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Approach to the patient with unexplained eosinophilia

Approach to the patient with unexplained eosinophilia
Literature review current through: Jan 2024.
This topic last updated: Mar 24, 2022.

INTRODUCTION — Peripheral blood eosinophilia (≥500 eosinophils/microL) may be caused by numerous conditions, including allergic, infectious, inflammatory, and neoplastic disorders (table 1). The evaluation should seek to identify the cause of eosinophilia and assess the patient for associated organ involvement.

This topic presents our approach to evaluation of unexplained peripheral blood eosinophilia. Causes of eosinophilia and eosinophilic involvement of specific organs are presented separately. (See "Eosinophil biology and causes of eosinophilia".)

Infectious causes of peripheral eosinophilia are presented separately. (See "Infectious causes of peripheral eosinophilia".)

TERMINOLOGY — We use the following terms in this topic:

Absolute eosinophil count (AEC) – The number of eosinophils in peripheral blood, calculated as follows:

White blood cell (WBC) count/microL X percentage of eosinophils = AEC (eosinophils/microL) (calculator 1)

Some laboratories provide the AEC as a component of the complete blood count (CBC) and differential, while others require calculation of the AEC by the clinician.

Eosinophilia – AEC ≥500 eosinophils/microL in most clinical laboratories [1,2]. Eosinophilia is not defined by the percentage of eosinophils (typically <5 percent in healthy individuals), because the percentage varies with the total WBC count and the proportion of other WBC lineages (eg, neutrophils, lymphocytes).

Hypereosinophilia – ≥1500 eosinophils/microL (with or without end-organ damage).

Hypereosinophilic syndromes (HES) – AEC ≥1500/microL (on two occasions ≥1 month apart) plus organ dysfunction attributable to eosinophilia. HES comprise diverse clinical syndromes, as discussed separately. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Definitions'.)

CAUSES OF EOSINOPHILIA — Eosinophilia may be caused by numerous conditions (table 1), including allergic, infectious, inflammatory, and neoplastic disorders. Normal eosinophil biology, the pathophysiology of eosinophilia, and a detailed discussion of the causes of eosinophilia are found separately. (See "Eosinophil biology and causes of eosinophilia", section on 'Major causes of eosinophilia'.)

IMPORTANT CONCEPTS — The cause of eosinophilia is best identified by the patient's history, clinical presentation, and specific laboratory testing, and it is important to be aware of the following concepts.

Importance of AEC — Keep in mind the following concepts regarding the absolute eosinophil count (AEC):

AEC does not accurately predict organ damage – Organ involvement cannot be accurately predicted by the AEC alone because eosinophils are primarily tissue-dwelling cells. Although complications of eosinophilia are more common in patients with higher AEC (eg, >1500/microL), some patients with persistent hypereosinophilia do not develop organ damage and, conversely, a patient with mild eosinophilia may have significant organ involvement. Organ damage must be evaluated by clinical evaluation and laboratory testing. (See 'Initial evaluation' below.)

AEC does not identify the cause – The degree of eosinophilia may help to narrow the differential diagnosis, but the AEC is not sufficient to establish the diagnosis. As an example, marked eosinophilia (eg, ≥20,000/microL) can be seen in drug hypersensitivity reactions or myeloid neoplasms, but is unlikely to be associated with asthma, allergic rhinitis, or atopic dermatitis.

Importantly, all patients with an AEC >1500/microL should be evaluated for hypereosinophilic syndrome, as described separately. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Evaluation and diagnosis'.)

Diagnostic vigilance

Consider diverse causes – It is important to consider many possible causes for eosinophilia. Even in apparently straightforward cases (eg, a child who has long-standing mild eosinophilia and atopy, a traveler returning from a parasite-endemic area with new eosinophilia and gastrointestinal complaints), there may be other, less apparent causes of eosinophilia.

Remain vigilant – It is especially important to consider other diagnoses when eosinophilia does not respond as expected to an intervention (eg, treatment of an infection, withdrawal of a presumed offending agent). Furthermore, a high degree of suspicion and thoughtful evaluation may be required to identify certain syndromes, such as primary immunodeficiencies, autoimmune illnesses, and eosinophilic granulomatosis with polyangiitis (EGPA; formerly called Churg-Strauss syndrome).

URGENCY OF EVALUATION — The urgency of evaluation is informed by the clinical status of the patient and the level of eosinophilia.

