Rheumatism and chronic fatigue, the two facets of post-chikungunya disease: the TELECHIK cohort study on Reunion island, 2018, Gérardin et al

[Andy]

Abstract
Prolonged fatigue is increasingly reported among chikungunya virus (CHIKV)-infected populations. We investigated the relationships between CHIKV exposure, long-lasting rheumatic musculoskeletal pain (LRMSP) and chronic fatigue. 1094 participants (512 CHIKV seropositive and 582 seronegative) of the TELECHIK population-based cohort were analysed considering the duration of the manifestations throughout an average 2-year follow-up. Weighted prevalence rates and prevalence ratios for LRMSP, idiopathic chronic fatigue (ICF), and chronic fatigue syndrome (CFS)-like illness, both latter syndromes adapted from Centers for Disease Control (CDC)-1994/Fukuda criteria, were compared. Population attributable fractions (PAF) were estimated to assess the contribution of CHIKV infection to each of the three phenotypes.

Among 362 adult subjects who had reported either rheumatic pain or fatigue at the onset of the infection, weighted prevalence rates of LRMSP, ICF and CFS-like illness were respectively of 32.9%, 38.7% and 23.9%, and of 8.7%, 8.5% and 7.4% among initially asymptomatic peers (P < 0.01, respectively). Each of the three outcomes was highly attributable to chikungunya (PAF of 43.2%, 36.2% and 41.0%, respectively). In the sub-cohort of CHIKV-infected subjects, LRMSP, ICF and CFS-like illness, which overlapped in 70%, accounted for 53% of the chronic manifestations. In addition to rheumatic disease, chronic fatigue could be considered in caring for patients with chronic chikungunya disease.

https://www.cambridge.org/core/jour...nion-island/9219D0C9D7B26C605C9452B0EADA61D6#

 

[Andy]

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

Outcome measures
Given regular criticisms on the lack of sensitivity of ME/CFS definitions [1], we truncated the Centers for Disease Control (CDC)-1994/Fukuda's definition [32] to only four criteria to keep sufficient sensitivity and be discriminative enough among the main chronic pain phenotypes. These criteria were chosen to fulfil a declarative survey (exclusion of lymphadenopathy, the only clinical criterion of the definition). Sore throat, the other declarative Fukuda's criterion was considered too sensitive to influenza cycles for being discriminative. In the absence of physical examination by a clinician or a psychiatrist, and in the absence of routine biological tests, we adapted the definition of ICF and CFS proposed by the CDC to enable the classification of complaints into LRMSP, ICF and CFS-like illness phenotypes.

Our definition of self-reported CFS-like illness fulfilled the definition of post-exertion malaise, taken as a major criterion, as previously required by the successive conceptual frameworks used for ME/CFS [1, 2, 32]. This fatigue must have lasted consecutively for at least 6 months and not be substantially alleviated by rest and result in a substantial reduction in previous levels of occupational, educational, social, or personal activities.

CFS-like illness
CFS-like illness was defined in the presence of both two abovementioned major criteria and at least, two of the following minor criteria: musculoskeletal pain, memory troubles/attention difficulties, new type of headaches (occurred after the time elapsed for acute-stage disease and lasting ⩾1 month. in the absence of migraine), sleeping disorders/unrefreshing sleep.

Minor symptoms had to occur concomitantly or after the onset of reported fatigue.

The new findings confirm the high disease burden of post-infective phenotypes, both at the population level and in CHIKV-infected subjects, on average 18 months after the end of the epidemic. The absence of previous herd immunity to CHIKV was a key determinant for the magnitude of this outbreak, with about 40% of the community infected with the virus [31]. This added probably to the high prevalence of LRMSP, ICF and CFS-like illness among CHIK+ subjects 2 years after the onset of infection, which may account for the heavy toll paid by the Reunionese population. From this point of view, the public health impact of CHIKV in Reunion island was far superior to that reported for RRV-related epidemic polyarthritis in Australia, whose spectrum of long-term manifestations is very similar [4, 29]. Consistent with this observation is the long-lasting deterioration of the quality of life with chikungunya [24, 26], whereas post-infective syndromes (LRMSP or fatigue phenotypes) in the setting of Sindbis-virus-related diseases [37] or RRV infection [4] are more rapidly reversible and affect less permanently the daily activities, as the putative consequences of comorbidities with RRV [29].

 

[Hutan]

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.

The symptoms associated with both phenotypes were very similar whichever the time-point (data not shown). Interestingly, at t1, the symptoms associated with LRMSP and ICF belonged all to the spectrum of CFS-like illness with exception of blurred vision (Fig. S2). Interestingly, hearing difficulties, mood disturbance and feeling of depression that do not belong to the spectrum of CFS-like illness were not clustered with fatigue symptoms (Fig. S3).

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.


