Eosinophilia has features of an immune response: an agent such as Trichinella spiralis invokes a primary response with relatively low levels of eosinophils, whereas repeated exposures result in an augmented or secondary eosinophilic response. Several compounds released by mast cells and basophils induce IgE-mediated eosinophil production Eosinophil Production and Function Eosinophils are granulocytes (white blood cells that contain granules in their cytoplasm) derived from the same progenitor cells as monocytes-macrophages, neutrophils, and basophils. They are... read more . Such substances include eosinophil chemotactic factor of anaphylaxis, leukotriene B4, complement complex (C5-C6-C7), and histamine (over a narrow range of concentration).
Peripheral eosinophilia is characterized as
Mild: 500 to 1500/mcL (0.5 to 1.5 × 109/L)
Moderate: 1500 to 5000/mcL (1.5 to 5 × 109/L)
Severe: > 5000/mcL (> 5 × 109/L)
Mild eosinophilia itself does not cause symptoms, but levels ≥ 1500/mcL (> 1.5 × 109/L) may cause organ damage if they persist. Organ damage typically occurs because of tissue inflammation and reaction to the cytokines and chemokines released by the eosinophils as well as to immune cells that are recruited to the tissues. Although any organ may be involved, the heart, lungs, spleen, skin, and nervous system are typically affected (for manifestations, see table Abnormalities in Patients With Hypereosinophilic Syndrome ).
Occasionally, patients with very severe eosinophilia (eg, eosinophil counts of > 100,000/mcL [> 100 × 109/L]), usually with eosinophilic leukemia, develop complications when eosinophils form aggregates that occlude small blood vessels, causing tissue ischemia and microinfarctions. Manifestations typically include those of brain or lung hypoxia (eg, encephalopathy, dyspnea, respiratory failure).
Idiopathic hypereosinophilic syndrome Hypereosinophilic Syndrome Hypereosinophilic syndrome is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in the... read more is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in patients who do not have parasitic, allergic, a clonal disorder of hematopoiesis, or other causes of eosinophilia.
Etiology of Eosinophilia
Eosinophilia may be
Primary: A clonal proliferation of eosinophils associated with hematologic disorders such as leukemias Overview of Leukemia Leukemia is a malignant condition involving the excess production of immature or abnormal leukocytes, which eventually suppresses the production of normal blood cells and results in symptoms... read more and myeloproliferative neoplasms Overview of Myeloproliferative Neoplasms Myeloproliferative neoplasms are clonal proliferations of bone marrow stem cells, which can manifest as an increased number of platelets, red blood cells (RBCs), or white blood cells (WBCs)... read more
Secondary: Caused by or associated with nonhematologic disorders (see table Important Disorders and Treatments Associated With Eosinophilia Important Disorders and Treatments Associated With Eosinophilia
)Idiopathic: Cause cannot be identified
The most common cause of eosinophilia in the US is
Allergic or atopic disorders (typically respiratory or dermatologic)
Other common causes of eosinophilia include
Infections (typically parasitic)
Certain tumors (hematologic or solid, benign or malignant)
Almost any parasitic invasion of tissues can elicit eosinophilia, but protozoa (amoeba) and noninvasive metazoa usually do not.
Of hematologic tumors, Hodgkin lymphoma Hodgkin Lymphoma Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more 
may elicit marked eosinophilia, whereas eosinophilia is less common in non-Hodgkin lymphoma Non-Hodgkin Lymphomas Non-Hodgkin lymphomas are a heterogeneous group of disorders involving malignant monoclonal proliferation of lymphoid cells in lymphoreticular sites, including lymph nodes, bone marrow, the... read more 
, chronic myeloid leukemia Chronic Myeloid Leukemia (CML) Chronic myeloid leukemia (CML) occurs when a pluripotent stem cell undergoes malignant transformation and clonal myeloproliferation, leading to a striking overproduction of mature and immature... read more , and acute lymphoblastic leukemia Acute Lymphoblastic Leukemia (ALL) Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer; it also strikes adults of all ages. Malignant transformation and uncontrolled proliferation of an abnormally differentiated... read more 
.
The pulmonary infiltrates with eosinophilic syndrome comprise a spectrum of clinical manifestations characterized by peripheral eosinophilia and eosinophilic pulmonary infiltrates Overview of Eosinophilic Pulmonary Diseases Eosinophilic pulmonary diseases are a heterogeneous group of disorders characterized by the accumulation of eosinophils in alveolar spaces, the interstitium, or both. Peripheral blood eosinophilia... read more but is usually of unknown cause.
