Review Article | Open Access
The Role of the Environmental Risk Factors in the Pathogenesis and Clinical Outcome of Atopic Dermatitis
Atopic dermatitis (AD) prevalence is rising worldwide. Literature data suggest the incidence of AD in developing countries is gradually getting close to that of developed ones, in which AD affects 20% of the paediatric population. Such an increment, associated with significant variations in prevalence among the various countries, underlines the importance of environmental factors in the disease onset. Among these, great importance is given to hygiene, intestinal microbiota, exposure to bacterial endotoxins, outdoor living with contact to animals, atmospheric pollution, weather, and diet. Genetic (alteration of the skin barrier function) as well as immunologic factors concur with the environmental ones. Only the systematical study of all these elements can best elucidate AD epidemiology.
Atopic dermatitis (AD, also atopic eczema) is the most common inflammatory disease in childhood and poses a great number of problems related to health and quality of life of patients [1–9]. An increase in the prevalence of AD is seen all over the world and accordingly causes much general interest in the identification of potential risks and protective environmental factors.
From 1990, the number of studies dedicated to the epidemiological research of AD has increased eightfold . The data about its prevalence collected by the International Study of Asthma and Allergies in Childhood (ISAAC) of 2 million children in 106 nations (the most comprehensive study of global scope) support an increase in most developing countries, in particular among 6-7-year-olds [6, 10–13]. In particular, they have been highlighted in children estimates of 10-12% throughout the United States, up to 20% in some US states [14, 15], and 7-10% in the adult population [14, 16]. A recent systematic review of 69 studies also confirmed that AD is a “worldwide phenomenon” with a life prevalence of well over 20% and a significant increase in low-income countries of Africa and East Asia [17–21].
All these studies show that the well known differences in the prevalence of AD, not only between different nations but also within the same country, are gradually levelling out as a consequence of the globalisation process . In fact, for example, after the reunification of the two Germanys, East Germany, within a short time span, saw an increase of AD from 16% in 1991 to 23.4 % in 1997 . Similar observations associated with urbanization in developing countries and migration of populations from areas with low prevalence to areas with high prevalence of AD have emerged [24, 25].
Thus, analysis of these data seems to reasonably suggest an important role of environmental factors in the pathogenic mechanism of AD together with genetic and immunologic ones.
2. Environmental Factors
Table 1 shows the risk factors that influence AD, some of them with a preventive effect, others aggravating.
Climate, a factor that potentially could explain the differences in prevalence between different populations, has received scant attention in relation to AD. Data on association with prevalence AD and temperature are conflicting [9, 26–29].
From an ISAAC Phase One study, where the variables latitude, altitude, average outside temperature, and relative outside humidity were factored in, it became apparent that symptoms of AD correlate positively with latitude and negatively with annual outside temperature . These results are confirmed by other similar studies in Spain , Taiwan , and the USA . UV light has a well known immunosuppressive effect , in part related to the fact that it facilitates the conversion of trans-urocanic acid in the filaggrin (FLG) of the skin barrier into cis-urocanic acid, with immunosuppressive effect [7, 35]. Also, because exposure to the sun/UVB increases serum levels of vitamin D, it can logically be assumed that the clinical improvement of AD through sun exposure can be mediated at the molecular level by the same vitamin. This data point is supported by the observation that vitamin D deficiency is associated with the presence of more severe AD manifestations in skin areas not exposed to light, which demonstrates a protective local effect of vitamin D . Low outside temperatures, especially in combination with skin irritants, are responsible for an aggravation of eczema . It is also true, however, that in some cases an aggravation of the disease occurrs during the summer . The climatic factors, therefore, need further study, also in relationship with pollen and skin barrier function.
2.2. Urban vs Rural Life
It is known that in populations of the same ethnicity and genetic background the risk of AD is higher in cities than in the countryside . This contrast between city and country life is supported by the systematic review of 26 studies . Environmental risk factors, which need to be considered relevant, are urbanisation, differences in hygiene, microbial infections, vaccination, use of antibiotics, environmental pollution, exposure to allergens, and diet. Further studies are needed in order to identify the risk factors of urban living in development of AD.
Given the fact that AD is still not very common in developing countries, we can ask if a “Western diet” (i.e., high intake of refined cereals, red and preserved meats, and saturated and unsaturated fatty acids) is a possible contributor to the increase in the disease. One ISAAC Phase Three study showed a significant protective effect of the frequent intake of fresh fruit (1-2x/week) and an aggravating effect of fast-food intake (≥ 3x/week) . Another ISAAC study came to similar conclusions, highlighting an inverse association between the prevalence of AD and the per capita intake of vegetables, cereal proteins, and fresh and frozen fish . This is confirmed in other studies, which show that a high intake of fish during pregnancy lowers the risk of AD in the first 5 years of life by 25-43% [42, 43]. A similar risk reduction was also reported in children with high intake of fish during late childhood [44, 45]. The protective effect of fish can be attributed to its high content in n-3 polyunsaturated fatty acids (n-3 PUFA), which is positively correlated with anti-inflammatory activity. The Western diet of the last decades is poor in n-3 PUFA, while proinflammatory n-6 PUFA, such as linoleic acid, is increased . This hypothesis is corroborated by studies showing that maternal consumption of n-6 PUFA during pregnancy is associated with an increase of AD in Japanese children of 2 years of age, and the consumption of margarine rather than butter in children leads to an increase of AD [40, 46, 47].
Despite some conflicting results [48, 49], case-controlled studies of AD sufferers have shown higher blood levels of linoleic acid (precursor of n-6 PUFA) and lower levels of n-3 PUFA [50, 51]. However, from studies in literature concerning the effects of diet on AD [52–56] emerges that a strict diet management is not effective in general in the treatment of AD . Further studies are therefore needed in this regard .
2.4. Breastfeeding and Weaning
It is a common belief that breastfeeding prevents allergies, including AD. The World Health Organization (WHO), in fact, recommends exclusive breastfeeding for the first 6 months and the European Ministries of Health advise the same, i.e., exclusive breastfeeding for at least 4 months, to prevent allergies [58, 59]. However, ISAAC Phase two studies conducted both in developed and in developing countries including 51.119 school-age children show only modest support for this thesis . Systematic research on various populations also did not show a statistically significant benefit of exclusive breastfeeding [61–66]. Further studies are necessary to determine the role of breastfeeding in childhood AD and the relation between breastfeeding and introducing solid foods.
2.5. Obesity and Exercise
A growing number of children in affluent societies are overweight. Various research suggests both an association and a dissociation between obesity and AD [67–78]. Even time spent in front of television (≥5 hours) has a positive association with the risk of AD, the same being stronger in obese vs overweight vs underweight/normal children with respect to time of exposure and response . It remains to be established whether these positive associations are causal, e.g., linked to inflammation of adipokines (molecules synthesised and secreted by adipose tissue), such as leptin and adiponectins, or related to dietary factors, that may encourage the development of AD through oxidative stress, since diets that exclude antioxidant foods, such as fruits and vegetables, are related to an increase in obesity and AD.
2.6. Air Pollution
Air pollution is the source of a wide variety of substances derived from industrial and nonindustrial processes. In normal conditions, air pollution usually excludes derivatives of natural phenomena such as volcanic eruptions and smoke of spontaneous forest fires, or radioactive material from military tests, and batteries. Mould and spores, however, are sometimes included because of the allergological damage they cause in a large population segment . Air pollutants can originate from indoor and outdoor environments and can penetrate the skin, binding to the stratum corneum, entering the systemic circulation .
Since a large portion of AD cases, about 1/3, is observed in the first year of life, it is imperative to consider the impact of prenatal exposure to air pollution. In a rather complex study involving 469 pregnant women, prenatal exposure to fine particulate matter (PM 2.5) and consequently postnatal exposure to the same and to cigarette smoke were monitored every 3 months for 1 year . It showed that the prevalence of AD during the first year of life doubles in presence of a high prenatal exposure to fine particulate matter and postnatal exposure to tobacco smoke. It also showed that high amounts of fish intake (>205g/week) rich in n-3 PUFA with anti-inflammatory action during pregnancy reduce the risk of AD by 25-43%. The same risk is further reduced when the intake of fish continues in the first years of life .
