The idiopathic hypereosinophilic syndrome · is 1-5x109/l or higher. Somedisorders usually give rise to counts above 1 5x109/l,'-forexample, drug reactions, intrinsic asthma (a surprising

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

The idiopathic hypereosinophilic syndromeM 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. Inaddition to weight loss, anaemia, amenorrhoea, general lethargy, anorexia, mouth ulcers, blistersof hands and feet, and petechial skin rash, she had features of involvement of the cardiovascularsystem as the major complication. She responded well to treatment.

After a comprehensive search of the published reports 18 cases of this syndrome wereidentified in children under 16 years. Fifteen of these children had involvement of thecardiovascular system as the major source of their morbidity and mortality. Summary of theclinical details and laboratory, biopsy, and necropsy findings of the involvement of the variousorgan systems of the 18 children is presented.

Hypereosinophilia of over 1 5x109/1 accompaniesvarious diseases. In some cases no cause can befound and the hypereosinophilia may be accompa-nied by multiple organ involvement, especially ofthe cardiovascular system, with high morbidity andmortality. The idiopathic hypereosinophilic syn-drome is primarily a disease of middle age, but anoccasional case has been encountered in children.

Case report

A 14 year old white girl presented six weeks after anillness that lasted 10 days, in which she haddeveloped mouth ulcers and blisters of the handsand feet. These had settled spontaneously, but thelethargy, nausea, and anorexia had persisted, andshe had complained of aching limbs. She haddescribed symptoms of increasing dyspnoea onminimal exertion and orthopnoea and developed afine petechial rash two days before presentation.Her menses, which had started a year earlier, hadstopped during the illness.She had had asthma for two years, which was

controlled with regular inhalations of beclometha-sone and occasional inhalations of salbutamol. Shewas allergic to feathers. There was no recentinfectious or relevant travel history.On examination she was unwell, with a tempera-

ture of 38°C, pulse rate 128 beats/minute, regular,respiratory rate of 28/minute, blood pressure 130/100, weight 46 kg (25th centile), and height 163 cm(60th centile). There was a sparse petechial rash onthe upper trunk and upper arms, with splinterhaemorrhages under her fingernails, and the pulps

of her fingertips were tender on palpation. She wasin congestive heart failure, with clinical evidence ofa pericardial effusion. A grade 2/4 pansystolicmurmur radiated from the apex to the axilla. Therewas no lymphadenopathy or splenomegaly, but theliver was enlarged, 2 cm below the costal margin atthe mid-clavicular line, and tender.

Investigations. Her haemoglobin concentration was9.3 g/dl, mean corpuscular volume 78-7 fl, meancorpuscular haemoglobin 26-7 pg, platelets 315x109/1, white blood cells 13*4x109/l (neutrophils45%, lymphocytes 15%, monocytes 1%, and eosi-nophils 39% (5 2x109/l), showing partial degranula-tion), and erythrocyte sedimentation rate 66 mm inthe first hour. The prothrombin and kaolin cephalinclotting times were normal. Bone marrow biopsyand trephine examination showed a hypercellularmarrow with pronounced eosinophilia but no evi-dence of malignancy. Chest x ray film showedconsiderable cardiac enlargement, with a globularshaped heart, pulmonary oedema with vascularredistribution, and a small right sided pleuraleffusion. M mode and 2D echocardiography showeda large pericardial effusion and areas of increasedechodensity in the region of the apex of the leftventricle and the posterior leaflet of the mitralvalve, suggesting endocardial thickening. An elec-trocardiogram (ECG) showed sinus tachycardia.The serum electrolytes, glucose, and liver func-

tion tests yielded normal results except for a lowalbumin concentration (32 g/l) and slightly raisedlactate dehydrogenase activity (351 IU/l (normal100-300 IU/l)). Serum concentrations of vitamin B12

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602 Alfaham, Ferguson, Sihra, and Davies

were 501-3 ng/l (normal 180-710 ng/l), of folate were2-2 [sg/l (normal >2 5 [g/l), and of ferritin were 70ng/ml (normal 10-64 ng/ml). Protein electrophoresis(in g/l) showed total protein 62, albumin 25,globulins 37, (alpha, 4 (normal 2-4), alpha2 10(5-8 5), beta 7 (7-11), and gamma 16 (18-16)), IgG19-22 (7-19), IgM 1 (0.50-2.2), and IgA 0-93 (0.9-4.5). Serum total IgE concentration was 154 KU/l(normal <70*3 KU/l), functional CH50 3-25 min(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). andC reactive protein 0-61 mg/dl (<0.6). Rheumatoidfactor was 240 IU/ml (<15). Antibodies for nuclear,mitochondrial, smooth muscle, parietal, canalicular,glomerular, and reticulin were negative. Anti-double stranded deoxyribonucleic acid (DNA) bind-ing capacity was 0-9 mg/l (normal <5 mg/I).

Serial blood cultures and faeces examination,throat swab, Paul-Bunnell test, and tests for viraltitres, hepatitis B surface antigen, and hepatitis AIgM yielded negative results. Antistreptolysin 0 was<100 Todd Units and antistreptococcal deoxyribo-nuclease B 1/75 (upper limit 1/200). Antibodies tocysticerci, filaria, fasciola, hydatid disease, tox-ocara, toxoplasma, Aspergillus fumigatus, Micro-polyspora faeni, and Thermoactinomyces vulgariswere negative. Tests on urine samples showedprotein 3+, white blood cells <1/HPF, few granularcasts and large number of epithelial cells and mucus,no growth, and a 24 hour protein excretion of 0-3 g.Her karyotype was normal.On the basis of the clinical syndrome, eosinophilia

without a recognisable cause, and the echocardio-gram findings, a diagnosis of idiopathic hypereosi-nophilic syndrome was made. She was begun on

treatment with prednisolone 2 mg/kg/day, frusemide.and folic acid, and was anticoagulated with warfarin.The signs of congestive heart failure improved

appreciably within two days and the petechial rashdisappeared within three days. The eosinophil countreturned to normal within two days. The erythrocytesedimentation rate, lactate dehydrogenase activity,rheumatoid factor, and serum IgE and folate con-centrations returned to normal. The endocardialechoes and pericardial effusion decreased within a

few days of beginning treatment and had completelydisappeared within three months. Signs of mildmitral regurgitation confirmed by Doppler ultra-sound persisted.

After her dramatic clinical improvement thesteroids were gradually withdrawn and were stoppedafter six weeks. She then developed mild broncho-spasm on excitement, which responded to inhaledsalbutamol with concomitant improvement in thepeak flow rate and forced expiratory volume in one

second/forced vital capacity percentage, and was

restarted on inhaled beclomethasone. Within twoweeks of stopping oral steroids her eosinophil countincreased to 1-5 x 109/l, and her total white blood cellcount was 8 Ox 109/l. She was restarted on predniso-lone at a dose of 10 mg on alternate days, afterwhich the eosinophil count returned to normal. Sheremains anticoagulated with warfarin.