Patients with eosinophilic drug reactions may be asymptomatic or have various syndromes, including interstitial nephritis Tubulointerstitial Nephritis Tubulointerstitial nephritis is primary injury to renal tubules and interstitium resulting in decreased renal function. The acute form is most often due to allergic drug reactions or to infections... read more 
, serum sickness Symptoms and Signs , cholestatic jaundice Jaundice Jaundice is a yellowish discoloration of the skin and mucous membranes caused by hyperbilirubinemia. Jaundice becomes visible when the bilirubin level is about 2 to 3 mg/dL (34 to 51 micromol/L)... read more 
, hypersensitivity vasculitis , and immunoblastic lymphadenopathy.
Eosinophilia-myalgia syndrome is rare; the cause is unknown. However, in 1989, several hundred patients were reported to have developed this syndrome after taking L-tryptophan for sedation or psychotropic support. This syndrome was probably caused by a contaminant rather than by L-tryptophan. The symptoms, including severe muscle pain, tenosynovitis, muscle edema, and rash, lasted weeks to months, and several deaths occurred.
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare syndrome characterized by fever, rash, eosinophilia, atypical lymphocytosis, lymphadenopathy, and signs and symptoms related to end-organ involvement (typically, heart, lungs, spleen, skin, nervous system).
Eosinophilic esophagitis Eosinophilic Esophagitis Eosinophilic esophagitis is a chronic immune-mediated disease of the esophagus resulting in eosinophil-predominant inflammation of the esophagus; it can cause reflux-like symptoms, dysphagia... read more 
is an increasingly recognized condition characterized by vomiting and dysphagia. To make a diagnosis, biopsy should show at least 15 eosinophils per high power field. Treatment includes proton pump inhibitors, budesonide, food elimination trials, and sometimes esophageal dilation (1 General reference Eosinophilia is defined as a peripheral blood eosinophil count > 500/mcL (> 0.5 × 109/L). Causes and associated disorders are myriad but often represent an allergic reaction... read more 
).
General reference
1. Muir A, Falk GW: Eosinophilic esophagitis: a review. JAMA 326: 1310–1318, 2021. doi: 10.1001/jama.2021.14920
Evaluation of Eosinophilia
The number of possible causes and associated disorders is very large. Common causes (eg, allergic, infectious, or neoplastic disorders) should be considered first, but even they are often difficult to identify, so a thorough history and physical examination are always required.
History
The questions most likely to be helpful pertain to the following:
Travel (suggesting possible parasite exposure)
Allergies
Drug use
Use of herbal products and dietary supplements, including L-tryptophan
Systemic symptoms (eg, fever, weight loss, myalgias, arthralgias, rashes, lymphadenopathy)
Systemic symptoms suggest that a minor allergic or drug cause is less likely, and a detailed evaluation for an infectious, neoplastic, connective tissue, or other systemic disorder should be done. Other important parts of the history include family history of blood dyscrasias and a complete review of systems, including symptoms of allergies and pulmonary, cardiac, gastrointestinal (GI), and neurologic dysfunction.
Physical examination
General physical examination should focus on the heart, skin, and neurologic and pulmonary systems. Certain physical findings may suggest causes or associated disorders. Examples include rash (allergic, dermatologic, or vasculitic disorders), abnormal lung findings (asthma, lung infections, or syndromes of pulmonary infiltration with eosinophilia), and generalized lymphadenopathy or splenomegaly (myeloproliferative disorders or cancer).
Testing
Eosinophilia is typically recognized when a complete blood count (CBC) is done for other reasons. Additional testing often includes the following (1 Evaluation reference Eosinophilia is defined as a peripheral blood eosinophil count > 500/mcL (> 0.5 × 109/L). Causes and associated disorders are myriad but often represent an allergic reaction... read more ):
Stool ova and parasite testing
Other tests to detect organ damage or for specific causes based on clinical findings
In general, if a drug or allergic cause is not suspected based on clinical findings, 3 stool specimens should be examined for ova and parasites; however, negative findings do not rule out a parasitic cause (eg, trichinosis Trichinosis Trichinosis is infection with Trichinella spiralis or related Trichinella species. Symptoms include initial gastrointestinal irritation followed by periorbital edema, muscle pain... read more 
requires a muscle biopsy; toxocariasis Toxocariasis Toxocariasis is human infection with nematode ascarid larvae that ordinarily infect animals. Symptoms are fever, anorexia, hepatosplenomegaly, rash, pneumonitis, asthma, or visual impairment... read more 
and filarial infections Overview of Filarial Nematode Infections Threadlike adult filarial worms reside in lymphatic or subcutaneous tissues. Gravid females produce live offspring (microfilariae) that circulate in blood or migrate through tissues. When ingested... read more require other tissue biopsies; duodenal aspirates may be needed to exclude specific parasites, such as Strongyloides Strongyloidiasis Strongyloidiasis is infection with Strongyloides stercoralis. Findings include abdominal pain and diarrhea, rash, pulmonary symptoms (including cough and wheezing), and eosinophilia.... read more 
).