Eosinophilia may be encountered in the course of evaluating other clinical conditions or as an incidental finding on a complete blood count (CBC) and differential. We use both the patient's clinical status and the level of absolute eosinophil count (AEC) to guide the urgency of evaluation. In the sections that follow, we offer examples of clinical presentations that inform the pace of evaluation. However, these examples should serve as illustrations rather than strict guidelines, and they should not override the clinician's judgment regarding urgency of evaluation.

Acutely ill or extremely high AEC — Hospitalization is generally warranted for patients who are acutely ill or who have an extremely high or rapidly rising AEC. Hospitalization permits management of medical emergencies while the cause of eosinophilia is being investigated. Importantly, management of medical emergencies should not be delayed by the diagnostic evaluation. Since therapy (eg, high dose glucocorticoids) can affect the results of diagnostic testing, every effort should be made to obtain appropriate studies before initiating emergency treatment. (See "Hypereosinophilic syndromes: Treatment", section on 'Studies to obtain urgently'.)

Emergency treatment may be needed for hemodynamic instability, severe respiratory compromise, delirium, coma, mononeuritis multiplex, or other life-threatening or disabling conditions that may reflect irreversible eosinophil-associated tissue damage to the heart, lungs, nervous system, or other organs. A decision to treat on an emergency basis should be based on the severity of illness and the likelihood of eosinophilia as the cause, rather than the level of AEC alone. Emergency management of the acutely ill patient with eosinophilia, including treatment with high dose steroids, leukapheresis, and/or cytoreduction is discussed separately. (See "Hypereosinophilic syndromes: Treatment", section on 'Immediate treatment for severe disease' and "Hyperleukocytosis and leukostasis in hematologic malignancies", section on 'Management of hyperleukocytosis'.)

An extremely high AEC alone (eg, ≥50,000/microL), significant cytopenias (eg, neutropenia, anemia, thrombocytopenia), or leukemic blasts on the blood smear should be evaluated urgently even if the patient is clinically stable, as it may reflect a potentially life-threatening disorder (eg, hematologic malignancy) or impending medical emergency. The decision to hospitalize should be made on a case-by-case basis. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Evaluation and diagnosis' and 'Suspected hematologic disorder' below.)

Symptomatic, but clinically stable — For the patient who is symptomatic but clinically stable, the urgency of evaluation depends on the clinical presentation, level of eosinophilia, and concern on the part of the clinician and/or patient.

In general, the AEC alone should not determine the urgency of evaluation in a clinically stable patient. However, patients with ≥5000 eosinophils/microL or rapidly rising AEC should be evaluated promptly. All patients with AEC ≥1500/microL should be evaluated for hypereosinophilic syndromes (HES). (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Evaluation and diagnosis'.)

For other symptomatic but clinically stable patients, the urgency of evaluation is informed by findings that may reflect organ involvement and/or the cause of eosinophilia, and by concerns on the part of the clinician and patient. As examples, patients with chest pain, elevated cardiac troponin, or an unexplained abnormal chest X-ray should be evaluated promptly, regardless of the AEC. Conversely, it may be reasonable to conduct the evaluation over a period of weeks or longer for a patient with an AEC of 1400/microL and eczema, previously diagnosed asthma, or a recently treated helminth infection.

Asymptomatic or incidental eosinophilia — All patients with AEC ≥1500/microL should have a CBC repeated in one to two weeks to determine if the eosinophilia is transient, stable, or rising; the CBC should be repeated even when eosinophilia is detected incidentally in an asymptomatic patient. Persistent AEC >1500/microL or a rising AEC should be evaluated promptly for HES, even though it is uncommon for such patients to be completely asymptomatic. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Evaluation and diagnosis'.)

For asymptomatic patients with eosinophilia <1500/microL, it may be reasonable to postpone a repeat CBC and evaluation for a month or longer. However, it is important to first ensure that there are no clinical findings suggestive of eosinophilic end-organ damage, no history of travel or residence in helminth-endemic areas, and no features suggestive of a malignancy (eg, significant anemia or thrombocytopenia, splenomegaly, lymphadenopathy) before deferring the evaluation.

Evaluation of the patient with incidental eosinophilia (ie, elevated AEC that was detected by routine testing, without associated symptoms) is described below. (See 'Incidental eosinophilia' below.)

INITIAL EVALUATION — The initial evaluation should assess the patient for clinical findings that may be attributable to eosinophilia, and seek to determine the underlying cause.

