What are the differential diagnoses and appropriate work‑up for a 45‑year‑old man with eosinophilia, elevated serum uric acid, and mild pain in multiple small hand joints without early‑morning stiffness?

Differential Diagnoses and Evaluation for a 45-Year-Old Man with Eosinophilia, Elevated Uric Acid, and Small Joint Pain

The most likely diagnosis in this patient is gout with concurrent allergic disease or medication-induced eosinophilia, though you must systematically exclude parasitic infections, eosinophilic granulomatosis with polyangiitis (EGPA), and hypereosinophilic syndrome before settling on a benign cause.

Immediate Priority: Assess for End-Organ Damage

Before pursuing the differential diagnosis, any patient with eosinophilia must be immediately evaluated for cardiac, pulmonary, or neurological compromise, as these can progress to irreversible damage and death 1. This is critical even with mild eosinophilia.

Urgent Red Flags to Assess Now

• Cardiac symptoms: chest pain, dyspnea, heart failure symptoms, or arrhythmias require immediate ECG, troponin, and NT-proBNP 1
• Pulmonary symptoms: persistent cough, wheezing, or infiltrates on imaging necessitate urgent chest X-ray and pulmonary function tests 1
• Neurological symptoms: altered mental status, focal deficits, or peripheral neuropathy demand prompt EMG evaluation 1

Primary Differential Diagnoses

1. Gout (Most Likely for Joint Pain)

The uric acid of 7.2 mg/dL with small joint pain in the hands strongly suggests gout, though the absence of early morning stiffness makes inflammatory arthritis less likely 2. Gout itself does not cause eosinophilia, so the two findings are likely unrelated or the eosinophilia is medication-induced (see below) 3.

Key point: Eleven patients with gout in one rheumatology series had concurrent eosinophilia, with only one using allopurinol, suggesting the association may be coincidental or related to other medications 3.

2. Allergic/Atopic Disease (Most Common Cause of Eosinophilia)

In non-endemic areas, 80% of mild eosinophilia cases are due to allergic disorders 1, 4. Between 50-80% of adults with mild eosinophilia have concurrent atopic conditions such as allergic rhinitis, atopic dermatitis, or asthma 4.

3. Medication-Induced Eosinophilia (Critical to Exclude)

NSAIDs correlate positively with eosinophilia 3, and if this patient is taking NSAIDs for joint pain, this could explain the eosinophilia. Allopurinol can cause DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms) with exfoliative dermatitis, hepatitis, interstitial nephritis, and eosinophilia 5. Nitrofurantoin is also specifically implicated 4.

4. Parasitic Infection (Must Exclude in Any Eosinophilia)

Helminth infections account for 19-80% of eosinophilia in returning travelers or migrants 1, 4. Even without travel history, Strongyloides can persist lifelong and cause fatal hyperinfection syndrome in immunocompromised patients 1, 4.

5. Eosinophilic Granulomatosis with Polyangiitis (EGPA)

EGPA should be considered with the combination of eosinophilia and joint symptoms, though the absence of asthma makes this less likely 6. EGPA typically presents with adult-onset asthma, recurrent nasal polyps, and peripheral neuropathy 6. ANCA testing is positive in only 30-40% of EGPA patients, with MPO-ANCA being most common 6.

6. Hypereosinophilic Syndrome (Diagnosis of Exclusion)

If eosinophilia ≥1.5 × 10⁹/L persists for more than 3 months after excluding infectious causes, referral to hematology is required 1. This is a diagnosis of exclusion after ruling out all secondary causes 6, 1.

