key: cord-0877425-wfduk0il
authors: Ombrello, Michael J.; Schulert, Grant S.
title: COVID-19 and Cytokine Storm Syndrome: Are there lessons from Macrophage Activation Syndrome?
date: 2021-03-05
journal: Transl Res
DOI: 10.1016/j.trsl.2021.03.002
sha: 39910f695771addd1f5c11a07512290a05610925
doc_id: 877425
cord_uid: wfduk0il

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.

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 1,2 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 3 ) . 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 4 (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 [5] [6] [7] [8] , and large-scale controlled trials of corticosteroids found clear benefit 9, 10 . The promise of immunomodulatory therapies was in stark contrast to other agents such as hydroxychloroquine with initial excitement that failed in rigorous study [11] [12] [13] , and antivirals which showed relatively small improvements without change in overall mortality 14 . 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) [15] [16] [17] .

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?

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 multi-organ failure resulting from the excessive and often selfperpetuating production of cytokines through unencumbered and amplified immune activation 18 .

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.

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 adultonset Still's disease) 19 but also including systemic lupus erythematosus 20 and Kawasaki disease 21 . 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 22 . 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 23, 24 . 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 23 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 28 .

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 26 . 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 26, 29 . It is the abnormal elevation of free IL-18 that is thought to drive pathologic IFN production, leading to MAS in sJIA. Indeed activation of IFN pathways has been associated with emergence of MAS 30, 31 , and drives the proinflammatory activation of macrophages to further sustain hyperinflammation 32 . These observations are recapitulated in a monogenic form of HLH/MAS caused by gain-of-function mutations in NLRC4 33, 34 . Mice or humans bearing gain-of-function mutations in NLRC4 demonstrate persistent elevation of IL-18 and recurrent episodes of MAS 26, 33, 34 . 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 [35] [36] [37] . 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 38, 39 (Figure 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.

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) 2 . 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) 40 . 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) 1 . 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 2,000 serum samples from more than 1,400 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 41 . 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 IFN plasma levels preceded clinical deterioration. Together, this points to excessive NF-kBdriven inflammation, along with impaired IFN viral control responses, in severe hyperinflammatory COVID-19 41 .

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 42 and autoantibodies directed against type I IFNs (IFN-a and/or IFN-w) 43 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 42, 43 . 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 mildmoderate 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 44 . 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 pro-inflammatory amplification loop observed in severe COVID-19 45, 46 (Figure 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 45 .

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 IFN (both found in severe COVID-19 and produced by COVID-infected PBMC) can drive proinflammatory cell death 47 . Co-administration of these cytokines in a mouse model led to hyperinflammation, multi-organ 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, IFN plays a central role in driving both primary HLH and MAS, further supporting a key role for this cytokine in cytokine storms. Another recent paper 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 48 . Interestingly, IL-33 has been shown to have prominent roles in the cytokine storm caused by HLH 49 .

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 lifethreatening 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 50 . Indeed, some patients with severe COVID-19 show evidence of catastrophic microvascular injury with complement activation 51 , which could suggest a phenotype similar to thrombotic microangiopathy 52 . 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 [53] [54] [55] . 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 53 . 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 54 . 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 56, 57 , COVID-19 patients rarely exhibit the marked elevations associated with increasing mortality in hyperferritinemic syndromes 58 . 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 ( Figure 1 ). As discussed above, the impaired type I interferon responses caused by genetic mutations or autoantibodies 42, 43 can lead to a failure to control primary SARS-CoV-2 infection in the lungs, including infection of alveolar macrophages driving persistent immune activation 59, 60 . Indeed, immune profiling of the pulmonary inflammatory response in severe COVID-19 shows expansion and IFN-driven activation of alveolar macrophages, IFNproducing T cells, and increased pulmonary levels of proinflammatory mediators (IL-6, IL-8, IL-1 ) and IFN-induced chemokines 59, 61, 62 . 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.

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 63 . 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 1) . These criteria were then applied retrospectively to a large cohort of COVID-19 patients admitted to a regional, multi-site 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 1) . 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 66 . These authors classified patients as having COVID hyperinflammation (COV-HI) with ferritin >1500 g/L, or CRP >15 mg/dL or doubling in 24h. In their retrospective cohort of patients admitted to two 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 67 . 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 68 , long-term experience has suggested that overall rates of MAS during biologic treatment is similar, though with somewhat altered clinical and laboratory features [69] [70] [71] [72] . In contrast, there is increasing evidence that treatment with highdose anakinra (recombinant IL-1 receptor antagonist) is effective for treating MAS 73, 74 , and is often used early after initiation of corticosteroids 75 . While anti-IL-6 treatment has proven very effective in CRS triggered by CAR-T therapy 76 There have also been several small case series of anakinra in severe COVID-19 showing decreased mortality 8, 83, 84 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) 85 . However, a randomized controlled trial of anakinra did not show any improvement and was stopped early for futility 16 . 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-1 , and IL-6, and associated with clinical improvement 86 , 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) 9 . A similar large study found improved survival with hydrocortisone treatment, although this trial was stopped before reaching statistical significance 10 , and a recent metaanalysis confirmed the overall benefit of corticosteroids in severe COVID-19 87 . Given this experience, corticosteroid treatment is now widely recommended for adults and children hospitalized with severe COVID-19 infection 88 . Interestingly recent new findings from the RECOVERY Trial examined use of tocilizumab in patients with and without concurrent steroid treatment 89 . 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 towards 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.