History — The history should elicit symptoms that may reflect organ involvement by eosinophils, including a complete review of systems, because of the protean manifestations of organ involvement by eosinophils. The history should seek to identify conditions that may cause eosinophilia, including asthma, atopy, rheumatologic conditions, infections, malignancy, potential exposures (eg, medications, diet, infections), and family history. It is important to determine if there has been a recent change in symptoms that might represent disease progression or a new diagnosis.

Patients should be questioned about the following symptoms:

Constitutional: Fever, night sweats, unintentional weight loss, fatigue (see 'Constitutional symptoms' below)

Cutaneous: Eczema, pruritus, urticaria, angioedema, rash, ulcers (see "Eosinophil biology and causes of eosinophilia", section on 'Dermatologic')

Cardiac: Dyspnea, chest pain, palpitations, symptoms of heart failure (see "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Cardiac disease')

Respiratory: Nasal/sinus symptoms, wheezing, cough, chest congestion (see "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)" and "Overview of pulmonary eosinophilia")

Gastrointestinal: Weight loss, abdominal pain, dysphagia, nausea, vomiting, diarrhea, food intolerance, changes in stools (see 'Gastrointestinal' below and 'Infectious causes' below and "Eosinophilic gastrointestinal diseases", section on 'Evaluation')

Nervous system: Transient ischemic attack, cerebrovascular accident, behavioral changes, confusion, balance problems, memory loss, change in vision, numbness, weakness, pain (see "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Neurologic disease' and "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Neurologic')

Other: Including symptoms attributable to lymphadenopathy or hepatosplenomegaly (ie, new abdominal or chest discomfort, early satiety), ocular findings, genitourinary complaints, myalgia, arthralgia, and anaphylaxis (see 'Other' below)

Disorders associated with these symptoms and evaluation to identify the cause of eosinophilia are described below and separately. (See 'Symptomatic patients' below and "Eosinophil biology and causes of eosinophilia", section on 'Major causes of eosinophilia'.)

Important aspects of the history also include:

Medications – Current and past medications should be reviewed in detail, since eosinophilia can be caused by almost any prescription or nonprescription drug, herbal remedy, or dietary supplement (table 2). Evaluation of medications as a potential cause of eosinophilia is discussed below. (See 'Suspect medication' below.)

Diet – Dietary history should explore ingestion of raw or undercooked fish or shellfish, meat, and vegetables as potential sources of parasitic infection (eg, Trichinella, Toxocara, Paragonimus), as discussed in more detail separately. Food allergies and self-imposed dietary restrictions should also be explored. (See "Eosinophil biology and causes of eosinophilia", section on 'Parasites and other infections' and "Clinical manifestations of food allergy: An overview", section on 'Gastrointestinal manifestations'.)

Other exposures – May include infectious exposures (see 'Infectious causes' below), including:

Occupation (eg, Strongyloides infection in miners, ascariasis in slaughterhouse workers)

Recreational activities (eg, schistosomiasis in river rafters in endemic areas)

Travel or residence in countries that may be associated with infectious exposures

Family history may be informative in rare cases of familial hematologic syndromes (see 'Children' below)

Physical examination — A thorough physical examination should seek evidence of organ involvement and/or possible causes of eosinophilia. The examination should include a complete skin examination and evaluation for lymphadenopathy and hepatosplenomegaly. Relevant physical findings include, rash, nasal/sinus findings, signs of cardiac and/or respiratory abnormalities, lymphadenopathy, hepatomegaly/splenomegaly, or neurologic findings. Consideration of these findings as manifestations of organ involvement and/or as clues to the cause of eosinophilia are discussed below. (See 'Clinical scenarios' below.)

Laboratory and diagnostic tests

Routine laboratory tests — A repeat complete blood count (CBC) with differential count to confirm the presence of eosinophilia, and a chemistry panel that includes electrolytes and liver function tests should be performed in all patients. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Evaluation and diagnosis'.)

Review of prior CBCs (both normal and abnormal) can provide valuable information about the duration and trajectory of eosinophilia, but it should be recognized that eosinophilia can transiently decrease with steroid treatment or intercurrent bacterial or viral infections. Eosinophilia may be the sole abnormality on the CBC, or it may be accompanied by other abnormalities. As examples, concurrent neutrophilia may suggest an infection or inflammatory condition, basophilia may reflect a myeloid malignancy or allergic disorder, and lymphocytosis may be associated with a lymphoid malignancy.

