Q Fever Related Community Infections, US Exposure to Coxiella burnetii

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Dillon , Gwendolyn R. Dillon doi: https://doi.org/10.1101/2025.03.23.25324484 Charles F. Dillon 1 Independent Researcher , Stamford, Connecticut, United States Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: cfdillon1{at}gmail.com Gwendolyn R. Dillon 2 Department of Chemistry, University of California , Davis, California, United States Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Coxiella burnetii is a significant infectious pathogen that causes Q fever. Q fever is thought to be uncommon in the US and most human cases are believed to occur in agricultural livestock workers. However, the extent of community exposure to C. burnetii isn’t known with certainty. Using nationally representative US National Health and Nutrition Examination Survey serologic, demographic and occupational history data, the magnitude of US adult general population exposure to C. burnetii excluding agricultural sector workers was estimated. Exposure was defined as positive serum IgG antibodies by immunofluorescence assay (e.g. current or past infection). 3.0% (95% CI 2.0-4.4) of the US population met criteria for C. burnetii exposure, some 6.2 million persons. Overall, 86.9% (95%CI: 75.5-98.4) of seropositives had no lifetime history of work in the agricultural sector (5.5 million persons). This was consistently true across all US demographic groups: age 20-59 years 87.3%, age 60+ years 85.7%, men 86.1%, women 87.6%, Non-Hispanic Whites 82%, Non-Hispanic Blacks 95.8%, Mexican Americans 89.4%, immigrants from Mexico 83.5% and other immigrants 96.8%. As half of C. burnetii infections result in acute Q fever and chronic Q fever conveys significant mortality, community level risks to the general public may be significant. 1. Introduction Coxiella burnetii is an important pathogen, the causal agent of Q fever, one of the select US national notifiable infectious diseases and a significant but treatable health hazard [ 1 - 3 ]. It is a potent gram-negative intracellular pathogen with a low infectious dose [ 4 , 5 ]. Half of those infected develop clinical illness, typically an acute respiratory illness or hepatitis. Infection can also be followed by chronic illness which carries significant mortality risk [ 1 , 6 ]. C. burnetii is hardy and capable of persisting in the environment for months to years, significantly increasing population exposure risks [ 7 ]. A primary route of transmission to humans is airborne inhalation of bacteria from infected animal birth products or contaminated dust and soils. 1 A major reservoir for C. burnetii is farm animals, specifically domesticated ruminants including cattle, sheep and goats [ 8 , 9 ]. However, since livestock workers are a small minority of the general population, Q fever has usually been considered uncommon in the US, a rare illness mainly affecting this one specific occupational group. The fact that relatively few Q fever cases are officially reported each year to the US National Notifiable Diseases Surveillance System (NNDSS) may have served to strengthen this perception (194 cases in 2022) [ 2 ]. However, Q fever in the US is considered a largely unreported disease [ 1 , 8 , 10 ]. How accurate is the impression that C. burnetii infection and clinical disease are mainly restricted to the agricultural industry? A review of Q fever case reports submitted to the NNDSS from 2000 to 2010 show that 79% of officially notified Q fever cases had no history of work in traditional high-risk occupations and 60% reported no contact with livestock [ 1 ]. These estimates could be a signal of significant C. burnetii exposures occurring in the US general population, however the reports were based on a voluntary reporting system (passive surveillance) that was not nationally representative. There is nationally representative data for the US prevalence of positive C. burnetii antibodies. A US National Health and Nutrition Examination Survey (NHANES) surplus sera study using 2003-04 specimens showed that some 3.1% of the US adult population were C. burnetii seropositive, an estimated 6.1 million persons [ 11 ]. These numbers are remarkable, indicating that exposure to and infection with C. burnetii is in fact common in the US. It also suggests that the prevalence of US Q fever cases could be much greater than officially notified case reports. Further, NHANES routinely obtains nationally representative work history data [ 12 ]. This captures the