Dermatologic Manifestations of Hypereosinophilic Syndrome 

Updated: Aug 21, 2019
Author: Felix Urman, MD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Hypereosinophilic syndrome (HES) encompasses a wide range of clinical manifestations sharing 3 features defined by Chusid et al[1] : (1) a peripheral eosinophil count of greater than 1.5 X 109/L for longer than 6 months; (2) evidence of organ involvement, thus excluding benign eosinophilia; and (3) an absence of other causes of eosinophilia, such as parasite infestation (most common cause of eosinophilia worldwide), allergy (most common cause of eosinophilia in the United States), malignancy, and collagen-vascular disease.

Also see Pediatric Hypereosinophilic Syndrome and Hypereosinophilic Syndrome.

Pathophysiology

Hypereosinophilic syndrome etiology can involve (1) primitive involvement of myeloid cells, essentially due to the occurrence of an interstitial chromosomal deletion on band 4q12 leading to the creation of the FIP1L1-PDGFRA fusion gene (F/P+ variant), or (2) increased interleukin (IL)–5 production by a clonally expanded T-cell population (lymphocytic variant), most frequently characterized by a CD3- CD4+ phenotype.[2, 3]

Multiple cytokines stimulate eosinophil production, including IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5.[4] In 3 patients with T-cell lymphomas, eosinophilia has been correlated with increased production of these cytokines by the lymphomas. IL-3 and GM-CSF act on other bone marrow–derived lineages, whereas the stimulatory activity of IL-5 appears to be limited to eosinophils and thus suggests it to be the dominant factor in eosinophil proliferation. At present, the source of IL-5 in hypereosinophilic syndrome has not been definitively determined, but evidence points to increased production by CD4+ T-lymphocyte clones.

However, IL-5 mRNA and protein have been found in eosinophils; therefore, the increase in this cytokine cannot be attributed merely to T cells. Also, because some patients with hypereosinophilic syndrome have concomitant neutrophilia, factors other than IL-5 are likely involved. GM-CSF and IL-3 have been shown to be produced by eosinophils, and GM-CSF production was demonstrated in the T-cell clones from patients with hypereosinophilic syndrome.

Eosinophils in hypereosinophilic syndrome infiltrate multiple organs where they inflict tissue damage through the release of granule proteins, including eosinophil peroxidase, major basic protein, eosinophil-derived neurotoxin, and eosinophil cationic protein. They also release proinflammatory cytokines (ie, interleukin 1 alpha, tumor necrosis factor–alpha, interleukin 6, interleukin 8, IL-3, IL-5, GM-CSF, macrophage inflammatory protein), which attract more eosinophils and other inflammatory cells to the area. Cardiac involvement is the most common cause of mortality in hypereosinophilic syndrome. In the heart, the infiltration by eosinophils results in endomyocardial fibrosis, with subsequent development of congestive heart failure (CHF) and death. This infiltration is necessary for tissue damage to occur because patients with peripheral eosinophilia due to other causes (eg, eosinophilic pneumonia) do not develop pathology similar to hypereosinophilic syndrome.

Fip1-like1-platelet-derived growth factor receptor alpha chain (FIP1L1-PDGFRA) mutation has been described in adult patients with hypereosinophilic syndrome.[5] Specifically, a novel oncogenic mutation (FIP1L1-PDGFRA), which results in a constitutively activated platelet-derived growth factor receptor-alpha (PDGFRA), has been invariably associated with a primary eosinophilic disorder and results in clonal lines of pathologic cells.[6]

Pardanani et al[7] examined both the prevalence and the associated clinicopathologic features of the mutation in FIP1L1-PDGFRA in 89 adults presenting with an absolute eosinophil count of higher than 1.5 X 109/L. Pardanani and his team[7] used a fluorescence in situ hybridization–based strategy to identify FIP1L1-PDGFRA in bone marrow cells. None of 8 patients with reactive eosinophilia demonstrated defects in FIP1L1-PDGFRA, whereas the rate of FIP1L1-PDGFRA in the remaining 81 patients with primary eosinophilia was 14% (11 patients). None (0%) of 57 patients with hypereosinophilic syndrome but 10 (56%) of 19 patients with systemic mast cell disease associated with eosinophilia (SMCD-eos) carried the mutated FIP1L1-PDGFRA. Thus, it seems FIP1L1-PDGFRA is not solely responsible for hypereosinophilic syndrome. However, a 40% partial response rate was observed in 10 hypereosinophilic syndrome cases after treatment with imatinib.

