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 Table of Contents  
CME ARTICLE
Year : 2019  |  Volume : 20  |  Issue : 2  |  Page : 93-100

Prevention of atopic dermatitis: Etiological considerations and identification of potential strategies


1 Department of Dermatology, Monash University, Eastern Health, Box Hill; Department of Paediatrics, University of Melbourne; Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Melbourne, Australia
2 Murdoch Children's Research Institute, Royal Children's Hospital, Parkville; Allergy and Lung Health Unit, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia

Date of Web Publication29-Mar-2019

Correspondence Address:
Prof. John C Su
Level 2/5 Arnold St., Box Hill 3128, Victoria
Australia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpd.IJPD_10_19

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  Abstract 


Research during the last decade has given many new insights into factors contributing to the development and evolution of atopic dermatitis (AD). Factors identified include skin barrier defects, proinflammatory predispositions, anomalies in the microbiome, and some environmental influences. There is now the possibility of personalizing therapy and potentially, of disease prevention. However, discerning the respective roles of early factors leading to AD development is complex. Stringent analysis for confounders must precede attribution of causality to any factor. This review examines current understandings of AD pathogenesis and related research approaches in AD primary prevention.

Keywords: Barrier, eczema, march, microbiome, probiotics


How to cite this article:
Su JC, Lowe AJ. Prevention of atopic dermatitis: Etiological considerations and identification of potential strategies. Indian J Paediatr Dermatol 2019;20:93-100

How to cite this URL:
Su JC, Lowe AJ. Prevention of atopic dermatitis: Etiological considerations and identification of potential strategies. Indian J Paediatr Dermatol [serial online] 2019 [cited 2019 Sep 19];20:93-100. Available from: http://www.ijpd.in/text.asp?2019/20/2/93/255193




  Introduction Top


The burden of atopic dermatitis (AD) is high. Moderate-to-severe childhood AD shows greater family impact than Type 1 diabetes.[1] Average annual personal costs have been estimated from Aus$330-1255/year (Australia, 1996) to US$274/month (USA, 2016).[1],[2] Annual population cost of eczema has been estimated to be US$5 billion in the United States.[3]

In Australia, 1 in 3 infants develop AD in infancy.[4] Of these, East-Asian infants, especially those of recent immigrants, are at particular risk compared with those of nonAsian parents, despite lower parental rates of allergy.[4] Eczema tops all skin diseases for years lived with disability and disability-adjusted life years.[5] About 90% of AD patients experience daily itch and two-thirds have sleep disturbance.[6],[7] Comorbidities include other atopic disorders, infections, obesity, growth disturbance, attention deficit hyperactivity disorder and mental health disease, speech disorder, headaches, organ-specific autoimmunity, and anemia.[8] Persistent disease is particularly costly and appears to correlate with later onset, preexisting duration, and severity.[9] However, persistent, early-onset (and more severe) disease appears to particularly herald possible future food and respiratory allergy, with their attendant burdens.[10],[11],[12]

Preventative medicine aims to prevent illness and its complications. Primary prevention seeks to prevent disease onset, by removing pathogenic factors, counteraction (e.g., immunization), or general health promotion.[13] Secondary prevention seeks early detection of disease onset/symptoms to arrest, reverse, and mitigate disease processes and progression (e.g., by screening). Tertiary prevention seeks to reduce impairments and disabilities of preexisting disease (e.g., prevention of complications) or to optimize patient adjustment, thereby minimizing biopsychosocial burden and handicap.

Two further categories of prevention address the very early life; these precede and overlap with primary prevention. Primal prevention refers to affective and physical interventions 'from conception to first anniversary' that may ultimately benefit later health, possibly through epigenetic mechanisms.[14] Primordial prevention refers to preventing the development of risk factors themselves. This article discusses the current understanding of potential strategies for primary AD prevention, including researched primal and primordial strategies.


  Pathogenic Factors in Atopic Dermatitis Top


AD pathogenesis involves genetic and environmental factors. These include the skin barrier, an atopic diathesis, the microbiome, and other factors involved in the environment-gene interplay.

Barrier disruption may result from gene mutation and/or environmental factors.

