The role of IL-6 and other mediators in the cytokine storm associated with SARS-CoV-2 infection
Authors: Ana Copaescu, Olivia Smibert, Andrew Gibson, Elizabeth J. Phillips, Jason A. Trubiano
Journal: Journal of Allergy and Clinical Immunology (2020)

The coronavirus disease 2019 pandemic caused by severe acute respiratory syndrome coronavirus 2 presents with a spectrum of clinical manifestations from asymptomatic or mild, self-limited constitutional symptoms to a hyperinflammatory state ("cytokine storm") followed by acute respiratory distress syndrome and death. The objective of this study was to provide an evidence-based review of the associated pathways and potential treatment of the hyperinflammatory state associated with severe acute respiratory syndrome coronavirus 2 infection. Dysregulated immune responses have been reported to occur in a smaller subset of those infected with severe acute respiratory syndrome coronavirus 2, leading to clinical deterioration 7 to 10 days after initial presentation. A hyperinflammatory state referred to as cytokine storm in its severest form has been marked by elevation of IL-6, IL-10, TNF-α, and other cytokines and severe CD4+ and CD8+ T-cell lymphopenia and coagulopathy. Recognition of at-risk patients could permit early institution of aggressive intensive care and antiviral and immune treatment to reduce the complications related to this proinflammatory state. Several reports and ongoing clinical trials provide hope that available immunomodulatory therapies could have therapeutic potential in these severe cases. This review highlights our current state of knowledge of immune mechanisms and targeted immunomodulatory treatment options for the current coronavirus disease 2019 pandemic. The coronavirus disease 2019 pandemic caused by severe acute respiratory syndrome coronavirus 2 presents with a spectrum of clinical manifestations from asymptomatic or mild, self-limited constitutional symptoms to a hyperinflammatory state ("cytokine storm") followed by acute respiratory distress syndrome and death. The objective of this study was to provide an evidence-based review of the associated pathways and potential treatment of the hyperinflammatory state associated with severe acute respiratory syndrome coronavirus 2 infection. Dysregulated immune responses have been reported to occur in a smaller subset of those infected with severe acute respiratory syndrome coronavirus 2, leading to clinical deterioration 7 to 10 days after initial presentation. A hyperinflammatory state referred to as cytokine storm in its severest form has been marked by elevation of IL-6, IL-10, TNF-α, and other cytokines and severe CD4+ and CD8+ T-cell lymphopenia and coagulopathy. Recognition of at-risk patients could permit early institution of aggressive intensive care and antiviral and immune treatment to reduce the complications related to this proinflammatory state. Several reports and ongoing clinical trials provide hope that available immunomodulatory therapies could have therapeutic potential in these severe cases. This review highlights our current state of knowledge of immune mechanisms and targeted immunomodulatory treatment options for the current coronavirus disease 2019 pandemic. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: September 2020. Credit may be obtained for these courses until August 31, 2021.Copyright Statement: Copyright © 2020-2021. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Ana Copaescu, MD, FRCPC, Olivia Smibert, MBBS, FRACP, Andrew Gibson, PhD, Elizabeth Phillips, MD, and Jason Trubiano, MBBS, BBiomedSci, PhD, FRACP (authors); Zuhair K. Ballas, MD (editor)Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: The authors declare that they have no relevant conflicts of interest. Z. K. Ballas (editor) disclosed no relevant financial relationships.Activity Objectives:1.To define the immunopathogenesis of the cytokine storm associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).2.To explore the role of the IL-6 in the SARS-CoV-2 inflammatory and viral responses.3.To describe the role of biological immunotherapies targeting the hyperinflammatory immune response in SARS-CoV-2.4.To outline the therapeutic strategy targeting upstream and downstream immunologic pathways in SARS-CoV-2.Recognition of Commercial Support: This CME activity has not received external commercial support.List of CME Exam Authors: Ana Copaescu, MD, FRCPC, and Elizabeth Jane Phillips, MD.