Blood smear — The peripheral blood smear should be reviewed by the clinician or the laboratory to assess eosinophil morphology and detect other hematologic abnormalities. Certain findings on the blood smear increase the likelihood of an underlying hematologic or malignant disorder, but aberrant morphology is not sufficient to diagnose a hematologic disorder or to exclude other causes. As an example, immature eosinophils (eg, blasts, other immature forms, mononuclear eosinophils) or dysplastic eosinophils may be seen with certain hematologic malignancies (table 3), but may also be seen in other conditions, including helminth infection and drug hypersensitivity reactions.

Evaluation and diagnosis of hematologic causes of eosinophilia are described separately. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Evaluation and diagnosis'.)

Tests for selected patients — Further testing should be individualized and informed by the clinical presentation and findings from the CBC and chemistry tests above. All patients with an absolute eosinophil count (AEC) >1500/microL should undergo evaluation for hypereosinophilic syndromes (HES). (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Evaluation and diagnosis'.)

The choice of further initial testing in patients with AEC <1500 is nuanced, and there is no menu of additional tests that should be performed in all patients. Following are tests that we obtain for selected patients in the initial evaluation of eosinophilia:

Cardiac troponin – We suggest testing serum cardiac troponin in patients with AEC ≥1500/microL, cardiac symptoms, or suggestive abnormalities on physical examination (eg, dyspnea, fatigue, palpitations, heart murmur, cardiac dysrhythmia).

Patients with elevated cardiac troponin should have electrocardiography and echocardiography to assess potential cardiac involvement. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Cardiac disease'.)

Vitamin B12 and tryptase – We suggest measuring serum vitamin B12 and tryptase in patients with AEC ≥1500/microL, abnormal blood smear, anemia or thrombocytopenia, splenomegaly, or symptoms consistent with systemic mastocytosis (eg, urticaria, anaphylaxis, flushing, or abdominal symptoms), as these findings may suggest an underlying hematologic/malignant or immunologic disorder, as described below. (See 'Suspected hematologic disorder' below.)

Imaging – We suggest obtaining a chest radiograph for patients with respiratory symptoms (eg, dyspnea, cough, wheezing, rhinosinusitis). For patients with an unexplained infiltrate or AEC ≥1500/microL, we suggest high resolution computed tomography (CT) and pulmonary function tests. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Pulmonary disease'.)

We also obtain high resolution CT for patients with possible eosinophilic granulomatosis with polyangiitis (EGPA; formerly called Churg-Strauss disease). Clinical findings suggestive of EGPA include asthma, upper airway/ear disease, rash or subcutaneous nodules, cardiomyopathy, pericarditis, mononeuritis multiplex, or unexplained renal disease, as described in detail separately. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)

Infectious evaluation – Infectious causes should be considered for most patients with eosinophilia, and they may be overlooked in the history unless specifically queried. The likelihood of an infectious cause is greater in patients whose travel or residence suggests possible exposure to parasites or other infections, and the evaluation should be informed by clinical findings and possible exposure to parasites and other infections. (See 'Symptomatic patients' below and 'Infectious causes' below.)

CLINICAL SCENARIOS — Although many eosinophilic disorders are protean in their manifestations, the clinical presentation may inform the evaluation of unexplained eosinophilia (table 1). The following scenarios are meant to provide some guidance for clinical evaluation of patients with eosinophilia, but it is important to maintain a broad differential diagnosis and remain vigilant for additional or evolving signs and symptoms, even when the cause may seem apparent from the initial evaluation.

Suspected hematologic disorder — It is important to have a low threshold for considering a hematologic disorder as the cause of eosinophilia because clinical presentations are protean and no specific clinical findings conclusively include nor exclude all cases.

A hematologic cause should be considered if findings from the initial evaluation do not persuasively point toward a clear secondary cause of eosinophilia or to a characteristic clinical syndrome (eg, eosinophilic esophagitis, episodic angioedema with eosinophilia, eosinophilic granulomatosis with polyangiitis). Findings that should prompt testing for a hematologic disorder include:

Absolute eosinophil count (AEC) ≥1500/microL

Dysplastic eosinophils or leukemic blasts

Unexplained anemia, neutropenia, polycythemia, or thrombocytopenia

Elevated serum B12 or tryptase levels

Lymphocytosis (≥4000/microL)

Unexplained lymphadenopathy, splenomegaly, or constitutional symptoms

Resistance of eosinophilia to glucocorticoid therapy

Evaluation of a suspected hematologic cause of eosinophilia is described separately. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Hematologic evaluation'.)

