\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,greek,english]{babel}



\usepackage{float}








\begin{document}

\title{Early intervention and prevention of allergic diseases}



\author[1]{Helen Brough}%
\author[2]{Bruce Lanser}%
\author[3]{Sayantani Sindher}%
\author[4]{Joyce Teng}%
\author[5]{Donald Leung}%
\author[6]{Carina Venter}%
\author[1]{Susan Chan}%
\author[1]{Alexandra Santos}%
\author[7]{Henry Bahnson}%
\author[8]{Emma Guttman-Yassky}%
\author[9]{Ruchi Gupta}%
\author[1]{Gideon Lack}%
\author[10]{Christina Ciaccio@bsd.uchicago.edu}%
\author[3]{Vanitha Sampath}%
\author[3]{Kari Nadeau}%
\author[11]{Cathryn Nagler}%
\affil[1]{King's College London Faculty of Life Sciences and Medicine}%
\affil[2]{National Jewish Health}%
\affil[3]{Stanford University School of Medicine}%
\affil[4]{Lucile Salter Packard Children's Hospital at Stanford}%
\affil[5]{National Jewish Health Division of Allergy \& Clinical Immunology}%
\affil[6]{University of Colorado Denver Children's Hospital Colorado Research Institute}%
\affil[7]{Benaroya Research Institute at Virginia Mason}%
\affil[8]{Rockefeller University}%
\affil[9]{Ann and Robert H Lurie Children's Hospital of Chicago}%
\affil[10]{University of Chicago Department of Medicine}%
\affil[11]{University of Chicago Pritzker School of Medicine}%


\vspace{-1em}



  
  \date{May 21, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Food Allergy (FA) is now one of the most common chronic diseases of
childhood often lasting throughout life and leading to significant
worldwide healthcare burden. The precise mechanisms responsible for the
development of this inflammatory condition are largely unknown; however,
a multifactorial aetiology involving both environmental and genetic
contributions is well accepted. A precise understanding of the
pathogenesis of FA is an essential first step to developing
comprehensive prevention strategies that could mitigate this epidemic.
As it is frequently preceded by atopic dermatitis and can be prevented
by early antigen introduction, the development of FA is likely
facilitated by the improper initial presentation of antigen to the
developing immune system. Primary oral exposure of antigens allowing for
presentation via a well-developed mucosal immune system, rather than
through a disrupted skin epidermal barrier, is essential to prevent FA.
In this review, we present the data supporting the necessity of 1) an
intact epidermal barrier to prevent epicutaneous antigen presentation,
2) the presence of specific commensal bacteria to maintain an intact
mucosal immune system and 3) maternal/infant diet diversity, including
vitamins and minerals, and appropriately timed allergenic food
introduction to prevent FA.%
\end{abstract}%



\sloppy


\textbf{Introduction:}

Atopic conditions, including atopic dermatitis (AD), food and
environmental allergies and asthma, have become an important public
health concern world-wide.\textsuperscript{1} This review will focus
primarily on early interventions to prevent food allergy
(FA).\textsuperscript{2-4} Recent studies reinforce the strong
connection between early severe AD and the development of FA. Pediatric
FA has become an epidemic in many countries, with increasing rates in
the past few decades, although substantial variations from 1\% to 10\%
exist by country. To date, some of the highest rates have been observed
in high-income countries such as the United Kingdom, United States, and
Australia, where population-based surveys and analyses of healthcare
utilization data suggest the burden of disease has substantially
increased.\textsuperscript{5-9} While there is consensus that prevalence
has increased in many parts of the world, the magnitude is difficult to
ascertain due to numerous factors, including a lack of systematic
population-based surveillance efforts incorporating repeated, validated
prevalence assessments, and high-quality estimates lacking from many
countries. Figure 1 visualizes the most recently available
population-based estimates of pediatric FA
prevalence.\textsuperscript{10-12}

It is also difficult to estimate FA prevalence globally or compare rates
by country because of the limited international coordination of disease
surveillance efforts, leading to heterogeneity in study design, FA case
definitions, and study populations.\textsuperscript{10,13}Even in
studies with similar populations, direct comparisons of prevalence rates
are challenging as there are variations in social, cultural, and
economic factors. Despite the literature gaps, extensive research into
paediatric FA epidemiology provides insight into possible FA aetiology
and promising disease prevention avenues. For example, an epidemiologic
finding of disparate rates of infant peanut allergy among genetically
similar populations in the UK and Israel led to insights regarding the
protective role of early life exposure to major food
allergens.\textsuperscript{14} These insights have now been tested in
randomized controlled trials (RCTs) and translated into clinical
practice guidelines that advocate the early introduction of allergenic
solids for primary prevention.\textsuperscript{15-17}

The multifactorial aetiology of FA is well-recognised, with
environmental and genetic factors contributing to FA development.
However, strategies to manage FA remain limited in most cases to strict
allergen avoidance and managing allergic reactions, including teaching
patients/caregivers to administer epinephrine during suspected
anaphylaxis, which can adversely impact patient/caregiver quality of
life. \textsuperscript{18} Food allergen immunotherapy appears to offer
transient protection but is allergen-specific, time-intensive, and side
effects limit tolerability.\textsuperscript{19} Even when gold standard
treatments exist, prevention remains the ultimate goal since it can
circumvent early morbidity from disease and ameliorate treatment burden.

AD often heralds the atopic march and frequently precedes the
development of FA, allergic asthma and allergic rhinitis. Whether AD is
the primary insult, or the earliest manifestation of other underlying
factors is not yet fully established. However, AD is a significant risk
factor for FA and may play a key role in FA prevention. Numerous studies
suggest a causal role of cutaneous sensitization in FA's development
where both the skin barrier and immunology are thought to be key
players.\textsuperscript{20}

The true global prevalence for AD is also unclear, with previous studies
indicating paediatric AD prevalence varying by
country.\textsuperscript{21} Between 1999-2004 the International Study
of Asthma and Allergies in Childhood incorporated a standardized
school-based sampling methodology and symptom questionnaire to estimate
current AD prevalence among 6-7-year-olds in 60 countries and estimates
for 13-14-year-olds in 96 countries. Subsequent studies have
independently verified the increase of increasing several countries.
These landmark findings are visualized in Figures 2 and 3. However, they
are nearly 20 years old, and no comparable effort to systematically
assess longitudinal changes in the global prevalence of AD has since
been undertaken.

The dietary impact of early life nutrition is another staple of FA
prevention. It has been studied to varying degrees, including the impact
of oral tolerance induction, breast and formula feeding, Vitamin D,
dietary diversity, and the role of pre-, pro-and syn-biotics. The
interaction of the skin and diet come together in the interplay between
oral tolerance induction and epicutaneous allergen exposure. This forms
the basis of the dual-allergen exposure hypothesis, which proposes that
epicutaneous food allergen exposure in early life is associated with the
development of FA, whilst early life oral exposure is
protective.\textsuperscript{22-24}

Finally, microbial factors may impact FA prevention with the mode of
delivery at birth, pet exposure and bacterial (\emph{S. aureus} )
colonisation. The roles of viruses and fungi are still unknown. This
review will explore AD, the infant diet, microbial factors, and the
complex interplay of all factors in FA development, focusing primarily
on early intervention to prevent FA. We conclude our review with a
discussion of future and ongoing research including key topics that must
be addressed.

\textbf{Cutaneous factors and environmental exposures in the development
of FA}

Early AD is implicated in the subsequent development of allergic
diseases, including FA, asthma, allergic rhinitis and is termed the
``atopic march''.\textsuperscript{2-4} In the ``outside-in'' hypothesis,
skin barrier defect allows penetration of allergens and microbes leading
to atopic sensitization whereas, in the ``inside-out'' paradigm, a
polarized immune response leads to a defective skin barrier (Figure
4).\textsuperscript{25}

Experimental models and clinical observations in humans support the
concept of epicutaneous food allergen
sensitization.\textsuperscript{20,26}The epidermis plays a key role in
preventing allergens, irritants and microbes from penetrating the skin
and eliciting the host immune response. These events are facilitated by
skin barrier dysfunction in AD, promoting the penetration of food
allergens from topical application or the environment. Lack et
al.\textsuperscript{23} first reported that peanut allergy was
associated with the topical application of skin creams containing peanut
protein. Subsequently, Fox et al.\textsuperscript{24} reported increased
FA in households that ate peanuts. In addition, Brough et
al.\textsuperscript{27} found house dust dose-dependent peanut
sensitization in patients with FLG mutations, and the impact of
developing allergy was greater in children with AD\textsuperscript{28}
and in children with egg allergy.\textsuperscript{29}These observations
supported a role for the ``outside-in'' process of food sensitization
where exposure to environmental peanut in an individual with skin
barrier dysfunction leads to enhanced FA.

The ``inside-out'' process implicates the immune response in making the
skin barrier more susceptible to skin epithelial dysfunction,
development of AD, and allergen entry. The current understanding of
'AD's pathogenesis is centered on the robust activation of Type 2 (IL-4,
IL-13, IL-31) and Type 22 (IL-22) cytokine axes in both skin and
serum.\textsuperscript{25,30-34}Model systems showed that type 2
cytokine activation inhibits keratinocyte terminal differentiation
products (i.e., filaggrin, loricrin), tight junctions (i.e., claudins),
and lipid products.\textsuperscript{35-38} Recent findings show that Th2
cytokines decrease antimicrobial peptides, causing AD skin to be more
prone to colonization of infectious organisms, such as \emph{S. aureus}
. Thus, IL-4 and IL-13 play a hallmark role in the Th2 immune response
in AD, contributing to both immune activation and skin barrier
dysfunction. IL-31, another Th2 cytokine, has been shown to interact
synergistically with IL-4, driving pruritus and contributing to the
inflammatory and barrier defects of AD.\textsuperscript{39-44} The Th22
axis also plays a role in suppressing the epidermal barrier and the
lichenification and increase of S100As in chronic AD
lesions.\textsuperscript{45,46}Additional proinflammatory axes,
including Th17, are preferentially upregulated in certain AD
populations, such as Asians and children, revealing the heterogeneous
nature of AD across its subtypes.\textsuperscript{47-51}Recently,
minimally invasive studies of the skin using tape strips, performed in
infants, children and adults with moderate-to-severe AD, show robust
upregulation of type 2 and 22 T-cell immune cytokines in both lesional
and non-lesional AD skin.\textsuperscript{52-54} The upregulation of
immune markers in involved and uninvolved skin showed high correlations
with disease severity scores and the functional barrier measure
trans-epidermal-water-loss (TEWL).\textsuperscript{55-57}

Allergic disease development is associated with a Th2 cell-mediated
inflammatory response\textsuperscript{58,59}described above. Allergic
disease is preceded by the formation of specific IgE (sIgE) antibodies
against environmental and food allergens, also known as the
sensitization phase. In epicutaneous sensitization, specific resident
dendritic cell (DC) subsets residing in the skin\textsuperscript{60}
sample antigens and present to na\selectlanguage{ngerman}ïve CD4\textsuperscript{+} T cells in
draining lymph nodes This promotes differentiation into
allergen-specific CD4\textsuperscript{+} T cells favouring B cell
isotype class switching to sIgE cells further driving the production of
IgE memory B cells\textsuperscript{61}. Through the maturation and
production of plasma cells, large amounts of sIgE antibodies are
produced. The sensitization phase drives the production of a large
memory pool of allergen-specific B cells and Th2 cells.

