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COVID-19 and cytokine storm syndrome: are there lessons from macrophage activation syndrome?

  • Michael J. Ombrello
    Correspondence
    Reprint requests: Michael J. Ombrello, MD, Children's Hospital Medical Center, Division of Rheumatology, MLC 4010, 3333 Burnet Avenue, Cincinnati, OH 45229;
    Affiliations
    Translational Genetics and Genomics Unit, Pediatric Translational Research Branch, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland
    Search for articles by this author
  • Grant S. Schulert
    Affiliations
    Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
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Published:March 05, 2021DOI:https://doi.org/10.1016/j.trsl.2021.03.002
      Although interest in “cytokine storms” has surged over the past decade, it was massively amplified in 2020 when it was suggested that a subset of patients with COVID-19 developed a form of cytokine storm. The concept of cytokine storm syndromes (CSS) encompasses diverse conditions or circumstances that coalesce around potentially lethal hyperinflammation with hemodynamic compromise and multiple organ dysfunction syndrome. Macrophage activation syndrome (MAS) is a prototypic form of CSS that develops in the context of rheumatic diseases, particularly systemic juvenile idiopathic arthritis. The treatment of MAS relies heavily upon corticosteroids and cytokine inhibitors, which have proven to be lifesaving therapies in MAS, as well as in other forms of CSS. Within months of the recognition of SARS-CoV2 as a human pathogen, descriptions of COVID-19 patients with hyperinflammation emerged. Physicians immediately grappled with identifying optimal therapeutic strategies for these patients, and despite clinical distinctions such as marked coagulopathy with endothelial injury associated with COVID-19, borrowed from the experiences with MAS and other CSS. Initial reports of patients treated with anti-cytokine agents in COVID-19 were promising, but recent large, better-controlled studies of these agents have had mixed results suggesting a more complex pathophysiology. Here, we discuss how the comparison of clinical features, immunologic parameters and therapeutic response data between MAS and hyperinflammation in COVID-19 can provide new insight into the pathophysiology of CSS.

      COVID-19 AND THE CYTOKINE STORM HYPOTHESIS

      The global COVID-19 pandemic has presented an urgent challenge to translational scientists internationally, to define the pathogenesis of SARS-CoV-2 infection and direct rationally designed therapeutic approaches. The earliest clinical reports from Wuhan
      • Chen G
      • Wu D
      • Guo W
      • et al.
      Clinical and immunological features of severe and moderate coronavirus disease 2019.
      ,
      • Zhou F
      • Yu T
      • Du R
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      suggested that patients with life-threatening COVID-19 shared clinical features which partially overlapped with macrophage activation syndrome (MAS), cytokine-release syndrome (CRS) and acute respiratory distress syndrome (ARDS), suggesting that a dysregulated host immune response may drive aspects of disease pathogenesis (reviewed in
      • Henderson LA
      • Canna SW
      • Schulert GS
      • et al.
      On the alert for cytokine storm: immunopathology in COVID-19.
      ). The hypothesis of a cytokine storm syndrome in severe COVID-19 increased in visibility with an initial case series suggesting dramatic clinical improvements in patients treated with the anti-IL-6 biologic tocilizumab
      • Xu X
      • Han M
      • Li T
      • et al.
      Effective treatment of severe COVID-19 patients with tocilizumab.
      (a mainstay of CRS management). As COVID-19 spread across the globe, further uncontrolled case series of anti-cytokine therapy (largely anti-IL-6 and IL-1) continued to show promise,
      • Klopfenstein T
      • Zayet S
      • Lohse A
      • et al.
      Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients.
      • Capra R
      • De Rossi N
      • Mattioli F
      • et al.
      Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia.
      • Guaraldi G
      • Meschiari M
      • Cozzi-Lepri A
      • et al.
      Tocilizumab in patients with severe COVID-19: a retrospective cohort study.
      • Navarro-Millán I
      • Sattui SE
      • Lakhanpal A
      • Zisa D
      • Siegel CH
      • Crow MK.
      Use of anakinra to prevent mechanical ventilation in severe COVID-19: a case series.
      and large-scale controlled trials of corticosteroids found clear benefit.
      • RECOVERY Collaborative Group H
      • Horby P
      • Lim WS
      • et al.
      Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report.
      ,
      • Angus DC
      • Derde L
      • Al-Beidh F
      • et al.
      Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial.
      The promise of immunomodulatory therapies was in stark contrast to other agents such as hydroxychloroquine with initial excitement that failed in rigorous study,
      • Cavalcanti AB
      • Zampieri FG
      • Rosa RG
      • et al.
      Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19.
      • Boulware DR
      • Pullen MF
      • Bangdiwala AS
      • et al.
      A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19.
      • Recovery Collaborative Group H
      • Horby P
      • Mafham M
      • et al.
      Effect of hydroxychloroquine in hospitalized patients with Covid-19.
      and antivirals which showed relatively small improvements without change in overall mortality.
      • Beigel JH
      • Tomashek KM
      • Dodd LE
      • et al.
      Remdesivir for the treatment of Covid-19—final report.
      However, continued basic and translational research into SARS-CoV-2 pathogenesis has found conflicting evidence as to the existence of a prominent cytokine storm in COVID-19, with clear differences from the pathogenesis of conditions such as MAS. More recently, randomized trials of anti-IL-1 and IL-6 agents have found little evidence of overall benefit (and in some cases concern for harm).
      • Stone JH
      • Frigault MJ
      • Serling-Boyd NJ
      • et al.
      Efficacy of tocilizumab in patients hospitalized with Covid-19.
      Group TC-19 C
      Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomized controlled trial.
      • Salvarani C
      • Dolci G
      • Massari M
      • et al.
      Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.
      Given this, should the idea of a cytokine storm syndrome in COVID-19 be reevaluated? In particular, what can we learn from prototypical cytokine storm syndromes such as MAS regarding the pathogenesis of a cytokine storm, how such conditions can be detected, and how best to utilize immunomodulatory therapies?

      WHAT IS CYTOKINE STORM?

      Cytokine storm is a descriptive term that, through evocative imagery of severe meteorological phenomena, seeks to convey the severity and potential power of hyperinflammatory states to wreak immune-mediated havoc on an individual. Cytokine storm syndromes refers to a diverse set of conditions that collectively manifest a clinical phenotype of hyperinflammation, hyperferritinemia, and multiorgan failure resulting from the excessive and often self-perpetuating production of cytokines through unencumbered and amplified immune activation.
      • Minoia F
      • Davi S
      • Alongi A
      • Ravelli A.
      Criteria for cytokinestorm syndromesle.
      The spectrum of cytokine storm syndromes spans wide ranging conditions with distinct underlying triggers that can include infectious, genetic, oncologic, rheumatic and iatrogenic etiologies. The CSS nomenclature provides a useful framework that highlights common clinical features and shared elements of their immune-mediated pathophysiology, despite their disparate underpinnings. At the same time, one must be cautious to avoid oversimplification and remain mindful of the important differences that exist between the CSSs, such as the degree of hyperferritinemia or the responsiveness to treatment with IL-6 directed therapies. Moreover, a genetically defined CSS, like familial hemophagocytic lymphohistiocytosis (fHLH), requires a different therapeutic attitude than an intrinsically self-limited CSS, such as the CRS that often follows the administration of chimeric antigen receptor-T cell therapy for leukemia. Despite these limitations the CSS paradigm can serve as a useful approach in the recognition of hyperinflammatory states, understanding drives of inflammation, and considering treatment strategies.

