Clinical Management Review
Contact Dermatitis in the Patient with Atopic
Dermatitis
Emily C. Milam, MDa, Sharon E. Jacob, MDb, and David E. Cohen, MD, MPHa New York, NY; and Loma Linda, Calif
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Copyright Statement: Copyright Ó 2019-2021. All rights reserved.
Overall Purpose/Goal: To provide excellent reviews on key aspects of
allergic disease to those who research, treat, or manage allergic disease.
Target Audience: Physicians and researchers within the field of
allergic disease.
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Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are
common T-cell-mediated inflammatory skin conditions that can
share clinical presentations. The variable expression of ACD
a
The Ronald O. Perelman Department of Dermatology, New York University School
b
of Medicine, New York, NY
Loma Linda University, Loma Linda, Calif
No funding was received for this work.
Conflicts of interest: D.E. Cohen has received consultancy fees from Ferndale
Laboratories, Medimetriks, Erchonia, Cutanea, Ferrer, SkinFix, Celegene, and
FIDE (FIDE receives industry sponsorship from AbbVie, Almirall, Bristol Myers,
Celgene, Dermavant, Dermira, Janssen, Kyowa Hakko Kirin, LEO, Lilly,
Novartis, Ortho Dermatologics, Pfizer, Sun Pharma, UCB); has stock or stock
options in Dermira, Medimetriks, and Brickell Biotech; and serves on the Dermira
Board of Directors. The rest of the authors declare that they have no relevant
conflicts of interest.
Received for publication August 16, 2018; revised manuscript received and accepted
for publication November 5, 2018.
Corresponding author: David E. Cohen, MD, MPH, The Ronald O. Perelman
Department of Dermatology, New York University School of Medicine, 240 E
38th St, Floor 11, New York, NY 10016. E-mail: David.Cohen@nyulangone.org.
2213-2198
Ó 2019 Published by Elsevier Inc. on behalf of the American Academy of Allergy,
Asthma & Immunology
https://doi.org/10.1016/j.jaip.2018.11.003
18
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List of Design Committee Members: Emily C. Milam, MD, Sharon E.
Jacob, MD, and David E. Cohen, MD, MPH (authors); Michael Schatz,
MD, MS (editor)
Learning objectives:
1. To describe the immunology and pathophysiology of atopic and
allergic contact dermatitis and how those processes may be interconnected.
2. To describe the potential mechanisms responsible for increased risk
of allergic contact dermatitis (ACD) among patients with atopic
dermatitis (AD).
3. To recognize the contact allergens commonly affecting patients with AD.
4. To evaluate ACD in atopic patients.
Recognition of Commercial Support: This CME has not received
external commercial support.
Disclosure of Relevant Financial Relationships with Commercial
Interests: D.E. Cohen has received consultancy fees from Ferndale
Laboratories, Medimetriks, Erchonia, Cutanea, Ferrer, SkinFix, Cele-
gene, and FIDE (FIDE receives industry sponsorship from AbbVie,
Almirall, Bristol Myers, Celgene, Dermavant, Dermira, Janssen, Kyowa
Hakko Kirin, LEO, Lilly, Novartis, Ortho Dermatologics, Pfizer, Sun
Pharma, UCB); has stock or stock options in Dermira, Medimetriks, and
Brickell Biotech; and serves on the Dermira Board of Directors. The
rest of the authors declare that they have no relevant conflicts of interest.
