Eosinophilia

Eosinophilia is defined as an absolute eosinophil count in the peripheral blood of ≥500 eosinophils/μL. The degree of eosinophilia can be categorized as follows:

• mild: 500-1500 eosinophils/μL

• moderate: 1500-5000 eosinophils/μL

• severe: >5000 eosinophils/μL

Differential Diagnosis includes:

• atopic disorders

• parasites

• medications (prescribed, herbal, or over the counter)

• autoimmune diseases (i.e., eosinophilic granulomatosis with polyangiitis, previously known as Churg- Strauss syndrome)

• malignancy

• eosinophilic gastrointestinal diseases

• adrenal insufficiency

Hypereosinophilic syndrome (HES) is characterized by an absolute eosinophil count ≥1500/μL on at least two occasions and signs of organ dysfunction attributable to the eosinophilia, provided other causes of organ damage have been excluded.

• End-organ involvement can include dermatologic, pulmonary, gastrointestinal, cardiac, and hematological abnormalities.

• Hypereosinophilic syndrome can be primary (in the setting of an underlying stem-cell, myeloid, or eosinophil neoplasm) or secondary to one of the disorders listed above.

• Chromosomal aberration (FIP1L1-PDGFRA fusion) is present in 10% to 15% of patients with HES (myeloproliferative variant) and is diagnosed by using fluorescence in situ hybridization (FISH) for the CHIC2 locus (which is absent in individuals with the FIP1L1-PDGFRA fusion).

Evaluation

History: A thorough history includes the following:

• symptoms of organ involvement

• medical conditions

• exposures (including prescription and over-the-counter medications)

• travel

• foods

• occupational and recreational exposures

• prior eosinophil counts if available

Physical examination should focus on evaluation of organ involvement and determination of an etiology.

• Drug-induced eosinophilia may or may not be associated with other manifestations of adverse drug reactions (e.g., fevers or rashes in drug-induced rash, eosinophilia, and systemic symptoms).

• Evaluation of other organs is indicated (e.g., lungs for drug-induced pulmonary eosinophilia, kidneys for drug-induced interstitial nephritis, heart for eosinophilic myocarditis, and liver for hepatitis).

Initial laboratory testing should include a repeat CBC with differential:

• If the eosinophil count remains ≥1500 eosinophils/μL on two separate occasions without explanation, additional laboratory testing should be performed.

• The presence and degree of tissue/organ involvement determines the urgency of the evaluation and treatment.

• Initial testing should include:

  • CBC with differential

  • peripheral smear

  • complete metabolic panel

  • B12

  • troponin

  • electrocardiogram (ECG)

  • chest radiograph

  • serologic testing for Strongyloides

  • flow cytometry for lymphocyte subsets

• Additional lab work depends on the clinical situation but may include ova and parasite stool evaluation, antineutrophil cytoplasmic antibody (ANCA) testing to evaluate for eosinophilic granulomatosis with polyangiitis (although sensitivity is only about 50%), serum immunoglobulin levels in patients with recurrent infections or signs of autoimmune disease, morning cortisol, and serum tryptase levels to evaluate for mastocytosis.

Bone-marrow aspiration and biopsy (with special stains for mast cells and reticulin) should be considered in patients with findings suggestive of a primary hematologic cause of eosinophilia, as well as cytogenetics and molecular testing for hematologic neoplasms associated with eosinophilia.

The following algorithm can be used to guide diagnosis and treatment of patients with HES.

(Reprinted from Practical approach to the patient with hypereosinophilia. J Allergy and Clinical Immunology 2010. Copyright (2010), with permission from Elsevier.)

Management

If a drug-induced cause of eosinophilia is suspected, the drug should be discontinued. Further management largely depends on the etiology of the eosinophilia. If the cause of eosinophilia cannot be determined, the patient should be referred to a specialist (this may include hematology, infectious diseases, or allergy-immunology). Of note, before initiation of glucocorticoids, it is imperative that the results of the Strongyloides serologies are reviewed or patients with a potential exposure are treated empirically with ivermectin (200 mcg/kg daily for 2 days), given the risk of disseminated Strongyloides with steroid treatment.

Mastocytosis

Mast-cell disorders can be divided into three categories: primary, secondary, and idiopathic. Primary mast-cell disorders include mastocytosis and monoclonal mast-cell activation.

Mastocytosis refers to diseases in which a clonal population of mast cells accumulates in one or more tissues. Mastocytosis can be broadly categorized into two groups: cutaneous (limited to the skin) or systemic (involving one or more extracutaneous organs).

Presentation

Several organ systems are most commonly involved in mast-cell disorders, including the skin, the mucosa of the GI tract and respiratory tracts, and the cardiovascular system. Common signs and symptoms of mast-cell activation include flushing, urticaria, diarrhea, wheezing, fatigue, and syncope or near-syncope.

In children, the majority of mastocytosis cases appear in the first year of life. The majority of childhood mastocytosis cases are limited to the skin. Cutaneous mastocytosis lesions include urticaria pigmentosa, diffuse cutaneous mastocytosis, and mastocytomas. Adult patients with cutaneous mastocytosis should be evaluated for systemic mastocytosis.

Diagnosis

Patients with one major and one or more minor features meet the diagnostic criteria for systemic mastocytosis.

Major criteria:

• mast-cell (MC) infiltration (>15 MCs aggregating) of bone marrow or other extracutaneous organs using special stains (such as MC tryptase)

Minor criteria:

• >25% of MCs in MC infiltrates in extracutaneous biopsies or bone-marrow smear is spindle-shaped or atypical

• activating point mutation of KIT in codon 816 (Asp816Val) present in extracutaneous organs

• extracutaneous CD117+ MCs co-express either CD2 or CD25 (flow cytometry)

• serum tryptase persistently >20 ng/ml

Evaluation

The evaluation of patients should include a detailed review of symptoms and possible triggers, physical examination for skin lesions such as urticaria pigmentosa, exclusion of secondary causes of mast-cell activation, and measurement of serum tryptase. Serum tryptase is the most specific marker of mast-cell activation and is persistently elevated (>20 ng/mL) in systemic mastocytosis. Additional workup that can be considered depending on clinical suspicion and organ involvement includes complete blood count, serum biochemistry, liver function tests, abdominal ultrasound, bone density scan, bone-marrow biopsy, blood and marrow smears, flow cytometry (to measure CD2 and CD25), and genetic analysis (to evaluate for hereditary alpha tryptasemia and KIT mutation D816V in bone-marrow mast cells).

The following algorithm shows steps that can be followed to diagnose mastocytosis:

(Source: Mast Cells, Mastocytosis, and Related Disorders, N Engl J Med 2015.)

Treatment

Treatment of cutaneous mastocytosis may include scheduled H1 antihistamines, systemic steroids, and consideration of cromolyn and/or H2 antihistamines. Similarly, for patients with symptoms of mast-cell activation, treatment considerations include nonsedating H1 antihistamines for patients with pruritus or urticaria; antileukotrienes and/or aspirin for patients with bronchospasm, flushing, itching, and abdominal cramping unresponsive to H1 antihistamines. Cromolyn (a mast-cell stabilizer) and H2 antihistamines can also be helpful for patients with hyperacidity and other gastrointestinal symptoms. Omalizumab can also be administered for patients whose symptoms are refractory to conservative treatments. All patients with systemic mastocytosis should be prescribed self-injectable epinephrine due to the increased risk of anaphylaxis. Additionally, given the increased risk for severe anaphylaxis in response to insect stings, patients with anaphylaxis following a known or possible hymenoptera sting should undergo skin testing or specific IgE testing and be offered venom immunotherapy if sensitized.