Prognostic factors

Female gender was associated both with more persistent fatigue and features of CFS-like illness than LRMSP. Age ⩾60 years was associated with each of the three post-infective syndromes. Extensive acute stage, a proxy of the severity of acute chikungunya illness, was associated with lingering LRMSP, lingering ICF and CFS-like illness. Post-epidemic CHIKV-specific IgG level increased the likelihood for lingering LRMSP but was protective for remitting-relapsing fatigue. Taken together, these results identified female gender as predictive of chronic fatigue and the humoral immune response as predictive of rheumatic pain, while age and extensive acute stage were indicative of both pathogeneses. Extensive acute stage illness was not associated with a hyperimmune response (data not shown).

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.

 

[Hutan]

we suggest that post-infective fatigue and musculoskeletal disorders be considered as minor phenotypes whereas CFS and rheumatoid-like arthritis be considered as possible extreme phenotypes of post-chikungunya disease, at the bottom or on the top of a likely complex disease, respectively. Further studies are needed to assess the heritability and better understand the pathogenesis of this puzzling problem, as classically proposed for complex diseases.

I'm not quite sure why they talk about 'at the bottom or on the top of a likely complex disease'.

CHIKV was found to persist in peri-synovium macrophages and trigger a long-lasting innate immune response

I'm finding all this particularly interesting given I might be having rheumatoid arthritis issues myself, at the moment.

 

[Hutan]

Chronic Chikungunya Arthritis and Rheumatoid Arthritis: What They Have in Common
Amaral et al
2019
https://www.amjmed.com/article/S0002-9343(19)30911-8/abstract

Abstract

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.​

Unfortunately paywalled.

 

[Hutan]

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
https://ard.bmj.com/content/68/9/1505.full
https://scihub.wikicn.top/10.1136/ard.2008.097626

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.

We report 21 cases of patients fulfilling the American College of Rheumatology (ACR) criteria for rheumatoid arthritis (RA) after Chikungunya infection that were diagnosed by a single rheumatologist (EB) in Reunion Island. The patients include (13 women; mean age 57.3 years, SD 12.2) had a history of Chikungunya fever, a positive Chikungunya test for IgM or IgG antibodies, RA according to ACR criteria, no other definite diagnosis of arthritis and persistent arthritis symptoms from the onset of Chikungunya infection to the diagnosis of RA.

At presentation, 18 patients (85.7%) had symmetric polyar- thritis. The mean delay between Chikungunya fever onset and RA diagnosis was 10 months (range 4–18). Laboratory tests showed: erythrocyte sedimentation rate 40.7 mm/h (SD 28.1) and C-reactive protein 37.3 mg/l (SD 41.1); 12 patients (57.1%) were positive for rheumatoid factor (RF), and only six patients (28.6%) for anti-cyclic citrullinated peptide (CCP) 2 antibodies; 14 patients (66.6%) were positive for HLA DRB1*04 or 01 alleles.

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.

 

[Hutan]

https://www.rheumatologynetwork.com...chikungunya-arthritis-vs-rheumatoid-arthritis
Q&A: Chronic Chikungunya Arthritis vs. Rheumatoid Arthritis
Jul 2020
Reading this article based on the Amaral paper I posted above, I'm not convinced the two conditions are different.

Similarities:

Chronic chikungunya arthritis has been associated with high circulating levels of pro-inflammatory cytokines, including IL-6, GM-CSF, IFN-α, and IL-17. IL-6 is well-recognized in rheumatoid arthritisjoint inflammation and increases the production of cartilage-destroying enzymes. In chronic chikungunya arthritis, inflammatory cytokines and chemokines, plasma levels of IL-6 and GM-CSF have been found to be significantly higher in patients with persistent arthralgia compared with those who had recovered. In another study, the cytokine profile in chronic chikungunya arthritis, including IFNα, IL-5, IL-6, IL-10, and particularly IL-7 and IL-15, was similar to rheumatoid arthritis. The profile of elevated levels of cytokines such as IL-1β, tumor necrosis factor (TNF), IL-6, and IL-17 during Chronic chikungunya arthritis resembles that observed in rheumatoid arthritis.

Chronic chikungunya arthritis can develop into a form of arthritis that meets the ACR / EULAR criteria for rheumatoid arthritis, including joint deformities.

Differences:

In chronic chikungunya arthritis, it presents with medium and/or large joint asymmetric mono- or oligoarthritis (less commonly). The signs and symptoms include memory and concentration problems and asthenia/depression can be more predominant than in rheumatoid arthritis. The serologies include anti-CHIKV IgM and/or IgG antibodies.

In rheumatoid arthritis, the signs and symptoms include an association with pulmonary (interstitial) disease and/or rheumatoid nodules. Serologies include anti-cyclic citrullinated peptide antibodies (anti-CCP); rheumatoid factor (RF).

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").

Many patients have received insufficient treatment for chronic chikungunya arthritis, progressing to joint deformities and disabling arthritis a few years after infection with the chikungunya virus. Our studies recommend starting methotrexate early as a treatment for these patients. We encourage clinicians not to underestimate chronic chikungunya arthritis by treating patients with analgesics or corticosteroids.

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:

However, in our studies, we recommend management with early use of methotrexate, due to the many cases of patients with deforming arthritis that we have received in our office.

 

[Jonathan Edwards]

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.

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.

 

[Jonathan Edwards]

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.

