@article{Tomasicchio2023,
abstract = {Rationale: In the upper respiratory tract replicating (culturable) SARS-CoV-2 is recoverable for {\~{}} 4 to 8 days after symptom onset, however, there is paucity of data about the frequency or duration of replicating virus in the lower respiratory tract (i.e. the human lung). Objectives: We undertook lung tissue sampling (needle biopsy), shortly after death, in 42 mechanically ventilated decedents during the Beta and Delta waves. An independent group of 18 ambulatory patents served as a control group. Methods: Lung biopsy cores from decedents underwent viral culture, histopathological analysis, electron microscopy, transcriptomic profiling and immunohistochemistry. Results: 38{\%} (16/42) of mechanically ventilated decedents had culturable virus in the lung for a median of 15 days (persisting for up to 4 weeks) after symptom onset. Lung viral culture positivity was not associated with comorbidities or steroid use. Delta but not Beta variant lung culture positivity was associated with accelerated death and secondary bacterial infection (p{\&}lt;0.05). Nasopharyngeal culture was negative in 23.1{\%} (6/26) of decedents despite lung culture positivity. This, hitherto, undescribed bio-phenotype of lung-specific persisting viral replication was associated with an enhanced transcriptomic pulmonary pro-inflammatory response but with concurrent viral culture positivity. Conclusions: Concurrent, rather than sequential active viral replication continues to drive a heightened pro-inflammatory response in the human lung beyond the second week of illness and was associated with variant-specific increased mortality and morbidity. These findings have potential implications for the design of interventional strategies and clinical management of patients with severe COVID-19 disease.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThe study was funded by the South African Medical Research Council.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethical approval was obtained from the Human Research Ethics Committee (HREC) of the University of Cape Town (HREC approval number 866/2020) and University of Witwatersrand (HREC approval number M200313). Biosafety approvals were obtained from the Faculty Biosafety Committee of the University of Cape Town (IBC008-2021).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesIndividual participant data will be made available to researchers who provide a protocol that is approved by their respective human research ethics committee. All protocols will be reviewed and approved by the MITS consortium trial steering committee up to five years following publication. A data sharing agreement (DTA) will need to be concluded between the representatives of the requesting institution and the University of Cape Town Lung Institute. Data sharing requests should be directed to keertan.dheda@uct.ac.za},
author = {Tomasicchio, Michele and Jaumdally, Shameem and Pooran, Anil and Esmail, Aliasgar and Wilson, Lindsay and Kotze, Andrea and Semple, Lynn and Meier, Stuart and Pillay, Komala and Roberts, Riyaadh and Kriel, Raymond and Meldau, Richard and Oelofse, Suzette and Mandviwala, Carley and Burns, Jessica and Londt, Rolanda and Davids, Malika and van der Merwe, Charnay and Roomaney, Aqeedah and Kuhn, Louie and Perumal, Tahlia and Scott, Alex and Hale, Martin and Baillie, Vicky and Mahtab, Sana and Williamson, Carolyn and Joseph, Rageema and Sigal, Alex and Joubert, Ivan and Piercy, Jenna and Thomson, David and Fredericks, David and Miller, Malcolm and Nunes, Marta and Madhi, Shabir and Dheda, Keertan},
doi = {10.1101/2023.03.06.23286834},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Tomasicchio et al. - 2023 - SARS-CoV-2 viral replication persists in the human lung for several weeks after symptom onset.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jan},
pages = {2023.03.06.23286834},
title = {{SARS-CoV-2 viral replication persists in the human lung for several weeks after symptom onset}},
url = {http://medrxiv.org/content/early/2023/08/23/2023.03.06.23286834.abstract},
year = {2023}
}

