Cytokine deficiencies in patients with Long-COVID, 2022, Vicente Planelles et al

Preprint
Plasma cytokine levels reveal deficiencies in IL-8 and gamma interferon in Long-COVID, 2022, Elizabeth S C P Williams et al
See post #8 for published version
Abstract

Up to half of individuals who contract SARS-CoV-2 develop symptoms of long-COVID approximately three months after initial infection. These symptoms are highly variable, and the mechanisms inducing them are yet to be understood.

We compared plasma cytokine levels from individuals with long-COVID to healthy individuals and found that those with long-COVID had 100% reductions in circulating levels of interferon gamma and interleukin-8 (IL-8). Additionally, we found significant reductions in levels of IL-6, IL-2, IL-17, IL-13, and IL-4 in individuals with long-COVID.

We propose immune exhaustion as the driver of long-COVID, with the complete absence of interferon gamma; and IL-8 preventing the lungs and other organs from healing after acute infection, and reducing the ability to fight off subsequent infections, both contributing to the myriad of symptoms suffered by those with long-COVID.

https://www.medrxiv.org/content/10.1101/2022.10.03.22280661v1

 

This is similar to ME research, where there are some signs of immune dysregulation, as if the immune system is activated in some ways and "exhausted" in others, but research is too preliminary to piece everything together.

 

What are the symptoms of an 'exhausted' system?

There are subsets of pwME that don't get reactivated herpes viruses, flu or cold viruses while others have them all the time. I didn't have viral infections during the first 11 years, but now I'm in the subset that gets reactivated herpes viruses all the time. I don't get the flu or colds.

 

Who knows? It is not a well-defined clinical condition.

I don't find the hypothesis of the paper terribly convincing due to a poor choice in controls. They need to compare to healthy controls who had been infected at a similar time to the cases, but managed to recover.

It is known that SARS-CoV-2 interferes with the production of type 1 interferons, and this is one of the primary reasons why COVID is so deadly - that the normal cytokine response from infected cells is inhibited until it is too late and the infection is out of control. The subsequent immune responses are likely to be biased as a result. (edit - to avoid misunderstanding, ifn-gamma is a type 2 interferon)

Hence the results may simply be a consequence of SARS-CoV-2 infection, rather than specific to LongCOVID.

 

This is what I was thinking too. Most people recover from PVFS, for some it can take a few years longer.

I think my case was the relapse from taking immune modulators that brought on all the reactivations of herpes viruses. It seems to have switched something on.

 

Intriguingly IL-8 is the one thing that might consistently be UP in ME, not down!!

 

This paper has now been published: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894377/ . They try to address the differences between their findings and other studies (which find the opposite) in the discussion. One thing they say is: "Even though the symptoms of long-COVID are thought to be similar or overlapping to those of ME/CFS, when we compare our long-COVID cytokine to those from ME/CFS patients there are glaring differences. Specifically, the pro-inflammatory cytokines IL-1β, TNFα, and IL-6 tend to be reported as being elevated in patients with ME/CFS [32], whereas we observed significant decreases in IL-6 levels in individuals with long-COVID, and no differences in levels of IL-1β and TNFα." However, the PHOSP-COVID trial found raised levels of inflammatory chemicals across the board, and especially of IL-6

 

Personally I don't have a 100% reduction in my interferon gamma levels. It was 3465 pg/mL for me about 5 years into my disease (after EBV). There was no range or comment included for this value for me, just the number itself. But it is not zero in my case.

They didn't measure IL-8 but IL-4 was 76 pg/mL for me, whatever that means. My Hashimoto's thyroiditis as an autoimmune disease may affect these levels though but I have no actual idea.

They calculated the Th1/Th2 ratio from these and I have mild Th2 excess (Il-4, as opposed to interferon gamma).

 

I think these are interesting observations of longCOVID patients, which tell us that something is different for them.

I am sceptical about interpreting it as immune exhaustion though.

I am not saying it is impossible, just that when the immune system does something it is usually due to signalling of some kind, a reaction to a real stimulus, not simply running out of stuff.

It may be that treating a patient as if they are exhausted might help them recover in a clinical context. But imho the question which needs answering is what is causing absence of IFNγ and IL-8. Total absence suggests there might be some kind of regulatory mechanism involved, because if it was exhaustion you would expect low levels, a trickle of throughput as it were. Absence suggests the shutdown of a pathway, which must have a cause.