|
Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 14, Number 27, 2008
Contents
Advances in Diagnosing Drug Hypersensitivity
Reactions
Executive Editors: A. Romano and M. Ventura
Editorial: Pp.
2767-2769
Pharmacogenetic Determinants of Immediate and Delayed Reactions
of Drug Hypersensitivity Pp. 2770-2777
J.L. Guéant, R.M. Guéant-Rodriguez, I.A. Gastin,
J.A. Cornejo-García, M. Viola, A. Barbaud, P.M. Mertes,
M. Blanca and A. Romano
[Abstract] [Purchase
Article]
Skin Tests in the Diagnosis of Drug Hypersensitivity
Reactions Pp. 2778-2791
K. Brockow and A. Romano
[Abstract] [Purchase
Article]
Provocation Tests in Diagnosing Drug Hypersensitivity
Pp. 2792-2802
P.-J. Bousquet, F. Gaeta, L. Bousquet-Rouanet, J.-Y. Lefrant,
P. Demoly and A. Romano
[Abstract] [Purchase
Article]
Cellular Tests in the Diagnosis of Drug Hypersensitivity
Pp. 2803-2808
M.L. Sanz, P.M. Gamboa and A.L. De Weck
[Abstract] [Purchase
Article]
Hypersensitivity Reactions to Neuromuscular Blocking
Agents Pp. 2809-2825
P.M. Mertes, I. Aimone-Gastin, R.M. Guéant-Rodriguez,
C. Mouton-Faivre, G. Audibert, J. O’Brien, D. Frendt,
M. Brezeanu, H. Bouaziz and J.L. Guéant
[Abstract] [Purchase
Article]
Cross-Reactive Reactions to Nonsteroidal Anti-Inflammatory
Drugs Pp. 2826-2832
M. Viola, D. Quaratino, F. Gaeta, G. Rumi, C. Caruso and
A. Romano
[Abstract] [Purchase
Article]
Allergic and Photoallergic Contact Dermatitis
from Ketoprofen: Evaluation of Cross-Reactivities by a Combination
of Photopatch Testing and Computerized Conformational Analysis
Pp. 2833-2439
C. Foti, D. Bonamonte, A. Conserva, L. Stingeni, P. Lisi,
N. Lionetti, L. Rigano and G. Angelini
[Abstract] [Purchase
Article]
Macrolides Allergy Pp. 2840-2862
L. Araújo and P. Demoly
[Abstract] [Purchase
Article]
Hypersensitivity Reactions to Anticoagulant Drugs
Pp. 2863-2873
K. Scherer, D.A. Tsakiris and A.J. Bircher
[Abstract] [Purchase
Article]
Hypersensitivity to Lamotrigine and Nonaromatic Anticonvulsant
Drugs: A Review Pp. 2874-2882
F. Gaeta, C. Alonzi, R.L. Valluzzi, M. Viola, M. Elia
and A. Romano
[Abstract] [Purchase
Article]
Hypersensitivity Reactions to Last Generation Chimeric,
Umanized and Human Recombinant Monoclonal Antibodies for Therapeutic
Use Pp. 2883-2891
G. Calogiuri, M.T. Ventura, L. Mason, Á. Valacca,
R. Buquicchio, N. Cassano and G.A. Vena
[Abstract] [Purchase
Article]
Hypersensitivity to Antineoplastic Agents
Pp. 2892-2901
M.C. Castells
[Abstract] [Purchase
Article]
Antiinflammatory Effects of H1-Antihistamines:
Clinical and Immunological Relevance Pp. 2902-2911
G.A. Vena, N. Cassano, R. Buquicchio and M.T. Ventura
[Abstract] [Purchase
Article]
Abstracts
[Back to top]
Editorial: Advances in Diagnosing Drug Hypersensitivity
Reactions
Like the previous one published in 2006 [1], this
volume addresses literature regarding the pathogenic mechanisms,
diagnosis, and prevention of drug hypersensitivity reactions,
in order to improve the management of a problem in constant
evolution. Specifically, the present issue provides an update
on the main diagnostic methods of such reactions and supplements
the information of the previous volume [1], discussing some
topics, such as hypersensitivity reactions to biologic agents,
nonaromatic anticonvulsants, macrolide antibiotics, anticoagulants,
and antineoplastic drugs, not included in the latter.
Also like the previous one [1], the present volume often refers
to the general guidelines for diagnosing drug hypersensitivity
reactions devised by the European Network for Drug Allergy
(ENDA), the European Academy of Allergology and Clinical Immunology
interest group on drug hypersensitivity; it contains articles
by researchers and clinicians belonging to the ENDA and to
the American Academy of Allergy, Asthma and Immunology Committee
on Adverse Reactions to Drugs and Biologicals.
