Immune System

Eosinophilia: differential and workup

Clinical Overview and When to Suspect Eosinophilia

— Mild: 500–1,500/µL

— Moderate: 1,500–5,000/µL

— Severe (hypereosinophilia, HE): ≥1,500/µL on two occasions ≥1 month apart or tissue eosinophilia

— Hypereosinophilic syndrome (HES) = HE + end-organ damage attributable to eosinophils

— Incidental CBC finding in an ambulatory adult ("eos 12%, AEC 1,800")

— Asthma + sinusitis + neuropathy → think EGPA

— Returning traveler with GI symptoms, rash, or pulmonary infiltrates → parasitic

— New rash after starting a drug 2–8 weeks earlier → DRESS

— Refractory atopic disease, persistent urticaria, chronic diarrhea, or unexplained cardiomyopathy with elevated eos

— Collagen vascular/autoimmune (EGPA, IgG4)

— Helminth/parasitic infection

— Idiopathic/clonal (HES, leukemia)

— Neoplasm (Hodgkin, solid tumor paraneoplastic)

— Allergy/Atopy/Asthma and Adrenal insufficiency

— Plus drugs — the single most common reversible cause in US outpatients

— AEC <1,500 with no symptoms → outpatient workup

— AEC ≥1,500 with symptoms or any organ involvement → expedited evaluation (days, not weeks)

— AEC >100,000 or leukoerythroblastic smear → emergent heme/onc; risk of leukostasis and thrombosis

Step 3 management: In an asymptomatic patient with mild eosinophilia, repeat the CBC in 4–6 weeks before launching an expensive workup — transient eosinophilia from a recent viral illness or unrecognized drug exposure is common and self-resolves. Document the trend before referring.

Board pearl: Eosinophil percentage can mislead — always calculate AEC = WBC × eos%. A "normal-looking" 8% in a leukopenic patient is not eosinophilia.

Definition by absolute eosinophil count (AEC), not percentage:

When to suspect on Step 3:

Conceptual framework — "CHINA" mnemonic for causes:

Severity-based urgency:

Presentation Patterns and Key History

— Ask about all prescription, OTC, herbal, and supplement use in the prior 8 weeks

— High-risk drugs: allopurinol, sulfonamides, lamotrigine, carbamazepine, phenytoin, vancomycin, minocycline, NSAIDs, PPIs, dapsone, abacavir, nevirapine

— DRESS triad: fever, rash, eosinophilia 2–8 weeks after drug initiation; ask about facial edema and lymphadenopathy

— Region-specific helminths: Strongyloides (Southeast Asia, Caribbean, Appalachia), schistosomiasis (Africa), filariasis (tropics), hookworm, Ascaris, Toxocara (puppies, sandboxes)

— Undercooked pork/wild game → Trichinella; raw fish → Anisakis; freshwater swimming → schistosome cercarial dermatitis

— Cardiac: dyspnea, edema (eosinophilic myocarditis, Löffler endocarditis)

— Neuro: mononeuritis multiplex, foot drop (EGPA)

— GI: dysphagia (EoE), chronic diarrhea, abdominal pain (eosinophilic gastroenteritis)

— Skin: urticaria, angioedema, purpura

— Constitutional: B symptoms → lymphoma, clonal HES

Board pearl: Adult-onset asthma + sinusitis + peripheral neuropathy + eosinophilia = EGPA until proven otherwise — check ANCA (MPO) and look for mono neuritis multiplex.

Step 3 management: Before ordering a $2,000 workup, perform a systematic medication reconciliation including supplements; stopping the offending drug resolves up to 30% of unexplained eosinophilia within 2–4 weeks. Document a clear stop date to track resolution.

Targeted history is the single highest-yield step — most eosinophilia is explained by exposures, not by exotic disease.

Drug history (broadest net):

Travel and exposure:

Atopic/respiratory: asthma onset in adulthood, chronic sinusitis, nasal polyps, eczema — sets up EGPA or ABPA

Systems review for organ involvement:

Family/social: atopic family history, occupational dust/mold, pet exposure, IV drug use

Physical Exam Findings and End-Organ Assessment

— Tachycardia, hypotension, or new murmur → consider eosinophilic myocarditis or Löffler endocarditis; can present as decompensated HF

— Fever → DRESS, parasitic infection, lymphoma, or vasculitis

— Diffuse morbilliform rash + facial edema → DRESS

— Palpable purpura on lower extremities → small-vessel vasculitis (EGPA)

— Urticaria, dermatographism → mast cell disorder or chronic spontaneous urticaria

— Linear serpiginous tracks on buttocks/abdomen → larva currens of Strongyloides

— Pruritic papules + lymphadenopathy → episodic angioedema with eosinophilia (Gleich syndrome)

— Nasal polyps, boggy turbinates → AERD, EGPA, ABPA

— Cervical/generalized lymphadenopathy → DRESS, lymphoma, Castleman, IgG4

— Wheeze (asthma, EGPA, ABPA), crackles (Löffler pneumonia, chronic eosinophilic pneumonia)

— New S3, JVD, peripheral edema, or mitral regurgitation murmur from endomyocardial fibrosis

— Document baseline volume status — guides need for echo/troponin

Key distinction: Eosinophilic fasciitis spares hands/face and shows the groove sign; scleroderma involves hands and shows sclerodactyly with Raynaud's — both can have peripheral eosinophilia but differ sharply on exam.