McPherson et al[8] reported a 33-year-old man with recurrent papular skin lesions and marked peripheral eosinophilia whose skin histopathology showed a proliferation of CD30+ T cells consistent with lymphomatoid papulosis and in whom molecular analysis of peripheral blood mononuclear cells demonstrated the presence of the FIP1L1/PDGFRA fusion gene.

Etiology

Hypereosinophilic syndrome is a clonal proliferation of eosinophils. By definition, hypereosinophilic syndrome is an idiopathic condition.

Some have speculated that hypereosinophilic syndrome is not primarily a disease of eosinophils but rather a disease of T cells that secrete cytokines that result in such clonal proliferations. Such clonal eosinophils are activated and have more eosinophilic mediators than normal eosinophils.

Some cases of hypereosinophilic syndrome turn into leukemia, and, as such, chromosomal abnormalities are at the root of some cases of hypereosinophilic syndrome. A study from the NIH[9] found chromosomal abnormalities in 8 of 33 patients examined. Such abnormalities can include the Philadelphia chromosome.

Epidemiology

Frequency

United States

The exact incidence of hypereosinophilic syndrome is hard to determine because it is a diagnosis of exclusion. It is a rare condition, although numerous reports exist in the literature. At the National Institutes of Health (NIH) between 1971 and 1982, 50 cases of hypereosinophilic syndrome were diagnosed and followed up.[9] The disease is rare in children.

International

Hypereosinophilic syndrome is rare, and the exact incidence is uncertain.

Race

No racial predilection is recognized for hypereosinophilic syndrome.

Sex

Male predominance (4-9:1 ratio) has been reported in historic series, but this is likely to reflect the quasi-exclusive male distribution of a sporadic hematopoietic stem cell mutation found in a characterized disease variant.[2]

Age

A study from the NIH[9] of 50 patients reported that the mean age of onset was 33 years. In 70% of patients, the onset of disease occurs between 20-50 years. Although rare, this disease hypereosinophilic syndrome does occur in children.[10] A review in 1987[11] from Wales found 18 published reports of hypereosinophilic syndrome in children younger than 16 years. The incidence seems to decrease in elderly persons. Kim et al reported encephalitis in idiopathic hypereosinophilic syndrome in a 14-year-old girl.[12]

Prognosis

Good prognostic factors include the following:

  • Good response to prednisone

  • Urticaria/angioedema lesions as the type of skin involvement

  • Absence of symptoms, particularly CHF

Poor prognostic factors include the following:

  • Anemia

  • Thrombocytopenia

  • WBC count greater than 90 X 109/L

  • Abnormal circulating cells

  • Abnormal bone marrow

  • Abnormal leukocyte alkaline phosphatase levels

  • Chromosomal abnormalities (eg, Philadelphia chromosome) suggestive of a myeloproliferative disorder

  • Early aggressive organ involvement (especially CHF)

Mortality/morbidity

The course of hypereosinophilic syndrome varies from relatively indolent to fulminant and rapidly fatal. The prognosis of hypereosinophilic syndrome has improved significantly since definition of hypereosinophilic syndrome and the development of imatinib. Ultimately, the mortality associated with hypereosinophilic syndrome id due to the occurrence of hypereosinophilic syndrome-related irreversible heart failure and the eventuality of malignant transformation of myeloid or lymphoid cells into a frank eosinophilic leukemia.[2]

Survival statistics vary. A review of 57 patients with advanced disease had a mean survival rate of 9 months and a 3-year survival rate of 12%; in another analysis of 40 patients, the 5-year survival rate was 80% and the 10-year survival rate was 42%. A study from the NIH in 1982[9] noted a mean duration of disease of 4.8 years (range, 1-24 y). How newer treatments, such as cyclosporine, have affected mortality and morbidity is unclear.

