No increased risk of mature B-cell non-Hodgkin lymphoma after Q fever detected: results from a 16-year ecological analysis of the Dutch population incorporating the 2007-2010 Q fever outbreak.

BACKGROUND: A causative role of Coxiella burnetii (the causative agent of Q fever) in the pathogenesis of B-cell non-Hodgkin lymphoma (NHL) has been suggested, although supporting studies show conflicting evidence. We assessed whether this association is present by performing a detailed analysis on the risk of mature B-cell NHL after Q fever during and after the largest Q fever outbreak reported worldwide in the entire Dutch population over a 16-year period. METHODS: We performed an ecological analysis. The incidence of mature B-cell NHL in the entire Dutch population from 2002 until 2017 was studied and modelled with reported acute Q fever cases as the determinant. The adjusted relative risk of NHL after acute Q fever as the primary outcome measure was calculated using a Poisson regression. RESULTS: Between January 2002 and December 2017, 266 050 745 person-years were observed, with 61 424 diagnosed with mature B-cell NHL. In total, 4310 persons were diagnosed with acute Q fever, with the highest incidence in 2009. The adjusted relative risk of NHL after acute Q fever was 1.02 (95% CI 0.97-1.06, P = 0.49) and 0.98 (95% CI 0.89-1.07, P = 0.60), 0.99 (95% CI 0.87-1.12, P = 0.85) and 0.98 (95% 0.88-1.08, P = 0.67) for subgroups of diffuse large B-cell lymphoma, follicular lymphoma or B-cell chronic lymphocytic leukaemia, respectively. Modelling with lag times (1-4 years) did not change interpretation. CONCLUSION: We found no evidence for an association between C. burnetii and NHL after studying the risk of mature B-cell NHL after a large Q fever outbreak in Netherlands.

Cost-effectiveness of Screening Program for Chronic Q Fever, the Netherlands.

In the aftermath of a large Q fever (QF) epidemic in the Netherlands during 2007-2010, new chronic QF (CQF) patients continue to be detected. We developed a health-economic decision model to evaluate the cost-effectiveness of a 1-time screening program for CQF 7 years after the epidemic. The model was parameterized with spatial data on QF notifications for the Netherlands, prevalence data from targeted screening studies, and clinical data from the national QF database. The cost-effectiveness of screening varied substantially among subpopulations and geographic areas. Screening that focused on cardiovascular risk patients in areas with high QF incidence during the epidemic ranged from cost-saving to €31,373 per quality-adjusted life year gained, depending on the method to estimate the prevalence of CQF. The cost per quality-adjusted life year of mass screening of all older adults was €70,000 in the most optimistic scenario.

Coxiella burnetii in non-Hodgkin lymphoma tissue samples: Innocent until proven otherwise?

PURPOSE: Coxiella burnetii has been suggested as a potential cause of B-cell non-Hodgkin lymphoma (B-NHL), as C. burnetii was detected in B-NHL tissues. To further investigate this potential relationship, we hypothesized that among subjects previously exposed to C. burnetii, the bacterium is more frequently detectable in tissues of patients with B-NHL (cases) compared to patients without B-NHL (controls). METHODS: We aimed to evaluate this hypothesis by assessing the presence of C. burnetii with polymerase chain reaction (PCR), immunofluorescence staining (IF) and fluorescent in-situ hybridization (FISH). Eligible patients were those previously exposed to C. burnetii. RESULTS: Samples were available for 13 cases and 16 controls. C. burnetii was demonstrated in tissues of 8/29 patients in total (28%), with either PCR, IF or FISH: in 5/13 cases (38%) and 3/16 controls (19%), p = 0.41. Negative and positive control samples were all negative and positive appropriately for all three diagnostic methods. CONCLUSIONS: In patients previously exposed to C. burnetii the bacterium was detected in tissue samples from subjects with and without B-NHL, without significant differences in the proportion positive samples. Therefore, we conclude that detection of C. burnetii in tissues of patients previously exposed to C. burnetii is a non-specific finding.

Primary and secondary arterial fistulas during chronic Q fever.

