Virological assessment of hospitalized patients with COVID-19

Virological assessment of hospitalized patients with COVID-19. Jefferson T, Heneghan C.

https://www.cebm.net/study/virological-assessment-of-hospitalized-patients-with-covid-19/

Published on July 27, 2020

Reference Wölfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID-19.  https://doi.org/10.1038/s41586-020-2196-x
Study type
Country Germany
Setting Hospital
Funding Details German Ministry of Research and the European Union and German Bundeswehr Medical Service Biodefense Research Program
Transmission mode Droplets, Orofecal
Exposures

Bottom Line

Nine cases of COVID-19 that provide proof of active virus replication in tissues of the upper respiratory tract.

Evidence Summary

There were no discernible differences in viral loads or detection rates when comparing naso-and oropharyngeal swabs. The earliest swabs were taken on day 1 of symptoms, which were often very mild or prodromal. All swabs from all patients taken between day 1 and day 5 tested positive. 

The average virus RNA load was 6.76 × 105 copies per the whole swab until day 5, and the maximum load was 7.11 × 108 copies per swab. The last swab sample that tested positive was taken on day 28 after the onset of symptoms. 

Stool samples were also positive but none grew live virus. Active replication of SARS-CoV-2 took place in the throat samples during the first five days after the onset of symptoms, as identified by the presence of viral mRNA. 

Concentrations of viral RNA were very high in initial samples but in all patients except one, the concentration of viral RNA in throat swabs seemed to be already on the decline at the time of the first presentation. Viral RNA concentrations in sputum declined more slowly, with a peak during

the first week of symptoms in three out of eight patients. Viral RNA concentrations in stools were also high and in some cases, the course of viral RNA concentration in stools seemed to reflect the course in sputum. In only one case did independent replication in the intestinal tract appear obvious from the course of stool RNA excretion. Whereas symptoms mostly diminished until the end of the first week, viral RNA remained detectable in throat swabs well into the second week. Stool and sputum samples remained RNA-positive over three weeks in 6/9 patients, in spite of full resolution of symptoms.

What did they do?

The study is a case series of virological investigation of nine COVID-19 cases who were initially diagnosed by RT–PCR from both oro-or nasopharyngeal swab specimens collected over the whole clinical course. Only three cases had comorbidities and all had mild illness.

The authors also tested other CoV and most common respiratory viruses (all were negative). 27 urine samples and 31 serum samples were tested, but none were positive for RNA from SARS-CoV2. 

The combination of very high concentrations of virus RNA and the occasional detection of cells in stools that contain subgenomic mRNA indicate active replication in the gastrointestinal tract.

Study reliability

The study is small and requires replication especially of the growth of stool isolates in the light of later discoveries of growth in enterocytes

Clearly defined setting Demographic characteristics described Follow-up length was sufficient Transmission outcomes assessed Main biases are taken into consideration
Unclear Partly Unclear Yes Unclear

What else should I consider?

This study requires replication with a bigger set of cases.

SARS-CoV-2 may have a more efficient transmission than SARS-CoV, through active pharyngeal viral shedding at a time at which symptoms are still mild and typical of infections of the upper respiratory tract.

The combination of very high concentrations of virus RNA and the occasional detection of cells in stools that contain subgenomic mRNA indicate active replication in the gastrointestinal tract. 

Active replication is also suggested to be detected more often than MERS-CoV, for which stool-associated RNA was found in only 14.6% of samples from 37 patients hospitalized in Riyadh (Saudi Arabia). 

If SARS-CoV-2 was only passively present in stool (such as after swallowing respiratory secretions), similar detection rates as for MERS-CoV would be expected. 

Replication in the GI tract is also supported by analogy with SARS-CoV, which was regularly excreted in the stool (from which it could be isolated in cell culture). [Leung  2003] Further studies should address whether SARS-CoV-2 shed in stools is rendered noninfectious though contact with the gut environment.  Of note is that there is no abrupt cessation of viral shedding on seroconversion but steady decline. 

Leung, W. K. et al. Enteric involvement of severe acute respiratory syndrome-associated coronavirus infection. Gastroenterology 125, 1011–1017 (2003).

About the authors

Carl Heneghan

Carl Heneghan

Carl is Professor of EBM & Director of CEBM at the University of Oxford. He is also a GP and tweets @carlheneghan. He has an active interest in discovering the truth behind health research findings

Tom Jefferson

Tom Jefferson

Tom Jefferson is a senior associate tutor and honorary research fellow, Centre for Evidence-Based Medicine, University of Oxford.