Review Interventions for the management of long covid post-covid condition: living systematic review, 2024, Zeraatkar, Flottorp, Garner, Busse+

SNT Gatchaman

SNT Gatchaman

Senior Member (Voting Rights)
Staff member
Interventions for the management of long covid post-covid condition: living systematic review
Dena Zeraatkar; Michael Ling; Sarah Kirsh; Tanvir Jassal; Mahnoor Shahab; Hamed Movahed; Jhalok Ronjan Talukdar; Alicia Walch; Samantha Chakraborty; Tari Turner; Lyn Turkstra; Roger S McIntyre; Ariel Izcovich; Lawrence Mbuagbaw; Thomas Agoritsas; Signe A Flottorp; Paul Garner; Tyler Pitre; Rachel J Couban; Jason W Busse

OBJECTIVES
To compare the effectiveness of interventions for the management of long covid (post-covid condition).

DESIGN
Living systematic review.

DATA SOURCES
Medline, Embase, CINAHL, PsycInfo, Allied and Complementary Medicine Database, and Cochrane Central Register of Controlled Trials from inception to December 2023.

ELIGIBILITY CRITERIA
Trials that randomised adults (≥18 years) with long covid to drug or non-drug interventions, placebo or sham, or usual care.

RESULTS
24 trials with 3695 patients were eligible. Four trials (n=708 patients) investigated drug interventions, eight (n=985) physical activity or rehabilitation, three (n=314) behavioural, four (n=794) dietary, four (n=309) medical devices and technologies, and one (n=585) a combination of physical exercise and mental health rehabilitation.

Moderate certainty evidence suggested that, compared with usual care, an online programme of cognitive behavioural therapy (CBT) probably reduces fatigue (mean difference −8.4, 95% confidence interval (CI) −13.11 to −3.69; Checklist for Individual Strength fatigue subscale; range 8-56, higher scores indicate greater impairment) and probably improves concentration (mean difference −5.2, −7.97 to −2.43; Checklist for Individual Strength concentration problems subscale; range 4-28; higher scores indicate greater impairment).

Moderate certainty evidence suggested that, compared with usual care, an online, supervised, combined physical and mental health rehabilitation programme probably leads to improvement in overall health, with an estimated 161 more patients per 1000 (95% CI 61 more to 292 more) experiencing meaningful improvement or recovery, probably reduces symptoms of depression (mean difference −1.50, −2.41 to −0.59; Hospital Anxiety and Depression Scale depression subscale; range 0-21; higher scores indicate greater impairment), and probably improves quality of life (0.04, 95% CI 0.00 to 0.08; Patient-Reported Outcomes Measurement Information System 29+2 Profile; range −0.022-1; higher scores indicate less impairment).

Moderate certainty evidence suggested that intermittent aerobic exercise 3-5 times weekly for 4-6 weeks probably improves physical function compared with continuous exercise (mean difference 3.8, 1.12 to 6.48; SF-36 physical component summary score; range 0-100; higher scores indicate less impairment).

No compelling evidence was found to support the effectiveness of other interventions, including, among others, vortioxetine, leronlimab, combined probiotics-prebiotics, coenzyme Q10, amygdala and insula retraining, combined L-arginine and vitamin C, inspiratory muscle training, transcranial direct current stimulation, hyperbaric oxygen, a mobile application providing education on long covid.

CONCLUSIONS
Moderate certainty evidence suggests that CBT and physical and mental health rehabilitation probably improve symptoms of long covid.

SYSTEMATIC REVIEW REGISTRATION
Open Science Framework https://osf.io/9h7zm/


Link | PDF (BMJ) [Open Access]
 
Speaking of these authors, I recently (while searching for something else) came across this Canadian Institute of Health Research grant award from 2022 also with Busse & Zeraatkar as PIs. Don't think their intention to do this was mentioned on the forum before:
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disabling, chronic illness with few effective interventions. For decades, guidelines and healthcare professionals have recommended graded exercise therapy-a program of gradually intensifying exercise-for patients with CFS/ME. A 2021 guideline by the National Institute for Health and Care Excellence (NICE), however, recommended against exercise therapy, contrary to previous guidelines.
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The guideline has since come under scrutiny, with the result that many clinicians have decided not to adopt the NICE recommendations. We propose to develop a novel clinical practice guideline for exercise therapy and CFS/ME that addresses the limitations of the NICE guideline and that adheres to internationally accepted standards for trustworthy guideline development. To do this, we will review and appraise all available research evidence and consider patient values and preferences.
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Patients with CFS/ME and healthcare providers will benefit from having access to trustworthy and rigorous summaries of the evidence and recommendations to optimize care. We will publish our guideline and supporting systematic reviews in the BMJ, as part of the BMJ Rapid Recommendations initiative-an initiative to produce trustworthy guidelines in response to practice-changing evidence.
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I'm wondering why this Long Covid review wasn't done under the Cochrane banner. Similarly for the alternative CFS/ME guideline that the above post mentions. Both Garner and Busse are heavily associated with Cochrane.

