Reeja Raj, Ramya Ramakrishnan, Carlos Vargas, Muhammad Khalid, Gopi Mohan, David McCall, Amber Gibson, Branko Cuglievan, Cesar Nunez, Brandon Brown, Monica Bray, Miriam B Garcia
Background and Clinical Significance: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by excessive activation of the immune system. Case Presentation: We present the case of an eight-month-old infant with influenza A(H1N1) who presented with seizures, hepatosplenomegaly, cytopenias, and markedly elevated levels of ferritin, IL-18, and CXCL9, raising concern for HLH. Despite initiation of HLH-directed and antiviral therapy, she succumbed to cardiorespiratory failure. Genetic testing revealed heterozygous variants in LYST and NLRC4, suggesting a potential genetic predisposition. Conclusions: This case underscores the challenge of distinguishing primary from secondary HLH and highlights the importance of balancing aggressive immunosuppression with infection control. Early genetic and cytokine profiling may assist in guiding personalized treatment strategies, enabling targeted interventions that avoid excessive immunosuppressive treatment in cases of reactive hyperinflammation while facilitating timely escalation of therapy in true or refractory HLH.