Symptomatic patients — Clinical findings from the initial evaluation may inform the further evaluation of eosinophilia. Skin, lung, heart, gastrointestinal tract, and nervous system are the most commonly affected organ systems, but almost any tissue can be infiltrated by eosinophils. The following examples of findings may suggest potential causes of eosinophilia, but the prominence of a particular symptom is not sufficient to establish the diagnosis, and the absence of a finding cannot exclude certain etiologies.

Constitutional symptoms — Symptoms of fever, sweats, unexplained weight loss, and profound fatigue are nonspecific and may be associated with numerous causes of eosinophilia. In many cases, clinical findings from other aspects of the history, physical examination, or screening laboratory studies will provide clues regarding the nature of an underlying disorder.

Possible causes of eosinophilia in association with constitutional symptoms include:

Infectious, especially in the setting of appropriate travel or residency, or if associated with gastrointestinal, respiratory, cutaneous, or other symptoms. (See 'Infectious causes' below.)

Medications, especially if associated with appropriate exposure and/or other manifestations (table 2). (See 'Suspect medication' below.)

Neoplastic disorders (eg, hypereosinophilic syndromes, lymphoma, solid tumors) should be considered in patients with lymphadenopathy, hepatomegaly, splenomegaly; anemia, thrombocytopenia, thrombocytosis; abnormal blood smear (eg, aberrant eosinophils, leukemic blasts or other immature forms), elevated serum vitamin B12 and/or tryptase levels, chromosomal abnormalities, or other findings. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'HES variants'.)

Eosinophilic granulomatosis with polyangiitis (EGPA, formerly called Churg-Strauss) should be considered, especially if associated with asthma, sinusitis, dyspnea, and/or mononeuritis multiplex. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)

Episodic angioedema with eosinophilia (EAE; also called Gleich syndrome), especially if associated with angioedema, weight gain, and malaise occurring at monthly intervals. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Episodic angioedema with eosinophilia (Gleich syndrome)'.)

Autoimmune syndromes or immune dysfunction associated with eosinophilia.

Gastrointestinal — Eosinophilia associated with diarrhea, abdominal pain, anorexia, or other gastrointestinal symptoms may be due to infectious, autoimmune, or other causes.

The evaluation must consider clinical findings, history of travel/residency, and potential infectious exposures. As an example, a history of travel or residency in countries that may be associated with infectious exposures should include evaluation for infectious causes. Conversely, a patient residing in the United States with no such exposures is more likely to have eosinophilic gastrointestinal disease; gastritis, enteritis, and/or colitis associated with hypereosinophilic syndromes (HES); EGPA; or inflammatory bowel disease. Evaluation of infectious and non-infectious gastrointestinal causes of eosinophilia are described separately. (See "Eosinophil biology and causes of eosinophilia", section on 'Parasites and other infections' and "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Evaluation and diagnosis' and "Eosinophilic gastrointestinal diseases", section on 'Diagnosis'.)

Referral to a gastroenterologist and/or clinician with expertise in eosinophil disorders should be considered if testing does not suggest an infectious cause for gastrointestinal complaints. (See 'Follow-up and referral' below and "Evaluation of fever in the returning traveler", section on 'Presence of eosinophilia'.)

Respiratory — Eosinophilia with cough, dyspnea, wheezing, chronic nasal complaints, abnormal chest X-ray or computed tomography (CT), and/or pulmonary emboli may be associated with diverse causes, including asthma/allergies, medications, autoimmune illnesses, infections, EGPA, and idiopathic conditions. Evaluation of pulmonary eosinophilia and/or other respiratory tract findings is described separately. (See "Overview of pulmonary eosinophilia", section on 'Diagnostic approach' and "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)

Cutaneous — Cutaneous manifestations (eg, rash, pruritus, dermographism, erythroderma, thickening) can be seen in association with almost any cause of eosinophilia (table 1). Examples include atopy, medications, parasitic infections, autoimmune/inflammatory conditions, HES and other hematologic causes, primary immunodeficiencies, and cholesterol embolization. We have a low threshold for skin biopsy to evaluate cutaneous lesions. Evaluation, including skin biopsy and/or referral to dermatology, is described separately. (See "Eosinophil biology and causes of eosinophilia", section on 'Dermatologic'.)

Evaluation for recurrent infections may be considered in adults with persistent unexplained dermatologic findings, and toxocariasis may be considered in the differential diagnosis for children who may have ingested soil or food contaminated by dog or cat feces. (See "Approach to the adult with recurrent infections" and "Toxocariasis: Visceral and ocular larva migrans".)

