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

[Wyva]

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]

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.

 

[BrightCandle]

That pretty much sums up the entire Long Covid situation.

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.

 

[Kitty]

That pretty much sums up the entire Long Covid situation.

Yes, what struck me about the abstract was that anyone could have written it. It's pretty much stating the obvious.

 

[Jonathan Edwards]

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.

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.

Yes, what struck me about the abstract was that anyone could have written it. It's pretty much stating the obvious.

So, yes.

That pretty much sums up the entire Long Covid situation.

It sums up the Twitterati approach to Long Covid. Much more interesting things get discussed on S4ME.

 

[N_Dina]

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.

 

[Jonathan Edwards]

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.

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.

 

[InitialConditions]

I have no idea why all these people are authors.

It sums up the Twitterati approach to Long Covid.

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.

 

[InitialConditions]

From the paper. Very poor going on multiple counts (REF).

 

[N_Dina]

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.

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.

 

[Jonathan Edwards]

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.

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.

 

[Jonathan Edwards]

From the paper. Very poor going on multiple counts (REF).

Priceless (REF).

 

[Jonathan Edwards]

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.

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).