Discussion

Eosinophilia. Eosinophilia is the term applied to anincrease in the total blood eosinophil concentra-tions. In normal individuals living in the UnitedKingdom the blood eosinophil count is less than0-55x109/l. The practice of referring to eosinophilconcentrations as 'percentages' may be misleadingand absolute figures (x 109/l) should be used.Usually, the presence of eosinophilia has no det-rimental effect on the body and there is evidencethat it may have a role in the body defencemechanisms. It accompanies many disease states,mainly allergic and parasitic (Table 1), or it can bean incidental finding, but occasionally patients witheosinophilia are found to have one of the moreserious and rarer causes, such as Hodgkin's disease. 'Treatment of the primary disease will usuallyresolve the eosinophilia.

Hypereosinophilia. Hypereosinophilia is the termapplied empirically when the blood eosinophil count

Table 1 Some recognised causes of eosinophilia. Alldisorders mentioned might cause hypereosinophilia. Thosethat might be associated with a very high eosinophil countare underlined

1 Allergic disorders: asthma, hay fever, allergic rhinitis, urticaria. eczema,pulmonary aspergillosis

2 Drug reactions3 Parasitic infestations: visceral larva migrans (toxocariasis). trichinosis,

ascariasis, hookworm disease, stronglyloidiasis, filariasis (tropicaleosinophilia), schistosomiasis, hydatid disease, malaria

4 Skin disorders: eczema, dermatitis herpetiformis, exfoliative dermatitis,psoriasis. pemphigus

5 Infections: brucellosis, scarlet fever, acute infectious lymphocytosis,infections due to mycobacteria, chlamydia, cytomegalovirus. andPneumocvtis carinii

6 Haematological: Fanconi's anaemia, thrombocytopenia with absent radii.post-splenectomy

7 Neoplastic disorders: Hodgkin's disease, lymphosarcoma, leukaemia,carcinoma of lung and gut

8 Connective tissue/vasculitis/granulomatous disorders, especially thoseinvolving the lungs: polyarteritis nodosa, Churg-Strauss syndrome,rheumatoid arthritis, systemic lupus erythematosis, scleroderma,cryptogenic pulmonary eosinophilia

9 Immune deficiency disorders: congenital immune deficiency syndromes,hyper-IgE with infections

111 Miscellaneous: liver cirrhosis, radiation treatment, Crohn's disease,ulcerative colitis, peritoneal dialysis, congenital heart disease, familialeosinophilia (? autosomal dominant), idiopathic hypereosinophilicsyndrome (including eosinophilic leukaemia)



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is 1-5 x109/l or higher. Some disorders usually giverise to counts above 1 5 x 109/l, '-for example, drugreactions, intrinsic asthma (a surprising fact com-

pared with patients with extrinsic asthma, in whomthe eosinophil count is usually below 1x 109/l),parasitic diseases, vasculitis and granulomatousdiseases, and neoplasms. Certain other diseases are

associated with striking eosinophilia: leucocytecounts of 30x 109/-1-00x 109/l or higher may be seenwhere 50-90% of the blood leucocytes may beeosinophils. Diseases that are more commonlyassociated with such high counts are underlined2 inTable 1, but in general any of the disease processesmentioned in the Table-that is, any cause ofeosinophilia-may be associated with hypereosi-nophilia of whatever degree.

Hypereosinophilia can be primary. This may bean isolated finding. On the other hand, it might beassociated with organ system dysfunction of varyingextent and severity, the cardiovascular and nervous

system and skin being most commonly involved-the idiopathic hypereosinophilic syndrome.

The idiopathic hypereosinophilic syndrome. In 1968Hardy and Anderson drew attention to the fact thatpersistent hypereosinophilia of any type could beassociated with a range of similar complications andthey grouped these together as the hypereosinophi-lic syndrome.3 Chusid et al confirmed this in 1975but restricted the diagnosis of hypereosinophilicsyndrome to patients in whom no underlying causefor the hypereosinophilia could be shown,4 so thatthe term idiopathic hypereosinophilic syndrome isapplied when the following criteria are fulfilled:

(1) Eosinophilia >,1 5x109/l;(2) Persists for at least six months or fatal in a

shorter time;(3) Results in organ system dysfunction;(4) Absence of a recognised cause for the eosi-

nophilia.The term encompasses various diagnostic terms

applied previously to a range of cases with almostsimilar natural history, physical findings, laboratorydata, and autopsy findings, including eosinophilicleukaemia, disseminated eosinophilic collagen dis-ease, and Loeffler's fibroplastic endocarditis witheosinophilia. The condition called eosinophilic gas-troenteritis is probably part of the wide range of thissyndrome.5The idiopathic hypereosinophilic syndrome has a

wide range of severity with at least three differentforms. Some patients only have hypereosinophiliawith lung involvement and angio-oedema. Otherspresent with (or develop) severe cardiac and centralnervous system complications. A third group haveeosinophil cytogenic abnormalities and other fea-

The idiopathic hypereosinophilic syndrome 603

tures of a leukaemic disease, characterised aseosinophilic leukaemia. Occasionally, the secondform terminates as a blast cell leukaemia.6 Hyper-eosinophilia as an isolated finding is not consideredto be a subgroup of this syndrome and probably hasno special clinical relevance, although the patientwill require regular reviews to exclude an occultunderlying disease process.

AetiologySeveral theories have been put forward to explainthe idiopathic hypereosinophilic syndrome. Someauthors have claimed that it is an autoimmunedisease.7 It is also possibly of a neoplastic nature.8Parrillo et al showed a variety of immunologicalabnormalities in the patients they studied.9 In mostof the cases described by Spry et al the findingssuggested that a parasitic or allergic disease hadpreceded the onset of hypereosinophilia, and somehad high serum IgE concentrations.'0 These findingsraised the possibility that an initial eosinopoieticstimulus may lead to a late and exaggerated re-sponse, which persists. Carey et al reported a case oftransient hypereosinophilia in an infant of a motherwith this syndrome and suggested that the infant'shypereosinophilia could be a response to an eosi-nophilia producing factor by the mother, withtransplacental transfer.' lA definitive cause for this syndrome, however,

has not been identified, but perhaps understandingthe factors that influence the production anddistribution of the eosinophil and the mechanisms oftissue damage might give some insight into itsaetiology.

Factors that influence blood and tissue eosinophilconcentration. Eosinophils normally constitute asmall proportion of the circulating leucocytes. Adiurnal variaton that is the converse of the variationin plasma corticosteroid concentrations occurs, withblood eosinophilia peaking at night. The productionof the eosinophil in the bone marrow is under thecontrol of the T lymphocytes. Lymphocytes alsoproduce factors that are chemotactic for eosinophils.Once eosinophils are released from the marrow theycirculate in the blood only briefly, with a half life ofsix to 12 hours. They leave the blood stream and aredistributed in tissues where they persist for at leastseveral days, being a tissue dwelling cell. They aremost abundant in those tissues with epithelialsurfaces exposed to the environment, including thegastrointestinal tract, the skin, and the upperrespiratory tract.'2Apart from the lymphocytes, several other factors

may influence eosinophil concentrations in bloodand tissue. On triggering and degranulating the mast



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Table 2 Summary of clinical, biopsy, and necropsy findings of 19 children with the idiopathic hypereosinophilic syndrome

Author (years) Ageat Sex Presentingsymptono Cardiovascular Nervoussystem Skinlmusclejoints Renal Pulmonary Gastrointestinaltract Hepaticonset system(years)

