CONTINUING MEDICAL EDUCATION

Allergic contact dermatitis

Patient diagnosis and evaluation
Christen M. Mowad, MD,a Bryan Anderson, MD,b Pamela Scheinman, MD,c Suwimon Pootongkam, MD,d,e
Susan Nedorost, MD,d and Bruce Brod, MDf
Danville, Hershey, and Philadelphia, Pennsylvania; Boston, Massachusetts;
Cleveland, Ohio; and Bangkok, Thailand

Learning objectives
After completing this learning activity participants should be able to identify patients suspected of allergic contact dermatitis who may benefit from patch testing and describe the
appropriate patch testing technique and testing materials in order to fully evaluate patients suspected of allergic contact dermatitis.

Disclosures
Editors
The editors involved with this CME activity and all content validation/peer reviewers of the journal-based CME activity have reported no relevant financial relationships with
commercial interest(s).
Authors
The authors involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s).
Planners
The planners involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). The editorial and education staff involved
with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s).

Allergic contact dermatitis resulting from exposure to a chemical or chemicals is a common diagnosis in the
dermatologists office. We are exposed to hundreds of potential allergens daily. Patch testing is the criterion
standard for diagnosing the causative allergens responsible for allergic contact dermatitis. Patch testing
beyond standard trays is often needed to fully diagnose patients, but not all dermatology practices have
access to this testing procedure or these allergens. In order to adequately evaluate patients, physicians must
understand the pathophysiology of the disease process and be well versed in the proper evaluation of
patients, indications for patch testing, proper testing procedure, and other diagnostic tools available and be
aware of new and emerging allergens. ( J Am Acad Dermatol 2016;74:1029-40.)
Key words: allergens; allergic contact dermatitis; atophy patch test; delayed-type hypersensitivity;
dermatitis; patch testing.

C ontact dermatitis, both irritant and allergic,

is a common entity in the dermatologists
office. Contact dermatitis is caused by
contact with 1 of the hundreds of chemicals to
Abbreviations used:
ACD:
AD:
APT:
allergic contact dermatitis
atopic dermatitis
atopy patch test
which individuals are exposed on a daily basis. LTT: lymphocyte transformation test
Management of patients with contact dermatitis can MCI: methylchloroisothiazolinone
MI: methylisothiazolinone
be challenging but rewarding for both patients and NACDG: North American Contact Dermatitis Group
physicians alikemost notably when a chemical or ROAT: repeat open application test
chemicals can be identified and removed from the SCD: systemic contact dermatitis
T.R.U.E.: Thin-layer Rapid Use Epicutaneous
patients environment resulting in clearing of a
dermatitis that may have been present for years.

From the Departments of Dermatology at Geisinger Medical
Center,a Danville, Penn State Milton S. Hershey Medical Center,b
Hershey, Brigham and Womens Hospital,c Boston, University
Hospitals Case Medical Center,d Cleveland, Chulalongkorn
University,e Bangkok, and University of Pennsylvania,f
Philadelphia.
Funding sources: None.
Conflicts of interest: None declared.
Accepted for publication February 8, 2015.
Correspondence to: Christen M. Mowad, MD, Department of
Dermatology, Geisinger Medical Center, 100 N Academy Ave,
Danville, PA 17821. E-mail: cmowad@geisinger.edu.
0190-9622/$36.00
2015 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2015.02.1139
Date of release: June 2016
Expiration date: June 2019

1029
1030 Mowad et al
Persistence, consideration of contact dermatitis as a
diagnosis, and a detective-like approach is often
needed to identify the causative chemical(s).
Allergic contact dermatitis (ACD) is common, but
the actual incidence of ACD is difficult to capture
because patients often self-diagnose or enter the
medical system at various points, such as the
emergency room, primary care offices, and urgent
care clinics. ACD should be considered in patients
with ongoing dermatitis. Identifying the causative
allergen(s) is crucial to the resolution of this process.
The criterion standard for diagnosing ACD is patch
testing; patients suspected of having ACD should
undergo this testing to elucidate the allergen(s)
responsible for the dermatitis. We present an ACD
update herein, including the tools used to evaluate
and diagnose patients.
Numerous groups have grown out of the specialty
of contact dermatitis. The North American Contact
Dermatitis Group (NACDG), founded in 1970, helped
arrange the 20-allergen kit sold in the United States
after the US Food and Drug Administration (FDA)
reclassified allergens in the United States, dramatically
changing allergen availability at the time. They
continue to publish on allergens in North America.
The International Contact Dermatitis Research Group,
European Environmental and Contact Dermatitis
Research Group, and the European Society of Con-
tact Dermatitis are some of the many international
groups dedicated to furthering the professional ex-
change and knowledge in the field. The American
Contact Dermatitis Society is an active group, holding
an annual meeting and having [850 members. This
group has developed a core allergen series, allergen
narratives in both English and Spanish describing[70
allergens to be used as patient education tools, and a
database called the Contact Allergen Management
Program (CAMP) that provides patients with products
that are safe to use given their known allergens.1
The history of patch testing and contact derma-
titis is too rich to be adequately outlined in this
review, but several detailed accounts have been
published.2-4
PATHOPHYSIOLOGY: BASIC SCIENCE
ACD is a type IV, delayed-type reaction that is
caused by skin contact with allergens that activate
antigen-specific T cells in a sensitized individual.
The sensitized T cells are primarily T-helper 1 (TH1)
type. In the sensitization phase, innate immunity
is activated through keratinocyte release of
interleukin (IL)-1a, IL-1b, tumor necrosis factore
alpha, granulocyte-macrophage colony-stimulating
factor, and ILs-8 and -18. Langerhans and dermal
dendritic cells uptake the allergen and migrate to
J AM ACAD DERMATOL
JUNE 2016
the regional lymph nodes to activate antigen-
specific T cells (ie, TH1, TH2, TH17, and regulatory
T [Treg] cells). These T cells then proliferate and
enter the circulation and site of exposure. When
reexposed to the allergen, antigen-specific T cells
are activated through the release of cytokines and
induce an inflammatory process. We now also
recognize that patients with atopic dermatitis (AD)
have barrier dysfunction that contributes to ACD in
that population.5
Dermal dendritic cells, as opposed to epidermal
Langerhans cells, play an important role in educating
nave T cells in the lymph node to become
antigen-specific effector cells during cutaneous
sensitization.6 The recognition of skin resident T
cells has enlightened our understanding of the role
of Langerhans cells. Langerhans cells have now been
shown to interact with skin resident T cells and
generally promote tolerance when encountering
antigens by stimulating Treg cells. However, in the
presence of pathogens, such as Candida albicans,
Langerhans cells stimulate T effector memory cells
and promote inflammation.7
An increased appreciation of epidermal immu-
nology increases our understanding of known
therapies and may lead to innovative treatments
and diagnostic tests. Systemic corticosteroids were
recently shown to encourage Treg cell proliferation
in patch test sites of patients with ACD to nickel.8
Topical 1,25-dihydroxyvitamin D also induces
Treg cells, probably by primarily affecting antigen-
presenting cells.9
PATCH TESTING
Indication for patch testing
Patch testing is the criterion standard in the
diagnosis of ACD. Patch testing attempts to recreate,
in vivo, an allergic reaction to nonirritating
concentrations of an allergen that is suspended in a
vehicle. The decision to perform patch testing and
which allergens to test depends on many factors.
