Patients with overlapping diagnoses of asthma and COPD: is livestock exposure a risk factor for comorbidity and coexisting symptoms and infections?

Patients with obstructive lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) are characterized by substantial morbidity. Among the different phenotypes that have been identified for asthma and COPD [1‐3], the largest one represents a patient group that has features and characteristics of both diseases [4, 5]. Overlapping diagnoses of COPD and asthma is commonly referred to as Asthma and COPD Overlap Syndrome (ACOS) [6]. The health-care burden of ACOS seems to be considerable; recent studies suggest that, compared to COPD or asthma only, ACOS patients have higher comorbidity and exacerbation rates, lower health-related quality of life and make more often use of healthcare [7‐9].

It is well documented that particulate matter and its components contribute to the development and exacerbation of respiratory diseases [10‐12]. Individuals with asthma for instance suffer more exacerbations and they appear to be at high risk of developing ACOS when exposed to air pollution [13, 14]. Livestock farming is one of the continuously expanding sources of ambient air pollution worldwide [15, 16]. In the international literature different population-based studies have described the relationship between livestock farming and health effects such as asthma, allergy, respiratory complaints, pneumonia, and lung function deficits [17‐25].

Fewer studies have focused on specific respiratory patient groups, although these seem to respond to a greater extent to exposure from livestock farms. In an experimental setting, the study of Sigurdarson et al. [26] demonstrated adverse reactions in individuals with asthma after being exposed to inhaled grain dust and Harting et al. [27] found that COPD patients had greater systemic responsiveness to ex vivo stimulation with swine dust extract than healthy volunteers. In a more recent epidemiological study in the Netherlands, it was shown that COPD patients living at shorter distance from livestock farms reported more respiratory symptoms [28] and had a higher exacerbation rate when compared with a control area in COPD [29]; however, no consistent associations were observed between individual exposure estimates and diagnosed comorbidity or exacerbations in COPD patients [29, 30].

Considering the growing evidence, it seems important to lay more emphasis on investigating whether the effects of livestock exposure on morbidity and symptomatic reactions are more pronounced among respiratory patients with other clinical phenotypes. To date, no epidemiological study has been conducted on the association between health outcomes and livestock density in patients with ACOS. The present study uses electronic health record data from general practices to address the following questions: 1) Does the prevalence of the examined health outcomes in those patients differ between areas with high livestock farm density (“study areas”) and rural areas with a substantially lower livestock density (“control areas”); 2) What is the association between indicators of exposure to livestock farms and comorbidities and symptoms and infections in ACOS patients? Following prior findings on other respiratory vulnerable subgroups, it is hypothesized that a) the prevalence of the investigated health outcomes will be higher in the “exposed” area; b) higher individual exposure, as indicated by the employed proxies, will be more consistently associated with higher prevalence of comorbid conditions and symptoms.

Asthma and COPD overlap syndrome is a recently recognized phenotype gaining attention due to the associated morbidity and rapid decline in lung function, compared to other respiratory conditions. While there is increasing evidence that livestock density can be an environmental risk factor for adverse effects in respiratory patients such as those with COPD [28, 29], its role in ACOS has not been previously investigated.

Determining the health effects of modifiable risk factors could decrease (multi)morbidity and burden of disease associated with ACOS. The present study comprises a first effort to fill this gap. General practice-registered patients with a dual diagnosis of asthma and COPD were included as a subgroup of respiratory patients potentially susceptible to livestock exposure. We used two approaches to assess the associations between exposure and various comorbid conditions and symptoms: First, we compared rural areas of high livestock density with other rural areas of substantially lower livestock density. Second, we tested the association between health outcomes and individual measures of livestock exposure, based on distance between patients’ home addresses and livestock farms.

In line with the broader literature, presence of comorbid conditions was found to be high in patients with ACOS [9, 37]. Overall, prevalence of the investigated outcomes did not differ significantly between the study and control area, but analyses in the study area showed several statistically significant associations with individual exposure. More specifically, presence of goats within 1000 m was associated with anxiety, allergic rhinitis and number of co-occurring symptoms. In addition, presence of cattle within 500 m was associated with pneumonia; the latter was clearly more prevalent among patients in the study area. Risk of pneumonia was consistently higher in relation to exposure estimates such as presence of goats within 1000 m and distance to the nearest farm, though these results did not reach statistical significance.