Bentley (1961)15 5 M Fever, macularrash, Postmortemexanona- Coma,decorticate, Macularand petec- Postmortemex- Drycough. Chestx Postmortemex- Hepatomegaly. Post-

Chusid (1975)4 5.5 M

pctcchial rash, coma tion: Myocardial posturc. Cerebrospi-petechiac and scar- nalfluidt No abnor-ring, mural thrombus mality. Postmortemin left ventricic examination: Myclo-

blastic infiltratc ofmeninges and brain

Pcriodic attacks of None Abnormal cice-fever, rash, di- troencephalogramarrhoea. and angio-odema

hial rash. Sub- amination: Petechiae ray: Lung infiltratcs. amination: Stomach mortem examination:cutaneous nodulcs in both kidncys. Postmortem ex- dilatation. Peteehiae Blast cclls infiltrationovcr parietal boncs. Blast cells infiltration amination: Hacmor- all over gastrointes-Biopsy: Lymphoid of kidncys and rhagic areas. Pul- tinal tractand eosinophil infil- bladder monary oedema andtration mycloblast infiltra-

tion

Rash, angio-oedema. Mild to moderate in- Transient infiltration None Biopsy: 'EosinophilicSkin biopsy: Perivas- termittent proteinur- triaditis'culitis, eosinophil in- iafiltration

De Vaan (1979)16 F Refusing to walk or Gallop rhythm and Nonestand sinus tachycardia.

Postmortem examina-tion: Endocardialthickening of leftatrium and suben-docardial fibrosis withiron pigment deposi-tion in myocardiumof both ventricies andleft atrium. Coronarythrombosis. Eosi-nophil infiltration, in-cluding blast cells inmyocardium

Donohue (19511)17 7 M Joint pains and feser Congestive heart fai- Nonelure, cardiomegaly,mild hypertension,systolic murmur, mit-ral regurgitation

Refusing to walk or Postmortem ex-stand. Skin biopsy: amination Eosi-Papillomatosis and nophil infiltration,scattered mature including blast cellseosinophil infiltra-tion and hyperker-atosis. Musclebiopsy: Some focalatrophy, no cosi-nophil infiltration

Subcutaneousoedema,arthralgia

Pncumonia. Post- Nonemortem examination:Increase in wcight oflungs. Vascularthrombi. Areas ofred blood ceil cxtra-vasation, fibrin inalveolar spaces, andformation of hyalincmembranes. Mac-rophages and cosi-nophils in alveolarspaces

None Bilateral basalcrepitations

Hepatomegaly. BiopsyDiffusc eosinophil infil-tration. Postonortem ex-amination Enlarged,eosinophil infiltration.ineluding blast cells

None Hepatomegaly

Engbaek (1942)18 7 M Headaches, fever. Congestive heart fai- Not describedneck stiffness, and lure, cardiomegaly.arthralgia Postmortem examina-

tion: Hypertrophy,dilatation and parietalthrombus in both vcn-tricles and myoeardialscarringlobliterationof coronarics

8 M Fatigue, anorexia,abdominal pain.vomiting, dyspnoea,cough, pains in backand neck

10 M Headache, fever.rash, hyperkeratosis.and scaling of face,arms, and legs, pro-nounced alopecia.conjunetivitis, myal-gia

Terminal acute heart Electroencephalo-failure. Postmortem gram: Dysrhythmicexamination: Biven-trieular hypertrophy,thrombus in right au-ricle and ventrieles.Endo-, myo-, andpericardial scarringand inflammatorycels infhltrate, mainlyeosinophils

Cardiomegaly. apical Nonesystolic murmur

Foasso (1984)19 6.7 F Sore throat. Tubercu- Congestive heart fai- Not describedlosis over previous 12 lure, cardiomegaly,months; on isoniazid, hypertension. Echo-rifampicin. etham- cardiogram: Dilatedbutal left ventriele and left

auncle. Catheterisa-don: Left ventricularlumen was reduced

Not described Not described Postmortem ex- Not describedamination Lungs in-durated, cyanotic,mottled, and in-flamed. Thrombi,oedema, and cosi-nophil infiltration

Pains in back and Moderate albuminur- Dyspnoca. cough. Abdominal pain andneck. Postmortem ex- ia. hyaline casts, and Chest x ray: Peri- vomitingamination: Eosi- red blood ccils in bronchial thickeningnophil infiltration of urine. Uraemia. and pleural effusion.muscle Postmortem ex- Postmortem ex-

amination. Eosi- amination: Eosi-nophil infiltration of nophil infiltratekidneys

See prescnting symp- Slight protcinuria Ateeetasis of right Nonetoms. Subcutaneous middle lobe. Pleuraloedema and redness, effusionover wrists andknees. Arthralgia.Biopsy ofskin andmuscle. Inflamma-tory cells, especiallyeosinophils andplasma cells. Non-specific changes insmall blood vessels,thrombosis, and en-darteritic changes

Ulceration of finger Mieroscopic haema- Pulmonary hyperten- Not describedtips. Swelling of right turia. Biopsy: Focal sion and ocdemasternoeeidomastoid. glomerulonephritisSkin biopsy: Peri-vascular inflamma-tory cell infiltration.Muscle biopsy: En-dothelial thiekeningand alteration ofmedia, no perivascu-lar inflammation

Engfeldt (1956):7Case I

Case 2

None

Hepatomegaly. Post-mortem examination:Eosinophil infiltration

Hepatomegaly

Hepatomegaly

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Lymphaticlspleen Total while blooed Eosin philcountcell counrt (x lO1) f(10l atal presentation presentation

Spienomegaly. 185 157 25Generalised lym-phadenopathy. Post-mortem examination:Blast cells in lymphnode and spleen

Lymphadenopathy 35 7 21 42during attacks.Lymph node biopsyHyperplastic germin-al centres. Increasedeosinophils

Generalised lvm- 499 19-96phadenopathy andsplenomcgaly.Lymph node biopsyFollicular hyperpla-sia and some cosi-nophils in blood ves-sels. Postmortem ex-amination Enlargedspleen and mesentriclymph nodc. Eosi-nophil infiltration.including blast cellsin both

Ccrvical lym-phadenopathy, sple-nomegaly

Postmortem ex-amination Sple-nomegaly. Eosi-nophil infiltration oflymph node andsplcen

Haemoglobinpgrdl) atpresenrarion

8

Platelets ax 1094) Peripheralblood BonemarrowatpresenattonKthite blood ell

morphologs

6() 64% Polvmorpho- loitiallv: cosinophilnuclcarcosinophils, hyperplasia. Termi-17% cosinophil nallv: an increase inmetamyneloctcs. mvcloblastic forms3 4"',, eosinophil (85 3%.)myelocytes

Other laboratorn Duranton Treatmenrfindings

Authors diagnosis

7 months C'ortionec, thcn Eosinophilic leukacmiabusulphan. thcncortisone, radiationto lungs. and6-mcrcaptopurinc

13 40() Most primitive cell Not described Raised IgE Rcportcd Prednisone on Idiopathic hypereosi-in thb circulation alivc 5 5 alternate days. in- nophilic svndrome man-was cosinophil years after creasing to dailv ifesting as periodic attackimyclocytc. No mor- prcscntation during attacks of fever. malaise, angio-phological abnor- oedema. and hypercosi-mality of cosi- nophilianophils