The sensitization phase is followed by the effector phase, which is
triggered by subsequent exposure to previously sensitized allergens.
This causes cross-linking of sIgE bound to receptor Fc\selectlanguage{greek}ε\selectlanguage{english}RI on sensitized
mast cells and basophils. Activation of these cells leads to the release
of inflammatory mediators triggering an allergic
reaction\textsuperscript{62}. The immune mechanisms linking the skin and
gut have their origins in skin injury-induced release of IL-33 from
keratinocytes, leading to intestinal mast cell hyperplasia and
food-induced anaphylaxis in mice.\textsuperscript{63} IL-33 blocking
antibodies have also been shown to prevent peanut allergy induced
anaphylaxis.\textsuperscript{64}

Interestingly, skin sampling in patients with peanut allergy but not AD
reveals low filaggrin levels but increased long-chained lipid species,
which may protect the skin from dryness and AD.\textsuperscript{65}
Other risk factors have been associated with peanut allergy, including
filaggrin mutations, severe infantile AD, environmental irritant
exposures such as detergents and \emph{S. aureus} colonization on the
skin.\textsuperscript{66-68}

Skin dysbiosis, often observed among individuals with AD, is often
characterized by reduced microbial diversity and the presence of one or
few dominant microbes. The loss of commensal microbes is likely due to
several factors including host genetics, local immune response,
environmental factors such as pH, temperature, humidity, hygiene
practice and exposure to antibiotics. It is estimated that 30\% to 100\%
of individuals with AD are colonized by S. \emph{aureus} , a dominant
pathogen implicated in this disease (Figure 5a).\textsuperscript{69}
\emph{S. aureus}affects the development of both innate and adaptive
immune responses. It can lead to uncontrolled inflammation by inducing
lymphocyte and macrophage activation. The increased presence of \emph{S.
aureus} in the dermis directly correlates with a Th2 response evident by
increased expression of IL-4, IL-13, IL-31 and TSLP.\textsuperscript{70}
These Th2 cytokines in turn suppress the production of antimicrobial
peptides (AMPs) by the skin that inhibits~\emph{S.
aureus}proliferation\emph{.\textsuperscript{71}}Therefore, it is not
surprising that colonization by~\emph{S. aureus} ~is associated with
increased AD severity and treatment thereof has been shown to decrease
disease severity.\textsuperscript{72,73}

\emph{Malassezia spp.,} previously known as Pityrosporum, is a genus of
lipophilic yeast. Its role in AD's pathogenesis was initially speculated
when some AD patients responded to topical and systemic antifungal
therapies.\textsuperscript{74-78} A large population study showed more
than 40\% of children with seborrheic dermatitis during early childhood
will develop AD later on, suggesting early sensitization of seborrheic
skin may result in the onset of AD.\textsuperscript{79} Most of the
Malassezia species lack fatty acid synthases genes, therefore relying on
exogenous fatty acid sources that are abundant at certain cutaneous
sites such as the head, neck and skin folds (Figure
5b).\textsuperscript{80} Although the pathogenesis of \emph{Malassezia
spp} in AD is not entirely clear, yeast is known to trigger a multitude
of immune responses. It is estimated that 80\% of adults with AD have
detectable \emph{Malassezia} IgE
antibodies.\textsuperscript{81-83}\emph{Malassezia spp.} in the
epidermis and dermis, can be recognized by keratinocytes and Langerhans
cells as well as dermal DCs. These antigen presenting cells in turn
activate downstream immunologic cascades that lead to the release of
proinflammatory cytokines such as TNF-alpha, IL6, IL-8, IL-10, and
IL-12p70. Induced expression of TLR2 and TLR4 on human keratinocytes and
DCs upon exposure to \emph{Malassezia spp.} have been observed,
suggesting direct activation of innate immune
response.\textsuperscript{84,85}In addition, the NLRP3 inflammasome in
skin DCs can also be activated by\emph{Malassezia spp} with subsequent
release of Th2 cytokines (e.g., IL-1beta, IL-4, 5, 13,) likely directly
contributing to AD pathogenesis.\textsuperscript{86,87}

Lamellar bilayer structural integrity is highly organized in normal
skin, seen under electron microscopy, but very abnormal in those with AD
and peanut allergy. The epidermis in AD with peanut allergy is
associated with high TEWL, high type 2 immune activation, \emph{S.
aureus} colonization, reduced filaggrin breakdown products, and a
reduced proportion of long-chained lipid products. These observations
suggest that a defective skin barrier in patients with AD and peanut
allergy may predispose affected individuals to epicutaneous allergen
sensitization. The availability of minimally invasive skin tape sampling
techniques may play an important role in identifying infants with early
epidermal barrier dysfunction who may benefit from timely initiation of
novel therapies for skin barrier dysfunction, non-lesional immune
activation, and microbial dysbiosis. Using this technique epidermal
profiling of lipids, proteins, and transcriptome identifies differences
in the epidermis between patients with peanut allergy and AD versus AD
alone.\textsuperscript{65,88}

Barrier protection is the cornerstone of AD management. Skin hydration
and prevention of TEWL are keys in maintaining skin barrier homeostasis.
Animal studies also suggest that changes in hydration and corneocyte
adhesion within stratum corneum affect the development and maturation of
epidermis.\textsuperscript{89} Although there has been considerable
controversy about whether early application of skin emollients can
prevent AD and FA,\textsuperscript{20} these studies have often not
targeted high-risk infants with pre-existing evidence for skin barrier
dysfunction, or the ingredients of emollients has not been optimized for
infant skin barrier repair. The use of topical steroids to prevent AD
flares and control subclinical inflammation is being evaluated as a
potential strategy to prevent FA in AD.\textsuperscript{20} Other novel
pathogenesis-based topical and systemic therapies targeting inflammation
of the skin have also been investigated for their roles in preventing
FA.\textsuperscript{90}

Petrolatum, a non-physiologic mineral lipid, is often considered a gold
standard ointment-based emollient that can prevent TEWL effectively for
4-6 hours. Therefore, to maintain optimal skin hydration, ointment-based
emollients should be applied 3 to 4 times daily to provide complete
protection. However, ointment-based emollients can also exacerbate AD;
therefore, alternatives must be considered. Lipids including ceramide,
fatty acids and cholesterol are mixed in appropriate ratio within
stratum corneum to maintain its integrity.\textsuperscript{91,92}Atopic
skin is known to be deficient in lipids especially ceramide and
hygroscopic amino acids that are the result of filaggrin breakdown
products.\textsuperscript{93,94}Newer generations of emollients
containing these lipids have been developed in recent
years.\textsuperscript{95,96}A recent study demonstrated a trilipid
cream was more effective than a paraffin-based emollient in reducing
TEWL and sIgE levels.\textsuperscript{20,97}However, efficacy in AD or
FA prevention is yet to be proven in a randomized clinical
trial.\textsuperscript{98} While treating AD patients with a
barrier-based approach, a liver X receptor agonist upregulated terminal
differentiation and lipid products in the skin of patients with AD,
consistent with its mechanism of action;\textsuperscript{99} however, it
was not associated with clinical benefit or suppression of immune
products (Th17/Th22/IL6). This suggests that although barrier-based
approaches may be valuable for disease prevention, the immune
abnormalities perpetuate the AD disease phenotypes and should be
targeted to resolve active AD.

The discovery of cytokine dysregulation in non-lesional skin from AD
patients suggest the role of systemic therapy especially for individuals
with severe disease. The increased understanding of AD's immune
pathogenesis led to the development of immune-based treatments targeting
Th2 cytokines.\textsuperscript{100-105}Downregulation of immune markers
in the skin of patients treated with such agents highly correlated with
reductions in disease severity scores, demonstrating clinical
improvement.\textsuperscript{33,106-111}Furthermore, the Th2-targeting
anti-IL-4R mAb dupilumab was shown to induce significant changes in the
microbiome of skin lesions, again supporting the key role of the Th2
cytokines in inducing the disease pathogenesis.\textsuperscript{112}

\textbf{Dietary factors}

The obvious dietary factor relevant to the establishment of oral
tolerance (and susceptibility to FA) is \textbf{food allergens} . Oral
tolerance is the active maintenance of both mucosal and systemic
non-responsiveness to ingested food allergens.\textsuperscript{113} The
induction of tolerance to dietary antigen is a multistep
process;\textsuperscript{114}\textbf{dietary vitamin A} plays a critical
role in its regulation. CD103\textsuperscript{+} dendritic cells (DC) in
the gut associated lymphoid tissue (GALT) express elevated levels of
retinal dehydrogenase (RALDH) enzymes which enhance their ability to
metabolize dietary vitamin A. Antigen-loaded CD103\textsuperscript{+} DC
migrate to the mesenteric lymph node (MLN) from the intestinal lamina
propria (LP). Retinoic acid (RA) produced by these DC and by stromal
cells in the MLN induce the expression of the gut homing receptors CCR9
and \selectlanguage{greek}α\selectlanguage{english}4\selectlanguage{greek}β\selectlanguage{english}7 favoring TGF-\selectlanguage{greek}β \selectlanguage{english}dependent conversion of Foxp3\textsuperscript{+}
regulatory T cells (Tregs). \textsuperscript{115-117}Committed Tregs
then home back to LP, expanding under the influence of IL-10 produced by
CX3CR1\textsuperscript{hi} macrophages. Some Tregs exit the mucosa via
the lymph or bloodstream to promote systemic tolerance.
\textsuperscript{114} Elegant studies in germ-free mice on an
antigen-free diet showed that, in the small intestine,
Foxp3\textsuperscript{+} Tregs are induced by exposure to dietary
antigen.\textsuperscript{118}In the large intestine, however,
Foxp3\textsuperscript{+} Tregs are induced by a subset of the
mucosa-associated bacteria which comprise the intestinal
microbiota.\textsuperscript{119}

The increasing prevalence of FA parallels increases in other
non-communicable diseases and can be explained, in part, by alterations
in the composition and function of the commensal microbiome.
21\textsuperscript{st} century lifestyle practices including increased
antibiotic use, low fiber/high fat diets, reduced exposure to infectious
diseases, Caesarean birth and formula feeding have collectively depleted
populations of bacteria beneficial to health.\textsuperscript{120-122}
In addition to dietary antigen induced Foxp3\textsuperscript{+} Tregs, a
bacteria-induced barrier protective response is required to prevent
allergic sensitization to
food.\textsuperscript{123,124}Clostridia-induced IL-22 production by
type 3 innate lymphoid cells (ILC3) is necessary and sufficient to
reduce intestinal epithelial permeability to dietary
allergen.\textsuperscript{123} IL-22 protects the intestinal epithelial
barrier by regulating epithelial proliferation and the production of
mucus and anti-microbial peptides.\textsuperscript{124} The mechanisms
by which intestinal bacteria, particularly those in the Clostridia
class, regulate mucosal immunity and allergic disease are increasingly
understood. Prominent among these is their ability to ferment short
chain fatty acids (SCFAs) from dietary fiber. SCFAs have potent
immunomodulatory effects correlated with host
health\textsuperscript{125} including induction of colonic
Tregs\textsuperscript{126} and improvement of allergy symptoms in a
mouse model.\textsuperscript{127} Butyrate, in particular, is an
important energy source for colonic epithelial
cells.\textsuperscript{128} Butyrate drives oxygen consumption by
colonocytes through \selectlanguage{greek}β-\selectlanguage{english}oxidation, which maintains a locally hypoxic niche
for butyrate-producing obligate anaerobes .\textsuperscript{129} Early
dysbiosis characterized by an impaired capacity to produce butyrate may
be a common feature of allergic
diseases.\textsuperscript{130}\textbf{Tryptophan metabolites} , from
both dietary and bacterial sources, also play a central role in
regulating tolerance in the gut. Catabolism of tryptophan to indole
derivatives produces ligands which bind to the aryl hydrocarbon receptor
on innate lymphoid cells (ILC3) and stimulate the production of IL-22 to
regulate epithelial barrier permeability. \textsuperscript{131}Finally
commensal bacteria can metabolize \textbf{bile acids} to produce
bioactive mediators which regulate T cell differentiation in the
intestinal lamina propria (Figure 6).\textsuperscript{132}

From the evidence from mouse models that food allergen exposure was
necessary for the development of tolerance, observational studies in
humans linking allergen avoidance in the first few years of life with
the development of FA further supported the dual allergen-exposure
hypothesis. Specifically, a cross-sectional study showed that peanut
consumption in Israel early in life was associated with a lower
prevalence of peanut allergy than a population with a similar ancestry
in the UK, where peanut was typically avoided in the first few years of
life.\textsuperscript{133} Whereas avoidance of food allergens in an
infant's diet was standard advice in many countries, advice has changed,
and oral tolerance induction is being used as a strategy to prevent
peanut and other FA by introducing peanuts and other food allergens
early into the diet of young infants.\textsuperscript{17} The LEAP study
showed that the rate of peanut allergy could be reduced by 86\% in
non-sensitised children and the LEAP-On study confirmed that this
protection against peanut allergy remained one year after complete
subsequent avoidance at five years of age in the children's
diet.\textsuperscript{134} The impact of early peanut introduction in
LEAP was peanut specific and did not protect against other
FA.\textsuperscript{135} The EAT study (a lower risk, exclusively
breastfed population) showed similar results for peanut in a per
protocol analysis.\textsuperscript{136} It also showed that consuming
cooked egg in infancy was associated with a reduction in egg allergy.
Since, subsequent studies and a meta-analysis have confirmed the
efficacy of this approach,\textsuperscript{133,137-139}and a recent
Japanese study has shown that early introduction of cow's milk in early
infancy protects against the development of milk
allergy.\textsuperscript{140}Introducing multiple foods early and
continuing to eat them regularly proved challenging for most families in
the EAT study. The study identified several factors associated with
reduced adherence to this strategy: increasing maternal age, feeding
difficulties in the neonate, and non-Caucasian ethnicity. This could
help identify families who might benefit from further support to
encourage early weaning.~\textsuperscript{141-143}

Many other dietary factors have been studied for their association with
FA and/or AD. Observational studies have been summarized in a number of
systematic reviews focusing on the maternal and infant
diet\textsuperscript{144,145}or the maternal diet during pregnancy
alone.\textsuperscript{144,146}Collectively over a hundred papers from
observational studies have been identified reporting dietary patterns,
diet diversity, fruit and vegetable intake, fat and fatty acid intake,
vitamin and mineral intake, and a wide range of other dietary exposures,
including alcohol, tea or coffee intake. Summarizing these studies using
meta-analysis is limited as study exposures and outcome definitions are
highly heterogeneous. A comprehensive review by the UK Food Standards
Agency focusing on maternal and infant dietary intake concludes that
there is no consistent evidence for associations between dietary
exposures and allergy outcomes based on observational
studies.\textsuperscript{144} Other systematic reviews have, however,
attempted to summarize findings from these studies.

