A to p i c D er ma ti ti s I s a B ar ri er

I s s u e , N o t an A l l e r g y I s s u e
a a,
Monica T. Kraft, MD , Benjamin T. Prince, MD, MSCI *

KEYWORDS
 Atopic dermatitis  Eczema  Atopic march  Food allergy  Allergic rhinitis
 Asthma

KEY POINTS
 Atopic dermatitis is a chronic, relapsing, and pruritic disease that typically presents in
early childhood and is the result of impaired epithelial barrier function and
immunodysregulation.
 Allergen sensitization through the skin is likely an important initial step in the development
of other allergic diseases in patients with atopic dermatitis.
 Although children with atopic dermatitis are more likely to produce specific Immunoglob-
ulin E to both food and environmental allergens, there is conflicting evidence that allergen
avoidance in these patients improves disease severity.
 The most effective treatments of atopic dermatitis are aimed at repairing and protecting
the skin barrier and decreasing inflammation.

INTRODUCTION

Atopic dermatitis (AD) is a chronic, relapsing, and pruritic illness that affects up to 10%
to 20% of children in developed countries and is associated with significant morbidity
and decreased quality of life.1 Within the United States, population studies have
shown a national prevalence of 10.7% of children younger than 18 years, with a
growing pool of evidence that the prevalence is increasing worldwide.2
Although the general term “eczema” was initially used to describe the condition, the
correlation between eczema and other atopic conditions led to Wise and Sulzberger
coining the term AD in 1933.3 More recently, longitudinal studies have demonstrated
that the presence of AD increases the risk of developing food allergy, allergic rhinitis,
and asthma later in life.4 This progression from AD to the manifestation of food allergy,
allergic rhinitis, and asthma is often referred to the atopic march of childhood.

Disclosure Statement: Nothing to disclose.

a
Department of Pediatrics, Division of Allergy and Immunology, Nationwide Children’s Hos-
pital, The Ohio State University College of Medicine, 700 Children’s Drive, Columbus, OH
43205, USA
* Corresponding author.
E-mail address: benjamin.prince@nationwidechildrens.org

Immunol Allergy Clin N Am 39 (2019) 507–519

https://doi.org/10.1016/j.iac.2019.07.005 immunology.theclinics.com
0889-8561/19/ª 2019 Elsevier Inc. All rights reserved.
508 Kraft & Prince

Although the exact cause of AD is not completely understood, it is thought to be the

result of a complex interaction of genetic and environmental factors that ultimately
leads to impaired epidermal barrier function and immune dysregulation. Because
sensitization to environmental proteins often occurs as a result of a more porous
skin barrier, it is a common misconception that allergy is at the root of the disease.
In contrast, AD tends to be the initial manifestation of the atopic march, and sensitiza-
tion through the skin is likely an important initial step in the development of other
allergic diseases that have been associated with AD.5
This article reviews the clinical presentation, pathophysiology, and genetic factors
associated with AD, briefly discusses proposed therapeutic strategies aimed at barrier
repair, and describes the associations between AD and other allergic diseases.

CLINICAL PRESENTATION OF ATOPIC DERMATITIS

Clinical Features and Diagnosis
The characteristic features of AD are dry skin and severe pruritus. Although the clinical
presentation can be variable, the disease typically begins in early childhood with a
large proportion of cases going into remission during later childhood. Garmhausen
and colleagues6 analyzed more than 700 patients with AD and described 5 distinct
subgroups based on symptom onset, disease course, and laboratory features. These
investigators found that about one-third of all patients with AD had a disease history
that began in early childhood and persisted until adulthood, and also noted that pa-
tients with early-onset AD were more likely to have other concomitant atopic condi-
tions. Others have described 3 main age-related stages: infantile (up to age
2 years), childhood (ages 2–12 years), and adult.7 The morphology of AD lesions varies
with age. Infants tend to have red, crusted, and weeping patches located primarily on
cheeks and extensor surfaces. Lesions become more papular in older children, local-
izing to flexural surfaces and often forming thickened, lichenified plaques. In adult-
hood, the disease can take on more of a relapsing and remitting course with
flexures and hands continuing to be problem areas.7
Diagnosis is based on clinical history and the presence of characteristic eczema-
tous lesions. Hanifin and Rajka8 developed the initial diagnostic standard for AD in
1980, describing 4 major criteria and nearly 2 dozen minor criteria encompassing
characteristics of the disease. Some of the minor criteria have been questioned since
the initial publication because they are thought to not be specific to AD.7 To remedy
this, the United Kingdom Working Party attempted to refine the original Hanifin and
Rajka criteria; however, their revision was not easily applied to young children.9 In
2003, the American Academy of Dermatology (AAD) again revised the Hanifin and
Rajka criteria to make it inclusive of all ages.10 The AAD criteria are the most widely
used in the United States and use essential characteristics of AD, important patient
features, and less specific associated skin findings.

