Effectiveness of Long-term Doxycycline Treatment and Cognitive-Behavioral Therapy on Fatigue Severity in Patients with Q Fever Fatigue Syndrome (Qure Study): A Randomized Controlled Trial.

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. Clinical Trials Registration: NCT01318356.

Chronic Q fever in the Netherlands 5 years after the start of the Q fever epidemic: results from the Dutch chronic Q fever database.

Coxiella burnetii causes Q fever, a zoonosis, which has acute and chronic manifestations. From 2007 to 2010, the Netherlands experienced a large Q fever outbreak, which has offered a unique opportunity to analyze chronic Q fever cases. In an observational cohort study, baseline characteristics and clinical characteristics, as well as mortality, of patients with proven, probable, or possible chronic Q fever in the Netherlands, were analyzed. In total, 284 chronic Q fever patients were identified, of which 151 (53.7%) had proven, 64 (22.5%) probable, and 69 (24.3%) possible chronic Q fever. Among proven and probable chronic Q fever patients, vascular infection focus (56.7%) was more prevalent than endocarditis (34.9%). An acute Q fever episode was recalled by 27.0% of the patients. The all-cause mortality rate was 19.1%, while the chronic Q fever-related mortality rate was 13.0%, with mortality rates of 9.3% among endocarditis patients and 18% among patients with a vascular focus of infection. Increasing age (P=0.004 and 0.010), proven chronic Q fever (P=0.020 and 0.002), vascular chronic Q fever (P=0.024 and 0.005), acute presentation with chronic Q fever (P=0.002 and P<0.001), and surgical treatment of chronic Q fever (P=0.025 and P<0.001) were significantly associated with all-cause mortality and chronic Q fever-related mortality, respectively.

Persistent high antibody titres against Coxiella burnetii after acute Q fever not explained by continued exposure to the source of infection: a case-control study.

BACKGROUND: From 2007 to 2010, (the southern part of) the Netherlands experienced a large Q fever epidemic, with more than 4,000 reported symptomatic cases. Approximately 1 - 5% of the acute Q fever patients develop chronic Q fever. A high IgG antibody titre against phase I of Coxiella burnetii during follow-up is considered a marker of chronic Q fever. However, there is uncertainty about the significance and cause of persistence of high IgG phase I antibody titres in patients that do not have any additional manifestations of chronic Q fever. We studied whether continued or repeated exposure to the source of infection could explain elevated IgG phase I antibody levels. METHODS: A case-control study was performed to analyze predictors for possible chronic Q fever. Possible chronic Q fever cases (n = 53) are patients with phase I IgG antibody titre ≥1:1,024 at any point in the 9 - 18 months after acute Q fever diagnosis, with a negative PCR test result for C. burnetii DNA and without other disease manifestations. Controls (n = 110) are acute Q fever patients that did not develop chronic Q fever, and who consistently had phase I IgG antibody titre <1:1,024 during the 9 - 18 months follow-up. Binary logistic regression was performed to analyze the effect of living close to an infected farm on the high antibody titres. A longitudinal analysis described the serological profiles of cases and controls. RESULTS: Proximity to infected farms and contact with animal placental material were not associated with an increased risk for possible chronic Q fever. Possible chronic Q fever patients have high IgG phase II as well as IgG phase I antibody titres, even after 48 months of follow-up. CONCLUSION: We were unable to explain the cause of persistent high IgG phase I titres among possible chronic Q fever patients by being continuously exposed to the source of infection.

Two cases with acute abdominal aneurysm and evidence of acute Q fever infection.

We report 2 patients with symptomatic aortic aneurysm and serologic evidence of acute Q fever with positive Coxiella burnetii PCR in blood/tissue. This suggests a role for acute Q fever in aneurysm progression. Diagnostic testing for Q fever infection in patients with symptomatic aneurysms in Q fever areas is recommended.

Identification of risk factors for chronic Q fever, the Netherlands.

