Environmental Risk Factors

Introduction

The etiology of Atopic Dermatitis (AD) is multifactorial with interaction between genetics, immune and environmental factors. Substantial research has been done to understand environmental risk factors of AD, since identification of potentially modifiable factors can aid in reducing exposure to harmful triggers to prevent or mitigate disease.

The prevalence of AD is higher in wealthier, developed regions. AD prevalence has also increased over the past 50 years worldwide, and continues to increase. Environmental risk factors of AD may be important contributors toward these trends. This chapter explores several clinically relevant, environmental exposures with potentially harmful effects in AD, including maternal exposures during pregnancy, skin irritants, climate and ultraviolet exposure, pollutants, tobacco smoke, water hardness, urban and rural living and diet (Table 3-1).

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Maternal Exposures During Pregnancy

Several maternal exposures during pregnancy were found to increase the risk of childhood AD. Avoidance of such prenatal exposures might lower the risk of ever developing or delay the onset of childhood AD. This is particularly important in children who may be at higher risk of developing AD, e.g., when the parents or siblings have a personal history of AD and/or other allergic disease.

Maternal Stress

Several maternal exposures during pregnancy have been investigated for their ability to increase the risk of childhood AD. A systematic review of six observational studies identified that maternal stress during pregnancy was consistently associated with increased risk of childhood AD. Five of the six studies found associations of stress related to employment and adverse life events with AD being active at ages 6 and 14 years; the sixth study found that only maternal stress during the second and third trimester was associated with an increased risk of AD. The mechanism behind this association remains unknown. Important confounding factors during maternal stress may also play a role in AD, including smoking, socioeconomic status and changes in diet.

Prenatal Antibiotics

In two prospective birth cohort studies, prenatal antibiotic exposure was found to be associated with a small but significantly increased risk of AD in early childhood.

Maternal Exposure to Cigarette Smoke

A systematic review of 23 observational studies found no association between maternal exposure to cigarette smoke and risk of childhood AD. This contrasts with childhood exposure to passive smoke or active smoking, which are both associated with an increased risk of AD, as will be discussed in a later section.

Prenatal Consumption of Alcohol

Inconsistent results exist regarding prenatal consumption of alcoholic beverages on risk of AD: two observational studies found that maternal consumption was associated with an increased risk of AD in infancy and at 7 years of age, whereas a third found no association. Other maternal exposures may lower the risk of AD in childhood, including the consumption of fish and use of probiotics. These are discussed in a later section on diet.

Irritants and Pruritogens

Intrinsic barrier dysfunction can be worsened when environmental factors trigger epidermal barrier breakdown, such as exposure to irritants in personal care products. Irritants and allergens can also interact with the immune system to promote inflammation. Unfortunately, AD patients appear to be more sensitive to certain irritants. In a study of patients with AD, inactive AD and allergic respiratory disease without dermatitis, a significantly lower threshold to irritancy by sodium lauryl sulfate was observed in all groups. Another study of patients with occupational irritant contact dermatitis and healthy controls found that patients with either history of AD or common filaggrin (FLG) gene null variants had significantly higher risk of irritant contact dermatitis; those having both AD and FLG variants were at highest risk. Currently, more than 3,700 compounds have been identified as potential contact allergens.

Common environmental exposures may act as pruritogens, i.e., agents that directly or indirectly trigger or worsen itch. Anecdotally, patients with AD often report worsened itch secondary to using personal care products containing fragrances, even without any positive reactions to fragrances observed during patch testing. Even in healthy subjects, cutaneous application of cinnamic aldehyde, a member of the fragrance family, rapidly induces itch, hyperkinesis, allokinesis, a vasomotor response and increased skin temperature. It is possible that patients with AD have greater susceptibility to such pruritogens.

