Li, S.

Abstract Hemophagocytic lymphohistiocytosis (HLH) is a rare but critical hyperinflammatory condition that affects around 1.5% of liver transplant patients, with mortality rates reaching up to 33%. This syndrome is characterized by intense, dysregulated activation of macrophages and T-cells, sparking a cytokine surge that leads to severe systemic inflammation and rapid organ failure. Prompt identification and early management are crucial to improve outcomes. Case Presentation: A 61-year-old man with Hepatitis C-induced end-stage liver disease (MELD score 20) underwent a deceased-donor liver transplant. Postoperative complications included atrial fibrillation, stress cardiomyopathy, and a right-sided pleural effusion treated with thoracentesis and extended course of antibiotics. Two weeks later, he presented with fever, hypotension, and nausea, prompting the initiation of IV Zosyn, Vancomycin and Posaconazole. Despite fluid resuscitation, he became hemodynamically unstable, necessitating ICU transfer for vasopressor support. While in the ICU, his condition worsened, with increased fever, tachycardia, anuria and hypoxic respiratory failure that required intubation and continuous renal replacement therapy. Marked hyperferritinemia (ferritin 62,000 µg/L) and hypofibrinogenemia (91 mg/dL) raised suspicion for HLH, with an H score of 244. Comprehensive infectious workup ruled out CMV, EBV, HSV, and other pathogens. Bone marrow biopsy confirmed hemophagocytosis (Figure 1), and flow cytometry ruled out malignant infiltration. Given the strong suspicion for HLH and no identifiable infectious trigger, he was initiated on Dexamethasone, Etoposide, and Ruxolitinib, which lowered ferritin levels and improved vasopressor requirements. However, mentation declined, and imaging revealed a right frontal subarachnoid hemorrhage, likely from disseminated intravascular coagulation, precluding surgical intervention. Despite transient improvement, he developed ventilator associated pneumonia secondary to Stenotrophomonas infections and vancomycin-sensitive Enterococcus bacteremia, leading to refractory hypoxemia. After family and multi-disciplinary team discussions, care was withdrawn. Discussion: HLH remains an exceedingly rare, rapidly fatal syndrome in liver transplant recipients, with only 11 cases documented. Early recognition of HLH can be challenging, as its features, such as fever, cytopenias, and organ dysfunction, overlap with common post-transplant complications, which can delay diagnosis. HLH can be differentiated into primary (genetic) and secondary (acquired) forms, with the latter more common among adults, often triggered by infection, malignancies and autoimmune disorders. Immunosuppressants may inadvertently modulate HLH risk by tempering macrophage and T-cell activation, yet, paradoxically, also predisposing patients to secondary triggers. Clinicians should maintain vigilance for HLH in post-transplant patients with unexplained systemic inflammation, as early intervention is critical, often with Etoposide based regimens to modulate hypercytokinemia, though prognosis remains guarded due to multiorgan failure.