Centenary theme section: ATOPIC DERMATITIS

REVIEW ARTICLE
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Prevention of Atopic Dermatitis

Hywel C. WILLIAMS and Joanne C. CHALMERS
Centre of Evidence-Based Dermatology, University of Nottingham, Nottingham, UK

Despite advances in atopic dermatitis (AD) treatments,

SIGNIFICANCE
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research into AD prevention has been slow. Systematic

reviews of prevention strategies promoting exclusive Just like we can prevent infectious diseases like polio, it
and prolonged breastfeeding, or interventions that re- should be possible to prevent eczema (atopic dermatitis),
duce ingested or airborne allergens during pregnancy food allergy and asthma. Most things that have been tried
and after birth have generally not shown convincing so far to prevent eczema including exclusive breastfeeding,
benefit. Maternal/infant supplements such as Vitamin timing of starting solids, supplements like Vitamin D and
D have also not shown any benefit with the possible reducing house dust mite do not seem to work. Taking pro-
exception of omega-3 fatty acids. Systematic reviews biotics (friendly gut bacteria) during pregnancy probably
suggest that probiotics could reduce AD incidence by reduces the risk of eczema by around 20%, although we
around 20%, although the studies are quite variable are still not sure what combination is best. New research is
and might benefit from individual patient data meta- trying to find out if special creams that make a baby’s skin
analysis. Skin barrier enhancement from birth to pre- barrier stronger can prevent eczema.
vent AD and food allergy has received recent interest,
and results from national trials are awaited. It is pos-
sible that trying to influence major immunological genetics of AD may have played a part in contributing
changes that characterise AD at birth through infant- to this recent trend (1, 2). Whilst identifying risk factors
directed interventions may be too late, and more atten- that can be manipulated is an essential part of prevention
tion might be directed at fetal programming in utero. research, understanding the mechanisms by which the
effects of prevention are mediated is interesting but not
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Key words: atopic dermatitis; atopic eczema; eczema; preven-

tion.
essential. For example, the benefits of stopping smoking
to prevent lung cancer became apparent from simple epi-
Accepted May 7, 2020; Epub ahead of print May 15, 2020 demiological research long before the mechanisms and
Acta Derm Venereol 2020; 100: adv00166. precise carcinogens were discovered (3). Prevention of
disease is arguably a much more logical and cost-effective
Corr: Prof. Hywel C. Williams, Nottingham University Hopsitals NHS Trust
Queen’s Medical Centre Campus, Nottingham, NG7 2UK, UK. E-mail: Hy- way to manage the burden of a disease such as AD than
[email protected] focussing solely on drug treatment of sick individuals
who seek medical help after a long chain of irreversible

D
pathological events (Fig. 2). Whilst some drugs such as
Advances in dermatology and venereology

espite the familiar adage that “prevention

is better than cure”, prevention of atopic
dermatitis (AD) has been a relatively neglec-
ted topic of research until recently. A PubMed
search (using the terms [atopic dermatitis OR
eczema] AND treatment (August 14th 2019)
revealed 19,755 hits, compared with just 3,150
when disease terms were combined with “pre-
vention”. Reasons for lack of research could
include a lack of interest in population-based
research in favour of basic science (Fig. 1),
lack of research skill capacity in prevention
research, lack of funding and a limited choice
of identifiable risk factors that are amenable
to public health manipulation. However,
the number of AD prevention studies has
increased over the last 10 years, especially
in the field of probiotics and interventions Fig. 1. A skewed interest toward cellular and molecular atopic dermatitis (AD)
mechanisms relative to research into AD populations. Research into AD over the
to enhance the skin barrier. Basic science last 50 years has been dominated by interest in cells rather than broader questions such
discoveries into the human microbiome and as whether disease prevention is possible.

doi: 10.2340/00015555-3516 This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta
Acta Derm Venereol 2020; 100: adv00166 Journal Compilation © 2020 Acta Dermato-Venereologica.
 Prevention of atopic dermatitis 381

penicillin for streptococcal infec-

tion can be curative, most only
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modify rather than cure chronic

diseases like AD, they are often
expensive, and all are associated
with potential adverse effects.
This article attempts to critically
review the current state of science
on the prevention of atopic derma-
titis. Throughout this article, we
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will refer to the disease of interest

as AD, which is synonymous with
atopic eczema or just “eczema” (4).
We use the term atopic dermatitis
to describe the clinical phenotype,
rather than the scientific defini-
tion of clinical phenotype plus
evidence of IgE sensitisation to Fig. 2. Where is intervention most effective? Although the concept of prevention of atopic dermatitis
environmental allergens. We start is rarely discussed at international meetings, an upstream approach is a far more logical approach to
reduce the burden of disease at a population level than the current approach of treating sick individuals
by introducing the reader to key with expensive drugs who present to secondary care after a long chain of pathological events.
considerations when designing or
critically appraising studies of AD prevention, using our of prevention, yet individuals who would have contracted
direct experience in designing and running a randomised these diseases are seldom “grateful” to those developing
controlled trial (RCT) of emollients to prevent AD. We and implementing vaccines as it is unclear who would
then explore the main interventions that have been used have contracted the disease in the first place. The re-
to try and prevent AD such as maternal and infant dietary cent re-emergence of measles due to misguided beliefs
restrictions or supplements, aeroallergen avoidance and about vaccine safety, termed “vaccine hesitancy”, are
approaches designed to enhance the external skin barrier. timely reminders of the “invisible” and powerful effects
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The authors have chosen to use systematic reviews of of population-based interventions (10).
evidence and RCTs as the evidence source where possible.
Systematic reviews were harvested from the Centre of Primary, secondary and tertiary prevention
Evidence-Based Dermatology international collection of
systematic reviews which is updated monthly by a senior Primary prevention typically refers to intervening before
information scientist (Dr. Douglas Grindlay) (5). Rather health effects occur. Secondary prevention implies de-
than summarise all 102 systematic reviews on AD preven- tecting a disease at an early stage to prevent worsening,
tion in this collection, we instead refer to overviews of whereas tertiary prevention is the reduction of symptoms
systematic reviews or the most recent and comprehensive or improvement in quality of life of those with established
Advances in dermatology and venereology

