In this cohort study, the association between early exposure to dogs and farm animals and the risk of asthma was evaluated and included all children born in Sweden. The association was assessed as the odds ratio (OR) for a current diagnosis of asthma at age 6 years for school-aged children and as the hazard ratio (HR) for incident asthma at ages 1 to 5 years for preschool-aged children. The primary outcome was childhood asthma diagnosis and medication used. Of the 1 011 051 children born during the study period, 376 638 preschool-aged (53 460 [14.2%] exposed to dogs and 1729 [0.5%] exposed to farm animals) and 276 298 school-aged children (22 629 [8.2%] exposed to dogs and 958 [0.3%] exposed to farm animals) were included in the analyses. Of these, 18 799 children (5.0%) in the preschool-aged children’s cohort experienced an asthmatic event before baseline, and 28 511 cases of asthma and 906 071 years at risk were recorded during follow-up (incidence rate, 3.1 cases per 1000 years at risk). In the school-aged children’s cohort, 11 585 children (4.2%) experienced an asthmatic event during the seventh year of life. Dog exposure during the first year of life was associated with a decreased risk of asthma in school-aged children (OR, 0.87; 95% CI, 0.81-0.93) and in preschool-aged children 3 years or older (HR, 0.90; 95%CI, 0.83-0.99) but not in children younger than 3 years (HR, 1.03; 95% CI, 1.00-1.07). Farm animal exposure was associated with a reduced risk of asthma in both school-aged children and preschool-aged children (OR, 0.48; 95%CI, 0.31-0.76, and HR, 0.69; 95%CI, 0.56-0.84), respectively. The authors conclude that exposure to dogs and farm animals during the first year of life reduce the risk of asthma in children at age 6 years.

Relevance: The origin and/or basis of childhood asthma have intrigued researchers for decades. About a quarter of a century back, Strachan observed a negative relationship between size of families and the development of atopic conditions [1]. He later suggested that higher levels of personal and household cleanliness were responsible for this, rather than small family size alone. In smaller families, there is less opportunity for ‘unhygienic’ contact between children and their older sibling(s) resulting in lowered incidence of infections but higher risk of atopic/allergic conditions [2]. This concept gained popularity as the ‘hygiene hypotheses’ wherein reduced exposure to microbes (through greater cleanliness, better sanitation facilities, widespread vaccination and antibiotic usage) is associated with greater risk of developing allergy/atopy. The proposed biologic explanation is the relative deficiency of a Th1 type immune response (which is associated with infections) that drives the immune system to a predominant Th2 type response which is associated with release of allergic mediators [3,4].

Some investigators explored other aspects of hygiene (or its lack) through exposure to pet animals, farm environments, farm animals etc; with variable conclusions. A recent series of systematic reviews suggested that contact with pet animals particularly dogs could reduce the risk of developing atopic dermatitis or eczema [5-7]. Similarly another systematic review documented a protective effect of early childhood (i.e., before 1 year) farm exposure on development of allergic sensitization [8]. In contrast, a detailed analysis across multiple birth cohorts in European countries failed to identify any relationship between exposure to pet animals in early childhood and later development of asthma or allergy [9]. This is contradictory to another review that suggested a protective effect of exposure to pet animals [10]. An older systematic review conversely suggested that exposure to dogs may actually increase the risk of developing asthma [11]. Of course, there are several reasons for contradictory conclusions from various reviews, including limitations with the original studies in terms of definitions, sample size, tools for outcome measurement, etc. Against this backdrop, the recent publication [12] of a large cohort study examining the relationship of exposure to pet dogs and farm animals (I=Intervention/ Exposure) in early childhood (P=Population), to later diagnosis of asthma (O=Outcome), is both timely and relevant.

Critical appraisal: Table I presents a formal critical appraisal of the study. In addition, there are some methodological refinements worth noting. In addition to the stringent inclusion and exclusion criteria, the authors tried to minimize design effect by including only one child per family in the main analysis. They also attempted to identify the effect of cessation of dog exposure among those who did and did not develop asthma. Three sensitivity analyses based on timing of exposure to dogs were conducted. Multiple additional sensitivity analyses based on definition of asthma, parental asthma status and birth order were also undertaken, making it possible to tease out some of the confounding effects observed in previous studies.

Some limitations are also worth mentioning. The methods used to ascertain exposure to the risk factors did not consider exposure to additional pets (furry or otherwise); which could also have a bearing on the outcome. The study also did not offer the opportunity to examine the effect (if any) of the so-called hypoallergenic pets. Although it may have been possible to study the effect of both risk factors together, this was not done.

The investigators could determine asthma in the seventh year, as well as pre-school age group separately; however they did not report whether the children in the latter group continued to have asthma by the seventh year of life. This would have been relatively easy, and added considerable academic and clinical value especially because the protective effects observed in this study appeared limited to older children (>3 years) despite early exposure (i.e before 1 year) to the risk factors. Although not an intended objective, this study provides valuable confirmation of asthma prevalence in Swedish children and also an estimate of incidence among pre-school age group. It also demonstrates a 2.5 fold higher prevalence of asthma among children whose parents had asthma.

