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Immunopathology of Hyperinflammation in COVID-19

Open ArchivePublished:September 10, 2020DOI:https://doi.org/10.1016/j.ajpath.2020.08.009
      The rapid spread of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2), has resulted in an unprecedented public health crisis worldwide. Recent studies indicate that a hyperinflammatory syndrome induced by SARS-CoV-2 contributes to disease severity and mortality in COVID-19. In this review, an overview of the pathophysiology underlying the hyperinflammatory syndrome in severe COVID-19 is provided. The current evidence suggests that the hyperinflammatory syndrome results from a dysregulated host innate immune response. The gross and microscopic pathologic findings as well as the alterations in the cytokine milieu, macrophages/monocytes, natural killer cells, T cells, and neutrophils in severe COVID-19 are summarized. The data highlighted include the potential therapeutic approaches undergoing investigation to modulate the immune response and abrogate lung injury in severe COVID-19.
      In December 2019, severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) was identified in Wuhan, China, as the cause of coronavirus disease 2019 (COVID-19).
      • Zhu N.
      • Zhang D.
      • Wang W.
      • Li X.
      • Yang B.
      • Song J.
      • Zhao X.
      • Huang B.
      • Shi W.
      • Lu R.
      • Niu P.
      • Zhan F.
      • Ma X.
      • Wang D.
      • Xu W.
      • Wu G.
      • Gao G.F.
      • Tan W.
      A novel coronavirus from patients with pneumonia in China, 2019.
      SARS-CoV-2 represents a novel strain in the coronavirus family, a group of enveloped, positive-sense, singled-stranded RNA viruses. Additional members of this family include the highly pathogenic strains SARS-CoV-1 and Middle East respiratory syndrome–coronavirus (MERS-CoV). SARS-CoV-2 shares significant phylogenetic homology with two bat-derived SARS-like coronaviruses, and primarily uses the angiotensin-converting enzyme (ACE)-2 receptor in humans for cell entry.
      • Lu R.
      • Zhao X.
      • Li J.
      • Niu P.
      • Yang B.
      • Wu H.
      • Wang W.
      • Song H.
      • Huang B.
      • Zhu N.
      • Bi Y.
      • Ma X.
      • Zhan F.
      • Wang L.
      • Hu T.
      • Zhou H.
      • Hu Z.
      • Zhou W.
      • Zhao L.
      • Chen J.
      • Meng Y.
      • Wang J.
      • Lin Y.
      • Yuan J.
      • Xie Z.
      • Ma J.
      • Liu W.J.
      • Wang D.
      • Xu W.
      • Holmes E.C.
      • Gao G.F.
      • Wu G.
      • Chen W.
      • Shi W.
      • Tan W.
      Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.
      After a likely zoonotic spillover event, efficient human-to-human transmission of SARS-CoV-2 was confirmed and resulted in the rapid global spread of COVID-19.
      • Li Q.
      • Guan X.
      • Wu P.
      • Wang X.
      • Zhou L.
      • Tong Y.
      • et al.
      Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia.
      The World Health Organization officially declared COVID-19 a pandemic in March 2020.
      Clinically, the disease presentation of COVID-19 is markedly heterogeneous. Patients range from being asymptomatic or having a mild upper respiratory illness to having severe viral pneumonia that requires hospitalization and may progress to cytokine storm, acute respiratory distress syndrome (ARDS), and death.
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • Zhang L.
      • Fan G.
      • Xu J.
      • Gu X.
      • Cheng Z.
      • Yu T.
      • Xia J.
      • Wei Y.
      • Wu W.
      • Xie X.
      • Yin W.
      • Li H.
      • Liu M.
      • Xiao Y.
      • Gao H.
      • Guo L.
      • Xie J.
      • Wang G.
      • Jiang R.
      • Gao Z.
      • Jin Q.
      • Wang J.
      • Cao B.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      • Guan W.-J.
      • Ni Z.-Y.
      • Hu Y.
      • Liang W.-H.
      • Ou C.-Q.
      • He J.-X.
      • et al.
      China Medical Treatment Expert Group for Covid-19
      Clinical characteristics of Coronavirus disease 2019 in China.
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • Crawford J.M.
      • McGinn T.
      • Davidson K.W.
      Northwell COVID-19 Research Consortium
      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.
      Nearly all patients with severe COVID-19 present with bilateral lung involvement.
      • Chen N.
      • Zhou M.
      • Dong X.
      • Qu J.
      • Gong F.
      • Han Y.
      • Qiu Y.
      • Wang J.
      • Liu Y.
      • Wei Y.
      • Xia Ja
      • Yu T.
      • Zhang X.
      • Zhang L.
      Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
      The acute onset of impaired oxygenation with noncardiogenic pulmonary infiltrates characterizes ARDS, which develops in 15% to 40% of patients with COVID-19–associated pneumonia.
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • Zhang L.
      • Fan G.
      • Xu J.
      • Gu X.
      • Cheng Z.
      • Yu T.
      • Xia J.
      • Wei Y.
      • Wu W.
      • Xie X.
      • Yin W.
      • Li H.
      • Liu M.
      • Xiao Y.
      • Gao H.
      • Guo L.
      • Xie J.
      • Wang G.
      • Jiang R.
      • Gao Z.
      • Jin Q.
      • Wang J.
      • Cao B.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • Crawford J.M.
      • McGinn T.
      • Davidson K.W.
      Northwell COVID-19 Research Consortium
      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.
      ,
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • Xiang J.
      • Wang Y.
      • Song B.
      • Gu X.
      • Guan L.
      • Wei Y.
      • Li H.
      • Wu X.
      • Xu J.
      • Tu S.
      • Zhang Y.
      • Chen H.
      • Cao B.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Wu C.
      • Chen X.
      • Cai Y.
      • Xia Ja
      • Zhou X.
      • Xu S.
      • Huang H.
      • Zhang L.
      • Zhou X.
      • Du C.
      • Zhang Y.
      • Song J.
      • Wang S.
      • Chao Y.
      • Yang Z.
      • Xu J.
      • Zhou X.
      • Chen D.
      • Xiong W.
      • Xu L.
      • Zhou F.
      • Jiang J.
      • Bai C.
      • Zheng J.
      • Song Y.
      Risk factors associated with acute respiratory distress syndrome and death in patients with Coronavirus disease 2019 pneumonia in Wuhan, China.
      Approximately 80% of patients with severe disease need supplemental oxygenation, of whom 30% to 40% require mechanical ventilation.
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • Zhang L.
      • Fan G.
      • Xu J.
      • Gu X.
      • Cheng Z.
      • Yu T.
      • Xia J.
      • Wei Y.
      • Wu W.
      • Xie X.
      • Yin W.
      • Li H.
      • Liu M.
      • Xiao Y.
      • Gao H.
      • Guo L.
      • Xie J.
      • Wang G.
      • Jiang R.
      • Gao Z.
      • Jin Q.
      • Wang J.
      • Cao B.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • Crawford J.M.
      • McGinn T.
      • Davidson K.W.
      Northwell COVID-19 Research Consortium
      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.
      ,
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • Xiang J.
      • Wang Y.
      • Song B.
      • Gu X.
      • Guan L.
      • Wei Y.
      • Li H.
      • Wu X.
      • Xu J.
      • Tu S.
      • Zhang Y.
      • Chen H.
      • Cao B.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Wu C.
      • Chen X.
      • Cai Y.
      • Xia Ja
      • Zhou X.
      • Xu S.
      • Huang H.
      • Zhang L.
      • Zhou X.
      • Du C.
      • Zhang Y.
      • Song J.
      • Wang S.
      • Chao Y.
      • Yang Z.
      • Xu J.
      • Zhou X.
      • Chen D.
      • Xiong W.
      • Xu L.
      • Zhou F.
      • Jiang J.
      • Bai C.
      • Zheng J.
      • Song Y.
      Risk factors associated with acute respiratory distress syndrome and death in patients with Coronavirus disease 2019 pneumonia in Wuhan, China.
      The estimated mortality rate in patients requiring mechanical ventilation approximates 70% to 90%, and pulmonary failure represents the primary cause of mortality due to COVID-19.
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • Crawford J.M.
      • McGinn T.
      • Davidson K.W.
      Northwell COVID-19 Research Consortium
      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.
      ,
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • Xiang J.
      • Wang Y.
      • Song B.
      • Gu X.
      • Guan L.
      • Wei Y.
      • Li H.
      • Wu X.
      • Xu J.
      • Tu S.
      • Zhang Y.
      • Chen H.
      • Cao B.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Wu C.
      • Chen X.
      • Cai Y.
      • Xia Ja
      • Zhou X.
      • Xu S.
      • Huang H.
      • Zhang L.
      • Zhou X.
      • Du C.
      • Zhang Y.
      • Song J.
      • Wang S.
      • Chao Y.
      • Yang Z.
      • Xu J.
      • Zhou X.
      • Chen D.
      • Xiong W.
      • Xu L.
      • Zhou F.
      • Jiang J.
      • Bai C.
      • Zheng J.
      • Song Y.
      Risk factors associated with acute respiratory distress syndrome and death in patients with Coronavirus disease 2019 pneumonia in Wuhan, China.
      Akin to SARS-CoV-1 and MERS-CoV, increasing evidence indicates that a hyperinflammatory response to SARS-CoV-2 contributes to disease severity and death in COVID-19.
      • Mehta P.
      • McAuley D.F.
      • Brown M.
      • Sanchez E.
      • Tattersall R.S.
      • Manson J.J.
      COVID-19: consider cytokine storm syndromes and immunosuppression.
      Patients with severe COVID-19 have elevated clinical inflammatory markers and increased serum cytokine and chemokine levels.
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • Zhang L.
      • Fan G.
      • Xu J.
      • Gu X.
      • Cheng Z.
      • Yu T.
      • Xia J.
      • Wei Y.
      • Wu W.
      • Xie X.
      • Yin W.
      • Li H.
      • Liu M.
      • Xiao Y.
      • Gao H.
      • Guo L.
      • Xie J.
      • Wang G.
      • Jiang R.
      • Gao Z.
      • Jin Q.
      • Wang J.
      • Cao B.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      These markers of inflammation are prognostic for the requirement of mechanical ventilation, the development of ARDS, and death in COVID-19.
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • Zhang L.
      • Fan G.
      • Xu J.
      • Gu X.
      • Cheng Z.
      • Yu T.
      • Xia J.
      • Wei Y.
      • Wu W.
      • Xie X.
      • Yin W.
      • Li H.
      • Liu M.
      • Xiao Y.
      • Gao H.
      • Guo L.
      • Xie J.
      • Wang G.
      • Jiang R.
      • Gao Z.
      • Jin Q.
      • Wang J.
      • Cao B.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • Xiang J.
      • Wang Y.
      • Song B.
      • Gu X.
      • Guan L.
      • Wei Y.
      • Li H.
      • Wu X.
      • Xu J.
      • Tu S.
      • Zhang Y.
      • Chen H.
      • Cao B.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Wu C.
      • Chen X.
      • Cai Y.
      • Xia Ja
      • Zhou X.
      • Xu S.
      • Huang H.
      • Zhang L.
      • Zhou X.
      • Du C.
      • Zhang Y.
      • Song J.
      • Wang S.
      • Chao Y.
      • Yang Z.
      • Xu J.
      • Zhou X.
      • Chen D.
      • Xiong W.
      • Xu L.
      • Zhou F.
      • Jiang J.
      • Bai C.
      • Zheng J.
      • Song Y.
      Risk factors associated with acute respiratory distress syndrome and death in patients with Coronavirus disease 2019 pneumonia in Wuhan, China.
      ,
      • Ruan 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.
      ,
      • Del Valle D.M.
      • Kim-schulze S.
      • Hsin-hui H.
      • Beckmann N.D.
      • Nirenberg S.
      • Wang B.
      • Lavin Y.
      • Swartz T.
      • Madduri D.
      • Stock A.
      • Marron T.
      • Xie H.
      • Patel M.K.
      • van Oekelen O.
      • Rahman A.
      • Kovatch P.
      • Aberg J.
      • Schadt E.
      • Jagannath S.
      • Mazumdar M.
      • Charney A.
      • Firpo-Betancourt A.
      • Mendu D.R.
      • Jhang J.
      • Reich D.
      • Sigel K.
      • Cordon-Cardo C.
      • Feldmann M.
      • Parekh S.
      • Merad M.
      • Gnjatic S.
      An inflammatory cytokine signature helps predict COVID-19 severity and survival.
      Postmortem analysis has identified a mononuclear inflammatory infiltrate with lymphocytes and macrophages in the lungs, as well as evidence of hemophagocytosis in the bone marrow and reticuloendothelial organs.
      • Xu Z.
      • Shi L.
      • Wang Y.
      • Zhang J.
      • Huang L.
      • Zhang C.
      • Liu S.
      • Zhao P.
      • Liu H.
      • Zhu L.
      • Tai Y.
      • Bai C.
      • Gao T.
      • Song J.
      • Xia P.
      • Dong J.
      • Zhao J.
      • Wang F.-S.
      Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
      • Fox S.E.
      • Akmatbekov A.
      • Harbert J.L.
      • Li G.
      • Quincy Brown J.
      • Vander Heide R.S.
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      • Carsana L.
      • Sonzogni A.
      • Nasr A.
      • Rossi R.S.
      • Pellegrinelli A.
      • Zerbi P.
      • Rech R.
      • Colombo R.
      • Antinori S.
      • Corbellino M.
      • Galli M.
      • Catena E.
      • Tosoni A.
      • Gianatti A.
      • Nebuloni M.
      Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study.
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • Ahuja S.
      • Beasley M.B.
      • Albrecht R.
      • et al.
      Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience.
      Collectively, this hyperinflammatory response shares many biological and clinical characteristics with the macrophage-activation syndrome seen in virus-induced hemophagocytic lymphohistiocytosis,
      • Ramos-Casals M.
      • Brito-Zerón P.
      • López-Guillermo A.
      • Khamashta M.A.
      • Bosch X.
      Adult haemophagocytic syndrome.
      suggesting a significant role of the host innate immune system in the immunopathology of COVID-19. Indeed, the efficacy of several immunomodulatory agents in attenuating the immune response to SARS-CoV-2 and in abrogating lung injury is being investigated. In this review, we discuss the inflammatory response in patients with COVID-19; in particular, we highlight the data that suggest that a dysregulated innate immune response drives the hyperinflammatory syndrome in severe COVID-19.

