Consensus-Based Guidelines for the Recognition, Diagnosis, and Management of Hemophagocytic Lymphohistiocytosis in Critically Ill Children and Adults.

Objective: Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome that often requires critical care support and remains difficult to diagnose. These guidelines are meant to aid in the early recognition, diagnosis, supportive care, and treatment of patients with hemophagocytic lymphohistiocytosis in ICUs.
Data Sources: The literature searches were performed with PubMed (MEDLINE).
Study Selection: Keywords and medical subject headings terms for literature search included "macrophage activation syndrome," hemophagocytic lymphohistiocytosis," and "hemophagocytic syndrome."
Data Extraction: The Histiocyte Society developed these consensus recommendations on the basis of published reports and expert opinions with level of evidence provided for each recommendation. They were endorsed by the Society of Critical Care Medicine.
Data Synthesis: Testing for hemophagocytic lymphohistiocytosis should be initiated promptly in all patients admitted to ICUs with an unexplained or disproportionate inflammatory response, especially those with rapid clinical deterioration. Meeting five or more of eight hemophagocytic lymphohistiocytosis 2004 diagnostic criteria serves as a valuable diagnostic tool for hemophagocytic lymphohistiocytosis. Early aggressive critical care interventions are often required to manage the multisystem organ failure associated with hemophagocytic lymphohistiocytosis. Thorough investigation of the underlying triggers of hemophagocytic lymphohistiocytosis, including infections, malignancies, and autoimmune/autoinflammatory diseases, is essential. Early steroid treatment is indicated for patients with familial hemophagocytic lymphohistiocytosis and is often valuable in patients with acquired hemophagocytic lymphohistiocytosis (i.e., secondary hemophagocytic lymphohistiocytosis) without previous therapy, including macrophage activation syndrome (hemophagocytic lymphohistiocytosis secondary to autoimmune/autoinflammatory disease) without persistent or relapsing disease. Steroid treatment should not be delayed, particularly if organ dysfunction is present. In patients with macrophage activation syndrome, whose disease does not sufficiently respond, interleukin-1 inhibition and/or cyclosporine A is recommended. In familial hemophagocytic lymphohistiocytosis and severe, persistent, or relapsing secondary macrophage activation syndrome, the addition of prompt individualized, age-adjusted etoposide treatment is recommended.
Conclusions: Further studies are needed to determine optimal treatment for patients with hemophagocytic lymphohistiocytosis in ICUs, including the use of novel and adjunct therapies.
Competing Interests: Dr. Horne serves as a speaker for Swedish Orphan Biovitrum (SOBI) and Novartis; Dr. Jordan serves as a consultant for Novimmune and SOBI; Dr. Hines receives research funding from Incyte and the Histiocytosis Association; Drs. K. Beutel, Lehmberg, and Henter serve as consultants for SOBI; Dr. La Rosée serves as a speaker and consultant for SOBI and Novartis. Dr. Hines’ institution received funding from the American Lebanese Syrian Associated Charities and Incyte. Drs. Hines, Beutel, Hays, and Henter disclosed the off-label product use of extracorporeal life support, Etoposide, dexamethasone, anakinra, cyclosporine, cyclophosphamide, alemtuzumab, Tocilizumab, ruxolitinib, plasmapheresis, cytokine adsorption, IV immunoglobulin, and methylprednisolone. Drs. Beutel, Horne, Lachmann, Machowicz, La Rosée, and Henter received funding from SOBI Adboard. Dr. Beutel received funding from Biotest AG. Dr. Horne’s institution received funding from Novartis. Dr. van Laar disclosed government work. Dr. Shakoory disclosed that there is a Cooperative and Development Research Agreements between her section at National Institutes of Health (NIH) and SOBI. Dr. Zinter received funding from the NIH American Thoracic Society grant (K23HL146936); he received support for article research from the NIH. Dr. Henter’s institution received funding from the Swedish Children’s Cancer Foundation and the Stockholm County Council (ALF project). The remaining authors have disclosed that they do not have any potential conflicts of interest. The above competing interests and Histiocyte Society involvement did not influence the content of these guidelines.
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