REVIEW

Nonimmediate Allergic Reactions Induced

by Drugs: Pathogenesis and Diagnostic
Tests
MJ Torres,1 C Mayorga,2 M Blanca1
1
2

Allergy Service, Carlos Haya Hospital, Mlaga, Spain

Research Laboratory for Allergic Diseases, Fundacin IMABIS-Carlos Haya Hospital, Mlaga, Spain

Abstract
Nonimmediate allergic reactions (NIRs) to drugs, which are the most common reactions induced by specific immunologic mechanisms,
can be induced by all commercially available drugs. NIRs can appear hours, days, or even weeks after drug intake. They elicit a spectrum
of manifestations, mostly affecting the skin, ranging from maculopapular exanthema and urticaria to other less common but more severe
entities such as acute generalized exanthematic pustulosis, drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity
syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The main pathologic event involved in NIRs is a T-cell effector
response and the wide heterogeneity of clinical symptoms may reflect differences in the underlying immunologic mechanisms. Despite their
clinical heterogeneity, NIRs share certain aspects such as the activation of T cells with increased expression of CD25 and HLA-DR. NIRs are
classified as type 1 helper (TH1) T-cell responses, characterized by the production of interferon-, tumor necrosis factor-, interleukin 2,
T-bet, and the cytotoxic markers perforin and granzyme B. Diagnosis is often complicated because of the difficulty of obtaining a reliable
clinical history, the important role played by cofactors such as viral diseases, and the low sensitivity of skin tests and in vitro tests. Further
studies are thus required in order to improve our understanding of NIRs and refine our diagnostic criteria.
Key words: Nonimmediate. Allergy. Drugs. Pathogenesis. T cells. Diagnosis.

Resumen
Las reacciones alrgicas no inmediatas (RNI) frente a frmacos, que son las reacciones ms comunes inducidas por mecanismos
inmunolgicos especficos, pueden desencadenarse por todos los frmacos disponibles en el mercado. Las RNI pueden aparecer horas,
das o incluso semanas despus de la toma del frmaco. Provocan un espectro de manifestaciones, la mayora de ellas afectando a la
piel, que abarcan desde el exantema maculopapular y la urticaria a otras entidades menos frecuentes pero ms graves como la pustulosis
aguda exantemtica generalizada, exantema por frmacos con eosinofilia y sntomas sistmicos /sndrome de hipersensibilidad inducida
por frmacos, Sndrome de Stevens-Johnson, y la necrolisis epidrmica txica. El principal evento patolgico implicado en las RNIs es
la respuesta T efectora y la amplia heterognea de sntomas clnicos podra reflejar las diferencias en los mecanismos inmunolgicos
subyacentes. A pesar de la heterognea clnica, las RNIs comparten ciertos aspectos como la activacin de las clulas T con aumento
de la expresin de CD25 y HLA-DR. Las RNIs se clasifican en respuestas de clula T de tipo 1 colaborador (TC1), caracterizadas por la
produccin de interfern-, el factor de necrosis tumoral-, interleucina 2, el T-bet, y los marcadores citotxicos perforina y granzima B.
El diagnstico con frecuencia es complicado por la dificultad en la obtencin de una historia clnica fiable, el importante papel jugado
por cofactores como las enfermedades virales, y la baja sensibilidad de las pruebas cutneas y pruebas in vitro. Son necesarios estudios
adicionales para mejorar nuestra comprensin de las RNIs y refinar nuestros criterios diagnsticos.
Palabras clave: Reaccin no inmediata. Alergia. Frmacos. Patognesis. Clulas T. Diagnstico.

