EOSINOPHILIA IN AIDS

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ALLERGIC DISEASE IN AIDS

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EOSINOPHILIA IN AIDS Hal M. Hoffman, MD, and David H. Broide, MBCHB

Eosinophilia is a relatively common finding in patients with AIDS and may be due to HIV infection alone or due to several eosinophilassociated disorders unrelated to HIV. There is evidence to support a special role for the eosinophil in the immunologic changes associated with AIDS. This article reviews the biology of the eosinophil in relation to the immunologic changes that occur with HIV infection. We outline the key features in the clinical assessment of eosinophilia in the AIDS patient, provide a differential diagnosis by organ system, and discuss therapeutic considerations. THE EOSINOPHIL

Structure and Function The eosinophil is a bone marrow-derived granulocyte readily identified on light microscopy by its bilobed nucleus and distinctive cytoplasmic granules that stain red with eosin. By electron microscopy, the mature eosinophil has large granules with a dense core and radiolucent matrix made up of several granular proteins. These cytoplasmic granule proteins are responsible for many of the eosinophil’s beneficial proinflammatory functions, such as parasite killing, and for its detrimental actions, such as tissue damage. The release of the cytoplasmic granular proteins is the process of degranulation that occurs in response to specific stimuli such as the binding of IgA to the eosinophil cell surface IgA receptors. The eosinophil responds to environmental signals through

From the Department of Medicine, Division of Allergy/Immunology, University of California at San Diego, La Jolla, California ~~~

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a variety of cell surface receptors, including the low-affinity IgG recept (Fcy RII or CD32), the low-affinity IgE receptor (Fce RII or CD23), tl IgA receptor, several complement component receptors, several cytokii receptors, the major histocompatibility complex class I1 (MHC 11), an the lymphocyte marker CD4. These cell surface receptors mediate man of the eosinophil’s functions, including activation, mediator release, dt granulation, adhesion, chemotaxis, and cell-cell interaction^.^^ Eosinophil-activating factors include platelet activating factor (PA€ and the cytokines (granulocyte-macrophage colony stimulating facto [6m-CSF]), interleukin-3 (IL-3), interleukin-5 (IL-5), and granulocyte macrophage colony stimulating factor (6m-CSF). These cytokines pro long eosinophil survival by preventing apoptosis (programmed cel death)75and also increase the eosinophil’s metabolic activity.s3In addition to cellular structural changes, eosinophil activation also stimulates the production and release of a number of proinflammatory lipid mediators such as leukotriene C,. Activated eosinophils also produce cytokines that have an important paracrine role in communicating with other cell types at sites of inflammation, as well as an autocrine role in eosinophil development and function.82

Eosinophilopoiesis and Migration

There are three anatomic phases in the eosinophil life cycle: bone marrow, blood, and tissue (Fig. 1). The pluripotent stem cell in the bone marrow differentiates over 5 to 6 days to a committed eosinophil progenitor and finally to a mature eosinophil before it is released into the blood~tream.~~ IL-5 is the cytokine primarily responsible for terminal differentiation of eosinophils in the bone marrow.79The blood phase of the eosinophil is the shortest, lasting only 8 to 18 hours, at which time the cell migrates out of the blood vessel into the tissue, where it remains until cell death. The eosinophil, much like the mast cell, resides predominantly in tissues with epithelial surface exposed to the external environment. The average eosinophil survives 2 to 5 days before it is cleared by macrophage engulfment, epithelial shedding, or cell death. Therefore, the average eosinophil circulates in the bloodstream for only a small percentage of its lifespan, and at any given time there are over 100 times more eosinophils in tissue than in plasma.32 The transmigration of the eosinophil from the bloodstream to the tissue is regulated by a group of cell surface proteins called adhesion molecules, and this process is characterized by eosinophil rolling, firm adhesion, and diapedesis (transendothelial migration). Eosinophil migration in the tissue is controlled by a number of cell-derived cytokines or chemokines which facilitate chemotaxis (directed migration across a concentration gradient) and chemokinesis (nondirectional movement). Eotaxin is the only lineage specific eosinophil chemotactic factor, and PAF is the most potent eosinophil chemotactic factor.32

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Figure 1. Life cycle of eosinophil. Pluripotent stem cell differentiates in bone marrow to a mature eosinophi1 before it is released into the bloodstream. Eosinophil migrates from the bloodstream through a process of rolling, firm adhesion, and diapedesis into the tissue. Eosinophil is directed by chemotaxis and releases granular proteins or mediators at sites of inflammation. Eosinophil survival is prolonged by interleukin-5 (IL-5), interleukin-3 (IL-3), and granulocyte-macrophage colony stimulating factor (GM-CSF); without these cytokines cell death results.

BONE MARROW

Cytokines Eicosanoids

Degranulation and Mediator Release

Granular Proteins

BLOOD VESSEL

Cell Death

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Cell Communication The eosinophil is not only an effector cell at the end of an immunologic cascade but also is an active partner in regulating the immune response by interacting with different cells in its environment including lymphocytes, other immune effector cells, and mesenchymal cells. CD4 + T lymphocytes direct eosinophil actions by releasing many of the cytokines that control development, migration, and activation.82There are two distinct patterns of cytokine production by T lymphocytes, referred to as Thl and Th2. The Thl pattern results in the production of interferon (IFN) y and IL-2, which promote cell-mediated functions as seen in delayed type hypersensitivity reactions. The Th2 cytokine pattern, which includes IL-4, IL-5, and IL-10, promotes B lymphocyte responses including IgE responses in allergic disease. The eosinophil is prominent in inflammatory reactions involving the Th2 profile, primarily because IL-5 plays such an important role in eosinophil proliferation. The presence of CD25 (IL-2 receptor) on the eosinophil allows for direct communication with lymphocytes; the presence of CD4 allows the eosinophil to interact with antigen-presenting cells; and the presence of human leukocyte antigen-DR (HLA-DR) allows the eosinophil to act as an antigen-presenting cell, eliciting antigen-specific lymphocyte responses.82The eosinophil responds to several mediators released by other immune cells such as mast cells, and by structural cells such as fibroblasts and epithelial cells in the tissues in which they reside.79

Roles of the Eosinophil The eosinophil has several potential roles in inflammatory processes, including participation in host defense against multicellular organisms, and it has been postulated that the eosinophil evolved to defend against multicellular parasitic organisms. Although the eosinophi1 is capable of phagocytizing and killing bacteria, this function in host defense is a minor part of. The eosinophil appears to be well suited to controlling helminthic infections with its helminthotoxic granular proteins and its ability to participate in antibody-dependent cellular cytotoxicity, complement dependent killing, and IgE-mediated responses to multicellular antigens.27The role of the eosinophil in helminthic infections is controversial, however, because some studies in mice suggest that the eosinophil is not essential for resistance to helminthic infections and that the eosinophil may be a redundant mechanism for parasite control. Others suggest that the eosinophil is part of a pathologic process initiated by the Th2 response and actually represents a breakdown of normal immune regulation. It is possible that the switch from a Thl to Th2 response pattern is induced by parasites themselves to improve their survival.32 The eosinophil plays a critical role in allergic and other inflammatory responses. It is recruited into inflammation sites, where it releases

