eMedicine Specialties > Dermatology > Allergy & Immunology

Hypereosinophilic Syndrome

Author: Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Columbia University; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Private Practice
Coauthor(s): Felix Urman, MD, Staff Physician, Department of Dermatology, St Luke's Roosevelt Hospital Center
Contributor Information and Disclosures

Updated: Feb 1, 2010

Introduction

Background

Hypereosinophilic syndrome (HES) encompasses a wide range of clinical manifestations sharing 3 features defined by Chusid et al¹ : (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 the eMedicine Pediatrics article Hypereosinophilic Syndrome and the Hematology article 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.

Pardanani et al⁶ 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 team⁶ 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 al⁷ 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.

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.⁸ The disease is rare in children.

International

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

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 1982⁸ 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.

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 NIH⁸ 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.⁹ A review in 1987¹⁰ from Wales found 18 published reports of hypereosinophilic syndrome in children younger than 16 years. The incidence seems to decrease in elderly persons.

Clinical

History

Hypereosinophilic syndrome is a multisystem disease, and the presenting complaint can vary depending on the organ involved. 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 series⁸ , common symptoms included fatigue (26%), cough (24%), breathlessness (16%), muscle pains or angioedema (14%), and fever (12%). Sweating and pruritus are common. Mucocutaneous manifestations 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 lupus¹¹ and leptomeningeal syndrome¹² for hypereosinophilic syndrome have been reported.

• Mucocutaneous manifestations of hypereosinophilic syndrome^13,14  
  • Common manifestations of hypereosinophilic syndrome 
    • Pruritus
    • Urticaria
    • Dermatographism
    • Angioedema
    • Erythematous papules, plaques, and nodules
    • Nonspecific rashes
  • Uncommon manifestations of hypereosinophilic syndrome 
    • Aquagenic pruritus¹⁵
    • Splinter hemorrhages
    • Palpable purpura
    • Livedoid discoloration
    • Wells syndrome¹⁶
    • Livedoid discoloration
    • Erythroderma
    • Vesicular disease
    • Eosinophilic vasculitis
    • Acral necrosis¹⁷
    • Petechiae
    • Erythema annulare centrifugum
    • Mucosal ulceration and erythema
    • Bullous pemphigoid (responded to imatinib)¹⁸
• Cardiac symptoms of hypereosinophilic syndrome^{19,20,21,22,23}  
  • 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.
• Neurologic symptoms of hypereosinophilic syndrome^24,25  
  • Thromboembolic complications are usually from the heart and present as strokes or transient ischemic attacks (TIAs).²⁶
  • 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 
  • 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^27,28  
  • 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 
  • 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 al²⁹ 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: Arthralgia, arthritis, Raynaud phenomenon, and Wells syndrome have been reported with hypereosinophilic syndrome.
• Ocular symptoms of hypereosinophilic syndrome 
  • 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 
  • 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: Oligospermia has been reported in a patient receiving imatinib therapy for the hypereosinophilic syndrome.

Physical

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

• Mucocutaneous signs of hypereosinophilic syndrome 
  • Urticarial wheals (see image below) and angioedema are common.
  • 
    

    

    Urticarial and erythematous rash.

    [ CLOSE WINDOW ]

    

    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.

    [ CLOSE WINDOW ]

    

    Petechiae on an erythematous base.

  • Splinter hemorrhages can result from cardiac thromboemboli.
  • Ulcers can occur on virtually any mucosal surface.
• Cardiac signs of hypereosinophilic syndrome 
  • 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 
  • 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 
  • 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 
  • 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 
  • Joint effusions can occur.
  • The characteristic color changes of Raynaud phenomenon may be observed.
• Ocular signs of hypereosinophilic syndrome: Occasional visual blurring may occur.

Causes

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 NIH⁸ found chromosomal abnormalities in 8 of 33 patients examined. Such abnormalities can include the Philadelphia chromosome.

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