Step 3 management: Any patient with eosinophilia AND a new murmur, troponin bump, or HF signs needs TTE plus cardiac troponin and BNP the same day — eosinophilic myocarditis can progress to fibrotic cardiomyopathy within weeks if untreated.

Vital signs first:

Skin (highest-yield exam):

HEENT:

Pulmonary:

Cardiac:

Abdomen: hepatosplenomegaly suggests clonal/myeloproliferative HES or lymphoma

Neurologic: asymmetric sensorimotor deficits (mononeuritis multiplex), foot drop → urgent EMG and ANCA testing

MSK: synovitis, myalgias → eosinophilic fasciitis (groove sign — depressed veins on raised arms)

Diagnostic Workup — Initial Labs and Imaging

— Repeat CBC with differential to confirm persistence (>1 month for HE definition)

— Peripheral smear reviewed by hematology — look for blasts, dysplastic eos, leukoerythroblastic features

— CMP (LFTs, Cr — DRESS, organ involvement)

— LDH, uric acid (high turnover, lymphoma, clonal disease)

— Troponin and NT-proBNP — screen for cardiac involvement even if asymptomatic when AEC ≥1,500

— ECG — low-voltage, ST changes, conduction disease

— Urinalysis — eosinophiluria, proteinuria, casts (vasculitis, interstitial nephritis)

— Total IgE, tryptase (mast cell), vitamin B12 (markedly elevated in myeloproliferative HES)

— HIV, hepatitis serologies (immunosuppression risk before steroids)

— Strongyloides IgG serology — mandatory before systemic steroids in any at-risk patient; missed strongyloidiasis + steroids = hyperinfection syndrome with gram-negative sepsis

— Stool O&P × 3 (low sensitivity), Schistosoma/Filaria serology if exposure

— CXR — Löffler, chronic eosinophilic pneumonia (peripheral "photographic negative of pulmonary edema"), ABPA

— CT chest/abdomen/pelvis if HE persists, lymphadenopathy, or B symptoms — assess for lymphoma, solid tumor, organomegaly

— TTE if AEC ≥1,500, any cardiac symptom, or elevated troponin/BNP

CCS pearl: For an inpatient admitted with new severe eosinophilia, order CBC with diff, CMP, LDH, troponin, BNP, UA, ECG, CXR, Strongyloides serology, HIV, tryptase, B12, and TTE on day 1 — and hold non-essential medications. Re-evaluate the medication list at every CCS time advance.

Confirm and characterize the eosinophilia first:

First-tier labs (every patient with persistent AEC ≥1,500 or symptoms):

Infection screening (especially before steroids):

Imaging:

Autoimmune panel when vasculitis suspected: ANCA (PR3, MPO), ANA, complement, RF, anti-CCP

Diagnostic Workup — Advanced and Confirmatory Studies

— Peripheral blood FISH or RT-PCR for FIP1L1-PDGFRA fusion — defines a treatable myeloid neoplasm exquisitely sensitive to imatinib

— Additional rearrangements: PDGFRB, FGFR1, JAK2, FLT3

— Serum tryptase >11.5 ng/mL → consider systemic mastocytosis (check KIT D816V)

— Bone marrow biopsy with cytogenetics, flow cytometry, and molecular studies if clonal disease suspected, smear abnormal, B12 markedly elevated, or AEC >5,000 unexplained

— Peripheral T-cell immunophenotyping (CD3−CD4+ or CD3+CD4−CD8− aberrant populations)

— TCR gene rearrangement studies

— Endoscopy with biopsies for EoE (≥15 eos/hpf in esophagus), eosinophilic gastroenteritis

— Skin biopsy for vasculitis (leukocytoclastic with eos), fasciitis (full-thickness to fascia)

— Nerve/muscle biopsy for EGPA when ANCA-negative

— Endomyocardial biopsy in suspected eosinophilic myocarditis when imaging equivocal

Key distinction: FIP1L1-PDGFRA–positive HES is a myeloid neoplasm (responds to low-dose imatinib 100–400 mg) — distinguish from lymphocytic-variant HES (clonal aberrant T cells producing IL-5; responds to steroids and mepolizumab, not imatinib).

Board pearl: Markedly elevated serum B12 plus splenomegaly plus dysplastic eos points to myeloid HES — send FIP1L1-PDGFRA before starting empiric steroids.