      Initial Pathologic Findings

      The pathologic examination of decedents from COVID-19 has provided important insights into the pathogenesis of the disease. The predominant pattern of lung injury associated with COVID-19 has been identified as diffuse alveolar damage accompanied by platelet–fibrin microthrombi in the pulmonary vessels. On postmortem analysis, gross examination have revealed heavy, congested, and diffusely edematous lung parenchyma, consistent with a clinical diagnosis of ARDS.
      • Fox S.E.
      • Akmatbekov A.
      • Harbert J.L.
      • Li G.
      • Quincy Brown J.
      • Vander Heide R.S.
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      Microscopy has identified diffuse alveolar hemorrhage in different phases.
      • Xu Z.
      • Shi L.
      • Wang Y.
      • Zhang J.
      • Huang L.
      • Zhang C.
      • Liu S.
      • Zhao P.
      • Liu H.
      • Zhu L.
      • Tai Y.
      • Bai C.
      • Gao T.
      • Song J.
      • Xia P.
      • Dong J.
      • Zhao J.
      • Wang F.-S.
      Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
      ,
      • Fox S.E.
      • Akmatbekov A.
      • Harbert J.L.
      • Li G.
      • Quincy Brown J.
      • Vander Heide R.S.
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      ,
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • Ahuja S.
      • Beasley M.B.
      • Albrecht R.
      • et al.
      Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience.
      Most cases have been in the early or intermediate proliferative phase with edema, while features consistent with the fibrotic phase were rare.
      • Xu Z.
      • Shi L.
      • Wang Y.
      • Zhang J.
      • Huang L.
      • Zhang C.
      • Liu S.
      • Zhao P.
      • Liu H.
      • Zhu L.
      • Tai Y.
      • Bai C.
      • Gao T.
      • Song J.
      • Xia P.
      • Dong J.
      • Zhao J.
      • Wang F.-S.
      Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
      ,
      • Fox S.E.
      • Akmatbekov A.
      • Harbert J.L.
      • Li G.
      • Quincy Brown J.
      • Vander Heide R.S.
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      ,
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • Ahuja S.
      • Beasley M.B.
      • Albrecht R.
      • et al.
      Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience.
      Histologic features accompanying the intra-alveolar and interstitial exudate have included capillary congestion, dilated alveolar ducts and collapsed alveoli, hyaline membrane formation, and desquamation of pneumocytes.
      • Carsana L.
      • Sonzogni A.
      • Nasr A.
      • Rossi R.S.
      • Pellegrinelli A.
      • Zerbi P.
      • Rech R.
      • Colombo R.
      • Antinori S.
      • Corbellino M.
      • Galli M.
      • Catena E.
      • Tosoni A.
      • Gianatti A.
      • Nebuloni M.
      Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study.
      ,
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • Ahuja S.
      • Beasley M.B.
      • Albrecht R.
      • et al.
      Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience.
      Desquamated pneumocytes have been reported to have an apparent viral cytopathic effect and were present in alveolar spaces.
      • Xu Z.
      • Shi L.
      • Wang Y.
      • Zhang J.
      • Huang L.
      • Zhang C.
      • Liu S.
      • Zhao P.
      • Liu H.
      • Zhu L.
      • Tai Y.
      • Bai C.
      • Gao T.
      • Song J.
      • Xia P.
      • Dong J.
      • Zhao J.
      • Wang F.-S.
      Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
      ,
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • Ahuja S.
      • Beasley M.B.
      • Albrecht R.
      • et al.
      Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience.
      Electron microscopy has identified viral particles within type 1 and type 2 pneumocytes,
      • Fox S.E.
      • Akmatbekov A.
      • Harbert J.L.
      • Li G.
      • Quincy Brown J.
      • Vander Heide R.S.
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      ,
      • Carsana L.
      • Sonzogni A.
      • Nasr A.
      • Rossi R.S.
      • Pellegrinelli A.
      • Zerbi P.
      • Rech R.
      • Colombo R.
      • Antinori S.
      • Corbellino M.
      • Galli M.
      • Catena E.
      • Tosoni A.
      • Gianatti A.
      • Nebuloni M.
      Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study.
      and immunofluorescence has localized SARS-CoV-2 antigen to the ACE2+ bronchiolar epithelium.
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • Ahuja S.
      • Beasley M.B.
      • Albrecht R.
      • et al.
      Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience.
      It has been reported that in the majority of cases, microthrombi were present in the small- and medium-sized pulmonary arterial vessels.
      • Fox S.E.
      • Akmatbekov A.
      • Harbert J.L.
      • Li G.
      • Quincy Brown J.
      • Vander Heide R.S.
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      • Carsana L.
      • Sonzogni A.
      • Nasr A.
      • Rossi R.S.
      • Pellegrinelli A.
      • Zerbi P.
      • Rech R.
      • Colombo R.
      • Antinori S.
      • Corbellino M.
      • Galli M.
      • Catena E.
      • Tosoni A.
      • Gianatti A.
      • Nebuloni M.
      Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study.
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • Ahuja S.
      • Beasley M.B.
      • Albrecht R.
      • et al.
      Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience.
      ,
      • Ackermann M.
      • Verleden S.E.
      • Kuehnel M.
      • Haverich A.
      • Welte T.
      • Laenger F.
      • Vanstapel A.
      • Werlein C.
      • Stark H.
      • Tzankov A.
      • Li W.W.
      • Li V.W.
      • Mentzer S.J.
      • Jonigk D.
      Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID-19.
      Increased levels of CD61+ megakaryocytes were also found in alveolar capillaries accompanying the microthrombi.
      • Fox S.E.
      • Akmatbekov A.
      • Harbert J.L.
      • Li G.
      • Quincy Brown J.
      • Vander Heide R.S.
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      ,
      • Carsana L.
      • Sonzogni A.
      • Nasr A.
      • Rossi R.S.
      • Pellegrinelli A.
      • Zerbi P.
      • Rech R.
      • Colombo R.
      • Antinori S.
      • Corbellino M.
      • Galli M.
      • Catena E.
      • Tosoni A.
      • Gianatti A.
      • Nebuloni M.
      Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study.
      Microthrombi have been identified in nearly all major organs, including the lung, heart, brain, and liver; the location of microthrombi appears to correlate with endothelial ACE2 expression.
      • Fox S.E.
      • Akmatbekov A.
      • Harbert J.L.
      • Li G.
      • Quincy Brown J.
      • Vander Heide R.S.
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      • Carsana L.
      • Sonzogni A.
      • Nasr A.
      • Rossi R.S.
      • Pellegrinelli A.
      • Zerbi P.
      • Rech R.
      • Colombo R.
      • Antinori S.
      • Corbellino M.
      • Galli M.
      • Catena E.
      • Tosoni A.
      • Gianatti A.
      • Nebuloni M.
      Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study.
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • Ahuja S.
      • Beasley M.B.
      • Albrecht R.
      • et al.
      Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience.
      These microthrombi likely contribute to organ dysfunction and mortality in COVID-19.
      • Fox S.E.
      • Akmatbekov A.
      • Harbert J.L.
      • Li G.
      • Quincy Brown J.
      • Vander Heide R.S.
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      • Carsana L.
      • Sonzogni A.
      • Nasr A.
      • Rossi R.S.
      • Pellegrinelli A.
      • Zerbi P.
      • Rech R.
      • Colombo R.
      • Antinori S.
      • Corbellino M.
      • Galli M.
      • Catena E.
      • Tosoni A.
      • Gianatti A.
      • Nebuloni M.
      Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study.
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • Ahuja S.
      • Beasley M.B.
      • Albrecht R.
      • et al.
      Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience.
      Ackermann et al
      • Ackermann M.
      • Verleden S.E.
      • Kuehnel M.
      • Haverich A.
      • Welte T.
      • Laenger F.
      • Vanstapel A.
      • Werlein C.
      • Stark H.
      • Tzankov A.
      • Li W.W.
      • Li V.W.
      • Mentzer S.J.
      • Jonigk D.
      Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID-19.
      reported on a study comparing postmortem findings of lung tissue from patients infected with COVID-19, influenza A (hemagglutinin type 1 and neuraminidase type 1; H1N1), and age-matched, uninfected controls. Alveolar capillary microthrombi were ninefold as prevalent in the lungs of COVID-19 patients compared to those in patients with influenza A.
      • Ackermann M.
      • Verleden S.E.
      • Kuehnel M.
      • Haverich A.
      • Welte T.
      • Laenger F.
      • Vanstapel A.
      • Werlein C.
      • Stark H.
      • Tzankov A.
      • Li W.W.
      • Li V.W.
      • Mentzer S.J.
      • Jonigk D.
      Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID-19.
      In addition, COVID-19 patients had increased numbers of ACE2+ endothelial cells and significant histologic changes to endothelial cell morphology, including disruption of intercellular junctions, cell swelling, and loss of contact with basement membrane.
      • Ackermann M.
      • Verleden S.E.
      • Kuehnel M.
      • Haverich A.
      • Welte T.
      • Laenger F.
      • Vanstapel A.
      • Werlein C.
      • Stark H.
      • Tzankov A.
      • Li W.W.
      • Li V.W.
      • Mentzer S.J.
      • Jonigk D.
      Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID-19.
      Consistent with the findings from a previous study evaluating endothelial cells from glomerular capillary loops,
      • Varga Z.
      • Flammer A.J.
      • Steiger P.
      • Haberecker M.
      • Andermatt R.
      • Zinkernagel A.S.
      • Mehra M.R.
      • Schuepbach R.A.
      • Ruschitzka F.
      • Moch H.
      Endothelial cell infection and endotheliitis in COVID-19.
      electron microscopy identified SARS-CoV-2 viral particles within alveolar endothelial cells.
      • Ackermann M.
      • Verleden S.E.
      • Kuehnel M.
      • Haverich A.
      • Welte T.
      • Laenger F.
      • Vanstapel A.
      • Werlein C.
      • Stark H.
      • Tzankov A.
      • Li W.W.
      • Li V.W.
      • Mentzer S.J.
      • Jonigk D.
      Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID-19.
      In vitro studies have also shown that SARS-CoV-2 can directly infect an engineered human blood vessel organoid via the ACE2 receptor.
      • Monteil V.
      • Kwon H.
      • Prado P.
      • Hagelkrüys A.
      • Wimmer R.A.
      • Stahl M.
      • Leopoldi A.
      • Garreta E.
      • Hurtado del Pozo C.
      • Prosper F.
      • Romero J.P.
      • Wirnsberger G.
      • Zhang H.
      • Slutsky A.S.
      • Conder R.
      • Montserrat N.
      • Mirazimi A.
      • Penninger J.M.
      Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2.
      These findings suggest that direct viral invasion by SARS-CoV-2 may trigger endotheliitis and contribute to endothelial injury in COVID-19. Further work is needed for confirming these data as well as for elucidating the mechanism underlying the prothrombotic state in COVID-19.
      In studies to date, all COVID-19 patients had a mononuclear inflammatory infiltrate in the lung parenchyma, composed primarily of lymphocytes and macrophages.
      • Xu Z.
      • Shi L.
      • Wang Y.
      • Zhang J.
      • Huang L.
      • Zhang C.
      • Liu S.
      • Zhao P.
      • Liu H.
      • Zhu L.
      • Tai Y.
      • Bai C.
      • Gao T.
      • Song J.
      • Xia P.
      • Dong J.
      • Zhao J.
      • Wang F.-S.
      Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
      • Fox S.E.
      • Akmatbekov A.
      • Harbert J.L.
      • Li G.
      • Quincy Brown J.
      • Vander Heide R.S.
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      • Carsana L.
      • Sonzogni A.
      • Nasr A.
      • Rossi R.S.
      • Pellegrinelli A.
      • Zerbi P.
      • Rech R.
      • Colombo R.
      • Antinori S.
      • Corbellino M.
      • Galli M.
      • Catena E.
      • Tosoni A.
      • Gianatti A.
      • Nebuloni M.
      Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study.
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • Ahuja S.
      • Beasley M.B.
      • Albrecht R.
      • et al.
      Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience.
      ,
      • Ackermann M.
      • Verleden S.E.
      • Kuehnel M.
      • Haverich A.
      • Welte T.
      • Laenger F.
      • Vanstapel A.
      • Werlein C.
      • Stark H.
      • Tzankov A.
      • Li W.W.
      • Li V.W.
      • Mentzer S.J.
      • Jonigk D.
      Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID-19.
      The lymphocytic infiltrate included both CD4+ and CD8+ T cells in the bronchiolar and alveolar interstitium, with a CD4+ T-cell predominance.
      • Fox S.E.
      • Akmatbekov A.
      • Harbert J.L.
      • Li G.
      • Quincy Brown J.
      • Vander Heide R.S.
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      ,
      • Carsana L.
      • Sonzogni A.
      • Nasr A.
      • Rossi R.S.
      • Pellegrinelli A.
      • Zerbi P.
      • Rech R.
      • Colombo R.
      • Antinori S.
      • Corbellino M.
      • Galli M.
      • Catena E.
      • Tosoni A.
      • Gianatti A.
      • Nebuloni M.
      Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study.
      ,
      • Ackermann M.
      • Verleden S.E.
      • Kuehnel M.
      • Haverich A.
      • Welte T.
      • Laenger F.
      • Vanstapel A.
      • Werlein C.
      • Stark H.
      • Tzankov A.
      • Li W.W.
      • Li V.W.
      • Mentzer S.J.
      • Jonigk D.
      Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID-19.
      CD4+ T cells appeared to aggregate around small vessels that often contained microthrombi.
      • Fox S.E.
      • Akmatbekov A.
      • Harbert J.L.
      • Li G.
      • Quincy Brown J.
      • Vander Heide R.S.
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      ,
      • Carsana L.
      • Sonzogni A.
      • Nasr A.
      • Rossi R.S.
      • Pellegrinelli A.
      • Zerbi P.
      • Rech R.
      • Colombo R.
      • Antinori S.
      • Corbellino M.
      • Galli M.
      • Catena E.
      • Tosoni A.
      • Gianatti A.
      • Nebuloni M.
      Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study.
      Large numbers of CD68+ macrophages and multinucleated cells were also identified and localized to the alveolar lumen.
      • Fox S.E.
      • Akmatbekov A.
      • Harbert J.L.
      • Li G.
      • Quincy Brown J.
      • Vander Heide R.S.
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      • Carsana L.
      • Sonzogni A.
      • Nasr A.
      • Rossi R.S.
      • Pellegrinelli A.
      • Zerbi P.
      • Rech R.
      • Colombo R.
      • Antinori S.
      • Corbellino M.
      • Galli M.
      • Catena E.
      • Tosoni A.
      • Gianatti A.
      • Nebuloni M.
      Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study.
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • Ahuja S.
      • Beasley M.B.
      • Albrecht R.
      • et al.
      Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience.
      The presence of macrophages appeared to correlate with disease advancement.
      • Fox S.E.
      • Akmatbekov A.
      • Harbert J.L.
      • Li G.
      • Quincy Brown J.
      • Vander Heide R.S.
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      These patient findings have been recapitulated in phenotypic studies using transgenic mice bearing human ACE2 infected with SARS-CoV-2, which showed the characteristic interstitial pneumonia with infiltration of lymphocytes and macrophages in the alveolar interstitium, as well as macrophages in the alveolar lumen.
      • Bao L.
      • Deng W.
      • Huang B.
      • Gao H.
      • Liu J.
      • Ren L.
      • et al.
      The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice.
      A recent study identified the presence of hemophagocytosis in the bone marrow and reticuloendothelial organs of patients with COVID-19. Bryce et al
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • Ahuja S.
      • Beasley M.B.
      • Albrecht R.
      • et al.
      Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience.
      reported a comprehensive autopsy series of 67 patients who succumbed to COVID-19. In that study, hemophagocytic macrophages were identified in the lymph nodes (9/11), spleen (9/22), bone marrow (4/6), heart, and liver. Abnormally high mean peak levels of C-reactive protein, ferritin, IL-6, IL-8, and tumor necrosis factor (TNF)-α accompanied the histopathologic findings in these patients. The presence of hemophagocytosis with concomitant elevations in inflammatory cytokines suggests that alveolar macrophage activation can induce a hemophagocytic lymphohistiocytosis phenotype in patients with severe COVID-19. Severe cases of SARS-CoV-1 infection shared similar pathologic findings.
      • Nicholls J.M.
      • Poon L.L.M.
      • Lee K.C.
      • Ng W.F.
      • Lai S.T.
      • Leung C.Y.
      • Chu C.M.
      • Hui P.K.
      • Mak K.L.
      • Lim W.
      • Yan K.W.
      • Chan K.H.
      • Tsang N.C.
      • Guan Y.
      • Yuen K.Y.
      • Malik Peiris J.S.
      Lung pathology of fatal severe acute respiratory syndrome.