Since 2007, the Netherlands has experienced a large Q fever outbreak. To identify and quantify risk factors for development of chronic Q fever after Coxiella burnetii infection, we performed a case-control study. Comorbidity, cardiovascular risk factors, medications, and demographic characteristics from 105 patients with proven (n = 44), probable (n = 28), or possible (n = 33) chronic Q fever were compared with 201 patients who had acute Q fever in 2009 but in whom chronic Q fever did not develop (controls). Independent risk factors for development of proven chronic Q fever were valvular surgery, vascular prosthesis, aneurysm, renal insufficiency, and older age.

Risk of chronic Q fever in patients with cardiac valvulopathy, seven years after a large epidemic in the Netherlands.

BACKGROUND: From 2007 through 2010, a large epidemic of acute Q fever occurred in the Netherlands. Patients with cardiac valvulopathy are at high risk to develop chronic Q fever after an acute infection. This patient group was not routinely screened, so it is unknown whether all their chronic infections were diagnosed. This study aims to investigate how many chronic Q fever patients can be identified by routinely screening patients with valvulopathy and to establish whether the policy of not screening should be changed. METHODS: In a cross-sectional study (2016-2017) in a hospital at the epicentre of the Q fever epidemic, a blood sample was taken from patients 18 years and older who presented with cardiac valvulopathy. The sample was tested for IgG antibodies against phase I and II of Coxiella burnetii using an immunofluorescence assay. An IgG phase II titre of ≥1:64 was considered serological evidence of a previous Q fever infection. An IgG phase I titre of ≥1:512 was considered suspicious for a chronic infection, and these patients were referred for medical examination. RESULTS: Of the 904 included patients, 133 (15%) had evidence of a previous C. burnetii infection, of whom 6 (5%) had a chronic infection on medical examination. CONCLUSIONS: In a group of high-risk patients with a heart valve defect, we diagnosed new chronic Q fever infections seven years after the epidemic, emphasizing the need for screening of this group to prevent complications in those not yet diagnosed in epidemic areas.

The Value of 18F-FDG PET/CT in Diagnosis and During Follow-up in 273 Patients with Chronic Q Fever.

In 1%-5% of all acute Q fever infections, chronic Q fever develops, mostly manifesting as endocarditis, infected aneurysms, or infected vascular prostheses. In this study, we investigated the diagnostic value of 18F-FDG PET/CT in chronic Q fever at diagnosis and during follow-up. Methods: All adult Dutch patients suspected of chronic Q fever who were diagnosed since 2007 were retrospectively included until March 2015, when at least one 18F-FDG PET/CT scan was obtained. Clinical data and results from 18F-FDG PET/CT at diagnosis and during follow-up were collected. 18F-FDG PET/CT scans were prospectively reevaluated by 3 nuclear medicine physicians using a structured scoring system. Results: In total, 273 patients with possible, probable, or proven chronic Q fever were included. Of all 18F-FDG PET/CT scans performed at diagnosis, 13.5% led to a change in diagnosis. Q fever-related mortality rate in patients with and without vascular infection based on 18F-FDG PET/CT was 23.8% and 2.1%, respectively (P = 0.001). When 18F-FDG PET/CT was added as a major criterion to the modified Duke criteria, 17 patients (1.9-fold increase) had definite endocarditis. At diagnosis, 19.6% of 18F-FDG PET/CT scans led to treatment modification. During follow-up, 57.3% of 18F-FDG PET/CT scans resulted in treatment modification. Conclusion:18F-FDG PET/CT is a valuable technique in diagnosis of chronic Q fever and during follow-up, often leading to a change in diagnosis or treatment modification and providing important prognostic information on patient survival.

Diagnostic strategies for excluding pulmonary embolism in clinical outcome studies. A systematic review.

