Risk Factors for Q Fever in the Netherlands

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1 Article ID: WMC ISSN Risk Factors for Q Fever in the Netherlands Corresponding Author: Mr. Thijs Veenstra, Epidemiologist, Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Anthonie van Leeuwenhoeklaan 9, 3721 MA - Netherlands Submitting Author: Mr. Thijs Veenstra, Epidemiologist, Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Anthonie van Leeuwenhoeklaan 9, 3721 MA - Netherlands Article ID: WMC Article Type: Research articles Submitted on:01-jul-2011, 12:22:20 PM GMT Article URL: Subject Categories:INFECTIOUS DISEASES Published on: 02-Jul-2011, 01:55:49 PM GMT Keywords:Risk Factors, Q Fever, Case Control Study, Outdoor Activities, Epidemic, Netherlands How to cite the article:veenstra T, Snijders B E, Schimmer B, Rietveld A, Van Dam S, Schneeberger P M, Dijkstra F, Van Der Sande M A, Van Der Hoek W. Risk Factors for Q Fever in the Netherlands. WebmedCentral INFECTIOUS DISEASES 2011;2(7):WMC Source(s) of Funding: This work was funded from the budget made available by the Ministry of Health, Welfare and Sport, The Hague, The Netherlands to the respiratory infections project (project number V/210231/01/PS) of the Centre for Infectious Disease Control, National Institute for Public Health and the Environment. Competing Interests: none declared Additional Files: Illustration additional file WebmedCentral > Research articles Page 1 of 10

2 Risk Factors for Q Fever in the Netherlands Author(s): Veenstra T, Snijders B E, Schimmer B, Rietveld A, Van Dam S, Schneeberger P M, Dijkstra F, Van Der Sande M A, Van Der Hoek W Summary Background - Living close to an infected farm has been established as a risk factor for human Q fever during the large, ongoing epidemic in the Netherlands. The aim of the present study was to identify other individual-level risk factors for Q fever, with an emphasis on outdoor activities. Methods - In a case control study, cases were notified Q fever patients within a municipal health region in the south of the Netherlands and controls were recruited via a newspaper advertisement that contained a link to a web-based questionnaire. Results - Male gender, living in an area within 1 km of the nearest affected goat farm and smoking were strong risk factors for acquiring Q fever. Contrary to what was expected, we found that contact with animal or farm waste products or having visited nature areas had a protective effect. Conclusion We did not find an increased risk for Q fever associated with outdoor activities. However, our control group may have included people with an earlier unnoticed seroconversion who were protected against clinical acute Q fever around the time of the study. Despite this methodological problem, the present study confirms the increased risk associated with living close to an infected goat farm. Introduction Since 2007, the Netherlands have been confronted with increasingly larger annual Q fever outbreaks among humans. In 2009 more than 2300 cases have been notified, making this Q fever outbreak the largest ever reported [1, 2]. The majority of cases were from the province of Noord Brabant, but the epidemic also spread to adjacent regions in the middle and south of the country. Q fever is a zoonotic infection caused by the intracellular bacterium Coxiella burnetii, which can be transmitted to humans from goats, sheep, and a range of other infected animal hosts. Infection with C. burnetii is mainly acquired through inhaling contaminated aerosols. The pathogen is highly infectious. Inhalation of only 1 10 organisms can be sufficient to cause infection [3, 4]. An estimated 60% of infections remain asymptomatic, in the other 40% the infection causes febrile illness, pneumonia, or hepatitis in the acute phase [5]. In the Dutch national register of notifiable diseases a possible occupational exposure or direct contact with small ruminants was reported for only few cases. Indirect transmission with infected aerosols from multiple infected small ruminant farms is the most likely explanation for infection and disease in the general population. Previous studies about the Q fever outbreak in the Netherlands showed that people living close to small ruminant farms that experienced an abortion wave due to Q fever had a much higher risk for acquiring Q fever than those living further away [6, 7]. Other risk factors established after the first described outbreak in 2007 were smoking tobacco and contact with manure, hay and straw [6]. Many questions about the role of various risk factors in the transmission chain still remain. Semi-structured questionnaires completed by notified Q fever cases suggested a role for daily outdoor recreational activities close to farms in an endemic area [8]. However, in the absence of a control group, the importance of such recreational activities remained uncertain. When notifications started to increase exponentially in 2009, the need became clear for a rapid assessment of the importance of several behavioural risk factors, as this might identify modifiable risks to assist future prevention and control. A case control design with a conventional seronegative control group was not considered feasible because of logistic reasons. We therefore selected controls through a newspaper advertisement requesting completion of web-based questionnaires. The current study aims to identify individual-level risk factors for patients who have experienced symptoms related to Q fever with special interest for outdoor activities. Methods Study population We performed a case control study in the municipal health service (MHS) region Hart voor Brabant in the south of the Netherlands. Cases were Q fever patients notified in this MHS region. Notification criteria were fever, or pneumonia, or hepatitis, with laboratory WebmedCentral > Research articles Page 2 of 10

