What are the differential diagnoses and recommended work‑up for a patient with high‑grade fever and rigors, mild splenomegaly, isolated eosinophilia, normal procalcitonin and modestly elevated CRP (~26 mg/L) without cytopenia?

Differential Diagnosis and Work-Up for Fever with Eosinophilia and Mild Splenomegaly

Primary Recommendation

In a patient with high-grade fever, rigors, isolated eosinophilia, mild splenomegaly, normal procalcitonin, and modestly elevated CRP (~26 mg/L) without cytopenia, the normal procalcitonin effectively excludes bacterial sepsis and should redirect your investigation toward parasitic infections (particularly helminthic), drug hypersensitivity reactions (especially DRESS syndrome), and fungal infections—in that order. 1, 2, 3

Critical Interpretation of Laboratory Findings

Procalcitonin Analysis

• Normal procalcitonin (<0.5 ng/mL) has 100% negative predictive value for bacterial sepsis in this clinical context, making bacterial infection highly unlikely despite the fever and elevated CRP 1, 2
• Procalcitonin rises to 2-10 ng/mL in severe sepsis and >10 ng/mL in septic shock; your patient's normal value excludes these diagnoses 1, 2
• The dissociation between normal procalcitonin and elevated CRP is the key diagnostic clue: this pattern is characteristic of non-bacterial inflammatory processes 3, 4

CRP Interpretation

• CRP of 26 mg/L (normal <5-10 mg/L) indicates moderate systemic inflammation but is non-specific 2
• This CRP level can occur with parasitic infections, drug reactions, or fungal infections—all of which spare procalcitonin elevation 3, 4

Eosinophilia Significance

• Isolated eosinophilia with fever most commonly indicates parasitic helminth infection worldwide, followed by drug hypersensitivity and fungal infections 5, 6
• The absence of cytopenia excludes hypereosinophilic syndrome with bone marrow involvement and makes hematologic malignancy less likely 5

Prioritized Differential Diagnosis

1. Parasitic Helminth Infection (Most Likely)

• This is the most common infectious cause of eosinophilia worldwide 5, 6
• Helminthic infections characteristically produce eosinophilia, fever, splenomegaly, and normal procalcitonin 5, 6
• Tissue-invasive helminths (Strongyloides, Toxocara, Trichinella, Schistosoma) are particularly associated with high-grade fever and marked eosinophilia 6

2. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS Syndrome)

• DRESS syndrome presents with fever, eosinophilia, elevated CRP (mean 109 mg/L), and notably can have elevated procalcitonin despite being non-infectious 4, 7
• In DRESS cases, procalcitonin can paradoxically elevate (median 0.69 ng/mL, range up to several ng/mL) even without bacterial infection, though your patient's normal procalcitonin makes active DRESS less likely 4, 7
• Common culprit drugs include anticonvulsants (carbamazepine, phenytoin), allopurinol, sulfonamides, and antibiotics 4, 7
• Hepatosplenomegaly occurs in DRESS and would explain the mild splenomegaly 7

3. Fungal Infection

• Fungal infections can cause eosinophilia and fever with normal procalcitonin, though less commonly than parasites 6
• Consider endemic mycoses (histoplasmosis, coccidioidomycosis) based on geographic exposure 6

4. Tumor-Associated Eosinophilia (Lower Priority)

• Usually accompanied by widely metastatic disease with other clinical manifestations 5
• The absence of cytopenia and relatively preserved clinical status makes this less likely 5

Recommended Diagnostic Work-Up Algorithm

Immediate First-Line Investigations

Step 1: Detailed Exposure History

• Travel history to endemic areas for parasites (tropical/subtropical regions, rural areas with poor sanitation) 5
• Dietary exposures: raw or undercooked meat (Trichinella), freshwater fish (liver flukes), contaminated water or produce 5
• Complete medication review: focus on drugs started 2-8 weeks before symptom onset (typical DRESS latency) 4, 7
• Occupational and recreational exposures: soil contact, freshwater swimming, animal contact 5

Step 2: Parasitology Testing

• Obtain three separate stool specimens for ova and parasites on different days to maximize sensitivity 8, 5
• Serologic testing for tissue-invasive helminths: Strongyloides, Toxocara, Trichinella, Schistosoma antibodies 5, 6
• Blood smear for microfilariae if appropriate geographic exposure 6

Step 3: Drug Hypersensitivity Evaluation

• If any medication was started within 2-8 weeks of symptom onset, consider empiric discontinuation of the most likely culprit drug 4, 7
• Obtain liver function tests (ALT, AST, bilirubin) to assess for hepatitis associated with DRESS 4, 7
• Monitor for rash development, lymphadenopathy, and facial edema (DRESS features) 4, 7

Second-Line Investigations (If First-Line Negative)

Step 4: Fungal Work-Up

• Fungal serologies based on geographic exposure (Histoplasma, Coccidioides, Blastomyces antibodies) 6
• Consider beta-D-glucan or galactomannan if invasive fungal infection suspected 6

Step 5: Imaging and Tissue Sampling

• Abdominal ultrasound or CT to characterize splenomegaly and assess for hepatomegaly, lymphadenopathy, or occult masses 7
• If splenomegaly is progressive or unexplained, consider bone marrow biopsy to exclude hematologic disorders 5

Step 6: Follow-Up Monitoring

• Repeat complete blood count with differential in 2-4 weeks to determine if eosinophilia persists or resolves 5
• If absolute eosinophil count >1.5 × 10⁹/L persists for >6 months without identified cause, rule out idiopathic hypereosinophilic syndrome 5

Critical Management Caveats

Do NOT Initiate Empiric Antibiotics

• Normal procalcitonin excludes bacterial sepsis with high confidence; empiric antibiotics are not indicated 1, 2, 3
• Unnecessary antibiotics may obscure the diagnosis and contribute to drug hypersensitivity 4, 7

Corticosteroid Timing

• Avoid corticosteroids until parasitic infection is excluded, as steroids can cause disseminated strongyloidiasis (potentially fatal hyperinfection syndrome) 6
• If DRESS syndrome is confirmed and parasites excluded, corticosteroids are the treatment of choice 4, 7

Serial Procalcitonin Monitoring

• Repeat procalcitonin if clinical status worsens or new symptoms develop to detect secondary bacterial infection 1, 2
• A rise in procalcitonin >50% from baseline indicates new bacterial infection requiring antimicrobial therapy 1, 2

Common Diagnostic Pitfalls to Avoid

1. Assuming bacterial infection based on fever and elevated CRP alone: Normal procalcitonin has superior specificity (77-83%) for bacterial infection compared to CRP (61%) 1, 2

2. Single stool examination for parasites: Sensitivity of single stool O&P is only 50-70%; three specimens on different days are required 5

3. Overlooking drug-induced eosinophilia: DRESS can present 2-8 weeks after drug initiation, and the temporal relationship may not be immediately obvious 4, 7

4. Premature corticosteroid administration: Always exclude Strongyloides before giving steroids to avoid potentially fatal hyperinfection 6