      Cytokine Storm

      Early studies reporting outcomes in COVID-19 identified that elevated clinical inflammatory markers were prognostic of disease severity and mortality.
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • Xiang J.
      • Wang Y.
      • Song B.
      • Gu X.
      • Guan L.
      • Wei Y.
      • Li H.
      • Wu X.
      • Xu J.
      • Tu S.
      • Zhang Y.
      • Chen H.
      • Cao B.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Ruan 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.
      Two multicenter, retrospective studies in hospitalized patients in China evaluated predictors of mortality in COVID-19.
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • Xiang J.
      • Wang Y.
      • Song B.
      • Gu X.
      • Guan L.
      • Wei Y.
      • Li H.
      • Wu X.
      • Xu J.
      • Tu S.
      • Zhang Y.
      • Chen H.
      • Cao B.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Ruan 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.
      Nonsurvivors had elevated C-reactive protein, lactate dehydrogenase, serum ferritin, and serum IL-6 levels at the time of hospital admission compared to those in survivors.
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • Xiang J.
      • Wang Y.
      • Song B.
      • Gu X.
      • Guan L.
      • Wei Y.
      • Li H.
      • Wu X.
      • Xu J.
      • Tu S.
      • Zhang Y.
      • Chen H.
      • Cao B.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Ruan 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.
      In addition, nonsurvivors had elevated inflammatory markers throughout the entire clinical course, and the clinical deterioration that preceded death tracked with increasing levels of inflammation.
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • Xiang J.
      • Wang Y.
      • Song B.
      • Gu X.
      • Guan L.
      • Wei Y.
      • Li H.
      • Wu X.
      • Xu J.
      • Tu S.
      • Zhang Y.
      • Chen H.
      • Cao B.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      The prevalence of ARDS was also higher in the group with elevated inflammatory markers.
      • Wu C.
      • Chen X.
      • Cai Y.
      • Xia Ja
      • Zhou X.
      • Xu S.
      • Huang H.
      • Zhang L.
      • Zhou X.
      • Du C.
      • Zhang Y.
      • Song J.
      • Wang S.
      • Chao Y.
      • Yang Z.
      • Xu J.
      • Zhou X.
      • Chen D.
      • Xiong W.
      • Xu L.
      • Zhou F.
      • Jiang J.
      • Bai C.
      • Zheng J.
      • Song Y.
      Risk factors associated with acute respiratory distress syndrome and death in patients with Coronavirus disease 2019 pneumonia in Wuhan, China.
      Consistent with these initial clinical findings, plasma sampling from patients with severe COVID-19 revealed a proinflammatory cytokine profile. The initial report included 41 patients admitted to the hospital with COVID-19–related pneumonia in Wuhan, China.
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • Zhang L.
      • Fan G.
      • Xu J.
      • Gu X.
      • Cheng Z.
      • Yu T.
      • Xia J.
      • Wei Y.
      • Wu W.
      • Xie X.
      • Yin W.
      • Li H.
      • Liu M.
      • Xiao Y.
      • Gao H.
      • Guo L.
      • Xie J.
      • Wang G.
      • Jiang R.
      • Gao Z.
      • Jin Q.
      • Wang J.
      • Cao B.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      Compared to healthy adults, patients with COVID-19 in that study had higher plasma concentrations of IL-1β, IL-1Rα, IL-7, IL-8, IL-10, basic fibroblast growth factor, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage (GM)-CSF, interferon (IFN)-γ, induced protein (IP)-10/CXCL10, monocyte chemotactic protein (MCP)-1/C-C motif chemokine ligand (CCL)-2, macrophage inflammatory protein (MIP)-1α/CCL3, MIP-1β/CCL4, platelet-derived growth factor, TNF-α, and vascular endothelial growth factor.
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • Zhang L.
      • Fan G.
      • Xu J.
      • Gu X.
      • Cheng Z.
      • Yu T.
      • Xia J.
      • Wei Y.
      • Wu W.
      • Xie X.
      • Yin W.
      • Li H.
      • Liu M.
      • Xiao Y.
      • Gao H.
      • Guo L.
      • Xie J.
      • Wang G.
      • Jiang R.
      • Gao Z.
      • Jin Q.
      • Wang J.
      • Cao B.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      The mean plasma concentrations of IL-2, IL-7, IL-10, G-CSF, IP-10/CXCL10, MCP-1/CCL2, MIP-1α/CCL3, and TNF-α were higher in the subgroup in the intensive care unit versus those in non–intensive care unit patients.
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • Zhang L.
      • Fan G.
      • Xu J.
      • Gu X.
      • Cheng Z.
      • Yu T.
      • Xia J.
      • Wei Y.
      • Wu W.
      • Xie X.
      • Yin W.
      • Li H.
      • Liu M.
      • Xiao Y.
      • Gao H.
      • Guo L.
      • Xie J.
      • Wang G.
      • Jiang R.
      • Gao Z.
      • Jin Q.
      • Wang J.
      • Cao B.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      A study in 21 patients with COVID-19 admitted with pneumonia reported similar findings; patients with moderate or severe disease had abnormally elevated levels of IL-1β, IL-2 receptor (R), IL-6, IL-8, IL-10, and TNF-α.
      • Chen G.
      • Wu D.
      • Guo W.
      • Cao Y.
      • Huang D.
      • Wang H.
      • Wang T.
      • Zhang X.
      • Chen H.
      • Yu H.
      • Zhang X.
      • Zhang M.
      • Wu S.
      • Song J.
      • Chen T.
      • Han M.
      • Li S.
      • Luo X.
      • Zhao J.
      • Ning Q.
      Clinical and immunological features of severe and moderate Coronavirus disease 2019.
      In a large-scale, retrospective study in 1484 patients at Mount Sinai Hospital (New York, NY), plasma levels of IL-6, IL-8, and TNF-α were higher in those with severe COVID-19.
      • Del Valle D.M.
      • Kim-schulze S.
      • Hsin-hui H.
      • Beckmann N.D.
      • Nirenberg S.
      • Wang B.
      • Lavin Y.
      • Swartz T.
      • Madduri D.
      • Stock A.
      • Marron T.
      • Xie H.
      • Patel M.K.
      • van Oekelen O.
      • Rahman A.
      • Kovatch P.
      • Aberg J.
      • Schadt E.
      • Jagannath S.
      • Mazumdar M.
      • Charney A.
      • Firpo-Betancourt A.
      • Mendu D.R.
      • Jhang J.
      • Reich D.
      • Sigel K.
      • Cordon-Cardo C.
      • Feldmann M.
      • Parekh S.
      • Merad M.
      • Gnjatic S.
      An inflammatory cytokine signature helps predict COVID-19 severity and survival.
      Moreover, IL-6 and TNF-α levels at the time of hospitalization were independently associated with disease severity and mortality in that multivariate analysis.
      • Del Valle D.M.
      • Kim-schulze S.
      • Hsin-hui H.
      • Beckmann N.D.
      • Nirenberg S.
      • Wang B.
      • Lavin Y.
      • Swartz T.
      • Madduri D.
      • Stock A.
      • Marron T.
      • Xie H.
      • Patel M.K.
      • van Oekelen O.
      • Rahman A.
      • Kovatch P.
      • Aberg J.
      • Schadt E.
      • Jagannath S.
      • Mazumdar M.
      • Charney A.
      • Firpo-Betancourt A.
      • Mendu D.R.
      • Jhang J.
      • Reich D.
      • Sigel K.
      • Cordon-Cardo C.
      • Feldmann M.
      • Parekh S.
      • Merad M.
      • Gnjatic S.
      An inflammatory cytokine signature helps predict COVID-19 severity and survival.
      Elevated plasma levels of IL-6, IL-8, and TNF-α also peaked before death in an autopsy series of COVID-19 patients, and correlated with pathologic evidence of hemophagocytosis.
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • Ahuja S.
      • Beasley M.B.
      • Albrecht R.
      • et al.
      Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience.
      These data suggest that a cytokine storm underpins the immunopathology of severe COVID-19.
      Tay et al
      • Tay M.Z.
      • Poh C.M.
      • Rénia L.
      • MacAry P.A.
      • Ng L.F.P.
      The trinity of COVID-19: immunity, inflammation and intervention.
      proposed a possible mechanism underlying the cytokine storm in severe COVID-19. SARS-CoV-2 is a cytopathic virus that induces the death of infected cells during viral replication.
      • Xu Z.
      • Shi L.
      • Wang Y.
      • Zhang J.
      • Huang L.
      • Zhang C.
      • Liu S.
      • Zhao P.
      • Liu H.
      • Zhu L.
      • Tai Y.
      • Bai C.
      • Gao T.
      • Song J.
      • Xia P.
      • Dong J.
      • Zhao J.
      • Wang F.-S.
      Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
      ,
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • Ahuja S.
      • Beasley M.B.
      • Albrecht R.
      • et al.
      Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience.
      ,
      • Schifanella L.
      • Anderson J.L.
      • Galli M.
      • Corbellino M.
      • Lai A.
      • Wieking G.
      • Grzywacz B.
      • Klatt N.R.
      • Haase A.T.
      • Schacker T.W.
      Massive viral replication and cytopathic effects in early COVID-19 pneumonia.
      Viral replication in epithelial cells may also cause high levels of pyroptosis,
      • Zhang H.
      • Zhou P.
      • Wei Y.
      • Yue H.
      • Wang Y.
      • Hu M.
      • Zhang S.
      • Cao T.
      • Yang C.
      • Li M.
      • Guo G.
      • Chen X.
      • Chen Y.
      • Lei M.
      • Liu H.
      • Zhao J.
      • Peng P.
      • Wang C.-Y.
      • Du R.
      Histopathologic changes and SARS-CoV-2 immunostaining in the lung of a patient with COVID-19.
      which is an inflammatory form of programed cell death observed in infection with cytopathic viruses.
      • Fink S.L.
      • Cookson B.T.
      Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells.
      Pyroptosis could represent an inciting event for the hyperinflammatory response to SARS-CoV-2 infection.
      • Yang M.
      Cell pyroptosis, a potential pathogenic mechanism of 2019-nCoV infection.
      • Yap J.K.Y.
      • Moriyama M.
      • Iwasaki A.
      Inflammasomes and pyroptosis as therapeutic targets for COVID-19.
      • St John A.L.
      • Rathore A.P.S.
      Early insights into immune responses during COVID-19.
      IL-1β is released from cells undergoing pyroptosis,
      • Yap J.K.Y.
      • Moriyama M.
      • Iwasaki A.
      Inflammasomes and pyroptosis as therapeutic targets for COVID-19.
      and high levels are present in both serum and bronchoalveolar fluid (BALF) in patients with severe COVID-19.
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • Zhang L.
      • Fan G.
      • Xu J.
      • Gu X.
      • Cheng Z.
      • Yu T.
      • Xia J.
      • Wei Y.
      • Wu W.
      • Xie X.
      • Yin W.
      • Li H.
      • Liu M.
      • Xiao Y.
      • Gao H.
      • Guo L.
      • Xie J.
      • Wang G.
      • Jiang R.
      • Gao Z.
      • Jin Q.
      • Wang J.
      • Cao B.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Liao M.
      • Liu Y.
      • Yuan J.
      • Wen Y.
      • Xu G.
      • Zhao J.
      • Cheng L.
      • Li J.
      • Wang X.
      • Wang F.
      • Liu L.
      • Amit I.
      • Zhang S.
      • Zhang Z.
      Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19.
      Pathogen-associated molecular patterns, such as viral RNA, are also released by infected epithelial cells. Neighboring lung epithelial cells and resident alveolar macrophages detect the pathogen-associated molecular patterns using several pattern-recognition receptors. The activation of the pattern-recognition receptors and IL-1R stimulates the secretion of proinflammatory cytokines, including IL-6, IFN-γ, MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4, and IP-10/CXCL4.
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • Zhang L.
      • Fan G.
      • Xu J.
      • Gu X.
      • Cheng Z.
      • Yu T.
      • Xia J.
      • Wei Y.
      • Wu W.
      • Xie X.
      • Yin W.
      • Li H.
      • Liu M.
      • Xiao Y.
      • Gao H.
      • Guo L.
      • Xie J.
      • Wang G.
      • Jiang R.
      • Gao Z.
      • Jin Q.
      • Wang J.
      • Cao B.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Chen G.
      • Wu D.
      • Guo W.
      • Cao Y.
      • Huang D.
      • Wang H.
      • Wang T.
      • Zhang X.
      • Chen H.
      • Yu H.
      • Zhang X.
      • Zhang M.
      • Wu S.
      • Song J.
      • Chen T.
      • Han M.
      • Li S.
      • Luo X.
      • Zhao J.
      • Ning Q.
      Clinical and immunological features of severe and moderate Coronavirus disease 2019.
      The cytokines then recruit activated macrophages and T cells to the site of infection, whereby these immune effector cells potentiate inflammation with additional cytokine secretion and destruction of lung parenchyma. Similar to SARS-CoV-1 and MERS-CoV, the cytokine profile observed in patients with COVID-19 is consistent with a predominant Th1 cell– and classic M1 macrophage–polarized response.
      • Mehta P.
      • McAuley D.F.
      • Brown M.
      • Sanchez E.
      • Tattersall R.S.
      • Manson J.J.
      COVID-19: consider cytokine storm syndromes and immunosuppression.
      ,
      • Mills C.D.
      • Kincaid K.
      • Alt J.M.
      • Heilman M.J.
      • Hill A.M.
      M-1/M-2 macrophages and the Th1/Th2 paradigm.
      Consequently, a proinflammatory feedback loop is established, triggering a cytokine storm that circulates and causes local tissue damage as well as systemic effects, such as septic shock, multiorgan failure, and hemophagocytosis in reticuloendothelial organs.
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • Zhang L.
      • Fan G.
      • Xu J.
      • Gu X.
      • Cheng Z.
      • Yu T.
      • Xia J.
      • Wei Y.
      • Wu W.
      • Xie X.
      • Yin W.
      • Li H.
      • Liu M.
      • Xiao Y.
      • Gao H.
      • Guo L.
      • Xie J.
      • Wang G.
      • Jiang R.
      • Gao Z.
      • Jin Q.
      • Wang J.
      • Cao B.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • Ahuja S.
      • Beasley M.B.
      • Albrecht R.
      • et al.
      Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience.
      ,
      • Zhang B.
      • Zhou X.
      • Qiu Y.
      • Feng F.
      • Feng J.
      • Jia Y.
      • Zhu H.
      • Hu K.
      • Liu J.
      • Liu Z.
      • Wang S.
      • Gong Y.
      • Zhou C.
      • Zhu T.
      • Cheng Y.
      • Liu Z.
      • Deng H.
      • Tao F.
      • Ren Y.
      • Cheng B.
      • Gao L.
      • Wu X.
      • Yu L.
      • Huang Z.
      • Mao Z.
      • Song Q.
      • Zhu B.
      • Wang J.
      Clinical characteristics of 82 death cases with COVID-19.
      Notably, the tropism of SARS-CoV-2 for ACE2+ type 2 pneumocytes may contribute to the development of cytokine storm. Viral binding by SARS-CoV-2 to the ACE2 receptor is primarily restricted to type 2 pneumocytes on the lung epithelium.
      • Ziegler C.G.K.
      • Allon S.J.
      • Nyquist S.K.
      • Mbano I.M.
      • Miao V.N.
      • Tzouanas C.N.
      • et al.
      HCA Lung Biological Network
      SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues.
      Although typically associated with surfactant production and alveolar repair, type 2 pneumocytes have a specialized role in the innate immune response. Type 2 pneumocytes express toll-like receptors (TLRs) that activate inflammatory NF-κB signaling in response to binding of viral RNA.
      • Pechkovsky D.V.
      • Goldmann T.
      • Ludwig C.
      • Prasse A.
      • Vollmer E.
      • Müller-Quernheim J.
      • Zissel G.
      CCR2 and CXCR3 agonistic chemokines are differently expressed and regulated in human alveolar epithelial cells type II.
      • Thorley A.J.
      • Grandolfo D.
      • Lim E.
      • Goldstraw P.
      • Young A.
      • Tetley T.D.
      Innate immune responses to bacterial ligands in the peripheral human lung--role of alveolar epithelial TLR expression and signalling.
      • Chuquimia O.D.
      • Petursdottir D.H.
      • Periolo N.
      • Fernández C.
      Alveolar epithelial cells are critical in protection of the respiratory tract by secretion of factors able to modulate the activity of pulmonary macrophages and directly control bacterial growth.
      The activation of NF-κB triggers the production of cytokines that can induce an inflammatory program in resident macrophages and recruit activated monocytes and T cells to the lung. Accordingly, increased IL-6 levels in hyperplastic type 2 pneumocytes infected with SARS-CoV-2 have been measured.
      • Schifanella L.
      • Anderson J.L.
      • Galli M.
      • Corbellino M.
      • Lai A.
      • Wieking G.
      • Grzywacz B.
      • Klatt N.R.
      • Haase A.T.
      • Schacker T.W.
      Massive viral replication and cytopathic effects in early COVID-19 pneumonia.
      ACE2+ infected pneumocytes also have been reported to express high levels of proinflammatory cytokines (ie, MCP-1/CCL2, TNF-α, IL-1β, and IL-6) in an autopsy series of patients with SARS-CoV-1 infection; cytokine expression was unchanged in uninfected cells.
      • He L.
      • Ding Y.
      • Zhang Q.
      • Che X.
      • He Y.
      • Shen H.
      • Wang H.
      • Li Z.
      • Zhao L.
      • Geng J.
      • Deng Y.
      • Yang L.
      • Li J.
      • Cai J.
      • Qiu L.
      • Wen K.
      • Xu X.
      • Jiang S.
      Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS.
      Direct invasion and stimulation of TLR-containing ACE2+ type 2 pneumocytes may therefore exacerbate cytokine production in COVID-19.
      Dysregulated IFN signaling also likely has an impact on the immunopathology of severe COVID-19. The findings from initial studies have suggested that SARS-CoV-2 can suppress IFN signaling and impair viral clearance from infected cells. SARS-CoV-2 was reported to be sensitive to pretreatment with types I and III IFNs in vitro.
      • Blanco-Melo D.
      • Nilsson-Payant B.E.
      • Liu W.-C.
      • Uhl S.
      • Hoagland D.
      • Møller R.
      • Jordan T.X.
      • Oishi K.
      • Panis M.
      • Sachs D.
      • Wang T.T.
      • Schwartz R.E.
      • Lim J.K.
      • Albrecht R.A.
      • tenOever B.R.
      Imbalanced host response to SARS-CoV-2 drives development of COVID-19.
      However, a study using infected cell lines, primary bronchial cells, and a ferret model with SARS-CoV-2 infection demonstrated decreased type I and III IFN signatures.
      • Blanco-Melo D.
      • Nilsson-Payant B.E.
      • Liu W.-C.
      • Uhl S.
      • Hoagland D.
      • Møller R.
      • Jordan T.X.
      • Oishi K.
      • Panis M.
      • Sachs D.
      • Wang T.T.
      • Schwartz R.E.
      • Lim J.K.
      • Albrecht R.A.
      • tenOever B.R.
      Imbalanced host response to SARS-CoV-2 drives development of COVID-19.
      Patients with severe COVID-19 also appeared to have an impaired type I IFN signature compared to that in mild or moderate cases.
      • Hadjadj J.
      • Yatim N.
      • Barnabei L.
      • Corneau A.
      • Boussier J.
      • Smith N.
      • Péré H.
      • Charbit B.
      • Bondet V.
      • Chenevier-Gobeaux C.
      • Breillat P.
      • Carlier N.
      • Gauzit R.
      • Morbieu C.
      • Pène F.
      • Marin N.
      • Roche N.
      • Szwebel T.-A.
      • Merkling S.H.
      • Treluyer J.-M.
      • Veyer D.
      • Mouthon L.
      • Blanc C.
      • Tharaux P.-L.
      • Rozenberg F.
      • Fischer A.
      • Duffy D.
      • Rieux-Laucat F.
      • Kernéis S.
      • Terrier B.
      Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients.
      Whole-blood transcriptome analysis revealed that the expression of type I IFN was inversely correlated with the viral load and NF-κB–driven inflammatory response (ie, IL-6 and TNF-α levels) in COVID-19 patients.
      • Hadjadj J.
      • Yatim N.
      • Barnabei L.
      • Corneau A.
      • Boussier J.
      • Smith N.
      • Péré H.
      • Charbit B.
      • Bondet V.
      • Chenevier-Gobeaux C.
      • Breillat P.
      • Carlier N.
      • Gauzit R.
      • Morbieu C.
      • Pène F.
      • Marin N.
      • Roche N.
      • Szwebel T.-A.
      • Merkling S.H.
      • Treluyer J.-M.
      • Veyer D.
      • Mouthon L.
      • Blanc C.
      • Tharaux P.-L.
      • Rozenberg F.
      • Fischer A.
      • Duffy D.
      • Rieux-Laucat F.
      • Kernéis S.
      • Terrier B.
      Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients.
      Moreover, a multicenter observational study reported that the administration of IFN-α2b early in the disease course of COVID-19 improved in-hospital mortality in infected patients.
      • Wang N.
      • Zhan Y.
      • Zhu L.
      • Hou Z.
      • Liu F.
      • Song P.
      • Qiu F.
      • Wang X.
      • Zou X.
      • Wan D.
      • Qian X.
      • Wang S.
      • Guo Y.
      • Yu H.
      • Cui M.
      • Tong G.
      • Xu Y.
      • Zheng Z.
      • Lu Y.
      • Hong P.
      Retrospective multicenter cohort study shows early interferon therapy is associated with favorable clinical responses in COVID-19 patients.
      These findings suggest that a weak IFN response during early infection with SARS-CoV-2 may allow for the development of severe COVID-19.
      Additional work is needed for ascertaining the mechanism that SARS-CoV-2 employs to impair IFN signaling. However, the findings from functional studies in other pathogenic coronaviruses, such as SARS-CoV-1 and MERS-CoV, have elucidated the viral proteins that antagonize IFN signaling and release. Example virulence mechanisms include the inhibition of TNF receptor–associated factor family member–associated NF-κB activator–binding kinase (TBK)-1–dependent phosphorylation, IFN regulatory factor 3 activation, and IFN production.
      • Chen X.
      • Yang X.
      • Zheng Y.
      • Yang Y.
      • Xing Y.
      • Chen Z.
      SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3-TBK1 complex.
      • Yang Y.
      • Ye F.
      • Zhu N.
      • Wang W.
      • Deng Y.
      • Zhao Z.
      • Tan W.
      Middle East respiratory syndrome coronavirus ORF4b protein inhibits type I interferon production through both cytoplasmic and nuclear targets.
      • Lui P.Y.
      • Wong L.Y.
      • Fung C.L.
      • Siu K.L.
      • Yeung M.L.
      • Yuen K.S.
      • Chan C.P.
      • Woo P.C.
      • Yuen K.Y.
      • Jin D.Y.
      Middle East respiratory syndrome coronavirus M protein suppresses type I interferon expression through the inhibition of TBK1-dependent phosphorylation of IRF3.
      A murine model of SARS-CoV-1 infection also showed that delayed type I IFN signaling and rapid viral replication induced a hyperinflammatory state with lung pathology.
      • Channappanavar R.
      • Fehr Anthony R.
      • Vijay R.
      • Mack M.
      • Zhao J.
      • Meyerholz David K.
      • Perlman S.
      Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice.
      These mice had an excessive accumulation of activated macrophages in the lung, as well as elevated cytokine levels and an inadequate virus-specific T-cell response.
      • Channappanavar R.
      • Fehr Anthony R.
      • Vijay R.
      • Mack M.
      • Zhao J.
      • Meyerholz David K.
      • Perlman S.
      Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice.
      As such, impaired viral clearance of SARS-CoV-2 due to the antagonism of IFN signaling might enable continuous TLR stimulation and pyroptosis of infected type 2 pneumocytes, thereby promoting the hyperinflammatory state observed in severe COVID-19.

