Contact allergy is caused by skin contact with low molecular weight haptens and may

evolve into allergic contact dermatitis if exposure exceeds the individual threshold. A substantial
number of studies have investigated the prevalence of contact allergy in the general population
and in unselected subgroups of the general population. A review of published research mainly
originating from North America and western Europe in the general population identifi ed that the
median prevalence of contact allergy to at least one allergen was 21.2% (range 12.5–40.6%), and
the weighted average prevalence was 19.5%, based on data collected on all age groups and all
countries between 1966 and 2007. The overall prevalence estimates do not seem to depend much
on age, race or geographical origin of the study group. The most prevalent contact allergens were
nickel, thimerosal and fragrance mix. In addition, cobalt, chromium, p ‐phenylenediamine (PPD)
and methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) were prevalent allergens in
several studies.

Most other epidemiological studies have been based on patients already attending
dermatology clinics, or have involved either specifi c occupational or other population groups such
as those with atopic eczema, which can of course skew the data and are discussed more fully in
the chapter. Niels Hjorth and Siegfried Fregert – two eminent contact dermatitis investigators –
are quoted as saying that ‘in a particular clinic the incidence of allergic contact dermatitis is
determined by the interest the dermatologist takes in allergic contact dermatitis’.

The diagnosis of allergic contact dermatitis can only be confi rmed by patch testing and
should always be used to exclude contact allergy as a complicating factor in stubborn cases of
eczematous diseases, as well as cases where allergic contact dermatitis is suspected from the
pattern or distribution of the eczema. It is particularly important in chronic cases of dermatitis that
are unresponsive to traditional treatments. Nevertheless, one of the UK’s most well‐respected
dermatologists and proponent of patch testing, Etain Cronin, sums up the problem succinctly:
‘Ideally every patient with eczema should be patch tested and the importance of this investigation
is now universally accepted. The simplicity of the technique belies its many pitfalls, the greatest
being to lack the knowledge required to select the correct allergens and to interpret the results’ [ 1
]. Calnan wrote in 1982 that ‘the greatest abuse of patch testing is failure to use it and that a number
of dermatologists have never patch tested a patient’ [ 2 ]. Equally or more serious than this may be
to patch test incorrectly and thus provide erroneous conclusions [3 ].

Patch testing, which is actually a bioassay, remains, at present, the only practical scientifi
c procedure for the diagnosis of allergic contact dermatitis. During the last few decades much
effort has been put into the standardization of allergens, vehicles, concentrations, tapes and the
scoring of test reactions. Despite this, both the investigator’s skill and experience are crucial
factors in providing accurate information to patients. Kligman argued that ‘Anyone can do a patch
test. Few do it well. Fewer still can properly interpret patch tests’ [ 4 ]. Some authors argue that
patch testing should only ever be done by dermatologists [ 5 ].

Despite all these potential diffi culties, it is imperative to collect patch test data over time
and across many centres, including in different countries. Constant surveillance allows for trends
to be determined and for epidemics to be recognized, which in turn have shaped the response of
regulatory authorities – for example, the epidemics of biocide contact dermatitis caused by methyl
dibromoglutaronitrile and methylisothiazolinone resulting in the withdrawal and the
recommendation of withdrawal, respectively, of such chemicals from cosmetics.

Allergens exist in the home environment and the occupational setting. Prevention
strategies include primary, secondary and tertiary prevention. In primary prevention the focus is
on minimizing the risk of inducing sensitization in workers and consumers. At the workplace,
primary prevention includes pre‐employment screening, minimizing contact between allergens
and the skin, and education to employees in at‐risk occupations. These strategies have all been
reported as effective.

The quantitative risk assessment (QRA) procedure currently developed by the cosmetic
industry for fragrances (primary prevention) has a major fl aw as it is not able to predict the
elicitation risk of chemicals. Hence the ‘acceptable exposure level’ does not protect those already
sensitized. About a third of all allergies against cosmetic products are caused by fragrance
allergies.