M. Schatz declares no relevant conflicts of interest.
among patients with AD represents the shades of gray of the
multifaceted relationship between the 2 disorders, where
increased allergen permeation in compromised epidermal
barriers augments antigen presentation and sensitization, with
subsequent immune dysregulation. Further studies are needed to
define the relationship and immunologic intersection points of
these 2 conditions. Ó 2019 Published by Elsevier Inc. on
behalf of the American Academy of Allergy, Asthma &
Immunology (J Allergy Clin Immunol Pract 2019;7:18-26)
Key words: Atopic dermatitis; Atopy; Allergic contact dermatitis;
Contact allergen; Patch testing; Immunology
Atopic dermatitis (AD) and allergic contact dermatitis (ACD)
are common inflammatory T-cell-mediated skin conditions that
may coexist. AD—commonly referred to as eczema—is a het-
erogeneous disorder primarily defined by xerotic skin and a re-
lapsing course of pruritus and acute and chronic dermatitis in
prototypical anatomic sites. AD is thought to result from a
disruption in skin barrier function, an aberrant immune
response, and neural activation. Conversely, ACD—the clinical
manifestation of contact sensitization—is a delayed type IV
J ALLERGY CLIN IMMUNOL PRACT
VOLUME 7, NUMBER 1
Abbreviations used
ACD- Allergic contact dermatitis
AD- Atopic dermatitis
CAPB- Cocamidopropyl betaine
FLG- Filaggrin gene
Ig- Immunoglobulin
IL- Interleukin
NACDG- North American Contact Dermatitis Group
TEWL- Transepidermal water loss
Th- T helper
hypersensitivity reaction occurring in response to re-exposure to
an exogenous allergen in a previously sensitized individual,
typically manifesting as an eczematous eruption at the site of
contact. That said, ectopic foci and systematized reactions are
reported.
Both AD and ACD are increasing in prevalence. The preva-
lence of AD has nearly tripled in industrialized countries over the
past three decades, with 15% to 30% of children affected and
2% to 10% of adults.1 The prevalence of ACD is more difficult
to pinpoint, but longitudinal patch testing data suggest that
sensitization rates are uptrending for certain allergens, including
certain metals, fragrances, and preservatives.2-6 Both conditions
are associated with high health care costs, lost work and/or school
days, and decreased quality of life.7
The relationship between AD and ACD is complex and
incompletely understood. Available evidence is, at times,
contradictory. Reviewing 50 years of literature highlights the
controversy surrounding this topic. Historically, research from
the 1970s to 1980s on murine and human models suggested that
AD could be protective against ACD, as reduced rates of sensi-
tization were noted after intentional repeated exposure to
common and highly potent allergens.8-10 In support of this,
leading theorists suggested that patients with AD were incapable
of mounting delayed hypersensitivity responses (and, therefore,
allergic contact reactions) due to relative deficiencies in
cell-mediated immunology (secondary to a predilection for a T
helper 2 [Th2]-driven inflammatory response) and epidermal
dysfunction.11
Recent data, however, suggest that “real life” patients with AD
may in fact have an increased risk of contact sensitization, spe-
cifically to “weaker” sensitizers.12,13 As supporting evidence,
patients with AD seem to have a predilection for sensitization to
haptens found in the topicals used to treat their AD (eg,
emollients, cleansers, and medications).14 This is concordant
with the fact that disrupted epidermis of a patient with AD
undergoes repeated and prolonged exposures to potential contact
allergens found within topical mainstays of an AD treatment
regimen.15,16
Yet others continue to expound that AD and ACD exist
independently of one another, and merely coexist in individuals
in a random pattern, a so-called chance coexistence hypothe-
sis.17,18 Supporting evidence for this points to insufficient data
delineating the intersection points of these diseases along their
spectrums.
This review article will further discuss more recent available
research and consensus opinions regarding the relationship
between AD and ACD.
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MILAM ET AL 19
BACKGROUND OVERVIEW
AD is a multifaceted immunologic skin disease with complex
genetic and environmental influences.19,20 An atopic diathesis
tends to cluster within families; however, there appear to be
genes specific to AD susceptibility.21 AD often coincides with or
precedes other disorders of atopy, including asthma, allergic
rhinoconjunctivitis, food allergies, and (less commonly) eosino-
philic esophagitis. The stepwise development of atopic disorders
is referred to as the atopic march.
Though AD is most commonly observed in infancy and
childhood, it can persist into or first develop in adulthood. An
estimated 45% of all cases start within the first 6 months of life,
60% within the first year, and 85% before age 5. Fortunately,
upwards of 70% of these children spontaneously resolve by
adolescence.22 The clinical presentations of AD vary with age.
