Increased levels of eosinophilic leukocytes in the blood can be idiopathic, or may result from a variety of conditions, including connective tissue diseases, helminthic infections, neoplasias, and allergic disorders. In this article, the term eosinophilia is defined as an increase in peripheral blood eosinophils to more than 600 cells per microliter (μL) of blood. Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1500/μL.[1]
Although emphasis is placed on the number of eosinophils circulating in the peripheral blood, an increase in eosinophils can be observed in other body fluids (eg, cerebrospinal fluid [CSF], urine) and many body tissues (eg, skin, lung, heart, liver, intestine, bladder, bone marrow, muscle, nerve). See the images below.
Eosinophils are derived from hematopoietic stem cells initially committed to the myeloid line and then to the basophil-eosinophil granulocyte lineage. Nonpathologic functions of eosinophils and the cationic enzymes of their granules include mediating parasite defense reactions, allergic response, tissue inflammation, and immune modulation.[2, 3]
Tissues of the pulmonary and gastrointestinal systems are the normal residence for eosinophils, but peripheral, or blood, eosinophilia (absolute eosinophil count [AEC] >600 cells/µL) indicates an eosinophilic disorder.[4] Untreated, the eosinophilia can be categorized as mild (AEC 600-1500 cells/µL), moderate (AEC 1500-5000 cells/µL) or severe (AEC >5000 cells/µL). An increase in tissue eosinophilia may be seen with or without concurrent peripheral eosinophilia.
A secondary or reactive increase in blood eosinophils, tissue eosinophils, or both is associated with a wide variety of conditions, as follows[5, 6] :
Primary eosinophilia is not a reactive phenomenon and can be described as either clonal or idiopathic in nature. If an underlying molecular or cytogenetic abnormality can be identified, the eosinophilia can be designated as a clonal disorder. If reactive causes are ruled out and no underlying clonal origin is proven, the eosinophilia is described as idiopathic.[7]
Given the broad spectrum of conditions linked to eosinophilia, this article emphasizes the diagnostic considerations that clinicians may want to focus on in patients with eosinophilia. The individual disease manifestations and therapies for the dozens of diseases associated with eosinophilia are not described in detail; other Medscape articles specifically address these conditions, such as the following:
Over the past 2 decades, substantial progress has been made in understanding the mechanisms of eosinophil production, eosinophil programmed cell death (apoptosis), and how eosinophil immunology contributes to both host defenses against infections and to tissue damage within the host in cases of allergic and autoimmune diseases.
The primary stimuli for eosinophil production are interleukin (IL)-5, IL-3, and the granulocyte-macrophage colony-stimulating factor (GM-CSF). These cytokines are also the primary signals that inhibit eosinophil programmed cell death. Thus, eosinophilia can be triggered via these 3 eosinophilopoietic cytokines by increased eosinophil production, by eosinophil longevity, or by a combination of these.[2, 3]
In addition, an evolving number of chemotactic cytokines (ie, chemokines) have been established as causing eosinophils to migrate from their site of production in the bone marrow into the blood and then into peripheral tissues. These chemokines include eotaxin-1, eotaxin-2, and RANTES (regulated on activation normal T cell expressed and secreted).
Eosinophils are the source of a large number of cytokines, including the following:
In addition to these cytokines, eosinophils are a source of several cationic proteins that also contribute to the immunologic responses against infectious disease agents and to tissue damage in allergic and autoimmune diseases. These cationic proteins include the following:
Secondary eosinophilia is a reactive phenomenon driven by eosinophilopoietic cytokine release by nonmyeloid cells. Eosinophilic differentiation occurs in the bone marrow from myeloid progenitors through the actions of GM-CSF, IL-3, and IL-5. Mature eosinophils are released into the bloodstream where they migrate quickly to peripheral tissues of the bronchial and gastrointestinal mucosa and skin. Their survival is short, unless apoptosis is blocked by cytokines (GM-CSF, IL-3, and IL-5).
Dysregulated production of these cytokines by various cell populations account for secondary hypereosinophilia such as seen in nonmyeloid malignancies (eg, Hodgkin lymphoma; transitional cell carcinoma [TCC] of the bladder; adenocarcinomas of the stomach, colon, and uterus; large cell undifferentiated lung carcinomas; and large cell cervical tumors), allergic reactions, parasitic infections, and other conditions.
