Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 371-387.e9 |
| Journal | Med (New York, N.Y.) |
| Volume | 3 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 10 Jun 2022 |
Keywords
- COVID-19
- SARS-CoV-2
- Translation to patients
- fecal RNA
- gastrointestinal infection
- viral shedding
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In: Med (New York, N.Y.), Vol. 3, No. 6, 10.06.2022, p. 371-387.e9.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection
AU - Natarajan, Aravind
AU - Zlitni, Soumaya
AU - Brooks, Erin F.
AU - Vance, Summer E.
AU - Dahlen, Alex
AU - Hedlin, Haley
AU - Park, Ryan M.
AU - Han, Alvin
AU - Schmidtke, Danica T.
AU - Verma, Renu
AU - Jacobson, Karen B.
AU - Parsonnet, Julie
AU - Bonilla, Hector F.
AU - Singh, Upinder
AU - Pinsky, Benjamin A.
AU - Andrews, Jason R.
AU - Jagannathan, Prasanna
AU - Bhatt, Ami S.
N1 - Funding Information: We thank Alexandria Boehm, Marlene Wolfe, and Nasa Sinnott-Armstrong for guidance on processing stool samples and detection of RNA; Angela Rogers for providing stool samples from participants admitted at Stanford Hospital; Rebecca Osbourne, Tiffany Nguyen, and the members of the Stanford Clinical and Translational Research Unit for assistance with stool sample receipt and processing; Elizabeth Ponder for coordinating initial stool sample collection kit distribution to study participants and providing information about funding from Chem-H; Catherine Blish and members of the Blish Lab for receiving and temporary storage of stool samples prior to biobanking; Dean Felsher for access to the QuantStudio 12K Flex qPCR machine; Yvonne Maldonado and Jonathan Altamirano for helping acquire funding to support this work; Said Attiya and Dhananjay Wagh for guidance on applying ddPCR assays; David Solow-Cordero for assistance setting up the Biomek FX and providing access; Luisa Jiminez and Sopheak Sim for assistance in using the Stanford Functional Genomics Facility and High-Throughput Bioscience Center; and Frida Salcedo for help acquiring reagents from Bio-Rad. We are grateful to the Peg-interferon-λ1a clinical trial team for coordinating procurement of stool samples from outpatients enrolled in this trial. Biorender has been a valuable resource for creating schematic illustrations. This work was supported by a ChemH-IMA grant (to A.S.B. and P.J.), the Stanford Dean’s Postdoctoral Fellowship (to A.N.), an AACR Fellowship (to S.Z.), and a NSF Graduate Research Fellowship Program grant (to A.H. and D.T.S.). The laboratory of A.S.B. is supported by NIH R01 AI148623 and R01 AI143757 , and H.H. and the research reported in this publication are supported by the National Center for Advancing Translational Sciences of NIH award UL1TR003142 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: We thank Alexandria Boehm, Marlene Wolfe, and Nasa Sinnott-Armstrong for guidance on processing stool samples and detection of RNA; Angela Rogers for providing stool samples from participants admitted at Stanford Hospital; Rebecca Osbourne, Tiffany Nguyen, and the members of the Stanford Clinical and Translational Research Unit for assistance with stool sample receipt and processing; Elizabeth Ponder for coordinating initial stool sample collection kit distribution to study participants and providing information about funding from Chem-H; Catherine Blish and members of the Blish Lab for receiving and temporary storage of stool samples prior to biobanking; Dean Felsher for access to the QuantStudio 12K Flex qPCR machine; Yvonne Maldonado and Jonathan Altamirano for helping acquire funding to support this work; Said Attiya and Dhananjay Wagh for guidance on applying ddPCR assays; David Solow-Cordero for assistance setting up the Biomek FX and providing access; Luisa Jiminez and Sopheak Sim for assistance in using the Stanford Functional Genomics Facility and High-Throughput Bioscience Center; and Frida Salcedo for help acquiring reagents from Bio-Rad. We are grateful to the Peg-interferon-λ1a clinical trial team for coordinating procurement of stool samples from outpatients enrolled in this trial. Biorender has been a valuable resource for creating schematic illustrations. This work was supported by a ChemH-IMA grant (to A.S.B. and P.J.), the Stanford Dean's Postdoctoral Fellowship (to A.N.), an AACR Fellowship (to S.Z.), and a NSF Graduate Research Fellowship Program grant (to A.H. and D.T.S.). The laboratory of A.S.B. is supported by NIH R01 AI148623 and R01 AI143757, and H.H. and the research reported in this publication are supported by the National Center for Advancing Translational Sciences of NIH award UL1TR003142. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. A.N. S.Z. E.F.B. and S.E.V. contributed equally to this work. A.N. designed experiments, extracted RNA from stool samples, assayed viral RNA using RT-qPCR and ddPCR, analyzed data, and wrote the manuscript. S.Z. designed experiments, assayed viral RNA using RT-qPCR and ddPCR, analyzed data, generated plots in R, and wrote the manuscript. E.F.B. and S.E.V. designed experiments, biobanked stool samples, extracted RNA from stool samples, and wrote the manuscript. A.D. and H.H. designed experiments, performed statistical analyses, generated plots in Python, and wrote the manuscript. R.M.P. analyzed data. A.H. D.T.S. and R.V. helped design experiments. K.B.J. J.P. H.F.B. U.S. B.A.P. J.A. and P.J. helped collect samples through the Lambda clinical trial and guided data analysis. A.S.B. helped design experiments, analyze data, and write the manuscript. S.Z. A.D. and H.H. performed and replicated the statistical analysis. A.N. E.F.B. S.E.V. and A.S.B. oversaw the statistical analysis. A.N. S.Z. E.F.B. S.E.V. A.D. H.H. and A.S.B. have unrestricted access to all data. A.N. S.Z. E.F.B. S.E.V. A.D. H.H. and A.S.B. prepared the first draft and reviewed and edited the manuscript. All authors read and approved the final manuscript and take responsibility for its content. The authors declare no competing interests. We worked to ensure gender balance in the study arms, recruited participants from diverse ethnic and socioeconomic backgrounds, and provided the study questionnaire and stool collection protocol in Spanish and English. Publisher Copyright: © 2022 Elsevier Inc.
