Biopsy: 'Eosinophilic fever, rash, di- troencephalogram Skin biopsy: Perivas- termittent proteinur- triaditis' arrhoea. and angio- culitis, eosinophil in- ia odema filtration

De Vaan (1979)16 F Refusing to walk or Gallop rhythm and None Refusing to walk or Postmortem ex- Pncumonia. Post- None Hepatomegaly. Biopsy stand sinus tachycardia. stand. Skin biopsy: amination Eosi- mortem examination: Diffusc eosinophil infil- Postmortem examina- Papillomatosis and nophil infiltration, Increase in wcight of tration. Postonortem ex- tion: Endocardial scattered mature including blast cells lungs. Vascular amination Enlarged, thickening of left eosinophil infiltra- thrombi. Areas of eosinophil infiltration. atrium and suben- tion and hyperker- red blood ceil cxtra- ineluding blast cells docardial fibrosis with atosis. Muscle vasation, fibrin in iron pigment deposi- biopsy: Some focal alveolar spaces, and tion in myocardium atrophy, no cosi- formation of hyalinc of both ventricies and nophil infiltration membranes. Mac- left atrium. Coronary rophages and cosi- thrombosis. Eosi- nophils in alveolar nophil infiltration, in- spaces cluding blast cells in myocardium Donohue (19511)17 7 M Joint pains and feser Congestive heart fai- None Subcutaneous None Bilateral basal None Hepatomegaly lure, cardiomegaly, oedema, crepitations mild hypertension, arthralgia systolic murmur, mit- ral regurgitation

Engbaek (1942)18 7 M Headaches, fever. Congestive heart fai- Not described Not described Not described Postmortem ex- Not described None copyright. neck stiffness, and lure, cardiomegaly. amination Lungs in- arthralgia Postmortem examina- durated, cyanotic, tion: Hypertrophy, mottled, and in- dilatation and parietal flamed. Thrombi, thrombus in both vcn- oedema, and cosi- tricles and myoeardial nophil infiltration scarringlobliteration of coronarics

Engfeldt (1956):7 8 M Fatigue, anorexia, Terminal acute heart Electroencephalo- Pains in back and Moderate albuminur- Dyspnoca. cough. Abdominal pain and Hepatomegaly. Post- Case I abdominal pain. failure. Postmortem gram: Dysrhythmic neck. Postmortem ex- ia. hyaline casts, and Chest x ray: Peri- vomiting mortem examination: vomiting, dyspnoea, examination: Biven- amination: Eosi- red blood ccils in bronchial thickening Eosinophil infiltration

cough, pains in back trieular hypertrophy, nophil infiltration of urine. Uraemia. and pleural effusion. http://adc.bmj.com/ and neck thrombus in right au- muscle Postmortem ex- Postmortem ex- ricle and ventrieles. amination. Eosi- amination: Eosi- Endo-, myo-, and nophil infiltration of nophil infiltrate pericardial scarring kidneys and inflammatory cels infhltrate, mainly eosinophils

Case 2 10 M Headache, fever. Cardiomegaly. apical None See prescnting symp- Slight protcinuria Ateeetasis of right None Hepatomegaly rash, hyperkeratosis. systolic murmur toms. Subcutaneous middle lobe. Pleural and scaling of face, oedema and redness, effusion arms, and legs, pro- over wrists and nounced alopecia. knees. Arthralgia. conjunetivitis, myal- Biopsy ofskin and gia muscle. Inflamma- on September 29, 2021 by guest. Protected tory cells, especially eosinophils and plasmacells. Non- specific changes in small blood vessels, thrombosis, and en- darteritic changes Foasso (1984)19 6.7 F Sore throat. Tubercu- Congestive heart fai- Not described Ulceration of finger Mieroscopic haema- Pulmonary hyperten- Not described Hepatomegaly losis over previous 12 lure, cardiomegaly, tips. Swelling of right turia. Biopsy: Focal sion and ocdema months; on isoniazid, hypertension. Echo- sternoeeidomastoid. glomerulonephritis rifampicin. etham- cardiogram: Dilated Skin biopsy: Peri- butal left ventriele and left vascular inflamma- auncle. Catheterisa- tory cell infiltration. don: Left ventricular Muscle biopsy: En- lumen was reduced dothelial thiekening and alteration of media, no perivascu- lar inflammation

Continued Arch Dis Child: first published as 10.1136/adc.62.6.601 on 1 June 1987. Downloaded from

The idiopathic hypereosinophilic syndrome 605

Lymphaticlspleen Total while blooed Eosin philcount Haemoglobin Platelets ax 1094) Peripheralblood Bonemarrow Other laboratorn Duranton Treatmenr Authors diagnosis cell counrt (x lO1) f(10l at pgrdl) at atpresenattonKthite blood ell findings al presentation presentation presenrarion morphologs Spienomegaly. 185 157 25 8 6() 64% Polvmorpho- loitiallv: cosinophil 7 months C'ortionec, thcn Eosinophilic leukacmia Generalisedlym- nuclcarcosinophils, hyperplasia. Termi- busulphan. thcn phadenopathy. Post- 17% cosinophil nallv: an increase in cortisone, radiation mortem examination: metamyneloctcs. mvcloblastic forms tolungs. and Blast cells in lymph 3 4"',, eosinophil (85 3%.) 6-mcrcaptopurinc node and spleen myelocytes