Eosinophilia is a feature of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, a rare delayed hypersensitivity reaction that typically develops 2 to 8 weeks after starting a drug. Many drugs have been linked to DRESS, including anticonvulsants, antibiotics, and allopurinol. The clinical features include skin rash (widely variable, but often maculopapular or erythematous), fever, lymphadenopathy, and inflammation of one or more organs (eg, liver, lung, brain, kidney, heart). Other hematologic abnormalities may include thrombocytopenia and atypical lymphocytes. DRESS may be fatal, with mortality rates depending on the severity of the organ involvement.[8, 9]
Primary eosinophilias include both clonal and idiopathic hypereosinophilic syndrome (HES). These disorders have very heterogeneous underlying pathophysiologies, not all of which are well-defined. They are by definition eosinophilia for longer than 6 months, without evidence of reactive cause and with signs and symptoms of organ involvement.[10]
In some neoplastic disorders, the hypereosinophilia is part of neoplastic clonal expansion affecting the myeloid lineage. This pathophysiology would describe the eosinophilia in the following disorders:
A number of hypereosinophilic syndrome (HES) cases exhibit clonal expansion of abnormal lymphocytes. Immunophenotypically, they are characterized by aberrant and immature T cells, which exhibit abnormal cytokine production. T-cell receptor gene rearrangements are demonstrated in many. These T cells produce high levels of IL-5, thought to cause the hypereosinophilia.
Eosinophilia is further classified as clonal or idiopathic, both clinically and pathologically. The World Health Organization (WHO) proposed criteria to distinguish idiopathic hypereosinophilic syndrome (HES) from chronic eosinophilic leukemia–not otherwise specified (CEL-NOS).[1] WHO diagnostic criteria for CEL-NOS are as follows:
The underlying chromosomal abnormalities leading to CEL have been described in some cases. A deletion on chromosome band 4q12 resulting in the FIP1L1-PDGFRA (FIR1- like-1–platelet-derived growth factor receptor–alpha) fusion gene causes an abnormal constitutively activated tyrosine kinase. These patients demonstrate CHIC2 gene deletion in peripheral blood mononuclear cells as a result of this fusion gene.
Another fusion gene involving BCR-PDGFRA has been seen in CML with marked eosinophilia. Mutations involving PDGFRB rearrangements have been described, as well as FGFR1 (fibroblast growth factor receptor–1) fusions.[3, 11, 12, 13] Clinical features of eosinophil leukemia result from accumulation of leukemic cells in bone marrow, liver, and spleen.[14] Inflammatory mediators from the eosinophils themselves cause tissue damage to the pericardium, myocardium, endocardium, and nervous system.
In 38 patients with chronic eosinophilia studied by array comparative genomic hybridization (aCGH), Arefi et al found that aCGH revealed clonality in eosinophils in most patients with myeloproliferative neoplasias. These authors suggested that aCGH could be a useful technique for defining clonality in these diseases.[15]
Finally, idiopathic hypereosinophilic syndrome (HES) is the diagnosis of exclusion in patients with marked prolonged (> 6 mo) eosinophilia with multiple organ involvement but without identifiable cytogenetic or molecular abnormalities. Organ damage occurs from release of the contents of eosinophilic granules. Some of these cases transform into identifiable entities. Because of the increasing ability to identify clonal markers, few cases now meet the classical definition of idiopathic HES; WHO considers HES to be a provisional diagnosis until a primary or secondary cause of eosinophilia is established.[16]
The mnemonic CHINA (ie, Connective tissue diseases, Helminthic infections, Idiopathic hypereosinophilic syndrome [HES], Neoplasia, Allergies) describes the categories of diseases that sometimes are associated with blood eosinophilia.
Connective tissue diseases include the following:
Helminthic (ie, worm) parasitic infections include the following:
Idiopathic HES is shown in the images below:
Neoplasias include the following:
Allergic/atopic diseases include the following:
In a retrospective review by Leverone et al of 2227 adults with peripheral blood eosinophilia, hematologic disorders comprised the most common cause (21.9%) of eosinophilia, followed by active bacterial infection (16.8%). The three most common specific causes of eosinophilia were asthma (6.4%), chronic lymphocytic leukemia (5.8%), and multiple myeloma (4.1%).[17]
In the United States, compared with developing countries, eosinophilia occurs most commonly due to allergic conditions, including drug reactions and atopic asthma. Parasitic infections are rare.
Idiopathic hypereosinophilic syndrome (HES) is rare condition. The World Health Organization estimates an age‐adjusted incidence rate of approximately 0.036 per 100,000.[16]
Helminthic infections are the most common cause of eosinophilia worldwide due to the high prevalence of helminthic parasite infections, several of which are estimated to involve hundreds of millions of people.
No racial predilection exists for eosinophilia, although the occurrence of eosinophilia-associated helminthic parasitic infections is more common in certain geographic areas of the world.
No male or female predilection exists in most subtypes of eosinophilia. However, there is a marked male predominance in clonal disorders involving the PDGFRB fusion gene and a small male predominance in clonal disorders of the FGFR1 gene.
People of all ages can be affected by eosinophilia.
The prognosis in patients with secondary eosinophilia depends on the underlying disease. Many helminthic infections develop into chronic diseases that cause morbidity but not mortality. Similarly, allergic reactions and conditions associated with eosinophilia usually do not cause mortality.