      MACROPHAGE ACTIVATION SYNDROME, A PROTOTYPIC FORM OF CYTOKINE STORM

      MAS is a prototypic form of CSS that develops in the context of many rheumatic diseases, most commonly the Still's disease spectrum (systemic juvenile idiopathic arthritis [sJIA] and adult-onset Still's disease)
      • Ravelli A
      • Grom AA
      • Behrens EM
      • Cron RQ.
      Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment.
      but also including systemic lupus erythematosus
      • Borgia RE
      • Gerstein M
      • Levy DM
      • Silverman ED
      • Hiraki LT.
      Features, treatment, and outcomes of macrophage activation syndrome in childhood-onset systemic lupus erythematosus.
      and Kawasaki disease.
      • Avcin T
      • Tse SM
      • Schneider R
      • Ngan B
      • Silverman ED.
      Macrophage activation syndrome as the presenting manifestation of rheumatic diseases in childhood.
      Formerly considered to be a form of secondary HLH, MAS is a systemic CSS that involves excessive activation and proliferation of T cells and well-differentiated, non-neoplastic macrophages with hemophagocytic activity.
      • Crayne CB
      • Albeituni S
      • Nichols KE
      • Cron RQ.
      The immunology of macrophage activation syndrome.
      Clinically, it is marked by extreme hyperferritinemia, hematocytopenias, hepatic dysfunction and coagulopathy. Because of the critical importance of distinguishing MAS from inflammation related to the underlying sJIA disease activity, criteria for the classification of MAS in the setting of sJIA have been developed and refined.
      • Ravelli A
      • Minoia F
      • Davì S
      • et al.
      2016 Classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a European league against rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborat.
      ,
      • Minoia F
      • Bovis F
      • Davì S
      • et al.
      Development and initial validation of the macrophage activation syndrome/primary hemophagocytic lymphohistiocytosis score, a diagnostic tool that differentiates primary hemophagocytic lymphohistiocytosis from macrophage activation syndrome.
      In the most widely used criteria, an expert consensus process was combined with comprehensive multivariate regression analyses of clinical and laboratory data from actual patients in an effort to bring greater objectivity to the classification of MAS in sJIA.
      • Ravelli A
      • Minoia F
      • Davì S
      • et al.
      2016 Classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a European league against rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborat.
      The model most predictive of the presence of MAS in febrile children with known or suspected sJIA included hyperferritinemia (>684 ng/mL), together with any 2 of the following additional criteria: platelet count ≤ 181 × 10−9/liter, aspartate aminotransferase >48 units/liter, triglycerides >156 mg/dl and fibrinogen ≤ 360 mg/dl. Among the variables included in the final model, univariate analysis of hyperferritinemia (>684 ng/mL) and platelet count ≤ 181 × 10−9/liter each showed very strong association with the presence of MAS.
      The pathogenic factors that underlie sJIA and the development of MAS remain unclear, but most cases of MAS develop in the context of either high disease activity or an intercurrent infection.
      • Minoia F
      • Davì S
      • Horne A
      • et al.
      Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients.
      Current evidence supports a model of MAS that involves the interplay of excessive production of the interleukin (IL)-1 superfamily member, IL-18, the overproduction of IFNγ, and the situational failure of cell-mediated cytotoxicity
      • Crayne CB
      • Albeituni S
      • Nichols KE
      • Cron RQ.
      The immunology of macrophage activation syndrome.
      (Fig 1). It has been suggested that IL-18 plays a central role in the pathophysiology of MAS, perpetuating and amplifying innate immune activation. Elevated levels of circulating IL-18 distinguish sJIA from other monogenic hereditary periodic fever syndromes.
      • Weiss ES
      • Girard-Guyonvarc'h C
      • Holzinger D
      • et al.
      Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome.
      Similarly, elevation of IL-18 is observed in the subset of sJIA patients at risk for developing MAS, ultimately differentiating MAS from disease flare.
      • Yasin S
      • Fall N
      • Brown RA
      • et al.
      IL-18 as a biomarker linking systemic juvenile idiopathic arthritis and macrophage activation syndrome.
      Importantly, IL-18 is naturally counter-regulated by a circulating antagonist, the IL-18 binding protein (IL-18BP), which renders IL-18 biologically inactive through high-affinity binding.
      • Zhou T
      • Damsky W
      • Weizman O-E
      • et al.
      IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy.
      Although both IL-18 and IL-18BP are induced by inflammatory cytokines, an imbalance between IL-18 and its antagonist exists in sJIA and MAS, resulting in elevated levels of bioactive or “free” IL-18.
      • Weiss ES
      • Girard-Guyonvarc'h C
      • Holzinger D
      • et al.
      Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome.
      This elevation of free IL-18 was shown to be a unique feature of sJIA/MAS that was not observed in other situations with IL-18 elevation, including viral infection or fHLH.
      • Weiss ES
      • Girard-Guyonvarc'h C
      • Holzinger D
      • et al.
      Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome.
      ,
      • Michels M
      • de Mast Q
      • Netea MG
      • et al.
      Normal free interleukin-18 (IL-18) plasma levels in dengue virus infection and the need to measure both total IL-18 and IL-18 binding protein levels.
      It is the abnormal elevation of free IL-18 that is thought to drive pathologic IFNγ production, leading to MAS in sJIA. Indeed activation of IFNγ pathways has been associated with emergence of MAS,
      • Bracaglia C
      • de Graaf K
      • Pires Marafon D
      • et al.
      Elevated circulating levels of interferon-γ and interferon-γ-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis.
      ,
      • Put K
      • Avau A
      • Brisse E
      • et al.
      Cytokines in systemic juvenile idiopathic arthritis and haemophagocytic lymphohistiocytosis: tipping the balance between interleukin-18 and interferon-γ.
      and drives the proinflammatory activation of macrophages to further sustain hyperinflammation.
      • GS S
      • AV P
      • T D
      • et al.
      Monocyte and bone marrow macrophage transcriptional phenotypes in systemic juvenile idiopathic arthritis reveal TRIM8 as a mediator of IFN-γ hyper-responsiveness and risk for macrophage activation syndrome.
      These observations are recapitulated in a monogenic form of HLH/MAS caused by gain-of-function mutations in NLRC4.
      • Romberg N
      • Al Moussawi K
      • Nelson-Williams C
      • et al.
      Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation.
      ,
      • Canna SW
      • de Jesus AA
      • Gouni S
      • et al.
      An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome.
      Mice or humans bearing gain-of-function mutations in NLRC4 demonstrate persistent elevation of IL-18 and recurrent episodes of MAS.
      • Weiss ES
      • Girard-Guyonvarc'h C
      • Holzinger D
      • et al.
      Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome.
      ,
      • Romberg N
      • Al Moussawi K
      • Nelson-Williams C
      • et al.
      Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation.
      ,
      • Canna SW
      • de Jesus AA
      • Gouni S
      • et al.
      An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome.
      Beyond IL-18, defective cell-mediated cytotoxicity may also contribute to MAS. Several studies have reported an enrichment of heterozygous mutations in fHLH genes, suggesting a genetic contribution to MAS risk.
      • Vastert SJ
      • van Wijk R
      • D'Urbano LE
      • et al.
      Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis.
      • Zhang K
      • Biroschak J
      • Glass DN
      • et al.
      Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC13-4 polymorphisms.
      • Kaufman KM
      • Linghu B
      • Szustakowski JD
      • et al.
      Whole exome sequencing reveals overlap between macrophage activation syndrome in systemic juvenile idiopathic arthritis and familial hemophagocytic lymphohistiocytosis.
      Indeed, the cytotoxicity defects observed in MAS are partial, but in situations where cytotoxic capacity is exceeded, the result is reduced killing by NK and cytotoxic T lymphocytes, prolonged engagement of CTLs with antigen presenting cells, hypersecretion of inflammatory cytokines, and failure to contract and resolve the inflammatory response
      • Schulert GS
      • Zhang M
      • Husami A
      • et al.
      Novel UNC13D intronic variant disrupting a NFκB enhancer in a patient with recurrent macrophage activation syndrome and systemic juvenile idiopathic arthritis.
      ,
      • Zhang M
      • Bracaglia C
      • Prencipe G
      • et al.
      A heterozygous RAB27A mutation associated with delayed cytolytic granule polarization and hemophagocytic lymphohistiocytosis.
      (Fig 1). While there remain significant gaps in the understanding of MAS, it broadly represents a well-defined and characterized CSS that can be compared and contrasted with similar hyperinflammatory states.
      Fig 1
      Fig 1Comparison of macrophage activation syndrome and COVID-cytokine storm syndrome. Typical antiviral responses (left panel) produce expansion of virus-specific cytotoxic T lymphocytes (CTL), which interact with antigen presenting cells (APC) and macrophages to limit and eliminate the infection. After clearing the infection, the expanded population of activated immune cells are eliminated by cytolytic cells and the immune system returns to its typical basal level of surveillance. In macrophage activation syndrome (MAS; middle panel), innate immune activation and IL-18 drive the expansion of CTLs, their engagement with APCs and their cross-talk with macrophages. The combined persistence of innate immune activation and an inadequate cytolytic capacity to eliminate activated immune cells leads to prolonged CTL-APC engagement and continued production of inflammatory mediators, amplified CTL-macrophage cross-talk, and the cytokine storm of MAS. In COVID-19 (right panel), infection with SARS-CoV-2 stimulates these same anti-viral immune pathways with CTL expansion. Dampened type I interferon responses allow prolonged persistence of infection of the lungs and activation of type II interferon responses contribute to persistent immune activation. Failure to clear the virus lead to prolonged type I interferon signaling, driving proinflammatory cytokine production. As was the case in MAS, it is possible that inadequate cytolytic capacity due to immune exhaustion and/or defective anti-viral responses leads to prolonged cross-talk between CTL, APCs and alveolar macrophages, contributing to COVID-CS. Beyond the proinflammatory mechanisms implicated in other cytokine storm syndromes, activation of the complement cascade has been observed in severe COVID-19 patients and its specific contribution to pathophysiology are not yet known.

