key: cord-1030225-y26r9g3m
authors: Henderson, Lauren A.; Canna, Scott W.; Schulert, Grant S.; Volpi, Stefano; Lee, Pui Y.; Kernan, Kate F.; Caricchio, Roberto; Mahmud, Shawn; Hazen, Melissa M.; Halyabar, Olha; Hoyt, Kacie J.; Han, Joseph; Grom, Alexei A.; Gattorno, Marco; Ravelli, Angelo; De Benedetti, Fabrizio; Behrens, Edward M.; Cron, Randy Q.; Nigrovic, Peter A.
title: On the Alert for Cytokine Storm: Immunopathology in COVID‐19
date: 2020-05-10
journal: Arthritis Rheumatol
DOI: 10.1002/art.41285
sha: af141c1129a0cabfcb833f13720ba03c7170837f
doc_id: 1030225
cord_uid: y26r9g3m

Poor outcomes in COVID‐19 correlate with clinical and laboratory features of cytokine storm syndrome. Broad screening for cytokine storm and early, targeted antiinflammatory therapy may prevent immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in cytokine storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID‐19.

Drs. Henderson and Canna contributed equally to this work. Dr. Henderson has received salary support from the Childhood Arthritis and Rheumatology Alliance and consulting fees from Sobi (less than $10,000). Dr. Canna has received research support from AB2 Bio related to a clinical trial. Dr. Schulert has received consulting fees from Sobi and Novartis (less than $10,000 each). Dr. Caricchio has received consulting fees from GlaxoSmithKline, Aurinia Pharmaceuticals, and Janssen (less than $10,000 each) and investigator-initiated research support from Janssen. Dr. Grom has received consulting fees from Novartis, AB2 Bio, and Sobi (less than $10,000 each) and research support from those companies. Dr. Gattorno has received consulting fees, speaking fees, and/or honoraria from Novartis and Sobi (less than $10,000 each) and research support from the Eurofever Project. Dr. Ravelli has received consulting fees, speaking fees, and/or honoraria from AbbVie, Bristol-Myers Squibb, Pfizer, Hoffmann-LaRoche, Novartis, Centocor, Angelini Holding, and Reckitt Benckiser (less than $10,000 each). Dr. De Benedetti has received research support paid to his institution from AbbVie, Hoffmann-La Roche, Pfizer, NovImmune, Novartis, Sobi, and Sanofi. Dr. Behrens has received research support from AB2 Bio to run a clinical trial. Dr. Cron has received consulting fees from Sobi, Novartis, and Pfizer (less than $10,000 each) and is a co-Principal Investigator of an investigatorinitiated clinical trial to study anakinra in secondary hemophagocytic lymphohistiocytosis funded by Sobi. Dr. Nigrovic has received salary support from the Childhood Arthritis and Rheumatology Research Alliance, consulting fees from Sobi, Pfizer, Quench Bio, XBiotech, and Bristol-Myers Squibb (less than $10,000 each) and from Simcere and Miach Orthopedics (more than $10,000 each), royalties from UpToDate Inc. and the American Academy of Pediatrics, and research support from Novartis, Sobi, Pfizer, and Bristol-Myers Squibb. No other disclosures relevant to this article were reported. storm syndrome, in which hyperinflammation and multiorgan disease arise through excessive cytokine release from uncontrolled immune activation ( Figure 1 ). Rheumatologists face this foe regularly in systemic juvenile idiopathic arthritis (JIA), adultonset Still's disease, and systemic lupus erythematosus, among other diseases. Macrophage activation syndrome (MAS), one form of cytokine storm syndrome, develops in at least 10% of patients with systemic JIA. Compared to systemic JIA patients without MAS, those with this complication are more likely to carry heterozygous variants in genes mediating the release of cytotoxic granules from natural killer (NK) cells and CD8+ T cells; biallelic mutations of these genes cause an inherited form of cytokine storm syndrome termed familial hemophagocytic lymphohistiocytosis (HLH). Reduced cytotoxicity impairs clearance of infected cells and elimination of activated macrophages, leading to massive release of proinflammatory mediators. One of these mediators, IL-6, further impairs NK cell function. Patients present with rapid onset of fever, cytopenias, coagulopathy, elevated transaminase levels, hyperferritinemia, and multiorgan dysfunction. Historically, the cornerstones of treatment were glucocorticoids, intravenous immunoglobulin (IVIG), and cyclosporine. Despite these interventions, mortality was as high as 20%. Identification of key mediators driving MAS-including IL-1β, IL-6, IL-18, and interferon-γ (IFNγ)-have inaugurated a new era of cytokine neutralization, potentially enabling a marked reduction in mortality (5, 6) . Herpes family viruses (e.g., Epstein-Barr virus) and influenza are major triggers of cytokine storm, both in systemic JIA and in patients without a preexisting immunologic diagnosis. As in systemic JIA-related MAS, the inflammatory cytokines IFNγ and IL-18 are key mediators of hyperinflammation in a murine model of repeated Toll-like receptor 9 stimulation, which mimics severe viral infection (6) . In one study of patients without underlying rheumatic disease who died of H1N1 influenza, 81% displayed fea-tures of cytokine storm, and 36% carried pathologic variants in the cyto lytic pathway (7) . Treatments effective in systemic JIA-related MAS can benefit patients with cytokine storm triggered by infections (8, 9) . Post hoc analysis of a phase III randomized controlled trial of anakinra (recombinant IL-1 receptor antagonist) in sepsis showed that patients with coagulopathy and elevated transaminase levels exhibited better survival with IL-1 blockade than with standard of care (65% versus 35%; hazard ratio for death 0.28, P = 0.007) (10) . Similarly, IL-6 blockade is effective in treating the related cytokine release syndrome from chimeric antigen receptor T cell (CAR-T) therapy (11) .

