Review Current status and future perspectives on the mechanistic and pathophysiological understanding of long COVID, 2026, Faghy et al

Wyva

Wyva

Senior Member (Voting Rights)
Mark A. Faghy, Rob C. I. Wüst, Daniel M. Altmann, Ruth EM Ashton, Sarah Barley McMullen, Rae Duncan, Andrew G. Ewing, Elke Hausmann, Sanjay Gupta, Mady Hornig, David Joffe, Binita Kane, M. Asad Khan, Micheal Natt, Rebecca Owen, David Putrino, Lindsay Skipper, Claire Taylor, Callum Thomas, David Tuller, Danielle Beckman, Arneaux Kruger & Etheresia Pretorius

Abstract​

Background​

Viral and infectious illnesses can exert profound and enduring effects on population health and well-being. In the aftermath of SARS-CoV-2 infection, post-acute sequelae, collectively referred to as Long COVID, have emerged as a major global health challenge, affecting more than 400 million people and contributing to estimated annual economic costs exceeding $1 trillion.

Scope of the review​

Long COVID encompasses a wide and heterogeneous spectrum of debilitating symptoms, including cognitive dysfunction, sleep disturbances, severe fatigue, and post-exertional malaise. Despite its substantial burden, fundamental uncertainties remain regarding its underlying pathophysiology, the development of robust diagnostic criteria, and the identification of effective therapeutic options.

Key insights​

This review synthesises current evidence on the biological mechanisms thought to contribute to Long COVID, spanning immune dysregulation, viral persistence, autonomic dysfunction, microvascular pathology, and other emerging hypotheses. We examine advances and limitations in contemporary diagnostic approaches and critically appraise existing treatment strategies, highlighting inconsistencies and gaps that hinder clinical consensus.

Implications​

By integrating interdisciplinary insights, this review underscores the urgent need for mechanistic clarity, validated diagnostic frameworks, and rigorously evaluated treatment pathways. Addressing these gaps will be essential to developing effective, evidence-based management strategies and mitigating the long-term impact of Long COVID on global health.

Plain language summary​

COVID-19 has caused millions of deaths worldwide, but its impact goes beyond the initial infection. Some people develop Long COVID, a condition where symptoms persist or appear months after infection, even in mild or asymptomatic cases. Long COVID affects multiple body systems and can involve over 200 symptoms, often resembling chronic fatigue syndrome. Its causes remain unclear, and there are no proven treatments or reliable diagnostic tests. Research into blood biomarkers and symptom patterns holds promise, but progress is slow due to the complexity of the condition. This review explores current knowledge, gaps, and future directions for research, diagnosis, and treatment.

Open access: https://www.nature.com/articles/s43856-025-01300-z
 
Kalliope said:
Only able to skim the abstract, but looking forward to read what people think of this article. Several familiar names among the authors and it seems to get some attention on social media.
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Sadly, it reads like an undergraduate literature review essay from a student with no interest in being critical or trying to work out what is really important or interesting and what is a negative result dressed up to look like something a bit positive.

I have no idea why all these people are authors. I wouldn't want to put my name to something so anodyne and ill-informed.
Kitty said:
Yes, what struck me about the abstract was that anyone could have written it. It's pretty much stating the obvious.
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So, yes.
BrightCandle said:
That pretty much sums up the entire Long Covid situation.
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It sums up the Twitterati approach to Long Covid. Much more interesting things get discussed on S4ME.
 
Whereas I wholeheartedly share your viewpoint on this review, not many people are aware of S4ME. In the age where attention is the major currency, this factor may affect funding from private sources significantly.
 
N_Dina said:
Whereas I wholeheartedly share your viewpoint on this review, not many people are aware of S4ME. In the age where attention is the major currency, this factor may affect funding from private sources significantly.
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I don't quite follow your meaning.

Chanting of fashionable mantras has been the norm in scientific funding circles for as long as I can remember. It was always easy to get money to repeat dead end work. I decided to take a different tack and I don't regret it. Life is short. It is worth focusing on things that really matter.
 
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Jonathan Edwards said:
I don't quite follow your meaning.

Chanting of fashionable mantras has been the norm in scientific funding circles for as long as I can remember. It was always easy to get money to repeat dead end work. I decided to take a different tack and I don't regret it. Life is short. It is worth focusing on things that really matter.
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Yes, I think I should have articulated this more precisely. I am incredibly upset that all the ill proven “facts” and theories are repeated all over again by the same set of authors as if they are some broken AI now (I truly respect some of the authors, though). This review could have been written any time in 2022-2026 and the content would have been the same. With absolutely no new knowledge synthesised.

That being said, I am also quite disappointed that some fundamental research initiatives like Sequence ME do not get the same kind of attention as very questionable projects from some of the aforementioned authors.
 
InitialConditions said:
You answered the question yourself. The majority of authors are active on X and are seen as 'patient friendly,' because they are not BPS or BPS-adjacent. That is what they have in common.
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Yes, but you don't just put the names of all the people you agree with on your paper. The point of a scientific paper is to say something different. The point of a multi-author viewpoint paper is to raise criticism of something passing as mainstream that stinks.
 
