Eosinophilia:
What does it mean?

By Jeffery J. Auletta, MD, and Susan B. Shurin, MD

The eosinophil can either enhance or suppress immune function, and it's associated with a wide variety of diseases. Little wonder a finding of eosinophilia often leaves pediatricians scratching their heads.

Try your hand at unraveling the eosinophil's mystery, which lies in its unique structure and association with a variety of clinical diseases. Each patient in the following clinical scenarios has a white blood cell differential with 20% eosinophils. Do you think the underlying process is neoplastic, infectious, or immunologic?

Case 1: A 6-month-old boy presents with severe eczema, nosebleeds, and a moist cough. A physical examination reveals height and weight below the fifth percentile, clear nasal discharge, and scattered petechiae on his head and chest. His total white blood cell count is 4,500 cells/µL with 75% neutrophils, 5% lymphocytes, and 20% eosinophils. His hemoglobin is 9.8 g/dL and his platelet count is 47,000/µL.

Case 2: An adolescent female presents with abdominal cramping and diarrhea. She has recently returned from a trip to North Carolina with her youth group to help flood victims of a recent hurricane. She states that she only drank bottled water and ate thoroughly cooked food. However, she had to wade through floodwaters on several occasions. Her physical exam reveals a moderately uncomfortable female with pedal and perianal pruritic skin lesions.

Case 3: An 8-year-old male presents with intermittent fevers that began a month ago. Recently, he has had night sweats heavy enough to completely saturate his bedding. Since a physical examination before camp six months ago, he has lost seven pounds. His current physical exam reveals left supraclavicular fullness and a hard 3 x 3 cm left axillary lymph node. His total white blood cell count is 5,500 cells/µL with 42% neutrophils, 35% lymphocytes, 3% monocytes, and 20% eosinophils. His hemoglobin is 11.2 g/dL and his platelets are 585,000/µL.

See the box at the end of the article for the correct categories and likely diagnoses.

The other member of the differential

Although its presence alone is rarely diagnostic, eosinophilia may serve as a harbinger of disease. Defining the eosinophil's physiologic role has opened the door to understanding its presence in certain diseases.

The eosinophil has a bilobed nucleus with cytoplasm containing specific granules that stain strongly with acid dyes (see Figure 1). Unlike neutrophils, which have both primary and secondary (specific) granules, eosinophils have a single granule. Its crystalloid core is surrounded by a matrix housing the enzymes and cytokines responsible for the cell's actions. The core consists of major basic protein, a cytotoxic protein. The surrounding matrix contains eosinophil peroxidase, an enzyme similar in function to myeloperoxidase within neutrophil primary granules. Other granule contents include eosinophil cationic proteins, activators of Hageman factor and plasmin, and eosinophil-derived neurotoxin, an inflammatory mediator of central and peripheral neural tissue damage. Collectively, these enzymes are responsible for the eosinophil's tissue effects.

Like other granulocytes, the eosinophil is derived from an undifferentiated stem cell influenced by specific hematopoietic growth factors in the bone marrow, particularly interleukin-5 (IL-5). Once released from the bone marrow, eosinophils quickly localize into certain peripheral tissues, including lungs, skin, and the gastrointestinal (GI) tract. Interestingly, the level of circulating eosinophils inversely follows the diurnal variation of cortisol; it is lower in the morning and higher in the evening. Thus patients with Addison disease may have eosinophilia secondary to cortisone deficiency.

A wide variety of stimuli are capable of activating eosinophils. These include platelet products such as leukotrienes and platelet activating factor (PAF), cytokines or chemokines such as tumor necrosis factor (TNF) and interleukins, and humoral opsonins such as C5a and IgE. Repetitive or prolonged antigen exposure that elicits immediate (IgE-mediated) and delayed (T cell-mediated) hypersensitivity reactions most effectively stimulates eosinophil production and function.

Depending upon host factors and chemokine activation, the eosinophil undergoes phenotypic and functional changes that allow it to act as either an immunoenhancing or an immunosuppressing cell. "Activated" eosinophils are less dense, have higher rates of glucose uptake and metabolism, and generate more reactive oxygen species than do "resting" eosinophils. Thus the eosinophil's major function of cytotoxicity, especially against helminth infections, requires close cell surface apposition with the target cell, resulting in extracellular release of reactive oxygen species. An additional but less efficient function of eosinophils is phagocytosis of bacteria, yeast, and protozoa.

Too much of a good thing?

