Idiopathic hypereosinophilic syndrome: a rare but fatal condition presenting with common symptoms.

Introduction: Idiopathic hypereosinophilic syndrome (IHES) is a leukoproliferative disorder characterized by cytokine-induced overproduction of eosinophils with resultant multiorgan infiltration and damage. The diagnostic criteria includes evidence of end organ damage, exclusion of all other causes of eosinophilia and sustained absolute eosinophil count (AEC) > 1,500 cells/mcl for at least 6 months.

Case: An 88-year-old Caucasian female presented with persistent severe chronic cough, weight loss and rhinorrhea unresponsive to various treatments. Her workup during admission revealed absolute eosinophil count of 17,447 and bone marrow biopsy showed eosinophilia with no lymphoproliferative process. After excluding all other causes of eosinophilia, a diagnosis of IHES was made and prednisone was started. Symptoms resolved and her absolute eosinophil count progressively decreased.

Conclusion: IHES mimics several other diseases. Mild eosinophilia should be worked up irrespective of age and sex. A high index of suspicion is required for earlier diagnosis and treatment, which could reduce morbidity and mortality.

Key Words: hypereosinophilic syndrome, eosinophilia, idiopathic eosinophilia

Case Report

An 88-year-old nonsmoking white female presented to an outpatient clinic in September 2003 with persistent nonproductive cough, shortness of breath, and rhinorrhea of 3 weeks' duration. She had lost 10 pounds over the previous 2 months. Her past medial history included hypertension, gastroesophageal reflux disease and sick sinus syndrome with pacemaker placement. She denied any pulmonary disease or seasonal or environmental allergies. Medications included hydrochlorothiazide, aspirin, lansoprazole, irbesartan, and multivitamins. Physical examination revealed normal vital signs and her cardiopulmonary examination revealed a 2/6 ejection systolic murmur in the aortic area.

Her outpatient workup showed a white blood cell count (WBC) of 5,700/[mm.sup.3] and eosinophils of 14%, with normal hemoglobin and platelet counts. Chest x-ray was unremarkable. Stool microscopy, ESR, antinuclear antibody, rheumatoid factor, complement components, ANCA, thyroid function tests, aspergillus antibody titer, Lyme antibody titer, and barium swallow study were normal. IgE was increased at 141 IU/mL (Normal < 114 IU/mL). Over the next 7 months, she did not respond to various antihistamines, antitussives, antibiotic agents or bronchodilators. Her symptoms persisted and her cough became severe, warranting inpatient admission in April 2004. Investigations showed an elevated WBC of 23,000 with 73% eosinophils and an absolute eosinophil count (AEC) of 17,447. Peripheral smear showed mature eosinophils without any blast forms. Chest x-ray showed bilateral patchy infiltrates and a chest CT scan revealed bilateral lung infiltrates. Transthoracic echocardiogram revealed new systolic dysfunction with an ejection fraction of 40%.

Bone marrow biopsy showed eosinophilia with eosinophils at all stages of maturation, normal blasts, and phenotypically normal T-lymphocytes with no evidence of a lymphoproliferative process (Fig. 1). After excluding other causes of eosinophilia, (parasitosis, malignancy and immunologic disease) diagnosis of IHES with pulmonary involvement was made. She was started on prednisone 40 mg orally once daily. Cough and rhinorrhea subsided within 24 hours. AEC decreased progressively and pulmonary infiltrates resolved gradually. She was discharged on prednisone 30 mg daily, which was tapered and discontinued after 5 months. Symptoms recurred within a month after stopping prednisone and the AEC levels increased to 14,790. Prednisone was restarted with appropriate response and the patient is currently asymptomatic on 10 mg of prednisone daily.