Hyperinflammation in COVID-19 is not MAS, and it may even be distinct from other forms of viral-induced cytokine storm, in that ferritin elevation is modest and severe endorgan disease is focused on the lung. Some patients with COVID-19 may simply have "garden-variety" ARDS associated with the tropism of the virus for the lung. However, critically ill patients with COVID-19 often demonstrate features suggestive of cytokine storm, including fever, characteristic changes in laboratory study findings, and ARDS. Lung tissue from patients with severe acute respiratory syndrome (SARS), the etiology of which has been attributed to a related coronavirus, showed hemophagocytosis-a central pathologic feature of cytokine storm-in 2 of 6 patients who succumbed to the disease (12) . Patients with SARS also exhibited high levels of IFNγ and IL-18, which are particularly important in cytokine storm syndrome (13) . Thus, the host's immune response and development of tissuefocused inflammation in the lung likely plays an important role in COVID-19. These considerations suggest that, beyond antiviral therapy and supportive care, it will be important to monitor hospitalized patients with COVID-19 for evidence of cytokine storm. Impending hyperinflammation can manifest as cytopenias (thrombocytopenia and lymphopenia), coagulopathy (low platelet and fibrinogen levels, and elevated d-dimer levels), tissue damage/hepatitis (elevated LDH, aspartate aminotransferase, and alanine aminotransferase levels), and macrophage/hepatocyte activation (elevated ferritin levels) (Table 1 and Supplementary Table 1 , available on the Arthritis & Rheumatology web site at http://onlin elibr ary.wiley.com/doi/10.1002/art.41285/ abstract). Cytokine measurement is a theoretically appealing approach, but IFNγ and IL-1β are not easily assessed in the peripheral blood and IL-6 levels have not yet been proven consistently predictive of poor outcomes. CXCL9, a stable chemokine, is a useful surrogate for IFNγ activity in MAS, as is adenosine deaminase 2 (ADA-2); however, real-time measurement of CXCL9 is not commonly available and ADA-2 testing remains available largely on a research basis. Experience suggests that trends in laboratory test findings, rather than threshold values, will be most infor mative. In a patient with COVID-19 who develops lymphopenia, worsening coagulopathy, hepatitis, and rising ferritin levels, it may make sense to target immune hyperactivity before end-organ manifestations, such as ARDS, ensue.