Other specific diagnostic tests are determined by the clinical findings (particularly travel history) and may include chest x-ray, urinalysis, liver and kidney tests, and serologic tests for parasitic and connective tissue disorders. If patients have generalized lymphadenopathy, splenomegaly, or systemic symptoms, blood tests are done. An elevated serum vitamin B12 level or abnormalities on the peripheral blood smear suggest an underlying myeloproliferative disorder, and a bone marrow aspirate and biopsy with cytogenetic studies may be helpful.
If routine evaluation does not reveal a cause, tests are done to detect organ damage. Testing can include some of the tests previously mentioned as well as lactate dehydrogenase (LDH) and liver tests (suggesting liver damage or possibly a myeloproliferative neoplasm Overview of Myeloproliferative Neoplasms Myeloproliferative neoplasms are clonal proliferations of bone marrow stem cells, which can manifest as an increased number of platelets, red blood cells (RBCs), or white blood cells (WBCs)... read more ), echocardiography, and pulmonary function tests. When hypereosinophilic syndrome is suspected, additional diagnostic evaluation Diagnosis Hypereosinophilic syndrome is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in the... read more may be needed. Once a specific cause has been determined, additional testing also may be needed.
Evaluation reference
1. Larsen RL, Savage NM: How I investigate eosinophilia. Int J Lab Hematol 41:153–161, 2019. doi: 10.1111/ijlh.12955
Treatment of Eosinophilia
Sometimes corticosteroids
Corticosteroid treatment of hypereosinophilic syndrome Immediate therapy Hypereosinophilic syndrome is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in the... read more is discussed elsewhere.
Drugs known to be associated with eosinophilia are stopped. Other identified causes are treated. Asthma mediated by eosinophils can sometimes be treated with antibodies against IL-5 (eg, mepolizumab, reslizumab) or with antibodies against the IL-5 receptor such as benralizumab (1 Treatment references Eosinophilia is defined as a peripheral blood eosinophil count > 500/mcL (> 0.5 × 109/L). Causes and associated disorders are myriad but often represent an allergic reaction... read more ). Dupilumab, an IL-4/IL-13 inhibitor, may be used to treat chronic eosinophilic pneumonia and allergic bronchopulmonary aspergillosis (2 Treatment references Eosinophilia is defined as a peripheral blood eosinophil count > 500/mcL (> 0.5 × 109/L). Causes and associated disorders are myriad but often represent an allergic reaction... read more ).
If no cause is detected, the patient is followed for complications. A brief trial with low-dose corticosteroids may lower the eosinophil count if eosinophilia is secondary (eg, to allergy, connective tissue disorder, or parasitic infection) rather than primary. Such a trial is indicated if eosinophilia is persistent and progressive in the absence of a treatable cause.
Treatment references
1. Pelaia C, Calabrese C, Vatrell A, et al: Benralizumab: from the basic mechanism of action to the potential use in the biological therapy of severe eosinophilic asthma. Biomed Res Int 2018. doi doi.org/10.1155/2018/4839230
2. Eldaabossi SAM, Awad A, Anshasi N: Meprolizumab and dupliumab as a replacement to systemic glucocorticoids for the treatment of chronic eosinophilic pneumonia and allergic bronchopulmonary aspergillus-Case series, Almoosa specialist hospital. Respir Med Case Rep 34:201520, 2021. doi: 10.1016/j.rmcr.2021.101520
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
budesonide |
PULMICORT, RHINOCORT |
mepolizumab |
NUCALA |
reslizumab |
CINQAIR |
benralizumab |
FASENRA |
dupilumab |
DUPIXENT |
