Chapter 32: Eosinophils and Related Disorders

• Eosinophils differentiate from the hematopoietic stem cell in the marrow, migrate into the blood, and circulate with a half-life of 18 hours before entering tissues. Eosinophils are primarily tissue dwelling, with 300 cells in the tissues for every blood eosinophil.

• The normal blood absolute eosinophil count in adults is less than 0.4 × 10⁹ cells/L; it is higher in neonates.

• The normal adult marrow contains approximately 3% eosinophils.

• The degree of eosinophilia is described as:

  — Mild (< 1.0 × 10⁹ eosinophils/L)

  — Moderate (1.0 to 5.0 × 10⁹ eosinophils/L)

  — Marked (> 5.0 × 10⁹ eosinophils/L)

• The most common causes of eosinophilia include:

  — Throughout the world: infections with helminthic parasites

  — In industrialized countries: asthma and other allergic disorders (drug allergy, allergic rhinitis, atopic dermatitis)

  — Allergic diseases: generally only mild eosinophilia

  — Major causes: listed in Table 32–1

• Eosinophils appear to have a role in both ameliorating inflammatory responses and producing tissue damage.

• They may be important in wound healing and may act as accessory cells in T cell–mediated reactions.

• Because eosinophils can kill parasites, it has been hypothesized that their principal role is to counter parasitic infection.

• Eosinophils can cause airway damage in asthma and severe tissue damage in hypereosinophilic syndromes.

Asthma

• Inhaled antigen produces:

  — An early response, with fall in forced expiratory volume caused by release of mediators from mast cells, may occur.

  — A late response, with influx of large numbers of eosinophils, activated T cells, and monocytes to the airways, is also possible.

  — Correlation exists between the numbers of airway eosinophils and the severity of asthma.

  — Basic proteins secreted by eosinophils are toxic for airway epithelium and may be a better guide to the degree of inflammation than eosinophil numbers.

Parasitic Disease

• The mechanism of eosinophilia in parasitic disease is similar to allergic disease.

• The more pronounced eosinophilia in parasitic disease is presumably caused by the systemic nature of the disease compared with the more localized nature of allergic disease.

• Eosinophils can kill a number of opsonized parasite larvae but not adult worms.

• Table 32–2 describes the major parasitic causes of eosinophilia.

Idiopathic Hypereosinophilic Syndrome (Myeloid and Lymphoid Variants)

• This is a rare disorder with an estimated prevalence of one in 50,000. It occurs sporadically with no geographic or environmental influences.

Definition

• Striking eosinophilia (> 1.5 × 10⁹/L persists for more than 6 months, with evidence of end-organ damage and no other explanation after comprehensive investigation.

Myeloid Type

• Monoclonal eosinophilia reflects the expression of chronic eosinophilic leukemia. Marrow contains principally eosinophilic myelocytes and mature eosinophils, some with hypersegmented nuclei (more than two segments).

  — Onset occurs with some or all of the following: anorexia, weight loss, fatigue, nausea, abdominal pain, diarrhea, nonproductive cough, pruritic rash, fever, night sweats, and venous thrombosis.

  — Skin signs include urticaria, papules, and pruritus.

  — Cardiac involvement may be marked by endomyocardial fibrosis, restrictive cardiomyopathy, mitral or tricuspid valve incompetence, ventricular failure, conduction defects, and arrhythmias.

  — Neurologic findings include neuropathies; these may lead to encephalopathy, polyneuropathy, or stroke.

  — Hepatosplenomegaly, interstitial pulmonary infiltrates, and pleural effusions can occur.

  — Nervous system dysfunction may be profound, including confusion, delirium, dementia, and coma.

  — Hematologic manifestations. All patients have leukocytosis with a striking eosinophilia, usually eosinophil counts greater than 1.5 × 10⁹/L, and counts of 50.0 × 10⁹/L or more are found in more than half the patients; eosinophilia may be progressive; anemia occurs in most patients; and thrombocytopenia is seen occasionally.

  — Cytogenetic abnormalities may be found in the leukemic eosinophilic cells in a proportion of patients. One of several translocations involving chromosome 5 may occur. Of particular importance is the occurrence of the FILIPI-PDGFR-α fusion gene because, if present, the patient will usually respond to tyrosine kinase inhibitor drugs, such as imatinib mesylate.

  — Elevated serum tryptase is common (suggesting unapparent mast cell involvement).

  — The disease is sometimes indolent but more often progressive and fatal.

  — Signs and symptoms may remit and relapse, but organ damage is usually progressive.

