NIH: Citizen Scientists Take on "Long Haul" COVID-19

[Gemini]

Among the many longer-term health problems that have been associated with COVID-19 are shortness of breath, fatigue, cognitive issues, erratic heartbeat, gastrointestinal issues, low-grade fever, intolerance to physical or mental activity, and muscle and joint pains.

COVID-19 survivors report that these symptoms flair up unpredictably, often in different combinations, and can be debilitating for days and weeks at a time.

https://directorsblog.nih.gov/2020/...-take-on-the-challenge-of-long-haul-covid-19/

 

[used_to_race]

From the article:

Respondents who reported testing positive for SARS-CoV-2 were tested on average earlier in their illness (by day 10) than those who reported testing negative (by day 16). The team noted that their findings parallel those in a recent published scientific study, which found false-negative rates for current PCR-based assays rose as the time between SARS-CoV-2 infection and testing increased [2]. In that published study, by day 21, the false-negative rate reached 66 percent. Only two symptoms (loss of smell and loss of taste) occurred more frequently in respondents who tested positive; the other 60 symptoms were statistically the same between groups. The citizen scientists speculate that testing is not capturing a subset of COVID patients, and more investigation is required.

It's not really a false-negative though - there is just a really low level of virus below the sensitivity of the test. They've cleared the virus and the symptoms caused by the immune system. These people are no longer infectious, even if they still feel terrible. Really you're only shedding large amounts of virus in the day or two before onset of symptoms and the 7 days after onset of symptoms. I would hate to see COVID long haulers make the same mistakes made by the ME/CFS community and obsess over chronic active infections when in many cases the evidence doesn't support such things.

 

[Gemini]

Making a Recovery: Of the 60 respondents who had recovered, the average time to recovery was 27 days.

The respondents who had not recovered had managed their symptoms for 40 days on average, with most dealing with health problems for 5 to 7 weeks.

The report shows that the chance of full recovery by day 50 is less than 20 percent.

Exercise Capacity: About 65 percent of respondents now consider themselves mostly sedentary. Most had been highly physically active before developing COVID-19.

Many long-haulers expressed concern that "overexertion causes relapses"

Edit: my bolding.

 

[ljimbo423]

Exercise Capacity: About 65 percent of respondents now consider themselves mostly sedentary. Most had been highly physically active before developing COVID-19.

Many long-haulers expressed concern that "overexertion causes relapses"

This sounds eerily familiar.

 

[Hip]

I would hate to see COVID long haulers make the same mistakes made by the ME/CFS community and obsess over chronic active infections when in many cases the evidence doesn't support such things.

On the other hand, if long-haul COVID does involve low-level intracellular viral infections as have been found in ME/CFS (numerous studies found chronic non-cytolytic enterovirus in the muscle tissue biopsies of ME/CFS patients), then it's possible immunomodulatory treatments like oxymatrine which sometimes help ME/CFS patients may also be useful for long-haul COVID.

Also, I think interferon therapy for long-haul COVID would be very important to try. Studies have shown interferon therapy is often very effective for enterovirus-associated ME/CFS; unfortunately though the ME/CFS returns 4 to 12 months after the end of the therapy, suggesting that interferon was not able to completely clear the virus, so it slowly grows back.

However, long-haul COVID patients might be luckier, and perhaps interferon therapy will fully cure them on a permanent basis.



It is interesting that coronavirus comes under the classification of a positive-sense single-stranded RNA virus (+ssRNA). Tellingly, enterovirus is also in this +ssRNA class.

I wonder if the ME/CFS might be caused by coronavirus sticking round in the body using the same non-cytolytic infection mechanism as enterovirus.

Two other viruses which are in the +ssRNA class, namely alphavirus and dengue virus, are known to form non-cytolytic infection. So this class of virus has a tendency to form non-cytolytic infections.

In fact, I had a friend once who caught dengue in Brazil, and developed a life-long ME/CFS-like illness.

