Effects of therapeutic interventions on long COVID: a meta-analysis of randomized controlled trials, 2025, Chang Tan et al

Mij

Mij

Senior Member (Voting Rights)

Summary​

Background​

Long COVID, characterized by persistent multi-organ symptoms post-SARS-CoV-2 infection, poses a substantial global health burden. While diverse therapeutic interventions have been proposed, their comparative efficacy remains uncertain due to fragmented evidence and methodological heterogeneity in prior studies. Therefore, we conducted a meta-analysis to comprehensively explore the effectiveness of diverse therapeutic interventions in long COVID.

Methods​

In this meta-analysis, we searched PubMed, Cochrane Library, Embase, Web of Science, SPORTDiscus (EBSCO), CINAHL (EBSCO), and Rehabilitation & Sports medicine source (EBSCO) from inception to July 20, 2025, for randomized controlled trials (RCTs) evaluating exercise training, respiratory muscle training, telerehabilitation, transcranial direct current stimulation (tDCS), olfactory training, palmitoylethanolamide with luteolin (PEA-LUT), and steroid sprays in adults with Long COVID. Primary outcomes included cardiopulmonary function, exercise capacity, fatigue, and olfactory recovery. Data were pooled using random-effects models, with sensitivity analyses (leave-one-out method) and Egger's test to assess robustness and publication bias. GRADE criteria evaluated evidence certainty. The study was registered with PROSPERO (CRD42024591704).

Findings​

We identified a total of 51 eligible trials, comprising 4026 participants. Significant differences were observed in the following outcomes in the context of exercise training: 6MWT (MD, 83.20; 95% CI 52.04–114.37), 30sSTS (MD, 3.05; 95% CI 1.96–4.13), SF-12 Mental Component Summary (SF-12-MCS) (MD, 3.10; 95% CI 0.78–5.43), VO2 peak (% predicted) (MD, 6.00; 95% CI 0.45–11.54), VO2 peak (L/kg/min) (MD, 1.61; 95% CI 0.40–2.81), VO2 peak (L/min) (MD, 0.14; 95% CI 0.03–0.25), mMRC dyspnea scale (MD, −1.04; 95% CI −1.73 to −0.35), the Multidimensional Functional Assessment of Daily Living Scale (MBDS) (MD, −4.61; 95% CI −8.19 to −1.03), and Visual Analogue Fatigue Scale (VAFS) (MD −1.69; 95% CI −3.07 to −0.31). Furthermore, significant differences were also found in the following key outcomes: 6MWT (MD, 89.54; 95% CI 9.86–169.23), MIP (% predicted) (MD, 15.79; 95% CI 2.73–28.84), MIP (cm H2O) (MD, 19.69; 95% CI 10.14–29.24), and mMRC (MD, −1.02; 95% CI −1.86 to −0.18) in respiratory muscle training; 6MWT (MD 34.14; 95% CI 2.54–65.74), 30sSTS (MD 1.41; 95% CI 0.67–2.15), and FSS (MD −1.59; 95% CI −2.64 to −0.53) in telerehabilitation; MFIS-physical (MD, −2.29; 95% CI −4.36 to −0.22) in tDCS; and TDI Score (MD, 4.66; 95% CI 2.16–7.15) in PEA-LUT.

Interpretation​

Exercise training should be prioritized for improving cardiopulmonary function and exercise capacity in Long COVID, supported by high-certainty evidence. Respiratory muscle training and PEA-LUT offer targeted benefits for respiratory strength and anosmia, while tDCS may address fatigue. Telerehabilitation, as a form of supervision, also improved the effectiveness of the intervention. In contrast, steroid sprays and olfactory training lack efficacy, highlighting the need for personalized, symptom-specific approaches. These findings advocate for updated clinical guidelines integrating multimodal therapies and underscore the urgency of large-scale trials to optimize dosing and long-term outcomes.
LINK
 
Effects of therapeutic interventions on long COVID: a meta-analysis of randomized controlled trials - eClinicalMedicine. No surprises here but good to see. What many of us who folliwed the evidence have been suggesting
 

Risk of bias​

The risk of bias of RCTs ranged from low to high, with 3 studies with low risk of bias, 12 with some concerns, and 33 with high risk. Lack of blinding or unclear description of blinding caused more bias. In more than half of the studies, there was a loss to follow-up rate exceeding 10%, which was the main source of risk of bias and affected up to 28 articles. The problem with randomization and blinding is primarily that the methods of implementation were not described in detail in the literature, so we do not know with certainty whether randomization and blinding were actually performed. Selective outcome reporting was the domain with better scores (eFigure 2).
Click to expand...