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81

Introduction
An adverse drug reaction is defined by the World Health
Organization as a response to a medicine which is noxious
and unintended, and which occurs at doses normally used in
man for the prophylaxis, diagnosis or therapy of disease, or
for the modification of physiological function [1]. Adverse
drug reactions are usually classified as type A if they are
predictable and related to the pharmacologic actions of a drug,
and type B if they are unpredictable and not usually related
to the pharmacologic actions of a drug [2]. Type A reactions
are most common and account for approximately 80% of all
adverse reactions. Immune-mediated adverse drug reactions,
also known as allergic drug reactions or drug hypersensitivity
reactions, account for approximately one seventh of all adverse
drug reactions and belong to the type-B category [3].
Allergic reactions can be produced by any of the 4
immunologic mechanisms proposed by Gell and Coombs [4].
Type I reactions, also called immediate-type reactions, occur
within less than an hour of drug administration and are
mediated by drug-specific immunoglobulin (Ig) E antibodies.
Typical clinical manifestations are urticaria and anaphylaxis.
Type II (cytotoxic) and type III (immune complex) reactions

are mediated by drug-specific IgG or IgM antibodies and are

less common. Finally, type IV reactions are mediated primarily
by T cells; they are also known as delayed hypersensitivity
reactions as they typically occur between an hour and several
days after drug intake. Delayed hypersensitivity reactions to
drugs have proven to be more complex than Gell and Coombs
first believed as they are now also categorized according to
cytokine patterns and the preferential activation of different
immunocytes.
Clinically, allergic reactions to drugs can be classified as
immediate, accelerated, or delayed, depending on the time
between drug intake and occurrence. Although this classification
was developed by Levine [6] on the basis of his experience with
penicillin allergy, it can be applied to all types of drug allergies.
A working classification for clinical use divides reactions into
immediate and nonimmediate reactions (NIRs) (ie, accelerated
or delayed reactions). Immediate reactions appear within an
hour, and often within just a few minutes, of drug intake and
their main clinical manifestations are urticaria/angioedema
and/or anaphylaxis [7]. NIRs can occur within hours, days, or
even weeks of drug intake and are characterized by a wide range
of clinical manifestations. In this review, we examine the latest
information published on NIRs.

Figure 1. A, maculopapular exanthema induced by metamizole. B, fixed drug eruption induced by a quinolone. C, bullous reaction in
Stevens-Johnson Syndrome induced by tetrazepam. D, toxic epidermal necrolysis induced by an anticonvulsant.

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Nonimmediate Reactions to Drugs

