Eosinophilia

Eosinophilia is a topic covered in the Washington Manual of Medical Therapeutics.

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General Principles

  • Eosinophils are granulocytes that developed from bone marrow pluripotent progenitor cells.
  • Eosinophil maturation is promoted by interleukin (IL)-5, IL-3, and granulocyte-macrophage colony-stimulating hormone (GM-CSF).
  • Eosinophils are normally seen in peripheral tissue such as mucosal tissues in the gastrointestinal and respiratory tracts. They are recruited to sites of inflammation.
  • Eosinophils can be involved in a variety of infectious, allergic, neoplastic, and idiopathic diseases.

Definition

  • A value >500 eosinophils/μL is defined as having eosinophilia.
  • The extent of eosinophilia can be categorized as mild (500–1500 cells/μL), moderate (1500–5000 cells/μL), or severe (>5000 cells/μL).
  • The degree of eosinophilia is not a reliable predictor of eosinophil-mediated organ damage.

Classification

  • Peripheral eosinophilia can be divided into primary, secondary, or idiopathic.
  • Primary eosinophilia is seen with hematologic disorders where there may be a clonal expansion of eosinophils (chronic eosinophilic leukemia) or a clonal expansion of cells that stimulate eosinophil production (chronic myeloid or lymphocytic disorders).
  • Secondary eosinophilia is also called reactive eosinophilia. It is a polyclonal expansion of eosinophils due to overproduction of IL-5. There are numerous causes such as parasites, allergic diseases, autoimmune disorders, toxins, medications, and endocrine disorders such as Addison disease.
  • Idiopathic eosinophilia is considered when primary and secondary causes are excluded.

Eosinophilia Associated With Atopic Disease

  • Mild eosinophila is more commonly seen in allergic rhinitis and asthma.
  • In allergic rhinitis, increased nasal eosinophilia is more common than peripheral blood eosinophilia.
  • Nonallergic rhinitis with eosinophilia syndrome is a form of chronic inflammatory rhinitis with persistent nasal eosinophilia (≥25%) in nonatopic patients. It has a propensity to develop nasal polyps, asthma, and aspirin intolerance (AERD).
  • Sputum eosinophilia is a common feature of asthma and suggests responsiveness to corticosteroid treatment.

Eosinophilia Associated With Pulmonary Infiltrates

This classification is inclusive of the pulmonary infiltrates with eosinophilia syndromes and the eosinophilic pneumonias.

  • Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity response to colonized Aspergillus fumigatus in the airways that occurs almost exclusively in asthmatics or cystic fibrosis patients. It is characterized by pulmonary infiltrates, central bronchiectasis, elevated serum IgE with peripheral eosinophilia, positive skin testing to A. fumigatus, and the presence of IgE or IgG antibody to Aspergillus.
  • Disseminated coccidioidomycosis can lead to marked eosinophilia.
  • Eosinophilic pneumonias consist of pulmonary infiltrates with lung eosinophilia and are only occasionally associated with blood eosinophilia.
    • Acute eosinophilic pneumonia is an idiopathic disease that presents with fever, cough, dyspnea, and hypoxemia occurring for days to weeks, typically in males and in individuals who have recently started to smoke tobacco.
    • Chronic eosinophilic pneumonia is an idiopathic disease that presents with fever, cough, dyspnea, and significant weight loss occurring for weeks to months, typically in females and nonsmokers. It is associated with peripheral blood eosinophilia. “The photographic negative of pulmonary edema” is a classic radiographic finding (radiographic pattern of predominately peripheral consolidation).
    • Löffler syndrome is a combination of blood eosinophilia and transient pulmonary infiltrates due to passage of helminthic larvae, usually Ascaris lumbricoides, through the lungs.
    • Tropical pulmonary eosinophilia is a hypersensitivity response in the lung to lymphatic filariae. Peripheral blood microfilariae are usually not detected.

