Linda M. Kampschreur

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

Previous cardiac valvular surgery, vascular prosthesis, aortic aneurysm, renal insufficiency, and older age increased risk.

Chronic Q Fever in the Netherlands 5 Years after the Start of the Q Fever Epidemic: Results from the Dutch Chronic Q Fever Database

ABSTRACT 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.

Microbiological Challenges in the Diagnosis of Chronic Q Fever

ABSTRACT 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.

Prevalence of Chronic Q Fever in Patients with a History of Cardiac Valve Surgery in an Area Where Coxiella burnetii Is Epidemic

ABSTRACT Chronic Q fever develops in 1 to 5% of patients infected with Coxiella burnetii. The risk for chronic Q fever endocarditis has been estimated to be ∼39% in case of preexisting valvulopathy and is potentially even higher for valvular prostheses. Since 2007, The Netherlands has faced the largest Q fever outbreak ever reported, allowing a more precise risk estimate of chronic Q fever in high-risk groups. Patients with a history of cardiac valve surgery were selected for microbiological screening through a cardiology outpatient clinic in the area where Q fever is epidemic. Blood samples were analyzed for phase I and II IgG against C. burnetii, and if titers were above a defined cutoff level, C. burnetii PCR was performed. Chronic Q fever was considered proven if C. burnetii PCR was positive and probable if the phase I IgG titer was ≥1:1,024. Among 568 patients, the seroprevalence of C. burnetii antibodies (IgG titer greater than or equal to 1:32) was 20.4% (n = 116). Proven or probable chronic Q fever was identified among 7.8% of seropositive patients (n = 9). Valve characteristics did not influence the risk for chronic Q fever. Patients with chronic Q fever were significantly older than patients with past Q fever. In conclusion, screening of high-risk groups is a proper instrument for early detection of chronic Q fever cases. The estimated prevalence of chronic Q fever is 7.8% among seropositive patients with a history of cardiac valve surgery, which is substantially higher than that in nonselected populations but lower than that previously reported. Older age seems to increase vulnerability to chronic Q fever in this population.

Coxiella burnetii infection (Q fever) in rheumatoid arthritis patients with and without anti-TNFα therapy

Q fever is a zoonosis caused by the intracellular bacterium Coxiella burnetii. The Netherlands experienced a major Q fever outbreak between 2007 and 2010, with an estimate of more than 40 000 infected individuals.1 Initial infection is asymptomatic in over 50% of the infected individuals or causes a mostly self-limiting febrile disease.2 However, chronic Q fever may develop months to years after initial infection. This serious, life-threatening condition presents mostly as endocarditis or infection of an aortic aneurysm or vascular prosthesis, and is accompanied by high IgG antibody titres against phase I C burnetii .3 Individuals most at risk for chronic Q fever are those with pre-existing valvulopathy, vascular aneurysm or prosthesis and yet undefined types of immune suppression.4 ,5 Tumour necrosis factor-α (TNFα) plays an important role in the defence against intracellular bacteria such as C burnetii . In vitro studies show that TNFα is involved in internalisation and intracellular killing of C burnetii in monocytes.6 ,7 In addition, C burnetii- infected TNFα knockout mice develop early bacteraemia and severe …

Delayed Diagnosis of Chronic Q Fever and Cardiac Valve Surgery

Untreated chronic Q fever causes a high number of complications and deaths. We present cases of chronic Q fever that were not diagnosed until after the patients underwent cardiac valve surgery. In epidemic areas, Q fever screening of valve surgery patients secures early initiation of treatment and can prevent illness and death.

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.

Exposure to Coxiella burnetii and risk of non-Hodgkin lymphoma: a retrospective population-based analysis in the Netherlands

BACKGROUND An association between Coxiella burnetii and non-Hodgkin lymphoma has been suggested. After a large Q fever epidemic in the Netherlands (2007-10), we postulated that the incidence of non-Hodgkin lymphoma would be increased during and after the epidemic in areas with a high endemicity of Q fever compared with those with low endemicity. METHODS We did a retrospective population-based analysis and calculated relative risks (RRs) of non-Hodgkin lymphoma during 1-year periods before, during, and after the Q fever epidemic, for areas with intermediate and high endemicity of Q fever compared with low endemic areas. We also calculated the RR of non-Hodgkin lymphoma in people with chronic Q fever compared with the general population. FINDINGS Between Jan 1, 2002, and Dec 31, 2013, 48 760 cases of non-Hodgkin lymphoma were diagnosed. The incidence of non-Hodgkin lymphoma ranged from 21·4 per 100 000 per year in 2002 to 26·7 per 100 000 per year in 2010. A significant association with non-Hodgkin lymphoma was noted in 2009 for areas with a high endemicity of Q fever compared with low endemic areas (RR 1·16, 95% CI 1·02-1·33; p=0·029); no further associations were noted in any other year or for areas with intermediate Q fever endemicity. Among 439 individuals with chronic Q fever, five developed non-Hodgkin lymphoma, yielding a crude absolute risk of 301·0 cases per 100 000 per year (RR 4·99, 95% CI 2·07-11·98; p=0·0003) compared with the general population in the Netherlands. INTERPRETATION These findings do not support the hypothesis that Q fever has a relevant causal role in the development of non-Hodgkin lymphoma. Several limitations, inherent to the design of this study, might lead to both underestimation and overestimation of the studied association. FUNDING Foundation Q-support and Institut Mérieux.

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.

Treatment of chronic Q fever : Clinical efficacy and toxicity of antibiotic regimens

Background Evidence on the effectiveness of first-line treatment for chronic Q fever, tetracyclines (TET) plus hydroxychloroquine (HCQ), and potential alternatives is scarce. Methods We performed a retrospective, observational cohort study to assess efficacy of treatment with TET plus quinolones (QNL), TET plus QNL plus HCQ, QNL monotherapy, or TET monotherapy compared to TET plus HCQ in chronic Q fever patients. We used a time-dependent Cox proportional hazards model to assess our primary (all-cause mortality) and secondary outcomes (first disease-related event and therapy failure). Results We assessed 322 chronic Q fever patients; 276 (86%) received antibiotics. Compared to TET plus HCQ (n = 254; 92%), treatment with TET plus QNL (n = 49; 17%), TET plus QNL plus HCQ (n = 29, 10%), QNL monotherapy (n = 93; 34%), or TET monotherapy (n = 54; 20%) were not associated with primary or secondary outcomes. QNL and TET monotherapies were frequently discontinued due to insufficient clinical response (n = 27, 29% and n = 32, 59%). TET plus HCQ, TET plus QNL, and TET plus QNL plus HCQ were most frequently discontinued due to side effects (n = 110, 43%; n = 13, 27%; and n = 12, 41%). Conclusions Treatment of chronic Q fever with TET plus QNL appears to be a safe alternative for TET plus HCQ, for example, if TET plus HCQ cannot be tolerated due to side effects. Treatment with TET plus QNL plus HCQ was not superior to treatment with TET plus HCQ, although this may be caused by confounding by indication. Treatment with TET or QNL monotherapy should be avoided; switches due to subjective, insufficient clinical response were frequently observed.