  — Episodes of venous thrombosis may complicate the course.

  — Therapy. In patients unresponsive to tyrosine kinase inhibitors, hydroxyurea and glucocorticoids may be of benefit in decreasing the eosinophil count and the risk of tissue injury. Other therapies include etoposide, interferon-α, cladribine, and leukapheresis. Allogeneic hematopoietic cell transplantation has been used in some patients.

  — Surgical replacement of severely damaged heart valves has been successful.

Lymphoid Type

• Polyclonal eosinophilia may be associated with a clonal T-lymphocyte disorder (lymphoma), with elaboration of eosinopoietic cytokines, especially interleukin-5. It is less common than the myeloid type.

  — Eosinophil-induced tissue damage is not a feature of the disease.

  — Therapy. Treatment is directed principally at the underlying lymphoma.

Other Types

• The causes of the remaining cases of hypereosinophilia that are neither chronic eosinophilic leukemia nor related to lymphoma are still unclear.

Eosinophilia–Myalgia Syndrome

• This syndrome was first described in 1989, with more than 1500 cases reported and 30 deaths in the next 2 years.

• It is caused by the ingestion of l-tryptophan, a nutritional supplement, containing a contaminant.

• Constant features are severe myalgia and eosinophil count greater than 1.0 × 10⁹/L.

• Common findings are arthralgias, cough, dyspnea, edema, hair loss, peripheral neuropathy, and scleroderma-like skin changes.

• Pathologic features mimic eosinophilic fasciitis (see below).

• Glucocorticoids have improved symptoms and signs.

Toxic Oil Syndrome

• In 1981, in Spain, more than 20,000 people developed a syndrome of fever, cough, dyspnea, neutrophilia, and eosinophilia. More than 300 deaths occurred.

• It is thought to be caused by ingestion of aniline-denatured rapeseed oil.

• Pulmonary infiltrates, pleural effusion, and hypoxemia were common findings.

• One-half the patients developed a chronic illness that mimicked the eosinophilia–myalgia syndrome (see above), with myalgias, eosinophilia, peripheral neuritis, scleroderma-like skin lesions, hair loss, and sicca syndrome.

• Glucocorticoids may have improved the pulmonary symptoms.

Reactive Hypereosinophilia and Neoplasms

• Marked eosinophilia has been reported in association with a variety of solid tumors and lymphomas (eg, Hodgkin lymphoma), believed to be caused by interleukin-5 and other cytokines elaborated by tumor cells.

• Eosinophilia usually occurs concomitantly with the clinical diagnosis of the tumor.

• Successful treatment of the malignancy may be associated with amelioration of eosinophilia.

• Unlike other types of reactive eosinophilia, the blood eosinophil count may not be suppressed by glucocorticoids.

Acute Eosinophilic Leukemia

• This is a rare form of acute myelogenous leukemia.

Eosinophilic Granulomatosis with Polyangiitis

• This rare disorder of unknown etiology is characterized by eosinophilic asthma, chronic rhinosinusitis, and small vessel vasculitis.

• Forty percent of patients are antineutrophil cytoplasmic antibody (ANCA)–positive, and these patients have more vasculitic and renal disease manifestations, but less cardiac disease, than ANCA-negative patients (although there is considerable overlap).

• Diagnostic hallmark is eosinophilic vasculitis with granuloma on biopsy.

• Most patients enter remission with high-dose oral glucocorticoids, although guidelines recommend use of other immunosuppressants, such as cyclophosphamide or azathioprine, to induce remission where there is evidence of life-threatening organ involvement.

Eosinophilic Fasciitis

• This rare syndrome is characterized by stiffness, pain, and swelling of the arms, forearms, thighs, legs, hands, and feet in descending order of frequency.

• Malaise, fever, weakness, and weight loss also occur.

• Absolute eosinophil counts of greater than 1.0 × 10⁹/L are found in most patients but may be intermittent.

• Biopsy is usually required for diagnosis and shows inflammation, edema, thickening, and fibrosis of the fascia and synovia.

• Aplastic anemia, cytopenias, pernicious anemia, and myelogenous leukemia have been associated.

• Excretion of eosinophils in the urine is seen most often in urinary tract infection or acute interstitial nephritis.

• Cerebrospinal fluid eosinophilia may occur with infection, shunts, allergic reactions involving the meninges, and Hodgkin lymphoma.

• The eosinophil count in hospitalized patients is less than 0.01 × 10⁹/L in only 0.1% of patients, often ascribed to glucocorticoids, acute infection or disease activity.