      CYTOKINE STORM IN SEVERE COVID-19

      During the first wave of COVID-19 disease in China, early reports noted that patients with poor outcomes after SARS-CoV-2 infection had clinical and laboratory features that overlapped with those seen in CSS such as MAS. Zhou and colleagues reported that in a large cohort of hospitalized patients, those who died from COVID-19 demonstrated cytopenias including lymphopenia, anemia, and thrombocytopenia; significantly elevated AST, d-dimer, and LDH; and significant hyperferritinemia (median 1435 vs 503 ng/mL in survivors).
      • Zhou F
      • Yu T
      • Du R
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      Similarly, patients with COVID-19 pneumonia who progressed to ARDS and death had high fevers, neutrophilia, elevated LDH and d-dimer, and hyperferritinemia (median 1029 vs 545 ng/mL).
      • Wu C
      • Chen X
      • Cai Y
      • et al.
      Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China.
      In a small cohort from Wuhan, patients with severe COVID-19 had lymphopenia with neutrophilia, elevated LDH, d-dimer, transaminases, and CRP, and hyperferriteinemia (median 1598 vs 337 ng/mL in moderate cases).
      • Chen G
      • Wu D
      • Guo W
      • et al.
      Clinical and immunological features of severe and moderate coronavirus disease 2019.
      This study also performed cytokine profiling, which demonstrated elevations in IL-6, IL-10, TNF, and sIL2-R in severe patients. Together, these laboratory findings suggested that patients with severe COVID-19 pneumonia had biochemical features reflecting that seen in CSS including cytopenias, liver dysfunction, coagulopathy, and hyperferritinemia.
      While the immunopathogenesis of SARS-CoV-2 infection is covered in much greater detail elsewhere in this issue, several studies characterizing the systemic inflammatory response in COVID-19 have similarly linked cytokine elevations to progression to severe disease. Del Valle et al reported evidence of a proinflammatory cytokine environment in severe COVID-19, examining nearly 2000 serum samples from more than 1400 patients hospitalized in New York City. Serum IL-6, IL-8, and TNF were all significantly elevated compared to both healthy donors and CAR T patients without signs of CRS. Interestingly, while IL-6 levels were overall higher in CAR T patients with CRS compared to COVID-19, levels in COVID-19 varied greatly. Further examination of IL-6 levels showed that IL-6 was associated with an increased risk of death (OR = 2.47). IL-6 was positively associated with inflammatory markers including CRP, d-dimer, and ferritin, as well as fever, but even adjusting for inflammatory markers, disease severity, and comorbidities, IL-6 was independently associated with COVID-19 mortality.
      Hadjadj et al further examined the peripheral immune response in 50 patients across a spectrum of COVID-19 severity.
      • Hadjadj J
      • Yatim N
      • Barnabei L
      • et al.
      Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients.
      Whole blood transcriptional profiling found patients with high disease severity had a progressive increase in expression of a large gene set highly enriched in inflammatory and innate immune response genes. In particular, both cytokine and chemokine related genes and NF-kB pathway genes, as well as circulating protein levels of IL-6 and TNF, were significantly increased as a function of disease activity. Interestingly, genes reflecting IFN activation were most upregulated in mild disease and reduced in more severe disease, and low IFNa plasma levels preceded clinical deterioration. Together, this points to excessive NF-kB-driven inflammation, along with impaired IFN viral control responses, in severe hyperinflammatory COVID-19.
      • Hadjadj J
      • Yatim N
      • Barnabei L
      • et al.
      Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients.
      Inadequate type I IFN signaling was further implicated in severe COVID-19 when 2 different host factors that dampen type I IFN responses were discovered among subjects with severe COVID-19. Loss of function mutations in genes of the type-I IFN pathway
      • Zhang Q
      • Bastard P
      • Liu Z
      • et al.
      Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.
      and autoantibodies directed against type I IFNs (IFN-a and/or IFN-w)
      • Bastard P
      • Rosen LB
      • Zhang Q
      • et al.
      Autoantibodies against type I IFNs in patients with life-threatening COVID-19.
      were independently strongly enriched among subjects with severe COVID-19, relative to subjects with a mild disease course. The mutations involved 7 type I IFN pathway genes, and in vitro investigations of the mutated proteins (and of the neutralizing effect of the autoantibodies) confirmed their negative effect on IFN signaling and/or the induction of the interferon-regulated gene-expression signature.
      • Zhang Q
      • Bastard P
      • Liu Z
      • et al.
      Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.
      ,
      • Bastard P
      • Rosen LB
      • Zhang Q
      • et al.
      Autoantibodies against type I IFNs in patients with life-threatening COVID-19.
      The link between severe disease and deficient IFN signaling was further bolstered by a study that compared whole blood single cell transcriptomic profiles of patients with mild-moderate COVID-19 to those of patients with severe disease. In stark contrast to the 11 subjects with mild-moderate COVID-19, in whom the interferon stimulated gene (ISG) signature was upregulated as expected, the 10 severe COVID-19 patients displayed a complete absence of ISG signature in every cell population examined; instead, there was prominent upregulation of a proinflammatory cytokine signature.
      • Zhou Z
      • Ren L
      • Zhang L
      • et al.
      Heightened innate immune responses in the respiratory tract of COVID-19 patients.
      It is possible that in COVID-19, the reduced IFN-I signaling may acutely produce an impotent antiviral effect, but that this evolves into a chronic IFN response that contributes to the proinflammatory amplification loop observed in severe COVID-19
      • Park A
      • Iwasaki A.
      Type I and Type III interferons - induction, signaling, evasion, and application to combat COVID-19.
      ,
      • Israelow B
      • Song E
      • Mao T
      • et al.
      Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling.
      (Fig 2). Taken together, these data suggest that both the strength and timing of type I IFN responses are important variables that influence host responses to COVID-19.
      • Park A
      • Iwasaki A.
      Type I and Type III interferons - induction, signaling, evasion, and application to combat COVID-19.
      Fig 2
      Fig 2Timing and strength of Type I IFN responses in COVID-19. Clearance of SARS-CoV2 is uniquely dependent on type I IFN signaling. Most healthy individuals with COVID-19 are capable of activating type I IFN pathways, clearing the viral infection and normalizing the host environment with only mild symptoms. In the context of large viral loads or impaired IFN signaling pathways, dampened or inadequate IFN responses may lead to failure of antiviral responses and viral persistence. Persistent viral infection leads to chronic and pathologic elevation of type I IFN signaling which that propagates the proinflammatory amplification loop that is indicative of severe COVID-19. Adapted from Park A, Iwasaki A. Type I and Type III Interferons - Induction, Signaling, Evasion, and Application to Combat COVID-19. Cell Host Microbe. 2020;27:870-878.
      Although impaired type I IFNs and IL-6 levels have been closely investigated in severe COVID-19, other cytokines have also been proposed to have key roles in COVID-19 hyperinflammation. Karki and colleagues have proposed a model that the synergy between high levels of TNF and IFNγ (both found in severe COVID-19 and produced by COVID-infected PBMC) can drive proinflammatory cell death.
      • Karki R
      • Sharma BR
      • Tuladhar S
      • et al.
      COVID-19 cytokines and the hyperactive immune response: synergism of TNF-α and IFN-γ in triggering inflammation, tissue damage, and death.
      Co-administration of these cytokines in a mouse model led to hyperinflammation, multiorgan dysfunction, shock, and death. This also caused a proinflammatory form of cell death with features of pyroptosis, apoptosis, and necroptosis they termed “PANoptosis.” Inhibition of this cell death was protective against mortality in several models of cytokine storm as well as a murine model of SARS-CoV-2 infection. This is notable in that, as discussed above, IFNγ plays a central role in driving both primary HLH and MAS, further supporting a key role for this cytokine in cytokine storms. Another recent article proposed a key role in COVID-19 for IL-33, an IL-1 family cytokine that could serve to both dampen IFN responses and sustain hyperinflammation.
      • Zizzo G
      • Cohen PL.
      Imperfect storm: is interleukin-33 the Achilles heel of COVID-19?.
      Interestingly, IL-33 has been shown to have prominent roles in the cytokine storm caused by HLH.
      • Rood JE
      • Rao S
      • Paessler M
      • et al.
      ST2 contributes to T-cell hyperactivation and fatal hemophagocytic lymphohistiocytosis in mice.
      Despite these findings, several recent authors have questioned whether severe COVID truly represents a cytokine storm, but rather is a typical inflammatory response to a life-threatening infection. First, COVID-19 has other clinical features that are not seen in CSS such as MAS, such as marked coagulopathy with endothelial injury and microthrombosis.
      • Goswami J
      • MacArthur TA
      • Sridharan M
      • et al.
      A review of pathophysiology, clinical features, and management options of COVID-19 associated coagulopathy.
      Indeed, some patients with severe COVID-19 show evidence of catastrophic microvascular injury with complement activation,
      • Magro C
      • Mulvey JJ
      • Berlin D
      • et al.
      Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases.
      which could suggest a phenotype similar to thrombotic microangiopathy.
      • Merrill JT
      • Erkan D
      • Winakur J
      • James JA.
      Emerging evidence of a COVID-19 thrombotic syndrome has treatment implications.
      More broadly, the model of cytokine storm implies that the inflammatory response (and cytokines in particular) are deleterious to the host, and fails to distinguish between an appropriate vs dysregulated immune response.
      • Sinha P
      • Matthay MA
      • Calfee CS.
      Is a "cytokine storm" relevant to COVID-19?.
      • Kox M
      • Waalders NJB
      • Kooistra EJ
      • Gerretsen J
      • Pickkers P.
      Cytokine levels in critically ill patients with COVID-19 and other conditions.
      • Mudd PA
      • Crawford JC
      • Turner JS
      • et al.
      Distinct inflammatory profiles distinguish COVID-19 from influenza with limited contributions from cytokine storm.
      For example, Sinha and colleagues note that while IL-6 levels are elevated in severe COVID-19, these levels are more than 10-fold lower than those typically seen in hyperinflammatory forms of ARDS.
      • Sinha P
      • Matthay MA
      • Calfee CS.
      Is a "cytokine storm" relevant to COVID-19?.
      Similar work from Kox et al demonstrated that IL-6 levels even in COVID-19 patients with ARDS were less than those seen in sepsis patients with ARDS, and comparable to levels seen in other severe disease states such as major trauma and out-of-hospital cardiac arrest.
      • Kox M
      • Waalders NJB
      • Kooistra EJ
      • Gerretsen J
      • Pickkers P.
      Cytokine levels in critically ill patients with COVID-19 and other conditions.
      Finally, while the majority of patients with severe COVID-19 have serum ferritin above defined cut-offs for cytokine storms such as MAS and HLH,
      • Ravelli A
      • Minoia F
      • Davì S
      • et al.
      2016 Classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborat.
      ,
      • Henter JI
      • Horne A
      • Arico M
      • et al.
      HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis.
      COVID-19 patients rarely exhibit the marked elevations associated with increasing mortality in hyperferritinemic syndromes.
      • Schulert GS
      • Canna SW.
      Convergent pathways of the hyperferritinemic syndromes.
      The counter-argument to this however is that while the paradigm of cytokine storm has been largely drawn from entities such as MAS, HLH, and CRS, it is not synonymous with a hyperferritinemic syndrome or an “IL-6-opathy”. Rather, the cytokine storm model describes disease states where inflammatory responses become dysregulated and create feed-forward loops of hyperinflammation that become deleterious to the host, and where targeted immunomodulatory therapy can improve outcomes. In severe COVID-19 particularly, this hyperinflammatory loop may largely operate in the lungs rather than in the circulation (Fig 1). As discussed above, the impaired type I interferon responses caused by genetic mutations or autoantibodies
      • Zhang Q
      • Bastard P
      • Liu Z
      • et al.
      Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.
      ,
      • Bastard P
      • Rosen LB
      • Zhang Q
      • et al.
      Autoantibodies against type I IFNs in patients with life-threatening COVID-19.
      can lead to a failure to control primary SARS-CoV-2 infection in the lungs, including infection of alveolar macrophages driving persistent immune activation.
      • Pandolfi L
      • Fossali T
      • Frangipane V
      • et al.
      Broncho-alveolar inflammation in COVID-19 patients: a correlation with clinical outcome.
      ,
      • Liu T
      • Jia P
      • Fang B
      Differential Expression of Viral Transcripts From Single-Cell RNA Sequencing of Moderate and Severe COVID-19 Patients and Its Implications for Case Severity.
      Indeed, immune profiling of the pulmonary inflammatory response in severe COVID-19 shows expansion and IFN-driven activation of alveolar macrophages, IFNγ-producing T cells, and increased pulmonary levels of proinflammatory mediators (IL-6, IL-8, IL-1β) and IFN-induced chemokines.
      • Pandolfi L
      • Fossali T
      • Frangipane V
      • et al.
      Broncho-alveolar inflammation in COVID-19 patients: a correlation with clinical outcome.
      ,
      • Liao M
      • Liu Y
      • Yuan J
      • et al.
      Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19.
      ,
      • Grant RA
      • Morales-Nebreda L
      • Markov NS
      • et al.
      Alveolitis in severe SARS-CoV-2 pneumonia is driven by self-sustaining circuits between infected alveolar macrophages and T cells.
      This supports a model of a lung-centric, self-sustaining inflammatory loop leading to cytokine storm, but with variable circulating levels of specific mediators. It is therefore critically important to identify such patients early who could benefit from targeted therapies.

