Discussion in ''Conditions related to ME/CFS' news and research' started by Andy, Mar 1, 2018.
I've stumbled back across this study and bearing in mind the current situation with Covid and LongCovid it might highlight the possible long term effects of widespread Covid infection.
CFS-like illness is defined as
It's a really interesting study @Andy, worth looking at more. (I haven't double checked all of this, as I'm getting tired.)
There is a spectrum of post-infective phenotypes, with a substantial overlap of musculoskeletal pain, fatigue and a whole range of other symptoms. And a lot of people having post-infective symptoms two years after infection - 76% of those with positive serology. If these findings applied more generally, it would suggest that fibromyalgia, chronic fatigue without identifiable PEM and ME/CFS are all names for subsets in a spectrum of pain, fatigue and other post-infection symptoms.
They suggest that blurred vision isn't a symptom of the CFS-like illness. That's only because they defined it that way. Variable blurred vision was a really noticeable and annoying feature of my illness in the early years. I think I may have just got used to it now.
And they suggest that mood disturbance wasn't associated with having fatigue symptoms.
They noted that more women than men got chikungunya in the first place (57% women), probably because they spent more time at home where the mosquitos are. The percentages of those who had long term symptoms about 2 years post-infection weren't very different (62% women) and might just be a result of the other factors mentioned as relevant - older age (probably more women); more severe initial illness (perhaps due to higher pathogen exposure, or to differences in the likelihood of being able to rest and be cared for while sick). They say though that women are more likely to exhibit the CFS-like symptom phenotype (as opposed to the two other phenotypes). The data behind that claim is in supplementary tables - I haven't looked yet.
I'm not quite sure why they talk about 'at the bottom or on the top of a likely complex disease'.
I'm finding all this particularly interesting given I might be having rheumatoid arthritis issues myself, at the moment.
Chronic Chikungunya Arthritis and Rheumatoid Arthritis: What They Have in Common
Amaral et al
Chikungunya virus (CHIKV) is a single-stranded RNA virus belonging to the family Togaviridae and genus Alphavirus that causes an acute febrile illness, chikungunya fever, which is transmitted to humans by Aedes species mosquitoes. During acute illness, patients have high fever, polyarthralgias or polyarthritis, maculopapular rash, headache, and myalgia that lasts for days to weeks. Following resolution of acute infection, a significant proportion of patients develop chronic chikungunya arthritis that can resemble rheumatoid arthritis. In this review, we first consider the historical background of infectious causes of inflammatory arthritis, and then the pathogenic and clinical manifestations of chronic chikungunya arthritis as a rheumatoid arthritis mimic.
We believe that chronic chikungunya arthritis may be a postinfectious inflammatory process, and that an understanding of the parallels and differences between chronic chikungunya arthritis and rheumatoid arthritis may offer insights into better diagnosis and treatment of both diseases.
As an opposing view, suggesting that there is real rheumatoid arthritis as part of the spectrum of post-infection illness, not just an RA-like post-infectious arthritis:
Rheumatoid arthritis after Chikungunya fever: a prospective follow-up study of 21 cases
This relates to the Reunion Island chikungunya outbreak. A co-author is a/the rheumatologist on the island. The article says 300,000 people were infected in a short space of time, so 21 cases is not a lot. It isn't said if there are other rheumatologists on the island who had their own caseloads.
It does sound though, like the 21 people had RA, and that onset probably was related to the Chik infection. There was bone erosion and there seemed to be a response to RA drugs.
The reason I'm posting about this is, if the Chik infection does cause fatigue and musculoskeletal pain and RA (and other symptoms), maybe the mechanisms for all of those things have some similarities. And the differences between the people who get one set of symptoms versus another versus none at all might be instructive.
Q&A: Chronic Chikungunya Arthritis vs. Rheumatoid Arthritis
Reading this article based on the Amaral paper I posted above, I'm not convinced the two conditions are different.
I don't find those very convincing. There is plenty of evidence of (small) finger joints being affected. The case report in the previous post did find positive RA serology in post-CHIKV arthritis. And of course people with post-CHIKV arthritis will have post-CHIKV serology - that's not proof that they don't have RA.
The memory and concentration problems and asthenia (abnormal physical weakness or lack of energy) sound like part of an ME/CFS spectrum of symptoms.
There are reports elsewhere of sub-cutaneous nodules in post-CHIKV arthritis (e.g. "we reported that 7% of participants with long term CHIKV (arthritis) complications reported joint nodules").
Maybe that's one reason why the post-CHIKV arthritic patients seem depressed?
Amaral is a Brazilian rheumatologist - he doesn't make post-CHIKV deforming arthritis sound very rare:
From what I can see these are completely separate diseases, but it is not necessarily easy to see that.
Remember that the clinical picture of rheumatoid arthritis is just the end result of chronic small immune complex mediated macrophage activation. Exactly the same appearance occurs in a proportion of people with lupus and a variety of other conditions (probably at least a score).
What makes RA an individual disease, inasmuch as any of these categories are cut and dried, is that we have reason to think it comes about through a particular mechanism that involves susceptibility through HLA-DR4, production f rheumatoid factor and anti citrulline antibodies and a process of evolution that fits a particular epidemiological profile - i.e. it is not precipitated by Chicungunya!
In other words two illnesses are not the same just because they look the same. Staphylococcal pyelonephritis and E coli pyelonephritis look very similar but one is staphylococcal and one coliform.
We have always understood in rheumatology that the category 'rheumatoid arthritis' as defined clinically includes at least 10-20% of people who do not have the disease I describe above but something you cannot tell apart from it other than by the tests. In recent times we have called these widespread inflammatory polyarthropathies (not otherwise specified). Chikungunya is another sometimes widespread inflammatory polyarthropathy, specified.