HIV

Eosinophilia is seen in about 20% of patients with HIV infection. The causes can be due to reactions to highly active antiretroviral therapy medications, adrenal insufficiency associated with cytomegalovirus infection, eosinophilic folliculitis, or underlying parasitic infection.

Eosinophilia Associated With Parasitic Infection

Various multicellular parasites or helminths such as Ascaris, hookworm, or Strongyloides can induce blood eosinophilia, whereas single-celled protozoan parasites such as Giardia lamblia do not. The level of eosinophilia reflects the degree of tissue invasion by the parasite. Eosinophilia is usually of the highest grade during the early phase of infection.

  • In cases of blood eosinophilia, Strongyloides stercoralis infection must be excluded because this helminth can set up a cycle of autoinfection leading to chronic infection with intermittent, sometimes marked, eosinophilia.
  • Tissue eosinophilia may not be accompanied by blood eosinophilia when the organism is sequestered within tissues (e.g., intact echinococcal cysts) or is limited to the intestinal lumen (e.g., Ascaris and tapeworms).
  • Among the helminths, the principal parasites that need to be evaluated are S. stercoralis, hookworm, and Toxocara canis. The diagnostic consideration can also vary according to geographic region.
  • There are some important caveats that need to be considered when evaluating patients for parasitic diseases and eosinophilia: Strongyloides can persist for decades without causing major symptoms and can elicit varying degrees of eosinophilia ranging from minimal to marked eosinophilia.
  • T. canis (visceral larva migrans) should be considered in children with a propensity to eat dirt contaminated by dog Ascaris eggs.

Eosinophilia Associated With Cutaneous Disease

  • Atopic dermatitis is classically associated with blood and skin eosinophilia.
  • Eosinophilic fasciitis (Shulman syndrome) is characterized by acute erythema, swelling, and induration of the extremities progressing to symmetric induration of the skin that spares the fingers, feet, and face. It can be precipitated by exercise.
  • Eosinophilic cellulitis (Wells syndrome) presents with recurrent swelling of an extremity without tactile warmth and failure with antibiotic therapy.
  • Eosinophilic pustular folliculitis is a pruritic skin eruption that can be seen in patients with HIV.
  • Episodic angioedema with eosinophilia (Gleich syndrome) is a rare disease that leads to recurrent attacks of fever, angioedema, urticaria, weight gain, and blood eosinophilia without other organ damage.
  • Angiolymphoid hyperplasia with eosinophilia: Presents with eosinophilia and papules, plaques, and nodules on the head and neck.
  • Kimura disease presents with eosinophilia and large subcutaneous masses on the head or neck. Typically seen in Asian men.

Eosinophilia Associated With Multiorgan Involvement

  • Drug-induced eosinophilia. Numerous drugs, herbal supplements, and cytokine therapies (e.g., GM-CSF and IL-2) can cause blood and/or tissue eosinophilia. Drug-induced eosinophilia typically responds to cessation of the culprit medication. Asymptomatic drug-induced eosinophilia does not necessitate cessation of therapy. However, end-organ involvement should always be investigated promptly.
  • Eosinophilic granulomatosis with polyangiitis (EGPA), also known as Churg–Strauss syndrome, is a small- and medium-vessel vasculitis with chronic rhinosinusitis, asthma, and peripheral blood eosinophilia (typically >1500 cells/μL). The onset of asthma and eosinophilia may precede the development of EGPA by several years.
    • It is noted to have intravascular and extravascular eosinophilic granuloma formation and lung involvement with transient infiltrates on chest radiograph. Other manifestations include mononeuropathy or polyneuropathy, subcutaneous nodules, rash, gastroenteritis, renal insufficiency, cardiac arrhythmias, and heart failure.
    • Half of patients have antineutrophil cytoplasmic antibodies directed against myeloperoxidase (p-ANCA). Biopsy of affected tissue reveals a necrotizing vasculitis with extravascular granulomas and tissue eosinophilia.
    • Initial treatment involves high-dose glucocorticoids with the addition of cyclophosphamide if necessary. Maintenance therapy with azathioprine is recommended after remission is achieved. Mepolizumab has recently been approved by the Food and Drug Administration (FDA) for treatment of EGPA as it has prolonged time in remission.1 Leukotriene modifiers, like all systemic steroid-sparing agents (including inhaled steroids and omalizumab), have been associated with unmasking of EGPA due to a decrease in systemic steroid therapy; however, no evidence exists that these drugs cause EGPA.2