      DIAGNOSIS AND MANAGING COVID-ASSOCIATED HYPERINFLAMMATION – LESSONS FROM MAS

      Given the above data suggesting that extreme immune dysregulation and cytokine storm occurs in only a subset of severe SARS-CoV-2 infection, it may be beneficial to apply previously designed diagnostic and classification criteria for disorders such as HLH and MAS to COVID-19 patients. Webb and colleagues approached this question systematically, performing a literature review to identify candidate criteria for other CSS, and then examining existing published data on COVID-19 to identify clinical and laboratory features of poor outcomes.
      • Webb BJ
      • Peltan ID
      • Jensen P
      • et al.
      Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study.
      Using the results of these searches, they developed a classification framework called cHIS (COVID-19 associated hyperinflammatory syndrome) with 6 core features of CSS that were also reported in severe SARS-CoV-2 infections including: fever, macrophage activation, liver inflammation, hematologic dysfunction, coagulopathy, and hypercytokinemia (Table I). These criteria were then applied retrospectively to a large cohort of COVID-19 patients admitted to a regional, multisite healthcare system in the western USA. Overall, 54% of patients had a daily cHIS score of 2 or greater at some point during their hospitalization. Scores of ≥2 vs <2 were associated with significantly increased length of stay, need for ICU care, mechanical ventilation, or death. Most interestingly, using the cHIS score as a time-dependent variable, they showed that a daily cHIS score of ≥2 was associated with significantly increased risk of clinical deterioration later in the hospitalization, potentially identifying patients who could benefit from immunomodulatory therapy before progression to respiratory failure.
      Table IDiagnostic and classification criteria for HLH and MAS, and proposed criteria for COVID-19 associated hyperinflammation
      CriteriaHLH and MASCOVID-19 hyperinflammation
      HLH-2004HScore2016 MAS criteriacHISCOV-HITemple criteria
      Fever≥38.5 C0 (<38.4), 33 (38.4–39.4), OR

      49 (>39.4)
      Fever>38.0 C
      Hyperferritinemia≥500 ng/mL0 (<2000), 35 (2000–6000), OR

      50 (>6000)
      ≥684 ng/mL≥700 ng/mL>1500 ng/mL>250 ng/mL
      OrganomegalySplenomegaly0 (no), 23 (H or SM), OR 38 (HSM)
      Cytopenia2 or more:

      Hg <9.0 g/dL OR

      Platelets <1009/L OR PMN <103/mL
      0 (1 line), 24 (2 lines), OR 34 (3 lines)Platelets ≤1819/LN:L ≥10 or both Hg ≤9.2 g/dL & Platelets ≤1109/LL <10.2%

      N >11.43/mL
      Hypertriglyceridemia/hypercytokinemiaTrig. ≥265 mg/dL

      OR

      Fibrin. ≤150 mg/dL
      0 (<1.5), 44 (1.5–4.0), OR 64 (>4.0)>156 mg/dLTrig. ≥150 mg/dL OR IL-6 ≥15 pg/mL OR CRP ≥15 mg/dLCRP >15 mg/dL OR doubling in 24h from >5 mg/dLCRP >4.6 mg/dL
      Hypofibrinogenemia0 (>250), OR 30 (≤250)≤360 mg/dL
      Elevated AST or LDH0 (<30), or 19 (≥30)AST >48U/mLAST ≥100 U/L or

      LDH ≥400 U/L
      AST >60 U/L

      ALT >87 U/L

      LDH >416 U/L
      Immunosuppression0 (no), OR 18 (yes)
      HemophagocytosisMarrow, spleen, or lymph node0 (no), OR 35 (yes)
      NK cell functionLow or absent
      Elevated sCD25≥2400 U/mL
      Elevated D-dimer≥1.5 μg/mL>4.93 μg/mL
      Hypoalbuminemia<2.8 g/dL
      Cardiac enzymesTroponin I >1.09 ng/mL
      Blood chemistryAnion gap <6.8 mmol/L