      Dysregulated Macrophage Activation

      A proinflammatory macrophage microenvironment defines the landscape of bronchoalveolar immune cells in patients with severe COVID-19. In line with initial pathologic findings, single-cell RNA sequencing (scRNA-seq) of BALF collected from COVID-19 patients identified an abundance of macrophages in severe disease.
      • Liao M.
      • Liu Y.
      • Yuan J.
      • Wen Y.
      • Xu G.
      • Zhao J.
      • Cheng L.
      • Li J.
      • Wang X.
      • Wang F.
      • Liu L.
      • Amit I.
      • Zhang S.
      • Zhang Z.
      Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19.
      ,
      • Zhou Z.
      • Ren L.
      • Zhang L.
      • Zhong J.
      • Xiao Y.
      • Jia Z.
      • Guo L.
      • Yang J.
      • Wang C.
      • Jiang S.
      • Yang D.
      • Zhang G.
      • Li H.
      • Chen F.
      • Xu Y.
      • Chen M.
      • Gao Z.
      • Yang J.
      • Dong J.
      • Liu B.
      • Zhang X.
      • Wang W.
      • He K.
      • Jin Q.
      • Li M.
      • Wang J.
      Heightened innate immune responses in the respiratory tract of COVID-19 patients.
      Further analysis revealed that the macrophages are primarily inflammatory monocyte derived, with a relative paucity of resident alveolar macrophages.
      • Liao M.
      • Liu Y.
      • Yuan J.
      • Wen Y.
      • Xu G.
      • Zhao J.
      • Cheng L.
      • Li J.
      • Wang X.
      • Wang F.
      • Liu L.
      • Amit I.
      • Zhang S.
      • Zhang Z.
      Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19.
      The macrophages in severe disease highly express the genes ficolin-1 (FCN1) and SPP1, while in moderate disease they preferentially express FABP4.
      • Liao M.
      • Liu Y.
      • Yuan J.
      • Wen Y.
      • Xu G.
      • Zhao J.
      • Cheng L.
      • Li J.
      • Wang X.
      • Wang F.
      • Liu L.
      • Amit I.
      • Zhang S.
      • Zhang Z.
      Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19.
      Consistent with the cytokine pattern in peripheral blood,
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • Zhang L.
      • Fan G.
      • Xu J.
      • Gu X.
      • Cheng Z.
      • Yu T.
      • Xia J.
      • Wei Y.
      • Wu W.
      • Xie X.
      • Yin W.
      • Li H.
      • Liu M.
      • Xiao Y.
      • Gao H.
      • Guo L.
      • Xie J.
      • Wang G.
      • Jiang R.
      • Gao Z.
      • Jin Q.
      • Wang J.
      • Cao B.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      macrophages expressing FCN1 and SPP1 in BALF have gene-expression signatures characteristic of classic M1 macrophages.
      • Liao M.
      • Liu Y.
      • Yuan J.
      • Wen Y.
      • Xu G.
      • Zhao J.
      • Cheng L.
      • Li J.
      • Wang X.
      • Wang F.
      • Liu L.
      • Amit I.
      • Zhang S.
      • Zhang Z.
      Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19.
      These macrophages express genes that encode peripheral monocyte-like markers (ie, S100A8, FCN1, and CD14), chemokines (ie, MCP1/CCL2, MIP1A/CCL3, and INP10/CXCL10), and inflammatory transcription factors (ie, NFKB, STAT1, STAT2, and IFN regulatory factors).
      A profibrotic subset of alternative M2 macrophages that express both profibrotic genes (ie, TREM2, TGFB1, and SPP1) and immunoregulatory genes (ie, A2M and GPR3) was also identified in patients with severe COVID-19.
      • Liao M.
      • Liu Y.
      • Yuan J.
      • Wen Y.
      • Xu G.
      • Zhao J.
      • Cheng L.
      • Li J.
      • Wang X.
      • Wang F.
      • Liu L.
      • Amit I.
      • Zhang S.
      • Zhang Z.
      Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19.
      These findings suggest that the pathogenic role of macrophages in severe COVID-19 may extend beyond acute inflammation to include pulmonary fibrosis. Early reports indicate fibrotic lung patterns with reduced diffusion and total lung capacity in survivors of severe COVID-19, as well as persistent ground-glass opacities on imaging at the time of hospital discharge.
      • Mo X.
      • Jian W.
      • Su Z.
      • Chen M.
      • Peng H.
      • Peng P.
      • Lei C.
      • Li S.
      • Chen R.
      • Zhong N.
      Abnormal pulmonary function in COVID-19 patients at time of hospital discharge.
      ,
      • Wang Y.
      • Dong C.
      • Hu Y.
      • Li C.
      • Ren Q.
      • Zhang X.
      • Shi H.
      • Zhou M.
      Temporal changes of CT findings in 90 patients with COVID-19 pneumonia: a longitudinal study.
      Gene expression of cytokines and chemokines has been reported to be markedly increased in lung macrophages. Based on scRNA-seq data, lung macrophages from patients with severe COVID-19 had increased expression of IL1B, IL6, TNF, and genes encoding several chemokines, including MCP1/CCL2, MIP1A/CCL3, MIP1B/CCL4, and MCP3/CCL7.
      • Liao M.
      • Liu Y.
      • Yuan J.
      • Wen Y.
      • Xu G.
      • Zhao J.
      • Cheng L.
      • Li J.
      • Wang X.
      • Wang F.
      • Liu L.
      • Amit I.
      • Zhang S.
      • Zhang Z.
      Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19.
      ,
      • Zhou Z.
      • Ren L.
      • Zhang L.
      • Zhong J.
      • Xiao Y.
      • Jia Z.
      • Guo L.
      • Yang J.
      • Wang C.
      • Jiang S.
      • Yang D.
      • Zhang G.
      • Li H.
      • Chen F.
      • Xu Y.
      • Chen M.
      • Gao Z.
      • Yang J.
      • Dong J.
      • Liu B.
      • Zhang X.
      • Wang W.
      • He K.
      • Jin Q.
      • Li M.
      • Wang J.
      Heightened innate immune responses in the respiratory tract of COVID-19 patients.
      ,
      • Xiong Y.
      • Liu Y.
      • Cao L.
      • Wang D.
      • Guo M.
      • Jiang A.
      • Guo D.
      • Hu W.
      • Yang J.
      • Tang Z.
      • Wu H.
      • Lin Y.
      • Zhang M.
      • Zhang Q.
      • Shi M.
      • Liu Y.
      • Zhou Y.
      • Lan K.
      • Chen Y.
      Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients.
      These chemokines are potent recruiters of inflammatory monocytes to the site of infection. Conversely, patients with moderate disease have been reported to express higher levels of CXCL16, which can bind to the CXCR6 receptor and attract CD8+ T cells that may be specific for SARS-CoV-2.
      • Liao M.
      • Liu Y.
      • Yuan J.
      • Wen Y.
      • Xu G.
      • Zhao J.
      • Cheng L.
      • Li J.
      • Wang X.
      • Wang F.
      • Liu L.
      • Amit I.
      • Zhang S.
      • Zhang Z.
      Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19.
      In both severe and moderate cases, the gene expression levels of the CXCR3 ligands CXCL9, CXCL10, and CXCL11 were higher compared to those in healthy controls.
      • Liao M.
      • Liu Y.
      • Yuan J.
      • Wen Y.
      • Xu G.
      • Zhao J.
      • Cheng L.
      • Li J.
      • Wang X.
      • Wang F.
      • Liu L.
      • Amit I.
      • Zhang S.
      • Zhang Z.
      Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19.
      These transcriptional changes in lung macrophages also correlated with BALF cytokine levels. Patients with severe disease had significantly higher levels of proinflammatory cytokines in BALF, especially IL-1β, IL-6, IL-8, TNF-α, and IFN-γ.
      • Liao M.
      • Liu Y.
      • Yuan J.
      • Wen Y.
      • Xu G.
      • Zhao J.
      • Cheng L.
      • Li J.
      • Wang X.
      • Wang F.
      • Liu L.
      • Amit I.
      • Zhang S.
      • Zhang Z.
      Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19.
      ,
      • Xiong Y.
      • Liu Y.
      • Cao L.
      • Wang D.
      • Guo M.
      • Jiang A.
      • Guo D.
      • Hu W.
      • Yang J.
      • Tang Z.
      • Wu H.
      • Lin Y.
      • Zhang M.
      • Zhang Q.
      • Shi M.
      • Liu Y.
      • Zhou Y.
      • Lan K.
      • Chen Y.
      Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients.
      Collectively, these data suggest that lung macrophages recruit inflammatory monocytes and produce cytokines that contribute to hyperinflammation in severe COVID-19.
      A significant expansion of inflammatory monocytes is also present in the peripheral blood of COVID-19 patients. Flow cytometric analysis have been used for identifying increased populations of CD14+CD16+, GM-CSF+CD14+, and IL-6+CD14+ subsets of inflammatory monocytes.
      • Zhou Y.
      • Fu B.
      • Zheng X.
      • Wang D.
      • Zhao C.
      • Qi Y.
      • Sun R.
      • Tian Z.
      • Xu X.
      • Wei H.
      Pathogenic T-cells and inflammatory monocytes incite inflammatory storms in severe COVID-19 patients.
      ,
      • Roschewski M.
      • Lionakis M.S.
      • Sharman J.P.
      • Roswarski J.
      • Goy A.
      • Monticelli M.A.
      • Roshon M.
      • Wrzesinski S.H.
      • Desai J.V.
      • Zarakas M.A.
      • Collen J.
      • Rose K.M.
      • Hamdy A.
      • Izumi R.
      • Wright G.W.
      • Chung K.K.
      • Baselga J.
      • Staudt L.M.
      • Wilson W.H.
      Inhibition of Bruton tyrosine kinase in patients with severe COVID-19.
      The percentage of CD14+CD16+ monocytes producing IL-6 was correlated with disease severity.
      • Zhou Y.
      • Fu B.
      • Zheng X.
      • Wang D.
      • Zhao C.
      • Qi Y.
      • Sun R.
      • Tian Z.
      • Xu X.
      • Wei H.
      Pathogenic T-cells and inflammatory monocytes incite inflammatory storms in severe COVID-19 patients.
      Data from scRNA-seq of peripheral blood mononuclear cells demonstrated similar findings, wherein CD14+IL-1β+ monocytes, IFN-activated monocytes, and IL1B-associated inflammasome signatures were observed.
      • Wen W.
      • Su W.
      • Tang H.
      • Le W.
      • Zhang X.
      • Zheng Y.
      • Liu X.
      • Xie L.
      • Li J.
      • Ye J.
      • Dong L.
      • Cui X.
      • Miao Y.
      • Wang D.
      • Dong J.
      • Xiao C.
      • Chen W.
      • Wang H.
      Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing.
      • Ong E.Z.
      • Chan Y.F.Z.
      • Leong W.Y.
      • Lee N.M.Y.
      • Kalimuddin S.
      • Haja Mohideen S.M.
      • Chan K.S.
      • Tan A.T.
      • Bertoletti A.
      • Ooi E.E.
      • Low J.G.H.
      A dynamic immune response shapes COVID-19 progression.
      • Guo C.
      • Li B.
      • Ma H.
      • Wang X.
      • Cai P.
      • Yu Q.
      • Zhu L.
      • Jin L.
      • Jiang C.
      • Fang J.
      • Liu Q.
      • Zong D.
      • Zhang W.
      • Lu Y.
      • Li K.
      • Gao X.
      • Fu B.
      • Liu L.
      • Ma X.
      • Weng J.
      • Wei H.
      • Jin T.
      • Lin J.
      • Qu K.
      Single-cell analysis of severe COVID-19 patients reveals a monocyte-driven inflammatory storm attenuated by tocilizumab.
      Akin to lung macrophages, inflammatory monocytes in the peripheral blood showed an enrichment of genes encoding cytokine signaling and inflammation characteristic of classic M1 macrophages.
      • Wen W.
      • Su W.
      • Tang H.
      • Le W.
      • Zhang X.
      • Zheng Y.
      • Liu X.
      • Xie L.
      • Li J.
      • Ye J.
      • Dong L.
      • Cui X.
      • Miao Y.
      • Wang D.
      • Dong J.
      • Xiao C.
      • Chen W.
      • Wang H.
      Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing.
      The scRNA-seq analysis additionally suggested that cytokine activation drives the systemic expansion of monocyte populations in the peripheral blood of COVID-19 patients.
      • Wen W.
      • Su W.
      • Tang H.
      • Le W.
      • Zhang X.
      • Zheng Y.
      • Liu X.
      • Xie L.
      • Li J.
      • Ye J.
      • Dong L.
      • Cui X.
      • Miao Y.
      • Wang D.
      • Dong J.
      • Xiao C.
      • Chen W.
      • Wang H.
      Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing.
      ,
      • Guo C.
      • Li B.
      • Ma H.
      • Wang X.
      • Cai P.
      • Yu Q.
      • Zhu L.
      • Jin L.
      • Jiang C.
      • Fang J.
      • Liu Q.
      • Zong D.
      • Zhang W.
      • Lu Y.
      • Li K.
      • Gao X.
      • Fu B.
      • Liu L.
      • Ma X.
      • Weng J.
      • Wei H.
      • Jin T.
      • Lin J.
      • Qu K.
      Single-cell analysis of severe COVID-19 patients reveals a monocyte-driven inflammatory storm attenuated by tocilizumab.
      Hence, the cytokine environment likely generated by type 2 pneumocytes and resident alveolar macrophages after SARS-CoV-2 infection triggered the expansion and recruitment of inflammatory monocytes to the lung.
      Pathologic stimulation of TLR/IL-1R signaling represents a significant mechanism activating inflammatory monocytes and macrophages in COVID-19. It has been shown that after TLR/IL-1R stimulation, Bruton tyrosine kinase (BTK) drives the signaling cascade that activates both NF-κB and nucleotide-binding oligomerization domain-containing protein–like receptor protein (NLRP)-3 inflammasome secretion of IL-1β.
      • Yap J.K.Y.
      • Moriyama M.
      • Iwasaki A.
      Inflammasomes and pyroptosis as therapeutic targets for COVID-19.
      ,
      • Page T.H.
      • Urbaniak A.M.
      • Espirito Santo A.I.
      • Danks L.
      • Smallie T.
      • Williams L.M.
      • Horwood N.J.
      Bruton's tyrosine kinase regulates TLR7/8-induced TNF transcription via nuclear factor-[kappa]B recruitment.
      • Ito M.
      • Shichita T.
      • Okada M.
      • Komine R.
      • Noguchi Y.
      • Yoshimura A.
      • Morita R.
      Bruton's tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury.
      • Bittner Z.A.
      • Liu X.
      • Dickhöfer S.
      • Kalbacher H.
      • Bosch K.
      • Andreeva L.
      • Marcu A.
      • Stevanovic S.
      • Mangan M.
      • Düwell P.
      • Lovotti M.
      • Herster F.
      • Löffler M.W.
      • Shankar S.
      • Tapia-Abellán A.
      • Wolz O.-O.
      • Schilling N.A.
      • Kümmerle-Deschner J.
      • Wagner S.
      • Delor A.
      • Grimbacher B.
      • Wu H.
      • Latz E.
      • Weber A.N.R.
      BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity.
      Accordingly, recent data showed increased phosphorylation of BTK in IL-6+CD14+ monocytes derived from patients with severe COVID-19.
      • Roschewski M.
      • Lionakis M.S.
      • Sharman J.P.
      • Roswarski J.
      • Goy A.
      • Monticelli M.A.
      • Roshon M.
      • Wrzesinski S.H.
      • Desai J.V.
      • Zarakas M.A.
      • Collen J.
      • Rose K.M.
      • Hamdy A.
      • Izumi R.
      • Wright G.W.
      • Chung K.K.
      • Baselga J.
      • Staudt L.M.
      • Wilson W.H.
      Inhibition of Bruton tyrosine kinase in patients with severe COVID-19.
      The entire population of monocytes had phosphorylated BTK,
      • Roschewski M.
      • Lionakis M.S.
      • Sharman J.P.
      • Roswarski J.
      • Goy A.
      • Monticelli M.A.
      • Roshon M.
      • Wrzesinski S.H.
      • Desai J.V.
      • Zarakas M.A.
      • Collen J.
      • Rose K.M.
      • Hamdy A.
      • Izumi R.
      • Wright G.W.
      • Chung K.K.
      • Baselga J.
      • Staudt L.M.
      • Wilson W.H.
      Inhibition of Bruton tyrosine kinase in patients with severe COVID-19.
      consistent with the notion of systemic monocytic activation. Transcriptomic profiling of whole blood and single monocytes revealed similar findings. Patients with severe COVID-19 had increased expression of TLR and IL1R and downstream signaling molecules (ie, MYD88, IRAK4, IRAK1, TRAF6, and RELA/p65).
      • Wen W.
      • Su W.
      • Tang H.
      • Le W.
      • Zhang X.
      • Zheng Y.
      • Liu X.
      • Xie L.
      • Li J.
      • Ye J.
      • Dong L.
      • Cui X.
      • Miao Y.
      • Wang D.
      • Dong J.
      • Xiao C.
      • Chen W.
      • Wang H.
      Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing.
      ,
      • Ong E.Z.
      • Chan Y.F.Z.
      • Leong W.Y.
      • Lee N.M.Y.
      • Kalimuddin S.
      • Haja Mohideen S.M.
      • Chan K.S.
      • Tan A.T.
      • Bertoletti A.
      • Ooi E.E.
      • Low J.G.H.
      A dynamic immune response shapes COVID-19 progression.
      The expression of these signaling molecules also tracked with disease severity in one patient with longitudinal samples.
      • Ong E.Z.
      • Chan Y.F.Z.
      • Leong W.Y.
      • Lee N.M.Y.
      • Kalimuddin S.
      • Haja Mohideen S.M.
      • Chan K.S.
      • Tan A.T.
      • Bertoletti A.
      • Ooi E.E.
      • Low J.G.H.
      A dynamic immune response shapes COVID-19 progression.
      Myeloid differentiation primary response protein 88 (MyD88) is an adaptor protein that triggers BTK activation and mediates signaling for IL-1, IL-18, and all TLRs except TLR3.
      • Akira S.
      • Uematsu S.
      • Takeuchi O.
      Pathogen recognition and innate immunity.
      MyD88−/− mice infected with SARS-CoV-1 exhibited decreased lung pathology and cytokine levels as well as impaired monocyte recruitment to the lung versus MyD88WT/WT mice.
      • Sheahan T.
      • Morrison T.E.
      • Funkhouser W.
      • Uematsu S.
      • Akira S.
      • Baric R.S.
      • Heise M.T.
      MyD88 is required for protection from lethal infection with a mouse-adapted SARS-CoV.
      Likewise, in a small cohort of severe COVID-19 patients, treatment with a BTK inhibitor normalized C-reactive protein and IL-6 levels and improved oxygenation.
      • Roschewski M.
      • Lionakis M.S.
      • Sharman J.P.
      • Roswarski J.
      • Goy A.
      • Monticelli M.A.
      • Roshon M.
      • Wrzesinski S.H.
      • Desai J.V.
      • Zarakas M.A.
      • Collen J.
      • Rose K.M.
      • Hamdy A.
      • Izumi R.
      • Wright G.W.
      • Chung K.K.
      • Baselga J.
      • Staudt L.M.
      • Wilson W.H.
      Inhibition of Bruton tyrosine kinase in patients with severe COVID-19.
      The findings from these studies indicate that targeting the TLR/IL-1R signaling cascade may attenuate the hyperinflammatory response in severe COVID-19.