Some common indications for patch testing
include: (1) distributions that are highly suggestive
of ACDfor example, ACD of the hands, feet, face,
and eyelid, as well as unilateral presentations; (2) a
clinical history that is highly suggestive of ACD;
(3) high-risk occupations for ACDfor example,
health care workers, cosmetologists, and florists, etc;
(4) dermatitis of unknown etiology; (5) worsening of
a previously stable dermatitis; and (6) dermatitis that
is unresponsive to treatment.
Patch testing is also indicated if ACD is thought
to develop secondarily in the course of another
endogenous inflammatory disease. This typically
occurs because of sensitization from topical
J AM ACAD DERMATOL
VOLUME 74, NUMBER 6
Table I. Patch testing chambers
Chamber name Company
IQ/IQ Ultra Chemotechnique Diagnostics, distributed by
Dormer Labs Inc, Toronto, Ontario
Finn SmartPractice Finland, Tuusula, Finland
AllergEAZE SmartPractice Canada, Calgary, Alberta, Canada
van der Bend Van der Bend BV, Brielle, The Netherlands
Hayes Test HAL Allergenen Laboratorium BV, Haarlem,
The Netherlands
T.R.U.E Test SmartPractice, Phoenix, AZ
T.R.U.E., Thin-layer Rapid Use Epicutaneous.
Table II. Allergen suppliers
Company
AllergEAZE SmartPractice Canada, Calgary, Alberta, Canada
Chemotechnique Diagnostics Dormer Laboratories, Inc, Toronto, Ontario, Canada
T.R.U.E Test SmartPractice, Phoenix, AZ
T.R.U.E., Thin-layer Rapid Use Epicutaneous.
treatments, either prescribed or over the counter, in
the treatment of diseases such as AD and psoriasis.10
Systemic contact dermatitis (SCD) describes a
cutaneous eruption from systemic exposure to an
allergen and is another indication for patch testing.11
There are multiple routes of exposure for the
elicitation of SCD, including oral, intramuscular,
intravenous, transepidermal, and subcutaneous.12
SCD has a wide spectrum of presentations, including:
(1) widespread erythematous papules or dermatitis13;
(2) deep-seated vesicles of the palms and fingers14;
(3) flexural erythema of the extremities15; (4)
confluent erythema of the anogenital region and
intertriginous areas16; (5) lip and perioral derma-
titis17-19; and (6) periocular swelling or dermatitis.19,20
TESTING PROCEDURE
Supplies
In addition to allergens, other supplies required
include tape, a refrigerator for storage of the
allergens, chambers, A Woods lamp, markers, and
maps.
Patch tests are used to identify the cause of ACD
and aim to reproduce an eczematous reaction to a
causative allergen applied to intact skin. Closed
patch testing involves the application of allergens
under occlusion to the skin of the upper aspect of the
back for a period of 2 days. Readings are generally
performed at that time, with additional delayed
readings.
Mowad et al 1031
Characteristics
10 square chambers per strip; polyethylene foam
chamber; filter paper incorporated into the chamber;
each unit has plastic cover for ease of storage
10 round aluminum chambers, 8 mm per strip; separate
filter paper
10 square, 8-mm chambers; inert acetal copolymer;
prefixed filter paper; rounded corners
Chambers can be fixed on tape
Notches in chambers allow filling without removing the
cover
Prefabricated and prepackaged chambers; 3 panels each
with 12 allergens
Distributor Contact information
info@allergeaze.com
www.dormer.ca
info@smartpractice.com
Allergens are placed in a patch test chamber. The
chamber is an inert material applied to a hypoaller-
genic tape providing excellent occlusion while
adhering the test unit to the skin. Each strip contains
a separate chamber for an individual allergen.
Chambers can be composed of aluminum or plastic
and have a diameter ranging from 8 to 10 mm.
Petrolatum-based allergens are placed directly into
the chamber; liquid-based allergens are placed onto
filter paper within the chamber. There are many
companies that supply patch testing chambers
(Table I). Reinforcement of patch test units with
supplemental tape is often recommended. Some of
the newer alternatives are water-resistant. More than
4350 chemicals have been identified as contact
allergens.21 Many cases of ACD are caused by a
relatively small number of allergens. Patients are
typically tested to a standard or screening series of
allergens. In more advanced patch testing centers,
specialty series are used that can be directed to
specific exposures based on the patients unique
background. In some instances, patients are patch
tested to nonecommercially available allergens and
extreme caution is necessary to avoid severe irritant
reactions, false-positive and -negative reactions, and
sensitizing to a new allergen. There are references
available to help guide the use of nonecommercially
available allergens.22
Several companies supply commercially available
allergens (Table II).
1032 Mowad et al
It is important to preserve the location of allergen
placement. Anatomic locator diagrams and digital
photography can be used to identify the location of
the patches. Fluorescent markers can be used to
outline the patch test units and prevent staining of
clothing. The use of a Woods lamp elucidates the
otherwise invisible markings.
On hairy areas of the back, it may be necessary to
use a clipper to remove excess body hair. In patients
with oily skin, it may be necessary to degrease the
skin gently with ethanol or other mild solvents
before the application of the patch test materials.23
Allergen selection
Allergen selection is dependent on history, phys-
ical examination, and allergen availability. Regional
dermatitis, such as localized eyelid or hand derma-
titis, might prompt testing to certain allergens.
Specific avocations or occupations may lead to
targeted allergen testing (ie, the plant tray for a florist
or a dental tray for the dental technician). More often
than not, a standard series is used as an initial starting
point, with other series added as indicated by history,
physical examination, and availability. In the United
States, there is 1 series approved by the FDA: the
Thin-layer Rapid Use Epicutaneous (T.R.U.E.) Test
(SmartPractice, Phoenix, AZ). It was initially intro-
duced in 1995 with 23 allergens and 1 control. This
easy to use, preimpregnated testing system increased
the number of patch tests performed.24 However,
many allergens were undetected because of the
limited number of allergens.25,26 Five additional
allergens were added to improve detection rates; in
2012, 7 more allergens were added, bringing the
current T.R.U.E Test to 35 allergens and 1 control,
which has improved the detection of allergy. Studies
have shown that almost 27% of allergens may still be
missed using this series.27,28 Allergens that have not
been approved by the FDA can be obtained from
other sources (Table II) and have been shown to
perform better, detecting a higher rate of causative
allergens. However, even expanded series beyond
what is approved by the FDA can fall short, empha-
sizing the need for a detailed history that can direct
expanded allergen selection.27,28 Specific categories,
such as botanicals, prove particularly difficult to test
for because adequate screening series are lacking and
the number of allergens is extensive.29 The choice of
allergens used in patch testing is in part dependent on
the resources in an individuals practice. The T.R.U.E.
Test is a good starting point for clinicians who do not
routinely perform extensive patch testing. However,
ACD and its causative allergens may be missed if
expanded testing beyond standard trays are not
performed. If expanded testing is not locally
J AM ACAD DERMATOL
JUNE 2016
available, referral to a patch test center should be
considered, because studies have shown that patch
testing is cost effective and has been shown to
decrease costs in patients with ACD.30
Patch test reading
All patch test systems are designed to occlude
allergens on the patients skin for 2 days, allowing for
adequate penetration of the allergen into the skin. An
initial interpretation is performed after patch tests are
removed. Adequate time is needed for the cutaneous
effects of occlusion, such as transient erythema, to
resolve. Supervised removal of the patch tests is
necessary to assess the adequacy of occlusion,
ensuring that the integrity of the patch test procedure
is not compromised. If loose tests are noted, retesting
should be considered.