\emph{Dietary patterns and food groups}

Dietary patterns, such as the Mediterranean diet, have not been
associated with reduced AD or FA in offsprings. During
pregnancy,\textsuperscript{145} no studies report on maternal dietary
patterns in lactation and AD or FA outcomes in the infant. However, two
systematic reviews tentatively conclude that fruit, vegetable, and
yogurt intake in pregnancy may prevent offspring AD and that margarine
and vegetable oil may increase the risk of
AD.\textsuperscript{144,146}Studies of the associations between intake
of particular foods and infant FA are lacking\textsuperscript{146} Diet
patterns in infancy have not been associated with infant AD. One study
indicates that a diet pattern of predominantly home-cooked food may
prevent FA. \textsuperscript{147}

\emph{Diet diversity}

Diet diversity is the number of different foods, food groups or food
allergens eaten over time, such as the first year of life. Recently
there has been considerable interest in the effect of infant diet
diversity in preventing allergic diseases. A task force report from the
European Academy of Allergy and Clinical Immunology
(EAACI)\textsuperscript{148} suggested that increased diet diversity in
infancy may reduce the risk of developing allergic diseases such as
asthma, AD, allergic rhinitis or FA in later childhood. Two
observational studies, have shown increased diet diversity in the first
year of life to be associated with reduced FA by
six\textsuperscript{147} and ten\textsuperscript{149} years. Using data
from Europe and the UK, these observational studies suggest that early
oral intake of a variety of foods and food allergens, once the infant is
developmentally ready, may reduce the incidence of FA in the first 10
years of life. Studies focusing on diet diversity in infancy and AD in
childhood are however less clear. One study found both an increased risk
and no effect on AD outcomes at different
timepoints.\textsuperscript{150} Another study reported a preventative
effect and no effect at different time
points.\textsuperscript{150,151}Three studies found both an increased
risk\textsuperscript{152,153}and a preventative
effect\textsuperscript{154-156} of increased diet diversity on AD
outcomes in childhood.

\emph{Vitamins and minerals}

Vitamin D insufficiency and deficiency have been associated with IgE
sensitization\textsuperscript{157} and FA in some
studies\textsuperscript{158}but not others.\textsuperscript{159}There is
little evidence from interventional studies of vitamin D supplementation
for primary allergy prevention\textsuperscript{160-163} as reviewed by
Yepes-Nunez, et al.\textsuperscript{164} The lack of evidence about the
role of vitamin D in FA risk is in part related to the multiple factors
influencing vitamin D levels that need to be accounted for when
designing studies. These factors include sun exposure, country and
latitude of residence, migratory status, skin colour, ethnicity, age,
diet, vitamin D supplementation (timing, formulation and dose), genetic
polymorphisms affecting metabolism, epigenetic changes contributing to
vitamin D levels, vitamin D binding protein, interaction with
disease-associated genetic polymorphisms (e.g., ORMDL3), definition of
vitamin D insufficiency/deficiency, and time-points to assess levels
(longitudinal versus cross-sectional)\textsuperscript{165}.

One systematic review indicated that intake of beta-carotene, vitamin E,
zinc, calcium, magnesium, and copper during pregnancy might be
protective of offspring AD\textsuperscript{146}. This review also
summarized a small number of papers indicating that copper and vitamin C
intake during pregnancy may reduce the risk of offspring FA. In
contrast, vitamin D intake was associated with an increased risk of
offspring FA. The amount of vitamins and minerals taken in these studies
did not align with healthy eating guidance, and the results should be
interpreted with caution\textsuperscript{146}.

Results from RCTs have been summarized in several guideline papers and
systematic reviews, with or without meta-analysis, to guide families.
Results from these meta-analyses largely support current recommendations
from the American Academy of Pediatrics
(AAP),\textsuperscript{166}EAACI,\textsuperscript{17} and the consensus
statement from the 3 North American allergy
societies.\textsuperscript{16} All refrain from making recommendations
on omega-3 fatty acids, vitamins, minerals, or pre-/pro-/syn-biotics for
allergy prevention.

\textbf{Conclusions}

The 2000 AAP policy\textsuperscript{167} recommended avoidance of
allergenic foods for breastfeeding mothers and delayed introducing
allergenic foods to infants to prevent FA was based on expert opinion
informed by a limited number of low quality
studies.\textsuperscript{168} These guidelines influenced infant feeding
practices for almost 20 years,\textsuperscript{169} while FA only
continued to increase, rather than decrease. These guidelines were
reversed in 2008, but not replaced with comprehensive guidelines, only
limited recommendations.\textsuperscript{168}With publication of data
from higher-quality studies, recent guidelines offer a comprehensive
approach to maternal/infant diet.\textsuperscript{16,17,166,170}The
foundation for these studies and ongoing efforts to study the prevention
of atopy was laid throughout the 1900s by pioneers in the field (Table
1).

It is critical to not only have consistent diagnostic criteria for the
conditions being studied, but also to have comparable outcomes that are
patient-relevant when possible. This will allow for valid and complete
comparisons across studies in diverse populations, including high and
general risk populations, regionally and globally. Reliable estimates of
the global burden of atopic disease and improved epidemiologic data for
these conditions is crucial to gain support for and acceptance of
prevention guidelines.

Interventions to prevent AD and FA targeted at the first few months of
life are not early enough for some babies. There~are likely~factors
already in place within the first few weeks of life, or earlier,
particularly in at-risk infants~who may start the march towards atopy
and a Th2 milieu in the womb.~ The proposed increased risk for FA with
more than daily application of moisturizer in the EAT study cohort
highlights the need for earlier assessments and interventions among
diverse and representative populations employing consistent disease
definitions using easily applied and clinically relevant
assessments.\textsuperscript{171} This finding further cautions against
drawing potentially premature conclusions when important confounders
cannot be adequately accounted for. These most recent findings add to
the conflicting evidence about the potential to prevent AD to reduce the
risk of FA.\textsuperscript{172} Further, this supports the need for
intervention trials designed from the outset to study FA using a broadly
accepted definition as the primary outcome, beginning in the first weeks
of life, with intentionally developed treatment groups and carefully
planned assessments in hopes of Stopping Eczema and ALlergy (SEAL,
NCT03742414). The SEAL Study will also attempt to answer ongoing
research questions identified in this review, summarized in Box 1.

It is unlikely that there is a single way to stop the atopic march once
underway or a master switch that could render all the external factors
discussed in this review ineffective at inducing a Th2 response. It
remains important to investigate these potential targets for prevention
(Figure 7) and continue to search for others. Given the remarkably
conflicting results within and between studies on the microbiome and a
wide variety of dietary factors, it seems that well-informed guidelines
in these areas are farther off in the future, and may require extensive
public health campaigns to slowly change behaviors if successful
approaches can be identified.

It is of course still necessary to provide recommendations before
definitive evidence that is applicable to diverse populations is
available. In the interim, recent updates from North
America\textsuperscript{16} and the UK\textsuperscript{17} are more
unified and coming aligned with those from
Australasia.\textsuperscript{170} There will certainly be disagreement
with some aspect of any guideline, but these do represent a responsible
approach toward prevention of atopic conditions, based on the presently
limited evidence base. Well-designed trials must continue, and future
trials move forward in the face of unprecedented challenges faced today
by study subjects, clinical researchers, and scientists so that the
field can move closer to an understanding of the complex mechanisms
driving allergic sensitization early in life. Effective strategies for
the prevention of atopic conditions, particularly AD and FA will almost
certainly be the result.