The eosinophil's dual nature is the key to its role in human diseases. The cytokines released from eosinophils not only protect the host from invading pathogens but can also promote inflammation, causing tissue damage from fibrosis and oxidative metabolites. Upsetting this delicate balance may be the reason that eosinophilia is a manifestation of an underlying immunodeficient state; this possibility is the focus of current research.

Eosinophilia can be defined by both the percentage and the absolute number of circulating cells. Normally, less than 5% of circulating granulocytes are eosinophils. Mild to moderate and marked or severe eosinophilia are defined as 5% to 15% (0.7 to 5 x 10⁹ cells/L) and greater than 20% (5 x 10⁹ cells/L) of circulating granulocytes, respectively.

While the array of diseases associated with peripheral blood eosinophilia is extensive (Table 1), allergic/immunologic, infectious, and malignant processes are most common.

TABLE 1

Causes of childhood eosinophilia

Allergy/immunology
Allergic rhinoconjunctivitis
Elevated IgE syndrome
IgA deficiency
Rheumatologic disorders (e.g., rheumatoid arthritis)
Seasonal/perennial allergies*
Wiskott-Aldrich syndrome

Dermatology and connective tissue
Connective tissue disorders (e.g., polyarteritis nodosa)
Eczema, atopic dermatitis*
Eosinophilic dermatitis
Eosinophilic fasciitis
Exfoliative dermatitis
Urticaria

Gastrointestinal
Allergic colitis
Eosinophilic gastroenteritis
Hepatitis, pancreatitis
Inflammatory bowel disease
Milk protein allergy*

Iatrogenic
Dialysis
Idiosyncratic drug reactions*
Postirradiation

Infectious
Parasitic*
   Ascariasis
   Cutaneous/visceral larva migrans
   Filariasis
   Schistosomiasis
   Strongyloidiasis
   Trichinosis
Nonparasitic
   Epstein-Barr virus
   Fungal (e.g., Aspergillus)
   Human immunodeficiency virus
   Tuberculosis

Malignancy
Chronic graft-versus-host disease
Eosinophilic leukemia
Hodgkin's and non-Hodgkin's lymphoma*
Malignant histiocytosis
Myelodysplastic syndromes

Respiratory
Allergic bronchopulmonary aspergillosis
Asthma*
Eosinophilic pneumonia
Hypersensitivity pneumonitis
Löffler syndrome

Allergic and immunologic disorders

A number of allergic or immunologic conditions and disorders are associated with eosinophilia.

Allergy. Atopic diseases are the most common causes of eosinophilia in North American children. Allergy and hay fever result in mild to moderate increases in peripheral eosinophils. Concentrating on inciting and instigating environmental exposures usually reveals the diagnosis; however, finding numerous eosinophils in nasal secretions may help confirm it.

Dermatology and connective tissue. Urticaria, eczema, and atopic dermatitis are the most common dermatologic conditions associated with eosinophilia. Typical historical and physical features are usually enough for making these clinical diagnoses. More serious dermatologic disorders such as bullous pemphigoid are rare in children.

Connective tissue diseases, though infrequent, also should be considered. For example, polyarteritis nodosa with fever, weight loss, abdominal and musculoskeletal pain, and mild to moderate peripheral eosinophilia is commonly misdiagnosed clinically as trichinosis. Tissue diagnosis demonstrating perivascular eosinophilic infiltration is needed.

Gastrointestinal diseases. Allergy- related diseases of the GI tract usually manifest as abdominal pain, diarrhea, peripheral eosinophilia, or eosinophilic infiltration of biopsied tissue. The age of those affected covers a wide range, from infancy (milk protein allergy) to adolescence (eosinophilic gastroenteritis). Specific food challenges usually trigger obvious symptoms.

Iatrogenic. The most common iatrogenic cause of eosinophilia is idiosyncratic drug exposure. Any drug has the potential for eliciting eosinophilia; no specific property of drugs has been shown to cause the response. Further, an atopic history does not necessarily predispose an individual to an eosinophilic drug reaction. Of course, drug allergies have a wide range of clinical expression, and eosinophilia is only one possibility.

Therapies with interleukin-2 (IL-2) and granulocyte-macrophage colony stimulating factor (GM-CSF) can cause marked eosinophilia through cytokine release and subsequent eosinophil activation. Other iatrogenic associations with eosinophilia include irradiation and dialysis treatments.

Immunodeficiency. Eosinophilia may also be associated with immunodeficiency syndromes. Usually these disorders involve a disruption of T-cell regulation that causes autoimmune phenomena. A history of rare or recurring infections and a laboratory evaluation that shows aberrant levels of circulating humoral or cellular components are diagnostic. Also helpful are physical findings of abnormal facies as in elevated IgE syndrome, skin manifestations as in Wiskott-Aldrich syndrome, or congenital anomalies as in Fanconi syndrome.