systematic reviews where possible (6, 7). We used the disease – i.e. where health care professionals normally
Global Resource for Eczema Trials (GREAT) database operate (11).
for RCTs that might not yet be included in systematic
reviews (8). Application of the Participant, Intervention, Comparator
and Outcomes framework to atopic dermatitis prevention
studies
SOME KEY BASIC CONSIDERATIONS
Participant, Intervention, Comparator and Outcomes
The power of prevention (PICO) is a framework used in evidence-based medicine
Because prevention strategies act at a population level, to understand the structure of RCTs and is useful when
their power is often not appreciated by individuals com- considering the design and critical appraisal of AD pre-
pared with treatments for a disease. Yet the power of vention trials (12).
prevention is potentially huge. In his article entitled “The Participants. Most AD prevention studies target a high-
power of prevention and what it requires” Woolf draws risk population e.g. babies born to families with a first-
our attention to the fact that whereas new diabetes drugs degree relative with AD or associated allergic diseases
that reduce glycohemoglobin levels by 0.5% often make such as asthma, hay-fever or food allergy. The advantage
the headlines, exercise, that can lower the incidence of of this approach is that parents who have experienced AD
diabetes by 50%, rarely achieves such publicity (9). The themselves or witnessed it in family members are often
conquest of many infectious diseases such as diphtheria, highly motivated (during pregnancy or soon after) to un-
smallpox, polio and measles are testament to the power dertake interventions that could prevent AD in their new

Theme issue: Atopic dermatitis

 382 H. C. Williams and J. C. Chalmers

baby. The disadvantage is that if the selected population Comparator. In the absence of a clear reference standard
is too narrow, the intervention may have a limited overall of an effective active treatment, control interventions for
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population impact. However, tackling an entire popula- AD prevention trials are typically “standard care” (which
tion such as all newborns is challenging, especially if the is often not defined), an attention control, or some form
behaviour change modification is substantial, as parents of placebo (e.g. inactive probiotics). Convincing parents
will be less motivated to act on something that will be of with a family history of AD to take part in a study with
little perceived benefit to their child. This phenomenon a 50:50 chance that their new baby will be allocated to
is known as the prevention paradox – a term coined by the “no treatment” group can be challenging, and unless
Rose to denote “a measure that brings large benefits to the equipoise is carefully explained, parents may drop out if
community offers little to each participating individual” they don’t get the “new active” intervention. Feasibility
(13). Fig. 3 illustrates the possible trade-off between high
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studies that test randomisation and retention are essential

and low risk approaches to AD prevention suggested and offer the opportunity to develop patient information
previously (14). materials with patients that imply active monitoring and
Intervention. An essential step in the prevention of any altruistic rewards to overcome the notion of “control
disease is a thorough knowledge of risk factors that can neglect” that can result in resentful demoralisation (17).
be manipulated. For example, filaggrin gene mutations Outcomes. Whereas clinical trials of people with AD
cannot be directly manipulated in utero at present (alt- (prevalent cases) seek to reduce disease severity, one is
hough it may be possible in time) whilst a reduction in trying to prevent new (incident) cases from developing in
house dust mite in the home environment is achievable. a prevention study. There is a lack of research on defining
Another key consideration is the acceptability of in- an incident case of AD. Simpson et al. (18) undertook a
terventions given that healthy people are being asked systematic review of definitions of an incident case of
to undergo elaborate changes to their lives in order to AD used in prevention studies. Of 102 included studies,
prevent disease in a proportion of people – the identity 27 did not define an incident case, 28 used the Hanifin &
whom will remain unknown to them. Here, there is often Rajka criteria (19), and 21 used definitions unique to that
a trade-off between intensity of intervention which might study without referencing the source. It is important to note
achieve a larger effect (such as applying emollient twice that “chronic relapsing course” (a major criterion for the
a day to their child for 2 years, wash only in soft water Hanifin & Rajka criteria), whilst acceptable for measuring
and use no soap) versus those that are likely to have wider cumulative incidence, is problematic when defining a new
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population reach (such as advice to use emollients once case which, by definition, has not yet become chronic. Yet
daily for the first year of life as in the BEEP trial) (15). diagnosing AD confidently in a baby on the first day they
Testing acceptability of interventions is essential before develop an eczematous rash is also fraught with problems as
proceeding to full scale evaluation (16). Assessing safety transient irritant eczematous dermatoses (which are proba-
is paramount in prevention studies. Whilst individuals bly not true AD) are common in infancy. Simpson et al. (20)
with severe AD might accept the risk of nausea and liver suggested a compromise whereby the UK refinement of the
disease from methotrexate therapy, healthy individuals Hanifin & Rajka criteria are used to denote a continuous or
will have a low threshold for rejecting interventions with intermittent itchy skin condition lasting at least 4 weeks.
even small risks, such as the slipping on emollients spilt Ideally outcome assessment should be separated from
Advances in dermatology and venereology

on a bathroom floor. Furthermore, minor adverse effects the intervention period by a clear margin to separate treat-
such as transient stinging after emollient application can ment effects from prevention effects. For example, in the
reduce adherence to an intervention. two small preliminary studies that suggested emollients
might prevent AD, outcomes were assessed at the end
of the intervention period, making it difficult to assess
whether the apparent benefit was due to emollients preven-
ting AD or actively treating new mild AD (16, 21). This
is why the main BEEP trial of emollients used during the
first year is assessing the primary outcome of AD (those
fulfilling the UK refinement of the Hanifin & Rajka criteria
in the last year) at the age of 2 years (15). Whilst complete
prevention of disease is the ultimate goal, prevention of
Fig. 3. Hypothetical example of the prevention yield from a high more severe forms of the disease (which cause the most
risk vs low risk prevention approach for atopic dermatitis. Depicts
morbidity and result in most healthcare usage) is also an
an average Western population where 40% of 1,000 adult couples have
a strong family history of atopy and 60% do not. If 30% of the high risk important goal in AD prevention trials. Because the shape
babies develop AD compared with 15% without such a family history, a of AD prevalence in any population is skewed to the left
high risk approach would only prevent 57% (120/120+90) of AD cases (Fig. 4), even small shifts in the reduction of population
at a population level. Adapted from Williams HC. Atopic Dermatitis. In:
Williams HC, Strachan DP (eds). The Challenge of Dermato-Epidemiology. severity can result in large gains in absolute terms for the
Boca Raton, CRC Press Inc., 1997. number switching from severe to moderate or mild to very

