Eosinophilia

• Eosinophilia means an eosinophil count in the blood above the normal range, usually above 500 per microlitre (0.5 x 10^9/L); hypereosinophilia means an absolute eosinophil count above 1500 per microlitre.
• Most eosinophilia is reactive: infections (especially helminths), allergy and atopy, asthma, drugs, autoimmune disease, vasculitis and neoplasm.
• Persistent marked eosinophilia can damage organs, most often skin, lung, heart, gut and nerve, through the release of toxic granule proteins.
• Evaluation asks what organ is involved and excludes primary (clonal) disease with tests such as tryptase, B12, FIP1L1::PDGFRA and bone marrow examination.
• Treatment targets the cause first; corticosteroids are first line for most secondary and idiopathic cases, imatinib for FIP1L1::PDGFRA disease, and mepolizumab for steroid-dependent idiopathic hypereosinophilic syndrome. ^[2]

By the end of this page you should be able to:

1. Define eosinophilia, hypereosinophilia and hypereosinophilic syndrome, and classify primary and secondary causes.
2. Explain how eosinophils injure tissue and which organs are at risk.
3. Work through the evaluation of a patient with a persistently raised eosinophil count.
4. Interpret thresholds (500 per microlitre, 1500 per microlitre, degree categories) correctly.
5. Recognise end-organ presentations such as Loeffler endocarditis, eosinophilic pneumonia and peripheral neuropathy.
6. Outline first-line treatment and the roles of corticosteroids, imatinib and mepolizumab, including the cardiac caution with imatinib.
7. State the difference between a single-organ eosinophilic disease and hypereosinophilic syndrome.

Eosinophils are a small population of white blood cells whose granules hold a potent cargo: major basic protein, eosinophil cationic protein, eosinophil peroxidase and a network of inflammatory cytokines. In health they are sent to the gut, the respiratory mucosa and sites of parasite infection, so an occasional eosinophil in the blood is expected. An absolute eosinophil count (AEC) above the normal upper limit, generally 0.5 x 10^9/L (500 per microlitre), is called eosinophilia. A modest rise is often a transient clue to a harmless trigger; a sustained rise, especially above 1.5 x 10^9/L, can mean serious underlying disease and, if it is accompanied by organ damage, a hypereosinophilic syndrome.

This page covers eosinophilia in adults and adolescents, the causes grouped by mechanism, the investigation that separates reactive from clonal disease, the damage eosinophils can do, and current management. The underlying blood-film and bone-marrow architecture is the same in children, although triggers and emphasis differ.

The upper limit of the normal absolute eosinophil count is 0.35 to 0.5 x 10^9/L (350 to 500 per microlitre), with eosinophils making up roughly 3 to 5% of circulating white cells. Eosinophilia is therefore an absolute eosinophil count above this range, and the figure most often used to define it in practice is above 500 per microlitre (0.5 x 10^9/L). Hypereosinophilia is a marked and persistent rise in the absolute eosinophil count above 1.5 x 10^9/L (1500 per microlitre). Within eosinophilia the degree is usefully described as mild (above the upper limit of normal to 1.5 x 10^9/L), moderate (1.5 to 5 x 10^9/L) or severe (above 5 x 10^9/L). These thresholds are arbitrary but guide how urgently and how extensively to investigate. ^[1]

The International Cooperative Working Group on Eosinophil Disorders (ICOG-EO, 2011) defines hypereosinophilia as an absolute eosinophil count above 1.5 x 10^9/L confirmed on two occasions at least four weeks apart, or immediately when the picture is life-threatening, together with tissue hypereosinophilia (more than 20% eosinophils among nucleated cells in the bone marrow, or conspicuous eosinophilic infiltration on biopsy). Hypereosinophilic syndrome is hypereosinophilia with organ damage or dysfunction that is directly attributed to the eosinophils, after reasonable exclusion of other causes. A single-organ eosinophilic disease (for example eosinophilic asthma, eosinophilic pneumonia, eosinophilic gastroenteritis or eosinophilic oesophagitis) is not classified as hypereosinophilic syndrome even when the count is high, because the role of the eosinophil in producing that damage has not been established; the condition can start in one organ and later declare a wider syndrome. ^[1]

Working labels you will meet:

• Reactive (secondary) eosinophilia: the eosinophils are non-clonal and are being driven by exogenous cytokines from an infection, allergy, drug or tumour. This is the commonest situation.
• Primary (clonal) eosinophilia: a myeloid neoplasm in which the eosinophil is part of the malignant clone, often carrying a fusion gene such as FIP1L1::PDGFRA.
• Idiopathic hypereosinophilic syndrome: reactive and clonal causes have been excluded.
• Hypereosinophilia of undetermined significance: marked count elevation without organ damage, often watched rather than treated.
• Lymphocyte-variant hypereosinophilia: a clonal population of T-cells with an abnormal phenotype (CD3+CD4-CD8- or CD3-CD4+) produces interleukin-5, driving the eosinophils; skin disease is prominent and the treatment differs.
• Familial eosinophilia: an autosomal dominant disorder with mild organ damage in some carriers.