Chronic graft-versus-host disease following allogeneic hematopoietic stem-cell transplantation is a major acquired immunodeficiency state associated with eosinophilia. Post-transplant eosinophilia can indicate chronic graft-versus-host disease and should elicit a search for organ damage, such as cholestatic liver disease, ocular sicca syndrome, and pulmonary bronchiolitis obliterans.

Respiratory. Asthma is the most common respiratory disease associated with eosinophilia. Higher eosinophil counts occur in intrinsic vs. extrinsic asthma, though there is no correlation between clinical pulmonary symptoms or function and the level of eosinophilia.

Pulmonary eosinophilic syndrome (Löffler syndrome) is a broad term encompassing clinical entities characterized by respiratory symptoms, pulmonary infiltrates, and eosinophilia. Common respiratory triggers are occupational and environmental irritants and allergens. Allergic bronchopulmonary aspergillosis, an immunologic disorder associated with chronic lung disease, presents with fever and productive cough. Laboratory findings include eosinophilia, elevated IgE levels, and sputum positive for Aspergillus fumigatus or its antibodies.

Infection

The infectious organisms most likely to cause eosinophilia are helminths, protozoa, fungi, and a few viruses and bacteria (Table 2). Parasitic infections, especially by helminths, are the most common cause of eosinophilia worldwide.

TABLE 2

Infections associated with eosinophilia

Helminths

Ascaris lumbricoides

Brugia, Wuchereria species

Necator americanus

Schistosoma species

Strongyloides stercoralis

Toxocara species

Trichinella spiralis

Ascariasis*

Filariasis*

Hookworm*

Schistosomiasis

Strongyloidiasis*

Trichinosis*

Visceral larva migrans*

Protozoa

Plasmodium species

Pneumocystis carinii

Sarcoptes scabiei

Toxoplasma gondii

Malaria

Pneumonia

Scabies

Toxoplasmosis

Fungi

Aspergillus fumigatus

Coccidioides immitis

Allergic bronchopulmonary aspergillosis*

Viruses

Epstein-Barr virus

Human immunodeficiency virus

Mononucleosis

AIDS

Bacteria

Mycobacterium tuberculosis

Tuberculosis

*Frequently associated with eosinophilia

Eosinophilia is not a constant feature of parasitic infections. Its presence is related to the parasite's life cycle. Parasites with tissue migration cycles create the greatest eosinophilic response, while intraluminal or encysted parasites cause none. Interestingly, travelers have a greater eosinophilic response to parasitic infection than residents of an area.

Fungal infections, especially aspergillosis and coccidioidomycosis, are nonparasitic infections associated with eosinophilia. Generally, bacterial and viral infections cause eosinopenia. Toxin-mediated streptococcal infections, such as scarlet fever, and Epstein-Barr virus are exceptions, occasionally causing mild eosinophilia.

Malignant disorders

Many malignancies including Hodgkin's and non-Hodgkin's lymphoma and acute lymphoblastic leukemia are associated with eosinophilia. Both T lymphoblasts and Reed-Sternberg cells can produce IL-3, IL-5, and GM-CSF. Local production of IL-5 in Hodgkin's disease is responsible for the marked lymph-node eosinophilia seen especially in mixed cellularity disease. Elevated peripheral eosinophils may portend metastasis and relapse, as well as signaling poor prognosis in some malignant diseases.

Eosinophilic leukemia is a rare disease characterized by progressive anemia, lymphadenopathy, hepatosplenomegaly, and increased eosinophils that show abnormal granulation in peripheral blood and bone marrow. With a presentation and therapeutic response to chemotherapy similar to acute myelogenous leukemia, eosinophilic leukemia has been included as a specific subset of acute myelomonocytic leukemia called M4Eo. A unique chromosomal translocation involving chromosome 16 is thought to be responsible for creating this malignant phenotype.

Myelodysplastic syndromes and malignant histiocytosis are other lymphoproliferative diseases associated with eosinophilia. The most common childhood neoplasm in which tissue eosinophilia increases is eosinophilic granuloma or Langerhans' cell histiocytosis. Patients with systemic forms of Langerhans' cell histiocytosis (such as Letterer-Siwe disease) may have peripheral blood eosinophilia, though the tissue and bone marrow eosinophilia is usually more impressive.