When initial workup is unrevealing and AEC remains ≥1,500, escalate:

Hematology/clonality workup (rule out clonal HE):

T-cell clonality (lymphocytic-variant HES):

Tissue diagnosis when organ-specific:

Cardiac MRI — gadolinium enhancement, apical thrombus, endomyocardial fibrosis; more sensitive than TTE for early Löffler

PFTs with bronchoprovocation for asthma/EGPA phenotyping; bronchoscopy with BAL if ABPA or chronic eosinophilic pneumonia

Risk Stratification and First-Line Management Logic

— AEC <1,500, asymptomatic, no organ involvement → outpatient, repeat CBC, treat identifiable cause (drug, atopy, parasites)

— AEC ≥1,500 with organ damage → hypereosinophilic syndrome → urgent treatment, often inpatient

— Any cardiac involvement, neurologic deficit, or thromboembolism → emergent corticosteroids after Strongyloides screen

— Drug-induced → stop drug; steroids only if DRESS with organ involvement

— Parasitic → antihelminthic (ivermectin for Strongyloides, albendazole for most others, praziquantel for schistosomes)

— Atopic/asthma → inhaled or systemic steroids, biologics

— Vasculitis (EGPA) → steroids ± rituximab or cyclophosphamide

— Clonal/FIP1L1-PDGFRA → imatinib first-line

— Idiopathic HES → corticosteroids, then mepolizumab as steroid-sparing

— Always empirically treat with ivermectin 200 µg/kg × 1–2 doses before high-dose steroids in anyone with potential Strongyloides exposure if serology pending or unavailable

— Screen HBV/HIV before immunosuppression

— Check baseline echo, ECG, troponin before any urgent steroid burst for HES

— AEC >100,000 or rising rapidly + signs of leukostasis → consider hydroxyurea, leukapheresis, hematology emergency

Step 3 management: For symptomatic HES without identified cause, start prednisone 1 mg/kg/day (or methylprednisolone 1 mg/kg IV if life-threatening) after Strongyloides empiric coverage. Expect a 50% drop in AEC within 24–48 hours; absence of response suggests clonal disease — escalate workup.

Board pearl: Steroids before ivermectin in unscreened patients from endemic regions is a classic exam trap — hyperinfection mortality exceeds 70%.

Branch point 1 — Severity and end-organ damage:

Branch point 2 — Cause-directed therapy whenever possible:

Branch point 3 — Pre-treatment safety:

Urgency threshold:

Pharmacotherapy — First-Line Regimens

— Prednisone 0.5–1 mg/kg/day PO (max ~60 mg) for moderate disease

— Methylprednisolone 1 mg/kg IV q6–12h for life-threatening cardiac, neuro, or thrombotic complications

— Taper over weeks to months guided by AEC, symptoms, and steroid-sparing agent introduction

— PJP prophylaxis if ≥20 mg prednisone for ≥4 weeks

— Bone protection, glucose monitoring, GI prophylaxis when high-risk

— 100 mg/day starting dose; often complete molecular response

— Monitor LFTs, cytopenias, fluid retention

— Add prednisone 1 mg/kg × 7–10 days at initiation if cardiac involvement — risk of acute LV dysfunction from massive eos lysis

— 300 mg SC monthly for HES; 100 mg for asthma; 300 mg for EGPA

— Steroid-sparing; reduces exacerbations; well tolerated

— Benralizumab and reslizumab are alternatives in asthma

— Ivermectin 200 µg/kg/day × 2 days (Strongyloides; repeat in 2 weeks)

— Albendazole 400 mg BID × 5–7 days (most others)

— Praziquantel 40 mg/kg single dose (schistosomes)

— EoE: PPI BID × 8 weeks, then swallowed fluticasone or budesonide; dupilumab for refractory

— ABPA: prednisone + itraconazole

CCS pearl: When starting steroids for HES with cardiac involvement, also order anticoagulation evaluation — intracardiac thrombus and arterial embolism are common; LMWH or warfarin per echo findings.

Board pearl: Mepolizumab is the steroid-sparing biologic of choice across the eosinophilic spectrum (HES, EGPA, asthma, EoE, CRSwNP).

Corticosteroids (mainstay for idiopathic and lymphocytic HES, EGPA, DRESS with organ involvement):

Imatinib (FIP1L1-PDGFRA–positive myeloid HES):

Mepolizumab (anti–IL-5, FDA-approved for HES, EGPA, severe eosinophilic asthma, EoE):

Hydroxyurea — for rapid cytoreduction in steroid-refractory HE or AEC >100,000

Interferon-α, cyclosporine, methotrexate — second-line steroid-sparing

Antihelminthics:

Cause-specific:

Procedures and Advanced Interventions

— Indicated for symptomatic leukostasis with AEC >100,000 or rapidly rising counts with end-organ ischemia

— Bridge to cytoreductive therapy; not definitive

— Confirms eosinophilic myocarditis when imaging is equivocal and treatment decisions hinge on diagnosis

— Sample right ventricular septum; risk of perforation, arrhythmia

— Three stages: acute necrotic, thrombotic, fibrotic

— Advanced fibrotic stage with severe MR/TR or restrictive physiology may require valve repair/replacement and endomyocardial stripping (endocardiectomy)

— Anticoagulation for intracavitary thrombus

— Esophageal dilation for EoE strictures refractory to medical therapy — small-caliber dilation with mucosal rent acceptable; counsel patient on post-procedure chest pain

— Repeat endoscopy with biopsies to assess histologic remission (<15 eos/hpf)

— Allogeneic HSCT for refractory clonal HES, FGFR1-rearranged neoplasms (poor prognosis), aggressive disease failing TKIs and biologics

— Nerve/sural biopsy (EGPA), skin/fascia biopsy (eosinophilic fasciitis), lymph node excisional biopsy (lymphoma, Castleman, Kimura)

— ICD for ventricular arrhythmia survivors from eosinophilic myocarditis; CRT if criteria met after fibrotic remodeling

Step 3 management: Before esophageal dilation in EoE, document trial of medical therapy (PPI ± topical steroid) and shared decision-making about perforation risk (~0.3%); start with small-caliber dilators and progress over multiple sessions ("start low, go slow, dilate to symptoms").