Another thing that may be of interest is that a hundred years ago, before penicillin, rheumatic fever could continue as a chronic process because the organism could not be cleared. A chronic deforming arthritis was recognised - known as Jaccoud's arthritis. Things are complicated because both for 'rheumatic fever' cases and 'Chikungunya' cases there is likely to be a proportion where the infection is coincidental to a non-infective inflammatory poly arthritis that would otherwise fall under 'RA'. But the rheumatic fever case shows that infection can produce chronic immune complex disease capable of resulting in a deforming arthropathy with small hand joint deformities like ulnar drift.
The papers on Chikungunya talk of using methotrexate but this seems to me to be purely speculative and pretty ill-advised. Just because methotrexate interferes with the process producing immune complexes in RA is no indication that it would affect the process producing small complexes in Chik. Moreover, I think there is a high chance that cases post-chik with deforming arthropathy represent the progression of tissue degeneration after the horse has bolted. Immune complex arthritis can destroy cartilage very quickly and once destroyed deformity may develop gradually over a period of years.
Ok, so the post-Chikungunya arthritis is an inflammatory polyarthropathy (with any RA-specific characteristics best explained by someone coincidentally developing RA around the time of the Chikungunya and/or the background level of RA markers found in healthy people).
And there is doubt that the methotrexate treatment (or any treatment) actually changes the course of the post-Chik disease, because the deformity outcome is determined by the cartilage damage that occurred during the acute disease? Presumably an identification of the cartilage damage soon after the acute illness and monitoring for further damage would confirm that?
So rheumatic fever can produce an infection-caused progressive arthritis because the pathogen is still there. There was the reference to this (quoted above):
so, if that is true, the CHIK arthritis could perhaps be like the rheumatic fever arthritis (Jacoud's arthritis)? Does methotrexate not help Jacoud's arthritis because the disease mechanism is different? Do you have to get rid of the pathogen to get stop the arthritis?
Maybe it's that idea of the CHIKV persisting in the body that needs to be examined to see if it is really true. Perhaps if it is, CHIKV persisting in different tissues might explain the apparent spectrum of post-infection musculoskeletal illness, chronic fatigue and chronic fatigue syndrome-like illness. ?
That is quite tricky to do. Nobody really nailed it in the days of longitudinal studies (1980-200). Now we have MRI but it might still be difficult to know the sequence of events. It could be nailed by really good methodology but I doubt anyone would fund it.
Yes, this is always tricky. Finding a bit of antigen may not tell us much and a lot of studies looking for antigens use poor immunohistochemical techniques anyway. Chronic infective arthropathy is of course well understood in things like TB, where the tissue has a typical response to live bacteria, but for a lot of infections it is hard to know. That is, of course, the big issue for borrelia.
Methotrexate treatment for post-Chik arthritis is ridiculously common for something that is not appropriate for the damage mechanism. Still, I guess we have seen widespread use of a treatment is not proof of efficacy. There are some trials where methotrexate seemed promising but the methodology has been less than ideal. A double blinded randomised placebo controlled study of a good size began recruiting last year, but won't be finished until 2025.
This is the study that provided the quote about virus being found in synovial tissue:
Persistent Chronic Inflammation and Infection by Chikungunya Arthritogenic Alphavirus in Spite of a Robust Host Immune Response
For the biopsies, they only had three people who had been infected with Chik and happened to be needing surgery. One had severe chronic arthralgia and the other two didn't have any arthralgia. So, the person with arthralgia was found to have Chik RNA and proteins in the perivascular synovial macrophages, 'surrounded by infiltrating NK and T cells' at 18 months after infection. The two wth no arthralgia didn't have any Chik RNA and proteins.
So, it's only one person. It's a shame there isn't more, and I surprised that there hasn't been more. Post mortems? Maybe biopsies are possible? I don't know, the report looks credible, but yeah, just one case.
The study looked at a range of indicators of ongoing infection in the people with arthralgia in a prospective cohort study - 49 hospitalised patients, divided into two groups 12 months after infection - the recovered, and the people with arthralgia.
High levels of IFN-α mRNA in PBMCs and circulating IL-12 persisted in the arthralgia group. "IL-12 is essential to initiate the activation of NK cells and macrophages to ward off infectious challenge, and interestingly, its level remained dramatically elevated in chronic CHIKVD patients (1650.88 ± 1385.79 pg/ml at M12) (Fig. 1C). In sharp contrast, IL-12 returned to background levels from D15 in the recovered group." So, that looks interesting.
Chik virus specific IgM (marker of current infection) persisted even after a year in both groups. In fact levels were higher in the recovered group. Persistence of IgM has been reported with other infections too e.g. flu. I don't think we can assume this confirms an ongoing infection.
There was evidence of higher T cell activation in the acute disease for those with arthralgia, but the sample sizes were small.
So, not quite like rheumatoid arthritis, and so influencing what treatment is likely to work. (Despite that, the authors remain convinced methotrexate treatment is helping.)
That 'RRV' is Ross River Virus, one of the pathogens considered in the Dubbo study which found a post-viral fatigue syndrome.
It doesn't seem such a hard question to answer conclusively - is the Chik virus (or RRV for that matter) surviving in protected reservoirs in the body? These people are convinced it is.
I think the problem here is the same as for looking for a whole lot of other 'persistent antigens'. The only people who seen their time looking are people who are convinced they are there. Maybe they are there, but that still begs the question as to whether it is relevant. Decades ago Ralph Schumacher showed all sorts of junk in synovial macrophages by electron microscopy. I found TB antigen in sarcoid arthritis - at least my collaborator's DNA primer gave a signal but a few months later he admitted the primer was useless.
These things would be fascinating to me if I had some first hand experience of the patients to put it in context. I find it hard to get very excited about it at long distance.
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