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: The examination authors declare no relevant conflicts of interest.The coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an enormous challenge for public health and clinicians globally. Increased understanding of the immunopathogenesis of SARS-CoV-2 infection as well as ongoing clinical trials of host target drugs such as hydroxychloroquine, direct antivirals, convalescent plasma (CP), and other immunomodulatory agents hold promise for future evidence-based and targeted therapies to reduce the morbidity and mortality of the most vulnerable populations. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: September 2020. Credit may be obtained for these courses until August 31, 2021. Copyright Statement: Copyright © 2020-2021. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Ana Copaescu, MD, FRCPC, Olivia Smibert, MBBS, FRACP, Andrew Gibson, PhD, Elizabeth Phillips, MD, and Jason Trubiano, MBBS, BBiomedSci, PhD, FRACP (authors); Zuhair K. Ballas, MD (editor) Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: The authors declare that they have no relevant conflicts of interest. Z. K. Ballas (editor) disclosed no relevant financial relationships. Activity Objectives:1.To define the immunopathogenesis of the cytokine storm associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).2.To explore the role of the IL-6 in the SARS-CoV-2 inflammatory and viral responses.3.To describe the role of biological immunotherapies targeting the hyperinflammatory immune response in SARS-CoV-2.4.To outline the therapeutic strategy targeting upstream and downstream immunologic pathways in SARS-CoV-2. Recognition of Commercial Support: This CME activity has not received external commercial support. List of CME Exam Authors: Ana Copaescu, MD, FRCPC, and Elizabeth Jane Phillips, MD. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: The examination authors declare no relevant conflicts of interest. Although infection is often asymptomatic or associated with mild to moderate self-limiting symptoms such as fever, dry cough, myalgia, and fatigue,1Zhou F. Yu T. Du R. Fan G. Liu Y. Liu Z. et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (18962) Google Scholar, 2Huang C. Wang Y. Li X. Ren L. Zhao J. Hu Y. et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (33291) Google Scholar, 3Wu C. Chen X. Cai Y. Xia J. Zhou X. Xu S. 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: 1-11Crossref Scopus (5839) Google Scholar, 4Herold T, Jurinovic V, Arnreich C, Hellmuth J, von Bergwelt-Baildon M, Klein M, et al. Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients [published online ahead of print April 10, 2020]. medRxiv. https://doi.org/10.1101/2020.04.01.20047381.Google Scholar, 5Chen G. Wu D. Guo W.Z. Cao Y. Huang D. Wang H. et al.Clinical and immunologic features in severe and moderate coronavirus disease 2019.J Clin Investig. 2020; 130: 2620-2629Crossref PubMed Scopus (3389) Google Scholar, 6Wang D. Hu B. Hu C. Zhu F. Liu X. Zhang J. et al.Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.JAMA. 2020; 323: 1061-1069Crossref PubMed Scopus (16387) Google Scholar a subset of patients with severe SARS-CoV-2 infection develop a clinically severe hyperinflammatory state or cytokine storm (CS) for which pulmonary involvement such as acute respiratory distress syndrome (ARDS) is a cardinal feature.1Zhou F. Yu T. Du R. Fan G. Liu Y. Liu Z. et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (18962) Google Scholar,7Ruan Q. Yang K. Wang W. Jiang L. Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China.Intensive Care Med. 2020; 46: 846-848Crossref PubMed Scopus (3421) Google Scholar Furthermore, a subgroup of previously healthy children has been diagnosed with a multisystem inflammatory syndrome associated with acute SARS-CoV-2 infection that appears distinct from the adult CS.8Riphagen S. Gomez X. Gonzalez-Martinez C. Wilkinson N. Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic.Lancet. 