approach to eosinophilia
Contents
Eosinophilia (AEC >0.5 x 10^9/L) — most commonly atopic disease in industrialised nations, helminths worldwide. The critical task: distinguish reactive causes (drugs, infection, allergy) from clonal eosinophilia (myeloid neoplasms with TK fusions) and hypereosinophilic syndrome (HES). Persistent AEC >1.5 x 10^9/L demands a structured workup and end-organ damage assessment — cardiac involvement is the major driver of morbidity.
classification
| Severity | AEC (x 10^9/L) |
|---|---|
| Mild | 0.5–1.5 |
| Moderate | 1.5–5.0 |
| Severe | >5.0 |
- Hypereosinophilia (HE): persistent AEC >1.5 x 10^9/L
- Hypereosinophilic syndrome (HES): HE + eosinophil-mediated end-organ damage + exclusion of other causes
differential diagnosis
Mnemonic: NAACP — Neoplasm, Allergy, Autoimmune, Infection (Chronic), Parasites
allergy & drugs (most common in practice)
- Typically mild eosinophilia with single-system involvement
- Asthma, allergic rhinitis, atopic dermatitis, ABPA, allergic GI disease
- Drug eosinophilia — NSAIDs, antimicrobials, anticonvulsants
- DRESS is the severe end: multiorgan involvement, AEC often >1.5 x 10^9/L
- Elevated IgE is nonspecific (allergic, infectious, and lymphocyte-variant HES)
infection
Most common cause worldwide — tissue-invasive helminths:
- Strongyloides, Toxocara, Trichinella, Schistosoma, Ascaris, hookworm, filariasis
- Fungal: Coccidioides, Histoplasma
- Viral: HIV
- Strongyloides serology is essential — stool O&P has poor sensitivity for this organism
autoimmune / inflammatory
- EGPA — the hallmark eosinophilic vasculitis; 2022 ACR/EULAR criteria: AEC ≥1 x 10^9/L (+5), obstructive airway disease (+3), nasal polyps (+3), extravascular eosinophilic inflammation (+2), mononeuritis multiplex (+1); threshold ≥6
- IBD, coeliac disease, IgG4-related disease, bullous pemphigoid, sarcoidosis, eosinophilic fasciitis
neoplasm (clonal eosinophilia)
Two major categories:
- MLN-eo-TK (myeloid/lymphoid neoplasms with eosinophilia and TK gene fusions) — PDGFRA, PDGFRB, FGFR1, JAK2. Most common: FIP1L1::PDGFRA (~10% of idiopathic eosinophilia, strong male predominance, exquisitely imatinib-sensitive)
- CEL-NOS — clonal eosinophilia without a specific TK fusion
- Other: CML, AML (M4Eo), MDS, CMML, systemic mastocytosis
- Lymphoid neoplasms (T-cell lymphoma, Hodgkin) → reactive eosinophilia via IL-5/IL-3/GM-CSF
Clonal clues: elevated tryptase, elevated B12, splenomegaly, blasts/dysplasia on smear, abnormal T-cell population
hypereosinophilic syndrome
Diagnosis of exclusion — all three required:
- AEC >1.5 x 10^9/L on ≥2 occasions, ≥1 month apart
- End-organ damage attributable to eosinophilia
- Exclusion of reactive and clonal causes
| Subtype | Features | Treatment response |
|---|---|---|
| Myeloproliferative (M-HES) | Anaemia, splenomegaly, elevated B12/tryptase, FIP1L1::PDGFRA | Imatinib (if PDGFRA+); steroid-refractory |
| Lymphocyte-variant (L-HES) | Aberrant CD3^-CD4^+ T-cells, elevated IgE, skin-predominant | Good steroid response |
| Idiopathic (I-HES) | No identifiable cause | Steroids first-line |
diagnostic algorithm
step 1: history and initial labs
- Medications (timeline vs eosinophilia onset), travel, atopy, B symptoms
- CBC with differential, peripheral smear, IgE, CRP
step 2: exclude reactive causes
- Stool O&P x3 + Strongyloides serology
- HIV testing
- Medication review — stop suspect drugs
- ANA, ANCA (MPO-ANCA most common in EGPA)
- Imaging as directed by symptoms
step 3: evaluate for clonal disease
Triggered by persistent HE, clonal clues, or failure to identify reactive cause:
- Serum B12, tryptase
- FISH: PDGFRA (CHIC2 deletion), PDGFRB, FGFR1, JAK2
- Bone marrow aspirate/biopsy with cytogenetics, flow cytometry, myeloid NGS panel
- T-cell immunophenotyping and clonality studies
step 4: assess end-organ damage
| Organ | Key manifestations | Investigations |
|---|---|---|
| Heart | Endomyocardial fibrosis, myocarditis, intracardiac thrombi (acute necrotic → thrombotic → fibrotic) | Troponin, NT-proBNP, ECG, echo, cardiac MRI |
| Lung | Infiltrates, [[Eosinophilic Lung Disease | eosinophilic pneumonia]], pleural effusions |
| Skin | Rash, pruritus, urticaria, angioedema | Biopsy |
| GI | Pain, diarrhoea, eosinophilic gastroenteritis | Endoscopy with mucosal biopsies |
| Neuro | Border-zone stroke, neuropathy, encephalopathy | MRI brain, EMG/NCS |
Troponin and cardiac MRI are the most sensitive early tools — echo may be normal in the acute necrotic phase. Cardiac involvement is the leading cause of morbidity and mortality in HES.
management
treat the underlying cause
- Reactive → antiparasitics, drug withdrawal, treat autoimmune disease
- Mild eosinophilia (<1.5 x 10^9/L) without organ damage → monitor
clonal disease
- Imatinib — first-line for PDGFRA-rearranged disease (100 mg daily; exquisite response). Also effective for PDGFRB (100–400 mg daily)
- Pemigatinib — for relapsed/refractory FGFR1-rearranged neoplasms
HES / idiopathic HE with organ damage
- Corticosteroids — first-line for acute end-organ damage, L-HES, idiopathic HES. High-dose IV for cardiac involvement
- Mepolizumab (anti-IL-5) 300 mg SC monthly — approved for idiopathic HES refractory to or intolerant of steroids
- Hydroxyurea / IFN-alpha — second-line for steroid-refractory disease
- Refractory L-HES — alemtuzumab, ruxolitinib, tofacitinib
- HSCT — reserved for aggressive/refractory HES and CEL
Rule out Strongyloides (risk of hyperinfection with immunosuppression) and exclude FIP1L1::PDGFRA (cardiac toxicity reported with steroids in this subtype — imatinib is the correct first-line).
what NOT to do
- Start steroids without checking Strongyloides serology — hyperinfection syndrome is fatal
- Assume mild eosinophilia is “just allergies” without a medication review
- Miss cardiac involvement — always check troponin in persistent HE, even if asymptomatic
- Delay FISH for PDGFRA in unexplained persistent eosinophilia — imatinib response is dramatic and delays worsen fibrotic damage
- Forget T-cell immunophenotyping — L-HES is clinically distinct and guides therapy