 

[Hutan]

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):

CHIKV was found to persist in peri-synovium macrophages and trigger a long-lasting innate immune response

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. ?

 

[Jonathan Edwards]

Presumably an identification of the cartilage damage soon after the acute illness and monitoring for further damage would confirm that?

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.

Maybe it's that idea of the CHIKV persisting in the body that needs to be examined to see if it is really true.

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.

 

[Hutan]

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
2010
https://www.jimmunol.org/content/184/10/5914

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.

We found that NK cells infiltrating the synovial tissue in close vicinity to chronically CHIKV-infected macrophages displayed an activated phenotype (NKRp44-positive) (49). In contrast, the lack of infiltrating CD8+ cells in the synovial tissue is surprising and may contribute to the persistence of CHIKV. The expression of antiviral type I IFNs was demonstrated in the PBMCs of chronic CHIKVD patients and in the synovial tissue with latent CHIKV infection.

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.

These findings are in agreement with a canonical chronic immune response reminiscent of but distinct from RA. The absence of polymorphonuclear cells in the synovial fluid and the paucity of proinflammatory cytokines, such as TNF-α and IL-1β, are important components to consider while selecting the best treatment regimen for chronic CHIKVD.

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.)

It is plausible that CHIKV persisting in immunoprivileged niches (called here sanctuaries) contributes directly to synovial tissue damage. RRV was shown to persist in synovial macrophages, and it is interesting that this behavior can be extrapolated to CHIKV (for review, see Ref. 2) and, in general, to many RNA viruses.

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.

 

[Jonathan Edwards]

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.

 

[rvallee]

Not many threads on Chikungunya, but this could be relevant. And the implications of this strategy are actually pretty significant, as there is no current method to detect cell-to-cell transfer, and we have remained stuck in the old "can't find the virus in the blood = no more virus" paradigm for all viruses.

Chikungunya Virus’s “Invisibility Shield” Uncovered – New Findings May Lead to Vaccines or Treatments
https://scitechdaily.com/chikunguny...d-to-vaccines-or-treatments/?expand_article=1

Scientists at the Albert Einstein College of Medicine have discovered that the virus causing chikungunya fever can spread directly from cell to cell—perhaps solving the longstanding mystery of how the virus, now emerging as a major health threat, can manage to escape antibodies circulating in the bloodstream.
...
“Previously, chikungunya virus was thought to spread in the body by infecting a cell, replicating within that cell, and then sending new copies of the virus into the bloodstream that then infect new cells,” said study leader Margaret Kielian, Ph.D., professor of cell biology and the Samuel H. Golding Chair in Microbiology at Einstein.

“However, we’ve found that the virus can also hijack a host cell’s cytoskeleton—the proteins that support cells and maintain their shape. The virus causes the infected cell to send out long thin extensions that make contact with uninfected neighboring cells, enabling the virus to safely and efficiently travel from one cell to another.”

Dr. Kielian and her colleagues have named these virus-induced structures intercellular long extensions, or ILEs. “This mode of viral transmission may not only shield some copies of the virus from the host’s immune response, but it may also explain why symptoms of chikungunya infection can persist for many months or years,” added first author Peiqi Yin, Ph.D., a postdoctoral fellow in Dr. Kielian’s lab.
...
The first part of the study involved the use of cultured mouse cells. The researchers exposed the cells to chikungunya virus that expressed a fluorescent reporter protein, allowing them to observe that infectious virus particles were indeed being transmitted from cell to cell via ILEs. Cell-to-cell transmission occurred even in the presence of high quantities of neutralizing antibodies that were added to the culture medium.​

The paper is "Chikungunya virus cell-to-cell transmission is mediated by intercellular extensions in vitro and in vivo", published in Nature microbiology: https://www.nature.com/articles/s41564-023-01449-0.

 

[Hutan]

Scientists at the Albert Einstein College of Medicine have discovered that the virus causing chikungunya fever can spread directly from cell to cell—perhaps solving the longstanding mystery of how the virus, now emerging as a major health threat, can manage to escape antibodies circulating in the bloodstream.

That's so interesting @rvallee. I only heard about this phenomenon recently, in relation to the persistence of the measles virus in the brain.
The viral origin of myalgic encephalomyelitis/chronic fatigue syndrome, 2023, Maureen R. Hanson

Definitely, this is an area that needs more research.

 

[LarsSG]

I think more research into post-chikungunya and post-dengue could be very valuable, because these have a clearly different presentation than typical ME that is more clearly linked to symptoms in the initial phase, i.e. the joint pain. Having that specific, localized symptom to grab onto might help researchers make progress where studying fatigue and PEM is more difficult. Either there is something happening in the joints or there is some damage there.

Of course, dengue and chikungunya are badly understudied for obvious reasons (noting this study happened because of a chikungunya outbreak in a part of France). I wonder if there is some way to encourage richer countries to support more research on post-dengue and post-chikungunya in affected countries. From a practical perspective, dengue and chikungunya are becoming more common in countries with reasonable public health resources (e.g. Buenos Aires in recent years, Cuba). I think there is also some dengue in Australia.