Are You Confident of the Diagnosis?
Hypereosinophilic syndrome (HES) is a heterogeneous group of disorders, first described in 1968 by Hardy and Anderson. The diagnostic criteria were later introduced in 1975 by Chusid. The syndrome is characterized by persistent peripheral eosinophilia of 1500 cells/microliter, evidence of end organ damage by eosinophil infiltration, and no identifiable secondary cause of eosinophilia including parasitic infections, allergic diseases, drug hypersensitivity reactions, connective tissue diseases and neoplasms.
Based on the various clinical features, prognoses, response to treatments and the recent advances in diagnostic techniques, two main variants of HES have been identified: myeloproliferative variant (M-HES) and lymphocytic variant (L-HES). Other variants have been described, including a rare familial form and undefined category. Cyclic angioedema with eosinophilia falls in the latter category. Overlap with known eosinophilic disorders such as Churg-Strauss syndrome, as well as an association with organ restricted eosinophilic disorders such as eosinophilic gastrointestinal disorders have also been identified.
Characteristic findings on physical examination
Clinical features vary considerably depending on subtypes and the organ system involved. Systemic or constitutional symptoms are common and include fatigue, fever, weight loss/gain and pruritus among others. Skin, heart, lung, and nervous system are involved in majority of patients. The eosinophilia may also be an incidental finding.
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The mucocutaneous involvement of patients with HES vary and include, but are not limited to, erythema, which ranges from focal erythema to erythrodermal; eczematous lesions; maculopapular eruptions; nodule; mucocutaneous ulcerations; urticaria; and /or angioedema and vasculitis (Figure 1). Erythema annulare centrifugum, livedo reticularis, necrotizing vasculitis and eosinophilic cellulitis have all been reported.
Patients may present with or develop skin lesions during the course of the disease. Skin lesions occur in more than 50% of patients with HES and can be the first manifestation. The skin lesions are particularly prevalent in L-HES and are commonly associated with pruritus. Eczema, erythroderma, urticaria and angioedema along with lymphadenopathy are common in this type.
It has a relatively benign course compared to M-HES and is less commonly associated with endomyocardial involvement; however it may evolve to lymphoma. The M-HES can present with skin lesions in addition to fever, weight loss, fatigue, enlarged liver and spleen. Splinter hemorrhage may precede the thromboembolic disease when endomyocardial involvement is present.
Mucosal ulcerations have been reported as a distinct feature of M-HES. Mucosal lesions are typically painful and may occur on oropharynx, lips, tongue, buccal and gingival surfaces, conjunctiva or genital mucosa as erosions, ulcerations, or aphthous-like lesions. Differential diagnoses include infectious and traumatic mucosal lesions, neoplasms, drug-induced, irradiation-induced and mucosal ulceration associated with systemic diseases such as inflammatory bowel disease or Behcet’s disease.
A subset of HES known as undefined HES has been described, which manifests as cyclic or episodic angioedema with urticaria and fever along with marked eosinophilia and increase in body weight. This type occurs in adults as well as children. The angioedema may involve face, neck, trunk, and extremities, and the attacks persist for days. The level of leukocytosis and eosinophilia correlate with severity of the episodes. Additionally there is increased level of polyclonal IgM and IgE. This type is typically associated with high levels of IL-5 during the episodes.
Diagnosis confirmation
The diagnosis of HES is confirmed using the following criteria: (1) persistent absolute peripheral eosinophil count greater than 1500/microliter; (2) exclusion of other causes of eosinophilia; (3) evidence of an organ damage from eosinophilic infiltration. Once the diagnosis is made, identification of the subtype is required by bone marrow biopsy with cytogenetics, fluorescent in-situ hybridization (FISH) for fusion protein between FIP1Like1 (FIP1L1), and platelet-derived growth factor receptor alpha (PDGFRA), also known as (F/P).
Who is at Risk for Developing this Disease?
The prevalence of HES is not known precisely. Although an incidence of 0.5-1 per 100,000 populations per year has been reported, a recent study suggested that the age-adjusted incidence is between 0.18-0.36 per 100,000 populations per year. The myeloproliferative variant has been reported to be 4-9 fold more prevalent in males. The syndrome typically presents between 20 to 50 years of age, and in one recent report a median age at diagnosis was 52.5 years.
What is the Cause of the Disease?
Etiology
The etiology of HES remains unknown.
Pathophysiology
M-HES commonly results from an interstitial deletion in chromosome, 4q12 leading to the formation of a fusion protein between FIP1Like1 (FIP1L1) and platelet derived growth factor receptor alpha (PDGFRA), also known as (F/P), which is an active tyrosine kinase. The M-HES is classified by the World Health Organization as chronic eosniophilic leukemia. The L-HES is caused by clonal expansion of T helper 2-lymphocytes which produce Interleukin 5 (IL-5).