greater part of a participant’s lifetime employment. However, the 2-year survey dataset was the minimum sample size for any NHANES analysis. Given an overall 3% C. burnetii seropositive rate, stable statistical estimates for occupational exposure analyses for many specific occupations including agricultural workers were not possible. It was not appreciated, however, that the statistical complement of the C. burnetii infection rate in agricultural workers, the seroprevalence in persons with no prior history of work in the agricultural sector, can be reliably estimated from the NHANES data and with precision. This seroprevalence estimate is presented here for the US and its major demographic subgroups. This metric is important as it can potentially provide an initial perspective on the scope of US population-level exposures to the general public outside the agricultural sector. 2. Materials and Methods NHANES is a series of cross-sectional, active surveillance surveys monitoring the health and nutritional status of the ambulatory, noninstitutionalized US civilian population. Each 2-year survey cycle is nationally representative. Data is collected by in-person household interviews with examinations and laboratory studies performed in mobile examination centers [ 13 ]. NHANES is a demographically based survey that uses a complex, multistage, survey design to estimate national level prevalences [ 14 ]. Oversampling is used to capture adequate data for key demographic sub-groups. The NHANES 2003-04 survey had a 70% adult health examination response rate [ 15 ]. 2.1 NHANES Occupational data NHANES fielded one of the standardized US National Center for Health Statistics (NCHS) occupational history surveillance instruments [ 12 ]. Data was collected by trained professional interviewers with in-field data quality control. Data collection also included demographic data (age, sex, ethnicity, and nativity). Data for the participant’s current and longest held jobs was also collected, and if applicable, data for an individual’s job during which their asthma had begun if not the current or longest held position. This captures the greater part of an individual’s work history but is not a complete listing of all jobs ever held. The NHANES dataset did not have a specific variable for work with livestock. The NHANES industry and occupation text data were coded by NCHS Division of Vital Statistics staff using the U.S. Census Bureau’s 2000 version of its Occupation and Industry Coding System [ 16 - 17 ]. For public release, the detailed US Census data codes were abstracted into 45 industry and 41 occupation groups [ 16 ] (Appendix A). A participant was classified as having worked in the agricultural sector if there was an industry or occupation code to indicate it. Industry codes included agricultural production, support services and forestry; occupation codes included farm operators, managers, supervisors, farm and nursery workers and related agricultural occupations [ 16 ] (Appendix A). Statistical analysis for most individual occupational titles was not possible due to small sample sizes, even when the data was regrouped into 17 occupational categories (Supplemental Table 1). We therefore condensed the data into four major socioeconomic groups using an occupational group classification system previously used by the US Centers for Disease Control and Prevention [ 18 ] (p. 231). These were professional, technical and office workers (occupation group codes 1-16); service workers (codes 17-24); agriculture and related work (codes 25-27); and factory, repair, construction, transport, freight/materials work [ 16 ] (codes 28-40). We also added categories for those who reported a history of work in more than one of the occupational groups and for those who had never worked. To assess whether our occupational data had sufficient sample size for the analyses, the total study person-years of work history were computed. For quality assurance purposes, age-specific NHANES 2003-04 civilian labor force participation rates were compared to known US Bureau of Labor Statistics (BLS) values [ 19 ], Supplemental Tables 2,3). 2.2 C. burnetii serology data The 2022 update of the NHANES 2003-04 C. burnetii stored surplus sera data was used for analysis [ 20 ]. Sera were screened for C. burnetii IgG antibodies (N=4,236) using an enzyme-linked immunosorbent assay (ELISA). Positive or equivocal ELISA results were then tested for IgG Phase 1 and 2 antibodies by immunofluorescence assay using the Philip et al. method adapted to C. burnetii [ 21 - 22 ] (purified Phase 1 Phase 2, strain Nine Mile; Rocky Mountain Laboratories). Exposure in this study was defined as a positive Phase 1 or 2 serum IgG antibody titer of ≥ 1:16 (e.g. current or past infection). 