Infantile eczema favors the cheeks, scalp, neck, and extensor
extremities, whereas classic childhood eczema favors flexural
regions and dorsal extremities. Later in life, AD is typically
characterized by lichenified plaques on flexural extremities, head,
and neck. In all cases, pruritus of the skin leads to scratching, loss
of sleep, and impairment of quality of life. Chronic rubbing and
scratching of skin can initiate or exacerbate flares, hence AD’s
description as “the itch that rashes.”23
ACD, conversely, is the clinical expression of delayed type IV
hypersensitivity to an exogenous agent in a sensitized person.
Acute ACD is characterized by skin erythema, vesiculation, scale,
and pruritus, whereas chronic ACD tends to have attenuated
erythema, lichenification (Figure 1), and the persistence of itch,
depicting activation of the deeper neural component.24 Clinical
presentation and pattern of distribution vary widely, and depend
on the particular contact allergen and the individual’s reactivity.
In most cases, ACD develops within the site of contact, which
helps provide clues to the inciting allergen. Patchy or diffuse
distributions may occur in cases of airborne or systemic exposure.
The hands, face, and eyelids are most commonly affected, as
these areas of the body tend to be uncovered and have more
direct contact with environmental exposures.
ACD is observed in both children and adults, occurring twice
as frequently in women as in men.25 The most common
confirmed contact allergens by patch testing are nickel,
fragrances, and preservatives. The development of ACD is
influenced by many factors, including the allergen’s potency and
sensitizing potential; the duration, frequency, and concentration
of exposure to the allergen; the presence of occlusion and/or local
irritation and trauma; and the susceptibility of the individual.24
The expression of ACD in atopic patients has confounded
investigators for decades. Available research is incongruous, and
the true prevalence ACD in patients with AD is unknown.
Reported rates of positive patch tests in children with suspected
AD range widely from 27% to 95.6%.26 This wide range reflects
the time point of patch testing (ie, mild vs moderate AD would
impact results), hapten profile (ie, exposure to a prototypical
interferon-driven allergen vs a weaker interleukin-4 [IL-4]
inducing allergen), and experience of the evaluating investigators.
Identifying ACD in patients with AD confers many challenges.
For one, the 2 disorders are sometimes difficult to distinguish
clinically, as both can present as eczematous dermatoses in
similar distributions.6 Second, histopathologic findings can be
similar in both conditions, particularly evidence of spongiosis.
Third, there is no current in vitro test for identifying ACD in
20 MILAM ET AL
FIGURE 1. Example of allergic contact dermatitis secondary to
nickel from metal found in clothing, such as pant buttons or a belt
buckle.
AD. As such, for over 100 years, epicutaneous patch testing has
remained the gold standard for diagnosing ACD. However, as
will be discussed further in a later section, patch testing results
can be difficult to interpret in a patient with inflamed skin or a
compromised skin barrier.
PATHOPHYSIOLOGY
The pathophysiology of AD is complex, with 3 key pillars: (1)
epidermal barrier dysfunction; (2) immune dysregulation; and
(3) alteration of the microbiome.22,27 Newer perspectives of AD
pathogenesis suggest a gene-environment interaction, in which
AD is triggered by environmental stimuli in a genetically pre-
disposed host.28
Conversely, ACD is a delayed type IV hypersensitivity reac-
tion that occurs in 2 phases: (1) epidermal allergen penetration
and presentation to allergen-specific naïve T cells, which are then
activated and clonally expanded to memory T cells (the “sensi-
tization phase”); and (2) on re-exposure to the allergen or a
cross-reacting allergen, stimulation of effector T cells and
downstream inflammation (the “elicitation phase”).24,29
Although the pathophysiology of AD and ACD is distinct,
they do share overlapping intersection points in structural and
immunologic pathways. For example, atopic patients’ defective
epidermal barrier permits easier entry for irritants and potential
allergens. With this, increased allergen penetrance may lead to
antigen presentation and sensitization, laying the groundwork for
developing ACD in subsequent exposures.30 In addition, the
prominent bacterial colonization of patients with AD activates
inflammatory cells that are also involved in potentiating contact
sensitization and ACD.31
Herein, we will discuss the main features of AD pathophysi-
ology, and potential intersection points where ACD may
heighten immunologic response and expression (Figure 2).
