In the Midst of a Cytokine Storm — The Hemophagocytic Syndrome (Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome)

Background Hemophagocytic syndrome (HPS)/hemophagocytic lymphohistiocytosis (HLH) is a life‐threatening hyperinflammatory syndrome characterized by immune dysregulation, cytokine overproduction, hemophagocytosis, cytopenias, and multiorgan dysfunction. Although diagnostic criteria are established in human medicine, standardized criteria and validated biomarkers are lacking in dogs and cats. Objective To review the pathogenesis, clinical and clinicopathologic features, diagnosis, and differential diagnoses of HPS/HLH, with emphasis on dogs and cats, and to propose a framework for establishing standardized diagnostic criteria for canine HPS. Methods Human and veterinary literature on HLH, HPS, and macrophage activation syndrome was reviewed, including diagnostic criteria, biomarkers, bone marrow morphology, immunohistochemistry, flow cytometry, and molecular diagnostics. Representative canine cases of secondary HPS and hemophagocytic histiocytic sarcoma were evaluated to illustrate diagnostic challenges. Results HPS results from dysregulated activation of cytotoxic lymphocytes and macrophages, with interferon‐γ playing a central role in sustaining hyperinflammation. In dogs and cats, HPS is most commonly associated with infections, neoplasia, and immune‐mediated disease. Clinical and laboratory findings are nonspecific, and although hemophagocytosis supports the diagnosis, it is neither required nor sufficient to establish HPS. Distinguishing reactive HPS from histiocytic neoplasia and other non‐neoplastic causes of hemophagocytic activity—including drug‐associated changes, post‐transfusion hemophagocytosis, and PIMA‐associated histiocytic activity—requires integration of cytomorphology, tissue distribution, immunophenotyping, and molecular diagnostics. Human HLH‐2004 criteria and the H‐score provide useful diagnostic frameworks, but neither has been validated for veterinary species. Conclusions HPS is a challenging and potentially fatal syndrome in dogs and cats, which requires comprehensive clinicopathologic evaluation. Prospective studies are needed to establish species‐specific diagnostic criteria and validate quantitative morphologic, immunophenotypic, molecular, and biomarker‐based approaches to distinguish HPS from infectious, immune‐mediated, and neoplastic disorders in which phagocytic activity is prominent.