Clinical Manifestations

Classification

82

EM

SJS

SJS-TEN

TEN

The skin is the most frequently involved target

<10%
<10%
10%-30%
>30%
Skin detachment
organ in NIRs, which produce clinical manifestations
ranging from maculopapular exanthema (MPE), the
Yes
No
No
No
Typical lesions
most frequent type of drug eruption, to urticaria and
other less common but more severe entities such as
acute generalized exanthematic pustulosis (AGEP),
Classification
High
Flat
Flat
Flat
drug rash with eosinophilia and systemic symptoms
(DRESS)/drug-induced hypersensitivity syndrome
(DIHS), Stevens-Johnson syndrome (SJS), and
Virus
toxic epidermal necrolysis (TEN) [8]. Erythema
Drugs
multiforme and fixed drug eruption are less common
manifestations [8]. Drug-induced contact dermatitis is
an occupational hazard, often affecting pharmaceutical Figure 2. Classification of bullous exanthemas. The less severe the reaction, the more
and healthcare workers [9], and serum sickness- likely it is to be induced by a virus. EM indicates erythema multiforme; SJS, Stevenslike reactions have been reported, mostly with Johnson Syndrome; TEN, toxic epidermal necrolysis.
betalactams [10]. Other clinical entities have also been
described, including the baboon syndrome, an erythematous
reaction that affects the buttocks, inner thighs, and axillae [11].
the long interval between drug intake and the onset of clinical
It can sometimes be difficult to identify NIRs because of the
symptoms, particularly in patients taking many drugs at the
wide spectrum of clinical manifestations and the fact that
same time.
these can be quite similar to those caused by infectious or
Several studies have reported the relevance of
autoimmune diseases. Figure 1 shows some typical clinical
aminopenicillins in the development of MPE and urticaria in
manifestations of NIRs.
patients with mild or moderate reactions [7]. Although less
The most common entities associated with NIRs are
frequent, these types of reactions have also been described
benign diseases such as exanthematic reactions and MPE,
for other drugs such as anticonvulsants [14], systemic
followed to a lesser extent by urticaria. When retrospectivecorticosteroids [15], and iodinated contrast media [16].
only information is available, it can sometimes be difficult to
Investigations of the drugs responsible for severe reactions
distinguish between different reactions, even in the presence
such as SJS and TEN have shown high relative risks for
of angioedema because certain severe exanthematic reactions
anti-infective sulfonamides (especially cotrimoxazole),
involve swelling. MPE can sometimes be intense, appear in
carbamazepine, phenytoin, phenobarbital, nonsteroidal
conjunction with subcutaneous edema, and persist for several
antiinflammatory drugs of the oxicam type, allopurinol,
weeks despite discontinuation of treatment.
chlormezanone, aminopenicillins, cephalosporins, quinolones,
DRESS/DIHS and bullous reactions with mucosal
and tetracycline antibiotics [17]. There have also been reports
involvement are considered severe diseases. Erythema
of strong associations in more recently launched drugs such
multiforme, which is less severe, is usually induced by a
as nevirapine and lamotrigine [18].
virus and characterized by the presence of typical target
lesions (Figure 2). SJS and TEN are the most severe type
of hypersensitivity reactions affecting the skin and are
Immunopathologic Mechanisms
characterized by extensive epidermal detachment and mucous
membrane erosion. In general, the more severe the reaction,
The wide heterogeneity of clinical manifestations found in
the greater the likelihood that the reaction has been induced
NIRs cannot be fully explained by the mechanisms described
by a drug. There is growing evidence that SJS and TEN are a
for type IV reactions by Gell and Coombs [4]. One attempt
single disease with common causes and mechanisms; the main
to explain these mechanisms involved subdividing T-cell
difference appears to lie in the extent of detachment, which
responses into 4 different types [5]: a) type IVa responses,
is limited (<10%) in the case of SJS and more widespread
for which T cells produce interferon (IFN)--activated
(>30%) in that of TEN (Figure 2) [12]. While rare (2 cases/
macrophages, whose typical clinical manifestation is eczema;
million population/year), SJS and TEN have high mortality
b) type IVb responses, mediated by T cells producing type 2
(20%-25%) [13].
helper (TH2) cytokines (interleukin (IL) 4 and IL 5, which in
turn induce B cells to produce antibodies and mast cell and
eosinophil responses, mainly in DRESS, MPE, and bullous
Drug Involvement
exanthema; c) type IVc responses, induced by CD4+ and
CD8+ T cells, which produce cytotoxic mediators that result
The true prevalence of NIRs is unknown, especially in
in keratinocyte apoptosis in MPE and massive apoptosis in
less severe reactions, for different reasons including confusion
TEN; and d) type IVd responses, characterized by neutrophil
with viral and autoimmune diseases. Moreover, linking
activation and recruitment induced by T cells via the production
symptoms to a particular drug can also be difficult because of
of a chemokine, CXCL8, whose typical clinical manifestation

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MJ Torres, et al

is AGEP. The basis of this classification system is that immune

cells other than T cells (neutrophils, eosinophils, macrophages,
and keratinocytes) are involved in type IV reactions. However,
this differentiation of responses into fixed compartments does
not clarify the situation since the same clinical manifestations
may occur in 2 different subtypes.
It has been proposed that drug-protein conjugates might
be processed and presented by antigen-presenting cells to
naive T cells after drug intake, inducing tolerance or effector
responses such as hypersensitivity reactions [19]. In the case of
hypersensitivity, the immune system develops either immediate
TH2-type responses, mediated by specific IgE antibodies, or
non-immediate TH1-type responses, mediated by specific
T cells. Most information available on NIRs concerns the
specific effector immune response mediated by T cells, but
little is known about the initial steps mediated by the innate
immune system, served mainly by dendritic cells.