      Cl >106 mmol/L

      K >4.9 mmol/L

      BUN/Cr >29
      Diagnosis5 of 8 criteria metSum of parameters ≥169Known or suspected sJIA + fever + elevated ferritin + ≥2 of 4 remaining criteria≥2 criteria – increased risk of mechanical ventilation and mortalityFerritin AND CRP AND 1 from each cluster:

      I: albumen, lymphocytes, neutrophils

      II: AST, ALT, d-dimer, LDH, troponin

      III: Blood chemistry
      Other authors have similarly used the cytokine storm paradigm to define criteria for COVID-19 patients at risk for severe disease. Caricchio and colleagues examined a large cohort of patients admitted to Temple University Hospital and diagnosed as suspected COVID-19 cytokine storm by consensus between treating pulmonologists and rheumatologists based on presence of hypoxia and elevated ferritin, CRP, d-dimer, LDH, and troponin.
      • Caricchio R
      • Gallucci M
      • Dass C
      • et al.
      Preliminary predictive criteria for COVID-19 cytokine storm.
      Notably, very few of these patients fulfilled established HLH criteria such as HLH-2004
      • Henter JI
      • Horne A
      • Arico M
      • et al.
      HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis.
      , 2016 MAS Criteria, or the H-score
      • Fardet L
      • Galicier L
      • Lambotte O
      • et al.
      Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome.
      (Table I). Rather, using logistic regression and principle component analysis they identified 12 laboratory variables in 3 related clusters that could predict development of cytokine storm. These included several variables included in criteria for other cytokine storms, but also many that were peculiar to COVID-19 such as altered blood chemistry and troponin elevation. These criteria were highly sensitive and specific for patients clinically diagnosed as cytokine storm, and classified patients at significantly increased risk for longer hospitalization and death. Manson and colleagues suggested a simpler approach of using more direct measures of systemic inflammation.
      • Manson JJ
      • Crooks C
      • Naja M
      • et al.
      COVID-19-associated hyperinflammation and escalation of patient care: a retrospective longitudinal cohort study.
      These authors classified patients as having COVID hyperinflammation (COV-HI) with ferritin >1500 μg/L, or CRP >15 mg/dL or doubling in 24h. In their retrospective cohort of patients admitted to 2 UK hospitals, 33% met COV-HI on admission, and were associated with worse clinical outcomes including higher mortality. Most interestingly, meeting COV-HI criteria was associated with next-day clinical deterioration or death, again suggesting a patient population for targeted interventions for developing or worsening cytokine storm.
      If it is possible to identify COVID-19 patients with features of cytokine storm, what are the most appropriate treatment approaches to reduce inflammation and improve clinical outcomes? Once again, the experience managing CSS such as MAS offers several possible approaches. The longstanding therapy for MAS has been high-dose steroids (up to 30mg/kg/d methylprednisolone), with calcinurin inhibitors such as cyclosporine for patients with refractory disease, and approaches used in HLH such as etoposide in life-threatening situations.
      • Schulert GS
      • Grom AA.
      Pathogenesis of macrophage activation syndrome and potential for cytokine-directed therapies.
      The introduction of cytokine-directed biologic therapy in rheumatic diseases such as SJIA with high risk for MAS has altered this treatment landscape. Despite several early case reports suggesting that initiation of biologic therapy could trigger MAS,
      • Nigrovic PA
      • Mannion M
      • Prince FH
      • et al.
      Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series.
      long-term experience has suggested that overall rates of MAS during biologic treatment is similar, though with somewhat altered clinical and laboratory features.
      • Schulert GS
      • Minoia F
      • Bohnsack J
      • et al.
      Effect of biologic therapy on clinical and laboratory features of macrophage activation syndrome associated with systemic juvenile idiopathic arthritis.
      • Grom AA
      • Ilowite NT
      • Pascual V
      • et al.
      Rate and clinical presentation of macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis treated with canakinumab.
      • De Benedetti F
      • Brunner HI
      • Ruperto N
      • et al.
      Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis.
      • Yokota S
      • Itoh Y
      • Morio T
      • et al.
      Tocilizumab in systemic juvenile idiopathic arthritis in a real-world clinical setting: results from 1 year of postmarketing surveillance follow-up of 417 patients in Japan.
      In contrast, there is increasing evidence that treatment with high-dose anakinra (recombinant IL-1 receptor antagonist) is effective for treating MAS,
      • Miettunen PM
      • Narendran A
      • Jayanthan A
      • Behrens EM
      • Cron RQ.
      Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patients.
      ,
      • Eloseily EM
      • Weiser P
      • Crayne CB
      • et al.
      Benefit of Anakinra in Treating Pediatric Secondary Hemophagocytic Lymphohistiocytosis.
      and is often used early after initiation of corticosteroids.
      • Mehta P
      • Cron RQ
      • Hartwell J
      • Manson JJ
      • Tattersall RS.
      Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome.
      While anti-IL-6 treatment has proven very effective in CRS triggered by CAR-T therapy,
      • Le RQ
      • Li L
      • Yuan W
      • et al.
      FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome.
      there is less experience with this treatment in other cytokine storms. Finally the anti-IFNγ monoclonal antibody emapalumab was recently FDA approved for treatment of HLH,
      • Locatelli F
      • Jordan MB
      • Allen C
      • et al.
      Emapalumab in children with primary hemophagocytic lymphohistiocytosis.
      and there are ongoing clinical trials of this in MAS in children with SJIA with promising early results.
      • De Benedetti F
      • Brogan P
      • Grom A
      • et al.
      Interferon-gamma (IFN-g) neutralization with emapalumab and time to response in patients with macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (s-JIA) who failed high-dose glucocorticoids.
      Despite this promising landscape, the overall experience of cytokine-directed therapy in severe COVID-19 has been mixed. Given the above findings regarding high levels of IL-6 in patients with severe SARS-CoV-2 infection, an early report of dramatic response in patients treated with the anti-IL-6 agent tocilizumab
      • Xu X
      • Han M
      • Li T
      • et al.
      Effective treatment of severe COVID-19 patients with tocilizumab.
      generated great enthusiasm and launched multiple randomized-clinical trials. While several further cohort studies reported promising results compared to historical or nonrandomly selected controls,
      • Klopfenstein T
      • Zayet S
      • Lohse A
      • et al.
      Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients.
      • Capra R
      • De Rossi N
      • Mattioli F
      • et al.
      Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia.
      • Guaraldi G
      • Meschiari M
      • Cozzi-Lepri A
      • et al.
      Tocilizumab in patients with severe COVID-19: a retrospective cohort study.
      ,
      • Toniati P
      • Piva S
      • Cattalini M
      • et al.
      Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in Brescia, Italy.
      ,
      • Radbel J
      • Narayanan N
      • Bhatt PJ.
      Use of tocilizumab for COVID-19-induced cytokine release syndrome: a cautionary case report.
      results of randomized trials have been somewhat contradictory. The CORIMUNO-19 open label trial of tocilizumab showed a potential decrease in need for noninvasive ventilation, intubation, or death at 14 days but no difference in mortality at 28 days.
      • Hermine O
      • Mariette X
      • Tharaux PL
      • et al.
      Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial.
      Several other trials of tocilizumab or the IL-6 inhibitor sarilumab either failed to meet their primary endpoints or were suspended for futility.
      • Stone JH
      • Frigault MJ
      • Serling-Boyd NJ
      • et al.
      Efficacy of tocilizumab in patients hospitalized with Covid-19.
      ,
      • Salvarani C
      • Dolci G
      • Massari M
      • et al.
      Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.
      ,
      • Furlow B
      COVACTA trial raises questions about tocilizumab's benefit in COVID-19.
      There have also been several small case series of anakinra in severe COVID-19 showing decreased mortality
      • Navarro-Millán I
      • Sattui SE
      • Lakhanpal A
      • Zisa D
      • Siegel CH
      • Crow MK.
      Use of anakinra to prevent mechanical ventilation in severe COVID-19: a case series.
      ,
      • Aouba A
      • Baldolli A
      • Geffray L
      • et al.
      Targeting the inflammatory cascade with anakinra in moderate to severe COVID-19 pneumonia: case series.
      ,
      • Pontali E
      • Volpi S
      • Antonucci G
      • et al.
      Safety and efficacy of early high-dose IV anakinra in severe COVID-19 lung disease.
      and one larger cohort study finding higher rates of clinical improvement in patients treated with high dose anakinra (10mg/kg/d IV) compared to low-dose (100mg twice daily subcutaneously).
      • Cavalli G
      • De Luca G
      • Campochiaro C
      • et al.
      Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study.
      However, a randomized controlled trial of anakinra did not show any improvement and was stopped early for futility.
      Group TC-19 C
      Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomized controlled trial.
      Further randomized controlled trials of anakinra, along with other biologic agents including emapalumab, are ongoing. Finally, approaches with broader cytokine blockade such as JAK inhibitors have also been considered for severe COVID-19. A small study found that baricitinib treatment significantly reduced serum levels of a broad range of cytokines including TNF, IL-1β, and IL-6, and associated with clinical improvement,
      • Bronte V
      • Ugel S
      • Tinazzi E
      • et al.
      Baricitinib restrains the immune dysregulation in patients with severe COVID-19.
      and led to the recent emergency-use authorization for baricitinib in combination with remdesivir for children and adults with severe COVID-19.
      With these underwhelming results, the most effective therapy for severe COVID-19 may remain corticosteroids. Several large studies have shown that corticosteroid treatment can reduce mortality in severe COVID-19, most notably in the RECOVERY Trial. Here, dexamethasone for up to 10 days significantly reduced 28-day mortality, with the most pronounced responses in those requiring mechanical ventilation (age-adjusted rate ratio 0.65) or receiving oxygen without invasive ventilation (rate ratio 0.82).
      • RECOVERY Collaborative Group H
      • Horby P
      • Lim WS
      • et al.
      Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report.
      A similar large study found improved survival with hydrocortisone treatment, although this trial was stopped before reaching statistical significance,
      • Angus DC
      • Derde L
      • Al-Beidh F
      • et al.
      Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial.
      and a recent metaanalysis confirmed the overall benefit of corticosteroids in severe COVID-19.
      • Sterne JAC
      • Murthy S
      • et al.
      WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group S
      Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis.
      Given this experience, corticosteroid treatment is now widely recommended for adults and children hospitalized with severe COVID-19 infection.