At least 31 risk loci for AD are identified, many with roles in barrier development and maintenance as well as immunity.[8],[15] Filaggrin null mutations occur in 40% of persons with moderate-severe AD compared with 10% of healthy Caucasians; loss-of-function mutations confers a three-fold AD risk and are more commonly associated with earlier, more severe disease.[16] Intragenic copy number variations also contribute dose-dependently to barrier defect.[17] Claudin-1, involucrin, loricrin, desmoglein 1, desmoplakin, LEKTI, and ceramides are also associated with AD risk.[16],[18],[19],[20],[21] Barrier protein modifiers in AD include Toll-like receptors (TLRs) and alarmins.[22],[23],[24],[25]

Impaired skin barrier enables the chemical induction of Th1 and Th2 responses.[26] An initial “nonIgE≵-infantile phase of eczema may progress to a sensitized “IgE-associated” phase. AD may remit, progress to respiratory allergy (the “atopic march≵), and/or develop auto-allergic self-sensitization to self-proteins.[16] Initial skin inflammation relates to innate immunity, whereas later (e.g., respiratory) allergy requires sensitization and adaptive immunity.[27],[28],[29],[30] AD may thus be stratified by the age of onset, endophenotype, and biomarker profiles to help personalize treatment and potential prevention strategies.[31]

Various factors affect the skin barrier such as low humidity, itching, age, and water, which can cause filaggrin proteolysis. High pH may damage the acid mantle, modify protein expression, and alter protease activity.[32]

Primary (genetic) immunological diatheses may be potential targets for primary prevention and therapy. These may affect T-cell signaling, cytoskeletal remodeling, cytokine signaling, T-cell repertoire, tolerance failure, metabolic disturbance, and mast cell deregulation.[33] The role of nonimmunological factors such as neuropeptides, neurotrophins, and growth factors is unclear.

The microbial diversity hypothesis proposes that life-style delimited microbe-host interaction deprives immunological training leading to Th2 skewing and AD.[34],[35] Whereas antibiotic use and cat exposure in the setting of impaired skin barrier appear to increase AD risk,[36],[37],[38] reduced AD has been related to exposure to helminths,[39] early day-care, endotoxin, unpasteurized farm milk, and animals.[40] Nonpathogenic microbes, possibly gastrointestinal, may cause antigen-presenting cells to mature into a pro-regulatory form, APCregs, driving Treg cells production.[41],[42],[43],[44]

Skin microbiome may also affect AD development. Reduced microbial diversity before AD onset and reduction of AD in infants with early commensal Staphylococcus have been observed.[45] TLRs in AD may modify the recognition of microbial molecular patterns, thus influencing adaptive immunity and percutaneous sensitization.[46] In AD, keratinocyte-derived antimicrobial peptides (AMPs) may be reduced and this may also increase S. aureus,[47] as may AD cytokines and biofilms.[48] Conversely, coagulase-negative Staphylococcus may produce strain specific AMPs that synergize with human LL-37 to kill S. aureus; such commensals may be reduced in AD.[49]

Vitamin D may also play a role in AD pathogenesis, but AD associations with maternal Vitamin D supplementation, cord blood levels, and serum levels are inconsistent.[50] Vitamin D supplementation may potentially improve severe pediatric AD.[51] Its stimulation of cathelicidin and beta-defensin may enhance filaggrin expression and complement its activity in stimulating TLRs, altering keratinocyte differentiation, suppressing dendritic cell maturation, inhibiting Th1 cell proliferation, attenuation of Th2 immunity and inhibiting B-cell function.[52] The relevance of this for AD prevention is unclear.

Itch is a sign of AD but may also play a role in pathogenesis. IL-31 can cause itch and can be induced by S. aureus superantigens and Th2-type cell stimulation.[42] IL-31RA1 receptor is found on IL-31RA1/TRPV1/TRPA1 cutaneous C-fiber and dorsal root ganglia neurons.[53] However, itch-related TRPV1, TRPV3, TRPV4, and TRPA1 channels on keratinocytes and sensory nerve fibers can also be directly triggered by thermal, mechanical, and chemical cutaneous stimuli.[53] These include textile fibers with mean diameters >30–32 μ.[53] Effects of physical and chemical microclimate stimuli on cutaneous inflammation are, to date, largely unstudied, but may have relevance for both primary and tertiary disease prevention.


