Chronic Q fever-related complications and mortality: data from a nationwide cohort.

OBJECTIVES: Chronic infection with Coxiella burnetii (chronic Q fever) can cause life-threatening conditions such as endocarditis, infected vascular prostheses, and infected arterial aneurysms. We aimed to assess prognosis of chronic Q fever patients in terms of complications and mortality. METHODS: A large cohort of chronic Q fever patients was assessed to describe complications, overall mortality and chronic Q fever-related mortality. Chronic Q fever-related mortality was expressed as a case fatality rate (number of chronic Q fever-related deaths/number of chronic Q fever patients). RESULTS: Complications occurred in 166 of 439 (38%) chronic Q fever patients: in 61% of proven (153/249), 15% of probable (11/74), and 2% of possible chronic Q fever patients (2/116). Most frequently observed complications were acute aneurysms (14%), heart failure (13%), and non-cardiac abscesses (10%). Overall mortality was 38% (94/249) for proven chronic Q fever patients (median follow-up 3.6 years) and 22% (16/74) for probable chronic Q fever patients (median follow-up 4.7 years). The case fatality rate was 25% for proven (63/249) chronic Q fever patients and 4% for probable (3/74) chronic Q fever patients. Overall survival was significantly lower in patients with complications, compared to those without complications (p <0.001). CONCLUSIONS: In chronic Q fever patients, complications occur frequently and contribute to the mortality rate. Patients with proven chronic Q fever have the highest risk of complications and chronic Q fever-related mortality. Prognosis for patients with possible chronic Q fever is favourable in terms of complications and mortality.

Chronic Q fever: patient and treatment-related factors influencing long-term quality of life.

BACKGROUND: Chronic Q fever is accompanied by high mortality and morbidity, and requires prolonged antibiotic treatment. Little is known on long-term quality of life (LQOL) in chronic Q fever patients treated with antibiotics. AIM: To identify patient and treatment-related factors associated with impaired LQOL in chronic Q fever patients treated with antibiotics, and to assess patients' perception on treatment. DESIGN: Cross-sectional study. METHODS: LQOL was assessed with a validated questionnaire from the Nijmegen Clinical Screening Instrument. Patients' perception on treatment was measured with three newly developed questions. RESULTS: We included 64 patients: LQOL was impaired in 55% (n = 35) after a median follow-up of 5 years. Median treatment duration was 27 months. In multivariable analysis, treatment duration was significantly associated with impaired LQOL (OR 1.07; 95%CI 1.02-1.12, P < 0.01 per month increase). Age, gender, number of antibiotic regimens, surgical intervention, complications, diagnostic classification, focus of infection or registration of side effects during treatment were not associated with impaired LQOL. After start of treatment, 17 patients (27%) perceived improvement of their condition. Disadvantages of treatment were experienced on a daily basis by 24 patients (69%) with impaired LQOL and 13 patients (46%) without impaired LQOL (P = 0.04). CONCLUSIONS: LQOL in chronic Q fever patients treated with antibiotics is impaired in more than half of patients 5 years after diagnosis. Antibiotic treatment duration was the only variable associated with impaired LQOL. The majority of patients experienced disadvantages on a daily basis, highlighting the high burden of disease and treatment.

The effect of measuring serum doxycycline concentrations on clinical outcomes during treatment of chronic Q fever.