Board pearl: FGFR1-rearranged myeloid/lymphoid neoplasm with eosinophilia ("8p11 syndrome") is aggressive, frequently progresses to AML/lymphoma, and warrants early allogeneic HSCT referral.

Leukapheresis:

Endomyocardial biopsy:

Cardiac surgery for Löffler endocarditis:

Endoscopic interventions:

Bone marrow transplant:

Procedural biopsies for diagnosis:

Implantable cardiac devices:

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher baseline burden of polypharmacy — drug-induced eosinophilia far more likely; review every medication started in prior 8 weeks

— Lower threshold for CT and malignancy workup — solid tumors (lung, GI, GU), lymphoma, and clonal myeloid disease all rise with age

— Steroid toxicity disproportionately harms older adults: osteoporosis, glucose dysregulation, delirium, infection, fracture

— Consider steroid-sparing biologics earlier (mepolizumab) and aggressive bone protection (calcium, vitamin D, DEXA, bisphosphonate if FRAX-positive)

— Acute interstitial nephritis (AIN) is itself a cause of eosinophilia and eosinophiluria; classic triad of rash, fever, eosinophilia present in <10% — low threshold to suspect with new AKI on PPI, NSAID, or beta-lactam

— Stop offending drug; consider short steroid course if no improvement in 5–7 days

— Dose adjustments: ivermectin no adjustment needed; albendazole no major renal adjustment; hydroxyurea reduce in CKD

— Avoid IV contrast unnecessarily during workup if AKI

— DRESS commonly causes hepatitis — stop drug, supportive care, steroids if severe (encephalopathy, INR >1.5)

— Imatinib metabolized hepatically — reduce dose, monitor LFTs; albendazole hepatotoxic

— Schistosomiasis can cause periportal fibrosis with eosinophilia — treat with praziquantel

Step 3 management: In an elderly patient on a PPI with new eosinophilia, AKI, and pyuria, the answer is almost always stop the PPI and recheck in 1–2 weeks before pursuing biopsy — empiric drug withdrawal is both diagnostic and therapeutic.

Board pearl: Eosinophiluria has poor sensitivity/specificity for AIN — clinical context and drug timing matter more than the urine eos stain.

Elderly considerations:

Renal impairment:

Hepatic impairment:

Frailty: weigh aggressive workup (bone marrow, repeated endoscopy) against goals of care

Special Populations — Pregnancy, Pediatrics, and Travelers

— Mild eosinophilia common with atopic disease; persistent HE warrants workup, but defer bone marrow biopsy and CT to postpartum when possible

— Asthma must be controlled — uncontrolled asthma carries higher fetal risk than ICS/LABA exposure

— Mepolizumab and omalizumab: limited pregnancy data; continue if needed for severe disease per shared decision

— Corticosteroids: prednisone preferred (placental 11β-HSD2 inactivates ~90%); avoid fluorinated steroids (dexamethasone, betamethasone) for maternal indications

— Hydroxyurea, methotrexate, cyclophosphamide are teratogenic — contraindicated

— Antihelminthics: ivermectin and praziquantel acceptable in 2nd/3rd trimester for symptomatic disease; albendazole avoided in 1st trimester

— Atopic dermatitis, asthma, food allergy, and parasites (Toxocara, pinworm-related, visceral larva migrans) dominate

— EoE classically presents with feeding difficulty, vomiting, failure to thrive in young children and dysphagia/food impaction in adolescents

— Consider immunodeficiency with very high IgE: hyper-IgE (Job) syndrome (recurrent skin/lung abscesses, retained primary teeth, coarse facies), Omenn, Wiskott-Aldrich

— Congenital HES rare; pediatric clonal disease workup mirrors adult

— Time course matters: eos peaks during tissue migration phase (Loeffler ~1–2 weeks after exposure; schistosomiasis Katayama fever ~4–8 weeks)

— Empiric ivermectin reasonable for at-risk traveler before steroid initiation

— Test for Strongyloides, schistosomiasis, filariasis based on geography

Key distinction: Hyper-IgE syndrome — eosinophilia, IgE >2,000, eczema, recurrent staph abscesses ("cold" abscesses), pneumatoceles, retained baby teeth — distinct from atopic dermatitis by infection pattern.

Step 3 management: Pregnant patient with newly diagnosed EGPA — start prednisone, defer cyclophosphamide; consider mepolizumab for steroid-sparing with maternal-fetal medicine co-management.