Table 1A\emph{: Major Milestones Laying the Foundation for Prevention
Studies}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
\begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{Topic}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{Year (reference)}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{Study or Publication Title}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{Author(s)}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{Key Findings and Contributions to Allergy}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{Notable Limitations}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{Study Population}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{Study Type}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{Level of Evidence\textsuperscript{173}}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ancient Maternal Dietary Avoidance\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2735-2598 BC\textsuperscript{174}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Interdictions Concerning Foods}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Chinese emperors Shen Nong and Huang Di\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Advised pregnant women to avoid shrimp, chicken, meat, and other agents
incriminated in skin lesions\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ancient Chinese History, lacking detailed methods\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Ancient Chinese\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
The first known official guideline recommending food avoidance to
prevent disease, via Emperor's decree\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
n/a\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Defining a Disease and a Medical Specialty\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1906\textsuperscript{175}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Allergy}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
von Pirquet C\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{``For this general concept of a changed reactivity I propose the
term Allergy. `Allos' implies deviation from the original state, from
the behaviour of the normal individual, as it is used in the words
Allorhythmia, Alloptropism.''}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Opinion\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
n/a\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Clinical observations\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
n/a\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Oral Tolerance Induction\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1908\textsuperscript{176}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{A case of egg poisoning}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Schofield AT\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
First modern oral desensitization for food allergy\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
London clinic patient\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Case Report\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Level 5\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Diagnosing Food Allergy and Inducing Oral Tolerance\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1912\textsuperscript{177}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{A case of allergy to common foods}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Schloss OM\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
The early development of food extracts for scratch testing;
identification of ovomucoid as the major egg allergen and its use for
oral desensitization\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Single case\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
New York clinic patient\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Case report\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Level 5\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
The Concept of Immunoglobulin E\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1921\textsuperscript{178}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
The Prausnitz-Kustner Test\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Prausnitz O \& Kustner H\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Demonstrated passive sensitization of the skin in health subjects by
transferring serum from a sensitized individual using the PK test\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Prausnitz (tolerated fish) \& K\selectlanguage{ngerman}üstner (allergic to fish)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Mechanistic\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Level 5\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Diagnosing Food Allergy\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1950\textsuperscript{179}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Allergy for corn and its derivatives: experiments with a masked
ingestion test for its diagnosis}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Loveless MH\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Amid widely varying reports of the incidence of corn allergy, recognized
that positive tests and patient histories often do not match a
``blindfold test,'' and appealed for standardized FA testing\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Survey of American Academy of Allergy members, case series from US
allergy clinics\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Case series and cohort\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Level 4\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
The Discovery of IgE\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1966-8\textsuperscript{180,181}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Immunoglobulin E, a new class of human immunoglobulin}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
K \& T Ishizaka; Johansson SGO \& Bennich H\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
The search for reagin concludes with the nearly simultaneous
identification of IgE, the critical component of an immediate
hypersensitivity reaction\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
The IgE receptor, discovered a few years later, confirmed the effector
functions of IgE\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Myeloma cell lines\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Mechanistic\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Level 4\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Diagnosing Food Allergy\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
1976\textsuperscript{182} 1988\textsuperscript{183}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\emph{Objective clinical and laboratory studies of immediate
hypersensitivity reactions to foods in asthmatic children;}
\emph{Double-blind, placebo-controlled food challenge (DBPCFC) as an
office procedure}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
May CD, Bock SA, et al.\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
The gold-standard of diagnosis, the double-blind, placebo-controlled
oral food challenge was described and became more accessible to the
practicing allergist; defined a SPT \textless{}3mm SPT as negative\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
US asthma center\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Cohort\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Level 4\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Mechanisms of Sensitization\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1996\textsuperscript{184}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
The dual exposure hypothesis\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Lack G \& Golding J\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
``Avoidance measures would serve only to reduce exposure to peanuts to
low levels, and this could paradoxically increase allergic sensitisation
to peanuts: low dose exposure to allergens favors production of IgE, and
as little as 1 \selectlanguage{greek}µ\selectlanguage{english}g of inhaled allergen a year may be sufficient to induce
allergic sensitization vias the airways.''\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Opinion, observed less peanut allergy in some cultures outside Britain
that also frequently consumed peanut\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
n/a\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Level 5\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Diagnosing food allergy\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
1997\textsuperscript{185} \& 2001\textsuperscript{186}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Food-specific IgE values predict OFC outcomes\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Sampson HA \& Ho DG; Sampson HA\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Proposes and validates predictive values or cut-offs, guiding the
decision to perform an OFC\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Highly atopic population, at high risk for FA\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
US tertiary care, academic allergy clinic\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Cohort\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Level 4\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
At the time of publication of most of these milestones, the existence of
food allergy was questioned by many in the medical community, including
most allergists. Despite how remarkable and significant these
achievements were for the field of allergy and immunology, it was not
until the end of the 20\textsuperscript{th} century that food allergy as
a field began to overcome the reputation of being scientifically weak.
Over the past three or four decades, due to increasing prevalence,
improved epidemiologic studies and increased awareness of food allergy
given the risk for severe reactions including fatal anaphylaxis, the
study of food allergy is contributing to the understanding of the
mechanisms of sensitization and the origins of
atopy.\textsuperscript{187,188} In 1982, Dr. May reflected on the
history of food allergy and commented: \emph{The probability of
encountering these obstacles in the future through repetition of the
errors of the past would be lessened by curbing certain tendencies that
interfere with learning from the lessons of the past, for example: (1)
lack of historical perspective, (2) incompetence in weighing evidence,
and (3) the faulty habit of adoption of opinion by feeling rather than
reasoning from facts.\textsuperscript{189}}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
At the time of publication of most of these milestones, the existence of
food allergy was questioned by many in the medical community, including
most allergists. Despite how remarkable and significant these
achievements were for the field of allergy and immunology, it was not
until the end of the 20\textsuperscript{th} century that food allergy as
a field began to overcome the reputation of being scientifically weak.
Over the past three or four decades, due to increasing prevalence,
improved epidemiologic studies and increased awareness of food allergy
given the risk for severe reactions including fatal anaphylaxis, the
study of food allergy is contributing to the understanding of the
mechanisms of sensitization and the origins of
atopy.\textsuperscript{187,188} In 1982, Dr. May reflected on the
history of food allergy and commented: \emph{The probability of
encountering these obstacles in the future through repetition of the
errors of the past would be lessened by curbing certain tendencies that
interfere with learning from the lessons of the past, for example: (1)
lack of historical perspective, (2) incompetence in weighing evidence,
and (3) the faulty habit of adoption of opinion by feeling rather than
reasoning from facts.\textsuperscript{189}}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
At the time of publication of most of these milestones, the existence of
food allergy was questioned by many in the medical community, including
most allergists. Despite how remarkable and significant these
achievements were for the field of allergy and immunology, it was not
until the end of the 20\textsuperscript{th} century that food allergy as
a field began to overcome the reputation of being scientifically weak.
Over the past three or four decades, due to increasing prevalence,
improved epidemiologic studies and increased awareness of food allergy
given the risk for severe reactions including fatal anaphylaxis, the
study of food allergy is contributing to the understanding of the
mechanisms of sensitization and the origins of
atopy.\textsuperscript{187,188} In 1982, Dr. May reflected on the
history of food allergy and commented: \emph{The probability of
encountering these obstacles in the future through repetition of the
errors of the past would be lessened by curbing certain tendencies that
interfere with learning from the lessons of the past, for example: (1)
lack of historical perspective, (2) incompetence in weighing evidence,
and (3) the faulty habit of adoption of opinion by feeling rather than
reasoning from facts.\textsuperscript{189}}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
At the time of publication of most of these milestones, the existence of
food allergy was questioned by many in the medical community, including
most allergists. Despite how remarkable and significant these
achievements were for the field of allergy and immunology, it was not
until the end of the 20\textsuperscript{th} century that food allergy as
a field began to overcome the reputation of being scientifically weak.
Over the past three or four decades, due to increasing prevalence,
improved epidemiologic studies and increased awareness of food allergy
given the risk for severe reactions including fatal anaphylaxis, the
study of food allergy is contributing to the understanding of the
mechanisms of sensitization and the origins of
atopy.\textsuperscript{187,188} In 1982, Dr. May reflected on the
history of food allergy and commented: \emph{The probability of
encountering these obstacles in the future through repetition of the
errors of the past would be lessened by curbing certain tendencies that
interfere with learning from the lessons of the past, for example: (1)
lack of historical perspective, (2) incompetence in weighing evidence,
and (3) the faulty habit of adoption of opinion by feeling rather than
reasoning from facts.\textsuperscript{189}}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
At the time of publication of most of these milestones, the existence of
food allergy was questioned by many in the medical community, including
most allergists. Despite how remarkable and significant these
achievements were for the field of allergy and immunology, it was not
until the end of the 20\textsuperscript{th} century that food allergy as
a field began to overcome the reputation of being scientifically weak.
Over the past three or four decades, due to increasing prevalence,
improved epidemiologic studies and increased awareness of food allergy
given the risk for severe reactions including fatal anaphylaxis, the
study of food allergy is contributing to the understanding of the
mechanisms of sensitization and the origins of
atopy.\textsuperscript{187,188} In 1982, Dr. May reflected on the
history of food allergy and commented: \emph{The probability of
encountering these obstacles in the future through repetition of the
errors of the past would be lessened by curbing certain tendencies that
interfere with learning from the lessons of the past, for example: (1)
lack of historical perspective, (2) incompetence in weighing evidence,
and (3) the faulty habit of adoption of opinion by feeling rather than
reasoning from facts.\textsuperscript{189}}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
At the time of publication of most of these milestones, the existence of
food allergy was questioned by many in the medical community, including
most allergists. Despite how remarkable and significant these
achievements were for the field of allergy and immunology, it was not
until the end of the 20\textsuperscript{th} century that food allergy as
a field began to overcome the reputation of being scientifically weak.
Over the past three or four decades, due to increasing prevalence,
improved epidemiologic studies and increased awareness of food allergy
given the risk for severe reactions including fatal anaphylaxis, the
study of food allergy is contributing to the understanding of the
mechanisms of sensitization and the origins of
atopy.\textsuperscript{187,188} In 1982, Dr. May reflected on the
history of food allergy and commented: \emph{The probability of
encountering these obstacles in the future through repetition of the
errors of the past would be lessened by curbing certain tendencies that
interfere with learning from the lessons of the past, for example: (1)
lack of historical perspective, (2) incompetence in weighing evidence,
and (3) the faulty habit of adoption of opinion by feeling rather than
reasoning from facts.\textsuperscript{189}}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
At the time of publication of most of these milestones, the existence of
food allergy was questioned by many in the medical community, including
most allergists. Despite how remarkable and significant these
achievements were for the field of allergy and immunology, it was not
until the end of the 20\textsuperscript{th} century that food allergy as
a field began to overcome the reputation of being scientifically weak.
Over the past three or four decades, due to increasing prevalence,
improved epidemiologic studies and increased awareness of food allergy
given the risk for severe reactions including fatal anaphylaxis, the
study of food allergy is contributing to the understanding of the
mechanisms of sensitization and the origins of
atopy.\textsuperscript{187,188} In 1982, Dr. May reflected on the
history of food allergy and commented: \emph{The probability of
encountering these obstacles in the future through repetition of the
errors of the past would be lessened by curbing certain tendencies that
interfere with learning from the lessons of the past, for example: (1)
lack of historical perspective, (2) incompetence in weighing evidence,
and (3) the faulty habit of adoption of opinion by feeling rather than
reasoning from facts.\textsuperscript{189}}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
At the time of publication of most of these milestones, the existence of
food allergy was questioned by many in the medical community, including
most allergists. Despite how remarkable and significant these
achievements were for the field of allergy and immunology, it was not
until the end of the 20\textsuperscript{th} century that food allergy as
a field began to overcome the reputation of being scientifically weak.
Over the past three or four decades, due to increasing prevalence,
improved epidemiologic studies and increased awareness of food allergy
given the risk for severe reactions including fatal anaphylaxis, the
study of food allergy is contributing to the understanding of the
mechanisms of sensitization and the origins of
atopy.\textsuperscript{187,188} In 1982, Dr. May reflected on the
history of food allergy and commented: \emph{The probability of
encountering these obstacles in the future through repetition of the
errors of the past would be lessened by curbing certain tendencies that
interfere with learning from the lessons of the past, for example: (1)
lack of historical perspective, (2) incompetence in weighing evidence,
and (3) the faulty habit of adoption of opinion by feeling rather than
reasoning from facts.\textsuperscript{189}}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
At the time of publication of most of these milestones, the existence of
food allergy was questioned by many in the medical community, including
most allergists. Despite how remarkable and significant these
achievements were for the field of allergy and immunology, it was not
until the end of the 20\textsuperscript{th} century that food allergy as
a field began to overcome the reputation of being scientifically weak.
Over the past three or four decades, due to increasing prevalence,
improved epidemiologic studies and increased awareness of food allergy
given the risk for severe reactions including fatal anaphylaxis, the
study of food allergy is contributing to the understanding of the
mechanisms of sensitization and the origins of
atopy.\textsuperscript{187,188} In 1982, Dr. May reflected on the
history of food allergy and commented: \emph{The probability of
encountering these obstacles in the future through repetition of the
errors of the past would be lessened by curbing certain tendencies that
interfere with learning from the lessons of the past, for example: (1)
lack of historical perspective, (2) incompetence in weighing evidence,
and (3) the faulty habit of adoption of opinion by feeling rather than
reasoning from facts.\textsuperscript{189}}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Table 1B\emph{: Major Milestones in Studying the Prevention of Atopy}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
\begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Area of Focus\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Year (Reference)\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Study Name or Publication Title\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Author\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Key findings or recommendations\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Notable Limitations\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Population Studied\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Type of Study\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Level of Evidence\textsuperscript{173}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Cutaneous Sensitization\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1994\textsuperscript{190}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Increased airways responsiveness in mice depends on local challenge with
antigen\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Saloga J, et al.\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
First evidence to support that sensitization could occur through
skin\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Murine skin differs from human skin\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Murine model\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Mechanistic\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Level 5\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Cutaneous Sensitization\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2003\textsuperscript{191}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Avon Longitudinal Study of Parents and Children (ALSPAC)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Lack G, et al.\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Peanut allergy associated with topical use of peanut oil infants, but
not with maternal consumption\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
UK, general population\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Population-based, longitudinal birth cohort\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Level 2\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
The Role of Filaggrin in AD\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
2006\textsuperscript{93}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
\emph{Common loss-of-function variants of the epidermal barrier protein
filaggrin are a major predisposing factor for atopic dermatitis}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Palmer CNA, et al.\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
AD was more common in homozygous or compound heterozygous for FLG null
alleles, and nearly absent in those without\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Only 2 mutations had been identified and analyzed, both common in those
of European ancestry, but rare in other ethnicities\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
9 Irish families with icthyosis vulgaris and/or AD; 2 cohorts of
Scottish children with and without asthma; Danish children from the
COPSAC study\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Multiple cohorts\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Level 2\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
The Role of Filaggrin in FA\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2011\textsuperscript{66}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Loss-of-function variants in the filaggrin gene are a significant
risk factor for peanut allergy}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Brown SJ, et al.\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
FLG loss-of-function mutations significantly increase the risk of peanut
allergy, suggesting a role for epithelial barrier dysfunction\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Different definitions of AD and criteria for diagnosing peanut allergy
were used in the different populations; difficult to distinguish the
role of AD from FLG status, and other variables affecting the
development of peanut allergy; the effect varied in different
populations despite all being predominantly white and of European
ancestry\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
English, Dutch, and Irish subjects with peanut allergy and controls;
replicated in a white, Canadian case-control population\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Case-control study\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Level 3\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Skin barrier Dysfunction and Transcutaneous Sensitization in FA\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2014\textsuperscript{27}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\emph{Peanut allergy: Effect of environmental peanut exposure in
children with filaggrin loss-of-function mutations}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Brough HA, et al.\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Exposure to peanut protein in household dust demonstrated a
dose-response relationship with measures of peanut sensitization and
allergy at 8 and 11y in children with FLG mutations, when controlling
for other factors; no effect of exposure was seen in children with
WT-FLG\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Peanut allergy not challenge-proven in all subjects; overall small
number of subjects with peanut allergy, FLG gene status, and exposure
history; excluded non-Caucasians as the 6 FLG mutations studied were
only defined in Caucasians\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
UK, high risk infants (family history of atopy)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Observational study within randomized controlled study\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Level 3\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Topical intervention for AD\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
2014\textsuperscript{192}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Application of moisturizer to neonates prevents development of atopic
dermatitis\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Horimoku K, et al.\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Daily application of an emulsion-based moisturizer starting at 1week of
life prevented AD in 1/3 of infants at 8m\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Control group could use petroleum jelly if desired, which may be
beneficial for SB, limiting the impact of the intervention\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Japan, high risk\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
RCT\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Level 2\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Oral Tolerance Induction\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
2015\textsuperscript{193} \& 2016\textsuperscript{194}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
LEAP \& LEAP-On\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
du Toit, et al.\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Early introduction and regular consumption of peanut in infants at high
risk for FA prevents peanut allergy, and likely induces durable, and
long-lasting tolerance\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Excluded infants with peanut SPT\textgreater{}4mm at entry\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
UK, high risk cohort\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Randomized, open-label, controlled trial\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Level 2\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Preventative Emollient Therapy for AD and FA\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
2018\textsuperscript{195}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
A randomised trial of a barrier lipid replacement strategy for the
prevention of atopic dermatitis and allergic sensitisation: The PEBBLES
Pilot Study\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Lowe AJ, et al.\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Twice daily application of emollient rich in ceramides to infants in the
first 3weeks of life through 6m demonstrated a trend towards less AD and
food sensitization at 12month; infants who had emollient applier BID for
at least 5/7 day per week did have a significant reduction in food
sensitization\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Food sensitization only assessed at 1y, not later in life and not
challenge-proven; Small n=80), pilot study.\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Australia, high risk infants (parental history of atopy)\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Pilot randomized, parallel, single-blind, controlled trial\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Level 3\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Assessing Skin Barrier Dysfunction\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2019\textsuperscript{196}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
The nonlesional skin surface distinguishes atopic dermatitis with food
allergy as a unique endotype\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Leung DYM, et al.\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Using a non-invasive, well-tolerated skin tape stripping method,
identifies unique immature skin barrier characteristics in the stratum
corneum that distinguish between children with AD and FA (AD+FA+) from
those with AD but without FA (AD+FA-)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Results require validation in larger, diverse populations with
challenge-proven allergy to a variety of foods, not just peanut\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
62 US children classified as AD+FA+, AD+FA- or controls\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Blinded, prospective mechanistic study\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Level 3\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Proactive Early AD Treatment and the Prevention of FA\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2019\textsuperscript{197}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Prevention of Allergy via Cutaneous Intervention (PACI) pilot\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Miyaji Y, et al.\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Earlier aggressive treatment of AD shortened its duration in infants,
and resulted in fewer food allergies at 2 years of life\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Smaller, retrospective pilot study; cohorts had significant differences
in baseline characteristics\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Japan\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Retrospective cohort\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Level 4\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Preventative Emollient Therapy for AD and FA\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2020\textsuperscript{198}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Barrier Enhancement for Eczema Prevention (BEEP)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Chalmers JR, et al.\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
No evidence for prevention of AD at 2y with daily emollient use, but
possible slight increase in infection risk, and nonsignificant increase
in FA (largely to egg) in the intervention group\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Choice of emollient; limited FA assessment; median time to initiation of
skin care at 11 days of life\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
UK, high risk\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Pragmatic, parallel group RCT\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Level 2\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Oral Tolerance Induction\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2020\textsuperscript{199}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Preventing food allergy in infancy and childhood\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
de Silva D, et al.\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Early introduction of cooked egg (not raw or pasteurized egg) likely
helps prevent egg allergy; avoiding supplementation with cow's
milk-based formula in the first week of life may slightly reduce milk
allergy; nearly every other dietary intervention reviewed has little to
no effect\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Many are small studies of lower certainty of evidence, findings need to
be validated in large, heterogeneous populations\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
n/a\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Systematic review with meta-analysis\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Level 2\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Preventative Emollient Therapy for AD and FA\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2020\textsuperscript{200}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Preventing Atopic Dermatitis and ALLergies in Children
(PreventADALL)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Skjerven HO, et al.\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Found no decrease in AD or FA at 12m with skin emollient use, early
complementary feeding or both\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Skin intervention started at 2 weeks of life using a bath oil and cream;
early food introduction began with peanut butter at 3m; overall poor
adherence in the intervention groups; low statistical power to assess FA
(results for FA at 3y forthcoming)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Scandinavian standard risk birth cohort\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Prospective interventional, cluster-randomized controlled trial\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Level 2\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Link between Emollient use and Food Allergy\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
2021\textsuperscript{171}\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Association of frequent moisturizer use in early infancy with the
development of food allergy\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Perkin M, et al.\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Observed an increased risk of food allergy with the application of
moisturizer more frequent than once daily\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
All but 1 case of FA developed in children with at least 1 atopic
parent; AD assessed at 3m enrolment visit only; the cohort frequently
used oils for baby massage, which may prevent formation of an intact
skin barrier; unable to control for some potential confounding
factors\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
UK, exclusively breastfed standard risk cohort enrolled in the EAT study
and randomized to standard vs early introduction of 6 foods with poor
protocol adherence\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Retrospective analysis of questionnaire data\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Level 3/4\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Box 1: Topics for future research}

