Hypereosinophilic Syndrome

What Is Hypereosinophilic Syndrome?

Hypereosinophilic Syndrome (HES) is a condition where there is an elevated count of eosinophils in the blood, exceeding 1.5 x 10⁹/L, for more than six months.

This syndrome also includes organ damage and/or dysfunction due to hypereosinophilia. The diagnosis can only be made if other disorders or conditions that can cause organ damage, like acute myeloid leukemia are excluded ^[1].

Eosinophils

Eosinophils are a type of white blood cells that play a major role in protecting organism from parasites, virus and bacterial infections. Eosinophils contain intracellular granules that contain a lot of biologically active substances.

When immune response happens and process of cellular activation takes place, these granules are released, causing toxic reaction to the infectious organism and the surrounding tissue. These cells are naturally found in thymus, gastrointestinal tract, spleen, ovaries, uterus and lymph nodes.

Eosinophils should not be present in the skin, lungs or esophagus, since in these locations they can cause serious inflammatory conditions. Normal eosinophil count is:

• Eosinophil blood count % -0.00-6.0
• Eosinophil blood count (absolute)- 30-350-500 cells per microliter.

Increased eosinophil count may be due to following conditions:

• Allergy
• Dermatologic disorders
• Parasite and bacterial infection
• Myeloproliferative disorders and some other malignancies, like Hodgkin disease and ovarian cancer
• Collagen-vascular diseases
• As a side effect of medications
• Cholecystitis
• Asthma
• Myelodysplastic syndrome

Low eosinophil counts, in case of immunodeficiency, do not demonstrate significant abnormalities ^[2]

Causes

There are many possible causes for hypereosinophylia. But in case of Hypereosinophilic Syndrome there is no known cause for elevated eosinophil levels to occur. However, studies suggest that all patients with HES have an underlying malignancy, either clonal myeloid or clonal T-cell population.

There have been reports of cases, where after as much as 25 years, Hypereosinophilic Syndrome develops into either acute myeloid leukemia or granulocytic sarcoma. In patients with HES, various molecular genetic changes can be observed. For example, aberration in a portion of the FIP1L1/ PDGFRA gene activate enzyme tyrosine kinase that induces eosinophilia.

Patients with changes in PDGFRA gene have high incidence of cardiovascular disease and poor prognosis without treatment. Another type of Hypereosinophilic Syndrome is with clonal immunophenotypically changed T-cells, which is associated with cutaneous manifestations and have a predisposition to developing T-cell lymphoma ^[3].

Symptoms

The symptoms of Hypereosinophilic Syndrome are very various and depend on many factors, such as the age of the patient, other conditions the patient is suffering from, as well as the and the affected part of the body.

Skin:

• Rash- urticaria and angioedema
• Itchiness

Cardiac

In early stages, usually asymptomatic

• Chest pain
• Dyspnea

Hematologic

• Nonspecific
• Fatigue
• Abdominal pain due to splenomegaly
• Thrombotic events

Neurologic

• Emboli or thrombi- stroke, transient ischemic episode
• Encephalopathy, causing CNS dysfunction
• Blurred vision
• Slurred speech
• Peripheral neuropathy

Respiratory

• Infiltrates in the lungs
• Angioedema
• Chronic cough, non-productive
• Pulmonary fibrosis
• Asthmatic symptoms
• Rhinitis

Rheumatologic

• Arthralgia, myalgia
• Raynaud phenomenon

Gastrointestinal

• Diarrhea
• Abdominal pain, nausea
• Small bowel necrosis (read about short bowel syndrome)
• Sclerosing cholangitis
• Weight loss ^[3,4]

Diagnosis

The diagnosis of HES is usually made by excluding other possible causes for eosinophilia and assessing the organ damage.

Blood tests

Blood tests will usually be first to show that there is eosinophilia. Usually, the numbers will be higher than 1.5 x 10⁹/L. Blood tests should be obtained at least on two different occasions. Usually other tests are also performed to exclude infection or other conditions.

Peripheral blood smear should be performed to evaluate blood contents under a microscope. Eosinophils are usually hypersegmentated, hypogranulated or hypergranulated. Serum tryptase levels (usually elevated in the type, associated with aberrations in FIP1L1/ PDGFRA gene complex). Other signs in the blood analysis:

• Anemia, present in 50% of cases
• Normal or elevated platelet counts
• Eosinophils are mature
• Nucleated red blood cells
• Leukocytosis might be present, exceeding 90,000/µL
• Elevated Interleukin-5 levels
• IgE levels might be elevated
• Elevated serum B-12 levels (Also see Wernicke-Kosakoff syndrome caused by decreased B-12 levels).
• Troponin levels- helps to evaluate cardiomyopathy ^[3,5]

Bone marrow biopsy

Bone marrow biopsy should be evaluate for:

• Bone marrow tryptase levels
• Morphologic features of myeloproliferative disorders
• Staining tests for myelofibrosis and mast cells
• Cytogenetic investigations for karyotype- changes can find Philadelphia chromosome and aneuploidy
• Molecular genetics- FIP1L1/PDGFRA; C-KIT mutation ^[3]

Other tests

To evaluate organ involvement and other possible conditions several tests should be performed, including:

• CT scanning for chest, abdomen, pelvis and brain, if neurological symptoms are present
• Electrocardiography
• Pulmonary function tests
• Echocardiography ^[3,4]

Treatment

This condition usually affects young and middle-age patients, therefore the treatment can becoe toxic over time.

FIP1L1/PDGFRA associated HES

F/P fusion gene associated Hypereosinophilic Syndrome are usually treated with tyrosine kinase inhibitor medication imatinib. Patients usually respond to treatment within days and many of the clinical manifestations, like dermatitis, GI involvement and CNS manifestations can be reversed.

The dose is usually 100mg/day. Imatinib therapy is usually combined with corticosteroids to prevent the effects of rapid release of eosinophils from organs.

Imatinib is usually well-tolerated, but it can cause several side effects:

• Edema
• Muscle pain
• Fatigue
• Cardiac effects
  • Congestive heart failure
  • Left ventricular dysfunction

FIP1L1/PDGFRA negative HES

For patients with F/P negative Hypereosinophilic Syndrome an ideal treatment plan has not been found. Usually corticosteroids are used as first line therapy starting with 60mg prednisone.

If there is response, the dosage is slowly lowered to the lowest possible effective dose. If there is no response to corticosteroid use, a second-line treatment is used. this includes hydroxycarbamide, IFN-α, anti-CD52 antibodies (alemtuzumab).

Ciclosporin has also been used, since it works against some functions of T-cells, but this treatment has not been well assessed. Patients with progressive disease and life-threatening organ damage may be candidates for allogenic stem cell transplantation. Also read about the new research for myelodysplastic syndrome ^[6].

Outcome

When the syndrome was first described, the mortality rate at 3 years was 88%. Now, scientists have better understanding of the underlying processes and there are various treatment options available.

The prognosis depends on the heart involvement and likelihood of developing hematological malignancies. Patients are at risk of sudden congestive heart failure and acute leukemia ^[6].

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References

1. General information for patients: http://patient.info/doctor/hypereosinophilic-syndrome
2. Eosinophils: http://emedicine.medscape.com/article/2090595-overview
3. HES detailed information for health care specialists: http://emedicine.medscape.com/article/202030-overview
4. Symptoms: http://www.aaaai.org/conditions-and-treatments/related-conditions/hypereosinophilic-syndrome
5. Diagnosis: http://www.msdmanuals.com/professional/hematology-and-oncology/eosinophilic-disorders/hypereosinophilic-syndrome
6. Treatment and prognosis: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2045078/