Another long-term study conducted with sufferers of AD in early childhood (from 3 months to 8 years) which took into account a variety of daily parameters (NO2, particulate matter, volatile organic compounds such as benzene, toluene, xylene, and styrene, temperature, and relative humidity), showed a significant SCORAD deterioration in the presence of high concentrations of particulate matter, toluene, and other volatile organic compounds. In particular, AD got worse in spring with high levels of styrene, in summer with high levels of toluene and NO2, in autumn with high levels of volatile organic compounds, and in winter with high levels of fine particulate matter . These data were confirmed by other researches [84–88].
Confirming the “outdoors” observations above, a move “indoors” into a clean house (reduction of fine particulate matter from 182,7 to 73.4 μg/ m3) and a hospital (in a “low pollutant room” after just 3-4 days) significantly improves the SCORAD of AD sufferers [89, 90]. A Swedish study showed a dose-dependent association between AD and lower ventilation in the houses, in particular, in the child’s bedrooms . A German study found association between indoor renovation activities (painting, floor covering, and new furniture) before birth and in the first years of life and lifetime prevalence of AD, likely in connection with high levels of volatile organic compounds (VOCs) . Cleanliness that needs to take into consideration chemical, physical, and biotic (dust, mites, microorganisms, particulates, volatile organic compounds, temperature, and relative humidity) parameters should be observed not only in the home and in hospitals, but also in kindergartens and schools. From the aforementioned data, it is clear that outdoor and indoor pollution can trigger and/or exacerbate AD.
The biomechanism of the effect of particulate matter is not entirely clear. It contains a great variety of toxic substances (polycyclic aromatic hydrocarbons, tobacco smoke, alloy smoke, and organic compounds derived from traffic, sulfates, nitrates, and metals). In particular, fine particulate matter crosses through the placenta, the skin, and the respiratory tract, has a slow index of sedimentation (and therefore remains suspended in the air for a long time), and has a “carrier” effect for dust mites and pollen due to its ability to link to proteins. Prenatal exposure to polycyclic hydrocarbons has various negative effects, such as the production of free radicals, activation of apoptosis, and the production of IgE and Th2 cytokine. Postnatal exposure increases the effects of prenatal exposure and likely damages the skin barrier, with a resulting inflammatory process [82–84, 93–99].
2.7. Tobacco Smoke
A controlled case study (83 patients/142 control subjects) showed a direct relationship between the cumulative number of cigarettes and the onset and/or worsening of AD in adults . The same significant relationship between environmental tobacco smoke and AD onset was also highlighted in nonsmokers. It is known that AD in adults more often takes on clinical character such as prurigo, involving especially the face and hands, and is associated with high values of IgE, asthma, and allergic rhinitis. From various studies it emerges that AD is significantly associated with active and passive smoking also in adolescents [101–106]. Under an immunological profile, tobacco smoke increases the levels of proinflammatory cytokines and reduces those of anti-inflammatory cytokines ; it causes oxidative damage, decreases skin barrier function [107, 108], and has an irritant effect on the skin .
Measured daily for about 2 years from 10 am to 6 pm, an excess of ozone (formed by the action of UV rays on the oxygen of the air) aggravates various skin conditions, thus requiring a greater number of visits to the doctor. After 7 days of increased ozone levels there is a significant increase of 3,84% of visits for AD, of 2.86% for contact dermatitis, and of 0.8% for urticaria . Ozone is a highly unstable and therefore very reactive oxidant; it reacts with the biomolecules of the skin and forms ozonides and free radicals. Low nontoxic doses of ozone increase the production of antioxidants, while high doses act as a proinflammatory cytokine [109, 110].
2.9. Skin Barrier and Allergic Sensitization
Recently, the strong association between genetic mutations of FLG in the epidermal barrier and atopy has attracted considerable interest with regard to the role, which alterations of this barrier might play in the development of AD and sensitisation [111–113]. The current hypothesis is that in subjects without skin barrier defects the epidermis is in a state of integrity with resulting normal “transepidermal water loss” (TEWL) and adequate protection from microorganisms and environmental allergens. Genetic mutations of FLG increase TEWL and are associated with sensitisation to aeroallergens and food [114–118]. In a similar context, the skin barrier acts as a mediator of sensitisation, which therefore becomes predominantly a “secondary phenomenon” in AD and a significant cause of aggravation and chronicity of the same.
2.10. Microbial Exposure
In two recent literature reviews, the relationship between microbial exposure and the risk of AD has been studied [119, 120]. The argument of the risk of the disease inversely related to hygiene has been widely studied in response to observations in different scenarios since the end of the 1980s [9, 121–124].
Many studies concerning the risk factors in AD regard the “hygiene hypothesis.” One study conducted on a very large cohort (> 10,000) of infants, which took into account the level of hygiene at 15 months (frequency of washing, use of household detergents, and baby wipes), showed a proportional increase in the risk of diseases between the age of 2.5 and 3.5 years with an increased level of hygiene . One Japanese study, on the contrary, on a cohort of 865 subjects, has found an inverse relationship between daily baths or showers vs less frequent ones .
2.10.2. Daycare Centers
The stay in nurseries seems to be associated with increased microbial exposure, in particular with respiratory infections, and some authors have reported a reduction in the risk of AD in children attending daycare in the first year of life [127, 128]. Others, however, have found the opposite effect [129, 130].
2.10.3. Animals and Farm Life
Various studies conducted in this area did not show a convincing protective effect of this lifestyle [131–137]. It is a very interesting fact that the consumption of unpasteurized farm milk during the first 2 years of life is an independent protective factor against the development of AD, even in families not living in the countryside. This inverse relationship is also independent from a family history of allergies. With boiling, cow’s milk loses its protective effect [134, 138, 139]. The mechanism of this protective effect remains uncertain and could be related to microbial contamination or other constituents of nonprocessed milk [139–141]. It has also been shown that direct contact with farm animals reduces the risk of AD in the first years of life, in particular where the mothers have regular contact with farm animals during pregnancy; this protective effect appears even more pronounced in those exposed during their prenatal life rather than postnatally [135, 136, 142], confirming that innate immunity may have a particular importance. This is causal for the well known argument about the contrast between “country child” compared to “city child.”
Many studies have been conducted on this subject [143–147]. They all found dogs to have a protective effect, especially in the first years of life [147, 148]. The role of cats is not as clear: where the mutations of FLG of the skin barrier are considered, there is a significantly higher risk of AD in those with mutations compared to children without mutations, suggesting that cat sensitisation may be favoured by a compromised skin barrier, which in turn contributes to the risk of AD [145, 146, 149].
2.10.5. Bacterial Endotoxins
Risk reduction through the exposure to farm animals and dogs, in particular during pregnancy, is attributed to endotoxins (lipopolysaccharides on the surface of Gram-negative bacteria), also because they are known to induce IL-10 and INF-gamma . Cohort studies have shown a risk reduction of AD of up to 50% with exposure to bacterial endotoxins [151–153], with the effect limited to high levels of exposure and/or the first year of life [151, 152].
The protective effect of helminth infections (Ascaris lumbricoides) on AD risk was demonstrated in a double-blind randomised controlled study with antiparasitic therapy conducted on more than 2500 pregnant women in an endemic helminth area in Uganda (these situations are today endemic in tropical areas due to lack of hygiene) during the last trimester of pregnancy: the AD risk up to the first year of life is increased by about 2 times in the treated group . It was also observed that lack of exposure to helminths seems to have no effect in subsequent years of life, confirming that the innate immune system protects from the risk of AD [155, 156].
2.10.7. Paediatric Infections and Vaccinations
A recent analysis of respiratory viral infections showed an AD risk reduction associated with prenatal exposure to the same infections, in particular in the last trimester of pregnancy and in the first 7 months of postnatal life . Other studies, however, have not confirmed the same results [158, 159]. As far as viral and bacterial childhood infections (chicken pox, mumps, measles, and whooping cough) are concerned, the majority of studies show positive observations or no correlation [160–165].
The antibiotics used in respiratory, gastrointestinal, and aural infections, rather than the infections themselves, are causally responsible for the risk of AD development . The same risk is increased by 41% in those receiving at least one cycle of antibiotics in the first years of life . There is also a significant dose-related association with an increased risk of 7% for each additional cycle of antibiotics with a particularly strong effect of broad-spectrum antibiotics . It is possible that the increase in risk from antibiotics is due to microbiome alterations in the host, with a subsequent alteration of the immune system or an increased immunological response to environmental allergens.