Extendibility: The authors themselves point to the immediate generalizability of their results to Sweden, and potential application to European countries. However there are several challenges in extrapolating these data to India. First, the proportion of ‘asthma’ attributable to atopy versus non-atopic mechanisms is unclear. Further India represents considerable diversity in terms of living conditions, environmental exposures, and access to health-care, making it difficult to replicate this type of study across the nation. Further, the relatively unregulated use of antibiotics, vaccines, and medications for asthma could further confound the discourse on the potential emphasis of the hygiene hypothesis in our setting.

Conclusions: This well-designed nation-wide cohort study suggests that exposure to dogs in early infancy could be associated with lower prevalence of asthma at the onset of school years, although these children had higher risk of developing pneumonia. Exposure to farm animals appeared to have consistent beneficial effects.

1. Strachan DP. Hay fever, hygiene, and household size. BMJ. 1989;299:1259-60.

2. Strachan DP, Harkins LS, Johnston ID, Anderson HR. Childhood antecedents of allergic sensitization in young British adults. J Allergy Clin Immunol. 1997;99:6-12.

3. Romagnani S. The increased prevalence of allergy and the hygiene hypothesis: missing immune deviation, reduced immune suppression, or both? Immunology. 2004;112:352-63.

4. Okada H, Kuhn C, Feillet H, Bach JF. The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update. Clin Exp Immunol. 2010;160:1-9.

5. Madhok V, Futamura M, Thomas KS, Barbarot S. What’s new in atopic eczema? An analysis of systematic reviews published in 2012 and 2013. Part 2. Treatment and prevention. Clin Exp Dermatol. 2015;40:349-54.

6. Torley D, Futamura M, Williams HC, Thomas KS. What’s new in atopic eczema? An analysis of systematic reviews published in 2010-11. Clin Exp Dermatol. 2013;38:449-56.

7. Pelucchi C, Galeone C, Bach JF, La Vecchia C, Chatenoud L. Pet exposure and risk of atopic dermatitis at the pediatric age: a meta-analysis of birth cohort studies. J Allergy Clin Immunol. 2013;132:616-22.

8. Campbell BE1, Lodge CJ, Lowe AJ, Burgess JA, Matheson MC, Dharmage SC. Exposure to ‘farming’ and objective markers of atopy: a systematic review and meta-analysis. Clin Exp Allergy. 2015;45:744-57.

9. Lødrup Carlsen KC, Roll S, Carlsen KH, Mowinckel P, Wijga AH, Brunekreef B, et al. Does pet ownership in infancy lead to asthma or allergy at school age? Pooled analysis of individual participant data from 11 European birth cohorts. PLoS One. 2012;7:e43214.

10. Lodge CJ, Allen KJ, Lowe AJ, Hill DJ, Hosking CS, Abramson MJ, et al. Perinatal cat and dog exposure and the risk of asthma and allergy in the urban environment: a systematic review of longitudinal studies. Clin Dev Immunol. 2012;2012:176484.

11. Takkouche B, González-Barcala FJ, Etminan M, Fitzgerald M. Exposure to furry pets and the risk of asthma and allergic rhinitis: a meta-analysis. Allergy. 2008;63:857-64.

12. Fall T, Lundholm C, Örtqvist AK, Fall K, Fang F, Hedhammar Å, et al. Early exposure to dogs and farm animals and the risk of childhood asthma. JAMA Pediatr. 2015;169:e153219.

13. Hossny E. Treatment of Asthma in Children 5 Years and Under Based on Different Global Guidelines. Available from: http://www.worldallergy.org/professional/allergic_ diseases_center/treatment_of_asthma_in_children/. Accessed December 15, 2015.

14. Global Initiate for Asthma (GINA). Pocket Guide for Asthma Management and Prevention in Children 5 Years and Younger. Available from: http://asthmafoundation. org.nz/wp-content/uploads/2012/03/GINA_Under5_ Pocket.pdf. Accessed December 15, 2015.

15. No authors listed. The Bradford Hill Criteria. Available from: http://www.southalabama.edu/coe/bset/johnson/bonus/Ch11/Causality%20criteria.pdf. Accessed December 15, 2015.

Relevance: Asthma is a chronic respiratory disorder that has become substantially more common over the past decades. One environmental factor for which particularly strong associations with asthma and allergic diseases have been described is exposure to farming environments in childhood [1]. Recent studies have identified new ways in which viral and microbial exposures in early life interact with host genetic background/variants to modify the risk for developing asthma and allergic diseases [2]. In this nationwide cohort study, a search is made for the association between early exposure to dogs and farm animals and the risk of asthma and included all first born children in Sweden in ten years.

