Eosinophilia

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:

• IL-2, IL-3, IL-4, IL-5, IL-7, IL-13, and IL-16
• Tumor necrosis factor–alpha (TNF-alpha),
• Transforming growth factor–beta (TGF-beta)
• RANTES

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:

• Eosinophil cationic protein (ECP)
• Eosinophil peroxidase (EPO)
• Charcot-Leyden crystal lysophospholipase
• Major basic protein (MBP)
• Eosinophil-derived neurotoxin (EDN)

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:

• Chronic myelogenous leukemia (CML), Philadelphia chromosome positive (Ph+) or BCR-ABL positive
• Acute myeloid leukemia (AML), including inv(16), t(16;66)(p13;q22)
• Myeloproliferative diseases
• Myelodysplastic syndromes

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:

• Absence of the Philadelphia chromosome or a rearrangement involving PDGFRA/B and FGFR1
• Exclusion of other acute or chronic primary marrow neoplasms associated with eosinophilia (eg, AML, myelodysplastic syndrome, systemic mastocytosis)
• Blasts of more than 2% in peripheral blood, or bone marrow blasts of more than 5% but less than 20% (the upper threshold is to exclude acute leukemia as a diagnosis)
• Evidence for a clonal marker

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:

• Eosinophilic granulomatosis with polyangiitis (Churg-Strauss Syndrome) (See the images below.)

  Granuloma with a central core of eosinophilic debris surrounded by a peripheral palisade of epithelioid histiocytes and eosinophils from a patient with Churg-Strauss syndrome (allergic granulomatosis).

  Magnified view of papules and nodules with central necrosis in a patient with Churg-Strauss syndrome (allergic granulomatosis).
• Rheumatoid arthritis
• Eosinophilic fasciitis (See the images below.)

  High-power photomicrograph of fascia shows heavy inflammatory infiltration with numerous eosinophils, lymphocytes, and occasional plasma cells in a patient with eosinophilic fasciitis.

  Lower back part of the legs in a patient with eosinophilic fasciitis shows hypopigmentation, induration, biopsy site, and asymmetric involvement.
• Eosinophilia-myalgia syndrome (due to tryptophan in the United States in 1989)
• Toxic-oil syndrome (due to contaminated rapeseed oil in Spain in 1981)
• Coccidioidomycosis

Helminthic (ie, worm) parasitic infections include the following:

• Ascariasis
• Schistosomiasis
• Trichinosis
• Visceral larva migrans
• Gnathostomiasis
• Strongyloidiasis
• Fascioliasis
• Paragonimiasis

Idiopathic HES is shown in the images below:

Indurated edematous plaques of hypereosinophilic syndrome on a patient's legs.

Erythroderma in a patient with hypereosinophilic syndrome.

Neoplasias include the following:

• Lymphoma (eg, Hodgkin lymphoma, non-Hodgkin lymphoma)
• Human T-cell lymphotropic virus I (HTLV-I) infection
• Adult T-cell leukemia/lymphoma (ATLL)
• Eosinophilic leukemia (very rare)
• Gastric or lung carcinoma (ie, paraneoplastic eosinophilia)

Allergic/atopic diseases include the following:

• Asthma
• Allergic rhinitis

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:

• Degree of organ involvement at diagnosis
• The timeliness of treatment
• Responsiveness to treatment
• Underlying cytogenetic and molecular pathophysiology

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]  

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:

• Worm infections (eg, Angiostrongylus cantonensis)
• Drug reactions (eg, phenytoin)
• Coccidioidomycosis meningitis

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:

• CT scans of the lungs, abdomen, pelvis, and brain evaluate for focal defects due to diverse causes of eosinophilia
• Worm infections of the liver (eg, Fasciola hepatica) can cause focal hepatic lesions
• Coccidioidomycosis can cause focal lesions in the lung, which are visible on a chest radiograph or CT scan
• Hodgkin or non-Hodgkin lymphoma can cause adenopathy in the abdomen, which is visible on a CT scan

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.

Egg of Schistosoma hematobium, with its typical terminal spine.

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:

• Hydroxyurea
• Chlorambucil
• Vincristine
• Cytarabine
• 2-Chlorodeoxyadenosine (2-CdA)
• Etoposide
• Cyclosporine ^[25]

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] :

• Assessment for allergic disorder; skin rashes; and cardiorespiratory, gastrointestinal, and constitutional symptoms
• A detailed travel history, particularly for tropical travel; travel even in the remote past may be relevant
• A detailed drug history

Recommendations regarding the laboratory workup include the following[21] :