GRADE assessment​

The GRADE assessments indicated the following quality ratings for all outcomes: 27% of the evidence was rated as very low, 57% as low, 11% as moderate, and 5% as high. Only two outcomes—MFIS-physical in tDCS and MIP in respiratory muscle training (% predicted)—received a high-quality rating (eTable 2).
Click to expand...
Our study has several limitations. Firstly, not all relevant RCTs were included due to various factors such as the unavailability of original articles, non-English language publications, or the use of different scales or experimental methods to assess the same symptoms, which limited the number of studies available for analysis. Secondly, the quality of the included literature was variable, with some studies exhibiting a high risk of bias. Thirdly, the included studies demonstrated limited longitudinal outcome assessments, with maximum follow-up durations capped at 180 days and the majority restricted to 4–12week observation periods. This collectively constitutes a notable methodological limitation regarding sustained therapeutic effect evaluation. Fourthly, the limited number of studies included for some outcomes resulted in a limited ability of sensitivity analyses to assess the robustness of those outcomes. Fifthly, although individualized multimodal interventions may be promising, our current analysis was unable to evaluate their effectiveness as a distinct category due to the limited number of relevant studies. The potential benefits of combining multiple interventions warrant further investigation in future clinical trials. Additionally, certain experiments were difficult to blind, which may have introduced subjective factors that influenced the original results, making the findings of this study susceptible to bias. Lastly, there was high heterogeneity across studies, likely due to differences in intervention methods, duration, frequency, and follow-up periods, which may have contributed to variability in the results.
Click to expand...
Another worthless meta analysis where the authors don’t know when to just exclude studies with terrible methodology. It’s fitting that it’s published in the Lancet..
 
Utsikt said:
worthless meta analysis where the authors don’t know when to just exclude studies with terrible methodology.
Click to expand...

it's amazing they can analyze all the findings and present the meta-results as somehow robust, but then tuck away at the back that almost all the trials are shit and 84% of the evidence is of low/very low quality. When limitations are so expansive that they undermine the credibility of the claimed results, they essentially indicate that the results are, as you suggest, worthless.
 
The eFigure2.x’s in the supplements are a red flag to me. I find it highly unlikely that most of the interventions were sufficiently blinded but I don’t have the energy or will to check.

I also don’t understand how you can have a category of «unclear bias». If the bias can’t be determined, shouldn’t it be assumed to be high risk? Benefit of the doubt doesn’t really work in science - then you could just leave out info that’s not in your favour and get a better score.
 
Last edited:
dave30th said:
it's amazing they can analyze all the findings and present the meta-results as somehow robust, but then tuck away at the back that almost all the trials are shit and 84% of the evidence is of low/very low quality.
Click to expand...
Which is very close to the figure NICE reported.

dave30th said:
When limitations are so expansive that they undermine the credibility of the claimed results, they essentially indicate that the results are, as you suggest, worthless.
Click to expand...
Hence any therapy recommended by the review has a high risk of harm.
 
The paper said:
Exercise training should be prioritized for improving cardiopulmonary function and exercise capacity in Long COVID, supported by high-certainty evidence
Click to expand...
This is simply false, and exposes just how useless evidence-based medicine is, how it's completely detached from reality, just as much as the bullshit RFK Jr is peddling out there. It's widely known that there are no treatments for LC. This has been the most over-used of those useless treatments. There is no evidence supporting this, and their interpretation is to "prioritize" "high-certainty evidence".

Seriously, pragmatic clinical trials need to be banned. They are worse than useless, they are completely misused and it ruins everything.
 
Dave did some good posts about the risk of bias while quoting Glasziou’s tweet. Glasziou blocked Dave from quoting his tweet. Now it just shows up like.

Click to expand...


Seems Glasziou isn’t very interested in thinking about limitations?

I don’t know him, is he BPS-Brained or something?

Edit: Looked him up and he authored the anomalies paper. Yeah… Checks out.
 