{"_id":"BGbJFwC7LtjuiNGzR","bibbaseid":"tomasicchio-jaumdally-pooran-esmail-wilson-kotze-semple-meier-etal-sarscov2viralreplicationpersistsinthehumanlungforseveralweeksaftersymptomonset-2023","author_short":["Tomasicchio, M.","Jaumdally, S.","Pooran, A.","Esmail, A.","Wilson, L.","Kotze, A.","Semple, L.","Meier, S.","Pillay, K.","Roberts, R.","Kriel, R.","Meldau, R.","Oelofse, S.","Mandviwala, C.","Burns, J.","Londt, R.","Davids, M.","van der Merwe, C.","Roomaney, A.","Kuhn, L.","Perumal, T.","Scott, A.","Hale, M.","Baillie, V.","Mahtab, S.","Williamson, C.","Joseph, R.","Sigal, A.","Joubert, I.","Piercy, J.","Thomson, D.","Fredericks, D.","Miller, M.","Nunes, M.","Madhi, S.","Dheda, K."],"bibdata":{"bibtype":"article","type":"article","abstract":"Rationale: In the upper respiratory tract replicating (culturable) SARS-CoV-2 is recoverable for \\  4 to 8 days after symptom onset, however, there is paucity of data about the frequency or duration of replicating virus in the lower respiratory tract (i.e. the human lung). Objectives: We undertook lung tissue sampling (needle biopsy), shortly after death, in 42 mechanically ventilated decedents during the Beta and Delta waves. An independent group of 18 ambulatory patents served as a control group. Methods: Lung biopsy cores from decedents underwent viral culture, histopathological analysis, electron microscopy, transcriptomic profiling and immunohistochemistry. Results: 38% (16/42) of mechanically ventilated decedents had culturable virus in the lung for a median of 15 days (persisting for up to 4 weeks) after symptom onset. Lung viral culture positivity was not associated with comorbidities or steroid use. Delta but not Beta variant lung culture positivity was associated with accelerated death and secondary bacterial infection (p<0.05). Nasopharyngeal culture was negative in 23.1% (6/26) of decedents despite lung culture positivity. This, hitherto, undescribed bio-phenotype of lung-specific persisting viral replication was associated with an enhanced transcriptomic pulmonary pro-inflammatory response but with concurrent viral culture positivity. Conclusions: Concurrent, rather than sequential active viral replication continues to drive a heightened pro-inflammatory response in the human lung beyond the second week of illness and was associated with variant-specific increased mortality and morbidity. These findings have potential implications for the design of interventional strategies and clinical management of patients with severe COVID-19 disease.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThe study was funded by the South African Medical Research Council.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethical approval was obtained from the Human Research Ethics Committee (HREC) of the University of Cape Town (HREC approval number 866/2020) and University of Witwatersrand (HREC approval number M200313). Biosafety approvals were obtained from the Faculty Biosafety Committee of the University of Cape Town (IBC008-2021).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesIndividual participant data will be made available to researchers who provide a protocol that is approved by their respective human research ethics committee. All protocols will be reviewed and approved by the MITS consortium trial steering committee up to five years following publication. A data sharing agreement (DTA) will need to be concluded between the representatives of the requesting institution and the University of Cape Town Lung Institute. Data sharing requests should be directed to keertan.dheda@uct.ac.za","author":[{"propositions":[],"lastnames":["Tomasicchio"],"firstnames":["Michele"],"suffixes":[]},{"propositions":[],"lastnames":["Jaumdally"],"firstnames":["Shameem"],"suffixes":[]},{"propositions":[],"lastnames":["Pooran"],"firstnames":["Anil"],"suffixes":[]},{"propositions":[],"lastnames":["Esmail"],"firstnames":["Aliasgar"],"suffixes":[]},{"propositions":[],"lastnames":["Wilson"],"firstnames":["Lindsay"],"suffixes":[]},{"propositions":[],"lastnames":["Kotze"],"firstnames":["Andrea"],"suffixes":[]},{"propositions":[],"lastnames":["Semple"],"firstnames":["Lynn"],"suffixes":[]},{"propositions":[],"lastnames":["Meier"],"firstnames":["Stuart"],"suffixes":[]},{"propositions":[],"lastnames":["Pillay"],"firstnames":["Komala"],"suffixes":[]},{"propositions":[],"lastnames":["Roberts"],"firstnames":["Riyaadh"],"suffixes":[]},{"propositions":[],"lastnames":["Kriel"],"firstnames":["Raymond"],"suffixes":[]},{"propositions":[],"lastnames":["Meldau"],"firstnames":["Richard"],"suffixes":[]},{"propositions":[],"lastnames":["Oelofse"],"firstnames":["Suzette"],"suffixes":[]},{"propositions":[],"lastnames":["Mandviwala"],"firstnames":["Carley"],"suffixes":[]},{"propositions":[],"lastnames":["Burns"],"firstnames":["Jessica"],"suffixes":[]},{"propositions":[],"lastnames":["Londt"],"firstnames":["Rolanda"],"suffixes":[]},{"propositions":[],"lastnames":["Davids"],"firstnames":["Malika"],