Barrier dysfunction
Disruption of the epidermal barrier is emblematic of AD.22 In
normal skin, the external stratum corneum layer comprises a
lipid-laden intercellular matrix, enriched in cholesterol, free fatty
acids, and ceramides.22 These hydrophobic substances reduce
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J ALLERGY CLIN IMMUNOL PRACT
JANUARY 2019
transepidermal water loss (TEWL) and resist penetration of
many substances. Although lipid-soluble haptens can easily
permeate the stratum corneum of normal skin, water-soluble
haptens are either impeded, or penetrate via transcellular routes
(ie, via the eccrine glands and pilosebaceous follicles, the “shunt
pathway”).32
Loss-of-function mutation in the filaggrin gene (FLG)—the
strongest known genetic risk factor for AD—greatly compro-
mises the stratum corneum. The FLG gene is a keratin filament-
aggregating protein that is essential to the structural integrity of
the skin.29 It contributes to epidermal hydration, skin pH, lipid
processing, and the prevention of TEWL.33,34 Its breakdown
products offer natural epidermal moisture and pH balance.
Mutations have been found in up to 20% to 50% of patients
with AD of European or Asian descent, and also in patients with
ichthyosis vulgaris (a common autosomal dominant disorder of
keratinization).29 In isolation, FLG mutations have been linked
to increased allergen and microbe penetration, as well as
increased susceptibility to irritants and allergenic haptens
like nickel.35,36
The skin of patients with AD appears to be primed for
inflammation. Atopic patients have evidence of epidermal barrier
impairment in uninvolved skin that is distant from areas of active
inflammation and in involved skin that clinically appears to be in
remission.37-39 This is in contrast to other inflammatory der-
matoses, such as rosacea, in which barrier impairment is limited
to sites of inflammation.40 On histologic examination, pheno-
typically normal-looking skin of patients with AD harbors a mild
infiltrate, also supporting the presence of residual and/or wide-
spread inflammation in the absence of clinically apparent
disease.41
Compromised epidermal barriers predispose patients with AD
to increased skin absorption of irritants and allergens. This, in
turn, leads to further breakdown of the skin barrier and further
compounded risk of allergen penetration.42,43 Environmental
exposure to pollution, climate, dust, pathogens, and chemicals
may contribute to a defective epidermal barrier, adding to
increased risk of allergen penetration in an already susceptible
patient.44 Increased chemical penetration in patients with AD
has been observed in various clinical and experimental studies. A
study by Jakasa et al45 demonstrated with tape stripping tests that
percutaneous permeation of 1% sodium lauryl sulfate (a surfac-
tant that is a common irritant) was increased in the uninvolved
skin of 20 tested patients with AD compared with 20 control
subjects without AD. In another study, urine of patients with
AD was shown to have increased levels of allergens common to
emollients, including parabens and phthalate metabolites.46
Immune dysregulation
The skin’s innate and adaptive immune systems are both
activated in patients with AD. Damage to the epidermis engages
the innate immune response, inciting keratinocytes to release
inflammatory cytokines and chemokines.22 This, in turn, leads
to antigen presentation by skin-resident Langerhans cells and
dermal dendritic cells, with subsequent development of memory
T cells prepared to respond in the event of further hapten
exposures.29,47 Akin to the immunologic pathways in AD, ACD
also involves activation of both the innate and adaptive immune
responses, with subsequent sensitization and potential for “elic-
itation” of the downstream inflammatory response on secondary
exposure to the contact allergen.
J ALLERGY CLIN IMMUNOL PRACT MILAM ET AL 21
VOLUME 7, NUMBER 1

FIGURE 2. Simplified overview of the pathophysiology seen in atopic dermatitis, and its relationship to cellular and immunologic
mechanisms seen in allergic contact dermatitis. IFN-a, Interferon-a; TNF-a, tumor necrosis factor-a; TSLP thymic stromal lymphopoietin.