7 63 Ncutrophils: Myolo- Hypercellular. Coombs and IgE 3 months Prednisolone, 6- Eosinophilic leukaomia ocytes t%, metamy- Somc disrupted un- normal. IgG and mercaptopunne a variant of juvcnileclocytcs 2%. band identifiablo ccIls IgM raised. chronic mycloidforms 4%/., seg- scemed to originate Latcx and antinuc- leukaemiamented 28%. Eosi- mainly from eosi- lear factor -ve.nophils: 411% band nophil scrios. In- "Rose" test +vc.and scegmented crease in eosinophil Sorum folate lowforms, no younger series at all matura- normal.forms. tion stages. Later Scrum vitamin B12Lymphocytes: 23%,', on. decrease in raised.Monocvtls: 1% megakaryocytesPlasma cellcs: /,

22-1 10-387 8 8 2101 Eosinophils dcfi- Blast forms 53%.cicnt in granules mveloblasts0-5°/n

cosinophil mvclo-cytes 2 5%, cosi-nophil metamvelo-cytes 2 5%, juvenilecosinophils 2.5%,adult eosinophils7-5%

101 2 78 936 Not described Not describod Eosinophils of Very cellular withmature type. Vari- enormous increascable size, number, in cosinophils, es-and distribution of pecially lobulatedgranules. 2-3 lobed formsnuclei

Reported Adrenocortico- Eosinophilic leukacmiaalive 12 years trophic hormone.later. ? Ann Eosinophils in-treatment creased twice on its

withdrawal

I weeks Eosinophilic lcukaemia

Lymphadenopathy 113and spicnomcgaly.Postmortem ex-amination Eosi-nophil infiltration ofsplcen and medias-tinal lymph nodc

Generaliscd lym- 21 7phadenopathy

79-1 Normochromic Normalanaomia

1()85 1() 8, normocytic Normalanaemia

Mature cosinophils Initially: Prolifera- Increased gamma- 8 months Adrenocortico- Disseminated cosinophi-initially. Later on, tion of granulocytes globulin. decreased trophic hormone lic collagen diseasemoreimmature andnumerous albumin. Wasser-forms mvelocytes, mainly mann reaction and

eosinophils. Later: lupus crythematosis40'. Mature cosi- cell -ve. Heter-nophils, 69% un- ophilic antitbtdiesdifferentiated cells -ve.and vere ferernthroblasts, neut-rophils, mvclocytes,or metamyeloctecs

Mature eosinophils Hvpercellular. 30% Decreased crum Reported Adrenocortico- Disscominated eosinophi-Of myeloid series albumin, pro- wcll 22 trophic hormone, ltic collagen diseasewer ecosinophils nounccd hoporgam- months later twice weekly.

maglobulinaemia. Lowertng of doseWasscermann reac- was followed bytion, heterophil relapseantibttdy. C(ombsand lupus erythc-matosis cell -ve.

498 Normal Normal Several blast ccils, Autoimmune, anti- 3 years 6 Diuretics, digitalis, Idiopathic hypcreosi-which disappeared nuclear factor and months and steroids nophilic syndromelater on circulating immune

complexs -vce.IgE normal

Continued

Not described



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Table 2 Summary of clinical, 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 Hepaticonset system(years)

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

M Myalgia, arthralgia, Congcstivc hart fai- Nono. Postmortem Myalgia, arthralgia. Not dcscribodfevcr, dclirium, facial lurc, cardiomcgaly, examinationt Cyster- Muscle btiopsy Non-and leg ocdcma, systolic murmur (mit- icus in loft putamen, specificprogrcssivc dyspnoca ral rcgurgitation). thought to bc an in-

Postmortem examina- cidcntal findingtion Ventriculardilatation and hyper-trophy. Thrombi inauricle and right ven-tricle. Extensive sub-cndocardial fibrosis.Thrombosis and in-flammatory cct infil-tration by lympho-cytos. plasma cells.and cosinophils inblood vessels ofmyocardium

F Fcver, soro throat, Acutc heart failurc. Extcnsivc involuntary Pains in fcct. Gcner- Urine Numerouspains in flct. anor- Cardiomcgaly. systo- chorciform hypor- alised coarsc brown/ cpithclial cells, nocxia, irritability lic murmur (mitral kincsia, pronounced macular rash. othcr abnormality

regurgitation). Post- hypotonia. abscnt Erythema annulare.mortem examination abdominal reflcxcs Joints ntormalLeft atrium greatly di-lated. Ventricies cn-larged, subendo- andmyocardial fibrosis,cspecially of loft. En-docardial fibrosis. im-mediately under thepostcrior lcaflet ofmitral valvc, extcnd-ing into chordec tcn-dinii. Dcstruction ofpostcrior Icaflet ofmitral valve. Arterialembolus in right lcg

M Dizzy spclls, fatiguc, Congestivc heart fai- Nonc None Noneshortness of breath lurc. cardiomcgaly.

systolic murmur (mit-ral rcgurgitation).Postmortem examina-tion: Extcnsivcen-docardial andmytcardial fibrosis inboth vcntricics, mostsevcrc at the apicalposition of right ven-tricle. Anterior leafletof mitral valve wasdestrtyed. Pericardialcffusion. No cosi-nophil infiltratc

M Fatiguc, anoroxia, Cuongostivc hcart fai- Not described Skeletal mustle Not describedwcight loss. fcvcr, lure, cardiomcgaly, biopsy: Normalcough systolic murmur (mit-

ral rcgurgitation).Postmortem examina-tion Bivcntricular cn-domyocardial fibrosis(mural thrombi in leftventriclc)

F Abdominal pain. di- Congcstivc hcart fai- Irritability, confu- Nonc Normal scrum crcatarrhoca, vomiting, lurc, cardiomcgaly. sion. rcstlcssncss. nine and urea. Post-fevcr Postmortem examina- coma. Postmortem mortemexamination

son Biventricular examination: Throm- Focal proliferativedilatation, thrombi in bi in cerebral artcr- glomcrulitisboth vcntricics and iolcs and vcnulcs,right atfium, contain- necrosis in thalamusing abundant cosi- and ccrcbclumnophils. Coronarythrombttsis andmyocardial necrosis

Chest x ray Infiltra- Not dcscribedtivc pulmonarychanges. Postmortemexamination: Throm-bi. infarcts, and in-flammatory ccils in-filtration by lympho-cytes, plasma cells,and cosinophils inblood vesscis of lungs

Hcpatomegaly. Post-mortem examinationEosinophil infiltration

Attacks of broncho- None Hcpatomcgalypncumonia, dysp-noea and wheczing,associated with car-diac decompensa-tion. Postmortem ex-amination Lungocdcma. Pncumonicchanges with cosi-nophil infiltration

Dyspnoca. Chestcx Postmortem Hcpatomcgaly Post-ray Incrcascd vascu- examination mortem examinationlar markings. Post- Ascitcs Livcrcongestionmortem examination:Pleural cffusion