      Prevention C for DC and. Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19). Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html. Accessed December 23, 2020.

      Interestingly recent new findings from the RECOVERY Trial examined use of tocilizumab in patients with and without concurrent steroid treatment.
      • Horby PW
      • Pessoa-Amorim G
      • Peto L
      • et al.
      Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial.
      These preliminary findings showed that the greatest reduction in 28-day mortality was in those receiving both tocilizumab and dexamethasone (27% vs 33% steroids alone) with no significant improvement in those without concomitant steroids. These findings were also notable in showing a trend toward greater benefit of tocilizumab in patients not requiring ventilator support, which could suggest cytokine blockade and corticosteroids work best at distinct phases of severe COVID-19. Further work is urgently needed to determine how and when to best utilize other immunomodulatory therapy as an adjuvant to in steroid-refractory or contraindicated patients.

      CONCLUSIONS

      While the paradigm of CSS remains new and somewhat ill-defined, it can be a useful framework to consider disorders where the dysregulated host inflammatory response becomes itself pathologic, such as in MAS. Although the precise nature and drivers of a CSS associated with SARS-CoV-2 infection remains to be defined, it is clear that increased systemic inflammation is associated with worse outcomes in COVID-19. It has also been shown with high-quality clinical trial data that patients with severe and critical COVID-19 benefit from immunomodulatory therapy with corticosteroids. Using the CSS framework in MAS as a guide, the critical questions remaining include: How can clinicians best identify COVID-19 patients progressing to cytokine storm? Are there particular genetic or other host factors that can predispose to a CSS during or after SARS-CoV-2 infection? And most importantly, how and when can therapeutic interventions for COVID-19 CSS be utilized, including corticosteroids and cytokine-directed biologic therapy? Given the continued global spread of SARS-CoV-2 pandemic, borrowing approaches from more well-defined disorders such as MAS may provide a helpful blueprint to approach these questions.

      Acknowledgements

      Conflicts of Interest: Dr. Ombrello has no conflicts of interest to disclose. Dr. Schulert has received consulting fees from Novartis and SOBI of <$10,000.
      Dr. Ombrello is supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases ( Z01-AR0411989 ) of the National Institutes of Health . Dr. Schulert is supported by the National Institute of Arthritis, Musculoskeletal, and Skin Disorders at the National Institutes of Health K08-AR072075 .
      Drs. Ombrello and Schulert have read and agree with the authorship agreement.