The Role of T cells in NIRs

The involvement of T cells in NIRs has been demonstrated;
not only do they prime the immunologic response by interacting
with dendritic cells, but they also act as effector cells inducing
tissue damage and inflammation [20].
One way of improving understanding of the pathologic
mechanisms underlying NIRs is to monitor acute response
by obtaining sequential samples (from blood, blister fluid,
and skin) during reactions. Such an approach has shown that
despite the clinical heterogeneity of NIRs, these reactions share
common aspects such as the activation of T cells with increased
expression of CD25 and HLA-DR [14]. As mentioned earlier,
the skin is the target organ of most NIRs; in such cases, the
T cells can express homing receptors such as the cutaneous
lymphocyte antigen (CLA) and chemokine receptors such as
CCR6 and CCR10 [21-24], which is found in higher levels in
more severe reactions such as SJS and TEN [23]. The above
markers have been detected simultaneously in both peripheral
blood and skin, in contrast to their chemokine ligands, CCL20
and CCL27, which have only been found in increased levels
in the skin [24], demonstrating that cell trafficking of the
T-cell subpopulation to cutaneous sites of inflammation takes
place [14,21-24].
NIRs have been commonly defined as TH1 reactions,
involving the production of IFN-, tumor necrosis factor
(TNF)-, IL 2, T-bet (a TH1 transcription factor) [25,26],
and the cytotoxic markers, perforin and granzyme B [26,27].
Several studies have found that the levels of these markers
vary according to clinical symptoms [14,25-27]. In 1 study,
a detailed analysis of the skin-homing CLA showed that this
antigen was increased in MPE compared to SJS/TEN, probably
because CLA cells are mainly located in the dermis in MPE
reactions whereas in SJS/TEN reactions, they migrate to
the epidermis and blisters, where there is severe destruction
leading to the loss of these cells [14]. Other studies have
reported a higher production of TH1 cytokines (IFN- and
TNF-), T-bet, and certain cytotoxic markers in more severe
reactions such as those seen in SJS/TEN [26,27], evidencing
a correlation with clinical severity.

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Another important difference between the different

clinical entities associated with NIRs is the subpopulation of
cells that participate in the reaction as effector cells. While
several authors have shown that CD4+ and CD8+ T cells are
involved in MPE and bullous exanthema, respectively [2830], others have reported that both types of cells may be
involved in SJS/TEN (CD4 cells in the dermis and CD8 cells
in the epidermis) [21,30-34]. Our group has found increased
CD4 cell levels in both the skin and peripheral blood in
SJS/TEN and to a lesser extent in MPE [14,16,21,22].
There may be several reasons for these differences but the
compartment evaluated is likely to have had a considerable
influence. The majority of studies in SJS/TEN have been
undertaken in skin and blister fluid, where it is more likely
to find cytotoxic cells expressing CD8+ T cells. Peripheral
blood mononuclear cells and the dermis, in contrast, are
predominantly composed of CD4+ T cells [35,36]. Recent
studies have also demonstrated the involvement of these
cells in increased cell counts in peripheral blood and skin
and in the increased production of cytokines, chemokines,
and cytotoxic markers [24,26].
As already described, T cells act as direct effector cells
by producing the cytotoxic mediators, perforin and granzyme
B, which induce death in target cells. They also play another
important role in NIRs by acting as chemoattractants
and activators of other immune cells such as neutrophils,
eosinophils, and keratinocytes. This is the case of AGEP,
a NIR characterized by the presence of sterile pustules on
an erythematous base and increased neutrophils. Several
studies have shown that T cells are specifically activated by
culprit drugs, as demonstrated by their specific proliferative
response. Moreover, they produce the neutrophil-attracting
chemokine IL 8, which may contribute to the accumulation of
polymorphonuclear neutrophils at the site of the lesion [37,38].
In MPE and DRESS/DHIS, skin-infiltrating T cells are able
to produce IL 5 and eotaxin (CCL-11). This is of particular
importance since these markers are both known to be key
factors in the regulation of the growth, differentiation, and
activation of eosinophils, which may be increased in such
reactions and contribute to the generation of tissue damage
through the release of various toxic granule proteins [39].
T cells can also activate epidermal keratinocytes, inducing
the massive apoptosis of these cells in TEN through 2 main
mechanisms: the perforin/granzyme B mechanism and the Fas/
Fas ligand (FasL) mechanism. Recent studies have shown that
apart from acting as target cells in TEN, keratinocytes may
also be cytolytically active [36,40]. If this were the case, the
recruited memory CD4+ and CD8+ T cells expressing CLA and
CCR10 in the skin would produce IFN-, inducing keratinocyte
activation to produce TNF- and FasL and trigger apoptosis.
Moreover, the production of TNF- would increase the
expression of MHC class I antigens in keratinocytes, making
them more sensitive to cytotoxic cells producing perforin and
granzyme B [14,21,23,24].
These data suggest that the final phenotype of drug
eruptions results from the nature of cytotoxic effector
T cells in MPE and bullous eruptions, and T cells releasing
specific chemokines for reactions mediated by neutrophils or
eosinophils (Figure 3).