Eosinophilia associated with nonmyeloid malignancies does not affect their individual prognosis, including mortality rates. The mortality and morbidity associated with clonal and idiopathic causes depends on the degree of tissue involvement, damage, or both at diagnosis; how quickly therapy is implemented; and treatment responsiveness.
The prognosis in patients with primary eosinophilias is determined by the following:
Obtaining a travel history is critical to assess whether a patient with eosinophilia has been to an area that is endemic for certain infections, including helminthic infections and coccidioidomycosis; the latter, which is the only fungal infection that is frequently associated with eosinophilia, is endemic in the southwestern United States and northern Mexico.[18]
Obtaining a medication and diet history is crucial to evaluate for allergic reactions associated with eosinophilia. In particular, the temporal relationship of medication changes to the onset of eosinophilia should be assessed. History of discontinued medications should also be obtained, as eosinophilia can persist long after cessation.
Obtaining a history of symptoms associated with lymphoma, especially Hodgkin lymphoma, is important.
Eosinophilic esophagitis should be considered in patients who present with dysphagia and/or food impaction, most commonly involving meat.[19]
A history that is suggestive of adrenal insufficiency, including the use and tapering of corticosteroids, can provide a clue that the observed eosinophilia is associated with adrenal insufficiency. Hypoadrenalism (ie, Addison disease) is the most common endocrine abnormality associated with eosinophilia.
Findings in the history may indicate specific organ involvement, such as respiratory or cardiovascular symptoms (eg, exertional dyspnea). Other signs and symptoms to ask about are fatigue, fever, muscle pain, rash, visual changes, and weakness.
A complete physical examination is required, because diseases associated with eosinophilia can involve any part of the body, including the skin, brain, eyes, lymph nodes, lungs, heart, liver, spleen, intestine, bone, and nervous system.
Cholesterol emboli due to atherosclerotic disease, with or without recent vascular catheterization, can present as eosinophilia and end-organ damage to the kidneys, skin, and lower extremities (causing blue/purple toes).
Venous thromboembolism (VTE) is the most common clinical thrombotic complication associated with hypereosinophilia.[20] An unprovoked thromboembolic event is an indicator of eosinophil-associated tissue damage.[21]
The differential diagnosis of eosinophilia includes the following[22] :
Laboratory studies begin with a complete blood cell (CBC) count with differential, to quantitate the percentage eosinophils and absolute number of eosinophils (AEC). Blood chemistries can indicate specific organ involvement (ie, liver, kidney).
Spinal fluid examination can assess cerebrospinal fluid (CSF) eosinophilia due to the following:
Patients with allergic symptoms should have a nasal smear for eosinophilia and Gram stain. Patients with asthma symptoms should have sputum examination for eosinophilia.[23]
In suspected cases of medication and some parasitic infections, evaluation of urine sediment may be helpful. Stool samples should be evaluated for ova and parasites if indicated by history.
If reactive causes are unlikely, a bone marrow biopsy should be done. Clues of clonality in peripheral blood include macrocytosis, thrombocytosis, left-shifted granulopoiesis and circulating blasts. In the bone marrow, myeloproliferation with dyshematopoiesis and reticulin fibrosis are suggestive of clonality. Staining for tryptase and immunophenotyping should be done.
If primary eosinophilia is suspected, screening of peripheral blood with fluorescent in situ hybridization (FISH) or reverse transcriptase–polymerase chain reaction (RT-PCR) is peformed to detect fusion genes. FISH for the CHIC2 gene deletion can indicate the presence of the FIP1L1-PDGFRA gene fusion, which places the disorder in the World Health Organization category of ‘myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1; these conditions are exquisitely responsive to imatinib.[1]
T-cell receptor gene rearrangement can be evaluated by flow cytometry. Measurement for elevated serum levels of tryptase (seen in systemic mastocytosis [SM] and FIP1L1-PDGFRA-positive disease), interleukin-5 (common in clonal T-cell disorders), and IgE can also be peformed.
Computed tomography (CT) scanning may be used as follows:
Echocardiography can be used to assess for thrombi (eg, mural, endocardial) due to hypereosinophilic syndrome (HES).
A bone marrow biopsy may be helpful (see Laboratory Studies).
The American Society for Gastrointestinal Endoscopy (ASGE) recommends biopsy be performed during endoscopy for removal of food impaction in suspected cases of eosinophilic esophagitis.[24]
A lumbar puncture may be performed to evaluate spinal fluid for CSF eosinophilia. CSF eosinophilia may be due to worm infections (eg, Angiostrongylus cantonensis), drug reactions, or coccidioidomycosis fungal meningitis.