In undefined HES, it is believed that periodic elevation of IL-5 stimulates bone marrow and activates eosinophils, which then migrate into skin and degranulate resulting in releasing mediators that cause increase vascular permeability. The mechanism of episodic increase in IL-5 level is not known.
Systemic Implications and Complications
Considering the great variability in pathogenesis and clinical presentations, the long-term course and prognosis is variable. This may range from minimal impairment requiring no treatment, to severe disease leading to disability. It is noteworthy that severity of organ involvement and prognosis do not correlate with the degree of peripheral eosinophilia.
Certain features were found to be associated with poor prognosis in initial studies. These included severe eosinophilia greater than 100,000/microliter, hepatosplenomegaly, and increased levels of vitamin B12 and alkaline phosphates. These features are now known to be seen in M-HES. Poor outcomes are related to severe organ damage, particularly heart failure and malignant transformations. M-HES can transform to acute myelogenous leukemia and L-HES to T-cell lymphomas.
Treatment Options
Treatment options for HES are summarized in Table I. Systemic corticosteroids are the mainstay and the first-line treatment for most patients, except for those with M-HES. In patients who have M-HES with F/P mutation, imatinib, a monoclonal antibody against tyrosine kinase, is the first-line therapy. Patients with M-HES who do not have a F/P mutation still respond to imatinib and that should be the first-line treatment for them as well.
Table I.
| First line treatment | Second line treatment | Refractory/intolerant to the first and second line |
| Corticosteroids | Hydroxyurea | Cytotoxic agents (cyclophosphamide, Methotrexate) |
| Vincristine (for eosinophils >100,000) | Interferon-alpha | Immunomodulators (cyclosporine, alemtuzumab, IVIG) |
| Imatinib (for M-HES) | Anti-IL5 ( currently research indications and compassionate use for L-HES) | Imatinib |
| Bone marrow transplantation (Non-myeloablative) |
Optimal Therapeutic Approach for this Disease
In M-HES with positive F/P mutation, imatinib mesylate, a tyrosine kinase inhibitor, has dramatically decreased the morbidity and mortality and is the first line and treatment of choice regardless of severity of disease. This therapy should also be considered in M-HES without F/P mutation.
It is noteworthy that clinical presentations of systemic mastocytosis with D816KIT mutation overlap with F/P positive M-HES; however the former does not respond to imatinib. Molecular testing and a scoring index are available to distinguish between these two conditions.
For patients with cardiac involvement or elevated troponin level, concurrent treatment with steroids is recommended during the first two weeks.
In L-HES, corticosteroids are the first-line treatment if patients are symptomatic. Most patients respond to 30-60mg prednisone. Once symptomatic improvement has been achieved and eosinophil count has normalized, slow tapering to 10mg over the course of months should be attempted. Monoclonal antibody against IL-5 has been successfully used in research trials for this type.
The mainstay of treatment for undefined HES that includes episodic or cyclic angioedema with eosinophilia is a corticosteroid. Treatment with steroids have been shown to improve symptoms and decrease levels of IL-5. Failure to respond to steroids may be an indication of worse prognosis. If skin lesions are present, biopsy of skin for histologic evaluation, direct immunofluorescence, and immunophenotype studies should be obtained. Flow cytometry for evaluation of T-cell receptors and light chain rearrangements are useful. Monitoring the response of skin lesions to treatment helps evaluate the systemic efficacy of the treatment.
In addition to modalities mentioned in Table I, psoralen ultraviolet A (PUVA) phototherapy, and extracorporeal photochemotherapy are sometimes used for treatment. Ulceration of oral and genital mucosal surfaces are typically associated with the more severe forms of HES, particularly M-HES, and endomyocardial fibrosis is a major complication. The importance of identifying this is to consider treatment with imatinib to which they usually respond.
Patient Management
A crucial step in management of patients suspected to have HES is to exclude the secondary causes of eosinophilia that require specific treatment not directed towards eosinophilia. Parasitic infestations, most importantly strongyloidosis, should be excluded by an enzyme-linked immunsorbant assay in all patients with plausible history of exposure. Treating with corticosteroids can lead to fatal dissemination of this parasite.
A history of allergic disorders and a careful drug history should be obtained. It has been recommended that all nonessential drugs or herbal medicines should be discontinued before the diagnosis of HES is made. Furthermore, connective tissue diseases and neoplasms, particularly hematologic malignancies, should be excluded.
Unusual Clinical Scenarios to Consider in Patient Management
The primary goal of treatment of HES is to decrease tissue eosinophilia and reduce eosinophil-associated damage to the tissue. Peripheral eosinophilia is a readily available laboratory value; however, it does not reliably predict the degree of tissue damage. In the absence of a reliable and validated biomarker, patients should be clinically followed closely. Serial echocardiograms are recommended every 6-12 months, particularly in M-HES, since cardiac involvement may be asymptomatic. Depending on clinical presentation, skin biopsy, pulmonary function test, scan imaging of chest or abdomen may be considered in follow up of patients.