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Nonimmediate Reactions to Drugs

Neutrophils

Inflammation

84

Blister

Pustule

Keratinocyte
death
Perforine,
Granzyme

Perforine
Granzyme
CXCL9
CXCL10
CCL20
CCL27

Lymphocytes
Eotaxin
RANTES
T cell migration
CXCR3
IFN
CLA
TNF
CCR6
Perforine
CCR10 Granzyme B

2nd
Neutrophil
migration

CXCLS

Keratinocyte
apoptosis

Perforin
Granzyme

Fas-FasL
interaction

Lymphocytes

1st
Lymphocyte
migration

Lymphocyte
migration

Eosinophil

CD4+ T cells

MPE

AGEP

SJS/TEN

Figure 3. Immunopathologic mechanisms involved in maculopapular exanthema (MPE), acute generalized exanthematous pustulosis (AGEP), and StevensJohnson syndrome/toxic epidermal necrolysis (SJS/TEN). CLA indicates cutaneous lymphocyte-associated antigen; TNF, tumor necrosis factor.

The Role of Dendritic cells in NIRs

Most information about T cellmediated drug reactions
concerns specific effector immune responses and the role of
drugs in generating interactions with specific T cells, either
directly or via drug metabolism and haptenation [41,42].
Little information, however, is available about the initial steps
mediated, mainly through dendritic cells, by the innate immune
system. Dendritic cells are professional antigen-presenting cells
that play a crucial role in the initiation of T-cell responses [43].
Their abilities are regulated in a process known as maturation,
during which they modulate the tolerant or effector immune
responses mediated by different subtypes of T cells [44]. While
immature and semimature dendritic cellswhich are highly
endocytic but poorly effective as antigen-presenting cells
have been associated with tolerant immunologic responses,
mature dendritic cells, which have no endocytic capacity,
migrate to the lymph nodes and efficiently present previously
captured and processed antigens to the T cells, which induce
effector responses. This concept, which is a key factor in the
discrimination of self-antigens or innocuous molecules from
pathogenic molecules, seems to be more complex, and other
factors are probably involved [19].
It is believed that a danger signal is required to trigger a
pathologic response in which the hapten-carrier is recognized
by the immune system and antibodies or T cells are
generated. Different types of danger signals exist, including
exogenous signalsrelated to infectious pathogens, also
called pathogen-associated-molecule patterns (PAMPS),
bacterial and viral genomes, flagellins, and endotoxins
such as lipopolysaccharide [44]and endogenous signals
such as TNF- and IL 1 [45,46]. These molecules interact

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with dendritic cells via a Toll-like receptor [47], inducing

the activation of a signaling cascade with the participation
of mitogen-activated protein kinases [48]. This dendritic
cell maturation process produces a series of cytokines and
chemokines that modulate a TH1 or TH2 response appropriate
to the danger signal induced.
A number of findings support the role of dendritic cells in
the response to haptens [48-50]. Contact dermatitis, a delayedtype hypersensitivity reaction to low-molecular-weight
compounds such as nickel is the best-studied model [51]. The
hapten by itself is able to produce a maturative state in dendritic
cells that induces a specific T-cell response [48,51]. This is the
case of sulfamethoxazole and its reactive metabolite nitroso
sulfamethoxazole, which have been shown to be associated
with the generation of the costimulatory signals required to
initiate a primary immune response [52].
Moreover, our group has studied the role of dendritic
cells in the generation and modulation of pathologic
T cellmediated NIRs to drugs and demonstrated that haptens
such as amoxicillin and heparins can induce changes in the
maturational status of dendritic cells, generating a specific
proliferative response in T cells in allergic patients but not
in tolerant controls [53,54]. These results suggest that certain
drugs may act not only as a target antigen for the immune
response in particular but also as a stimulus for dendritic cell
maturation. Another possible explanation for the generation
of effector responses to drugs is that the interaction with
dendritic cells occurs in maturational conditions. This
maturation could be caused by concomitant factors such
as the presence of exogenous signals such as PAMPS or of
endogenous signals, with cytokines such as TNF- induced
by an inflammatory process.