However, in recent years Europe has successfully implemented a whole set of regulations
aimed at reducing the exposure of the workforce and consumers to contact allergens. Examples
are the ‘Nickel Directive’, limiting the release of nickel in contact with skin to 0.5 μg/cm 2 per
week [ 6 ], and the ‘Chromium Directive’, limiting chromium (CrVI) to 2 ppm in the total dry
weight of cement [ 7 ]. The directive on detergents requires the listing of preservatives and certain
fragrances if their content in detergents and similar household products exceeds 100 ppm [ 8 ].
Detergents are thus treated as rinse‐off cosmetics. Furthermore, details of the product formulation
have to be released when necessary, such as to investigate adverse reactions. As a result nickel
allergy among young patients showed a decline in several countries such as Germany, Sweden and
Denmark .In Denmark, the frequency of nickel allergies dropped from 26.9% before the European
Union (EU) directive to 12.4% thereafter

Defiinition

Allergic contact dermatitis is an eczematous reaction that occurs as an immunological

response following exposure to a substance to which the immune system has previously been
sensitized.

Pathophysiology

Sensitization and elicitation

The immunology of skin disease is discussed in detail in Chapter 8 . There are two main processes
involved in allergic contact dermatitis: (i) sensitization (induction or afferent limb of sensitivity);
and (ii) elicitation (or efferent limb) of contact dermatitis. Four different types of delayed‐type
hypersensitivity reactions to exogenous chemicals, of which allergic contact dermatitis is a form,
have been proposed [ 1 ]:

1. Th1‐mediated, with the release of interferon γ (IFN‐γ) and tumour necrosis factor α (TNF‐
α), and the activation of monocytes and macrophages in allergic contact dermatitis, bullous
exanthema and the tuberculin skin test.
2. Th2‐mediated, with the release of interleukin 5 (IL‐5), IL‐4, IL‐13 and eotaxin, resulting
in eosinophilic infl ammation seen in maculopapular and bullous exanthema.
 3. Mediated by cytotoxic CD4+ and CD8+ T cells, with the release of perforin, granzyme and
Fas ligand, resulting in allergic contact dermatitis and maculopapular, pustular and bullous
exanthema.
4. Release of CXCL‐8 and granulocyte–macrophage colony‐ stimulating factor (GM‐CSF)
by T cells, resulting in the recruitment of neutrophils in pustular exanthema.

It is clear that dendritic cells and the local tissue microenvironment are crucial factors in the
development of allergic contact dermatitis. Within the immune system, dendritic cells are the cell
type that primes naive T cells and thus forms a crucial link between the innate and adaptive
immune system. The precise role of dendritic cells in allergic contact dermatitis is still under
investigation; in particular, the contributions of the respective cellular pools are still disputed.
Newer studies have identifi ed that allergic contact dermatitis has been associated with defective
T reg cells and indeed it has become clear that T reg cells infl uence sensitization as well as
elicitation. Originally, T reg cells were defi ned as CD4+ CD25+ T cells and were mainly
associated with self‐tolerance. We now know that this defi nition comprises a heterogeneous cell
population that includes natural T reg and inducible T reg cells. The skin contains predominantly
inducible T reg cells, which can be triggered by Langerhans cells as well as dermal dendritic cells.
However, the precise phenotypes of T reg cells involved in allergic contact dermatitis are still not
known. Finally, T reg cells are involved in the control and eventual termination of the infl
ammatory response.

Sensitisation

The induction of sensitivity is the primary event, which has to take place before the clinical
expression of dermatitis can occur. The main events are described below.

- Binding of allergen to skin components

Broadly speaking, the chemicals that result in allergic contact dermatitis are too small to be
recognized by the immune system. Allergens penetrating the skin may be suffi ciently chemically
reactive that they bind covalently with skin peptides directly or, alternatively, metabolism may
result in a reaction product that is able to bind. The products formed associate with major
histocompatibility complex (MHC) class II molecules [ 3 ]. Interference in the process of protein
binding to thiol and amino groups in cysteine and lysine residues has been shown to interfere with
the process of sensitization [ 4 ]. Chemicals may also bind directly to MHC class II molecules,
inducing a sensitization reaction. MHC class II molecules are coded on the human leukocyte
antigen (HLA) D region genes, and are present on epidermal dendritic cells and Langerhans cells.
Epicutaneously applied allergen associates with these antigen‐presenting cells within 6 h.

- Recognition of ‘complete’ or conjugated antigen.