3 confirmation (PCR or serology) of recent C. burnetii infection. The MHS had already interviewed the cases as part of the mandatory notification procedure with questions mainly designed to support source finding. As a routine, these cases had been asked for an address if they agreed to answer additional questions at a later stage. We approached all cases with an onset of illness between 1 May and 30 June 2009 and who had provided a functional address. Between 10 July and 24 August 2009 they were sent an with an invitation to complete an online questionnaire. Non respondents were sent a reminder . Cases under the age of 16 and above 80 years of age were not approached as these age categories were expected to have very different activity patterns compared to the 16 to 80 years age group. A control population was recruited through an advertisement in the Saturday edition of a regional newspaper on 30 May This edition has a circulation of copies. The advertisement covered ¼ of a page. In the advertisement, inhabitants of the Q fever affected region who had not experienced clinical Q fever were asked to participate in a study that aimed to identify personal risk factors. In the days following, several other local media paid attention to the study. Controls were included when their municipality of residence was present in the list of municipalities of cases. We aimed for a 1:4 case control ratio. Data collection The online questionnaire was generated using the online survey tool Questback. Questionnaires for cases and controls were largely identical. Cases were asked questions concerning the four weeks before onset of illness. For cases the recall period (period between onset of illness and completing the questionnaire) varied from 3 weeks to 3 months. Controls were asked the same questions about the four weeks prior to the date of completing the questionnaire. The questionnaire contained questions about gender, age, municipality of residence, (possible) history of Q fever, general health status, smoking behaviour, occupation, ownership or recent contact with pets, farm animals or animal products, food consumption, and several outdoor activities. Outdoor activities included recent farm visits (visit to family or friends, excursion or open day, occupation related, farm shop visit, farm camping), and frequency of shopping by foot or bike, sitting outside, working around home, wandering, jogging, biking, horse riding, fishing, and other sport activities. In addition, participants were asked to select areas they had visited from a list of 92 recreational and nature areas. These areas were located in and around the municipal health region Hart voor Brabant. Locations of infected dairy goat farms in the area were obtained from the website of the Food and Consumer Product Safety Authority. We included farms that had been declared positive in 2009 after the present study, assuming that animals from these farms would have shedded bacteria for a longer period of time. Data analysis Compound variables were created for many factors of interest, based on the frequency distribution. The overall level of outdoor activities was categorized as intensive if the respondent reported more than three activities that scored above the median for the entire study population. An overall variable for having visited any nature area was used in addition to the variables containing information per area. Odds ratios with corresponding 95% confidence intervals were calculated using logistic regression analyses. Variables that were statistically significant at the 5% level were used in a multivariate logistic regression analysis. Potential collinearity was tested with a multivariate linear regression producing collinearity diagnostics (variance of inflation factor). Distance between house and nearest infected dairy goat farm was calculated with ArcGis 9 software. All other analyses were performed using SPSS, version 18.0 (SPSS Inc.). Results Of the 639 cases that were notified within the MHS region with an onset of illness in May or June 2009, we retrieved functioning addresses of 206 cases (32%). Thirty seven cases did not respond and 13 respondents were excluded because of non-eligible age or municipality, or an incomplete questionnaire. Therefore, 156 cases were included for further analyses. A total of 1129 potential control persons responded to the newspaper advertisement and completed the online questionnaire. We excluded 247 controls because the municipality of residence was outside the target area or did not have Q fever notifications in Also controls under the age of 16 years or for whom information on age or gender was missing were excluded. This resulted in 872 controls that were available for the analysis. Median age of the cases was 47 years (interquartile range 40-58). Controls were on average two years younger than cases and four years younger than the total group of patients that were notified within this WebmedCentral > Research articles Page 3 of 10

