Beyond septic shock: a fatal case of infection-driven hemophagocytic lymphohistiocytosis in a critically ill elderly patient

Abstract Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that may closely mimic severe sepsis, particularly in critically ill adults. We present a fatal case of infection-driven HLH initially obscured by septic shock in a 69-year-old woman with chronic obstructive pulmonary disease (COPD), heart failure, and prior malignancy. She was first hospitalized with Klebsiella pneumoniae pneumonia, respiratory failure, and non–ST-elevation myocardial infarction (NSTEMI), showing clinical improvement after antibiotics and supportive therapy. During this admission, she developed new-onset pancytopenia and hyperferritinemia and was discharged with outpatient hematology follow-up. Five days later, she presented again with septic shock, hypoxemia, and worsening cytopenias. Laboratory evaluation during the second admission revealed marked hyperinflammation, including ferritin > 100,000 nanograms per milliliter (ng/mL), lactate dehydrogenase (LDH) 7,938 units per liter (U/L), D-dimer 12,192 nanograms per milliliter fibrinogen equivalent units (ng/mL FEU), and fibrinogen 43 milligrams per deciliter (mg/dL). Immune profiling demonstrated profound CD4 + T-cell, CD8 + T-cell, B-cell, and natural killer (NK) cell depletion. Infectious evaluation identified parainfluenza virus, Epstein–Barr virus (EBV) immunoglobulin G (IgG), and methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia as potential triggers. She met 6 out of 7 HLH-2024 criteria, with an H-score of 284 (> 99% probability). High-dose dexamethasone and supportive therapy were initiated; however, etoposide and bone marrow biopsy were deferred due to escalating multiorgan failure. Despite aggressive management, she succumbed to refractory shock. This case highlights the diagnostic challenge of distinguishing HLH from septic shock in critically ill adults and emphasizes the need for heightened clinical suspicion.