  Prevention-Theory and Evidence Top


Barrier-directed measures

Xerosis and increased transepidermal water loss may result from defects of epidermal structural and protective proteins (e.g., filaggrin and S-100 proteins), decreased extracellular ceramides, altered stratum corneum pH, or overexpression/defects of chymotryptic enzymes, thus allowing increased penetration of skin by allergens and microbes.[54] Macharia et al. found that fewer patients developing AD use petrolatum jelly than healthy infants, but data from prospective studies have only appeared in the past 4 years.[55]

The way emollients restore skin barrier is incompletely understood and molecular effects may be more complex than previously thought. Recent studies revealed cytokine changes following moisturization (i.e., up-regulation of key AMPs and innate genes, improved expression of epidermal differentiation markers, improved skin pH, and altered skin microbiome).[56],[57] Studies comparing efficacies of moisturizers in AD (of both affected and healthy skin) are few; apparent differences in efficacy for the prevention and delay of AD relapse have been attributed to respective effects on skin barrier repair.[58] Four published studies on barrier enhancement for AD onset prevention are discussed below, using different moisturizers.

After showing the feasibility and safety of emollient use in 22 infants from the age of 3 weeks to 6 months,[59] an American-British trial randomized 124 high-risk babies to either a treatment arm of at least daily full-body moisturizer starting from 3 weeks of age (allowing parents to decide from a number of different emollients) or a no emollient control arm. Infants were followed for 6 months. A relative risk reduction of 50% for development of AD was found in the treatment arm, with no difference in adverse effects.[60] An extension of this protocol (BEEP) is underway, studying in 1400 infants, the effect of this intervention on the primary outcome of AD at 24 months of age.[61] The interventions used for the 1st year of life comprise Doublebase Gel and Diprobase cream, which both do not have sodium lauryl sulphate.

In a multi-center Norwegian study of 56 infants with xerosis, a similar reduction was observed in the prevalence of dry skin at 6 months among the 24 infants managed proactively by frequent oil baths (2–4 to 5–7 times a week) and fatty face cream moisturization (skin normalized in 75% and only 4% developed AD). This compared favorably with an observation-only cohort (37.5% normalized, 19% developed AD).[62]

A prospective, randomized, controlled, Japanese study of 118 neonates showed 32% lower cumulative incidence of AD at 32 weeks for infants treated with daily emulsion-type moisturizer than for the controls (P = 0.12 log-rank test).[63] They did not find a difference in allergic sensitization to egg white between the two groups; this was not explained.

By comparison, for our own study, we chose a ceramide-based emollient, Epiceram, which has physiological proportions of ceramides, cholesterol, and free fatty acids, a pH of 5, and shown previously by us to be safe for neonatal use.[64] High-risk infants were randomized 1:1 into an observation arm, and a treatment arm comprising twice daily whole-body application of Epiceram (approximately 6 g), starting within 3 weeks of life, for 6 months. We found a trend to reduced AD risk at 6 and 12 months with intention-to-treat analysis.[65] Per protocol analysis, only looking at infants using treatment at least 5 days a week, showed a significant reduction in food sensitization at 12 months (0% of 21 vs. 19% of 36; P = 0.04); treated infants who developed sensitization, started treatment relatively late. Beneficial effects, therefore, appeared to persist beyond the treatment period. The benefits of moisturization in the treatment group may have been underestimated because 39% of controls vs. 18% of the treatment group also used nonstudy-related emollients for an average of 3 or more days a week.

Longer-term studies and those comparing specific and different moisturizers, including virgin coconut oil and those with prebiotics, could be beneficial.[66] Studying the role of moisturizers on secondary prevention alongside other topical measures like TCIs would also be valuable.

GI-directed measures: Prebiotics and probiotics, formula, and breastfeeding

Given the observed dysbiosis observed in AD, it has been suggested that probiotics may have benefits for both prevention and treatment of AD. Probiotics are live microorganisms that may confer benefits to the host, whereas prebiotics are nondigestible carbohydrates that stimulate the growth of probiotic bacteria in the intestines. Synbiotics refer to combinations of both these categories.