The ‘danger model’ supposes that sensitization to MHC‐bound antigen does not occur unless other
co‐stimulatory factors are also present and that it is produced as a consequence of cell ‘stress’. IL‐
1β, TNF‐α and GM‐CSF are all required for the activation, maturation and migration of
Langerhans cells [ 5 ]. The production of these cytokines by injured keratinocytes may lead to
Langerhans cell migration and subsequent sensitization. The danger hypothesis has been adapted
to contact hypersensitivity, and evidence produced to support a role for irritant dermatitis in the
generation of contact hypersensitivity [ 6 ]. In the absence of these co‐factors it is assumed that
tolerance would develop. Sensitization is possible only if the connection to the regional lymph
nodes is intact [ 7 ]. The allergen‐carrying Langerhans cells travel via the afferent lymphatics to
the paracortical areas of the regional lymph nodes, where they become apposed to T lymphocytes.
The binding is assisted not only by physical factors – the ruffl ed membrane and dendritic nature
of the Langerhans cells and the intricate structure of the paracortical areas – but also by specialist
cellular adhesion molecules (CAMs). These CAMs act at different loci to encourage binding. For
example, leukocyte functional antigen‐1 (LFA‐1) on CD4 helper cells interacts with intercellular
adhesion molecule‐1 (ICAM‐1) on Langerhans cells, and CD2 on T cells binds to LFA‐3 in plasma
membranes on most nucleated cells. With recognition of the antigen, many mediators or cytokines
are released by this apposition, for example IL‐1 by antigen‐presenting cells and IL‐2 by T
lymphocytes.

Proliferation and dissemination of sensitized T lymphocytes.

The cytokines cause blast formation in the lymph nodes and the proliferation of antigen‐specifi c
cytotoxic CD8+ (Tc1) and CD4+ (Th1) lymphocytes [ 8 ]. The type of T‐cell response generated
is dependent on the pathway by which the antigen is processed: small lipid‐soluble molecules such
as urushiol enter the cytoplasm and are presented on MHC class I as an endogenous antigen; polar
haptens are more likely to be presented on MHC class II as an exogenous antigen [9 ]. The T cells
disseminate via the efferent lymphatics throughout the body and interact with Langerhans cells
and residual antigen in the skin. Contact hypersensitivity is mediated through a subset of T cells
that express cutaneous lymphocyte‐associated antigen (CLA). Localization to areas of infl
ammation occurs via the production of the chemokine CCL27 by basal keratinocytes, which binds
to dermal glycoprotein. CLA‐positive lymphocytes also express CCR10, the receptor for CCL27
[ 10 ]. The cytotoxic T cells induce keratinocyte death through the release of Fas ligand and
perforin‐mediated pathways [11 ].

Elicitation

On fi rst exposure to a strong sensitizer such as DNCB, most subjects develop a local reaction after
5–25 days. During this period, sensitization has been accomplished, and the residues of the allergen
in the skin react with the newly formed, sensitized T lymphocytes. Such a response has been
termed a ‘late’ reaction. There is evidence to suggest that allergen‐specifi c T lymphocytes persist
at the site of original contact for some months following an initial sensitization exposure, and this
may explain the ‘re‐test’ or ‘fl are‐ up’ reactions that are sometimes observed during patch testing,
following re‐exposure at a distant site [ 6 ]. If a sensitized person is re‐exposed to a specifi c
allergen in suffi cient concentration, the clinical reaction subsequently develops much more
quickly, usually within 24–48 h. However, depending on the degree of sensitivity, penetration and
other factors, this may vary from a few hours to many days. Antigen may be presented not only
by antigen‐presenting Langerhans cells but also by IL‐1‐secreting keratinocytes that acquire
Ia/HLA‐DR status, augmenting the cascade of cytokine, immune cell and infl ammatory response.
This cascade is autoregulating, and although the mechanism of this is not well understood it
probably involves CD4+ T cells. A delayed reaction time (sometimes also referred to as a ‘late’
reaction) describes a delayed elicitation response following antigenic challenge in persons who are
already sensitized. There has been confusion over the use of this term, as it has been used not only
to describe reactions that have taken more than the usual 4 days to develop, but also acute primary
sensitization reactions which, in normal clinical practice, often present as more sudden and fl orid
reactions around 21 days after challenge. A delayed reaction time is found with low degrees of
sensitivity (when there are very few memory T cells), following exposures to small amounts of
allergen (when it takes longer to augment the T‐cell response) and in situations of delayed
penetration of allergens (e.g. neomycin in petrolatum).
Pemeriksaan Penunjang

Therapy

Prognoses