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MJ Torres, et al

Role of Viral Infection in NIRs

patients with infectious mononucleosis, an acute disease

induced by EBV [60]. Exanthema occurs in 5% to 13% of
patients with infectious mononucleosis, but this rate increases
considerably in those receiving ampicillin (29%-69% of adults
and up to 100% of children) [61]. Although some authors have
reported that this is not a true sensitization [56,62], others
have shown true immunologic sensitization by skin testing
and the lymphocyte transformation test (LTT). Moreover,
the response is not transient [63,64]. Several reports have
shown an association between a high frequency of SJS and
TEN in patients with HIV and early reactivation of EBV and
cross-reactivity with drugs [60]. The best studied drug-allergy
reaction associated with viral infection, however, is DRESS/
DIHS, which has been linked to the reactivation of HHV-6
[65-67]. The clinical symptoms of this disease often resemble
those induced by cutaneous viral infections. Some authors
have shown that the slow resolution of DRESS/DIHS is due to
HHV-6 reactivation [68], favored by hypogammaglobulinemia,
which can occur during treatment with certain drugs such as
anticonvulsants [69]. This suggests that anticonvulsants may
not only activate cytotoxic T cells involved in the allergic

NIRs can also occur as the result of interaction between

a particular drug and different factors. A key factor is
the underlying disease, especially in the case of viral
infections. Several viruses have been related to allergic
reactions to drugs, including human herpes virus 6 (HHV-6),
cytomegalovirus, Epstein-Barr virus (EBV) and, more recently,
paramyxovirus.
Viruses can interact with the immune system at several
points: during drug metabolism, during the presentation of
a drug to lymphocytes by dendritic cells, and during the
production of cytokine and chemokine in the effector response
(Figure 4) [55,56]. Conserved microbial products which
interact with pattern-recognition receptors such as Toll-like
receptors can induce the maturation of dendritic cells, and this
may be of relevance to the increased risk of hypersensitivity
reactions associated with viral infections such as EBV, HHV,
and HIV [57-59].
The drug-induced clinical entity most often associated
with viral infections is ampicillin-induced exanthema in

VIRUS

Drug

Metabolizing
enzymes

Drug
metabolites

Inflammation

Perforin
Granzyme

DC maturation

Gradient

VIRUS
Immature
DC
Mature
DC

Mature
DC

T cell
migration

Chemokine
production

IL-12
IL-4

VIRUS

IL10
Cytokine
production

VIRUS

T cells
Figure 4. Virus-immune system interaction points in allergic reactions to drugs. DC indicates dendritic cell; IL, interleukin.

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Nonimmediate Reactions to Drugs

86

Figure 5. Positive delayed-reading intradermal test results for radiocontrast media (A) and aminopenicillins (C). Positive patch test results for anticonvulsants
(B) and tetrazepam (D).

reaction to these drugs but also induce immunosuppression

that might also promote virus reactivation, thus delaying
resolution.
The cooperative role between viruses and drugs in the
induction of NIRs is unclear. Our group has demonstrated
that amoxicillin induces changes in the maturational status of
dendritic cells towards semimature dendritic cells, producing
specific T-cell proliferation [53]. The fact that patients may
have a confirmed NIR but a negative LTT to a particular drug
might be due to the absence of concomitant viral stimulation,
which has been shown to induce fully mature dendritic cells.
Preliminary studies with drugs and a Toll-like receptor agonist
have shown an increase in dendritic cell maturation and a
positive LTT response only in patients with drug-induced MPE
and an infectious disease (data not published). This indicates
that both elements might be necessary in order to mimic the
immunologic mechanisms involved in the in vivo reaction.
Furthermore, viral infections can induce skin symptoms
similar to those produced in drug allergy reactions, an
important factor when establishing a differential diagnosis,

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especially in children. On comparing viral-induced and druginduced exanthematic reactions in children, our group found a
higher expression of the homing receptor CLA and activation
marker CD69, as well as a TH1 cytokine pattern in children
with drug-induced reactions [70]. Children with viral reactions,
in contrast, had a nondefined cytokine pattern.