Other — Evaluation of eosinophilia in association with lymphadenopathy, organomegaly, renal, cardiac, neurologic, ocular, or other findings is guided by the nature of the symptoms and other findings. Consideration should be given to eosinophilic disorders that are notoriously protean in their clinical manifestations, including HES and EGPA. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)

Evaluation, diagnosis, and management may be aided by referral to an appropriate specialist or a clinician with experience in eosinophilic disorders. (See "Eosinophil biology and causes of eosinophilia", section on 'Disorders with eosinophilic involvement of specific organs' and 'Follow-up and referral' below.)

Suspect medication — Eosinophilia can be caused by almost any prescription or nonprescription drug, herbal remedy, or dietary supplement. Certain medications are more likely to be associated with involvement of specific organs (table 2).

Drug-induced eosinophilia may be isolated (ie, no other clinical findings are present) or it may be accompanied by systemic illness. DRESS (drug reaction with eosinophilia and systemic symptoms) is a rare, potentially life-threatening, drug-induced hypersensitivity reaction that includes eosinophilia (with or without atypical lymphocytosis) and organ involvement that may be manifest as clinical findings in skin, liver, heart, lung, kidney, or other organs. DRESS should be suspected in a patient with eosinophilia who received a new drug treatment in the previous two to six weeks and presents with fever, rash, facial edema, lymphadenopathy, abnormalities of liver function tests, and/or evidence of organ involvement. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

Defining a medication as the cause of eosinophilia requires clinical judgment, because no laboratory test alone can confirm the role of a specific medicine. The temporal relationship between drug administration and eosinophilia is helpful, but the time course of eosinophilia does not always follow a consistent pattern. Furthermore, eosinophilia may not resolve for weeks to months after discontinuing the offending agent.

Our approach to management of medications is informed by the patient's clinical status:

Symptomatic or ill – For the symptomatic or ill patient, essential medications can generally be continued, unless they are directly implicated based on timing, the clinical picture, and/or the nature of the offending agent (table 2). Management includes discontinuation of all nonessential medications and symptom-directed therapy, with or without systemic corticosteroids. Further details of management are discussed separately. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

Follow-up of the ambulatory patient is informed by the response of symptoms, AEC, and other laboratory studies to changes in medications, and is influenced by concerns on the part of the clinician and patient. (See 'Follow-up and referral' below.)

Asymptomatic – For patients with eosinophilia and no evidence of organ involvement, we suggest discontinuing nonessential medications and re-evaluation, including repeat CBC in one to two months. (See 'Follow-up and referral' below.)

Additional details of the evaluation of medications as the cause of eosinophilia are provided separately. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)", section on 'Diagnostic approach'.)

If eosinophilia does not improve or resolve with medication withdrawal, other underlying causes should be considered and referral to a specialist may be beneficial. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Referral'.)

Infectious causes — Infectious causes should be a consideration in nearly all patients with eosinophilia and may be overlooked in the history unless it is specifically queried. Infectious causes of peripheral eosinophilia are discussed in detail separately. (See "Infectious causes of peripheral eosinophilia".)

Immune disorders — Eosinophilia may be encountered in patients with certain immunodeficiencies (eg, hyper-IgE syndrome, Omenn syndrome, autoimmune lymphoproliferative syndrome [ALPS]) and autoimmune disorders (eg, sarcoidosis, rheumatoid arthritis, inflammatory bowel disease, IgG4 disease) (table 1). Diagnostic testing is informed by the clinical presentation and results from the initial evaluation. (See "Eosinophil biology and causes of eosinophilia", section on 'Major causes of eosinophilia' and 'Initial evaluation' above.)

Scenarios for eosinophilia associated with autoimmune syndromes or related findings (eg, hemolytic anemia, Hashimoto thyroiditis, inflammatory arthritis) include:

In patients with vasculitis, rhinosinusitis, and/or asthma we suggest anti-neutrophil cytoplasmic antibody (ANCA; although it is positive in fewer than half of patients) and other evaluation for EGPA. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)

Patients with suspected vasculitis, including EGPA, should have a high resolution chest CT and other studies appropriate to their symptoms, and consideration of biopsy of involved tissue, if possible. (See "Overview of and approach to the vasculitides in adults" and "Vasculitis in children: Evaluation overview".)