Jason Busse is a consultant to Prisma Health and is associated with the Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Handbook is a guide for conducting, reporting, and maintaining Cochrane reviews.
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When I enquired about doing a new review of CBT for ME/CFS, I was told that the authors would need to have a mix of viewpoints, that the review couldn't be carried out by people with a preconceived idea about CBT's ineffectiveness. Maybe someone in Cochrane doesn't have an appetite for more controversy?
 
Assertion 1:
Risk factors for the development of long covid include female sex, greater comorbidity, and patient reported psychological distress.19 20 21
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(This assertion is important, because if people who get Long Covid get it because of mental health problems, there might be a rationale for applying CBT therapy.)

#19 Maglietta et al
Prognostic Factors for Post-COVID-19 Syndrome: A Systematic Review and Meta-Analysis.
forum thread
Hospitalised Covid-19 patients. Female sex was found to be associated with the development of post-infection persisting symptoms. Psychological factors and co-morbidities are not mentioned as being associated with the development of persisting post-infection symptoms.

#20 Notarte et al,
Age, Sex and Previous Comorbidities as Risk Factors Not Associated with SARS-CoV-2 Infection for Long COVID-19: A Systematic Review and Meta-Analysis.
forum thread
This study says nothing about psychological distress of any sort. It only found that sex (being female) and some medical non-psychological co-morbidities (eg pulmonary disease) were associated with Long Covid. It noted that most of the studies had a substantial risk of bias.

#21 Wang et al.Associations of Depression, Anxiety, Worry, Perceived Stress, and Loneliness Prior to Infection With Risk of Post-COVID-19 Conditions.
forum thread
This study found that levels of depression and anxiety prior to infection were somewhat associated with the presence of one or more symptoms from a list of symptoms (which included depression and anxiety) after infection. All sorts of selection biases.

If this is the best evidence the authors could find for pre-existing psychological issues being associated with Long Covid, then there really isn't anything credible. The two reviews of multiple studies did not find any association. The one cited study that does claim an association is very flawed.
 
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Something that is notable from this is the paucity of trials assessing PEM in LC. Searching the supplementary data & the spreadsheet on osf.io I think there is only one included trial where PEM was assessed as an outcome measure (?), a trial of leronlimab (Gaylis, 2022), although the authors also mention that the REGAIN triallists monitored patients for PEM but did not report any instances of it.

The commentary below was particularly annoying - anyone think it might be useful to put together a BMJ rapid response addressing it?
Both CBT and physical activity have long been shown to improve health and quality of life for people living with other chronic diseases. Notably, both graduated physical activity and CBT have been found effective for myalgic encephalomyelitis (chronic fatigue syndrome or ME/CFS)—a condition with a striking resemblance to long covid that often emerges after viral infection.

CBT and graduated physical activity are offered to patients with long covid and ME/CFS based on the observation that patients often reduce activity in response to their symptoms. Consequently, patients may become physically deconditioned, develop disrupted sleep-wake patterns, and hold unhelpful beliefs about fatigue. Interventions such as CBT and supervised physical activity which gradually reintroduce patients to activity may help with reconditioning, regularising patterns of activity, optimising rest and sleep, and addressing patients’ unhelpful beliefs about fatigue and activity. Despite supporting evidence, the role of exercise and CBT for long covid and other post-viral fatigue syndromes remains contentious, with some interpreting their success as evidence that the condition is “not real.” Our findings suggest it is reasonable to offer CBT and mental and physical rehabilitation to patients.

We emphasise that the effectiveness of CBT and physical rehabilitation for long covid neither indicates the condition is psychological nor negates a possible somatic cause. It is possible that CBT and physical rehabilitation only offer patients mechanisms to cope with symptoms from biological causes.
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SNT Gatchaman said:
No compelling evidence was found to support the effectiveness of other interventions, including ..amygdala and insula retraining
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and yet
Amygdala and Insula Retraining Tied to Reduction in Fatigue With Long COVID
Furthermore, patients randomly assigned to the neuroplasticity program saw significant gains in energy

MONDAY, July 24, 2023 (HealthDay News) -- Amygdala and insula retraining (AIR), a neuroplasticity program, may be a viable means of reducing fatigue and increasing energy among patients with long COVID, according to a study published online July 17 in the Evidence-Based Complementary and Alternative Medicine Journal.

Loren L. Toussaint, Ph.D., from Luther College in Decorah, Iowa, and Alexandra J. Bratty, M.B.A., Ph.D., from AB Research Consulting in Las Vegas, randomly assigned 100 participants (aged 21 to 65 years) with postviral symptoms at least three months after an acute COVID-19 infection to AIR or control.