A second or delayed reading should take place 72
to 168 hours after the allergens were initially
applied. This reading is critically important to
distinguish irritant reactions from true allergic re-
actions and to identify allergic reactions that do not
appear at the time of patch removal.31 Depending
on the allergen, delayed readings beyond that time
may be necessary.32 Examples of allergens that
require delayed readings include neomycin, nickel,
and topical corticosteroids.33
Allergens are typically placed on the upper
aspect of the back because it is the area most studied
for reproducibility in patch testing. When testing
only a limited number of allergens, or if all allergens
will not fit on the patients back, it is acceptable to
place them on the outer upper arm (ie, for retesting).
While it is sometimes necessary to place patches on
areas other than the upper back (ie, the arms, legs,
and abdomen), these areas are nonstandard
placement sites and may be associated with
false-negative or -positive reactions.
The accuracy of patch testing patients on systemic
immunosuppression has not been well established
with large studies. In 1 small prospective study,
positive reactions were seen in patients who were
taking azathioprine, cyclosporine, methotrexate, my-
cophenolate mofetil, infliximab, adalimumab, and
etanercept.34 In a small, placebo-controlled study,
oral prednisone (20 mg/day) was found to suppress
the number of positive nickel reactions in patients
with known sensitivity to nickel.35 Ideally, patients
would no longer be taking immunosuppressive drugs
before patch testing, but this is not always possible.
Practical considerations
There are several important items that may affect
the choice of patch testing. For example, clinicians
should delay patch testing if the patient has a recent
J AM ACAD DERMATOL
VOLUME 74, NUMBER 6
Table III. Classification of patch test readings
according to the International Contact Dermatitis
Research Group
Reaction Definition
?1 Doubtful reaction; faint erythema only
11 Weakly positive reaction; erythema, infiltration,
and possible papules
21 Strongly positive reaction; erythema,
infiltration, papules, and vesicles
31 Extreme positive reaction; intense erythema,
infiltration, and coalescing vesicles
Negative reaction
IR Irritant reaction: patterns include follicular,
glazed erythema, and ulceration
NT Not tested
history of sun exposure because of the potential for
false-negative reactions.36 Patch testing a patient
with widespread dermatitis can result in false-
positive reactions. In addition, patients should avoid
corticosteroid creams on the test area in the days
before testing.
Oral corticosteroid use with prednisolone [10 mg
daily or an equivalent is a relative contraindication to
testing, because it may suppress positive reactions.35
Positive patch test results can be seen in patients who
are taking other immunosuppressive drugs if there is
no possibility of stopping them.34 Antihistamines may
be continued throughout testing unless one is look-
ing to evaluate for contact urticaria.37 If the patient is
pregnant, patch testing should be deferred until after
pregnancy, although there is neither strong evidence
of any deleterious effects on pregnancy outcomes
nor evidence that the immunologic changes of
pregnancy affect the accuracy of patch testing.38
Finally, if the patients skin contains excess sebum
or hair, hair removal and gentle degreasing can be
performed with ethanol or another mild solvent.
Reading and grading the results of patch testing is
somewhat subjective and dependent on descriptive
morphology. This creates a large degree of variation
in how patch tests are read by different clinicians.
There is a range of intensity from mild to severe that
includes erythema, edema, vesicles, and bullae. For a
reaction to be considered positive, there should be at
least some degree of erythematous infiltration or
papules. Erythema without any infiltration would be
considered a sign of a doubtful or irritant reaction.
Unfortunately, there is still a lack of complete
consensus on how to grade patch test readings.
The clinician generally grades the positive readings
from 1 1 to 3139 (Table III).
Potential reasons for false-negative
reactions. False-negative reactions can be caused
Mowad et al 1033
by: (1) failure to perform a delayed reading; (2)
testing to an inappropriately low concentration of
allergen; (3) poor patch test placement or loosening
of patch tests; and (4) concurrent immunosuppres-
sion (eg, sunlight, topical or systemic corticosteroids,
and other immunosuppressive drugs).
Potential reasons for false-positive react-
ions. False-positive reactions can be caused by:
(1) testing with borderline irritants (eg, metals,
formaldehyde, and epoxy); (2) testing beyond the
irritancy threshold; (3) excited skin syndrome (ie,
angry back syndrome); and (4) patients with a
background of dermatitis.
Relevance
Once allergens have been identified through
patch testing, the relevance of the allergens to the
clinical scenario must be determined. Relevance
can be past, present, or unknown. An allergen with
past relevance is an allergen identified on patch
testing and correlating with a past dermatitis. For
example, a patient with hand dermatitis, a positive
reaction to neomycin, and a history of reactions
when using over the counter antibiotics has past
relevance. The neomycin is relevant to the history,
but not to the current hand dermatitis because the
patient has no current exposure to neomycin.
Present relevance is what the clinician and patient
are searching for through the patch test process.
Present relevance is determined when the allergen
is identified in the patients environment and
removal of the allergen clears the dermatitis.
Unknown relevance is when a patient is found to
react to an allergen and no current or past exposure
is identified. Certain allergens, such as formalde-
hyde releasers, when found to be positive, have a
high rate of relevance. Other allergens, such as
thimerosal, do not often have high relevance to the
current dermatitis and as such have been dropped
from testing by the NACDG and many patch test
centers.40,41
Other diagnostic tests
Patch testing is the criterion standard for diag-
nosing ACD, but there are problems with this test.
Many subjects without clinically problematic derma-
titis will have positive patch tests to nickel, cobalt,
thimerosal, fragrance, and colophony.42 Therefore, a
positive patch test does not equate to a diagnosis of
ACD. The patch test may indicate past relevance or
the patient may have another diagnosis unrelated to
the positive patch test. Other diagnostic tests include
repeat open application tests (ROATs), lymphocyte
transformation tests (LTTs), and atopy patch tests
(APTs).
1034 Mowad et al
Repeat open application tests. ROATs can be
used to verify that an antigen causing a positive patch
test will lead to dermatitis when present at usage
concentrations. A ROAT may need to be conducted
for several weeks.43 A ROAT is performed by
applying approximately 0.1 mL of the test substance
(ie, leave-on personal care products) twice daily to an
area approximately 5 3 5 cm, such as the antecubital
area and upper arm.44 While a positive response
usually occurs in 2 to 4 days, it is advisable to extend
the applications beyond 7 days to capture late-
appearing reactions. Scented cosmetics, including
deodorants and moisturizers, can require consider-
ably more time to cause reactionsup to 28 days
or 56 applications. Ideally, it is recommended to
perform the ROAT at 3 distinct sites because of the
variability in reactivity on different areas of the skin.
Such sites include the antecubital fossa, back skin,
and the outer aspect of the upper arm.45 ROATs with
deodorants may be performed in the axilla under
conditions of ordinary use.46-48 The size of the test
area does not seem to affect the final results, although
the response may be delayed if a small area is used.49
Regarding evaluation, the scoring of ROAT reactions
should be reported.50 The evaluation of the severity
of reactions can be positive, negative, or question-
able. It is practically done by visual examination
alone, although some bioengineering equipment,
including laser Doppler velocimetry, can be used,
as can the measurement of transepidermal water
loss.51,52 In positive tests, erythematous papules,
follicular papules, and vesicular lesions may occur.
As with patch testing to nonstandardized sub-
stances, testing in nonsensitized control subjects rules
out irritant reactions. Testing control subjects can be
considered in suspected cases of irritant reactions
from a ROAT when reactions are seen after the first
few applications. Several studies with various aller-
gens have shown correlation between the elicitation
thresholdthe concentration giving a visible skin
reaction by patch testingand ROATs.47,52-56 Some
studies do not show correlations between the patch
test and a ROAT. The patients who had positive patch
test results to lower concentrations did not neces-
sarily have positive ROAT results.47,48,57-59 Individual
factors, such as patch test sensitivity, regional skin
reactivity, exposure dose, time of exposure, and
percutaneous penetration may play significant roles
on results and degree of reactivity.60 In addition,
negative results of a ROAT on normal skin may
become positive on diseased skin.