2020; 395: 1607-1608Abstract Full Text Full Text PDF PubMed Scopus (1738) Google Scholar Although the individual components of CS are varied, IL-6 has emerged of particular interest in the context of SARS-CoV-2 infection after being identified as the most significant predictor of mortality in recent retrospective studies of patient survival in COVID-19.1Zhou F. Yu T. Du R. Fan G. Liu Y. Liu Z. et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (18962) Google Scholar Herein, we review the current understanding of the origin and mechanisms of CS associated with SARS-CoV-2 infection, with focus on the identification and implication of IL-6 and other proinflammatory cytokines and pathways in CS-driven ARDS, and discuss the potential utility of anti–IL-6 and other cytokine-targeting immunomodulatory biologics for the treatment of this critically ill population. We searched PubMed for peer-reviewed articles published between January 1, 2000, and April 18, 2020 (date of last search), with the terms ("IL-6" OR "interleukin-6" OR "cytokine") AND ("sepsis" OR "SIRS" OR "systemic inflammatory response syndrome" OR "non-infectious systemic inflammatory response syndrome" OR "ARDS" OR "acute respiratory distress syndrome" OR "cytokine storm" OR "inflammatory response" OR "septic shock" OR "critically ill" OR "organ dysfunction" OR "infection") AND ("ICU" OR "intensive care unit" OR "ED" OR "emergency department"). A second search was oriented on treatment, with the terms ("IL-6" OR "interleukin-6" OR "IL-1" OR "interleukin-1" OR "TNF" OR "tumor necrosis factor" OR "interferon gamma" OR "STING" OR "interferon pathway") AND ("sepsis" OR "SIRS" OR "systemic inflammatory response syndrome" OR "ARDS" OR "acute respiratory distress syndrome" OR "cytokine storm" OR "inflammatory response" OR "septic shock" OR "critically ill" OR "organ dysfunction" OR "infection") AND ("IL-6 inhibitor" OR "interleukin-6 inhibitor" OR "JAK-STAT" OR "tocilizumab" OR "humanized IL-6R antibody" OR "anakinra" OR "IL-1 inhibitor"). Please refer to Fig E1 in this article's Online Repository at www.jacionline.org for details concerning the number of articles entered in PubMed with the "cytokine storm" keywords. All recent articles on COVID-19/SARS-CoV-2 were reviewed including preprints from bioRxiv and medRxiv as a more real-time resource, but realizing the lack of peer review limitation. To carefully include the proposed trials for COVID-19, we researched the ClinicalTrials.gov/trials website. Articles published in English were selected and reviewed. There was a focus on clinical trials, meta-analysis, randomized controlled trials, and systematic reviews as well as novel and significant studies. Finally, we also identified several new references from those listed in the reviewed articles. Please note that although there is increasing information about SARS-CoV-2 and its immune consequences, most of the literature available on COVID-19 and SARS-CoV-2 infection originates from the onset of the pandemic, in China, with various publications from disease phenotype to immunopathogenesis and follow-up. The release of large quantities of proinflammatory cytokines is termed CS and is associated with various infective precipitants and other hyperinflammatory states.9Chousterman B.G. Swirski F.K. Weber G.F. Cytokine storm and sepsis disease pathogenesis.Semin Immunopathol. 2017; 39: 517-528Crossref PubMed Scopus (851) Google Scholar,10Tisoncik J.R. Korth M.J. Simmons C.P. Farrar J. Martin T.R. Katze M.G. Into the eye of the cytokine storm.Microbiol Mol Biol Rev. 2012; 76: 16-32Crossref PubMed Scopus (1379) Google Scholar Virally associated causes of particular relevance are the 2003 SARS coronavirus (SARS-CoV) infection that infected more than 8000 globally, primarily in Asia and Canada (Toronto) with an 11% mortality rate,11Zhang X. Wu K. Wang D. Yue X. Song D. Zhu Y. et al.Nucleocapsid protein of SARS-CoV activates interleukin-6 expression through cellular transcription factor NF-kappaB.Virology. 2007; 365: 324-335Crossref PubMed Scopus (110) Google Scholar, 12Huang K.J. Su I.J. Theron M. Wu Y.C. Lai S.K. Liu C.C. et al.An interferon-gamma-related cytokine storm in SARS patients.J Med Virol. 2005; 75: 185-194Crossref PubMed Scopus (583) Google Scholar, 13Channappanavar R. Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology.Semin Immunopathol. 2017; 39: 529-539Crossref PubMed Scopus (1864) Google Scholar, 14de Jong M.D. Simmons C.P. Thanh T.T. Hien V.M. Smith G.J. Chau T.N. et al.Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia.Nat Med. 2006; 12: 1203-1207Crossref PubMed Scopus (1572) Google Scholar and the 2012 Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) with a reported case-fatality rate of 35%.15Choi W.S. Kang C.I. Kim Y. Choi J.P. Joh J.S. Shin H.S. et al.Clinical presentation and outcomes of Middle East respiratory syndrome in the Republic of Korea.Infect Chemother. 2016; 48: 118-126Crossref PubMed Scopus (111) Google Scholar, 16Saad M. Omrani A.S. Baig K. Bahloul A. Elzein F. Matin M.A. et al.Clinical aspects and outcomes of 70 patients with Middle East respiratory syndrome coronavirus infection: a single-center experience in Saudi Arabia.Int J Infect Dis. 2014; 29: 301-306Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar, 17Azhar E.I. Hui D.S.C. Memish Z.A. Drosten C. Zumla A. The Middle East respiratory syndrome (MERS).Infect Dis Clin North Am. 2019; 33: 891-905Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar Although SARS-CoV-2 belongs to the same Betacoronavirus genus as SARS-CoV and MERS-CoV, the case fatality associated with both SARS-CoV and MERS-CoV significantly exceeds that of SARS-CoV-2 but the number of cases worldwide associated with SARS-CoV and MERS-CoV is much lower.18Petrosillo N. Viceconte G. Ergonul O. Ippolito G. Petersen E. COVID-19, SARS and MERS: are they closely related?.Clin Microbiol Infect. 2020; 26: 729-734Abstract Full Text Full Text PDF PubMed Scopus (784) Google Scholar Genomic evidence suggests that SARS-CoV and SARS-CoV-2 share the same human cell receptor for host entry, the angiotensin-converting enzyme 2 (ACE2).19Wan Y. Shang J. Graham R. Baric R.S. Li F. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus.J Virol. 2020; 94 (e00127-20)Crossref Scopus (3201) Google Scholar SARS-CoV-2 binds with increased affinity to the ACE2 receptor compared with SARS-CoV, a possible explanation for the widely spread community transmission from asymptomatic hosts.18Petrosillo N. Viceconte G. Ergonul O. Ippolito G. Petersen E. COVID-19, SARS and MERS: are they closely related?.Clin Microbiol Infect. 2020; 26: 729-734Abstract Full Text Full Text PDF PubMed Scopus (784) Google Scholar The clinical correlates of increased inflammation or CS are persistent hypotension, hypothermia or hyperthermia, and end-organ dysfunction, while the laboratory features include hematological anomalies (leukocytosis or leukopenia, thrombocytopenia, and disseminated intravascular coagulation with high fibrinogen, triglycerides, and ferritin), elevated IL-2R (CD25), elevated IL-6, and general markers of end-organ dysfunction (such as elevated creatinine and deranged liver function tests).10Tisoncik J.R. Korth M.J. Simmons C.P. Farrar J. Martin T.R. Katze M.G. Into the eye of the cytokine storm.Microbiol Mol Biol Rev. 2012; 76: 16-32Crossref PubMed Scopus (1379) Google Scholar The CS clinical phenotype is variable and regroups systemic signs of inflammation, multiorgan failure, and mortality.20Behrens E.M. Koretzky G.A. Review: cytokine storm syndrome: looking toward the precision medicine era.Arthritis Rheumatol. 2017; 69: 1135-1143Crossref PubMed Scopus (222) Google Scholar The hyperinflammatory state associated with severe viral infection shares significant features with CS, and genetic factors associated with hemophagocytic lymphohistiocytosis (HLH) have been identified, suggesting that these conditions may in fact be part of the same spectrum.21Filipovich A. McClain K. Grom A. Histiocytic disorders: recent insights into pathophysiology and practical guidelines.Biol Blood Marrow Transplant. 2010; 16: S82-S89Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar HLH is caused by an abnormal regulation of activated macrophages and lymphocytes, leading to a hyperinflammatory state.21Filipovich A. McClain K. Grom A. Histiocytic disorders: recent insights into pathophysiology and practical guidelines.Biol Blood Marrow Transplant. 2010; 16: S82-S89Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar IFN-γ is an important cytokine responsible for the organ damage leading to mortality in HLH.20Behrens E.M. Koretzky G.A. Review: cytokine storm syndrome: looking toward the precision medicine era.Arthritis Rheumatol. 2017; 69: 1135-1143Crossref PubMed Scopus (222) Google Scholar Other cytokines such as IL-6, TNF-α, IL-1, and IL-18 are also increased during HLH.22Schulert G.S. Grom A.A. Macrophage activation syndrome and cytokine-directed therapies.Best Pract Res Clin Rheumatol. 