In HES patients with skin lesions, response to treatment of skin lesions is not only important for symptom relief but also serves as a marker for disease activity. In critically ill patients with severe cardiac, neurologic and/or dermatologic involvement, empirical intravenous corticosteroid administration should be considered. In these patients, if there is a possibility of exposure to strongyloides, empiric treatment with the antihelminthic agent ivermectin has been recommended.
What is the Evidence?
Gleich, GJ, Leiferman, KM. “The hypereosinophilic syndromes: current concepts and treatments”. Br J Haematol. vol. 145. 2009. pp. 271-85. (HES encompass a spectrum of diseases with peripheral eosinophilia and tissue damage as common features. M-HES responds to imatinib, whereas L-HES responds to treatment with a monoclonal antibody to IL-5.)
Ionescu, MA, Murata, H, Janin, A. “Oral mucosa lesions in hypereosinophilic syndrome: an update”. Oral Dis. vol. 14. 2008. pp. 115-22. (Oral mucosa ulcerations can be early manifestation of severe forms of HES, mainly M-HES, which is characterized by an increased risk of myeloid malignancies and a response to imatinib. The target of imatinib is a kinase resulting from a deletion on chromosome 4. FIP1L1-PDGFR alpha fusion gene is a marker of response to imatinib. Exclusion of other causes of oral ulcers, early recognition of HES in patients with oral ulcerations, and determination of the lymphocytic or myeloproliferative variants are important to initiate an effective therapy.)
Klion, A. “Hypereosinophilic syndrome: current approach to diagnosis and treatment”. Annu Rev Med. vol. 60. 2009. pp. 293-306. (Characterization of the variants of HES at the molecular and immunologic levels shows differences in pathogenesis, response to treatment, and prognosis. Availability of tyrosine kinase inhibitors and monoclonal antibodies, has dramatically altered the approach to the diagnosis and treatment of HES.)
Klion, AD. “Approach to the therapy of hypereosinophilic syndromes”. Immunol Allergy Clin North Am. vol. 27. 2007. pp. 551-60. (With the introduction of new diagnostic methods and treatment modalities, HES is considered a heterogeneous group of disorders for which a single approach to treatment is insufficient. The article discusses treatment modalities for M- HES, L-HES and other subtypes of HES.)
Klion, AD. “How I treat hypereosinophilic syndromes”. Blood. vol. 114. 2009. pp. 3736-41. (This article reviews an approach to the diagnosis, classification, and treatment of patients with HES.)
Leiferman, KM, Gleich, GJ, Peters, MS. “Dermatologic manifestations of the hypereosinophilic syndromes”. Immunol Allergy Clin North Am. vol. 27. 2007. pp. 415-41. (Skin is a commonly affected organ in hypereosinophilic syndromes (HES). Cutaneous lesions are common and important presenting signs, could be debilitating, and usually reflect disease activity in HES. Recognition of dermatologic manifestations is important in approaching diagnosis and treatment of HES. This article reviews cutaneous involvement in HES and other eosinophil-associated skin diseases.)
PU Bochner, BS, Butterfield, JH, Gleich, GJ, Huss-Marp, J, Kahn, JE. “Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy”. J Allergy Clin Immunol J Allergy Clin Immunol. vol. 124. 2009. pp. 1319-25 e3. (This large retrospective clinical analysis of patients with HES provides useful information regarding treatment. Prospective trials to optimize treatment is encouraged.)
Roufosse, FE, Goldman, M, Cogan, E. “Hypereosinophilic syndromes”. Orphanet J Rare Dis. vol. 2. 2007. pp. 37(In this informative summary of HES and recent advances in underlying pathogenesis, the authors emphasize that therapeutic management should be tailored to disease severity and detection of pathogenic variants. For F/P+ patients, imatinib is the first-line therapy. For others, corticosteroids are administered initially followed by steroid sparing agents such as interferon alpha.)
Sheikh, J, Weller, PF. “Clinical overview of hypereosinophilic syndromes”. Immunol Allergy Clin North Am. vol. 27. 2007. pp. 333-55. (Based on recent evidence, the clinical features, complications, treatment options, and prognoses differ among the myeloproliferative, lymphocytic, and undefined variants of HES.)
HJ Crane, MM, Copeland, K, Williams, WV. “Hypereosinophilic syndrome: an update”. Am J Hematol. vol. 80. 2005. pp. 148-57. (The limitations on the use therapeutic agents for HES include efficacy, tolerability, and toxicity. New treatments are a tyrosine kinase inhibitor, and an anti-IL-5 monoclonal antibody, which can improve clinical outcomes.)
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