Efficacy of cognitive behavioral therapy targeting severe fatigue following COVID-19: results of a randomized controlled trial 2023, Kuut, Knoop et al

[Grigor]

Efficacy of cognitive behavioral therapy targeting severe fatigue following COVID-19: results of a randomized controlled trial.

Tanja A Kuut, Fabiola Müller, Irene Csorba, Annemarie Braamse, Arnoud Aldenkamp, Brent Appelman, Eleonoor Assmann-Schuilwerve, Suzanne E Geerlings, Katherine B Gibney, Richard A A Kanaan,
Kirsten Mooij-Kalverda, Tim C Olde Hartman, Dominique Pauëlsen, Maria Prins, Kitty Slieker, Michele van Vugt, Stephan P Keijmel, Pythia Nieuwkerk, Chantal P Rovers, Hans Knoop.

Abstract
Background
Severe fatigue following COVID-19 is prevalent and debilitating. This study investigated the efficacy of cognitive behavioral therapy (CBT) for severe fatigue following COVID-19.

Methods
A multicenter, 2-arm randomized controlled trial was conducted in the Netherlands with patients being severely fatigued 3-12 months following COVID-19. Patients (n = 114) were randomly assigned (1:1) to CBT or care as usual (CAU). CBT, targeting perpetuating factors of fatigue, was provided for 17 weeks. The primary outcome was the overall mean difference between CBT and CAU on the fatigue severity subscale of the Checklist Individual Strength, directly post CBT or CAU (T1), and after six months (T2). Secondary outcomes were differences in proportions of patients meeting criteria for severe and/or chronic fatigue, differences in physical and social functioning, somatic symptoms and problems concentrating between CBT and CAU.

Results
Patients were mainly non-hospitalized and self-referred. Patients who received CBT were significantly less severely fatigued across follow-up assessments than patients receiving CAU (-8.8, (95% confidence interval (CI)) -11.9 to -5.8); P < 0.001), representing a medium Cohen’s d effect size (0.69). The between-group difference in fatigue severity was present at T1 -9.3 (95% CI -13.3 to -5.3) and T2 -8.4 (95% CI -13.1 to -3.7). All secondary outcomes favored CBT. Eight adverse events were recorded during CBT, and 20 during CAU. No serious adverse events were recorded.

Conclusions
Among patients, who were mainly non-hospitalized and self-referred, CBT was effective in reducing fatigue. The positive effect was sustained at six month follow-up.

https://academic.oup.com/cid/advanc...id/ciad257/7157021?searchresult=1&login=false

Thread on the study protocol:
ReCOVer: A RCT testing the efficacy of CBT for preventing chronic post-infectious fatigue among patients diagnosed with COVID-19.

 

[Peter T]

Yet another:

Subjective outcomes in an open label trial with no active control (‘care as usual’ is not a meaningful control to allow the conclusion that this intervention is any better than any other pseudo therapeutic interaction of the same interaction level).

(Not totally clear how ‘concentration’, was measured though I assume that was also measured by questionnaire. At least they attempted to record adverse events)

Also I found no mention of PEM or whether any subjects met the diagnostic criteria for ME/CFS, only focused on severity of fatigue or if the fatigue was chronic, so no serious consideration of the potential lack of homogeneity found in Long Covid.

(edit - corrected typos, also not clear if they understood the distinction between chronic fatigue and chronic fatigue syndrome. Not to even discuss this in a condition where potentially up to 50% of Long Covid sufferers meet the diagnostic criteria for ME/CFS is a concerning omission.)

 

[Grigor]

My post on LinkedIn about the paper.

The new Dutch CBT trial for #longCOVID. From my initial scan.

All subjective outcome measures. The actometer that was used at the beginning of the trial to assess patients activity that could've provided objective evidence of improvements was not used? Neither right after the trial nor at 6 months.

Sounds very familiar where with studies in "CFS" and QFS the disappointing objective outcomes measure never seem to match the "positive" subjective outcome measures. So what do those physical function questionnaires really mean?

https://lnkd.in/gUEUc3j

Patients might simply report improvements because they received more attention than those with regular care that didn't. We all know the care that people with #LongCovid isn't that great in the Netherlands.

The majority of the patients were self referred and probably more motivated to participate increasing the bias when you solely rely on subjective outcome measures.

The effect size is really small. Considering these facts I'd say the effect is nothing more than participants reporting biases.

The study reports there was no harm, but that's not what I heard from patients involved.

Overal a similarly disappointing study as we've seen with "CFS" and QFS but admittingly a lot more nuanced about it's effect, but unfortunately still based on a rather harmful CBT model.

Why don't we invest in proper psychological support instead of this type of CBT? At least in ME it seems to be ineffective and patient report that it can be harmful to them when they're suffering from post-exertional malaise. It's not for nothing that we see centers like the CDC, NICE but also the Dutch and Belgian health council change their advice about this particular form of CBT.

https://lnkd.in/dYVJBaQT

.