2014; 28: 277-292Crossref PubMed Scopus (115) Google Scholar Several genes that play a role in the pathway of natural killer cells and CD8+ T cells have been described as causal for the development of the familial form of HLH. Some examples include the lysosomal trafficking regulator mutation described in the Chediak-Higashi syndrome, the RAB27A mutation in the Griscelli syndrome as well as other mutations in perforin (PRF1). The main clinical and laboratory manifestations of HLH are fever, cytopenia, coagulopathy, liver dysfunction, hyperferritinemia, decreased or absent natural killer–cell function, increased soluble CD25 (IL-2R), and presence of hemophagocytosis on bone marrow biopsy or other organs.21Filipovich A. McClain K. Grom A. Histiocytic disorders: recent insights into pathophysiology and practical guidelines.Biol Blood Marrow Transplant. 2010; 16: S82-S89Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar The secondary form of HLH has been described in influenza during the 2009 H1N1 pandemic, the largest cohort describing 9 cases with a mortality rate of 89% (8 of 9 cases).23Beutel G. Wiesner O. Eder M. Hafer C. Schneider A.S. Kielstein J.T. et al.Virus-associated hemophagocytic syndrome as a major contributor to death in patients with 2009 influenza A (H1N1) infection.Crit Care. 2011; 15: R80Crossref PubMed Scopus (77) Google Scholar The macrophage activation syndrome (MAS) has similar clinical features to HLH and is considered a related disorder that occurs primarily in patients with rheumatologic diseases.24Schulert G.S. Grom A.A. Pathogenesis of macrophage activation syndrome and potential for cytokine- directed therapies.Annu Rev Med. 2015; 66: 145-159Crossref PubMed Scopus (273) Google Scholar The excessive inflammatory response described in MAS is characterized by an increased IL-1β, with successful reports on the use of anakinra, an IL-1 receptor antagonist.25Miettunen P.M. Narendran A. Jayanthan A. Behrens E.M. Cron R.Q. 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 (Oxford). 2011; 50: 417-419Crossref PubMed Scopus (210) Google Scholar,26Shakoory B. Carcillo J.A. Chatham W.W. Amdur R.L. Zhao H. Dinarello C.A. et al.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.Crit Care Med. 2016; 44: 275-281Crossref PubMed Scopus (622) Google Scholar In a cohort of 19 adult patients with secondary HLH/MAS, 63.1% (12 of 19) had systemic infections as precipitating causes.27Schulert G.S. Zhang M. Fall N. Husami A. Kissell D. Hanosh A. et al.Whole-exome sequencing reveals mutations in genes linked to hemophagocytic lymphohistiocytosis and macrophage activation syndrome in fatal cases of H1N1 influenza.J Infect Dis. 2016; 213: 1180-1188Crossref PubMed Scopus (119) Google Scholar This group used anakinra in 12 of 19 patients and reported 4 deaths among those patients treated with anakinra.27Schulert G.S. Zhang M. Fall N. Husami A. Kissell D. Hanosh A. et al.Whole-exome sequencing reveals mutations in genes linked to hemophagocytic lymphohistiocytosis and macrophage activation syndrome in fatal cases of H1N1 influenza.J Infect Dis. 2016; 213: 1180-1188Crossref PubMed Scopus (119) Google Scholar The concept of shared immunologic features between HLH, MAS, and CS has been entertained with extensive discussion that these diseases could be part of an overlapping immunopathology with shared but also distinctive triggers and genetic features.20Behrens E.M. Koretzky G.A. Review: cytokine storm syndrome: looking toward the precision medicine era.Arthritis Rheumatol. 2017; 69: 1135-1143Crossref PubMed Scopus (222) Google Scholar To assess the possible genetic predisposition of individuals with no past medical history to develop HLH secondary to severe H1N1 influenza, Schulert et al27Schulert G.S. Zhang M. Fall N. Husami A. Kissell D. Hanosh A. et al.Whole-exome sequencing reveals mutations in genes linked to hemophagocytic lymphohistiocytosis and macrophage activation syndrome in fatal cases of H1N1 influenza.J Infect Dis. 2016; 213: 1180-1188Crossref PubMed Scopus (119) Google Scholar performed whole-exome sequencing in 14 patients, 13 of whom had evidence of hemophagocytosis at autopsy, and detected 5 heterozygous variants in lysosomal trafficking regulator (2 of whom also had a heterozygous PRF1 mutation).27Schulert G.S. Zhang M. Fall N. Husami A. Kissell D. Hanosh A. et