The Qure study: Q-fever fatigue syndrome - response to treatment.

Abstract publicatie Qure-studie:

Background. Approximately 20% of patients with acute Q fever will develop chronic fatigue, referred to as Q fever fatigue syndrome (QFS). The objective of this randomized controlled clinical trial was to assess the efficacy of either long-term treatment with doxycycline or cognitive-behavioral therapy (CBT) in reducing fatigue severity in patients with QFS.

Methods. Adult patients were included who met the QFS criteria according to the Dutch guideline: a new onset of severe fatigue lasting ≥6 months with significant disabilities, related to an acute Q fever infection, without other somatic or psychiatric comorbidity explaining the fatigue. Using block randomization, patients were randomized between oral study medication and CBT (2:1) for 24 weeks. Second, a double-blind randomization between doxycycline (200 mg/day, once daily) and placebo was performed in the medication group. Primary outcome was fatigue severity at end of treatment (EOT; week 26), assessed with the Checklist Individual Strength subscale Fatigue Severity.

Results. Of 155 patients randomized, 154 were included in the intention-to-treat analysis (doxycycline, 52; placebo, 52; CBT, 50). At EOT, fatigue severity was similar between doxycycline (40.8 [95% confidence interval {CI}, 37.3–44.3]) and placebo (37.8 [95% CI, 34.3–41.2]; difference, doxycycline vs placebo, −3.0 [97.5% CI, −8.7 to 2.6]; P = .45). Fatigue severity was significantly lower after CBT (31.6 [95% CI, 28.0–35.1]) than after placebo (difference, CBT vs placebo, 6.2 [97.5% CI, .5–11.9]; P = .03).

Conclusions. CBT is effective in reducing fatigue severity in QFS patients. Long-term treatment with doxycycline does not reduce fatigue severity in QFS patients compared to placebo.

So far no data on effective treatment for Q fever Fatigue Syndrome (QFS) are availabe. At present, it is unclear whether effective treatment for QFS is possible. The objective of this study is to assess the efficacy of two treatment strategies for fatigue and disabilities in QFS: long term treatment with doxycycline or cognitive behavioral therapy (CBT). These treatment modalities will be compared with placebo.

Primary outcome CIS: At baseline, 8 weeks and 24 weeks after start treatment.



Secondary outcomes:

1. SIP score: At baseline and 24 weeks after start treatment;

2. SCL90: At baseline and 24 weeks after start treatment;

3. Coxiella serology and PCR: At baseline and 26 weeks after start treatment.

Allocation will be randomized:

1. CBT for 24 weeks (n=60);

2. Long-term antibiotic therapy using doxycycline 200 mg once daily for 24 weeks (n=60);

3. Placebo for 24 weeks (n=60)).



At first, randomization will occur between CBT or medication (ratio 1:2). If patients are randomized to the medication group, a second double-blinded randomization will be done by the study pharmacist (department of Clinical Pharmacy, Radboud University Nijmegen Medical Centre). Obviously, allocation to the CBT intervention cannot be blinded. However, the assessor performing the post-treatment assessment does not know if the patient has been allocated to CBT as patients will be instructed not to give this information. The double-blinded randomization assignment will be known to the study pharmacist only.



In more detail, the intervention groups consist of:

1. Cognitive Behavioral Therapy (CBT): CBT will consist of a protocolized intervention of 12 sessions during a period of 24 weeks. It starts with goal setting and psycho-education on the possible role of cognitions and behavior in maintaining the fatigue. The maintaining factors will subsequently be addressed (regulation of sleep-wake cycle, gradual increasing activity, reformulating fatigue related cognitions);

2. Doxycycline: Antibiotic therapy will consist of doxycycline once daily 200 mg (1 capsule) for 24 weeks. Patients will be monitored 4, 8, 16 and 26 weeks after start for side effects (rash, liver enzymes). Antibiotics will be stopped in case of side effects or pregnancy;

3. Placebo: Patients in the placebo group will receive once daily 1 placebo capsule identical in appearance to the doxycycline capsules for 24 weeks and have the same visits and monitoring for side effects as the patients randomized to doxycycline.