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mediators that affect its own actions as well as those of other cells. In the asthmatic lung it may act on mast cells, contractile smooth muscle, and mucous secreting cells. The release of eosinophilic granular proteins has the potential to cause epithelial desquamation and bronchial hyperactivity characteristic of allergic disorder^.^^ The eosinophil may play a role in wound healing as well as the pathology of fibrosis because of its release of the important mediator transforming growth factor p.82 Additionally, some studies point to the role of the eosinophil in tumor re~istance.~~ THE EOSINOPHIL AND HIV

Eosinophils may be affected through direct intracellular infection with HIV and by the consequences of HIV infection of other immunologic cells. Eosinophils express CD4 on their surface, so that the HIV gp120 protein can bind to the eosinophil and presumably infect the cell as it does CD4+ T lymphocytes, monocytes, and macro phage^.^^ This has been demonstrated in vitro with experimentally infected isolated eosinophilss5and IL-5-stimulated bone marrow cells,3O and in vivo with carefully isolated eosinophils from patients infected with HIV.19 Therefore, the eosinophil may act as a primary host cell or a major reservoir for HIV.30It has been suggested that HIV infection of eosinophils could lead to cytolysis with release of granular proteins and alteration of inflammatory mediator release resulting in local tissue effectss5or chemotactic defects as has been suggested in monocyte and macrophage infection with HIV.87 Several immunologic changes that occur with HIV infection and AIDS have either direct or indirect bearing on the eosinophil and its actions. The primary immunologic consequence of HIV infection is depressed cell-mediated immunity, with a progressive depletion of CD4 + lymphocytes. Researchers have suggested that HIV progression induces a shift from a Thl cytokine pattern to a Th2 pattern.15,16, 6o This is supported by the finding in AIDS patients of increased production of the Th2 cytokines IL-4,15,6o IL-5,13 IL-6: and IL-10,17 as well as increased B-cell activity.16Additionally, HIV-infected patients have been found to have decreased IFN y?7,65 decreased IL-2,15 and reduced cytolytic potential.60The predominant source of Th2 cytokines is CD4 + T lymphocytes, but the number of these cells is decreased in advanced disease. Researchers suggest that CD8 + or CD4 - CD8 - cells may mimic the Th2 pattern of CD4 + cells, producing IL-4, which leads to increased IgE production, and IL-5, resulting in an increased number of eo~inophils.~~ This is consistent with the fact that patients with AIDS have an increased incidence of elevated IgE and eosinophilia of blood,58,70, 86 bone marrow,3l,35 and which do not appear to be related to superimposed allergic disease or parasitic infe~ti0n.l~ Some investigators have indicated that eosinophilia is a sensitive indicator of disease progression,13 although others disagree.77It is possible that HIV infection in-

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duces the Thl-Th2 switch to prevent potentially immunoprotective Thl responses and allow for progression of AIDS. Certain host factors may direct the cytokine response pattern toward a Th2 response and result in the faster progression of disease in some patients.16 One factor that has received attention and is particularly pertinent is parasitic infection, especially in HIV patients in endemic areas such as Africa, where the progression of the disease appears to be faster? Helminthic infection was shown to impair immune protection to viral infections and delay viral clearance.' Immunologic crossreactivity has been described between a regulatory protein in HIV and an antigen present on the parasite Schistosoma. This implies that prior immunologic responses to parasitic infections may have an influence on HIV infection.21,45 The role of the eosinophil in parasitic infections, its prominence in the Th2 response, the possible impact of parasitic infections on HIV infection, and the higher incidence of eosinophilia in patients with AIDS all indicate that the eosinophil is affected by HIV and may have an impact on infection by and progression of HIV. ASSESSMENT OF EOSlNOPHlLlA

Normal values of peripheral blood eosinophil counts range from 35 to 350/mm3, with means for adults of 125/mm3 and children of 225/ mm3. However, the most accepted definition of eosinophilia in blood is counts greater than 450 to 5OO/m1n~.~~ Eosinophil count determinations should be performed using a manual differential, because an automatic differential often reports hypogranular eosinophils as neutrophils, which underestimates the percentage of eosinophils in the blood. This inaccuracy of automatic counts has been observed in HIV patients, who often have activated hypogranular eosinophils in the Eosinophil counts are determined routinely by multiplying the total leukocyte count by the number of eosinophils out of 100 white blood cells. The problem with this method is that with relatively low numbers of eosinophils in the blood compared with other cells, a small error in sampling may result in a relatively large error in calculating the total eosinophil count. This can be avoided by counting more than 100 white cells when one is obtaining absolute eosinophil counts.80Because eosinophils are increased transiently in the blood with exercise and also in the early morning when endogenous corticosteroid production is lowest, these factors must also be c o n ~ i d e r e d . ~ ~ Although the degree of blood eosinophilia does not always correlate with specific diseases, some authors have suggested general guidelines based on the level of eosinophil counts. Levels between 300 and 1000/ mm3 are usually associated with atopic disease and asthma, whereas moderate elevations between 1000 and 5000/mm3can be seen in adverse drug reactions, Churg-Strauss syndrome, and some helminthic infections. Extremely high leveIs of eosinophils, sometimes over 30,000/mm3, are associated with idiopathic hypereosinophilic syndrome or eosino-

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philic leukemia.78The level of eosinophilia correlates with the magnitude of helminthic larval invasion of tissue,SOand it is possible that eosinophil counts are an indicator of clinical deterioration in AIDS patients.70 Because most of the life cycle of the eosinophil is spent in tissue, peripheral blood eosinophil counts are a limited window to the total eosinophil numbers in the body, and are not always related to the level in the tissue. For this reason it is often important to obtain tissue specific specimens or fluids to accurately assess eosinophil-associated organ system involvement. Tissue eosinophils on biopsy (e.g., lung, gut, skin, muscle, kidney, and lymph node) or scraping (e.g., nose or conjunctivae) are not usually reported quantitatively outside of research settings; therefore, a qualitative assessment is generally adequate. It is important to survey more than one area of tissue, because the presence of collections of eosinophils may be highly variable. The presence of scattered eosinophils in tissue is not abnormal, but infiltrates of large numbers of eosinophils and the presence of the eosinophil's granular proteins or their effects can be p a t h ~ l o g i cEosinophil .~~ percentages or counts can be measured in fluid lavage (bronchoalveolar),aspiration (pleural effusion, peritoneal, cerebrospinal, and bone marrow), and collection (urine), but normal levels are not always available. Traditionally, greater than 1% eosinophils in bronchoalveolar lavage (BAL) fluid is considered abnormal*and greater than 10% eosinophils in a pleural effusion is considered abnormal.53The presence of any eosinophils in the urine or cerebrospinal fluid is ~ignificant.~~

KEY FEATURES OF PATIENT EVALUATION History and Physical Examination Although worldwide the msst common cause of eosinophilia is helminthic infections, in North America allergic disease, especially drug reactions, is more commonly seen.80Therefore, a detailed drug history is imperative and should include prescription and nonprescription medications, vitamin preparations, vaccines, and illicit drugs with dates of usage for each. A temporal relationship between the initiation of the drug and onset of symptoms is often the only clue, and the disappearance of symptoms after discontinuing the offending agent supports the diagnosis of a drug reaction. Because in AIDS patients there are often several medications started or taken at once, the identification of the responsible medication can be difficult. A past allergic reaction, including reactions to medications, aeroallergens, or foods, would increase suspicion of an allergic etiology especially if there were a history of a recent exposure to the same or a similar agent. To assess possible exposure to helminthic parasite infections, the history should include a documentation of travel, specific ingestions (contaminated drinking water, undercooked foods), and possible exposures (swimming, walking barefoot, animals, animal feces, and insects).