N_Dina said:
That being said, I am also quite disappointed that some fundamental research initiatives like Sequence ME do not get the same kind of attention as very questionable projects from some of the aforementioned authors.
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Absolutely.
There is really exciting stuff out there from Ponting and others. Why do we still have to listen to 'Nessun Dorma' for the ninethousandth time from these people (some of whom one might have expected to keep their powder dry).
 
Jonathan Edwards said:
Yes, but you don't just put the names of all the people you agree with on your paper. The point of a scientific paper is to say something different. The point of a multi-author viewpoint paper is to raise criticism of something passing as mainstream that stinks.
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I am in full agreement. It's not a way to do science. The LC world is now no less polarized than the ME/CFS world.
 
I thought this was a good overview of the various hypotheses and (often limited) evidence. I note this was written probably two years ago, submitted in Aug 2024, a full year before DecodeME’s initial findings. Good that donations covered publishing fees it’s open access under Creative Commons so text and figures can be re-used.

I liked this section, though we would probably have omitted references to energy and just said “capacity”:


Chronic fatigue is one of the most prevalent and debilitating symptoms reported by individuals with Long COVID, characterised by an inability to perform physical or cognitive tasks that would typically fall within their normal energy capacity. Approximately 50%-80% of patients also experience PEM, a hallmark feature involving the worsening or emergence of new symptoms following physical, mental, or cognitive exertion that exceeds a highly individual and variable threshold.
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The onset of PEM typically occurs within 48 hours of exertion and may persist for days, weeks, or even months. There is substantial overlap between the clinical presentation and proposed pathophysiological mechanisms of Long COVID and ME/CFS, in which PEM is a core diagnostic criteria. Given the strong association between exertion and symptom exacerbation, many patients identify PEM as a primary contributor to their reduced functional capacity and diminished quality of life. As such, patients often remain physically inactive to avoid PEM. Interventions such as graded exercise therapy, designed to increase activity levels over time, have been linked to adverse outcomes in this population and are considered high-risk for inducing PEM.
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However, current evidence suggests that the mechanisms responsible for reduced exercise capacity and excessive fatigue in Long COVID differ from those driving PEM specifically.
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It probably wasn’t feasible to expand on this but it could have been emphasised that remaining inactive is necessary but often naturally resisted in early disease experience. This may be mentioned in the pacing section.
 
I can't say I agree that it's pointless to state that there has been no progress. Medicine seems to have no meaningful process outside of people pointing the obvious again and again, it's that no one acts on it that makes it all useless. That's supposed to be the other mechanism, but it's not just turned off on purpose, it's welded shut and guarded by giant mauling dogs.
Currently, no curative treatments for Long COVID have been established, mainly due to its poorly understood and likely heterogeneous pathophysiological basis. Progress has also been hampered by the absence of clear diagnostic criteria and validated biomarkers.
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I agree that this does sum it up. There has been zero progress, on all fronts. It is a problem. Unfortunately there is no one in charge of making progress, and no one in charge generally speaking who cares about this. Everyone in charge is perfectly happy with pretending this isn't happening.

Haven't dug into the paper itself. It is despairing that no progress has been made, but only so many ways of saying it, and it should be said again and again while it remains true. This should warrant more pressing language, and more initiatives, and more accountability, but academia's role in this is pretty limited to this. We have a similar situation in patients getting yet another article pointing out the same thing. It's never a bad thing.
 
Liface said:
I challenged Pretorius on Twitter about this paper:

I'm not sure this is the correct way to go about critique, but I'm just tired of reading these same review papers over and over.
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I think that the progress you and others here miss is that this review was published in the Nature portfolio. And the authors managed to present an overview of the research and what are the most pressing and interesting questions more resesarch should go into in one of the most prestigious journals.

As a patient I find this very helpful and yet another step forward to convince more doctors, politicians and the interested public that ME/CFS is real, a somatic illness, and that more money for biomedical research is desperately needed.

With publications like these I am a lot less afraid to go see a new specialist of whom I don't know whether they are supportive of the biomedical understanding of ME because I now know that the the biomedical research community has been won over that ME is a biomedical question.
 
rvallee said:
It is despairing that no progress has been made.
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I would like to make you aware of the fact that the question whether there's research progress has different answers according to the research questions you're most interested in.

As a patient who's convinced that herpes reactivation plays a central role in ME/CFS I am seeing the biomedical evidence that the immune system indeed is fighting a virus slowly building over the past years while research that's trying to go directly after specific viruses is under way and promising.

Also I just realised that fully independently from ME/CFS research leading top university Long Covid researchers are arguing that one of the most promising research questions is to look into pathogens and the role of "co-infections" as they call it in the LC field.

If you don't see progress into the questions that you root for you might want to ask yourself whether you are betting on the wrong horse.
 
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