Cough. Chest x ray Not dcscribed Clinically not describcd.Bilatcral alveolar Postmortem examina-pncumonitis. Biopsy tion Chronic passivcHypersensitivity congestion and ccntri-pneumonitis iobular necrosis

Dyspnoca. Chest x Abdominal pain, Hcpatomegaly. Pro-ray: Lincar opacitics diarrhoea, and longed prothombinin both bases. Post- vomiting timc. Postmortem ex-mortem examination amination Thrombi inRcd and congested. sinusoids and cosinophilVascular thrombosis infiltrationand lung infarct

Continued

Hcrrcry-Gocpfcrt 9Kr985) ) 7

Knoff (1958)22 7-5

Libanoff(1976)23 9

Olson (1982)24 9

Raschc (1973)25 5 Iti-

,n



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Lymphatic/spleen Total whie blood Eosin6phil count Haemoglobin Platelets (xol09/1 Peripheralblood Bone marrow Otherlaboratorv Duration Treatment Authors'diagnosiscell count (xIY/I) (x10 1) at Ig/dl) at atpresentation white blood cell findingsatpresentation presentation presentatton morphology

Spicnomegaly. 38-3 19-9 Moderatc Not dcscribed Ncutrophil: band Pronounccdin- Wasscrmannreac- When last None. The fcvcr. Eosinophilia infcetiosaGeneralisedlym- anacmia' forms3%.seg- crcasc in cosi- tion -vc. secn7 spnomcgaly. andphadenopathy. 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 tancouslynode biopsy: Eosi- Lymphocytcs 13% min normal school, butnophil and poly- Monocytes 1%. gencraliscdmorph infiltration. Normal granulcs in lymphadcno-Fibrosis. In general, cosinophils pathy.picture is oflym- lcueyio3isphadcnitis, no other (19-6x 109/1).speific changes. no and cosi-parasites and no cal- nophiliacification (2-3o5h Il9

had per-sisted. On rc-peated cx-amination ofblood, stools,and urineduring theabovc 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 syndromcLymph 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, lupusSpicen and lymph nophils (98%) crythematosis cclsnodc cnlarged. Eosi- and antinucicarnophil infiltration factor -vc

Gencraliscd lym- 27phadenopathy. Spic-nomcgaly

18 3 Hypochromic Not deseribed Neutrophils: seg- Hypersegmentation Direct Coombs test 10 5 months Initially thought to Fibroplastic panctal en-

anaemia mented 13%. hand of the neutrophils. -vc. Albumin re- be rheumatic fever; docarditis with bloodforms3%. metamy- Pronounced cosi- ducd. Alpha1 and penicillin, Glutisal cosiniophiliaclicytes 1%. Eosi- nophilia. Eosi- alpha and gam- (salicylamide +nophils: segmented nophils 13-5%, cosi- maglioulins raised ethenazamide). and54.. band forms nophil precursors Nirvanol (a hydan-13%, myclocytes 21%. Mature cosi- toin) with some im-I'Y%. nonphlsshow degra- provcmcnt. Later:Monocytcs 2%. nulation. No cvi- cortisone (5 days)Lymphocytes 13% dencc oflcukaemia

Splenomcgaly. Post- 181-5 169-65 101 2 121)mortem examination:Splccn congcstion

Clinically nut dc- 55

scribed. Postmortemexamination: Lymphnodc and spiccnshowed cxtramcdul-lary hacmatopoicsis

Incrcasc in cosi- Albumin and 3 years Not described Eosinophilic leukaemianiiphils at myclo- globulin normalcytc. metamyclo-cytc. and scgmentedells ccl. Slight

incrpasm inplasma cclis

48-4 Not dcscribed Not described Maturc cosinophils Initially: cosinophil Rheumatoid factor months Diethyl carbama- Hypercisinophilic syn-

hyperplasia without -vc zinc with no im- dromc. prcicukacmiaan increasc in imma- provcmcnt. Predni- statcture forms. Second sonchiopsy: Hypcrccilu-larity and incrcasedmycloblasts (7%)

Spicnomegaly. Post- 152mortem examination:Spicnic infarcts.Eosinophil infiltra-tion Oflymph nodcand spiccn

130-72 8 195 8'% Scgmcnted Myclocytc: Erythro- Lupus crythemato- 25 days Digitalis. antibiitic. Acute rapidly fatal casc ofneutrophils. 1% cytc ratio= 20: 1. sis cell -c. Total stcroids Logfflcr's cndocarditisneutrophil band Predominant ccls scrum protein. pro-fbrms. 5'% lympho- wcre cosinophil tcincluc-cytcs, 83% cosi- myclocytcs. trophorcsis. andnophils. 2°% cosi- metamyclocytcs. immunoglobulinnophil band forms. and maturc cosi- nsrmal1'Y. cosinophil nophils. Poitmor-myclocytes tem examination:

Hyperplasia of cosi-nophil scrics withorderly maturation Continued



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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 Hepaticonset svsrem(years)

Spry (1983)10 14 M Diarrhoea, fever, None None None None Nonc Diarrhoea, abdomin- Noneswcating, abdominalpain

al pain. Biopsy In-flammatory ccil infil-tration, containingmany cosinophils incaccum. largc bowel.and ecCtum

Taligren (1974)26 3 M Persistent febrilc up- Postmoneem examina- Postmortem examina- Macular and pctec- Postmortem ex- Dyspnoea, cough. Bleedingper respiratory tract tion Cardiomegaly, nion: Brain swelling. hial rash. Arthralgia, amination Enlarged Chest x ray Miliaryinfeetion, drv cough, pericardial effusion, Leukaemic infiltrate slight swelling of kidneys. Leukaemic infiltrates. Postmor-dyspnoea, athralgia. epicardiai prtechiae. and atypieal eosi- knees infiltrate and atypical tem examinationand slight knees Haematoma in right nophils in lep- eosinophils Lungs enlarged.swelling atria[alal, white mili- tomeninges Leukaemic infiltrate

ary myocardial infil- and atypical rosi-trate. Leukaemic in- nophilsfiltrate and atypicalcosinophils inmyocardium

Thomsen (1939)27 11 M Sore throat, cervical Congestive heart fai- None Generalised oedema. Postmortem ex- Postmortem ex- Nonelymphadenopathy, lure, cardiomegaly, especially of face. amination Enlarged amination Oedemafever pericarditis. Postmor- Migratory polyarthri- kidneys and blast cells infil-

tem exanination tis and joint deformi- tratePericardial thickening tiesand petechiae. Heartdilated, right halfhypertrophic. Rightauricle enlarged, witha 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. Diarrhoeafever, chest pain, lure, cardiomegaly. ness of hands. Hyper- matous rash. Muscle Chest x ray Diffuse nausea, abtingling, and numb- Postmortem exa,nina- regfcxia, clonus, and weakness granular infiltrate pain. Perf(ness of hands tion Heart dilated. bilateral Babinski and enlarged hilar antral ulce

Mural thrombosis and syndrome lymph node. Post-fibroplastic parietal mortem examinationendocarditis Multiple infarctions

and diffuse pneumo-

Hepatomegaly. 1 ,!mortem e-xamination:Liver enlargement.Leukaemia infiltrateand atypical eosinophils