2.3 Statistical methods Data assembly and statistical analysis utilized SAS ™ (release 9.4, SAS Institute, Inc., Cary, NC) and SUDAAN ™ (release 11.0.1, Research Triangle Institute, NC). Survey design variables (strata and primary sampling units) and health examination sample weights were used to account for differential probabilities of participant selection, to adjust for survey nonresponse and noncoverage, and to provide nationally representative estimates. Standard errors were estimated using Taylor series linearization. Prevalence estimates were age-adjusted using direct standardization. T-tests were used to compare estimates with p ≤.05 considered significant. NCHS criteria and software were employed to assess the statistical reliability of estimated prevalences and proportions, based on effective sample size, relative confidence interval widths and degrees of freedom [ 23 - 25 ]. Where statistical reliability criteria were not met, select prevalence estimates without confidence intervals are presented for perspective. 3. Results 3.1 Overall US C. burnetii seroprevalence Overall, 175 of 4,236 survey participants were C. burnetii seropositive, an estimated 3.0% US prevalence (95%CI 2.0-4.4) ( Table 1 ). This corresponds to 6.2 million adults in the general popu - lation (95%CI 4.1-9.0 million). Infection risk was significantly increased at older ages: 4.2% in those ages 60+ years vs. 2.7% in younger adults (t=2.52, p=.02). Men showed higher prevalence of infection than women 3.8% vs. 2.3% (t=2.23, p=.04), however the numbers of individuals affected in both sexes was substantial, 3.8 million infections among men (95%CI 2.5-5.5) and 2.5 million among women (95%CI 1.4-4.1). Mexican Americans had significantly increased risk of infection, 7.5% compared to 2.8% in Non-Hispanic Whites (t=5.71, p<.01). Seroprevalence was 1.4% in the Non-Hispanic Black population (95%CI 0.6-2.8). 2.4% (95% CI 1.4-3.6) of US born participants had positive antibodies whereas foreign born participants had higher infection rates: 8.6% (95%CI 6.2.-11.5) of those born in Mexico and 6.9% (95%CI 3.6-11.7) of those born in other countries were positive. View this table: View inline View popup Download powerpoint Table 1. Coxiella burnetii Seroprevalence in US Adults with No History of Agricultural Work. 3.2 Occupational sample data descriptives NHANES 2003-04 dataset had a total of 59,214 person-years of work for the occupational history analysis, 1 person-year defined as one year an individual worked ( Table 2 ). There were a total of 25,410 person-years of work among those who were currently working, 732 person-years among the unemployed and 32,072 person-years worked for those who were not currently working. The latter included those retired (24,022 person-years), the disabled, homemakers, personal illness, and others (Supplemental Table 4). View this table: View inline View popup Download powerpoint Table 2. NHANES 2003-04 Overall and Age-Specific Person-Years of Work Counts. The overall NHANES 2003-04 US civilian labor force participation rate in the study sample was 66.5% (95%CI 64.3-68.7) ( Table 3 ). This was consistent with the Bureau of Labor Statistics estimates for 2003 (66.2%) and 2004 (66.0%). The NHANES age-specific labor force participation rates for the current study sample age range (adults 20+ years) were also consistent with BLS estimates. As BLS reports do not routinely provide standard error estimates, the NHANES and BLS age-specific estimates were not further compared. View this table: View inline View popup Download powerpoint Table 3. US Labor Force Participation Rates: BLS Compared to NHANES 2003-04. 3.3 C. burnetii seroprevalence in those with no history of agricultural work Table 1 and Figure 1 also show the population prevalences and percentages of C. burnetii seropositive participants who had no previous history of agricultural work. The US adult population C. burnetii seroprevalence in the group with no history of agricultural work was 2.7% (95%CI 1.8-3.8). This was 86.9% (95%CI 75.5-98.4) of all study C. burnetii seropositives, equivalent to 5.5 million persons (95%CI 3.7-7.8). Results for the detailed demographic sub-groups were similar. 