Lymphadenopathy 35 7 21 42 13 40() Most primitive cell Not described Raised IgE Rcportcd Prednisone on Idiopathic hypereosi- during attacks. in thb circulation alivc 5 5 alternate days. in- nophilic svndrome man- Lymph node biopsy was cosinophil years after creasing to dailv ifesting as periodic attacki Hyperplastic germin- myclocytc. No mor- prcscntation during attacks of fever. malaise, angio- al centres. Increased phological abnor- oedema. and hypercosi- eosinophils mality of cosi- nophilia nophils

Generalised lvm- 499 19-96 7 63 Ncutrophils: Myolo- Hypercellular. Coombs and IgE 3 months Prednisolone, 6- Eosinophilic leukaomia o phadenopathy and cytes t%, metamy- Somc disrupted un- normal. IgG and mercaptopunne a variant of juvcnile splenomcgaly. clocytcs 2%. band identifiablo ccIls IgM raised. chronic mycloid Lymph node biopsy forms 4%/., seg- scemed to originate Latcx and antinuc- leukaemia Follicular hyperpla- mented 28%. Eosi- mainly from eosi- lear factor -ve. sia and some cosi- nophils: 411% band nophil scrios. In- "Rose" test +vc. nophils in blood ves- and scegmented crease in eosinophil Sorum folate low sels. Postmortem ex- forms, no younger series at all matura- normal. amination Enlarged forms. tion stages. Later Scrum vitamin B12 spleen and mesentric Lymphocytes: 23%,', on. decrease in raised. lymph nodc. Eosi- Monocvtls: 1% megakaryocytes nophil infiltration. Plasma cellcs: /, including blast cells in both

Ccrvical lym- 22-1 10-387 8 8 2101 Eosinophils dcfi- Blast forms 53%. Reported Adrenocortico- Eosinophilic leukacmia phadenopathy, sple- cicnt in granules mveloblasts0-5°/n alive 12 years trophic hormone. nomegaly cosinophil mvclo- later. ? Ann Eosinophils in- cytes 2 5%, cosi- treatment creased twice on its nophil metamvelo- withdrawal cytes 2 5%, juvenile cosinophils 2.5%, adult eosinophils 7-5% Postmortem ex- 101 2 78 936 Not described Not describod Eosinophils of Very cellular with I weeks Eosinophilic lcukaemia amination Sple- mature type. Vari- enormous increasc copyright. nomegaly. Eosi- able size, number, in cosinophils, es- nophil infiltration of and distribution of pecially lobulated lymph node and granules. 2-3 lobed forms splcen nuclei

Lymphadenopathy 113 79-1 Normochromic Normal Mature cosinophils Initially: Prolifera- Increased gamma- 8 months Adrenocortico- Disseminated cosinophi- and spicnomcgaly. anaomia initially. Later on, tion of globulin. decreased trophic hormone lic collagen disease Postmortem ex- moreimmature andnumerous albumin. Wasser- amination Eosi- forms mvelocytes, mainly mann reaction and nophil infiltration of eosinophils. Later: lupus crythematosis http://adc.bmj.com/ splcen and medias- 40'. Mature cosi- cell -ve. Heter- tinal lymph nodc nophils, 69% un- ophilic antitbtdies differentiated cells -ve. and vere fer ernthroblasts, neut- rophils, mvclocytes, or metamyeloctecs Generaliscd lym- 21 7 1()85 1() 8, normocytic Normal Mature eosinophils Hvpercellular. 30% Decreased crum Reported Adrenocortico- Disscominated eosinophi- phadenopathy anaemia Of myeloid series albumin, pro- wcll 22 trophic hormone, ltic collagen disease wer ecosinophils nounccd hoporgam- months later twice weekly. maglobulinaemia. Lowertng of dose Wasscermann reac- was followed by tion, heterophil relapse

antibttdy. C(ombs on September 29, 2021 by guest. Protected and lupus erythc- matosis cell -ve.

Not described 498 Normal Normal Several blast ccils, Autoimmune, anti- 3 years 6 Diuretics, digitalis, Idiopathic hypcreosi- which disappeared nuclear factor and months and steroids nophilic syndrome later on circulating immune complexs -vce. IgE normal

Continued Arch Dis Child: first published as 10.1136/adc.62.6.601 on 1 June 1987. Downloaded from

606 Alfaham, Ferguson, Sihra, and Davies Table 2 Summary ofclinical, biopsy, and necropsy findings of 19 children with the idiopathic hypereosinophilic syndrome (continued)

Author (years) Age at .Sex Presentingsymptoms Cardiovascular Nervoussystem .Skinlmusclejoints Renal Pulmonary Gastrointrestinaltract Hepatic onset system (years)

Goldstcin (1952)20 7 M Fsver. Pain in abdo- Nonc Nonc Nonc Nonc Nonc. Chest x ray None Nonc mcn and right axilla No abnormality