Schistosoma hematobium typically causes eosinophilia and hematuria due to infection of the bladder. All patients with blood eosinophilia who have lived or traveled in Africa and have either gross or microscopic hematuria should have their urine examined for the eggs of S hematobium. Cystoscopy can used for definitive diagnosis but is usually unnecessary to make the diagnosis, because the terminal-spined eggs of this species of schistosome can often be found in the urine if specifically sought. See the image below.
A detailed discussion of therapeutics for the many individual causes of eosinophilia, including parasitic and malignancy-associated forms, is beyond the scope of this article. General guidelines only are addressed here.
Most cases of secondary eosinophilia are treated on the basis of their underlying causes. Allergic and connective tissue disorders may be amenable to corticosteroid treatment. Parasitic and fungal infections can be worsened or disseminated by use of steroids, so those conditions should be ruled out if they are indicated by patient history.
In patients with primary eosinophilia without organ involvement, no treatment may be necessary. Cardiac function should be evaluated at regular intervals, however, as peripheral eosinophilia does not necessarily correlate with organ involvement. Steroid responsiveness should be evaluated, both for prognosis (steroid-responsive patients do better) and to guide treatment when needed.
Choices for systemic treatment of primary eosinophilia with organ involvement initially include corticosteroids, and interferon (IFN)-alpha for steroid-resistant disease.[16] Other agents for steroid-resistant disease, which are usually given as long-term maintenance regimens to control organ involvement, include the following:
In patients with PDGFRA and PDGFRB mutations, imatinib has achieved complete and durable remissions and has become established as definitive first-line therapy. However, relapse may occur after discontinuation of imatinib.[1, 26]
Hypereosinophilic syndrome (HES) in patients with unknown or wild-type PDGFRA has a low response rate to imatinib.[27] However, treatment with antibodies and antibody-based agents (eg, mepolizumab, alemtuzumab, brentuximab vedotin) directed against targets expressed on the surface of eosinophils has proved effective in some patients with HES.[28]
In refractory cases, many investigational combinations of chemotherapeutic agents, tyrosine kinase inhibitors (eg, imatinib[29] ), and monoclonal antibodies are being studied. Nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) can also be considered in drug-refractory cases. Despite case reports of successful HSCT in patients with aggressive disease, its role in the treatment of HES is not well established.[16]
Consultation with infectious disease and hematology-oncology physicians can help determine the cause and treatment of eosinophilia.
A guideline on the diagnosis and treatment of eosinophilia from the British Committee on Standards in Haematology advises that the underlying cause of eosinophilia should be sought and possible eosinophil-associated end-organ damage should be evaluated (Grade 1B). A detailed medical history should be taken and a thorough physical examination should be performed (Grade 1C). The history should include the following[21] :
Recommendations regarding the laboratory workup include the following[21] :
Assessment for possible eosinophil-associated end-organ damage should include the following[21] :
Emergency treatment includes the following[21] :
Treatment of clonal eosinophilia includes the following[21] :
Patients with the lymphocytic variant of hypereosinophilic syndrome (HES) can be managed in the same manner as those with idiopathic HES (grade 2B). Recommendations for treatment of idiopathic HES ae as follows[21] :
The guidelines recommend consideration of hematopoietic stem cell transplantation (HSCT) for patients with any of the following (Grade 2C)[21] :
Specific medications for the many infectious, allergic, and hematologic-oncologic diseases associated with eosinophilia are beyond the scope of this article, which focuses on the causes of eosinophilia. A brief overview is provided under the heading of Medical Care.
Overview
What is the pathophysiology of eosinophilia?
What is the pathophysiology of secondary eosinophilia?
What is the role of eosinophilia in the pathophysiology of DRESS syndrome?
What is the pathophysiology of primary eosinophilia?
What is the pathophysiology of eosinophilia in neoplastic disorders?
What is the pathophysiology of hypereosinophilic syndrome (HES)?
What is the role of genetics in the pathophysiology of eosinophilia?
What is the prevalence of eosinophilia in the US?
What is the global prevalence of eosinophilia?
What are the racial predilections of eosinophilia?
What are the sexual predilections of eosinophilia?
Which age group has the highest prevalence of eosinophilia?
What is the prognosis of eosinophilia?
Presentation
What is the focus of the clinical history to evaluate eosinophilia?
What is included in the physical exam to evaluate eosinophilia?
DDX
Which conditions are included in the differential diagnoses of eosinophilia?
Workup
What is the role of lab tests in the workup of eosinophilia?
What is the role of CT scanning in the workup of eosinophilia?
What is the role of echocardiography in the workup of eosinophilia?
What is the role of bone marrow biopsy in the workup of eosinophilia?
What is the role of lumbar puncture in the workup of eosinophilia?
What is the role of urine analysis in the workup of eosinophilia?
Treatment
Which specialist consultations are beneficial to patients with eosinophilia?
Guidelines