Idiopathic disorders

Often the cause of eosinophilia is unknown. The most dramatic example is the hypereosinophilic syndrome. Rare in children, this syndrome is diagnosed by three clinical criteria: eosinophilia >1.5 x 10⁹ cells/L for at least six months; eosinophilic inflammation and organ infiltration, especially of the liver, spleen, skin, and heart; and the absence of any known cause of eosinophilia. Patients, typically male, die from cardiopulmonary dysfunction secondary to fibrosis and thrombosis. This syndrome differs from eosinophilic leukemia in that patients with leukemia have abnormal eosinophilic granulations, myeloblasts in the bone marrow, and a clinical course including anemia, thrombocytopenia, or other findings that suggest bone marrow failure.

Idiopathic eosinophilia may be caused by production of IL-5 by abnormal clones of T cells. To characterize this process, it is necessary to examine blood using flow cytometry. This technique can identify an expanded clone of T cells and also receptor gene rearrangement within T cells. Erythroderma has been the most consistent clinical finding. Neither IgE nor lymphocyte count is consistently elevated in this syndrome.

Premature infants commonly have increased numbers of eosinophils, perhaps because foreign protein has been absorbed from the GI tract. Additionally, these patients frequently are on medications and have fungal infections, both known to be associated with eosinophilia.

A careful evaluation

Since eosinophilia is associated with such a long and varied list of diseases, a practical approach to the evaluation is needed. A detailed history will help the pediatrician tailor the laboratory assessment. Inquiries about atopy-related diseases, diet, drug exposure, and recent travel are essential. The physical examination should be guided by a thorough review of systems, with particular attention to the respiratory system, skin, lymph nodes, and abdomen.

A directed laboratory evaluation is usually suggested by the history and physical examination. If eosinophilia is present without an obvious cause, the following tests should be done:

• stool examination for ova and parasites

• serologic evaluation for parasites not detectable by stool examination, such as Toxocara canis

• atopy and tuberculin testing

• chest radiograph

Repeat laboratory evaluations including serial blood counts and stool examinations are required. Bimonthly granulocyte differentials allow monitoring of serum eosinophilia, while at least three stool samples are needed to ensure parasitic isolation. Further assessments of hepatic and renal function, quantitative immunoglobulins, and an erythrocyte sedimentation rate may be helpful. If significant eosinophilia persists after two months, a more extensive workup including referral to a pediatric hematologist is warranted.

Summing up

Eosinophilia is associated with a vast array of childhood diseases. Most common in North America is atopic disease—allergy and asthma. Most common worldwide is infection by parasites. The three causes of marked eosinophilia are parasites, malignancy, and the hypereosinophilic syndrome.

A thorough history and physical examination are the basis for successful evaluation of childhood eosinophilia. Treatment of diseases associated with eosinophilia will improve when future research is able to precisely define the eosinophil's role in these processes.

Answers to clinical scenarios:

(1) Immunologic. Male gender, young age, eczema, thrombocytopenia, and lymphopenia suggest Wiskott-Aldrich syndrome. (2) Infectious. Suspicious for strongyloidiasis. Examination of stool or duodenal aspirate sample may demonstrate characteristic larvae. (3) Neoplastic. Probable lymphoma, especially Hodgkin's disease in view of night sweats and eosinophilia.

SUGGESTED READING

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Dinauer MC: The phagocyte system and disorders of granulopoiesis and granulocyte function, in Nathan DG, Orkin SH (eds.): Nathan and Oski's Hematology of Infancy and Childhood. Philadelphia, WB Saunders Company, 1998, pp 889-967

Moore TA, Nutman TB: Eosinophilia in the returning traveler. Infect Dis Clin North Am 1998;12(2):503

Rothenberg ME: Eosinophilia. N Engl J Med 1998; 338(22):1592

Sanderson CJ: Interleukin-5, eosinophils, and disease. Blood 1992;79(12):3101

Simon HU, Plotz SG, Dummer R, et al: Abnormal clones of T cells producing interleukin-5 in idiopathic eosinophilia. N Engl J Med 1999;341:1112

Venge P: The eosinophil granulocyte in allergic inflammation. Pediatr Allergy Immunol 1993;4(suppl 4):19

Weller PF, Bubley GJ: The idiopathic hypereosinophilic syndrome. Blood 1994;83(10):2759

DR. AULETTA is a Fellow, Pediatric Hematology/ Oncology and Infectious Diseases, Rainbow Babies and Children's Hospital, Cleveland, OH.

DR. SHURIN is Professor, Department of Pediatrics, Case Western Reserve University, and Chief, Division of Pediatric Hematology/ Oncology at Rainbow Babies and Children's Hospital.

Susan Shurin, Jeffrey Auletta. Eosinophilia: What does it mean?.

Contemporary Pediatrics

2000;6:61.