#longCOVID

https://lnkd.in/d6uss77C

 

[RedFox]

The actometer that was used at the beginning of the trial to assess patients activity that could've provided objective evidence of improvements was not used? Neither right after the trial nor at 6 months.

That's heavily suspicious. Perhaps they stopped using the actimeters because they realized it wouldn't show any actual improvement. Or maybe there's a more innocent explanation, but the purpose of sticking to your methodology is to stay above suspicion of such shenanigans.

 

[Solstice]

That's heavily suspicious. Perhaps they stopped using the actimeters because they realized it wouldn't show any actual improvement. Or maybe there's a more innocent explanation, but the purpose of sticking to your methodology is to stay above suspicion of such shenanigans.

It's deliberate. There are people in that list that have pointed out the errors in their research and they don't care as long as it brings the results they need.

 

[Jaybee00]

Ugh!

 

[NelliePledge]

More precious research funding down the drain of pace style “studies”

 

[Sean]

All subjective outcome measures. The actometer that was used at the beginning of the trial to assess patients activity that could've provided objective evidence of improvements was not used? Neither right after the trial nor at 6 months.

I wonder where they learned that trick?

 

[Charles B.]

Ugh!

Ben Ryan has been a hellacious supporter of the Gaffney and Shure perspective throughout the pandemic

 

[Medfeb]

Another potential issue in addition to the above - The study inclusion criterion for reduced function included either limits in physical function or limits in social function.

Limitations in physical functioning operationalized as a score of ≤ 65 on the physical functioning subscale of the SF-36[20] and/or social functioning operationalized as a score of ≥ 10 on the WSAS.[21]​

The question is whether some of those who have limits only in social function might be helped by targeting the cognitive-behavioral factors this study claims perpetuates them - e.g. sleep, low activity, unhelpful beliefs about fatigue, fears and worries, poor coping with pain, etc

If so, together with issues noted above, those non-specific criteria could add to possibility of seeing a positive signal in at least some patients and thus in the trial. Given what this claims to be targeting, it seems disingenuous to use such mixed criteria.

Maybe I missed it but didn't see them report these groups separately.

 

[Hutan]

During the study period, 73% of patients (40/55) in the CBT group and 91% of patients (51/56) in the CAU group received care outside of the study with a mean number of consulted health care practitioners of 1.1 (1.0) and 2.4 (1.6), respectively. These were mainly the GP, a physician in an outpatient clinic or a physical therapist, the latter most often for guided exercise. (Supplementary Appendix, table S4).

So, the control group were getting instruction on exercise.
And the CBT group were getting instruction on how to answer surveys positively...

 

[Hutan]

CIS- Subjective fatigue is a subset of the CIS fatigue questionnaire.
There are 8 questions, with Likert scales from 1 to 7. e.g. "I feel tired"; the questions relate to the past two weeks.
17.3 is an average for healthy people (ME Pedia);
at the 6 month mark, the CBT group was at 31.5 and the care as usual group was at 39.9.
So both groups were, on average, a long way from being recovered.

The scale is prone to a ceiling effect, so it's much easier to show a reduction in fatigue than an increase.

The difference in the outcomes on that questionnaire between the two treatments is equivalent to one point on the 1 to 7 scale. So e.g. "I feel tired" - where 1 is 'no, that's true' and 7 is 'yes, that's true'. So, given all the participants have on average improved a bit, or become a bit better at managing their illness over the 6 months, how hard would it be for the people with CBT to be swayed by instruction that their focus on symptoms is partly causing their fatigue to answer just a little more positively.

We are definitely in subjective outcome territory here.

As for health care usage/costs:
for CBT:

The mean number of interactions between the therapist and patient was 11.8 (3.5), consisting of 4.6 (4.2) interactions by email, 4.0 (3.8) video consults, 2.9 (3.0) face-to-face consults and 0.3 (0.7) telephone consults.

The average number of health care practitioner consults in addition to this was 1.1
There's also the admin cost of the programme.

for care as usual:
The average number of health care practitioner consults (e.g. doctor or physical therapist) was 2.4

So, even if we just consider video and face-to-face consults by a health care practitioner, the CBT group received 8 consults versus 2.4 in the care as usual group. That's a substantial increase in cost for what is probably a largely illusory benefit. And, that is before we count the cost of telling people that they should ignore their symptoms and not trust their body.

 

[Hutan]

The study reports there was no harm, but that's not what I heard from patients involved.

Thanks @Grigor, is there anything about that that you can share?

Edit - and when was the study undertaken?

 

[Hutan]

Link to the protocol:
A randomised controlled trial testing the efficacy of Fit after COVID, a cognitive behavioural therapy targeting severe post-infectious fatigue following COVID-19 (ReCOVer): study protocol

 

[Hutan]

The primary outcome, the fatigue severity subscale of the Checklist Individual Strength (CIS-fatigue), is assessed in both groups before randomisation (T0), directly post CBT or following care as usual (T1), and at follow-up 6 months after the second assessment (T2). In addition, a long-term follow-up (T3), 12 months after the second assessment, is performed in the CBT group only.