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Because eosinophils can affect so many organ systems, a complete review of systems is necessary. General symptoms of fever, night sweats, weight loss, anorexia, malaise, weakness, myalgia, or arthralgia may suggest systemic conditions involving parasite infections, autoimmune disease, or neoplastic disorders, but these may be difficult to differentiate from AIDS-related symptoms. Eosinophils are primarily distributed in the lungs, gastrointestinal tract, and skin, so that particular attention should be paid to symptoms associated with these organ systems. Cough, dyspnea, or chest pain suggest respiratory involvement; vomiting, diarrhea, abdominal pain, or blood in the stool indicates gastrointestinal disease and possibly helminthic infection; whereas rash and edema point to dermatologic involvement. A general physical examination in the evaluation of eosinophilia should focus on the skin, upper and lower respiratory tract, and abdomen. Skin manifestations are very common in patients with AIDS, so that it may be difficult to establish the significance of a rash. Classic allergic signs in the nose and conjunctivae may point to an atopic disease, although these are also common findings in AIDS patients. Respiratory signs such as wheezing or altered breath sounds can be seen in eosinophilic pneumonia, asthma, allergic bronchopulmonary aspergillosis (ABPA), and many pulmonary infections. Epigastric tenderness in association with gastrointestinal symptoms could signify eosinophilic gastroenteritis with muscle layer i n ~ o l v e m e n t General .~~ signs, including lymphadenopathy and hepatomegaly, are common in patients with AIDS and may suggest an underlying systemic disease that could be related to the eosinophilia. A neurologic examination may reveal signs of peripheral neuropathy or past CNS embolic phenomenon which, although not specific, are seen in idiopathic hypereosinophilic syndrome (IHS). Laboratory Evaluation

The laboratory evaluation should be directed by the history and physical findings. A screening laboratory evaluation includes a complete blood count to evaluate other bone marrow-derived cells for indications of infection or myeloproliferative disorders, an erythrocyte sedimentation rate to screen for general inflammatory conditions such as autoimmune disease, and a chemistry panel to evaluate renal and hepatic involvement. If parasite infections are suspected, repeated stool collection for ova and parasite examination are warranted, although this may not be sufficient, and more invasive procedures such as gastric aspirates, intestinal biopsy, or bronchoalveolar lavage (BAL) may be required. Serologic tests for specific organisms are helpful in confirming the diagnosis,80 but false-positive serologic test results have been reported in patients with immunologic abnormalities such as AIDS.44If allergic disease is suspected, a serum IgE level may be helpful, although IgE may also be elevated with helminthic infections or HIV infection alone.

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Immediate hypersensitivity skin tests or RAST tests can confirm a specific agent as an allergen. The presence of specific IgE and precipitins to Aspergillus as well as proximal bronchiectasis on chest CT scan are diagnostic for ABPA. If autoimmune disease is suspected, testing for specific autoantibodies such as antineutrophil cytoplasmic antibodies (ANCA) in suspected Churg-Strauss syndrome should be done. Chest X-ray films and pulmonary function tests are indicated in any patient with respiratory symptoms and eosinophilia. Evaluation of specific organ systems requires obtaining tissue by biopsy or fluid by aspiration to make a diagnosis. Bronchoalveolar lavage (BAL) is an important tool in the diagnosis of respiratory disorders in AIDS patients, with Pnetimocystis carinii pneumonitis as a common cause of BAL eosinophilia in these patients. Skin biopsy may be necessary to diagnose dermatologic conditions in HIV-infected patients. Other diagnostic tests that may be indicated depending on the presentation include endoscopy with bowel biopsy for suspected eosinophilic gastroenteritis, muscle biopsy to evaluate eosinophilic fasciitis, bone marrow aspiration and lymph node biopsy to diagnose hematologic and neoplastic disease, cerebrospinal fluid to evaluate meningitis, and renal biopsy and urinalysis to diagnose interstitial nephritis (See Table 1). DIAGNOSTIC CONSIDERATIONS

Although there are several disorders with concomitant eosinophilia that are unique or more prevalent in patients with AIDS (Table 2), it is important to consider the many eosinophilic disorders that are unrelated to HIV infection (Table 3). The differential diagnosis of eosinophilia is extensive and involves many organ systems. We discuss first eosinophilrelated systemic diseases followed by diseases affecting specific organ systems, with particular attention to HIV-associated diseases. Helminthic Infections

Because the most common cause of eosinophilia worldwide is helminthic parasite infections, some of the most common disorders associated with peripheral blood and tissue eosinophilia are ascariasis, hookworm infection, toxocariasis (visceral larval migrans), trichinosis, strongyloidiasis, filariasis, schistosomiasis, fascioliasis, and paragonimia ~ i sThe .~~ common denominator in these parasite infections is the occurrence of tissue invasion, and eosinophilia usually is not seen in infections by organisms that remain in the lumen of the gastrointestinal tract such as trichuris and enterobius. The clinical presentation varies depending on the organism, and many patients are asymptomatic or have only general symptoms of fever or weight loss. Many of the helminthic parasitic organisms have complex life cycles that can affect many organs, including the stomach, intestine, liver, bile ducts, lungs, heart, blood

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Table 1. CLINICAL ASSESSMENT OF EOSlNOPHlLlA ~~~~~~

History Recent travel (ingestions or exposures) Animal exposure (including feces, insects) Drug history (prescription, nonprescription, illicit) Allergic history Complete review of systems Physical Examination General: lymphadenopathy Skin: rash HEENT: allergic signs Cardiac: S3,rhythm disturbance Respiratory: wheezing, pleural effusion, consolidation Abdomen: tenderness, hepatomegaly Nervous system: peripheral neuropathy Laboratory Tests (Directed by history and physical examination results) Review past eosinophil counts for time of onset of eosinophilia Absolute eosinophil count Complete blood count and differential Sedimentation rate Chemistry panel Serologic tests for parasites Serologic tests for rheumatologic disease (e.g., ANCA) Stool for ova and parasites Bone marrow biopsylaspiration Tissue biopsy/aspiration Echocardiogram Chest x-ray Immediate hypersensitivityskin testing

Table 2. EOSINOPHIL-ASSOCIATED DISEASES IN AIDS Commonly Seen Drug reactions Atopic diseases (e.g., asthma, allergic rhinitis) Eosinophilic pustular folliculitis Reported Strongyloidiasis lsospora belli infection Cytomegabvirus injection Coccidiomycosis Kaposi’s sarcoma AIDS-related lymphomas Angiolymphoid hyperplasia with eosinophilia Dermatopathic lymphadenopathy Lymphocytic interstitial pneumonitis Pneurnocysfiscarinii pneumonia (BAL) Acute eosinophilic pneumonia (BAL)