Hcrrcry-Gocpfcrt 9 M Myalgia, arthralgia, Congcstivc hart fai- Nono. Postmortem Myalgia, arthralgia. Not dcscribod Chest x ray Infiltra- Not dcscribed Hcpatomegaly. Post- Kr985) ) 7 fevcr, dclirium, facial lurc, cardiomcgaly, examinationt Cyster- Muscle btiopsy Non- tivc pulmonary mortem examination and leg ocdcma, systolic murmur (mit- icus in loft putamen, specific changes. Postmortem Eosinophil infiltration progrcssivc dyspnoca ral rcgurgitation). thought to bc an in- examination: Throm- Postmortem examina- cidcntal finding bi. infarcts, and in- tion Ventricular flammatory ccils in- dilatation and hyper- filtration by lympho- trophy. Thrombi in cytes, plasma cells, auricle and right ven- and cosinophils in tricle. Extensive sub- blood vesscis of lungs cndocardial fibrosis. Thrombosis and in- flammatory cct infil- tration by lympho- cytos. plasma cells. and cosinophils in blood vessels of myocardium Knoff (1958)22 7-5 F Fcver, soro throat, Acutc heart failurc. Extcnsivc involuntary Pains in fcct. Gcner- Urine Numerous Attacks of broncho- None Hcpatomcgaly copyright. pains in flct. anor- Cardiomcgaly. systo- chorciform hypor- alised coarsc brown/ cpithclial cells, no pncumonia, dysp- cxia, irritability lic murmur (mitral kincsia, pronounced macular rash. othcr abnormality noea and wheczing, regurgitation). Post- hypotonia. abscnt Erythema annulare. associated with car- mortem examination abdominal reflcxcs Joints ntormal diac decompensa- Left atrium greatly di- tion. Postmortem ex- lated. Ventricies cn- amination Lung larged, subendo- and ocdcma. Pncumonic myocardial fibrosis, changes with cosi- cspecially of loft. En- nophil infiltration docardial fibrosis. im- mediately under the postcrior lcaflet of mitral valvc, extcnd- ing into chordec tcn- http://adc.bmj.com/ dinii. Dcstruction of postcrior Icaflet of mitral valve. Arterial embolus in right lcg

Libanoff(1976)23 9 M Dizzy spclls, fatiguc, Congestivc heart fai- Nonc None None Dyspnoca. Chestcx Postmortem Hcpatomcgaly Post- shortness of breath lurc. cardiomcgaly. ray Incrcascd vascu- examination mortem examination systolic murmur (mit- lar markings. Post- Ascitcs Livcrcongestion ral rcgurgitation). mortem examination: Postmortem examina- Pleural cffusion tion: Extcnsivcen- docardial and mytcardial fibrosis in both vcntricics, most on September 29, 2021 by guest. Protected sevcrc at the apical position of right ven- tricle. Anterior leaflet of mitral valve was destrtyed. Pericardial cffusion. No cosi- nophil infiltratc Olson (1982)24 9 M Fatiguc, anoroxia, Cuongostivc hcart fai- Not described Skeletal mustle Not described Cough. Chest x ray Not dcscribed Clinically not describcd. wcight loss. fcvcr, lure, cardiomcgaly, biopsy: Normal Bilatcral alveolar Postmortem examina- cough systolic murmur (mit- pncumonitis. Biopsy tion Chronic passivc ral rcgurgitation). Hypersensitivity congestion and ccntri- Postmortem examina- pneumonitis iobular necrosis tion Bivcntricular cn- domyocardial fibrosis (mural thrombi in left ventriclc)

Raschc (1973)25 5 F Abdominal pain. di- Congcstivc hcart fai- Irritability, confu- Nonc Normal scrum crcatIti- Dyspnoca. Chest x Abdominal pain, Hcpatomegaly. Pro- arrhoca, vomiting, lurc, cardiomcgaly. sion. rcstlcssncss. nine and urea. Post- ray: Lincar opacitics diarrhoea, and longed prothombin fevcr Postmortem examina- coma. Postmortem mortemexamination,n in both bases. Post- vomiting timc. Postmortem ex- son Biventricular examination: Throm- Focal proliferative mortem examination amination Thrombi in dilatation, thrombi in bi in cerebral artcr- glomcrulitis Rcd and congested. sinusoids and cosinophil both vcntricics and iolcs and vcnulcs, Vascular thrombosis infiltration right atfium, contain- necrosis in thalamus and lung infarct ing abundant cosi- and ccrcbclum nophils. Coronary thrombttsis and myocardial necrosis Continued Arch Dis Child: first published as 10.1136/adc.62.6.601 on 1 June 1987. Downloaded from

The idiopathic hypereosinophilic syndrome 607

Lymphatic/spleen Total whie blood Eosin6philcount Haemoglobin Platelets (xol09/1 Peripheralblood Bone marrow Otherlaboratorv Duration Treatment Authors'diagnosis cell count (xIY/I) (x10 1) at Ig/dl)at atpresentation white blood cell findings atpresentation presentation presentatton morphology Spicnomegaly. 38-3 19-9 Moderatc Not dcscribed Ncutrophil: band Pronounccdin- Wasscrmannreac- When last None. The fcvcr. Eosinophilia infcetiosa Generalisedlym- anacmia' forms3%.seg- crcasc in cosi- tion -vc. secn7 spnomcgaly. and phadenopathy. Tcn- mcnted forms 31%. nophils. Othcrwisc Mantoux tcst 1/ monthslatcr anacmia dis- dcrlymph node in Eosinophil scg- normal 1000 +vc. was well and appeared spon- right axilla. Lymph mcnted forms 52%. Globulin and albu- attending tancously node biopsy: Eosi- Lymphocytcs 13% min normal school, but nophil and poly- Monocytes 1%. gencraliscd morph infiltration. Normal granulcs in lymphadcno- Fibrosis. In general, cosinophils pathy. picture is oflym- lcueyio3is phadcnitis, no other (19-6x 109/1). speific changes. no and cosi- parasites and no cal- nophilia cification (2-3o5h Il9 had per- sisted. On rc- peated cx- amination of blood, stools, and urine during the abovc period. no parasitcs