In preparing this volume, we have taken into account the needs
of readers who wish to keep abreast of the latest developments
regarding hypersensitivity reactions to drugs, particularly
those concerning their diagnosis and prevention.
In the first article, Guéant and coworkers [2] focus
their attention on the genetic risk factors of hypersensitivity
reactions to drugs such as β-lactams,
carbamazepine, and abacavir. Most studies regard HLA haplotype
association, single nucleotide polymorphisms, or polymorphisms
in genes encoding drug-metabolizing enzymes. With regard to
β-lactams,
the genetic factors involved in IgE-mediated mechanisms appear
to be connected with TNFA –308G>A, class switching
to IgE by B cells (variants of IL13 and of IL4RA), and expression
of IgE receptors on target cells (variant of the FcεRIβ
gene). As far as delayed T-cell-mediated reactions to drugs
are concerned, an association of HLA-B*1502 and HLA-B*5801
has been observed in patients with Stevens-Johnson syndrome
and toxic epidermal necrolysis connected with carbamazepine
and HLA-B*5701 with abacavir hypersensitivity. HLA-B*5701
seems to be a strong predictor in whites, and the prospective
HLA-B*5701 screening enables HIV patients at risk for abacavir
hypersensitivity reactions to be identified, thus playing
a crucial role in the effective prevention of such reactions.
Carbamazepine hypersensitivity is also influenced by gene
variants of cytochrome P450 enzymes on the generation of reactive
metabolites, while CYP2C9*2 and CYP2C9*3 polymorphisms influence
the bioactivation of sulphamethoxazole in prohapten. The pharmacogenetic
studies on aspirin hypersensitivity have identified distinct
types of predictors, such as HLA genotypes, a polymorphism
in the promoter of the FcεRIα
gene, and variants in genes of enzymes from arachidonic acid
pathway.
The following three articles [3-5] provide data on the main
in vivo and in vitro diagnostic tests. The
review by Brockow and Romano [3] addresses literature data
regarding the diagnosis of drug hypersensitivity reactions
by skin (prick, intradermal) and patch tests. Even though
these tests are the most readily available tools for the evaluation
of drug hypersensitivity reactions, their diagnostic value
for many drugs have not been fully established yet. However,
reliable skin test procedures for the diagnosis of drug hypersensitivity
have been defined, and test concentrations have been validated
for many drugs, such as β-lactams,
neuromuscular blocking agents (NMBAs, or muscle relaxants),
and iodinated contrast media. In many cases, skin tests can
provide information about the culprit drug and the mechanism
involved in certain reactions, and allow the physician to
avoid hazardous provocation tests. Skin tests should be performed
according to the clinical features of hypersensitivity reactions.
In immediate reactions (i.e., occurring within one hour after
the last drug administration), an IgE-mediated mechanism can
be demonstrated by a positive skin prick and/or intradermal
test after 20 minutes, whereas in non-immediate reactions
(i.e., occurring more than one hour after the last drug administration),
a T-cell involvement can be found by a positive patch test
and/or a delayed-reading intradermal test. The predictive
value of skin tests varies with the drug tested and is especially
high with β-lactams
(penicillins, cephalosporins, carbapenems, and monobactams),
NMBAs, insulins, platins, streptokinase, and chymopapain.
For this reason, these tests have also been carried out in
order to identify the patients at risk, such as candidates
for chemonucleolysis with chymopapain, or patients undergoing
sequential therapeutic courses with platins. Moreover, skin
testing with cephalosporins and carbapenems has proved to
be a useful tool for finding safe alternatives in the patients
with a well-demonstrated IgE-mediated hypersensitivity to
penicillins.
The paper by Bousquet and coworkers [4] focuses on drug provocation
tests (DPTs) that are widely considered to be the “gold
standard” for establishing or excluding the diagnosis
of hypersensitivity to a certain drug. In effect, the DPT
not only reproduces hypersensitivity symptoms, but also any
other adverse clinical manifestation, irrespective of the
pathogenic mechanism. This review article provides information
on the indications and contraindications of DPTs, as well
as on the related specific protocols, emphasizing their usefulness
in diagnosing drug hypersensitivity. In effect, a positive
DPT result optimizes allergen avoidance, while a negative
one allows a false label of drug hypersensitivity to be removed.
For these reasons, DPTs are often carried out to exclude a
diagnosis of hypersensitivity to β-lactams,
when other reliable allergologic tests are negative. DPTs
are also performed, when the sensitivity of allergologic tests
for evaluating allergic reactions to certain drugs, such as
non-β-lactam
antibiotics, heparins, glucocorticoids, and nonsteroidal anti-inflammatory
drugs (NSAIDs), is limited. However, the DPT can be harmful
and thus should only be considered after balancing the risk/benefit
ratio in the individual patient.