Eosinophilia itself is common in clinical practice and is usually reactive; its incidence depends on local patterns of parasites, allergy and drug use. Hypereosinophilic syndrome is rare, with all variants together estimated at up to 6.3 per 100,000 person-years globally, and the idiopathic form estimated at around 10 per million. Men and women are affected about equally. The true prevalence is probably underestimated because a mild case with a single organ can masquerade as asthma, skin disease or gastroenteritis. ^[2]

It is useful to separate what drives the count (extrinsic cytokine drive) from what owns the cell (clonal mutation). The primary disorders are covered first, then the reactive causes, because the reactive ones make up most of what you will see.

Primary (clonal) causes include:

• Myeloid and lymphoid neoplasms with PDGFRA, PDGFRB, FGFR1, or JAK2 rearrangements. FIP1L1::PDGFRA is the commonest in clinical series and usually presents in middle-aged men. It is detected by FISH for CHIC2 allele deletion, since the deletion on chromosome 4 is too small to be seen on conventional karyotype.
• Chronic eosinophilic leukaemia, not otherwise specified (CEL-NOS), with an increase in bone marrow blasts or clonal evidence in the eosinophil lineage.
• Other myeloid neoplasms: systemic mastocytosis, chronic myeloid leukaemia, acute myeloid leukaemia, myelodysplastic syndromes and myeloproliferative-myelodysplastic overlap.
• Lymphocyte-variant hypereosinophilia.

Risk factors for clonal disease include middle age, male sex, and unexplained counts above 1500 per microlitre with high tryptase or B12.

Reactive (secondary) causes are grouped in the table. The classic memory aid groups them as neoplasm, allergy and atopy, asthma, collagen disease and vasculitis, parasites and drugs; adrenal insufficiency is added because cortisol deficiency releases the eosinophil from its normal inhibition. ^[1]

Please note that end-organ single-organ problems such as eosinophilic pneumonia or eosinophilic gastroenteritis behave like organ-restricted eosinophilic disease rather than true multi-organ hypereosinophilic syndrome, even though they appear in the differential.

Eosinopoiesis is driven mainly by interleukin-5, with interleukin-3 and granulocyte-macrophage colony-stimulating factor also contributing. Interleukin-33, interleukin-4 and interleukin-13 are added for trafficking and tissue activation, particularly in allergy and asthma. In secondary eosinophilia the drive is extrinsic: T-cells or tumour cells release these cytokines in response to an infection, allergen, drug or neoplasm. In primary disease a mutation inside the myeloid clone does the same job without any external trigger.

The damage is mechanical and chemical rather than infectious. Activated eosinophils degranulate, releasing major basic protein and eosinophil cationic protein, which damage endothelium and epithelium directly; they generate reactive oxygen species; they promote clotting; and their persistent activation leads to fibrosis. Because of this, any organ rich in eosinophil receptors and capillaries can be scarred: endocardium and myocardium, peripheral nerves, skin, lung interstitium and gastrointestinal mucosa. Thromboembolic complications, including cerebral and coronary events, occur in about a quarter of patients in some series. Eosinophil extracellular trap release appears to add to vascular injury in severe disease. ^[1]

Why organs at different times? The count alone is a poor guide to who will be damaged. The picture depends on how activated the cells are, how long the elevation has lasted, and which tissue is exposed to them. Idiopathic disease has the widest variation.

One downstream warning matters for treatment: if hypereosinophilic cells are sitting quietly in the myocardium, the first dose of imatinib can make them degranulate and produce a cardiogenic shock that is reversible only with steroids, circulatory support and stopping the drug.

The presentation spans a spectrum from a single abnormal laboratory result to multi-system disease. A typical patient has fatigue and a raised count that has drifted upward over months; another presents with a stroke, heart failure or a rash.