Theme issue: Atopic dermatitis

 Prevention of atopic dermatitis 383

mild/subclinical disease. Time to onset of AD is another outcome assessment (e.g. visible eczema recorded by in-
outcome that can be considered although it is debatable vestigators blinded to intervention status) to mitigate the
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whether simply delaying onset of a miserable disease to risk of information bias. Studies should present findings
an older age is really a bonus. Given that AD is closely as absolute risk reductions as well as the more impressive
related to other “atopic” diseases such as food allergy, sounding relative risk reductions in order to provide a
asthma and hay fever, AD prevention studies also need more realistic indicator of population benefit.
to evaluate whether benefits are seen in these diseases
too. Measuring other atopic diseases present their own
challenges, e.g. true food allergy has a low incidence THE EVIDENCE
making it unlikely that beneficial effects will be precisely Primary prevention
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measured even in large studies, and conditions like asthma

have a later age of onset adding to the cost of following The 2011 overview of systematic reviews of primary pre-
up individuals from RCTs that start at birth to older ages. vention. In an attempt to reconcile the increasing number
Reducing bias. In addition to standard approaches to re- of Cochrane and non-Cochrane systematic reviews on
duce RCT biases such as registration of study protocols AD prevention, a group (including the two authors)
before recruitment starts and ensuring randomisation is undertook an overview of all such systematic reviews in
truly random and concealed, two biases require special 2011 (search date up to August 2010). Quantitative and
consideration in AD prevention trials. The first is per- qualitative methods were used to collate and combine
formance bias which results from treating intervention data where possible using Cochrane methods. Included
and control groups differently. More attention given to reviews had to include some quantitative data that could
the intervention group can result in different ancillary be combined, search date within the last 5 years, and in-
behaviours that can affect AD risk, so it is important cluded participants between the ages of zero and 18 years.
that both groups are treated in the same way in terms of Seven systematic reviews containing 39 RCTs and 11,897
regularity of contact and incentives from the research participants met the inclusion criteria. All 7 reviews were
team, and any post-randomisation behaviours that could considered methodologically sound, although the data
confound the study result are recorded. Sometimes such from the review on probiotics had to be re-analysed as
behaviours can include contamination of the intervention data from one trial had been included more than once
in the control group (because they think they are missing in the same meta-analysis. Interventions included use of
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out on something beneficial), which can be a particular hydrolysed formula milk (extensive and partial), extended
problem if the intervention is something that can be easily duration of exclusive breastfeeding, dietary supplemen-
accessed by participants without the need for healthcare tation with omega-3 and omega-6 oils, maternal dietary
professionals, such as reduction of house dust mites in antigen avoidance during pregnancy, lactation or both,
the home. Contamination should therefore be measured soy formula milks, along with prebiotics and probiotics.
and explored in the analysis. A second challenge lies in Participants were from a mixture of high and lower risk
the fact that because many interventions such as emol- families, although risk was rarely adequately defined.
lient application or installing a water softener cannot be None of the pooled interventions showed clear evidence of
blinded, it is essential to include some form of objective benefit for AD prevention. A subgroup analysis of those at
Advances in dermatology and venereology

high risk of developing AD based on just one RCT found

that prebiotics (ingested substances that favour the growth
of beneficial bacteria in the gut) decreased AD incidence
by 58% (RR: 0.42; 95% CI: 0.21, 0.84) compared with
no prebiotics. Data on whether those developing AD were
truly atopic was missing from most of the studies, and in
those that did, there was no evidence that the interventions
decreased atopy. One non-randomised study suggested
that prolonged exclusive breastfeeding (at least 6 months)
reduced AD incidence by 60% (RR 0.40, 95% CI 0.21 to
0.78). Despite the lack of any convincing signals for any
of the interventions tested, the risk estimates for most
interventions had low precision, indicating that some inter-
ventions with no evidence of benefit could still be useful.
Fig. 4. Schematic representation of atopic dermatitis severity
(x-axis) versus number with atopic dermatitis in two hypothesized
populations. Even if atopic dermatitis cannot be prevented completely,
The post 2011 overview era
shifting the population severity distribution of disease to the left (red curve) Interventions that are ingested by mothers and/or infants.
could have a huge impact on pushing more into subclinical disease and
reducing the absolute proportion with severe disease who suffer the most Also known as the “inside out” approach, ingested mater-
and who consume most health resources. nal/infant interventions include exclusive breastfeeding,

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 384 H. C. Williams and J. C. Chalmers

