untitled Do farm-grown lungs breathe better? Jon Genuneit,1 Erika von Mutius2 In Thorax, Campbell et al1 report an asso- ciation of growing up on a farm with better adult lung function. On closer investigation, this effect was confined to the FEV1 in female participants in the study. A novel finding and a paper worth reading—but what may be harder to glean is its relevance and implication for future research. The ‘farm-effect’ on allergic disease has been well established in numerous studies. Recent systematic reviews with meta-analyses show a strong protective effect of growing up on a farm on child- hood atopy2 and a lesser effect on child- hood asthma.3 In these meta-analyses, the effect estimates for the ‘farm-effect’ on asthma were much more heterogeneous than those on any atopic sensitisation.2 3 This may be driven by the mix of differ- ent farm exposures shown to be import- ant.4 It has also been suggested that the increased heterogeneity in estimates of the ‘farm-effect’ on asthma is partly driven by the mix of asthma phenotypes in the respective studies.3 Indeed, the present study by Campbell et al is one of the few studies presenting results completely stratified by atopy to investigate this further. Here, the authors conclude that protective effects on atopic asthma, atopic bronchial hyper- responsiveness (BHR) and atopic nasal symptoms in comparison to non-atopic subjects without asthma, BHR and nasal symptoms, respectively, exist. On closer investigation of the presented data, these associations are fully driven by the ‘farm effect’ on atopy. No separate ‘farm-effect’ on asthma, BHR or nasal symptoms shows up when comparing diseased with non-diseased separately within the two strata of atopic and non-atopic subjects. It has been previously shown that effect esti- mates for atopic asthma depend on the choice of the reference group in case of strong overall effects on atopy.5 It is remarkable that early life exposure to farming environments has sustained effects on adult atopic sensitisation. However, added effects on asthma, BHR and nasal symptoms as suggested by previ- ous studies in childhood6 and adulthood7 are not supported by the present study.1 The result of a ‘farm-effect’ on lung function has been investigated to a lesser extent, and direct comparison with previ- ous studies is hindered by differing scaling of the lung function parameters. Higher FEV1/FVC values among those growing up on a farm have been found in one pre- vious study among atopic children only6 but not in two other studies among all children.8 9 The association in the present study was attenuated after further adjust- ment, including adjustment for parental smoking, but no stratification for atopy was presented. Personal smoking did not seem to confound the association but residual confounding due to crude mea- sures of smoking history cannot be excluded. The stronger association with higher FEV1 in the present study was more apparent in women and varied across par- ticipating centres. Such an isolated lung function parameter is hard to interpret in the absence of findings for FVC and the FEV1/FVC ratio, as FEV1 can represent lung volume and airway obstruction. Whether the on-average 110 mL higher FEV1 in women who grew up on a farm can be replicated in other studies, whether this effect persists after accounting for atopy, and whether it is clinically meaning- ful remains, thus, to be elucidated. What may be more interesting in this context is the sex-specificity of the ‘farm- effect’. A stronger effect on women has been previously shown among adults10–12 as well as children and adolescents,8 13 14 although it has been reversed,15 absent or only marginally statistically significant in the data of other studies.16 17 The sex- specificity may point towards (1) unaccounted-for disease heterogeneity between women and men, (2) differing exposure to farming environments, including occupational exposure in adult life but also other exposure in early life, (3) differing confounding lifestyle factors, such as smoking and (4) differing physio- logical, hormonal or growth character- istics affecting lung physiology. Whereas personal smoking, body weight and body height have been adjusted for in the present study, other proposed factors remain as possible explanations. Age at onset of asthma may also play a role since one report on childhood and adolescence has shown that sex-specific associations of exposure to farming with asthma are age-dependent.14 Of note, the study population in the present study covers a wide age range. Although age is adjusted for, previous publications, including another one also using European Community Respiratory Health Survey (ECRHS) data, have indi- cated cohort effects.18 19 Cohort effects may exist if the mode of farming changed over time, for example, farms were recently only run part-time which attenu- ates the effect.20 21 Moreover, no infor- mation on age at onset of atopy or atopic asthma is shown. The ‘farm-effect’ docu- mented in the present study may be a sus- tained effect from childhood onwards. Alternatively, it may be an effect on later- onset atopy or atopic asthma, as indicated by data from the RHINE study which includes part of the ECRHS study popula- tion.12 Arguably, a substantial portion of adult-onset or late-onset disease may be misclassified due to lack of recall of child- hood disease in mid-adult ages. While critics may argue for alternative explanations of the ‘farm-effect’ (eg, gen- etics, access to or utilisation of healthcare), its environmental component seems estab- lished beyond reasonable doubt. One good example is the dramatic increase of atopy in a rural region of Poland accompanied by a decrease of exposure to farming during the same time.22 Another prominent example is the exploitation of two