Individuals with signs of adrenal dysfunction (eg, malaise, weakness, weight loss, orthostatic hypotension, skin hyperpigmentation) and those at risk for adrenal hemorrhage or necrosis should have cortisol testing, as described separately. (See "Clinical manifestations of adrenal insufficiency in adults" and "Determining the etiology of adrenal insufficiency in adults".)

Children — Causes of eosinophilia in children are comparable to those in adults, and a similar approach to evaluation is appropriate. A retrospective study of 291 subjects with hypereosinophilia, which included 37 children, reported that clinical and laboratory characteristics at presentation were similar between children and adults, but median peak AEC was nearly twice as high in children [3].

Notable aspects of eosinophilia in children include:

Asthma and atopic disease are the most common causes of mild to moderate eosinophilia in children; however, close attention should be paid to the frequency and type of infections, since immunodeficiency syndromes typically present in childhood and can be associated with atopic disease and peripheral blood and tissue eosinophilia. (See "Primary humoral immunodeficiencies: An overview" and "Combined immunodeficiencies: An overview" and "Approach to the child with recurrent infections".)

Food allergy and eosinophilic esophagitis are also more common causes of eosinophilia in the pediatric age group and can be missed if an appropriate history is not elicited; the only clue to the diagnosis of eosinophilic esophagitis in a child may be occasional vomiting. (See "Clinical manifestations of food allergy: An overview" and "History and physical examination in the patient with possible food allergy" and "Clinical manifestations and diagnosis of eosinophilic esophagitis (EoE)".)

Some infections are more or less prevalent in children. As examples, visceral larva migrans (eg, Toxocara species), which is acquired by ingestion of eggs from soil contaminated with animal feces, is seen almost exclusively in young children, whereas filariasis, which requires repeated exposure to the bites of infected insect vectors, increases with age and is rare in children <4 years old. (See "Toxocariasis: Visceral and ocular larva migrans".)

Although certain hematologic malignancies (eg, acute lymphoblastic leukemia/lymphoblastic lymphoma) are more common in children than in adults, the frequency of other causes of eosinophilia (eg, myeloid neoplasms, EGPA, EAE, autoimmune disorders) is much lower but not well defined in children versus adults [3].

Some primary immunodeficiency syndromes are associated with eosinophilia, and may be more common in children than in adults [3]. Examples include hyperimmunoglobulin E syndrome (most often found in children with recurrent pneumonias or abscesses); or autoimmune lymphoproliferative syndrome (ALPS), Omenn syndrome, IPEX, or ZAP-70 deficiency, which are usually seen in infants or young children. Inherited and acquired causes of immunodeficiencies that may be associated with eosinophilia are discussed separately. (See "Eosinophil biology and causes of eosinophilia", section on 'Other rare causes'.)

Rare familial causes of eosinophilia (eg, eosinophilic esophagitis, autosomal dominant familial hypereosinophilia) may be encountered in children or adults [4]. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Familial HES'.)

Incidental eosinophilia — An incidental finding of eosinophilia on CBC and differential is a common clinical scenario. The urgency of evaluation is guided by evidence of organ damage and level of eosinophilia, but even for an asymptomatic patient, incidental detection of eosinophilia ≥5000/microL should be evaluated promptly. (See 'Urgency of evaluation' above.)

Our approach to the evaluation of incidental eosinophilia is informed by the AEC, evidence of organ involvement, and the level of concern on the part of practitioner and patient:

For AEC ≥1500/microL we suggest evaluation for hypereosinophilic syndromes, as described separately. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Evaluation and diagnosis'.)

For eosinophilia ≥500 to <1500/microL with no evidence of organ involvement, subsequent evaluation should be guided by findings of the initial evaluation. Common causes of asymptomatic mild eosinophilia include atopy/asthma, allergy, medications, and infection. There is no consensus regarding the optimal schedule and nature of follow-up for asymptomatic patients with no evidence of organ damage from the initial evaluation. Follow-up of incidental eosinophilia is described below. (See 'Follow-up and referral' below.)

FOLLOW-UP AND REFERRAL — There is no consensus regarding the optimal follow-up of eosinophilia.

Our approach is:

Known cause of eosinophilia – For patients in whom a cause of eosinophilia was identified, follow-up is guided by management of the underlying disease.

Unexplained persistent eosinophilia – For patients with persistent unexplained eosinophilia:

For evidence of organ involvement, we suggest referral to an appropriate specialist (eg, pulmonary, cardiology, gastroenterology, dermatology, infectious diseases) for follow-up that is guided by the degree of organ dysfunction. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Referral'.)

