Long period dynamics of viral load and antibodies for SARS-CoV-2 infection: an observational cohort study
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Abstract
OBJECTIVE
To investigate the dynamics of viral RNA, IgM, and IgG and their relationships in patients with SARS-CoV-2 pneumonia over an 8-week period.
DESIGN
Retrospective, observational case series.
SETTING
Wenzhou Sixth People’s Hospital
PARTICIPANTS
Thirty-three patients with laboratory confirmed SARS-CoV-2 pneumonia admitted to hospital. Data were collected from January 27 to April 10, 2020.
MAIN OUTCOME MEASURES
Throat swabs, sputum, stool, and blood samples were collected, and viral load was measured by reverse transcription PCR (RT-PCR). Specific IgM and IgG against spike protein (S), spike protein receptor binding domain (RBD), and nucleocapsid (N) were analyzed.
RESULTS
At the early stages of symptom onset, SARS-CoV-2 viral load is higher in throat swabs and sputum, but lower in stool. The median (IQR) time of undetectable viral RNA in throat swab, sputum, and stool was 18.5 (13.25-22) days, 22 (18.5-27.5) days, and 17 (11.5-32) days, respectively. In sputum, 17 patients (51.5%) had undetectable viral RNA within 22 days (short persistence), and 16 (48.5%) had persistent viral RNA more than 22 days (long persistence). Three patients (9.1%) had a detectable relapse of viral RNA in sputum within two weeks of their discharge from the hospital. One patient had persistent viral RNA for 59 days or longer. The median (IQR) seroconversion time of anti-S IgM, anti-RBD IgM, and anti-N IgM was 10.5 (7.75-15.5) days, 14 (9-24) days, and 10 (7-14) days, respectively. The median (IQR) seroconversion time of anti-S IgG, anti-RBD IgG, and anti-N IgG was 10 (7.25-16.5) days, 13 (9-17) days, and 10 (7-14) days, respectively. By week 8 after symptom onset, IgM were negative in many of the previously positive patients, and IgG levels remained less than 50% of the peak levels in more than 20% of the patients. In about 40% of the patients, anti-RBD IgG levels were 4-times higher in convalescence than in acute phase. SARS-CoV-2 RNA coexisted with antibodies for more than 50 days. Anti-RBD IgM and IgG levels, including anti-RBD IgM levels at presentation and peak time, were significantly higher in viral RNA short persistence patients than in long persistence patients.
CONCLUSION
This study adds important new information about the features of viral load and antibody dynamics of SARS-CoV-2. It is clear from these results that the viral RNA persists in sputum and stool specimens for a relatively long time in many patients. Anti-RBD may also serve as a potential protective antibody against SARS-CoV-2 infection, as viral persistence appears to be related to anti-RBD levels. Earlier treatment intervention also appears to be a factor in viral persistence.
WHAT IS ALREADY KNOWN ON THIS TOPIC
There are several reports about the serum antibodies against SARS-CoV-2. However, most of them evaluate diagnostic accuracy. Only two articles report dynamics of SARS-CoV-2 viral RNA and antibodies with serial samples, but the observation periods are within 30 days. None of the studies investigate the profiles of SARS-CoV-2 viral load and antibodies in a long period. Three reports investigate profiles in respiratory samples, but there are no reports on the dynamics of the viral load in stool samples.
WHAT THIS STUDY ADDS
In both sputum and stool, SARS-CoV-2 RNA persists for a long time. The anti-RBD antibodies may involve in the clearance of SARS-CoV-2 infection. After eight weeks from symptom onset, IgM were negative in many of the previously positive patients, and IgG levels remained less than 50% of the peak levels in more than 20% of the patients. In about 40% of the patients, anti-RBD IgG levels increased 4-time higher in convalescence than in acute phase. Long persistence of SARS-CoV-2 viral RNA in sputum and stool presents challenges for management of the infection. The IgM/IgG comb test is better than single IgM test as a supplement diagnostic tool. Anti-RBD may be a protective antibody, and is valuable for development of vaccines.
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SciScore for 10.1101/2020.04.22.20071258: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: This study was approved by the Ethics Commission of Wenzhou Central Hospital (L2020-01-036). Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources All analyses were done with SPSS version 24.0 (IBM, Armonk, NY, USA). SPSSsuggested: (SPSS, RRID:SCR_002865)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our study has some …
SciScore for 10.1101/2020.04.22.20071258: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: This study was approved by the Ethics Commission of Wenzhou Central Hospital (L2020-01-036). Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources All analyses were done with SPSS version 24.0 (IBM, Armonk, NY, USA). SPSSsuggested: (SPSS, RRID:SCR_002865)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our study has some limitations. First, the patient number in our study is relatively small, and only 33 patients were included in this study. This is, of course, a common weakness of studies of emerging infectious diseases. Second, samples for viral RNA and antibody detection were collected weekly and not on a daily basis. It was also difficult to collect samples at exactly one-week intervals. In some patients, initial samples were even missed due to the emerging situation for SARS-CoV-2 infection. In conclusion, this study adds important new information about the features of viral load and antibody dynamics of SARS-CoV-2. It is clear from these results that the viral RNA persists in sputum and stool specimens for a relatively long time in many patients. Anti-RBD may also serve as a potential protective antibody against SARS-CoV-2 infection, as viral persistence appears to be related to anti-RBD levels. Earlier treatment intervention also appears to be a factor in viral persistence. Further studies are needed to better understand the virological and immunological features of SARS-CoV-2 infection, which are important for the prevention, treatment and control of the spread of this disease.
