Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection, 2022, Natarajan et al

[Hutan]

https://www.cell.com/med/fulltext/S2666-6340(22)00167-2

Highlights
1.Approximately half of COVID-19 patients shed fecal RNA in the week after infection
2. 4% patients with COVID-19 shed fecal viral RNA 10 months after diagnosis.
3. Presence of fecal SARS-CoV-2 RNA is associated with gastrointestinal symptoms.
4.SARS-CoV-2 likely infects gastrointestinal tissue.

Abstract
Background
COVID-19 manifests with respiratory, systemic, and gastrointestinal (GI) symptoms.1,2SARS-CoV-2 RNA is detected in respiratory and fecal samples, and recent reports demonstrate viral replication in both the lung and intestinal tissue.3–5 Although much is known about early fecal RNA shedding, little is known about the 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.6

Methods
We analyze the dynamics of fecal RNA shedding up to 10 months after COVID-19 diagnosis in 113 individuals with mild to moderate disease. We also correlate 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 and after 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 find 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 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.

 

[Hutan]

"Context and Significance

Gastrointestinal symptoms and SARS-CoV-2 RNA shedding in feces point to the gastrointestinal tract as a possible site of infection in COVID-19. Researchers from Stanford University measured the dynamics over time of fecal viral material in patients with mild to moderate COVID-19 followed for 10 months post-diagnosis. The authors found that fecal viral RNA shedding was correlated with gastrointestinal symptoms in patients who had cleared their respiratory infection. They also observed fecal shedding can continue to 7 months post-diagnosis In conjunction with recent related findings, this work presents compelling evidence of SARS-CoV-2 infection in the gastrointestinal tract and suggests a possible role for long-term infection of the gastrointestinal tract in syndromes such as “long COVID”.

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."

 

[Hutan]

This study was mentioned in an article posted about here:
Long Covid in the media and social media 2022

https://www.bloomberg.com/news/arti...ing-in-feces-offers-clues-to-long-covid-cause

 

[Hutan]

It seems highly likely that SARS-CoV-2 does, at least sometimes, infect the gastrointestinal tract:

However, there is mounting evidence of possible SARS-CoV-2 infection of the GI tract. Specifically, presence of SARS-CoV-2 RNA,5,22–24 protein antigen22,25 and virions5,24,26 in GI biopsies all point to a potential infection of the GI tract. Additional supportive evidence of a GI infection by SARS-CoV-2 is the presence of a gut immune response27 as well as inflammation measured by markers such as fecal calprotectin28,29 in individuals with COVID-19.

Finally, in vitro experiments reveal that SARS-CoV-2 is able to successfully infect enteroid models of the gut30–32 and intestinal cell lines.33 This phenomenon of possible GI tract involvement is not surprising as bovine coronavirus (BCoV) and human enteric coronavirus (HECoV-4408), both of the same genus as SARS-CoV-2 (Betacoronaviruses), can infect respiratory and GI tissues.34 Taken together, the data indicate that the GI tract may be an important site of SARS-CoV-2 infection.34

Autopsies of patients with COVID-19 have recovered live virus from intestinal biopsies:

Additionally, the largest autopsy series of patients with COVID-19, to date, recently demonstrated consistent evidence of infection of the small intestine by SARS-CoV-2; they also recovered live virus from these intestinal biopsies.5

The stool sample collection method in this study inactivated the virus. They recommend further studies aimed at collecting live virus:

We were also unable to collect stool samples in a way that would enable recovery of live virus. As this was an outpatient study during the early part of the pandemic, we required participants to collect stool themselves at home, and then mail the stool kits to us. For safety and practical purposes, we thus had to provide participants with kits that were rated for virus inactivation. Future studies, which facilitate the careful, consistent collection of stool samples from individuals with COVID-19 in a safe setting, might enhance the likelihood of more accurate measurement of live virus. This would be more direct evidence of SARS-CoV-2 being viable in the gut

They note that the NIH RECOVER study is collecting intestinal biopsies that should help answer the question of whether there is long lasting infection of the gastrointestinal tract.