2.10.9. Microbiome of the Intestinal Tract and the Skin
The intestinal microflora of children in the first years of life that subsequently develop AD has mostly Staphylococcus aureus and coliform bacteria and less lactobacillus and bifidobacteria [169, 170]. After intrauterine sterility, skin, intestines, and respiratory tract are colonised immediately after birth by a broad spectrum of bacterial agents . Various studies analyze the effect of the gut microbiota on the onset and severity of AD. However, the results of these studies are conflicting: some are in favor of a positive effect of probiotics on the severity of AD, with concomitant alteration in the gut microbial composition; others show no effects of probiotics on the severity of AD despite a concomitant change in the gut microbial composition [172–178]. According to some studies, the subjects with AD have a different gut microbiome compared to healthy individuals, while according to others there would be no differences. Various reasons can explain these conflicting results: methodological differences, difficulties in isolation and identification of gut bacterial species, and complexity of interaction between the gut microbiota and external factors . Therefore the role of the gut microbiome in AD remains rather controversial; further studies are needed in this regard .
3. Interaction between Environmental Factors, Genetic Factors, and Immune System
To better understand the various problems so far exposed, it is important to study the relationship between environmental factors, genetic factors, and immunological factors. In addition to those genetic factors involving FLG, there must be an involvement of other genes, since more than 50% of subjects with AD do not show FLG mutations [179, 180]. Another example of genetic-environmental interaction is provided by the observation that exposure to endotoxins reduces the risk of AD and sensitisation only in subjects with a specific phenotype of the lipopolysaccharide receptor CD14 encoded in chromosome 5q31.1 . Along the same line, other studies on the impact of environmental exposure to farm life in the first years of life showed a strong innate immunity response through the regulation of the expression of CD14, TLR2, TLR4, TLR5, and TLR9 receptors, not only at the level of peripheral blood cells, but also in leukocytes in the blood of the umbilical cord, with dose-related effect in response to exposure to a high number of farm animals and consumption of unpasteurized milk [139, 142, 181]. These results are confirmed in the observation that maternal consumption of unpasteurized cow's milk modulates the production of cytokines in young age children .
The epidemiology of AD has made considerable progress in recent years with studies on a global scale. Surely, the more the conducted studies are, the more complex this disease appears: we expect them to have to do with several distinct entities with the same clinical manifestations rather than with a single disease. The increasing global prevalence of AD cannot be attributed to genetics alone, suggesting that environmental factors may trigger or flare dermatitis in predisposed subjects. On the other hand, it is doubtful that the environment exposure that is harmful in AD may be sufficient to cause the affliction without the underlying predisposition. Rather, environmental risk factors have pruritogen and inflammatory action, besides worsening skin barrier function. The future research, therefore, should be addressed to study in depth the gene-environmental interaction in order to better understand the complex pathophysiology of AD.
Understanding the mechanisms of the environmental risk factors is crucial for the therapeutic targets and the prevention of the disease. For example, recognition of the role of microbiome or exposure to climate, food, and other exogenous factors may result, respectively, in new treatment approaches  and new treatment strategies to prevent flares . Other main areas for future research are furthermore the protective effect of the unprocessed cow’s milk and helminth parasites .
In conclusion, the pathophysiology of AD seems more complex than up to now recognized. It is mandatory over the next future to define the role of the various inflammatory pathways, as well as the impact of environmental risk factor on cutaneous inflammation in AD. New methods for assessing the genotypes and clinical phenotypes of AD will allow to identify the various patient subsets with regard to the various protective and aggravating environmental factors which enter into the determinism of the disease [9, 184].
Conflicts of Interest
The authors declare that they have no conflicts of interest.
- A. M. Drucker, A. R. Wang, W. Li et al., “The burden of atopic dermatitis: summary of a report for the national eczema association,” Journal of Investigative Dermatology, 2016.
- J. G. Holm, T. Agner, M.-L. Clausen, and S. F. Thomsen, “Quality of life and disease severity in patients with atopic dermatitis,” Journal of the European Academy of Dermatology and Venereology, vol. 30, no. 10, pp. 1760–1767, 2016.
- H. J. Jang, S. Hwang, Y. Ahn, D. H. Lim, M. Sohn, and J. H. Kim, “Family quality of life among families of children with atopic dermatitis,” Asia Pacific Allergy, vol. 6, no. 4, p. 213, 2016.
- R. J. G. Arnold, A. Donnelly, L. Altieri, K. S. Wong, and J. Sung, “Assessment of outcomes and parental effect on quality-of-life endpoints in the management of atopic dermatitis,” Managed Care Interface, vol. 20, no. 2, pp. 18–23, 2007.
- L. J. Meltzer and M. Moore, “Sleep disruptions in parents of children and adolescents with chronic illnesses: Prevalence, causes, and consequences,” Journal of Pediatric Psychology, vol. 33, no. 3, pp. 279–291, 2008.
- E. L. Simpson, A. D. Irvine, L. F. Eichenfield et al., “Update on epidemiology, diagnosis, and disease course of atopic dermatitis,” Seminars in Cutaneous Medicine and Surgery, vol. 35, no. 5S, pp. S84–S88, 2016.
- C. Flohr and J. Mann, “New insights into the epidemiology of childhood atopic dermatitis,” Allergy: European Journal of Allergy and Clinical Immunology, vol. 69, no. 1, pp. 3–16, 2014.
- A. Patrizi, G. Girolomoni, and C. Gelmetti, Linee Guida E Raccomandazioni SIDeMaST, Pacini, Pisa, Italy, 2014.
- R. Kantor and J. I. Silverberg, “Environmental risk factors and their role in the management of atopic dermatitis,” Expert Review of Clinical Immunology, vol. 13, no. 1, pp. 15–26, 2017.
- H. Williams, C. Robertson, A. Stewart et al., “Worldwide variations in the prevalence of symptoms of atopic eczema in the international study of asthma and allergies in childhood,” The Journal of Allergy and Clinical Immunology, vol. 103, pp. 125–138, 1999.
- M. I. Asher, S. Montefort, B. Björkstén et al., “Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys,” The Lancet, vol. 368, no. 9537, pp. 733–743, 2006.
- N. B. Silverberg, “A practical overview of pediatric atopic dermatitis, part 1: epidemiology and pathogenesis,” Cutis; Cutaneous Medicine for the Practitioner, vol. 97, no. 4, pp. 267–271, 2016.
- J. A. Odhiambo, H. C. Williams, T. O. Clayton, C. F. Robertson, and M. I. Asher, “Global variations in prevalence of eczema symptoms in children from ISAAC phase three,” The Journal of Allergy and Clinical Immunology, vol. 124, no. 6, pp. 1251–1258, 2009.
- J. I. Silverberg and E. L. Simpson, “Association between severe eczema in children and multiple comorbid conditions and increased healthcare utilization,” Pediatric Allergy and Immunology, vol. 24, no. 5, pp. 476–486, 2013.
- T. E. Shaw, G. P. Currie, C. W. Koudelka, and E. L. Simpson, “Eczema prevalence in the United States: Data from the 2003 national survey of children’s health,” Journal of Investigative Dermatology, vol. 131, no. 1, pp. 67–73, 2011.
- J. I. Silverberg, N. K. Garg, A. S. Paller, A. B. Fishbein, and P. C. Zee, “Sleep disturbances in adults with eczema are associated with impaired overall health: A US population-based study,” Journal of Investigative Dermatology, vol. 135, no. 1, pp. 56–66, 2015.
- I. A. G. Deckers, S. McLean, S. Linssen, M. Mommers, C. P. van Schayck, and A. Sheikh, “Investigating international time trends in the incidence and prevalence of atopic eczema 1990–2010: a systematic review of epidemiological studies,” PLoS ONE, vol. 7, article e39803, 2012.
- Y.-K. Tay, K.-H. Kong, L. Khoo, C.-L. Goh, and Y.-C. Giam, “The prevalence and descriptive epidemiology of atopic dermatitis in Singapore school children,” British Journal of Dermatology, vol. 146, no. 1, pp. 101–106, 2002.
- Y. Belyhun, A. Amberbir, G. Medhin et al., “Prevalence and risk factors of wheeze and eczema in 1-year-old children: The Butajira birth cohort, Ethiopia,” Clinical & Experimental Allergy, vol. 40, no. 4, pp. 619–626, 2010.