Made this thread on the review:


1) A new review on Long Covid recommends 'exercise training' but it's based on low-quality trials with high risk of bias and problematic inclusion criteria. Some didn't even focus on Long Covid patients, just people who survived COVID-19.

2) The review included 25 trials on exercise training. In comparison, a BMJ review from last year found only 1. The authors were thus extremely lenient in their inclusion criteria. We scanned these papers, and most were of low quality and published in obscure journals.

3) Some of the studies included patients who were still in the acute phase or patients who were COVID survivors with no clear requirement of having ongoing symptoms. See, for example:

Rodríguez-Blanco 2022
https://pubmed.ncbi.nlm.nih.gov/34783270/
De Araújo 2023
https://pubmed.ncbi.nlm.nih.gov/38046546/

4) Other studies included patients who "had COVID-19 but continued to experience dyspnea" (shortness of breath).

Some examples:
Demir 2025
https://pubmed.ncbi.nlm.nih.gov/40325938/
Kaddoussi 2024
https://pubmed.ncbi.nlm.nih.gov/39416495/

5) These studies focused on patients who were hospitalised and received mechanical ventilation for 48 hours or who who had critical COVID-19 and received intensive care treatment.

Romanet 2023
https://pubmed.ncbi.nlm.nih.gov/37271020/
Longabardi 2023
https://bjsm.bmj.com/content/57/20/1295

6) Other studies only included "older adults impacted by COVID-19" where the minimum age was 60 or 65.

Examples:
Kaczmarczyk 2024
https://pubmed.ncbi.nlm.nih.gov/38541937/
Pleguezuelos 2024
https://pubmed.ncbi.nlm.nih.gov/38937986/

7) All these categories are very different from the ME/CFS subgroup within Long Covid. Some of the other exercise trials also explicitly excluded patients who experienced post-exertional malaise (PEM).

See for example:
Sick 2025
https://pubmed.ncbi.nlm.nih.gov/39665835/

8 ) The authors (and editors of the journal) are to blame for combining all these different populations and trials to make clinical recommendations. This is far from best practice.

9) But the concept of 'Long Covid' also enables this by grouping all these different patients into one category.
There's a risk that these recommendations will also be applied to the ME/CFS subgroup within Long Covid and that this will be counterproductive or harmful.

10) Link to the review:
Tan et al. 2025. Effects of therapeutic interventions on long COVID: a meta-analysis of randomized controlled trials.
https://www.thelancet.com/.../PIIS2589-5370(25)00344-X/
 
Didn't feel like going deeper into the evidence because the included populations were so diverse and dissimilar to ME/CFS.

Also got the impression that the reviewers didn't care much about quality of evidence. Only briefly scanned the studies but of the 25 included I don't think there's one trial that is robust and sound.
 
Yann04 said:
Edit: Looked him up and he authored the anomalies paper. Yeah… Checks out.
Click to expand...
Jonathan Edwards said:
He also co-authored the individualised version of the Larun review that hit the fan and never saw the light of day.
Click to expand...
Pretty sure Glasziou was also heavily involved in the RACGP* guidelines on "incremental exercise' (aka GET) for ME/CFS, updated only last year.

RACGP - Incremental physical activity for chronic fatigue syndrome/myalgic encephalomyelitis

CFS is primarily a disorder of young to middle-aged adults and is about twice as common in women than in men with the worldwide prevalence between 0.2% and 2.6%
www.racgp.org.au www.racgp.org.au
Sly Saint

Thread 'Australia: RACGP: GET for CFS'

Very PACE trial based information.

eg"
Adverse effects
Surveys by patient groups of their members have suggested that GET may be harmful to some people with CFS. However, this finding is believed to be due to inappropriately planned or progressed exercise programs, possibly undertaken independently or under supervision from a person without appropriate experience.

Availability
GET should be supervised by a physiotherapist or exercise therapist, preferably with specific experience and training in applying GET to patients with CFS.

The PACE trial has produced a...
  • Like

Note that the only two relevant references are PACE and Cochrane, with no mention of NICE. (There is a third ref, but that is for LC studies. Not clear what the relevance of that is to this guideline.)

*Royal Australian College of General Practitioners
 
You must log in or register to reply here.
Back
Top Bottom