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Autosomal recessive mutations in RAB27A are associated with Griscelli syndrome type 2 (GS2), characterized by hypopigmentation and development of early-onset, potentially fatal hemophagocytic lymphohistiocytosis (HLH). We describe a 35-year old male who presented with recurrent fever, was diagnosed with Epstein-Barr virus-driven chronic lymphoproliferation, fulfilled clinical HLH criteria, and who carried a novel homozygous RAB27A c.551G > A p.(R184Q) variant. We aimed to evaluate the contribution of the identified RAB27A variant in regard to the clinical phenotype as well as cellular and biochemical function. The patient displayed normal pigmentation as well as RAB27A expression in blood-derived cells. However, patient NK and CD8 + T cell exocytosis was low. Ectopic expression of the RAB27A p.R184Q variant rescued melanosome distribution in mouse Rab27a-deficient melanocytes, but failed to increase exocytosis upon reconstitution of human RAB27A-deficient CD8 + T cells. Mechanistically, the RAB27A p.R184Q variant displayed reduced binding to SLP2A but augmented binding to MUNC13-4, two key effector proteins in immune cells. MUNC13-4 binding was particularly strong to an inactive RAB27A p.T23N/p.R184Q double mutant. RAB27A p.R184Q was expressed and could facilitate melanosome trafficking, but did not support lymphocyte exocytosis. The HLH-associated RAB27A variant increased Munc13-4 binding, potentially representing a novel mode of impairing RAB27A function selectively in hematopoietic cells., (© 2022. The Author(s).)

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., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome induced by aberrantly activated macrophages and cytotoxic T cells. The primary (genetic) form, caused by mutations affecting lymphocyte cytotoxicity and immune regulation, is most common in children, whereas the secondary (acquired) form is most frequent in adults. Secondary HLH is commonly triggered by infections or malignancies but may also be induced by autoinflammatory/autoimmune disorders, in which case it is called macrophage activation syndrome (MAS; or MAS-HLH). Most information on the diagnosis and treatment of HLH comes from the pediatric literature. Although helpful in some adult cases, this raises several challenges. For example, the HLH-2004 diagnostic criteria developed for children are commonly applied but are not validated for adults. Another challenge in HLH diagnosis is that patients may present with a phenotype indistinguishable from sepsis or multiple organ dysfunction syndrome. Treatment algorithms targeting hyperinflammation are frequently based on pediatric protocols, such as HLH-94 and HLH-2004, which may result in overtreatment and unnecessary toxicity in adults. Therefore, dose reductions, individualized tailoring of treatment duration, and an age-dependent modified diagnostic approach are to be considered. Here, we present expert opinions derived from an interdisciplinary working group on adult HLH, sponsored by the Histiocyte Society, to facilitate knowledge transfer between physicians caring for pediatric and adult patients with HLH, with the aim to improve the outcome for adult patients affected by HLH., (© 2019 by The American Society of Hematology.)

Human herpes virus 8 (HHV-8)-associated secondary hemophagocytic lymphohistiocytosis is a rare but critical immuno-hematological entity in immunocompetent patients. Establishing a diagnosis is challenging as is the monitoring of disease activity and therapeutic effects. We report a case of a HHV-8-associated hemophagocytic lymphohistiocytosis in a HIV-negative adult patient with multicentric Castleman's disease. As a novel finding, we report the use of certain inflammatory parameters, primarily interleukin-10 combined with viral load monitoring of the causative infectious agent in this case HHV-8 to monitor the clinical course of the hemophagocytic lymphohistiocytosis in the setting of bacterial septic complications.