The paper by Sanz and coworkers [5] emphasizes the usefulness
of the basophil activation test (BAT), which quantifies the
basophil activation by flow cytometry, for evaluating immediate
reactions to many drugs, such as NMBAs, β-lactams,
and NSAIDs, especially pyrazolone derivatives. The BAT seems
to be more sensitive and specific than other in vitro
diagnostic techniques. In effect, this test reproduces hypersensitivity
mechanisms involved in immediate hypersensitivity reactions,
allowing the physician to diagnose both allergic and non-allergic
hypersensitivity reactions to drugs, particularly those for
which serum specific IgE assays are not available. When considering
NMBAs, the BAT sensitivity ranges between 36% and 97.7%, with
specificity around 95%. In evaluating immediate reactions
to β-lactams,
the BAT sensitivity is about 50% and its specificity 90%,
whereas in assessing NSAID hypersensitivity reactions, its
sensitivity varies between 66% and 75%, and specificity is
about 93%. However, this technique needs further validation
by multicenter studies with common protocols. In any case,
the BAT should be considered complementary to skin tests and
serum specific IgE assays. In fact, the combination of the
BAT with the latter tests increases the sensitivity of allergologic
workups, thus reducing the need for drug provocation tests.
The review by Mertes et al. [6] provides both personal
and literature data on hypersensitivity reactions to NMBAs,
the drugs that are most frequently responsible for immediate
hypersensitivity reactions during anesthesia. In particular,
this article analyzes the different pathogenic mechanisms
involved in such reactions. Most hypersensitivity reactions
to NMBAs are IgE-mediated; with regard to non-allergic hypersensitivity
reactions, identified mechanisms correspond to direct histamine
release or interactions with muscarinic and nicotinic receptors.
The latter reactions cannot be clinically distinguished from
IgE-mediated ones. Therefore, any suspected hypersensitivity
reaction must be investigated, using combined pre- and post-operative
testing. In this connection the authors highlight the usefulness
of skin testing with responsible NMBAs, as well as that of
the sepharose radioimmunoassay of serum-specific IgE and the
BAT. In the allergologic work-up, performing allergologic
tests with NMBAs other than the culprit one allow physicians
to identify cross-reactive compounds, as well as safe alternatives.
The paper by Viola et al. [7] addresses literature
data regarding subjects with hypersensitivity reactions to
different NSAIDs (cross-reactors). This pattern of reactivity
is frequently observed among patients with ASA-exacerbated
respiratory diseases, as well as among those with chronic
idiopathic urticaria (CIU). However, acute urticaria and/or
angioedema, as well as mixed reactions – characterized
by urticaria and/or angioedema plus respiratory symptoms (bronchospasm,
cough, rhinorrhea, hoarseness) – may occur in individuals
without underlying risk factors, such as CIU, within a few
minutes and up to 24 hours after ingestion of different NSAIDs.
Although much research has been performed in order to improve
diagnostic methods, there are no fully validated allergologic
tests for evaluating subjects with cross-reactive reactions
to NSAIDs, therefore, the challenge test is considered the
universally accepted standard for establishing or excluding
a diagnosis of NSAID hypersensitivity in such patients. With
regard to their management, culprit drugs should be avoided
by sensitive patients; therapeutic options range from the
administration of alternative drugs – such as weak COX-1
inhibitors (acetaminophen), as well as preferential (nimesulide,
meloxicam) and highly selective (celecoxib, etoricoxib, parecoxib)
COX-2 inhibitors – to desensitization to the culprit
ones, especially in the patients with imperative indications
for ASA.
As far as NSAIDs are concerned, the review by Foti et
al. [8] focuses on the cross-reactivity or co-sensitization
in the patients with allergic contact dermatitis to ketoprofen
(KP). This study aims to identify the substances most frequently
associated with sensitization to KP, and to evaluate, by means
of computerized conformational analysis, whether this association
is due to a cross-allergy or co-sensitization. Patients with
allergic reactions to KP frequently show allergic reactions
to substances with a benzophenone group, such as benzophenone-3,
fenofibrate, amiodarone, tiaprofenic acid and suprofen, and
with fragrance mix. The association of the positivity to KP
and to the last substance is so frequent that it cannot be
considered fortuitous.
The review by Araújo and Demoly [9] provides both personal
and literature data on hypersensitivity reactions to macrolides.
The authors describe about 200 such reactions, showing that
erythromycin, spiramycin, and azithromycin were the most implicated
drugs, and urticaria the most common manifestation. Non-immediate
reactions were more frequent than immediate ones. The underlying
mechanisms of these manifestations remain to be completely
clarified. On the basis of positive responses to patch tests
or lymphocyte transformation tests, a cell-mediated pathogenic
mechanism has been demonstrated in a few non-immediate reactions.