In addition, fragrances (including fragrance mix and balsam of Peru) have been identified as causes of true allergic contact dermatitis in AD patients. Fragrances are included in the majority of household products, including perfume, soap, cosmetics, shampoo and conditioner, moisturizers, laundry detergent, fabric softener, etc. It can therefore be helpful to provide patients with recommendations for personal care products that are free of fragrances and other common irritants. Of note, a recent study of the 174 bestselling moisturizers found that 45% had at least one fragrance or cross-reacting ingredient. Patients should be advised that product-labeling terms such as “fragrance-free,” “hypoallergenic,” or “dermatologist recommended” are commercial claims that require little substantiation and are often incorrect.

Preservatives, added to cosmetics to prevent product deterioration or consumer infection, are also important triggers of contact dermatitis, including formaldehyde, isothiazolinones, methyldibromo glutaronitrile, iodopropynyl butylcarbamate and parabens. Active ingredients in hair and nail-care products, including nail polishes, artificial nails and permanent hair coloring have also been identified as triggers of contact dermatitis. In particular, several studies have shown higher rates of reactions to specific ingredients in AD patients, including lanolin, methylisothiazolinone and/or methylchloroisothiazolinone, cocaimidopropyl betaine and formaldehyde-releasing preservatives.

AD patients should avoid clothing that might aggravate their itch. Cotton is typically recommended for AD patients, since it is soft and breathable. Synthetic fabrics and wool are abrasive and can produce itching and skin irritation. Anecdotally, fine cashmere is typically well tolerated by AD patients, albeit more expensive. Silk garments, although nonabrasive, are closely woven and impede the flow of air. Rarely, some patients may even be allergic to the sericin protein in silk. Silk garments made from antimicrobially-protected, knitted, sericin-free silk have been developed (DermaSilk, DreamSkin) and investigated as specialty clothing for AD patients. However, a randomized clinical trial of silk therapeutic garments for the management of AD found that the addition of these garments to standard of care was unlikely to improve disease severity or be cost-effective compared to standard care alone in children with moderate or severe AD. Anecdotally, tight fitting clothing (regardless of the material) can also trigger itch in AD patients.

Harmful Effects of Excess Bathing, Hot Water and Bath Soaps

Depending on the manner in which it is carried out, bathing can have differing effects on the skin. Although bathing can hydrate the skin, greater transepidermal water loss may occur if the water is left to evaporate from the skin. For this reason, the application of moisturizers immediately after bathing is necessary to prevent transepidermal water loss and ultimately maintain good skin hydration. Up to once daily bathing is recommended in AD. A systematic review and meta-analysis comparing four studies of the efficacy of bleach baths vs water baths alone found that regular water baths alone were effective at reducing AD severity, as judged by reductions of the Eczema Area and Severity Index (EASI) and body surface area at 4 weeks. Moreover, bleach baths were not significantly more effective than water baths alone. These results demonstrate that regular bathing is helpful and should be encouraged in AD patients. However, there is insufficient evidence to provide recommendations in the current treatment guidelines on taking a shower vs bathing in a tub or optimal bathing frequency for those with AD.

Nevertheless, it is commonly recommended that the duration of bathing should be limited to short periods of time, such as 5 or 10 minutes, with the use of warm or cool water (but not hot water). Some patients with AD admit enjoying near-scalding temperatures, as they claim it provides a temporary relief from itch. However, hot water has a drying effect on the skin, which can lead to worsening signs and symptoms, and should therefore be avoided. For areas of significantly inflamed skin, longer baths of 20 minutes, followed by the application of anti-inflammatory therapies on damp skin (“soak and smear” or “prehydration”) can be helpful.

Soaps interact with the stratum corneum in a manner that can cause damage to the skin barrier, dry skin and irritation. Therefore, limited use of non-soap cleansers that are free of fragrances and other common irritants, and neutral-to-low in pH is recommended.