A report published from the Mayo Clinic in 2013 noted a review of 247 cases of hypereosinophilic syndrome encompassing 19 years of data. Of these 247 patients, 23 died of a variety of hypereosinophilic syndrome–related diseases.[13]

Some hypereosinophilic syndrome cases resolve spontaneously, as was noted in a 2012 report of a 4-month-old infant.[14]

Patient Education

Instruct patients about the potential symptoms and the importance of rapid intervention.

 

Presentation

History

Hypereosinophilic syndrome is a multisystem disease, and the presenting complaint can vary depending on the organ involved. It is possible for hypereosinophilic syndrome to only involve the skin.[15] The presentation can be acute (eg, stroke), as when cardiac and neurologic systems are involved, or, more commonly, hypereosinophilic syndrome has an insidious onset. In an NIH series[9] , common symptoms included fatigue (26%), cough (24%), breathlessness (16%), muscle pains or angioedema (14%), and fever (12%). Sweating and pruritus are common. Acute respiratory distress has been noted in hypereosinophilic syndrome as a presenting sign.[16] An interesting case in a child noted isolated bilateral uveitis with hypereosinophilic syndrome.[17] Gangrene and vasculitis are manifestation of hypereosinophilic syndrome in the skin.[18]

Mucocutaneous manifestations[19, 20] occur in 25-50% of patients. Eosinophilia was incidentally detected in 12% of patients with hypereosinophilic syndrome. Patients with hypereosinophilic syndrome can have low-grade fevers. Some patients with hypereosinophilic syndrome experience alcohol intolerance with abdominal pain, flushing, nausea, weakness, or diarrhea. Rare associations with lupus[21] and leptomeningeal syndrome[22] for hypereosinophilic syndrome have been reported.

A literature review in 2012 found that therapy-resistant eczema, angioedema, atypical urticarial lesions (some lasting >24 hours and thus not true urticaria), pruriginous papules, and nodules are among the most common skin findings in hypereosinophilic syndrome.[23]

Common mucocutaneous manifestations of hypereosinophilic syndrome are as follows:

  • Pruritus

  • Urticaria

  • Dermatographism

  • Angioedema

  • Erythematous papules, plaques, and nodules

  • Nonspecific rash

Uncommon mucocutaneous manifestations of hypereosinophilic syndrome are as follows:

  • Aquagenic pruritus[24]

  • Splinter hemorrhages and Janeway lesions[25]

  • Palpable purpura

  • Livedoid discoloration

  • Wells syndrome[26]

  • Livedoid discoloration

  • Erythroderma

  • Vesicular disease

  • Eosinophilic vasculitis

  • Acral necrosis[27]

  • Petechiae

  • Erythema annulare centrifugum

  • Mucosal ulceration and erythema

  • Bullous pemphigoid (responded to imatinib)[28]

  • CD30+ clonal T-cell lymphoid proliferation[29]

  • Gangrene[18]

Cardiac symptoms of hypereosinophilic syndrome are as follows[30, 31, 32, 33, 34] :

  • The heart is commonly involved, and thromboembolic complications resulting from cardiac involvement can lead to multisystem disease.

  • Heart damage evolves through 3 stages: (1) an acute necrotic stage (with a mean disease duration of 5.5 wk), (2) a thrombotic stage (10-mo mean duration of eosinophilia), and (3) a fibrotic stage (after approximately 2-y duration of disease).

  • In summary, hypereosinophilic syndrome can result in endomyocardial fibrosis, valvular disease and lesions, mural thrombus formation, cardiomegaly due to infiltration of the myocardium with eosinophils, and pericardial effusion.

  • Symptoms are most common during the thrombotic and fibrotic phases and include chest pain, dyspnea, and orthopnea.

  • Serious cardiac complications occur with an indolent maculopapular rash accompanied by pigmentary alteration.[35]

  • Eosinophilic endomyocarditis with splinter hemorrhages and Janeway lesions are reported.[25]  

Neurologic symptoms of hypereosinophilic syndrome are as follows[36, 37] :

  • Thromboembolic complications are usually from the heart and present as strokes or transient ischemic attacks (TIAs).[38]

  • Primary CNS dysfunction usually presents with symptoms of encephalopathy, such as behavior changes, confusion, blurry vision, memory loss, ataxia, and upper motor neuron signs.