Hepatomegaly. Post-mortem exaintationBlast cells infiltration

a, vomiting, Hepatomegaly. Post-bdominal mortem examination:forated Massive liverenlarge-er ment. Hoavy infiltrate

of immature eosinophilsand blast forms

Present case 14 F Weight loss, anaemia. Congestive heart fai- Nonebreathiessness, lure, cardiomegaly,anorexia, lethargy. hypertension, systolicnausea, diarrhoea murmur (mitral re-and vomiting, ame- gurgitation), pericar-norrhoea, petechial dial effusionrash, mouth ulcers.blisters of hands andfeet, with Joint andlimb pain

Peteehial rash, joint Haematuriaand limb pains

Cough, breathiess- Diarrhoea andness. Chestx ray In- vomitingterstital lung oede-ma. vascular redis-tribution, small rightsided pieural effusion

Hepatomegaly



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Lymphatic/spleen Total white blogd Eosti philcount Haemoglobin Platelets (x10911) Peripheral blood Bone marrow Other laboratory Duration Treatment Authors'diagnosiscoai count (x 100/1) (xl(d1) at (gidl) at at presentation white blood cell findingsat 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 mcntSalazopyrinc. SalazopyrineDiarrhoca re-turns withinone day ofstopping it

Lymphadenopathy 79and spienomegaly.Postmortem ex-amination: Lymphnode and spleen;leukaemic infiltrateand atypical eosi-nophils

Gcneralised Iym- 42phadenopathy. Sple-nomcgaly. Postmor-tem examination:Blast cells infiltrationof lymph node andsplecn

57-275 Normal Normal 725% Segmcnted Initially: Increase in Mycoplasma orale It months 6-Mcrcaptopurine, Eosinophilic leukaemia.cosinophils, 2% mycloid cells pre- typc I isolated from prednisolone. mycoplasma could bccosinophil myclo- dominantly cosi- bone marrow. Cold methotrexatc, vin- cause, result or fortuitouscytes and metamy- nophils at various agglutinins raised. cristineclocytes stages of matura- Cryoprecipitate

tion. 'Paraleucob- +ve. IgM G and Alasts' were scen. raisnd. AntinuclearLater: Myclocytes factor -ve.with few 'para- Rheumatoid factorleucoblasts' domin- -ve, later bocameated +vc. Lupus crythe-

matosis cell -ve.

31-08 10-3 140 Eosinophilsshowed Initially: Increase in Reduced serum 12months Splenic radiation Eosinophilicleukacmiaslightly basophilic stem cells and ceIls albumin. Wasser- and bone radiationcytoplasm, contain- of eosinophil series. mann reaction anding variable, mostly Later: Myeloblasts Widal's test -vcfew coarse granules. made 43% andLatcr mycloblasts 'erythropoiesis com-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 Icukaemiapathy and sple- nophils of differcnt Mycloid hyperplasia Lupuscrythemato- busulphannomegaly. Postmor- sizc. vacuolatcd and cosinophilia sis ccil -vc.tem examination: cytoplasm, targe un-Massivc splenomeg- cvenly distributedaly and lymphadeno- granulcs, decrcasedpathy. Heavy infil- numberofgranulestrate of immature and mixed baso-cosinophils and blast cosinophilic gra-forms nules. Nuclear

hypo- and mainlyhypcrsegmentation

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 svndromenulation philia bulin and IgG well nophils raised when

raised. Albumin prednisolonc waslow. Antinuclear stoppedfactor -ve. Serumfolate low. Serumvitamin B12 highnormal



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cells and basophils, peptides are released that arestrongly chemotactic for eosinophils,8 12 such aseosinophil chemotactic factor of anaphylaxis. Hista-mine has also been shown to be chemotactic foreosinophils. As IgE is directly involved in thetriggering of mast cells with subsequent degranula-tion the association of eosinophilia with IgE medi-ated immediate hypersensitivity reaction can beexplained by such chemotactic mechanisms. Eosi-nophil chemotactic factors that are derived from thecomplement system include the proteolytic fragmentof C5, C5a, and the trimolecular complex C567.Other recognised factors are leucotriene B4 andsubstances produced by some parasites.12On the other hand, factors that have an eosi-

nopenic effect on blood concentrations includecorticosteroids and beta adrenergic agonists, as wellas an eosinopenic factor present in inflamma-tory exudate, which may account for the welldocumented eosinopenic response that is associatedwith most bacterial and viral infections, apart from afew exceptions (see Table 1).1 12

Mechanisms of tissue damage in the idiopathichypereosinophilic syndrome. In addition to theirpossible beneficial role, there is evidence that theeosinophils may occasionally be harmful to the host.For example, in asthma, it was generally held untilrecently that the eosinophils were protective, des-troying the mast cell products that induce suchclinical features of asthma as bronchoconstrictionand changes in blood supply to the lungs. Severalgroups now feel, however, that the eosinophils maybe responsible for some of the serious complicationsof asthma, including bronchial epithelial cell injuryand even pulmonary fibrosis. It is the proteins in thedistinctive cytoplasmic granules of the eosinophilthat are suspected of damaging the lungs.'The cytotoxic effect of eosinophil granular basic

proteins on parasites has led to an examination ofthe potential cytotoxicity for mammalian cells. 12Cultured intestinal, splenic, cutaneous, and per-ipheral blood mononuclear cells are damaged bymajor basic proteins. There is evidence that theseenzymes play a major role in the pathogenesis of theidiopathic hypereosinophilic syndrome.8 Of theseproteins, the eosinophilic major basic protein, aswell as the eosinophilic cationic protein, were foundto be raised in the serum samples of patients withthis syndrome.8 11) Furthermore, degranulated eosi-nophils in peripheral blood smears are common inidiopathic hypereosinophilic syndrome and theirpresence seems to be a valuable indication ofendocardial disease.'3 In vitro experiments with ratmyocardial cells support the idea that componentsof the granules are released from the circulating

eosinophil and directly damage the myocardium.14Eosinophilic cationic protein may also be partiallyresponsible for the thromboembolic phenomenacharacteristic of this syndrome. Eosinophil granulescontain potent neurotoxin, which causes demyelina-tion and damage Perkinje cells in laboratory ani-mals. It might be that the same, or similar, neuro-toxin causes disease in patients with this syndrome. 12Other potential mechanisms of tissue damage

include tissue infiltration with eosinophils (spaceoccupying) and thromboembolic phenomena relatedto thrombi associated with endomyocardial disease.

IncidenceIdiopathic hypereosinophilic syndrome mainlyaffects patients between 20 and 50 years of age. Theincidence is not known, but over 150 patients fromdifferent age groups have now been described. Aftera comprehensive search of the published reports 18cases of this syndrome were identified in childrenunder 16 years.4 7 10 15 28Summary of the clinical details and laboratory,

biopsy, and autopsy findings of the involvement ofthe various organ systems of the 18 childrenreported in these reports and the present case isshown in Table 2. Fourteen boys and five girls wereaffected-that is, the male predominance is lesspronounced than in older age groups.

