What is the most likely diagnosis causing leukopenia, diarrhea, and thrombocytopenia in a 32‑year‑old man?

Differential Diagnosis: Leukopenia, Diarrhea, and Thrombocytopenia in a 32-Year-Old Male

The most likely diagnoses to consider are HIV infection, severe fever with thrombocytopenia syndrome (SFTS), or other tick-borne illnesses, with HIV being the most common cause of this triad in a young adult without travel or tick exposure history. 1, 2, 3

Initial Diagnostic Approach

Exclude Pseudothrombocytopenia First

• Before any further workup, collect blood in a heparin or sodium citrate tube and repeat the platelet count to exclude EDTA-dependent platelet agglutination, which causes false thrombocytopenia in up to 0.1% of samples. 4, 5, 6
• A qualified hematologist or pathologist must review the peripheral blood smear to confirm true thrombocytopenia and identify morphologic abnormalities. 4, 5, 6

Critical History Elements

• Recent tick bites (within 5-7 days) strongly suggest tick-borne illness such as SFTS or novel phlebovirus infection. 7, 3
• Sexual contact history, particularly with individuals from high HIV prevalence countries, is essential as HIV commonly presents with this triad. 1
• Complete medication review including prescription drugs, over-the-counter medications, herbal supplements, and quinine-containing beverages. 5, 6
• Recent travel history to endemic areas for brucellosis, Q fever, or viral hemorrhagic fevers. 1
• Recent viral illness, vaccinations, or blood transfusions. 5, 6

Most Likely Diagnoses by Clinical Context

HIV Infection (Most Common in General Population)

• HIV infection is the most common cause of combined leukopenia, thrombocytopenia, and gastrointestinal symptoms in young adults. 1, 2
• Thrombocytopenia in HIV results from both immune-mediated platelet destruction and inadequate platelet production. 2
• Leukopenia and neutropenia occur from bone marrow suppression through abnormal cytokine expression. 2
• Diarrhea is common from opportunistic infections (Salmonella, Campylobacter, Shigella). 1
• HIV testing should be routinely offered to all patients presenting with unexplained blood dyscrasia (leukopenia, thrombocytopenia), diarrhea, or mononucleosis-like syndrome. 1

Severe Fever with Thrombocytopenia Syndrome (If Tick Exposure)

• SFTS presents with acute fever, leukopenia, thrombocytopenia, and gastrointestinal symptoms (diarrhea, nausea, vomiting) following tick bite 5-7 days prior. 7, 3
• The mortality rate averages approximately 20%, and the disease can rapidly progress to multiple organ failure. 3
• Transmitted primarily by Haemaphysalis longicornis, Amblyomma testudinarium, Ixodes nipponensis, and Rhipicephalus microplus ticks. 3
• Human-to-human transmission has been reported. 3

Brucellosis (If Animal/Endemic Exposure)

• Initial investigation often reveals mild transaminitis and pancytopenia. 1
• Presents with non-specific symptoms; serology is key to diagnosis. 1
• Bone marrow culture has the highest sensitivity and is the investigation of choice. 1

Essential Laboratory Workup

Mandatory Initial Tests

• Complete blood count with differential and reticulocyte count to determine if bicytopenia is isolated or part of pancytopenia. 5, 6
• Peripheral blood smear examination by a qualified hematologist or pathologist. 4, 5, 6
• HIV, hepatitis C virus, and hepatitis B virus testing for all adult patients with suspected immune-mediated bicytopenia. 1, 5, 6, 8
• Haptoglobin, indirect bilirubin, and LDH levels to assess for hemolysis. 1
• Direct Coombs test to exclude immune hemolytic anemia. 1

Additional Testing Based on Clinical Context

• Blood cultures with prolonged incubation (up to 4 weeks) if brucellosis suspected—discuss special precautions with laboratory. 1
• Bone marrow examination indicated if age >60 years, systemic symptoms present, or abnormalities in peripheral smear require investigation. 5, 6
• Helicobacter pylori testing where eradication may have clinical impact. 5, 6
• Antiphospholipid antibodies, antinuclear antibodies, and thyroid function tests when autoimmune disease suspected. 5

Critical Pitfalls to Avoid

• Failing to exclude pseudothrombocytopenia leads to unnecessary workup and potential misdiagnosis. 4, 5
• Missing HIV diagnosis by not routinely testing patients with unexplained blood dyscrasias and diarrhea. 1
• Overlooking tick-borne illness in patients with recent outdoor exposure, as SFTS has high mortality without supportive care. 3
• HCV infection is associated with leukopenia and thrombocytopenia as commonly as in patients with liver cirrhosis, potentially due to direct effect on hematopoiesis. 8

Management Considerations

• For HIV-associated thrombocytopenia, optimal management of the underlying HIV infection is essential; mild cytopenia in asymptomatic patients may need no specific management. 2
• Immune-mediated thrombocytopenia may be treated with combination of zidovudine, corticosteroids, IVGG, and splenectomy. 2
• For SFTS, no specific antiviral treatment is established; supportive care is critical as the disease can rapidly progress to multiple organ failure. 3
• Erythropoietin and judicious red blood cell transfusions for anemia; G-CSF and GM-CSF for neutropenia in HIV patients. 2