Differentiating Persistent Sepsis From Pembrolizumab-Induced Secondary Hemophagocytic Lymphohistiocytosis and Concurrent Immune-Mediated Nephritis: A Diagnostic and Therapeutic Challenge.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome that can occur as an immune-related adverse event following immune checkpoint inhibitor therapy. Early diagnosis is challenging because its clinical features frequently overlap with severe sepsis, particularly in oncology patients who have recently received marrow-suppressing cytotoxic regimens. We report the case of a 39-year-old woman with triple-negative breast cancer who underwent neoadjuvant chemo-immunotherapy with carboplatin, paclitaxel, epirubicin, cyclophosphamide, and pembrolizumab. Two weeks after her last cycle, she presented with fever, a generalized rash, and purulent discharge from a peripherally inserted central catheter site, with blood cultures initially positive for Gram-positive bacteria. Despite prompt microbiological clearance with broad-spectrum antimicrobials, she developed persistent daily pyrexia, progressive liver function derangement, severe anemia, bilateral pleural effusions, and stage 3 acute kidney injury requiring continuous renal replacement therapy. Serial assessments revealed marked hyperferritinemia, hypertriglyceridemia, elevated aspartate aminotransferase, and an increasing HScore. Bone marrow biopsy showed treatment-related dyspoiesis without overt hemophagocytosis, which did not preclude the diagnosis of pembrolizumab-associated secondary HLH and concurrent immune-mediated nephritis. Targeted treatment with high-dose methylprednisolone, anakinra, and subsequently mycophenolate mofetil led to clinical recovery. The patient was successfully liberated from continuous renal replacement therapy; her cytopenias and kidney function improved, and her hyperinflammatory markers and HScore normalized. Anakinra was discontinued, and she was discharged on oral mycophenolate mofetil and prednisolone. This case underscores the complexity of distinguishing checkpoint inhibitor-associated HLH from persistent infection. Serial clinical scoring, multidisciplinary input, and substituting conventional cytotoxic HLH protocols with targeted biological therapies and organ-preserving immunosuppressants are essential to resolve the hyperinflammatory cascade while preserving renal function.