Gcncralised Iym- Not specified Not specified Not dcscribed Not described At some stagc whitc Incrcased cosi- Total scrum protein 6 months Not described Idiopathic hypercosi- phadenopathy. blood c9cl count was nophils of normal 82 g/100 ml, inver- nophilic syndromc Lymph node biopsy: 85lxo10 /I. with 75% morphology Post- sionofalbumin/ Non-specific. Post- cosinophilsof nor- mortem examina- globulin ratio. mortem examination: mal morphology tion: Incrcascd eosi- Latcx test, lupus Spicen and lymph nophils (98%) crythematosis ccls nodc cnlarged. Eosi- and antinucicar nophil infiltration factor -vc copyright. Gencraliscd lym- 27 18 3 Hypochromic Not deseribed Neutrophils: seg- Hypersegmentation Direct Coombs test 10 5 months Initially thought to Fibroplastic panctal en- phadenopathy. Spic- anaemia mented 13%. hand of the neutrophils. -vc. Albumin re- be rheumatic fever; docarditis with blood nomcgaly forms3%. metamy- Pronounced cosi- ducd. Alpha1 and penicillin, Glutisal cosiniophilia clicytes 1%. Eosi- nophilia. Eosi- alpha and gam- (salicylamide + nophils: segmented nophils 13-5%, cosi- maglioulins raised ethenazamide). and 54.. band forms nophil precursors Nirvanol (a hydan- 13%, myclocytes 21%. Mature cosi- toin) with some im- I'Y%. nonphlsshowdegra- provcmcnt. Later: Monocytcs 2%. nulation. No cvi- cortisone (5 days) Lymphocytes 13% dencc oflcukaemia http://adc.bmj.com/

Splenomcgaly. Post- 181-5 169-65 101 2 121) Incrcasc in cosi- Albumin and 3 years Not described Eosinophilic leukaemia mortem examination: niiphils at myclo- globulin normal Splccn congcstion cytc. metamyclo- cytc. and scgmented ells ccl. Slight incrpasm in plasma cclis on September 29, 2021 by guest. Protected

Clinically nut dc- 55 48-4 Not dcscribed Not described Maturc cosinophils Initially: cosinophil Rheumatoid factor months Diethyl carbama- Hypercisinophilic syn- scribed. Postmortem hyperplasia without -vc zinc with no im- dromc. prcicukacmia examination: Lymph an increasc in imma- provcmcnt. Predni- statc nodc and spiccn ture forms. Second sonc showed cxtramcdul- hiopsy: Hypcrccilu- lary hacmatopoicsis larity and incrcased mycloblasts (7%)

Spicnomegaly. Post- 152 130-72 8 195 8'% Scgmcnted Myclocytc: Erythro- Lupus crythemato- 25 days Digitalis. antibiitic. Acute rapidly fatal casc of mortem examination: neutrophils. 1% cytc ratio= 20: 1. sis cell -c. Total stcroids Logfflcr's cndocarditis Spicnicinfarcts. neutrophil band Predominant ccls scrum protein. pro- Eosinophil infiltra- fbrms. 5'% lympho- wcre cosinophil tcincluc- tion Oflymph nodc cytcs, 83% cosi- myclocytcs. trophorcsis. and and spiccn nophils. 2°% cosi- metamyclocytcs. immunoglobulin nophil band forms. and maturc cosi- nsrmal 1'Y. cosinophil nophils. Poitmor- myclocytes tem examination: Hyperplasia of cosi- orderlynophil scricsmaturationwith Continued Arch Dis Child: first published as 10.1136/adc.62.6.601 on 1 June 1987. Downloaded from

608 Alfaham, Ferguson, Sihra, and Davies Table 2 Summary ofclinical, biopsy, and necropsyfindings of19 children with the idiopathic hypereosinophilic syndrome (continued)

Author (years) Age at Sex Presentingsymptomc Cardiovascular Nervoussystem Skinimusclejoints Renal Pulmonary Gastrointestinaltract Hepatic onset svsrem (years) Spry (1983)10 14 M Diarrhoea, fever, None None None None Nonc Diarrhoea, abdomin- None swcating, abdominal al pain. Biopsy In- pain flammatory ccil infil- tration, containing many cosinophils in caccum.largc bowel. and ecCtum

Taligren (1974)26 3 M Persistent febrilc up- Postmoneem examina- Postmortem examina- Macular and pctec- Postmortem ex- Dyspnoea, cough. Bleeding Hepatomegaly. 1 ,! per respiratory tract tion Cardiomegaly, nion: Brain swelling. hial rash. Arthralgia, amination Enlarged Chest x ray Miliary mortem e-xamination: infeetion, drv cough, pericardial effusion, Leukaemic infiltrate slight swelling of kidneys. Leukaemic infiltrates. Postmor- Liver enlargement. dyspnoea, athralgia. epicardiai prtechiae. and atypiealeosi- knees infiltrate and atypical tem examination Leukaemia infiltrate and slight knees Haematoma in right nophils in lep- eosinophils Lungs enlarged. and atypical eosinophils swelling atria[alal, white mili- tomeninges Leukaemic infiltrate ary myocardial infil- and atypical rosi- trate. Leukaemic in- nophils filtrate and atypical cosinophils in myocardium

