The Qure study: Q fever fatigue syndrome – response to treatment; a randomized placebo-controlled trial

BMC Infectious Diseases

Chantal P Bleeker-Rovers⁴  Hans Knoop¹  Jos WM van der Meer⁴  Gijs Bleijenberg¹  Tom Sprong³  Corine E Delsing²  Stephan P Keijmel⁴ 

[1]Expert Centre for Chronic Fatigue, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500, Nijmegen, HB, the Netherlands

[2]Department of Internal Medicine, Medical Spectrum Twente, P.O. Box 50000, 7500, Enschede, KA, the Netherlands

[3]Department of Internal Medicine and division of Infectious Diseases, Canisius Wilhelmina Hospital, P.O. Box 9015, 6500, Nijmegen, GS, the Netherlands

[4]Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500, Nijmegen, HB, the Netherlands

关键词: Placebo;    Cognitive behavioral therapy;    Doxycycline;    Treatment;    Study protocol;    QFS;    Q fever fatigue syndrome;    Q fever;    Coxiella burnetii;   

Others  :  1149045
DOI  :  10.1186/1471-2334-13-157

 received in 2013-03-11, accepted in 2013-03-21,  发布年份 2013

【 摘 要 】

Background

Q fever is a zoonosis that is present in many countries. Q fever fatigue syndrome (QFS) is one of the most frequent sequelae after an acute Q fever infection. QFS is characterized by persistent fatigue following an acute Q fever infection, leading to substantial morbidity and a high socio-economic burden. The occurrence of QFS is well-documented, and has been described in many countries over the past decades. However, a treatment with proven efficacy is not available. Only a few uncontrolled studies have tested the efficacy of treatment with antibiotics on QFS. These studies suggest a positive effect of long-term treatment with a tetracycline on performance state; however, no randomized controlled trials have been performed. Cognitive behavioral therapy (CBT) has been proven to be an effective treatment modality for chronic fatigue in other diseases, but has not yet been tested in QFS. Therefore, we designed a trial to assess the efficacy of long-term treatment with the tetracycline doxycycline and CBT in patients with QFS.

Methods/design

A randomized placebo-controlled trial will be conducted. One-hundred-eighty adult patients diagnosed with QFS will be recruited and randomized between one of three groups: CBT, long-term doxycycline or placebo. First, participants will be randomized between CBT and medication (ratio 1:2). A second double-blinded randomization between doxycycline and placebo (ratio 1:1) will be performed in the medication condition. Each group will be treated for six months. Outcome measures will be assessed at baseline and post intervention. The primary outcome measure is fatigue severity. Secondary outcome measures are functional impairment, level of psychological distress, and Coxiella burnetii PCR and serology.

Discussion

The Qure study is the first randomized placebo-controlled trial, which evaluates the efficacy of long-term doxycycline and of cognitive behavioral therapy in patients with QFS. The results of this study will provide knowledge about evidence-based treatment options for adult patients with QFS.

Trial registration

ClinicalTrials.gov: http://NCT01318356 webcite, and Netherlands Trial Register: NTR2797