Natural History
AD follows a chronic or chronic-relapsing course over months to years, and the natural
history of the disease is variable based on age of presentation and other clinical fea-
tures. Although most patients will have resolution of AD by late childhood, in a propor-
tion of cases the disease will persist into adulthood. Kim and colleagues11 performed a
meta-analysis of more than 45 studies including more than 110,000 subjects, and
found that 80% of childhood AD did not persist past 8 years of age and a small per-
centage (less than 5%) persisted by more than 20 years after diagnosis. Another large
longitudinal cohort study of more than 7000 patients showed that AD symptoms may
 Atopic Dermatitis Is a Barrier Issue 509

persist longer than originally believed, as it was not until 20 years of age that 50% of
patients reported at least one lifetime 6-month symptom-free and treatment-free
period.12 Peters and colleagues13 performed a large prospective cohort study in
Germany and found that genetic factors, early allergen sensitization, and a high-risk
work environment were significant predictors of disease persistence through late
adolescence.

PATHOPHYSIOLOGY OF ATOPIC DERMATITIS

Although food and environmental allergies are commonly implicated in the pathogen-
esis of AD, it is now well known that the disease is the result of skin barrier dysfunction
and inappropriate immune response to skin antigens.14

Normal Skin Structure

The skin, specifically the epidermis, acts as a physical and immunologic protective
barrier against the outside world. The epidermis is made up of keratinized stratified
squamous epithelium in 4 main cell layers: the stratum basale, the stratum spinosum,
the stratum granulosum, and the outermost layer, the stratum corneum.15 The stratum
corneum (made up of structural proteins, tight-junction proteins, ceramides, fatty
acids, and cholesterol) is responsible for the primary barrier function of the epidermis.
The stratum corneum itself is organized into 2 compartments, the corneocytes and the
extracellular matrix, which prevent water loss and protect against microbial patho-
gens.16 The structural makeup of the stratum corneum and the molecular organization
of its multiple lipid bilayers creates the epidermis’ permeable barrier. Absorption
across the epidermis is primarily intercellular, through the lipid bilayer, and thus
lipophilic molecules penetrate across the skin more readily than hydrophilic
compounds.17 Additional diffusion across the epidermis is accomplished paracellu-
larly through tight-junction proteins that provide adhesive functions between
keratinocytes.14

Structural Changes that Occur in Atopic Dermatitis

The main epithelial structural changes in AD that are thought to be responsible for dis-
ease pathogenesis include keratinocyte dysfunction and altered lipid composition,
which lead to increased permeability of the stratum corneum and increased transepi-
dermal water loss (Box 1).
Defects in terminal differentiation of keratinocytes have been identified in patients
with AD through comparisons between skin lesions in patients with psoriasis, AD,
and normal human skin. Ong and colleagues18 compared skin biopsy specimens
from patients with psoriasis, AD, and healthy controls and found that patients with
AD had a deficiency in the expression of antimicrobial peptides (cathelicidins and
b-defensins). This has been suggested as a contributing factor for the superimposed
skin infections that are frequently seen in patients with AD. In addition, elevations in
proteases have been described in acute flares of AD, which have been associated
with impaired barrier function and reduced skin capacitance.19
Changes in the intercellular lipid composition and structure of the stratum corneum
can also contribute to the increased skin permeability seen in AD. Ishikawa and
colleagues20 found that total levels of ceramides were significantly lower in the
affected sites of patients with AD compared with normal skin sites in healthy individ-
uals. Janssens and colleagues21 found that ceramide chain length and lipid organiza-
tion were directly correlated with the skin barrier defects in patients with AD, even in
nonlesional skin.
510 Kraft & Prince