popula- tions, the Amish and the Hutterites.23 In this comparison, the model of exposure to farming environments is distilled to its environmental core. Not all protection from atopy relates to farming in this study. Campbell et al1 also define a ‘biodiversity score’ based on child- hood exposure to cats, dogs, day care, bedroom-sharing and older siblings. One might argue that the aforementioned factors are proxies for other than microbial exposures and that the simple dichotomi- sation and assumed additive effects are not the optimal operationalisation. Moreover, upbringing in a village also shows some protection, but it remains unclear whether this effect is to some extend attributable to the ‘biodiversity score’. Possibly, the effect of such a score is only discernible in inner- city environments where other outdoor exposures (eg, greenness) are lacking. Nonetheless, the analyses show that the protective ‘farm-effect’ is stronger than what individuals brought up in inner cities can experience by exposure to pets, day care and siblings. Also, given that these 1Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany; 2Dr. von Hauner Children’s Hospital, Ludwig Maximilians University Munich, Munich, Germany Correspondence to Dr Jon Genuneit, Institute of Epidemiology and Medical Biometry, Ulm University, Helmholtzstr. 22, Ulm D89081, Germany; jon.genuneit@uni-ulm.de 202 Genuneit J, von Mutius E. Thorax March 2017 Vol 72 No 3 Editorial o n A p ril 5 , 2 0 2 1 b y g u e st. P ro te cte d b y co p yrig h t. h ttp ://th o ra x.b m j.co m / T h o ra x: first p u b lish e d a s 1 0 .1 1 3 6 /th o ra xjn l-2 0 1 6 -2 0 9 2 8 0 o n 2 D e ce m b e r 2 0 1 6 . D o w n lo a d e d fro m o n A p ril 5 , 2 0 2 1 b y g u e st. P ro te cte d b y co p yrig h t. h ttp ://th o ra x.b m j.co m / T h o ra x: first p u b lish e d a s 1 0 .1 1 3 6 /th o ra xjn l-2 0 1 6 -2 0 9 2 8 0 o n 2 D e ce m b e r 2 0 1 6 . D o w n lo a d e d fro m o n A p ril 5 , 2 0 2 1 b y g u e st. P ro te cte d b y co p yrig h t. h ttp ://th o ra x.b m j.co m / T h o ra x: first p u b lish e d a s 1 0 .1 1 3 6 /th o ra xjn l-2 0 1 6 -2 0 9 2 8 0 o n 2 D e ce m b e r 2 0 1 6 . D o w n lo a d e d fro m https://www.brit-thoracic.org.uk/ http://thorax.bmj.com/ http://thorax.bmj.com/ http://thorax.bmj.com/ http://thorax.bmj.com/ exposures are probably as difficult to inter- vene on as is the place of upbringing, we should consider keeping on searching for the most important environmental expo- sures underlying the farm-effect for future preventive efforts. So, do farm-grown lungs breathe better? The present study does not add much to answer this question. But in add- ition to all the previous evidence, it is another reminder from a large-scale study that effects of childhood exposure to farming environments on atopy and thereby atopic disease may well extend into adulthood. This makes the mechan- isms underlying the ‘farm-effect’ particu- larly important for future preventive efforts. How shall we proceed? Exploring disease heterogeneity and sub-phenotypes including age at onset as well as investigat- ing sex-specificity should be added to the investigative toolbox. In addition, making use of model populations may be promis- ing in future efforts to unravel elements in the mix of exposures or pathophysio- logical mechanisms that are associated with growing up on a farm. Contributors JG and EvM drafted this manuscript together and both approved the final version. Competing interests None declared. Provenance and peer review Commissioned; externally peer reviewed. To cite Genuneit J, von Mutius E. Thorax 2017;72:202–203. Received 12 September 2016 Revised 8 November 2016 Accepted 9 November 2016 Published Online First 2 December 2016 ▸ http://dx.doi.org/10.1136/thoraxjnl-2015-208154 Thorax 2017;72:202–203. doi:10.1136/thoraxjnl-2016-209280 REFERENCES 1 Campbell B, Raherison C, Lodge CJ, et al. The effects of growing up on a farm on adult lung function and allergic phenotypes: an international population-based study. Thorax 2017;72:236–44. 2 Campbell BE, Lodge CJ, Lowe AJ, et al. Exposure to “farming” and objective markers of atopy: a systematic review and meta-analysis. Clin Exp Allergy 2015;45:744–57. 3 Genuneit J. Exposure to farming environments in childhood and asthma and wheeze in rural populations: a systematic review with meta-analysis. Pediatr Allergy Immunol 2012;23:509–18. 4 Ege MJ, Frei R, Bieli C, et al. Not all farming environments protect against the development of asthma and wheeze in children. J Allergy Clin Immunol 2007;119:1140–7. 5 Pekkanen J, Lampi J, Genuneit J, et al. 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Genuneit J, von Mutius E. Do farm-grown lungs breathe better? Thorax 2017;72:202–3. The authors include the additional Conflicts of Interest for their article: Erika von Mutius is listed as inventor on the following patents: ► Publication number EP 1411977: Composition containing bacterial antigens used for the prophylaxis and the treatment of allergic diseases. ► Publication number EP1637147: Stable dust extract for allergy protection ► Publication number EP 1964570: Pharmaceutical compound to protect against allergies and inflammatory diseases Erika von Mutius is listed as inventor and has received royalties on the following patent: ► Publication number EP2361632: Specific environmental bacteria for the protection from and/or the treatment of allergic, chronic inflammatory and/or autoimmune disorders. © author(s) (or their employer(s)) 2019. no commercial re-use. see rights and permissions. Published by bmJ. Thorax 2019;74:924. doi:10.1136/thoraxjnl-2016-209280corr1 924 Prayle AP. Thorax September 2019 Vol 74 No 9 http://crossmark.crossref.org/dialog/?doi=10.1136/thoraxjnl-2019-213903&domain=pdf&date_stamp=2019-08-10 Do farm-grown lungs breathe better? References