Hypereosinophilic syndrome has the potential to disrupt every organ in the body and, although it more frequently presents insidiously, sudden and acute deterioration is not uncommon and affects mostly the nervous and cardiovascular system. HES can also be discovered incidentally in up to 12% of patients [11].

Cardiac damage is the major cause of death and pathogenesis generally proceeds along three stages. The first stage is characterized by acute necrosis; clinical manifestations are usually absent. The second stage leads to the formation of thrombi and, in the final stage, there is widespread endomyocardial fibrosis. Patients usually complain of chest pain, dyspnea and orthopnea.

HES can also result in widespread hematologic complications. Anemia associated with the disease can manifest in fatigue and other non-specific symptoms. Thrombosis can result either from cardiac disease or hypercoagulability and targets especially the nervous system. Splenomegaly occurs in 40% of patients and should be suspected in patients complaining of left upper quadrant pain. 

Neurologic involvement manifests with embolic or thrombotic events, which are frequently the initial presenting symptoms of HES. In addition, up to 50% of patients report peripheral neuropathy. The latter has a variable expression and can be symmetric or asymmetric, sensory, pure motor or mixed. 

Lung involvement results from infiltration of eosinophils along the base and periphery and manifests with a nonproductive, chronic and persistent cough. Patients may also develop pleural effusions, secondary to congestive heart failure and can result in dyspnoic symptoms. Other common respiratory complications include angioedema and rhinitis.

Joint and skin involvement are common and patients frequently complain of non-specific skin changes, dermatographism, angioedema, arthralgia and myalgia. Raynaud's phenomenon can also occur, but is uncommon.

Gastrointestinal involvement manifests principally with diarrhea, nausea and abdominal pain. Thrombosis seldom results in small bowel necrosis and some patients develop sclerosing cholangitis.

Finally, patients can develop symptoms that are not organ-specific, such as fever, night sweats, anorexia and weight loss. The latter two seem to occur mostly with cardiac disease although reports are variable.

The workup of hypereosinophilic syndrome is broad and extensive, given the range of organs and systems affected. Workup starts with hematologic studies, including a complete blood count, a peripheral smear, a bone marrow aspiration and a biopsy. Leukocytosis above 90,000 cells per microliter is a bad prognostic indication. The peripheral blood smear will generally show mature eosinophils with rare cell precursors, in addition to hypogranularity, hypergranularity and hypersegmentation. Usually, eosinophils with hypogranularity and vacuoles are more common in cardiac disease [12]. Signs of myleoproliferative disorder include leukocyte precursor anemia, thrombocytopenia or thrombocytosis, in addition to tear drops and nucleated red blood cells. 

Serum tryptase levels need to be assessed and elevated levels generally indicate either FIP1LI HES or systemic mastocytosis with chronic eosinophilic leukemia (SM-CEL). Genetic studies can also be done to detect FIP1LI-PDGFRA and C-KIT mutations and help in determining sensitivity to imatinib.

Assessment of organ damage is conducted with computed tomographhy (CT) of the chest, abdomen and pelvis, electrocardiography (ECG), echocardiography and pulmonary function tests. Elevation of troponin levels can signal the presence of cardiomyopathy and a risk of cardiogenic shock with the initiation of imatinib therapy. 

Treatment of HES is classified into immediate therapy, definitive therapy directed specifically at the disorder and supportive therapy.

Immediate therapy consists of high doses of IV corticosteroids in the context of severe eosinophilia or complications of hyperleukocytosis. If the patient responds and the eosinophil count decreases by more than 50% after 24 hours, the same dose of corticosteroid can be administered on a routine basis. If the response is negative, an alternative regimen with hydroxyurea can be attempted. Lowering the white blood cell count is critical and treatment targeting eosinophilia should be initiated immediately.

Definitive therapy is dependent on the subtype of HES. Tyrosine kinase inhibitors (TKIs) are particularly effective in patients with a positive FIP1L1/PDGFRA fusion gene. Imatinib is usually the first line drug administered and some studies indicate a response rate approaching 100%. Courses of other TKIs can be attempted in cases where imatinib is not effective or well-tolerated. Corticosteroids are the treatment of choice for patients with cardiac damage. 

On the other hand, symptomatic or asymptomatic patients who are FIP1L1/PDGFRA negative are treated with a 5 day course of corticosteroids, and positive response is usually immediate. Evidence of organ damage necessitates treatment with the same dose for two weeks, followed by a gradual tapering. In case there's no evidence of organ damage, patients are monitored for a period of 6 months. In cases where patients cannot tolerate a tapering of corticosteroids, alternative drugs such as hydroxyurea and interferon-α can be administered [13] [14].

Supportive therapy is mostly targeted at treating the complications and organ damage resulting from HES. Antiplatelet drugs such as clopidogrel, aspirin or ticlodipine are used to prevent thrombosis. Anticoagulation is only indicated in cases of left ventricular thrombosis, as well as transient ischemic attacks that persist after aspirin treatment. On the other hand, cardiac complications, such as inflitrative cardiomyopathy, valvular lesions and heart failure necessitate medical and sometimes surgical intervention. Asymptomatic HES patients do not require any continuous treatment, but need to be followed up for the development of any complications. In particular, serum troponin is measured every 3 to 6 months along with the performance of pulmonary function tests and echocardiography every 6 to 12 months [15]. 

Refractory cases that do not respond to the treatments mentioned above are usually managed with chemotherapeutic drugs such as chlorambuic, etoposide, vincristine, 2-chlorodeoxyadenosine and cytarabine or with hematopoietic stem cell transplantation (HSCT). These treatment modalities are particularly effective in patients resistant to imatinib [16].

