Eosinophils

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Chapter 123 Eosinophils

Eosinophils are distinguished from other leukocytes by their morphology, constituent products, and association with specific diseases. Eosinophils are nondividing fully-differentiated cells with a diameter of ≈8 µm and a bilobed nucleus. They differentiate from stem cell precursors in the bone marrow under the control of T cell–derived interleukin (IL)-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), and, especially, IL-5. Their characteristic membrane-bound specific granules stain reddish brown with eosin and consist of a crystalline core made up of major basic protein (MBP) surrounded by a matrix containing the eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN). These basic proteins are cytotoxic for the larval stages of helminthic parasites such as Schistosoma mansoni and are also thought to contribute to much of the inflammation associated with asthma, causing sloughing of epithelial cells and contributing to clinical dysfunction (Chapter 138).

Both eosinophil MBP and ECP are also present in large quantities in the airways of patients who have died of asthma and are thought to inflict epithelial cell damage leading to airway hyperresponsiveness. Eosinophil granule contents also contribute to Loeffler endocarditis associated with hypereosinophilic syndrome. MBP has the potential to activate other proinflammatory cells, including mast cells, basophils, neutrophils, and platelets. Eosinophils have the capacity to generate large amounts of the lipid mediators platelet-activating factor and leukotriene-C4, both of which can cause vasoconstriction, smooth muscle contraction, and mucus hypersecretion. Eosinophils are a source of a number of proinflammatory cytokines, including IL-1, IL-3, IL-4, IL-5, IL-9, IL-13, and GM-CSF; they can also function as antigen-presenting cells. Thus, eosinophils have considerable potential to initiate and sustain inflammatory response of the innate and acquired immune systems.

Eosinophil migration from the vasculature into the extracellular tissue is mediated by the binding of leukocyte adhesion receptors to their ligands or counterstructures on the postcapillary endothelium. Similar to neutrophils (see Fig. 121-2), transmigration begins as the eosinophil selectin receptor binds to the endothelial carbohydrate ligand in loose association, which promotes eosinophils rolling along the endothelial surface until they encounter a priming stimulus such as a chemotactic mediator. Eosinophils then establish a high-affinity bond between integrin receptors and their corresponding immunoglobulin-like ligand. Unlike neutrophils, which become flattened before transmigrating between the tight junctions of the endothelial cells, eosinophils can use unique integrins, known as VLA-4, to bind to vascular cell adhesion molecule (VCAM)-1, which enhances eosinophil adhesion and transmigration through endothelium. Eosinophils are recruited to tissues in inflammatory states by the chemokine eotaxin. These unique pathways account for selective accumulation of eosinophils in allergic and inflammatory disorders. Eosinophils normally dwell primarily in tissues, especially tissues with an epithelial interface with the environment, including the respiratory, gastrointestinal, and lower genitourinary tracts. The life span of eosinophils may extend for weeks within tissues.

IL-5 selectively enhances eosinophil production, adhesion to endothelial cells, and function. Considerable evidence shows that IL-5 has a pivotal role in promoting eosinophil accumulation. It is the predominant cytokine in allergen-induced pulmonary late-phase reaction, and antibodies against IL-5 block eosinophil infiltration into the lungs in animal models associated with airway hyperresponsiveness following allergen challenge. Eosinophils also bear unique receptors for several chemokines, including RANTES, eotaxin, monocyte chemotactic protein (MCP)–3, and MCP-4. These chemokines appear to be key mediators in the induction of tissue eosinophilia.

Blood eosinophil numbers do not always reflect the extent of eosinophil involvement in disease-affected tissues. Eosinopenia occurs after corticosteroid administration and with some bacterial and viral infections.

Diseases Associated With Eosinophilia

The absolute eosinophilia count is used to quantitate eosinophilia. Calculated as the white blood cell (WBC) count/µL × percent of eosinophils, it is usually <450 cells/µL and varies diurnally, with eosinophil numbers higher in the early morning and diminishing as endogenous glucocorticoid levels rise.