Lymphocyte transformation tests
Patch testing is considered inconvenient by some
patients because it requires bathing restrictions and 3
J AM ACAD DERMATOL
JUNE 2016
visits to a dermatologist. Patients with generalized
dermatitis may not have enough unaffected skin for
patch testing. The LTT is an in vitro test in which
peripheral blood lymphocytes are incubated in the
presence of various antigens and thymidine for
7 days. The hapten-specific T cells in sensitized
individuals proliferate, indicating sensitization.61
The LTT may represent a helpful tool to detect the
cause of allergic contact sensitization. LTTs have
some advantages of an in vitro test and none of the
risks of patch testing. LTTs have been performed to
assess sensitizations to drugs, nickel, and other
metals.62-68
Hagemann et al69 reported a LTT in a patient with
minoxidil allergy, which was helpful because minox-
idil may cause irritant reactions. LTTs may be consid-
ered in the diagnosis of ACD in some situations; for
example, p-phenylenediamine (PPD) and its deriva-
tives are strong allergens, and iatrogenic sensitizations
and severe patch test reactions to PPD may occur. In
addition, a LTT may be used to test some contact
allergens with unknown potential toxicity.70
Attempts to use peripheral blood for in vitro
testing have had limited success. The nonspecific
proliferation of lymphocytes in the presence of
nickel can occur, and we cannot conclude that a
LTT is a standard test for clinically relevant sensiti-
zation to metals.71 Factors including timing of the
LTT in relation to epicutaneous testing or accidental
exposure need to be considered. The limitations of a
LTT include its sensitivity, limited availability, and
the limited number of allergens that are tested. A
combination of LTT and the measurement of various
cytokines released by lymphocytes has been used to
better help assess ACD.72-74
The diagnosis and management of metal hyper-
sensitivity reactions to implanted devices remains
challenging and controversial. Patch testing is
considered the criterion standard for diagnosing
ACD on the skin, and a LTT is a way to evaluate
the reactions of circulating lymphocytes (ie, it is not
specifically targeted to the skin) with some concerns
regarding its reproducibility and relevance. A posi-
tive patch test to a metal component of the implant is
1 of 4 major criteria, and a positive in vitro test to
metals (ie, LTT) is 1 of 5 minor criteria for metal
hypersensitivity reactions to metallic implants pub-
lished previously.75 These criteria may be useful for
guiding decision-making. Ultimately, the decision
regarding further intervention and the use of an
alternate material in a subsequent device replace-
ment depends on the patient and the surgeon. LTT
may be considered in doubtful/questionable cases;
however, its clinical significance in implant intoler-
ance remains to be established and validated.76
J AM ACAD DERMATOL
VOLUME 74, NUMBER 6
The subject of metal hypersensitivity to implanted
devices continues to be studied and debated.
Atopy patch tests. It has been previously re-
ported that patients with AD do not have a predis-
position to develop ACD. However, more recent
studies have shown at least similar prevalence or
higher prevalence of contact sensitization in AD
compared with non-AD (depending on aller-
gens).77-79 The prevalence of contact sensitization
to certain chemicals used in topical products (ie,
fragrances, ethylenediamine, and neomycin) was
higher in individuals with AD and filaggrin mutation
when compared with filaggrin nonmutation carriers
without AD. The same study from Denmark also
found that contact sensitization to $1 allergen, but
not nickel and thimerosal, was significantly associ-
ated with AD (odds ratio, 2.53). Thimerosal and
nickel sensitization were excluded because these
contact allergies are typically caused by vaccination
and ear piercing, both of which bypass the epidermis.
Nickel and thimerosal sensitization was similar in
individuals with and without filaggrin mutations.80
Sensitization to certain antigens may be even
more common in patients with AD. In vitro predic-
tive tests of T cellemediated immunity usually fail to
recognize antigens that may use antigen-specific
immunoglobulin E (IgE) in the presentation process,
such as proteins and propylene glycol. Atopy patch
tests (APTs) are performed by applying protein
allergensusually used to elicit standard IgE-
dependent reactions tested by the skin prick test,
such as foods and aeroallergensin an occlusive
chamber for 48 hours.81 Although all aspects of AD
are not the result of allergy, the diagnostic criteria for
AD were modified by Hanifin and Rajka82 in 1980 to
include positive skin prick test results for food and/
or airborne allergens as minor criteria. APT results
are evaluated at 48 to 72 hours after application. The
sensitivity and specificity varies widely depending
on the allergen(s).83 The mechanism of an APT is not
exactly the same as skin prick tests or conventional
patch tests because it is thought to be IgE-dependent
but cell-mediated.84 When allergen is captured
by IgE, it binds to the IgE receptor on antigen-
presenting cells. Antigen presentation results in a T
cellemediated allergen specific immune response,
which is responsible for the eczematous reaction.85
Positive APTs in patients with AD indicate hypersen-
sitivity to food and inhalant allergens as a possible
trigger of skin lesions.86-90
The relationship between AD and food allergy is
evidenced by the provocation of AD flares by foods
in some children with AD.86,88 Because of barrier
dysfunction and drooling, atopic infants often have
perioral irritant dermatitis. This may exemplify
Mowad et al 1035
cutaneous sensitization via inflamed perioral skin
leading to food allergy. Ingestion of the food can
cause exacerbation of AD. In this sense, food allergy
in patients with AD can be considered a type of SCD.
Double-blind, placebo-controlled food challenges
(DBPCFCs) remain the criterion standard for diag-
nosing food allergy. However, the patient must
remain in a controlled environment for at least
48 hours to assess for flares of dermatitis. This makes
DBPCFCs for delayed-type hypersensitivity both
time- and cost-prohibitive.
Skin prick tests seem to reflect IgE-mediated or
early reactions to food challenges, whereas the APT
may have a diagnostic efficacy for late phase re-
actions.91 Previous studies have confirmed the use-
fulness of APTs for diagnosing cows milk, hens
egg, wheat, and soy allergies.91,92 However, some
studies found its role controversial because APTs
conducted with food are not standardized.93-95
Patients with atopic dermatitis may have a lowered
irritant threshold, contributing to false-positive
patch tests. Microbial proliferation in patch tests
may also trigger AD.
Children with atopic dermatitis develop flexural
contact dermatitis around the time they begin to play
outdoors. Some of them have exacerbation of skin
lesions after contact with or inhalation of aeroaller-
gens (ie, house dust mites, pollen, or animal dander)
and improve after avoidance.90,96 Positive APT re-
sults to aeroallergens are found more frequently in
patients with eczematous lesions in an air-exposed
pattern.96-99 Previous studies revealed low sensitivity
of APTs for aeroallergens (18-66%) and higher
specificity (64-91%) compared to skin prick tests
(50-85%) and serum IgE (52-85%).89,97 Although
positive APT results to house dust are also encoun-
tered in individuals without AD, their frequency and
intensity are lower compared to patients with AD,
and may be irritant responses caused by protease
content.100,101
APTs require standardization but may provide
more diagnostic information than the detection of
purely IgE-mediated sensitization. Patients with AD
who do not respond to treatment should be evalu-
ated for precipitating factors, such as food and
aeroallergen hypersensitivity, in addition to evalua-
tion for conventional contact dermatitis and infec-
tions. Allergen avoidance may subsequently lead to a
decrease in the exacerbation of AD and help prevent
unnecessary diet restriction based solely on skin
prick tests.