Background: First choice treatment for chronic Q fever is doxycycline plus hydroxychloroquine. Serum doxycycline concentration (SDC) >5 µg/mL has been associated with a favourable serological response, but the effect on clinical outcomes is unknown. Objectives: To assess the effect of measuring SDC during treatment of chronic Q fever on clinical outcomes. Methods: We performed a retrospective cohort study, to assess the effect of measuring SDC on clinical outcomes in patients treated with doxycycline and hydroxychloroquine for chronic Q fever. Primary outcome was the first disease-related event (new complication or chronic Q fever-related mortality); secondary outcomes were all-cause mortality and PCR-positivity. Multivariable analysis was performed with a Cox proportional hazards model, with shared-frailty terms for different hospitals included. Results: We included 201 patients (mean age 68 years, 83% male): in 167 patients (83%) SDC was measured, 34 patients (17%) were treated without SDC measurement. First SDC was >5 µg/mL in 106 patients (63%), all with 200 mg doxycycline daily. In patients with SDC measured, dosage was adjusted in 41% (n = 68), concerning an increase in 64 patients. Mean SDC was 4.1 µg/mL before dosage increase, and 5.9 µg/mL afterwards. SDC measurement was associated with a lower risk for disease-related events (HR 0.51, 95% CI 0.26-0.97, P = 0.04), but not with all-cause mortality or PCR-positivity. Conclusions: SDC measurement decreases the risk for disease-related events, potentially through more optimal dosing or improved compliance. We recommend measurement of SDC and striving for SDC >5 µg/mL and <10 µg/mL during treatment of chronic Q fever.

Prevotella intermedia infection causing acute and complicated aortitis-A case report.

INTRODUCTION: Aortitis is a general term that refers to all conditions involving an inflammation of the aortic wall. This case report describes the surgical approach of a patient with infectious and symptomatic aortitis caused by the rare vector Prevotella intermedia. PRESENTATION OF CASE: A 44-year old male patient was admitted with fever and general discomfort after a period of sore throat in a non-teaching hospital. After two weeks he developed acute abdominal and back pain accompanied by sweating and elevated infection parameters. Computed tomography angiography revealed atherosclerotic changes of the infrarenal aorta with a locally contained rupture of the aorta alongside peri-aortal signs of inflammation (and aortitis aspects). An urgent aortic reconstruction was performed according to Nevelsteen. The blood cultures turned out positive for Prevotella intermedia. Postoperatively the patient received antibiotics for six weeks. The patient recovered uneventful from this infection and surgical procedure. DISCUSSION: A complicated and acute aortitis is a rare but potentially life-threatening disease. The aetiology can be ordered into two main groups; inflammatory and infectious. Diagnosis is based upon symptoms, biochemical values, microbiological results and imaging modalities. Treatment depends on aetiology and should be discussed in an experienced multidisciplinary setting. Infectious aortitis should be treated with antibiotics for at least six weeks with close monitoring of the patient's clinic and biochemical values, even after surgery. CONCLUSION: Prevotella intermedia is a rare causative agent for aortitis. Acute aortitis is a challenging clinical entity which should be managed in an equipped medical center by an experienced multidisciplinary team.

Molecular and Serological Intraocular Fluid Analysis of Coxiella burnetii-seropositive Patients with Concurrent Idiopathic Uveitis.

PURPOSE: Previous studies have suggested a link between Q fever and uveitis. We determined whether Coxiella burnetii causes intraocular infection in C. burnetii-seropositive patients with idiopathic uveitis. METHODS: From a retrospective observational case series, paired aqueous humor and serum samples from 10 C. burnetii-seropositive patients with idiopathic uveitis were examined for intraocular antibody production by using the Goldmann-Witmer coefficient and by polymerase chain reaction (PCR). RESULTS: Although intraocular IgG against C. burnetii was detected, no intraocular antibody production was observed (low Goldmann Wittmer coefficients). All PCR results were negative. CONCLUSIONS: Uveitis due to an intraocular infection with C. burnetii is unlikely.

Serology in chronic Q fever is still surrounded by question marks.

Detection of antibodies using immunofluoresence tests (IFAT) is recommended for diagnosis of chronic Q fever, but other commercial antibody assays are also available. We compared an enzyme-linked immunosorbent assay (ELISA) (Virion/Serion) and a complement fixation test (CFT) (Virion/Serion) for the detection of Coxiella burnetii IgG phase I and IgA phase I in early- and follow-up serum samples from patients with chronic Q fever, diagnosed according to an algorithm that involves IFAT. For this, we tested sera of 49 patients, including 30 proven, 14 probable and five possible chronic Q fever cases. Sensitivity of CFT for diagnosis of chronic Q fever was suboptimal (85 %), as eight patients, including five with chronic Q fever, tested negative at time of diagnosis, whereas IgG phase I antibodies were detected in these five patients by ELISA. Sensitivity of ELISA was higher, although three probable patients were missed. No differences in ELISA IgA phase I detection between proven chronic Q fever and probable were observed; instead possible patients were in majority IgA negative (60 %). Serological examination using ELISA and CFT in follow-up sera from 26 patients on treatment was unsatisfactory. Like IFAT, all kinetic options were possible: decreasing, remaining stable or even increase during time. This study demonstrated that the sensitivity of CFT-based phase I antibody detection is low and therefore not recommended for diagnosis of chronic Q fever. Based on our results, serological follow-up to guide treatment decisions was of limited value.

Correlations between peripheral blood Coxiella burnetii DNA load, interleukin-6 levels, and C-reactive protein levels in patients with acute Q fever.

From 2007 to 2010, the Netherlands experienced the largest reported Q fever outbreak, with >4,000 notified cases. We showed previously that C-reactive protein is the only traditional infection marker reflecting disease activity in acute Q fever. Interleukin-6 is the principal inducer of C-reactive protein. We questioned whether increased C-reactive protein levels in acute Q fever patients coincide with increased interleukin-6 levels and if these levels correlate with the Coxiella burnetii DNA load in serum. In addition, we studied their correlation with disease severity, expressed by hospital admission and the development of fatigue. Interleukin-6 and C-reactive protein levels were analyzed in sera from 102 patients diagnosed with seronegative PCR-positive acute Q fever. Significant but weak negative correlations were observed between bacterial DNA loads expressed as cycle threshold values and interleukin-6 and C-reactive protein levels, while a significant moderate-strong positive correlation was present between interleukin-6 and C-reactive protein levels. Furthermore, significantly higher interleukin-6 and C-reactive protein levels were observed in hospitalized acute Q fever patients in comparison to those in nonhospitalized patients, while bacterial DNA loads were the same in the two groups. No marker was prognostic for the development of fatigue. In conclusion, the correlation between interleukin-6 and C-reactive protein levels in acute Q fever patients points to an immune activation pathway in which interleukin-6 induces the production of C-reactive protein. Significant differences in interleukin-6 and C-reactive protein levels between hospitalized and nonhospitalized patients despite identical bacterial DNA loads suggest an important role for host factors in disease presentation. Higher interleukin-6 and C-reactive protein levels seem predictive of more severe disease.

Screening for Coxiella burnetii seroprevalence in chronic Q fever high-risk groups reveals the magnitude of the Dutch Q fever outbreak.

The Netherlands experienced an unprecedented outbreak of Q fever between 2007 and 2010. The Jeroen Bosch Hospital (JBH) in 's-Hertogenbosch is located in the centre of the epidemic area. Based on Q fever screening programmes, seroprevalence of IgG phase II antibodies to Coxiella burnetii in the JBH catchment area was 10·7% [785 tested, 84 seropositive, 95% confidence interval (CI) 8·5-12·9]. Seroprevalence appeared not to be influenced by age, gender or area of residence. Extrapolating these data, an estimated 40 600 persons (95% CI 32 200-48 900) in the JBH catchment area have been infected by C. burnetii and are, therefore, potentially at risk for chronic Q fever. This figure by far exceeds the nationwide number of notified symptomatic acute Q fever patients and illustrates the magnitude of the Dutch Q fever outbreak. Clinicians in epidemic Q fever areas should be alert for chronic Q fever, even if no acute Q fever is reported.

Early diagnosis and treatment of patients with symptomatic acute Q fever do not prohibit IgG antibody responses to Coxiella burnetii.

Little is known about the effect of timing of antibiotic treatment on development of IgG antibodies following acute Q fever. We studied IgG antibody responses in symptomatic patients diagnosed either before or during development of the serologic response to Coxiella burnetii. Between 15 and 31 May 2009, 186 patients presented with acute Q fever, of which 181 were included in this retrospective study: 91 early-diagnosed (ED) acute Q fever patients, defined as negative IgM phase II enzyme-linked immunosorbent assay (ELISA) and positive PCR, and 90 late-diagnosed (LD) acute Q fever patients, defined as positive/dubious IgM phase II ELISA and positive immunofluorescence assay (IFA). Follow-up serology at 3, 6, and 12 months was performed using IFA (IgG phase I and II). High IgG antibody titers were defined as IgG phase II titers of ≥1:1,024 together with IgG phase I titers of ≥1:256. At 12 months, 28.6% of ED patients and 19.5% of LD patients had high IgG antibody titers (P = 0.17). No statistically significant differences were found in frequencies of IgG phase I and IgG phase II antibody titers at all follow-up appointments for adequately and inadequately treated patients overall, as well as for ED and LD patients analyzed separately. Additionally, no significant difference was found in frequencies of high antibody titers and between early (treatment started within 7 days after seeking medical attention) and late timing of treatment. This study indicates that early diagnosis and antibiotic treatment of acute Q fever do not prohibit development of the IgG antibody response.

Shifting priorities in the aftermath of a Q fever epidemic in 2007 to 2009 in The Netherlands: from acute to chronic infection.

From 2007 to 2009, the Netherlands faced large seasonal outbreaks of Q fever, in which infected dairy goat farms were identified as the primary sources. Veterinary measures including vaccination of goats and sheep and culling of pregnant animals on infected farms seem to have brought the Q fever problem under control. However, the epidemic is expected to result in more cases of chronic Q fever among risk groups in the coming years. In the most affected area, in the south of the country, more than 12% of the population now have antibodies against Coxiella burnetii. Questions remain about the follow-up of acute Q fever patients, screening of groups at risk for chronic Q fever, screening of donors of blood and tissue, and human vaccination. There is a considerable ongoing research effort as well as enhanced veterinary and human surveillance.

Chronic Q fever: review of the literature and a proposal of new diagnostic criteria.

A review was performed to determine clinical aspects and diagnostic tools for chronic Q fever. We present a Dutch guideline based on literature and clinical experience with chronic Q fever patients in The Netherlands so far. In this guideline diagnosis is categorized as proven, possible or probable chronic infection based on serology, PCR, clinical symptoms, risk factors and diagnostic imaging.

Acute Q fever related in-hospital mortality in the Netherlands.

INTRODUCTION: A large outbreak of acute Q fever has been reported in the Netherlands with over 3500 cases from 2007 to 2009, during which 749 patients were hospitalised. In foreign cohorts, reported mortality rates in patients hospitalised with acute Q fever, ranged from 0.9 to 2.4%. We analysed mortality among hospitalised patients with acute Q fever in the Netherlands. METHODS: Physicians from hospitals in the afflicted region were asked to provide details about patients who died with a diagnosis of acute Q fever between 2007 and 2009. RESULTS: Nine patients (seven males, median age 72 years) from six hospitals were reported, who died within approximately one month following hospitalisation for acute Q fever. Six definite acute Q fever cases and three probable cases were identified. Six patients presented with infiltrates on the chest X-ray and a median CURB-65 score of 3. Median time of hospitalisation was 13 days (range 1-33). All patients had serious, often coinciding, underlying conditions including chronic cardiovascular disease, chronic lung disease, diabetes mellitus and malignancy. CONCLUSION: The mortality rate of patients hospitalised because of acute Q fever was estimated at approximately 1%. Patients who died with acute Q fever were often male, of older age, and had chronic coinciding underlying conditions, which gives an a priori higher risk of death.