delay or early introduction of foods other than milk, dietary among infants and toddlers that included two older cohort
restrictions, and dietary supplements. Although breastfee- studies suggested a possible benefit for AD prevention,
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ding (exclusive or prolonged) has clear benefits for infants, and called for new studies that evaluated such foods in a
a systematic review of 16 moderate quality observational more contemporary setting (33). A systematic review in
studies suggests that it does not appear to be protective 2019 of 22 pooled trials published between January 2008
of AD (22). One large cluster RCT (the PROBIT trial in and May 2018 showed a reduction in AD incidence (RR
Belarus) that promoted breastfeeding found a reduction 0.81, 95% CI: 0.70–0.93) for those receiving probiotic
in self-reported flexural eczema but not lung function, a supplementation during pregnancy and/or infancy. Sub-
finding that needs to be replicated (23). Around a half of group analysis suggested that benefits were strongest for
milk feeding studies have been judged to be at high risk those receiving Lactobacillus and Bifidobacterium, for
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of bias (24). A Cochrane review of 5 trials failed to show those in whom probiotic supplementation occurred during
any benefit of maternal avoidance of allergenic foods for pregnancy and infancy and in preventing AD developing
AD prevention (25). A 2019 systematic review of mainly in the first two years of life rather than later (34). Sources
observational studies of complementary feeding (whereby of study heterogeneity was also assessed and found to be
other foods and drinks complement human or formula mainly accounted by follow-up time (I2 62.7%) and length
milk) found no clear evidence between the age at which of probiotic supplementation (I2 53.5%). A more extensive
complementary feedings is started and the risk of AD, food systematic review that pooled 28 studies (27 good quality
allergy or asthma (moderate evidence) (26). The same RCTs and one high quality cohort study, search date from
review found limited to strong evidence that introducing inception to March 2018) showed a beneficial effect on
allergenic foods in year one of life to try and induce tole- AD prevention for probiotics compared with controls (OR
rance does not increase AD or food allergy risk, but may 0.69; 95% CI 0.58–0.82, Fig. 5) (35). Analysis of studies
prevent egg and peanut allergy. The one well-conducted whereby probiotics were provided only prenatally or post-
RCT included in the review found no benefit for AD pre- natally did not show such benefit, prompting the authors
vention from early introduction of allergenic foods (27). to conclude that benefits are only realised when probiotics
Interest in vitamin D supplementation as a possible are started during pregnancy and continued in the infant
preventative intervention stems from the association for the first 6 months of life. A broader and high-quality
between low vitamin D levels and increased incidence systematic review of diet during pregnancy and infancy
and severity of AD. Vitamin D is also known to have arrived at similar conclusions regarding a protective effect
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a regulatory influence on skin barrier function and the of probiotics on AD development from 19 probiotic trials
immune system and skin barrier function, both of which (risk ratio 0.78; 95% CI 0.68–0.90; I2 61% and an absolute
are involved in AD development (28). A 2017 systematic risk reduction of 44 cases per 1,000; 95% CI 20–64) (24).
review (search date January 2016) found one RCT and Subgroup analysis suggested that it was maternal rather
3 non-RCTs that addressed vitamin D supplementation than infant probiotic supplementation that was important
in women and children as a means of preventing allergic for realising a protective benefit. The evidence of prebiotics
diseases found no clear evidence of benefit but with low alone was weak due to high risk of bias, inconsistency,
certainty of evidence (29). A more recent and well con- imprecision, and indirectness of study results.
ducted RCT found no clear benefit of infant vitamin D Although the World Allergy Organisation guideline pa-
Advances in dermatology and venereology

supplementation in the primary prevention of AD (30). A nel has determined that there is a net benefit of probiotics
systematic review of omega-3 long-chain polyunsaturated for AD prevention, concerns regarding the heterogen-
fatty acids (such as from fish) intake during pregnancy eity of studies remains (36). A comprehensive review of
found mixed results for AD prevention from observational probiotics across all human diseases concluded that the
studies, but a possible protective effect in the 3 included evidence for benefit in allergic diseases was still uncertain
RCTs for early onset AD (31). and a stimulus for further studies rather than firm clinical
The evidence that ingested probiotics (non-pathogenic recommendations (37). A high-quality individual patient
live bacteria or yeasts that can restore a dysfunctional data (IPD) meta-analysis – a type of systematic review
pro-inflammatory gut microbiome) or prebiotics (non- that gathers and combines data belonging to individual
digestible food ingredients that encourage beneficial patient who take part in clinical trials rather than aggre-
bacteria to thrive) or both (synbiotics) can prevent AD gate data – would better identify who benefits most from
is gathering momentum (32). The field is complicated probiotics, when and why (38).
as probiotics and prebiotics refer to a very wide range of Interventions directed at the external skin surface. The
ingredients, and they can be given to the mother during main “outside in” approaches for preventing AD, sensitisa-
pregnancy, during lactation, to the infant after birth and tion and food allergy have included attempts to reduce air-
various combinations of these and for different periods, borne allergens such as house dust mite at the time of birth,
leading to considerable heterogeneity which impacts on increasing exposure to an anthroposophic environment
the ability to combine studies. One systematic review ex- and measures to enhance the skin barrier. A systematic
ploring the possible health benefits of yoghurt consumption review of house dust mite avoidance strategies (alone or

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 Prevention of atopic dermatitis 385

and 4 months of age and (iv) both skin and complementary

feeding strategies. Results of BEEP and PreventADALL
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are not available at the time of writing. Two trials were

published in 2019, both of which used complex emollients
containing ingredients such as ceramide designed to en-
hance the skin barrier (44, 45). The first study suggested
that emollient therapy may reduce AD incidence, but this
was not statistically significant, and there was no effect of
emollient on barrier measurements (46). The second larger
study was a factorial trial of emollient and synbiotics and
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found no evidence of a protective effect of either interven-

tion (44). At least 10 other similar prevention trials that
explore the potential of different skin barrier products to
prevent AD in high and low risk populations (46). Together,
most of these studies now form part of a prospectively-
planned meta-analysis consortium called SCiPAD (Skin
care intervention for prevention of atopic disease) (47, 48).
Other direct to skin approaches such as “probiotic creams”
that serve to influence the early skin microbiome towards
one that is less favourable for the development of AD are
Fig. 5. The preventive effect of probiotics in atopic dermatitis.
Forest plot depicting a meta-analysis that used a random effects model
also worthy of further research (49).
combining 28 evaluated studies. Although the summary odds ratio (OR) Combined approaches. Whilst it might be easier to imple-
suggests clear benefit (OR 0.69; 95% confidence interval (CI) 0.58–0.82;
ment one simple intervention to prevent AD, it might be
p < 0.0001), there was considerable heterogeneity between the studies
(I2 = 53.6%) (33). Reproduced with kind permission from the American possible to combine multiple interventions each of which
Journal of Clinical Dermatology. has a small beneficial effect, especially if they interact to
produce more than the sum of the whole. The hazard of
with allergen avoidance) that included 7 RCTs (search date a “throw in everything that might work” strategy is that
October 2014) concluded such modalities do not decrease they can become black boxes that are not amenable to
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the risk of developing AD. Studies that have found strong replication, unless the components are separated using
associations between early exposures to anthroposophic designs such as factorial trials as currently being done in
environments such as farm animals have been limited to the PreventADALL study (50).
observational studies so far, but are a fruitful source of
ideas for new possible primary interventions (39). Since Secondary prevention
the discovery of a strong association between AD and Treating AD more aggressively when it first appears in
loss-of-function mutations in FLG, the gene encoding an attempt to alter the subsequent course of disease in
filaggrin – an essential protein for healthy skin barrier terms of remission or decreasing severity is an attractive
Advances in dermatology and venereology