The cardiovascular system in the idiopathichypereosinophilic syndromeInvolvement of the cardiovascular system is themain source of morbidity and mortality. Sixteenchildren showed evidence of this. Cardiovascularinvolvement in these children was generally similarto that in adult patients in its frequency anddistribution.The cardiovascular involvement in this syndrome

is nearly always biventricular, but it spares theoutflow tracts. Characteristically, patients developendocarditis with overlying thrombosis and, later,endomyocardial fibrosis. Involvement of the sup-porting structures of the atrioventricular valvesoften results in mitral and sometimes tricuspidregurgitation. The endocardial thrombi give rise toperipheral emboli, which further complicate theclinical picture. Patients with this syndrome are alsoat increased risk of developing thromboembolicdisease in blood vessels of medium to large size.Disease in small blood vessels also occurs, withthickening of intimal tissue.6

Cases that were previously called Loeffler's eosi-nophilic endocarditis are probably synonymous withhypereosinophilic syndrome with severe cardiacinvolvement. It is now accepted that there is a rangeof eosinophilic heart disease, varying in severity



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from Loeffler's eosinophilic endocarditis, the mostacute and fatal form, to Ugandan type endomyocar-dial fibrosis. The heart in the condition described in1948 in West Africa by Davies, originally calledendocardial fibrosis and later endomyocardialfibrosis,29 is indistinguishable from the heart of a

patient with Loeffler's fibroplastic parietal endo-carditis, or eosinophilic leukaemia. Further, en-

domyocardial fibrosis is also known to present innon-tropical countries.There have been reports of patients who present

with an initial hypereosinophilic illness, survive, andare found at necropsy to have endomyocardialfibrosis, sometimes with features identical to Ugan-dan type endomyocardial fibrosis.31 Endomyocar-dial fibrosis seems to be the burnt out phase of an

eosinophilic heart disease.Hearts from patients with heart failure secondary

to other causes of hypereosinophilia also hadnecropsy appearances similar to those of patientswith the idiopathic hypereosinophilic syndrome.Thus the common denominator of the cardiac lesionis probably the eosinophilia itself and not an

unrecognised underlying factor.8In a study of 50 patients Harley et al defined the

non-cardiovascular characteristics that distinguishpatients at risk of developing endomyocardial fibro-sis from those who remained free of heart disease.31Patients with clinically overt heart disease were

more likely (p<OO5) to be male and HLA-Bw44positive and have splenomegaly, thrombocytopenia,raised serum vitamin B12 concentrations, and hypo-granulated or vacuolated eosinophils and abnormalearly myeloid precursors in the peripheral blood.Those patients with heart disease were also more

likely to have fibrosis and decreased megakaryocytesin the bone marrow. In contrast, those who remainedfree of heart disease tended to be female and haveangio-oedema, hypergammaglobulinaemia, raisedserum IgE concentration, and circulating immunecomplexes. Appreciation of this relative degree ofrisk for the major complication of the idiopathichypereosinophilic syndrome should prove useful inthe early identification and appropriate treatment ofpatients in whom endomyocardial fibrosis mightdevelop.

Involvement of other organs/systemsThe clinical manifestation and pathological findingsof the involvement of the various systems in thosechildren who had cardiovascular involvement mighthave been secondary to the latter either in the formof congestive heart failure, causing, for example,pulmonary or gastrointestinal symptoms or hepa-tomegaly, or embolic phenomenon, originatingfrom intracardiac thrombosis. In many cases,


however, the primary involvement of the varioussystems was also proved by biopsy or necropsyfindings (Table 2).

In addition to the involvement of the cardiovascu-lar system, which was the major problem in ourpresent case, there are certain other features thatneed some emphasis.

(1) Previous history of asthma. None of the other18 children had a similar history. Also thereare a few well described adult patients whohad both bronchial asthma and thissyndrome.6 10

(2) Dramatic response to corticosteroids.(3) Raised serum rheumatoid factor. This has

rarely been observed in patients with thissyndrome.9 32 Furthermore, the concentra-tion decreased after treatment.

(4) The serum IgE concentration returned tonormal after treatment. This has also beenreported by Bush.32 The changes in serumIgE concentration might be of benefit inmonitoring progress, as is the eosinophilcount.

(5) Low total white blood cell count at presenta-tion, which, like initial high serum IgE con-centration, has been reported to be associatedwith a better response to treatment.

(6) In our case, her illness initially started withmouth ulcers and blisters of hands and feet.This combination has not been reportedbefore. Presentation of the idiopathic hyper-eosinophilic syndrome with mouth ulcers hasbeen reported in two patients, who were 26and 51 years old.33 In these patients, however,there was ulceration of other mucous mem-branes, including the genitalia.

TreatmentThe idiopathic hypereosinophilic syndrome is a raredisorder, but one that is accompanied by highmorbidity and mortality. Recent vigorous treatmentregimens, however, directed at lowering the eosi-nophil count with symptomatic treatment of com-plications of the organ systems, has brought about atremendous improvement in survival and prognosis.The mainstay of treatment is corticosteroids. Hyd-roxyurea is used in patients who do not respond oronly partially respond to steroids.34 Its use may alsobe required to allow the steroid dosages to bereduced in patients who require maintenance treat-ment. Vincristine has also been used recently in anumber of patients with aggressive disease. Anti-coagulants are required in most patients.'11 Drugsthat inhibit platelet function-for example, dipyr-idamole, have also been used. Leucophoresis andplasma exchange do not seem to have any clinical



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benefit, unless the patient also had increased wholeblood viscosity and widespread vessel occlusions.

Patients without dysfunction of organ systems arenot treated and are followed closely at three to sixmonthly intervals.34 If patients show dysfunction oforgan systems they are treated initially with corticos-teroids. If the disease stabilises or improves thesteroid is continued on an alternate day regimen.Ultimately, it is tapered to the lowest possible dosethat will control that disease. If the disease pro-gresses despite steroids a cytotoxic agent, specificallyhydroxyurea, is added with the aim of maintainingthe leucocyte count at less than 1Ox109/1 with anormal eosinophil count.

PrognosisFavourable prognostic factors that indicate betterresponse to treatment are high serum IgE concen-tration, the presence of angioneurotic oedema, andunmistakable eosinopenia within a few hours afterthe first dose of prednisolone. Unfavourable prog-nostic signs are pronounced leucocytosis andmyeloblasts in peripheral blood and congestiveheart failure.4 34 It is also important to look for thepossibility of high serum vitamin B12 and low serumfolate concentrations, abnormal leucocyte alkalinephosphatase activity, chromosomal abnormalities,and basophilia of more than 3%. These leukaemicmarkers as a group seem to have a predictive valuein terms of symptomatology and response to treat-ment. Those with positive findings had more severedisease.4

Eosinophilic leukaemiaMany patients of various age groups with thissyndrome, including eight children in our review,were reported as having eosinophilic leukaemia.Although this is one extreme of this syndrome, mostpatients do not seem to have leukaemia. Rickles andMiller suggested the following criteria for a diagnosisof eosinophilic leukaemia.35

(1) Pronounced and persistent eosinophilia,associated with immature forms, either in theperipheral blood or bone marrow.

(2) Greater than 5% blast forms in the bonemarrow.

(3) Tissue infiltration by immature cells of pre-dominantly eosinophilic type.

(4) An acute natural history measured in months,accompanied by anaemia, thrombocytopenia,increased susceptibility to infection, and/orhaemorrhage.