Mastocytosis

Systemic mastocytosis is characterized by infiltration of mast cells into various organs including the skin, liver, lymph nodes, bone marrow, and spleen. Peripheral eosinophilia can be seen in up to 20% of cases of systemic mastocytosis, and bone marrow biopsies often show an excess number of eosinophils.

Endocrine Disorders

Adrenal insufficiency (e.g., Addison disease) in critically ill patients is associated with low-grade eosinophilia.

Hypereosinophilic Syndrome

A proliferative disorder of eosinophils characterized by sustained eosinophilia >1500 cells/μL for ≥1 month documented on two occasions with eosinophil-mediated damage to organs such as the heart, gastrointestinal tract, kidneys, brain, and lung. All other causes of eosinophilia should be excluded to make the diagnosis.3

  • Hypereosinophilic syndrome (HES) occurs predominantly in men between the ages of 20–50 years and presents with insidious onset of fatigue, cough, and dyspnea.
  • Approximately 10%–15% HES patients have myeloproliferative disorders. Myeloproliferative variants of HES are characterized by constitutive expression of FIP1L1/PDGFRA fusion protein and elevated serum vitamin B12 levels. HES patients with FIP1L1/PDGFRA respond well to imatinib.
  • Lymphocytic-variant HES (L-HES) accounts for 17%–26% HES patients. Unusual IL-5–producing T cells are found in L-HES.
  • Cardiac disease is a major cause of morbidity and mortality in patients with HES. At presentation, patients typically are in the late thrombotic and fibrotic stages of eosinophil-mediated cardiac damage with signs of a restrictive cardiomyopathy and mitral regurgitation. An echocardiogram may detect intracardiac thrombi, endomyocardial fibrosis, or thickening of the posterior mitral valve leaflet. Neurologic manifestations range from peripheral neuropathy to stroke or encephalopathy. Bone marrow examination reveals increased eosinophil precursors.
  • Acute eosinophilic leukemia is a rare myeloproliferative disorder that is distinguished from HES by several factors: an increased number of immature eosinophils in the blood and/or marrow, >10% blast forms in the marrow, and symptoms and signs compatible with an acute leukemia. Treatment is similar to other leukemias.
  • Lymphoma. Eosinophilia can present in any T- or B-cell lymphoma. As many as 5% of patients with non-Hodgkin lymphoma and up to 15% of patients with Hodgkin lymphoma have modest peripheral blood eosinophilia. Eosinophilia in Hodgkin lymphoma has been correlated with IL-5 messenger RNA expression by Reed–Sternberg cells.
  • Atheroembolic disease. Cholesterol embolization can lead to eosinophilia, eosinophiluria, renal dysfunction, livedo reticularis, purple toes, and increased erythrocyte sedimentation rate (ESR).
  • Immunodeficiency. Hyper-IgE syndrome, autoimmune lymphoproliferative syndrome, and Omenn syndrome can present with recurrent infections, dermatitis, and eosinophilia.

Epidemiology

In industrialized nations, peripheral blood eosinophilia is most often due to atopic disease, whereas helminthic infections are the most common cause of eosinophilia in the rest of the world.

Pathophysiology

Eosinophilic granules contain basic proteins, which bind to acidic dye. Once activated, eosinophils produce major basic protein, eosinophil cationic protein, eosinophil-derived neurotoxin, and eosinophil peroxidase, which are toxic to bacteria, helminths, and normal tissue.

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