Pregnancy:

Pediatrics:

Returning travelers:

Complications and Adverse Outcomes

— Three stages of eosinophilic endomyocardial disease (Löffler):

— Acute necrotic (weeks): myocyte injury, troponin leak, arrhythmia

— Thrombotic (months): mural thrombi, peripheral embolization, stroke

— Fibrotic (months–years): restrictive cardiomyopathy, severe AV-valve regurgitation

— Sudden cardiac death from VT/VF; heart failure, embolic stroke

— Both arterial and venous; risk persists across all HES subtypes

— Splenic, hepatic, mesenteric, cerebral infarcts described

— Anticoagulation often required but does not fully mitigate risk

— Mononeuritis multiplex (EGPA — foot drop, wrist drop)

— Encephalopathy, embolic stroke, peripheral neuropathy

— Acute eosinophilic pneumonia → ARDS; chronic eosinophilic pneumonia → fibrosis

— ABPA → bronchiectasis, mucus plugging

— EoE strictures, food impaction, perforation with dilation

— Eosinophilic gastroenteritis → ascites, obstruction, protein loss

— DRESS → fulminant hepatitis, myocarditis, thyroiditis (may appear weeks–months after recovery — counsel about delayed thyroid disease)

— Strongyloides hyperinfection syndrome post-steroid — disseminated larvae, gram-negative bacteremia/meningitis, >70% mortality

— Steroid toxicity (DM, osteoporosis, infection)

— Imatinib-associated acute LV dysfunction from massive eos degranulation

— Cyclophosphamide infertility, bladder cancer, hemorrhagic cystitis

Board pearl: Patients recovering from DRESS need TSH monitoring at 6 weeks and 3 months — delayed autoimmune thyroiditis (and rarely T1DM) is a well-documented late sequela.

Step 3 management: Any HES patient with intracardiac thrombus on echo → therapeutic anticoagulation (warfarin or DOAC) plus systemic steroids and cardiology co-management; consider serial echo every 3–6 months to track regression.

Cardiac (the highest-morbidity complication):

Thromboembolism:

Neurologic:

Pulmonary:

GI:

Dermatologic/systemic:

Treatment-related:

When to Escalate Care — ICU, Consults, and Inpatient Triage

— Hemodynamic instability from eosinophilic myocarditis or vasculitis

— Acute respiratory failure (acute eosinophilic pneumonia, ARDS)

— Massive stroke or mesenteric ischemia from eosinophil-related thrombosis

— Leukostasis with AEC >100,000 and end-organ ischemia

— DRESS with fulminant hepatitis, myocarditis, or hemodynamic compromise

— New HES with cardiac, neuro, or pulmonary involvement requiring IV steroids

— Suspected hyperinfection syndrome

— Severe DRESS without organ failure but with progressing rash, fever, lymphadenopathy

— AEC ≥5,000 with rapid rise even if asymptomatic

— Hematology/Oncology — clonal workup, bone marrow, imatinib decisions

— Allergy/Immunology — atopic phenotypes, mepolizumab management, immunodeficiency workup

— Rheumatology — EGPA, eosinophilic fasciitis, IgG4-related disease

— Cardiology — any troponin/BNP elevation or echo abnormality

— Infectious disease — returning traveler, hyperinfection, atypical infection

— Dermatology — DRESS, biopsy guidance

— Gastroenterology — EoE, eosinophilic gastroenteritis

— Suspected FIP1L1-PDGFRA or FGFR1 disease for molecular testing and HSCT evaluation

— Refractory HES needing biologics not available locally

CCS pearl: On an inpatient case with rapidly rising eos and new troponin elevation, the correct early actions are: stop nonessential meds, IV methylprednisolone (after ivermectin), TTE, cardiology consult, telemetry, troponin q6h × 3, BNP, and hematology consult. Delay these and the case will progress to cardiogenic shock at the next time advance.

Board pearl: A new murmur in a patient with HE is a board emergency — answer is immediate echo, not outpatient referral.

Immediate ICU criteria:

Inpatient (non-ICU) admission criteria:

Consultations to obtain (CCS-style):

Transfer to tertiary care:

Key Differentials — Same-Category (Eosinophilic) Causes

— DRESS — fever, rash, lymphadenopathy, organ involvement

— Simple drug eosinophilia — asymptomatic, resolves with drug withdrawal

— AIN — AKI ± rash, fever

— Eosinophilic pneumonitis (nitrofurantoin, daptomycin, minocycline)

— Asthma, allergic rhinitis, atopic dermatitis — mild eosinophilia, rarely >1,500

— Chronic rhinosinusitis with nasal polyps (CRSwNP), AERD (Samter triad: asthma + nasal polyps + ASA sensitivity)

— EoE — dysphagia, food impaction, ≥15 eos/hpf esophagus

— Eosinophilic gastritis/enteritis/colitis

— Acute eosinophilic pneumonia — young smokers, ARDS, BAL eos >25%

— Chronic eosinophilic pneumonia — middle-aged women with asthma, peripheral infiltrates

— ABPA — asthma/CF, central bronchiectasis, IgE >1,000, Aspergillus precipitins

— EGPA — asthma, sinusitis, eosinophilia >10%, neuropathy, MPO-ANCA in 40%

— FIP1L1-PDGFRA myeloid neoplasm; PDGFRB, FGFR1, JAK2 rearrangements

— Chronic eosinophilic leukemia, NOS

— Lymphocytic-variant HES (clonal T cells driving IL-5)

— Systemic mastocytosis with eosinophilia

Key distinction: Chronic eosinophilic pneumonia classically shows peripheral ("reverse pulmonary edema") infiltrates in a woman with asthma and dramatic steroid response, whereas EGPA adds eosinophilic vasculitis with extrapulmonary features (neuropathy, cardiac, renal).