This article also provides data on rare cases of IgE-mediated
reactions, such as anaphylactic shock, urticaria, and angioedema,
which were positive to skin tests and/or serum specific IgE
assays. Cross-reactivity among macrolides has been reported,
particularly between spiramycin and erythromycin. However,
further studies in large samples of subjects with macrolide
hypersensitivity are needed, in order to better evaluate this
phenomenon. Because of the poor sensitivity of both skin tests
and patch tests with macrolides observed in many studies,
the authors highlight the crucial role of drug provocation
tests in the diagnosis of hypersensitivity reactions to these
antibiotics.
The paper by Scherer and coworkers [10] reports hypersensitivity
reactions to drugs with anticoagulant activity, such as heparins,
hirudins, coumarins, and platelet aggregation inhibitors,
discussing their pathogenic mechanisms, diagnostic tools,
and management options. Excluding hypersensitivity reactions
to ASA, the most common hypersensitivity manifestations are
the erythematous plaques usually confined to heparin injection
sites, but sometimes accompanied by a maculopapular rash.
In evaluating such reactions, delayed-reading intradermal
tests are more sensitive than patch tests. However, subcutaneous
provocation tests are considered to be the most reliable diagnostic
method, because intradermal testing may produce false-negative
results. Provocation tests may also be used to identify safe
alternatives. Anaphylactic reactions to heparins and hirudins
are rare; they can be evaluated by immediate-reading skin
tests, which are indicated not only to identify the pathogenic
mechanism, but also to find safe alternatives. In cases of
necrosis from heparins or coumarins, all in vivo
tests are contraindicated.
The article by Gaeta et al. [11] analyzes various
aspects of hypersensitivity reactions to lamotrigine and nonaromatic
anticonvulsant drugs (valproate, gabapentin, and topiramate),
particularly the pathogenic mechanisms, diagnosis, and prevention.
However, most literature data are reports of single cases
or small series. These antiepileptic drugs are associated
with hypersensitivity reactions, mainly cutaneous eruptions.
The underlying mechanisms of these manifestations remain to
be completely elucidated. A cell-mediated pathogenic mechanism
has been demonstrated in some reactions on the basis of positive
responses to patch tests or lymphocyte transformation tests.
Moreover, an in vitro lymphocyte toxicity assay,
which exposes the patient's lymphocytes to arene oxides, has
detected lymphocyte susceptibility to toxic metabolites in
the patients with hypersensitivity reactions to lamotrigine.
Subjects with a history of hypersensitivity reactions displaying
negative results in allergologic tests can be challenged with
the suspected drugs. Challenge tests can also be used to identify
safe alternatives.
The review by Calogiuri et al. [12] analyzes literature
data concerning hypersensitivity reactions to biological agents,
which are employed to treat many diseases, such as psoriasis,
solid tumors, and bronchial asthma. In particular, this article
aims to clarify their pathogenic mechanisms, as well as to
identify potential risk factors and means of prevention.
In the last article [13], Castells demonstrates the usefulness
of rapid desensitizations with chemotherapy agents and monoclonal
antibodies, which allow patients with a compelling need of
irreplaceable drugs to be treated with them, even though they
were responsible for hypersensitivity reactions, including
anaphylaxis. This review provides both personal and literature
data on this topic, reporting available protocols for most
chemotherapy agents, including taxanes, platins, doxorubicin,
and monoclonal antibodies. Candidate patients include those
who present IgE-mediated reactions, particularly to platins,
or non-allergic hypersensitivity ones during the chemotherapy
infusion or shortly after. The author describes a universal
12-step protocol devised by herself and applied effectively
and safely to 413 cases of intravenous and intraperitoneal
rapid desensitizations using taxanes, platins, doxorubicin,
liposomal doxorubicin, rituximab, and other chemotherapy drugs.
We hope this issue will meet the needs of readers who work
in the constantly evolving field of drug hypersensitivity.
References:
[1] Ventura MT, Romano A. An update on the diagnosis of allergic
and non-allergic drug hypersensitivity. Curr Pharm Des 2006;
12 (No. 26): 3305-410.
[2] Guéant JL, Guéant-Rodriguez RM, Aimone Gastin
I, Cornejo-García JA, Viola M, Barbaud A, et al.
Pharmacogenetic determinants of immediate and delayed reactions
of drug hypersensitivity. Curr Pharm Des 2008; 14(27): 2770-2777.
[3] Brockow K, Romano A. Skin tests in the diagnosis of drug
hypersensitivity reactions. Curr Pharm Des 2008; 14(27): 2778-2791.
[4] Bousquet PJ, Gaeta F, Bousquet-Rouanet L, Lefrant JY,
Demoly P, Romano A. Provocation tests in diagnosing drug hypersensitivity.
Curr Pharm Des 2008; 14(27): 2792-2802.
[5] Sanz ML, Gamboa PM, De Weck AL. Cellular tests in the
diagnosis of drug hypersensitivity. Curr Pharm Des 2008; 14(27):
2803-2808.