- H. Sugiura, N. Umemoto, H. Deguchi et al., “Prevalence of childhood and adolescent atopic dermatitis in a Japanese population: Comparison with the disease frequency examined 20 years ago,” Acta Dermato-Venereologica, vol. 78, no. 4, pp. 293-294, 1998.
- A. Kanwar and D. De, “Epidemiology and clinical features of atopic dermatitis in India,” Indian Journal of Dermatology, vol. 56, no. 5, pp. 471–475, 2011.
- C. Flohr, S. K. Weiland, G. Weinmayr et al., “The role of atopic sensitization in flexural eczema: findings from the international study of asthma and allergies in childhood phase two,” The Journal of Allergy and Clinical Immunology, vol. 121, no. 1, pp. 141–147, 2008.
- T. Schäfer, U. Krämer, D. Vieluf, D. Abeck, H. Behrendt, and J. Ring, “The excess of atopic eczema in East Germany is related to the intrinsic type,” British Journal of Dermatology, vol. 143, no. 5, pp. 992–998, 2000.
- C. Burrel-Morris and H. C. Williams, “Atopic dermatitis in migrant populations,” in Atopic Dermatitis: The Epidemiology, Causes and Prevention of Atopic Eczema, H. C. Williams, Ed., pp. 169–182, Cambridge University Press, 2000.
- C. Flohr, “Is there a rural/urban gradient in the prevalence of eczema?” British Journal of Dermatology, vol. 162, article 951, 2010.
- K. A. Engebretsen, J. D. Johansen, S. Kezic, A. Linneberg, and J. P. Thyssen, “The effect of environmental humidity and temperature on skin barrier function and dermatitis,” Journal of the European Academy of Dermatology and Venereology, vol. 30, no. 2, pp. 223–249, 2016.
- J. P. Thyssen, M. J. Zirwas, and P. M. Elias, “Potential role of reduced environmental UV exposure as a driver of the current epidemic of atopic dermatitis,” The Journal of Allergy and Clinical Immunology, vol. 136, no. 5, pp. 1163–1169, 2015.
- G. H. Nguyen, L. K. Andersen, and M. D. Davis, “Climate change and atopic dermatitis: is there a link?” International Journal of Dermatology, vol. 58, no. 3, pp. 279–282, 2019.
- P. Kathuria and J. I. Silverberg, “Association of pollution and climate with atopic eczema in US children,” Pediatric Allergy and Immunology, vol. 27, no. 5, pp. 478–485, 2016.
- S. K. Weiland, A. Hüsing, D. P. Strachan, P. Rzehak, and N. Pearce, “Climate and the prevalence of symptoms of asthma, allergic rhinitis, and atopic eczema in children,” Occupational and Environmental Medicine, vol. 61, no. 7, pp. 609–615, 2004.
- M. M. Suárez-Varela, L. García-Marcos Alvarez, M. D. Kogan et al., “Climate and prevalence of atopic eczema in 6- to 7-year-old school children in Spain. ISAAC PhASE III,” International Journal of Biometerology, vol. 52, no. 8, pp. 833–840, 2008.
- Y.-L. Lee, H.-J. Su, H.-M. Sheu, H.-S. Yu, and Y. L. Guo, “Traffic-related air pollution, climate, and prevalence of eczema in Taiwanese school children,” Journal of Investigative Dermatology, vol. 128, no. 10, pp. 2412–2420, 2008.
- J. I. Silverberg, J. Hanifin, and E. L. Simpson, “Climatic factors are associated with childhood eczema prevalence in the United States,” Journal of Investigative Dermatology, vol. 133, no. 7, pp. 1752–1759, 2013.
- G. Byremo, G. Rød, and K. H. Carlsen, “Effect of climatic change in children with atopic eczema,” Allergy: European Journal of Allergy and Clinical Immunology, vol. 61, no. 12, pp. 1403–1410, 2006.
- H. Miajlovic, P. G. Fallon, A. D. Irvine, and T. J. Foster, “Effect of filaggrin breakdown products on growth of and protein expression by Staphylococcus aureus,” The Journal of Allergy and Clinical Immunology, vol. 126, no. 6, pp. 1184–1190, 2010.
- M. Vestita, A. Filoni, M. Congedo, C. Foti, and D. Bonamonte, “Vitamin D and atopic dermatitis in childhood,” Journal of Immunology Research, vol. 2015, Article ID 257879, 7 pages, 2015.
- U. Krämer, S. Weidinger, U. Darsow, M. Möhrenschlager, J. Ring, and H. Behrendt, “Seasonality in symptom severity influenced by temperature or grass pollen: Results of a panel study in children with eczema,” Journal of Investigative Dermatology, vol. 124, no. 3, pp. 514–523, 2005.
- T. Hugg, R. Ruotsalainen, M. S. Jaakkola, V. Pushkarev, and J. J. Jaakkola, “Comparison of allergic diseases, symptoms and respiratory infections between Finnish and Russian school children,” European Journal of Epidemiology, vol. 23, no. 2, pp. 123–133, 2008.
- M. E. Schram, A. M. Tedja, R. Spijker, J. D. Bos, H. C. Williams, and P. I. Spuls, “Is there a rural/urban gradient in the prevalence of eczema? A systematic review,” British Journal of Dermatology, vol. 162, no. 5, pp. 964–973, 2010.
- P. Ellwood, M. I. Asher, L. García-Marcos et al., “ISAAC phase III study group. Do fast foods cause asthma, rhinoconjunctivitis and eczema? global findings from the international study of asthma and allergies in childhood (ISAAC) phase three,” Thorax, vol. 68, no. 4, pp. 351–360, 2013.
- P. Ellwood, M. I. Asher, B. Björkstén, M. Burr, N. Pearce, and C. F. Robertson, “Diet and asthma, allergic rhinoconjunctivitis and atopic eczema symptom prevalence: an ecological analysis of the international study of asthma and allergies in childhood (ISAAC) data,” European Respiratory Journal, vol. 17, no. 3, pp. 436–443, 2001.
- S. M. Willers, G. Devereux, L. C. A. Craig et al., “Maternal food consumption during pregnancy and asthma, respiratory and atopic symptoms in 5-year-old children,” Thorax, vol. 62, no. 9, pp. 773–779, 2007.
- I. Romieu, M. Torrent, R. Garcia-Esteban et al., “Maternal fish intake during pregnancy and atopy and asthma in infancy,” Clinical & Experimental Allergy, vol. 37, no. 4, pp. 518–525, 2007.
- B. Alm, N. Åberg, L. Erdes et al., “Early introduction of fish decreases the risk of eczema in infants,” Archives of Disease in Childhood, vol. 94, no. 1, pp. 11–15, 2009.
- T. Oien, O. Storro, and R. Johnsen, “Do early intake of fish and fish oil protect against eczema and doctor-diagnoses asthma at 2 year of age? A cohort study,” Journal of Epidemiology & Community Health, vol. 64, no. 2, pp. 124–129, 2010.
- S. Sausenthaler, I. Kompauer, M. Borte et al., “Margarine and butter consumption, eczema and allergic sensitization in children. The LISA birth cohort study,” Pediatric Allergy and Immunology, vol. 17, no. 2, pp. 85–93, 2006.
- Y. Miyake, S. Sasaki, K. Tanaka, S. Ohfuji, and Y. Hirota, “Maternal fat consumption during pregnancy and risk of wheeze and eczema in Japanese infants aged 16-24 months: The Osaka Maternal and Child Health Study,” Thorax, vol. 64, no. 9, pp. 815–821, 2009.
- R. M. Stoney, R. K. Woods, C. S. Hosking, D. J. Hill, M. J. Abramson, and F. C. Thien, “Maternal breast milk long-chain n-3 fatty acids are associated with increased risk of atopy in breastfed infants,” Clinical Experimental Allergy, vol. 34, no. 2, pp. 194–200, 2004.
- A. J. Lowe, F. C. Thien, R. M. Stoney et al., “Associations between fatty acids in colostrum and breast milk and risk of allergic disease,” Clinical & Experimental Allergy, vol. 38, pp. 1745–1751, 2008.
- S. O. Shaheen, R. B. Newson, A. J. Henderson, P. M. Emmett, A. Sherriff, and M. Cooke, “Umbilical cord trace elements and minerals and risk of early childhood wheezing and eczema,” European Respiratory Journal, vol. 24, no. 2, pp. 292–297, 2004.