Box 1
Pathogenic changes that lead to epithelial barrier dysfunction and immunodysregulation in
atopic dermatitis

Epidermal Changes
 Defective terminal differentiation of keratinocytes
 Structural changes within the stratum corneum
 Increases in protease production
 Decreased amounts of ceramides with altered lipid composition
 Increased transepidermal water loss
Immunologic Changes
 Mechanical trauma–induced TSLP, IL-33, and IL-25 production
 Marked production of Th2 and Th22 cytokines
 Increased production of IL-31, leading to itch
 Abnormal signaling in pattern recognition receptor pathways
 Decreased production of antimicrobial peptides (defensins, cathelicidins)
Microbiome Changes
 Decreased bacterial diversity
 Increased colonization with toxin-producing strains of S aureus

Impairment of the stratum corneum results in an increase in transepidermal water

loss (TEWL) or a decrease in water-holding ability (capacitance). Studies have shown
significantly higher TEWL and lower capacitance in the lesional skin of patients with
AD compared with normal controls.22 Other studies have demonstrated similar find-
ings of compromised skin barrier function and increased TEWL even in nonlesional
skin of patients with AD.23

Immunologic Changes that Occur in Atopic Dermatitis

In addition to the dysfunction of the epidermal barrier in AD, research into the patho-
genesis of AD has highlighted the role of immunologic pathways in cutaneous inflam-
mation and barrier dysfunction (see Box 1).
Hyperinflammatory state of atopic dermatitis
In patients with AD, disruption of the skin barrier is associated with the release of
proinflammatory cytokines that promote chemoattractants and adhesional molecules
to recruit T cells to cutaneous sites. In response to mechanical trauma, epithelial cells
release thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25.24–26 This is
associated with an increase in type 2 innate lymphoid cells (ILC2s) that drive the pro-
duction of IL-5 and IL-13 and ultimately lead to T helper 2 (Th2) cell differentiation and
inflammation. In addition to the inflammatory response produced by barrier disruption,
others have reported on the increased expression of Th2, Th22, and Th1 cells in non-
lesional skin of patients with AD compared with healthy subjects.21 This finding sug-
gests that systemic immune activation plays a role in the pathogenesis of eczema.
Immunologic changes in atopic dermatitis contribute to barrier dysfunction
In patients with AD, there is marked activation of Th2 and Th22 axes, causing profound
increases in IL-4, IL-5, IL-13, IL-31, and IL-22.27 These cytokines play a significant role
 Atopic Dermatitis Is a Barrier Issue 511

in the pathogenesis of AD. IL-4 and IL-13 have been shown to affect keratinocyte
differentiation, leading to a decreased expression of genes that are important for bar-
rier function.28 IL-22 acts synergistically with IL-17 to increase inflammation and
contribute to barrier abnormalities.29 IL-31 is thought to be responsible for the patho-
gnomonic itch in eczema, and overexpression of IL-31 mRNA has been described in
both lesional and nonlesional skin of patients with AD.30 Subsequent scratching
further disrupts the skin barrier, and the “itch-scratch” response has been shown in
mouse models to enhance both Th1- and Th2-mediated inflammation.31 Because of
their role in the pathogenesis of AD, IL-4, IL-13, and IL-31 have subsequently become
the targets of treatment with biological therapies.