  • Peripheral neuropathies present as symmetric or asymmetric sensory changes, pure motor deficits, mixed sensory and motor defects, or paresthesias. The cause is poorly understood. Peripheral neuropathies cause 50% of all neurologic complications.

Pulmonary symptoms of hypereosinophilic syndrome are as follows:

  • Pulmonary symptoms may result from CHF, pulmonary emboli from the right side of the heart, or infiltration of the lungs by eosinophils.

  • The most common symptom is a chronic, nonproductive cough. Dyspnea may occur due to CHF or pleural effusions (which are sometimes primarily caused by hypereosinophilic syndrome). Bronchospasm asthmatic symptoms can occur.

Hematologic symptoms of hypereosinophilic syndrome are as follows[39, 40] :

  • Nonspecific symptoms, such as fatigue due to anemia or easy bruising due to thrombocytopenia, can occur. Eosinophils can cause vasculitis; therefore, vasculitis in different organs, including the skin, can be associated with hypereosinophilic syndrome. Some cases evolve into eosinophilic leukemia or other forms of leukemia.

  • Thrombotic episodes often occur and present with neurologic complications. The thrombotic events may occur secondary to heart dysfunction, or they may be caused by hypercoagulability. The mechanism of hypercoagulability remains to be fully defined.

GI symptoms of hypereosinophilic syndrome are as follows:

  • GI involvement can occur secondary to embolic disease from the heart or from eosinophil infiltration of the GI tract, the liver, or the spleen.

  • Splenomegaly presents with left upper quadrant pain and occurs in about 40% of patients.

  • Diarrhea occurs in 20% of patients.

  • Abdominal pain, vomiting, and nausea can occur. The stomach may become dilated.

  • Liver and gall bladder dysfunction and ascites can also result. A report has noted hypereosinophilic syndrome and sclerosing cholangitis. In such cases, the symptoms and blood parameters of liver dysfunction can be associated with eosinophilia and high serum IgE levels. During corticosteroid therapy, these parameters improve, and morphologic improvements of the bile ducts can also usually be observed. The pathogenesis of sclerosing cholangitis may be explained, in part, by the concept of hypereosinophilic syndrome or allergic reaction.

  • Ulcers, hepatitis, gastritis, colitis, pancreatitis, Budd-Chiari syndrome, and cholangitis can occur.

  • Watanabe et al[41] reported a 64-year-old man with hypereosinophilic syndrome. This patient had from dysphagia, swelling of the oral mucosa and the posterior cervical muscles, abdominal pain, and diarrhea. This elderly man had an abnormal number of eosinophils in his blood. CT scanning revealed thickening of the posterior wall of the pharynx, esophagus, and GI tract. A lower lip tissue specimen demonstrated a moderate infiltration of eosinophils.

Rheumatologic symptoms of hypereosinophilic syndrome are as follows:

  • Arthralgia

  • Arthritis

  • Raynaud phenomenon

  • Wells syndrome

Ocular symptoms of hypereosinophilic syndrome are as follows:

  • Visual symptoms, especially blurring, can occur.

  • Adie syndrome (pupillotonia), keratoconjunctivitis, and episcleritis can occur.

  • Retinal and blood vessel abnormalities can occur, more often as a result of microthrombi than arteritis.

Constitutional symptoms of hypereosinophilic syndrome are as follows:

  • Many patients experience fever and night sweats.

  • Anorexia and weight loss are uncommon presenting symptoms; these symptoms are often related to an underlying cardiac disease.

Other symptoms of hypereosinophilic syndrome are as follows:

  • Oligospermia - Reported in a patient receiving imatinib therapy for the hypereosinophilic syndrome

  • Heart involvement - Occurred in a pregnant woman with multiple sclerosis[42]

Physical Examination

The signs and symptoms are dependent on the organ system involved.

Mucocutaneous signs of hypereosinophilic syndrome are as follows:

  • Urticarial wheals (see image below) and angioedema are common.

    Urticarial and erythematous rash. Urticarial and erythematous rash.
  • Dermatographism occurs in as many as 75% of patients.