NEW/EMERGING ALLERGENS
Advances in technology and the continually
evolving nature of industry results in the introduction
1036 Mowad et al
of many new chemicals into the environment and
personal care products. This results in new consumer
exposure and potential new allergens. The number
of new products developed annually is substantial;
the number of new allergens is sizeable. Clinicians
must be aware that new, yet to be described
allergens may be responsible for a patients ACD.
Only with investigative work by the patient, physi-
cian, and in certain cases, the patients employer can
one determine the new allergen. With the contin-
uous development of new chemicals, dermatologists
play a critical role in discovering and reporting novel
allergens. Most of the new allergens discovered are
reported in case reports or series.
Dimethyl fumarate is the perfect example of a new
allergen that led to widespread consumer exposure.
It was not until dermatologists identified the problem
and then isolated the responsible chemical that the
outbreak was solved.102 In 2007, several cases of
ACD were discovered in Finland that were caused by
fabric from a chair and couch that were manufac-
tured in China. Over the next year, cases were
reported in other countries. Expert dermatologists
in the field of ACD eventually discovered the cause
to be dimethyl fumarate. This chemical, contained in
small sachets placed in the furniture, was being used
as an antifungal agent. The investigative work of
dermatologists means that dimethyl fumarate is un-
likely to be a major cause of ACD in the future. The
evidence was so strong and overwhelming that use
of this allergen by manufacturers has essentially
stopped. In addition, the European Union banned
the import of any products with dimethyl fumarate,
and as a result this allergen is no longer a problem.102
Sorbitans, which are emulsifiers, have been
around for many years, and their ability to cause
ACD has been well documented. Sorbitan as a cause
of ACD has been an emerging problem because
they are widely used in topical corticosteroid
preparations.103
In addition to new allergens, common allergens
evolve over time. ACD to fragrances is well docu-
mented. Because of the plethora of fragrance chem-
icals found in consumer products, it is not feasible to
patch test an individual to each and every fragrance
available. Mixtures of fragrances have been devel-
oped as screening tools to detect an underlying
fragrance allergy. The first fragrance mixture
(fragrance mix I) was developed in the late 1970s
and has been shown to be a good screening agent for
underlying fragrance allergy. Approximately 75% of
individuals with a fragrance allergy will react to
fragrance mix I.104 Myroxylon pereirae has been
around longer and is also used as a screening agent
for fragrance products. Approximately 50% of
J AM ACAD DERMATOL
JUNE 2016
individuals with a fragrance allergy will react to this
chemical. In an attempt to stay abreast of the new
fragrance chemicals introduced into consumer prod-
ucts and increase the ability to detect fragrance
allergies with screening allergens, fragrance mix II
was developed. When compared with fragrance mix
I, the new mix was able to detect a higher percentage
of individuals than fragrance mix I alone.104 Studies
have estimated that fragrance mix II increases
the ability to detect fragrance allergy by 10% to
28%.104,105 As more fragrances are brought to mar-
ket, clinicians will need to continually monitor and
adjust testing mixtures to achieve the best overall
yield from patch testing.104,105
Recent attention has been given to a resurgence of
methylisothiazolinone (MI) as a contact allergen.
This preservative has been known to be a cause of
ACD for decades. Typically methylchloroisothiazoli-
none (MCI) and MI have been patch tested together
in a mixture of MCI/MI. More recently, MI has been
used on its own, resulting in cases of ACD.106
Because MI is now being used as a stand-alone
preservative in various cosmetic and personal care
products, it is recommended to patch test to the
combination of MCI/MI and MI alone. Some cases of
MI allergy will not be detected with the mix in part
because when used alone, MI is used at a higher
concentration than when used with MCI; when
tested alone, it is tested at a higher concentration
than when tested with MCI.106,107
Old allergens sometimes become allergens with
more current relevance. Nickel exposure through
cell phones, an increasing number of body piercings,
and the metal allergy in stenting procedures has
brought to light a renewed interest in nickel
allergy.108 Regulation of nickel in other countries
has led to decreases in nickel sensitivity. To date, this
has not occurred in the United States.108 PPD,
commonly known as a hair dye allergen, also had
renewed interest when this chemical was found in
temporary henna tattoos. The adulteration of henna
tattoos with PPD to prolong duration and enhance
the color led to several reports of ACD in vaca-
tioners.109 These 2 older allergens took on new
relevance in these current settings.
Table IV is an abbreviated list of some new or
emerging allergens that have been reported in the
last several years.
The field of ACD is continually evolving as new
allergens are introduced into the marketplace and
therefore into our patients environments. Clinicians
must remain ever vigilant to the possibility of ACD
and patch test when appropriate so as to best
manage and treat patients with suspected contact
dermatitis. This simple in-office procedure can be
J AM ACAD DERMATOL
VOLUME 74, NUMBER 6
Table IV. Newly reported or emerging allergens in
the last 10 years110-123
2-hydroxyethyl salicylate
Aliphatic polyisocyanates
Bisabolol
Butylhydroxytoulene
Carmine
Cetyl alcohol
Decyl glucosides
Dimethyl fumarate
Majantol
Methyl aminolevulinate
Methylene bis-benzotriazolyl tetramethylbutylphenol
Octyldodecyl xyloside
Peppermint
Sorbitans
Uranyl acetate
Sodium dehydroacetate
extremely valuable in the resolution of chronic
dermatoses.
REFERENCES
1. Schalock PC, Dunnick CA, Nedorost S, et al. American Contact
Dermatitis Society Core Allergen Series Committee. Derma-
titis. 2013;24:7-9.
2. Lachapelle JM. Evolution of patch testing. Dermatitis. 2009;
20:316-321.
3. Lachapelle JM. Giant steps in patch testing: a historical
memoir. Phoenix (AZ): Smart Practice; 2010.
4. Smith DR. The continuing rise of contact dermatitis, Part 1:
The academic discipline. Contact Dermatitis. 2009;61:189-193.
5. Gittler JK, Kreuger JG, Guttman-Yassky E. Atopic dermatitis
results in intrinsic barrier and immune abnormalities: impli-
cations for contact dermatitis. J Allergy Clin Immunol. 2013;
131:300-313.
6. Kaplan DH, Jenison MC, Saeland S, Shlomchik WD,
Shlomchik MJ. Dermal Langerhans celledeficient mice
develop enhanced contact hypersensitivity. Immunity. 2005;
23:611-620.
7. Senschal J, Clark RA, Gehad A, Baecher-Allen CM, Kupper TS.
Human epidermal Langerhans cells maintain immune ho-
meostasis in skin by activating skin resident regulatory T
cells. Immunity. 2012;36:873-884.
8. Stary G, Klein I, Bauer W, et al. Glucocorticosteroids modify
Langerhans cells to produce TGF-b and expand regulatory T
cells. J Immunol. 2011;186:103-112.
9. Schwarz A, Navid F, Sparwasser T, Cluasen BE, Schwarz T.
1,25-dihydroxyvitamin D. experts similar immunosuppressive
effects as UVR but is dispensable for local UVR- induced
immunosuppression. J Invest Dermatol. 2012;132:2762-2769.
10. Sulzberger MB. The patch test e who should and should not
use it and why. Contact Dermatitis. 1975;1:117-119.
11. Fisher AA. Contact dermatitis. Philadelphia (PA): Lea &
Febiger; 1973. pp. 293-305.
