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Q fever is a worldwide zoonosis caused by the bacterium Coxiella burnetii (C. burnetii). Small ruminants, in particular sheep and goats, have been associated with community Q fever outbreaks in other countries. Just prior to the Dutch Q fever epidemic, a nationwide survey indicated that only 2.4% of the Dutch population had been ever infected with C. burnetii, and this low prevalence may have contributed to the magnitude of this epidemic. In May 2007, inhabitants from a village in Noord-Brabant, were diagnosed with pneumonia, and C. burnetii was found to be the causal agent. In the following 3 years, Q fever became an important public health problem in The Netherlands, warranting a continuous enhanced surveillance and control. The epidemic curves of notified Q fever cases pointed at multiple simultaneously active sources with a clear seasonal pattern peaking in spring and early summer, following the lambing and kidding season. This thesis presents several epidemiological outbreak investigations focusing on identification of potential farm sources. GIS-based attack rate analysis turned out to be a promising tool to facilitate source detection in an outdoor environment and played an important role in implicating dairy goat farms affected by Q fever-induced abortion storms as the main source of the Dutch Q fever epidemic. This epidemic provided opportunities to gain knowledge about the nature of this zoonotic infection in several occupational groups with intensive livestock contact. In a ‘One Health’ research project, Q-VIVE, the C. burnetii seroprevalence in farm residents and on-farm herds was assessed, while farm-based and individual risk factors for C. burnetii seropositivity were identified to eventually formulate targeted advice and better control and preventive strategies. Seroprevalence figures were comparably high for residents of dairy goat farms (69%; 95%CI 63%-74%), dairy sheep farms (67% ; 95%CI 48%-82%), dairy cattle farms (72%; 95%CI 69%-75%) and livestock veterinarians (65%; 95%CI 69%-75%), and slightly lower for residents of non-dairy sheep farms (51%; 95%CI 45%-57%), indicating a high lifetime risk to acquire a C. burnetii infection. For veterinary students sampled over all study years, the overall seroprevalence was lower (19%; 95%CI 16%-22%).Both knowledge of the risk factors of C. burnetii seropositivity in infected animals and in farm residents were crucial in understanding the transmission routes and risks of human C. burnetiiinfection. For all sectors, a higher risk of infection was found for farms with a large herd size. Also farm location was a risk factor; being located in the provinces of Noord-Brabant and Limburg or in an area near small ruminant farms that tested positive in the mandatory bulk tank milk (BTM)-monitoring program. We furthermore identified several study-related and occupational risk factors associated with C. burnetii seropositivity in veterinary students and in workers involved in the culling of 50,000 sheep and goats. Among those who showed no signs of exposure to C. burnetii prior to the culling, 17.5% seroconverted for C. burnetii antibodies despite the use of personal protective equipment. Prolonged time working in close proximity to the animals was a risk factor for seroconversion.

Between 2007 and 2009, one of the largest Q fever epidemics documented worldwide occurred in the Netherlands. This epidemic originated from dairy goat farms and resulted in over 3,500 notified human acute Q fever cases. After an episode of acute Q fever, the causative bacterium Coxiella burnetii may persist intracellularly, causing progression to chronic disease in approximately 2% of patients with confirmed acute Q fever. Chronic Q fever mainly presents as endocarditis or vascular infections with a high morbidity and mortality. Early detection and prompt treatment improve the prognosis of patients with chronic Q fever. The established way to detect chronic Q fever is to provide follow-up and check antibody levels of all acute Q-fever patients, but there is no consensus on its frequency and duration. The Q fever epidemic in the Netherlands allowed for long-term follow-up of a large cohort of acute Q-fever patients and validation of current follow-up strategies. More than 1,900 patients diagnosed at the Jeroen Bosch Hospital (’s-Hertogenbosch) with follow-up checks available in the first year after the acute episode were invited to have a blood sample taken approximately four years after the acute infection. The antibody levels were determined for 1,289 participants. Patients suspected for chronic Q fever were referred for further clinical examinations. Overall, 4.5% of the 1,289 participants had an antibody profile suggesting chronic Q feverduring the four years. The majority (89.7%) had already been identified within the first year after the acute episode. Based on these results, a single follow-up check twelve months after diagnosis is recommended for all the acute Q fever patients that have no risk factors for chronic Q fever (heart valve/vascular disease or prosthesis). Additional serological and clinical follow-up is recommended for patients with IgG phase I titres ≥1:512. Dutch Laboratories for Medical Microbiology implemented their own follow-up strategies. Large differences were found in follow-up rates within 15 months after diagnosis when comparing a laboratory that provided an active follow-up service by approaching patients directly and two laboratories that only tested on requests of physicians (95% versus 25% follow-up rate, respectively; odds ratio 54, 95% confidence interval 43−67). A study among 183 hospitalized Dutch acute Q fever patients showed that they mostly presented with fever and pneumonia. Hospitalized acute Q fever pneumonia patients were younger, had less co-morbidity, and lower pneumonia severity scores than hospitalized patients with another community-acquired pneumonia. PCR testing is a valuable tool in diagnosing acute Q fever in outbreak situations when the symptom onset is less than 15 days earlier. Patients who later developed serologic profiles indicative of chronic Q fever infection (IgG phase I ≥1:1,024) had significantly higher C. burnetii DNA loads during the acute phase than patients who did not develop such a serologic profile. When the antibody response develops, serology becomes the most important diagnostic tool. Immunofluorescence assay (IFA), enzyme-linked immunosorbent assay (ELISA), and complement fixation test (CFT) perform equally well in diagnosing acute Q fever but two serum samples are needed for the definitive laboratory diagnosis.