87.3% of seropositive US adults ages 20-59 years, and 85.7% of adults ages 60+ years reported no history of work in agriculture. Also, seropositive men and women had similar rates for no history of agricultural work: 86.1% (95% CI 72.4-99.9) for men and 87.6% for women (95%CI 70.0-100). As a group, 89.4% (95%CI 79.6-99.2) of seropositive Mexican Americans reported no history of prior agricultural work. Further, 83.5% (95% CI 68.6-98.4) of seropositive persons born in Mexico reported no history of agricultural work. Download figure Open in new tab Figure 1. Percent of Seropositives with No History of Agricultural Work. 3.4 Length of residence data for US immigrants Higher rates of positive C. burnetii serology in US foreign born residents could potentially reflect infections acquired prior to US immigration. Mexican Americans were a large demographic sub-group and constituted the majority of US immigrants in 2003-04. Because of low subsample sample sizes, most length of residence data for foreign-born Mexican Americans could not be statistically analyzed. However, for perspective, of the 854 Mexican American participants in the sample, an estimated 41% were native born US citizens and 59% were born in Mexico. An estimated 25% of those born in Mexico were naturalized US Citizens; virtually all (96%) of these had resided in the US for 10 or more years and 63% for ≥20 years. Among all Mexican born non-US citizens, an estimated 46% had lived in the US 10 years or more and 19% for ≥20 years. Among seropositive Mexico born non-citizens, an estimated 59% had US residence ≥10 years and 9% ≥ 20 years. 3.5 Occupational data analysis Direct analysis of seropositive risks in the 41 NHANES occupational group job titles was not feasible due to sample size limitations. This problem persisted when the data was further condensed into 17 occupational groups. Supplemental Table 1 shows the crude data distribution for the 17 job categories ordered by the percent C. burnetii seropositive. Table 4 shows that when more general level socioeconomic groups were compared, manufacturing, repair, construction, transportation and freight/materials workers had the highest seroprevalence, 3.9% (2.4-5.8) and professional, technical and office workers had the lowest, 2.0% (1.1-3.3). This was a statistically significant difference (t=3.17, p<.01). View this table: View inline View popup Download powerpoint Table 4. Coxiella burnetii Seroprevalences in Major US Occupational Groups. 4. Discussion As initially recognized in the 1950’s, C. burnetii infections are endemic in almost all countries, causing disease in both humans and animals [1,26-31). The United States is no exception. A US clinical laboratories serology study, US Q fever notifiable disease reports and the nationally representative US National Inpatient Sample survey document C. burnetii infections, Q fever cases and hospitalizations occurring throughout the US [ 1 , 32 - 35 ]. The NHANES survey seroprevalence data adds further important population-based perspective on US Q fever related exposures. The NHANES C. burnetii seroprevalence results are older data, however the dataset is unique with its large-scale, nationally representative, population-based, in-person active surveillance sampling. Additionally, NHANES 2003-04 had a high survey response rate. The overall and age-specific NHANES 2003-04 estimates for current labor force participation rates in the 20+ years study age range were consistent with official US Bureau of Labor Statistics values, an added indication that the NHANES 2003-04 occupation data are nationally representative (e.g. sampling frame external validation). The 2-year NHANES work history sample size (the total person-years worked) was more than sufficient to estimate prevalences and the percentages of seropositive adults with no history of work in the agricultural sector. Rather than being rare, C. burnetii infection was shown to be common in the US: 3% of the adult population, or some 6.2 million persons, had positive serology. Overall, 87% of those C. burnetii seropositive reported no prior history of work in the agricultural sector, equivalent some 5.5 million persons in the US. This finding was consistent across all the major US demographic sub-groups, including US citizens and immigrants. Also, the general-level occupational group analysis here shows that manufacturing, repair, construction, transportation and freight/materials workers in the community may have significant C. burnetii exposures. This is consistent with the prior disease outbreaks and case reports. Collectively the above findings are remarkable as farm