Hypereosinophilic Syndrome

Idiopathic hypereosinophilic syndrome is a collection of leucoproliferative disorders with sustained overproduction of eosinophils, varying from an asymptomatic phenomenon to a life-threatening multisystem disease. There is a wide range of clinical presentations.
Diagnostic features include:

• Eosinophilia above 1.5 x 10⁹/L, lasting more than six months.
• Absence of other recognised causes of eosinophilia, such as infestation, allergy, collagen diseases and malignancy, so that it is really a diagnosis of exclusion.
• Evidence of organ involvement. This distinguishes it from benign hypereosinophilia.

This is a rare disease.

• The American National Institutes of Health (NIH) studied just 50 cases between 1971 and 1982.¹
• It is even rarer in children and in 1987 a review of the literature found just 18 cases reported in children under 16.² There may be significant differences in the disease between adults and children.³
• The NIH study of 50 patients found a mean age of onset of 33 with 70% being between the ages of 20 and 70.¹
• Men outnumber women 9:1

This depends upon the organ or organs involved in a highly variable and multisystem disease.
The presentation can be acute as with stroke or, more commonly, it has an insidious onset. In the NIH series, common symptoms included fatigue (26%), cough (24%), breathlessness (16%), muscle pains or angioedema (14%), and fever (12%). Sweating and pruritus were common. Skin or mucous membrane involvement occurs in 25 to 50% of patients. Eosinophilia was an incidental finding in 12% of patients.

• Some patients have alcohol intolerance with abdominal pain, flushing, nausea, weakness, or diarrhoea.
• Fever and night sweats are common.
• Anorexia and weight loss are unusual presentations but may develop, especially with cardiac disease.

Dermatological features

Common dermatological presentations include:

• Pruritus
• Urticaria
• Dermatographism
• Angioedema
• Erythematous papules, plaques, and nodules
• Nonspecific rashes

More manifestations have been described but they are rarer.

Cardiological features

The heart is often involved, and thromboembolism may cause distant complications.
Damage to the heart progresses through three stages⁴

• An acute necrotic stage lasts 5 or 6 weeks
• A thrombotic stage lasts around 10 months
• After about two years of disease a fibrotic stage sets in

This may cause endomyocardial fibrosis, disease of valves and mural thrombosis. There is cardiomegaly due to infiltration of the myocardium with eosinophils, and pericardial effusion.

Symptoms tend to occur in the second and third stages and include chest pain, dyspnoea, and orthopnoea.

Neurological features

These may well be secondary to cardiovascular problems and due to thromboembolism with stroke or transient ischaemic attacks (TIAs).⁵

• There may be signs of cerebral malfunction with behavioural changes, confusion, blurred vision, loss of memory, ataxia, and upper motor neurone signs.
• Peripheral neuropathy produces changes that may or may not be symmetrical. They include pure motor deficits, mixed sensory and motor loss, or paraesthesia. The cause is not clear. Peripheral neuropathy accounts for half of all neurological complications.

Pulmonary problems

• The lungs may suffer from CHF, pulmonary emboli, or infiltration of the lungs by eosinophils.
• The most common presentation is a chronic, dry productive cough. Dyspnoea may be due to CHF or pleural effusion. Asthma can also occur.

Haematological problems

• Nonspecific symptoms may include fatigue from anaemia or easy bruising due to thrombocytopenia.
• Eosinophils can cause vasculitis in various organs, including the skin. Occasionally the condition may evolve into eosinophilic leukaemia or other types of leukaemia.
• A hypercoagulation state may aggravate the problem of thromboembolism.

Gastrointestinal features

• Embolism can occur to the gut, including the liver and spleen
• Splenomegaly produces left upper quadrant (LUQ) pain in about 40% of patients.
• Diarrhoea affects 20% of patients.
• Abdominal pain, vomiting, and nausea may occur and a dilated stomach.
• Liver and gallbladder abnormalities may accompany ascites. It may even be associated with sclerosing cholangitis.
• Ulcers, hepatitis, gastritis, colitis, pancreatitis, Budd-Chiari syndrome, and cholangitis have all been reported.

