Matthew Halma

1/ Six years in, where does long COVID actually stand? A state-of-the-field thread — what the science established, what the clinic can offer, and what policy did to both. Some of it is better than the discourse suggests. Some of it is much worse. 🧵

Excited to share a powerful new open resource for understanding post-acute infection syndromes (PAIS) PAIS Cohort Database – a catalogue of 25+ design-verified post-viral, post-bacterial, and post-vaccine cohorts. It aggregates cohorts from Long COVID, ME/CFS triggers (EBV, Ross River, Q-fever, Lyme, etc.), SARS-1, Ebola, Chikungunya, Giardiasis, and more — with standardized observations for symptoms, functional outcomes, and biomarkers. Link: research.opensourcemed.info/pais-cohorts.h… Key features: Every reported result stored as comparable Observations (proportions, means, qualitative findings) Clear missingness tracking and comparability signatures Exportable JSON/CSV for easy meta-analysis Raw, queryable data so researchers can compare apples-to-apples

I am aiming to put together a resource aggregating the various post-viral syndrome + IACC cohorts so that a meta-analysis can be done easily and we can summarize the current field to garner maximum information. We will host it at research.opensourcemed.info alongside our other free resources. Follow and support our initiatives at opensourcemed.info

1/ Long COVID is not a new disease. It's the largest instance of a pattern medicine has been documenting — and then forgetting — for over a century. Once you line up the other post-infectious syndromes, the shared structure is hard to unsee. And it points at something we can only test one way. 🧵

@MatthewHalma A suggestion, from a patient with a different complex chronic illness: Look at molecules which land in the bloodstream as a result of the infection, and of the immune system fighting the infection. Consider those molecules as haptens on binding sites on circulating proteins.

@BillBottrell Hadn't heard of post-viral syndromes from H1N1, though I knew post-influenza is a thing. There's potentially a lot of data stretching back and looking at other viruses inducing IACCs. Unfortunately a lot of people affected who just got logged as having a 'mysterious illness'

@MatthewHalma My anecdote: 2009 "Swine Flu". A very bad case. Chronic fatigue switched on for roughly 3 years. (Fatigue only-no apparent brain involvement) Then a mild case of Covid-19 in early 2020- Long Covid switched on with all the usual symptoms.

CHIKV is similar to Dengue as well, a biobank project is applicable for both the acute phase of the illness (highly relevant for affected regions), and relevant for post-viral illnesses across the globe, making a neglected tropical disease interesting... and fundable, by agencies in the developed world. CHIKV, like Dengue, has no approved direct-acting antiviral, a significant shame, as its relatively low hanging fruit. A biobank project could evaluate acute therapeutics while providing data for IACCs.

THE OPPORTUNITY 11/ Chikungunya is expanding geographically. Outbreaks are explosive, seasonal, and datable, with a sharp febrile onset that brings people to clinics during acute infection. Which means the prospective inception cohort nobody managed to build for COVID is buildable here — and repeatedly. Réunion in 2005–06 produced TELECHIK because a health system decided to follow its own outbreak. That's the whole reason we have population-based data on this at all. The next big outbreak is another chance. It will be missed unless someone has protocols and freezers ready before it starts. The pattern across this series keeps repeating: the syndrome is real, the cohorts are small and scattered, the assays don't match, and the samples were never banked. Chikungunya is the case where we could still fix that prospectively — the trigger is coming back. 📷 CDC - cdc.gov/chikungunya/pd…

10/ And the mechanism question is more tractable here than almost anywhere else, because the affected tissue is accessible. Joint tissue can be biopsied. Synovial fluid can be aspirated. Post-COVID muscle has been biopsied, though we know the virus is neurovirulent, which is difficult to do a biopsy.

9/ Now on how chikungunya fits within the broader post-viral literature. Post-chikungunya was studied as a rheumatological disease for a decade because joint pain is what patients present with. The focus on arthritis is something that differs from Long COVID, though plenty of LC present with joint pain. With post-chikungunya, the focus was on the rheumatological symptoms, though it shares fatigue with other post-viral symptoms. THere's a question of what's specific to a given virus (arthritis to post-chikungunya) vs. what's shared (fatigue). Second transferable point: chikungunya shows the syndrome doesn't require a respiratory virus, a herpesvirus, or a severe acute illness. An arthritogenic alphavirus does it too. Ross River virus — same genus — produces a comparable tail.

8/ Marimoutou et al. (2012) is useful here. A uniform occupational cohort with an uninfected comparison group removes most of the objections that get thrown at long COVID cohorts — self-selection, recall, no denominator, healthy-control mismatch. Significant recurring health challenges at 30 months.