12. Veien NK. Ingested food in systemic allergic contact derma-
titis. Clin Dermatol. 1997;15:547-555.
13. Menne T, Weismann K. Hematogenous contact eczema
following oral administration of neomycin. Hautarzt. 1984;
35:319-320 [abstr].
Mowad et al 1037
14. Hindson C. Contact eczema from methyl salicylate repro-
duced by oral aspirin (acetyl salicylic acid). Contact Dermatitis.
1977;3:348-349.
15. Hamilton TZ, Zug KA. Systemic contact dermatitis to raw
cashew nuts in pesto sauce. Am J Contact Dermat. 1998;9:
51-54.
16. Andersen KE, Hjorth N, Menne T. The baboon syndrome:
systemically-induced allergic contact dermatitis. Contact
Dermatitis. 1984;10:97-100.
17. Masterpol K, Gottlieb AB, Scheinman PL. Systemic contact
dermatitis presenting as lichen planus of the lip. Dermatitis.
2010;21:218-219.
18. Cressey BD, Scheinman PL. Systemic allergic dermatitis of the
lips resulting from allergy to an antimicrobial agent in
contact lens disinfecting solution. Contact Dermatitis. 2012;
67:239-240.
19. Matiz C, Jacob SE. Systemic contact dermatitis in children:
how an avoidance diet can make a difference. Pediatr
Dermatol. 2011;28:368-374.
20. Cressey BD, Scheinman PL. Periocular dermatitis from sys-
temic exposure to nickel in a palatal expander and dental
braces. Dermatitis. 2012;23:179.
21. Carol LY, Taylor JS. Contact Dermatitis and Related Disorders.
In: Dale DC, Federmann DD, eds. ACP Medicine. Hamilton, ON:
BC Decker Inc; September 2008. Available at: http://www.
acpmedicine.com. Accessed August 6, 2009.
22. de Groot AC. Patch testing. Test Concentrations and Vehicles
for 4350 Chemicals. 3rd ed. Wapserveen: Acdegroot Publish-
ing; 2008.
23. La-chapelle J, Maibach HI. Patch Testing and Prick Testing. 2nd
ed. Heidelberg: Springer-Verlag Berlin; 2009.
24. Warshaw EM, Nelson D. Prevalence of patch testing and
methodology of dermatologists in the US: results of a
cross-sectional survey. Am J Contact Dermat. 2002;13(2):53-58.
25. Larkin A, Rietschel R. The utility of patch tests using larger
screening series of allergens. Am J Contact Dermat. 1998;9(3):
142-145.
26. Saripalli YV, Achen F, Belsito DV. The detection of clinically
relevant contact allergens using a standard screening tray of
twenty-three allergens. J Am Acad Dermatol. 2003;49(1):65-69.
27. Warshaw EM, Belsito DV, Taylor JS, et al. North American
Contact Dermatitis Group Patch Test results for 2009-1010.
Dermatitis. 2013;24(2):50-59.
28. Fransway AF, Zug KA, Belsito DV, et al. North American
Contact Dermatitis Group. Patch test results for 2007-2008.
Dermatitis. 2013;24(1):10-21.
29. Simpson EL, Law SV, Storrs FJ. Prevalence of botanical extract
allergy in patients with contact dermatitis. Dermatitis. 2004;
15(2):67-72.
30. Rajagopalan R, Anderson R, Sarma S, et al. An economic
evaluation of patch testing in the diagnosis and manage-
ment of allergic contact dermatitis. Am J Contact Dermat.
1998;9(3):149-154.
31. Uter WJ, Geier J, Schnuch A. Good clinical practice in patch
testing: readings beyond day 2 are necessary a confirmatory
analysis. Am J Contact Derm. 1996;7:231.
32. Davis MD, Bhate K, Rohlinger AL, Farmer SA, Richardson DM,
Weaver AL. Delayed patch test reading after 5 days: the Mayo
Clinic experience. J Am Acad Dermatol. 2008;5:225-233.
33. Jonker MJ, Bruynzeel DP. The outcome of an additional
patch-test reading on days 6 or 7. Contact Dermatitis. 2000;
42:330.
34. Wee JS, White JM, McFadden JP, et al. Patch testing in
patients treated with systemic immunosuppression and
cytokine inhibitors. Contact Dermatitis. 2010;62:165-169.
1038 Mowad et al
35. Anveden I, Lindberg M, Andersen KE, et al. Oral prednisolone
suppresses allergic but not irritant patch test reactions in
individuals hypersensitive to nickel. Contact Dermatitis. 2004;
50:298-303.
36. Damian DL, Barnetson RS, Halliday GM. Effects of low-dose
ultraviolet radiation on in vivo human cutaneous recall
responses. Australas J Dermatol. 2001;42:161-167.
37. Grob JJ, Castelain M, Richard MA, et al. Anti-inflammatory
properties of cetirizine in a human contact dermatitis model.
Clinical evaluation of patch tests is not hampered by
antihistamines. Acta Derm Venereol. 1998;78:194-197.
38. Hogan D: Skin Allergies. Belsito D, Vinson RP, Callen JP,
Gelfand JM, James WD. (eds): Web MD Allergies Guide.
Available at: http://www.webmd.com/allergies/guide/skin-
allergies. Accessed November 24, 2007.
39. Wilkinson DS, Fregert S, Magnusson B, et al. Terminology of
contact dermatitis. Acta Derm Venereol. 1970;50:287-292.
40. Belsito DV. Thimerosal: contact (non)allergen of the year. Am
J Contact Dermat. 2002;13(1):1-2.
41. Warshaw EW, Belsito DV, Taylor JS, et al. North American
Contact Dermatitis Group Patch Test Results: 2009-2010.
Dermatitis. 2013;24(2):50-59.
42. Dotterud LK, Smith-Sivertsen T. Allergic contact sensitization
in the general adult population: a population-based study
from Northern Norway. Contact Dermatitis. 2007;56:10-15.
43. Svedman C, Engfeldt M, Api AM, et al. A pilot study aimed at
finding a suitable eugenol concentration for a leave-on
product for use in a repeated open application test. Contact
Dermatitis. 2012;66:137-139.
44. Hannuksela M, Salo H. The repeated open application test
(ROAT). Contact Dermatitis. 1986;14:221-227.
45. Hannuksela M. Sensitivity of various skin sites in the repeated
open application test. Am J Contact Dermat. 1991;2:102-104.
46. Bruze M, Johansen JD, Andersen KE, et al. Deodorants: an
experimental provocation study with isoeugenol. Contact
Dermatitis. 2005;52:260-267.
47. Svedman C, Bruze M, Johansen JD, et al. Deodorants: an
experimental provocation study with hydroxycitronellal.
Contact Dermatitis. 2003;48:217-223.
48. Bruze M, Johansen JD, Andersen KE, et al. Deodorants: an
experimental provocation study with cinnamic aldehyde. J
Am Acad Dermatol. 2003;48:194-200.
49. Hannuksela A, Niinima ki A, Hannuksela M. Size of the test
area does not affect the result of the repeated open
application test. Contact Dermatitis. 1993;28(5):299-300.
50. Johansen JD, Bruze M, Andersen KE, et al. The repeated open
application test: suggestions for a scale of evaluation. Con-
tact Dermatitis. 1998;39(2):95.
51. Berardesca E, Maibach HI. Bioengineering and the patch test.
Contact Dermatitis. 1988;18:3-9.
52. Farm G. Repeated open application test (ROAT) in patients
allergic to colophony-evaluated visually and with bioengi-
neering techniques. Acta Derm Venereol (Stockh). 1998;78:
130-135.