Skin Microbiome Changes that Occur in Atopic Dermatitis

There is evidence that changes in the skin microbiome in patients with AD contribute
to epithelial barrier dysfunction and exacerbate underlying immunodysregulation.
Kong and colleagues32 reported that skin bacterial diversity was decreased in AD
compared with healthy controls. Patients with AD showed a greater proportion of
Staphylococcus species (especially Staphylococcus aureus) during disease flares,
with the presence of S aureus also being linked to increased disease severity. Other
studies have identified S aureus colonization in greater than 90% of eczema lesions.33
It is thought that the Th2 inflammation seen in AD facilitates S aureus binding by down-
regulating keratinocyte production of antimicrobial peptides.34 It has been shown that
S aureus toxin production can lead to exacerbations in AD by causing regulatory T cell
dysfunction and promoting inflammation.35 Additionally S aureus can produce an
extracellular protease, which has been suggested to disrupt the epidermal barrier.36

GENETIC CAUSES OF ATOPIC DERMATITIS

Studies of twin populations have historically demonstrated the heritability of AD.37,38

Multiple genetic factors have been identified to be associated with the development
of AD, with most genes playing a role in skin barrier integrity.

Genes Important for Skin Structure

Several of the genes that have been associated with the development of AD are
located on chromosome 1q21 in an area termed the epidermal differentiation complex
(EDC).39 These genes code for proteins that are important for epithelial keratinocytes
to produce the tough, cornified envelope of the epidermis that is integral for the barrier
function. The strongest known genetic risk factors for AD are loss-of-function (LOF)
mutations in the filaggrin gene (FLG), which is located in the EDC.40 FLG provides in-
structions for making the large protein called profilaggrin. Profilaggrin is ultimately
cleaved to produce filaggrin, which is one of the final proteins necessary for the pro-
cess of cornification. LOF mutations in FLG were first identified during studies inves-
tigating ichythyosis vulgaris, a disorder of keratinization and epidermal dysfunction.41
Later studies have consistently demonstrated that LOF variants in filaggrin were also
associated with AD.42 The discovery of decreased filaggrin expression in patients with
AD contributed significantly to the understanding of the pathogenesis of eczema.
FLG2 and SPRR3 are 2 other genes located within the EDC that have been implicated
in AD, both of which code for proteins that are important for the structure of the cor-
nified envelope.43
Other genes not located within the EDC identified in patients with AD include
SPINK5,44 CLDN1,45 and TMEM79.46 All of these genes code for proteins that are
important for epidermal homeostasis and barrier function.
512 Kraft & Prince

THERAPEUTIC STRATEGIES OF BARRIER REPAIR IN ATOPIC DERMATITIS

Primary Prevention
There is evidence to support the proposal that the application of emollients early in life
leads to a decreased incidence of AD. Because the stratum corneum is more perme-
able in infants younger than 1 year, it had been hypothesized that early emollient use
could prevent AD in infants at risk for disease.47 Horimukai and colleagues48 per-
formed the first randomized controlled trial of emollient use during the first months
of life and found that approximately 32% fewer neonates developed AD in the treat-
ment group. Although allergic sensitization was associated with eczematous skin,
the study did not find a statistically significant effect of emollient use on the prevention
of allergic sensitization as measured by allergen-specific immunoglobulin E (IgE).
Simpson and colleagues47 performed a randomized controlled trial evaluating emol-
lient use in neonates at high risk for AD in the United States and United Kingdom.
The investigators found that infants who used daily, full-body emollients had a relative
risk reduction of 50% for incidence of AD at 6 months. Lowe and colleagues49 evalu-
ated emollient use in an Australian population of neonates and found that prophylactic
emollient use for the first 6 months of life was associated with a trend toward reduced
incidence of AD and food sensitization at both 6 and 12 months of age, although this
study’s results did not reach statistical significance.