4 MHS region in May and June 2009 (Table 1). Cases were predominantly male while controls were predominantly female (P<0.01). Among cases and controls only a small proportion was employed in agriculture or animal husbandry. The proportion of controls that was employed in health care was much higher compared with the cases (17.4% versus 5.1%) and also higher compared with the general population (6.0%, retrieved from data from Statistics Netherlands[9]). The proportion of respondents without employment was not significantly different between cases and controls. Table 2 shows that male gender, current smoking and living in an area within 1 km of the nearest affected goat farm were statistically significant risk factors in the univariate analyses. Surprisingly, contact with cows, contact with animal or farm waste products, contact with animals after death or (still) birth, practising more than 3 out of 10 outdoor activities, and visiting a nature area all had a statistically significant protective effect (Table 2; OR s < 1). The results of the multivariate analyses show that gender, current smoking and living in an area within 1 km of the nearest affected goat farm remained statistically significant risk factors or became even stronger risk factors (Table 2). Contact with animal or farm waste products and visit to any nature area showed a statistically significant protective effect after adjusting for all other risk factors that were significant at a 5% level in the univariate analyses (Table 2). Contact with cows, contact with animals after animal death or (still) birth, and more than 3 out of 10 outdoor activities did not appear as a risk factor in the multivariate analyses (Table 2). There was no evidence for multicollinearity between variables (variance inflation factor always <1.2). Discussion In this study we found that male gender, living in an area within 1 km of the nearest affected goat farm and smoking are strong risk factors for acquiring Q fever. Our results with respect to smoking are in accordance with previous studies that have also found that smoking is an important risk factor for the acquisition of a C. burnetii infection [6, 10]. It has been hypothesized that smokers may be more exposed to outdoor contaminated aerosols than non-smokers as a result of outdoor smoking. However, we did not collect information on smoking habits to confirm this. Furthermore, the increased risk of smokers may be due to their regular hand mouth contact or an increased risk for respiratory infections in general as a result of alterations in structural and immune defences [11]. A previous study in the Netherlands showed that the risk for acquiring Q fever is dependent on the distance to a dairy goat farm with abortion problems with a sharply decreasing incidence with increasing distance [7]. In the current study living in an area within 1 km of the nearest affected goat farm yielded a statistically significant risk factor but not for other distance categories. Contrary to our expectations, having had contact with animal or farm waste products or having visited nature areas had a protective effect (OR < 1). However, the exposure in the questionnaire referred to the past four weeks. Furthermore, we hypothesize that controls who reported having had contact with animal or farm waste products or having visited nature areas were more likely to be exposed to C. burnetii early in the outbreak that already started in As serological profiles of controls were not known, we were not able to exclude controls who had experienced an asymptomatic seroconversion. This may imply that our control group included a considerable number of people with an unnoticed seroconversion after three years of C. burnetii circulation [12]. In a screening programme among blood donors in 2009, 66/543 (12%) had antibodies to C. burnetii (Personal communication, Prof. H.L. Zaaijer, Sanquin Blood Supply Foundation, Department of Blood-borne Infections). In a previous study it has been shown that around 60% of infected persons are reported to remain asymptomatic [13]. In a case control study performed in 2007 a total of 34% of seropositive individuals did not experience any complaints compatible with Q fever [8]. The sampling of our controls may have several disadvantages. Although, our community controls came from the same municipalities as the cases and also reported exposures over the same time period, it should be noted that the controls were self-selected. Hence our control group did not represent a random sample of the source population. Clearly, women and health care workers were overrepresented and respondents might have had a better general health status, engaging in more outdoor activities than the overall source population. Besides, the fact that smoking was identified as a risk factor for Q fever may partly be interpreted as a putative consequence of the over-representation of health workers among the controls (i.e. comprising 21% smokers versus 28% amongst the general population) [14]. Recall bias in the case population may have occurred. The activities to be reported by cases had to occur WebmedCentral > Research articles Page 4 of 10

