What are the likely diagnoses and recommended investigations and management for a 23‑year‑old woman with a two‑week history of high‑grade fever and chills, peripheral smear showing reactive (atypical) lymphocytes, mild splenomegaly, and elevated serum glutamic‑oxaloacetic transaminase (SGOT) and serum glutamic‑pyruvic transaminase (SGPT)?

Likely Diagnosis: Infectious Mononucleosis (EBV or CMV) with Consideration of Hemophagocytic Lymphohistiocytosis

The most likely diagnosis in this 23-year-old woman with two weeks of high-grade fever, reactive lymphocytes, mild splenomegaly, and elevated transaminases is infectious mononucleosis, most commonly caused by Epstein-Barr virus (EBV) or cytomegalovirus (CMV), but hemophagocytic lymphohistiocytosis (HLH) must be urgently excluded given the prolonged fever and systemic involvement. 1

Primary Differential Diagnoses

Infectious Mononucleosis (Most Likely)

• EBV or CMV infectious mononucleosis presents with prolonged fever (mean duration 18 days in CMV cases), hepatosplenomegaly, reactive (atypical) lymphocytes on peripheral smear, and moderately elevated transaminases (AST/ALT). 2
• Reactive lymphocytes represent a polyclonal immune response to antigenic stimulation and are readily identified by their increased size and active DNA synthesis. 3
• CMV infectious mononucleosis specifically shows fever in 100% of cases, splenomegaly in 20%, hepatomegaly in 33%, with lymphomonocytic cells exceeding 50% in 76% of patients and moderately elevated LDH, AST, and ALT. 2

Hemophagocytic Lymphohistiocytosis (Must Exclude)

• HLH is a life-threatening hyperinflammatory syndrome triggered by viral infections (particularly EBV and CMV) and presents with persistent high fever, hepatosplenomegaly, and cytopenias. 1
• The HLH-2004 diagnostic criteria require at least 5 of 8 findings: fever, splenomegaly, cytopenias affecting ≥2 lineages, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis on bone marrow, low/absent NK cell activity, ferritin ≥500 μg/L, and elevated soluble CD25. 1
• Critical point: Patients with viral infections targeting the monocyte-macrophage system may develop HLH despite appropriate antimicrobial treatment, requiring immunosuppression when HLH criteria are met and clinical deterioration continues. 1

Tickborne Rickettsial Diseases (Geographic Consideration)

• Ehrlichiosis and anaplasmosis present with fever, thrombocytopenia, elevated transaminases, and mild splenomegaly, though reactive lymphocytes are less prominent than neutropenia. 4
• These diagnoses are relevant if there is outdoor/wooded area exposure or tick bite history, even if not recalled by the patient. 4

Recommended Investigations

Immediate Priority Testing

• Complete blood count with differential to assess for cytopenias (particularly thrombocytopenia and anemia), absolute lymphocyte count, and confirm reactive lymphocytes. 1
• Peripheral blood smear examination with particular attention to: reactive lymphocytes morphology, schistocytes (to exclude TTP), and intracellular morulae (for ehrlichiosis). 4
• Ferritin level (critical for HLH screening; ≥500 μg/L is one HLH criterion, but levels >10,000 μg/L are highly suggestive). 1
• Triglycerides and fibrinogen to assess for hypertriglyceridemia (≥265 mg/dL) and hypofibrinogenemia (≤150 mg/dL), both HLH criteria. 1

Infectious Workup

• EBV serology: VCA-IgM, VCA-IgG, EBNA-IgG to distinguish acute from past infection. 2
• CMV serology: CMV IgM and IgG with CMV PCR viral load if IgM positive. 5, 2
• Blood cultures to exclude bacterial sepsis. 4
• Monospot or heterophile antibody test (though may be negative in CMV mononucleosis and early EBV infection). 2

Additional Laboratory Studies

• LDH, indirect bilirubin, haptoglobin to assess for hemolysis. 2
• Coagulation studies (PT, APTT, INR, D-dimer) to exclude disseminated intravascular coagulation (DIC) and thrombotic thrombocytopenic purpura (TTP). 4, 6
• Soluble CD25 (IL-2 receptor) if HLH is suspected based on initial screening tests. 1

If HLH Criteria Are Met

• Bone marrow aspiration and biopsy to look for hemophagocytosis (though absence does not exclude HLH). 1
• NK cell activity testing (low or absent activity is an HLH criterion). 1

Geographic/Exposure-Based Testing

• Ehrlichia and Anaplasma serology with PCR if there is outdoor/tick exposure history or if patient is from endemic areas. 4
• Dengue serology if there is travel to endemic regions (dengue hemorrhagic fever presents with atypical lymphocytosis, thrombocytopenia, and elevated transaminases). 7

Management Algorithm

Step 1: Assess for Life-Threatening Conditions (First 6 Hours)

• Immediately calculate HLH probability using available data:
  • Fever >38.5°C for >7 days: Present
  • Splenomegaly: Present (mild)
  • Cytopenias ≥2 lineages: Check CBC urgently
  • Ferritin: Obtain stat
  • Triglycerides/fibrinogen: Obtain stat
• If ≥3 HLH criteria are present or ferritin >10,000 μg/L: Initiate empiric HLH treatment with high-dose corticosteroids (dexamethasone 10 mg/m² or methylprednisolone 1-2 mg/kg) while awaiting confirmatory testing. 1

Step 2: Supportive Care and Monitoring

• Hydration and antipyretics for symptomatic relief.
• Monitor vital signs every 4-6 hours for hemodynamic instability.
• Serial CBC every 12-24 hours to track cytopenias progression.
• Avoid NSAIDs if thrombocytopenia is present (platelet count <100,000/μL).

Step 3: Specific Treatment Based on Etiology

• If EBV/CMV mononucleosis without HLH: Supportive care is primary treatment; antiviral therapy (ganciclovir/valganciclovir) is NOT routinely indicated for immunocompetent patients with CMV mononucleosis. 2
• If HLH is confirmed: Continue high-dose corticosteroids, add IVIG in severe cases, and monitor response every 12 hours (ferritin, cell counts, triglycerides, clinical status). 1
• If inadequate response to corticosteroids: Escalate to second-line agents (cyclosporine A, anakinra, or tocilizumab); consider etoposide-based therapy if refractory. 1
• If ehrlichiosis is confirmed or highly suspected: Doxycycline 100 mg PO/IV twice daily for 7-14 days, but continue monitoring for HLH development despite appropriate antibiotic therapy. 4, 1

Critical Pitfalls to Avoid

• Do not dismiss prolonged fever (>2 weeks) as "just viral" without excluding HLH, as mortality remains high (especially with delayed diagnosis) and early recognition with prompt treatment is essential to prevent irreversible organ damage. 1
• Do not wait for bone marrow biopsy results to initiate HLH treatment if clinical suspicion is high and ≥5 HLH criteria are met, as hemophagocytosis may not be present early in disease course. 1
• Do not assume reactive lymphocytes exclude bacterial infection or HLH; reactive lymphocytes are a nonspecific finding seen in viral infections, bacterial infections, autoimmune disorders, and drug reactions. 3
• Do not overlook geographic/exposure history: Tickborne diseases (ehrlichiosis, anaplasmosis) and dengue can present identically and require specific antimicrobial therapy. 4, 7
• Do not confuse this presentation with isolated immune thrombocytopenia (ITP): The presence of fever, splenomegaly, and elevated transaminases immediately excludes isolated ITP. 6