Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Using autopsies to dissect COVID-19 pathogenesis

Nature Microbiology volume 8, pages 1986–1994 (2023)Cite this article

Subjects

Abstract

The emergence of SARS-CoV-2 has resulted in millions of deaths as a result of COVID-19. Suitable models were missing at the beginning of the pandemic, and studies investigating disease pathogenesis relied on patients who had succumbed to COVID-19. Since then, autopsies of patients have substantially contributed to our understanding of the pathogenesis of COVID-19 and associated major organ complications. Here we summarize how autopsies have complemented experimental studies, mainly in animal models, and how they have facilitated critical knowledge of COVID-19 to improve daily clinical practice and develop therapeutic interventions. Employing advanced histopathologic and molecular genetic methods in post-mortem tissues, the COVID-19 pandemic has highlighted the importance of autopsies for virology research and clinical practice in current and emerging infectious diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Autopsies have contributed to our understanding of COVID-19 mortality.
Fig. 2: COVID-19 causes of death according to findings from a multicentre nationwide autopsy study.
Fig. 3: Key mechanisms, with histomorphological correlates from autopsy studies, of COVID-19 pulmonary disease.

Similar content being viewed by others

References

  1. Zhu, N. et al. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 382, 727–733 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Andersen, K. G., Rambaut, A., Lipkin, W. I., Holmes, E. C. & Garry, R. F. The proximal origin of SARS-CoV-2. Nat. Med. 26, 450–452 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lytras, S., Xia, W., Hughes, J., Jiang, X. & Robertson, D. L. The animal origin of SARS-CoV-2. Science 373, 968–970 (2021).

    Article  CAS  PubMed  Google Scholar 

  4. Infection Prevention and Control for the Safe Management of a Dead Body in the Context of COVID-19: Interim Guidance, 24 March 2020 (World Health Organization, 2020).

  5. Msemburi, W. et al. The WHO estimates of excess mortality associated with the COVID-19 pandemic. Nature 613, 130–137 (2023).

    Article  CAS  PubMed  Google Scholar 

  6. Muñoz-Fontela, C. et al. Animal models for COVID-19. Nature 586, 509–515 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Munster, V. J. et al. Respiratory disease in rhesus macaques inoculated with SARS-CoV-2. Nature 585, 268–272 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Beer, J. et al. Impaired immune response drives age-dependent severity of COVID-19. J. Exp. Med. 219, e20220621 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Winkler, E. S. et al. SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function. Nat. Immunol. 21, 1327–1335 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Liu, Q. et al. Gross examination report of a COVID-19 death autopsy. Fa Yi Xue Za Zhi 36, 21–23 (2020).

    CAS  PubMed  Google Scholar 

  11. Wichmann, D. et al. Autopsy findings and venous thromboembolism in patients with COVID-19. Ann. Intern. Med. 173, 268–277 (2020).

    Article  PubMed  Google Scholar 

  12. The REMAP-CAP, ACTIV-4a and ATTACC Investigators. Therapeutic anticoagulation with heparin in critically ill patients with COVID-19. N. Engl. J. Med. 385, 777–789 (2021).

    Article  Google Scholar 

  13. Puelles, V. G. et al. Multiorgan and renal tropism of SARS-CoV-2. N. Engl. J. Med. 383, 590–592 (2020).

    Article  PubMed  Google Scholar 

  14. De Cock, K. M., Zielinski-Gutiérrez, E. & Lucas, S. B. Learning from the dead. N. Engl. J. Med. 381, 1889–1891 (2019).

    Article  PubMed  Google Scholar 

  15. Trypsteen, W., Van Cleemput, J., Snippenberg, W. V., Gerlo, S. & Vandekerckhove, L. On the whereabouts of SARS-CoV-2 in the human body: a systematic review. PLoS Pathog. 16, e1009037 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wu, Z. & McGoogan, J. M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72,314 cases from the Chinese Center for Disease Control and Prevention. JAMA 323, 1239–1242 (2020).