function, interest has increased on the potential benefits notion. One such study of aggressive early treatment is
of skin barrier enhancement as a means of preventing AD underway in Japan, in which 650 infants who develop
and food allergy (40). Impaired skin barrier may precede AD between the ages of 7–13 weeks old will be ran-
eczema development and may be the route by which sen- domly assigned to enhanced topical anti-inflammatory
sitisation to food allergens occurs (41, 42). Stimulated by treatment or conventional treatment with the aim of
the results of two small pilot RCTs that suggested a large preventing food allergy and reducing AD severity (51).
benefit from using emollients on the skin of infants born Poorly controlled disease resulting in skin damage from
to families with atopy, two large prevention RCTs have scratching can lead to a cascade that results in indivi-
been set up to test the hypothesis that emollients from duals developing autoimmunity towards their own skin
birth can prevent AD (15, 16, 21, 43). The first of these components, a phenomenon that might be key to driving
studies (Barrier Enhancement for Eczema Prevention disease chronicity (52). Other non-pharmacological
(BEEP) trial) is investigating daily emollient for the first approaches such as behavioural methods to limit skin
year of life in babies born to atopic families. The second, damage from scratching when AD first appears are also
the Preventing Atopic Dermatitis and Allergies in children worth considering in this context (53). Like primary pre-
study (PreventADALL), is a factorial trial – a trial whereby vention, secondary prevention should not be taken lightly,
two or more interventions are carried out and assessed especially with regards to safety. If for example, only
simultaneously. The PreventADALL trial compares (i) 10% of those given early aggressive treatment with pro-
no intervention with (ii) skin care (oil-bath at least 5 days/ longed topical corticosteroids benefit from such therapy,
week to age 9 months) and (iii) consecutive introduction of then 90% arguably undergo “overtreatment” and incur
allergenic foods (peanut, milk, wheat, and egg) between 3 side effects in order to benefit the few.

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 386 H. C. Williams and J. C. Chalmers

So far, prevention of related diseases such as food al-

lergy and asthma have only been considered in the context
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of early interventions that primarily aim to prevent AD,

but another important question to consider in relation to
secondary prevention of AD is whether interventions that
are initiated when AD is first identified can prevent the
development of conditions such as asthma. Such a concept
was the basis of the Early Treatment of the Atopic Child
study (ETAC) whereby 795 children with new onset AD
between 1 and 2 years of age were randomised to cetirizine
or placebo for 18 months. Cetirizine was chosen because
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it might inhibit eosinophil tracking to the lungs as well as

its anti-histamine effect. The ETAC study did not show
that asthma could be prevented by such an approach (54).
Although urticaria rates were less in the intervention group, Fig. 6. The concept of getting control then keeping control in atopic
dermatitis. A more subtle interpretation of tertiary prevention is the
severity of AD was not reduced in the cetirizine group principle of inducing remission of atopic dermatitis with an initial blast of
either, throwing doubt on the value of anti-histamines in the topical treatment followed by prevention of disease flares with weekly pulses
treatment of AD – an observation that has been confirmed of two consecutive days of topical treatment (also known as the Centre of
in a subsequent Cochrane review (55, 56). A follow-up Evidence-Based Dermatology “get control and keep control” approach).
When contrasted against more traditional reactive approaches, the proactive
RCT from ETAC called the EPAAC study explored the use approach results in more disease being pushed into a subclinical state and
of levocetirizine for the prevention of asthma in children hence better overall disease control. Reproduced with kind permission from
with AD who were sensitised to grass and/or house dust the Journal of Allergy and Clinical Immunology.

mite was stopped due to lack of benefit (57).

in 4 of those with adult AD appear to develop it for the
Tertiary prevention first time in adulthood (63). Less is known about the risk
factors for adult-onset AD in order to identify candidates
In its broadest sense tertiary prevention refers to disease for prevention studies (64). One study of 67,643 US wo-
treatment, prevention of deterioration, disease compli- men postulated that niacin intake might protect against
cations and sequelae. In relation to AD, one of the most
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adult AD since niacin has been found to decrease trans-

important advances in disease treatment over the last 30 epidermal water loss. Instead, it found that adult AD was
years has been the concept of proactive treatment (two paradoxically increased with niacin intake, a finding that
consecutive days per week) for those who have been needs to be replicated (65).
stabilised. This has been shown to dramatically reduce
the number of subsequent flares (58). A meta-analysis by
Schmitt et al. showed that topical fluticasone reduced the CONCLUSIONS
risk of further flares by around half (relative risk 0.46, 95%
The last few decades of research into the prevention of
CI 0.38–0.55) with more modest reductions in flares with
AD have thrown up very few signals of simple, safe
Advances in dermatology and venereology

weekly topical tacrolimus (RR 0.78, 95% CI 0.60–1.00)

interventions that are likely to be effective at a popula-
(59). When considering prevention of flares, it is equally
tion level. Errors in the design and reporting of studies
important to consider induction of remission before proac-
tend to be repeated rather than learned, and the same old
tive therapy is initiated – the concept of “get control then
interventions are often tested again and again with little
keep control” as illustrated schematically in Fig. 6 (60).
new insight. Past research has also been concerned with a
Another review suggested that Vitamin D supplementa-
rather fruitless obsession with allergic factors despite the
tion for early disease may have a small beneficial effect
fact that around half of people with “atopic” dermatitis are
in reducing later disease severity (61). Given that AD is
not atopic in the scientific sense (66). The main exception
a chronic relapsing condition, prevention of flares and
to the lack of positive findings for AD prevention has been
embracing the concept of overall disease control have
the use of probiotics. Probiotic use has consistently shown
become key considerations in improving quality of life
modest benefit and good safety when tested in different
of AD sufferers (62). Better prediction of flares in what
populations around the world, prompting the World Allergy
often appears a random process offers exciting prospects
Organisation guideline panel to determine that there is a
for personalised medicine.
likely net benefit from using probiotics resulting primarily
from prevention of eczema. The WAO guideline panel sug-
What about adult-onset atopic dermatitis? gests using probiotics in: (i) pregnant women at high risk of
Most of the evidence discussed relates to early life. This having an allergic child; (ii) women who are breastfeeding
is with good reason as AD typically starts in the first few infants at high risk of developing allergy; and (iii) infants
years of life. Recent studies have drawn attention to the at high risk of developing allergy. New evidence is likely
importance of AD in adults, pointing out that around one to emerge on barrier enhancement as a strategy for AD
Theme issue: Atopic dermatitis
 Prevention of atopic dermatitis 387

prevention over the next 5 years, especially through the 11. Gordon RS, Jr. An operational classification of disease preven-
tion. Public health reports (Washington, DC: 1974) 1983; 98:
SCiPAD prospectively planned meta-analysis.
ActaDV