\begin{itemize}
\tightlist
\item
  Definitions of disease that are easy to apply, widely accepted and
  clinically relevant
\item
  Accurate estimates of the global epidemiologic burden of atopy
\item
  Incorporate patient-relevant outcomes for food allergy and AD into
  trial designs
\item
  Earlier timing of interventions to address skin barrier dysfunction
  (SBD)
\item
  Randomized trials focusing on maternal and early life nutrition with
  robust measurements of food, macro and micronutrient intake and
  clearly defined study outcomes
\item
  Current efforts should be broadened to more fully understand the
  mechanisms underlying initiation, maintenance, loss, and redevelopment
  of tolerance
\item
  Fully characterize the molecular mechanisms underlying the phenotypes
  of SBD that place some, but not all patients with AD at a
  significantly increased risk for atopy, particularly food allergy
\item
  Distinguish other SBD phenotypes, as seen in seborrheic dermatitis and
  psoriasis from those in AD identifying potential targets to maintain
  tolerance later in life
\item
  Identify targeted treatment approaches to heal the SBD associated
  specifically predisposing to atopy
\item
  Ongoing evaluation of environmental exposures including irritants,
  pollution, pollen, bacteria, viruses and fungi
\item
  Begin to better understand the complex interaction of the commensal
  microbiome of the gut and skin with potentially pathogenic bacteria
  and fungi
\item
  Focus the study of environmental and microbial factors on identifying
  modifiable risks for manageable public health interventions benefiting
  the majority of the global population
\end{itemize}

\textbf{References}

1. Loh W, Tang M. The Epidemiology of Food Allergy in the Global
Context. \emph{Int J Environ Res Public Health.} 2018;15.

2. Lowe A, Leung D, Tang M, Su J, Allen K. The skin as a target for
prevention of the atopic march.\emph{Ann Allergy Asthma Immunol.}
2018;120(2):145-151.

3. Dharmage S, Lowe A, Matheson M, Burgess J, Allen K, Abramson M.
Atopic dermatitis and the atopic march revisited. \emph{Allergy.}
2014;69(1):17-27.

4. Davidson WF, Leung DY, Beck LA, et al. Report from the National
Institute of Allergy and Infectious Diseases workshop on ``Atopic
dermatitis and the atopic march: Mechanisms and interventions''. \emph{J
Allergy Clin Immunol.}2019;143(3):894-913.

5. Perkin M, Logan K, Tseng A, Raji B, Ayis S, Peacock J. Randomized
Trial of Introduction of Allergenic Foods in Breast-Fed Infants. \emph{N
Engl J Med.} 2016;374(18):1733-1743.

6. Gupta R, Warren C, Smith B. The Public Health Impact of Parent-
Reported Childhood Food Allergies in the United States.
\emph{Pediatrics.} 2018;142(6).

7. Osborne NJ, Koplin JJ, Martin PE, et al. Prevalence of
challenge-proven IgE-mediated food allergy using population-based
sampling and predetermined challenge criteria in infants. \emph{J
Allergy Clin Immunol.} 2011;127(3):668- 676.

8. Peters R, Koplin J, Gurrin L. The prevalence of food allergy and
other allergic diseases in early childhood in a population-based study:
HealthNuts age 4- year follow-up.\emph{J Allergy Clin Immunol.}
2017;140(1):145- 153.

9. Tang M, Mullins R. Food allergy: is prevalence increasing?
\emph{Intern Med J.} 2017;47(3):256-261.

10. Warren C, Jiang J, Gupta R. Epidemiology and Burden of Food Allergy.
\emph{Curr Allergy Asthma Rep.}2020;20(2).

11. Lyons SA, Clausen M, Knulst AC, et al. Prevalence of Food
Sensitization and Food Allergy in Children Across Europe. \emph{J
Allergy Clin Immunol Pract.} 2020;8(8):2736-2746 e2739.

12. Venter C, Pereira B, Voigt K, et al. Prevalence and cumulative
incidence of food hypersensitivity in the first 3 years of life.
\emph{Allergy.} 2008;63(3):354-359.

13. Prescott S, Pawankar R, Allen K. A global survey of changing
patterns of food allergy burden in children.\emph{World Allergy Organ
J.} 2013;6(1).

14. Du Toit G, Katz Y, Sasieni P. Early consumption of peanuts in
infancy is associated with a low prevalence of peanut allergy. \emph{J
Allergy Clin Immunol.}2008;122(5):984-991.

15. Togias A, Cooper SF, Acebal ML, et al. Addendum guidelines for the
prevention of peanut allergy in the United States: Report of the
National Institute of Allergy and Infectious Diseases-sponsored expert
panel. \emph{J Allergy Clin Immunol.} 2017;139(1):29-44.

16. Fleischer DM, Chan ES, Venter C, et al. A Consensus Approach to the
Primary Prevention of Food Allergy Through Nutrition: Guidance from the
American Academy of Allergy, Asthma, and Immunology; American College of
Allergy, Asthma, and Immunology; and the Canadian Society for Allergy
and Clinical Immunology. \emph{J Allergy Clin Immunol Pract.}
2021;9(1):22-43 e24.

17. Halken S, Muraro A, de Silva D, et al. EAACI guideline: Preventing
the development of food allergy in infants and young children (2020
update). \emph{Pediatr Allergy Immunol.} 2021.

18. Warren C, Otto A, Walkner M, Gupta R. Quality of Life Among Food
Allergic Patients and Their Caregivers. \emph{Curr Allergy Asthma Rep.}
2016;16(5).

19. Macdougall JD, Burks AW, Kim EH. Current Insights into Immunotherapy
Approaches for Food Allergy.\emph{ImmunoTargets Ther.} 2021;10:1.

20. Brough H, Nadeau K, Sindher S. Epicutaneous sensitization in the
development of food allergy: What is the evidence and how can this be
prevented? \emph{Allergy.}2020;75(9):2185-2205.

21. Odhiambo J, Williams H, Clayton T, Robertson C, Asher M. Global
variations in prevalence of eczema symptoms in children from ISAAC Phase
Three. \emph{J Allergy Clin Immunol.} 2009;124(6):1251-1258.

22. Strid J, Hourihane J, Kimber I, Callard R, Strobel S. Epicutaneous
exposure to peanut protein prevents oral tolerance and enhances allergic
sensitization. \emph{Clin Exp Allergy.} 2005;35(6):757-766.

23. Lack G, Fox D, Northstone K, Golding J. Factors Associated with the
Development of Peanut Allergy in Childhood. \emph{N Engl J Med.}
2003;348(11):977-985.

24. Fox A, Sasieni P, du Toit G, Syed H, Lack G. Household peanut
consumption as a risk factor for the development of peanut allergy.
\emph{J Allergy Clin Immunol.}2009;123(2):417-423.

25. Leung DY, Guttman-Yassky E. Deciphering the complexities of atopic
dermatitis: Shifting paradigms in treatment approaches. \emph{J Allergy
Clin Immunol.}2014;134(4):769-779.

26. Leung DY, Berdyshev E, Goleva E. Cutaneous barrier dysfunction in
allergic diseases. \emph{J Allergy Clin Immunol.} 2020;145(6):1485-1497.

27. Brough HA, Simpson A, Makinson K, et al. Peanut allergy: effect of
environmental peanut exposure in children with filaggrin
loss-of-function mutations. \emph{J Allergy Clin Immunol.}
2014;134(4):867-875 e861.

28. Brough H, Liu A, Sicherer S. Atopic dermatitis increases the effect
of exposure to peanut antigen in dust on peanut sensitization and likely
peanut allergy. \emph{J Allergy Clin Immunol.} 2015;135(1):164-170.

29. Brough H, Kull I, Richards K, Hallner E, Soderhall C, Douiri A.
Environmental peanut exposure increases the risk of peanut sensitization
in high-risk children.\emph{Clin Exp Allergy.} 2018;48(5):586-593.

30. Guttman-Yassky E, Krueger J, Lebwohl M. Systemic immune mechanisms
in atopic dermatitis and psoriasis with implications for treatment.
\emph{Exp Dermatol.}2018;27(4):409-417.

31. Ewald D, Malajian D, Krueger J. Meta-analysis derived atopic
dermatitis (MADAD) transcriptome defines a robust AD signature
highlighting the involvement of atherosclerosis and lipid metabolism
pathways. \emph{BMC Med Genomics.} 2015;8(1).

32. Su\selectlanguage{ngerman}árez-Fariñas M, Ungar B, Correa da Rosa J, Ewald D, Rozenblit M,
Gonzalez J. RNA sequencing atopic dermatitis transcriptome profiling
provides insights into novel disease mechanisms with potential
therapeutic implications. \emph{J Allergy Clin Immunol.}
2015;135(5):1218-1227.

33. Renert-Yuval Y, Thyssen JP, Bissonnette R, et al. Biomarkers in
atopic dermatitis-a review on behalf of the international eczema
council. \emph{J Allergy Clin Immunol.}2021.

34. Brunner P, Guttman-Yassky E, Leung D. The immunology of atopic
dermatitis and its reversibility with broad-spectrum and targeted
therapies. \emph{J Allergy Clin Immunol.}2017;139(4s):S65-s76.

35. Czarnowicki T, Krueger J, Guttman-Yassky E. Skin Barrier and Immune
Dysregulation in Atopic Dermatitis: An Evolving Story with Important
Clinical Implications.\emph{J Allergy Clin Immunol.} 2014;2(4):371-379.

36. Guttman-Yassky E, Suárez-Fariñas M, Chiricozzi A. Broad defects in
epidermal cornification in atopic dermatitis identified through genomic
analysis. \emph{J Allergy Clin Immunol.} 2009;6(124):1235-1244.

37. Berdyshev E, Goleva E, Bronova I, et al. Lipid abnormalities in
atopic skin are driven by type 2 cytokines. \emph{JCI insight.}
2018;3(4).

38. Danso M, Van Drongelen V, Mulder A. TNF-\selectlanguage{greek}α \selectlanguage{english}and Th2 cytokines induce
atopic dermatitis-like features on epidermal differentiation proteins
and stratum corneum lipids in human skin equivalents. \emph{J
Investigative Derma.} 2014;7(134):1941-1950.

39. Wang F, Kim B. A Paradigm of Neuroimmune Crosstalk. \emph{Immunity.}
2020;52(5):753-766.

40. Stott B, Lavender P, Lehmann S, Pennino D, Durham S, Schmidt-Weber
C. Human IL-31 is induced by IL-4 and promotes TH2-driven inflammation.
\emph{J Allergy Clin Immunol.}2013;2(132):446-454.

41. Saleem M, Oussedik E, D'Amber V, Feldman S. Interleukin-31 pathway
and its role in atopic dermatitis: a systematic review. \emph{J
Dermatolog Treat.} 2017;28(7):591-599.

42. Oetjen LK, Mack MR, Feng J, et al. Sensory Neurons Co-opt Classical
Immune Signaling Pathways to Mediate Chronic. \emph{Cell.}
2017;1(171):217-228.

43. Raap U, Weibmantel S, Gehring M, Eisenberg A, Kapp A. F\selectlanguage{ngerman}ölster\selectlanguage{english}-Holst
R. IL\selectlanguage{english}-31 significantly correlates with disease activity and Th2 cytokine
levels in children with atopic dermatitis. \emph{Pediatr Allergy
Immunol.} 2012;3(23):285-288.