Hygiene Hypothesis

According to the “hygiene hypothesis,” early life exposure to pathogens can influence the immature immune system away from allergic inflammation, thus protecting against developing AD and allergic disease. Increased hygiene and reduced pathogen exposures may account for the increasing prevalence of AD over the past 50 years, as well as regional differences in disease prevalence. Many observations have indirectly supported the hygiene hypothesis. For example, one study found that US children born in less developed countries had much lower odds of AD and allergic disease than children born in the United States. However, after residing in the United States for 10 or more years, the odds of AD increased, suggesting that protective effects from early life exposures may eventually wear off. Several studies also demonstrated lower odds of AD and allergic disease in children from rural or farming communities. Several pathogens have been suggested to play a protective role against atopy in general, including bacterial endotoxins, helminthes, herpesviridae and varicella-zoster virus. Consumption of unpasteurized milk and exposure to farm animals, dogs and early daycare have also been proposed to play protective roles. Other types of infections, such as respiratory syncytial virus, may increase the risk of disease. Additional studies are required to determine which types of early infections are protective against AD, and by which mechanisms they have their effect.

Although early life exposure to pathogens may protect against AD, infections in patients with established AD can have harmful effects with additional complications. Infections with herpes simplex and Coxsackie virus in patients with AD can lead to eczema herpeticum and Coxsakium, respectively. Due to barrier defects, patients with AD are at increased risk of colonization of both lesional and nonlesional skin with Staphylococcal aureus, have decreased microbial diversity and increased bacterial skin infections.

Climate

Climate factors have been regarded as having a significant role in AD for some time; however, until recently, support was limited to anecdotal evidence. Climate in each geographic region is determined by a combination of factors, including temperature, humidity and precipitation, as well as related factors, such as ultraviolet (UV) exposure (Figure 3-1). These factors are discussed below.

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Temperature

AD prevalence is higher in geographical regions with lower mean annual outdoor temperatures in both the US and internationally. One study that looked at multiple meteorological variables and symptom severity in AD found that rising air temperature, from very cold (1.4°F) to moderate (64.4°F), was associated with decreased pruritus. The mechanisms for how higher temperatures may be protective in AD are uncertain. One possibility is that people in warmer climates use less indoor heating, which may trigger or aggregate AD. People in warmer climates also spend more time outdoors, consequently having more UV exposure, which may protect against AD.

Although the prevalence of AD is lower in regions with higher mean annual temperatures, studies indicate that higher temperatures are not tolerated well by patients with established AD. Heat may induce perspiration, which is one of the most commonly reported aggravators in children with AD. The worsening of AD symptoms with increasing temperature likely explains patient preference for lighter clothing, which permits better skin ventilation and heat dissipation. Patients should be counseled to recognize heat and sweat as common triggers of AD, as well as potential strategies to minimize these exposures (e.g., temperature control) and/or mitigate their harmful effects (e.g., proactive treatment with emollients and prescription topical therapy).

Humidity

Humidity may have several effects on skin affected by AD. Higher humidity may have a beneficial effect by offsetting transepidermal water loss; however, higher humidity may also induce perspiration, which can irritate and aggravate pruritus. Conflicting results exist for the association between outdoor humidity and AD prevalence. Indoor relative humidity has been shown to be inversely associated with AD prevalence in multiple studies, ie, higher indoor humidity is associated with lower prevalence of AD. That is, increased use of indoor heating during cold weather and other factors that lower indoor humidity, are associated with increased AD prevalence. There is insufficient evidence to recommend the use of humidifiers in the management of AD. However, given their ability to increase indoor humidity and potentially offset the drying effects of indoor heating, they may be recommended as an adjunctive treatment in AD. Additional epidemiologic research on the effect of humidity on AD and clinical research on effective management strategies is warranted.

UV Radiation

Narrowband UVB and UVA1 are established modalities of phototherapy for children and adults with AD refractory to topical treatments. As demonstrated by Silverberg and colleagues, the prevalence of childhood AD was lower among US states with the highest quartile UV index. Conversely, AD prevalence rates were higher in states with increased stratospheric ozone, which filters UVB and UVC. This relationship has also been supported in other geographical regions, including Spain. The beneficial effects of UV radiation in preventing AD are likely multifactorial, including photoimmunosuppression and increased vitamin D. However, as demonstrated by a prospective cohort study, greater long-term sun exposure is associated with poorly controlled disease in patients with established AD. This may be due to confounding effects increased temperature and/or humidity in regions with higher UV radiation, which in turn trigger heat and sweat that aggravate AD symptoms. On the other hand, it may be that a subset of AD patients experiences flares upon exposure to intense UV radiation. Some authors have reported “photosensitive AD,” which is a poorly described and controversial subset of patients that may experience flares upon UV exposure. AD patients that experience flares upon exposure to UV radiation may require appropriate sun protection to reduce flares.