Hypereosinophilic syndrome has a variable prognosis, depending on treatment response, severity of organ damage and the possibility to cause a myeloproliferative and neoplastic disorder. It follows a chronic and progressive path and is potentially fatal, especially when the heart is involved. Development into a myeloproliferative disorder can occur after many years and its risk increases when leukocytosis is above 90,000 cells per microliter. Although early studies report a 3 year survival rate of 12%, later studies show a marked improvement in prognosis with a mean of 80% 5-year survival rate and 42% survival rate at 15 years [1] [10].

Studies on tissue from patients diagnosed with HES have so far determined two major causative mechanisms. The first one involves a sporadic mutation in myeloid progenitor cells of the bone marrow, leading to an increase in subpopulations of cells which differentiate into eosinophils. The second mechanism responsible for HES is termed L-HES or the "lymphocytic variant", whereby some lymphocytic T-cells increase their production of eosinophilic cytokines, leading to an expansion of the eosinophil cell line [5]. Granulocyte-macrophage colony stimulating factor (GM-CSF), IL-3 and IL-5 have all been shown to act as eosinophil growth factors, although only IL-5 is specific for eosinophils [3] [4] [8] [9].

HES is a rare disorder and epidemiological reports remain scarce, making it difficult to estimate the exact prevalence. It is known, however, that the disease is more common among men than women, with a ratio of 9:1. All age groups can be affected, although the disease displays a peak in the fourth decade and, in general, has a predilection for patients in the age range of 20 to 50 years old. Studies based on annual hospital discharges and on claims database for outpatient management in the United States have estimated that up to a third of patients with chronic myelogenous leukemia have HES [6]. Improvements in the definition of HES diagnostic criteria, as well as detailed patient registries are required for a more accurate estimation of prevalence.

Normal eosinophils are part of the myeloid cell lineage and play a critical role in the inflammatory cascade. Their cytoplasmic granules contain cationic molecules that are the most important mediators of tissue damage in the body. They also release free radicals and possess a respiratory burst oxidative pathway that further promotes damage in infiltrated tissue.

Organ damage resulting from hypereosinophilia is not directly related to the level of eosinophils in the blood and is thought to be mediated by eosinophilic infiltration of tissue. Eosinophils can also aggregate in blood vessels, particularly when levels are extremely elevated (>100,000 per microliter), resulting in widespread ischemia and tissue microinfractions. The most dangerous complication involves the heart and involves myocardial fibrosis, congestive heart failure and, ultimately, death. The fibrosis is severe and affects mostly the endocardium in either ventricles, leading to significant restrictive cardiomyopathy and inflow obstruction.

Based on pathophysiological mechanisms responsible for hypereosinophilia, HES can be broadly classified into myeloproliferative and lymphoproliferative subtypes. An FIP1L1/PDGFRA fusion gene associated with tyrosine kinase activity and resulting from an interstitial deletion at the CHIC2 site on chromosome 4 is responsible for the myeloproliferative variant. Patients affected by this mutation tend to be predominantly male and respond to a low dose of imatinib. They rarely develop lymphoblastic or acute myeloid leukemia, although they frequently have endomyocardial fibrosis. 

The lymphoproliferative phenotype is characterized by a rearrangement of T-cell receptors, resulting in an aberrant population of T-cells with abnormal eosinophilic cytokine production. Patients with this subtype usually respond to corticosteroids and can develop T-cell lymphoma.

Individuals with HES need to be followed up for early detection and prevention of the complications that can accompany the disease. Periodical assessment of the eosinophil count is recommended, as well as measurements of serum troponin every 3 months, pulmonary function tests and an echocardiogram every 6 months.

Hypereosinophilic syndromes (HES) describe a range of disorders chiefly characterized by persistent and unexplained elevation of eosinophil levels, in the presence of organ damage and absence of any evidence of a known cause, such as parasitic infections or allergic reactions [1] [2].

Because HES can affect almost every organ in the body, patients present with a broad range of symptoms: non-specific ones such as fever, weight loss or night sweats, alongside more organ-specific manifestations such as strokes, heart dysfunction or pleural effusions. Workup is broad and directed at providing evidence for organ involvement as well as hematologic tests to assess possible subtypes of HES. Initial treatment with steroids is targeted at lowering the eosinophil count and is followed by more specific regimens that address subtypes, as well as potential complications. HES can be fatal if not properly treated, but recent advances have significantly improved outcomes.

Hypereosinophilic syndrome is a rare disorder characterized by a significant elevation of eosinophil count above 1,500 cells per microliter in the absence of a well-defined cause. The condition can affect all age groups, but particularly targets men who are 20 to 50 years old. An increase in the number and action of eosinophils can potentially affect all organs including the heart, liver, nervous system, skin and lungs. The heart is especially vulnerable and its involvement can lead to heart failure, heart attacks and damaged heart valves.

Patients with hypereosinophilic syndrome can present with a wide range of symptoms including weight loss, night sweats, fatigue, swelling, rashes, weakness, confusion, coma, chest pain, cough and abdominal pain. Diagnosis is established after blood tests show a persistent elevation of eosinophil count in the presence of symptoms and without evidence of an allergic reaction, a parasitic infection or another definite cause.

Hypereosinophilic syndrome is fatal in patients who are not treated or properly monitored. Recent advances, however, have markedly improved survival among patients and, nowadays, more than 80% survive with adequate treatment. Patients who are asymptomatic are usually treated with a single dose of corticosteroids and then monitored closely for the next 3 to 6 months. Others need to be treated with steroids, hydroxyurea or cancer drugs.

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