• Skin (the commonest, reported in about two thirds of patients with hypereosinophilic syndrome): pruritus, urticaria, angioedema, eczema-like or nodular rashes. Intense itch can dominate the illness.
• Respiratory (about 44%): cough, wheeze, dyspnoea, pulmonary infiltrates, pleural effusion; mucus plugging and adult-onset eosinophilic asthma.
• Gastrointestinal (about 38%): abdominal pain, diarrhoea, vomiting, sometimes ascites or hepatomegaly.
• Cardiac (ultimately about 20%): chest discomfort, dyspnoea, palpitations, signs of heart failure, thromboembolism. Loeffler endocarditis is the classic: mural thrombus forms on the damaged endocardium, mural thrombi embolise, and restriction of the ventricles produces a restrictive cardiomyopathy.
• Neurological: peripheral neuropathy (mononeuritis multiplex or a distal symmetric polyneuropathy), central events from emboli, and, rarely, encephalitis.
• Constitutional: fever, weight loss, night sweats and malaise, particularly in paraneoplastic and clonal disease.

About half of patients with idiopathic hypereosinophilic syndrome also have asthma, often adult-onset, and many have chronic rhinitis or nasal polyps. This overlaps with eosinophilic granulomatosis with polyangiitis, and the distinction is discussed below.

On examination look for hepatosplenomegaly (favours a myeloproliferative process), lymphadenopathy, cardiac murmurs or gallop, focal neurology and rash. Systemic mastocytosis may be accompanied by urticaria pigmentosa and flushing.

If you are reading the Pulmonary eosinophilic syndromes topic as well, that page and this one agree that blood eosinophilia is usually defined as more than 500 cells per microlitre, with bone-marrow and tissue thresholds as above. The pulmonary page concentrates on the lung-specific syndromes; here the eosinophil count itself is the organising problem.

Two separate questions arise: what caused this eosinophilia, and which condition does this patient's syndrome resemble? The first is the aetiological list above. The second is the differential against other hypereosinophilic and inflammatory states.

Hypereosinophilic syndrome and EGPA share asthma and nasal disease and can be hard to tell apart. Vasculitis supports EGPA, but it can be missed, especially in patients already on corticosteroids, and about 60 to 70% of EGPA patients are ANCA-negative. The working label HES/EGPA overlap is used when there is idiopathic hypereosinophilia with EGPA-like features (asthma, rhinosinusitis) but no ANCA and no biopsy-proven vasculitis. ^[3]

Evaluation has three jobs: confirm the elevation, find the affected organ, and exclude clonal disease.

1. Repeat the count and index it. Document the absolute eosinophil count, the trend over weeks or months, and the total white count. An unexpected differential should be checked against a blood film so that reactive or blasts are not missed.
2. History with the specific inclusions that change the differential: travel and immigration (parasites), all prescription and over-the-counter drugs including recent antibiotics, antiepileptics, allopurinol and proton-pump inhibitors, atopic and asthmatic disease, autoimmune features (rash, joint pain, neurological symptoms), and red flags for malignancy.
3. Parasite work-up directed by travel: stool culture or microscopy, and serology for Strongyloides, Schistosoma, Toxocara, Trichinella and filaria when appropriate. Strongyloides serology is particularly important because empiric steroids for a misdiagnosed eosinophilia can precipitate hyperinfection.
4. Organ screening chosen from the presentation: troponin and echocardiography for cardiac involvement; lung function testing, chest imaging and bronchoscopy with lavage for pulmonary disease; endoscopy and biopsy for gastrointestinal disease; skin biopsy for rash.
5. Autoimmune and inflammatory testing: total and specific IgE, antineutrophil cytoplasmic antibodies, antinuclear antibodies, IgG subclasses where IgG4-related disease is suspected, and complement where indicated.
6. Clonal exclusion: serum vitamin B12, serum tryptase, FIP1L1::PDGFRA by fluorescence in-situ hybridisation or RT-PCR on blood or marrow, BCR::ABL1, standard karyotype, T-cell receptor gene rearrangement studies, immunophenotyping of blood or marrow, and a myeloid next-generation sequencing panel.
7. Bone marrow examination: morphology, blast percentage, eosinophil fraction (more than 20% supports tissue hypereosinophilia), fibrosis, immunohistochemistry for CD117 and CD25 when tryptase is raised, and cytogenetics.
8. Imaging to stage disease and find malignancy: chest radiograph or high-resolution CT when pulmonary; echocardiography for cardiac function and thrombus; CT of chest, abdomen and pelvis when malignancy is suspected.

The yield of this list depends on presentation. A patient with atopic asthma and a count of 800 per microlitre needs a light touch; one with 1800 per microlitre, weight loss and neuropathy needs all of it.