Thomsen (1939)27 11 M Sore throat, cervical Congestive heart fai- None Generalised oedema. Postmortem ex- Postmortem ex- None Hepatomegaly. Post- lymphadenopathy, lure, cardiomegaly, especially of face. amination Enlarged amination Oedema mortem exaintation fever pericarditis. Postmor- Migratory polyarthri- kidneys and blast cells infil- Blast cells infiltration tem exanination tis and joint deformi- trate Pericardial thickening ties and petechiae. Heart dilated, right half hypertrophic. Right auricle enlarged, with a parietal thrombus. Myocardial and en- docardial fibrosis

Yam (1972)28 12 M Cough, rhinorhoca, Congestive heart fai- Tingling and numb- Petechiac. Erythe- None Cough, chest pain. Diarrhoeaa, vomiting, Hepatomegaly. Post- fever, chest pain, lure, cardiomegaly. ness of hands. Hyper- matous rash. Muscle Chest x ray Diffuse nausea, abbdominal mortem examination: tingling, and numb- Postmortem exa,nina- regfcxia, clonus, and weakness granular infiltrate pain. Perf(forated Massive liverenlarge- ness of hands tion Heart dilated. bilateral Babinski and enlarged hilar antral ulceer ment. Hoavy infiltrate Mural thrombosis and syndrome lymph node. Post- of immature eosinophils fibroplastic parietal mortem examination and blast forms endocarditis Multiple infarctions and diffuse pneumo- copyright.

Present case 14 F Weight loss, anaemia. Congestive heart fai- None Peteehial rash, joint Haematuria Cough, breathiess- Diarrhoea and Hepatomegaly breathiessness, lure, cardiomegaly, and limb pains ness. Chestx ray In- vomiting anorexia, lethargy. hypertension, systolic terstital lung oede- nausea, diarrhoea murmur (mitral re- ma. vascular redis- and vomiting, ame- gurgitation), pericar- tribution, small right norrhoea, petechial dial effusion sided pieural effusion rash, mouth ulcers. blisters of hands and feet, with Joint and http://adc.bmj.com/ limb pain on September 29, 2021 by guest. Protected Arch Dis Child: first published as 10.1136/adc.62.6.601 on 1 June 1987. Downloaded from

The idiopathic hypereosinophilic syndrome 609

Lymphatic/spleen Total white blogd Eosti philcount Haemoglobin Platelets (x10911) Peripheralblood Bone marrow Other laboratory Duration Treatment Authors'diagnosis coai count (x 100/1) (xl(d1) at (gidl) at at presentation white blood cell findings at presentation presentation presentatton morphology Nonc 27 14-63 Not dcscribcd Not dcscribcd Vacuolatcd and Not describcd Iron deficiency Reported as Incompletc rc- Hypereosinophilic syn- dcgranulated anacmia. High doing wclt sponse to prcdniso- drome with isolated gas- cosinophils scrum IgG aftcr 4 years lonc. Very good trointcstinal tract involvce- whilc on rcsponse to mcnt Salazopyrinc. Salazopyrine Diarrhoca re- turns within one day of stopping it

Lymphadenopathy 79 57-275 Normal Normal 725% Segmcnted Initially: Increase in Mycoplasma orale It months 6-Mcrcaptopurine, Eosinophilic leukaemia. and spienomegaly. cosinophils, 2% mycloid cells pre- typc I isolated from prednisolone. mycoplasma could bc Postmortem ex- cosinophil myclo- dominantly cosi- bone marrow. Cold methotrexatc, vin- cause, result or fortuitous amination: Lymph cytes and metamy- nophils at various agglutinins raised. cristine node and spleen; clocytes stages of matura- Cryoprecipitate leukaemic infiltrate tion. 'Paraleucob- +ve. IgM G and A and atypical eosi- lasts' were scen. raisnd. Antinuclear nophils Later: Myclocytes factor -ve. with few 'para- Rheumatoid factor leucoblasts' domin- -ve, later bocame ated +vc. Lupus crythe- matosis cell -ve.

Gcneralised Iym- 42 31-08 10-3 140 Eosinophilsshowed Initially: Increase in Reduced serum 12months Splenic radiation Eosinophilicleukacmia phadenopathy. Sple- slightly basophilic stem cells and ceIls albumin. Wasser- and bone radiation nomcgaly. Postmor- cytoplasm, contain- of eosinophil series. mann reaction and tem examination: ing variable, mostly Later: Myeloblasts Widal's test -vc Blast cells infiltration few coarse granules. made 43% and of lymph node and Latcr mycloblasts 'erythropoiesis com- splecn appeared in increas- pietly paralysed' ing numbers

Hilar lymphadeno- 71 5l-12 12.8 Not described Mainly maturc cosi- Hyperccilular. Coombs test -vc. 4 months Prednisolone, Eosinophilic Icukaemia pathy and sple- nophils of differcnt Mycloid hyperplasia Lupuscrythemato- busulphan nomegaly. Postmor- sizc. vacuolatcd and cosinophilia sis ccil -vc. tem examination: cytoplasm, targe un- Massivc splenomeg- cvenly distributed aly and lymphadeno- granulcs, decrcased pathy. Heavy infil- numberofgranules trate of immature and mixed baso- copyright. cosinophils and blast cosinophilic gra- forms nules. Nuclear hypo- and mainly hypcrsegmentation None 13-4 5-2 9-3 315 Eosinophils, show- Hypercellular. Pro- IgE, rheumatoid After 15 Prednisolone, alter- Idiopathic hypereosi- ing partial degra- nounced eosino- factor. alpha2 glo- months doing nate days. Eosi- nophilic svndrome nulation philia bulin and IgG well nophils raised when raised. Albumin prednisolonc was low. Antinuclear stopped factor -ve. Serum folate low. Serum vitamin B12 high

normal http://adc.bmj.com/ on September 29, 2021 by guest. Protected Arch Dis Child: first published as 10.1136/adc.62.6.601 on 1 June 1987. Downloaded from