• All patients should have a full blood count, peripheral smear examination, and routine tests of kidney and liver function, a bone profile, lactate dehydrogenase, erythrocyte sedimentation rate and/or C-reactive protein, and vitamin B12 assay (Grade 1C).
• Patients who are otherwise well with mild to moderate eosinophilia between 0.5 and 1.5 × 10 ⁹/L may not require further testing. Patients with systemic symptoms and those with persistent eosinophilia (at least 1.5 × 10 ⁹/L), irrespective of suspected organ damage, should be considered for additional testing for an underlying cause.
• Specific causes of reactive eosinophilia, based on clinical suspicion, should be confirmed or excluded at an early stage by appropriate testing (Grade 1C).
• Patients with an eosinophil count of at least 1.5 × 10 ⁹/L with no obvious cause should be investigated for a possible hematological neoplasm with clonal eosinophilia, initially by peripheral blood analysis for FIP1L1-PDGFRA by fluorescence in situ hybridization (FISH) or nested reverse transcription polymerase chain reaction (RT-PCR) (Grade 1C).
• Serum tryptase estimation should be performed if the differential diagnosis includes chronic eosinophilic leukemia or systemic mastocytosis (Grade 1B).
• In the absence of an identifiable cause and with negative peripheral blood analysis for FIP1L1-PDGFRA by FISH or nested RT-PCR, a bone marrow aspirate, trephine biopsy, and cytogenetic analysis should be performed; the possibility of an underlying lymphoma or of the lymphocytic variant of hypereosinophilic syndrome should be evaluated, including consideration of immunophenotyping of peripheral blood and bone marrow lymphocytes and analysis for T-cell receptor gene rearrangement (Grade 1C). The possibility of systemic mastocytosis or other myeloid neoplasm should be considered.

Assessment for possible eosinophil-associated end-organ damage should include the following[21] :

• End-organ damage should be assessed using chest radiography and/or computed tomography (CT) of the thorax, echocardiography, serum troponin T, and pulmonary function testing (Grade 1C).
• An unprovoked thromboembolic event should be recognized as a possible manifestation of eosinophil-associated tissue damage (Grade 2C).
• In patients with end-organ damage, the frequency of further serial evaluations of organ function should be determined by the severity and extent of organ compromise and/or by worsening of the eosinophilia (Grade 2C).

Emergency treatment includes the following[21] :

• Patients requiring emergency treatment for severe or life-threatening eosinophilia should receive high-dose corticosteroids (Grade 1B).
• Patients receiving corticosteroids, in whom there is a risk of strongyloides infection, should receive concomitant ivermectin to prevent potentially fatal hyperinfection (Grade 1B).

Treatment of clonal eosinophilia includes the following[21] :

• Patients with clonal eosinophilia with FIP1L1-PDGFRA (including patients presenting with acute leukemia), should be treated with low-dose imatinib (Grade 1B).
• Patients with clonal eosinophilia with PDGFRB rearrangement or ETV6-ABL1 fusion should receive standard-dose imatinib (Grade 1B).
• Patients with clonal eosinophilia with ETV6-FLT3 fusion should be considered for sunitinib or sorafenib therapy (Grade 2B)
• Patients with clonal eosinophilia with JAK2 rearrangement should be considered for ruxolitinib therapy (Grade 2B)
• Patients with acute myeloid leukemia (AML) with clonal eosinophilia and no molecular or cytogenetic abnormality suggesting likely response to a tyrosine kinase inhibitor should be offered standard acute myeloid leukemia induction therapy (Grade 1A).
• Patients with other hematological neoplasms with clonal eosinophilia should have treatment directed at management of the neoplasm.
• Patients with organ damage or dysfunction relating to the eosinophilia should also receive treatment with corticosteroids (Grade 1C).

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] :

• First-line treatment is with corticosteroids (see emergency treatment above).
• Patients with idiopathic HES who do not respond adequately to corticosteroids, or who require prolonged corticosteroid therapy, or who are intolerant of corticosteroids, should be considered for a short trial (4-6 weeks) of imatinib; immunomodulatory agents (interferon alpha, cyclosporine, or azathioprine); myelosuppressive therapy (hydroxycarbamide); or monoclonal antibody therapy with mepolizumab (anti-interleukin 5), this last preferably as part of a clinical trial (Grade 2B).
• Alemtuzumab, an anti-CD52 monoclonal antibody, should be considered for patients with severe idiopathic HES unresponsive to other therapies, and may be useful in patients with idiopathic HES–associated cardiac and cerebral dysfunction (Grade 2B).

The guidelines recommend consideration of hematopoietic stem cell transplantation (HSCT) for patients with any of the following (Grade 2C)[21] :

• Clonal eosinophilia with FGFR1 rearrangement
• Chronic eosinophilic leukemia, not otherwise specified
• HES refractory to or intolerant of both conventional tyrosine kinase inhibitor (TKI) therapy and experimental medical therapy, where available; intolerance of such therapy, or progressive end-organ damage

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.