Latitude

Analysis from the ISAAC study found that the prevalence of childhood AD symptoms was positively associated with latitude (ie, prevalence increases with distance from the equator). Consistent with this, an Australian study found that the prevalence of AD in children ages 4 to 5 and 8 to 9 years was higher in central and southern regions. In contrast, a Brazilian study found no association between latitude and prevalence in children 6 to 7 years of age, and an inverse relationship in adolescents. The associations with latitude, as with other climate variations, is likely related to a combination of effects from temperature, UV radiation, vitamin D levels and behavioral differences.

Precipitation

Higher mean annual precipitation is associated with increased prevalence of AD, as demonstrated by studies in the United States and Spain. In an analysis of meteorological events on the severity of itch, snowfall and thunderstorms were associated with increased and decreased pruritus, respectively. Snowfall is obviously more common in regions with higher latitude, colder temperature, lower UV exposure. While thunderstorms can occur all year long, they occur more commonly in the spring and summer time. Thus, the associations of AD with snowfall and thunderstorms may be due to confounding from other environmental variables. The entire association between higher precipitation and AD may be indirectly related to other factors, such as concomitantly lower UV levels and temperatures, more time spent indoors and greater exposure to the drying effects of indoor heating. Regardless of the exact mechanisms, precipitation and other climate factors may have important ramifications for the population-based epidemiology of AD and play important roles in relapses and remittances in individual AD patients.

Air Pollutants

Air pollutants are particulate or gaseous airborne substances that are harmful to human health. They bind to the stratum corneum to become metabolized or even penetrate the epidermis to enter the systemic circulation through dermal capillaries. Although air pollutants are known risk factors for asthma, their role in AD is less established.

Indoor Air Pollutants

Indoor air pollutants arise from a variety of sources, including stoves, construction material, biological sources and combustion products. AD has been associated with poor indoor ventilation, particularly in the child’s bedroom. Multiple studies found AD to be associated with indoor renovation activities, such as painting, floor covering and wallpaper changing, possibly related to exposure to high levels of volatile organic compounds. A South Korean study demonstrated that even moving into a newly built house during the first year of life was associated with a higher risk of developing AD later in life.

Outdoor Air Pollutants

Outdoor air pollutants originate from both natural (eg, wildfires, dust storms) and man-made sources (e.g., motor vehicles, biomass burning) and include combustion products such as sulfur dioxide (SO₂), carbon monoxide (CO), nitrogen dioxide (NO₂), as well as particulate matter (PM).

Traffic-related pollution has been shown to have an important impact on the prevalence of AD. In a study of 317,926 Taiwanese children, a significant association was found between traffic-related pollution and AD in both sexes. Similar findings have been found in other studies. A German cohort study found that rates of AD in the first 6 years of life increased with proximity of residential address to the neatest main road, a proxy measure for traffic-related air pollutants. The highest rates of AD occurred in children <50 meters from a main road.

Two longitudinal studies have assessed the relationship between daily ambient outdoor pollution and childhood AD symptom severity. A South Korean study of 41 children aged 8 to 12 years collected symptom diaries for 67 days and found significant associations between pruritus severity and daily ambient PM concentrations. A longer-term study of 22 Korean children also found associations of AD symptoms with levels of outdoor air pollutants.

In a US population-based study, the prevalence of childhood AD was negatively associated with mean annual nitrate, organic carbon, PM_2.5 (particulate matter <2.5 micrometers in diameter), and PM₁₀ (particulate matter 2.5 to 10 micrometers in diameter), which may be related to the co-occurrence of these pollutants with protective climactic factors.

Despite the multiple studies demonstrating associations between AD and various pollutants or their proxies, causality of pollutants in AD has not been established. Currently, there are no established clinical or public health interventions that have been shown to reduce the prevalence or modify the disease course of AD.