  • Erythematous, pruritic papules and plaques are the other major dermatologic manifestation.

  • Blistering lesions and necrotic ulcers secondary to dermal microthrombi have been reported.

  • Petechiae, generalized erythroderma, erythema annulare centrifugum, and Raynaud phenomenon are other cutaneous manifestations, as seen in the image below.

    Petechiae on an erythematous base. Petechiae on an erythematous base.
  • Splinter hemorrhages can result from cardiac thromboemboli.

  • Ulcers can occur on virtually any mucosal surface.

  • Dermatopathic lymphadenopathy[43]

Cardiac signs of hypereosinophilic syndrome are as follows:

  • Signs of heart disease vary depending on the stage of involvement, and they become more prominent in the latter stages of the disease.

  • Splinter hemorrhages, arrhythmias, murmurs (particularly mitral and tricuspid regurgitation), restrictive cardiomyopathy, cardiomegaly, as well as other CHF manifestations all occur and have a worse prognosis. The symptoms of hypereosinophilic syndrome can resemble restrictive cardiac disease.

Neurologic signs of hypereosinophilic syndrome are as follows:

  • Acute neurologic deficits are usually the result of thromboembolic disease.

  • Primary CNS involvement manifests as changes in mental status, ataxia, increased deep muscle tone, increased deep tendon reflexes, and a positive Babinski sign. Seizures can occur but are less common.

  • When peripheral nerves are involved, patients exhibit sensory and/or motor deficits. Radiculopathies, muscle atrophy from denervation, and mononeuritis multiplex have been reported. Generalized weakness has been noted but is not a diagnostic sign of hypereosinophilic syndrome.

Pulmonary signs of hypereosinophilic syndrome are as follows:

  • Pleural effusions are common as a result of CHF.

  • Diffuse or focal crackles may be appreciated as a result of pulmonary infiltration by eosinophils or by ensuing pulmonary fibrosis.

  • Pleuritic chest pain and hypoxia can be caused by pulmonary emboli originating from the right side of the heart.

GI signs of hypereosinophilic syndrome are as follows:

  • Because hypereosinophilic syndrome can affect every abdominal organ, complaints of abdominal pain need to be immediately evaluated.

  • Bowel necrosis, with the classic "pain out of proportion to examination," due to thromboembolic disease is life threatening.

  • Splenomegaly is common.

Rheumatologic signs of hypereosinophilic syndrome are as follows:

  • Joint effusions can occur.

  • The characteristic color changes of Raynaud phenomenon may be observed.

Ocular signs of hypereosinophilic syndrome include, occasionally, visual blurring.

Complications

Because hypereosinophilic syndrome is a multisystem disease, the complications depend on the organs involved. Cardiac involvement leading to CHF and death is the most feared complication. Three types of neurologic complications occur: thromboembolic, primary CNS dysfunction, and peripheral neuropathies (see Physical in Presentation).

 

DDx

Diagnostic Considerations

Also consider the following:

  • Eosinophilic leukemia
  • Leukemia
  • Drug reactions
  • Eosinophilic toxocariasis
  • Episodic angioedema with eosinophilia
  • Hypersensitivity diseases
  • Parasitic infections
  • Churg-Strauss syndrome [44]

Differential Diagnoses

 

Workup

Laboratory Studies

Hematology

The eosinophil count is greater than 1.5 X 109/L. Eosinophils can exhibit structural abnormalities, such as cytoplasmic vacuolization and nuclear hypersegmentation. On a peripheral smear, eosinophils may be normal in appearance, but often some morphologic abnormalities, such as a decrease in granule number and size, are observed.

Neutrophilia is common, but bandemia is infrequent. Extremely high leukocyte counts and immature forms may indicate a leukemia and have a worse prognosis.

Leukocyte alkaline phosphatase levels can be elevated or decreased.

Of patients with hypereosinophilic syndrome (HES), 50% have anemia. Teardrop cells and nucleated erythrocytes can often be found on a peripheral smear.

Thrombocytopenia is seen in 31% of patients; however, 16% of patients have an elevated platelet count.

The erythrocyte sedimentation rate may be elevated.

Vitamin levels

Vitamin B-12 and vitamin B-12–binding protein levels may be elevated.[45]

Folate levels can be below the reference range.