610 Alfaham, Ferguson, Sihra, and Davies cells and , peptides are released that are eosinophil and directly damage the myocardium.14 strongly chemotactic for eosinophils,8 12 such as Eosinophilic cationic protein may also be partially eosinophil chemotactic factor of anaphylaxis. Hista- responsible for the thromboembolic phenomena mine has also been shown to be chemotactic for characteristic of this syndrome. Eosinophil granules eosinophils. As IgE is directly involved in the contain potent neurotoxin, which causes demyelina- triggering of mast cells with subsequent degranula- tion and damage Perkinje cells in laboratory ani- tion the association of eosinophilia with IgE medi- mals. It might be that the same, or similar, neuro- ated immediate hypersensitivity reaction can be toxin causes disease in patients with this syndrome. 12 explained by such chemotactic mechanisms. Eosi- Other potential mechanisms of tissue damage nophil chemotactic factors that are derived from the include tissue infiltration with eosinophils (space complement system include the proteolytic fragment occupying) and thromboembolic phenomena related of C5, C5a, and the trimolecular complex C567. to thrombi associated with endomyocardial disease. Other recognised factors are leucotriene B4 and substances produced by some parasites.12 Incidence On the other hand, factors that have an eosi- Idiopathic hypereosinophilic syndrome mainly nopenic effect on blood concentrations include affects patients between 20 and 50 years of age. The corticosteroids and beta adrenergic agonists, as well incidence is not known, but over 150 patients from as an eosinopenic factor present in inflamma- different age groups have now been described. After tory exudate, which may account for the well a comprehensive search of the published reports 18 documented eosinopenic response that is associated cases of this syndrome were identified in children with most bacterial and viral infections, apart from a under 16 years.4 7 10 15 28 few exceptions (see Table 1).1 12 Summary of the clinical details and laboratory, biopsy, and autopsy findings of the involvement of Mechanisms of tissue damage in the idiopathic the various organ systems of the 18 children hypereosinophilic syndrome. In addition to their reported in these reports and the present case is possible beneficial role, there is evidence that the shown in Table 2. Fourteen boys and five girls were copyright. eosinophils may occasionally be harmful to the host. affected-that is, the male predominance is less For example, in asthma, it was generally held until pronounced than in older age groups. recently that the eosinophils were protective, des- troying the mast cell products that induce such The cardiovascular system in the idiopathic clinical features of asthma as bronchoconstriction hypereosinophilic syndrome and changes in blood supply to the lungs. Several Involvement of the cardiovascular system is the groups now feel, however, that the eosinophils may main source of morbidity and mortality. Sixteen http://adc.bmj.com/ be responsible for some of the serious complications children showed evidence of this. Cardiovascular of asthma, including bronchial epithelial cell injury involvement in these children was generally similar and even pulmonary fibrosis. It is the proteins in the to that in adult patients in its frequency and distinctive cytoplasmic granules of the eosinophil distribution. that are suspected of damaging the lungs.' The cardiovascular involvement in this syndrome The cytotoxic effect of eosinophil granular basic is nearly always biventricular, but it spares the proteins on parasites has led to an examination of outflow tracts. Characteristically, patients develop the potential cytotoxicity for mammalian cells. 12 endocarditis with overlying thrombosis and, later, on September 29, 2021 by guest. Protected Cultured intestinal, splenic, cutaneous, and per- endomyocardial fibrosis. Involvement of the sup- ipheral blood mononuclear cells are damaged by porting structures of the atrioventricular valves major basic proteins. There is evidence that these often results in mitral and sometimes tricuspid enzymes play a major role in the pathogenesis of the regurgitation. The endocardial thrombi give rise to idiopathic hypereosinophilic syndrome.8 Of these peripheral emboli, which further complicate the proteins, the eosinophilic major basic protein, as clinical picture. Patients with this syndrome are also well as the eosinophilic cationic protein, were found at increased risk of developing thromboembolic to be raised in the serum samples of patients with disease in blood vessels of medium to large size. this syndrome.8 11) Furthermore, degranulated eosi- Disease in small blood vessels also occurs, with nophils in peripheral blood smears are common in thickening of intimal tissue.6 idiopathic hypereosinophilic syndrome and their Cases that were previously called Loeffler's eosi- presence seems to be a valuable indication of nophilic endocarditis are probably synonymous with endocardial disease.'3 In vitro experiments with rat hypereosinophilic syndrome with severe cardiac myocardial cells support the idea that components involvement. It is now accepted that there is a range of the granules are released from the circulating of eosinophilic heart disease, varying in severity Arch Dis Child: first published as 10.1136/adc.62.6.601 on 1 June 1987. Downloaded from