The inflammatory cascade of AD is primarily driven by
CD4þ Th2 cells, especially in its acute phase. The Th2 cascade
of AD leads to production of IL-4, IL-5, and IL-13; eosinophil
and mast cell recruitment; and a production of allergen-specific
immunoglobulin (Ig)E.22 Th2 inflammatory responses have
been shown to induce an acquired filaggrin deficiency, in which
there is decreased expression of filaggrin molecules in both
lesional and nonlesional skin.48,49 With time, AD eventually
evolves to a chronic phase marked primarily by Th1 and Th22
cytokines, mainly defined by IL-12 and interferon gamma pro-
duction.22 In this progressive state, the AD immune system is
primed to engage in a heightened Th1-driven inflammatory
response, increasing the probability of contact sensitization.
In ACD, the inflammatory response is not unified, and often
depends on the specific allergen. Research on nickel ACD sug-
gests an innate immune response defined by Th1, Th17, and
Th2 pathways (commonly encountered cytokines in intrinsic
AD), whereas rubber and fragrance ACD are predominately Th2
driven.50 Conversely, ACD to the highly sensitizing agent uru-
shiol (or Rhus, found in poison ivy) induces hypersensitivity in a
more direct, cytotoxic manner, involving T lymphocytes specific
to the hapten.51 The heterogeneity of each allergen’s inflam-
matory response provides a plausible explanation for the
discrepancies in sensitization rates seen in AD.
Cutaneous microbiome
AD is associated with a high burden of microbial colonization,
particularly Staphylococcus aureus, which is observed in more than
90% of patients with AD.22 This supercolonization is attributed
to many factors, including epidermal pH dysregulation, defects
of the lipid layer, increased TEWL, and deficiencies in innate
immunity.52,53
In normal skin, filaggrin byproducts contribute to acidifica-
tion, thereby creating a protective epicutaneous pH buffer.
Inability to acidify the skin can result in microbial proliferation,
and S. aureus is particularly adept at exploiting pH dysregula-
tion.54 Staphylococcal peptides instigate eczematous inflamma-
tion by upregulating secretion of IL-4, IL-5, and IgE, further
propagating a Th2-heavy milieu and the continuation of
cutaneous inflammation and pruritus.47,53
Th2 cytokines seen in AD impair antimicrobial peptide
responses to pathogens. This, in combination with barrier

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22 MILAM ET AL J ALLERGY CLIN IMMUNOL PRACT
JANUARY 2019

FIGURE 3. Example of closed patch testing, in which allergens are applied in standard amounts to chambers mounted on nonocclusive
tape strips. Steps of patch testing typically occur over 4-5 days and include (A) initial placement of patch test wells, (B) removal of patch
test approximately 48 hours after placement, and observation of irritant reactions, and (C) final patch test reading after 72-96 hours of
application, and observation of allergic reactions. This patient had a profound allergic contact dermatitis to nickel, as well as chemicals
found in dyes and fragrances, including paraphenylenediamine, textile dye mix, and hydroperoxides of limonene.

EVIDENCE REGARDING ACD OCCURRING IN AD

FIGURE 4. Syringes of patch testing chemicals, which are sys-
tematically injected into each testing chambers before patch
testing. Small amounts of test allergens are diluted in a vehicle
such as water, alcohol, or petrolatum.
disruption, allows for increased pathogen penetration. Bacterial
colonization in AD may also stimulate an inflammatory envi-
ronment and lead to an enhanced contact sensitization by
disturbing the adaptive immune response.42
Although the relationship between AD and ACD remains
unclear and the results of experimental and retrospective studies
are highly variable, a preponderance of recent evidence suggests
that patients with AD have similar, if not increased, rates of
sensitization to certain contact allergens.55 Commonly reported
contact allergens among patients with AD include lanolin,
preservatives, metals (such as nickel, chromium, and cobalt),
antibiotics (such as neomycin and bacitracin), sesquiterpene
lactone mix, compositae mix, and fragrances, among
others.15,16,18,25,55-60
Many relevant allergens are found in personal care and topical
prescription products commonly used by atopic patients.56 As is
true of ACD in general, prolonged and frequent periods of
exposure to potential allergens confer greater sensitization risks.