53. Johansen JD, Andersen KE, Rastogi SC, et al. Threshold
responses in cinnamic-aldehyde-sensitive subjects: results
and methodological aspects. Contact Dermatitis. 1996;34:
165-171.
54. Johansen JD, Andersen KE, Menne T. Quantitative aspects of
isoeugenol contact allergy assessed by use and patch tests.
Contact Dermatitis. 1996;34:414-418.
55. Menne T. Relationship between use test and threshold patch
test concentration in patients sensitive to 5-chloro-2-methyl-
4-isothia- zolin-3-one and 2-methyl-4-isothiazolin-3-one (MCIMI).
Contact Dermatitis. 1991;24:375.
J AM ACAD DERMATOL
JUNE 2016
56. Johansen JD, Frosch PJ, Svedman C, et al. Hydroxyisohexyl
3-cyclo- hexene carboxaldehyde e known as Lyral: quanti-
tative aspects and risk assessment of an important fragrance
allergen. Contact Dermatitis. 2003;48:310-316.
57. Flyvholm MA, Hall BM, Agner T, et al. Threshold for occluded
formaldehyde patch test in formaldehyde-sensitive patients.
Relationship to repeated open application test with a prod-
uct containing a formaldehyde releaser. Contact Dermatitis.
1997;36:26-33.
58. Basketter D, Horev L, Slodovnik D, Merimes S, Trattner A,
Ingber A. Investigation of the threshold for allergic reactivity
to chromium. Contact Dermatitis. 2001;44:70-74.
59. Villarama CD, Maibach HI. Correlations of patch test reactivity
and the repeated open application test (ROAT)/provocative
use test (PUT). Food Chem Toxicol. 2004;42:1719-1725.
60. Andersen KE, Johansen JD, Bruze M, et al. The timeedosee
response relationship for elicitation of contact dermatitis in
isoeugenol allergic individuals. Toxicol Appl Pharmacol. 2001;
170:166-171.
61. Caron GA, Sarkany I, Williams HS, Todd AP. Radioactive
method of the measurement of lymphocyte transformation
in vitro. Lancet. 1965;2:1266-1268.
62. Rasanen L, Sainio H, Lehto M, Reunala T. Lymphocyte
proliferation test as a diagnostic aid in chromium contact
sensitivity. Contact Dermatitis. 1991;25:25-29.
63. Lindemann M, Rietschelw F, Zabelw M, Grosse-Wilde H.
Detection of chromium allergy by cellular in vitro methods.
Clin Exp Allergy. 2008;38:1468-1475.
64. Summer B, Sander CA, Przybilla B, Thomas P. Molecular
analysis of T-cell clonality with concomitant specific T-cell
proliferation in vitro in nickel-allergic individuals. Allergy.
2001;56:767-770.
65. Luque I, Leyva L, Jose Torres M, et al. In vitro T-cell responses
to beta-lactam drugs in immediate and nonimmediate
allergic reactions. Allergy. 2001;56:611-618.
66. Basketter D, Menne T. Lymphocyte transformation test in
patients with allergic contact dermatitis. Contact Dermatitis.
2005;53:1.
67. Rasanen L, Tuomi ML. Diagnostic value of the lymphocyte
proliferation test in nickel contact allergy and provocation in
occupational coin dermatitis. Contact Dermatitis. 1992;27(4):
250-254.
68. Thomas P, Bandl WD, Maier S, Summer B, Przybilla B. Hyper-
sensitivity to titanium osteosynthesis with impaired fracture
healing, eczema, and T-cell hyperresponsiveness in vitro:
case report and review of the literature. Contact Dermatitis.
2006;55(4):199-202.
69. Hagemann T, Schlutter-Bohmer B, Allam JP, Bieber T, Novak N.
Positive lymphocyte transformation test in a patient with
allergic contact dermatitis of the scalp after short-term use of
topical minoxidil solution. Contact Dermatitis. 2005;53:53-55.
70. Merk HF. Lymphocyte transformation test as a diagnostic test in
allergic contact dermatitis. Contact Dermatitis. 2005;53(4):246.
71. Pappas A, Orfanos CE, Bertram R. Non-specific lymphocyte
transformation in vitro by nickel acetate. A possible source of
errors in lymphocyte transformation test(LLT). J Invest
Dermatol. 1970;55:198-200.
72. Cederbrant K, Anderson C, Andersson T, Marcusson-Stahl M,
Hultman P. Cytokine production, lymphocyte proliferation
and T-cell receptor Vbeta expression in primary peripheral
blood mononuclear cell cultures from nickel-allergic individ-
uals. Int Arch Allergy Immunol. 2003;132:373-379.
73. Cavani A, Mei D, Guerra E, et al. Patients with allergic contact
dermatitis to nickel and nonallergic individuals display
different nickel-specific T cell responses. Evidence for the
J AM ACAD DERMATOL
VOLUME 74, NUMBER 6
presence of effector CD81and regulatory CD41 T cells. J
Invest Dermatol. 1998;111:621-628.
74. Minang JT, Arestrom I, Troye-Blomberg M, Lundeberg L,
Ahlborg N. Nickel, cobalt, chromium, palladium and gold
induce a mixed Th1- and Th2-type cytokine response in vitro
in subjects with contact allergy to the respective metals. Clin
Exp Immunol. 2006;146:417-426.
75. Schalock PC, Thyssen JP. Patch testers opinions regarding
diagnostic criteria for metal hypersensitivity reactions to
metallic implants. Dermatitis. 2013;24:183-185.
76. Schalock PC, Menne T, Johansen JD, et al. Hypersensitivity
reactions to metallic implants-diagnostic algorithm and
suggested patch test series for clinical use. Contact Derma-
titis. 2012;66:4-19.
77. deGroot AC. The frequency of contact allergy in atopic
patients with dermatitis. Contact Dermatitis. 1990;22:273-277.
78. Bieber T. Atopic Dermatitis. N Engl J Med. 2008;358:1483-1494.
79. Eyerich K, Novak N. Immunology of atopic eczema: over-
coming the Th1/Th2 paradigm. Allergy. 2013;68:974-982.
80. Thyssen JP, Johansen JD, Linneberg A, et al. The association
between null mutations in the filaggrin gene and contact
sensitization to nickel and other chemicals in the general
population. Br J Dermatol. 2010;162:1278-1285.
81. Turjanmaa K, Darsow U, Niggemann B, Rance F, Vanto T,
Werfel T. EAACI/GA2LEN Position paper: Present status of the
atopy patch test. Allergy. 2006;61:1377-1384.
82. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis.
Acta Derm Venerol (Stockh). 1980;92:44-47.
83. Lipozencic J, Wolf R. The diagnostic value of atopy patch
testing and prick testing in atopic dermatitis: facts and
controversies. Clin Dermatol. 2010;28:38-44.
84. Bruijnzeel-Koomen C, Van Wichen DF, Toonstra J, Berrens L,
Bruynzeel PL. The presence of IgE molecules on epidermal
Langerhans cells from patients with atopic dermatitis. Arch
Dermatol Res. 1986;278:199-205.
85. Wistokat-W ulfing A, Schmidt P, Darsow U, Ring J, Kapp A,
Werfel T. Atopy patch test reactions are associated with
T-lymphocyte mediated allergen-specific immune responses
in atopic dermatitis. Clin Exp Allergy. 1999;29:513-521.
86. Darsow U, Ring J. Airborne and dietary allergens in atopic
eczema: a comprehensive review of diagnostic tests. Clin Exp
Dermatol. 2000;25:544-551.