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Table 3. EOSINOPHIL-ASSOCIATED DISEASES Collagen Vascular Disease Allergic Diseases Churg-Strauss Drug hypersensitivity reactions Hypersensitivity vasculitis Asthma Eosinophilic fasciitis Allergic rhinoconjunctivitis Rheumatoid arthritis Urticaria Sjogren’s syndrome Atopic dermatitis Scleroderma Allergic bronchopulmonary aspergillosis Dermatomyositis Allergic gastroenteritis Respiratory Diseases Infections Tropical pulmonary eosinophilia (filariasis) Helminthic Parasites Eosinophilic pneumonia Ascariasis Loffler’s syndrome Trichinosis Acute eosinophilic pneumonia Toxocariasis Chronic eosinophilic pneumonia Strongyloidiasis Bronchoconcentric granulomatosis Hookworm infection Interstitial lung diseases Filariasis Hypersensitivity pneumonitis Schistosomiasis Dermatologic Diseases Paragonimiasis Fascioliasis Episodic angioedema with eosinophilia Eosinophilic cellulitis Protozoan Parasites Eosinophilic pustular folliculitis lsospora belli Scabies Pneumocystis carinii Autoimmune Mediated Bullous Diseases Bacteria Bullous pemphigoid Herpes gestationis Chronic brucellosis Pemphigus Chronic tuberculosis Dermatitis herpetiformis Secondary syphilis Scarlet fever Gastrointestinal Diseases Lepromatous leprosy Eosinophilic gastroenteritis VIruses Inflammatory bowel disease Chronic hepatitis Parvo B19 Measles Renal Diseases Rubella Interstitial nephritis Varicella Chronic peritoneal dialysis Other Immunodeficiency Diseases Coccidiomycosis Wiskott-Aldrich svndrome Chlamydia IgA deficiency Neoplastic and Myeloproliferative Diseases H~~~~l g syndrome ~ Carcinomas (esp. ovarian) Nezelof‘s syndrome Lymphomas Idiopathic Hypereosinophilic Syndrome Hodgkin’s Miscellaneous Diseases Mycosis fungoides Eosinophilic myalgia syndrome Sezary’s syndrome Addison’s disease LvmDhomatoid Dapulosis Angioimmunoblastic lymphadenopathy Dressler’s syndrome Angioblastic lymphoid hyperplasia Angiolymphoid hyperplasia with eosinophilia Histiocytosis Systemic mastoctosis Leukemias Eosinophilic leukemia Acute lymphocytic leukemia Acute myelogenous leukemia Chronic myelogenous leukemia

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vessels, lymphatic vessels, skin, muscle, urinary tract, and brain. One helminthic infection that has been described in HIV is hyperinfection with Strongyloides stercoralis, but the CDC no longer includes this infection as part of the case definition of AIDS.26It is associated with a high mortality and may or may not be associated with peripheral blood eosinophilia.% Other Infections Although several protozoan, bacterial, and viral infections have been associated with eosinophilia, patients with these infections more frequently present without eosinophilia. In addition, other causes of eosinophilia (e.g., atopy, drug reactions) have not been rigorously excluded in these reported patients. The only parasitic protozoan infection associated with blood eosinophilia is Isosporu belli, an intestinal coccidian parasite that causes diarrheasoand has been reported in AIDS patients.87 Pneurnocystis carinii, the most common protozoan infection in AIDS, does not usually cause peripheral blood eosinophilia but has been associated with elevated eosinophil percentages in BAL fluid specimens.2,28 Pneurnocystis carinii pneumonia presents with dyspnea, nonproductive cough, and fever, and diagnosis is made by identification of the organism in sputum or BAL fluid. There are a limited number of nonparasitic infections that are associated with eosinophilia. Bacterial infections usually cause eosinopenia and, when present as superinfections with parasite infections, can actually mask the parasite-induced eosinophilia.81 Eosinophilia has been reported with chronic brucellosis, lepromatous leprosy, chronic tuberculosis, secondary syphilis, and scarlet fever. The viruses that occasionally cause eosinophilia are parvo B19, measles, rubella, and varicella. Eosinophilia has also been reported in cytomegalovirus (CMV) infection, which is a common complication of AIDS56and can result in chorioretinitis, pneumonia, esophagitis, colitis, and several neurologic disorders." Chlamydia infection, especially when involving the respiratory tract in infants, may cause eosinophilia. Coccidiomycosis, a systemic mycosis endemic to arid regions of North and South America, is becoming recognized as an important pathogen in AIDS patients. It can result in severe pulmonary disease, commonly presents with blood e0sinophilia,5~ and is diagnosed by culture and identification of the organism in BAL or transbronchial biopsy. Allergic Disease Peripheral blood and tissue eosinophilia is associated with all of the atopic diseases, including asthma, ABPA, allergic rhinoconjunctivitis, acute urticaria, atopic dermatitis, and drug hypersensitivity. Eosinophils are increased in the bronchial secretions and lung tissue in asthma and

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ABPA, in nasal secretions and nasal and conjunctival tissue in allergic rhinoconjunctivitis, and in the skin in urticaria and eczema. In allergic drug reactions eosinophilia may be found in the peripheral blood only or may be found in many organ sites, including skin in urticaria, kidney in drug-induced interstitial nephritis, liver in drug-induced hepatitis, and lungs in hypersensitivity pneumonitis. Allergic causes of eosinophilia are particularly important in HIVinfected patients because of their higher incidence of allergic rhinitis and conjunctivitis sympt0ms,6~increased reactivity on immediate hypersensitivity skin testing and IgE RAST potential testing,” and increased frequency of adverse reactions to The latter finding may be partly explained by these patients’ increased exposure to multiple drugs, but may also be secondary to changes in drug metab0lism.3~Many AIDS patients have hypersensitivity reactions to antibiotics (especially sulfona m i d e ~as ) ~well ~ as drugs used in the treatment of HIV such as didanosine,5l and paclitaxel.” Idiopathic Hypereosinophilic Syndrome

Idiopathic hypereosinophilic syndrome (IHS) is a heterogeneous group of disorders characterized by organ dysfunction and peripheral blood eosinophilia greater than 1500/mm3 (usually in the 50,000100,000/mm3range) that is persistent for more than 6 months. IHS can affect almost any organ system. The most significant involvement of IHS is that of the heart, which accounts for most of the morbidity and mortality associated with this condition and necessitates regular monitoring for progressive cardiac failure. Neurologic abnormalities include diffuse dysfunction with behavior and cognitive changes, peripheral neuropathy of a symmetric nature, or embolic events in the brain or eye. Presenting pulmonary signs and symptoms include cough, bronchospasm, dyspnea, and infiltrates or effusions. Gastrointestinal symptoms such as diarrhea, nausea, vomiting, and abdominal cramps can also be seen, and patients may have hepatomegaly. Patients may also have weakness, fatigue, fever, myalgia, rash, or rhinitis. Diagnosis of IHS is made only after other causes of eosinophilia are excluded.27Bone marrow biopsy usually shows greater than 30% eosinophils and tissue biopsy is characterized by increased eosinophils and eosinophil granular protein-mediated tissue damage.47Several patients with AIDS have been reported with similar manifestations to those of IHS with marked eosinophilia and organ dysfuncti~n.~~, Collagen Vascular Disease

Churg-Strauss syndrome (allergic granulomatosis with angiitis) is a systemic vasculitis with multiorgan involvement and prominent eosinophilia. Patients present with asthma, rhinitis and sinusitis, fever, and

