Are they really QUREd?

The Qure[i] study compares the efficacy of treatment with Doxycycline versus placebo and placebo versus Cognitive Behaviour Therapy using CFS-protocol in patients diagnosed with QFS, Q-fever Fatigue Syndrome. According to this study QFS is occurring in approximately 20% of cases following a symptomatic acute Q fever infection. In contrast to chronic Q fever, which also occurs after asymptomatic C. burnetii infection, no viable C. burnetii is present.

qure a

qure b

1. The number of participants is relatively low. That certainly applies to the CBT Group as there is a major dropout. In spite of all statistical measures, the power of the research decreases as a result.
2. The diagnostic criteria for QFS include only fatigue> 6 months and q fever. Possibly there are additional symptoms, but they are not necessary for the diagnosis. These criteria are not comparable to the CDC criteria for CFS where at least 4 additional complaints from 8 are required. The QFS requirements are comparable to the too non-specific Oxford criteria for chronic fatigue. Incidentally, the Fukuda or CDC criteria have now been ruled out by the CDC as too non-specific. Investigations into the effectiveness of CBT / GET on the basis of these Oxford criteria and the CDC or Fukuda criteria have been excluded by the AHRQ as evidence for the effectiveness, because the criteria are too loose.
3. The study into cognitive behavioral therapy is not blinded as a result of the nature of the treatment. That requires special demands to the result measurement. A subjective measurement must then at least be accompanied by an objective measurement[ii].We know from medical trials that differences can be observed with subjective self-report measures that will not be found with objective measures.

4. The CBT treatment includes a strong message that determines how the patient must respond to the subjective questionnaires. Active treatment condition carry strong message about how patients should respond to outcome assessment with improvement.[iii]
5. An objective measurement of the activity level is missing in the final measurement, while an actometer was used at the start.
6. There is no indication of the extent to which patients in the CBT group have achieved the formulated goals, whereas this is precisely what the treatment focuses on.
7. Subjective measures only give a limited picture of the factuality. [iv]
8. CBT for CFS is aimed at changing the beliefs and behaviors of fatigue. The study (-protocol) claims that the model of sickness pepetuating beliefs has been demonstrated in studies in CFS patients. However, that is incorrect. Although the fatigue scores improved, the physical activity of the patients did not increase. The model of the pepetuating factors by Vercoulen et al 1998[v] has thus been invalidated.
Sunnquist and Jason (2017)[vi] also indicate that the model can not be demonstrated in CFS. : This model may not accurately represent the experience of individuals with CFS, especially those who fulfill more stringent case definitions.
9. There is a large dropout in the CGT group (15.7%). There is also a relatively large dropout in other CBT studies[vii]. The fact that there is such a large dropout may say something about negative effects of the treatment and should be investigated. No such analysis has been reported in the publication.
10. According to this study, there is a statistically significant improvement in the CIS F score in the CBT group. How relevant is this statistically significant improvement? The score of 31.6 still does not match the score <27 used in other studies as normal. (Knoop et al, 2007)[viii]. What is the value of such a result if the level of activity is not increased when that is precisely the objective?
11. It is striking that the only score (SIP 8) that indicates at least something about physical functioning does not show a substantial improvement. The score of 786.8 in the CBT group is so bad that in other studies it is considered severe impairment and leads to inclusion in research. This score is also completely inadequate compared to the normal value in this study (450). As normal value, a score of 203 is used in other studies (Knoop et al. 2007).
12. Although the SCL 90 is said to show a significant change in the score at the CBT group, here too the question is how relevant the differences are in practice. We only see average total scores that are all in the lower ranges of the scoring options (total range is 90-450).
13. Although the placebo treatment (= a placebo drug) is a good comparison to doxycycline treatment, it is by its nature not a good control for CBT treatment.
14. The comparison of the number of Adverse Events says little about safety. The available data in the publication say nothing about the nature of the events at the CGT group. Are the AEs comparable? The conclusion based on the ratio in the numbers or percentages AE that CGT would be safe is not sufficiantly substantiated.
15. The serology and PCR in Table 1 show that there are no differences between the different groups, that they all have experienced q fever (IgG and IgM). At this time, no chronic infection would have been measured, e.g. the negative C burnetii PCR. In Table 2 it is special that one does not show the outcome between DOX and CBT. The p-values ​​are very meager and the authors claim that the patients do not have chronic q fever. That is very debatable[ix]
16. There is no follow-up measurement available and it can therefore not be established whether the (inadequate) changes that have occurred are also retained in due course. The results of the follow-up are to be published in the short term.

In general: the QURE study does not provide evidence for the efficacy of Cognitive Behavioral Therapy with a gradual activity protocol in patients with QFS.
a. The CBT treatment does not lead to an acceptable (subjective) fatigue level. The outcome value of the CIS-F is still higher than in other studies is considered normal.
b. The physical functioning according to the SIP8 is far from normal and shows a score at group level that would lead to inclusion in research.
c. The model of the sustaining factors is (again) invalidated by this research.
d. The conclusions regarding the safety of the CBT treatment lack a solid substantiation.


[i] 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



[iv] Wiborg JF, Knoop H, Stulemeijer M (2010) How does cognitive behaviour therapy

reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity.

Psychol Med 40: 1281-1287

[v] Vercoulen JH, Swanink CM, Galama J, et al. (1998) The persistence of fatigue in chronic fatigue syndrome and multiple sclerosis: development of a model. J Psychosom Res 45(6): p. 507 – 517.

[vi] Sunnquist M, Jason LA, A reexamination of the cognitive behavioral model of chronic fatigue syndrome Journal of clinical psychology 74 (7): 1234-1245

[vii] Prins JB, Bleijenberg G, Bazelmans E (2001) Cognitive behaviour therapy for chronic fatigue

syndrome: a multicentre randomised controlled trial. Lancet 357: 841-847.

[viii] 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.

[ix]Wielders CCH, Wijnbergen PCA, Renders NHM, Schellekens JJA, Schneeberger PM, Wever PC, Hermans MHA (2013) High Coxiella burnetii DNA Load in Serum during Acute Q Fever Is Associated with Progression to a Serologic Profile Indicative of Chronic Q Fever, Journal of Clinical Microbiology 51: 3192–3198


Auteur: Lou Corsius

MSc Health Sciences

2 gedachten over “Are they really QUREd?”

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