87. Ring J, Darsow U, Behrendt H. Role of aeroallergens in atopic
eczema: proof of concept with the atopy patch test. J Am
Acad Dermatol. 2001;45:49-52.
88. Niggemann B. The role of the atopy patch test (APT) in
diagnosis of food allergy in infants and children with atopic
dermatitis. Pediatr Allergy Immunol. 2001;12:37-40.
89. Darsow U, Vieluf D, Ring J. Evaluating the relevance of
aeroallergen sensitization in atopic eczema with the atopy
patch test: a randomized, double-blind multicenter study. J
Am Acad Dermatol. 1999;40:187-193.
90. Clark RA, Adinoff AD. The relationship between positive
aeroallergen patch test reactions and aeroallergen exacer-
bations of atopic dermatitis. Clin Immunol Immunopathol.
1989;53:S132-S140.
91. Niggemann B, Reibel S, Wahn U. The atopy patch test (APT)-
a useful tool for the diagnosis of food allergy in children with
atopic dermatitis. Allergy. 2000;55:281-285.
92. Majamaa H, Moisio P, Holm K, Kautiainen H, Turjanmaa K.
Cows milk allergy: diagnostic accuracy of skin prick and
patch tests and specific IgE. Allergy. 1999;54:346-351.
93. Isolauri E, Turjanmaa K. Combined skin prick and patch
testing enhances identification of food allergy in infants with
atopic dermatitis. J Allergy Clin Immunol. 1996;97:9-15.
Mowad et al 1039
94. Osterballe M, Andresen KE, BinslevJensen C. The diagnostic
accuracy of the atopy patch test in diagnosing hypersensi-
tivity to cows milk and hens egg in unselected children with
and without atopic dermatitis. J Am Acad Dermatol. 2004;51:
556-562.
95. Heine RG, Verstege A, Mehl A, Staden U, Rolinck-
Werninghaus C, Niggemann B. Proposal for a standardized
interpretation of the atopy patch test in children with atopic
dermatitis and suspected food allergy. Pediatr Allergy Immu-
nol. 2006;17:213-217.
96. Tan B, Weald D, Strickland I, Friedman P. Double-blind
controlled trial of effect of house dust-mite allergen avoid-
ance on atopic dermatitis. Lancet. 1996;347:15-18.
97. Samochocki Z, Owczarek W, Zabielski S. Can atopy patch
tests with aeroallergens be an additional diagnostic criterion
for atopic dermatitis? Eur J Dermatol. 2006;16:151-154.
98. Whitmore SE, Sherertz EF, Belsito DV, Maibach HI,
Nethercott JR. Aeroallergen patch testing for patients pre-
senting to contact dermatitis clinics. J Am Acad Dermatol.
1996;35:700-704.
99. Schafer T, Heinrich J, Wjst M, Adam H, Ring J, Wichmann HE.
Association between severity of atopic eczema and degree of
sensitization to aeroallergens in schoolchildren. J Allergy Clin
Immunol. 1999;104:1280-1284.
100. Seidenari S, Giusti F, Pellacani G, Bertoni L. Frequency and
intensity of responses to mite patch tests are lower in
nonatopic subjects with respect to patients with atopic
dermatitis. Allergy. 2003;58:426-429.
101. Ingordo V, Dalle Nogare R, Colecchia B, DAndria C. Is the
atopy patch test with house dust mites specific for atopic
dermatitis? Dermatology 2004;209:276-283.
102. Bruze M, Zimerson E. Dimethyl fumarate. Dermatitis. 2011;22:
3-7.
103. Cressey BD, Kumar N, Scheinman PL. Contact allergy to
sorbitans: a follow-up study. Dermatitis. 2012;23(4):158-161.
104. Krautheim A, Uter W, Schnuch A, Geier J. Patch testing with
fragrance mix II: results of the IVDK 2005-2008. Contact
Dermatitis. 2010;63:262-269.
105. Heisterberg MV, Andersen KE, Avnstorp C, et al. Fragrance
mix II in the baseline series contributes significantly to
detection of fragrance allergy. Contact Dermatitis. 2010;63:
270-276.
106. Urwin R, Wilkinson M. Methylchloroisothiazolinone and
methylisothiazolinone contact allergy: a new epidemic.
Contact Dermatitis. 2013;68:253-255.
107. Lundov MD, Opstrup MS, Johansen JD. Methyisothiazolinone
contact allergy- a growing epidemic. Contact Dermatitis.
2013;69:271-275.
108. Kornik R, Zug KA. Nickel. Dermatitis. 2008;19(1):3-8.
109. DeLeo VA. P-phenylenediamine. Dermatitis. 2006;17(2):
53-55.
110. Pereira N, Coutinho I, Andrade P, Goncalo M. The UV filter
Tinosorb M, containing decyl glucoside, is a frequent cause
of allergic contact dermatitis. Dermatitis. 2013;24:41-43.
111. Foti C, Antelmi A, Guida S, Romita P, Bonamonte D. Sodium
dehydroacetate: an emerging allergen. Dermatitis. 2012;23:
243-244.
112. Wilkinson M, Powis RA. Octyldodecyl xyloside: a novel
contact allergen. Contact Dermatitis. 2011;65:302-304.
113. Aalto-Korte K, Pesonen M, Kuuliala O, Alanko K, Jolanki R.
Contact allergy to aliphatic polyisocyanates based on hex-
amethylene-1,6-diisocyanate (HDI). Contact Dermatitis. 2010;
63:357-363.
114. Aakhus AE, Warshaw E. Allergic contact dermatitis from cetyl
alcohol. Dermatitis. 2011;22:56-57.
1040 Mowad et al
115. Shvartsbeyn M, Tuchinda P, Gaitens J, et al. Patch testing
with uranyl acetate in veterans exposed to depleted uranium
during the 1991 Gulf war and the Iraqi conflict. Dermatitis.
2011;22:33-39.
116. Jacob SE, Matiz C, Herro EM. Compositae-associated allergic
contact dermatitis from bisabolol. Dermatitis. 2011;22:102-105.
117. Dever TT, Herro EM, Jacob SE. Butylhydroxytoluenefrom jet
fuels to cosmetics? Dermatitis. 2012;23:90-91.
118. Schnuch A, Geier J, Uter W, Frosch PJ. Majantola new
important fragrance allergen. Contact Dermatitis. 2007;57:48-50.
119. Gonzalez-P
erez R, Trebol I, Garca-Ro I, Arregui MA, Soloeta R.
Allergic contact dermatitis from methylene-bis-benzotriazolyl
tetramethylbutylphenol (Tinosorb M). Contact Dermatitis.
2007;56:121.
J AM ACAD DERMATOL
JUNE 2016
120. Cordoba S, Garca-Donoso C, Villanueva CA, Borbujo J. Allergic
contact dermatitis from a veterinary anti-inflammatory gel
containing 2-hydroxyethyl salicylate. Dermatitis. 2011;22:
171-172.
121. Pastor-Nieto MA, Jimenez-Blazquez E, Sanchez-Herreros C,
Belmar-Flores P. Allergic contact dermatitis caused by
methyl aminolevulinate. Actas Dermosifiliogr. 2013;104:
168-170.
122. Suzuki K, Hirokawa K, Yagami A, Matsunaga K. Allergic
contact dermatitis from carmine in cosmetic blush. Derma-
titis. 2011;22:348-349.
123. Tran A, Pratt M, DeKoven J. Acute allergic contact dermatitis
of the lips from peppermint oil in a lip balm. Dermatitis. 2010;
21:111-115.