Secondary and Tertiary Prevention

Cleansing and moisturization are the mainstay of treatment in AD, and current recom-
mendations are for a short bath or shower followed immediately by the application of
emollient moisturizer when the skin is still slightly wet.50 This approach promotes
improved hydration of the skin, whereas bathing alone without moisturization may
result in decreased skin hydration. Adding diluted bleach to bathwater or other anti-
septic cleansers provides antibacterial activity that can help in the management of
AD given the increased colonization with S aureus and other pathogens.51
Emollients have remained a mainstay for the treatment of AD, providing a lipid-rich
moisturizer that compensates for the lipid and ceramide deficiencies in AD skin.50 In
addition, studies have shown that aggressive emollient use as maintenance and pre-
vention therapy in AD can reduce the number of prescriptions for topical corticoste-
roids and other medications in severe disease.52 There is no single emollient that
has emerged as the ideal maintenance therapy, and previous randomized controlled
trials have shown similar efficacy for over-the-counter petroleum-based emollients
and prescription barrier creams for monotherapy in AD.53
For more intensive moisture replacement, wet-wrap therapy can be used alone or in
conjunction with topical steroids. This approach involves the application of a layer of
wet cotton garments over topical treatment, and has been shown to improve AD
severity and reduce the need for systemic immunosuppressive therapies.54

ASSOCIATION BETWEEN ATOPIC DERMATITIS AND ALLERGIC DISEASE

General Overview of the Atopic March and IgE-Mediated Disease
As previously discussed, the atopic march describes the typical progression of allergic
diseases in childhood, with AD presenting early and food allergy, allergic rhinitis, and
asthma presenting later. Proposed molecular mechanisms for the atopic march sug-
gest that skin sensitization after allergen exposure induces local inflammation with Th2
cells that subsequently migrate through the blood to other sites including the respira-
tory mucosa of the lungs and nasal passages. Mouse models have shown that epicu-
taneous exposure to food protein antigens (such as ovalbumin and peanut protein)
 Atopic Dermatitis Is a Barrier Issue 513

leads to Th2-mediated skin inflammation and a systemic immune response.55 Using

data from a cohort of preschool children with peanut allergy, Lack and colleagues56
identified that the use of creams containing peanut oil during the first 6 months of
life was significantly associated with increased risk for peanut allergy. Other studies
have detected increased TEWL in the neonatal period in infants who later developed
food allergy, further suggesting a link between skin barrier impairment and sensitiza-
tion to food allergens.57
In studying the impact of AD on the manifestation of other allergic diseases, it is
important to differentiate between sensitization, defined as the detection of IgE anti-
bodies to a specific allergen through either serum or skin-prick testing (SPT), and
the presence of clinical allergic disease. Many studies use environmental and food
sensitization as an analog of allergic disease; however, the presence of allergen sensi-
tization does not perfectly correlate with the presence of true allergy.

Atopic Dermatitis, Asthma, and Allergic Rhinitis

Atopic dermatitis is a risk factor for asthma and allergic rhinitis
Multiple birth cohort studies have described an association between early eczema and
subsequent development of asthma. Horwood and colleagues58 first identified early
eczema as a risk factor for the development of asthma in a cohort of New Zealand chil-
dren in their 1984 study. Subsequent cohort studies have also shown that early
eczema was associated with increased risk of wheezing and asthma later in
childhood.59–61
Studies of the German Multicenter Atopy Study cohort identified a significant asso-
ciation between AD and wheeze at age 7 years, but reported that most of these chil-
dren also had documented wheezing in early childhood, which the authors argue is
suggestive of a comanifesting disease process.62 However, the Melbourne Atopic
Cohort Study (MACS) showed that even after controlling for sensitization and early
wheeze, AD was still significantly associated with an increased risk of asthma in
boys.63 More recently, data from the Canadian Healthy Infant Longitudinal Develop-
ment Study found that AD without allergic sensitization was not associated with an
increased risk of asthma.4 The investigators argue that the combination of AD and
allergic sensitization had interactive effects on asthma and food allergy risk. Additional
studies of the MACS cohort have demonstrated that early-onset severe AD is most
strongly associated with development of asthma and hay fever later in childhood.64

Environmental allergen avoidance strategies have shown limited improvement of

atopic dermatitis
Despite the association between aeroallergens and AD, there is limited evidence to
suggest that avoidance strategies improve AD severity. In several prospective, ran-
domized controlled studies of avoidance strategies for house dust mite, there were
no differences in sensitization to dust mite or incidence of AD when compared with
those without avoidance strategies.65–67 In fact, in 2 studies AD was more prevalent
in the treatment group (ie, those using mattress covers to prevent dust mite exposure)
compared with the control group.67,68 In a Cochrane review including 7 studies of
more than 300 children and adults with AD, the authors found mixed evidence
regarding treatment response to dust mite avoidance in patients with AD.69