5 from 7 to 16 weeks prior to the administration of the questionnaire (a four week period before onset, plus 3 weeks to 3 months recall period). In contrast, controls had to record the same kind of activities that occurred within 4 weeks prior the administration of the questionnaire. Controls were excluded when there were no cases reported from the same municipality but the ratio of cases and controls per municipality was not accounted for. Although the distribution was relatively equal, in a future study a stricter geographical match could be of value to eliminate bias caused by spatial differences. Despite the clear methodological weaknesses we were able to rapidly recruit a sufficiently large control group through a newspaper advertisement and using a web-based questionnaire. This warrants exploration for future studies when the disease of interest is of concern to the local population. Future studies might reveal more risk factors if recruitment of an unbiased control population is feasible. Acknowledgements This work was funded from the budget made available by the Ministry of Health, Welfare and Sport, The Hague, The Netherlands to the respiratory infections project (project number V/210231/01/PS) of the Centre for Infectious Disease Control, National Institute for Public Health and the Environment. We thank Ben Bom (RIVM) for performing the calculations with ArcGis 9 software Keypoints Euro Surveill, (12). 3.Parker, N.R., J.H. Barralet, and A.M. Bell, Q fever. Lancet, (9511): p Hatchette, T.F., et al., Goat-associated Q fever: a new disease in Newfoundland. Emerg Infect Dis, (3): p Terheggen, U. and P.A. Leggat, Clinical manifestations of Q fever in adults and children. Travel Med Infect Dis, (3): p Karagiannis, I., et al., Investigation of a Q fever outbreak in a rural area of The Netherlands. Epidemiol Infect, (9): p Schimmer, B., et al., The use of a geographic information system to identify a dairy goat farm as the most likely source of an urban Q-fever outbreak. BMC Infect Dis, (1): p van Steenbergen, J.E., et al., [Q fever in the Netherlands: 2008 and expectations for 2009]. Ned Tijdschr Geneeskd, (14): p CBS, Statistics Netherlands Orr, H.J., et al., Case-control study for risk factors for Q fever in southwest England and Northern Ireland. Euro Surveill, (10): p Carolan, B.J., et al., Decreased expression of intelectin 1 in the human airway epithelium of smokers compared to nonsmokers. J Immunol, (8): p van der Hoek, W., et al., [Three years of Q fever in the Netherlands: faster diagnosis]. Ned Tijdschr Geneeskd, : p. A Raoult, D., T. Marrie, and J. Mege, Natural history and pathophysiology of Q fever. Lancet Infect Dis, (4): p Statline, Living close to an affected goat farm was identified as a risk factor for acquiring Q fever which confirmed the result of a previous study. Our findings suggest that involvement in outdoor activities is not a risk factor for acquiring Q fever. Unnoticed seroconversion should be taken into account in future case control studies that focus on risk factors for Q fever. References 1.Schimmer, B., et al., Sustained intensive transmission of Q fever in the south of the Netherlands, Euro Surveill, (19). 2.van der Hoek, W., et al., Q fever in the Netherlands: an update on the epidemiology and control measures. WebmedCentral > Research articles Page 5 of 10

6 Illustrations Illustration 1 Table 1. Demographic background of cases, controls, and of all Q fever notifications in the study period Cases All notifications* Controls N=156 N=872 N=639 Median age in years 47 (SD 14.2) 45 (SD 13.2) 49 (SD 15.9) Gender male 102 (65.4%) 298 (34.2%) 407 (63.7%) Employment: Agriculture 1 (0.6%) 39 (4.5%) - Health care 8 (5.1%) 152 (17.4%) - No employment 38 (24.4%) 197 (22.6%) - Other occupations 105 (67.3%) 478 (54.8%) - SD, standard deviation *All patients notified within the municipal health service region Hart voor Brabant with onset of illness in May or June 2009 Includes animal husbandry WebmedCentral > Research articles Page 6 of 10

7 Illustration 2 Table 2. Univariate and multivariate analysis of risk factors for Q fever among respondents Exposure Cases Controls OR 95% CI OR 95% CI (N=156) (N=872) (univariate) (multivariate) n (%) n (%) Male gender 102 (65) 298 (34) Age >45 years 84 (54) 432 (50) Distance to nearest affected dairy goat farm 1km 7 (5) 13 (2) km 28 (18) 115 (13) km 25 (16) 118 (14) km 13 (8) 91 (11) km 22 (14) 173 (20) WebmedCentral > Research articles Page 7 of 10 1

8 Occupation in agriculture 1 (1) 39 (5) Unemployed 38 (24) 197 (23) Current smoker 67 (43) 180 (21) Ever received blood transfusion 16 (10) 85 (10) Possession of any animal 93 (60) 515 (60) Contact with sheep * 35 (22) 247 (28) Contact with goats 42 (27) 222 (26) Contact with cows 26 (17) 214 (25) Visit to farm 42 (27) 272 (31) Contact with animal or farm 28 (19) 296 (37) waste products Contact with animals after 14 (9) 141 (16) animal death or (still) birth Consumption of raw milk 59 (38) 337 (39) WebmedCentral > Research articles Page 8 of 10 2

9 product More than 3 out of 10 outdoor 66 (47) 487 (63) activities classified intense Visit to pet farm 11 (7) 100 (12) Visit to zoo 11 (7) 82 (10) Visit to any animal event 7 (5) 32 (4) Visit to any nature area 65 (43) 517 (60) OR, odds ratio; CI, confidence interval * This and all following variables refer to past 4 weeks Reference categories: female; age 45;> 5 km to nearest affected dairy goat farm; any other or no occupation; employed; no current smoker; never received blood transfusion; no possession of animal; no contact with sheep, goats, cows; no visit to farm, no contact with waste products or animal after death; no consumption of raw milk product; 3 outdoor activities classified as intense; no visit to pet farm, zoo, animal event, nature area WebmedCentral > Research articles Page 9 of 10 3

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