Pleural fluid

This analysis typically reveals a transudate; however, exudative effusions containing eosinophils can be present.

Chromosome analysis[46]

Chromosomal abnormalities are diverse, with the most common being aneuploidy.

The Philadelphia chromosome has occasionally been found.

Clonality of eosinophils has been observed.

Immunoglobulins levels

High immunoglobulin E (IgE) levels are found in 38% of patients. Elevations in immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M (IgM) levels are less common.

Urine analysis

Proteinuria, hematuria, albuminuria, and/or hyaline casts may be present.

Blood chemistry analysis

Renal and liver function test values can be elevated.

Gene studies

Martinaud et al reported a 49-year-old man with hypereosinophilic syndrome who had both a FIP1L1-PDGFRA fusion gene rearrangement and T-cell clonality.[6]

Imaging Studies

Cardiac studies

Echocardiography can be used to assess thrombus formation, fibrosis, pump function, and valvular dysfunction.[47] Mitral and tricuspid dysfunction may also be detected.

ECG often reveals T-wave inversion and can be used to evaluate arrhythmias.

Cardiac catheterization and angiography can be used to evaluate myocardial function and valvular dysfunction.

Pulmonary studies

Chest radiography and CT can demonstrate pleural effusions, pulmonary infiltrates and fibrosis, and cardiomegaly.

Neurologic studies

Head CT and MRI can reveal strokes; TIAs; and increased cerebrospinal fluid (CSF) pressure, particularly from inflammation of central nerve tissue.

Peripheral nerve conduction studies are useful in assessing neuropathies.

GI studies

Abdominal CT can be used to evaluate hepatosplenomegaly, the hepatic vein (Budd-Chiari syndrome), and intestinal infarction.

Angiography can be used to assess the mesenteric vascular supply when embolic disease is suspected.

Endoscopy and barium studies can be used to evaluate ulcerations.

Procedures

Endocardial biopsy can help in diagnosing hypereosinophilic syndrome, particularly early in the disease when other cardiac signs and symptoms are not yet present. Right ventricular biopsy can be performed to evaluate for endomyocardial involvement.

Pleural fluid aspiration should be performed in patients with an effusion.

Bone marrow aspiration and biopsy, with evaluation of cytogenetics, can reveal myelofibrosis or a leukemia.

Because cutaneous lesions are nonspecific, skin biopsy may be necessary to confirm the diagnosis and to rule out other causes.

Fluorescein angiography may be performed even if patients do not have ocular symptoms. Fluorescein angiography has demonstrated that more than 50% of patients with hypereosinophilic syndrome have choroidal abnormalities, including patchy and delayed filling, and retinal vessel abnormalities.

Histologic Findings

The histopathologic findings vary. Several reports have noted microthrombi in blood vessels along with a variable superficial, deep, and interstitial perivascular infiltrate of eosinophils and other inflammatory cells. One report describing 3 patients linked an eosinophilic vasculitis to a recurrent purpuric rash. In a patient with multiple indurated plaques, a dermal infiltrate with eosinophils with flame figures was found. In eosinophilia with recurrent angioedema, a clinical syndrome thought to be a variant of hypereosinophilic syndrome, the infiltrate is primarily mononuclear with few eosinophils.

Biopsy samples of mucosal ulcerations typically demonstrate a mixed cell infiltrate without vasculitis.

Endocardial biopsy findings vary depending on the stage of the disease. In early disease, eosinophil infiltration with eosinophil microabscesses and myocardial necrosis are found. In advanced disease, fibrosis predominates.

In patients with neuropathy, peripheral nerve biopsy samples usually show axonal loss and no evidence of vasculitis or eosinophil infiltration.

 

Treatment

Medical Care

For FIP1L1-PDGFRA fusion gene patients, imatinib is first-line therapy.[48] Imatinib's adverse effects and expense warrant consideration before using it. Specifically, imatinib, which blocks the effects of platelet-derived growth factor, has transformed the care of a large subset of patients with hypereosinophilic syndrome (HES) and can be helpful. It can lead to a sustained drop in the eosinophil count. However, because the causes of hypereosinophilic syndrome are variable, some patients might need other therapies.