    Article  CAS  PubMed  Google Scholar 

  17. von Stillfried, S. et al. First report from the German COVID-19 autopsy registry. Lancet Reg. Health Eur. 15, 100330 (2022).

    Article  Google Scholar 

  18. Lamers, M. M. & Haagmans, B. L. SARS-CoV-2 pathogenesis. Nat. Rev. Microbiol. 20, 270–284 (2022).

    Article  CAS  PubMed  Google Scholar 

  19. Damiani, S. et al. Pathological post-mortem findings in lungs infected with SARS-CoV-2. J. Pathol. 253, 31–40 (2021).

    Article  CAS  PubMed  Google Scholar 

  20. Menter, T. et al. Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction. Histopathology 77, 198–209 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Matthay, M. A. et al. Acute respiratory distress syndrome. Nat. Rev. Dis. Primers 5, 18 (2019).

  22. Acosta, M. A. T. & Singer, B. D. Pathogenesis of COVID-19-induced ARDS: implications for an ageing population. Eur. Respir. J. 56, 2002049 (2020).

    Article  CAS  Google Scholar 

  23. Nienhold, R. et al. Two distinct immunopathological profiles in autopsy lungs of COVID-19. Nat. Commun. 11, 5086 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Delorey, T. M. et al. COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets. Nature 595, 107–113 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Melms, J. C. et al. A molecular single-cell lung atlas of lethal COVID-19. Nature 595, 114–119 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kory, P. & Kanne, J. P. SARS-CoV-2 organising pneumonia: ‘Has there been a widespread failure to identify and treat this prevalent condition in COVID-19?’. BMJ Open Respir. Res. 7, e000724 (2020).

    Article  PubMed  Google Scholar 

  27. Dorward, D. A. et al. Tissue-specific immunopathology in fatal COVID-19. Am. J. Respir. Crit. Care Med. 203, 192–201 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rendeiro, A. F. et al. The spatial landscape of lung pathology during COVID-19 progression. Nature 593, 564–569 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nie, X. et al. Multi-organ proteomic landscape of COVID-19 autopsies. Cell 184, 775–791.e14 (2021).

  30. Junqueira, C. et al. FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation. Nature 606, 576–584 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wu, H. et al. Postmortem high-dimensional immune profiling of severe COVID-19 patients reveals distinct patterns of immunosuppression and immunoactivation. Nat. Commun. 13, 269 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ackermann, M. et al. The fatal trajectory of pulmonary COVID-19 is driven by lobular ischemia and fibrotic remodelling. eBioMedicine https://doi.org/10.1016/j.ebiom.2022.104296 (2022).

  33. Varga, Z. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 395, 1417–1418 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ackermann, M. et al. Pulmonary vascular endothelialitis, thrombosis and angiogenesis in COVID-19. N. Engl. J. Med. 383, 120–128 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Perico, L. et al. Immunity, endothelial injury and complement-induced coagulopathy in COVID-19. Nat. Rev. Nephrol. 17, 46–64 (2021).

    Article  PubMed  Google Scholar 

  36. Bryce, C. et al. Pathophysiology of SARS-CoV-2: the Mount Sinai COVID-19 autopsy experience. Mod. Pathol. 34, 1456–1467 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Krasemann, S. et al. Assessing and improving the validity of COVID-19 autopsy studies—a multicentre approach to establish essential standards for immunohistochemical and ultrastructural analyses. eBioMedicine https://doi.org/10.1016/j.ebiom.2022.104193 (2022).

  38. Fajnzylber, J. et al. SARS-CoV-2 viral load is associated with increased disease severity and mortality. Nat. Commun. 11, 5493 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Corey, L. et al. SARS-CoV-2 variants in patients with immunosuppression. N. Engl. J. Med. 385, 562–566 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Van Cleemput, J. et al. Organ-specific genome diversity of replication-competent SARS-CoV-2. Nat. Commun. 12, 6612 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Legrand, M. et al. Pathophysiology of COVID-19-associated acute kidney injury. Nat. Rev. Nephrol. 17, 751–764 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Braun, F. et al. SARS-CoV-2 renal tropism associates with acute kidney injury. Lancet 396, 597–598 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hanson, P. J. et al. Characterization of COVID-19-associated cardiac injury: evidence for a multifactorial disease in an autopsy cohort. Lab. Invest. 102, 814–825 (2022).