Supporting this notion, a 2009 retrospective study showed that
Dutch children with AD had significantly higher rates of sensi-
tization to lanolin and fragrances.61 Another retrospective
analysis of 26,479 patients patch tested with the North American
Contact Dermatitis Group (NACDG) screening series found
that patients with positive reactions to lanolin were more likely to
have a history of AD.62 Similarly, a recent retrospective chart
review by Rastogi et al14 demonstrated that patients with AD
have significantly more positive patch test reactions to certain
allergens common to their treatment products—including
lanolin, fragrance mix II, budesonide, tixocortol, bacitracin, and
chlorhexidine—compared with patients without AD. Of note,
although a diagnosis of active AD was a risk factor for
polysensitization in this cohort, there was no significant differ-
ence in the overall number of positive patch test results between
patients with AD and patients without AD, further suggesting
that AD does not necessarily confer protection against ACD.
A retrospective review by Jacob et al63 assessing patch test
results from 1142 American children confirmed prior reports
that patients with AD had significantly higher sensitization

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J ALLERGY CLIN IMMUNOL PRACT
VOLUME 7, NUMBER 1
rates to cocamidopropyl betaine (CAPB), wool alcohol, lanolin,
tixocortol pivalate, and parthenolide/Compositae, but lower
frequency of reactions to other allergens such as methyl-
isothiazolinone, cobalt, and chromium. Of interest, a recent
retrospective study by Malajian and Belsito64 reviewed data
from 2305 patients (of unclear age range) patch tested to the
NACDG standard series and found that the patients with AD
in their cohort were statistically more likely to have a positive
patch test to at least 1 allergen, especially to nickel (P ¼ .0003),
cobalt (P ¼ .0002), and chromium (P ¼ .11), further
supporting the concept of variable expression in ACD among
patients with AD. Of note, Machler et al13 recently reported
nickel dermatitis attenuation through blockade of the Th2/IL-
4 pathway, which suggests that the variable expression could
partially be accounted for by simultaneous activation and
regulation of dual and competing pathways. Notably, Malajian
and Belsito’s study found no significant difference in sensiti-
zation rates to fragrance mix I or balsam of Peru in their
population, and fragrance mix II and corticosteroids were not
included in their study design.
A 2016 retrospective, single-center study of 2614 Italian
children under 11 years of age found an overall similar rate of
contact sensitization among children with AD (47.3% preva-
lence) and without AD (46.1% prevalence); however, children
with AD had a greater prevalence of positive patch test reactions
to potassium dichromate (P < .001), Compositae mix (P ¼ .01),
and disperse blue (P ¼ .03).65 Likewise, a 2015 cross-sectional
study by Isaksson et al66 reviewed patch testing data of 82
children with AD, and found coexisting ACD in 22 (26.8%) of
patients, most commonly from lanolin (11%), potassium
dichromate (7.3%), and nickel sulfate (4.9%). Patients with
hand and/or foot eczema were significantly more likely to have
ACD than those without (P ¼ .009).65
A series of recent studies by Shaughnessy et al67,68 comparing
NACDG patch testing data in patients with AD and patients
without AD found that patients with AD had increased rates of
sensitization to formaldehyde-releasing preservatives, and sur-
factants such as CAPB. On the basis of these results, Shaugh-
nessy et al and others have suggested that atopics should avoid
certain allergens as a prophylactic measure.69,70 Although clinical
outcomes have shown significant improvement with pre-emptive
avoidance strategy (of known high sensitizers), it would be
difficult to obtain longitudinal data to support that exposure
avoidance truly mitigates risk of sensitization.
Conflicting evidence against AD D ACD
Initial evidence against ACD occurring in patients with AD
mostly comes from older, smaller studies in which patients with
atopy failed to respond to potent sensitizers such as dinitro-
chlorobenzene, p-nitrosodimethylaniline, or Rhus.6,8,9,71-74
Historically, it was believed that Th1- and Th2-driven re-
sponses were mutually exclusive, and that because patients with
AD demonstrate a Th2-skewed inflammatory response, this
rendered them incapable of developing a delayed hypersensitivity
response (which is hallmarked by Th1 cytokines). Supporting
differences noted were in cytokines, defective neutrophil
chemotaxis, and a relative deficiency in cell-mediated immunity.
