key: cord-0867412-o0c1ehyb authors: Canna, Scott W.; Cron, Randy Q. title: Highways to hell: mechanism based management of Cytokine Storm Syndromes date: 2020-09-29 journal: J Allergy Clin Immunol DOI: 10.1016/j.jaci.2020.09.016 sha: f401e0628f73533b6c3fdefa48a76f27091e2140 doc_id: 867412 cord_uid: o0c1ehyb Since the first textbook devoted to Cytokine Storm Syndromes (CSS) was published in 2019, the world has changed dramatically and the term’s visibility has broadened. Herein, we define CSS broadly to include life/organ-threatening systemic inflammation and immunopathology regardless of the context in which it occurs, recognizing that the indistinct borders of such a definition limit its utility. Nevertheless, we are focused on the pathomechanisms leading to CSS, including impairment of granule-mediated cytotoxicity, specific viral infections, excess IL-18, and Chimeric Antigen Receptor (CAR) T-cell therapy. These mechanisms are often reflected in distinct clinical features, functional tests, and/or biomarker assessments. Moreover, these mechanisms often indicate specific, definitive treatments. This mechanism-focused organization is vital to both advancing the field and understanding the complexities in individual patients. However, increasing evidence suggests these mechanisms interact and overlap. Likewise, the utility of a broad term like “Cytokine Storm” is that it reflects a convergence on a systemic inflammatory phenotype that, regardless of cause or context, may be amenable to “inflammo-stabilization.” CSS research must improve our appreciation of its various mechanisms and their interactions and treatments, but it must also identify the signs and interventions that may broadly prevent CSS-induced immunopathology. , but 54 patients can be called HLH based on a molecular diagnosis (usually via genetic testing) alone. These 55 criteria function better for classification than diagnosis, as some elements do not return quickly while 56 others are often not present early in disease (e.g. hemophagocytosis). Practitioners frequently need to 57 initiate immunomodulatory treatment while this work-up is incomplete. 58 59 HLH can occur as primary HLH (including familial HLH, or FHL), meaning genetically-defined, or 60 secondary (or reactive or acquired) HLH, which occurs due to infection, malignancy, or rheumatic 61 disease. Infection is by far the most common cause of secondary HLH. Initially, the genetic perturbations 62 associated with "primary HLH" were restricted to profound defects in genes known or strongly 63 suspected to be associated with granule-mediated cellular cytotoxicity. FHL is a subset of Primary HLH 64 restricted to perturbations in five distinct genes/loci (Chr9q deletion, PRF1, UNC13D, STX11, and 65 STXBP2). With time, a broader range of genetic causes of HLH have been discovered, many of which 66 appear to cause hyperinflammation without impairing cytotoxicity. Likewise, less severe cytotoxic 67 impairments may cause HLH at a later-onset HLH or only with certain triggers 2, 3 . Thus, it is not currently 68 clear how much of a genetic attribution a patient must have to be called Primary HLH, or whether this 69 term is restricted only to genetic defects that impair cytotoxicity. Often lumped with primary HLH are two X-linked Lymphoproliferative (XLP) disorders that cause CSS 72 most often (but not exclusively) in the context of Epstein-Barr Virus (EBV) infection. XLP1 is associated 73 J o u r n a l P r e -p r o o f with NKT cell deficiency and several signaling abnormalities. XLP2, however, has less association with 74 EBV, no malignancy risk, no known cytotoxic impairment, and now appears to be more related to innate 75 immune activation 3-5 . The HLH criteria do not reflect a more modern appreciation of the utility of each element. For instance, 78 ferritin elevation has become a pre-requisite for diagnosis, whereas other features suffer from lack of 79 specificity (NK function), sensitivity (fibrinogen), or both (hemophagocytosis). The HScore was 80 developed to fill this gap, broadening the features contributing to a diagnosis and weighting more 81 important elements 6 . Its utility has been somewhat limited by its complexity (although several online 82 calculators exist, including http://saintantoine.aphp.fr/score/) and its being developed predominantly 83 using data from adult malignancy-associated HLH. When not all variables are available to calculate the 84 HScore, its sensitivity suffers. Problems with CSS nomenclature 138 A patient with lupus who develops CSS in the context of EBV viremia could be simultaneously and 139 accurately called "MAS", "viral sepsis", "sepsis-MAS", "EBV-HLH", "secondary HLH", "acquired HLH", or 140 "reactive HLH". Each of these terms carries with it a context and may suggest a specific 141 immunomodulatory treatment. Often these paradigms are at odds with each other 36 . Improving the CSS 142 nomenclature will require an unprecedented collaboration that crosses disciplines and age boundaries, Convergent pathways of the hyperferritinemic syndromes Whole-601 exome sequencing reveals overlap between macrophage activation syndrome in 602 systemic juvenile idiopathic arthritis and familial hemophagocytic 603 lymphohistiocytosis Sequencing Reveals Mutations in Genes Linked to Hemophagocytic 606 Lymphohistiocytosis and Macrophage Activation Syndrome in Fatal Cases of H1N1 607 Influenza A single 609 amino acid change, A91V, leads to conformational changes that can impair 610 processing to the active form of perforin Heterozygosity 612 for the common perforin mutation, p.A91V, impairs the cytotoxicity of primary 613 natural killer cells from healthy individuals CD8 T Cell Memory Increases 615 Immunopathology in the Perforin-Deficient Model of Hemophagocytic 616 Genetic 618 Deficiency of Interferon-gamma Reveals Interferon-gamma Manifestations of Murine Hemophagocytic Lymphohistiocytosis Hemophagocytic 622 lymphohistiocytosis in 2 patients with underlying IFN-gamma receptor deficiency Recommendations