The idiopathic hypereosinophilic syndrome 611 from Loeffler's eosinophilic endocarditis, the most however, the primary involvement of the various acute and fatal form, to Ugandan type endomyocar- systems was also proved by biopsy or necropsy dial fibrosis. The heart in the condition described in findings (Table 2). 1948 in West Africa by Davies, originally called In addition to the involvement of the cardiovascu- endocardial fibrosis and later endomyocardial lar system, which was the major problem in our fibrosis,29 is indistinguishable from the heart of a present case, there are certain other features that patient with Loeffler's fibroplastic parietal endo- need some emphasis. carditis, or eosinophilic leukaemia. Further, en- (1) Previous history of asthma. None of the other domyocardial fibrosis is also known to present in 18 children had a similar history. Also there non-tropical countries. are a few well described adult patients who There have been reports of patients who present had both bronchial asthma and this with an initial hypereosinophilic illness, survive, and syndrome.6 10 are found at necropsy to have endomyocardial (2) Dramatic response to corticosteroids. fibrosis, sometimes with features identical to Ugan- (3) Raised serum rheumatoid factor. This has dan type endomyocardial fibrosis.31 Endomyocar- rarely been observed in patients with this dial fibrosis seems to be the burnt out phase of an syndrome.9 32 Furthermore, the concentra- eosinophilic heart disease. tion decreased after treatment. Hearts from patients with heart failure secondary (4) The serum IgE concentration returned to to other causes of hypereosinophilia also had normal after treatment. This has also been necropsy appearances similar to those of patients reported by Bush.32 The changes in serum with the idiopathic hypereosinophilic syndrome. IgE concentration might be of benefit in Thus the common denominator of the cardiac lesion monitoring progress, as is the eosinophil is probably the eosinophilia itself and not an count. unrecognised underlying factor.8 (5) Low total white blood cell count at presenta- In a study of 50 patients Harley et al defined the tion, which, like initial high serum IgE con- non-cardiovascular characteristics that distinguish centration, has been reported to be associated copyright. patients at risk of developing endomyocardial fibro- with a better response to treatment. sis from those who remained free of heart disease.31 (6) In our case, her illness initially started with Patients with clinically overt heart disease were mouth ulcers and blisters of hands and feet. more likely (p

612 Alfaham, Ferguson, Sihra, and Davies benefit, unless the patient also had increased whole occurs secondary to a defined condition-for blood viscosity and widespread vessel occlusions. example, drug reactions and parasitic disease' 2 4 Patients without dysfunction of organ systems are -so that early identification and prompt treatment not treated and are followed closely at three to six of the primary condition, which usually results in the monthly intervals.34 If patients show dysfunction of disappearance of the hypereosinophilia, may pre- organ systems they are treated initially with corticos- vent these complications. teroids. If the disease stabilises or improves the steroid is continued on an alternate day regimen. We thank Professor C J F Spry for reading the paper and for his Ultimately, it is tapered to the lowest possible dose helpful advice, Mrs T Wisniewski for technical help, Mr G Titley that will control that disease. If the disease pro- for his help in the search of the publications, and the Medical gresses despite steroids a cytotoxic agent, specifically Illustration Department at the Royal Gwent Hospital. hydroxyurea, is added with the aim of maintaining the leucocyte count at less than 1Ox109/1 with a normal eosinophil count. References Spry CJF. Eosinophilia. Practitioner 1982;226:79-88. Prognosis 2 Lukens JN. Eosinophilia in children. Pediatr Clin North Am Favourable prognostic factors that indicate better 1972;19:969-81. response to treatment are high serum IgE concen- 3 Hardy WR, Anderson RE. The hypereosinophilic syndromes. Ann Intern Med 1968;68:1220-9. tration, the presence of angioneurotic oedema, and 4 Chusid MJ, Dale DC, West BC, Wolff SM. The hypereosinophi- unmistakable within a few hours after lic syndrome: analysis of fourteen cases with review of the the first dose of prednisolone. Unfavourable prog- literature. Medicine (Baltimore) 1975;54:1-27. 5 Trounce JQ, Tanner MS. Eosinophilic gastroenteritis. Arch Dis nostic signs are pronounced leucocytosis and Child 1985;60:1186-8. myeloblasts in peripheral blood and congestive 6 Spry CJF. The hypereosinophilic syndrome: clinical features, heart failure.4 34 It is also important to look for the laboratory findings and treatment. Allergy 1982;37:539-51. possibility of high serum vitamin B12 and low serum 7 Engfeldt B, Zetterstrom R. Disseminated eosinophilic "collagen