Board pearl: BAL eosinophilia >25% essentially defines acute eosinophilic pneumonia; peripheral blood eos may be normal initially.

Drug reactions (most common in US adults):

Atopic/allergic:

Eosinophilic GI diseases:

Eosinophilic lung disease:

Vasculitis:

Clonal/neoplastic eosinophilia:

Idiopathic HES — diagnosis of exclusion after the above

Key Differentials — Other-Category Causes

— Strongyloides — chronic, larva currens, autoinfection, hyperinfection

— Schistosoma — Katayama fever, hematuria, hepatic fibrosis

— Filariasis (Loa loa, Wuchereria, Onchocerca), tropical pulmonary eosinophilia

— Toxocara (visceral larva migrans), Trichinella, Ascaris, hookworm

— Coccidioidomycosis (peripheral eos with primary pulmonary infection)

— HIV (especially with adrenal involvement, drug reactions, or eosinophilic folliculitis)

— Scabies (crusted/Norwegian)

— Hodgkin lymphoma (classic), T-cell lymphomas (mycosis fungoides, Sézary)

— Solid tumors paraneoplastic — lung, GI, cervical, renal

— Acute lymphoblastic leukemia with eosinophilia (t(5;14))

— IgG4-related disease (autoimmune pancreatitis, retroperitoneal fibrosis, sialadenitis)

— Eosinophilic fasciitis (Shulman) — peau d'orange, groove sign

— Rheumatoid arthritis, SLE (occasional)

— Inflammatory bowel disease

— Adrenal insufficiency — eosinophilia from loss of cortisol's eos-suppressive effect; classic stem with hyponatremia, hyperkalemia, hypotension

— Post-cath/vascular procedure, livedo, blue toes, AKI, eosinophilia, low complement

Board pearl: Eosinophilia + hyponatremia + hyperkalemia + hypotension = adrenal insufficiency — check cortisol/ACTH stim before chasing exotic causes.

Key distinction: Protozoal infections (giardia, malaria, amebiasis, toxoplasmosis) generally do not cause eosinophilia — eosinophilia in a returning traveler steers you toward helminths.

Infections (especially helminths — protozoa generally do NOT cause eosinophilia):

Malignancy (non-eosinophil-primary):

Autoimmune/connective tissue:

Endocrine:

Cholesterol embolization syndrome:

Graft-versus-host disease post allogeneic transplant

Miscellaneous: hyper-IgE syndromes, Omenn, Wiskott-Aldrich, IPEX

Secondary Prevention, Discharge Plan, and Long-Term Management

— Document the eliminated offending drug on the allergy list with reaction type (DRESS, AIN, simple eosinophilia) — prevents future reintroduction

— Cross-reactivity counseling (e.g., aromatic anticonvulsants — carbamazepine, phenytoin, lamotrigine — cross-react; choose levetiracetam or valproate instead)

— Provide a written medication safety list and update the EHR allergy module

— HES: chronic steroid taper to lowest effective dose; introduce mepolizumab early as steroid-sparing; monitor AEC monthly initially

— FIP1L1-PDGFRA: continue imatinib indefinitely (off-label discontinuation only after sustained molecular remission >2 years in trials); monitor for relapse

— EGPA: induction prednisone ± rituximab/cyclophosphamide → maintenance with rituximab, azathioprine, MTX, or mepolizumab; ANCA and AEC trend

— EoE: indefinite PPI or topical steroid; periodic endoscopy to confirm histologic remission; consider food elimination diet

— ABPA: prednisone taper, itraconazole 4–6 months, monitor IgE

— Asthma with eosinophilic phenotype: ICS-LABA + biologic (mepolizumab/benralizumab/dupilumab) for AEC ≥150 with exacerbations

— Pre-treatment: influenza, COVID, pneumococcal (PCV20 or PCV15+PPSV23), zoster (RZV ≥18 if immunocompromised), HBV

— Avoid live vaccines on biologics/steroids ≥20 mg × 2+ weeks

Step 3 management: A DRESS survivor needs TSH at 6 weeks and 3 months, EHR allergy update, cross-reactant counseling, and primary care follow-up within 1–2 weeks to track resolution of organ involvement.