OBJECTIVE: After primary infection with Coxiella burnetii, patients may develop acute Q fever, which is a relatively mild disease. A small proportion of patients (1%-5%) develop chronic Q fever, which is accompanied by high mortality and can be manifested as infected arterial or aortic aneurysms or infected vascular prostheses. The disease can be complicated by arterial fistulas, which are often fatal if they are left untreated. We aimed to assess the cumulative incidence of arterial fistulas and mortality in patients with proven chronic Q fever. METHODS: In a retrospective, observational study, the cumulative incidence of arterial fistulas (aortoenteric, aortobronchial, aortovenous, or arteriocutaneous) in patients with proven chronic Q fever (according to the Dutch Chronic Q Fever Consensus Group criteria) was assessed. Proven chronic Q fever with a vascular focus of infection was defined as a confirmed mycotic aneurysm or infected prosthesis on imaging studies or positive result of serum polymerase chain reaction for C. burnetii in the presence of an arterial aneurysm or vascular prosthesis. RESULTS: Of 253 patients with proven chronic Q fever, 169 patients (67%) were diagnosed with a vascular focus of infection (42 of whom had a combined vascular focus and endocarditis). In total, 26 arterial fistulas were diagnosed in 25 patients (15% of patients with a vascular focus): aortoenteric (15), aortobronchial (2), aortocaval (4), and arteriocutaneous (5) fistulas (1 patient presented with both an aortocaval and an arteriocutaneous fistula). Chronic Q fever-related mortality was 60% for patients with and 21% for patients without arterial fistula (P < .0001). Primary fistulas accounted for 42% and secondary fistulas for 58%. Of patients who underwent surgical intervention for chronic Q fever-related fistula (n = 17), nine died of chronic Q fever-related causes (53%). Of patients who did not undergo any surgical intervention (n = 8), six died of chronic Q fever-related causes (75%). CONCLUSIONS: The proportion of patients with proven chronic Q fever developing primary or secondary arterial fistulas is high; 15% of patients with a vascular focus of infection develop an arterial fistula. This observation suggests that C. burnetii, the causative agent of Q fever, plays a role in the development of fistulas in these patients. Chronic Q fever-related mortality in patients with arterial fistula is very high, in both patients who undergo surgical intervention and patients who do not.

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.

Seroprevalence of Coxiella burnetii antibodies and chronic Q fever among post-mortal and living donors of tissues and cells from 2010 to 2015 in the Netherlands.

BackgroundAfter a large Q fever outbreak in the Netherlands in the period from 2007 to 2010, the risk of Q fever transmission through tissue and cell transplantation from undiagnosed chronic Q fever cases became a potential issue. Aim: We aimed to evaluate the risk of Q fever transmission through tissue and cell transplantation. Methods: We performed a retrospective observational cohort study among 15,133 Dutch donors of tissues and stem cells from 2010 to 2015 to assess seroprevalence of Coxiella burnetii antibodies, to identify factors associated with presence of C. burnetii antibodies, and to assess the proportion of undiagnosed chronic Q fever cases. Results: The study population consisted of 9,478 (63%) femoral head donors, 5,090 (34%) post-mortal tissue donors and 565 (4%) cord blood donors. Seroprevalence of C. burnetii antibodies gradually decreased after the outbreak, from 2.1% in 2010 to 1.4% in 2015, with a significant trend in time (p < 0.001). Of 301 seropositive donors, seven (2.3%) were newly detected with chronic Q fever (0.05% of all screened donors). Conclusion: This study shows that seroprevalence of C. burnetii antibodies among donors of tissues and cells in the Netherlands after 2014 was similar to pre-outbreak levels in the general population. The proportion of newly detected chronic Q fever patients among donors of tissues and cells was smaller than 0.1%. This study may prompt discussion on when to terminate the screening programme for chronic Q fever in donors of tissues and cells in the Netherlands.

Case report: Coxiella burnetii vascular infection and lymphoma in the Netherlands.

OBJECTIVES AND DESIGN: Non-Hodgkin lymphoma has been linked to infection with Coxiella burnetii, potentially through overproduction of IL-10 during infection with C. burnetii. MATERIALS AND METHODS: Description of a case report. RESULTS: We describe a patient with retroperitoneal non-Hodgkin lymphoma and vascular infection with C. burnetii. Immunofluorescence staining and fluorescence in situ hybridization targeting specific C. burnetii 16S rRNA were performed on the retroperitoneal lymphoma tissue sample obtained at diagnosis of NHL. Both were strongly positive for the presence of C. burnetii. CONCLUSIONS: This case provokes questions regarding a potential association between C. burnetii and NHL, and underlines the importance of further exploration of this association.