Patients with increased IL-5 production due to clonally expanded T-cell population (lymphocytic variant) initially receive corticosteroids, followed by agents including hydroxycarbamide, interferon-alfa, and imatinib.[49, 50] Mepolizumab, an anti-IL-5 antibody, may be an effective corticosteroid-sparing agent for patients with lymphocytic hypereosinophilic syndrome.[2, 51] Other agents used to treat hypereosinophilic syndrome include alemtuzumab and reslizumumab.[52, 53, 54, 55]

The goal of therapy is to control organ damage, which, in many cases, especially those involving the heart, does not correlate with the level of hypereosinophilia. Thus, no therapy is necessary in asymptomatic disease without any evidence of organ damage. However, because cardiac damage can develop insidiously, patients need close clinical and echocardiographic follow-up care.

Previously, corticosteroids were the first line of therapy for hypereosinophilic syndrome. With the development of imatinib, while corticosteroids might be the optimal initial therapy, imatinib can be seen as the most potent and durable treatment for hypereosinophilic syndrome. The steroids should rapidly (usually within 4 h) decrease the eosinophil count. If steroids fail to reduce the eosinophil count, they may be discontinued. (Some patients have symptomatic improvement without changes in eosinophil counts.) Patients who respond to steroids (usually those with urticaria/angioedema and high IgE levels) usually have a good prognosis. A short trial of corticosteroids in patients who are asymptomatic may help predict the future response to therapy.

Chemotherapeutic agents (ie, hydroxyurea, vincristine, etoposide [VP16-213], chlorambucil) have been used with variable success in patients whose conditions were unresponsive to steroids.[56, 57, 58]

Experimental treatment with anti–IL-5 antibody SCH55700 and alemtuzumab has been reported to be effective.[59] Biologic response modifiers, such as interferon alfa and cyclosporine, have been used.[60]

In 2007, Taverna et al[61] noted that infliximab is a therapy for idiopathic hypereosinophilic syndrome.

Leukapheresis is sometimes used. It removes eosinophils from the blood. Leukapheresis results in short-lived reductions in eosinophil counts and is largely unsuccessful as a therapy modality. It can be used in emergency situations in patients with extremely high eosinophil counts.

Anticoagulants and antiplatelet agents are used in patients with evidence of thrombosis or thromboembolism because thromboembolic manifestations are often a part of hypereosinophilic syndrome and cause many of its worst symptoms. No data exist that show whether anticoagulation treatment has any benefit. The effectiveness of anticoagulation treatment is anecdotal because some patients continue to have thrombotic complications despite therapy. Many patients still form clots despite anticoagulation therapy.

Phototherapy with psoralen and UV-A (PUVA), dapsone (papulonodular lesions), and sodium chromoglycate have been used with anecdotal success for patients with pruritus. Narrow band UV-B phototherapy might be effective as well, but its use has not been described.

Antihistamines can be used, but they are only add-on therapies and not primary treatments. Antihistamines that have a good effect include cetirizine, hydroxyzine, and doxepin. Because doxepin can affect the heart, it should be used with caution in patients with hypereosinophilic syndrome. Sedating antihistamines, such as hydroxyzine and doxepin, can provide symptomatic relief.

Complications, such as CHF, should be treated aggressively.

Bone marrow transplantation after chemotherapy has rarely been used in severe cases of hypereosinophilic syndrome, but, because of the morbidity involved with this treatment, it should be used sparingly.

Long-term remission of hypereosinophilic syndrome has been reported following allogeneic stem cell transplantation in spite of transient eosinophilia posttransplant.

Prompt hospitalization and treatment of disease and therapy complications in hypereosinophilic syndrome are essential. If the patient has experienced cardiac or other systemic collapse, the patient must be transferred to the ICU. Because hypereosinophilic syndrome is usually a slowly progressing disease, transfer is not often necessary.

Surgical Care

Splenectomy can reduce the pain due to splenic enlargement and is also beneficial in cases of thrombocytopenia secondary to hypersplenism. However, leukocyte and eosinophil counts can increase following splenectomy.