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. 

Clinical and immunological features of severe and moderate coronavirus disease 2019

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

On the alert for cytokine storm: Immunopathology in COVID-19. Arthritis Rheumatol

Effective treatment of severe COVID-19 patients with tocilizumab

Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients

Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia

Tocilizumab in patients with severe COVID-19: a retrospective cohort study

Use of Anakinra to Prevent Mechanical Ventilation in Severe COVID-19: A Case Series

Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe

Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19

A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19

Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19

Remdesivir for the Treatment of Covid-19 -Final Report

Efficacy of Tocilizumab in Patients Hospitalized with Covid-19

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

Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial

Criteria for Cytokine Storm Syndromesle

Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment

Features, Treatment, and Outcomes of Macrophage Activation Syndrome in Childhood-Onset Systemic Lupus Erythematosus

Macrophage activation syndrome as the presenting manifestation of rheumatic diseases in childhood

The Immunology of Macrophage Activation Syndrome

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

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

Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients

Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome

IL-18 as a biomarker linking systemic juvenile idiopathic arthritis and macrophage activation syndrome

IL-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 need to measure both total IL-18 and IL-18 binding protein levels

Elevated circulating levels of interferon-γ and interferon-γ-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis

Cytokines in systemic juvenile idiopathic arthritis and haemophagocytic lymphohistiocytosis: tipping the balance between interleukin-18 and interferon-γ

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

Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation

An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome

Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis

Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC13-4 polymorphisms

Whole exome sequencing reveals overlap between macrophage activation syndrome in systemic juvenile idiopathic arthritis and familial hemophagocytic lymphohistiocytosis. Arthritis Rheumatol

Novel UNC13D intronic variant disrupting a NFκB enhancer in a patient with recurrent macrophage activation syndrome and systemic juvenile idiopathic arthritis. Arthritis Rheumatol

A Heterozygous RAB27A Mutation Associated with Delayed Cytolytic Granule Polarization and Hemophagocytic Lymphohistiocytosis

Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease

Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Heightened Innate Immune Responses in the Respiratory Tract of COVID-19 Patients

Type I and Type III Interferons -Induction, Signaling, Evasion, and Application to Combat COVID-19

Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling

COVID-19 cytokines and the hyperactive immune response: Synergism of TNF-α and IFN-γ in triggering inflammation, tissue damage, and death

Imperfect storm: is interleukin-33 the Achilles heel of COVID-19?

ST2 contributes to T-cell hyperactivation and fatal hemophagocytic lymphohistiocytosis in mice

A Review of Pathophysiology, Clinical Features, and Management Options of COVID-19 Associated Coagulopathy. Shock

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases

Emerging evidence of a COVID-19 thrombotic syndrome has treatment implications

Is a &quot

Cytokine Levels in Critically Ill Patients With COVID-19 and Other Conditions

Distinct inflammatory profiles distinguish COVID-19 from influenza with limited contributions from cytokine storm. Sci Adv

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

HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer

Convergent pathways of the hyperferritinemic syndromes

Broncho-alveolar inflammation in COVID-19 patients: a correlation with clinical outcome

Differential Expression of Viral Transcripts From Single-Cell RNA Sequencing of Moderate and Severe COVID-19 Patients and Its Implications for Case Severity

Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19

Alveolitis in severe SARS-CoV-2 pneumonia is driven by self-sustaining circuits between infected alveolar macrophages and T cells. bioRxiv

Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study

Preliminary predictive criteria for COVID-19 cytokine storm

Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome

COVID-19-associated hyperinflammation and escalation of patient care: a retrospective longitudinal cohort study

Pathogenesis of macrophage activation syndrome and potential for cytokine-directed therapies

Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series

Effect of Biologic Therapy on Clinical and Laboratory Features of Macrophage Activation Syndrome Associated With Systemic Juvenile Idiopathic Arthritis

Rate and Clinical Presentation of Macrophage Activation Syndrome in Patients With Systemic Juvenile Idiopathic Arthritis Treated With Canakinumab

Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis

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

Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patients

Benefit of Anakinra in Treating Pediatric Secondary Hemophagocytic Lymphohistiocytosis

Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome

FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell-Induced Severe or Life-Threatening Cytokine Release Syndrome

Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis

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

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

Use of Tocilizumab for COVID-19-Induced Cytokine Release Syndrome: A Cautionary Case Report

Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial

COVACTA trial raises questions about tocilizumab's benefit in COVID-19

Targeting the inflammatory cascade with anakinra in moderate to severe COVID-19 pneumonia: case series

Safety and efficacy of early high-dose IV anakinra in severe COVID-19 lung disease

Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study

Baricitinib restrains the immune dysregulation in patients with severe COVID-19

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Metaanalysis

Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, openlabel, platform trial. medRxiv