Many diseases are associated with moderate (1,500-5,000 cells/µL) or severe (>5,000 cells/µL) eosinophilia (Table 123-1). Patients with sustained blood eosinophilia may develop organ damage, especially cardiac damage as found in the idiopathic hypereosinophilic syndrome, and should be monitored for evidence of cardiac disease. Many cases of moderately severe eosinophilia often have no clear etiology.

Infectious Diseases

Eosinophilia is often associated with infection with multicellular helminthic parasites, which are the most common cause in developing countries. Severe eosinophilia in children is most commonly due to visceral larva migrans. The level of eosinophilia tends to parallel the magnitude and extent of tissue invasion, especially by larvae. Eosinophilia often does not occur in established parasitic infections that are well contained within tissues or are solely intraluminal in the gastrointestinal tract, such as Giardia lamblia and Enterobius vermicularis infection.

In evaluating patients with unexplained eosinophilia, the dietary history and geographic or travel history may indicate potential exposures to helminthic parasites. It is frequently necessary to examine the stool for ova and larvae at least 3 times. Additionally, the diagnostic parasite stages of many of the helminthic parasites that cause eosinophilia never appear in feces. Thus, normal results of stool examinations do not absolutely preclude a helminthic cause of eosinophilia; diagnostic blood tests or tissue biopsy may be needed. Toxocara causes visceral larva migrans usually in toddlers with pica (Chapter 290). Most young children are asymptomatic, but some develop fever, pneumonitis, hepatomegaly, and hypergammaglobulinemia accompanied by severe eosinophilia. Isohemagglutinins are frequently elevated. Serology can establish the diagnosis.

Two fungal diseases may be associated with eosinophilia: aspergillosis in the form of allergic bronchopulmonary aspergillosis (Chapter 229.1) and coccidioidomycosis (Chapter 232) following primary infection, especially in conjunction with erythema nodosum.

Hypereosinophilic Syndrome

The idiopathic hypereosinophilic syndrome is a heterogeneous group of disorders characterized by sustained overproduction of eosinophils. The 3 diagnostic criteria for this disorder are (1) eosinophilia >1,500 cells/µL persisting for ≥6 mo, (2) absence of another diagnosis to explain the eosinophilia, and (3) signs and symptoms of organ involvement. The clinical signs and symptoms of hypereosinophilic syndrome can be heterogeneous because of the diversity of potential organ (pulmonary, cutaneous, neurologic, serosal, gastrointestinal) involvement. Loeffler endocarditis, one of the most serious and life-threatening complications, can cause heart failure due to endomyocardial thrombosis and fibrosis. Eosinophilic leukemia, a clonal myeloproliferative variant, may be distinguished from idiopathic hypereosinophilic syndrome by demonstrating a clonal interstitial deletion on chromosome 4q12 that fuses the platelet-derived growth factor receptor-alpha (PDGFRA) and FIP1-like-1 (FIP1L1) genes; this disorder is treated with imatinib mesylate, which helps target the fusion oncoprotein.

Therapy is aimed at suppressing eosinophilia and is initiated with corticosteroids. Imatinib mesylate, a tyrosine kinase inhibitor, may be effective in F1P1L1-PDGFRA negative patients. Hydroxyurea may be beneficial in patients unresponsive to corticosteroids. Specific anti IL-5 monoclonal antibodies (mepolizumab) targets this cytokine, which has a central role in eosinophil differentiation, mobilization and activity. With therapy, the eosinophil count declines and corticosteroid doses may be reduced. For patients with prominent organ involvement who fail to respond to therapy, the mortality is ≈75% after 3 yr.

Miscellaneous Diseases

Eosinophilia is observed in many patients with primary immunodeficiency syndromes, especially hyper-IgE syndrome (Chapter 116), Wiskott-Aldrich syndrome, and Omenn syndrome. Eosinophilia is also frequently present in the syndrome of thrombocytopenia with absent radii and in familial reticuloendotheliosis with eosinophilia. Mild eosinophilia is found in 20% of patients with Hodgkin disease and in gastrointestinal disorders including ulcerative colitis, Crohn disease during symptomatic phases, gastroenteritis that is associated with milk precipitins, and chronic hepatitis. Primary eosinophilic gastroenteritis usually involves the esophagus and stomach.