Additional evidence includes experimental studies in which
patients with AD have increased elicitation thresholds, as well as
serum studies showing a relatively decreased number of
circulating T lymphocytes among adults with AD.11,73,75-77
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MILAM ET AL 23
Recurrent and persistent cutaneous infections in this popula-
tion, including dermatophytoses, S. aureus, and herpes simplex
virus, also suggest a compromised innate immunity.72,78
Some recent epidemiologic data and meta-analyses suggest
that ACD prevalence among patients with AD and patients
without AD is comparable. As one example, a 2017 meta-
analysis by Hamann et al79 reviewed 74 articles that reported
on contact sensitization among adult and pediatric patients
with and without AD. They found no significant difference in
the overall prevalence of contact sensitization between the 2
groups. Zafrir et al80 reported that rate of positive patch tests
was equivalent among Israeli children with and without a
personal or family history of atopy, both overall and with
stratification to specific allergens; however, this study was
limited by its retrospective design and because the comparison
included patients with a family history of atopy, but no per-
sonal history of AD.
A 2014 descriptive study that reviewed 4 years of patch testing
results from 2221 Danish patients found similar frequencies of
positive patch test reactions within the AD and non-AD cohorts,
but a significantly higher frequency of multiple sensitizations in
patients with severe AD compared with those with mild AD.81
Klas et al82 patch tested 410 patients, of whom 44% had no
history of atopic disease and 46% were classed as “definitely
atopic.” They concluded that atopics are at least as likely to have
ACD as non-atopics.
Yet others have observed a greater incidence of ACD in pa-
tients without AD. In findings from a systematic review by
Simonsen et al57 comparing patch testing results among children
with and without AD, the prevalence of ACD was significantly
higher among children without AD, with substantial variability
in sensitization rates to certain allergens. However, in a follow-up
cross-sectional analysis of 100 Danish children with AD, it was
noted that 30% demonstrated at least 1 positive patch test
reaction, and 17% were noted to have 1 or more relevant contact
allergies that had previously gone unrecognized, with metals
being the most common offenders.83 ACD to ingredients com-
mon to skincare products was found in 8% of the children.
There was a significant correlation between AD disease severity
and risk of ACD.
Although the literature offers an array of mixed data, available
studies are often limited by their retrospective design, small
sample size, narrow age range, restricted geographical distribu-
tion, and lack of consistency in methods or patch testing appli-
cation and interpretation. Prospective, controlled, and
randomized studies are necessary.
Regardless of findings disputing the statistical significance
of their relationship, the high yield of positive patch test re-
actions among patients with AD demonstrate that ACD is a
real and not uncommon comorbid condition in this popula-
tion. Current epidemiological and experimental studies are
unable to account for all factors that could mediate their
relationship and, despite this clarity, ACD appears to be a
potential aggravator of AD in clinical practice. Patients with
AD suspected of having a superimposed ACD warrant evalu-
ation with patch testing.
DIAGNOSING ACD IN PATIENTS WITH AD
A diagnosis of ACD is established by patch testing, the
diagnostic gold standard (Figures 3 and 4). Although patch
24 MILAM ET AL
testing is a tried and true modality for identifying ACD, it is not
without pitfalls. Patch testing patients with active dermatitis can
prove challenging, particularly if existing inflammation limits the
surface area available for testing. As such, patch testing in
patients with AD and interpretation of the results should be
approached with careful consideration of the patient’s relevant
exposures and the extent of active dermatitis at the time of
testing.