Cardiac surgery for annuloplasty, thrombectomy, and valve replacement has a definite role in treating heart disease due to hypereosinophilic syndrome. Bioprosthetic valves should be used because mechanical valves are more prone to thrombosis.

Rarely, in neurologic dysfunction, underlying edema of the brain and an increase in CSF pressure may be present. If these result, the patient must immediately undergo surgery by a neurosurgeon to insert a shunt or other means for normalizing CSF pressure to prevent herniation.

Consultations

Hypereosinophilic syndrome is a multisystem disorder. It is often hard to diagnosis because its symptoms are not specific. Consultation from all medical specialties can be helpful in making the diagnosis. In particular, consultation with a cardiologist, a hematologist, and a dermatologist can be helpful.

Prevention

At this time, no prevention of hypereosinophilic syndrome is known.

Long-Term Monitoring

Careful clinical, laboratory, and imaging follow-up care is necessary to ensure that new disease symptoms and signs are identified and that appropriate therapy is promptly instituted.

Multidisciplinary interaction between a hematologist, a dermatologist, a cardiologist, a surgeon, and other subspecialists should be readily available when necessary.

Patients can have waxing and waning disease; thus, long-term treatment of this condition might be necessary.

 

Medication

Medication Summary

Therapy is geared toward reducing organ damage. Corticosteroids are the initial drugs of choice, and prednisone produces a response in approximately 66% of patients. A response to prednisone manifests as a reduction in the eosinophil count within 48 hours. Usually, the response is more rapid. Rarely, treatment is not needed; a case of hypereosinophilic syndrome with skin findings in a 4-month-old with spontaneous resolution without treatment has been reported.[62]

Imatinib, which blocks the effects of platelet-derived growth factor, has transformed the care of a large subset of patients with hypereosinophilic syndrome and can be helpful. It can lead to a sustained drop in the eosinophil count. However, because the causes of hypereosinophilic syndrome are variable, predicting the responsiveness of a patient to imatinib mesylate therapy remains difficult.

For conditions unresponsive to prednisone, chemotherapeutic and biologic agents can be used. The toxicity of these agents should always be considered, and the risk-benefit ratio of these treatments must be assessed.

Corticosteroids

Class Summary

These agents rapidly suppress peripheral eosinophil counts. They have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

Prednisone is an immunosuppressant for treatment of autoimmune disorders; it may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Prednisone stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.

Antineoplastics

Class Summary

These agents interfere with cell division, thus reducing eosinophil production. They are particularly toxic to rapidly dividing cells.

Hydroxyurea (Hydrea)

Hydroxyurea interferes with DNA synthesis. It is used to reduce the total leukocyte count to less than 10,000/μ L. Hydroxyurea requires 7-14 days for effectiveness.

Vincristine (Oncovin, Vincasar)

Vincristine inhibits cellular mitosis by the inhibition of intracellular tubulin function, binding to microtubule and spindle proteins in the S phase. It is used to reduce the total leukocyte count to less than 10,000/μ L. Vincristine is effective in 1-3 days and spares bone marrow toxicity but may cause paresthesias.

Chlorambucil (Leukeran)

Chlorambucil alkylates and cross-links strands of DNA, inhibiting DNA replication and RNA transcription. It is used to reduce the total leukocyte count to less than 10,000/μ L.

Immunomodulators

Class Summary

These agents are empirically applied to many diseases as immunomodulators.

Interferon alfa 2a and 2b (Intron A, Roferon)

Interferon alfa 2a and 2b are reported to reduce eosinophil counts in some patients.

Immunosuppressants

Class Summary

These agents inhibit key factors in the immune system that are responsible for immune reactions.

Cyclosporine (Neoral, Sandimmune)

Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions. Cyclosporine is not approved for this use; it may be combined with prednisone.

Imatinib mesylate (Gleevec)

Imatinib mesylate is specifically designed to inhibit tyrosine kinase activity of the bcr-abl kinase in Ph+ leukemic CML cell lines. It is used to treat CML in blast crisis, the accelerated phase, or in the chronic phase after a failure with interferon alfa therapy. Imatinib mesylate is well absorbed after oral administration, with maximum concentrations achieved within 2-4 hour. Elimination is primarily in feces in form of metabolites.