Although the hypereosinophilic syndrome wasoriginally defined in the context of primary eosi-nophilia, it is now recognised that the same involve-ment of organ systems may arise when eosinophilia

occurs secondary to a defined condition-forexample, drug reactions and parasitic disease' 2 4-so that early identification and prompt treatmentof the primary condition, which usually results in thedisappearance of the hypereosinophilia, may pre-vent these complications.

We thank Professor C J F Spry for reading the paper and for hishelpful advice, Mrs T Wisniewski for technical help, Mr G Titleyfor his help in the search of the publications, and the MedicalIllustration Department at the Royal Gwent Hospital.

References

Spry CJF. Eosinophilia. Practitioner 1982;226:79-88.2 Lukens JN. Eosinophilia in children. Pediatr Clin North Am

1972;19:969-81.3 Hardy WR, Anderson RE. The hypereosinophilic syndromes.Ann Intern Med 1968;68:1220-9.

4 Chusid MJ, Dale DC, West BC, Wolff SM. The hypereosinophi-lic syndrome: analysis of fourteen cases with review of theliterature. Medicine (Baltimore) 1975;54:1-27.

5 Trounce JQ, Tanner MS. Eosinophilic gastroenteritis. Arch DisChild 1985;60:1186-8.

6 Spry CJF. The hypereosinophilic syndrome: clinical features,laboratory findings and treatment. Allergy 1982;37:539-51.

7 Engfeldt B, Zetterstrom R. Disseminated eosinophilic "collagendisease": a clinical and pathological study of a clinical entityrelated to Loeffler's syndromes. Acta Med Scand 1956;153:337-53.Fauci AS, Harley JB, Roberts WC, Ferrans VJ, Gralnick HR,Bjornson BH. The idiopathic hypereosinophilic syndrome:clinical, pathophysiologic and therapeutic considerations. AnnIntern Med 1982;97:78-92.

9 Parrillo JE, Lawley TJ, Frank MM, Kaplan AP, Fauci AS.Immunologic reactivity in hypereosinophilic syndrome.J Allergy Clin Immunol 1979;64:113-21.

" Spry CJF, Davies J, Tai PC, Olsen EGJ, Oakley CM, Good-win JF. Clinical features of fifteen patients with the hyper-eosinophilic syndrome. Q J Med 1983;52:1-22.Carey JP, Burke AC, Carter WH. Transient hypereosinophiliain the infant of a mother with hypereosinophilic syndrome. ArchIntern Med 1982;142:1754-5.

12 Weller PF. Eosinophilia. J Allergy Clin Immunol 1984;73:1-10.13 Olsen EG, Spry CJF. The pathogenesis of Loffler's endomyocar-

dial disease and its relationship to endomyocardial fibrosis. ProgCardiol 1979;8:281-303.

4 Tai PC, Hayes DJ, Clark JB, Spry CJF. Toxic effects ofeosinophil secretion products on isolated rat'beart cells in vitro.Biochem J 1982;204:75-80.

'5 Bentley HP, Reardon AE, Knoedler JP, Krivit W. Eosinophilicleukemia: report of a case, with review and classification. Am JMed 1961;30:310-22.De Vaan GAM, van Haelst UJG. Hypereosinophilia syndromeor eosinophilic leukaemia: a case report of a one year old infant.Helv Paediatr Acta 1979;34:271-9.

17 Donohue WL, Snelling CE, Jackson SH, et al. Pituitaryadrenocorticotropic hormone (ACTH) therapy in eosinophilicleukaemia. JAMA 1950;143:154-7.

18 Engbaek HC, Heerup L, Thomsen S. Om den eosinofileleukaemi og "eosinophilia Leukaemoides". Nord Med1942;14:1535-51.

19 Foasso M-F, Hermier M, Age C, Mermillon M, Francois R. Lesyndrome hypereosinophilique avec atteinte endomyocardiquechez l'enfant; analyse critique de la litterature a propos d'un cas.Pediatrie 1984;39:147-55.



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The idiopathic hypereosinophilic syndrome 6132(1 Goldstein von R. Eosinophilia infectiosa. Annales Paediatrici

1952;179:216-26.21 Herrera-Goepfert R, Larraza-Hernandez 0. Sindrome

hipereosinofilico. Bol Med Hosp Infant Mex 1985;42:201-6.22 Knorr D, Scheppe KJ. Endocarditis parietalis fibroplastica mit

Bluteosinophilie (Loffler) bei einem siebenjahrigen Kind. Zeits-chiftfur Kinderheilkunde 1958;81:102-12.

23 Libanoff AJ, McMahon NJ, Eosinophilia and endomyocardialfibrosis. Am J Cardiol 1976;37:438-41.

24 Olson TA, Virmani R, Ansinelli RA, et al. Cardiomyopathy in achild with hypereosinophilic syndrome. Pediatr Cardiol1982;3: 161-9.

25 Rasche RFH, Kelsch RD, Weaver DK. Loffler's endocarditis inchildhood. Br Heart J 1973;35:774-6.

26 Tallgren LG, Wegelius R, Andersson LC, Jansson E. Eosi-nophilic leukaemia: recovery of mycoplasma orale from thebone marrow. Acta Med Scand 1974;195:87-92.

27 Thomsen S, Plum P. Eosinophilic leukemia. Acta Med Scand1939;101:1 16-37.

28 Yam LT, Li Cy, Necheles RF, Katayama I. Pseudocosinophilia.eosinophilic endocarditis and eosinophilic leukaemia. Am J Med1972;53: 193.

29 Davies JNP. Endocardial fibrosis in Africans. East Afr Med J1948;25: 10-4.

3() Chew CYC, Ziady GM, Raphael MJ, Nellen M, Oakley CM.

Primary restrictive cardiomyopathy:non-tropical endomyocar-dial fibrosis and hypereosinophilic heart disease. Br Heart J1977;39:399-413.

31 Harley JB, Fauci AS, Gralnick HR. Noncardiovascular findingsassociated with heart disease in idiopathic hypereosinophilicsyndrome. Am J Cardiol 1983;52:321-4.

32 Bush RK, Geller M, Busse WW, Flaherty DK, Dickie HA.Response to corticosteroids in hypereosinophilic syndrome:association with increased serum IgE levels. Arch Intern Med1978;138:1244-6.

33 Leiferman KM, O'Duffy JD, Perry HO, et al. Recurrentincapacitating mucosal ulcerations. A prodrome of thehypereosinophilic syndrome. JAMA 1982;247:1018-20.

34 Parrillo JE, Fauci AS, Wolff SM. The hypereosinophilicsyndrome: dramatic response to therapeutic intervention. TransAssoc Am Physicians 1977;90:135-44.

35 Rickles FR, Miller DR. Eosinophilic leukemoid reaction: reportof a case, its relationship to eosinophilic leukemia and review ofthe pediatric literature. J Pediatr 1972;80:418-28.

Correspondence to Dr M A Alfaham, Department of ChildHealth, University Hospital of Wales, Heath Park, Cardiff CF44XN, Wales.

Received 5 January 1987



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The idiopathic hypereosinophilic syndrome · is 1-5x109/l or higher. Somedisorders usually give rise to counts above 1 5x109/l,'-forexample, drug reactions, intrinsic asthma (a surprising

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