107–109.
In terms of future research, it is worth exploring new 12. Richardson WS, Wilson MC, Nishikawa J, Hayward RS. The
risk factors rather than doing more studies on the same well-built clinical question: a key to evidence-based decisions.
ACP journal club 1995; 123: A12–13.
interventions that do not look promising. The comprehen- 13. Rose G. Strategy of prevention: lessons from cardiovascular
sive overview of systematic reviews of epidemiology of disease. Br Med J 1981; 282: 1847–1851.
allergic diseases conducted by Genuniet et al. (67) is a good 14. Williams HC. Atopic dermatitis. In: Williams HC, Strachan DP
(editors). The Challenge of Dermato-Epidemiology. Boca Raton,
place to start and by reconsidering the host of non-specific, CRC Press Inc., 1997, p. 125-144.
specific and internal factors that make up the “exposome” 15. Chalmers JR, Haines RH, Mitchell EJ, Thomas KS, Brown SJ Ridd
for AD (67, 68). Rather than considering reduction of M, et al. Effectiveness and cost-effectiveness of daily all-over-
body application of emollient during the first year of life for
Acta Dermato-Venereologica

harmful exposures, exploration of increasing potentially preventing atopic eczema in high-risk children (The BEEP trial):
beneficial substances might be considered. Given the protocol for a randomised controlled trial. Trials 2017; 18: 343.
inverse relationship between helminth exposure and al- 16. Simpson EL, Chalmers JR, Hanifin JM, Thomas KS, Cork MJ
McLean WHI, et al. Emollient enhancement of the skin bar-
lergic sensitisation, derivative products that switch off the rier from birth offers effective atopic dermatitis prevention. J
dysfunctional immune response could be explored further Allergy Clin Immunol 2014; 134: 818–823.
(69). The foetal environment may be a better place to focus 17. Torgerson DJ, Sibbald B. Understanding controlled trials. What
is a patient preference trial? BMJ 1998; 316: 360.
than the infant environment. Rather than conducting more
18. Simpson EL, Keck LE, Chalmers JR, Williams HC. How should
probiotic trials, stopping and conducting a more refined an incident case of atopic dermatitis be defined? A systematic
analysis of the 28 or so existing studies using individual review of primary prevention studies. J Allergy Clin Immunol
2012; 130: 137–144.
patient data meta-analysis may help to bridge the gap
19. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis.
between cautious recommendation and implementation in Acta Derm Venereol 1980; Suppl 92: 44–47.
order to benefit future generations of children who might 20. Williams HC, Burney PG, Pembroke AC, Hay RJ. The U.K. Working
otherwise be destined to a life with AD. Party’s Diagnostic Criteria for Atopic Dermatitis. III. Indepen-
dent hospital validation. Br J Dermatol 1994; 131: 406–416.
21. Horimukai K, Morita K, Narita M, Kondo M, Kitazawa H, Nozaki
M, et al. Application of moisturizer to neonates prevents de-
ACKNOWLEDGEMENT velopment of atopic dermatitis. J Allergy Clin Immunol 2014;
134: 824–830 e826.
Conflicts of interest: Both authors are involved in the Barrier 22. Gungor D, Nadaud P, LaPergola CC, Dreibelbis C, Ping Wong YP,
Enhancement for Eczema Prevention (BEEP) study funded by Terry N, et al. Infant milk-feeding practices and food allergies,
ActaDV

the UK National Institute for Health Research Health Technology allergic rhinitis, atopic dermatitis, and asthma throughout
Assessment Programme. the life span: a systematic review. Am J Clin Nutr 2019; 109:
772s–799s.
23. Flohr C, Henderson AJ, Kramer MS, Patel R, Thompson J,
Rifas-Shiman SL, et al. Effect of an intervention to promote
REFERENCES breastfeeding on asthma, lung function, and atopic eczema at
1. Kim JE, Kim HS. microbiome of the skin and gut in atopic der- age 16 years: follow-up of the PROBIT randomized trial. JAMA
matitis (AD): understanding the pathophysiology and finding Pediatr 2017: 172; e174064.
novel management strategies. J Clin Med 2019; 8: pii: E444. 24. Garcia-Larsen V, Ierodiakonou D, Jarrold K, Cunha S, Chivinge
2. Brown SJ. Molecular mechanisms in atopic eczema: insights J, Robinson Z, et al. Diet during pregnancy and infancy and
gained from genetic studies. J Pathol 2017; 241: 140–145. risk of allergic or autoimmune disease: A systematic review
Advances in dermatology and venereology