Tobacco Smoke Exposure

Exposure to cigarette and cigar smoking is a major global health concern, since smoke exposure irritates the skin, affects both humoral and cellular immunity, causes oxidative damage and diminished skin barrier function. Although a strong association exists between childhood asthma and environmental tobacco smoke exposure, there are conflicting results surrounding epidemiological studies investigating the relationship between tobacco smoke and AD.

Given the conflicting findings, a systematic review and meta-analysis of 86 studies from 39 countries was performed to determine whether active smoking, passive exposure to tobacco smoke, and maternal smoking during pregnancy were associated with AD. The studies consisted of a total of 680,176 patients, of which 598,296 were children. The analysis found that a diagnosis of AD was associated with higher odds of active smoking (OR 1.87; 95% CI, 1.32-2.63) and exposure to passive smoke (OR 1.18; 95% CI, 1.01-1.38), but not maternal smoking during pregnancy (OR 1.06; 95% CI, 0.80-1.40). All studies of active smoking were cross sectional, thus preventing the determination of whether smoking preceded AD onset or vice versa. Regardless, these results indicate that patients with AD are more likely to be exposed to tobacco, which highlights their potentially increased risk for tobacco-related comorbidities, including malignancy and cardiovascular disease.

Water Hardness

Hard water contains high mineral content, typically calcium and magnesium ions. Exposure to hard water has been hypothesized to aggravate the skin of patients with AD since calcium and magnesium are skin irritants at high concentrations, and greater quantities of soap are needed to achieve lather when cleansing with hard water. An observational study in the United Kingdom found water hardness to be associated with higher lifetime and 1-year prevalence rates in 4- to 11-year-olds, but not in those 11 to 16 years of age. Similar results were found in Japanese ecological study and Belgian cross-sectional study, where AD prevalence rates were higher in areas with hard water. However, in an observer-blinded, randomized trial, no therapeutic benefit on AD severity was found when ion-exchange water softeners were used in regions of the UK with hard water. Thus, there is inconclusive evidence surrounding the association between water hardness and AD or the use of expensive water filtration systems to reduce water hardness.

Urban vs Rural Living

Urban living may be associated with increased stress, greater proximity to traffic and related pollutants, higher exposure to other pollutants, and fewer protective exposures, among other lifestyle and cultural factors that may impact skin care. A 2010 systematic review of 26 studies found some evidence of a higher risk for eczema in urban vs rural areas. Of the 26 studies analyzed, 11 showed significantly higher risk for AD, one showed significantly lower risk, and 14 found no significant association. Future studies are required to pinpoint precise factors that may predispose people to AD in urban environments.

Diet

As evidenced by a recent Cochrane review that analyzed evidence from five trials enrolling 952 patients, maternal antigen avoidance during pregnancy does not appears to protect against AD in the first 18 months of life. Longer-term studies are lacking. However, evidence indicates that maternal consumption of fish during pregnancy may be protective. In a questionnaire-based follow-up study of a prospective birth cohort, no association was found between pediatric AD and maternal consumption of most foods, except for fish. Consistently, an inverse association between high maternal fish intake and AD was demonstrated in another prospective birth cohort in the first 2 years of life, and at 1 year of age in a third study. Early introduction of fish during infancy may also protect against childhood AD. The anti-inflammatory properties of omega-3 polyunsaturated fatty acids are hypothesized to be responsible for the protective effects of fish consumption against AD.

Pediatric AD is associated with specific dietary habits in childhood and adolescence. As demonstrated in the multinational, multiphase, cross-sectional International Study of Asthma and Allergies

in Childhood (ISAAC) study, fast food, butter, margarine and pasta were positively associated with AD at ages 13 to 14 years. In contrast, milk was inversely associated with AD in the same age group. In children aged 6 to 7 years, fast food was positively associated with AD, whereas eggs, fruit, meat and milk were inversely associated with AD. Thus, a healthy balanced diet may help prevent or mitigate AD in children. Although potential confounding effects of adiposity were not addressed in multivariate models, excess adiposity may have a harmful role in pediatric and adult AD. Additional studies are required to determine the optimal dietary recommendations for patients with AD.

