Precision immunomodulation for pediatric hemophagocytic lymphohistiocytosis in intensive care

ABSTRACT Hemophagocytic lymphohistiocytosis (HLH) and related cytokine storm syndromes are life‐threatening hyperinflammatory disorders that frequently intersect with pediatric critical care. Critically ill children may present with fever, shock, cytopenias, liver dysfunction, coagulopathy, hyperferritinemia, respiratory failure, neurologic deterioration, and multiple organ dysfunction, creating substantial overlap with severe sepsis. Traditional diagnostic criteria remain foundational but do not identify the dominant mechanism or optimal therapy for an individual child. In this review, precision immunomodulation is defined operationally as matching the suspected trigger and clinical phenotype with pathway‐informed biomarkers when available, drug‐delivery feasibility during organ failure, and the plan for definitive disease control. Interferon‐gamma activity may be supported by CXCL9; interleukin (IL)‐1/IL‐18 biology may support anakinra in macrophage activation syndrome; broader cytokine signaling may support Janus kinase inhibition in selected refractory HLH; and IL‐6‐directed therapy is primarily syndrome‐ and grade‐directed in immune effector cell cytokine release syndrome. These markers are supportive rather than validated treatment thresholds. Targeted therapy must proceed alongside antimicrobial therapy, source control, organ support, infection surveillance, and early hematopoietic stem cell transplantation planning when indicated. This review provides a bedside framework for phenotype assignment, biomarker interpretation, intensive care unit‐focused targeted therapy, extracorporeal bridge strategies, and reassessment at 24–72 h.