3. Doll R, Hill AB. Smoking and carcinoma of the lung; preliminary and meta-analysis. PLoS medicine 2018; 15: e1002507.
report. BMJ 1950; 2: 739–748. 25. Kramer MS, Kakuma R. Maternal dietary antigen avoidance
4. Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, during pregnancy or lactation, or both, for preventing or
Lockey RF,, et al. Revised nomenclature for allergy for global treating atopic disease in the child. Cochrane Database Syst
use: Report of the Nomenclature Review Committee of the Rev 2012: Cd000133.
World Allergy Organization, October 2003. J Allergy Clin Im- 26. Obbagy JE, English LK, Wong YP, Butte NF, Dewey KG, Fleischer
munol 2004; 113: 832–836. DM, et al. Complementary feeding and food allergy, atopic
5. Centre of Evidence Based Dermatology systematic reviews dermatitis/eczema, asthma, and allergic rhinitis: a systematic
on eczema https://www.nottingham.ac.uk/research/groups/ review. Am J Clin Nutr 2019; 109: 890s–934s.
cebd/resources/eczema-systematic-reviews.aspx, accessed 27. Perkin MR, Logan K, Tseng A, Raji B, Ayis S, Peacock J, et al.
14th August 2019. Randomized trial of introduction of allergenic foods in breast-
6. Foisy M, Boyle RJ, Chalmers JR, Simpson EL, Williams HC. fed infants. N Engl J Med 2016; 374: 1733–1743.
Overview of Reviews The prevention of eczema in infants and 28. Palmer DJ. Vitamin D and the development of atopic eczema.
children: an overview of Cochrane and non-Cochrane reviews. J Clin Med 2015; 4: 1036–1050.
Evid Based Child Health 2011; 6: 1322–1339. 29. Yepes-Nunez JJ, Brozek JL, Fiocchi A, Pawankar R, Cuello-
7. Nankervis H, Thomas KS, Delamere FM, Barbarot S, Rogers Garcia C, Zhange Y, et al. Vitamin D supplementation in primary
NK, Williams HC. Scoping systematic review of treatments allergy prevention: Systematic review of randomized and non-
for eczema. Programme Grants for Applied Research 2016. randomized studies. Allergy 2018; 73: 37–49.
8. Global Resource for Eczema Trials (GREAT Database), Centre 30. Rueter K, Jones AP, Siafarikas A, Lim E-M, Bear N, Noakes PS,
of Evidence Based Dermatology, www.greatdatabase.org.uk/ et al. Direct infant UV light exposure is associated with eczema
GD4/Home/Index.php – accessed 14th August 2019. and immune development. J Allergy Clin Immunol 2019; 143:
9. Woolf SH. The power of prevention and what it requires. JAMA 1012–1020.e1012.
2008; 299: 2437–2439. 31. Best KP, Gold M, Kennedy D, Martin J, Makrides M. Omega-3
10. Quinn SC, Jamison AM, Freimuth VS. Measles outbreaks and long-chain PUFA intake during pregnancy and allergic disease
public attitudes towards vaccine exemptions: some cautions outcomes in the offspring: a systematic review and meta-
and strategies for addressing vaccine hesitancy. Hum Vaccin analysis of observational studies and randomized controlled
Immunother 2019; 22: 1–5. trials. Am J Clin Nutr 2016; 103: 128–143.

Theme issue: Atopic dermatitis

 388 H. C. Williams and J. C. Chalmers

32. Szari S, Quinn JA. Supporting a healthy microbiome for the infantile atopic dermatitis to prevent development of food al-
primary prevention of eczema. Clin Rev Allergy Immunol lergy: a multicenter, investigator-blinded, randomized, parallel
ActaDV

2019; 57: 286–293. group controlled trial (PACI Study)-protocol for a randomized
33. Donovan SM, Rao G. Health benefits of yogurt among infants controlled trial. Clin transl allergy 2018; 8: 47.
and toddlers aged 4 to 24 months: a systematic review. Nutri- 52. Tang TS, Bieber T, Williams HC. Does “autoreactivity” play a
tion reviews 2019; 77: 478–486. role in atopic dermatitis? J Allergy Clin Immunol 2012; 129:
34. Yin DG, He Z, Duan XY, Fan FX, Liao XB, Wang QC. Zhongguo 1209–1215.e1202.
Dang Dai Er Ke Za Zhi 2019; 21: 82–88. 53. Bewley A. Habit reversal therapy quickly and significantly con-
35. Li L, Han Z, Niu X, Zhang G, Jia Y, Zhang S, et al. Probiotic tributes to the management of children with atopic eczema.
supplementation for prevention of atopic dermatitis in infants Br J Dermatol 2018; 178: 584–585.
and children: a systematic review and meta-analysis. Am J 54. Warner JO. A double-blinded, randomized, placebo-controlled
Clin Dermatol 2019; 20: 367–377. trial of cetirizine in preventing the onset of asthma in children
36. Fiocchi A, Pawankar R, Cuello-Garcia C, Ahn K, Al-Hammadi with atopic dermatitis: 18 months’ treatment and 18 months’
S, Agarwal A, et al. World Allergy Organization-McMaster Uni- posttreatment follow-up. J Allergy Clin Immunol 2001; 108:
Acta Dermato-Venereologica

versity Guidelines for Allergic Disease Prevention (GLAD-P): 929–937.

Probiotics. The World Allergy Organization Journal 2015; 8: 4. 55. Matterne U, Bohmer MM, Weisshaar E, Jupiter A, Carter B,
37. Rondanelli M, Faliva MA, Perna S, Giacosa A, Peroni G, Castel- Apfelbacher CJ. Oral H1 antihistamines as ‘add-on’ therapy
lazzi AM. Using probiotics in clinical practice: Where are we to topical treatment for eczema. Cochrane Database Syst Rev
now? A review of existing meta-analyses. Gut Microbes 2017; 2019; 1: Cd012167.
8: 521–543. 56. Diepgen TL. Long-term treatment with cetirizine of infants with
38. Riley RD, Lambert PC, Abo-Zaid G. Meta-analysis of individual atopic dermatitis: a multi-country, double-blind, randomized,
participant data: rationale, conduct, and reporting. BMJ 2010; placebo-controlled trial (the ETAC trial) over 18 months. Pediatr
340: c221. Allergy Immunol 2002; 13: 278–286.
39. Campbell BE, Lodge CJ, Lowe AJ, Burgess JA, Matheson MC, 57. https://clinicaltrials.gov NCT00152464 – Prolongation of the
Dharmage SC. Exposure to ‘farming’ and objective markers EPAAC™ trial (The Early Prevention of Asthma in Atopic Child-
of atopy: a systematic review and meta-analysis. Clin Exp ren) – 36 months study to evaluate the efficacy and safety
Allergy 2015; 45: 744–757. of levocetirizine (LCTZ) in preventing the onset of asthma
40. Loset M, Brown SJ, Saunes M, Hveem K. Genetics of atopic in young atopic children. https://clinicaltrials.gov/ct2/show/
dermatitis: From DNA sequence to clinical relevance. Derma- NCT00160563. Published 2005. Accessed 16th August, 2019.
tology 2019; 235: 355–364. 58. Wollenberg A, Ehmann LM. Long term treatment concepts and
41. Kelleher M, Dunn-Galvin A, Hourihane JO, Murray D, Campbell proactive therapy for atopic eczema. Ann Dermatol 2012; 24:
le, McClean WHI, et al. Skin barrier dysfunction measured by 253–260.
transepidermal water loss at 2 days and 2 months predates 59. Schmitt J, von Kobyletzki L, Svensson A, Apfelbacher C. Efficacy
and predicts atopic dermatitis at 1 year. J Allergy Clin Immunol and tolerability of proactive treatment with topical corticoste-
2015; 135: 930–935.e931. roids and calcineurin inhibitors for atopic eczema: systematic
42. Broeks SA, Brand PL. Atopic dermatitis is associated with a review and meta-analysis of randomized controlled trials. Br
fivefold increased risk of polysensitisation in children. Acta J Dermatol 2011; 164: 415–428.
ActaDV