Atopic Dermatitis and Food Allergy

Atopic dermatitis increases the risk of food sensitization and allergy
There is evidence to support the notion that AD increases the risk of food sensitization.
In the MACS, involving more than 600 infants, the presence of AD before 6 months of
514 Kraft & Prince

age increased the risk of developing a new positive SPT result at 1 year.70 In addition,
early-onset persistent AD has been associated with allergic sensitization to food aller-
gens within the first 2 years of life.71 In a large Australian cohort study, up to 50% of
patients with early-onset and severe AD had developed challenge-proven food allergy
by 12 months of age, and overall infants with AD were approximately 5 times more
likely to develop food allergy in comparison with infants without AD.72
As previously described, LOF mutations in FLG are an important part of the patho-
genesis of skin barrier disruption in AD. Some studies have also reported an increased
risk of food allergy in patients with LOF mutations in FLG.73,74 However, others have
shown that FLG mutations do not increase the risk of food allergy over and above that
of food sensitization.75

Elimination diets in eczema have shown no prolonged benefit

Despite the association between early-onset severe AD and the prevalence of food al-
lergy, it is noteworthy that studies evaluating elimination or exclusion diets as treat-
ment of AD have not shown prolonged benefit.76 An early study of avoidance of
milk and egg in children with AD showed some improvement in pruritus and sleepless-
ness,77 although a different study of milk- and egg-exclusion diets showed no signif-
icant benefit.78 Whereas 2 studies showed a significant clinical improvement in
SCORAD index for eczema severity in patients with cow’s milk allergy/intolerance
and AD after milk elimination,79,80 pooled data in a comprehensive review including
these studies found no difference in AD severity at 2 to 3 months or 6 to 8 months.76
One study of children with egg sensitivity and AD did show some improvement in
eczema severity score after egg elimination.81 However, trials of elemental diets in
adults and children with AD have not demonstrated improvement in AD symptoms
or severity.82,83 Lastly, a trial of a limited, few-foods diet in which all foods were
excluded except for 5 to 8 failed to show benefit in AD symptoms or severity.84

Prolonged food avoidance may lead to immediate IgE-mediated reactions

With the growing evidence to support early introduction to prevent food allergy and the
limited evidence to support elimination diets for the treatment of AD, it is important to
be aware of the risks associated with elimination diets. There have been multiple case
reports of patients on elimination diets for AD who previously tolerated the eliminated
food developing acute allergic reactions after accidental ingestion or reintroduction of
the food.85–87 Furthermore, a retrospective chart review performed by Chang and col-
leagues88 found that 19% of patients who had eliminated food for treatment of AD
developed new, immediate allergic reactions after reintroduction to the food.

SUMMARY

AD is a chronic, relapsing disease that typically manifests in early childhood and im-
proves with age in most individuals. It is the result of genetic and environmental factors
that lead to impaired epidermal barrier function, increased TEWL, and immune dysre-
gulation. Primary prevention strategies of replenishing epithelial water loss and main-
taining the skin barrier early in life with daily emollient application have shown success.
In patients with established AD, the most effective treatments are aimed at repairing
and protecting the skin barrier and decreasing inflammation.
Many studies have demonstrated that AD is the start of an atopic march that leads
to the development of other allergic diseases later in life, likely as a result of antigen
exposure through a more porous and inflamed skin barrier. Although children with
AD are more likely to produce specific IgE to both food and environmental allergens,
there is conflicting evidence that allergen avoidance in these patients significantly
 Atopic Dermatitis Is a Barrier Issue 515

improves disease severity. Furthermore, food-elimination diets in patients with AD

may increase the risk of developing immediate, life-threatening reactions to the
removed food. Given these findings, it is important to educate and counsel parents
of children with AD about the disease pathogenesis, proven treatment strategies,
and the limited benefit and even potential harm associated with strict allergen
avoidance.

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