 

[used_to_race]

On the other hand, if long-haul COVID does involve low-level intracellular viral infections as have been found in ME/CFS (numerous studies found chronic non-cytolytic enterovirus in the muscle tissue biopsies of ME/CFS patients), then it's possible immunomodulatory treatments like oxymatrine which sometimes help ME/CFS patients may also be useful for long-haul COVID.

It's good that you point this out but I think this is a little misleading. Most of the studies in this long list look at antibodies, which are not evidence of persistent infection in any way. The detection of viral nucleic acid is somewhat more concerning, but it's not the gold standard for detection of infectious virus. I don't have an explanation for why the nucleic acid is there 20 years later, but I'm not an expert. It warrants further study in my opinion but this was never confirmed. I always thought EBV was known to periodically reactivate even in healthy individuals so this isn't necessarily proof of anything for EBV.

Between some of the brain and muscle biopsy studies listed, I think it for sure merits further study for detection of viable virus (plaque assay seems to be the gold standard) but even based on the existing evidence it doesn't seem to explain a majority of cases.

Two other viruses which are in the +ssRNA class, namely alphavirus and dengue virus, are known to form non-cytolytic infection. So this class of virus has a tendency to form non-cytolytic infections.

Are there any textbook-like resources you can provide that discuss non-cytolytic infection as a concept?

 

[Hip]

Most of the studies in this long list look at antibodies, which are not evidence of persistent infection in any way.

That's true, but it's interesting that in ME/CFS patients with enterovirus infection in their muscles — as demonstrated by PCR — you find these chronically high antibody levels. So the high antibody levels correlate to these non-cytolytic enterovirus infections, suggesting the ongoing non-cytolytic infection may be the cause of these elevated antibodies.

But I agree, elevated antibodies are not themselves direct proof of an ongoing infection.

Note also that some healthy controls have these non-cytolytic infections in their muscles; thus the the presence of these infection in the muscles cannot be the sole cause of ME/CFS.

I don't have an explanation for why the nucleic acid is there 20 years later, but I'm not an expert.

These chronic non-cytolytic enterovirus infections were a mystery for many decades. They were mainly observed and studied in chronic enterovirus myocarditis (in the heart muscle tissues), and these enigmatic infections left virologists scratching their heads for years.

The big mystery was that in chronic enterovirus heart muscle infections, you would find enterovirus RNA, but researchers were almost never able to culture lytic enterovirus infections from these heart tissue biopsies. That really made no sense: if there is an infection producing viral RNA, it should also produce viral particles which you should be able to culture in vitro.

It's only in recently years that this anomaly has been understood: we now know that non-cytolytic infections produce almost no lytic viral particles, as they are primarily an intracellular infection, comprising naked, self-replicating enteroviral RNA that lives inside human cells.

Are there any textbook-like resources you can provide that discuss non-cytolytic infection as a concept?

Sadly there's little in the way of good textbook introductions to non-cytolytic enterovirus. But I did write this MEpedia article on the subject a while back (it took me about a month of solid work to do write it, not to mention many years prior to that trying to understand non-cytolytic infections).

The bottom of the MEpedia article has links to further tutorial info; in particular, the videos by Prof Nora M. Chapman are where I got much of my info from (Prof Chapman is the discoverer of the mechanism of non-cytolytic infection).

And also I posted this easier-to-understand thread on non-cytolytic infection, which you might like to read, just to give an overview.

If you find any errors, please let me know; it is a very difficult subject to work with under brain fog conditions.

 

[Gemini]

Also, I think interferon therapy for long-haul COVID would be very important to try.

@Hip glad you mentioned interferon therapy.

In a prevention trial in China none of over 2900 medical staff members given daily interferon alpha nasal drops contracted the virus. "An Experimental trial of recombinant human interferon alpha drops to prevent coronavirus disease 2019 in medical staff in an epidemic area," [medRxiv, Meng, et al.]