      Impaired Natural Killer Cell Response

      Studies have shown that peripheral natural killer (NK) cells are depleted and exhibit an exhausted phenotype in patients with severe COVID-19. Peripheral NK cell counts were significantly lower in COVID-19 patients with severe disease versus those in patients with mild disease or in healthy controls.
      • Wen W.
      • Su W.
      • Tang H.
      • Le W.
      • Zhang X.
      • Zheng Y.
      • Liu X.
      • Xie L.
      • Li J.
      • Ye J.
      • Dong L.
      • Cui X.
      • Miao Y.
      • Wang D.
      • Dong J.
      • Xiao C.
      • Chen W.
      • Wang H.
      Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing.
      ,
      • Wilk A.J.
      • Rustagi A.
      • Zhao N.Q.
      • Roque J.
      • Martínez-Colón G.J.
      • McKechnie J.L.
      • Ivison G.T.
      • Ranganath T.
      • Vergara R.
      • Hollis T.
      • Simpson L.J.
      • Grant P.
      • Subramanian A.
      • Rogers A.J.
      • Blish C.A.
      A single-cell atlas of the peripheral immune response in patients with severe COVID-19.
      • Zheng M.
      • Gao Y.
      • Wang G.
      • Song G.
      • Liu S.
      • Sun D.
      • Xu Y.
      • Tian Z.
      Functional exhaustion of antiviral lymphocytes in COVID-19 patients.
      • Wang F.
      • Nie J.
      • Wang H.
      • Zhao Q.
      • Xiong Y.
      • Deng L.
      • Song S.
      • Ma Z.
      • Mo P.
      • Zhang Y.
      Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia.
      • Giamarellos-Bourboulis E.J.
      • Netea M.G.
      • Rovina N.
      • Akinosoglou K.
      • Antoniadou A.
      • Antonakos N.
      • Damoraki G.
      • Gkavogianni T.
      • Adami M.-E.
      • Katsaounou P.
      • Ntaganou M.
      • Kyriakopoulou M.
      • Dimopoulos G.
      • Koutsodimitropoulos I.
      • Velissaris D.
      • Koufargyris P.
      • Karageorgos A.
      • Katrini K.
      • Lekakis V.
      • Lupse M.
      • Kotsaki A.
      • Renieris G.
      • Theodoulou D.
      • Panou V.
      • Koukaki E.
      • Koulouris N.
      • Gogos C.
      • Koutsoukou A.
      Complex immune dysregulation in COVID-19 patients with severe respiratory failure.
      Whereas antiviral cytotoxic CD56dim NK cells were primarily depleted in ventilator-dependent patients, all COVID-19 patients had decreased cytokine-producing CD56high NK cells peripherally.
      • Wilk A.J.
      • Rustagi A.
      • Zhao N.Q.
      • Roque J.
      • Martínez-Colón G.J.
      • McKechnie J.L.
      • Ivison G.T.
      • Ranganath T.
      • Vergara R.
      • Hollis T.
      • Simpson L.J.
      • Grant P.
      • Subramanian A.
      • Rogers A.J.
      • Blish C.A.
      A single-cell atlas of the peripheral immune response in patients with severe COVID-19.
      The uniform reduction of CD56high NK cells suggests that peripheral NK cells do not directly contribute cytokines toward the cytokine storm in COVID-19. The percentage of peripheral NK cells expressing the activation markers CD16, CD107a, IFN-γ, IL-2, and TNF-α was also significantly lower in COVID-19 patients compared to healthy controls, as was the mean fluorescence intensity of cytotoxic granzyme B.
      • Zheng M.
      • Gao Y.
      • Wang G.
      • Song G.
      • Liu S.
      • Sun D.
      • Xu Y.
      • Tian Z.
      Functional exhaustion of antiviral lymphocytes in COVID-19 patients.
      ,
      • Wang F.
      • Nie J.
      • Wang H.
      • Zhao Q.
      • Xiong Y.
      • Deng L.
      • Song S.
      • Ma Z.
      • Mo P.
      • Zhang Y.
      Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia.
      scRNA-seq revealed evidence of exhausted NK cells with increased transcription of the inhibitory receptor genes LAG3, PDCD1, and HAVCR2.
      • Wilk A.J.
      • Rustagi A.
      • Zhao N.Q.
      • Roque J.
      • Martínez-Colón G.J.
      • McKechnie J.L.
      • Ivison G.T.
      • Ranganath T.
      • Vergara R.
      • Hollis T.
      • Simpson L.J.
      • Grant P.
      • Subramanian A.
      • Rogers A.J.
      • Blish C.A.
      A single-cell atlas of the peripheral immune response in patients with severe COVID-19.
      Both NK and CD8+ T cells also had increased expression of the immune checkpoint natural killer group 2 member A (NKG2A), which inhibits cell cytotoxicity.
      • Zheng M.
      • Gao Y.
      • Wang G.
      • Song G.
      • Liu S.
      • Sun D.
      • Xu Y.
      • Tian Z.
      Functional exhaustion of antiviral lymphocytes in COVID-19 patients.
      The successful treatment of COVID-19 is associated with the reversal of functional NK cell exhaustion, as evidenced by the down-regulation of NKG2A in the convalescent period.
      • Zheng M.
      • Gao Y.
      • Wang G.
      • Song G.
      • Liu S.
      • Sun D.
      • Xu Y.
      • Tian Z.
      Functional exhaustion of antiviral lymphocytes in COVID-19 patients.
      It remains unclear whether the peripheral NK cell depletion is due to the trafficking of cells to infected lung tissue or cell death. A study employing bulk RNA-seq analyzed the immune composition of BALF from COVID-19 patients collected a median of 8 days after symptom onset.
      • Zhou Z.
      • Ren L.
      • Zhang L.
      • Zhong J.
      • Xiao Y.
      • Jia Z.
      • Guo L.
      • Yang J.
      • Wang C.
      • Jiang S.
      • Yang D.
      • Zhang G.
      • Li H.
      • Chen F.
      • Xu Y.
      • Chen M.
      • Gao Z.
      • Yang J.
      • Dong J.
      • Liu B.
      • Zhang X.
      • Wang W.
      • He K.
      • Jin Q.
      • Li M.
      • Wang J.
      Heightened innate immune responses in the respiratory tract of COVID-19 patients.
      The results demonstrated no change in the proportion of activated NK cells, while COVID-19 patients had a decreased proportion of resting NK cells in BALF versus healthy controls.
      • Zhou Z.
      • Ren L.
      • Zhang L.
      • Zhong J.
      • Xiao Y.
      • Jia Z.
      • Guo L.
      • Yang J.
      • Wang C.
      • Jiang S.
      • Yang D.
      • Zhang G.
      • Li H.
      • Chen F.
      • Xu Y.
      • Chen M.
      • Gao Z.
      • Yang J.
      • Dong J.
      • Liu B.
      • Zhang X.
      • Wang W.
      • He K.
      • Jin Q.
      • Li M.
      • Wang J.
      Heightened innate immune responses in the respiratory tract of COVID-19 patients.
      Conversely, a study using scRNA-seq of BALF collected a median of 12 days after symptom onset reported increased NK cells in COVID-19 patients.
      • Liao M.
      • Liu Y.
      • Yuan J.
      • Wen Y.
      • Xu G.
      • Zhao J.
      • Cheng L.
      • Li J.
      • Wang X.
      • Wang F.
      • Liu L.
      • Amit I.
      • Zhang S.
      • Zhang Z.
      Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19.
      The discrepant findings between studies could have been attributed to the timing differences in BALF sample collection, and suggest that NK cells may be recruited to the lung later in the disease course of COVID-19.
      • McKechnie J.L.
      • Blish C.A.
      The innate immune system: fighting on the front lines or fanning the flames of COVID-19?.
      Trafficking of NK cells is further supported by the expansion of lung macrophages that produce CXCR3 ligands (CXCL9, CXCL10, and CXCL11) in COVID-19.
      • Liao M.
      • Liu Y.
      • Yuan J.
      • Wen Y.
      • Xu G.
      • Zhao J.
      • Cheng L.
      • Li J.
      • Wang X.
      • Wang F.
      • Liu L.
      • Amit I.
      • Zhang S.
      • Zhang Z.
      Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19.
      CXCR3 has been previously shown to promote NK cell recruitment to the lung in influenza infection.
      • Carlin L.E.
      • Hemann E.A.
      • Zacharias Z.R.
      • Heusel J.W.
      • Legge K.L.
      Natural killer cell recruitment to the lung during influenza A virus infection is dependent on CXCR3, CCR5, and virus exposure dose.
      It is possible that cell death may also contribute to peripheral NK-cell depletion, given that the transcription of TP53 and apoptosis pathways in peripheral lymphocytes are up-regulated in COVID-19 patients.
      • Xiong Y.
      • Liu Y.
      • Cao L.
      • Wang D.
      • Guo M.
      • Jiang A.
      • Guo D.
      • Hu W.
      • Yang J.
      • Tang Z.
      • Wu H.
      • Lin Y.
      • Zhang M.
      • Zhang Q.
      • Shi M.
      • Liu Y.
      • Zhou Y.
      • Lan K.
      • Chen Y.
      Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients.
      While the absence of ACE2 receptors makes SARS-CoV-2 infection of NK cells unlikely,
      • Ziegler C.G.K.
      • Allon S.J.
      • Nyquist S.K.
      • Mbano I.M.
      • Miao V.N.
      • Tzouanas C.N.
      • et al.
      HCA Lung Biological Network
      SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues.
      circulating cytokines could play a role, given that peripheral NK-cell counts are inversely correlated with serum IL-6 levels.
      • Wang F.
      • Nie J.
      • Wang H.
      • Zhao Q.
      • Xiong Y.
      • Deng L.
      • Song S.
      • Ma Z.
      • Mo P.
      • Zhang Y.
      Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia.
      Additional studies are nonetheless needed for delineating the processes involved in peripheral NK-cell depletion, including whether the cytokine storm leads to NK-cell apoptosis.
      The cytokine milieu also may confer the exhausted phenotype of peripheral NK cells in COVID-19. In particular, studies have reported that IL-6 and TNF-α impaired the cytolytic function of NK cells.
      • Guo C.
      • Li B.
      • Ma H.
      • Wang X.
      • Cai P.
      • Yu Q.
      • Zhu L.
      • Jin L.
      • Jiang C.
      • Fang J.
      • Liu Q.
      • Zong D.
      • Zhang W.
      • Lu Y.
      • Li K.
      • Gao X.
      • Fu B.
      • Liu L.
      • Ma X.
      • Weng J.
      • Wei H.
      • Jin T.
      • Lin J.
      • Qu K.
      Single-cell analysis of severe COVID-19 patients reveals a monocyte-driven inflammatory storm attenuated by tocilizumab.
      ,
      • Zheng M.
      • Gao Y.
      • Wang G.
      • Song G.
      • Liu S.
      • Sun D.
      • Xu Y.
      • Tian Z.
      Functional exhaustion of antiviral lymphocytes in COVID-19 patients.
      ,
      • Wang F.
      • Nie J.
      • Wang H.
      • Zhao Q.
      • Xiong Y.
      • Deng L.
      • Song S.
      • Ma Z.
      • Mo P.
      • Zhang Y.
      Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia.
      ,
      • Cifaldi L.
      • Prencipe G.
      • Caiello I.
      • Bracaglia C.
      • Locatelli F.
      • De Benedetti F.
      • Strippoli R.
      Inhibition of natural killer cell cytotoxicity by IL-6: implications for the pathogenesis of macrophage activation syndrome.
      • Ivagnès A.
      • Messaoudene M.
      • Stoll G.
      • Routy B.
      • Fluckiger A.
      • Yamazaki T.
      • Iribarren K.
      • Duong C.P.M.
      • Fend L.
      • Caignard A.
      • Cremer I.
      • LeCesne A.
      • Adam J.
      • Honoré C.
      • Mir O.
      • Chaigneau L.
      • Berger A.
      • Validire P.
      • Christidis C.
      • Brun-Ly V.L.
      • Smyth M.J.
      • Mariette X.
      • Salomon B.L.
      • Kroemer G.
      • Rusakiewicz S.
      • Zitvogel L.
      TNFR2/BIRC3-TRAF1 signaling pathway as a novel NK cell immune checkpoint in cancer.
      • Vabret N.
      • Britton G.J.
      • Gruber C.
      • Hegde S.
      • Kim J.
      • Kuksin M.
      • et al.
      Sinai Immunology Review Project
      Immunology of COVID-19: current state of the science.
      In healthy donor NK cells, in vitro stimulation of the soluble IL-6R by IL-6 reduced the production of perforin and granzyme, which can be reversed by IL-6R antagonism with tocilizumab.
      • Cifaldi L.
      • Prencipe G.
      • Caiello I.
      • Bracaglia C.
      • Locatelli F.
      • De Benedetti F.
      • Strippoli R.
      Inhibition of natural killer cell cytotoxicity by IL-6: implications for the pathogenesis of macrophage activation syndrome.
      These findings suggest that IL-6 might hasten the down-regulation of granzyme expression on NK cells reported in COVID-19.
      • Zheng M.
      • Gao Y.
      • Wang G.
      • Song G.
      • Liu S.
      • Sun D.
      • Xu Y.
      • Tian Z.
      Functional exhaustion of antiviral lymphocytes in COVID-19 patients.
      However, additional experiments are needed for confirming these findings in NK cells derived from COVID-19 patients. The decreased expression of CD16 on NK cells indicates that reduced NK-cell licensing is also likely occurring; CD16 expression was reported to be inversely correlated with serum IL-6 levels in COVID-19 patients.
      • Wang F.
      • Nie J.
      • Wang H.
      • Zhao Q.
      • Xiong Y.
      • Deng L.
      • Song S.
      • Ma Z.
      • Mo P.
      • Zhang Y.
      Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia.
      In addition, ligand-receptor analysis with scRNA-seq of peripheral blood revealed interactions between inflammatory monocytes and NK cells in severe COVID-19.
      • Guo C.
      • Li B.
      • Ma H.
      • Wang X.
      • Cai P.
      • Yu Q.
      • Zhu L.
      • Jin L.
      • Jiang C.
      • Fang J.
      • Liu Q.
      • Zong D.
      • Zhang W.
      • Lu Y.
      • Li K.
      • Gao X.
      • Fu B.
      • Liu L.
      • Ma X.
      • Weng J.
      • Wei H.
      • Jin T.
      • Lin J.
      • Qu K.
      Single-cell analysis of severe COVID-19 patients reveals a monocyte-driven inflammatory storm attenuated by tocilizumab.
      The data showed that TNF-α may interact with its receptor, TNFR1, on NK cells.
      • Guo C.
      • Li B.
      • Ma H.
      • Wang X.
      • Cai P.
      • Yu Q.
      • Zhu L.
      • Jin L.
      • Jiang C.
      • Fang J.
      • Liu Q.
      • Zong D.
      • Zhang W.
      • Lu Y.
      • Li K.
      • Gao X.
      • Fu B.
      • Liu L.
      • Ma X.
      • Weng J.
      • Wei H.
      • Jin T.
      • Lin J.
      • Qu K.
      Single-cell analysis of severe COVID-19 patients reveals a monocyte-driven inflammatory storm attenuated by tocilizumab.
      The impact of this cytokine–receptor interaction in COVID-19 needs investigation, but in the tumor microenvironment it results in the down-regulation of the major NK cell–activating receptor NKp46, especially on CD56high NK cells.
      • Ivagnès A.
      • Messaoudene M.
      • Stoll G.
      • Routy B.
      • Fluckiger A.
      • Yamazaki T.
      • Iribarren K.
      • Duong C.P.M.
      • Fend L.
      • Caignard A.
      • Cremer I.
      • LeCesne A.
      • Adam J.
      • Honoré C.
      • Mir O.
      • Chaigneau L.
      • Berger A.
      • Validire P.
      • Christidis C.
      • Brun-Ly V.L.
      • Smyth M.J.
      • Mariette X.
      • Salomon B.L.
      • Kroemer G.
      • Rusakiewicz S.
      • Zitvogel L.
      TNFR2/BIRC3-TRAF1 signaling pathway as a novel NK cell immune checkpoint in cancer.
      Taken together, these findings suggest that crosstalk with monocytes and macrophages via cytokines might mediate NK-cell dysfunction and impair the clearance of SARS-CoV-2.
      • Vabret N.
      • Britton G.J.
      • Gruber C.
      • Hegde S.
      • Kim J.
      • Kuksin M.
      • et al.
      Sinai Immunology Review Project
      Immunology of COVID-19: current state of the science.
      Persistent infection with SARS-CoV-2 could subsequently exacerbate the proinflammatory feedback loop underlying the cytokine storm in severe COVID-19.