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constitutional symptoms, but may develop peripheral neuropathy, and rash, as well as occasionally liver, gastrointestinal, and kidney involvement. Laboratory findings in Churg-Strauss syndrome are most notable for blood eosinophilia over 5000/mm3, elevated IgE levels, elevated erythrocyte sedimentation rate, and positive antineutrophil cytoplasmic antibodies. Biopsy of affected tissue shows vasculitis with eosinophilic infiltrate and occasional extravascular granulomas. Patients are treated with corticosteroids and other immunosuppressive agent^.^ Eosinophilic fasciitis (Schulman’s syndrome) is defined by painful acute swelling and erythema leading to firm induration of the extremity and is often associated with a number of systemic symptoms.53Eosinophilia myalgia syndrome is a similar condition but is associated specifically with L-tryptophan ingestion and toxic These patients present with eosinophilia of 1000 to 36,000/mm3, intense myalgia, rash, fever, and swelling of the extremities. Additional manifestations include respiratory symptoms, weight loss, arthralgias, muscle weakness, paresthesias, scleroderma-like induration, and alopecia. Muscle biopsy in these conditions shows chronic inflammation and fibrosis. Some patients respond to corticosteroids but relapse as they are tapered, whereas others with advanced disease have minimal response.4l Several of the other autoimmune diseases are occasionally associated with peripheral blood eosinophilia, including rheumatoid arthritis, Sjogren’s syndrome, scleroderma, and dermatomy~sitis.~~

Neoplastic and Myeloproliferative Disease Carcinoma of the ovary is the most common neoplasm associated with eosinophilia, although other tumors such as epidermoid carcinomas of the cervix, uterus, penis, lip, and tongue, villous carcinoma of the , adenocarcinoma of the colon have bladder, carcinoma of the l ~ gand also been reported in association with e~sinophilia.~~ One investigator found eosinophilia in patients with Kaposi’s sarcoma and AIDS.14 Several lymphomas, including H ~ d g k i n ‘ sand ~ ~ other AIDS-related lymphomas,68have been described with eosinophilia. Others include mycosis fungoides, Sezary’s syndrome, lymphomatoid papulosis, angiolymphoid hyperplasia, and dermatopathic lymphaden~pathy.~~ The latter two dis42 Acute eases have been reported in AIDS patients with eosinophilia.22, lymphocytic leukemia, acute myelogenous leukemia, and chronic myelogenous leukemia are also occasionally seen with eosinophilia, and by definition eosinophilic leukemia is always associated with eosinophilia. Lastly, eosinophilia can be seen in patients undergoing cancer therapy with cytotoxic agents or radiation therapy.53

Respiratory Diseases A wide spectrum of eosinophil-associated respiratory disorders has been described. Many of these conditions present with peripheral blood

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eosinophilia, but all have eosinophilic lung infiltration recognized by BAL or lung biopsy. The main groups of pulmonary disease with associated eosinophilia include the idiopathic eosinophilic pneumonias, allergic disorders, interstitial lung diseases, and infectious diseases. The eosinophilic pneumonias include Loffler’s syndrome, acute eosinophilic pneumonia, chronic eosinophilic pneumonia, and bronchoconcentric granulomatosis. Loffler’s syndrome is a benign self-limited condition characterized by cough, transient migratory pulmonary infiltrates, and blood eo~inophilia.~~ Acute eosinophilic pneumonia presents with fever of less than one months duration, diffuse alveolar or interstitial infiltrate, acute respiratory failure, and variable blood eosinophilia. High levels of BAL eosinophilia is diagnostic of this condition, and establishing an early diagnosis of eosinophilic pneumonia is important because of its excellent response to corticoster~ids.~~ Although uncommon in AIDS, this condition has been reported in association with HIV50,55 and pentamidine treatment in an HIV-infected patient.25Chronic eosinophilic pneumonia is commonly diagnosed in middle-aged women who have cough, dyspnea, fever, malaise, weight loss, and night sweats. These patients have peripheral blood and BAL eosinophilia. Chest X-ray films may demonstrate peripheral or upper lobe infiltrates such as the classic description, “photographic negative of pulmonary edema,” but can also exhibit diffuse bilateral patchy h1filtrates.3~Bronchoconcentric granulomatosis is a rare condition that has a presentation similar to chronic eosinophilic pneumonia, but has variable blood eosinophilia. Diagnosis is confirmed by the presence of culture-negative peribronchial granulomas on lung bi0psy.5~All of these conditions respond to corticosteroids. The classic allergic disease of the lung, asthma, has been referred to as “chronic eosinophilic bronchitis” because it is associated with peripheral blood, lung tissue, and BAL eosinophilia.’ Allergic bronchopulmonary aspergillosis (ABPA) is 3 hypersensitivity response to endobronchial fungal colonization by Aspergillus and has a presentation similar to asthma. In addition to eosinophilia, patients with ABPA have elevated IgE levels, positive immediate skin test result to Aspergillus, specific IgE and IgG to Aspergillus, and radiographic evidence of pulmonary infiltrate^?^ Both asthma and ABPA respond to corticosteroids. Hypersensitivity pneumonitis (extrinsic allergic alveolitis) is sometimes associated with eosinophilia in the early stages. As in allergic asthma there is a heightened reactivity to an antigen, but the inflammatory response involves the alveolar air exchange portion of the lung instead of the bronchioles.62Drug-induced pneumonitis with eosinophilia has been reported primarily as a reaction to antibiotics, but is also seen with antiinflammatory agents, gold, and cocaine.20Dyspnea, fever, and cough are the common presenting symptoms, and avoidance of the offending agent is the treatment of choice. In one study, the most common cause of BAL eosinophilia was interstitial lung diseases such as sarcoidosis, systemic lupus erythematosus (SLE), histiocytosis X, and idiopathic pulmonary fibrosis. The last was the most common diagnosis among the interstitial lung diseases

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and was often associated with peripheral blood eosinophilia.’ Another group found increased peripheral blood eosinophil percentages among HIV-infected children with lymphocytic interstitial pneumonitis (LIP), a common manifestation of pediatric AIDS.71LIP often has an insidious onset, with dyspnea, cough, and weight loss. Diagnosis is often made by chest X-ray, which typically shows diffuse or focal reticular interstitial infiltrates, but definitive diagnosis is made by histologic examination of lung tissue, showing lymphoid nodules.38 Dermatologic Diseases

In most of the dermatologic conditions associated with eosinophilic inflammation in the skin, blood eosinophilia will be present. These dermatologic disorders may be the primary disorder or may be a systemic manifestation of another eosinophil-associated condition. Although a rash is present in many of the eosinophil-associated diseases, the most common cause of rash and eosinophilia is drug hypersensitivity reactions. The rash may take the form of urticaria, eczema, morbilliform eruption, erythema multiforme, or toxic epidermal n e c r ~ l y s i s .Other ~~ inflammatory dermatoses that are associated with eosinophilia are atopic dermatitis, acute urticaria, and episodic angioedema with eosinophilia, a condition characterized by fever and acute weight gain from marked tissue swelling.53 Peripheral blood eosinophilia is also seen in graft versus host disease as well as autoimmune mediated bullous diseases including bullous pemphigoid, herpes gestationis, pemphigus, and dermatitis herpetiformis. Dermatologic parasite infection and scabies infestation are also associated with eosin~philia.~~ Two conditions that are classically associated with eosinophil involvement are eosinophilic cellulitis and eosinophilic pustular folliculitis. Eosinophilic cellulitis (Well’s disease) is a self-limited condition lasting 3 to 4 weeks. Patients initially complain of a burning or itching sensation associated with redness or local induration on an extremity. The rash consists of superficial urticaria1 papules with subcutaneous edema or infiltrative erythema with an annular pattern that spreads outwardly to involve an extremity and clears centrally before resolving. The diagnosis is made by skin biopsy and patients respond well to oral steroids.53 Eosinophilic pustular folliculitis (Ofuji’s disease) was a rare condition prior to the HIV epidemic. This condition is episodic and is characterized by sterile mildly pruritic erythematous follicular papulopustules measuring 1 to 2 mm on the face and trunk and occasionally on the palms and soles. The pustules coalesce to form a plaque or annular ring and resolve with scaling and hyperpigmentation.18,40 It was originally described in healthy adults and in a milder form in infants, but now it is commonly associated with AIDS. Some authors suggest that the AIDSassociated condition, while histologically similar, is distinct from classic Ofuji’s because of its intensely pruritic nature and lack of leuko~ytosis.~~