- R. B. Newson, S. O. Shaheen, A. J. Henderson et al., “Umbilical cord and material blood red cell fatty acids and early childhood wheezing and eczema,” The Journal of Allergy and Clinical Immunology, vol. 114, no. 3, pp. 531–537, 2004.
- T. Bronsnick, E. C. Murzaku, and B. K. Rao, “Diet in dermatology: part I. atopic dermatitis, acne, and nonmelanoma skin cancer,” Journal of the American Academy of Dermatology, vol. 71, no. 6, pp. 1039.e1–1039.e2, 2014.
- J. Chung, S.-O. Kwon, H. Ahn, H. Hwang, S.-J. Hong, and S.-Y. Oh, “Association between dietary patterns and atopic dermatitis in relation to GSTM1 and GSTT1 polymorphisms in young children,” Nutrients, vol. 7, no. 11, pp. 9440–9452, 2015.
- C. Tait and R. D. Goldman, “Dietary exclusion for childhood atopic dermatitis,” Canadian Family Physician, vol. 61, no. 7, pp. 609–611, 2015.
- S. Y. Kim, S. Sim, B. Park, J. Kim, H. G. Choi, and K. N. Dileepan, “High-fat and low-carbohydrate diets are associated with allergic rhinitis but not asthma or atopic dermatitis in children,” PLoS ONE, vol. 11, article e0150202, 2016.
- M. Schlichte, A. Vandersall, and R. Katta, “Diet and eczema: a review of dietary supplements for the treatment of atopic dermatitis,” Dermatology Practical & Conceptual, vol. 6, no. 3, pp. 23–29, 2016.
- N. R. Lim, M. E. Lohman, and P. A. Lio, “The role of elimination diets in atopic dermatitis—a comprehensive review,” Pediatric Dermatology, vol. 34, no. 5, pp. 516–527, 2017.
- WHO: Global Strategy for Infant and Young Child Feeding, World Health Organization, Geneva, Switzerland, 2002.
- C. Flohr, G. Nagel, G. Weinmayr, A. Kleiner, D. P. Strachan, and H. C. Williams, “Lack of evidence for a protective effect of prolonged breastfeeding on childhood eczema: lessons from the international study of asthma and allergies in childhood (ISAAC) phase two,” British Journal of Dermatology, vol. 165, no. 6, pp. 1280–1289, 2011.
- Y. W. Yang, C. L. Tsai, and C. Y. Lu, “Exclusive breastfeeding and incident atopic dermatitis in childhood: A systematic review and meta-analysis of prospective cohort studies,” British Journal of Dermatology, vol. 161, no. 2, pp. 373–383, 2009.
- H.-Y. Wang, M. M. M. Pizzichini, A. B. Becker et al., “Disparate geographic prevalences of asthma, allergic rhinoconjunctivitis and atopic eczema among adolescents in five Canadian cities,” Pediatric Allergy and Immunology, vol. 21, no. 5, pp. 867–877, 2010.
- C. M. Blattner and J. E. Murase, “A practice gap in pediatric dermatology: Does breast-feeding prevent the development of infantile atopic dermatitis?” Journal of the American Academy of Dermatology, vol. 71, no. 2, pp. 405-406, 2014.
- C. Little, C. Blattner, and J. Young, “Can breastfeeding and maternal diet prevent atopic dermatitis?” Dermatology Practical & Conceptual, vol. 7, no. 3, pp. 63–65, 2017.
- F. Turati, P. Bertuccio, C. Galeone et al., “Early weaning is beneficial to prevent atopic dermatitis occurrence in young children,” Allergy, vol. 7, pp. 878–888, 2016.
- J. H. Kim, “Role of breast-feeding in the development of atopic dermatitis in early childhood,” Allergy, Asthma & Immunology Research, vol. 9, no. 4, pp. 285–287, 2017.
- J. E. Lee, K. R. Kim, K. S. Rha et al., “Prevalence of ocular symptoms in patients with allergic rhinitis: korean multicenter study,” The Journal of Allergy and Clinical Immunology, vol. 27, pp. e135–e139, 2013.
- T. Yao, L. Ou, K. Yeh et al., “Associations of age, gender, and bmi with prevalence of allergic diseases in children: patch study,” Journal of Asthma & Allergy Educators, vol. 48, no. 5, pp. 503–510, 2011.
- C. S. Murray, D. Canoy, I. Buchan et al., “Body mass index in young children and allergic disease: Gender differences in a longitudinal study,” Clinical & Experimental Allergy, vol. 41, no. 1, pp. 78–85, 2011.
- J. I. Silverberg, E. Kleiman, H. Lev-Tov et al., “Association between obesity and atopic dermatitis in childhood: a case-control study,” The Journal of Allergy and Clinical Immunology, vol. 127, no. 5, pp. 1180–1186, 2011.
- J. I. Silverberg, N. B. Silverberg, and M. Lee-Wong, “Association between atopic dermatitis and obesity in adulthood,” British Journal of Dermatology, vol. 166, no. 3, pp. 498–504, 2012.
- A. J. Sybilski, F. Raciborski, A. Lipiec et al., “Obesity - A risk factor for asthma, but not for atopic dermatitis, allergic rhinitis and sensitization,” Public Health Nutrition, vol. 18, no. 3, pp. 530–536, 2015.
- S.-B. Lonne-Rahm, I. Sundström, K. Nordlind, and L.-M. Engström, “Adult atopic dermatitis patients and physical exercise: A Swedish questionnaire study,” Acta Dermato-Venereologica, vol. 94, no. 2, pp. 185–187, 2014.
- K. K. Byberg, G. E. Eide, M. R. Forman et al., “Body mass index and physical activity in early childhood are associated with atopic sensitization, atopic dermatitis and asthma in later childhood,” Clinical and Translational Allergy, vol. 6, no. 1, pp. 1–9, 2016.
- J. H. Lee, K. D. Han, H. M. Jung et al., “Association between obesity, abdominal obesity, and adiposity and the prevalence of atopic dermatitis in young Korean adults: The Korea National Health and Nutrition Examination Survey 2008-2010,” Allergy, Asthma & Immunology Research, vol. 8, no. 2, pp. 107–114, 2016.
- M.-S. Lim, C. H. Lee, S. Sim, S. K. Hong, and H. G. Choi, “Physical activity, sedentary habits, sleep, and obesity are associated with asthma, allergic rhinitis, and atopic dermatitis in korean adolescents,” Yonsei Medical Journal, vol. 58, no. 5, pp. 1040–1046, 2017.
- Z. Ali, C. S. Ulrik, T. Agner, and S. F. Thomsen, “Association between atopic dermatitis and the metabolic syndrome: A systematic review,” Dermatology, vol. 234, no. 3-4, pp. 79–85, 2018.
- Z. Ali, C. S. Ulrik, T. Agner et al., “Is atopic dermatitis associated with obesity? a systematic review of observational studies,” Journal of the European Academy of Dermatology and Venereology, vol. 32, no. 8, pp. 1246–1255, 2018.
- A. Paller, J. C. Jaworski, E. L. Simpson et al., “Major comorbidities of atopic dermatitis: beyond allergic disorders,” American Journal of Clinical Dermatology, vol. 19, no. 6, pp. 821–838, 2018.
- E. A. Mitchell, R. Beasley, B. Björkstén, J. Crane, L. García-Marcos, and U. Keil, “ISAAC phase three study group. the association between BMI, vigorous physical activity and television viewing and the risk of symptoms of asthma, rhinoconjunctivitis and eczema in children and adolescents: ISAAC phase three,” Clinical & Experimental Allergy, vol. 43, no. 1, pp. 73–84, 2013.
- P. J. Lanther, “Air pollution,” in Occupational Health and Safety, International Labour Office (ILO), Geneva, Switzerland, article 64, 1971.
- K. Ahn, “The role of air pollutants in atopic dermatitis,” The Journal of Allergy and Clinical Immunology, vol. 134, no. 5, pp. 993–999, 2014.
- W. Jedrychowski, F. Perera, U. Maugeri et al., “Effects of prenatal and perinatal exposure to fine air pollutants and maternal fish consumption on the occurrence of infantile eczema,” International Archives of Allergy and Immunology, vol. 155, no. 3, pp. 275–281, 2011.
- J. Kim, E.-H. Kim, I. Oh et al., “Symptoms of atopic dermatitis are influenced by outdoor air pollution,” The Journal of Allergy and Clinical Immunology, vol. 132, no. 2, pp. 495–497, 2013.