Idiopathic hypereosinophilic syndrome is diagnosed by:

• a sustained eosinophil count of at least 1.5 x 10^9/L (1500 per microlitre) recorded more than once at least two weeks apart; ^[2]
• associated organ dysfunction attributable to eosinophilia, with tissue infiltration or the typical pattern of damage;
• exclusion of reactive and clonal causes, including lymphocyte-variant disease.

Some centres still cite the older Chusid criteria requiring more than 1500 for more than six months; the modern view shortens the time window so that organ damage is not allowed to develop while waiting. Either way, when the disease is life-threatening the time criterion is waived.

Degree of eosinophilia (mild, moderate, severe) is a separate description from the syndrome diagnosis and helps communicate risk. End-organ damage is what turns hypereosinophilia into hypereosinophilic syndrome. Cardiac involvement in particular is a turning point, because it carries the risk of sudden thromboembolism and restrictive heart failure.

Treatment follows the cause first and the count second. The practical steps are:

1. Treat the underlying cause whenever one is found. Helminth infection gets antiparasitic treatment first, with steroid suppression avoided until the parasite is controlled. Drug reactions need withdrawal of the culprit; corticosteroids help the systemic features. Adrenal insufficiency responds to replacement. Neoplasm needs oncology-directed treatment. EGPA is managed as a vasculitis.

2. Corticosteroids are first-line management for most secondary and idiopathic cases, because most eosinophil degranulation is cytokine-driven and steroid-responsive. Typical practice starts with prednisolone or prednisone at roughly 0.5 to 1 mg per kilogram daily (up to 1 mg/kg in fulminant presentations), tapering slowly once the count falls and the organ manifestations improve. Inflammatory and cardiac disease may need higher or intravenous doses. Long-term steroids carry the usual hazards (osteoporosis, diabetes, hypertension, myopathy, glaucoma), so the aim is the lowest effective maintenance dose.

3. Mepolizumab, an anti-interleukin-5 monoclonal antibody, is approved for hypereosinophilic syndrome of at least six months' duration without an identifiable non-haematological secondary cause. The dose is 300 mg given subcutaneously every four weeks, administered as three separate 100 mg injections at least 5 cm (about 2 inches) apart. It is prescribed for steroid-dependent or steroid-refractory idiopathic disease. Because it is an interleukin-5 antagonist, pre-existing helminth infection should be treated before starting, and if a new infection does not respond to antihelminthic therapy the drug is withheld until it resolves. Cardiac improvement is not immediate, and a cardiac assessment is warranted before and during treatment when the heart is involved. ^[2][4]

4. Imatinib is first-line for FIP1L1::PDGFRA-positive and myeloproliferative variants. The label recommends 100 mg daily when the fusion kinase is demonstrated, raised to 400 mg if response is insufficient; for other hypereosinophilic or chronic eosinophilic leukaemia cases the recommended dose is 400 mg daily. Median response times are short, with complete haematological remission in most patients. Two cautions matter: myelodysplastic and mast-cell disease with eosinophilia may need a different starting dose, and cardiogenic shock from eosinophil degranulation can occur on initiation when there is occult myocardial infiltration. In that situation an echocardiogram and serum troponin are taken before starting, and systemic steroids (1 to 2 mg per kilogram) are given concomitantly for one to two weeks. ^[2][5]

Other and later-line options include hydroxyurea as second-line, interferon-alpha for some idiopathic cases, other cytotoxic or immunomodulatory drugs, bone marrow transplantation for resistant or aggressive disease, and benralizumab (an anti-interleukin-5 receptor alpha antibody) which has shown rapid and deep eosinophil depletion in refractory disease.

The figure below sets out the order of decisions.

The complications are the end-organ damage itself rather than side effects of treatment. Cardiac thrombus and emboli, restrictive cardiomyopathy and heart failure; stroke and peripheral neuropathy; chronic eosinophilic pneumonia and lung restriction; protein-losing enteropathy and malabsorption; renal and central nervous system involvement in advanced vasculitic forms; and malignant transformation in a minority with clonal variants. Drug therapy adds its own: long-term corticosteroid toxicity, imatinib-associated fluid retention, neutropenia and thrombocytopenia, and the cardiac degranulation event described above. Mepolizumab can unmask or worsen a helminth infection.

Reactive eosinophilia has an excellent prognosis once the trigger is removed. Idiopathic hypereosinophilic syndrome, which was fatal within three years in most patients in the 1970s, now has a five-year survival above 90% with targeted therapy and sensible steroid use. Prognosis worsens when the heart, central nervous system or bone marrow is involved, and when a clonal neoplasm with poor-risk genetics (FGFR1 or JAK2 rearrangements, chronic eosinophilic leukaemia not otherwise specified) is present. FIP1L1::PDGFRA disease has a comparatively good prognosis with imatinib. ^[1]

There is no screening programme. Practical prevention is to review drug exposure before and during therapy, to treat helminth reservoirs in endemic areas, to keep corticosteroid replacement adequate in adrenal insufficiency, and to reduce the burden of atopic disease. In a patient already known to have hypereosinophilic syndrome, regular cardiac surveillance with echocardiography and troponin is a sensible low-cost precaution, because early heart involvement is reversible.