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 18. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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SciScore for 10.1101/2020.04.22.20071258: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement This study was approved by the Ethics Commission of Wenzhou Central Hospital ( L2020-01-036) . Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Antibodies Sentences Resources A total of 171 serum samples were available for the analysis of SARS-CoV-2 S , RBD , and N specific IgM and IgG antibodies . IgGsuggested: NoneAnti-RBD antibodies appeared later than anti-S ( anti-RBD IgM vs. anti-S IgM , P=0.007; anti-RBD IgG vs. anti-S IgG , P=0.006) . anti-Ssuggested: None…SciScore for 10.1101/2020.04.22.20071258: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement This study was approved by the Ethics Commission of Wenzhou Central Hospital ( L2020-01-036) . Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Antibodies Sentences Resources A total of 171 serum samples were available for the analysis of SARS-CoV-2 S , RBD , and N specific IgM and IgG antibodies . IgGsuggested: NoneAnti-RBD antibodies appeared later than anti-S ( anti-RBD IgM vs. anti-S IgM , P=0.007; anti-RBD IgG vs. anti-S IgG , P=0.006) . anti-Ssuggested: None<div style="margin-bottom:8px"> <div><b>anti-RBD IgM</b></div> <div>suggested: None</div> </div> <div style="margin-bottom:8px"> <div><b>anti-S IgM</b></div> <div>suggested: None</div> </div> <div style="margin-bottom:8px"> <div><b>P=0.007; anti-RBD IgG</b></div> <div>suggested: None</div> </div> <div style="margin-bottom:8px"> <div><b>anti-S IgG</b></div> <div>suggested: None</div> </div> </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">Anti-RBD antibodies appeared later than anti-N , but the difference was not statistically significant ( anti-RBD IgM vs. anti-N IgM , P=0.054; anti-RBD IgG vs. anti-N IgG , P=0.078) .</td><td style="min-width:100px;border-bottom:1px solid lightgray"> <div style="margin-bottom:8px"> <div><b>Anti-RBD</b></div> <div>suggested: None</div> </div> <div style="margin-bottom:8px"> <div><b>anti-N</b></div> <div>suggested: None</div> </div> <div style="margin-bottom:8px"> <div><b>anti-N IgM , P=0.054; anti-RBD IgG</b></div> <div>suggested: None</div> </div> <div style="margin-bottom:8px"> <div><b>anti-N IgG</b></div> <div>suggested: None</div> </div> </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">Three patients ( 9.1 % ) were negative for all three IgM antibodies .</td><td style="min-width:100px;border-bottom:1px solid lightgray"> <div style="margin-bottom:8px"> <div><b>IgM</b></div> <div>suggested: None</div> </div> </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">These results raise concerns about the existence of protective antibodies against SARS-CoV-2, since one of the key roles of protective antibodies is to clear viral infection. 27 To and colleagues reported that anti-SARS-CoV-2-N or anti-SARS-CoV-2-RBD IgG levels correlated with virus neutralization titre.</td><td style="min-width:100px;border-bottom:1px solid lightgray"> <div style="margin-bottom:8px"> <div><b>SARS-CoV-2</b></div> <div>suggested: (Sino Biological Cat# 40143-R019, <a href="https://scicrunch.org/resources/Any/search?q=AB_2827973">AB_2827973</a>)</div> </div> <div style="margin-bottom:8px"> <div><b>anti-SARS-CoV-2-N</b></div> <div>suggested: None</div> </div> <div style="margin-bottom:8px"> <div><b>anti-SARS-CoV-2-RBD IgG</b></div> <div>suggested: None</div> </div> </td></tr><tr><td style="min-width:100px;text-align:center; padding-top:4px;" colspan="2"><b>Software and Algorithms</b></td></tr><tr><td style="min-width:100px;text=align:center"><i>Sentences</i></td><td style="min-width:100px;text-align:center"><i>Resources</i></td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">All analyses were done with SPSS version 24.0 ( IBM , Armonk , NY , USA) .</td><td style="min-width:100px;border-bottom:1px solid lightgray"> <div style="margin-bottom:8px"> <div><b>SPSS</b></div> <div>suggested: (SPSS, <a href="https://scicrunch.org/resources/Any/search?q=SCR_002865">SCR_002865</a>)</div> </div> </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">Discussion We investigated the serial viral load and dynamics of antibodies from patients infected with SARS-CoV-2 over an eight-week period following the onset of symptoms.</td><td style="min-width:100px;border-bottom:1px solid lightgray"> <div style="margin-bottom:8px"> <div><b>SARS-CoV-2</b></div> <div>suggested: (Sino Biological Cat# 40143-R019, <a href="https://scicrunch.org/resources/Any/search?q=AB_2827973">AB_2827973</a>)</div> </div> </td></tr></table>Results from OddPub: We did not find a statement about open data. We also did not find a statement about open code. Researchers are encouraged to share open data when possible (see Nature blog).
About SciScore
SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, please follow this link.
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