disease": a clinical and pathological study of a clinical entity copyright. folate concentrations, abnormal leucocyte alkaline related to Loeffler's syndromes. Acta Med Scand 1956;153: phosphatase activity, chromosomal abnormalities, 337-53. and basophilia of more than 3%. These leukaemic Fauci AS, Harley JB, Roberts WC, Ferrans VJ, Gralnick HR, markers as a group seem to have a predictive value Bjornson BH. The idiopathic hypereosinophilic syndrome: clinical, pathophysiologic and therapeutic considerations. Ann in terms of symptomatology and response to treat- Intern Med 1982;97:78-92. ment. Those with positive findings had more severe 9 Parrillo JE, Lawley TJ, Frank MM, Kaplan AP, Fauci AS. disease.4 Immunologic reactivity in hypereosinophilic syndrome. J Allergy Clin Immunol 1979;64:113-21. http://adc.bmj.com/ " Spry CJF, Davies J, Tai PC, Olsen EGJ, Oakley CM, Good- Eosinophilic leukaemia win JF. Clinical features of fifteen patients with the hyper- Many patients of various age groups with this eosinophilic syndrome. Q J Med 1983;52:1-22. syndrome, including eight children in our review, Carey JP, Burke AC, Carter WH. Transient hypereosinophilia were reported as having eosinophilic leukaemia. in the infant of a mother with hypereosinophilic syndrome. Arch Intern Med 1982;142:1754-5. Although this is one extreme of this syndrome, most 12 Weller PF. Eosinophilia. J Allergy Clin Immunol 1984;73:1-10. patients do not seem to have leukaemia. Rickles and 13 Olsen EG, Spry CJF. The pathogenesis of Loffler's endomyocar- Miller suggested the following criteria for a diagnosis dial disease and its relationship to endomyocardial fibrosis. Prog of eosinophilic leukaemia.35 Cardiol 1979;8:281-303. on September 29, 2021 by guest. Protected (1) Pronounced and persistent 4 Tai PC, Hayes DJ, Clark JB, Spry CJF. Toxic effects of eosinophilia, eosinophil secretion products on isolated rat'beart cells in vitro. associated with immature forms, either in the Biochem J 1982;204:75-80. peripheral blood or bone marrow. '5 Bentley HP, Reardon AE, Knoedler JP, Krivit W. Eosinophilic (2) Greater than 5% blast forms in the bone leukemia: report of a case, with review and classification. Am J marrow. Med 1961;30:310-22. De Vaan GAM, van Haelst UJG. Hypereosinophilia syndrome (3) Tissue infiltration by immature cells of pre- or eosinophilic leukaemia: a case report of a one year old infant. dominantly eosinophilic type. Helv Paediatr Acta 1979;34:271-9. (4) An acute natural history measured in months, 17 Donohue WL, Snelling CE, Jackson SH, et al. Pituitary adrenocorticotropic hormone (ACTH) therapy in eosinophilic accompanied by anaemia, thrombocytopenia, leukaemia. JAMA 1950;143:154-7. increased susceptibility to infection, and/or 18 Engbaek HC, Heerup L, Thomsen S. Om den eosinofile haemorrhage. leukaemi og "eosinophilia Leukaemoides". Nord Med Although the hypereosinophilic syndrome was 1942;14:1535-51. defined in the context of eosi- 19 Foasso M-F, Hermier M, Age C, Mermillon M, Francois R. Le originally primary syndrome hypereosinophilique avec atteinte endomyocardique nophilia, it is now recognised that the same involve- chez l'enfant; analyse critique de la litterature a propos d'un cas. ment of organ systems may arise when eosinophilia Pediatrie 1984;39:147-55. Arch Dis Child: first published as 10.1136/adc.62.6.601 on 1 June 1987. Downloaded from

The idiopathic hypereosinophilic syndrome 613 2(1 Goldstein von R. Eosinophilia infectiosa. Annales Paediatrici Primary restrictive cardiomyopathy:non-tropical endomyocar- 1952;179:216-26. dial fibrosis and hypereosinophilic heart disease. Br Heart J 21 Herrera-Goepfert R, Larraza-Hernandez 0. Sindrome 1977;39:399-413. hipereosinofilico. Bol Med Hosp Infant Mex 1985;42:201-6. 31 Harley JB, Fauci AS, Gralnick HR. Noncardiovascular findings 22 Knorr D, Scheppe KJ. Endocarditis parietalis fibroplastica mit associated with heart disease in idiopathic hypereosinophilic Bluteosinophilie (Loffler) bei einem siebenjahrigen Kind. Zeits- syndrome. Am J Cardiol 1983;52:321-4. chiftfur Kinderheilkunde 1958;81:102-12. 32 Bush RK, Geller M, Busse WW, Flaherty DK, Dickie HA. 23 Libanoff AJ, McMahon NJ, Eosinophilia and endomyocardial Response to corticosteroids in hypereosinophilic syndrome: fibrosis. Am J Cardiol 1976;37:438-41. association with increased serum IgE levels. Arch Intern Med 24 Olson TA, Virmani R, Ansinelli RA, et al. Cardiomyopathy in a 1978;138:1244-6. child with hypereosinophilic syndrome. Pediatr Cardiol 33 Leiferman KM, O'Duffy JD, Perry HO, et al. Recurrent 1982;3: 161-9. incapacitating mucosal ulcerations. A prodrome of the 25 Rasche RFH, Kelsch RD, Weaver DK. Loffler's endocarditis in hypereosinophilic syndrome. JAMA 1982;247:1018-20. childhood. Br Heart J 1973;35:774-6. 34 Parrillo JE, Fauci AS, Wolff SM. The hypereosinophilic 26 Tallgren LG, Wegelius R, Andersson LC, Jansson E. Eosi- syndrome: dramatic response to therapeutic intervention. Trans nophilic leukaemia: recovery of mycoplasma orale from the Assoc Am Physicians 1977;90:135-44. bone marrow. Acta Med Scand 1974;195:87-92. 35 Rickles FR, Miller DR. Eosinophilic : report 27 Thomsen S, Plum P. Eosinophilic leukemia. Acta Med Scand of a case, its relationship to eosinophilic leukemia and review of 1939;101:1 16-37. the pediatric literature. J Pediatr 1972;80:418-28. 28 Yam LT, Li Cy, Necheles RF, Katayama I. Pseudocosinophilia. eosinophilic endocarditis and eosinophilic leukaemia. Am J Med Correspondence to Dr M A Alfaham, Department of Child 1972;53: 193. Health, University Hospital of Wales, Heath Park, Cardiff CF4 29 Davies JNP. Endocardial fibrosis in Africans. East Afr Med J 4XN, Wales. 1948;25: 10-4. 3() Chew CYC, Ziady GM, Raphael MJ, Nellen M, Oakley CM. Received 5 January 1987 copyright. http://adc.bmj.com/ on September 29, 2021 by guest. Protected