worker exposure to livestock is usually considered to be the cause of most US C. burnetii infections. Nevertheless, results here suggest that general population exposures to C. burnetii may be common and may exceed those of live-stock workers. Additional focused studies are needed to more rigorously define the population-level burden of these community level exposures. Table 5 summarizes known and probable C. burnetii reservoirs, transmission settings and pathways relevant to community and non-farm related occupational exposures [ 36 - 125 ]. The table emphasizes North American studies so is not globally comprehensive. View this table: View inline View popup Download powerpoint Table 5. coxiella burnetii Reservoirs, Transmission pathways. The results here have some precedents in the literature. In a recent update to the US national NNDSS Q fever case notifications for 2008 to 2017, 60% of officially reported cases had no exposure to animals prior to the onset of their illness and only 40% were employed in high-risk occupations [ 10 ]. Also, in the recent large-scale regional Q fever epidemic in the Netherlands, only 3.2% of officially notified Q fever cases had worked in the agriculture sector and 0.5% worked in the meat-processing industry [ 126 - 127 ]. A recent comprehensive global review of Q fever out-breaks showed that half occurred in communities and not in traditional at-risk occupational settings [ 26 ]. Of community outbreaks, only half were associated with living in proximity to live-stock holdings. Indirect transmission via environmental contamination and airborne spread were the most common infection routes, particularly for large scale urban outbreaks. Also significantly, a US national-scale environmental survey has demonstrated widespread C. burnetii contamination in US dust and soils [ 7 ]. Positive samples were found in livestock operations as expected but also in non-agricultural locations such as post offices, retail stores, schools, a bank, a government building and a community center. Given C. burnetii’s environmental viability and low infectious dose, aerosolization of pathogenic bacteria from such contaminated dust and soils could pose a significant health hazard to the general public. 4.1 Limitations This study provides a US C. burnetii exposure assessment but should not be interpreted as an assessment of the US prevalence of actual clinical disease, e.g. of acute or chronic Q fever. Seroprevalence exposure assessments are typically employed to model disease risks, to identify high risk settings and to characterize vulnerable population subgroups. An example, is to provide guidance for planning preventive vaccination programs. Currently preventive animal and human Q fever vaccines are only available in Australia [ 31 , 128 - 129 ]. The human vaccine is contraindicated in those with prior C. burnetii infection, so pre-vaccination skin testing and serology screening is required. Vaccines are under development to address this limitation as well as to improve immunologic targeting [ 129 ]. We could not determine whether foreign born participants had C. burnetii exposure in the US or their home country. However, as seropositivity generally wanes with time, especially over decades, the length of immigrant residence in the US provides some initial perspective on whether infection may have occurred pre-immigration or in the US. In the study time frame Mexican Americans were the majority of US immigrants. However a substantial proportion of foreign-born Mexican American immigrants had lived in the US for one or more decades, so a large fraction of these may have been exposed to C. burnetii in the US. Also, like native born US citizens, most Mexican American immigrants reported no prior history of work in the agriculture sector, 83.3% vs. 83.5% respectively. This cross-sectional study employed the NHANES occupational history questionnaire, a robust general-purpose public health surveillance epidemiology instrument. However, it lacks additional detail typically seen in Q fever outbreak investigations. A future specifically designed NHANES study could be fielded to specifically address this limitation. In this regard, there are two biases in the current study that function in opposite directions. First, while the agricultural sector work variable used here is based on the participant’s current as well as longest held job data and captures a significant proportion of an individual’s work history, it does not provide a complete employment history so some prior work