44. Neis M, Peters B, Dreuw A. Enhanced expression levels of IL-31
correlate with IL-4 and IL-13 in atopic and allergic contact dermatitis.
\emph{J Allergy Clin Immunol.}2006;4(118):930-937.

45. Nograles K, Zaba L, Guttman\selectlanguage{english}-Yassky E. Th17 cytokines interleukin
(IL)\selectlanguage{english}-17 and IL\selectlanguage{english}-22 modulate distinct inflammatory and
keratinocyte\selectlanguage{english}-response pathways. \emph{Br J Dermatol.}
2008;159(5):1092-1102.

46. Sa S, Valdez P, Wu J. The effects of IL-20 subfamily cytokines on
reconstituted human epidermis suggest potential roles in cutaneous
innate defense and pathogenic adaptive immunity in psoriasis. \emph{J
Immunol.} 2007;178(4):2229-2240.

47. Suarez-Farinas M, Dhingra N, Gittler J, Shemer A, Cardinale I, de
Guzman Strong C. Intrinsic atopic dermatitis shows similar TH2 and
higher TH17 immune activation compared with extrinsic atopic dermatitis.
\emph{J Allergy Clin Immunol.}2013;132(2):361-370.

48. Nomura T, Wu J, Kabashima K, Guttman-Yassky E. Endophenotypic
Variations of Atopic Dermatitis by Age, Race, and Ethnicity. \emph{J
Allergy Clin Immunol.} 2020;8(6):1840-1852.

49. Noda S, Suarez-Farinas M, Ungar B. The Asian atopic dermatitis
phenotype combines features of atopic dermatitis and psoriasis with
increased TH17 polarization. \emph{J Allergy Clin Immunol.}
2015;136(5):1254-1264.

50. Chan T, Sanyal R, Pavel A. Atopic dermatitis in Chinese patients
shows T(H)2/T(H)17 skewing with psoriasiform features. \emph{J Allergy
Clin Immunol.}2018;142(3):1013-1017.

51. Wen H, Czarnowicki T, Noda S. Serum from Asian patients with atopic
dermatitis is characterized by T(H)2/T(H)22 activation, which is highly
correlated with nonlesional skin measures. \emph{J Allergy Clin
Immunol.} 2018;142(1):324-328.

52. He H, Bissonnette R, Wu J. Tape strips detect distinct immune and
barrier profiles in atopic dermatitis and psoriasis. \emph{J Allergy
Clin Immunol.} 2020.

53. Pavel A, Renert-Yuval Y, Wu J. Tape-strips from early-onset
pediatric atopic dermatitis highlight disease abnormalities in
non-lesional skin. \emph{Allergy.} 2020.

54. Guttman-Yassky E, Diaz A, Pavel A. Use of Tape Strips to Detect
Immune and Barrier Abnormalities in the Skin of Children With
Early-Onset Atopic Dermatitis. \emph{JAMA Dermatol.} 2019.

55. Esaki H, Brunner P, Renert-Yuval Y. Early-onset pediatric atopic
dermatitis is TH2 but also TH17 polarized in skin. \emph{J Allergy Clin
Immunol.} 2016;138(6):1639-1651.

56. Brunner P, Israel A, Zhang N, Leonard A, Wen H-C, Huynh T. Early-
onset pediatric atopic dermatitis is characterized by
TH2/TH17/TH22-centered inflammation and lipid alterations. \emph{J
Allergy Clin Immunol.} 2018;141(6):2094-2106.

57. Brunner P, He H, AB, Pavel The blood proteomic signature of
early-onset pediatric atopic dermatitis shows systemic inflammation and
is distinct from adult long-standing disease. \emph{J Am Acad Dermatol.}
2019;81(2):510-519.

58. Chinthrajah R, Hernandez J, Boyd S, Galli S, Nadeau K. Molecular and
cellular mechanisms of food allergy and food tolerance. \emph{J Allergy
Clin Immunol.} 2016;137(4):984-997.

59. Werfel T, Allam J, Biedermann T, Eyerich K, Gilles S, Guttman-Yassky
E. Cellular and molecular immunologic mechanisms in patients with atopic
dermatitis. \emph{J Allergy Clin Immunol.} 2016;138(2):336-349.

60. Humeniuk P, Dubiela P, Hoffmann-Sommergruber K. Dendritic cells and
their role in allergy: uptake, proteolytic processing and presentation
of allergens. \emph{Int J Mol Sci.} 2017;18(7):1491.

61. Satitsuksanoa P, Daanje M, Akdis M, Boyd SD, van de Veen W. Biology
and dynamics of B cells in the context of IgE-mediated food allergy.
\emph{Allergy.} 2020.

62. Palomares O, Akdis M, Martin-Fontecha M, Akdis C. Mechanisms of
immune regulation in allergic diseases: the role of regulatory T and B
cells. \emph{Immunol Rev.}2017;278(1):219-236.

63. Leyva-Castillo J-M, Galand C, Kam C, et al. Mechanical skin injury
promotes food anaphylaxis by driving intestinal mast cell expansion.
\emph{Immunity.} 2019;50(5):1262-1275. e1264.

64. Chinthrajah S, Cao S, Liu C, et al. Phase 2a randomized,
placebo-controlled study of anti-IL-33 in peanut allergy. \emph{JCI
Insight.} 2019;4(22).

65. Leung DY, Calatroni A, Zaramela LS, et al. The nonlesional skin
surface distinguishes atopic dermatitis with food allergy as a unique
endotype. \emph{Sci Transl Med.}2019;11(480).

66. Brown SJ, Asai Y, Cordell HJ, et al. Loss-of-function variants in
the filaggrin gene are a significant risk factor for peanut allergy.
\emph{J Allergy Clin Immunol.}2011;127(3):661-667.

67. Keet C, Pistiner M, Plesa M, et al. Age and eczema severity, but not
family history, are major risk factors for peanut allergy in infancy.
\emph{J Allergy Clin Immunol.}2021;147(3):984-991. e985.

68. Martin P, Eckert J, Koplin J. Which infants with eczema are at risk
of food allergy? Results from a population-based cohort. \emph{Clin Exp
Allergy.} 2015:255-264.

69. Park HY, Kim CR, Huh IS, et al. Staphylococcus aureus Colonization
in Acute and Chronic Skin Lesions of Patients with Atopic Dermatitis.
\emph{Ann Dermatol.}2013;25(4):410-416.

70. Blicharz L, Rudnicka L, Samochocki Z. Staphylococcus aureus: an
underestimated factor in the pathogenesis of atopic dermatitis?
\emph{Postepy Dermatol Alergol.}2019;36(1):11-17.

71. Nguyen HLT, Trujillo-Paez JV, Umehara Y, et al. Role of
Antimicrobial Peptides in Skin Barrier Repair in Individuals with Atopic
Dermatitis. \emph{Int J Mol Sci.}2020;21(20).

72. Huang JT, Abrams M, Tlougan B, Rademaker A, Paller AS. Treatment of
Staphylococcus aureus colonization in atopic dermatitis decreases
disease severity. \emph{Pediatrics.}2009;123(5):e808-814.

73. Simpson EL, Villarreal M, Jepson B, et al. Patients with Atopic
Dermatitis Colonized with Staphylococcus aureus Have a Distinct
Phenotype and Endotype. \emph{J Invest Dermatol.}2018;138(10):2224-2233.

74. Broberg A, Faergemann J. Topical antimycotic treatment of atopic
dermatitis in the head/neck area. A double-blind randomised study.
\emph{Acta Derm Venereol.}1995;75(1):46-49.

75. Back O, Bartosik J. Systemic ketoconazole for yeast allergic
patients with atopic dermatitis. \emph{J Eur Acad Dermatol Venereol.}
2001;15(1):34-38.

76. Lintu P, Savolainen J, Kortekangas-Savolainen O, Kalimo K. Systemic
ketoconazole is an effective treatment of atopic dermatitis with
IgE-mediated hypersensitivity to yeasts and Asthma Proceedings.
\emph{Allergy.}2001;56:512-517.

77. Kanda N, Enomoto U, Watanabe S. Anti-mycotics suppress interleukin-4
and interleukin-5 production in anti-CD3 plus anti-CD28-stimulated T
cells from patients with atopic dermatitis. \emph{J Invest Dermatol}
2001;117:1635-1646.

78. Kaffenberger BH, Mathis J, Zirwas MJ. A retrospective descriptive
study of oral azole antifungal agents in patients with patch
test-negative head and neck predominant atopic dermatitis. \emph{J Am
Acad Dermatol.} 2014;71:480-483.

79. Halkjaer LB, Loland L, Buchvald FF, et al. Development of atopic
dermatitis during the first 3 years of life: the Copenhagen prospective
study on asthma in childhood cohort study in high-risk children.
\emph{Arch Dermatol.} 2006;142(5):561-566.

80. Jagielski T, Rup E, Ziolkowska A, Roeske K, Macura AB, Bielecki J.
Distribution of Malassezia species on the skin of patients with atopic
dermatitis, psoriasis, and healthy volunteers assessed by conventional
and molecular identification methods. \emph{BMC Dermatol.} 2014;14:3.

81. Kato H, Sugita T, Ishibashi Y, Nishikawa A. Detection and
quantification of specific IgE antibodies against eight Malassezia
species in sera of patients with atopic dermatitis by using an
enzyme-linked immunosorbent assay.\emph{Microbiol Immunol.}
2006;50(11):851-856.

82. Watanabe S, Kano R, Sato H, Nakamura Y, Hasegawa A. The effects of
Malassezia yeasts on cytokine production by human keratinocytes. \emph{J
Invest Dermatol.}2001;116(5):769-773.

83. Devos SA, van der Valk PG. The relevance of skin prick tests for
Pityrosporum ovale in patients with head and neck dermatitis.
\emph{Allergy.} 2000;55(11):1056-1058.

84. Brasch J, Morig A, Neumann B, Proksch E. Expression of antimicrobial
peptides and toll-like receptors is increased in tinea and pityriasis
versicolor. \emph{Mycoses.}2014;57(3):147-152.

85. Baroni A, Orlando M, Donnarumma G, et al. Toll-like receptor 2
(TLR2) mediates intracellular signalling in human keratinocytes in
response to Malassezia furfur. \emph{Arch Dermatol Res.}
2006;297(7):280-288.

86. Ishibashi Y, Sugita T, Nishikawa A. Cytokine secretion profile of
human keratinocytes exposed to Malassezia yeasts. \emph{FEMS Immunol Med
Microbiol.}2006;48(3):400-409.

87. Kroger S, Neuber K, Gruseck E, Ring J, Abeck D. Pityrosporum ovale
extracts increase interleukin-4, interleukin-10 and IgE synthesis in
patients with atopic eczema.\emph{Acta Derm Venereol.}
1995;75(5):357-360.

88. Goleva E, Calatroni A, LeBeau P, et al. Skin tape proteomics
identifies pathways associated with transepidermal water loss and
allergen polysensitization in atopic dermatitis. \emph{J Allergy Clin
Immunol.} 2020;146(6):1367-1378.

89. Imayama S, Ueda S, Isoda M. Histologic changes in the skin of
hairless mice following peeling with salicylic acid. \emph{Arch
Dermatol.} 2000;136(11):1390-1395.

90. Wu J, Guttman-Yassky E. Efficacy of biologics in atopic dermatitis.
\emph{Expert Opin Biol Ther.}2020;20(5):525-538.

91. Feingold KR, Elias PM. Role of lipids in the formation and
maintenance of the cutaneous permeability barrier. \emph{Biochim Biophys
Acta.} 2014;1841(3):280-294.

92. Van Smeden J, Bouwstra JA. Stratum Corneum Lipids: Their Role for
the Skin Barrier Function in Healthy Subjects and Atopic Dermatitis
Patients. \emph{Curr Probl Dermatol.} 2016;49:8-26.

93. Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. Common
loss-of-function variants of the epidermal barrier protein filaggrin are
a major predisposing factor for atopic dermatitis. \emph{Nat Genet.}
2006;38(4):441-446.

94. Sandilands A, Sutherland C, Irvine AD, McLean WI. Filaggrin in the
frontline: role in skin barrier function and disease. \emph{J Cell Sci.}
2009 122(9):1285--1294.

95. Van Zuuren E, Fedorowicz Z, Arents B. Emollients and moisturizers
for eczema: abridged Cochrane systematic review including GRADE
assessments. \emph{Br J Dermatol.}2017;177(5):1256-1271.

96. van Zuuren EJ, Fedorowicz Z, Christensen R, Lavrijsen A, Arents BWM.
Emollients and moisturisers for eczema. \emph{Cochrane Database Syst
Rev.} 2017;2(2):Cd012119.

97. Sindher S, Alkotob SS, Shojinaga MN, et al. Increases in plasma
IgG4/IgE with trilipid vs paraffin/petrolatum-based emollients for dry
skin/eczema. \emph{Pediatr Allergy Immunol.} 2020;31(6):699-703.

98. Miller DW, Koch SB, Yentzer BA, et al. An over-the-counter
moisturizer is as clinically effective as, and more cost-effective than,
prescription barrier creams in the treatment of children with
mild-to-moderate atopic dermatitis: a randomized, controlled trial.
\emph{J Drugs Dermatol.}2011;10(5):531-537.

99. Czarnowicki T, Dohlman AB, Malik K, et al. Effect of short-term
liver X receptor activation on epidermal barrier features in mild to
moderate atopic dermatitis: A randomized controlled trial. \emph{Ann
Allergy Asthma Immunol.} 2018;120(6):631-640 e611.

