This is part 2 of our comment on the Qure-study. This comment regards the outcomes of the Follow-up study. (Part 1 can be found here[i])
Nederlandse vertaling aan het eind van dit artikel.
Introduction The Qure study [ii] compared the efficacy of treatment with Doxycycline versus Placebo and Placebo versus Cognitive Behaviour Therapy for CFS in patients diagnosed with QFS, Q-fever Fatigue Syndrome. The conclusion of that study was that CBT for CFS had a positive effect on fatigue severity according to the outcomes of CIS-F (Checklist Individual Strength sublist Fatigue). In November 2018 the authors published the one-year follow-up study[iii] . Their conclusion is that the beneficial effect (as they call it) of CBT on fatigue severity at EOT was not maintained 1 year thereafter. Nevertheless they still recommend CBT as treatment for QFS. They suggest further investigation on tailoring CBT more to QFS, possibly followed by booster sessions. That however, is a controversial conclusion. A conclusion that we will dispute in this comment.
Comparison of outcomes
In the overview below, the outcomes at grouplevel are presented at the start of the treatment (Baseline) at the end of treatment (Endpoint) and at a moment 12 to 15 months after ending the treatment (Follow-up) . The outcomes of treatment with Doxycycline at Follow-up were compared to the outcomes in the Placebo Group at the same moment. The outcomes of the CBT treatment at Follow-up were equally compared to the Placebo outcomes. The initially statisticly significant better scores of the CBT –group for fatigue severity have disappeared. There is no longer a statistically difference between Placebo and Doxycycline, nor is there a statistically significant difference between CBT and Placebo.
The CBT scores got considerably worse at Follow-up, while the Placebo score on CIS-F even improved (although modestly). The outcome scores on SIP8 (Physical functioning) that were totally insufficient for all three groups at the endpoint, got worse for the CBT-group but improved for the Doxycycline- and the Placebo-group. The result at follow-up is that the Placebo-group has better scores on CIS-F and on SIP8 (although still insufficient) than both treatment groups.
Despite these findings the authors still suggest to advise CBT as a therapy of choice: Due to its initial positive effect and side effects of long-term doxycycline use, CBT is still advised as therapy of choice for QFS patients. At present, it is still the only well-investigated treatment modality for QFS patients with a positive effect.
Discussion The conclusion of the authors is incomprehensible. We will explain that in the following observations:
- Contrary to what the authors claim, there is no beneficial effect as a result from CBT. The initial fatigue severity score in the CBT-group on CIS F (31,6) was very poor in itself. As we have shown in part 1 of this comment, a score of 31.6 is still far above a score of <27 that is used in other fatigue researches.[iv] (a higher score is worse)
- The fact that the SIP 8 scores at Endpoint were still very high, indicates that patients did not function very well. The therapy has not been beneficial at all. These scores are still high enough for the patients to be included in research again.
- At follow-up the score on CIS F had got worse for the CBT-group. There is no longer a statistically significant difference between the CBT-group and the Placebo-group on CIS F. When we look closer we can conclude that the Placebo-group scored better than at Endpoint and now scores even better than CBT at Follow-up.
- We see the same effect on the SIP 8 scores: the scores of the CBT-group got worse, while the Placebo-group scores ameliorated. The SIP 8 scores in the Follow-up group are now better than those of the CBT-group.
- The better results in the Placebo group, although not yet statistically significant, confirm earlier findings from the scores of CFS patients. In the study by Bazelmans et al[v] the authors phrased it as follows: for functional impairment, the effect was opposite to what was expected. Looking at the improvement and the better scores on SIP 8 and CIS F in the non-intervention/Placebo group in the Qure study, this is once more an indication that CBT with a graded activity protocol is impeding the naturally-occurring recovery process.
- The findings in this follow-up study confirm the concerns of patients suffering with QFS as well as with CFS: the CBT treatment with a graded activity protocol will lead to deterioration because patient learn during this treatment not to trust on the signs of their body that they have overstretched their possibilities. In the long end this will lead to deterioration. Although authors in several studies contest this conclusion and claim CBT treatment with graded activity is safe, these findings seem to confirm the experiences of the patients.
- What would have been the cause of the initially “beneficial effect” on fatigue severity? As Professor James Coyne described [vi] multiple flaws in psychotherapy research will influence the outcomes. The following flaws have been found in the Qure study:
Subjective self-report outcomes Note: subjective outcome measures do not necessarily reflect the actual or factual situation
Deliberate exclusion of relevant objective outcomes. Note: As described in part one, no objective measures were reported, although an actometer has been used in this study.