Considering the lack of studies on the effects of livestock exposure in this patient group, a direct comparison with prior findings was not feasible. A previous study on patients with COPD (without asthma) living in the same study area showed a comparatively lower prevalence rates of symptoms and infections and no convincing evidence for an association between livestock exposure and health outcomes [30]. Another study [28], showed a higher risk for self-reported respiratory symptoms among individuals with COPD who lived within 500 m from cattle, but that was not statistically significant. In the general population, a higher risk of pneumonia when living in the vicinity of livestock farms is well-documented, but only in relation to goat and poultry [22‐25].

A plausible biological mechanism to explain the significant association observed between presence of goats and anxiety is unknown. Nevertheless, people who live in close proximity of goat farms, seem to have a more negative attitude towards farming [39], which might be related to the Q-fever outbreak in the study area several years prior to the study [40]. Concerns regarding the health effects of environmental exposures as well as perceived exposure are well-documented determinants of various clusters of “non-specific” symptoms [41‐43], but this is highly unlikely for GP-diagnosed disorders or infections such as pneumonia [39].

For some health outcomes we could verify the risk of living nearby livestock farms. Although it is yet unclear which environmental agents could be responsible for the observed associations, it was recently shown that livestock farms are a source of endotoxins in the areas included in the present study [44]. Moreover, the proxies of livestock exposure that we used were significantly associated with measured endotoxin concentrations [45]. Despite our focus on risk, interestingly enough, a lower prevalence of comorbid conditions was often observed in the control area, and in some cases, in relation to exposure proxies in the study area. Currently the mechanisms of how exposure and other factors interact and develop across time are not well-understood. The analysis described in this article contributes to this lacuna, but further research into these mechanisms is needed to determine which risk mitigation interventions are recommended from a public health perspective.

An important strength of the study was the use of objective outcome data from medical records of general practices, based on a reliable registration system. We also employed two approaches to assess associations; a study vs. control area comparison and use of individual exposure estimates of livestock exposure. In addition, exposure was objectively assessed based on different proxies and information on livestock farm licenses and health outcome data were obtained for the same year.

The cross-sectional design constitutes a study limitation. Second, analyses were not adjusted for covariates such as history of tobacco use and socioeconomic status, since this information was not provided/registered in the EHRs. Nevertheless, previous research has shown that controlling for socioeconomic status or smoking habits did not alter the associations between livestock exposure and health outcomes [28, 46]. Third, considering that this study focused on neighbouring residents and the fact that data on occupational livestock exposure were not available, we excluded patients living within 50 m from a farm. It is therefore possible that not all occupationally exposed people have been excluded, but this probably concerns a small fraction of the sample. A previous investigation in the same study area, using questionnaire data on occupational exposure, showed that only about 2.5% of the residents were living or working on a livestock farm, after exclusion of subjects living within 50 m from a farm [28]. Fourth, only health outcomes were included for which people visit a general practitioner; this could have influenced the prevalence of symptoms, to some extent. Fifth, the lack of a universally accepted case-definition and objective biomarkers of ACOS is an obstacle to the investigation and understanding of its pathophysiology and epidemiology [4, 5, 47]. As a result, estimation of prevalence as well as exacerbation risk is highly depended on the case definitions used in different studies. We therefore employed a rather arbitrary definition that requires further validation. Also considering that this is one of the first studies to explore ACOS comorbidity based on EHR data within the context of environmental health, we cannot ensure comparability with previous research. Finally, a larger sample would increase the study power for the identification of possible exposure-outcome associations.

In conclusion, this study supports the hypothesis that livestock farm exposures may increase susceptibility to respiratory infections in patients with overlapping diagnoses of asthma and COPD. However, we found no convincing evidence for an association between estimates of livestock density and prevalence of chronic comorbid conditions. Focusing on patient subgroups with different respiratory phenotypes can enhance our knowledge of the risk of environmental exposures in residents with compromised respiratory health.