Dermatologic Manifestations of Hypereosinophilic Syndrome Clinical Presentation

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]

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.

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• 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.

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• 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.

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).