in agriculture may not be accounted for. On the other hand, the NHANES survey agricultural work variable available used here is a general-level one that includes both the crop production and the livestock sectors. As levels of US employment solely in the crop production sector are substantial, a significant fraction of those reporting a history of agricultural work in this study had no work contact with livestock [ 130 ]. A primary limitation of this study is the retrospective analysis of stored sera data, however this does not reflect on NHANES’s capabilities. Stored sera studies are highly useful as seen here. Nevertheless, NHANES’s primary purpose is to field in-person, designed for purpose, active surveillance public health studies, such as its US national surveillance programs for infectious diseases and environmental exposures monitoring. In any given year, NHANES samples 15 selected US Census tracts. The 2-year sample used here is a minimum required for NHANES analyses. Given an overall 3% C. burnetii US seroprevalence, there was reduced study power and ability to provide key subgroup estimates such as infection risks for those working in most occupations including agriculture. A 6-year sample of NHANES stored sera (90 US Census tracts) would be required to address this limitation, and for example, to assess detailed exposure risks in the 17 occupational groups listed in Supplemental Table 1 [ 131 ]. Data Availability This research was based on publicly available NHANES data. https://www.n.cdc.gov/nchs/nhanes/continuousnhanes/default.aspx?BeginYear=2003 Supplementary Materials The following supporting information can be downloaded at: www.mdpi.com/xxx/s1, Table 1 : Coxiella burnetii Seropositivity by History of Work in 17 Occupational Groups; Table 2 : US Bureau of Labor Statistics 2003 Labor Force Participation Rates; Table 3 : US Bureau of Labor Statistics 2004 Labor Force Participation Rates; Table 4 : Person-Years Worked -Adults Not Currently Employed. Author Contributions Conceptualization, C.D. and M.D.; methodology, C.D and M.D.; software, C.D and G.D.; formal analysis, C.D., G.D and M.D; writing original draft, C.D., G.D and M.D.; writing – review and editing. C.D., G.D and M.D.; visualization, C.D.; project supervision, C.D. All authors have read and agreed to the published version of the manuscript. Funding This research received no external funding. Institutional Review Board Statement The study was conducted in accordance with the Declaration of Helsinki and approved by the US National Center for Health Statistics Ethics Review Board, Protocol Code #98-12. https://www.cdc.gov/nchs/nhanes/about/erb.html Informed Consent Statement NHANES obtained written informed consent from all subjects involved in the study. This included permission to publish deidentified results in scientific journals and reports. https://www.n.cdc.gov/Nchs/Nhanes/ContinuousNhanes/Documents.aspx?BeginYear=2003 Conflicts of Interest The authors declare no conflicts of interest. Disclaimer/Publisher’s Note The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. Acknowledgments We would like to acknowledge the helpful assistance of Nicholas Schaffer, Economist at the U.S. Bureau of Labor Statistics Division of Information Services for providing the BLS 2003 and 2004 age and sex-specific current US labor force participation data used in this paper. We also thank Dr. Michael Dillon, Senior Scientist at the US Lawrence Livermore National Laboratory for his work in paper conceptual development, data analysis strategy and manuscript development. Abbreviations The following abbreviations are used in this manuscript: NHANES US National Health & Nutrition Examination Survey NCHS US National Center for Health Statistics BLS US Bureau of Labor Statistics NNDSS US National Notifiable Diseases Surveillance System ELISA Enzyme-linked immunosorbent assay References ↵ Anderson A. , Bijlmer H. , Fournier P-E. , Graves S. , Hartzell J. , Kersh G.J. , Limonard G. , Marrie T.J. , Massung R.F. , Mc-Quiston J. H. , et al. 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Na-tional Health and Nutrition Examination Survey: Analytic Guidelines, 1999-2010 . Vital Health Stat 2 . 2013 , 161 , 1 – 24 . OpenUrl View the discussion thread. Back to top Previous Next Posted March 24, 2025. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Q Fever Related Community Infections, US Exposure to Coxiella burnetii Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. 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