The researchers found a significant decrease in participants' fatigue and a significant increase in their energy after the three-month AIR intervention. Fatigue reduction was nearly four times higher in the AIR group versus the control group, while the absolute reduction in mean scores for the AIR group was more than double that of the control group. Similarly, the effect size in energy enhancement among AIR participants was twice that of the control group, and the absolute increase in energy mean scores for the AIR group was almost double that of the control group.


"These findings are both timely and pertinent, as so little is known about how to treat long COVID and so many patients suffer from it after the acute infection of COVID-19," the authors write.

Bratty is the CEO of AB Research Consulting, which provides consulting services to The Gupta Program, the commercial version of the AIR intervention; Bratty's company was compensated for this work by independent donors.
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Amygdala and Insula Retraining Tied to Reduction in Fatigue With Long COVIDAmygdala and Insula Retraining Tied to Reduction in Fatigue With Long COVID

thread on research paper here Trial Report - Neuroplasticity Intervention, Amygdala and Insula Retraining (AIR), Significantly Improves Overall Health ..., 2024, Bratty | Science for ME

I learnt that I could change the symptoms I was experiencing with my brain, by retraining the bodily reactions with my conscious thoughts, feelings, and behaviour. Over the following weeks, with support, I learnt how to do this. I suddenly believed I would recover completely.
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PG Paul Garner: on his recovery from long covid - The BMJ

eta:
so not brain retraining then, just back to the CBT,GET 'therapy'.....
definitely not Carlsberg.
 
Eric Topol shared it on Twitter saying:

A systematic review of 24 randomized trials for #LongCovid https://bmj.com/content/387/bmj-2024-081318 open-access @bmj_latest
No drug, diet, or device intervention has supportive evidence for efficacy. CBT, rehab provided some relief of symptoms (moderate certainty). We're still in desperate need for a validated treatment!

Danny Altmann just retweeted Topol with the following comment:

Hi @EricTopol
- it was noteworthy that coverage somehow latched onto CBT and rehab sometimes being better than nothing. Surely the real take-home was that >4y on, we have nothing substantive to offer some 400 million people globally. We should be able to do better than this..

https://twitter.com/user/status/1861922439753540047


https://twitter.com/user/status/1862171351206805877
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SNT Gatchaman said:
Moderate certainty evidence suggested that, compared with usual care, an online programme of cognitive behavioural therapy (CBT) probably reduces fatigue (mean difference −8.4, 95% confidence interval (CI) −13.11 to −3.69; Checklist for Individual Strength fatigue subscale; range 8-56, higher scores indicate greater impairment) and probably improves concentration (mean difference −5.2, −7.97 to −2.43; Checklist for Individual Strength concentration problems subscale; range 4-28; higher scores indicate greater impairment).
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This is all based on the 1 Dutch trial by Hans Knoop (Kuut et al. 2023, discussed here). A study on COPD patients found the minimal importance difference for the CIS-fatigue scale to be 9.3 points, so bigger than the 8.4 difference found in the CBT trial. The reviewers rated the Kuut 2023 study at high risk of bias because of lack of blinding but this resulted in only 1 downgrading in GRADE hierarchy from high to moderate certainty of evidence.

Curiously, the RCT on hyperbaric oxygen therapy also reported positive effects but here the evidence was downgraded by two levels (from High to Low) 'due to very serious imprecision' even though for some outcomes the 95% confidence intervals do not cross 0.

SNT Gatchaman said:
Moderate certainty evidence suggested that, compared with usual care, an online, supervised, combined physical and mental health rehabilitation programme probably leads to improvement in overall health, with an estimated 161 more patients per 1000 (95% CI 61 more to 292 more) experiencing meaningful improvement or recovery, probably reduces symptoms of depression (mean difference −1.50, −2.41 to −0.59; Hospital Anxiety and Depression Scale depression subscale; range 0-21; higher scores indicate greater impairment), and probably improves quality of life (0.04, 95% CI 0.00 to 0.08; Patient-Reported Outcomes Measurement Information System 29+2 Profile; range −0.022-1; higher scores indicate less impairment).
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This all seems to be based on 1 trial on 'People who were still suffering from breathlessness three months after being discharged from hospital with COVID-19-related acute respiratory distress syndrome.'
https://pubmed.ncbi.nlm.nih.gov/37271020/
EDIT: It seems to be the REGAIN trial that we has was discussed here:
https://www.s4me.info/threads/clini...9-condition-regain-study-2024-mcgregor.37174/

SNT Gatchaman said:
Moderate certainty evidence suggested that intermittent aerobic exercise 3-5 times weekly for 4-6 weeks probably improves physical function compared with continuous exercise (mean difference 3.8, 1.12 to 6.48; SF-36 physical component summary score; range 0-100; higher scores indicate less impairment).
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This compares 2 forms of exercise, so provides no evidence that exercise is helpful or not.
 
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