100. Renert-Yuval Y, Guttman-Yassky E. New treatments for atopic
dermatitis targeting beyond IL-4/IL-13 cytokines. \emph{Ann Allergy
Asthma Immunol.} 2020;124(1):28-35.

101. Li R, Hadi S, Guttman-Yassky E. Current and emerging biologic and
small molecule therapies for atopic dermatitis. \emph{Expert Opin Biol
Ther.} 2019;19(4):367-380.

102. Diaz A, Guttman-Yassky E. Topical agents for the treatment of
atopic dermatitis. \emph{Expert Rev Clin Immunol.} 2019;15(4):369-382.

103. He H, Guttman-Yassky E. JAK Inhibitors for Atopic Dermatitis: An
Update. \emph{Am J Clin Dermatol.}2019;20(2):181-192.

104. Simpson E, Imafuku S, Poulin Y. A Phase 2 Randomized Trial of
Apremilast in Patients with Atopic Dermatitis. \emph{J Investigative
Derma.} 2019;139(5):1063-1072.

105. Wollenberg A, Howell MD, Guttman-Yassky E, et al. Treatment of
atopic dermatitis with tralokinumab, an anti--IL-13 mAb. \emph{J Allergy
Clin Immunol.}2019;143(1):135-141.

106. Olesen C, Pavel A, Wu J. Tape-strips provide a minimally-invasive
approach to track therapeutic response to topical corticosteroids in
atopic dermatitis patients.\emph{J Allergy Clin Immunol.} 2020.

107. Bissonnette R, Pavel A, Diaz A. Crisaborole and atopic dermatitis
skin biomarkers: An intrapatient randomized trial. \emph{J Allergy Clin
Immunol.} 2019;144(5):1274-1289.

108. Pavel A, Song T, Kim H-J, Del Duca E, Krueger J, Dubin C. Oral
Janus kinase/SYK inhibition (ASN002) suppresses inflammation and
improves epidermal barrier markers in patients with atopic dermatitis.
\emph{J Allergy Clin Immunol.}2019;144(4):1011-1024.

109. Guttman-Yassky E, Pavel A, Zhou L. GBR 830, an anti-OX40, improves
skin gene signatures and clinical scores in patients with atopic
dermatitis. \emph{J Allergy Clin Immunol.} 2019;144(2):482-493.

110. Hamilton J, Suarez-Farinas M, Dhingra N. Dupilumab improves the
molecular signature in skin of patients with moderate-to-severe atopic
dermatitis. \emph{J Allergy Clin Immunol.} 2014;134(6):1293-1300.

111. Bissonnette R, Maari C, Forman S, et al. The oral Janus
kinase/spleen tyrosine kinase inhibitor ASN002 demonstrates efficacy and
improves associated systemic inflammation in patients with
moderate-to-severe atopic dermatitis: results from a randomized
double-blind placebo-controlled study. \emph{Br J
Dermatol.}2019;181(4):733-742.

112. Callewaert C, Nakatsuji T, Knight R. IL-4R\selectlanguage{greek}α \selectlanguage{english}Blockade by Dupilumab
Decreases Staphylococcus aureus Colonization and Increases Microbial
Diversity in Atopic Dermatitis.\emph{J Invest Dermatol.}
2020;140(1):191-202.

113. Pabst O, Mowat AM. Oral tolerance to food protein. \emph{Mucosal
Immunol.} 2012;5(3):232-239.

114. Hadis U, Wahl B, Schulz O, et al. Intestinal tolerance requires gut
homing and expansion of FoxP3+ regulatory T cells in the lamina propria.
\emph{Immunity.}2011;34(2):237-246.

115. Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle R. All-trans retinoic
acid mediates enhanced T reg cell growth, differentiation, and gut
homing in the face of high levels of co-stimulation. \emph{J Exp Med.}
2007:1765-1774.

116. Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, et al. A
functionally specialized population of mucosal CD103+ DCs induces Foxp3+
regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism.
\emph{J Exp Med.}2007;204(8):1757-1764.

117. Sun CM, Hall JA, Blank RB, et al. Small intestine lamina propria
dendritic cells promote de novo generation of Foxp3 T reg cells via
retinoic acid. \emph{J Exp Med.}2007;204(8):1775-1785.

118. Kim KS, Hong SW, Han D, et al. Dietary antigens limit mucosal
immunity by inducing regulatory T cells in the small intestine.
\emph{Science.} 2016;351(6275):858-863.

119. Atarashi K, Tanoue T, Shima T, et al. Induction of colonic
regulatory T cells by indigenous Clostridium species. \emph{Science.}
2011;331(6015):337-341.

120. Iweala OI, Nagler CR. The Microbiome and Food Allergy. \emph{Annu
Rev Immunol.} 2019;37:377-403.

121. Feehley T, Plunkett CH, Bao R, et al. Healthy infants harbor
intestinal bacteria that protect against food allergy. \emph{Nat Med.}
2019;25(3):448-453.

122. Bao R, Hesser LA, He Z, Zhou X, Nadeau KC, Nagler CR. Fecal
microbiome and metabolome differ in healthy and food-allergic twins.
\emph{J Clin Invest.} 2021;131(2).

123. Stefka AT, Feehley T, Tripathi P, et al. Commensal bacteria protect
against food allergen sensitization. \emph{Proc Natl Acad Sci U S
A.}2014;111(36):13145-13150.

124. Wesemann DR, Nagler CR. The Microbiome, Timing, and Barrier
Function in the Context of Allergic Disease. \emph{Immunity.}
2016;44(4):728-738.

125. Tan JK, McKenzie C, Marino E, Macia L, Mackay CR.
Metabolite-Sensing G Protein-Coupled Receptors-Facilitators of
Diet-Related Immune Regulation. \emph{Annu Rev Immunol.}
2017;35:371-402.

126. Furusawa Y, Obata Y, Fukuda S, et al. Commensal microbe-derived
butyrate induces differentiation of colonic regulatory T cells.
\emph{Nature.} 2013;504(7480):446-450.

127. Tan J, McKenzie C, Vuillermin PJ, et al. Dietary Fiber and
Bacterial SCFA Enhance Oral Tolerance and Protect against Food Allergy
through Diverse Cellular Pathways.\emph{Cell Rep.}
2016;15(12):2809-2824.

128. Donohoe DR, Garge N, Zhang N, et al. The microbiome and butyrate
regulate energy metabolism and autophagy in the mammalian colon.
\emph{Cell Metab.} 2011;13(5):517-526.

129. Byndloss MX, Olsan EE, Rivera-Chavez F, et al. Microbiota-activated
PPAR-gamma signaling inhibits dysbiotic Enterobacteriaceae expansion.
\emph{Science.}2017;357(6351):570-575.

130. Macia L, Mackay CR. Dysfunctional microbiota with reduced capacity
to produce butyrate as a basis for allergic diseases. \emph{J Allergy
Clin Immunol.}2019;144(6):1513-1515.

131. Zelante T, Iannitti RG, Cunha C, et al. Tryptophan catabolites from
microbiota engage aryl hydrocarbon receptor and balance mucosal
reactivity via interleukin-22.\emph{Immunity.} 2013;39(2):372-385.

132. Hang S, Paik D, Yao L, et al. Bile acid metabolites control TH17
and Treg cell differentiation.\emph{Nature.} 2019;576(7785):143-148.

133. Garcia-Larsen V, Lerodiakonou D, Jarrold K. Diet during pregnancy
and infancy and risk of allergic or autoimmune disease: A systematic
review and meta-analysis. \emph{PLoS Med.} 2018;15(2).

134. Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of peanut
consumption in infants at risk for peanut allergy. \emph{N Engl J Med.}
2015;372(9):803-813.

135. du Toit G, Sayre PH, Roberts G, et al. Allergen specificity of
early peanut consumption and effect on development of allergic disease
in the Learning Early About Peanut Allergy study cohort. \emph{J Allergy
Clin Immunol.}2018;141(4):1343-1353.

136. Perkin MR, Logan K, Tseng A, et al. Randomized Trial of
Introduction of Allergenic Foods in Breast-Fed Infants. \emph{N Engl J
Med.} 2016;374(18):1733-1743.

137. de Silva D, Halken S, Singh C, et al. Preventing food allergy in
infancy and childhood: systematic review of randomised controlled
trials. \emph{Pediatr Allergy Immunol.}2020;31(7):813-826.

138. Obbagy JE, English LK, Wong YP, et al. Complementary feeding and
food allergy, atopic dermatitis/eczema, asthma, and allergic rhinitis: a
systematic review. \emph{Am J Clin Nutr.} 2019;109(Suppl\_7):890s-934s.

139. Burgess JA, Dharmage SC, Allen K, et al. Age at introduction to
complementary solid food and food allergy and sensitization: A
systematic review and meta-analysis.\emph{Clin Exp Allergy.}
2019;49(6):754-769.

140. Urashima M, Mezawa H, Okuyama M, et al. Primary Prevention of Cow's
Milk Sensitization and Food Allergy by Avoiding Supplementation With
Cow's Milk Formula at Birth: A Randomized Clinical Trial. \emph{JAMA
Pediatr.} 2019;173(12):1137-1145.

141. Fisher HR, Du Toit G, Bahnson HT, Lack G. The challenges of
preventing food allergy: Lessons learned from LEAP and EAT. \emph{Ann
Allergy Asthma Immunol.}2018;121(3):313-319.

142. Perkin MR, Logan K, Marrs T, et al. Enquiring About Tolerance (EAT)
study: Feasibility of an early allergenic food introduction regimen.
\emph{J Allergy Clin Immunol.}2016;137(5):1477-1486.e1478.

143. Koplin JJ, Peters RL, Dharmage SC, et al. Understanding the
feasibility and implications of implementing early peanut introduction
for prevention of peanut allergy.\emph{J Allergy Clin Immunol.}
2016;138(4):1131-1141.e1132.

144. Venter C, Agostoni C, Arshad SH, et al. Dietary factors during
pregnancy and atopic outcomes in childhood: a systematic review from the
European Academy of Allergy and Clinical Immunology. \emph{Pediatr
Allergy Immunol.} 2020;31(8):889-912.

145. Netting M, Middleton P, Makrides M. Does maternal diet during
pregnancy and lactation affect outcomes in offspring? A systematic
review of food-based approaches.\emph{Nutrition.} 2014;30:1225-1241.

146. Grimshaw K, Maskell J, Oliver E. Diet and food allergy development
during infancy: birth cohort study findings using prospective food diary
data. \emph{J Allergy Clin Immunol.} 2014;133(2):511-519.

147. Venter C, Greenhawt M, Meyer R, et al. EAACI position paper on diet
diversity in pregnancy, infancy and childhood: Novel concepts and
implications for studies in allergy and asthma. \emph{Allergy.}
2020;3(75):497-523.

148. Roduit C, Frei R, Depner M. Increased food diversity in the first
year of life is inversely associated with allergic diseases. \emph{J
Allergy Clin Immunol.}2014;133(4):1056-1064.

149. Sausenthaler S, Heinrich J, Koletzko S. Early diet and the risk of
allergy: what can we learn from the prospective birth cohort studies
GINIplus and LISAplus? \emph{Am J Clin Nutr.} 2011;94(6 ):2012-2017.

150. Zutavern A, Brockow, Schaaf B. Timing of solid food introduction in
relation to eczema, asthma, allergic rhinitis, and food and inhalant
sensitization at the age of 6 years: results from the prospective birth
cohort study LISA.\emph{Pediatrics.} 2008;121(1):44-52.

151. Zutavern A, Brockow I, Schaaf B. Timing of solid food introduction
in relation to atopic dermatitis and atopic sensitization: results from
a prospective birth cohort study.\emph{Pediatrics.} 2006;117(2):401-411.

152. Fergusson D, Horwood L, Shannon F. Risk factors in childhood
eczema. . \emph{J Epidemiol Community Health.} 1982;36(2):118-122.

153. Nwaru B, Takkinen H, M, Kaila Food diversity in infancy and the
risk of childhood asthma and allergies. \emph{J Allergy Clin Immunol.}
2014;133(4):1084-1091.

154. Roduit C, Frei R, G, Loss Development of atopic dermatitis
according to age of onset and association with early-life exposures.
\emph{J Allergy Clin Immunol.}2012;130(1):130-136.

155. Turati F, Bertuccio P, Galeone C. Early weaning is beneficial to
prevent atopic dermatitis occurrence in young children. \emph{Allergy.}
2016;71(6):878-888.

156. Sharief S, Jariwala S, Kumar J, Muntner P, Melamed M. Vitamin D
levels and food and environmental allergies in the United States:
results from the National Health and Nutrition Examination Survey
2005-2006. \emph{J Allergy Clin Immunol.}2011;127(5):1195- 1202.

157. Allen KJ, Koplin J, Ponsonby A. Vitamin D insufficiency is
associated with challenge-proven food allergy in infants. \emph{J
Allergy Clin Immunol.} 2013;131(4):1109- 1116.

158. Hennessy \selectlanguage{ngerman}Á, Hourihane JOB, Malvisi L, et al. Antenatal vitamin D
exposure and childhood eczema, food allergy, asthma and allergic
rhinitis at 2 and 5 years of age in the atopic disease\selectlanguage{english}-specific Cork
BASELINE Birth Cohort Study.\emph{Allergy.} 2018;73(11):2182-2191.

