What is the recommended treatment for an immunocompetent adult presenting with fever, sore throat, mild splenomegaly suggestive of Epstein‑Barr virus (EBV) or cytomegalovirus (CMV) infectious mononucleosis, possible hemophagocytic lymphohistiocytosis (HLH) based on elevated ferritin, triglycerides, low fibrinogen and cytopenias, and a history that raises concern for a tick‑borne infection?

Treatment of Suspected Infection-Triggered HLH with Possible Tick-Borne Disease

Immediately initiate empiric doxycycline 100 mg orally or intravenously twice daily while simultaneously starting high-dose corticosteroids (methylprednisolone 1 g IV daily for 3-5 consecutive days) to address both the potential tick-borne infection and the developing HLH. 1, 2

Immediate Diagnostic Workup

Before treatment, obtain the following to confirm HLH and identify triggers:

• Complete blood count with differential and peripheral blood smear to look for intracellular morulae (diagnostic of ehrlichiosis), assess cytopenias, and evaluate for atypical lymphocytes 1
• HLH-specific parameters: ferritin, triglycerides, fibrinogen, soluble CD25 (sIL-2R), and NK cell activity 1, 2
• Coagulation studies (PT, aPTT, D-dimer) to exclude DIC and assess for hypofibrinogenemia 1
• Blood cultures to rule out bacterial sepsis 1
• Infectious workup: EBV viral capsid antigen IgM/IgG, EBNA IgG, CMV IgM/IgG, EBV and CMV quantitative PCR, Ehrlichia/Anaplasma serology and PCR 1, 2
• Bone marrow aspiration and biopsy to screen for hemophagocytosis and exclude underlying malignancy (particularly T-cell or NK-cell lymphoma) 1, 2

Rationale for Dual Empiric Therapy

Why Doxycycline Cannot Be Delayed

Tick-borne rickettsial diseases (ehrlichiosis, anaplasmosis) require immediate doxycycline treatment because delay leads to severe disease and fatal outcomes. 1 The clinical presentation—fever, thrombocytopenia, mild splenomegaly, elevated transaminases, and cytopenias—is highly consistent with ehrlichiosis or anaplasmosis 1. Even without confirmed tick exposure (many patients don't recall a bite), the laboratory pattern of leukopenia, thrombocytopenia, and mild transaminase elevation strongly suggests tick-borne rickettsial disease 1.

Why Corticosteroids Must Be Started Simultaneously

Patients infected by pathogens targeting the monocyte-macrophage system (including Ehrlichia and rickettsial organisms) may develop HLH, and while they usually respond well to specific antimicrobial treatment, immunosuppression is necessary when HLH criteria are met and the patient continues to deteriorate despite appropriate antibiotics. 1, 2 This patient meets at least 5 of 8 HLH-2004 criteria: fever, splenomegaly, cytopenias (≥2 lineages), elevated ferritin, low fibrinogen, and elevated triglycerides 2.

The critical management principle is that antimicrobial treatment alone may be insufficient once HLH has developed—the hyperinflammatory cascade requires direct immunosuppression. 1, 2

Treatment Algorithm

First 24-48 Hours

1. Continue doxycycline 100 mg IV/PO twice daily for the full 7-14 day course 1

2. Administer methylprednisolone 1 g IV daily for 3-5 consecutive days as first-line HLH therapy 1, 2

3. Consider adding IVIG in severe cases with marked cytopenias or clinical deterioration 1

4. Provide supportive care: hydration, antipyretics, monitor vital signs every 4-6 hours 1

5. Reassess every 12 hours with repeat ferritin, triglycerides, fibrinogen, CBC, and clinical status 1, 2

If Inadequate Response After 48 Hours

Add second-line immunosuppression if ferritin continues rising, cytopenias worsen, or clinical deterioration persists:

• Cyclosporine A (2-7 mg/kg/day) 1
• Anakinra (IL-1 blockade: 2-10 mg/kg/day subcutaneously in divided doses) 1
• Consider tocilizumab (IL-6 blockade) if cytokine storm features predominate 1

For Refractory Cases

Etoposide-based therapy should be considered only as a last resort in refractory HLH, given significant toxicity and concern for effect on lymphocytes 1, 2. However, avoid etoposide if the primary trigger is infection-related HLH responding to antimicrobials, as immunosuppression from the HLH-94 protocol should be avoided in patients with pathogens targeting the monocyte-macrophage system. 1

Special Considerations for EBV/CMV Co-infection

If EBV or CMV is confirmed as a co-trigger:

• Add rituximab (anti-CD20 therapy) for EBV-triggered HLH with continuously increasing or sustained high EBV DNA levels 1, 2
• Initiate appropriate antiviral therapy (ganciclovir/valganciclovir for CMV) and monitor viral loads during treatment 1
• Recognize that rituximab cannot replace anti-T-cell therapy with corticosteroids ± etoposide; it is adjunctive 1

Note that dual positive IgM for both EBV and CMV can occur in primary EBV infection due to abnormal humoral immunity, and seroconversion to EBNA IgG positivity with reduced CMV IgM titer (but persistently negative CMV IgG) confirms EBV as the primary pathogen. 3

Critical Pitfalls to Avoid

1. Do not delay doxycycline while awaiting serologic confirmation of tick-borne disease—empiric treatment is essential when clinical and laboratory features suggest ehrlichiosis/anaplasmosis 1

2. Do not delay HLH-directed therapy while waiting for all HLH-2004 criteria to be met—empirical treatment should begin when clinical suspicion is high with ferritin >5,000-10,000 ng/mL, progressive cytopenias, and persistent fever 1, 2

3. Do not withhold immunosuppression due to concern about infection—once HLH criteria are met, the hyperinflammatory syndrome itself becomes life-threatening and requires treatment alongside antimicrobials 1, 2

4. Do not overlook malignancy screening—particularly T-cell or NK-cell lymphoma, which is strongly associated with HLH and may be the underlying trigger rather than infection alone 1, 2

5. Do not assume hemophagocytosis must be present—it is neither sensitive nor specific and may be absent on initial bone marrow examination 2

6. Monitor for CNS involvement—perform lumbar puncture if grade 3-4 neurotoxicity develops, as HLH can cause meningoencephalitis 1, 2

Monitoring and Escalation Criteria

Transfer to ICU if any of the following develop:

• Shock or hemodynamic instability requiring vasopressors 1, 2
• Platelet count <30 g/L 2
• Grade ≥3 neurotoxicity or altered mental status 1, 2
• Respiratory failure requiring mechanical ventilation 1
• Multiorgan dysfunction not responding to initial therapy 1

Monitor the following parameters every 12-24 hours:

• Ferritin (rapidly rising levels indicate active disease) 2
• Platelet count (rapidly reflects HLH activity; drops indicate disease flares) 2
• Triglycerides and fibrinogen 1, 2
• Temperature and spleen size 2
• Liver function tests 1, 2

Prognosis and Long-term Considerations

Factors associated with higher mortality include:

• Shock at presentation 2
• Platelet count <30 g/L 2
• Malignancy-associated HLH (particularly T-cell lymphomas) 1, 2
• Delayed diagnosis and treatment initiation 2

EBV-associated HLH in adults carries a particularly poor prognosis (>95% mortality in some series), especially with high LDH levels, poor performance status, and bone marrow suppression. 4 Early recognition and aggressive treatment with the HLH-2004 protocol has shown improved outcomes 4.

For male patients with EBV-driven HLH, consider genetic or flow cytometric analysis for X-linked lymphoproliferative syndrome (XLP1), as 24% develop malignancy, usually Hodgkin lymphoma. 5