      Role of T Cells in Hyperinflammation

      The occurrence of a profound lymphopenia in patients with COVID-19 is well established. The absolute lymphocyte count is prognostic of disease severity and mortality, with significant reductions in peripheral CD4+ and CD8+ T cells reported in both moderate and severe cases of COVID-19.
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • Zhang L.
      • Fan G.
      • Xu J.
      • Gu X.
      • Cheng Z.
      • Yu T.
      • Xia J.
      • Wei Y.
      • Wu W.
      • Xie X.
      • Yin W.
      • Li H.
      • Liu M.
      • Xiao Y.
      • Gao H.
      • Guo L.
      • Xie J.
      • Wang G.
      • Jiang R.
      • Gao Z.
      • Jin Q.
      • Wang J.
      • Cao B.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • Xiang J.
      • Wang Y.
      • Song B.
      • Gu X.
      • Guan L.
      • Wei Y.
      • Li H.
      • Wu X.
      • Xu J.
      • Tu S.
      • Zhang Y.
      • Chen H.
      • Cao B.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Wu C.
      • Chen X.
      • Cai Y.
      • Xia Ja
      • Zhou X.
      • Xu S.
      • Huang H.
      • Zhang L.
      • Zhou X.
      • Du C.
      • Zhang Y.
      • Song J.
      • Wang S.
      • Chao Y.
      • Yang Z.
      • Xu J.
      • Zhou X.
      • Chen D.
      • Xiong W.
      • Xu L.
      • Zhou F.
      • Jiang J.
      • Bai C.
      • Zheng J.
      • Song Y.
      Risk factors associated with acute respiratory distress syndrome and death in patients with Coronavirus disease 2019 pneumonia in Wuhan, China.
      ,
      • Ruan 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.
      ,
      • Chen G.
      • Wu D.
      • Guo W.
      • Cao Y.
      • Huang D.
      • Wang H.
      • Wang T.
      • Zhang X.
      • Chen H.
      • Yu H.
      • Zhang X.
      • Zhang M.
      • Wu S.
      • Song J.
      • Chen T.
      • Han M.
      • Li S.
      • Luo X.
      • Zhao J.
      • Ning Q.
      Clinical and immunological features of severe and moderate Coronavirus disease 2019.
      ,
      • Zheng M.
      • Gao Y.
      • Wang G.
      • Song G.
      • Liu S.
      • Sun D.
      • Xu Y.
      • Tian Z.
      Functional exhaustion of antiviral lymphocytes in COVID-19 patients.
      ,
      • Giamarellos-Bourboulis E.J.
      • Netea M.G.
      • Rovina N.
      • Akinosoglou K.
      • Antoniadou A.
      • Antonakos N.
      • Damoraki G.
      • Gkavogianni T.
      • Adami M.-E.
      • Katsaounou P.
      • Ntaganou M.
      • Kyriakopoulou M.
      • Dimopoulos G.
      • Koutsodimitropoulos I.
      • Velissaris D.
      • Koufargyris P.
      • Karageorgos A.
      • Katrini K.
      • Lekakis V.
      • Lupse M.
      • Kotsaki A.
      • Renieris G.
      • Theodoulou D.
      • Panou V.
      • Koukaki E.
      • Koulouris N.
      • Gogos C.
      • Koutsoukou A.
      Complex immune dysregulation in COVID-19 patients with severe respiratory failure.
      Serum cytokine levels are inversely correlated with CD4+ and CD8+ T-cell counts, and improved cytokine levels have been associated with the reversal of lymphopenia in the convalescent period of recovered patients.
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • Zhang L.
      • Fan G.
      • Xu J.
      • Gu X.
      • Cheng Z.
      • Yu T.
      • Xia J.
      • Wei Y.
      • Wu W.
      • Xie X.
      • Yin W.
      • Li H.
      • Liu M.
      • Xiao Y.
      • Gao H.
      • Guo L.
      • Xie J.
      • Wang G.
      • Jiang R.
      • Gao Z.
      • Jin Q.
      • Wang J.
      • Cao B.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • Xiang J.
      • Wang Y.
      • Song B.
      • Gu X.
      • Guan L.
      • Wei Y.
      • Li H.
      • Wu X.
      • Xu J.
      • Tu S.
      • Zhang Y.
      • Chen H.
      • Cao B.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Del Valle D.M.
      • Kim-schulze S.
      • Hsin-hui H.
      • Beckmann N.D.
      • Nirenberg S.
      • Wang B.
      • Lavin Y.
      • Swartz T.
      • Madduri D.
      • Stock A.
      • Marron T.
      • Xie H.
      • Patel M.K.
      • van Oekelen O.
      • Rahman A.
      • Kovatch P.
      • Aberg J.
      • Schadt E.
      • Jagannath S.
      • Mazumdar M.
      • Charney A.
      • Firpo-Betancourt A.
      • Mendu D.R.
      • Jhang J.
      • Reich D.
      • Sigel K.
      • Cordon-Cardo C.
      • Feldmann M.
      • Parekh S.
      • Merad M.
      • Gnjatic S.
      An inflammatory cytokine signature helps predict COVID-19 severity and survival.
      ,
      • Zheng M.
      • Gao Y.
      • Wang G.
      • Song G.
      • Liu S.
      • Sun D.
      • Xu Y.
      • Tian Z.
      Functional exhaustion of antiviral lymphocytes in COVID-19 patients.
      ,
      • Giamarellos-Bourboulis E.J.
      • Netea M.G.
      • Rovina N.
      • Akinosoglou K.
      • Antoniadou A.
      • Antonakos N.
      • Damoraki G.
      • Gkavogianni T.
      • Adami M.-E.
      • Katsaounou P.
      • Ntaganou M.
      • Kyriakopoulou M.
      • Dimopoulos G.
      • Koutsodimitropoulos I.
      • Velissaris D.
      • Koufargyris P.
      • Karageorgos A.
      • Katrini K.
      • Lekakis V.
      • Lupse M.
      • Kotsaki A.
      • Renieris G.
      • Theodoulou D.
      • Panou V.
      • Koukaki E.
      • Koulouris N.
      • Gogos C.
      • Koutsoukou A.
      Complex immune dysregulation in COVID-19 patients with severe respiratory failure.
      In decedents who had lymphopenia, autopsy evaluations have revealed the extensive cell death of lymphocytes in the lymph nodes and spleen; SARS-CoV-2–infected spleens and lymph nodes also were found to have overexpressed the apoptotic protein Fas.
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • Ahuja S.
      • Beasley M.B.
      • Albrecht R.
      • et al.
      Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience.
      ,
      • Chen Y.
      • Feng Z.
      • Diao B.
      • Wang R.
      • Wang G.
      • Wang C.
      • Tan Y.
      • Liu L.
      • Wang C.
      • Liu Y.
      • Liu Y.
      • Yuan Z.
      • Ren L.
      • Wu Y.
      The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly decimates human spleens and lymph nodes.
      Likewise, transcriptomic analysis identified up-regulation of apoptotic pathways in lymphocytes from the peripheral blood of COVID-19 patients.
      • Xiong Y.
      • Liu Y.
      • Cao L.
      • Wang D.
      • Guo M.
      • Jiang A.
      • Guo D.
      • Hu W.
      • Yang J.
      • Tang Z.
      • Wu H.
      • Lin Y.
      • Zhang M.
      • Zhang Q.
      • Shi M.
      • Liu Y.
      • Zhou Y.
      • Lan K.
      • Chen Y.
      Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients.
      Hemophagocytic macrophages present in the spleen and lymph nodes accompanied the lymphocyte depletion,
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • Ahuja S.
      • Beasley M.B.
      • Albrecht R.
      • et al.
      Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience.
      suggesting a role for aberrantly activated macrophages in lymphopenia. These macrophages have been found to express high levels of IL-6, which may promote lymphocyte necrosis and apoptosis.
      • Chen Y.
      • Feng Z.
      • Diao B.
      • Wang R.
      • Wang G.
      • Wang C.
      • Tan Y.
      • Liu L.
      • Wang C.
      • Liu Y.
      • Liu Y.
      • Yuan Z.
      • Ren L.
      • Wu Y.
      The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly decimates human spleens and lymph nodes.
      Indeed, antagonism of the IL-6R with tocilizumab resulted in increased peripheral lymphocyte counts in COVID-19.
      • Giamarellos-Bourboulis E.J.
      • Netea M.G.
      • Rovina N.
      • Akinosoglou K.
      • Antoniadou A.
      • Antonakos N.
      • Damoraki G.
      • Gkavogianni T.
      • Adami M.-E.
      • Katsaounou P.
      • Ntaganou M.
      • Kyriakopoulou M.
      • Dimopoulos G.
      • Koutsodimitropoulos I.
      • Velissaris D.
      • Koufargyris P.
      • Karageorgos A.
      • Katrini K.
      • Lekakis V.
      • Lupse M.
      • Kotsaki A.
      • Renieris G.
      • Theodoulou D.
      • Panou V.
      • Koukaki E.
      • Koulouris N.
      • Gogos C.
      • Koutsoukou A.
      Complex immune dysregulation in COVID-19 patients with severe respiratory failure.
      Trafficking of peripheral T cells to the lung also likely contributes to the lymphopenia. As previously discussed (Initial Pathologic Findings), autopsy studies have reported a pulmonary lymphocytic interstitial infiltrate with CD4+ and CD8+ T cells,
      • Xu Z.
      • Shi L.
      • Wang Y.
      • Zhang J.
      • Huang L.
      • Zhang C.
      • Liu S.
      • Zhao P.
      • Liu H.
      • Zhu L.
      • Tai Y.
      • Bai C.
      • Gao T.
      • Song J.
      • Xia P.
      • Dong J.
      • Zhao J.
      • Wang F.-S.
      Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
      • Fox S.E.
      • Akmatbekov A.
      • Harbert J.L.
      • Li G.
      • Quincy Brown J.
      • Vander Heide R.S.
      Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.
      • Carsana L.
      • Sonzogni A.
      • Nasr A.
      • Rossi R.S.
      • Pellegrinelli A.
      • Zerbi P.
      • Rech R.
      • Colombo R.
      • Antinori S.
      • Corbellino M.
      • Galli M.
      • Catena E.
      • Tosoni A.
      • Gianatti A.
      • Nebuloni M.
      Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study.
      • Bryce C.
      • Grimes Z.
      • Pujadas E.
      • Ahuja S.
      • Beasley M.B.
      • Albrecht R.
      • et al.
      Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience.
      and scRNA-seq of BALF identified a heterogeneous expansion of CD8+ T cells.
      • Liao M.
      • Liu Y.
      • Yuan J.
      • Wen Y.
      • Xu G.
      • Zhao J.
      • Cheng L.
      • Li J.
      • Wang X.
      • Wang F.
      • Liu L.
      • Amit I.
      • Zhang S.
      • Zhang Z.
      Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19.
      Additional studies are needed for clarifying the mechanism and functional impact of lymphopenia, such as on the clearance of SARS-CoV-2.
      The T-cell composition of surviving lymphocytes may exacerbate the hyperinflammatory state in COVID-19. In conjunction with IL-6– and GM-CSF–producing monocytes, patients with severe COVID-19 have been found to have increased proportions of pathogenic Th1 CD4+ T cells that express IL-6, GM-CSF, and IFN-γ.
      • Zheng M.
      • Gao Y.
      • Wang G.
      • Song G.
      • Liu S.
      • Sun D.
      • Xu Y.
      • Tian Z.
      Functional exhaustion of antiviral lymphocytes in COVID-19 patients.
      In particular, patients requiring intensive care unit admission had significantly higher proportions of Th1 cells co-expressing GM-CSF and IFN-γ.
      • Zheng M.
      • Gao Y.
      • Wang G.
      • Song G.
      • Liu S.
      • Sun D.
      • Xu Y.
      • Tian Z.
      Functional exhaustion of antiviral lymphocytes in COVID-19 patients.
      These Th1 cells can produce proinflammatory cytokines that contribute to the cytokine storm and migrate to the lung to potentiate tissue damage. Zheng et al
      • Zheng M.
      • Gao Y.
      • Wang G.
      • Song G.
      • Liu S.
      • Sun D.
      • Xu Y.
      • Tian Z.
      Functional exhaustion of antiviral lymphocytes in COVID-19 patients.
      postulated that GM-CSF links the activation of inflammatory monocytes and Th1 cells in severe cases. Moreover, flow cytometry has revealed decreased levels of immunosuppressive T-regulatory cells in patients with severe COVID-19.
      • Chen G.
      • Wu D.
      • Guo W.
      • Cao Y.
      • Huang D.
      • Wang H.
      • Wang T.
      • Zhang X.
      • Chen H.
      • Yu H.
      • Zhang X.
      • Zhang M.
      • Wu S.
      • Song J.
      • Chen T.
      • Han M.
      • Li S.
      • Luo X.
      • Zhao J.
      • Ning Q.
      Clinical and immunological features of severe and moderate Coronavirus disease 2019.
      scRNA-seq of peripheral blood similarly identified depleted T-regulatory cells, as well as up-regulated inflammatory and cytokine pathways in CD4+ T cells.
      • Wen W.
      • Su W.
      • Tang H.
      • Le W.
      • Zhang X.
      • Zheng Y.
      • Liu X.
      • Xie L.
      • Li J.
      • Ye J.
      • Dong L.
      • Cui X.
      • Miao Y.
      • Wang D.
      • Dong J.
      • Xiao C.
      • Chen W.
      • Wang H.
      Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing.
      These findings collectively suggest that the reduction in T-regulatory cells disrupts immune homeostasis and promotes a central role for CD4+ Th1 cells in the pathogenesis of COVID-19–related hyperinflammation.