159. Thorisdottir B, Gunnarsdottir I, Vidarsdottir A, Sigurdardottir S,
Birgisdottir B, Thorsdottir I. Infant Feeding, Vitamin D and IgE
Sensitization to Food Allergens at 6 Years in a Longitudinal Icelandic
Cohort. \emph{Nutrients.} 2019;11(7).

160. Hollams E, Teo S, Kusel M. Vitamin D over the first decade and
susceptibility to childhood allergy and asthma. \emph{J Allergy Clin
Immunol.} 2017;139(2):472-481.

161. Litonjua AA, Carey VJ, Laranjo N. Effect of Prenatal
Supplementation With Vitamin D on Asthma or Recurrent Wheezing in
Offspring by Age 3 Years: The VDAART Randomized Clinical Trial.
\emph{JAMA Dermatol.} 2016;315(4):362-370.

162. Rosendahl J, Pelkonen A, Helve O. High-Dose Vitamin D
Supplementation Does Not Prevent Allergic Sensitization of Infants.
\emph{J Pediatr.} 2019:139-145.

163. Yepes-Nunez J, Brozek J, Fiocchi A. Vitamin D supplementation in
primary allergy prevention: Systematic review of randomized and
non-randomized studies.\emph{Allergy.} 2018;73(1):37-49.

164. Hawrylowicz C, Santos A. Vitamin D: can the sun stop the atopic
epidemic? \emph{Curr Opin Allergy Clin Immunol.} 2020;20(2):181-187.

165. Greer F, Sicherer SH, Burks A. Committee On N, Section On A,
Immunology. The Effects of Early Nutritional Interventions on the
Development of Atopic Disease in Infants and Children: The Role of
Maternal Dietary Restriction, Breastfeeding, Hydrolyzed Formulas, and
Timing of Introduction of Allergenic Complementary Foods.
\emph{Pediatrics.} 2019;143(4).

166. Greer FR, Sicherer SH, Burks AW, Committee On N, Section On A,
Immunology. The Effects of Early Nutritional Interventions on the
Development of Atopic Disease in Infants and Children: The Role of
Maternal Dietary Restriction, Breastfeeding, Hydrolyzed Formulas, and
Timing of Introduction of Allergenic Complementary Foods.
\emph{Pediatrics.} 2019;143(4).

167. American Academy of Pediatrics. Committee on Nutrition.
Hypoallergenic infant formulas.\emph{Pediatrics.} 2000;106(2 Pt
1):346-349.

168. Greer FR, Sicherer SH, Burks AW, American Academy of Pediatrics
Committee on N, American Academy of Pediatrics Section on A, Immunology.
Effects of early nutritional interventions on the development of atopic
disease in infants and children: the role of maternal dietary
restriction, breastfeeding, timing of introduction of complementary
foods, and hydrolyzed formulas.\emph{Pediatrics.} 2008;121(1):183-191.

169. Gupta RS, Bilaver LA, Johnson JL, et al. Assessment of Pediatrician
Awareness and Implementation of the Addendum Guidelines for the
Prevention of Peanut Allergy in the United States. \emph{JAMA Netw
Open.} 2020;3(7):e2010511.

170. Joshi PA, Smith J, Vale S, Campbell DE. The Australasian Society of
Clinical Immunology and Allergy infant feeding for allergy prevention
guidelines. \emph{Med J Aust.}2019;210(2):89-93.

171. Perkin MR, Logan K, Marrs T, et al. Association of frequent
moisturizer use in early infancy with the development of food allergy.
\emph{J Allergy Clin Immunol.}2021;147(3):967-976 e961.

172. Kelleher MM, Cro S, Cornelius V, et al. Skin care interventions in
infants for preventing eczema and food allergy. \emph{Cochrane Database
of Systematic Reviews.} 2021(2).

173. Group OCfE-BMLoEW. The Oxford 2011 Levels of Evidence. In:2011.

174. Cohen SG. Food allergens: landmarks along a historic trail. \emph{J
Allergy Clin Immunol.}2008;121(6):1521-1524, 1524 e1521.

175. Kay AB. 100 years of 'Allergy': can von Pirquet's word be rescued?
\emph{Clin Exp Allergy.}2006;36(5):555-559.

176. Schofield A. A case of egg poisoning. \emph{The Lancet.}
1908;171(4410):716.

177. Schloss OM. A case of allergy to common foods. \emph{American
Journal of Diseases of Children.}1912;3(6):341-362.

178. Prausnitz C, Kustner H. Studien uber die Uberempfindlichkeit.
\emph{Zentralbl Bakteriol.}1921;86:160-169.

179. Loveless MH. Allergy for corn and its derivatives: experiments with
a masked ingestion test for its diagnosis. \emph{J Allergy.}
1950;21(6):500-509.

180. Platts-Mills TAE. The continuing effect of the discovery of IgE by
Kimishige Ishizaka. \emph{J Allergy Clin Immunol.} 2018;142(3):788-789.

181. Immunoglobulin E, a new class of human immunoglobulin. \emph{Bull
World Health Organ.}1968;38(1):151-152.

182. Bock SA, Lee WY, Remigio L, Holst A, May CD. Appraisal of skin
tests with food extracts for diagnosis of food hypersensitivity.
\emph{Clin Allergy.}1978;8(6):559-564.

183. Bock SA, Sampson HA, Atkins FM, et al. Double-blind,
placebo-controlled food challenge (DBPCFC) as an office procedure: a
manual. \emph{J Allergy Clin Immunol.}1988;82(6):986-997.

184. Lack G, Golding J. Peanut and nut allergy. Reduced exposure might
increase allergic sensitisation.\emph{BMJ.} 1996;313(7052):300.

185. Sampson HA, Ho DG. Relationship between food-specific IgE
concentrations and the risk of positive food challenges in children and
adolescents. \emph{J Allergy Clin Immunol.}1997;100(4):444-451.

186. Sampson HA. Utility of food-specific IgE concentrations in
predicting symptomatic food allergy.\emph{J Allergy Clin Immunol.}
2001;107(5):891-896.

187. Sampson HA. Food allergy: Past, present and future. \emph{Allergol
Int.} 2016;65(4):363-369.

188. Smith M. Another person's poison. \emph{Lancet.}
2014;384(9959):2019-2020.

189. May CD. Food allergy: lessons from the past. \emph{J Allergy Clin
Immunol.} 1982;69(3):255-259.

190. Saloga J, Renz H, Larsen GL, Gelfand EW. Increased airways
responsiveness in mice depends on local challenge with antigen. \emph{Am
J Respir Crit Care Med.}1994;149(1):65-70.

191. Lack G, Fox D, Northstone K, Golding J, Avon Longitudinal Study of
P, Children Study T. Factors associated with the development of peanut
allergy in childhood. \emph{N Engl J Med.} 2003;348(11):977-985.

192. Horimukai K, Morita K, Narita M, et al. Application of moisturizer
to neonates prevents development of atopic dermatitis. \emph{J Allergy
Clin Immunol.} 2014;134(4):824-830 e826.

193. Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of peanut
consumption in infants at risk for peanut allergy. \emph{N Engl J Med.}
2015;372(9):803-813.

194. Du Toit G, Sayre PH, Roberts G, et al. Effect of Avoidance on
Peanut Allergy after Early Peanut Consumption. \emph{N Engl J Med.}
2016;374(15):1435-1443.

195. Lowe AJ, Su JC, Allen KJ, et al. A randomized trial of a barrier
lipid replacement strategy for the prevention of atopic dermatitis and
allergic sensitization: the PEBBLES pilot study. \emph{Br J Dermatol.}
2018;178(1):e19-e21.

196. Leung DYM, Calatroni A, Zaramela LS, et al. The nonlesional skin
surface distinguishes atopic dermatitis with food allergy as a unique
endotype. \emph{Sci Transl Med.} 2019;11(480).

197. Miyaji Y, Yang L, Yamamoto-Hanada K, Narita M, Saito H, Ohya Y.
Earlier aggressive treatment to shorten the duration of eczema in
infants resulted in fewer food allergies at 2 years of age. \emph{J
Allergy Clin Immunol Pract.}2020;8(5):1721-1724 e1726.

198. Chalmers JR, Haines RH, Bradshaw LE, et al. Daily emollient during
infancy for prevention of eczema: the BEEP randomised controlled trial.
\emph{Lancet.}2020;395(10228):962-972.

199. de Silva D, Halken S, Singh C, et al. Preventing food allergy in
infancy and childhood: Systematic review of randomised controlled
trials. \emph{Pediatr Allergy Immunol.}2020;31(7):813-826.

200. Skjerven HO, Rehbinder EM, Vettukattil R, et al. Skin emollient and
early complementary feeding to prevent infant atopic dermatitis
(PreventADALL): a factorial, multicentre, cluster-randomised trial.
\emph{Lancet.}2020;395(10228):951-961.



\textbf{Legends:}

Figure 1. Prevalence of Paediatric FA Around the World adapted from
Warren C, Jiang J, Gupta

R.Epidemiology and Burden of Food Allergy. \emph{Curr Allergy Asthma
Rep.} 2020;20(2), Lyons SA,

Clausen M, Knulst AC, et al. Prevalence of Food Sensitization and Food
Allergy in Children

Across Europe. \emph{J Allergy Clin Immunol Pract.} 2020;8(8):2736-2746
e2739 and Venter C, Pereira B, Voigt K, et al. Prevalence and cumulative
incidence of food hypersensitivity

in the first 3 years of life. \emph{Allergy.} 2008;63(3):354-359.

Figure 2: Prevalence of Current Eczema Symptoms (ISAAC Phase III: Ages
6-7 adapted from Odhiambo J, Williams H, Clayton T, Robertson C, Asher
M. Global variations in prevalence of eczema symptoms in children from
ISAAC Phase Three.\emph{J Allergy Clin Immunol.} 2009;124(6):1251-1258

Figure 3: Prevalence of Current Eczema Symptoms (ISAAC Phase III: Ages
13-14) adapted from from Odhiambo J, Williams H, Clayton T, Robertson C,
Asher M. Global variations in prevalence of eczema symptoms in children
from ISAAC Phase Three.\emph{J Allergy Clin Immunol.}
2009;124(6):1251-1258

Figure 4: In the ``outside-in'' hypothesis, skin barrier defect allows
penetration of allergens and

microbes leading to atopic sensitization whereas, in the ``inside-out''
paradigm, a polarized

immune response leads to a defective skin barrier. Adapted from Leung
DY, Guttman-Yassky E.

Deciphering the complexities of atopic dermatitis: Shifting paradigms in
treatment approaches.

\emph{J Allergy Clin Immunol.} 2014;134(4):769-779.

Figure 5: Skin dysbiosis, especially colonization of\emph{Staphylococcus
aureus} and\emph{~Malassezia spp.,} is often seen among young children
with atopic dermatitis. (a) \emph{S. aureus}colonization on a six-month
child; (b). heavy colonization of\emph{Malassezia spp.,} also known as
Pityrosporum, on the scalp of an infant.

Figure 6: Dietary compounds and their conversion by commensal bacteria
influence oral tolerance. Several dietary components and digestive
products contribute heavily to the function of the gut immune system.
Gut-resident CD103\textsuperscript{+} dendritic cells (DCs) directly
convert dietary vitamin A to retinoic acid (RA) for further downstream
immune signaling. Conversely, tryptophan, liver-derived bile acids, and
fiber must first be metabolized by commensal bacteria such as
Clostridia. These bacteria degrade tryptophan into several compounds
that can bind to the aryl-hydrocarbon receptor (Ahr) of ILC3s, playing a
role in IL-22 production. Secondary bile acids and short chain fatty
acids (SCFAs), including butyrate, signal directly to epithelial cells
as well as local immune cell populations residing in the lamina propria.
Collectively, these compounds enhance epithelial barrier integrity by
stimulating Paneth cells to produce anti-microbial peptides, goblet
cells to produce mucus, and epithelial cells to produce tight junction
and adherens proteins. In addition, they induce populations of
tolerogenic lymphocytes such as peripherally induced regulatory T cells
(iTregs) and IgA-producing plasma cells. Together, these functions are
essential for the maintenance of oral tolerance.

Figure 7: Diagram of possible causal associations between genetics, skin
exposures, diet leading to eczema and/or food allergy. The interplay
between genetics, diet, and skin/microbiome exposure are connected by
arrows showing the direction of causality hypothesized to ultimately
influence food allergy. The relevant causal factors of the dual allergen
exposure hypothesis are outlined by the blue rectangle. This hypothesis
postulates that allergen exposure through the skin leads to the
development of food allergy. The degree of a broken skin barrier
involved with eczema is thought to interact with allergen exposure to
increase the probability of allergy development with increasing barrier
disfunction. While early introduction of food and diet diversity has
been proven to prevent food allergy (dark green), other factors such as
breastfeeding, commensal bacteria metabolizing bile acids, tryptophan
from dietary/commensal bacterial sources, dietary fiber, vitamins,
pre-pro- and syn-biotics have weaker evidence base for this (light
green). Reducing eczema severity has yet to be consistently shown as a
preventative causal mechanism. Nevertheless, eczema severity exists as
one of the strongest predictors of food allergy, and therapies to heal a
broken skin barrier remain as a leading mechanism to mediate the
prevention of food allergy.

\selectlanguage{english}
\FloatBarrier
\end{document}