Paediatrica 2017; 106: 485–488. 60. Tang TS, Bieber T, Williams HC. Are the concepts of induction
43. Rehbinder EM, Winger AJ, Landro L, Asarnoj A, Berents TL, of remission and treatment of subclinical inflammation in atopic
Carlsen KH, et al. Dry skin and skin barrier in early infancy. dermatitis clinically useful? J Allergy Clin Immunol 2014; 133:
Br J Dermatol 2019; 181: 218–219. 1615–1625.e1611.
44. McClanahan D, Wong A, Kezic S, Samrao A, Hajar T, Hill E, et 61. Hattangdi-Haridas SR, Lanham-New SA, Wong WHS, Ho
al. A randomized controlled trial of an emollient with ceramide MHK, Darling AL. Vitamin D deficiency and effects of vitamin
and filaggrin-associated amino acids for the primary prevention d supplementation on disease severity in patients with atopic
of atopic dermatitis in high-risk infants. J Eur Acad Dermatol dermatitis: a systematic review and meta-analysis in adults
Venereol 2019; 33: 2087–2094. and children. Nutrients 2019; 11: E1854.
45. Dissanayake E, Tani Y, Nagai K, Sahara M, Mitsuishi C, Togawa 62. Chalmers JR, Thomas KS, Apfelbacher C, Williams, HC, Prin-
Y, et al. Skin care and synbiotics for prevention of atopic der- sen CA, Spuls PI, et al. Report from the fifth international
matitis or food allergy in newborn infants: A 2 x 2 factorial, consensus meeting to harmonize core outcome measures for
Advances in dermatology and venereology

randomized, non-treatment controlled trial. Int Arch Allergy atopic eczema/dermatitis clinical trials (HOME initiative). Br J
and Immunol 2019; 180: 202–211. Dermatol 2018; 178: e332–e341.
46. Lowe A, Su J, Tang M, Lodge CJ, Matheson M, Allen KJ, et 63. Lee HH, Patel KR, Singam V, Rastogi S, Silverberg JI. A sys-
al. PEBBLES study protocol: a randomised controlled trial to tematic review and meta-analysis of the prevalence and phe-
prevent atopic dermatitis, food allergy and sensitisation in notype of adult-onset atopic dermatitis. J Am Acad Dermatol
infants with a family history of allergic disease using a skin 2019; 80: 1526–1532.e1527.
barrier improvement strategy. BMJ Open 2019; 9: e024594. 64. Abuabara K, Ye M, McCulloch CE, Sullivan A, Margolis DJ,
47. Kelleher M, Cro S. SCiPAD (Skin care intervention for preven- Strachan DP, et al. Clinical onset of atopic eczema: Results
tion of atopic disease) https://skin.cochrane.org/sites/skin. from 2 nationally representative British birth cohorts followed
cochrane.org/files/public/uploads/cs_cochrane_jan_2019_ through midlife. J Allergy Clin Immunol 2019; 144: 710–719.
ipd_meta-analysis.pdf 2019. 65. Drucker AM, Li WQ, Park MK, Li T, Qureshi AA, Cho E. Niacin
48. Kelleher MM, Cro S, Cornelius V, Axon E, Lodrup Carlsen KC, intake and incident adult-onset atopic dermatitis in women. J
Skjerven HO, et al. Skincare interventions in infants for pre- Allergy Clin Immunol 2017; 139: 2020–2022.e2022.
venting eczema and food allergy. Cochrane Database Syst Rev 66. Flohr C, Weiland SK, Weinmayr G, Björkstén B, Bråbäck L,
2020; 2: CD013534. Brunekreef B, et al. The role of atopic sensitization in flexural
49. Totte J, de Wit J, Pardo L, Schuren F, van Doorn M, Pasmans S. eczema: findings from the International Study of Asthma and
Targeted anti-staphylococcal therapy with endolysins in atopic Allergies in Childhood Phase Two. J Allergy Clin Immunol 2008;
dermatitis and the effect on steroid use, disease severity and 121: 141–147.e144.
the microbiome: study protocol for a randomized controlled 67. Genuneit J, Seibold AM, Apfelbacher CJ, Konstantinou GN,
trial (MAAS trial). Trials 2017; 18: 404. Koplin JJ, Grutta SLa, et al. Overview of Systematic Reviews
50. Lodrup Carlsen KC, Rehbinder EM, Skjerven HO, Hauger Carl- in Allergy Epidemiology. Allergy 2017; 72: 849–856.
sen M, Fatnes TA, Fugelli P, et al. Preventing Atopic Dermatitis 68. Stefanovic N, Flohr C, Irvine AD. The exposome in atopic
and ALLergies in Children – the PreventADALL study. Allergy dermatitis. Allergy 2020; 75: 63–74.
2018; 73: 2063–2070. 69. Flohr C, Quinnell RJ, Britton J. Do helminth parasites protect
51. Yamamoto-Hanada K, Kobayashi T, Williams HC, Mikami, M, against atopy and allergic disease? Clin Exp Allergy 2009;
Saito-Abe M, Morita K, et al. Early aggressive intervention for 39: 20–32.

Theme issue: Atopic dermatitis