      References

        • Chen G
        • Wu D
        • Guo W
        • et al.
        Clinical and immunological features of severe and moderate coronavirus disease 2019.
        J Clin Invest. 2020; 130: 2620-2629https://doi.org/10.1172/JCI137244
        • Zhou F
        • Yu T
        • Du R
        • et al.
        Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
        Lancet (London, England). 2020; 395: 1054-1062https://doi.org/10.1016/S0140-6736(20)30566-3
        • Henderson LA
        • Canna SW
        • Schulert GS
        • et al.
        On the alert for cytokine storm: immunopathology in COVID-19.
        Arthritis Rheumatol. 2020; https://doi.org/10.1002/art.41285
        • Xu X
        • Han M
        • Li T
        • et al.
        Effective treatment of severe COVID-19 patients with tocilizumab.
        Proc Natl Acad Sci U S A. 2020; 117: 10970-10975https://doi.org/10.1073/pnas.2005615117
        • Klopfenstein T
        • Zayet S
        • Lohse A
        • et al.
        Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients.
        Med Mal Infect. 2020; https://doi.org/10.1016/j.medmal.2020.05.001
        • Capra R
        • De Rossi N
        • Mattioli F
        • et al.
        Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia.
        Eur J Intern Med. 2020; 76https://doi.org/10.1016/j.ejim.2020.05.009
        • Guaraldi G
        • Meschiari M
        • Cozzi-Lepri A
        • et al.
        Tocilizumab in patients with severe COVID-19: a retrospective cohort study.
        Lancet Rheumatol. 2020; 2: e474-e484https://doi.org/10.1016/S2665-9913(20)30173-9
        • Navarro-Millán I
        • Sattui SE
        • Lakhanpal A
        • Zisa D
        • Siegel CH
        • Crow MK.
        Use of anakinra to prevent mechanical ventilation in severe COVID-19: a case series.
        Arthritis Rheumatol (Hoboken, NJ). 2020; https://doi.org/10.1002/art.41422
        • RECOVERY Collaborative Group H
        • Horby P
        • Lim WS
        • et al.
        Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report.
        N Engl J Med. 2020; https://doi.org/10.1056/NEJMoa2021436
        • Angus DC
        • Derde L
        • Al-Beidh F
        • et al.
        Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial.
        JAMA. 2020; 324: 1317-1329https://doi.org/10.1001/jama.2020.17022
        • Cavalcanti AB
        • Zampieri FG
        • Rosa RG
        • et al.
        Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19.
        N Engl J Med. 2020; 383: 2041-2052https://doi.org/10.1056/NEJMoa2019014
        • Boulware DR
        • Pullen MF
        • Bangdiwala AS
        • et al.
        A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19.
        N Engl J Med. 2020; 383: 517-525https://doi.org/10.1056/NEJMoa2016638
        • Recovery Collaborative Group H
        • Horby P
        • Mafham M
        • et al.
        Effect of hydroxychloroquine in hospitalized patients with Covid-19.
        N Engl J Med. 2020; 383: 2030-2040https://doi.org/10.1056/NEJMoa2022926
        • Beigel JH
        • Tomashek KM
        • Dodd LE
        • et al.
        Remdesivir for the treatment of Covid-19—final report.
        N Engl J Med. 2020; 383: 1813-1826https://doi.org/10.1056/NEJMoa2007764
        • Stone JH
        • Frigault MJ
        • Serling-Boyd NJ
        • et al.
        Efficacy of tocilizumab in patients hospitalized with Covid-19.
        N Engl J Med. 2020; https://doi.org/10.1056/NEJMoa2028836
        • Group TC-19 C
        Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomized controlled trial.
        Lancet Respir Med. 2021; (Published.)
        • Salvarani C
        • Dolci G
        • Massari M
        • et al.
        Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.
        JAMA Intern Med. 2020; https://doi.org/10.1001/JAMAINTERNMED.2020.6615
        • Minoia F
        • Davi S
        • Alongi A
        • Ravelli A.
        Criteria for cytokinestorm syndromesle.
        in: Cron RQ Behrens EM Cytokine storm syndromes. Springer Nature, Switzerland AG, 2019: 61-79
        • Ravelli A
        • Grom AA
        • Behrens EM
        • Cron RQ.
        Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment.
        Genes Immun. 2012; 13: 289-298https://doi.org/10.1038/gene.2012.3
        • Borgia RE
        • Gerstein M
        • Levy DM
        • Silverman ED
        • Hiraki LT.
        Features, treatment, and outcomes of macrophage activation syndrome in childhood-onset systemic lupus erythematosus.
        Arthritis Rheumatol (Hoboken, NJ). 2018; 70: 616-624https://doi.org/10.1002/art.40417
        • Avcin T
        • Tse SM
        • Schneider R
        • Ngan B
        • Silverman ED.
        Macrophage activation syndrome as the presenting manifestation of rheumatic diseases in childhood.
        J Pediatr. 2006; 148: 683-686https://doi.org/10.1016/j.jpeds.2005.12.070
        • Crayne CB
        • Albeituni S
        • Nichols KE
        • Cron RQ.
        The immunology of macrophage activation syndrome.
        Front Immunol. 2019; 10: 119https://doi.org/10.3389/fimmu.2019.00119
        • Ravelli A
        • Minoia F
        • Davì S
        • et al.
        2016 Classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a European league against rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborat.
        Arthritis Rheumatol (Hoboken, NJ). 2016; 68: 566-576https://doi.org/10.1002/art.39332
        • Minoia F
        • Bovis F
        • Davì S
        • et al.
        Development and initial validation of the macrophage activation syndrome/primary hemophagocytic lymphohistiocytosis score, a diagnostic tool that differentiates primary hemophagocytic lymphohistiocytosis from macrophage activation syndrome.
        J Pediatr. 2017; 189 (e3): 72-78https://doi.org/10.1016/j.jpeds.2017.06.005
        • Minoia F
        • Davì S
        • Horne A
        • et al.
        Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients.
        Arthritis Rheumatol (Hoboken, NJ). 2014; 66: 3160-3169https://doi.org/10.1002/art.38802
        • Weiss ES
        • Girard-Guyonvarc'h C
        • Holzinger D
        • et al.
        Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome.
        Blood. 2018; 131: 1442-1455https://doi.org/10.1182/blood-2017-12-820852
        • Yasin S
        • Fall N
        • Brown RA
        • et al.
        IL-18 as a biomarker linking systemic juvenile idiopathic arthritis and macrophage activation syndrome.
        Rheumatology. 2019; https://doi.org/10.1093/rheumatology/kez282
        • Zhou T
        • Damsky W
        • Weizman O-E
        • et al.
        IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy.
        Nature. 2020; 583: 609-614https://doi.org/10.1038/s41586-020-2422-6
        • Michels M
        • de Mast Q
        • Netea MG
        • et al.
        Normal free interleukin-18 (IL-18) plasma levels in dengue virus infection and the need to measure both total IL-18 and IL-18 binding protein levels.
        Clin Vaccine Immunol. 2015; 22https://doi.org/10.1128/CVI.00147-15
        • Bracaglia C
        • de Graaf K
        • Pires Marafon D
        • et al.
        Elevated circulating levels of interferon-γ and interferon-γ-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis.
        Ann Rheum Dis. 2017; 76: 166-172https://doi.org/10.1136/annrheumdis-2015-209020
        • Put K
        • Avau A
        • Brisse E
        • et al.
        Cytokines in systemic juvenile idiopathic arthritis and haemophagocytic lymphohistiocytosis: tipping the balance between interleukin-18 and interferon-γ.
        Rheumatology (Oxford). 2015; 54: 1507-1517https://doi.org/10.1093/rheumatology/keu524
        • GS S
        • AV P
        • T D
        • et al.
        Monocyte and bone marrow macrophage transcriptional phenotypes in systemic juvenile idiopathic arthritis reveal TRIM8 as a mediator of IFN-γ hyper-responsiveness and risk for macrophage activation syndrome.
        Ann Rheum Dis. 2020; https://doi.org/10.1136/ANNRHEUMDIS-2020-217470
        • Romberg N
        • Al Moussawi K
        • Nelson-Williams C
        • et al.
        Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation.
        Nat Genet. 2014; 46: 1135-1139https://doi.org/10.1038/ng.3066
        • Canna SW
        • de Jesus AA
        • Gouni S
        • et al.
        An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome.
        Nat Genet. 2014; 46: 1140-1146https://doi.org/10.1038/ng.3089
        • Vastert SJ
        • van Wijk R
        • D'Urbano LE
        • et al.
        Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis.
        Rheumatology. 2010; 49: 441-449https://doi.org/10.1093/rheumatology/kep418
        • Zhang K
        • Biroschak J
        • Glass DN
        • et al.
        Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC13-4 polymorphisms.
        Arthritis Rheum. 2008; 58: 2892-2896https://doi.org/10.1002/art.23734
        • Kaufman KM
        • Linghu B
        • Szustakowski JD
        • et al.
        Whole exome sequencing reveals overlap between macrophage activation syndrome in systemic juvenile idiopathic arthritis and familial hemophagocytic lymphohistiocytosis.
        Arthritis Rheumatol. 2014; https://doi.org/10.1002/art.38793
        • Schulert GS
        • Zhang M
        • Husami A
        • et al.
        Novel UNC13D intronic variant disrupting a NFκB enhancer in a patient with recurrent macrophage activation syndrome and systemic juvenile idiopathic arthritis.
        Arthritis Rheumatol. 2018; https://doi.org/10.1002/art.40438
        • Zhang M
        • Bracaglia C
        • Prencipe G
        • et al.
        A heterozygous RAB27A mutation associated with delayed cytolytic granule polarization and hemophagocytic lymphohistiocytosis.
        J Immunol. 2016; 196: 2492-2503https://doi.org/10.4049/jimmunol.1501284
        • Wu C
        • Chen X
        • Cai Y
        • et al.
        Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China.
        JAMA Intern Med. 2020; 180: 934-943https://doi.org/10.1001/jamainternmed.2020.0994
        • Hadjadj J
        • Yatim N
        • Barnabei L
        • et al.
        Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients.
        Science. 2020; 369: 718-724https://doi.org/10.1126/science.abc6027
        • Zhang Q
        • Bastard P
        • Liu Z
        • et al.
        Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.
        Science. 2020; 370https://doi.org/10.1126/SCIENCE.ABD4570
        • Bastard P
        • Rosen LB
        • Zhang Q
        • et al.
        Autoantibodies against type I IFNs in patients with life-threatening COVID-19.
        Science. 2020; 370https://doi.org/10.1126/SCIENCE.ABD4585
        • Zhou Z
        • Ren L
        • Zhang L
        • et al.
        Heightened innate immune responses in the respiratory tract of COVID-19 patients.
        Cell Host Microbe. 2020; 27: 883-890https://doi.org/10.1016/j.chom.2020.04.017