[6] Mertes PM, Gastin I, Guéant-Rodriguez RM, Mouton-Faivre
C, Audibert G, O’Brien J, et al. Hypersensitivity
reactions to neuromuscular blocking agents. Curr Pharm Des
2008; 14(27): 2809-2825.
[7] Viola M, Quaratino D, Gaeta F, Rumi G, Caruso C, Romano
A. Cross-reactive reactions to nonsteroidal anti-inflammatory
drugs. Curr Pharm Des 2008; 14(27): 2826-2832.
[8] Foti C, Bonamonte D, Conserva A, Stingeni L, Lisi P, Lionetti
N, et al. Allergic and photoallergic contact dermatitis
from ketoprofen: Evaluation of cross-reactivities by a combination
of photopatch testing and computerized conformational analysis.
Curr Pharm Des 2008; 14(27): 2833-2839.
[9] Araújo L, Demoly P. Macrolide allergy. Curr Pharm
Des 2008; 14(27): 2840-2862.
[10] Scherer K, Tsakiris DA, Bircher AJ. Hypersensitivity
reactions to anticoagulant drugs. Curr Pharm Des 2008; 14(27):
2863-2873.
[11] Gaeta F, Alonzi C, Valluzzi RL, Viola M, Elia M, Romano
A. Hypersensitivity to lamotrigine and nonaromatic anticonvulsant
drugs: a review. Curr Pharm Des 2008; 14(27): 2874-2882.
[12] Calogiuri G, Ventura MT, Mason L, Valacca A, Buquicchio
R, Cassano N, et al. Hypersensitivity reactions to
last generation chimeric, humanized, and human recombinant
monoclonal antibodies for therapeutic use. Curr Pharm Des
2008; 14(27): 2883-2891.
[13] Castells MC. Desensitization in hypersensitivity to antineoplastic
agents. Curr Pharm Des 2008; 14(27): 2892-2901.
Prof. Antonino Romano
Department of Internal Medicine
and Geriatrics, UCSC Allergy Unit
Complesso Integrato Columbus Rome
Italy
Prof. Mariateresa Ventura M.D
Division of Allergology and Clinical Immunology
Department of Internal Medicine
Immunology and Infectious Diseases (MIDIM)
University of Bari
Italy
[Back to top]
[Purchase
Article]
Pharmacogenetic Determinants of Immediate and Delayed Reactions
of Drug Hypersensitivity
J.L. Guéant, R.M. Guéant-Rodriguez, I.A. Gastin,
J.A. Cornejo-García, M. Viola, A. Barbaud, P.M. Mertes,
M. Blanca and A. Romano
Drug allergy refers to a hypersensitivity reaction for
which either an IgE or T-cell-mediated mechanism is demonstrated.
The recognition of the drug by B and T cells is influenced
by variants of HLA genes. The genetic factors involved in
IgE-mediated mechanisms have been studied mainly in β-lactam
reactions, and they appear to be related to human leukocyte
antigen presentation (HLA A2 and DRw52), TNFA –308G>A,
class switching to IgE by B cells (variants of IL-13 and of
IL-4RA), and expression of IgE receptors on target cells (variant
of the FcεRIβ
gene). Delayed T-cell-mediated reactions are also associated
with HLA alleles. Studies have reported an association of
HLA-B*1502 and HLA-B*5801 in patients with the Stevens-Johnson
syndrome or toxic epidermal necrolysis provoked by carbamazepine,
as well as of HLA-B*5701 with abacavir hypersensitivity. HLA-B*5701
seems to be a strong predictor in whites, but not in Hispanics
or Africans. Carbamazepine hypersensitivity is also influenced
by gene variants of cytochrome P450 enzymes on the generation
of reactive metabolites, while CYP2C9*2 and CYP2C9*3 polymorphisms
influence the bioactivation of sulfamethoxazole in prohapten.
Pharmacogenetic studies on aspirin hypersensitivity have identified
distinct types of predictors, such as HLA genotypes, a polymorphism
in the promoter of the FcεRIα
gene, and variants in genes of enzymes from the arachidonic
acid pathway. In the future, identification of genetic predictors
will benefit from genomewide association studies that also
take ethnic differences into account. Ideally, predictors
will help to prevent ad-verse reactions, as suggested by a
recent study on the effectiveness of prospective HLA-B*5701
screening to prevent hy-persensitivity reactions to abacavir
in HIV patients.