Pregnancy. Eosinophilia in pregnancy most often has a benign reactive cause. Persistent marked elevation should still be investigated. Corticosteroids are used when indicated; mepolizumab and imatinib are generally avoided or used only when maternal disease threatens life, with specialist advice.

Children. Eosinophilia is very common in children and usually allergic or parasitic. Hypereosinophilic syndrome is rare; CE-NOS and myeloid variants in childhood need haematology referral. Imatinib paediatric dosing for hypereosinophilic syndrome is not established in young children.

Older adults. Late-onset clonal and paraneoplastic eosinophilia becomes more likely; a new unexplained count above 1500 per microlitre in an older patient warrants thorough malignancy work-up.

Immunocompromised. HIV-associated eosinophilia is usually due to secondary infections or malignancy rather than the virus itself. Steroid treatment of suspected reactive disease in an immunocompromised patient needs care and usually specialist input.

The whole syndrome can be recognised and much of the damage prevented without expensive testing if the basic logic is applied.

• A blood count with a differential is the entry test. Confirmation of a trend is more useful than a single value. A manual differential or a blood film substitutes for flow cytometry.
• Travel and drug history is free and carries most of the diagnostic weight. Strongyloides serology, when unavailable, should be replaced by empiric treatment or by a stool examination with Baermann concentration rather than by skipping the question.
• Cardiac involvement is detected with a focused history, examination and a basic echocardiogram; serum troponin is added when an echo is unavailable. Early high-dose prednisolone helps cardiac disease, and when it is accompanied by acute decompensation steroids should be given without waiting.
• Prednisolone or prednisone is cheap and widely available and is the backbone of treatment. Hydroxyurea is available in many formularies for resistant or high-count disease.
• Imatinib and mepolizumab are expensive and often unavailable; where they are missing, referral networks or compassionate-access programmes are the realistic route, with prednisolone used to hold the disease until access is arranged.
• Laboratory confirmation of clonal disease (FISH for CHIC2 deletion, RT-PCR, marrow examination) may require referral. In practice, a good response to steroids plus a normal myeloid screen supports a working diagnosis of idiopathic disease.
• Prevention of strongyloidiasis hyperinfection (treat before steroids) costs very little and saves lives.
• The eosinophilic pulmonary syndromes page covers the lung-specific investigations and treatments in more detail; many of its principles, notably stool testing before immunosuppression, apply here too.

• Eosinophilia is an absolute eosinophil count above 500 per microlitre; hypereosinophilia is above 1500 per microlitre.
• Reactive causes dominate: parasites, allergy, atopy, asthma, drugs, vasculitis, neoplasm and adrenal insufficiency.
• Clonal disease is defined by mutations such as FIP1L1::PDGFRA and is treated with imatinib.
• Hypereosinophilic syndrome is hypereosinophilia plus organ damage attributed to the eosinophil; single-organ eosinophilic disease is not the syndrome.
• Common end-organ sites are skin, lung, heart, gut and nerve; thrombosis occurs in about a quarter of patients in some series.
• Counts alone do not predict damage; the duration and activation state of the cells matter.
• Corticosteroids are first-line for most secondary and idiopathic hypereosinophilia; aim for the lowest effective maintenance dose.
• Mepolizumab 300 mg subcutaneously every four weeks is approved for hypereosinophilic syndrome of at least six months without an identifiable non-haematological secondary cause.
• Imatinib starts at 100 mg daily with a fusion kinase and 400 mg daily otherwise; cardiac echo and troponin are checked first because of the risk of imatinib-triggered cardiac degranulation.
• Treat helminth infection before prescribing steroids or mepolizumab.
• Prognosis has improved markedly: five-year survival in idiopathic hypereosinophilic syndrome is now above 90%.
• In low-resource settings, prednisolone, careful history, targeted parasite tests and referral for cardiac assessment do most of the work.

• Pulmonary eosinophilic syndromes (plain text cross-check)
• Adrenal insufficiency
• Asthma
• Hodgkin lymphoma
• Chronic eosinophilic leukaemia
• Eosinophilic granulomatosis with polyangiitis

This page is complete. All medical statements are drawn from the references listed in the front matter.