Diagnosis
A common feature of NIRs is that symptoms appear 24
to 48 hours after drug intake, although they may occasionally
appear after a few hours and in some cases even after several
days. Because of the wide variety of possible clinical entities,
the clinical history does not always provide a well-defined
description of the past episode. The time of onset of symptoms
and their severity are factors to be taken into account, not
only in the evaluation of NIRs but also in the determination
of diagnostic tests required.
Difficulties in diagnosis reside in the lack of sensitivity of

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MJ Torres, et al

currently available tests, the absence of cofactors that may have

been present at the time of the reaction, and the possibility that
symptoms were not immunologically mediated. The different
diagnostic methods currently available are described below.
Skin Tests
The diagnostic value of skin testing has not been fully
evaluated and experiences in different centres are rarely shared.
Reliable skin test procedures for the diagnosis of NIRs are
thus generally lacking and test concentrations are unknown or
poorly validated for most drugs. Delayed-reading intradermal
and/or patch tests have been used for many years. The main
advantage of drug patch tests is that they can be performed with
any commercially available drug form. While intradermal tests
are more sensitive, they need to be performed with an injectable
form or a pure, sterile preparation of the drug (Figure 5).
Both intradermal and patch tests have been widely used in
the diagnosis of NIRs to betalactams, with reported sensitivity
ranging from 2.6% (positive responses to patch tests in 8
of 298 patients tested with phenoxymethyl penicillin) [71]
to 37.8% (positive responses to patch tests and/or delayedreading intradermal tests with penicillins in 98 of 259
patients) [72]. New evidence seems to indicate that skin test
sensitivity is lower than previously believed. A recent study
that prospectively evaluated 22 patients with confirmed MPE
or urticarial exanthema due to betalactam intake found that only
2 (9%) had a positive delayed-reading intradermal/patch test
despite confirmation of the reproducibility of the reaction by
a drug provocation test [73]. Similar results have been found
in children [74]. This indicates that the sensitivity of skin
testing is lower than previously thought, at least in patients
with exanthematic reactions to betalactams, although it may
be higher in more severe reactions such as desquamative
exanthemas.
Similar results have been detected for other drugs. In a group
of 21 patients with NIRs to systemic corticosteroids confirmed
by drug provocation testing, for example, just 2 patients had
a positive patch and intradermal test [15]. Patch testing was
recently seen to be useful for the diagnosis of exanthema
induced by cardiovascular or antiepileptic drugs (positive patch
test results in 10 [4%] of 247 patients for amoxicillin and in 6
[3.9%] of 152 patients for benzylpenicillin) [71].