[Back to top]
[Purchase
Article]
Skin Tests in the Diagnosis of Drug Hypersensitivity Reactions
K. Brockow and A. Romano
Adverse drug reactions (ADRs) are an area of concern
for pharmaceutical drug development. Among these, drug hypersensitivity
reactions are neither dose-dependent nor predictable, and
affect only predisposed individuals. Clinical and immunological
studies suggest that IgE-mediated (type I) and cell-mediated
(type-IV) pathogenic mechanisms are involved in many immediate
(i.e., occurring within 1 hour after the last drug administration)
and non-immediate (i.e., oc-curring more than 1 hour after
the last drug administration) hypersensitivity reactions,
respectively. Skin prick, patch, and intradermal tests are
the most readily available tools for the evaluation of hypersensitivity
drug reactions. The diagnostic value of skin tests for many
drugs still has not been fully established. Reliable skin
test procedures for the diagnosis of drug hypersensitivity
have been defined, and test concentrations have been validated
for many drugs. Skin tests should be carried out according
to the clinical features of ADRs. In immediate drug reactions,
an IgE-mediated mechanism can be demonstrated by a positive
skin prick and/or intradermal test after 20 minutes, whereas
in non-immediate reactions, a T-cell involvement can be found
by a positive patch test and/or a late-reading intradermal
test. The predictive value of skin tests varies with the drug
tested and is especially high with β-lactams,
muscle relaxants, insulins, platinum salts, strepto-kinase,
and chymopapain. Further diagnostic tests are required in
the assessment of drug hypersensitivity reactions. How-ever,
skin tests can provide information about the culprit drug
and the mechanism involved in certain reactions. The present
review addresses literature data regarding the diagnosis of
drug hypersensitivity reactions by skin tests.
[Back to top]
[Purchase
Article]
Provocation Tests in Diagnosing Drug Hypersensitivity
P.-J. Bousquet, F. Gaeta, L. Bousquet-Rouanet, J.-Y. Lefrant,
P. Demoly and A. Romano
A position paper by the European Network for Drug Allergy
(ENDA), the European Academy of Allergology and Clinical Immunology
(EAACI) interest group on drug hypersensitivity, defines drug
provocation tests (DPTs) as “the controlled administration
of a drug in order to diagnose drug hypersensitivity reactions”.
The DPT is widely considered to be the “gold standard”
to establish or exclude the diagnosis of hypersensitivity
to a certain substance, as it not only reproduces hypersensitivity
symptoms, but also any other adverse clinical manifestation,
irrespective of the mechanism. The DPT can be harmful and
thus should only be considered after balancing the risk-benefit
ratio in the individual patient.
The ENDA position paper specifies two main indications for
DPTs with the suspected compounds:
1. to exclude hypersensitivity in non-suggestive histories
of drug hypersensitivity and in patients with non-specific
symptoms, such as vagal symptoms under local anesthesia;
2. to establish a firm diagnosis in suggestive histories of
drug hypersensitivity with negative, non-conclusive, or non-available
allergologic tests.
A positive DPT result optimizes allergen avoidance, while
a negative one allows a false label of drug hypersensitivity
to be removed. For these reasons, DPTs are often carried out
to exclude a diagnosis of hypersensitivity to β-lactams
when other allergologic tests are negative. DPTs are also
performed when the sensitivity of allergologic tests for evaluating
al-lergic reactions to certain drugs, such as non-β-lactam
antibiotics, heparins, and glucocorticoids, is limited. On
the other hand, DPTs are also performed to diagnose hypersensitivity
reactions to nonsteroidal anti-inflammatory drugs in subjects
with the cross-reactive pattern, because both skin tests and
in vitro diagnostic methods are ineffective in such
patients.
[Back to top]
[Purchase Article]
Cellular Tests in the Diagnosis of Drug Hypersensitivity
M.L. Sanz, P.M. Gamboa and A.L. De Weck
The application of flowcytometry in the study of basophil
activation for the diagnosis of allergic diseases has given
interesting results in recent years. The quantification of
basophil activation by flowcytometry has been proven to be
a useful tool for the assessment of the immediate-type response
to allergens mediated by IgE or by other mechanisms in drug
allergic patients.
Up to now, most basophil activation test studies reported
in the literature have used CD69 or CD203c as markers to quantify
basophil activation after antigen-specific stimulation. Some
technical variations such as the use of whole blood or isolated
leukocytes, the addition of IL-3, the conditions of storage
of the blood sample, the time of incubation with allergens
and their concentration can affect the results of the basophil
activation tests.
The basophil activation test is more sensitive and specific
than other in vitro diagnostic techniques in drug
allergy. In various studies, its sensitivity in allergy to
muscle relaxant drugs ranges between 36 and 97.7%, with a
specificity around 95%. For betalactam antibiotics, basophil
activation test sensitivity is 50% and its specificity 90%.
For NSAIDs, sensitivity varies between 66% and 75%; specificity
is about 93%.
Basophil activation test reproduces in vitro hypersensitivity
mechanisms involved in immediate-type allergic reactions,
allows the diagnosis of allergic and pseudo-allergic reactions
particularly for drugs, which are often not detectable by
serological techniques, such as determination of specific
IgE.
