What is the differential diagnosis for a patient with fever, mild thrombocytopenia, lymphocytosis, transaminitis, and diarrhea, considering potential exposures and medical history?

Differential Diagnosis: Fever, Mild Thrombocytopenia, Lymphocytosis, Transaminitis, and Diarrhea

The most critical diagnoses to consider are tickborne rickettsial diseases (particularly ehrlichiosis/anaplasmosis), Epstein-Barr virus (EBV) infection, and severe fever with thrombocytopenia syndrome (SFTS), with brucellosis as an important consideration in patients with relevant exposures.

High-Priority Infectious Etiologies

Tickborne Rickettsial Diseases (Ehrlichiosis/Anaplasmosis)

• This constellation of findings is highly characteristic of human monocytic ehrlichiosis (HME) or anaplasmosis. 1
• Thrombocytopenia (platelet count 50-150 × 10⁹/L) combined with elevated transaminases (AST/ALT often 400-500 U/L) strongly suggests tickborne rickettsial disease 1
• Lymphocytosis with band forms (left shift) is typical, though absolute lymphopenia may also occur 1
• Altered mental status occurs in up to 20% of HME cases, and diarrhea/gastrointestinal symptoms are common 1
• Examine peripheral blood smear specifically for intracellular morulae in monocytes or granulocytes 1
• Seasonality (spring through fall) and tick exposure history are critical diagnostic clues 1

Brucellosis

• Presents with fever, mild transaminitis, and pancytopenia (including thrombocytopenia) 1
• Hepatomegaly, splenomegaly, and lymphadenopathy are common physical findings 1
• Key exposure history: consumption of unpasteurized dairy products, occupational exposure (farmers, veterinarians, abattoir workers), or direct contact with infected animal tissues 1
• Bone marrow culture has the highest diagnostic sensitivity; blood cultures require prolonged incubation (up to 4 weeks) with special laboratory precautions 1

Epstein-Barr Virus (EBV) Infection

• Can present with fever, atypical lymphocytosis, thrombocytopenia, and transaminitis 2
• Neutropenia with atypical lymphocytes on peripheral smear is characteristic 2
• Hepatosplenomegaly and pharyngitis are common associated findings 2
• EBV polymerase chain reaction (PCR) provides definitive diagnosis 2

Severe Fever with Thrombocytopenia Syndrome (SFTS)

• Endemic to China, Korea, and Japan; presents with fever, thrombocytopenia, leukopenia, and gastrointestinal symptoms (diarrhea, nausea, vomiting) 3, 4, 5
• Elevated liver enzymes and progression to hemophagocytic lymphohistiocytosis are characteristic 3, 4
• Mortality rate approximately 20%; rapid clinical deterioration with multiple organ failure can occur 5
• Geographic exposure history (East Asia) and tick bite history are essential 5

Secondary Considerations

Bacterial Causes of Bloody Diarrhea with Systemic Manifestations

• Shigellosis can cause leukemoid reaction, fever, and bloody diarrhea 1
• Salmonella and Yersinia infections may cause sustained fever with bacteremia, particularly in older patients with atherosclerosis 1
• However, lymphocytosis is atypical for acute bacterial gastroenteritis, which typically shows neutrophilic predominance 1

Q Fever (Coxiella burnetii)

• Similar demographic and exposure profile to brucellosis (unpasteurized dairy, animal contact) 1
• Presents with non-specific symptoms including fever and transaminitis 1
• Serology becomes positive by the third week of illness in up to 90% of patients 1

HIV Seroconversion

• Can present with fever, lymphocytosis (mononucleosis-like syndrome), thrombocytopenia, and diarrhea 1
• Obtain sexual history and assess for risk factors: sexual contact with individuals from high HIV prevalence countries, unexplained lymphadenopathy, or macular-papular rash 1

Critical Diagnostic Algorithm

Immediate Laboratory Evaluation

1. Complete blood count with differential and peripheral blood smear examination - specifically look for morulae, atypical lymphocytes, and schistocytes 1
2. Comprehensive metabolic panel - assess renal function (creatinine) and electrolytes for hemolytic uremic syndrome (HUS) risk 1
3. Coagulation studies - PT/PTT to evaluate for disseminated intravascular coagulation 1
4. Blood cultures (before antibiotics) - hold for prolonged incubation if brucellosis suspected 1

Stool Evaluation

• Single diarrheal stool specimen for culture and Shiga toxin testing if bloody diarrhea present 1, 6
• Avoid routine bacterial cultures if patient has been hospitalized >3 days without initial diarrhea (unless HIV-positive or outbreak investigation) 1
• Do not send ova and parasite examination unless patient was admitted with diarrhea, is HIV-positive, or part of outbreak investigation 1

Specific Serologic/Molecular Testing

• Acute serology for Rickettsia rickettsii, Ehrlichia chaffeensis, and Anaplasma phagocytophilum 1
• PCR for ehrlichiosis/anaplasmosis if available 1
• Brucella serology and bone marrow culture if exposure history supports 1
• EBV PCR and monospot test 2
• HIV testing if risk factors present 1

Geographic and Exposure-Specific Testing

• SFTS virus PCR if patient has traveled to or resides in East Asia (China, Korea, Japan) 3, 4, 5
• Q fever serology if animal/dairy exposure 1

Empirical Treatment Considerations

When to Initiate Empirical Doxycycline

Empirical doxycycline (100 mg orally or IV twice daily) should be initiated immediately if tickborne rickettsial disease is suspected, without waiting for confirmatory testing. 1

• Thrombocytopenia + transaminitis + fever in endemic season (spring-fall) warrants empirical treatment 1
• Delay in treatment significantly increases morbidity and mortality 1

When to Avoid Empirical Antibiotics

• Do not give empirical antibiotics for bloody diarrhea in immunocompetent patients while awaiting stool culture results 6
• Exception: infants <3 months, documented fever with bloody diarrhea suggesting shigellosis, or signs of septicemia 6
• Never use antibiotics if STEC O157 or Shiga toxin 2-producing E. coli is suspected due to increased HUS risk 1, 6

Common Pitfalls to Avoid

1. Missing tickborne disease due to absence of reported tick bite - many patients do not recall tick exposure 1
2. Assuming viral gastroenteritis and missing serious bacterial or rickettsial infection - lymphocytosis does not exclude bacterial causes 1
3. Failing to monitor for HUS development - daily platelet counts and creatinine for 14 days if STEC infection confirmed 1
4. Overlooking geographic exposure history - SFTS is geographically restricted but has high mortality 5
5. Not examining peripheral blood smear - morulae identification can provide rapid diagnosis of ehrlichiosis/anaplasmosis 1
6. Delaying doxycycline in suspected rickettsial disease - waiting for confirmatory testing increases mortality 1