Patch testing is often employed in an unchanged format for
patients with AD; however, the validity and relevance of results
may be questionable in a patient prone to inflamed skin. This is
of particular concern among atopic patients, who demonstrate a
lower irritancy threshold, even in nonlesional skin that is distant
from areas of active inflammation. Irritant reactions can be
difficult to distinguish from true reactions, leading to false-
positive results.56 As patients with AD tend to have more
frequent irritant reactions to commonly tested allergens such as
nickel, cobalt, and chromium, this is of pertinent concern.84
Conversely, patients with severe AD have also been reported to
have a paradoxically higher rate of false-negative reactions,
possibly owing to the skin’s underlying altered inflammatory
milieu.85
Despite these issues, patch testing remains the most reliable
method of identifying contact allergies in atopic patients and can
assist in detecting a remediable comorbidity.
A workgroup of AD and ACD experts crafted a consensus
opinion to better guide clinicians on how to approach patch
testing in patients with AD. They recommend that providers
consider patch testing in patients with AD who have dermatitis
that fails to improve with topical therapy; with atypical/changing
distribution of dermatitis, or a pattern suggestive of ACD; with
treatment-resistant hand eczema in the working population; with
adult- or adolescent-onset AD; and/or before initiating systemic
immunosuppressants for the AD.85 The onset of nummular
eczematous lesions within patients with AD should also be an
impetus for patch testing.56
Of note, a significant number of atopic patients are children.
There are no universally established patch testing guidelines
specific to the pediatric population, which represents a consid-
erable subset of patients with AD. That said, a workgroup of
physicians attending the 2017 American Contact Dermatitis
Society pioneers meeting recently proposed a baseline patch
testing series comprising 38 allergens intended for children aged
6 to 18 years.86 The series included selections and omissions
from the commercially available Thin-Layer Rapid Use
Epicutaneous (T.R.U.E., Smartpractice, Phoenix, Ariz) test, and
also included notable haptens currently only testable by
comprehensive testing (eg, propolis, propylene glycol, CAPB, the
steroid hydrocortisone-17-butyrate).
Available retrospective and prospective studies have reported
an expansive array of sensitization rates in the pediatric popula-
tion, ranging from 26.6% to 95.6%.55 Unfortunately, it is
difficult to compare the available studies given the variety of
methodologies used and lack of consistency among patch testing
series or interpretation of results. Patch testing in children may
be limited by the surface area available for testing, and tailoring
the patch test series to fewer specific allergens may help enhance
relevance of results. Jacob et al87 found that individually
customized test series allowed for more precise and relevant
results, with 92.6% of children having at least 1 positive patch
test reaction demonstrating definite or probable current
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J ALLERGY CLIN IMMUNOL PRACT
JANUARY 2019
relevance. Recently, a European taskforce focused on ACD in
children published a position paper advocating for a narrowed
series of 9 test allergens, which includes nickel, fragrances, a
rubber accelerator, and preservatives.84 They offer a second list of
allergens to be added to the series depending on clinical history
and exposures, including additional metals and certain cortico-
steroids and antibiotics, among others.
CONCLUSION
Although available medical literature is seemingly contradic-
tory given the bias from which the findings are approached, a
preponderance of data supports a significant and clinically
impactful incidence of ACD among atopic patients. The path-
ophysiologic shades of gray relationship between the 2 disorders
is complex, and hinges on increased allergen permeation due to
compromised epidermal barriers, augmented antigen presenta-
tion and sensitization with subsequent immune dysregulation,
and the patient population’s increased exposure to potentially
sensitizing agents. More laboratory and controlled epidemiologic
studies are needed to further delineate the incidence of ACD in
patients with AD and the underlying mechanisms of action.
Patch testing is an important diagnostic tool that is likely
underutilized in this patient population. Patients with AD
suspected of having a superimposed ACD should be patch tested,
with careful consideration of exposures and potentially relevant
allergens. It is often prudent to include allergens found in
treatment regimens of patients with AD, including lanolin,
fragrances, preservatives, and corticosteroids, among others.
The most important aspect of treatment of ACD is identifi-
cation and avoidance of allergens. With diligent avoidance of
allergens, most cases can be remitted, and most notably, patients
with AD with concomitant ACD can become better controlled.
Acknowledgments
The authors would like to acknowledge Calvin Sung, a
medical student at University of California Riverside School of
Medicine, for creating the pathophysiology diagram seen in
Figure 2.
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