"suffixes":[]},{"propositions":["van","der"],"lastnames":["Merwe"],"firstnames":["Charnay"],"suffixes":[]},{"propositions":[],"lastnames":["Roomaney"],"firstnames":["Aqeedah"],"suffixes":[]},{"propositions":[],"lastnames":["Kuhn"],"firstnames":["Louie"],"suffixes":[]},{"propositions":[],"lastnames":["Perumal"],"firstnames":["Tahlia"],"suffixes":[]},{"propositions":[],"lastnames":["Scott"],"firstnames":["Alex"],"suffixes":[]},{"propositions":[],"lastnames":["Hale"],"firstnames":["Martin"],"suffixes":[]},{"propositions":[],"lastnames":["Baillie"],"firstnames":["Vicky"],"suffixes":[]},{"propositions":[],"lastnames":["Mahtab"],"firstnames":["Sana"],"suffixes":[]},{"propositions":[],"lastnames":["Williamson"],"firstnames":["Carolyn"],"suffixes":[]},{"propositions":[],"lastnames":["Joseph"],"firstnames":["Rageema"],"suffixes":[]},{"propositions":[],"lastnames":["Sigal"],"firstnames":["Alex"],"suffixes":[]},{"propositions":[],"lastnames":["Joubert"],"firstnames":["Ivan"],"suffixes":[]},{"propositions":[],"lastnames":["Piercy"],"firstnames":["Jenna"],"suffixes":[]},{"propositions":[],"lastnames":["Thomson"],"firstnames":["David"],"suffixes":[]},{"propositions":[],"lastnames":["Fredericks"],"firstnames":["David"],"suffixes":[]},{"propositions":[],"lastnames":["Miller"],"firstnames":["Malcolm"],"suffixes":[]},{"propositions":[],"lastnames":["Nunes"],"firstnames":["Marta"],"suffixes":[]},{"propositions":[],"lastnames":["Madhi"],"firstnames":["Shabir"],"suffixes":[]},{"propositions":[],"lastnames":["Dheda"],"firstnames":["Keertan"],"suffixes":[]}],"doi":"10.1101/2023.03.06.23286834","file":":C$\\$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Tomasicchio et al. - 2023 - SARS-CoV-2 viral replication persists in the human lung for several weeks after symptom onset.pdf:pdf","journal":"medRxiv","keywords":"OA,fund_ack,original","mendeley-tags":"OA,fund_ack,original","month":"jan","pages":"2023.03.06.23286834","title":"SARS-CoV-2 viral replication persists in the human lung for several weeks after symptom onset","url":"http://medrxiv.org/content/early/2023/08/23/2023.03.06.23286834.abstract","year":"2023","bibtex":"@article{Tomasicchio2023,\r\nabstract = {Rationale: In the upper respiratory tract replicating (culturable) SARS-CoV-2 is recoverable for {\\~{}} 4 to 8 days after symptom onset, however, there is paucity of data about the frequency or duration of replicating virus in the lower respiratory tract (i.e. the human lung). Objectives: We undertook lung tissue sampling (needle biopsy), shortly after death, in 42 mechanically ventilated decedents during the Beta and Delta waves. An independent group of 18 ambulatory patents served as a control group. Methods: Lung biopsy cores from decedents underwent viral culture, histopathological analysis, electron microscopy, transcriptomic profiling and immunohistochemistry. Results: 38{\\%} (16/42) of mechanically ventilated decedents had culturable virus in the lung for a median of 15 days (persisting for up to 4 weeks) after symptom onset. Lung viral culture positivity was not associated with comorbidities or steroid use. Delta but not Beta variant lung culture positivity was associated with accelerated death and secondary bacterial infection (p{\\&}lt;0.05). Nasopharyngeal culture was negative in 23.1{\\%} (6/26) of decedents despite lung culture positivity. This, hitherto, undescribed bio-phenotype of lung-specific persisting viral replication was associated with an enhanced transcriptomic pulmonary pro-inflammatory response but with concurrent viral culture positivity. Conclusions: Concurrent, rather than sequential active viral replication continues to drive a heightened pro-inflammatory response in the human lung beyond the second week of illness and was associated with variant-specific increased mortality and morbidity. 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Biosafety approvals were obtained from the Faculty Biosafety Committee of the University of Cape Town (IBC008-2021).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesIndividual participant data will be made available to researchers who provide a protocol that is approved by their respective human research ethics committee. All protocols will be reviewed and approved by the MITS consortium trial steering committee up to five years following publication. A data sharing agreement (DTA) will need to be concluded between the representatives of the requesting institution and the University of Cape Town Lung Institute. 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