【 授权许可】

   
2013 Keijmel et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Kaplan MM, Bertagna P: The geographical distribution of Q fever. Bull World Health Organ 1955, 13(5):829-860.
• [2]Rijksinstituut voor Volksgezondheid en Milieu [in Dutch]. http://rivm.nl/Onderwerpen/Ziekten_Aandoeningen/Q/Q_koorts webcite
• [3]Van der Hoek W, Hogema BM, Dijkstra F, Rietveld A, Wijkmans CJ, Schneeberger PM, Zaaijer HL: Relation between Q fever notifications and Coxiella burnetii infections during the 2009 outbreak in The Netherlands. Euro Surveill 2012, 17(3):20058.
• [4]Kampschreur LM, Hagenaars JC, Wielders CC, Elsman P, Lestrade PJ, Koning OH, Oosterheert JJ, Renders NH, Wever PC: Screening for Coxiella burnetii seroprevalence in chronic Q fever high-risk groups reveals the magnitude of the Dutch Q fever outbreak. Epidemiol Infect 2013, 141:847-851.
• [5]Wegdam-Blans MCA, Kampschreur LM, Delsing CE, Bleeker-Rovers CP, Sprong T, van Kasteren MEE, Notermans DW, Renders NHM, Bijlmer HA, Lestrade PJ, Koopman MPG, Nabuurs-Franssen MH, Oosterheert JJ: Chronic Q fever: review of the literature and a proposal of new diagnostic criteria. J Infect 2012, 64:247-259.
• [6]Fournier PE, Marrie TJ, Raoult D: Diagnosis of Q fever. J Clin Microbiol 1998, 36(7):1823-1834.
• [7]Million M, Thuny F, Richet H, Raoult D: Long-term outcome of Q fever endocarditis: a 26-year personal survey. Lancet Infect Dis 2010, 10(8):527-535.
• [8]Ayres JG, Smith EG, Flint N: Protracted fatigue and debility after acute Q fever. Lancet 1996, 347:978-979.
• [9]Ayres JG, Flint N, Smith EG, Tunnicliffe WS, Fletcher TJ, Hammond K, Ward D, Marmion BP: Post-infection fatigue syndrome following Q fever. QJM 1998, 91:105-123.
• [10]Marmion BP, Shannon M, Maddocks I, Storm P, Penttila I: Protracted debility and fatigue after acute Q fever. Lancet 1996, 347:977-978.
• [11]Wildman MJ, Smith EG, Groves J, Beattie JM, Caul EO, Ayres JG: Chronic fatigue following infection by Coxiella burnetii (Q fever): ten-year follow-up of the,1989 UK outbreak cohort. Qjm-an Int J Med 2002, 95:527-538.
• [12]Limonard GJM, Nabuurs-Franssen MH, Weers-Pothoff G, Wijkmans C, Besselink R, Horrevorts AM, Schneeberger PM, Groot CAR: One-year follow-up of patients of the ongoing Dutch Q fever outbreak: clinical, serological and echocardiographic findings. Infection 2010, 38:471-477.
• [13]Morroy G, Peters JB, van Nieuwenhof M, Bor HHJ, Hautvast JLA, van der Hoek W, Wijkmans CJ, Vercoulen JH: The health status of Q-fever patients after long-term follow-up. BMC Infect Dis 2011, 11:97. BioMed Central Full Text
• [14]Dutch guideline Q fever fatigue syndrome [in Dutch]. http://www.rivm.nl/dsresource?objectid=rivmp:118226&type=org&disposition=inline webcite
• [15]Marmion BP: A guide to Q fever and Q fever vaccination. CSL Biotherapies 2009, 44-47.
• [16]Hatchette TF, Hayes M, Merry H, Schlech WF, Marrie TJ: The effect of C-burnetii infection on the quality of life of patients following an outbreak of Q fever. Epidemiol Infect 2003, 130:491-495.
• [17]Economische gevolgen van de uitbraak van Q-koorts [in Dutch]. http://www.seo.nl/pagina/article/economische-gevolgen-van-de-uitbraak-van-q-koorts/ webcite
• [18]Helbig K, Harris R, Ayres J, Dunckley H, Lloyd A, Robson J, Marmion BP: Immune response genes in the post-Q-fever fatigue syndrome, Q fever endocarditis and uncomplicated acute primary Q fever. Qjm-an Int J Med 2005, 98(8):565-574.
• [19]Penttila IA, Harris RJ, Storm P, Haynes D, Worswick DA, Marmion BP: Cytokine dysregulation in the post-Q-fever fatigue syndrome. QJM 1998, 91(8):549-560.
• [20]Arashima Y, Kato K, Komiya T, Kumasaka K, Matsukawa Y, Murakami M, Takahashi K, Ikeda T, Arakawa Y: Improvement of chronic nonspecific symptoms by long-term minocycline treatment in Japanese patients with Coxiella burnetii infection considered to have post-Q fever fatigue syndrome. Intern Med 2004, 43:49-54.
• [21]Iwakami E, Arashima Y, Kato K, Komiya T, Matsukawa Y, Ikeda T, Arakawa Y, Oshida S: Treatment of chronic fatigue syndrome with antibiotics: pilot study assessing the involvement of coxiella burnetii infection. Intern Med 2005, 44:1258-1263.
• [22]Ledina D, Bradaric N, Milas I, Ivic I, Brncic N, Kuzmicic N: Chronic fatigue syndrome after Q fever. Med Sci Mon 2007, 13:CS88-CS92.
• [23]Prins JB, van der Meer JW, Bleijenberg G: Chronic fatigue syndrome. Lancet 2006, 367(9507):346-355.
• [24]Zwarts MJ, Bleijenberg G, van Engelen BG: Clinical neurophysiology of fatigue. Clin Neurophysiol 2008, 119(1):2-10.