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Suggested underlying causes include fungal infection and mite infestation.*Several treatments have been applied with mixed results, including oral and topical steroids, antihistamines, dapsone, oral sulfones, indomethacin, itraconazole,6 permethrin? and ultraviolet B light therapy.'O Other dermatologic allergic reactions are discussed elsewhere in this issue. Gastrointestinal Disease

Tissue eosinophilia in the gastrointestinal tract is seen in many systemic conditions with prominent eosinophilia such as IHS and autoimmune diseases. Likewise, eosinophils infiltrate the gastrointestinal tract in helminthic infections and allergic gastroenteritis secondary to foods, food additives, and Eosinophilic gastroenteritis is an inflammatory disease of unknown etiology that may involve any segment of the gastrointestinal tract from the esophagus to the rectum, as well as the gallbladder, liver, spleen, and peritoneum. It is characterized by abdominal symptoms, peripheral eosinophilia, and eosinophil infiltration of tissue. Although most patients have abdominal pain and weight loss, other symptoms vary with the layer of the bowel wall involved. Mucosal involvement leads to diarrhea, blood in the stool, and hypoalbuminemia, resulting in anemia and edema. Muscle layer involvement presents with vomiting and epigastric tenderness, whereas serosal involvement is characterized by vomiting, abdominal distention, and ascites. Diagnosis is made by endoscopy and biopsy, which shows bowel edema, thickening, and eosinophilic infiltrate. Patients usually respond well to steroids.74 Other Organ Involvement

The presence of eosinophils in the cerebrospinal fluid often suggests infectious meningitis such as hist0plasmosis,4~coccidiomycosis,61angiostrongylosis,4syphilis, and tuberc~losis~~ but has also been reported with aseptic meningitis.@Some autoimmune vasculitides such as SLE and and tissue giant cell arteritis occasionally result in CSF eo~inophilia,5~ eosinophils have also been reported in chronic subdural he ma to ma^.^^ Interstitial nephritis secondary to drug hypersensitivity is the most common cause of eosinophiluria. Some vasculitides such as ChurgStrauss syndrome result in tissue eosinophilia in the kidneys.53Chronic peritoneal dialysis can result in blood and peritoneal eosinophilia.*' Cardiomyopathy is seen in several systemic eosinophilic conditions such as IHS, helminthic infections, and some vasculitides, and results in high morbidity and mortality. For this reason, close monitoring of the heart by echocardiogram is warranted in most chronic systemic eosinophilic diseases.53Dressler's syndrome (postmyocardial infarction syndrome) also has been associated with eosinophilia.81

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TREATMENT AND MANAGEMENT CONSIDERATIONS

Because allergic diseases are the most common cause of eosinophilia in North America, determination of the possible offending agent is paramount. Patients with HIV are often on multiple drugs, both prescription and nonprescription, and medication changes are made frequently. The temporal relationship to the development and resolution of eosinophilia in relation to the institution and discontinuation of the incriminated medication is the strongest clue to a drug-induced eosinophilia. Therefore, discontinuation of a medication based on the risks and benefits to the patient is often required to diagnose and treat the allergic reaction. Specific dietary or environmental allergens may need to be avoided as well. In some instances desensitization to medications is warranted. Corticosteroids are the treatment of choice for many of the eosinophilic diseases. There are theoretical contraindications to using these agents in immunocompromised patients because of the potent negative effect on lymphocyte survival and function in already lymphopenic HIV patients; however, there is some evidence to suggest that HIVinfected lymphocytes are resistant to glucocorticoid effects secondary to altered receptor interaction^.^^ There is also concern that the use of steroids may enhance the risk of developing tuberculosis or other AIDSrelated diseases such as cryptococcal meningiti~.~ However, several studies suggest a role for corticosteroids in severe PCP without increased risk of AIDS-related diseases.% Treatment of IHS is directed at decreasing the eosinophil count. Initially corticosteroids are used, but if that is ineffective, then hydroxyurea or cytotoxic drugs should be tried.12 Leukapheresis has been reported to be beneficial in some patients.27Recently IFN-a has shown efficacy in decreasing eosinophil counts and lowering the required maintenance dose of corti~osteroids.3~ It is important to exclude helminthic infection, especially Strongyloides, because systemic steroids can exacerbate this condition.34There are several effective antihelminthic medications available that treat specific infections,8Obut a discussion of these is beyond the scope of this article. CONCLUSION

Given the wide variety of disorders that may cause eosinophilia in a patient with AIDS, a comprehensive approach must be taken in their evaluation. Because most eosinophils are located in various tissues of the body, assessment usually includes tissue biopsy or fluid aspiration in addition to measurement of eosinophils in peripheral blood. Further specific diagnostic studies should be obtained only when indicated by evidence in the history and physical examination. The differential diagnosis includes both systemic and specific organ disorders, of all levels of severity, from almost all diagnostic categories.

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Worldwide, the most common cause of eosinophilia is helminthic infection, but in North America, the most common cause is drug reaction and atopy. Although eosinophilia may be the direct result of HIV infection, the goal should still be accurate diagnosis and treatment of disorders that are known to cause eosinophilia. ACKNOWLEDGMENTS The authors wish to thank Dr. Sherry Soefje for editorial support.