BACKGROUND: Pulmonary embolism is a common clinical disorder that is associated with high morbidity and mortality if untreated. It is important to confirm or rule out the diagnosis in patients with clinical suspicion of the disease. PURPOSE: To evaluate various diagnostic strategies for excluding pulmonary embolism. DATA SOURCES: MEDLINE (1966 to February 2003), EMBASE, and DARE; study investigators; and reference lists. STUDY SELECTION: Prospective clinical outcome studies. DATA EXTRACTION: The researchers recorded the frequency of symptomatic venous thromboembolism over 3 months of follow-up in patients in whom pulmonary embolism had been excluded according to various strategies. Strategies were divided into three categories according to the number of rounds of diagnostic tests needed to exclude pulmonary embolism. DATA SYNTHESIS: 25 studies involving more than 7000 patients were included. In all referred patients, two strategies-normal results on pulmonary angiography or lung scintigraphy and normal d -dimer levels combined with low clinical probability-safely excluded pulmonary embolism (failure rates < or = 3%). In the second round of diagnostic tests, in patients who had had a nondiagnostic lung scan, both pulmonary angiography and serial leg testing for venous thrombosis were accurate and safe. When d -dimer testing combined with clinical probability was inconclusive, a normal perfusion lung scan safely excluded pulmonary embolism. Accumulating evidence shows that normal results on spiral computed tomography may also safely exclude the disease. CONCLUSIONS: Many diagnostic strategies to exclude pulmonary embolism have been evaluated in consecutive patients. Interest is likely to increase in a simple, fast strategy, starting with a normal perfusion lung scan or a combination of normal d -dimer levels and low clinical probability. After the initial round of testing, a reliable diagnostic method, such as angiography or lung scintigraphy, is warranted.

Ruling out clinically suspected pulmonary embolism by assessment of clinical probability and D-dimer levels: a management study.

D-dimer test combined with clinical probability assessment has been proposed as the first step in the diagnostic work-up of patients with suspected pulmonary embolism (PE). In a prospective management study we investigated the safety and efficiency of excluding PE by a normal D-dimer combined with a low or moderate clinical probability. Of the 202 study patients this combination ruled out PE in 64 (32%) patients. The 3-month thromboembolic risk in these patients was 0% (95% CI, 0.0-5.6%). The prevalence of PE in the entire cohort was 29% (59 patients), whereas in the low, moderate and high clinical probability groups this was 25%, 26% and 50%, respectively. We conclude that ruling out suspected PE by a normal D-dimer combined with a low or moderate clinical probability appears to be a safe and efficient strategy. The accuracy of the clinical probability assessment is modest.

Characteristics of hospitalized acute Q fever patients during a large epidemic, The Netherlands.

BACKGROUND: From 2007 to 2009, The Netherlands experienced a major Q fever epidemic, with higher hospitalization rates than the 2-5% reported in the literature for acute Q fever pneumonia and hepatitis. We describe epidemiological and clinical features of hospitalized acute Q fever patients and compared patients presenting with Q fever pneumonia with patients admitted for other forms of community-acquired pneumonia (CAP). We also examined whether proximity to infected ruminant farms was a risk factor for hospitalization. METHODS: A retrospective cohort study was conducted for all patients diagnosed and hospitalized with acute Q fever between 2007 and 2009 in one general hospital situated in the high incidence area in the south of The Netherlands. Pneumonia severity scores (PSI and CURB-65) of acute Q fever pneumonia patients (defined as infiltrate on a chest x-ray) were compared with data from CAP patients. Hepatitis was defined as a >twofold the reference value for alanine aminotransferase and for bilirubin. RESULTS: Among the 183 hospitalized acute Q fever patients, 86.0% had pneumonia. Elevated liver enzymes (alanine aminotransferase) were found in 32.3% of patients, although hepatitis was not observed in any of them. The most frequent clinical signs upon presentation were fever, cough and dyspnoea. The median duration of admission was five days. Acute Q fever pneumonia patients were younger, had less co-morbidity, and lower PSI and CURB-65 scores than other CAP patients. Anecdotal information from attending physicians suggests that some patients were admitted because of severe subjective dyspnoea, which was not included in the scoring systems. Proximity to an infected ruminant farm was not associated with hospitalization. CONCLUSION: Hospitalized Dutch acute Q fever patients mostly presented with fever and pneumonia. Patients with acute Q fever pneumonia were hospitalized despite low PSI and CURB-65 scores, presumably because subjective dyspnoea was not included in the scoring systems.

