Hypereosinophilic Syndrome

1 What is Hypereosinophilic Syndrome?

HES) is traditionally defined as peripheral blood eosinophilia > 1500/μL persisting≥6 mo.

HES was previously considered to be idiopathic but is now known to result from various disorders, some of which have known causes.

One limitation of the traditional definition is that it does not include those patients with some of the same abnormalities (e.g. chromosomal defects) that are known causes of HES but who do not fulfill the traditional HES diagnostic criteria for degree or duration of eosinophilia.

Another limitation is that some patients with eosinophilia and organ damage that characterize HES require treatment earlier than the 6 mo necessary to confirm the traditional diagnostic criteria.

HES is rare, has an unknown prevalence, and most often affects people age 20 through 50. Only some patients with prolonged eosinophilia develop organ dysfunction that characterizes hypereosinophilic syndrome. Although any organ may be involved, the heart, lungs, spleen, skin, and nervous system are typically affected. Cardiac involvement can cause significant morbidity and mortality.

Subtypes

There are two broad sub types:

  • Myeloproliferative variant
  • Lymphoproliferative variant

2 Symptoms

Generalised symptoms of hypereosinophilic syndrome include:

Diarrhoea is common, as are abdominal pain and nausea.

Other symptoms depend on which organ is involved and extent of involvement, for example:

Organ involvement in HES

This can be varied and depending on the organ involved can produce diverse symptoms:

  • Blood involvement manifests as thrombocytopenia, hypercoagulability.
  • Cardiac conditions cased are cardiomyopathy, valve abnormalities, pericardial effusion, thromboembolic disease.
  • Respiratory include pneumonitis, pulmonary emboli, pleural effusion and eosinophilic infiltrates.
  • Dermatological manifestations are dermatitis, urticaria, papular rashes.
  • Ear, nose and throat - sinusitis.
  • Gastrointestinal tract - tract inflammation, infarction of the gut secondary to emboli, splenomegaly, ascites, hepatitis, pancreatitis.
  • Neurological - acute cerebrovascular accident, confusion, ataxia, peripheral neuropathy.
  • Opthalmological - episcleritis, retinal thrombi.
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3 Causes

The cause of Hypereosinophilic syndrome is other underlying conditions.

Familial eosinophilia: It is an autosomal dominant disorder with a stable eosinophil count and a benign clinical course. Acquired eosinophilia is further divided into secondary, clonal, and idiopathic eosinophilia.

Secondary eosinophilia: Secondary eosinophilia is a cytokine-derived (interleukin-5) reactive phenomenon. In developing countries, parasitic diseases are the most common cause, whereas in developed countries, allergic diseases are the most common cause.

Other causes include the following:

Clonal eosinophilia: Causes include the following:

  • Acute leukemia – Pre-B acute lymphoblastic leukemia (ALL), acute myeloid leukemia M4 with bone marrow eosinophilia (AML-M4Eo)
  • Chronic myeloid disorders

Molecularly defined disorders include the following:

  • BCR-ABL chronic myeloid leukemia
  • PDGFRA (platelet-derived growth factor receptor, alpha polypeptide)–rearranged eosinophilia – Systemic mastocytosis–chronic eosinophilic leukemia (SM-CEL)
  • PDGFRβ-rearranged eosinophilia
  • KIT-mutated systemic mastocytosis

Clinicopathologically assigned disorders include the following:

  • Myelodysplastic syndrome (MDS)
  • Myeloproliferative disorders (MPDs) – Classic MPD ( polycythemia) and atypical MPD (chronic eosinophilic leukemia, systemic mastocytosis, chronic myelomonocytic leukemia)

Idiopathic eosinophilia: Idiopathic eosinophilia is a diagnosis of exclusion when secondary and clonal causes of eosinophilia are excluded. Hypereosinophilic syndrome is a subset of idiopathic eosinophilia characterized by persistent eosinophilia (AEC >1500/µL) of longer than 6 months' duration associated with organ damage.

However, long-term follow-up and X-linked clonality studies indicate that at least some patients with hypereosinophilic syndrome have an underlying clonal myeloid malignancy or a clonal or phenotypically abnormal T-cell population, suggesting a true secondary process.

The best-described aberration is the interstitial deletion on chromosome 4q12, resulting in fusion of the 5’ portion of the FIP1L1 gene to the 3’ portion of thePDGFRA gene. This fusion gene encodes for the FIP1L1–PDGFR alpha protein, the constitutively activated tyrosine kinase activity that induces eosinophilia.

Chronic eosinophilic leukemia: Chronic eosinophilic leukemia is caused by autonomous proliferation of clonal eosinophilic precursors.

Simplified criteria for the diagnosis of chronic eosinophilic leukemia include the following:

  • Eosinophil count of at least 1500/µL.
  • Peripheral blood blast count of >2% and a bone marrow blast cell count that is >5% but <19% of all nucleated cells.
  • Criteria for atypical chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia, and chronic granulocytic leukemia (BCR-ABL–positive CML) are not met.
  • Myeloid cells are demonstrated to be clonal (e.g. by detection of clonal cytogenetic abnormality or by demonstration of a much skewed expression of X chromosome genes).

4 Making a Diagnosis

Diagnosis of hypereosinophilic syndrome is a diagnosis of exclusion, that is, it is diagnosed after excluding other causes of secondary eosinophilia.

Certain diagnostic modalities used are:

  • Defining criteria of a documented absolute eosinophil count (AEC) greater than 1500/µL on at least two occasions should be evaluated for hypereosinophilic syndrome, regardless of the presence of symptoms.
  • CBC
  • Peripheral blood smear
  • Bone marrow tryptase
  • Immunophenotyping of mast cells
  • Molecular genetic studies to detect mutations which help in determining further drug sensitivity for treatment purposes.
  • Bone marrow biopsies and examinations
  • HLA typing
  • T-cell immunophenotyping
  • T-cell receptor gene rearrangement
  • IL-5 levels
  • Computed tomography (CT) scanning of the chest, abdomen, and pelvis to look for lymphadenopathy and splenomegaly
  • Elevated IgE and Vit B12 levels

5 Treatment

Treatment for hypereosinophilic syndrome primarily consists of reducing eosinophil levels and preventing further damage to organs.

Corticosteroids, such as Prednisone, are good for reducing eosinophil levels and antineoplastics are useful for slowing eosinophil production. Surgical therapy is rarely utilized, however splenectomy can reduce the pain due to spleen enlargement. If there is damage to the heart (in particular the valves), then prosthetic valves can replace the current organic ones. 

Follow-up care is vital for the survival of the patient; as such the patient should be checked for any signs of deterioration regularly.

After promising results in drug trials (95% efficiency in reducing blood eosinophil count to acceptable levels) it is hoped that in the future, hypereosinophilic syndrome and diseases related to eosinophils such as asthma and Churg-Strauss syndrome, may be treated with the monoclonal antibody Mepolizumab currently being developed to treat the disease.

If this becomes successful, it may be possible for corticosteroids to be eradicated and thus reduce the amount of side effects encountered.

6 Risks and Complications

Hypereosinophilic syndrome has many and varied complications. Their development depends entirely on which organ systems are involved in the disease process.

The most serious complication of hypereosinophilic syndrome is cardiac involvement, which can lead to myocardial fibrosis, chronic heart failure and death.

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