• [25]Gielissen MF, Verhagen S, Witjes F, Bleijenberg G: Effects of cognitive behavior therapy in severely fatigued disease-free cancer patients compared with patients waiting for cognitive behavior therapy: a randomized controlled trial. J Clin Oncol 2006, 24(30):4882-4887.
• [26]Castell BD, Kazantzis N, Moss-Morris RE: Cognitive behavioral therapy and graded exercise for chronic fatigue syndrome: a meta-analysis. Clin Psychol-Sci Pr 2011, 18(4):311-324.
• [27]Price JR, Mitchell E, Tidy E, Hunot V: Cognitive behaviour therapy for chronic fatigue syndrome in adults [Cochrane review]. Cochrane Database Syst Rev 2008, 3:CD001027.
• [28]Malouff JM, Thorsteinsson EB, Rooke SE, Bhullar N, Schutte NS: Efficacy of cognitive behavioral therapy for chronic fatigue syndrome: a meta-analysis. Clin Psychol Rev 2008, 28:736-745.
• [29]Wegdam-Blans MCA, Kampschreur LM, Nabuurs-Franssen MH, Renders NHM, Delsing CE, Bijlmer HA: Nederlandse consensus chronische Q-koorts [in Dutch]. Tijdschrift voor Infectieziekten 2011, 6(2):71-73.
• [30]Prins J, Bazelmans E, van der Werf S, van der Meer J, Bleijenberg G: Cognitive behaviour therapy for chronic fatigue syndrome: Predictors of treatment outcome. Psychosom Med 2002, 64(1):90.
• [31]Van der Werf SP, Prins JB, Vercoulen JH, van der Meer JW, Bleijenberg G: Identifying physical activity patterns in chronic fatigue syndrome using actigraphic assessment. J Psychosom Res 2000, 49(5):373-379.
• [32]Rolain JM, Mallet MN, Raoult D: Correlation between serum doxycycline concentrations and serologic evolution in patients with Coxiella burnetii endocarditis. J Infect Dis 2003, 188(9):1322-1325.
• [33]Tummers M, Knoop H, Bleijenberg G: Effectiveness of stepped care for chronic fatigue syndrome: a randomized noninferiority trial. J Consult Clin Psychol 2010, 78(5):724-731.
• [34]Vercoulen JHMM, Swanink CMA, Fennis JFM, Galama JMD, Vandermeer JWM, Bleijenberg G: Dimensional assessment of chronic fatigue syndrome. J Psychosom Res 1994, 38(5):383-392.
• [35]Vercoulen JHM, Alberts M, Bleijenberg G: De checklist individual strength (CIS). Gedragstherapie 1999, 32:131-136.
• [36]Dittner AJ, Wessely SC, Brown RG: The assessment of fatigue: a practical guide for clinicians and researchers. J Psychosom Res 2004, 56(2):157-170.
• [37]Bergner M, Bobbitt RA, Carter WB, Gilson BS: The sickness impact profile: development and final revision of a health status measure. Med Care 1981, 19(8):787-805.
• [38]Jacobs HM, Luttik A, Touw-Otten FW, de Melker RA: The sickness impact profile; results of an evaluation study of the Dutch version. Ned Tijdschr Geneeskd 1990, 134(40):1950-1954.
• [39]Debruin AF, Dewitte LP, Stevens F, Diederiks JPM: Sickness impact profile - the state-of-the-Art of a generic functional status measure. Soc Sci Med 1992, 35(8):1003-1014.
• [40]Derogatis L: Brief Symptom Inventory (BSI) 18 Administration, scoring and procedures manual. edn. Minneapolis MN: NCS Pearson, Inc; 2000.
• [41]Frazier PA, Tix AP, Barron KE: Testing moderator and mediator effects in counseling psychology research. J Couns Psychol 2004, 51(1):115-134.
• [42]Knoop H, van Kessel K, Moss-Morris R: Which cognitions and behaviours mediate the positive effect of cognitive behavioural therapy on fatigue in patients with multiple sclerosis? Psychol Med 2012, 42(1):205-213.
• [43]Ray C, Weir W, Stewart D, Miller P, Hyde G: Ways of coping with chronic fatigue syndrome: development of an illness management questionnaire. Soc Sci Med 1993, 37(3):385-391.
• [44]Ray C, Jefferies S, Weir WRC: Coping with chronic fatigue syndrome - illness responses and their relationship with fatigue, functional impairment and emotional status. Psychol Med 1995, 25(5):937-945.
• [45]Vercoulen JH, Swanink CM, Galama JM, Fennis JF, Jongen PJ, Hommes OR, van der Meer JW, Bleijenberg G: The persistence of fatigue in chronic fatigue syndrome and multiple sclerosis: development of a model. J Psychosom Res 1998, 45(6):507-517.
• [46]White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O’Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M: Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011, 377:823-836.
• [47]Heins MJ, Knoop H, Prins JB, Stulemeijer M, van der Meer JW, Bleijenberg G: Possible detrimental effects of cognitive behaviour therapy for chronic fatigue syndrome. Psychother Psychosom 2010, 79(4):249-256.
• [48]Van Breukelen GJ: ANCOVA versus change from baseline: more power in randomized studies, more bias in nonrandomized studies [corrected]. J Clin Epidemiol 2006, 59(9):920-925.
• [49]Knoop H, van der Meer JW, Bleijenberg G: Guided self-instructions for people with chronic fatigue syndrome: randomised controlled trial. Br J Psychiatry 2008, 193(4):340-341.