    Article  CAS  PubMed  Google Scholar 

  44. Zheng, Y.-Y., Ma, Y.-T., Zhang, J.-Y. & Xie, X. COVID-19 and the cardiovascular system. Nat. Rev. Cardiol. 17, 259–260 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bräuninger, H. et al. Cardiac SARS-CoV-2 infection is associated with pro-inflammatory transcriptomic alterations within the heart. Cardiovasc. Res. 118, 542–555 (2022).

    Article  PubMed  Google Scholar 

  46. Varatharaj, A. et al. Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. Lancet Psychiatry 7, 875–882 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Schwabenland, M. et al. Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T-cell interactions. Immunity 54, 1594–1610 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Matschke, J. et al. Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol. 19, 919–929 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lee, M.-H. et al. Microvascular injury in the brains of patients with COVID-19. N. Engl. J. Med. 384, 481–483 (2020).

    Article  PubMed  Google Scholar 

  50. Schurink, B. et al. Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study. Lancet Microbe 1, e290–e299 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Stein, S. R. et al. SARS-CoV-2 infection and persistence in the human body and brain at autopsy. Nature 612, 758–763 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Yang, A. C. et al. Dysregulation of brain and choroid plexus cell types in severe COVID-19. Nature 595, 565–571 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Fullard, J. F. et al. Single-nucleus transcriptome analysis of human brain immune response in patients with severe COVID-19. Genome Med. 13, 118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Mavrikaki, M., Lee, J. D., Solomon, I. H. & Slack, F. J. Severe COVID-19 is associated with molecular signatures of aging in the human brain. Nat. Aging 2, 1130–1137 (2022).

    Article  PubMed  Google Scholar 

  55. Jackson, C. B., Farzan, M., Chen, B. & Choe, H. Mechanisms of SARS-CoV-2 entry into cells. Nat. Rev. Mol. Cell Biol. 23, 3–20 (2022).

    Article  CAS  PubMed  Google Scholar 

  56. Muus, C. et al. Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics. Nat. Med. 27, 546–559 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Alexandersen, S., Chamings, A. & Bhatta, T. R. SARS-CoV-2 genomic and subgenomic RNAs in diagnostic samples are not an indicator of active replication. Nat. Commun. 11, 6059 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Burton, J. L. & Underwood, J. Clinical, educational and epidemiological value of autopsy. Lancet 369, 1471–1480 (2007).

    Article  PubMed  Google Scholar 

  59. Fusco, F. M. et al. A 2009 cross-sectional survey of procedures for post-mortem management of highly infectious disease patients in 48 isolation facilities in 16 countries: data from EuroNHID. Infection 44, 57–64 (2016).

    Article  PubMed  Google Scholar 

  60. Heinrich, F. et al. Postmortem antigen-detecting rapid diagnostic tests to predict infectivity of SARS-CoV-2-associated deaths. Emerg. Infect. Dis. 28, 244–247 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Marsoof, A. The disposal of COVID-19 dead bodies: impact of Sri Lanka’s response on fundamental rights. J. Hum. Rights Pract. 13, 669–689 (2021).

    Article  PubMed  Google Scholar 

  62. Walker, D. H. et al. Pathologic and virologic study of fatal Lassa fever in man. Am. J. Pathol. 107, 349–356 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Okokhere, P. et al. Clinical and laboratory predictors of Lassa fever outcome in a dedicated treatment facility in Nigeria: a retrospective, observational cohort study. Lancet Infect. Dis. 18, 684–695 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Keita, A. K. et al. Resurgence of Ebola virus in 2021 in Guinea suggests a new paradigm for outbreaks. Nature 597, 539–543 (2021).