for the Use of Etoposide-Based Therapy and Bone Marrow Transplantation for the Treatment of HLH: Consensus Statements by the HLH 627 Steering Committee of the Histiocyte Society Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: 631 Recommendations from the North American Consortium for Histiocytosis 632 (NACHO) immunochemotherapy and bone marrow transplantation Emapalumab in 638 Children with Primary Hemophagocytic Lymphohistiocytosis Mixed hematopoietic or T-cell chimerism above a minimal 641 threshold restores perforin-dependent immune regulation in perforin-deficient 642 mice Cell type specific infection of Epstein-Barr virus (EBV) in EBV-644 associated hemophagocytic lymphohistiocytosis and chronic active EBV infection Molecular mechanisms of EBV-driven cell cycle 647 progression and oncogenesis EBV and Apoptosis: The Viral Master Regulator of Cell 649 Fate? Viruses Defective NKT cell development in mice and humans lacking the adapter SAP, the 652 X-linked lymphoproliferative syndrome gene product Restimulation-induced apoptosis of T cells is impaired in patients with X-linked 656 lymphoproliferative disease caused by SAP deficiency Pediatric hemophagocytic lymphohistiocytosis Antiviral Drugs for EBV Treatment of primary Epstein-Barr virus infection in patients with X-linked 664 lymphoproliferative disease using B-cell-directed therapy Use of rituximab in conjunction 666 with immunosuppressive chemotherapy as a novel therapy for Epstein Barr virus-667 associated hemophagocytic lymphohistiocytosis Treatment 670 of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with 671 rituximab-containing chemo-immunotherapeutic regimens Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody 675 TGN1412 Identification of Predictive Biomarkers for Cytokine Release Syndrome after 678 Chimeric Antigen Receptor T-cell Therapy for Acute Lymphoblastic Leukemia Occult macrophage activation 681 syndrome in patients with systemic juvenile idiopathic arthritis Levels of interleukin-18 and its binding inhibitors in the blood circulation of 685 patients with adult-onset Still's disease Highly 687 elevated serum levels of interleukin-18 in systemic juvenile idiopathic arthritis but 688 not in other juvenile idiopathic arthritis subtypes or in Kawasaki disease: comment 689 on the article by Kawashima et al Distinct 692 cytokine profiles of systemic-onset juvenile idiopathic arthritis-associated 693 macrophage activation syndrome with particular emphasis on the role of 694 interleukin-18 in its pathogenesis Interleukin-18 696 for predicting the development of macrophage activation syndrome in systemic 697 juvenile idiopathic arthritis Interleukin-18 diagnostically distinguishes and pathogenically promotes human 700 and murine macrophage activation syndrome IL-18 as a biomarker linking systemic juvenile idiopathic arthritis and macrophage 703 activation syndrome IL-705 18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy Normal free interleukin-18 (IL-18) plasma levels in dengue virus infection and the 709 need to measure both total IL-18 and IL-18 binding protein levels High 712 circulating levels of free interleukin-18 in patients with active SLE in the presence 713 of elevated levels of interleukin-18 binding protein Elevated 715 serum levels of free interleukin-18 in adult-onset Still's disease Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation An activating 721 NLRC4 inflammasome mutation causes autoinflammation with recurrent 722 macrophage activation syndrome Severe 726 autoinflammation in 4 patients with C-terminal variants in cell division control 727 protein 42 homolog (CDC42) successfully treated with IL-1beta inhibition A novel 730 disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant 731 CDC42 function Inflammatory Gene Expression Profile and Defective Interferon-gamma and 734 Granzyme K in Natural Killer Cells From Systemic Juvenile Idiopathic Arthritis 735 Patients Unopposed IL-18 signaling leads to severe TLR9-induced macrophage activation 738 syndrome in mice Longitudinal 740 analyses reveal immunological misfiring in severe COVID-19 multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still's disease Life-746 threatening NLRC4-associated hyperinflammation successfully treated with 747 Interleukin-18 inhibition IL-749 18 as therapeutic target in a patient with resistant systemic juvenile idiopathic 750 arthritis and recurrent macrophage activation syndrome Hemorrhagic Fever Represent Reactive Hemophagocytic Syndrome? Plasma interleukin-18 levels are a biomarker of innate immune responses that 757 predict and characterize tuberculosis-associated immune reconstitution 758 inflammatory syndrome Lysinuric protein intolerance: reviewing 760 concepts on a multisystem disease Alert for Cytokine Storm: Immunopathology in COVID-19 American College of Rheumatology Clinical Guidance for Pediatric Patients with 767 CoV-2 and Hyperinflammation in COVID-19. Version 1. Arthritis Rheumatol Cardiopulmonary bypass-induced inflammation: is it important? Follistatin-772 like protein 1 and the ferritin/erythrocyte sedimentation rate ratio are potential 773 biomarkers for dysregulated gene expression and macrophage activation 774 syndrome in systemic juvenile idiopathic arthritis Erythrocyte Sedimentation Rate Ratio: Simple Measure to Identify Macrophage 777 Activation Syndrome in Systemic Juvenile Idiopathic Arthritis Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report. N Engl 781 Recommendations for the management of hemophagocytic 784 lymphohistiocytosis in adults Interleukin 1 Receptor Antagonist Anakinra, Intravenous Immunoglobulin, and 787 Corticosteroids in the Management of Critically Ill Adult Patients With 788 Hemophagocytic Lymphohistiocytosis Anakinra in Treating Pediatric Secondary Hemophagocytic Lymphohistiocytosis Tocilizumab 793 masks the clinical symptoms of systemic juvenile idiopathic arthritis-associated 794 macrophage activation syndrome: the diagnostic significance of interleukin-18 and 795 interleukin-6