Therapeutic benefits of probiotics have not been consistently demonstrated in studies of childhood and adult AD. Possible effects of probiotics that may facilitate AD prevention includes increased intestinal microflora diversity, reduced fermentation products, inhibited S. aureus attachment, Th2 response inhibition, Th1 response stimulation, regulatory T-cell upregulation, and skin barrier enhancement.[67] Some early reports reported a small increase in adverse effects like recurrent wheezing/bronchitis with probiotics.[68]

Recent meta-analyses of perinatal use of probiotics suggest an associated reduction of AD incidence of 20%–24% and a preventative role, especially when given during the late antenatal period (last 2 weeks of pregnancy) and first 3–6 months of life.[67] Long-term effects are unclear. The pooled relative risk ratio of AD has been suggested to be 0.74 (95% confidence interval (CI): 0.67, 0.82), but this is limited by the heterogeneity of studies.[69] What is most unclear for probiotics are the exact identity of the most beneficial strain(s), the ideal timing of administration, the optimal dose, the preferred mode of delivery, and effects of concurrent prebiotics.[42],[70]

Some of these effects may be strain specific and modulated by TLRs. Meta-analyses of Pelucchi et al.[71] and Panduru (2015)[72] found a possible 20%–24% reduction in the likelihood of developing AD with prenatal and postnatal probiotics use, particularly for Lactobacillus and Bifidobacterium, but consistent longer-term benefits have not been established.

The ProPACT study, for example, showed nonresponse to probiotics among children with divergent microbiota and overrepresentation of Bifidobacterium dentium, but a positive response in others, a finding possibly suggesting an important relationship between the timing of exposures and benefits of specific microbiota constitutions; this will need further study.[73] They found a reduced Th22 cell proportion following perinatal (36 weeks gestation until 3 months postnatal) maternal probiotic supplementation as follows: a combination of Lactibacillus rhamnosus GG,  Bifidobacterium animalis Scientific Name Search ctis Bb-12, and  Lactobacillus acidophilus Scientific Name Search 5.[74] Th22 cells were reduced in children who did not develop AD on probiotics and increased in children who developed AD. With an overall relative risk of 0.43 (P = 0.025) for probiotics, mediation analysis attributed a RR of 0.73 to the Th22 reduction, and a RR of 0.59 to other pathways. Generation of CD4+ FoxP3+ Tcells by multi-strain probiotics has been described in mice with preexisting AD.[75]

Similarly benefits of prebiotics in early infancy have been suggested by meta-analyses of early life data, (up to 32% AD reduction for a galacto-oligosaccharide and fructo-oligosaccharide combination, according to Osborn and Sinn), but long-term data are lacking. Intrinsic infantile microbiota may affect the response.[76]

Synbiotics are mixtures of prebiotics and probiotics. Two perinatal primary prevention studies have looked at the effects of galacto-oligosaccharides administered together with probiotics, showing a pooled relative risk compared with placebo of 0.44 (95% CI: 0.11, 1.83. P =0.26).[77] As such, while the available evidence is consistent with a potentially important preventive effect, it is too early to advocate this as a strategy.

The effect of hydrolyzed formula on AD prevention is contested. The German GINI study suggested a reduced AD cumulative incidence relative risk (0.75, 95% CI: 0.59, 0.96) for infants fed partial whey hydrolysate; extensive casein hydrolysate reduced cumulative incidence (risk ratio: 0.60 95% CI: 0.46, 0.77) and cumulative prevalence (Odds ratio: 0.42 95% CI: 0.23, 0.79).[78] However, a recent rigorous systematic review failed to demonstrate the effectiveness of hydrolyzed formula for the prevention of AD.[79],[80]

There is some evidence for a link between breastfeeding (which also contains probiotics and prebiotics)[81] and reduced AD incidence, but this is still contested.[82],[83] However, there is no support for maternal dietary allergen avoidance during pregnancy.