Of all the drugs suspected to cause NIRs, betalactams have

been studied most extensively. Most patients that develop
an exanthematic reaction after betalactam administration
and have negative skin tests tolerate drug provocation tests
well [71-74,76,77]. In a study by Romano et al [72], only 3
(2.5%) of 117 subjects reacted to drug provocation testing
with suspect penicillins. Nonetheless, some patients with clear
NIRs are diagnosed by a positive drug provocation test. In a
study by Padial et al [73], only 2 (9%) of 22 adult patients
with exanthematic reactions to betalactams diagnosed by drug
provocation testing had a positive delayed-reading intradermal
skin test. Similar results were recently found in 20 children
with exanthematic reactions and positive drug provocation
tests (only 1 positive skin test) [74]. This indicates that drug
provocation testing is the most important diagnostic tool in the
particular case of exanthematic reactions to betalactams.
In-Vitro Diagnostic Tests: The Lymphocyte
Transformation Test
The LTT, which is based on the principle that T cells can
proliferate in the presence of a specific antigen, has been the
most widely used test over the last 30 years to detect T-cell
sensitization to a drug in vitro. The usefulness of this test in
the diagnosis of NIRs, however, has been debated. Reports
published to date have been characterized by small series,
a wide range of drugs and clinical entities, sensitivity rates
of 60% to 70% and rather low specificity (85%) [78-80].
Furthermore, this test is not available everywhere and is still
considered a research tool.
In a study by our group, 57% of patients with a NIR to
betalactams had a positive LTT to at least one of the penicillins
tested [80]. We detected diverse response patterns and certain
patients with selective in vivo responses to amoxicillin
responded in vitro to benzylpenicillin and/or amoxicillin, even
though they tolerated benzylpenicillin.
A recent study analyzing the role of dendritic cells in the
enhancement of amoxicillin-specific lymphocyte proliferation
in patients with NIRs to amoxicillin showed that compared to
traditional antigen-presenting cells such as B cells or monocytes,
dendritic cells improved LTT sensitivity [53]. Similar results
have been obtained for NIRs to heparins [54].
Immunohistochemistry

Drug Provocation Tests

Because intradermal or patch testing often has insufficient
sensitivity in patients with NIRs, a large proportion of patients
need to be given the drug to establish a diagnosis or, perhaps
more often, to confirm tolerance. Drug provocation testing
is the best tool with which to confirm a causal relationship
between drug administration and a NIR. It involves the
careful administration of a suspect agent in a specialized
centre and close monitoring for symptoms, in particular skin
manifestations [75]. Drug provocation testing, however, is
not generally recommended and is actually contraindicated in
some cases such as generalized bullous fixed drug eruptions,
AGEP, SJS, TEN, DRESS/DIHS, systemic vasculitis, specificorgan manifestations (blood-cytopenia, hepatitis, nephritis,
pneumonitis) and drug-induced autoimmune diseases [76].

J Investig Allergol Clin Immunol 2009; Vol. 19(2): 80-90

NIRs usually affect the skin, which is an easily accessible

organ for biopsy. Samples can be taken from the acute reaction
site or from tissue that has yielded a positive drug provocation
or skin test result. While immunohistochemistry findings help
in the investigation of underlying immunologic mechanisms,
they do not provide information about the drug involved or
discriminate between different types of reactions. The most
common finding is a mononuclear cell infiltrate composed
mainly of activated T cells expressing DR antigens, CD69
activation markers, and the skin-homing receptor CLA in
both CD4+ and CD8+ T cells (with a general predominance
of CD4+ cells) [14].
There are, however, a number of differences between mild
and severe reactions. In MPE, for example, a predominant
perivascular mononuclear cell infiltrate with increased numbers

2009 Esmon Publicidad

Nonimmediate Reactions to Drugs

of eosinophils in the papillary dermis has been found, with

up to 20% of the cells expressing perforin and granzyme B
and enhanced IL 12 expression [81]. SJS/TEN, in contrast,
is characterized by the presence of many dead keratinocytes
with minimum T-cell infiltration, probably due to the loss of
superficial skin layers [81]. In AGEP, keratinocytes express
high levels of IL 8, a chemokine that recruits neutrophils to
the epidermis.

11.
12.

13.

Conclusions
NIRs to drugs are the most common hypersensitivity
reactions and can be induced by all commercially available
drugs. The reactions cause a wide heterogeneity of clinical
symptoms, reflecting differences in the immunologic
mechanisms involved. A T-cell effector response is the main
pathologic event. Diagnosis is often complex because of the
difficulty in obtaining a reliable clinical history, the importance
of concomitant factors such as viral diseases, and the low
sensitivity of skin tests and in vitro tests. More studies are
needed in order to improve our understanding of NIRs and
refine our diagnostic criteria.

14.

15.

16.

Funding Sources
FIS grant network RIRAAF (RD07/0064) from the Spanish
Government.

17.

18.

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Maria Jose Torres Jan

Allergy Service, Hospital Civil
Plaza Hospital Civil s/n
29009 Malaga, Spain
[email protected]

J Investig Allergol Clin Immunol 2009; Vol. 19(2): 80-90