References 1. Actor JK, Shirai M, Kullberg MC, et al: Helminth infection results in decreased virusspecific CD8' cytotoxic T-cell and Thl cytokine responses as well as delayed virus clearance. Proc Natl Acad Sci USA 90:948, 1993 2. Allen JN, Davis WB, Pacht ER Diagnostic significance of increased bronchoalveolar lavage fluid eosinophils. Am Rev Respir Dis 142642, 1990 3. Backman KS, Zull D, Patterson R Diagnostic complexity in a patient with asthma, pulmonary infiltrates, and eosinophilia. Ann Allergy Asthma Immunol 75:391, 1995 4. Badiaga S, Levy PY, Brougui P, et al: Eosinophilic meningitis: Review of the literature and a new case originating from Reunion Island. Bulletin de la Societe de Pathologie Exotique 86277,1993 5. Bentwich 2, Weisman Z, Moroz C, et al: Immune dysregulation in Ethiopian immigrants in Israel: Relevance to helminth infections? Clin Exp Immunol 103239, 1996 6. Berger TG, Heon V, King C, et al: Itraconozole therapy for human immunodeficiency virus-associated eosinophilic folliculitis. Arch Dermatol 131:358, 1995 7. Bemstein B, Flomenberg P, Letzer D Disseminated cryptococcal disease complicating steroid therapy for Pne&ocystis carinii pneumonia in a patient with AIDS. South Mea 187557, 1994 8. Blauvelt A, Plott RT, Spooner K, et al: Eosinophil folliculitis associated with the acquired immunodeficiency syndrome responds well to permethrin. Arch Dermatol 131:360, 1995 9. Breen EC, Rezai AR, Nakajima K, et a1 Infection with HIV is associated with elevated IL-6 levels and production. J Immunol 144480, 1990 10. Buchness MR, Lim HW,Hatcher VA, et al: Eosinophilic pustular folliculitis in the acquired immunodeficiency syndrome: Treatment with ultraviolet B phototherapy. N Engl J Med 318:1183,1988 11. Butkus-Small C, Kaufman A, Armenaka M, et al: Sinusitis and atopy in human immunodeficiency virus infection. J Infect Dis 167283, 1993 12. Butterfield JH, Leiterman Kh4, Gleich GJ: Eosinophil-associated diseases. In Frank MM, Austen KF, Claman HN, et a1 (eds): Sampter's Immunologic Diseases, ed 5. Boston, Little Brown, 1995, p 501 13. Caterino-de-Araujo A The CD4+T-cell network and the cytokine profile after HIV-1 infection. Brazil J Med Biol Res 28:2, 1995 14. Caterino-de-Araujo A: HIV-1 infection and eosinophilia. Immunol Today 15:498, 1994 15. Clerici M, Hakim FT, Venzan DJ, et al: Changes in interleukin-2 and interleukin-4 production in asymptomatic human immunodeficiency virus seropositive patients. J Clin Invest 91:759, 1993 16. Clerici M, Shearer G M A TH1+TH2 switch is a critical step in the etiology of HIV infection. Immunol Today 14107,1993 17. Clerici M, WYM TA, Berzofsky JA, et al: Role of interleukin-10 in T helper cell dysfunction in asymptomatic individuals infected with the human immunodeficiency virus. J Clin Invest 93:768, 1994

226

HOFFMAN & BROIDE

18. Colton AS, Schachner L, Kowalczyk AP: Eosinophilic pustular folliculitis. J Am Acad Dermatol 14:469, 1986 19. Conway B, Baskar P, Bechtel LJ, et al: Eosinophil as host cells for HIV-1. J Arch Virol 127373, 1992 20. Cooper.JAD, Zitnik RJ, Matthay RA: Mechanisms of drug-induced pulmonary disease. Annu Rev Med 39395,1988 21. Cox FEG: The worm and the virus. Nature 347618, 1990 22. D’Offizi G, Ferrara R, Donati P, et al: Angiolymphoid hyperplasia with eosinophils in HIV infection. AIDS 92313, 1995 23. Drabick JJ, Magill AJ, Smith KJ, et al: Hypereosinophilic syndrome associated with HIV infection. South Med J 87525, 1994 24. Drew WL, Buhles W, Erlich KS: Management of herpes virus infections (CMV, HSV, VZV). In Sande MA, Volberding PA (eds): The Medical Management of AIDS, ed 4. Philadelphia, WB Saunders, 1995, p 512 25. Dupon M, Malou M, Rogues AM, et al: Acute eosinophilic pneumonia induced by inhaled pentamidine isethionate. Br Med. J 306:109, 1993 26. Estambale BBA, Knight R: Protozoan infections and HIV-1 infection: A review. East Afr Med J 69:373, 1992 27. Fauci A S The idiopathic hypereosinophilic syndrome: Clinical, pathophysiologic, and therapeutic considerations. Ann Intern Med 9778, 1982 28. Fleury-Feith J, Van Nhieu JT, Picard C, et al: Bronchoalveolar lavage eosinophilia associated with Pneumocystis carinii pneumonitis in AIDS patients: Comparative study with non-AIDS patients. Chest 95:1198, 1989 29. Frazier TC, Stafford CT: Asthma, hypereosinophilia and peripheral neuropathy in a migrant farm worker. Ann Allergy Asthma Immunol 74:17, 1995 30. Freedman AR, Gibson FM, Fleming SC, et al: Human immunodeficiency virus infection of eosinophils in human bone marrow cultures. J Exp Med 174:1661, 1991 31. Geller SA, Muller R, Greenberg ML, et al: Acquired immunodeficiency syndrome: Distinctive features of bone marrow biopsies. Arch Pathol Lab Med 109:138, 1985 32. Gleich GJ, Kita H, Adolphson C R Eosinophils. In Frank MM, Austen KF, Claman HN, et a1 (eds): Sampter’s Immunologic Diseases, ed 5. Boston, Little Brown, 1995, p 205 33. Golden J, Frim DM, Chapman PH, et a1 Marked tissue eosinophilia within organizing chronic subdural hematom membranes. Clin Neuropathol 2312, 1994 34. Goldman MH, Bochner BS, Essayan DM: Cough, shortness of breath, and eosinophilia in a 68-year-old man. Ann Allergy Asthma Immunol 77:177, 1996 35. Gonzalez Aza C, Grilo Reina A, Lopez Martin JC, et al: Changes in bone marrow among HIV-positive and HIV-negative parenteral drug addicts. Medicina Clinica 10489, 1995 36. Grieco MH: Immunoglobulins and hypersensitivity in human immunodeficiency virus (HIV) infection. J Allergy Clin Immunol 84:1, 1989 37. Harb GE, Jacobson MA. Human immunodeficiency virus (HIV) infection: Does it increase susceptibility to adverse drug reactions? Drug Safety 9:1, 1993 38. Inselman L S Pulmonary disorders in pediatric acquired immune deficiency syndromes. In Chemick V, Kendig EL (eds): Kendig’s Disorders of the Respiratory Tract in Children, ed 5. Philadelphia, WB Saunders, 1990, p 993 39. Jederlinic PJ, Sicilian L, Gaensler EA Chronic eosinophilic pneumonia: A report of 19 cases and a review of the literature. Medicine 67154, 1988 40. Jenkins D, Fisher BK, Chalvardjian A, et al: Eosinophilic pustular folliculitis in a patient with AIDS. Int J Dermatol 2734,1988 41. Jimenez SA, Varga J: The eosinophilia-myalgia syndrome and eosinophilic fasciitis. Curr Opin Rheumatol 3:986, 1991 42. Kaplan MH, Hall WW, Susin M, et a 1 Syndrome of severe skin disease, eosinophilia, and dermatopathic lymphadenopathy in patients with HTLV-I1 complicating human immunodeficiency virus infection. Am J Med 91:300,1991 43. Kawa SK, Thompson E B Lymphoid cell resistance to glucocorticoids in HIV infection. J Steroid Biochem Molec Biol 57:259, 1996 44. Kern W, Kirsten C, Forster P, et al: Specificity of routine parasite serological tests

.