        • Park A
        • Iwasaki A.
        Type I and Type III interferons - induction, signaling, evasion, and application to combat COVID-19.
        Cell Host Microbe. 2020; 27: 870-878https://doi.org/10.1016/j.chom.2020.05.008
        • Israelow B
        • Song E
        • Mao T
        • et al.
        Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling.
        J Exp Med. 2020; 217https://doi.org/10.1084/jem.20201241
        • Karki R
        • Sharma BR
        • Tuladhar S
        • et al.
        COVID-19 cytokines and the hyperactive immune response: synergism of TNF-α and IFN-γ in triggering inflammation, tissue damage, and death.
        bioRxiv Prepr Serv Biol. 2020; https://doi.org/10.1101/2020.10.29.361048
        • Zizzo G
        • Cohen PL.
        Imperfect storm: is interleukin-33 the Achilles heel of COVID-19?.
        Lancet Rheumatol. 2020; 2: e779-e790https://doi.org/10.1016/S2665-9913(20)30340-4
        • Rood JE
        • Rao S
        • Paessler M
        • et al.
        ST2 contributes to T-cell hyperactivation and fatal hemophagocytic lymphohistiocytosis in mice.
        Blood. 2016; 127: 426-435https://doi.org/10.1182/blood-2015-07-659813
        • Goswami J
        • MacArthur TA
        • Sridharan M
        • et al.
        A review of pathophysiology, clinical features, and management options of COVID-19 associated coagulopathy.
        Shock. 2020; https://doi.org/10.1097/SHK.0000000000001680
        • Magro C
        • Mulvey JJ
        • Berlin D
        • et al.
        Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases.
        Transl Res. 2020; 220: 1-13https://doi.org/10.1016/j.trsl.2020.04.007
        • Merrill JT
        • Erkan D
        • Winakur J
        • James JA.
        Emerging evidence of a COVID-19 thrombotic syndrome has treatment implications.
        Nat Rev Rheumatol. 2020; 16: 581-589https://doi.org/10.1038/s41584-020-0474-5
        • Sinha P
        • Matthay MA
        • Calfee CS.
        Is a &quot;cytokine storm&quot; relevant to COVID-19?.
        JAMA Intern Med. 2020; 180: 1152-1154https://doi.org/10.1001/jamainternmed.2020.3313
        • Kox M
        • Waalders NJB
        • Kooistra EJ
        • Gerretsen J
        • Pickkers P.
        Cytokine levels in critically ill patients with COVID-19 and other conditions.
        JAMA. 2020; 324https://doi.org/10.1001/jama.2020.17052
        • Mudd PA
        • Crawford JC
        • Turner JS
        • et al.
        Distinct inflammatory profiles distinguish COVID-19 from influenza with limited contributions from cytokine storm.
        Sci Adv. 2020; https://doi.org/10.1126/sciadv.abe3024
        • Ravelli A
        • Minoia F
        • Davì S
        • et al.
        2016 Classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborat.
        Ann Rheum Dis. 2016; 75: 481-489https://doi.org/10.1136/annrheumdis-2015-208982
        • Henter JI
        • Horne A
        • Arico M
        • et al.
        HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis.
        Pediatr Blood Cancer. 2007; 48: 124-131https://doi.org/10.1002/pbc.21039
        • Schulert GS
        • Canna SW.
        Convergent pathways of the hyperferritinemic syndromes.
        Int Immunol. 2018; 30: 195-203https://doi.org/10.1093/intimm/dxy012
        • Pandolfi L
        • Fossali T
        • Frangipane V
        • et al.
        Broncho-alveolar inflammation in COVID-19 patients: a correlation with clinical outcome.
        BMC Pulm Med. 2020; 20https://doi.org/10.1186/S12890-020-01343-Z
        • Liu T
        • Jia P
        • Fang B
        Differential Expression of Viral Transcripts From Single-Cell RNA Sequencing of Moderate and Severe COVID-19 Patients and Its Implications for Case Severity.
        Front Microbiol. 2020; 11https://doi.org/10.3389/FMICB.2020.603509
        • Liao M
        • Liu Y
        • Yuan J
        • et al.
        Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19.
        Nat Med. 2020; 26https://doi.org/10.1038/S41591-020-0901-9
        • Grant RA
        • Morales-Nebreda L
        • Markov NS
        • et al.
        Alveolitis in severe SARS-CoV-2 pneumonia is driven by self-sustaining circuits between infected alveolar macrophages and T cells.
        bioRxiv. 2020; (2020.08.05.238188)https://doi.org/10.1101/2020.08.05.238188
        • Webb BJ
        • Peltan ID
        • Jensen P
        • et al.
        Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study.
        Lancet Rheumatol. 2020; 2 (10.1016/S2665-9913(20)30343-X): e754-e763
        • Caricchio R
        • Gallucci M
        • Dass C
        • et al.
        Preliminary predictive criteria for COVID-19 cytokine storm.
        Ann Rheum Dis. 2020; https://doi.org/10.1136/annrheumdis-2020-218323
        • Fardet L
        • Galicier L
        • Lambotte O
        • et al.
        Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome.
        Arthritis Rheumatol (Hoboken, NJ). 2014; 66: 2613-2620https://doi.org/10.1002/art.38690
        • Manson JJ
        • Crooks C
        • Naja M
        • et al.
        COVID-19-associated hyperinflammation and escalation of patient care: a retrospective longitudinal cohort study.
        Lancet Rheumatol. 2020; 2: e594-e602https://doi.org/10.1016/S2665-9913(20)30275-7
        • Schulert GS
        • Grom AA.
        Pathogenesis of macrophage activation syndrome and potential for cytokine-directed therapies.
        Annu Rev Med. 2015; 66: 145-159https://doi.org/10.1146/annurev-med-061813-012806
        • Nigrovic PA
        • Mannion M
        • Prince FH
        • et al.
        Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series.
        Arthritis Rheum. 2011; 63: 545-555https://doi.org/10.1002/art.30128
        • Schulert GS
        • Minoia F
        • Bohnsack J
        • et al.
        Effect of biologic therapy on clinical and laboratory features of macrophage activation syndrome associated with systemic juvenile idiopathic arthritis.
        Arthritis Care Res. 2018; https://doi.org/10.1002/acr.23277
        • Grom AA
        • Ilowite NT
        • Pascual V
        • et al.
        Rate and clinical presentation of macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis treated with canakinumab.
        Arthritis Rheumatol. 2016; 68: 218-228https://doi.org/10.1002/art.39407
        • De Benedetti F
        • Brunner HI
        • Ruperto N
        • et al.
        Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis.
        N Engl J Med. 2012; 367: 2385-2395https://doi.org/10.1056/NEJMoa1112802
        • Yokota S
        • Itoh Y
        • Morio T
        • et al.
        Tocilizumab in systemic juvenile idiopathic arthritis in a real-world clinical setting: results from 1 year of postmarketing surveillance follow-up of 417 patients in Japan.
        Ann Rheum Dis. 2016; 75: 1654-1660https://doi.org/10.1136/annrheumdis-2015-207818
        • Miettunen PM
        • Narendran A
        • Jayanthan A
        • Behrens EM
        • Cron RQ.
        Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patients.
        Rheumatology. 2011; 50: 417-419https://doi.org/10.1093/rheumatology/keq218
        • Eloseily EM
        • Weiser P
        • Crayne CB
        • et al.
        Benefit of Anakinra in Treating Pediatric Secondary Hemophagocytic Lymphohistiocytosis.
        Arthritis Rheumatol (Hoboken, NJ). 2020; 72https://doi.org/10.1002/ART.41103
        • Mehta P
        • Cron RQ
        • Hartwell J
        • Manson JJ
        • Tattersall RS.
        Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome.
        Lancet Rheumatol. 2020; 2: e358-e367https://doi.org/10.1016/S2665-9913(20)30096-5
        • Le RQ
        • Li L
        • Yuan W
        • et al.
        FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome.
        Oncologist. 2018; 23: 943-947https://doi.org/10.1634/theoncologist.2018-0028
        • Locatelli F
        • Jordan MB
        • Allen C
        • et al.
        Emapalumab in children with primary hemophagocytic lymphohistiocytosis.
        N Engl J Med. 2020; 382: 1811-1822https://doi.org/10.1056/NEJMoa1911326
        • De Benedetti F
        • Brogan P
        • Grom A
        • et al.
        Interferon-gamma (IFN-g) neutralization with emapalumab and time to response in patients with macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (s-JIA) who failed high-dose glucocorticoids.
        Arthritis Rheumatol. 2019; 71: 5229-5231
        • Toniati P
        • Piva S
        • Cattalini M
        • et al.
        Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in Brescia, Italy.
        Autoimmun Rev. 2020; 19102568https://doi.org/10.1016/j.autrev.2020.102568
        • Radbel J
        • Narayanan N
        • Bhatt PJ.
        Use of tocilizumab for COVID-19-induced cytokine release syndrome: a cautionary case report.
        Chest. 2020; 158: e15-e19https://doi.org/10.1016/j.chest.2020.04.024
        • Hermine O
        • Mariette X
        • Tharaux PL
        • et al.
        Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial.
        JAMA Intern Med. 2020; https://doi.org/10.1001/JAMAINTERNMED.2020.6820
        • Furlow B
        COVACTA trial raises questions about tocilizumab's benefit in COVID-19.
        Lancet Rheumatol. 2020; 2https://doi.org/10.1016/S2665-9913(20)30313-1
        • Aouba A
        • Baldolli A
        • Geffray L
        • et al.
        Targeting the inflammatory cascade with anakinra in moderate to severe COVID-19 pneumonia: case series.
        Ann Rheum Dis. 2020; 79: 1381-1382https://doi.org/10.1136/annrheumdis-2020-217706
        • Pontali E
        • Volpi S
        • Antonucci G
        • et al.
        Safety and efficacy of early high-dose IV anakinra in severe COVID-19 lung disease.
        J Allergy Clin Immunol. 2020; 146https://doi.org/10.1016/J.JACI.2020.05.002
        • Cavalli G
        • De Luca G
        • Campochiaro C
        • et al.
        Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study.
        Lancet Rheumatol. 2020; 2https://doi.org/10.1016/S2665-9913(20)30127-2
        • Bronte V
        • Ugel S
        • Tinazzi E
        • et al.
        Baricitinib restrains the immune dysregulation in patients with severe COVID-19.
        J Clin Invest. 2020; 130: 6409-6416https://doi.org/10.1172/JCI141772
        • Sterne JAC
        • Murthy S
        • et al.
        • WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group S
        Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis.
        JAMA. 2020; 324: 1330-1341https://doi.org/10.1001/jama.2020.17023
      1. Prevention C for DC and. Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19). Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html. Accessed December 23, 2020.

        • Horby PW
        • Pessoa-Amorim G
        • Peto L
        • et al.
        Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial.
        medRxiv. 2021; (2021.02.11.21249258)https://doi.org/10.1101/2021.02.11.21249258