Immunopathology of Hyperinflammation in COVID-19
2020; Elsevier BV; Volume: 191; Issue: 1 Linguagem: Inglês
10.1016/j.ajpath.2020.08.009
ISSN1525-2191
Autores Tópico(s)Long-Term Effects of COVID-19
ResumoThe 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. 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).1Zhu 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.N Engl J Med. 2020; 382: 727-733Crossref PubMed Scopus (16620) Google Scholar 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.2Lu R. Zhao X. Li J. Niu P. Yang B. Wu H. Wang W. Song H. Huang B. Zhu N. Bi Y. Ma X. 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COVID-19: consider cytokine storm syndromes and immunosuppression.Lancet. 2020; 395: 1033-1034Abstract Full Text Full Text PDF PubMed Scopus (6114) Google Scholar Patients with severe COVID-19 have elevated clinical inflammatory markers and increased serum cytokine and chemokine levels.4Huang 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.Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (29360) Google Scholar These markers of inflammation are prognostic for the requirement of mechanical ventilation, the development of ARDS, and death in COVID-19.4Huang 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. 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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.Lancet Respir Med. 2020; 8: 420-422Abstract Full Text Full Text PDF PubMed Scopus (5774) Google Scholar, 14Fox 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.Lancet Respir Med. 2020; 8: 681-686Abstract Full Text Full Text PDF PubMed Scopus (800) Google Scholar, 15Carsana 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.Lancet Infect Dis. 2020; 20: 1135-1140Abstract Full Text Full Text PDF PubMed Scopus (779) Google Scholar, 16Bryce 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.medRxiv. 2020; ([Epub] doi:10.1016/2020.05.18.20099960)Google Scholar Collectively, this hyperinflammatory response shares many biological and clinical characteristics with the macrophage-activation syndrome seen in virus-induced hemophagocytic lymphohistiocytosis,17Ramos-Casals M. Brito-Zerón P. López-Guillermo A. Khamashta M.A. Bosch X. Adult haemophagocytic syndrome.Lancet. 2014; 383: 1503-1516Abstract Full Text Full Text PDF PubMed Scopus (774) Google Scholar 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. 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.14Fox 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.Lancet Respir Med. 2020; 8: 681-686Abstract Full Text Full Text PDF PubMed Scopus (800) Google Scholar Microscopy has identified diffuse alveolar hemorrhage in different phases.13Xu 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.Lancet Respir Med. 2020; 8: 420-422Abstract Full Text Full Text PDF PubMed Scopus (5774) Google Scholar,14Fox 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.Lancet Respir Med. 2020; 8: 681-686Abstract Full Text Full Text PDF PubMed Scopus (800) Google Scholar,16Bryce 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.medRxiv. 2020; ([Epub] doi:10.1016/2020.05.18.20099960)Google Scholar Most cases have been in the early or intermediate proliferative phase with edema, while features consistent with the fibrotic phase were rare.13Xu 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.Lancet Respir Med. 2020; 8: 420-422Abstract Full Text Full Text PDF PubMed Scopus (5774) Google Scholar,14Fox 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.Lancet Respir Med. 2020; 8: 681-686Abstract Full Text Full Text PDF PubMed Scopus (800) Google Scholar,16Bryce 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.medRxiv. 2020; ([Epub] doi:10.1016/2020.05.18.20099960)Google Scholar 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.15Carsana 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.Lancet Infect Dis. 2020; 20: 1135-1140Abstract Full Text Full Text PDF PubMed Scopus (779) Google Scholar,16Bryce 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.medRxiv. 2020; ([Epub] doi:10.1016/2020.05.18.20099960)Google Scholar Desquamated pneumocytes have been reported to have an apparent viral cytopathic effect and were present in alveolar spaces.13Xu 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.Lancet Respir Med. 2020; 8: 420-422Abstract Full Text Full Text PDF PubMed Scopus (5774) Google Scholar,16Bryce 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.medRxiv. 