EOSINOPHILIA IN AIDS

227

in autoimmune disorders, neoplastic disease, EBV-induced mononucleosis, and HIV infection. Klinische Wochenschrift 65:898, 1987 45. Khalife J, Grzych JM, Pierce R, et a1 Immunological crossreactivity between the human immunodeficiency virus type 1 virion infectivity factor and a 170-kD surface antigen of Schistosorna rnansoni. J Exp Med 172:1001, 1990 46. Lessnau KD, Can S, Talavera W: Disseminated Strongyloides stercoralis in human immunodeficiency virus-infected patients. Chest 104:119, 1993 47. Liesveld JL, Abboud C N State of the a r t Hypereosinophilic syndromes. Blood Reviews 529, 1991 48. Ligresti DJ: Rash and eosinophilia. In Lebwohl M (ed): Difficult Diagnosis in Dermatology, ed 1. New York, Churchill Livingstone, 1988, p 187 49. Livramento JA, Machado LR, Nobrega JP, et al: Histoplasmosis of the central nervous system: Study of cerebrospinal fluid in 8 patients. Arquivos de Neuro-Psiquiatria 51:80, 1993 50. Llibre JM, Tor J, Fuensanta M: Acute eosinophilic pneumonia. N Engl J Med 322634, 1990 51. Lor E, Liu YQ: Didanosine-associated eosinophilia with acute thrombocytopenia. Ann Pharmacol2723, 1993 52. Lucey DR, Dorsky DI, Nicholson-Weller A, et al: Human eosinophils express CD, protein and bind human immunodeficiency virus 1 gp120. J Exp Med 169:327, 1989 53. Mahanty S, Nutman TB: Eosinophilia and eosinophil-related disorders. In Middleton E Jr, Reed CE, Ellis EF, et al (eds): Allergy: Principles and Practice, ed 4. St. Louis, Mosby, 1993, p 1077 54. Mantos A, Podzamczer D, Martinez-Lacasa J, et al: Steroids do not enhance the risk of developing tuberculosis or other AIDS-related diseases in HIV infected patients treated for Pneumocystzs carinii pneumonia. AIDS 91037, 1995 55. Mayo J, Collazos J, Martinez E, et al: Acute eosinophilic pneumonia in a patient infected with the human immunodeficiency virus. Tubercle and Lung Disease 76:77, 1995 56. McWhinney PHM, Nathwani D: Eosinophils, HIV infection, and zidovudine. AIDS 4817, 1990 57. Murray HW, Rubin BY, Masur H, et al: Impaired production of lymphokines and immune (gamma) interferon in the acquired immunodeficiency syndrome. N Engl J Med 310:883, 1984 58. Paganelli R, Fanales-Belasio E, Scala E, et al: Serum eosinophil cationic protein (ECP) in human immunodeficiency virus (HIV) infection. J Allergy Clin Immunol88:416,1991 59. Paganelli R, Scala E, Anosetegui IJ, et a1 CD8' T lymphocytes provide helper activity for IgE synthesis in human immunodeficiency virus-infected patients with hyper IgE. J Exp Med 181:423, 1995 60. Paganelli R, Scala E, Mezzaroma I, et al: Immunologic aspects of hyperimmunoglobulinemia E-like syndrome in patients with AIDS. J Allergy Clin Immunol 95:995, 1995 61. Ragland AS, Augura E, Ismail Y, et al: Eosinophilic pleocytosis in coccidiodal meningitis: Frequency and significance. Am J Med 95254,1993 62. Reynolds HY: Hypersensitivity pneumonitis: Correlation of cellular and immunologic changes with clinical phases of disease. Lung 166:189, 1988 63. Rosenthal D, LeBoit PE, Klumpp L, et al: Human immunodeficiency virus-associated eosinophilic folliculitis: A unique dermatosis associated with advanced human immunodeficiency virus infection. Arch Dermatol 127206, 1991 64. Ross JS, Magro C, Szyfelbein W, et al: Cerebrospinal fluid pleocytosis in aseptic meningitis: Cytomorphic and immunocytochemical features. Diagn Cytopathol 7532, 1991 65. Rossol S, Voth R, Laubenstein HI', et al: Interferon production in patients infected with HIV-1. J Infect Dis 159:815, 1989 66. Roubenoff R, Cote T, Watson R, et al: Eosinophilia-myalgia syndrome due to Ltryptophan ingestion: Report of four cases and review of the Maryland experience. Arthritis Rheum 33:930, 1990 67. Samoszuk M: IgE in Reed-Stemberg cells of Hodgkin's disease with eosinophilia. Blood 791518, 1992

228

HOFFMAN & BROIDE

68. Samoszuk M, Ravel J, Ramzi E: Epstein-Barr virus and interleukin-5 mRNA in acquired immunodeficiency syndrome-related lymphomas with eosinophilia. Hum Pathol 23:1355, 1992 69. Sample S, Chemoff DN, Lenahan GA, et a1 Elevated serum concentrations of IgE antibodies to environmental antigens in HIV-seropositive male homosexuals. J Allergy Clin Immunol86:876, 1990 70. Sanchez-Borges M, Orozco A, Di Biagio E, et al: Eosinophilia in early-stage human immunodeficiency virus infection. J Allergy Clin Immunol92:494, 1993 71. Sandhaus LM, Scudder R Hematologic and bone marrow abnormalities in pediatric patients with human immunodeficiency virus (HIV) infection. Pediatr Pathol 9277, 1989 72. Saville MW, Lietzau J, Pluda JM, et al: Treatment of HIV-associated Kaposi's sarcoma with paclitaxel. Lancet 34626, 1995 73. Smith KJ, Skelton HG, Drabick JJ, et al: Hypereosinophilia secondary to immunodysregulation in patients with HIV-1 disease. Arch Dermatol 130:119, 1994 74. Steffen RM, Wyllie R, Petras RE, et a 1 The spectrum of eosinophilic gastroenteritis: Report of six pediatric cases and review of the literature. Clin Pediatr 30:404, 1991 75. Stem M, Meagher L, Savill J, et a 1 Apoptosis in human eosinophils: Programmed cell death in the eosinophil leads to phagocytosis by macrophages and is modulated by l 1992 IL-5. J I m m ~ n o1483543, 76. Thomson S, Sheridan B Erroneous automated eosinophil counts in HIV-infected individuals. Br J Biomed Sci 52165, 1995 77. van der Graaf W, Borleffs JCC: Eosinophilia in patients with HIV-1 infection. Eur J Haematol52246, 1994 78. Weber RW: Adverse drug effects and the spectrum of eosinophilic pulmonary disorders. Ann Allergy Asthma Immunol 74:451, 1995 79. Weller PF: Cytokine regulation of eosinophil function. Clin Immunol Immunopathol 62555, 1992 80. Weller PF: Eosinophilia in travelers. Travel Med 76:1413, 1992 81. Weller P F Eosinophlic syndromes. In Bennet SC, Plum F (eds): Cecil's Textbook of Medicine, ed 20. Philadelphia, WB Saunders, 1996, p 956 82. Weller PF: Eosinophils: structure and functions. Curr Opin Immunol 6235, 1994 83. Weller PF: The immunobiology of eosinophils. N Engl J Med 3241110, 1991 84. Weller P F Roles of eosinophils in allergy. Curr Opin Immunol 4782, 1992 85. Weller PF, Marshall WL, Lucey DR, et a1 Infection, apoptosis and killing of mature human eosinophils by human immunodeficiency virus-1. Am J Respir Cell Mol Biol 13610, 1995 86. Wright DN, Nelson RP, Ledford DK, et al: Serum IgE and human immunodeficiency virus (HIV) infection. J Allergy Clin Immunol 85:445, 1990 87. Zumla A, Croft S L Chemotherapy and immunity in opportunistic parasitic infections in AIDS. Parasitology 105593, 1992

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