Ophthalmic features

• Visual symptoms, especially blurred vision, may occur.
• Adie's syndrome, keratoconjunctivitis, and episcleritis can occur.
• Problems of the retina and blood supply are more often due to microthrombi than arteritis.

Rheumatic features

Arthralgia, arthritis, Raynaud's phenomenon, and Wells' syndrome⁶ (eosinophilic cellulitis) have all been reported.

Many of the physical signs can be surmised from the presentation, such as a presentation of peripheral neuropathy or CHF. Others are less obvious and worthy of mention:

Skin

• Urticaria with wheals and angioedema is common and dermatographism can be demonstrated in three quarters of patients.
• Erythematous, pruritic papules and plaques are also common.
• Blistering lesions and necrotic ulcers may result from small thrombi in the skin.
• Petechiae, erythroderma and erythema annulare centrifugum may also be seen.
• Splinter haemorrhages can result from cardiac emboli.
• Ulcers can occur on almost any mucosa.

Heart

Arrhythmias, murmurs, especially from mitral and tricuspid regurgitation, features of restrictive cardiomyopathy and also cardiomegaly may also be found.

Nervous system

• Acute neurological deficits are usually the result of thromboemboli.
• CNS involvement may cause changes in mental status, ataxia, increased deep muscle tone, increased deep tendon reflexes, and a positive Babinski's sign. Seizures can occur but are rarer.
• When peripheral nerves are involved, the expected neurological deficit follows.
• Radiculopathies, muscle atrophy from denervation, and mononeuritis multiplex have been reported.

Gut

• Splenomegaly is common
• Mesenteric emboli can cause ischaemic bowel pain with typical "pain out of proportion to examination". This is important and requires early intervention before gangrenous bowel threatens life.

Rheumatology

• Joint effusions can occur.
• Raynaud's phenomenon produce the characteristic colour changes.

• Eosinophilic leukaemia
• Other leukaemias
• Drug reactions
• Hypersensitivity diseases
• Parasitic infections

Haematology

• The eosinophil count is greater than 1.5 x 10⁹/L and persists for six months as part of the diagnostic criteria. Eosinophils may have structural abnormalities, such as cytoplasmic vacuolisation and nuclear hypersegmentation.
• Neutrophilia is common. Extremely high leukocyte counts and immature forms may suggest leukaemia and a worse prognosis.
• Leukocyte alkaline phosphatase (LAP) levels can be high or low.
• Half of patients have anaemia. Teardrop cells and nucleated erythrocytes can often be found on a peripheral smear.
• Thrombocytopenia is seen in around a third but a sixth have an elevated platelet count.
• The ESR may be raised.

Biochemistry

• Folate is often low but vitamin B12 and its binding protein may be elevated.⁷
• Pleural fluid usually has the features of a transudate
• IgE levels are high in nearly 40% and IgG and IgM are less commonly elevated.
• There may be renal damage so that urinalysis shows albuminuria, haematuria, and hyaline casts.
• Abnormal LFTs may be found.

Electrophysiology

• ECG may show inverted T waves and can be used to assess arrhythmia.
• Neurophysiological studies may be helpful in neuropathy.

Imaging studies

• Echocardiography can be used to assess thrombus formation, fibrosis, ejection fraction, and valve function.
• CXR and CT scan can demonstrate pleural effusions, pulmonary infiltrates and fibrosis, and cardiomegaly.
• Head CT and MRI scans may be required to assess strokes and TIAs.

Invasive procedures

• Endocardial biopsy can help in diagnosis before other cardiac signs and symptoms are present. Right ventricular biopsy can help evaluate endomyocardial involvement.
• Pleural effusion should be aspirated and examined.
• Bone marrow aspiration and biopsy may show myelofibrosis or a leukaemia.
• Because skin lesions are nonspecific, skin biopsy may be helpful.
• Fluorescein angiography may be performed even if patients do not have visual problems. Fluorescein angiography has demonstrated that more than 50% of patients have choroidal abnormalities, including patchy and delayed filling, and retinal vessel abnormalities.

Because this is such a rare disease, treatment tends to be based on consensus rather than randomised controlled trials. It may well be adjusted according to the patient's presentation. The aim is to restrict organ damage and this may not be related to haematological abnormalities. Damage may also be quite insidious in onset. The heart is a very important organ in this disease and regular echocardiographic monitoring may be useful.