Estimated prevalence of chronic Q fever among Coxiella burnetii seropositive patients with an abdominal aortic/iliac aneurysm or aorto-iliac reconstruction after a large Dutch Q fever outbreak.

OBJECTIVES: The aim of this study was to estimate the seroprevalence of Q fever and prevalence of chronic Q fever in patients with abdominal aortic and/or iliac disease after the Q fever outbreak of 2007-2010 in the Netherlands. METHODS: In November 2009, an ongoing screening program for Q fever was initiated. Patients with abdominal aortic and/or iliac disease were screened for presence of IgM and IgG antibodies to phase I and II antigens of Coxiella burnetii using immunofluorescence assay and presence of C. burnetii DNA in sera and/or vascular wall tissue using polymerase chain reaction (PCR). RESULTS: A total of 770 patients with abdominal aortic and/or iliac disease were screened. Antibodies against C. burnetii were detected in 130 patients (16.9%), of which 40 (30.8%) patients showed a serological profile of chronic Q fever. Three patients presented with acute Q fever, one of which developed to chronic Q fever over time. The number of aneurysm-related acute complications in patients with chronic Q fever was significantly higher compared to patients negative for Q fever (p = 0.013); 9.0% (30/333) vs. 30.0% (6/20). Eight out of 46 patients with past resolved Q fever (8/46, 17.4%) presented with aneurysm-related acute complications (no significant difference). CONCLUSION: The prevalence of chronic Q fever in C. burnetii seropositive patients with abdominal aortic and/or iliac disease living in an epidemic area in the Netherlands is remarkably high (30.8%). Patients with an aneurysm and chronic Q fever present more often with an aneurysm-related acute complication compared to patients without evidence of Q fever infection.

Microbiological challenges in the diagnosis of chronic Q fever.

Diagnosis of chronic Q fever is difficult. PCR and culture lack sensitivity; hence, diagnosis relies mainly on serologic tests using an immunofluorescence assay (IFA). Optimal phase I IgG cutoff titers are debated but are estimated to be between 1:800 and 1:1,600. In patients with proven, probable, or possible chronic Q fever, we studied phase I IgG antibody titers at the time of positive blood PCR, at diagnosis, and at peak levels during chronic Q fever. We evaluated 200 patients, of whom 93 (46.5%) had proven, 51 (25.5%) had probable, and 56 (28.0%) had possible chronic Q fever. Sixty-five percent of proven cases had positive Coxiella burnetii PCR results for blood, which was associated with high phase I IgG. Median phase I IgG titers at diagnosis and peak titers in patients with proven chronic Q fever were significantly higher than those for patients with probable and possible chronic Q fever. The positive predictive values for proven chronic Q fever, compared to possible chronic Q fever, at titers 1:1,024, 1:2,048, 1:4,096, and ≥1:8,192 were 62.2%, 66.7%, 76.5%, and ≥86.2%, respectively. However, sensitivity dropped to <60% when cutoff titers of ≥1:8,192 were used. Although our study demonstrated a strong association between high phase I IgG titers and proven chronic Q fever, increasing the current diagnostic phase I IgG cutoff to >1:1,024 is not recommended due to increased false-negative findings (sensitivity < 60%) and the high morbidity and mortality of untreated chronic Q fever. Our study emphasizes that serologic results are not diagnostic on their own but should always be interpreted in combination with clinical parameters.