To the Editor
Environmental exposures in early life play a major role in allergic disease susceptibility. Notably, children raised on farms are at lower risk for these diseases compared to children raised in either rural or urban non-farm settings.1 Exposure to farm-related microbes during early life may enhance mechanisms of immune tolerance.2, 3 Early life immune development likely influences respiratory viral infection outcomes. Low interferon responses in cord blood cells are associated with greater severity of viral illnesses and increased risk of wheezing.4, 5 These results suggest that by altering immune development in early life, farm exposures might reduce the risk of both allergic diseases and respiratory illnesses in childhood.
To test this hypothesis, we utilized a large epidemiologic study population in rural Wisconsin (the Marshfield Epidemiologic Study Area, or “MESA”).6 Within MESA, a cohort of children ages 5-17 years born onto dairy farms were compared to children who grew up in similar rural areas but lacked farm exposure. A random sample of 1,000 out of 9,510 children were selected for the survey based on a weighted sampling strategy to overselect for probable farm residency and asthma (see Online Supplement). Completed surveys and detailed outcomes information were available for 268 children who lived on a farm from birth to five years and 247 children who never lived on a farm.
Early life exposures were determined by parental questionnaires. Clinical outcomes included asthma, eczema, hay fever and respiratory illnesses (Supplemental Table 1), and were determined by parental questionnaire and extraction of data from electronic medical records.
We first calculated descriptive statistics using chi-square (discrete variables) or t-test (continuous variables) to compare demographic, early exposure characteristics, and clinical features between children with early farm exposure and with no farm exposure. Children with early farm exposure were significantly more likely to be exposed to indoor pets (82.1% vs 62.3%, p=0.003) and less likely to have attended day care (38.6% vs 63.1%, p=0.002) compared to non-farm children. Family history of asthma/atopic disease, breastfeeding incidence, and exposure to second-hand smoke were not significantly different between the study groups (Supplemental Table 2).
For the clinical outcomes, the frequency of asthma was similar in both groups (Supplemental Table 3). Conditions that were significantly less common in farm-exposed children including allergic rhinitis based on medical record (5.2% vs 12.4%, p=0.02) and chronic skin rash or eczema based on interview (6.8% vs 19.5%, p<0.001). Most striking was a significant decreased frequency of early life severe respiratory illnesses based on interview (15.7% vs 31.4%, p=0.006) and medical record (6.8% vs 17.6%, p<0.001) in farm children compared to non-farm children.
We conducted logistic regression analysis to identify relationships between early life exposures and outcomes. In the univariate analysis, farm exposure was significantly associated with a decreased risk for allergic rhinitis based on medical record (OR=0.39, 95% CI: 0.17-0.86, Figure 1A) with a similar trend based on interview (OR=0.54, 95% CI: 0.28-1.04, p=0.07, Figure 2A). Breastfeeding was significantly positively associated with allergic rhinitis based on medical record (OR=3.67, 95% CI: 1.62-8.34, Figure 1A). A family history of asthma or atopy was significantly associated with increased risk for allergic rhinitis based on interview (OR=4.05, 95% CI: 1.64-10.04, Figure 2A). Day care was significantly associated with a reduced risk of eczema based on medical record (OR=0.35, 95% CI: 0.15-0.80, Figure 1B), while early farm exposure, early household pets, and household smoking were all significantly associated with a reduced eczema risk based on interview (Figure 2B). Early farm exposure was significantly associated with reduced risk of early life severe respiratory illness based on both medical record and interview (OR=0.45, 95% CI: 0.24-0.85 [medical record]; OR=0.41, 95% CI: 0.21-0.79 [interview], Figures 1C and 2C).
Figure 1.
Early farm exposure and risk for early respiratory illness or atopic disease based on medical record. A-C. Logistic regression analysis of Univariate analysis with measured outcome noted above graph. D. Multivariable weighted logistic regression of early farm exposure using full main effects models adjusted for age (continuous), sex, family size (number of siblings), household smoking, daycare, breastfeeding, family history (atopy or asthma).
Figure 2.
Logistic regression analysis of early farm exposure and risk for early respiratory illness or atopic disease based on interview. A-C. Univariate analysis with measured outcome noted above graph. D. Multivariable weighted logistic regression of early farm exposure using full main effects models adjusted for age (continuous), sex, family size (number of siblings), household smoking, daycare, breastfeeding, family history (atopy or asthma).
In multivariable analyses controlling for age, sex, family size, household smoking, daycare, breastfeeding, and family history, early farm exposure remained a statistically significant protective factor for respiratory illness (OR=0.44, 95%CI: 0.21-0.91) and allergic rhinitis based on medical record (OR=0.33, 95%CI: 0.12-0.89, Figure 1D). Using interview data, early farm exposure was a protective factor for eczema (OR=0.30, 95% CI: 0.14-0.65, Figure 2D).
Our study confirmed previous findings that living on a farm at an early age may be protective against eczema and allergic rhinitis. In addition, Wisconsin farm children had a lower incidence of early life severe respiratory illnesses, as defined by parental recall or by the medical record. Our results are in agreement with recent studies in Western Europe, where farm exposures are inversely related to allergic disease and transient wheezing illnesses, predominantly associated with recurrent infections.7, 8, 9 Our results extend these findings to US farming exposures, and also demonstrate inverse relationships between early life farm exposures and severe respiratory illnesses. Our finding that day care attendance was not associated either with early childhood severe respiratory illness or with asthma adds to the conflicting data on this association.