Testing for Food Allergies

Patients and parents often request allergy testing to identify potential triggers to avoid in the hopes of curing or reducing the severity of AD. However, establishing a connection between food allergens and AD flare-ups is of limited utility. Although patients with AD are at higher risk of food and environmental allergies, the AD per se is not typically caused or worsened by allergens present in foods. Positive allergy tests may only indicate sensitization rather than a causal connection to AD severity or disease course. Regardless, assessment for personal and family history of allergies should be done during history taking, since it is important to establish the presence of true food allergies. The American Academy of Dermatology (AAD) recommends limited food allergy testing (cow’s milk, eggs, wheat, soy and peanut) in children with AD <5 years of age who have moderate to severe AD and persistent disease despite optimized management and topical therapy, or a reliable history of an immediate allergic reaction after ingesting a specific food, or both. Controlled food challenges are the gold standard in verifying a positive skin test. Importantly, even if a food allergy is present, allergy avoidance is unlikely to cure AD, so effective treatment centered around good skin care and topical and/or systemic therapies remains crucial.

Breast-Feeding

Conflicting results exist regarding the protective effects of breast-feeding on the development of AD. A prospective cohort of 256 infants found that prolonged breast-feeding was associated with a significantly lower prevalence of AD at 1 and 3 years of age. One meta-analysis of 18 studies found that breast-feeding throughout the first 3 months of life was protective in children with a family history of atopy, but that this effect diminished in those without. Another meta-analysis failed to show that exclusive breast-feeding for at least 3 months was protective against AD, even in those with a family history of atopy. Additional research is necessary to determine whether breast-feeding is truly protective against childhood AD.

Probiotics and Prebiotics

Probiotic supplementation, the introduction of live bacteria into the gut, has been studied as both a protective and therapeutic measure in AD. The mechanism for prevention relates back to the hygiene hypothesis, whereby early exposure to gut microbes is hypothesized to upregulate Th-1 cytokine production, or steer the immune system away a from a skewed Th-2 response. Meta-analyses of placebo-controlled trials demonstrated that maternal use of probiotics during pregnancy and/or infancy was associated with lower rates of AD in the children. However, there was insufficient evidence for the use of probiotic supplementation in the treatment of existing AD.

Prebiotic supplementation is the provision of nourishment directed at facilitating the proliferation of biologically desirable gut microflora. Two studies have demonstrated that prebiotic oligosaccharide supplementation during infancy has prophylactic benefits against developed AD, possibly through the promotion of bacterial growth or immunomodulatory effects.

Prevention of AD Through Early Moisturization

The key role of barrier defects in the pathogenesis of AD and other atopic diseases has further emphasized the importance of moisturizers in the treatment of AD, irrespective of severity. Moisturizers have been demonstrated to be effective at more than just hydration of the skin. They are also effective at improving AD severity with decreased signs and symptoms of AD and reducing the amount of prescription treatments necessary for disease control. For instance, petrolatum application increases expression of barrier proteins and antimicrobial peptides and decreases proinflammatory cytokines. Preliminary studies suggest that proactive application of emollients to infants at risk for AD, beginning as neonates, can even reduce AD development and/or severity. In one prospective, randomized controlled trial, an emulsion-type moisturizer was applied daily during the first 32 weeks of life to 59 neonates at high risk for AD. Approximately 32% fewer neonates who received the moisturizer had AD by week 32 than control subjects (P=0.012). In a second randomized controlled pilot study of 124 neonates at high risk for AD, parents in the control arm were asked to apply full-body emollient therapy at least once per day starting within 3 weeks of birth. Compared to the no-emollient group, a statistically significant protective effect was found with the use of daily emollient on the cumulative incidence of AD (50% relative risk reduction; P=0.017). Longitudinal studies are currently investigating the ability of early emollient application to decrease sensitization to antigens and development of other atopic disease.