Discussion

Idiopathic hypereosinophilic syndrome is a rare, leukoproliferative multisystem disorder characterized by sustained over production of eosinophils. Eosinophils infiltrate organs and express their toxins causing damage that is sometimes irreversible. It usually occurs in middle-aged males (9:1 M:F). Diagnostic criteria for IHES includes: a) eosinophil count of > 1.500 cells/mm for > 6 months, b) exclusion of other causes of eosinophilia, and c) signs and symptoms of end-organ damage. (1) Clinical presentation varies widely and depends on the organs affected. Heart, CNS, lungs and skin are predominantly involved. (2) The common pulmonary manifestations are chronic persistent cough, rhinitis and less commonly, bronchospasm. The most serious complication of IHES is cardiac which could present as fibrosis or thickening of ventricles with a low ejection fraction and resultant cardiomyopathy, which could possibly explain the systolic dysfunction in our patient. (3)

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Differential diagnosis for IHES includes parasitic infections, malignancy, Churg-Strauss syndrome; immune diseases (like hyper IgE syndrome) and vasculitis. Differentiating IHES from chronic eosinophilic pneumonia (CEP) is sometimes difficult. Rhinorrhea, echocardiographic findings, elevated IgE, very high bone marrow and peripheral eosinophilia and absence of fever suggest IHES more than chronic eosinophilic pneumonia (CEP) in this case. This patient presented with common symptoms that mimic less severe conditions. This could sometimes delay diagnosis of IHES, therefore having a high index of suspicion, especially in the presence of eosinophilia, irrespective of age or sex. There could be significant eosinophilic infiltration into organs with mild or absent peripheral eosinophilia; therefore patients with mild eosinophilia should be extensively worked up to identify a cause, especially if symptomatic.

Mortality rate for IHES ranges from 70 to 80% at 3 years if left untreated. Steroids remain the mainstay of therapy and most patients respond well with decreasing eosinophil counts and the dose can be tapered to the lowest effective dose. (4,5) Chemotherapeutic agents like hydroxyurea, interferon alfa, and cytarabine have been used in severe organ damage. (6) Recently, biologic agents like imatinib mesylate have shown some promising results. (7) Response to steroid therapy and elevated IgE levels are good prognostic indicators for IHES. Presence of high white blood cell count, myelodysplastic features and cardiac involvement portends poor prognosis. (8) Furthermore, eosinophil count and echocardiogram (if cardiac involvement is present) should be obtained at 6-month intervals while patients are on therapy to monitor response. (8)

References

1. Chusid MJ, Dale DC, West BC, et al. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore) 1975;54:1-27.

2. Spry CJ. The hypereosinophilic syndrome: clinical features, laboratory findings and treatment. Allergy 1982;37:539-551.

3. Parrillo JE, Borer JS, Henry WL, et al. The cardiovascular manifestations of the hypereosinophilic syndrome. Prospective study of 26 patients, with review of the literature. Am J Med 1979;67:572-582.

4. De Vriese AS, Kips JC, Vogelaers DP, et al. Pitfalls in the diagnosis of hypereosinophilic syndrome: a report of two cases. J Intern Med 1997;241:165-170.

5. Fauci AS, Harley JB, Roberts WC, et al. The idiopathic hypereosinophilic syndrome. Clinical, pathophysiologic, and therapeutic considerations. Ann Intern Med 1982;97:78-92.

6. Butterfield JH, Gleich GJ. Interferon-alpha treatment of six patients with the idiopathic hypereosinophilic syndrome. Ann Intern Med 1994;121:648-653.

7. Gleich GJ, Leiferman KM, Pardanani A, et al. Treatment of hypereosinophilic syndrome with imatinib mesilate. Lancet 2002;359:1577-1578.

8. Weller PF, Bubley GJ. The idiopathic hypereosinophilic syndrome. Blood 1994;83:2759-2779.

Ayodele Osowo, MD, James Fetten, MD, and Sankar Navaneethan, MD, MPH

From the Departments of Medicine and Hematology and Oncology, Unity Health System, Rochester, NY.

Reprint requests to Ayodele Osowo, MD, Park Ridge Hospital, 1555 Long Pond Road, Rochester, NY 14626. Email: [e-mail]

Accepted October 14, 2005.

RELATED ARTICLE: Key Points

* Mild eosinophilia should be worked up irrespective of age and sex, especially if symptomatic.

* IHES mimics several other less serious diseases, therefore clinicians should have a high index of suspicion.

* Early diagnosis and treatment improves survival and reduces morbidity.