The plan was to do a followup at 12 months, but only for the CBT group - which is completely useless.

The efficacy of CBT for fatigue has mostly been tested in populations with a long duration of fatigue and impairments, often several years. There is evidence that a long symptom duration is associated with a less favourable outcome of CBT [36]. Thus early intervention may help to prevent severe fatigue becoming chronic. On the other hand, in glandular fever, considerable spontaneous recovery from acute fatigue in the first three months after an infection [37] is observed. Three months following the acute phase of COVID-19 may therefore be the optimum time point to start an intervention.

How transparent can you get? CBT doesn't work very well in people who have been sick for a long time. There's a high natural rate of recovery in the first three months after an infection (in glandular fever). Therefore, let's do CBT soon after a Covid-19 infection, so that all the people who would naturally improve will attribute their improvement to CBT.

Here's the information about protocol versions and the timing of the start of the trial:

Patient recruitment started in November 2020 with version 3 of the protocol. At the time of submission, 89 participants have been randomly assigned. The trial is being conducted in accordance with the protocol version 4, dated 21 April 2021.

Revision:

Version 1, date 27-07-2020

Version 2, date 01-09-2020: Questions of the medical ethics committee about the actigraph, AE’s and SAE’s, privacy and feasibility are answered. This information is added to the protocol.

Version 3, date 12-10-2020: the upper limit for including patients was extended from initially 6 months to 9 months after diagnosis or hospital discharge (inclusion criterion b).

Version 4, date 21-04-2021: the upper limit for including patients was extended from initially 6 months to 12 months after diagnosis or hospital discharge (inclusion criterion b); One of the original criteria to confirm COVID-19 (inclusion criterion a), i.e. typical symptoms and was part of a household in which another person was tested positive by PCR two weeks before or after the first day of illness, was removed because of the increased test capacity; new corona-virus tests are added to the inclusion criteria; CDC questionnaire is added to the T1 measurement.

Patients learn to identify unhelpful thoughts and replace them with helpful thoughts, gain more self-efficacy and learn to focus less on their fatigue.

Patients learn how to communicate with significant others about their fatigue, be assertive and adapt expectations about their environment.

Patients learn about the difference between severe fatigue and normal fatigue.

 

[Hutan]

Re the actigraph - there should have been objective data on activity levels.

At T0 and T1, data on physical activity level and sleep are also gathered by using an actigraph and completing a sleep diary.

Activity: An actigraph is used to assess the participant’s level of physical activity. The actigraph is worn around the wrist for 14 consecutive days and nights for a reliable estimate of daily activity for 12 full days. The actigraph has been shown to be a reliable and valid instrument for the assessment of physical activity [53, 67].

There's no mention of the actigraph in the published paper. Both cohorts should have been assessed for activity at T1.

 

[Hutan]

This study received support from the Australian NHMRC and ZonMW - it's not good enough.

Table 3 of the protocol has a long list of things that were to be measured e.g.

The criteria for CFS are assessed by the US Centers for Disease Control and Prevention (CDC) criteria revised in 2003

was to be assessed at T1, T2 and T3.

 

[InitialConditions]

This plot is objectively worse than those I used to make in GCSE I.T. when I was just learning Excel. Absolutely no care at all. Looks like shit.

On a technical note, the error bars are somehow not lined up with the datapoints themselves. I'm not even sure how you'd manage that (maybe it's an artefact of the plotting software). I have absolutely no faith in any of this work.

 

[Hutan]

This plot is objectively worse than those I used to make in GCSE I.T. when I was just learning Excel. Absolutely no care at all. Looks like shit.

Just noting those error bars on the chart and in Table 3 are said to be standard errors. I've said before, if a paper plots SE's, then I reckon it's a fair bet that it is a rubbish paper.

(Edited - wrong)
Standard error of the mean is the standard deviation divided by the square root of the sample size. Say the sample size is 57. the square root is about 7.55. So the standard deviation at T2 is 1.7 *7.55. That's about 12.8! The standard deviation is 12.8. If we approximate a 95% confidence interval to plus or minus two standard deviations, then the values at T2 on that chart should have error bars of 25.6 either side of the point.

Try drawing those error bars on the chart above. If I haven't made a mistake, and it's quite possible that I have, then the result means very little. (Bear in mind that the lowest possible score on the scale is 8, and the highest possible score is 56.)

(And if you look at the standard errors in Table 3 - they look suspiciously repetitive. I would not be surprised if there was a problem in that table.)

 

[Grigor]

Thanks @Grigor, is there anything about that that you can share?

Edit - and when was the study undertaken?

I will discuss with this person is he/she wants to share their story.