Macro- and microenvironment

There is growing interest in diverse, environmental conditions, as potential risk factors for AD. Skin is protected by various mechanisms, including its acid mantle,[84] which can be affected by water hardness(32), through increased surfactant deposition on skin, and possibly by chlorine.[85] A recent study of 53,000 children from the Danish National Birth Cohort looking at the prevalence of physician diagnosed AD from parental interviews at 6 and 18 months suggested an overall AD prevalence of 15%, ranging from 13.5% in regions with the softest water to 17.1% in those with the hardest domestic water.[86] Relative prevalence increased by 5% per 5-degree increase in water hardness. Independently, AD relative prevalence for babies born in fall was 24% compared with 18% for those born in winter. This study presents compelling evidence to further examine the effects of the macroenvironment on the development of AD although the respective importance of water content, climate, sunlight, and Vitamin D is not clear.

Studies on the skin microenvironment on the management of AD are very few. Many teachings regarding clothing in AD have been based on anecdotal experience and dated, poorly conducted studies.[53] Our recent publication on the effects of superfine merino wool on infants with mild-to-moderate AD suggested a beneficial effect of superfine wool compared with standard clothing, thus challenging previously generalized beliefs regarding adverse effects of wool on the skin.[87] Changes in textile technology and understandings of both fiber properties and skin physiology compel our further examination of the skin microenvironment and its effects on AD development and response. By contrast, another study failed to demonstrate advantages of adding in silk clothing to standard care of AD.[88]

Miscellaneous strategies

Reduction of AD has been associated with breast feeding promotion in one intervention trial and numerous observational studies, with biologic plausibility.[89],[90],[91] However, this is contested by a sizeable number of other cohort studies, some of which suggest increased AD risk with prolonged or exclusive breastfeeding.[92]

A systematic review and meta-analysis of controlled studies (n = 9, including four randomized controlled studies) examining Vitamin D supplementation and AD symptoms suggested a higher mean difference in AD symptoms after supplementation (mean-5.81, 95% CI: −9.03, −2.59) in established AD.[52] However, the protective effect of Vitamin D on AD development is both supported[93],[94] and refuted.[95],[96],[97],[98]

An association between proper observation of vaccination schedules, particularly with oral live-attenuated poliovirus and bacillus Calmette-Guerin, and reduced atopic disease incidence has been described, but it lacks confirmation.[99] There is little support for the utility of systemic and cutaneous allergen avoidance in primary prevention of AD; conversely there are potential adverse effects of allergen avoidance on the development of immunological tolerance and general infant health to be considered.[100] An appraisal of 7 RCTs examining dust mite avoidance for the primary prevention of AD in high-risk infants have failed to demonstrate any benefit.[101] The role of antihistamines is limited and given their neurological adverse effects and the limited evidence for any pathogenic role of histamine in AD, they are not recommended in practice.[102]

Long-chain n-3 fatty acids have shown effects in the therapy of AD and in the reduction of allergic sensitization.[103],[104] Reduced prevalence of IgE-mediated AD in offspring of pregnant women treated with n-3 fatty acids is reported in two of five human studies.[105] Studies in fecund mice suggest that changes in offspring microbiome may contribute to the prevention of anaphylaxis. In a separate mouse study, B-carotene and lycopene were reported to prevent the induction by a low zinc/magnesium diet of AD-like changes in mice.[106] A summary of key AD prevention strategies with levels of evidence is shown in [Table 1].[90],[107]
Table 1: Potential primary prevention strategies

Click here to view



  Conclusion Top


Primary prevention of AD has the potential to alleviate a huge personal and social disease burden. There is, as yet, inconclusive evidence supporting the role of various interventions, including early infant moisturization, probiotics/prebiotics, Vitamin D supplementation, and long-chain n-3 fatty acids. Larger cohorts using standardized protocols that are followed over longer periods of time are required. At the same time, there remain other potential steps for prevention that may be variably dependent on genotype, endophenotype, clinical phenotype, and specific environmental considerations. With better understanding of AD risk factors and the evident success of more targeted and personalized therapeutic options for AD, the possibility of nuanced primary prevention strategies is becoming increasingly real and thus calls for further research into this area.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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