PY - 2022/6/10
Y1 - 2022/6/10
N2 - Background: COVID-19 manifests with respiratory, systemic, and gastrointestinal (GI) symptoms.1, SARS-CoV-2 RNA is detected in respiratory and fecal samples, and recent reports demonstrate viral replication in both the lung and intestinal tissue.2–4 Although much is known about early fecal RNA shedding, little is known about long-term shedding, especially in those with mild COVID-19. Furthermore, most reports of fecal RNA shedding do not correlate these findings with GI symptoms.5 Methods: We analyzed the dynamics of fecal RNA shedding up to 10 months after COVID-19 diagnosis in 113 individuals with mild to moderate disease. We also correlated shedding with disease symptoms. Findings: Fecal SARS-CoV-2 RNA is detected in 49.2% [95% confidence interval, 38.2%–60.3%] of participants within the first week after diagnosis. Whereas there was no ongoing oropharyngeal SARS-CoV-2 RNA shedding in subjects at 4 months, 12.7% [8.5%–18.4%] of participants continued to shed SARS-CoV-2 RNA in the feces at 4 months after diagnosis and 3.8% [2.0%–7.3%] shed at 7 months. Finally, we found that GI symptoms (abdominal pain, nausea, vomiting) are associated with fecal shedding of SARS-CoV-2 RNA. Conclusions: The extended presence of viral RNA in feces, but not in respiratory samples, along with the association of fecal viral RNA shedding with GI symptoms suggest that SARS-CoV-2 infects the GI tract and that this infection can be prolonged in a subset of individuals with COVID-19. Funding: This research was supported by a Stanford ChemH-IMA grant; fellowships from the AACR and NSF; and NIH R01-AI148623, R01-AI143757, and UL1TR003142.
AB - Background: COVID-19 manifests with respiratory, systemic, and gastrointestinal (GI) symptoms.1, SARS-CoV-2 RNA is detected in respiratory and fecal samples, and recent reports demonstrate viral replication in both the lung and intestinal tissue.2–4 Although much is known about early fecal RNA shedding, little is known about long-term shedding, especially in those with mild COVID-19. Furthermore, most reports of fecal RNA shedding do not correlate these findings with GI symptoms.5 Methods: We analyzed the dynamics of fecal RNA shedding up to 10 months after COVID-19 diagnosis in 113 individuals with mild to moderate disease. We also correlated shedding with disease symptoms. Findings: Fecal SARS-CoV-2 RNA is detected in 49.2% [95% confidence interval, 38.2%–60.3%] of participants within the first week after diagnosis. Whereas there was no ongoing oropharyngeal SARS-CoV-2 RNA shedding in subjects at 4 months, 12.7% [8.5%–18.4%] of participants continued to shed SARS-CoV-2 RNA in the feces at 4 months after diagnosis and 3.8% [2.0%–7.3%] shed at 7 months. Finally, we found that GI symptoms (abdominal pain, nausea, vomiting) are associated with fecal shedding of SARS-CoV-2 RNA. Conclusions: The extended presence of viral RNA in feces, but not in respiratory samples, along with the association of fecal viral RNA shedding with GI symptoms suggest that SARS-CoV-2 infects the GI tract and that this infection can be prolonged in a subset of individuals with COVID-19. Funding: This research was supported by a Stanford ChemH-IMA grant; fellowships from the AACR and NSF; and NIH R01-AI148623, R01-AI143757, and UL1TR003142.
KW - COVID-19
KW - SARS-CoV-2
KW - Translation to patients
KW - fecal RNA
KW - gastrointestinal infection
KW - viral shedding
UR - http://www.scopus.com/inward/record.url?scp=85131666936&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.medj.2022.04.001
DO - https://doi.org/10.1016/j.medj.2022.04.001
M3 - Article
C2 - 35434682
SN - 2666-6359
VL - 3
SP - 371-387.e9
JO - Med (New York, N.Y.)
JF - Med (New York, N.Y.)
IS - 6
ER -