- J. Huss-Marp, B. Eberlein-König, K. Breuer et al., “Influence of short-term exposure to airborne Der p 1 and volatile organic compounds on skin barrier function and dermal blood flow in patients with atopic eczema and healthy individuals,” Clinical & Experimental Allergy, vol. 36, no. 3, pp. 338–345, 2006.
- S. Song, K. Lee, Y.-M. Lee et al., “Acute health effects of urban fine and ultrafine particles on children with atopic dermatitis,” Environmental Research, vol. 111, no. 3, pp. 394–399, 2011.
- W. Liu, J. Cai, C. Huang et al., “Associations of gestational and early life exposures to ambient air pollution with childhood atopic eczema in Shanghai, China,” Science of the Total Environment, vol. 572, pp. 34–42, 2016.
- Y.-M. Kim, J. Kim, K. Jung, S. Eo, and K. Ahn, “The effects of particulate matter on atopic dermatitis symptoms are influenced by weather type: Application of spatial synoptic classification (SSC),” International Journal of Hygiene and Environmental Health, vol. 221, no. 5, pp. 823–829, 2018.
- J. Lee, D. Lamichhane, M. Lee et al., “Preventive effect of residential green space on infantile atopic dermatitis associated with prenatal air pollution exposure,” International Journal of Environmental Research and Public Health, vol. 15, article 102, 2018.
- J. H. Lee, J. Kim, S. W. Lee et al., “The clinical effects of hospitalization in a low pollutant room on atopic dermatitis,” Asia Pacific Allergy, vol. 1, no. 2, p. 87, 2011.
- H. O. Kim, J. H. Kim, and S. J. Cho, “Improvement of atopic dermatitis severity after reducing indoor air pollution,” Annals of Dermatology, vol. 25, article 292, 2013.
- C. G. Bornehag, J. Sundell, L. Hägerhed-Engman, and T. Sigsgaard, “Association between ventilation rates in 390 Swedish homes and allergic symptoms in children,” Indoor Air, vol. 15, no. 4, pp. 275–280, 2005.
- O. Herbarth, G. J. Fritz, M. Rehwagen, M. Richter, S. Röder, and U. Schlink, “Association between indoor renovation activities and eczema in early childhood,” International Journal of Hygiene and Environmental Health, vol. 209, no. 3, pp. 241–247, 2006.
- K. A. Wood and R. J. Youle, “The role of free radicals and p53 in neuron apoptosis in vivo,” The Journal of Neuroscience, vol. 15, no. 8, pp. 5851–5857, 1995.
- J. Dejmek, I. Solanský, I. Beneš, J. Leníček, and R. J. Šrám, “The impact of polycyclic aromatic hydrocarbons and fine particles on pregnancy outcome,” Environmental Health Perspectives, vol. 108, no. 12, pp. 1159–1164, 2000.
- K. Donaldson, V. Stone, P. J. A. Borm et al., “Oxidative stress and calcium signaling in the adverse effects of environmental particles (PM10),” Free Radical Biology & Medicine, vol. 34, no. 11, pp. 1369–1382, 2003.
- C. Lee, H. Chuang, C. Hong et al., “Lifetime exposure to cigarette smoking and the development of adult-onset atopic dermatitis,” British Journal of Dermatology, vol. 164, pp. 483–489, 2011.
- B. Eberlein-König, B. Przybilla, P. Kühnl et al., “Influence of airborne nitrogen dioxide or formaldehyde on parameters of skin function and cellular activation in patients with atopic eczema and control subjects,” The Journal of Allergy and Clinical Immunology, vol. 101, no. 1, pp. 141–143, 1998.
- I. Lehmann, M. Rehwagen, U. Diez et al., “Enhanced in vivo IgE production and T cell polarization toward the type 2 phenotype in association with indoor exposure to VOC: results of the LARS study,” International Journal of Hygiene and Environmental Health, vol. 204, no. 4, pp. 211–221, 2001.
- K. Kim, “Influences of environmental chemicals on atopic dermatitis,” Toxicological Research, vol. 31, no. 2, pp. 89–96, 2015.
- F. Xu, S. Yan, M. Wu et al., “Ambient ozone pollution as a risk factor for skin disorders,” British Journal of Dermatology, vol. 165, no. 1, pp. 224-225, 2011.
- H. Burke, J. Leonardi-Bee, A. Hashim et al., “Prenatal and passive smoke exposure and incidence of asthma and wheeze: systematic review and meta-analysis,” Pediatrics, vol. 129, no. 4, pp. 735–744, 2012.
- J. V. Been, U. B. Nurmatov, B. Cox, T. S. Nawrot, C. P. Van Schayck, and A. Sheikh, “Effect of smoke-free legislation on perinatal and child health: A systematic review and meta-analysis,” The Lancet, vol. 383, no. 9928, pp. 1549–1560, 2014.
- R. Kantor, A. Kim, J. Thyssen et al., “Association of atopic dermatitis with active and passive smoking: A systematic review and meta-analysis,” Journal of the American Academy of Dermatology, vol. 75, pp. 1119–1126, 2016.
- H.-J. Yang, “Impact of perinatal environmental tobacco smoke on the development of childhood allergic diseases,” Korean Journal of Pediatrics, vol. 59, no. 8, pp. 319–327, 2016.
- S. Y. Kim, S. Sim, and H. G. Choi, “Atopic dermatitis is associated with active and passive cigarette smoking in adolescents,” PLoS ONE, vol. 12, Article ID e0187453, 2017.
- M. Shinohara and K. Matsumoto, “Fetal tobacco smoke exposure in the third trimester of pregnancy is associated with atopic eczema/dermatitis syndrome in infancy,” Pediatric Allergy, Immunology, and Pulmonology, vol. 30, no. 3, pp. 155–162, 2017.
- M. Fotopoulou, M. Iordanidou, E. Vasileiou, G. Trypsianis, A. Chatzimichael, and E. Paraskakis, “A short period of breastfeeding in infancy, excessive house cleaning, absence of older sibling, and passive smoking are related to more severe atopic dermatitis in children,” European Journal of Dermatology, vol. 28, no. 1, pp. 56–63, 2018.
- M. Egawa, Y. Kohno, and Y. Kumano, “Oxidative effects of cigarette smoke on the human skin,” International Journal of Cosmetic Science, vol. 21, no. 2, pp. 83–98, 1999.
- G. Valacchi, V. Fortino, and V. Bocci, “The dual action of ozone on the skin,” British Journal of Dermatology, vol. 153, no. 6, pp. 1096–1100, 2005.
- C. N. Palmer, A. D. Irvine, A. Terron-Kwiatkowski et al., “Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor atopic dermatitis,” Nature Genetics, vol. 38, pp. 441–446, 2006.
- A. D. Irvine, W. H. I. McLean, and D. Y. M. Leung, “Filaggrin mutations associated with skin and allergic diseases,” The New England Journal of Medicine, vol. 365, no. 14, pp. 1315–1327, 2011.
- I. Marenholz, R. Nickel, F. Ruschendorf et al., “Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march,” The Journal of Allergy and Clinical Immunology, vol. 118, no. 4, pp. 866–871, 2006.
- B. E. Kim and D. Y. Leung, “Significance of skin barrier dysfunction in atopic dermatitis,” Allergy, Asthma & Immunology Research, vol. 10, no. 3, pp. 207–215, 2018.
- S. Weidinger, M. O'Sullivan, T. Illig et al., “Filaggrin mutations, atopic eczema, hay fever, and asthma in children,” The Journal of Allergy and Clinical Immunology, vol. 121, no. 5, pp. 1203–1209, 2008.
- A. H. Ziyab, W. Karmaus, M. Yousefi et al., “Interplay of filaggrin loss-of-function variants, allergic sensitization, and eczema in a longitudinal study covering infancy to 18 years of age,” PLoS ONE, vol. 7, article e32721, 2012.
- C. Flohr, D. Pascoe, and H. C. Williams, “Atopic dermatitis and the “hygiene hypothesis”: too clean to be true?” British Journal of Dermatology, vol. 152, no. 2, pp. 202–216, 2005.
- S.-J. Yi, C. Shon, K.-D. Min et al., “Association between exposure to traffic-related air pollution and prevalence of allergic diseases in children, Seoul, Korea,” BioMed Research International, vol. 2017, Article ID 4216107, 11 pages, 2017.