[Back to top]
[Purchase
Article]
Hypersensitivity Reactions to Neuromuscular Blocking Agents
P.M. Mertes, I. Aimone-Gastin, R.M. Guéant-Rodriguez,
C. Mouton-Faivre, G. Audibert, J. O’Brien, D. Frendt,
M. Brezeanu, H. Bouaziz and J.L. Guéant
Neuromuscular blocking agents are the leading drugs responsible
for immediate hypersensitivity reactions during anaesthesia.
Most hypersensitivity reactions represent IgE-mediated allergic
reactions. Their incidence is estimated to be between 1 in
3 000 to 1 in 110 000 general anaesthetics. However striking
variations have been reported among countries.
The mechanism of sensitisation seems to implicate the presence
of a substituted ammonium ion in the molecule. Due to lack
of exposure prior to the reaction in a large number of reactors,
it has been hypothesised that sensitisation may involve other,
as yet undefined, substituted (quaternary and tertiary) ammonium
ion containing compounds such as pholcodine, present in the
environment of the patient. This hypothesis is still under
investigation. The mechanism of non-IgE mediated hypersensitivity
reactions is less well known. Identified mechanisms correspond
to direct histamine release or interactions with muscarinic
and nicotinic receptors.
Allergic reactions cannot be clinically distinguished from
non-IgE-mediated reactions. Therefore, any suspected hyper-sensitivity
reaction must be investigated using combined pre and postoperative
testing. Because of the frequent but not systematic cross-reactivity
observed with muscle relaxants, every available neuromuscular
blocking agent should be tested, using intradermal tests to
confirm the responsibility of the suspected drug which should
be definitely excluded. Cross-sensitivity investigation will
also try to identify the safety of drugs that can be potentially
used in future anaesthesia. The determination of basophil
activation investigations using direct leukocyte histamine
release test or flow cytometry would be of particular interest
to investigate cross sensitisation in complement to skin tests.
There is no demonstrated evidence supporting systematic pre-operative
screening in the general population at this time. However,
since no specific treatment has been shown to reliably prevent
anaphylaxis, allergy assessment must be performed in all high-risk
patients.
In view of the relative complexity of allergy investigation,
and of the differences between countries, an active policy
to identify patients at risk and to provide any necessary
support from expert advice to anaesthetists and allergologists
through the constitution of allergo-anaesthesia centres in
every country should be promoted.
[Back to top]
[Purchase
Article]
Cross-Reactive Reactions to Nonsteroidal Anti-Inflammatory
Drugs
M. Viola, D. Quaratino, F. Gaeta, G. Rumi, C. Caruso and
A. Romano
Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs)
are among the most frequent causes of adverse drug reactions,
particularly in patients with asthma and chronic idiophatic
urticaria. Many subjects report cutaneous and/or respiratory
symptoms and, less frequently, anaphylactic shock after the
administration of one (single-reactors) or different (cross-reactors)
drugs of this class.
Diagnosis: There are no reliable cutaneous or in
vitro tests which allow NSAID hypersensitivity to be
identified in patients with cross-reactive reactions; therefore,
the challenge test is considered the "gold standard”
for establishing or excluding a diagnosis of NSAID hypersensitivity
in such patients.
Management: Culprit drugs should always be avoided
by patients with suspected or well-established multiple hypersensitivity
to NSAIDs. The therapeutic options range from the administration
of alternative drugs – such as weak cyclooxy-genase
(COX)-1 inhibitors and/or preferential or highly selective
COX-2 inhibitors to desensitization to the culprit ones.
Conclusion: In patients with different NSAID-induced
reactions, the challenge test with both culprit drugs and
alternative ones is the only method to establish a reliable
diagnosis of NSAID hypersensitivity and to find some alternative
therapeutic options, respectively. In specific cases, drug
desensitization can also be performed. However, further studies
are required to improve management of such patients.
[Back to top]
[Purchase
Article]
Allergic and Photoallergic Contact Dermatitis from Ketoprofen:
Evaluation of Cross-Reactivities by a Combination of Photopatch
Testing and Computerized Conformational Analysis
C. Foti, D. Bonamonte, A. Conserva, L. Stingeni, P. Lisi,
N. Lionetti, L. Rigano and G. Angelini
Allergic contact dermatitis (ACD) and photo-ACD are cell-mediated
delayed hypersensitivity reactions of the skin caused by a
wide range of substances. Topical ketoprofen (KP), a nonsteroidal
anti-inflammatory drug (NSAID), can induce ACD and photo-ACD.