The US Centers for Disease Control and Prevention provided an unqualified recommendation against the use of glucocorticoids for the treatment of COVID-19, based on prior experience with influenza, SARS, and coronavirus-induced Middle East re spiratory syndrome (MERS) (14) . However, a Cochrane review of glucocorticoids as adjunctive therapy in influenza found that the evidence was of low quality, largely because of confounding by indication (15) . The literature with regard to glucocorticoids in patients with MERS and SARS has reported similar findings, although some data suggest that glucocorticoids could delay viral clearance (16) . Importantly, these data reflect treatment of "all comers" with influenza, MERS, or SARS, rather than therapy targeted to patients with evidence of hyperinflammation. Of note, in one COVID-19 case series, the mortality rate was lower in patients with ARDS who were treated with methylprednisolone compared with those who did not receive glucocorticoids (46% versus 62%; hazard ratio for death 0.38, P = 0.003), although, again, the possibility of confounding by indication is difficult to exclude (2) .

Experience from hyperinflammation in HLH, MAS, and cytokine release syndrome suggests that early intervention is essential to avoiding life-threatening tissue damage. In patients with COVID-19 who exhibit evidence of cytokine storm, treatment with glucocorticoids, IVIG, and/or anticytokine therapies should be considered, with the aim of reverting hyperinflammation before ARDS occurs ( Table 2 and Supplementary Table 2 (8, 17) . Glucocorticoids remain a key first-line option, and clinical trials are urgently needed to test their efficacy and to identify optimal dosing, especially given the clear advantage of glucocorticoids in worldwide availability and cost. IL-1 blockade has shown particular promise as a treatment for cytokine storm syndrome, and high-dose regimens are safe even in the context of overt sepsis (5, 10) . Tocilizumab (anti-IL-6 receptor) is effective in cytokine release syndrome associated with CAR-T therapy, a syndrome notably reminiscent of COVID-19 in that many patients develop ARDS (11) . Emapalumab (anti-IFNγ) is approved by the US Food and Drug Administration for the treatment of HLH and may be effective in MAS. JAK inhibition appears promising; however, the safety of these medications in severe viral infection remains unknown.

Clinical trials are currently enrolling patients with COVID-19 to study the safety and efficacy of glucocorticoids and cytokine blockade strategies utilizing neutralization of IL-1, IL-6, and IFNγ (Table 2 ). Absent the opportunity to enroll patients in one of these studies, we would consider immunosuppression in patients with COVID-19 who have incipient cytokine storm. Ideally, treatment decisions will be undertaken with the help of a multidisciplinary team familiar with the triggers, manifestations, and treatments of cytokine storm (17) . Glucocorticoids will likely be useful. Cytokine blockers may play an important role as well, while we must remain cognizant of the ongoing need for these medications in patients with chronic rheumatologic conditions. Unfortunately, many patients with COVID-19 will become critically ill before high-quality evidence of treatment efficacy is available, leaving us to extrapolate as best we can from the available evidence and from current clinical experience in cytokine storm syndromes.

All authors drafted the article, revised it critically for important intellectual content, and approved the final version to be published.

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

Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China

Clinical and immunologic features in severe and moderate coronavirus disease 2019

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Benefit of anakinra in treating pediatric secondary hemophagocytic lymphohistiocytosis

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

Whole-exome sequencing reveals mutations in genes linked to hemophagocytic lymphohistiocytosis and macrophage activation syndrome in fatal cases of H1N1 influenza

A personalized diagnostic and treatment approach for macrophage activation syndrome and secondary hemophagocytic lymphohistiocytosis in adults

How we manage hyperferritinemic sepsis-related multiple organ dysfunction syndrome/macrophage activation syndrome/secondary hemophagocytic lymphohistiocytosis histiocytosis

Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial

Chimeric antigen receptor T cells for sustained remissions in leukemia

Lung pathology of fatal severe acute respiratory syndrome

An interferon-γ-related cytokine storm in SARS patients

Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19)

Corticosteroids as adjunctive therapy in the treatment of influenza: an updated Cochrane systematic review and meta-analysis

Effects of early corticosteroid treatment on plasma SARS-associated coronavirus RNA concentrations in adult patients

Calm in the midst of cytokine storm: a collaborative approach to the diagnosis and treatment of hemophagocytic lymphohistiocytosis and macrophage activation syndrome