Infection-associated hemophagocytic lymphohistiocytosis: A comprehensive review

Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal hyperinflammatory syndrome characterized by uncontrolled immune activation, excessive cytokine release, and phagocytosis of hematopoietic cells by activated histiocytes. HLH is classified as primary (genetic) or secondary (acquired), with infections being the most common trigger of secondary forms. Viral pathogens, particularly Epstein–Barr virus and other herpesviruses, are most frequently implicated, while bacterial (e.g., Mycobacterium tuberculosis, Staphylococcus aureus, multidrug-resistant Acinetobacter), parasitic (e.g., Leishmania donovani, Plasmodium spp.), and fungal (e.g., Candida, Cryptococcus, Histoplasma, Aspergillus) infections are also important contributors. Diagnosis is challenging due to nonspecific features such as prolonged fever, cytopenias, hepatosplenomegaly, and hyperferritinemia, with laboratory markers including elevated soluble IL-2 receptor, ferritin, and soluble CD163 providing supportive evidence. Bone marrow examination demonstrating hemophagocytosis further aids diagnosis. Timely recognition and intervention are essential, as untreated HLH carries uniformly high mortality. Management involves treating the underlying infection and, in severe or refractory cases, combining antimicrobial therapy with immunosuppressive or immunomodulatory agents. This review highlights the spectrum of infection-associated HLH, and its clinical presentation along with diagnostic approach.