Adult-onset hemophagocytic lymphohistiocytosis triggered by sars-cov-2 and EBV coinfection: A diagnostic challenge resolved with the HLH-94 protocol

Abstract Background Hemophagocytic lymphohistiocytosis (HLH) is a rare, quickly progressive immune activation syndrome, more frequently recognized in pediatric populations. In adults, HLH is usually misdiagnosed due to its overlap with sepsis and cytokine storm syndromes. Viral infections such as Epstein-Barr virus (EBV) and SARS-CoV-2 are known triggers. Mortality in adult HLH can exceed 50% without prompt treatment. Case Presentation A 35-year-old previously healthy man presented to SUNY Upstate University Hospital with fevers, hypotension, confusion, and pancytopenia. He was initially treated for presumed septic shock for 3 days with broad-spectrum antibiotics. Labs revealed hemoglobin 7.1 g/dL, platelets 34K, ANC 0.9K, ferritin >40,000 ng/mL, triglycerides 510 mg/dL, AST/ALT 320/290 U/L, and LDH 850 U/L. Soluble IL-2 receptor was markedly elevated at 17,500 U/mL. CT abdomen showed hepatosplenomegaly. PCR testing returned positive for both EBV and SARS-CoV-2. Bone marrow biopsy demonstrated hemophagocytosis. He met 6 of 8 HLH-2004 diagnostic criteria. A multidisciplinary team including hematology, infectious disease, and ICU started HLH-directed therapy per HLH-94 protocol: dexamethasone (10 mg/m²/day) and etoposide. Fevers resolved within 48 hours, and cytopenias improved by day 5. Ferritin decreased to 9,600 ng/mL by day 10. The patient completed induction therapy and remained in remission on tapering etoposide. Discussion The diagnostic complexity of adult HLH requires high clinical suspicion when sepsis is unresponsive to antibiotics. EBV and SARS-CoV-2 coinfection likely contributed synergistically to cytokine dysregulation. To our knowledge, this is one of fewer than 15 reported adult HLH cases triggered by dual EBV and SARS-CoV-2 infection. Prompt diagnosis and coordinated multidisciplinary intervention were critical to the treatment of the patient. Emerging therapies such as ruxolitinib, a JAK1/2 inhibitor, have shown promise in refractory or steroid-resistant HLH. While our patient responded to HLH-94 induction alone, ruxolitinib may represent a valuable adjunct in future cases, especially in virally driven hyperinflammatory states. Conclusion Adult HLH should be considered in patients with persistent fevers, cytopenias, and hyperferritinemia unresponsive to standard infection management. This case demonstrates how timely diagnosis and early implementation of the HLH-94 protocol, in collaboration with a multidisciplinary team, can reverse multiorgan failure in high-mortality syndromes like HLH.