      Neutrophils and Neutrophil Extracellular Traps

      Increasing evidence indicates that the dysregulated myeloid response to SARS-CoV-2 extends to neutrophils in severe COVID-19. An elevated absolute neutrophil count and neutrophil/lymphocyte ratio have been reported to be prognostic of ARDS and death in COVID-19.
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • Zhang L.
      • Fan G.
      • Xu J.
      • Gu X.
      • Cheng Z.
      • Yu T.
      • Xia J.
      • Wei Y.
      • Wu W.
      • Xie X.
      • Yin W.
      • Li H.
      • Liu M.
      • Xiao Y.
      • Gao H.
      • Guo L.
      • Xie J.
      • Wang G.
      • Jiang R.
      • Gao Z.
      • Jin Q.
      • Wang J.
      • Cao B.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • Xiang J.
      • Wang Y.
      • Song B.
      • Gu X.
      • Guan L.
      • Wei Y.
      • Li H.
      • Wu X.
      • Xu J.
      • Tu S.
      • Zhang Y.
      • Chen H.
      • Cao B.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ,
      • Wu C.
      • Chen X.
      • Cai Y.
      • Xia Ja
      • Zhou X.
      • Xu S.
      • Huang H.
      • Zhang L.
      • Zhou X.
      • Du C.
      • Zhang Y.
      • Song J.
      • Wang S.
      • Chao Y.
      • Yang Z.
      • Xu J.
      • Zhou X.
      • Chen D.
      • Xiong W.
      • Xu L.
      • Zhou F.
      • Jiang J.
      • Bai C.
      • Zheng J.
      • Song Y.
      Risk factors associated with acute respiratory distress syndrome and death in patients with Coronavirus disease 2019 pneumonia in Wuhan, China.
      ,
      • Ruan 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.
      ,
      • Del Valle D.M.
      • Kim-schulze S.
      • Hsin-hui H.
      • Beckmann N.D.
      • Nirenberg S.
      • Wang B.
      • Lavin Y.
      • Swartz T.
      • Madduri D.
      • Stock A.
      • Marron T.
      • Xie H.
      • Patel M.K.
      • van Oekelen O.
      • Rahman A.
      • Kovatch P.
      • Aberg J.
      • Schadt E.
      • Jagannath S.
      • Mazumdar M.
      • Charney A.
      • Firpo-Betancourt A.
      • Mendu D.R.
      • Jhang J.
      • Reich D.
      • Sigel K.
      • Cordon-Cardo C.
      • Feldmann M.
      • Parekh S.
      • Merad M.
      • Gnjatic S.
      An inflammatory cytokine signature helps predict COVID-19 severity and survival.
      ,
      • Chen G.
      • Wu D.
      • Guo W.
      • Cao Y.
      • Huang D.
      • Wang H.
      • Wang T.
      • Zhang X.
      • Chen H.
      • Yu H.
      • Zhang X.
      • Zhang M.
      • Wu S.
      • Song J.
      • Chen T.
      • Han M.
      • Li S.
      • Luo X.
      • Zhao J.
      • Ning Q.
      Clinical and immunological features of severe and moderate Coronavirus disease 2019.
      Patients with severe COVID-19 also had increased levels of neutrophil extracellular traps (NETs),
      • Middleton E.A.
      • He X.-Y.
      • Denorme F.
      • Campbell R.A.
      • Ng D.
      • Salvatore S.P.
      • Mostyka M.
      • Baxter-Stoltzfus A.
      • Borczuk A.C.
      • Loda M.
      • Cody M.J.
      • Manne B.K.
      • Portier I.
      • Harris E.
      • Petrey A.C.
      • Beswick E.J.
      • Caulin A.F.
      • Iovino A.
      • Abegglen L.M.
      • Weyrich A.S.
      • Rondina M.T.
      • Egeblad M.
      • Schiffman J.D.
      • Yost C.C.
      Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome.
      ,
      • Zuo Y.
      • Yalavarthi S.
      • Shi H.
      • Gockman K.
      • Zuo M.
      • Madison J.A.
      • Blair C.
      • Weber A.
      • Barnes B.J.
      • Egeblad M.
      • Woods R.J.
      • Kanthi Y.
      • Knight J.S.
      Neutrophil extracellular traps in COVID-19.
      which are webs of DNA material with antimicrobials and oxidant enzymes extruded by neutrophils to control infections. Serum samples collected from patients hospitalized with COVID-19 had higher levels of cell-free DNA, myeloperoxidase (MPO)–DNA complexes, and citrullinated histone H3 (Cit-H3) compared to those from patients with mild/moderate disease and healthy controls
      • Middleton E.A.
      • He X.-Y.
      • Denorme F.
      • Campbell R.A.
      • Ng D.
      • Salvatore S.P.
      • Mostyka M.
      • Baxter-Stoltzfus A.
      • Borczuk A.C.
      • Loda M.
      • Cody M.J.
      • Manne B.K.
      • Portier I.
      • Harris E.
      • Petrey A.C.
      • Beswick E.J.
      • Caulin A.F.
      • Iovino A.
      • Abegglen L.M.
      • Weyrich A.S.
      • Rondina M.T.
      • Egeblad M.
      • Schiffman J.D.
      • Yost C.C.
      Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome.
      ,
      • Zuo Y.
      • Yalavarthi S.
      • Shi H.
      • Gockman K.
      • Zuo M.
      • Madison J.A.
      • Blair C.
      • Weber A.
      • Barnes B.J.
      • Egeblad M.
      • Woods R.J.
      • Kanthi Y.
      • Knight J.S.
      Neutrophil extracellular traps in COVID-19.
      ; the latter two markers are considered specific for NET remnants. Elevated plasma MPO–DNA complexes have been associated with a decreased PaO2/FiO2 ratio, a need for mechanical ventilation, and death in COVID-19.
      • Middleton E.A.
      • He X.-Y.
      • Denorme F.
      • Campbell R.A.
      • Ng D.
      • Salvatore S.P.
      • Mostyka M.
      • Baxter-Stoltzfus A.
      • Borczuk A.C.
      • Loda M.
      • Cody M.J.
      • Manne B.K.
      • Portier I.
      • Harris E.
      • Petrey A.C.
      • Beswick E.J.
      • Caulin A.F.
      • Iovino A.
      • Abegglen L.M.
      • Weyrich A.S.
      • Rondina M.T.
      • Egeblad M.
      • Schiffman J.D.
      • Yost C.C.
      Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome.
      ,
      • Zuo Y.
      • Yalavarthi S.
      • Shi H.
      • Gockman K.
      • Zuo M.
      • Madison J.A.
      • Blair C.
      • Weber A.
      • Barnes B.J.
      • Egeblad M.
      • Woods R.J.
      • Kanthi Y.
      • Knight J.S.
      Neutrophil extracellular traps in COVID-19.
      Increasing levels of MPO–DNA complexes also tracked with oxygen deterioration in patients with longitudinal samples.
      • Zuo Y.
      • Yalavarthi S.
      • Shi H.
      • Gockman K.
      • Zuo M.
      • Madison J.A.
      • Blair C.
      • Weber A.
      • Barnes B.J.
      • Egeblad M.
      • Woods R.J.
      • Kanthi Y.
      • Knight J.S.
      Neutrophil extracellular traps in COVID-19.
      The milieu of patients with COVID-19 appears to promote the formation of NETs, as the exposure of healthy neutrophils to serum collected from hospitalized COVID-19 patients has been reported to trigger significant NETosis.
      • Middleton E.A.
      • He X.-Y.
      • Denorme F.
      • Campbell R.A.
      • Ng D.
      • Salvatore S.P.
      • Mostyka M.
      • Baxter-Stoltzfus A.
      • Borczuk A.C.
      • Loda M.
      • Cody M.J.
      • Manne B.K.
      • Portier I.
      • Harris E.
      • Petrey A.C.
      • Beswick E.J.
      • Caulin A.F.
      • Iovino A.
      • Abegglen L.M.
      • Weyrich A.S.
      • Rondina M.T.
      • Egeblad M.
      • Schiffman J.D.
      • Yost C.C.
      Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome.
      ,
      • Zuo Y.
      • Yalavarthi S.
      • Shi H.
      • Gockman K.
      • Zuo M.
      • Madison J.A.
      • Blair C.
      • Weber A.
      • Barnes B.J.
      • Egeblad M.
      • Woods R.J.
      • Kanthi Y.
      • Knight J.S.
      Neutrophil extracellular traps in COVID-19.
      Further work is needed for delineating the mechanism of NET formation in COVID-19, but the activation of neutrophils by viral nucleic acids and cytokines might have a role.
      • Middleton E.A.
      • He X.-Y.
      • Denorme F.
      • Campbell R.A.
      • Ng D.
      • Salvatore S.P.
      • Mostyka M.
      • Baxter-Stoltzfus A.
      • Borczuk A.C.
      • Loda M.
      • Cody M.J.
      • Manne B.K.
      • Portier I.
      • Harris E.
      • Petrey A.C.
      • Beswick E.J.
      • Caulin A.F.
      • Iovino A.
      • Abegglen L.M.
      • Weyrich A.S.
      • Rondina M.T.
      • Egeblad M.
      • Schiffman J.D.
      • Yost C.C.
      Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome.
      • Zuo Y.
      • Yalavarthi S.
      • Shi H.
      • Gockman K.
      • Zuo M.
      • Madison J.A.
      • Blair C.
      • Weber A.
      • Barnes B.J.
      • Egeblad M.
      • Woods R.J.
      • Kanthi Y.
      • Knight J.S.
      Neutrophil extracellular traps in COVID-19.
      • Barnes B.J.
      • Adrover J.M.
      • Baxter-Stoltzfus A.
      • Borczuk A.
      • Cools-Lartigue J.
      • Crawford J.M.
      • Daßler-Plenker J.
      • Guerci P.
      • Huynh C.
      • Knight J.S.
      • Loda M.
      • Looney M.R.
      • McAllister F.
      • Rayes R.
      • Renaud S.
      • Rousseau S.
      • Salvatore S.
      • Schwartz R.E.
      • Spicer J.D.
      • Yost C.C.
      • Weber A.
      • Zuo Y.
      • Egeblad M.
      Targeting potential drivers of COVID-19: neutrophil extracellular traps.
      Importantly, NETs may contribute to the development of lung injury and microthrombi in COVID-19. Dysregulated NETosis has been previously shown to cause excessive lung injury and immunothrombosis in response to other respiratory viruses and bacteria.
      • Porto B.N.
      • Stein R.T.
      Neutrophil extracellular traps in pulmonary diseases: too much of a good thing?.
      A recent study that evaluated autopsy lung specimens for NETs reported pathologic evidence suggestive of dysregulated NETosis in COVID-19.
      • Middleton E.A.
      • He X.-Y.
      • Denorme F.
      • Campbell R.A.
      • Ng D.
      • Salvatore S.P.
      • Mostyka M.
      • Baxter-Stoltzfus A.
      • Borczuk A.C.
      • Loda M.
      • Cody M.J.
      • Manne B.K.
      • Portier I.
      • Harris E.
      • Petrey A.C.
      • Beswick E.J.
      • Caulin A.F.
      • Iovino A.
      • Abegglen L.M.
      • Weyrich A.S.
      • Rondina M.T.
      • Egeblad M.
      • Schiffman J.D.
      • Yost C.C.
      Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome.
      Immunofluorescence revealed a neutrophilic infiltrate in the lungs, with numerous Cit-H3+ and MPO+ neutrophils as well as lattices of extracellular DNA with Cit-H3 and MPO.
      • Middleton E.A.
      • He X.-Y.
      • Denorme F.
      • Campbell R.A.
      • Ng D.
      • Salvatore S.P.
      • Mostyka M.
      • Baxter-Stoltzfus A.
      • Borczuk A.C.
      • Loda M.
      • Cody M.J.
      • Manne B.K.
      • Portier I.
      • Harris E.
      • Petrey A.C.
      • Beswick E.J.
      • Caulin A.F.
      • Iovino A.
      • Abegglen L.M.
      • Weyrich A.S.
      • Rondina M.T.
      • Egeblad M.
      • Schiffman J.D.
      • Yost C.C.
      Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome.
      In addition, the study reported the co-localization of Cit-H3+ neutrophils likely undergoing NETosis with platelet factor 4–positive platelets in pulmonary blood vessels,
      • Middleton E.A.
      • He X.-Y.
      • Denorme F.
      • Campbell R.A.
      • Ng D.
      • Salvatore S.P.
      • Mostyka M.
      • Baxter-Stoltzfus A.
      • Borczuk A.C.
      • Loda M.
      • Cody M.J.
      • Manne B.K.
      • Portier I.
      • Harris E.
      • Petrey A.C.
      • Beswick E.J.
      • Caulin A.F.
      • Iovino A.
      • Abegglen L.M.
      • Weyrich A.S.
      • Rondina M.T.
      • Egeblad M.
      • Schiffman J.D.
      • Yost C.C.
      Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome.
      suggesting a possible role of NET and platelet interaction in microthrombi formation in COVID-19. Whether excessive immunothrombosis by NETs triggers platelet aggregation and the prothrombotic state in COVID-19 warrants investigation.

      Multisystem Inflammatory Syndrome in Children

      Recent case series of children have identified a hyperinflammatory vasculopathy associated with COVID-19, deemed the multisystem inflammatory syndrome in children (MIS-C).
      • Feldstein L.R.
      • Rose E.B.
      • Horwitz S.M.
      • Collins J.P.
      • Newhams M.M.
      • Son M.B.F.
      • et al.
      Overcoming COVID-19 Investigators; CDC COVID-19 Response Team: Multisystem inflammatory syndrome in UNITED STATES children and adolescents.
      • Dufort E.M.
      • Koumans E.H.
      • Chow E.J.
      • Rosenthal E.M.
      • Muse A.
      • Rowlands J.
      • Barranco M.A.
      • Maxted A.M.
      • Rosenberg E.S.
      • Easton D.
      • Udo T.
      • Kumar J.
      • Pulver W.
      • Smith L.
      • Hutton B.
      • Blog D.
      • Zucker H.
      Multisystem inflammatory syndrome in children in New York State.
      • Lee P.Y.
      • Day-Lewis M.
      • Henderson L.A.
      • Friedman K.
      • Lo J.
      • Roberts J.E.
      • Lo M.S.
      • Platt C.D.
      • Chou J.
      • Hoyt K.J.
      • Baker A.L.
      • Banzon T.
      • Chang M.H.
      • Cohen E.
      • de Ferranti S.
      • Dionne A.
      • Habiballah S.
      • Halyabar O.
      • Hausmann J.S.
      • Hazen M.
      • Janssen E.
      • Meidan E.
      • Nelson R.W.
      • Nguyen A.A.
      • Sundel R.P.
      • Dedeoglu F.
      • Nigrovic P.A.
      • Newburger J.W.
      • Son M.B.F.
      Distinct clinical and immunological features of SARS-COV-2-induced multisystem inflammatory syndrome in children.
      • Verdoni L.
      • Mazza A.
      • Gervasoni A.
      • Martelli L.
      • Ruggeri M.
      • Ciuffreda M.
      • Bonanomi E.
      • D'Antiga L.
      An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.
      This syndrome has been reported to have a wide range of clinical presentations that overlap with Kawasaki disease, toxic shock syndrome, and macrophage-activation syndrome/hemophagocytic lymphohistiocytosis. Nearly all patients with MIS-C have presented with fever.
      • Feldstein L.R.
      • Rose E.B.
      • Horwitz S.M.
      • Collins J.P.
      • Newhams M.M.
      • Son M.B.F.
      • et al.
      Overcoming COVID-19 Investigators; CDC COVID-19 Response Team: Multisystem inflammatory syndrome in UNITED STATES children and adolescents.
      • Dufort E.M.
      • Koumans E.H.
      • Chow E.J.
      • Rosenthal E.M.
      • Muse A.
      • Rowlands J.
      • Barranco M.A.
      • Maxted A.M.
      • Rosenberg E.S.
      • Easton D.
      • Udo T.
      • Kumar J.
      • Pulver W.
      • Smith L.
      • Hutton B.
      • Blog D.
      • Zucker H.
      Multisystem inflammatory syndrome in children in New York State.
      • Lee P.Y.
      • Day-Lewis M.
      • Henderson L.A.
      • Friedman K.
      • Lo J.
      • Roberts J.E.
      • Lo M.S.
      • Platt C.D.
      • Chou J.
      • Hoyt K.J.
      • Baker A.L.
      • Banzon T.
      • Chang M.H.
      • Cohen E.
      • de Ferranti S.
      • Dionne A.
      • Habiballah S.
      • Halyabar O.
      • Hausmann J.S.
      • Hazen M.
      • Janssen E.
      • Meidan E.
      • Nelson R.W.
      • Nguyen A.A.
      • Sundel R.P.
      • Dedeoglu F.
      • Nigrovic P.A.
      • Newburger J.W.
      • Son M.B.F.
      Distinct clinical and immunological features of SARS-COV-2-induced multisystem inflammatory syndrome in children.
      • Verdoni L.
      • Mazza A.
      • Gervasoni A.
      • Martelli L.
      • Ruggeri M.
      • Ciuffreda M.
      • Bonanomi E.
      • D'Antiga L.
      An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.
      Multiple organ systems have been reported to be involved in most patients, with the gastrointestinal (92%), cardiovascular (80%), hematologic (76%), mucocutaneous (74%), and respiratory (70%) systems most commonly involved.
      • Feldstein L.R.
      • Rose E.B.
      • Horwitz S.M.
      • Collins J.P.
      • Newhams M.M.
      • Son M.B.F.
      • et al.
      Overcoming COVID-19 Investigators; CDC COVID-19 Response Team: Multisystem inflammatory syndrome in UNITED STATES children and adolescents.
      The majority of patients have required admission to the intensive care unit for treatment.
      • Feldstein L.R.
      • Rose E.B.
      • Horwitz S.M.
      • Collins J.P.
      • Newhams M.M.
      • Son M.B.F.
      • et al.
      Overcoming COVID-19 Investigators; CDC COVID-19 Response Team: Multisystem inflammatory syndrome in UNITED STATES children and adolescents.
      • Dufort E.M.
      • Koumans E.H.
      • Chow E.J.
      • Rosenthal E.M.
      • Muse A.
      • Rowlands J.
      • Barranco M.A.
      • Maxted A.M.
      • Rosenberg E.S.
      • Easton D.
      • Udo T.
      • Kumar J.
      • Pulver W.
      • Smith L.
      • Hutton B.
      • Blog D.
      • Zucker H.
      Multisystem inflammatory syndrome in children in New York State.
      • Lee P.Y.
      • Day-Lewis M.
      • Henderson L.A.
      • Friedman K.
      • Lo J.
      • Roberts J.E.
      • Lo M.S.
      • Platt C.D.
      • Chou J.
      • Hoyt K.J.
      • Baker A.L.
      • Banzon T.
      • Chang M.H.
      • Cohen E.
      • de Ferranti S.
      • Dionne A.
      • Habiballah S.
      • Halyabar O.
      • Hausmann J.S.
      • Hazen M.
      • Janssen E.
      • Meidan E.
      • Nelson R.W.
      • Nguyen A.A.
      • Sundel R.P.
      • Dedeoglu F.
      • Nigrovic P.A.
      • Newburger J.W.
      • Son M.B.F.
      Distinct clinical and immunological features of SARS-COV-2-induced multisystem inflammatory syndrome in children.
      • Verdoni L.
      • Mazza A.
      • Gervasoni A.
      • Martelli L.
      • Ruggeri M.
      • Ciuffreda M.
      • Bonanomi E.
      • D'Antiga L.
      An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.
      Invasive and noninvasive mechanical ventilation for respiratory insufficiency or failure has been needed in 20% and 17% of patients, respectively.
      • Feldstein L.R.
      • Rose E.B.
      • Horwitz S.M.
      • Collins J.P.
      • Newhams M.M.
      • Son M.B.F.
      • et al.
      Overcoming COVID-19 Investigators; CDC COVID-19 Response Team: Multisystem inflammatory syndrome in UNITED STATES children and adolescents.
      The mortality rate from MIS-C has been estimated as approximately 0% to 2%.
      • Feldstein L.R.
      • Rose E.B.
      • Horwitz S.M.
      • Collins J.P.
      • Newhams M.M.
      • Son M.B.F.
      • et al.
      Overcoming COVID-19 Investigators; CDC COVID-19 Response Team: Multisystem inflammatory syndrome in UNITED STATES children and adolescents.
      • Dufort E.M.
      • Koumans E.H.
      • Chow E.J.
      • Rosenthal E.M.
      • Muse A.
      • Rowlands J.
      • Barranco M.A.
      • Maxted A.M.
      • Rosenberg E.S.
      • Easton D.
      • Udo T.
      • Kumar J.
      • Pulver W.
      • Smith L.
      • Hutton B.
      • Blog D.
      • Zucker H.
      Multisystem inflammatory syndrome in children in New York State.
      • Lee P.Y.
      • Day-Lewis M.
      • Henderson L.A.
      • Friedman K.
      • Lo J.
      • Roberts J.E.
      • Lo M.S.
      • Platt C.D.
      • Chou J.
      • Hoyt K.J.
      • Baker A.L.
      • Banzon T.
      • Chang M.H.
      • Cohen E.
      • de Ferranti S.
      • Dionne A.
      • Habiballah S.
      • Halyabar O.
      • Hausmann J.S.
      • Hazen M.
      • Janssen E.
      • Meidan E.
      • Nelson R.W.
      • Nguyen A.A.
      • Sundel R.P.
      • Dedeoglu F.
      • Nigrovic P.A.
      • Newburger J.W.
      • Son M.B.F.
      Distinct clinical and immunological features of SARS-COV-2-induced multisystem inflammatory syndrome in children.
      • Verdoni L.
      • Mazza A.
      • Gervasoni A.
      • Martelli L.
      • Ruggeri M.
      • Ciuffreda M.
      • Bonanomi E.
      • D'Antiga L.
      An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.
      An important finding in MIS-C has been the high incidence of cardiovascular involvement. In reports from the United States and Europe, the majority of patients had elevated brain natriuretic peptide and troponin levels.
      • Feldstein L.R.
      • Rose E.B.
      • Horwitz S.M.
      • Collins J.P.
      • Newhams M.M.
      • Son M.B.F.
      • et al.
      Overcoming COVID-19 Investigators; CDC COVID-19 Response Team: Multisystem inflammatory syndrome in UNITED STATES children and adolescents.
      • Dufort E.M.
      • Koumans E.H.
      • Chow E.J.
      • Rosenthal E.M.
      • Muse A.
      • Rowlands J.
      • Barranco M.A.
      • Maxted A.M.
      • Rosenberg E.S.
      • Easton D.
      • Udo T.
      • Kumar J.
      • Pulver W.
      • Smith L.
      • Hutton B.
      • Blog D.
      • Zucker H.
      Multisystem inflammatory syndrome in children in New York State.
      • Lee P.Y.
      • Day-Lewis M.
      • Henderson L.A.
      • Friedman K.
      • Lo J.
      • Roberts J.E.
      • Lo M.S.
      • Platt C.D.
      • Chou J.
      • Hoyt K.J.
      • Baker A.L.
      • Banzon T.
      • Chang M.H.
      • Cohen E.
      • de Ferranti S.
      • Dionne A.
      • Habiballah S.
      • Halyabar O.
      • Hausmann J.S.
      • Hazen M.
      • Janssen E.
      • Meidan E.
      • Nelson R.W.
      • Nguyen A.A.
      • Sundel R.P.
      • Dedeoglu F.
      • Nigrovic P.A.
      • Newburger J.W.
      • Son M.B.F.
      Distinct clinical and immunological features of SARS-COV-2-induced multisystem inflammatory syndrome in children.
      • Verdoni L.
      • Mazza A.
      • Gervasoni A.
      • Martelli L.
      • Ruggeri M.
      • Ciuffreda M.
      • Bonanomi E.
      • D'Antiga L.
      An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.
      Nearly half of the patients had hypotension or cardiogenic shock, which prompted vasopressor support in one-quarter of patients.
      • Feldstein L.R.
      • Rose E.B.
      • Horwitz S.M.
      • Collins J.P.
      • Newhams M.M.
      • Son M.B.F.
      • et al.
      Overcoming COVID-19 Investigators; CDC COVID-19 Response Team: Multisystem inflammatory syndrome in UNITED STATES children and adolescents.
      • Dufort E.M.
      • Koumans E.H.
      • Chow E.J.
      • Rosenthal E.M.
      • Muse A.
      • Rowlands J.
      • Barranco M.A.
      • Maxted A.M.
      • Rosenberg E.S.
      • Easton D.
      • Udo T.
      • Kumar J.
      • Pulver W.
      • Smith L.
      • Hutton B.
      • Blog D.
      • Zucker H.
      Multisystem inflammatory syndrome in children in New York State.
      • Lee P.Y.
      • Day-Lewis M.
      • Henderson L.A.
      • Friedman K.
      • Lo J.
      • Roberts J.E.
      • Lo M.S.
      • Platt C.D.
      • Chou J.
      • Hoyt K.J.
      • Baker A.L.
      • Banzon T.
      • Chang M.H.
      • Cohen E.
      • de Ferranti S.
      • Dionne A.
      • Habiballah S.
      • Halyabar O.
      • Hausmann J.S.
      • Hazen M.
      • Janssen E.
      • Meidan E.
      • Nelson R.W.
      • Nguyen A.A.
      • Sundel R.P.
      • Dedeoglu F.
      • Nigrovic P.A.
      • Newburger J.W.
      • Son M.B.F.
      Distinct clinical and immunological features of SARS-COV-2-induced multisystem inflammatory syndrome in children.
      • Verdoni L.
      • Mazza A.
      • Gervasoni A.
      • Martelli L.
      • Ruggeri M.
      • Ciuffreda M.
      • Bonanomi E.
      • D'Antiga L.
      An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.
      On echocardiography, ventricular dysfunction (ejection fraction <55%) was identified in approximately half of patients.
      • Feldstein L.R.
      • Rose E.B.
      • Horwitz S.M.
      • Collins J.P.
      • Newhams M.M.
      • Son M.B.F.
      • et al.
      Overcoming COVID-19 Investigators; CDC COVID-19 Response Team: Multisystem inflammatory syndrome in UNITED STATES children and adolescents.
      • Dufort E.M.
      • Koumans E.H.
      • Chow E.J.
      • Rosenthal E.M.
      • Muse A.
      • Rowlands J.
      • Barranco M.A.
      • Maxted A.M.
      • Rosenberg E.S.
      • Easton D.
      • Udo T.
      • Kumar J.
      • Pulver W.
      • Smith L.
      • Hutton B.
      • Blog D.
      • Zucker H.
      Multisystem inflammatory syndrome in children in New York State.
      • Lee P.Y.
      • Day-Lewis M.
      • Henderson L.A.
      • Friedman K.
      • Lo J.
      • Roberts J.E.
      • Lo M.S.
      • Platt C.D.
      • Chou J.
      • Hoyt K.J.
      • Baker A.L.
      • Banzon T.
      • Chang M.H.
      • Cohen E.
      • de Ferranti S.
      • Dionne A.
      • Habiballah S.
      • Halyabar O.
      • Hausmann J.S.
      • Hazen M.
      • Janssen E.
      • Meidan E.
      • Nelson R.W.
      • Nguyen A.A.
      • Sundel R.P.
      • Dedeoglu F.
      • Nigrovic P.A.
      • Newburger J.W.
      • Son M.B.F.
      Distinct clinical and immunological features of SARS-COV-2-induced multisystem inflammatory syndrome in children.
      • Verdoni L.
      • Mazza A.
      • Gervasoni A.
      • Martelli L.
      • Ruggeri M.
      • Ciuffreda M.
      • Bonanomi E.
      • D'Antiga L.
      An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.
      Approximately 8% to 21% of patients also had coronary artery aneurysm identified in either the left descending artery or the right coronary artery, consistent with a Kawasaki-like vasculitis presentation of MIS-C.
      • Feldstein L.R.
      • Rose E.B.
      • Horwitz S.M.
      • Collins J.P.
      • Newhams M.M.
      • Son M.B.F.
      • et al.
      Overcoming COVID-19 Investigators; CDC COVID-19 Response Team: Multisystem inflammatory syndrome in UNITED STATES children and adolescents.
      • Dufort E.M.
      • Koumans E.H.
      • Chow E.J.
      • Rosenthal E.M.
      • Muse A.
      • Rowlands J.
      • Barranco M.A.
      • Maxted A.M.
      • Rosenberg E.S.
      • Easton D.
      • Udo T.
      • Kumar J.
      • Pulver W.
      • Smith L.
      • Hutton B.
      • Blog D.
      • Zucker H.
      Multisystem inflammatory syndrome in children in New York State.
      • Lee P.Y.
      • Day-Lewis M.
      • Henderson L.A.
      • Friedman K.
      • Lo J.
      • Roberts J.E.
      • Lo M.S.
      • Platt C.D.
      • Chou J.
      • Hoyt K.J.
      • Baker A.L.
      • Banzon T.
      • Chang M.H.
      • Cohen E.
      • de Ferranti S.
      • Dionne A.
      • Habiballah S.
      • Halyabar O.
      • Hausmann J.S.
      • Hazen M.
      • Janssen E.
      • Meidan E.
      • Nelson R.W.
      • Nguyen A.A.
      • Sundel R.P.
      • Dedeoglu F.
      • Nigrovic P.A.
      • Newburger J.W.
      • Son M.B.F.
      Distinct clinical and immunological features of SARS-COV-2-induced multisystem inflammatory syndrome in children.
      • Verdoni L.
      • Mazza A.
      • Gervasoni A.
      • Martelli L.
      • Ruggeri M.
      • Ciuffreda M.
      • Bonanomi E.
      • D'Antiga L.
      An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.
      The immunologic findings in MIS-C have been similar to those described in adults with severe COVID-19. Nearly all MIS-C patients had multiple laboratory markers of inflammation, including an elevated erythrocyte sedimentation rate, C-reactive protein, and ferritin.
      • Feldstein L.R.
      • Rose E.B.
      • Horwitz S.M.
      • Collins J.P.
      • Newhams M.M.
      • Son M.B.F.
      • et al.
      Overcoming COVID-19 Investigators; CDC COVID-19 Response Team: Multisystem inflammatory syndrome in UNITED STATES children and adolescents.
      • Dufort E.M.
      • Koumans E.H.
      • Chow E.J.
      • Rosenthal E.M.
      • Muse A.
      • Rowlands J.
      • Barranco M.A.
      • Maxted A.M.
      • Rosenberg E.S.
      • Easton D.
      • Udo T.
      • Kumar J.
      • Pulver W.
      • Smith L.
      • Hutton B.
      • Blog D.
      • Zucker H.
      Multisystem inflammatory syndrome in children in New York State.
      • Lee P.Y.
      • Day-Lewis M.
      • Henderson L.A.
      • Friedman K.
      • Lo J.
      • Roberts J.E.
      • Lo M.S.
      • Platt C.D.
      • Chou J.
      • Hoyt K.J.
      • Baker A.L.
      • Banzon T.
      • Chang M.H.
      • Cohen E.
      • de Ferranti S.
      • Dionne A.
      • Habiballah S.
      • Halyabar O.
      • Hausmann J.S.
      • Hazen M.
      • Janssen E.
      • Meidan E.
      • Nelson R.W.
      • Nguyen A.A.
      • Sundel R.P.
      • Dedeoglu F.
      • Nigrovic P.A.
      • Newburger J.W.
      • Son M.B.F.
      Distinct clinical and immunological features of SARS-COV-2-induced multisystem inflammatory syndrome in children.
      • Verdoni L.
      • Mazza A.
      • Gervasoni A.
      • Martelli L.
      • Ruggeri M.
      • Ciuffreda M.
      • Bonanomi E.
      • D'Antiga L.
      An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.