Discharge medication reconciliation:

Cause-specific long-term plans:

Vaccinations before/after immunosuppression:

Bone health on chronic steroids: calcium 1,000–1,200 mg, vitamin D 800–1,000 IU, DEXA, bisphosphonate per ACR guidelines

PJP prophylaxis: TMP-SMX when prednisone ≥20 mg ≥4 weeks plus second immunosuppressant

Follow-Up, Monitoring, and Counseling

— Acute: AEC, CBC, CMP weekly for the first month after steroid initiation

— Stabilization: AEC monthly for 6 months

— Maintenance: AEC every 3 months once stable; biologic-specific monitoring per drug label

— Cardiac: TTE at baseline, 3 months, then annually if HES; sooner with symptoms or rising troponin

— Pulmonary: PFTs every 6–12 months in eosinophilic asthma, EGPA, ABPA

— Endoscopy: EoE — repeat after 8–12 weeks of therapy to confirm <15 eos/hpf, then symptom-driven

— Renal: UA and creatinine every 3–6 months on cyclophosphamide; lifelong bladder cancer screening after cumulative exposure

— Imatinib: LFTs, CBC monthly × 3, then quarterly; molecular response by PDGFRA PCR every 3–6 months

— Mepolizumab: monitor for hypersensitivity, herpes zoster reactivation

— Methotrexate: CBC, LFTs, Cr every 2–3 months; folic acid daily

— Azathioprine: TPMT/NUDT15 before starting; CBC/LFTs every 1–3 months

— Corticosteroids: glucose, BP, DEXA, eye exam (cataract/glaucoma) annually

— Adherence to taper — do not self-discontinue steroids

— Recognize relapse: return of asthma, neuropathy, rash, fevers, weight loss

— Travel precautions: avoid endemic helminth areas during immunosuppression

— Sun protection on immunosuppressants; skin cancer surveillance

— Reproductive counseling before teratogens (cyclophosphamide, MTX) — sperm/oocyte banking

— Cardiac rehab post-myocarditis

— Speech/swallow evaluation post EoE dilation if persistent dysphagia

Board pearl: In FIP1L1-PDGFRA HES, molecular monitoring by RT-PCR is the gold standard for relapse detection — AEC may normalize before molecular remission and rise after molecular relapse.

Monitoring cadence by phase:

Organ surveillance:

Therapy-specific labs:

Counseling priorities:

Rehab:

Ethical, Legal, and Patient Safety Considerations

— Document discussion of infection risk (especially Strongyloides hyperinfection), malignancy risk with prolonged therapy, infertility risk with cyclophosphamide, teratogenicity

— Shared decision-making about biologics vs. chronic steroids, with cost transparency (mepolizumab ~$30,000/year retail)

— Pediatric and adolescent patients: assent plus parental consent

— DRESS patients discharged with multiple holds need explicit handoff to PCP within 1–2 weeks including: implicated drug, cross-reactive drugs to avoid, TSH follow-up timeline, and active steroid taper schedule

— Medication reconciliation at every transition — emergency department, hospital, SNF, primary care — to avoid reintroduction of the offending agent

— Closed-loop communication when a specialist starts a biologic — PCP needs to know about live vaccine restrictions and infection precautions

— DRESS and other severe ADRs to FDA MedWatch

— Notifiable parasitic diseases vary by state (schistosomiasis, trichinellosis often reportable)

— Occupational exposures (eosinophilia in a worker with new chemical/dust exposure → OSHA considerations)

— Counsel about contraception during teratogenic therapy; document discussion

— Maternal-fetal medicine co-management for biologic continuation

— Biologic prior authorization barriers — document AEC, exacerbations, steroid burden

— Patient assistance programs for uninsured patients

— Returning immigrants and refugees may have undiagnosed Strongyloides for decades — empiric ivermectin screening before steroids is the standard of care

— Language-concordant counseling about long-term immunosuppression

Step 3 management: When a clinician restarts a drug previously implicated in DRESS because the allergy was undocumented, the systems-level fix is closed-loop EHR allergy reconciliation at admission and discharge, not blaming the individual prescriber.

Informed consent for immunosuppression:

Transition-of-care safety (Step 3–flavored, high-yield):

Mandatory and recommended reporting:

Pregnancy and reproductive ethics:

Cost and access:

Health equity:

High-Yield Associations and Rapid-Fire Clinical Facts

Board pearl: When the stem says "eosinophilia" plus any one of (new asthma, new neuropathy, new cardiomyopathy, post-drug rash, dysphagia, travel), the first action is to anchor the syndrome, not to order an exhaustive shotgun workup.