A strength of our study is the near complete capture of medical events through access to an electronic medical record system which dates back to the early 1960s. One potential limitation of our findings is that our definition of severe respiratory illness was based on a clinical diagnosis and lacks pathogen detection data. Furthermore, there are some differences in findings for outcomes based on interview vs chart abstraction, possibly related to differences in ascertaining outcomes from these two sources. A prospective birth cohort study, Wisconsin Infant Study Cohort, is in progress and will help to address these shortcomings and test for additional effects of farm exposures on immune maturation, antiviral responses, and viral illnesses during early childhood. Additional studies to test whether farm exposures are related to beneficial respiratory health outcomes in minority children would also be of interest.
In summary, farming environments in Wisconsin are associated with a reduced risk for developing common childhood allergic and infectious conditions. These studies support and extend studies of traditional farming environments in Europe, and further suggest that exposure to factors related to farming may lessen susceptibility to respiratory illnesses, perhaps by promoting the development of antiviral defenses. Given the considerable morbidity caused by childhood respiratory infections and paucity of effective treatments, understanding mechanisms of these relationships is important to direct new strategies to prevent respiratory illnesses in childhood.
Supplementary Material
Supplemental Table 1. Definitions for Asthma, Allergic Disease, and Severe Respiratory Illness
Supplemental Table 2. Demographic and Early Exposure Characteristics
Supplemental Table 3. Early Farm Exposure and Atopic Diseases and Severe Respiratory Illnesses Frequency in Children with Early Farm Exposure Compared to No Farm Exposure
Acknowledgments
We are grateful for funding from the Robert G. Zach, the Marshfield Clinic Research Foundation, and NIH-NIAID grant U19 AI104317, and the project was supported by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant UL1TR000427.
Declaration of all sources of funding: The study was funded by the Marshfield Clinic Research Foundation through a major grant from the Robert G Zach Family Foundation, NIH-NIAID grant U19 AI104317, and by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant UL1TR000427.
Footnotes
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References
- 1.von Mutius E, Vercelli D. Farm living: effects on childhood asthma and allergy. Nat Rev Immunol. 2010;10:861–8. doi: 10.1038/nri2871. [DOI] [PubMed] [Google Scholar]
- 2.Schaub B, Liu J, Hoppler S, Schleich I, Huehn J, Olek S, et al. Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells. J Allergy Clin Immunol. 2009;123:774–82. doi: 10.1016/j.jaci.2009.01.056. e5. [DOI] [PubMed] [Google Scholar]
- 3.Ege MJ, Mayer M, Normand AC, Genuneit J, Cookson WOCM, Braun-Fahrlander C, et al. Exposure to environmental microorganisms and childhood asthma. NEJM. 2011 doi: 10.1056/NEJMoa1007302. [DOI] [PubMed] [Google Scholar]
- 4.Gern JE, Brooks GD, Meyer P, Chang A, Shen K, Evans MD, et al. Bidirectional interactions between viral respiratory illnesses and cytokine responses in the first year of life. J Allergy Clin Immunol. 2006;117:72–8. doi: 10.1016/j.jaci.2005.10.002. [DOI] [PubMed] [Google Scholar]
- 5.Copenhaver CC, Gern JE, Li Z, Shult PA, Rosenthal LA, Mikus LD, et al. Cytokine response patterns, exposure to viruses, and respiratory infections in the first year of life. Am.J.Respir. Crit Care Med. 2004;170:175–80. doi: 10.1164/rccm.200312-1647OC. [DOI] [PubMed] [Google Scholar]
- 6.DeStefano F, Eaker ED, Broste SK, Nordstrom DL, Peissig PL, Vierkant RA, et al. Epidemiologic research in an integrated regional medical care system: the Marshfield Epidemiologic Study Area. J Clin Epidemiol. 1996;49:643–52. doi: 10.1016/0895-4356(96)00008-x. [DOI] [PubMed] [Google Scholar]
- 7.Fuchs O, Genuneit J, Latzin P, Buchele G, Horak E, Loss G, et al. Farming environments and childhood atopy, wheeze, lung function, and exhaled nitric oxide. J Allergy Clin Immunol. 2012;130:382–8. doi: 10.1016/j.jaci.2012.04.049. e6. [DOI] [PubMed] [Google Scholar]
- 8.Loss G, Depner M, Ulfman LH, van Neerven RJ, Hose AJ, Genuneit J, et al. Consumption of unprocessed cow's milk protects infants from common respiratory infections. J Allergy Clin Immunol. 2015;135:56–62. doi: 10.1016/j.jaci.2014.08.044. [DOI] [PubMed] [Google Scholar]
- 9.Loss GJ, Depner M, Hose AJ, Genuneit J, Karvonen AM, Hyvarinen A, et al. The Early Development of Wheeze. Environmental Determinants and Genetic Susceptibility at 17q21 Am J Respir Crit Care Med. 2016;193:889–97. doi: 10.1164/rccm.201507-1493OC. [DOI] [PubMed] [Google Scholar]
Associated Data
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Supplementary Materials
Supplemental Table 1. Definitions for Asthma, Allergic Disease, and Severe Respiratory Illness
Supplemental Table 2. Demographic and Early Exposure Characteristics
Supplemental Table 3. Early Farm Exposure and Atopic Diseases and Severe Respiratory Illnesses Frequency in Children with Early Farm Exposure Compared to No Farm Exposure