Structured Diagnostic Workup

Step 1: Obtain Absolute Eosinophil Count

Calculate the absolute eosinophil count from the CBC with differential 1, 7. The severity determines urgency:

• Mild (0.5-1.5 × 10⁹/L): Most commonly allergic or medication-induced 1, 4
• Moderate-severe (≥1.5 × 10⁹/L): Requires systematic exclusion of secondary causes before considering primary (clonal) causes 1
• >5.0 × 10⁹/L at any time: Carries significant risk of morbidity and mortality 1

Step 2: Detailed History (Critical Elements)

• Travel history: Fresh water exposure in Africa/tropical regions (schistosomiasis), raw/undercooked meat consumption, timing of travel relative to eosinophilia onset 1, 4
• Medication review: NSAIDs, allopurinol, beta-lactam antibiotics, nitrofurantoin 1, 4, 3, 5
• Atopic symptoms: Allergic rhinitis, asthma, eczema, seasonal variation 4
• Constitutional symptoms: Fever, weight loss, night sweats (suggest malignancy or vasculitis) 1
• Gastrointestinal symptoms: Dysphagia or food impaction (suggest eosinophilic esophagitis) 1, 4

Step 3: Initial Laboratory Studies

Mandatory basic tests 1:

• Complete blood count with manual differential
• Comprehensive metabolic panel with uric acid, LDH, liver function tests
• Serum tryptase levels (elevated in myeloproliferative neoplasms with PDGFRA fusion and systemic mastocytosis) 6, 1, 7
• Vitamin B12 levels (elevated in myeloproliferative variants) 6, 1, 7
• Peripheral blood smear to evaluate dysplasia, monocytosis, or circulating blasts 6, 1

Parasite evaluation (essential even without travel history) 1, 4:

• Three separate concentrated stool specimens for ova and parasites 1, 4
• Strongyloides serology (critical because it can persist lifelong and cause fatal hyperinfection) 1, 4
• Schistosomiasis serology if any fresh water exposure in endemic areas 1, 4

ANCA testing 6:

• MPO-ANCA and PR3-ANCA by ELISA (not just immunofluorescence) to evaluate for EGPA 6

Additional tests based on clinical suspicion 6:

• Quantitative serum immunoglobulin levels (including IgE) 6
• Aspergillus IgE if pulmonary symptoms present 6
• Antinuclear antibodies and antineutrophil cytoplasmic antibodies if vasculitis suspected 6

Step 4: Joint Evaluation for Gout

• Synovial fluid analysis from affected hand joints to confirm monosodium urate crystals (gold standard for gout diagnosis)
• Musculoskeletal ultrasound or dual-energy CT to detect urate deposits if synovial fluid cannot be obtained

Step 5: Advanced Studies if Eosinophilia Persists

If eosinophilia ≥1.5 × 10⁹/L persists for more than 3 months after excluding or treating infectious causes, hematology referral is mandatory 1.

Bone marrow evaluation 6, 1:

• Bone marrow aspirate and biopsy with immunohistochemistry for CD117, CD25, tryptase, and reticulin/collagen stains for fibrosis
• Conventional cytogenetics
• FISH and/or nested RT-PCR for tyrosine kinase fusion gene rearrangements (PDGFRA, PDGFRB, FGFR1, PCM1-JAK2)
• Next-generation sequencing (NGS) using myeloid mutation panels to establish clonality when no tyrosine kinase fusion genes detected 6, 1

Common Pitfalls to Avoid

1. Do not assume normal eosinophil counts exclude eosinophilic disease: Peripheral eosinophilia occurs in only 10-50% of adults with eosinophilic esophagitis 4, and many helminth-infected patients have normal counts 4

2. Do not delay parasitic workup: Even without travel history, Strongyloides serology is mandatory because of the risk of fatal hyperinfection syndrome 1, 4

3. Do not attribute eosinophilia to gout: Gout does not cause eosinophilia; look for concurrent medication use (NSAIDs, allopurinol) or allergic disease 3, 5

4. Do not miss medication-induced eosinophilia: Review all medications, especially NSAIDs (which this patient likely takes for joint pain) and allopurinol (which may be started for the elevated uric acid) 3, 5

5. Do not ignore the absence of early morning stiffness: This makes inflammatory arthritis (rheumatoid arthritis) less likely and supports gout as the cause of joint pain 2