Eosinophilia + new asthma + sinusitis + mononeuritis multiplex → EGPA (check MPO-ANCA)

Eosinophilia + facial edema + rash + LFT rise 2–6 weeks after a new drug → DRESS (HHV-6 reactivation common)

Eosinophilia + dysphagia + food impaction in a young atopic adult → EoE (15+ eos/hpf)

Eosinophilia + peripheral pulmonary infiltrates + middle-aged woman with asthma → chronic eosinophilic pneumonia

Eosinophilia + young male smoker + ARDS, BAL eos >25% → acute eosinophilic pneumonia

Eosinophilia + B12 markedly elevated + splenomegaly → myeloid HES / FIP1L1-PDGFRA

Eosinophilia + Aspergillus precipitins + IgE >1,000 + asthma/CF + central bronchiectasis → ABPA

Eosinophilia + Samter triad (asthma, nasal polyps, ASA sensitivity) → AERD

Eosinophilia + hyponatremia + hyperkalemia + hypotension → adrenal insufficiency

Eosinophilia + livedo + AKI + blue toes after cath → cholesterol embolization

Eosinophilia + crusted skin + immunocompromise → Norwegian scabies

Eosinophilia + ground glass + young woman + miscarriages + lymphadenopathy → consider IgG4-related disease or lymphoma

Eosinophilia + peau d'orange forearms + groove sign → eosinophilic fasciitis

Eosinophilia + recurrent staph abscesses + retained primary teeth → hyper-IgE (Job) syndrome

Eosinophilia + larva currens + immigrant from endemic area → Strongyloides

Eosinophilia + Katayama fever after freshwater swimming in Africa → schistosomiasis

Eosinophilia + apical thrombus on echo → Löffler endocarditis — anticoagulate

Steroids before ivermectin in at-risk patient → hyperinfection syndrome with gram-negative sepsis

Imatinib 100 mg dramatically resolves eos → FIP1L1-PDGFRA fusion

Mepolizumab = anti-IL-5 = HES, EGPA, eos asthma, EoE, CRSwNP

Board Question Stem Patterns

— Best next step: stop allopurinol, supportive care, systemic steroids

— Avoid: rechallenge ever; warn about cross-reactivity (febuxostat is alternative)

— Best next step: Strongyloides IgG serology and empiric ivermectin

— Avoid: starting steroids before screening

— Best next step: MPO-ANCA, nerve conduction studies, high-dose steroids

— Diagnosis: EGPA; consider mepolizumab for maintenance

— Best next step: peripheral blood FIP1L1-PDGFRA PCR; start prednisone + low-dose imatinib

— Echo and cardiac MRI; anticoagulate if thrombus

— Best next step: EGD with biopsies (proximal and distal esophagus); ≥15 eos/hpf confirms

— Treat with PPI BID × 8 weeks, then swallowed steroid if persistent

— Best next step: morning cortisol + ACTH; cosyntropin stim

— Best next step: BAL (eos >25% diagnostic); steroids; smoking cessation

— Best next step: supportive care, statin, avoid further instrumentation; biopsy if uncertain

Step 3 management: Pattern recognition beats exhaustive testing — once the syndrome is named, choose the single most targeted confirmatory test the question allows.

Stem 1 — Drug reaction (most common): 45-year-old started allopurinol 4 weeks ago presents with fever, diffuse morbilliform rash, facial edema, transaminase elevation, AEC 4,500.

Stem 2 — Pre-steroid screening: Patient from Southeast Asia with persistent eosinophilia about to start prednisone for HES.

Stem 3 — EGPA: Adult with worsening asthma, chronic sinusitis, new foot drop, AEC 6,000.

Stem 4 — FIP1L1-PDGFRA: Man with eosinophilia, splenomegaly, B12 >2,000, new troponin elevation.

Stem 5 — EoE: 28-year-old with food impaction and chronic dysphagia, atopic history.

Stem 6 — Adrenal insufficiency masquerading: Fatigue, hyperpigmentation, hyponatremia, hyperkalemia, AEC 800.

Stem 7 — Acute eosinophilic pneumonia: Young male recent smoking start, fever, hypoxia, diffuse infiltrates; peripheral eos normal.

Stem 8 — Cholesterol embolization: Post-cath patient with livedo, AKI, blue toes, low C3.

One-Line Recap

Eosinophilia workup is a stepwise process: confirm with absolute eosinophil count, characterize by severity and duration, identify reversible causes (drugs, atopy, parasites) before pursuing clonal and idiopathic disease, and never give systemic steroids in an at-risk patient without empiric ivermectin or Strongyloides screening.

Board pearl: When in doubt on Step 3 — repeat the CBC, reconcile the medication list, and screen for Strongyloides before reaching for prednisone.

Diagnostic anchor: AEC ≥1,500 × 2 (>1 month apart) or with end-organ damage = hypereosinophilia; add organ injury → hypereosinophilic syndrome (HES).

Workup ladder: Repeat CBC + smear → drug/travel/atopy history → CMP, troponin, BNP, ECG, TTE, UA, IgE, tryptase, B12, Strongyloides serology, HIV → CT, bone marrow with FIP1L1-PDGFRA and T-cell clonality if unexplained.

Treatment logic: Cause-directed first (stop drug, treat parasite, control asthma); idiopathic/lymphocytic HES → prednisone 1 mg/kg after empiric ivermectin, then mepolizumab as steroid-sparing; myeloid (PDGFRA+) HES → imatinib; EGPA → steroids + rituximab/cyclophosphamide or mepolizumab.

Safety triad to never miss: (1) empiric ivermectin before steroids in any potentially exposed patient; (2) screen for cardiac involvement with troponin/BNP/echo in every HE patient; (3) document the implicated drug and cross-reactants in the EHR allergy list at every transition of care.