A British study of 101 hospitalized COVID patients given the drug SNG001, based on interferon beta,
had a 79 percent chance of not needing ventilation or dying. The researchers say it's vital to administer it directly to the lungs via an inhaler. [The Week, August 7, 2020]

Some research groups are reporting the coronavirus virus may delay, muffle or disable interferon, one of the body's frontline defenders against viral invasion; several COVID interferon treatment trials are underway.
["Can interferons stop COVID-19 before it takes hold? Science, July 10, 2020; "Scientists Uncover Biological Signatures of Worst COVID-19 Cases," New York Times, August 4, 2020]

https://www.nytimes.com/2020/08/04/health/coronavirus-immune-system.html?searchResultPosition=1

 

[Gemini]

Studies have shown interferon therapy is often very effective for enterovirus-associated ME/CFS;

@Hip very good point.

If coronavirus is disrupting "normal" interferon functioning as some recent research indicates could a similar interferon "disruption" occur in ME/CFS re: an enteroviral infection do you think?

If so, happening early on in an infection would this occur upstream from many of the later ME/CFS symptoms such as the circulatory problems recently reviewed by @Cort? @alex3619?

 

[Hip]

If coronavirus is disrupting "normal" interferon functioning as some recent research indicates could a similar interferon "disruption" occur in ME/CFS re: an enteroviral infection do you think?

Disrupting the immune system in this sort of way is termed immune evasion.

All pathogens use various immune evasion techniques to avoid being killed by the immune system. A pathogen may simultaneously deploy half a dozen or more different immune evasion tactics.

Most of these immune evasion tricks used by pathogens "hack" the immune system in order to thwart the immune response. It's all part of the ongoing war between pathogens and their host.

Enteroviruses use a number of known immune evasion tactics, and probably many more which we don't yet know. For example enterovirus cunningly removes the MHC proteins from the cells it infects, which then makes those cells "invisible" to CD8 immune surveillance, because CD8 T-cells recognize infected cells via the MHC system. So if you remove MHC, the immune system's CD8 T-cells become "blind" to these infected cells.



There is also one theory (not proven) that non-cytolytic enterovirus RNA avoids being targeted by type 1 interferon by deleting the part of its RNA genome which interferon targets. That makes it invulnerable to the type 1 interferon response, and could explain why non-cytolytic enterovirus is able to persist for years or decades inside cells.

And this could explain why interferon therapy is unable to completely eradicate enterovirus from ME/CFS patients.


I also wonder whether some of these immune evasion tactics might lead to various immune-mediated diseases, such as autoimmune diseases, or diseases like ME/CFS. If a pathogen is hacking into the immune system and rendering the immune system slightly dysfunctional, that dysfunction might have a knock-on effect that leads to disease.

 

[Hipsman]

In a prevention trial in China none of over 2900 medical staff members given daily interferon alpha nasal drops contracted the virus. "An Experimental trial of recombinant human interferon alpha drops to prevent coronavirus disease 2019 in medical staff in an epidemic area," [medRxiv, Meng, et al.]

From study:

Secondly, SARS-CoV-2 nucleic acid tests and serum antibodies tests were not performed for the subjects in this study, so it was impossible to determine whether IFN-α has prevents infection with SARS-CoV-2; instead, the development of COVID-19 pneumonia was the main evaluation indicator. The main reason for using this outcome was that no COVID-19 diagnostic kits had been approved at the beginning of the study. .

They study didn't account for asymptomatic cases, still very good result, might try interferon alpha nasal drops

 

[Gemini]

If a pathogen is hacking into the immune system and rendering the immune system slightly dysfunctional, that dysfunction might have a knock-on effect that leads to disease.

Excellent review of pathogen-host immune response esp. enterovirus hacking, @Hip.

Along those lines the NYTimes article above says studies show coronaviruses' "hacking" may also extend from interferon into B and T cell responses in severe cases.

To fix that "might require an immunological reset--drugs that could, in theory restore the balance in the body and resurrect lines of communication between bamboozled cells."

What I find so promising is that COVID research is focusing on the first steps of the pathogen-host response, something we've wanted to study in ME/CFS for decades.