al.Whole-exome sequencing reveals mutations in genes linked to hemophagocytic lymphohistiocytosis and macrophage activation syndrome in fatal cases of H1N1 influenza.J Infect Dis. 2016; 213: 1180-1188Crossref PubMed Scopus (119) Google Scholar Children appear protected from SARS-CoV-2 infection and are more likely to be asymptomatic or have less severe infection compared with their adult counterparts.28Gudbjartsson D.F. Helgason A. Jonsson H. Magnusson O.T. Melsted P. Norddahl G.L. et al.Spread of SARS-CoV-2 in the Icelandic population.N Engl J Med. 2020; 382: 2302-2315Crossref PubMed Scopus (866) Google Scholar,29Deza Leon M.P. Redzepi A. McGrath E. Abdel-Haq N. Shawaqfeh A. Sethuraman U. et al.COVID-19 associated pediatric multi-system inflammatory syndrome.J Pediatric Infect Dis Soc. 2020; 9: 407-408Crossref PubMed Scopus (30) Google Scholar However, more recently, a pediatric multisystem inflammatory syndrome has been described that appears distinct from the adult CS associated with acute SARS-CoV-2 infection and may follow mild or asymptomatic SARS-CoV-2 infection in previously healthy children. This illness has been reported in children aged from early childhood to adolescence, has Kawasaki-like features, and has been reported in areas with a high SARS-CoV-2 prevalence in children exposed to positive COVID-19 family members. In multiple cases, the child had positive SARS-CoV-2 serology but negative SARS-CoV-2 PCR result. Deaths of at least 3 children associated with this syndrome have been reported in the United States and the United Kingdom.8Riphagen S. Gomez X. Gonzalez-Martinez C. Wilkinson N. Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic.Lancet. 2020; 395: 1607-1608Abstract Full Text Full Text PDF PubMed Scopus (1738) Google Scholar Children with this syndrome have presented with similar features to Kawasaki disease,29Deza Leon M.P. Redzepi A. McGrath E. Abdel-Haq N. Shawaqfeh A. Sethuraman U. et al.COVID-19 associated pediatric multi-system inflammatory syndrome.J Pediatric Infect Dis Soc. 2020; 9: 407-408Crossref PubMed Scopus (30) Google Scholar,30Jones V.G. Mills M. Suarez D. Hogan C.A. Yeh D. Segal J.B. et al.COVID-19 and Kawasaki disease: novel virus and novel case.Hosp Pediatr. 2020; 10: 537-540Crossref PubMed Scopus (564) Google Scholar with high fever, rash, conjunctivitis, and diarrhea, and shown evidence of myocardial involvement, with elevated troponins, arrhythmia, shock, abnormal echocardiographic vascular findings, and coronary artery aneurysms. They have shown evidence of a hyperinflammatory state with elevated ferritin, triglycerides, and D-dimers. Treatments have included high-dose intravenous immunoglobulin and aspirin, as suggested for Kawasaki disease.30Jones V.G. Mills M. Suarez D. Hogan C.A. Yeh D. Segal J.B. et al.COVID-19 and Kawasaki disease: novel virus and novel case.Hosp Pediatr. 2020; 10: 537-540Crossref PubMed Scopus (564) Google Scholar Currently, the specific immunopathogenic link to SARS-CoV-2 infection and the role of adjunctive immunomodulatory and anticytokine therapy in this syndrome is unknown. The airway epithelium is part of the first line of defense in presence of an airborne viral pathogen recognized as a pathogen-associated molecular pattern and/or damage-associated molecular pattern that bind to pattern recognition receptors such as Toll-like receptors on the surface of macrophages.9Chousterman B.G. Swirski F.K. Weber G.F. Cytokine storm and sepsis disease pathogenesis.Semin Immunopathol. 2017; 39: 517-528Crossref PubMed Scopus (851) Google Scholar The resident-activated alveolar macrophages, after several intracellular signaling cascades, generate TNF, IL-1β, and IL-6 and trigger a systemic inflammatory response (Fig 1).31Faix J.D. Biomarkers of sepsis.Crit Rev Clin Lab Sci. 2013; 50: 23-36Crossref PubMed Scopus (433) Google Scholar This simultaneously prompts a well-coordinated local innate response composed of specific enzymes (defensins, mucins, lysozymes), nitric oxide, reactive oxygen species, platelet-activating factor, and other cytokines.32Chalmers S. Khawaja A. Wieruszewski P.M. Gajic O. Odeyemi Y. Diagnosis and treatment of acute pulmonary inflammation in critically ill patients: the role of inflammatory biomarkers.World J Crit Care Med. 2019; 8: 59-71Crossref Google Scholar Other key components of the innate immunity against viral infe