While intestinal biopsies from patients with mild to moderate COVID-19 would be highly informative, to date these samples have been understandably difficult to obtain. In upcoming large studies, such as the Researching COVID to Enhance Recovery (RECOVER, NIH) study, a subset of patients will be getting such biopsies, and the results of these large-scale studies will be illuminating.

They also note that it would be useful to try to determine the variant of the virus in what appears to be extended shedding, to see if it is the same as the initial infection. This would help rule out the concern that 'extended shedding' is in fact re-infection.

I thought this was an interesting and thoughtful paper. That NIH RECOVER study is one to watch closely. I think too, we need to see biopsies from a range of body parts in people with Long Covid (probably best done in autopsies), to see if the virus is persisting.

 

[Wyva]

I think too, we need to see biopsies from a range of body parts in people with Long Covid (probably best done in autopsies), to see if the virus is persisting.

There is also a similar one that has been recently approved by the Hungarian Medical Research Council:

Title: Detection of certain components (proteins, RNA) of SARS-CoV-2 in COVID-19 and post-Covid-19 by organ
Applicant: Semmelweis University MSc II. s. Institute of Pathology
Supervisor: Dr. András Kiss

Hopefully there will be enough good quality studies on this.

 

[ME/CFS Skeptic]

Figure 4A shows the relationship between viral RNA in the stool and having symptoms. I would assume that if there was a causal relationship, the odds ratios would have been bigger?

 

[Midnattsol]

I wonder how this influence tight junction proteins. Immune system activation is associated with decreased epithelium barrier integrity, but so is a number of other things also. It's not just the expression of these proteins that can be affected, but also their localization at the cell membrane (which is annoying as "just" looking at protein expression might not be enough to say anything about if the proteins are doing what they are supposed to do).

 

[Andy]

Podcast: Coronapod: ‘viral ghosts’ support idea that SARS-CoV-2 reservoirs could be behind long COVID

"Millions of people around the world have been left managing the complex and amorphous syndrome that is long COVID. But the underlying cause of these myriad symptoms is not clear. One hypothesis is that the virus is able to find a safe haven in the body from which it can bide its time and potentially re-emerge — a viral reservoir. Now researchers studying long COVID have found evidence of SARS-CoV-2 in a series of organs around the body, most notably the gut, months after the infection appears to have been cleared from the respiratory system. Although there is still a long way to go before the reservoir hypothesis can be confirmed, these data provide compelling new support for the theory. In this episode of Coronapod, we discuss how the studies were carried out, why the question of long COVID’s cause is so difficult to crack, and what more needs to be done to get a firm answer."

https://www.nature.com/articles/d41586-022-01331-9


Coronavirus ‘ghosts’ found lingering in the gut

"In the chaos of the first months of the coronavirus pandemic, oncologist and geneticist Ami Bhatt was intrigued by widespread reports of vomiting and diarrhoea in people infected with SARS-CoV-2. “At that time, this was thought to be a respiratory virus,” she says. Bhatt and her colleagues, curious about a possible link between the virus and the gastrointestinal symptoms, began to collect stool samples from people with COVID-19.

Thousands of miles away from Bhatt’s laboratory at Stanford Medicine in California, gastroenterology internist Timon Adolph was puzzled by accounts of gut symptoms in infected people. Adolph and his colleagues at the Medical University of Innsbruck in Austria started to assemble specimens, too — gastrointestinal-tissue biopsies.

Two years into the pandemic, the scientists’ foresight has paid off: both teams have recently published results1,2 suggesting that pieces of SARS-CoV-2 can linger in the gut for months after an initial infection. The findings add to a growing pool of evidence supporting the hypothesis that persistent bits of virus — coronavirus “ghosts”, Bhatt has called them — could contribute to the mysterious condition called long COVID."

https://www.nature.com/articles/d41586-022-01280-3

Both podcast and article also discuss this study, Post-acute COVID-19 is characterized by gut viral antigen persistence in inflammatory bowel diseases, 2022, Zollner et al, as well.