    Article  CAS  PubMed  Google Scholar 

  65. Diallo, B. et al. Resurgence of Ebola virus disease in Guinea linked to a survivor with virus persistence in seminal fluid for more than 500 days. Clin. Infect. Dis. 63, 1353–1356 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Keita, M. et al. Subsequent mortality in survivors of Ebola virus disease in Guinea: a nationwide retrospective cohort study. Lancet Infect. Dis. 19, 1202–1208 (2019).

    Article  PubMed  Google Scholar 

  67. Khan, M. et al. Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb. Cell 184, 5932–5949 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Krasemann, S. et al. The blood–brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2. Stem Cell Rep. 17, 307–320 (2022).

    Article  CAS  Google Scholar 

  69. Carithers, L. J. et al. A novel approach to high-quality postmortem tissue procurement: the GTEx Project. Biopreserv. Biobanking 13, 311–319 (2015).

    Article  Google Scholar 

  70. Cable, J. et al. Lessons from the pandemic: responding to emerging zoonotic viral diseases—a Keystone Symposia report. Ann. NY Acad. Sci. 1518, 209–225 (2022).

    Article  PubMed  Google Scholar 

  71. Ferreira, P. G. et al. The effects of death and post-mortem cold ischemia on human tissue transcriptomes. Nat. Commun. 9, 490 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Pechal, J. L., Schmidt, C. J., Jordan, H. R. & Benbow, M. E. A large-scale survey of the postmortem human microbiome, and its potential to provide insight into the living health condition. Sci. Rep. 8, 5724 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Layne, S. P., Walters, K.-A., Kash, J. C. & Taubenberger, J. K. More autopsy studies are needed to understand the pathogenesis of severe COVID-19. Nat. Med. 28, 427–428 (2022).

    Article  CAS  PubMed Central  Google Scholar 

  74. Jonigk, D. et al. Organ manifestations of COVID-19: what have we learned so far (not only) from autopsies? Virchows Arch. 481, 139–159 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank T. L. E. Wong for proofreading the final version of the manuscript. Original figures were created using Adobe Illustrator (Adobe) and BioRender.com.

Author information

Authors and Affiliations

  1. Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Fabian Heinrich

  2. Institute of Pathology, Kantonsspital Baselland, Liestal, Switzerland

    Kirsten D. Mertz

  3. University of Basel, Basel, Switzerland

    Kirsten D. Mertz

  4. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Markus Glatzel & Susanne Krasemann

  5. Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany

    Martin Beer

Authors
  1. Fabian Heinrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kirsten D. Mertz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Markus Glatzel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martin Beer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Susanne Krasemann
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

F.H. and S.K. conceptualized the manuscript and drafted the figures. K.D.M. contributed and critically reviewed pathology-related content and histological images. M.G. contributed and critically reviewed neuropathology-related content. M.B. contributed and critically reviewed microbiology- and animal-model-related content. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Susanne Krasemann.

Ethics declarations

Competing interests

The Institute of Legal Medicine (F.H.) and Institute of Neuropathology (S.K. and M.G.) were funded by the research consortium NATON (Nationales Obduktionsnetzwerk; National Autopsy Network). The NATON project (grant no. 01KX2121) is part of the National Network University Medicine, funded by the Federal Ministry of Education and Research, Germany. The National Network University Medicine is coordinated at the Charité–Universitätsmedizin Berlin and supervised by the German Aerospace Center (DLR Project Management Agency). The funders had no role in study design, data collection and analysis, the decision to publish or manuscript preparation.

Peer review

Peer review information

Nature Microbiology thanks Edwin Veldhuis Kroeze, Jan von der Thüsen and Linos Vandekerckhove for their contributions to the peer review of this Work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Heinrich, F., Mertz, K.D., Glatzel, M. et al. Using autopsies to dissect COVID-19 pathogenesis. Nat Microbiol 8, 1986–1994 (2023). https://doi.org/10.1038/s41564-023-01488-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41564-023-01488-7

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing