Julia C.J.P. Hagenaars

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.

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.

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.

Genetic Variation in Pattern Recognition Receptors and Adaptor Proteins Associated With Development of Chronic Q Fever

BACKGROUND Q fever is an infection caused by Coxiella burnetii. Persistent infection (chronic Q fever) develops in 1%-5% of patients. We hypothesize that inefficient recognition of C. burnetii and/or activation of host-defense in individuals carrying genetic variants in pattern recognition receptors or adaptors would result in an increased likelihood to develop chronic Q fever. METHODS Twenty-four single-nucleotide polymorphisms in genes encoding Toll-like receptors, nucleotide-binding oligomerization domain-like receptor-2, αvβ3 integrin, CR3, and adaptors myeloid differentiation primary response protein 88 (MyD88), and Toll interleukin 1 receptor domain-containing adaptor protein (TIRAP) were genotyped in 139 patients with chronic Q fever and in 220 controls with cardiovascular risk-factors and previous exposure to C. burnetii. Associations between these single-nucleotide polymorphisms and chronic Q fever were assessed by means of univariate logistic regression models. Cytokine production in whole-blood stimulation assays was correlated with relevant genotypes. RESULTS Polymorphisms in TLR1 (R80T), NOD2 (1007fsX1), and MYD88 (-938C>A) were associated with chronic Q fever. No association was observed for polymorphisms in TLR2, TLR4, TLR6, TLR8, ITGAV, ITGB3, ITGAM, and TIRAP. No correction for multiple testing was performed because only genes with a known role in initial recognition of C. burnetii were included. In the whole-blood assays, individuals carrying the TLR1 80R-allele showed increased interleukin 10 production with C. burnetii exposure. CONCLUSIONS Polymorphisms in TLR1 (R80T), NOD2 (L1007fsX1), and MYD88 (-938C>A) are associated with predisposition to development of chronic Q fever. For TLR1, increased interleukin 10 responses to C. burnetii in individuals carrying the risk allele may contribute to the increased risk of chronic Q fever.

Histological characteristics of the abdominal aortic wall in patients with vascular chronic Q fever

The aim of this study was to describe specific histological findings of the Coxiella burnetii‐infected aneurysmal abdominal aortic wall. Tissue samples of the aneurysmal abdominal aortic wall from seven patients with chronic Q fever and 15 patients without evidence of Q fever infection were analysed and compared. Chronic Q fever was diagnosed using serology and tissue PCR analysis. Histological sections were stained using haematoxylin and eosin staining, Elastica van Gieson staining and immunohistochemical staining for macrophages (CD68), T lymphocytes (CD3), T lymphocyte subsets (CD4 and CD8) and B lymphocytes (CD20). Samples were scored by one pathologist, blinded for Q fever status, using a standard score form. Seven tissue samples from patients with chronic Q fever and 15 tissue samples from patients without Q fever were collected. Four of seven chronic Q fever samples showed a necrotizing granulomatous response of the vascular wall, which was characterized by necrotic core of the arteriosclerotic plaque (P = 0.005) and a presence of high numbers of macrophages in the adventitia (P = 0.007) distributed in typical palisading formation (P = 0.005) and surrounded by the presence of high numbers of T lymphocytes located diffusely in media and adventitia. Necrotizing granulomas are a histological finding in the C. burnetii‐infected aneurysmal abdominal aortic wall. Chronic Q fever should be included in the list of infectious diseases with necrotizing granulomatous response, such as tuberculosis, cat scratch disease and syphilis.

Genetic variation in TLR10 is not associated with chronic Q fever, despite the inhibitory effect of TLR10 on Coxiella burnetii-induced cytokines in vitro.

Coxiella burnetii, the causative agent of Q fever, is recognized by TLR2. TLR10 can act as an inhibitory receptor on TLR2-derived immune responses. Therefore, we investigated the role of TLR10 on C. burnetii-induced cytokine production and assessed whether genetic polymorphisms in TLR10 influences the development of chronic Q fever. HEK293 cells, transfected with TLR2, TLR10 or TLR2/TLR10, and human peripheral blood mononuclear cells (PBMCs) in the presence of anti-TLR10, were stimulated with C. burnetii. In both assays, the absence of TLR10 resulted in increased cytokine responses after C. burnetii stimulation. In addition, the effect of single nucleotide polymorphisms (SNPs) in TLR10 was examined in healthy volunteers whose PBMCs were stimulated with C. burnetii Nine Mile or the Dutch outbreak isolate C. burnetii 3262. Individuals bearing SNPs in TLR10 displayed increased cytokine production upon C. burnetii 3262 stimulation. Furthermore, 139 chronic Q fever patients and 220 controls were genotyped for TLR10 N241H, I775V and I369L. None of these polymorphisms were associated with increased susceptibility to chronic Q fever. In conclusion, TLR10 has an inhibitory effect on in vitro cytokine production by C. burnetii, but the presence of TLR10 polymorphisms does not lead to an increased risk of developing chronic Q fever.

Vascular chronic Q fever: quality of life.

The aim of this study was to evaluate the quality of life in patients with vascular chronic Q fever at time of diagnosis and during follow-up. Based upon the SF-36 questionnaire, the mean physical and mental health of each patient were assessed at 3-month intervals for up to 18 months. A total of 26 patients were included in the study. At time of diagnosis, the mean physical health and mental health score was 50·6 [95% confidence interval (CI) 46·7-54·4] and 44·6 (95% CI 41·6-47·5), respectively. During treatment, the mean physical health score declined significantly by 1·7 points each 3 months (P < 0·001) to 40·8 (95% CI 34·4-45·1). The mean mental health score significantly and steadily increased towards 51·2 (95% CI 46·9-54·3) during follow-up (P = 0·026). A total of 23% of patients were cured after 18 months of follow-up. In conclusion, quality of life at time of diagnosis for patients with vascular chronic Q fever is lower compared to a similar group of patients, matched for age and gender, with an aortic abdominal aneurysmal disease, and physical health decreases further after starting treatment. Considering the low percentage of cure, the current treatment of vascular chronic Q fever patients may require a separate strategy from that of endocarditis in order to increase survival.

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.

Dysregulation of serum gamma interferon levels in vascular chronic Q Fever patients provides insights into disease pathogenesis.

ABSTRACT A large community outbreak of Q fever occurred in the Netherlands in the period 2007 to 2010. Some of the infected patients developed chronic Q fever, which typically includes pathogen dissemination to predisposed cardiovascular sites, with potentially fatal consequences. To identify the immune mechanisms responsible for ineffective clearance of Coxiella burnetii in patients who developed chronic Q fever, we compared serum concentrations of 47 inflammation-associated markers among patients with acute Q fever, vascular chronic Q fever, and past resolved Q fever. Serum levels of gamma interferon were strongly increased in acute but not in vascular chronic Q fever patients, compared to past resolved Q fever patients. Interleukin-18 levels showed a comparable increase in acute as well as vascular chronic Q fever patients. Additionally, vascular chronic Q fever patients had lower serum levels of gamma interferon-inducible protein 10 (IP-10) and transforming growth factor β (TGF-β) than did acute Q fever patients. Serum responses for these and other markers indicate that type I immune responses to C. burnetii are affected in chronic Q fever patients. This may be attributed to an affected immune system in cardiovascular patients, which enables local C. burnetii replication at affected cardiovascular sites.