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Evidence of Severe Acute Respiratory Syndrome Coronavirus 2 Replication and Tropism in the Lungs, Airways, and Vascular Endothelium of Patients With Fatal Coronavirus Disease 2019: An Autopsy Case Series.
J Infect Dis. 2021 03 03; 223(5):752-764.JI

Abstract

BACKGROUND

The coronavirus disease 2019 (COVID-19) pandemic continues to produce substantial morbidity and mortality. To understand the reasons for the wide-spectrum complications and severe outcomes of COVID-19, we aimed to identify cellular targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tropism and replication in various tissues.

METHODS

We evaluated RNA extracted from formalin-fixed, paraffin-embedded autopsy tissues from 64 case patients (age range, 1 month to 84 years; 21 COVID-19 confirmed, 43 suspected COVID-19) by SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR). For cellular localization of SARS-CoV-2 RNA and viral characterization, we performed in situ hybridization (ISH), subgenomic RNA RT-PCR, and whole-genome sequencing.

RESULTS

SARS-CoV-2 was identified by RT-PCR in 32 case patients (21 COVID-19 confirmed, 11 suspected). ISH was positive in 20 and subgenomic RNA RT-PCR was positive in 17 of 32 RT-PCR-positive case patients. SARS-CoV-2 RNA was localized by ISH in hyaline membranes, pneumocytes, and macrophages of lungs; epithelial cells of airways; and endothelial cells and vessel walls of brain stem, leptomeninges, lung, heart, liver, kidney, and pancreas. The D614G variant was detected in 9 RT-PCR-positive case patients.

CONCLUSIONS

We identified cellular targets of SARS-CoV-2 tropism and replication in the lungs and airways and demonstrated its direct infection in vascular endothelium. This work provides important insights into COVID-19 pathogenesis and mechanisms of severe outcomes.

Authors+Show Affiliations

Infectious Diseases Pathology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.Infectious Diseases Pathology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.Infectious Diseases Pathology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.Infectious Diseases Pathology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.Respiratory Viruses Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.Respiratory Viruses Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.Infectious Diseases Pathology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.Infectious Diseases Pathology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.Infectious Diseases Pathology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.Respiratory Viruses Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.Respiratory Viruses Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.Respiratory Viruses Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.Infectious Diseases Pathology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.Infectious Diseases Pathology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.Infectious Diseases Pathology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.Infectious Diseases Pathology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.Infectious Diseases Pathology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.Infectious Diseases Pathology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

33502471

Citation

Bhatnagar, Julu, et al. "Evidence of Severe Acute Respiratory Syndrome Coronavirus 2 Replication and Tropism in the Lungs, Airways, and Vascular Endothelium of Patients With Fatal Coronavirus Disease 2019: an Autopsy Case Series." The Journal of Infectious Diseases, vol. 223, no. 5, 2021, pp. 752-764.
Bhatnagar J, Gary J, Reagan-Steiner S, et al. Evidence of Severe Acute Respiratory Syndrome Coronavirus 2 Replication and Tropism in the Lungs, Airways, and Vascular Endothelium of Patients With Fatal Coronavirus Disease 2019: An Autopsy Case Series. J Infect Dis. 2021;223(5):752-764.
Bhatnagar, J., Gary, J., Reagan-Steiner, S., Estetter, L. B., Tong, S., Tao, Y., Denison, A. M., Lee, E., DeLeon-Carnes, M., Li, Y., Uehara, A., Paden, C. R., Leitgeb, B., Uyeki, T. M., Martines, R. B., Ritter, J. M., Paddock, C. D., Shieh, W. J., & Zaki, S. R. (2021). Evidence of Severe Acute Respiratory Syndrome Coronavirus 2 Replication and Tropism in the Lungs, Airways, and Vascular Endothelium of Patients With Fatal Coronavirus Disease 2019: An Autopsy Case Series. The Journal of Infectious Diseases, 223(5), 752-764. https://doi.org/10.1093/infdis/jiab039
Bhatnagar J, et al. Evidence of Severe Acute Respiratory Syndrome Coronavirus 2 Replication and Tropism in the Lungs, Airways, and Vascular Endothelium of Patients With Fatal Coronavirus Disease 2019: an Autopsy Case Series. J Infect Dis. 2021 03 3;223(5):752-764. PubMed PMID: 33502471.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evidence of Severe Acute Respiratory Syndrome Coronavirus 2 Replication and Tropism in the Lungs, Airways, and Vascular Endothelium of Patients With Fatal Coronavirus Disease 2019: An Autopsy Case Series. AU - Bhatnagar,Julu, AU - Gary,Joy, AU - Reagan-Steiner,Sarah, AU - Estetter,Lindsey B, AU - Tong,Suxiang, AU - Tao,Ying, AU - Denison,Amy M, AU - Lee,Elizabeth, AU - DeLeon-Carnes,Marlene, AU - Li,Yan, AU - Uehara,Anna, AU - Paden,Clinton R, AU - Leitgeb,Brooke, AU - Uyeki,Timothy M, AU - Martines,Roosecelis B, AU - Ritter,Jana M, AU - Paddock,Christopher D, AU - Shieh,Wun-Ju, AU - Zaki,Sherif R, PY - 2020/12/07/received PY - 2021/01/22/accepted PY - 2021/1/28/pubmed PY - 2021/3/13/medline PY - 2021/1/27/entrez KW - COVID-19 KW - SARS-CoV-2 KW - autopsy KW - in situ hybridization KW - replication SP - 752 EP - 764 JF - The Journal of infectious diseases JO - J Infect Dis VL - 223 IS - 5 N2 - BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic continues to produce substantial morbidity and mortality. To understand the reasons for the wide-spectrum complications and severe outcomes of COVID-19, we aimed to identify cellular targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tropism and replication in various tissues. METHODS: We evaluated RNA extracted from formalin-fixed, paraffin-embedded autopsy tissues from 64 case patients (age range, 1 month to 84 years; 21 COVID-19 confirmed, 43 suspected COVID-19) by SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR). For cellular localization of SARS-CoV-2 RNA and viral characterization, we performed in situ hybridization (ISH), subgenomic RNA RT-PCR, and whole-genome sequencing. RESULTS: SARS-CoV-2 was identified by RT-PCR in 32 case patients (21 COVID-19 confirmed, 11 suspected). ISH was positive in 20 and subgenomic RNA RT-PCR was positive in 17 of 32 RT-PCR-positive case patients. SARS-CoV-2 RNA was localized by ISH in hyaline membranes, pneumocytes, and macrophages of lungs; epithelial cells of airways; and endothelial cells and vessel walls of brain stem, leptomeninges, lung, heart, liver, kidney, and pancreas. The D614G variant was detected in 9 RT-PCR-positive case patients. CONCLUSIONS: We identified cellular targets of SARS-CoV-2 tropism and replication in the lungs and airways and demonstrated its direct infection in vascular endothelium. This work provides important insights into COVID-19 pathogenesis and mechanisms of severe outcomes. SN - 1537-6613 UR - https://www.unboundmedicine.com/medline/citation/33502471/Evidence_of_Severe_Acute_Respiratory_Syndrome_Coronavirus_2_Replication_and_Tropism_in_the_Lungs_Airways_and_Vascular_Endothelium_of_Patients_With_Fatal_Coronavirus_Disease_2019:_An_Autopsy_Case_Series_ L2 - https://academic.oup.com/jid/article-lookup/doi/10.1093/infdis/jiab039 DB - PRIME DP - Unbound Medicine ER -