2020; ([Epub] doi:10.1016/2020.05.18.20099960)Google Scholar Electron microscopy has identified viral particles within type 1 and type 2 pneumocytes,14Fox 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.Lancet Respir Med. 2020; 8: 681-686Abstract Full Text Full Text PDF PubMed Scopus (800) Google Scholar,15Carsana 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.Lancet Infect Dis. 2020; 20: 1135-1140Abstract Full Text Full Text PDF PubMed Scopus (779) Google Scholar and immunofluorescence has localized SARS-CoV-2 antigen to the ACE2+ bronchiolar epithelium.16Bryce 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.medRxiv. 2020; ([Epub] doi:10.1016/2020.05.18.20099960)Google Scholar It has been reported that in the majority of cases, microthrombi were present in the small- and medium-sized pulmonary arterial vessels.14Fox 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.Lancet Respir Med. 2020; 8: 681-686Abstract Full Text Full Text PDF PubMed Scopus (800) Google Scholar, 15Carsana 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.Lancet Infect Dis. 2020; 20: 1135-1140Abstract Full Text Full Text PDF PubMed Scopus (779) Google Scholar, 16Bryce 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.medRxiv. 2020; ([Epub] doi:10.1016/2020.05.18.20099960)Google Scholar,18Ackermann 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.N Engl J Med. 2020; 383: 120-128Crossref PubMed Scopus (3364) Google Scholar Increased levels of CD61+ megakaryocytes were also found in alveolar capillaries accompanying the microthrombi.14Fox 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.Lancet Respir Med. 2020; 8: 681-686Abstract Full Text Full Text PDF PubMed Scopus (800) Google Scholar,15Carsana 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.Lancet Infect Dis. 2020; 20: 1135-1140Abstract Full Text Full Text PDF PubMed Scopus (779) Google Scholar 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.14Fox 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.Lancet Respir Med. 2020; 8: 681-686Abstract Full Text Full Text PDF PubMed Scopus (800) Google Scholar, 15Carsana 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.Lancet Infect Dis. 2020; 20: 1135-1140Abstract Full Text Full Text PDF PubMed Scopus (779) Google Scholar, 16Bryce 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.medRxiv. 2020; ([Epub] doi:10.1016/2020.05.18.20099960)Google Scholar These microthrombi likely contribute to organ dysfunction and mortality in COVID-19.14Fox 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.Lancet Respir Med. 2020; 8: 681-686Abstract Full Text Full Text PDF PubMed Scopus (800) Google Scholar, 15Carsana 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.Lancet Infect Dis. 2020; 20: 1135-1140Abstract Full Text Full Text PDF PubMed Scopus (779) Google Scholar, 16Bryce 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.medRxiv. 2020; ([Epub] doi:10.1016/2020.05.18.20099960)Google Scholar Ackermann et al18Ackermann 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.N Engl J Med. 2020; 383: 120-128Crossref PubMed Scopus (3364) Google Scholar 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.18Ackermann 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.N Engl J Med. 2020; 383: 120-128Crossref PubMed Scopus (3364) Google Scholar 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.18Ackermann 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.N Engl J Med. 2020; 383: 120-128Crossref PubMed Scopus (3364) Google Scholar Consistent with the findings from a previous study evaluating endothelial cells from glomerular capillary loops,19Varga 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.Lancet. 2020; 395: 1417-1418Abstract Full Text Full Text PDF PubMed Scopus (3970) Google Scholar electron microscopy identified SARS-CoV-2 viral particles within alveolar endothelial cells.18Ackermann 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.N Engl J Med. 2020; 383: 120-128Crossref PubMed Scopus (3364) Google Scholar In vitro studies have also shown that SARS-CoV-2 can directly infect an engineered human blood vessel organoid via the ACE2 receptor.20Monteil 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.Cell. 2020; 181: 905-913.e7Abstract Full Text Full Text PDF PubMed Scopus (1442) Google Scholar 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.13Xu 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.Lancet Respir Med. 2020; 8: 420-422Abstract Full Text Full Text PDF PubMed Scopus (5774) Google Scholar, 14Fox 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.Lancet Respir Med. 2020; 8: 681-686Abstract Full Text Full Text PDF PubMed Scopus (800) Google Scholar, 15Carsana 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 I
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