Active treatment conditions carry a strong message how patients should respond to outcome assessment with improvement. Note: patients may have learned to give (socially) desirable answers that do not reflect the factuality.
Specifying a clinically significant improvement that required only that a primary outcome be less than needed for entry into the trial. Note: in this case the authors defined a clinically meaningful improvement as a reduction of 9 points plus a score <35 on CIS F. However, What is the value of such a result if the level of activity is not increased when that is precisely the objective?
In general: the QURE study and the follow-up study prove that Cognitive Behavioural Therapy with a gradual activity protocol is not effective in patients with QFS.
- The CBT treatment eventually led to a higher fatigue level than the Placebo treatment did.
- The physical functioning according to the SIP8 was far from normal at EOT and got worse in the CBT-group at follow-up while the Placebo group improved and scored better at follow-up than the CBT-groep did..
- The model of the sustaining factors is (again) invalidated by this research.
- The conclusions regarding the safety of the CBT treatment lack a solid substantiation, especially since the CBT-group had poorer scores at follow-up. Together with the considerable drop-out in the CBT-group this may be an indication of the adverse effect of the CBT-treatment with graded activity protocol.
- CBT with a graded activity protocol is neither efficacious nor safe in patient sufferings with QFS, as we also have seen before in CFS-patients.
- There is no reasonable underpinning to advise CBT as a possible treatment for QFS.
[ii] Keijmel SP, Delsing CE, Bleijenber G et al (2017) Effectiveness of long-term doxycycline treatment and cognitive behavioral therapy on fatigue severity in patients with Q-fever fatigue syndrome Clinical Infectious Diseases, 64(8):998-1005
[iii] Raijmakers, PH, Keijmel, SP, Breukers, MC, Bleijenberg, G et al (2018) Long-term effect of cognitive behavioural therapy and doxycycline treatment for patients with Q fever fatigue syndrome: One-year follow-up of the Qure study Journal of Psychosomatic Research 116:62-67
[iv] Knoop H, Bleijenberg G, Gielissen MF (2007) Is a full recovery possible after cognitive behavioural therapy for chronic fatigue syndrome? Psychother Psychosom 76: 171-176.
[v] Bazelmans E, Prins JB, Lulofs R (2005) Cognitive behaviour group therapy for chronic fatigue syndrome: a non-randomised waiting list controlled study. Psychother Psychosom 74: 218-224.
In het onderstaande overzicht worden de uitkomsten op groepsniveau weergegeven aan het begin van de behandeling (baseline), aan het einde van de behandeling (eindpunt) en op een moment 12 tot 15 maanden na het beëindigen van de behandeling (follow-up).
Ondanks deze bevindingen suggereren de auteurs nog steeds om CBT te adviseren als een aanbevolen therapie : vanwege het initiële positieve effect en de bijwerkingen van langdurig doxycycline gebruik, wordt CBT nog steeds geadviseerd als therapie bij uitstek voor QFS-patiënten. Op dit moment is het nog steeds de enige goed onderzochte behandelingsmethode voor QFS-patiënten met een positief effect
2. Het feit dat de SIP 8-scores bij de eindpuntmeting nog steeds erg hoog waren, geeft aan dat patiënten niet goed functioneerden. De therapie was helemaal niet gunstig. Deze scores zijn nog steeds hoog genoeg om de patiënten opnieuw in onderzoek te in te sluiten.
1. De CGT-behandeling leidde uiteindelijk tot een hoger vermoeidheidsniveau dan de Placebo-behandeling.
2. Het fysieke functioneren volgens de SIP8 was bij EOT lang niet normaal en werd bij de follow-up slechter in de CGT-groep, terwijl de Placebo-groep verbeterde en bij follow-up beter scoorde dan de CGT-groep deed.
3. Het model van de in standhoudende factoren wordt (wederom) weersproken door dit onderzoek.
4. De conclusies met betrekking tot de veiligheid van de CGT-behandeling missen een degelijke onderbouwing, temeer daar de CGT-groep slechtere scores had bij de follow-up. Samen met de aanzienlijke uitval in de CGT-groep kan dit een aanwijzing zijn voor het nadelige effect van de CBT-behandeling met graded activityprotocol.
5.CBT met een graded activityprotocol is niet effectief noch veilig voor patiënten lijdend aan QFS, zoals we ook eerder hebben gezien bij CVS-patiënten.
6. Er is geen redelijke onderbouwing om CGT te adviseren als mogelijke behandeling voor QFS.