For a progressive rise in absolute eosinophil count (AEC), we suggest re-evaluation for an underlying cause, and consideration of referral to a specialist with expertise in diagnosis and management hypereosinophilia. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Referral'.)

For patients with no evidence of organ damage:

-AEC ≥1500/microL: There is no agreed-upon schedule, and follow-up will vary based on the level of AEC and concern on the part of the clinician and/or patient. As examples, a patient with unexplained AEC 10,000/microL might be evaluated monthly for at least a year, whereas a patient with AEC 1600/microL might be seen every six months

-AEC ≥500 to <1500/microL: Follow-up in six months to one year

-Eosinophilia resolved: No further follow-up is needed

Spontaneous resolution of eosinophilia without treatment may be due to removal of an offending agent (ie, transient exposure), clearance of an infection, and/or downregulation of host responses (eg, with chronic helminth infection). Resolution of eosinophilia after a transient exposure is unpredictable, although in the case of drug hypersensitivity and removal of the offending agent, resolution can take many months.

SUMMARY

Definitions – Eosinophilia (≥500 eosinophils/microL) and hypereosinophilia (≥1500 eosinophils/microL) may be encountered in the course of evaluating other clinical conditions or as an incidental finding on a complete blood count (CBC) and differential (calculator 1). (See 'Terminology' above.)

Causes – Eosinophilia may be caused by numerous conditions (table 1), including allergic diseases, medication reactions (table 2), infectious (table 4), inflammatory, and neoplastic disorders (table 3). Causes and evaluation of eosinophilia in children are similar to those of adults, but some disorders are more common in children (eg, asthma, atopy, allergies, certain leukemias) (see 'Children' above). Eosinophil biology and pathophysiology, and the causes of eosinophilia are discussed separately. (See "Eosinophil biology and causes of eosinophilia", section on 'Major causes of eosinophilia'.)

Absolute eosinophil count (AEC) does not predict organ involvement – The AEC alone does not accurately predict the likelihood of organ involvement nor define the underlying cause of eosinophilia. It is important to consider many possible causes in the evaluation of a patient with eosinophilia. (See 'Important concepts' above.)

Determining the urgency of evaluation – The patient's presentation, AEC, and evidence of organ involvement inform the urgency and nature of the evaluation (see 'Urgency of evaluation' above):

Acutely ill or extremely high AEC – We suggest hospitalization and urgent evaluation for patients with hemodynamic instability, severe respiratory compromise, delirium, coma, other life-threatening conditions, extreme elevations of AEC, or worrisome findings on blood smear (eg, leukemic blasts). (See 'Acutely ill or extremely high AEC' above.)

Management of medical emergencies should not be delayed by the diagnostic evaluation of eosinophilia. Patients with an acute illness due to leukostasis or organ dysfunction from eosinophil infiltration may require urgent treatment with high dose steroids, leukapheresis, and/or cytoreduction as described separately. (See "Hypereosinophilic syndromes: Treatment", section on 'Immediate treatment for severe disease'.)

Symptomatic, clinically stable – For symptomatic but clinically stable patients, the urgency of evaluation is informed by the presence of symptoms or other findings that may reflect organ involvement, and by the AEC and concerns on the part of the clinician and patient. (See 'Symptomatic, but clinically stable' above.)

Asymptomatic or incidental eosinophilia – Evaluation of asymptomatic patients with no clinical findings suggestive of organ damage or concerning travel/residency history is informed by the AEC and concerns of the clinician and patient. (See 'Asymptomatic or incidental eosinophilia' above.)

Initial evaluation – Initial evaluation for all patients should include history with a complete review of systems to elicit the wide range of symptoms that may reflect organ involvement or an underlying cause of eosinophilia and possible exposures including medications, diet, and travel/residence; physical examination; CBC and differential; review of the blood smear; and other laboratory studies. (See 'Initial evaluation' above.)

Specific clinical scenarios – Signs and symptoms, in combination with the results from the initial evaluation should direct further evaluation. (See 'Tests for selected patients' above and 'Clinical scenarios' above.)

Monitoring over time – The nature and timing of follow-up evaluation is guided by the underlying cause, level of eosinophilia, clinical setting, organ involvement, and concerns of the patient and practitioner, as described above. (See 'Follow-up and referral' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges extensive contributions of Donald H Mahoney, Jr, MD to earlier versions of this topic review.

Topic 5691 Version 28.0

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