Critical Appraisal: This study shows dog exposure during the first year of life was associated with a decreased risk of asthma in school-aged children (OR, 0.87; 95%CI, 0.81-0.93) and in preschool-aged children 3 years or older (HR, 0.90; 95%CI, 0.83-0.99) but not in children younger than 3 years (HR, 1.03; 95%CI, 1.00-1.07). Statistically, the variations in CI, OR and HR are very marginal to suggest a definite hypothesis. It is also not explained why children younger than 3 years age did not got the protection from animal exposure. (HR, 1.03; 95%CI, 1.00-1.07).It is not clear why secondary outcomes of bronchiolitis, pneumonia and lower respiratory tract infections were considered. These diagnoses were not relevant in this study! The authors speculated that dog exposure may increase an infant’s overall exposure to microorganisms and allergens, some of which increase the risk for respiratory tract infections and others that modulate the immune system in such a way that decreases the risk of allergy-related asthma in school-aged children. This speculation has no proved support shown in this study. The limitation in the study are 1) details of different asthma phenotypes were not studied , 2) dog registry and family history of asthma and allergy were not fully covered and 3) children only during their seventh year of age were examined leaving children at other ages unevaluated.

Discussion: Susceptibility to asthma and allergic diseases is complex and involves genetic variants and environmental exposures (bacteria, viruses, smoking, and pet ownership), alteration of our microbiome and potentially large-scale manipulation of the environment over the past century [2]. Pooled analysis of individual participant data of 11 prospective European birth cohorts in 1990 showed that pet ownership in early life did not appear to either increase or reduce the risk of asthma or allergic rhinitis symptoms in children aged 6–10 years. Missing from all these studies of childhood exposures is a comprehensive longitudinal study that follows children exposed to both livestock and crop farming into their adult years. This type of study is particularly necessary, because studies have reported an increased risk of respiratory disease in adult farmers compared to non-farmers. It is currently not clear if the apparent protective effect of farm exposures in childhood persists into adulthood [3].

Clinical Application: The age-old "hygiene hypothesis" is highly debated. Based on these observations, it is not feasible to accept the inference of this study to be used in clinical practice at present. There is a need of a robust longitudinal, multi-centric (stratified through different economic and environmental conditions) trial on effect of farm animal exposure in early life in the future outcome on asthma.

1. Takkouche B, Gonzalez-Barcala FJ, Etminan M, FitzgeraldM. Exposure to furry pets and the risk of asthma and allergic rhinitis: a meta-analysis. Allergy. 2008; 63:857-64.

2. Daley D. The evolution of the hygiene hypothesis: the role of early-life exposures to viruses and microbes and their relationship to asthma and allergic diseases. Cur Opin Allergy Clin Immunol. 2014;14:390-6.

3. Naleway AL. Asthma and atopy in rural children: is farming protective? Clin Med Res. 2004; 2:5-12.

The respiratory and immune systems both continue to develop after birth and are vulnerable to both pre and post-natal environmental exposures that act on underlying genetic predisposition to asthma [1]. Family history of allergies and asthma is a major risk factor for persistent asthma. Environmental risk factors include frequent respiratory viral infections, sensitization to aeroallergens from household/ambient air pollution, second hand tobacco smoke or bio-aerosols [2]. A majority of all mammalian allergens are spread as airborne particles, and several have been detected in environments where furry animals are kept. The Can F I allergens found in canines can often induce an IgE response in humans. Among domestic pets, allergic reactions to cats are the most common [3]. The verdict on allergy to dogs and farm animals is less clear and equivocal. The association between early exposure to animals and subsequent risk for asthma is at best inconsistent and most reviews report substantial heterogeneity. The authors acknowledge that differences in study designs, age of outcome measurements, and how confounders, exposures and outcomes are assessed influence the results of the studies. An important determinant of lung function and capacity is physical environment. Children living in farms have more physical activity and less ambient air pollution which can explain better lung capacities, but this social mileu is rarely adjusted for in large cohort studies that rely on population data bases with information available on limited socio-demographic and environmental variables. Another important confounder is history of allergy to fur animals in the family. Those families with history of allergy to canines are less likely to have canine pets. Therefore it is unclear whether early exposure to canines reduces the likelihood of asthma or whether those families who have these genetic allergies are less to have pets. Individual genetic predisposition, social mileu, nutritional qualities are likely contributors to an individual child’s susceptibility to environment toxicants. So a rigorous environmental history in pediatric practice should include family history of environmental triggers, including allergies to canines.

1. Sly PD, Boner AL, Björksten B, Bush A, Custovic A, Eigenmann PA, et al. Early identification of atopy in the prediction of persistent asthma in children. Lancet. 2008;372:1100-6.

2. Landrigan PJ, Etzel RA. Asthma, allergy, and the environment. In: Landrigan PJ, Etzel RA, editors. Text Book of Children’s Environmental Health. New York: Oxford University Press; 2014.

3. Lindgren S, Belin L, Dreborg S, Einarsson R, Pahlman I. Breed-specific dog-dandruff allergens. J Allergy Clin Immunol. 1988;82:196-204.