- H. Takano and K.-I. Inoue, “Environmental pollution and allergies,” Journal of Toxicologic Pathology, vol. 30, no. 3, pp. 193–199, 2017.
- C. Flohr and L. Yeo, “Atopic dermatitis and the hygiene hypothesis revisited,” Current Problems in Dermatology, vol. 41, pp. 1–34, 2011.
- D. P. Strachan, “Hay fever, hygiene, and household side,” British Medical Journal, vol. 299, no. 6710, pp. 1259-1260, 1989.
- W. Karmaus and C. Botezan, “Does a higher number of siblings protect against the development of allergy and asthma? A review,” Journal of Epidemiology and Community Health, vol. 56, no. 3, pp. 209–217, 2002.
- A. M. Hughes, S. Crouch, T. Lightfoot et al., “Eczema, birth order, and infection,” American Journal of Epidemiology, vol. 167, no. 10, pp. 1182–1187, 2008.
- C. Cramer, E. Link, M. Horster et al., “Elder siblings enhance the effect of filaggrin mutations on childhood eczema: Results from the 2 birth cohort studies LISAplus and GINIplus,” The Journal of Allergy and Clinical Immunology, vol. 125, no. 6, pp. 1254–1260, 2010.
- A. Sherriff and J. Golding, “Alspac study team. hygiene levels in a contemporary population cohort are associated with wheezing and atopic eczema in preschool infants,” Archives of Disease in Childhood, vol. 87, no. 1, pp. 26–29, 2002.
- Y. Miyake, Y. Ohya, K. Tanaka et al., “Osaka maternal and child health study group. home environment and suspected atopic eczema in japanese infants: the osaka maternal and child health study,” Pediatric Allergy and Immunology, vol. 18, no. 5, pp. 425–432, 2007.
- J. C. Celedón, R. J. Wright, A. A. Litonjua et al., “Day care attendance in early life, maternal history of asthma, and asthma at the age of 6 years,” American Journal of Respiratory and Critical Care Medicine, vol. 167, no. 9, pp. 1239–1243, 2003.
- S. Dom, J. H. J. Droste, M. A. Sariachvili et al., “Pre- and post-natal exposure to antibiotics and the development of eczema, recurrent wheezing and atopic sensitization in children up the age of 4 years,” Clinical & Experimental Allergy, vol. 40, article 1378, 2010.
- L. Hagerhed-Engman, C.-G. Bornehag, J. Sundell et al., “Day-care attendance and increased risk for respiratory and allergic symptoms in preschool age,” Allergy: European Journal of Allergy and Clinical Immunology, vol. 61, no. 4, pp. 447–453, 2006.
- C. Cramer, E. Link, C.-P. Bauer et al., “Association between attendance of day care centres and increased prevalence of eczema in the German birth cohort study LISAplus,” Allergy: European Journal of Allergy and Clinical Immunology, vol. 66, no. 1, pp. 68–75, 2011.
- O. S. Von Ehrenstein, E. Von Mutius, S. Illi, L. Baumann, O. Böhm, and R. Von Kries, “Reduced risk of hay fever and asthma among children of farmers,” Clinical & Experimental Allergy, vol. 30, no. 2, pp. 187–193, 2000.
- M. Kilpeläinen, E. O. Terho, H. Helenius et al., “Farm environment in childhood prevents the development of allergies,” Clinical & Experimental Allergy, vol. 30, no. 2, pp. 201–208, 2000.
- L. Bråbäck, A. Hjern, and F. Rasmussen, “Trends in asthma, allergic rhinitis and eczema among Swedish conscripts from farming and non-farming environments. A nationwide study over three decades,” Clinical & Experimental Allergy, vol. 34, no. 1, pp. 38–43, 2004.
- M. R. Perkin and D. P. Strachan, “Which aspects of the farming lifestyle explain the inverse association with childhood allergy?” The Journal of Allergy and Clinical Immunology, vol. 117, no. 6, pp. 1374–1381, 2006.
- J. Douwes, N. Travier, K. Huang et al., “Lifelong farm exposure may strongly reduce the risk of asthma in adults,” Allergy: European Journal of Allergy and Clinical Immunology, vol. 62, no. 10, pp. 1158–1165, 2007.
- J. Douwes, S. Cheng, N. Travier et al., “Farm exposure in utero may protect agains asthma, hay fever and eczema,” European Respiratory Journal, vol. 32, no. 3, pp. 603–611, 2008.
- K. Wickens, J. M. Lane, P. Fitzharris et al., “Farm residence and exposures and the risk of allergic diseases in New Zealand children,” Allergy: European Journal of Allergy and Clinical Immunology, vol. 57, no. 12, pp. 1171–1179, 2002.
- D. Ferrandiz-Mont, N. Wahyuniati, H.-J. Chen, M. Mulyadi, T. M. Zanaria, and D.-D. Ji, “Hygiene practices: Are they protective factors for eczema symptoms?” Immunity Inflammation and Disease, vol. 6, no. 2, pp. 297–306, 2018.
- G. Loss, S. Apprich, M. Waser et al., “The protective effect of farm milk consumption on childhood asthma and atopy: The GABRIELA study,” The Journal of Allergy and Clinical Immunology, vol. 128, pp. 766–773, 2011.
- M. Waser, K. B. Michels, C. Bieli et al., “Inverse association of farm milk consumption with asthma and allergy in rural and suburban population across the Europe,” Clinical & Experimental Allergy, vol. 37, no. 5, pp. 661–670, 2007.
- E. Von Mutius, “Maternal farm exposure/ingestion of unpasteurized cow's milk and allergic disease,” Current Opinion in Gastroenterology, vol. 28, no. 6, pp. 570–576, 2012.
- C. Roduit, J. Wohlgensinger, R. Frei et al., “Prenatal animal contact and gene expression of innate immunity receptors at birth are associated with atopic dermatitis,” The Journal of Allergy and Clinical Immunology, vol. 127, pp. 179–185, 2011.
- C. Pelucchi, C. Galeone, J.-F. Bach, C. La Vecchia, and L. Chatenoud, “Pet exposure and risk of atopic dermatitis at the pediatric age: A meta-analysis of birth cohort studies,” The Journal of Allergy and Clinical Immunology, vol. 132, pp. 616–622, 2013.
- J. D. Bufford, C. L. Reardon, Z. Li et al., “Effects of dog ownership in early childhood on immune development and atopic diseases,” Clinical & Experimental Allergy, vol. 38, no. 10, pp. 1635–1643, 2008.
- H. Bisgaard, A. Simpson, C. N. Palmer et al., “Gene-environment interaction in the onset of eczema in infancy: filaggrin loss-of-function mutations enhanced by neonatal cat exposure,” PLoS Medicine, vol. 5, article e131, 2008.
- M. L. A. Schuttelaar, M. Kerkhof, M. F. Jonkman et al., “Filaggrin mutations in the onset of eczema, sensitization, asthma, hay fever and the interaction with cat exposure,” Allergy: European Journal of Allergy and Clinical Immunology, vol. 64, no. 12, pp. 1758–1765, 2009.
- T. Schäfer, B. Stieger, R. Polzius, and A. Krauspe, “Associations between cat keeping, allergen exposure, allergic sensitization and atopic diseases: results from the Children of Lubeck Allergy and Environment Study (KLAUS),” Pediatric Allergy and Immunology, vol. 20, no. 4, pp. 353–357, 2009.
- S. M. Langan, C. Flohr, and H. C. Williams, “The role of furry pets in eczema: a systematic review,” Archives of dermatology, vol. 143, pp. 1570–1577, 2007.
- S. Thorsteinsdottir, J. P. Thyssen, J. Stokholm, N. H. Vissing, J. Waage, and H. Bisgaard, “Domestic dog exposure at birth reduces the incidence of atopic dermatitis,” Allergy: European Journal of Allergy and Clinical Immunology, vol. 71, no. 12, pp. 1736–1744, 2016.
- H. Okada, C. Kuhn, H. Feillet et al., “The “hygiene hypothesis” for autoimmune and allergic diseases: an update,” Clinical and Experimental Immunology, vol. 160, pp. 1–9, 2010.
- G. Bolte, W. Bischof, M. Borte, I. Lehmann, H.-E. Wichmann, and J. Heinrich, “Early endotoxin exposure and atopy development in infants: Results of a birth cohort study,” Clinical & Experimental Allergy, vol. 33, no. 6, pp. 770–776, 2003.
