Thread by @dgurdasani1

There's more & more evidence accumulating that COVID-19 causes a chronic illness in many, and that this correlates with virus persistence in tissues. We should really start thinking about this as an illness where virus persists chronically in a significant proportion of people.🧵

I think there's enough evidence to support this now- yet we still keep seeing comparisons with the flu- when the comparisons perhaps need to be with other viruses that are associated with virus persistence and chronic illness and inflammation in a proportion of those infected.

Gut persistence of SARS-CoV-2 has been shown to happen since 2020 - through studies of continuous/intermittent shedding of virus in stool for >1 month. But the correlation of this with long COVID symptoms wasn't examined until recently.
ncbi.nlm.nih.gov/pmc/articles/P…

This study in patients with inflammatory bowel disese (IBD) looked at virus persistence - and found SARS-CoV-2 RNA and nucleocapsid protein (a virus protein) in gut mucosa of 50-70% of patients. Finding these correlated strongly with long COVID symptoms.
sciencedirect.com/science/articl…

Virus was not culturable (so no evidence it was replicating)- suggesting that persistence of virus antigen rather than replicating virus. Worth noting that even replicating virus can be difficult to isolate on culture, so it doesn't rule it out entirely.

Of course this was a study in patients with IBD, some of whom were on immunosuppression, so may not be generalisable to the community. So what do we find in more population based studies?

In another study about 5% of people tested PCR positive from nasopharynx at median 90 days post infection- & had an activated immune response specific to SARS-CoV-2 suggesting virus persistence. But their contacts did not seem to get infected.
thelancet.com/journals/ebiom…

In another study of 113 people with mild to moderate acute SARS-CoV-2 infection 13% were shedding virus in stool at 4 months, & 4% at *7 months* post-infection - so not rare! And shedding virus in stool was associated with gut symptoms.

cell.com/med/fulltext/S…

Also shown to happen in the gut in children- this is a case of a 11 yr old girl who had persistence of virus in gut 3 months after infection- associated with inflammation of the colon, and gut symptoms:
journals.lww.com/jpgnr/fulltext…

What about other tissues?
This preprint reports autopsies from multiple tissues in 44 patients at different points from acute infection - up to 7 months after acute infection. Some patients included did not die from COVID-19, but other causes.

researchsquare.com/article/rs-113…

They found virus RNA in multiple tissues including in the brain up to 7 months post-infection. They also looked for sub-genomic RNA (may indicate replication, but not definitive), and found this also in multiple tissues, persisting for long periods of time (vertical lined boxes)

Overall, they reported that ~40% of patients autopsied had virus RNA in at least one tissue after 31 days post-infection in this cohort. Of course, the cohort is an autopsy cohort so not generalisable to the general population, but shows the potential for virus persistence.

Virus culture also was done, and virus was isolated from multiple tissues (lung, bronchus, sinus turbinate, heart, mediastinal lymph node, small intestine, and adrenal gland) but only up to day 7 - showing that the virus can infect most organs at least in the acute phase.

Another important preprint out just a wk ago from a Harvard group looking at plasma samples from 63 people with prior COVID of whom 37 had long COVID. Of the 26 who'd had infection but not long COVID, 10 had had severe disease (admitted to ICU).

medrxiv.org/content/10.110…

The researchers detected the spike protein
in 60% of the long COVID patients at multiple points up to 12 months (blue points and lines in figure below) post-infection but *not at all* in the COVID-19 post-infection but not long COVID patients

The authors concluded that circulating full length spike protein in plasma suggest viral reservoirs may be present in patients with long COVID.

So:
-virus persistence occurs for long periods of time - and is not uncommon even in those with mild-moderate disease.
-Persistence seems to correlate with long COVID symptoms
-whether this is antigenic persistence or replicating virus in reservoirs is not entirely clear yet

This has many ramifications. As @drclairetaylor has suggested, this could potentially explain the immune activation seen in those with long COVID. There are multiple studies now, that show long COVID symptoms are associated with inflammatory markers in blood.

This study showed that 28 inflammatory markers combined predicted long COVID at 8 months with 80% accuracy (this is for those who're still saying long COVID is psychosomatic!). So inflammatory markers separate out those with and without long COVID.
nature.com/articles/s4159….

Elevated levels of CCL-11 have been identified in long COVID patients who report brain fog, compared to those who did not - all indicating immune dysregulation plays an important role in long COVID.

https://twitter.com/VirusesImmunity/status/1482768696896626691?s=20&t=H05qd_DYtvOK5bT68TECIw

How much of this is due to virus persistence (antigenic? or replicating?) - as persistence is likely to lead to immune activation. Could this lead to other impacts seen like vascular damage, microclotting?
And if so, how do we clear the reservoirs of the virus in tissue?

Remember this isn't persistence in the way described in the blood of immunosuppressed patients. This is virus antigen or protein seen in the tissue or blood of patients who aren't immunosuppressed, but have long COVID. So even in people who weren't immunosuppressed.

I think we need urgent answers to these questions. In the meantime, I'd strongly recommend not exposing yourself to a virus that leads to persistence in what seems to be a significant proportion of people - given we don't know the long-term implications yet.

And what we do know looks worrying. We don't know how to clear this persistent virus (whether antigen or replicating) yet. Think of other viruses that persist in this way. Would we ever thing of exposing ourselves to them - knowing they persistent & cause chronic illness?

I don't think so & neither should we with SARS-CoV-2. The more we learn about long COVID, the more it seems that SARS-CoV-2 isn't just an acute infection, but a persisting virus in a significant proportion of people. And not one that one should take lightly. It's not the flu.