7/ Paixão et al. ran the larger systematic review and meta-analysis two years later, reaching broadly similar conclusions about chronic disease burden. Paixão, E. S. et al. Trans. R. Soc. Trop. Med. Hyg. 112, 301–316 (2018) pubmed.ncbi.nlm.nih.gov/30007303/ Underneath the meta-analyses sit four cohorts, and they're worth naming individually because their designs differ so much. 1) Soumahoro et al. (2009) — retrospective cohort on health status and quality of life. Contributes the evidence for fatigue, arthralgia, myalgia, hair loss and depression. PLoS ONE 4, e7800 journals.plos.org/plosone/articl… 2) Gérardin et al. (2011) — TELECHIK, a population-based cohort on perceived morbidity and community burden. This is the one carrying the neurocognitive deficits, hearing loss, and blurred vision findings. Population-based matters: it's an actual denominator. BMC Med. 9, 5 bmcmedicine.biomedcentral.com/articles/10.11… 3) Duvignaud et al. (2018) — also TELECHIK, and the conceptually important one. Its title says it: rheumatism and chronic fatigue as the two facets of post-chikungunya disease. Not an arthritis with tiredness attached. Two linked faces of one syndrome. Epidemiol. Infect. 146, 633–641 pubmed.ncbi.nlm.nih.gov/29557321/ 4) Marimoutou et al. (2012) — methodologically the strongest, and almost nobody cites it. A comparative cohort of infected versus uninfected French military policemen on Réunion, assessed at 30 months. Occupationally matched. Real controls. It contributes arthralgia, joint stiffness, joint swelling and fatigue. Medicine 91, 212–219 pubmed.ncbi.nlm.nih.gov/22732949/

6/And note the heterogeneity, because it's the interesting part. Indian studies: 27.27%. French studies: 50.25%. An almost twofold gap. Either genuine population differences, or, more likely, case definition and ascertainment doing most of the work. The same problem that plagues every PAIS estimate.

5/ But use the conservative figures, because they're the ones that survive scrutiny. Restricted to studies with ≥200 patients: 34.14%. Restricted to follow-up of 18 months or longer: 32.13% (22.21–42.04). Chronic arthritis specifically, rather than rheumatism broadly: 13.66% (9.31–18.00). So ranging from 1 in 7 to 1 in 3, depending on how you define it.

THE EVIDENCE 4/The headline number, from a 2016 meta-analysis of 18 studies covering 5,702 patients: pooled prevalence of post-chikungunya chronic inflammatory rheumatism was 40.22% (95% CI 31.11–49.34). acrjournals.onlinelibrary.wiley.com/doi/10.1002/ac… This is highly useful for biobanking, roughly a coin flip chance that the individual develops long term symptoms.

3/ Here's what the review lists as significantly elevated versus healthy controls in post-chikungunya: fatigue, arthralgia, myalgia, joint stiffness, joint swelling, neurocognitive deficits, sleep problems, hair loss, depression, irritability, hearing loss, blurred vision. Without knowing it was from chikungunya, you could easily mistake it for long COVID.

3/ Here's what the review lists as significantly elevated versus healthy controls in post-chikungunya: fatigue, arthralgia, myalgia, joint stiffness, joint swelling, neurocognitive deficits, sleep problems, hair loss, depression, irritability, hearing loss, blurred vision. Without knowing it was from chikungunya, you could easily mistake it for long COVID.

2/ Start with the framing from Choutka and Iwasaki's review, which is the best map of this territory. nature.com/articles/s4159… Their argument: PAISs share a systemic core, and the pathogen's tropism determines which symptoms sit on top. Rheumatic complaints dominate post-chikungunya the way IBS dominates post-Giardia. nature.com/articles/s4159…

1/ Of all the post-acute infection syndromes, chikungunya has the biggest numbers and the least attention. Roughly a third of infected people are still symptomatic 18 months later. It's been studied in population-based cohorts with uninfected controls — a standard long COVID research rarely reaches. 🧵

@barsanuphius77 King Arthur, the Guy Ritchie one

Instead of The Odyssey you can watch: - The Lord of the Rings - The Last Samurai - 300 - Gladiator - Vikings - Troy - Kingdom of Heaven - Braveheart Anything else?

@VioletaQSmith Sars COV 2 and herpes can disrupt iron levels, which can have an impact on viral entry, but I'm not familiar with it

@MatthewHalma Losing brain power, but just want to ask if anyone knows if iron accumulation is upstream or downstream from the pathogens.

IMO, Balaji looks like an ungrateful guest in Malaysia, speaking down to Malaysia's leadership in threatening tones. He is implictly and explicitly requesting that Malaysia no longer have territorial sovereignty within its borders. It would make Malaysia look weak to come to the table with him. I think he has overplayed his hand. To save face, Malaysia needs to respond assertively.