- M. S. Perzanowski, R. L. Miller, P. S. Thorne et al., “Endotoxin in inner-city homes: Associations with wheeze and eczema in early childhood,” The Journal of Allergy and Clinical Immunology, vol. 117, no. 5, pp. 1082–1089, 2006.
- A. Simpson, S. L. John, F. Jury et al., “Endotoxin exposure, CD14, and allergic disease: An interaction between genes and the environment,” American Journal of Respiratory and Critical Care Medicine, vol. 174, no. 4, pp. 386–392, 2006.
- H. Mpairwe, E. L. Webb, L. Muhangi et al., “Anthelminthic treatment during pregnancy is associated with increased risk of infantile eczema: Randomised-controlled trial results,” Pediatric Allergy and Immunology, vol. 22, no. 3, pp. 305–312, 2011.
- P. J. Cooper, M. E. Chico, M. G. Vaca et al., “Effect of albendazole treatments on the prevalence of atopy in children living in communities endemic for geohelminth parasites: a cluster-randomised trial,” The Lancet, vol. 367, no. 9522, pp. 1598–1603, 2006.
- C. Flohr, R. J. Quinnell, and J. Britton, “Do helminth parasites protect against atopy and allergic disease?” Clinical & Experimental Allergy, vol. 39, no. 1, pp. 20–32, 2009.
- A. Zutavern, S. von Klot, U. Gehring, S. Krauss-Etschmann, and J. Heinrich, “Pre-natal and post-natal exposure to respiratory infection and atopic diseases development: a historical cohort study,” Respiratory Research, vol. 7, aticle 81, 2006.
- K. Wickens, T. Ingham, M. Epton et al., “New Zealand asthnma and allergy cohort study group. the association of early life exposure to antibiotics and the development of asthma, eczema and atopy in a birth cohort: confounding or causality?” Clinical & Experimental Allergy, vol. 38, no. 8, pp. 1318–1324, 2008.
- M. Mommers, C. Thijs, F. Stelma et al., “Timing of infection and development of wheeze, eczema, and atopic sensitization during the first 2 yr of life: The KOALA Birth Cohort Study,” Pediatric Allergy and Immunology, vol. 21, no. 6, pp. 983–989, 2010.
- J. Reimerink, F. Stelma, B. Rockx et al., “Early-life rotavirus and norovirus infections in relation to development of atopic manifestation in infants,” Clinical & Experimental Allergy, vol. 39, no. 2, pp. 254–260, 2009.
- H. Rosenlund, A. Bergstrom, J. S. Alm et al., “Allergic disease and atopic sensitization in children in relation to measles vaccination and measles infection,” Pediatrics, vol. 123, no. 3, pp. 771–778, 2009.
- J. I. Silverberg, K. B. Norowitz, E. Kleiman et al., “Association between varicella zoster virus and atopic dermatitis in early and late childhood: a case-control study,” The Journal of Allergy and Clinical Immunology, vol. 126, no. 2, pp. 300–305, 2010.
- J. I. Silverberg, E. Kleiman, N. B. Silverberg, H. G. Durkin, R. Joks, and T. A. Smith-Norowitz, “Chickenpox in childhood is associated with decreased atopic disorders, IgE, allergic sensitization, and leukocyte subsets,” Pediatric Allergy and Immunology, vol. 23, no. 1, pp. 50–58, 2012.
- J. Schmitt, N. M. Schmitt, W. Kirch, and M. Meurer, “Early exposure to antibiotics and infections and the incidence of atopic eczema: a population-based cohort study,” Pediatric Allergy and Immunology, vol. 21, no. 2, part 1, pp. 292–300, 2010.
- M. Schlaud, R. Schmitz, C. Poethko-Müller, and R. Kuhnert, “Vaccinations in the first year of life and risk of atopic disease – Results from the KiGGS study,” Vaccine, vol. 35, no. 38, pp. 5156–5162, 2017.
- L. M. Thøstesen, J. Kjaergaard, G. T. Pihl et al., “Neonatal BCG vaccination and atopic dermatitis before 13 months of age: A randomized clinical trial,” Allergy, vol. 73, no. 2, pp. 498–504, 2018.
- T. Tsakok, T. M. McKeever, L. Yeo, and C. Flohr, “Does early life exposure to antibiotics increase the risk of eczema? A systematic review,” British Journal of Dermatology, vol. 169, no. 5, pp. 983–991, 2013.
- T. M. McKeever, S. A. Lewis, C. Smith et al., “Early exposure to infections and antibiotics and the incidence of allergic disease: a birth cohort study with the west midlands general practice research database,” The Journal of Allergy and Clinical Immunology, vol. 109, no. 1, pp. 43–50, 2002.
- M. Kalliomäki, P. Kirjavainen, E. Eerola, P. Kero, S. Salminen, and E. Isolauri, “Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing,” The Journal of Allergy and Clinical Immunology, vol. 107, no. 1, pp. 129–134, 2001.
- B. Björkstén, E. Sepp, K. Julge, T. Voor, and M. Mikelsaar, “Allergy development and the intestinal microflora during the first year of life,” The Journal of Allergy and Clinical Immunology, vol. 108, no. 4, pp. 516–520, 2001.
- E. A. Grice and J. A. Segre, “The skin microbiome,” Nature Reviews Microbiology, vol. 9, no. 4, pp. 244–253, 2011.
- T. Bieber, “Atopic dermatitis,” The New England Journal of Medicine, vol. 358, no. 14, pp. 1483–1494, 2008.
- L. Nylund, M. Nermes, E. Isolauri, S. Salminen, W. M. de Vos, and R. Satokari, “Severity of atopic disease inversely correlates with intestinal microbiota diversity and butyrate-producing bacteria,” Allergy, vol. 70, no. 2, pp. 241–244, 2015.
- C. L. Thomas and P. Fernández-Peñas, “The microbiome and atopic eczema: More than skin deep,” Australasian Journal of Dermatology, vol. 58, no. 1, pp. 18–24, 2017.
- U. Wollina, “Microbiome in atopic dermatitis,” Clinical, Cosmetic and Investigational Dermatology, vol. 10, pp. 51–56, 2017.
- K. B. Fieten, J. E. E. Totté, E. Levin et al., “Fecal microbiome and food allergy in pediatric atopic dermatitis: A cross-sectional pilot study,” International Archives of Allergy and Immunology, vol. 175, no. 1-2, pp. 77–84, 2018.
- J.-F. Stalder, J. W. Fluhr, T. Foster, M. Glatz, and E. Proksch, “The emerging role of skin microbiome in atopic dermatitis and its clinical implication,” Journal of Dermatological Treatment, article 1, 2018.
- M. Pascal, M. Perez-Gordo, T. Caballero et al., “Microbiome and allergic diseases,” Frontiers in Immunology, vol. 9, pp. 1584–1593, 2018.
- E. Pedersen, L. Skov, J. Thyssen, and P. Jensen, “Role of the gut microbiota in atopic dermatitis: a systematic review,” Acta Dermato-Venereologica, 2018.
- S. Stemmler and S. Hoffjan, “Trying to understand the genetics of atopic dermatitis,” Molecular and Cellular Probes, vol. 30, no. 6, pp. 374–385, 2016.
- Y. Liang, C. Chang, and Q. Lu, “The genetics and epigenetics of atopic dermatitis-filaggrin and other polymorphisms,” Clinical Reviews in Allergy & Immunology, vol. 5, pp. 315–328, 2016.
- M. J. Ege, R. Frei, C. Bieli et al., “Not all farming environments protect against the development of asthma and wheeze in children,” The Journal of Allergy and Clinical Immunology, vol. 119, no. 5, pp. 1140–1147, 2007.
- T. Nakatsuji and R. L. Gallo, “Dermatological therapy by topical application of non-pathogenic bacteria,” Journal of Investigative Dermatology, vol. 134, no. 1, pp. 11–14, 2014.
- R. Sidbury, W. L. Tom, J. N. Bergman et al., “Guidelines of care for the management of atopic dermatitis: Section 4. Prevention of disease flares and use of adjunctive therapies and approaches,” Journal of the American Academy of Dermatology, vol. 71, pp. 1218–1233, 2014.
- T. Bieber, M. Cork, and S. Reitamo, “Atopic dermatitis: a candidate for disease-modifying strategy,” Allergy, vol. 67, no. 8, pp. 969–975, 2012.
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