• Steroids are the first line of therapy. Usually they will reduce the eosinophil count within four hours. If they fail to reduce the eosinophil count, they may be stopped but some patients have improvement of symptoms without changes in eosinophils. If a response to steroids occurs, especially in patients with urticaria or angioedema and high IgE levels, the prognosis is good. A short trial of corticosteroids in patients who are asymptomatic may help predict the future response to therapy.
• When steroids have failed, agents such as hydroxyurea, vincristine, and chlorambucil have sometimes, but not invariably, been successful. Interferon alpha and ciclosporin have also been used.
• Imatinib blocks the effects of platelet-derived growth factor and this has vast implications for a large subset of patients; however, not all will benefit. It can lead to a sustained fall in the eosinophil levels.⁸ Because the causes of the disease are variable, predicting the response to this treatment is difficult.
• Anticoagulants and antiplatelet agents are used because thromboembolism is a major problem. There are no data on the effectiveness of such interventions but anecdotes suggest that some patients continue to have thrombotic complications despite therapy.
• Antihistamines can be used for symptomatic relief only.
• CHF should be treated energetically in the usual way.
• Splenectomy may benefit thrombocytopenia and LUQ pain.
• Surgery is sometimes required for heart valve lesions.
• Bone marrow transplants and allogenic stem cell transplants have been used but are not a common mode of treatment.

Good prognosis

Good prognosis is suggested by:

• Good response to prednisone
• Urticaria or angioedema as the type of skin involvement
• Lack of symptoms, especially absence of CHF

Poor prognosis

The following are bad signs:

• Anaemia
• Thrombocytopenia
• Raised white cell count
• Abnormal blood cells of any type
• Abnormal bone marrow
• Abnormal LAP levels
• Early organ involvement, especially CHF

In this rare disease with a highly variable presentation and progress, survival statistics vary. A study from the NIH in 1982¹ noted a mean duration of disease of 4.8 years (range 1 to 24 years). About 70% respond to steroids. The five-year survival rate is 80% with CHF being the most common cause of death. The longer the survival, the greater the chance of leukaemic change.

1. Fauci AS, Harley JB, Roberts WC, et al; NIH conference. The idiopathic hypereosinophilic syndrome. Clinical, pathophysiologic, and therapeutic considerations.; Ann Intern Med. 1982 Jul;97(1):78-92. [abstract]
2. Alfaham MA, Ferguson SD, Sihra B, et al; The idiopathic hypereosinophilic syndrome.; Arch Dis Child. 1987 Jun;62(6):601-13. [abstract]
3. Katz HT, Haque SJ, Hsieh FH; Pediatric hypereosinophilic syndrome (HES) differs from adult HES.; J Pediatr. 2005 Jan;146(1):134-6. [abstract]
4. Davies J, Spry CJ, Sapsford R, et al; Cardiovascular features of 11 patients with eosinophilic endomyocardial disease.; Q J Med. 1983 Winter;52(205):23-39. [abstract]
5. Moore PM, Harley JB, Fauci AS; Neurologic dysfunction in the idiopathic hypereosinophilic syndrome.; Ann Intern Med. 1985 Jan;102(1):109-14. [abstract]
6. Bogenrieder T, Griese DP, Schiffner R, et al; Wells' syndrome associated with idiopathic hypereosinophilic syndrome.; Br J Dermatol. 1997 Dec;137(6):978-82. [abstract]
7. Zittoun J, Farcet JP, Marquet J, et al; Cobalamin (vitamin B12) and B12 binding proteins in hypereosinophilic syndromes and secondary eosinophilia.; Blood. 1984 Apr;63(4):779-83. [abstract]
8. Coutre S, Gotlib J; Targeted treatment of hypereosinophilic syndromes and chronic eosinophilic leukemias with imatinib mesylate.; Semin Cancer Biol. 2004 Aug;14(4):307-15. [abstract]

• Scheinfeld NS; Hypereosinophilia Syndrome. emedicine, January 2006.
• DermNet NZ; Hypereosinophilic syndrome. Includes some good pictures.