Patients with ACD and/or photo-ACD to KP frequently show concomitant
sensitization to other substances. The aim of this study was
to identify the substances most frequently associated with
sensitization to KP, and to evaluate, by means of computerized
conformational analysis, whether this association could be
due to cross-allergy. 15 subjects with ACD and photo-ACD to
KP were tested with the SIDAPA (Società Italiana di
Dermatologia Allergologica Professionale ed Ambientale) patch
test standard series, including fragrance mix and its components
(eugenol, isoeugenol, oak moss, geraniol, hydroxycitronellal,
amylcinnamaldehyde, cinnamyl alcohol and cinnamaldehyde) and
with the SIDAPA photopatch test series. Allergic reactions
to cinnamyl alcohol were noted in all patients, whereas some
patients also showed positive reactions to fenticlor, octocrylene
and benzophenone-10.
Computerized conformational analysis demonstrated that the
structure of cinnamyl alcohol is similar to that of KP, whereas
the structures of benzophenone-10, octocrylene and fenticlor
are completely different. These results suggest that in patients
with contact allergy to KP, concomitant positive reactions
to cinnamyl alcohol are due to cross-sensitization, whereas
simultaneous allergic reactions to fenticlor, octocrylene
and benzophenone-10 should be regarded as co-sensitizations.
[Back to top]
[Purchase Article]
Macrolides Allergy
L. Araújo and P. Demoly
Macrolides are characterised by their basic structure
which is made up of a lactonic cycle with 2 osidic chains.
They are classified according to the number of carbon atoms
in the cycle : 14 membered macrolides (erythromicin, roxithromycin,
dirithromycin, clarithromycin...), 15 membered (azithromycin)
and 16 membered (spiramycin, josamycin, midecamycin...) macrolides.
Epidemiological studies show that macrolides are amongst the
safest antibiotics, but in these series, no drug allergy work
up was performed. An immediate IgE dependent hypersensitivity
has been shown with erythromycin in some cases. The mechanism
is unknown and the skin tests are negative in most other cases.
It would appear that the macrolide allergies are unlikely
to be class allergies. Eviction is the treatment of choice.
Desensitization has been successful in a few cases.
[Back to top]
[Purchase
Article]
Hypersensitivity Reactions to Anticoagulant Drugs
K. Scherer, D.A. Tsakiris and A.J. Bircher
Drugs with anticoagulant activity, including heparins, hirudins,
coumarins, and platelet aggregation inhibitors belong to the
most widely used drugs. Hypersensitivity reactions from these
agents are rare. However, due to their widespread use, they
may have a considerable impact on patient safety and treatment.
Accurate diagnosis of potentially life-threatening adverse
events and identification of alternatives is mandatory. We
review hypersensitivity reactions caused by the different
groups of anticoagulant agents and discuss the pathophysiological
mechanisms, diagnostic possibilities and management options.
According to patients histories the most common hypersensitivity
reaction is intolerance to acetylsalicylic acid (ASA). Also
localized erythematous plaques, occurring to subcutaneous
application of heparins are rather common. Other hyper-sensitivity
reactions are rare but may be life-threatening, e.g. skin
necrosis due to heparin-induced thrombocytopenia. Rarely anaphylactoid
reactions have been observed to ASA, heparin, and hirudin.
Skin and provocation tests with immediate and late readings
are the most reliable diagnostic tools for heparin- or hirudin-induced
urticaria/anaphylaxis or heparin-induced delayed plaques.
Provocation tests may be used to identify safe alternatives.
In cases of necrosis from heparins or coumarins, all in
vivo tests are contraindicated. Most in vitro
tests are not universally available, and with the exception
of platelet aggregation tests, they have a low sensitivity.
In some anticoagulant-associated hypersensitivity reactions
detailed allergologic investigation may help to identify safe
treatment alternatives. Typically, several tests are needed,
and therefore the test procedures are time consuming.
[Back to top]
[Purchase
Article]
Hypersensitivity to Lamotrigine and Nonaromatic Anticonvulsant
Drugs: A Review
F. Gaeta, C. Alonzi, R.L. Valluzzi, M. Viola, M. Elia
and A. Romano
Lamotrigine and nonaromatic antiepileptic drugs (valproate,
gabapentin, and topiramate) are associated with hypersensitivity
reactions, mainly cutaneous eruptions. The underlying mechanisms
of these manifestations are not yet completely understood.
A cell-mediated pathogenic mechanism has been demonstrated
in some cases on the basis of positive patch tests and/or
lymphocyte transformation tests. Moreover, an in vitro
lymphocyte toxicity assay, which exposes the patient's lymphocytes
to arene oxides, has detected lymphocyte susceptibility to
toxic metabolites in patients with hy-persensitivity reactions
to lamotrigine. Subjects with a history of mild hypersensitivity
reactions and negative allergologic tests can be challenged
with the suspected drugs. Challenge tests can also be useful
to identify safe alternatives.
Our study reports hypersensitivity reactions to lamotrigine
and to nonaromatic antiepileptic drugs, especially those as-sessed
by allergologic tests.
[Back to top]
[Purchase
Article]
Hypersensitivity Reactions to Last Generation Chimeric, Umanized
and Human Recombinant Monoclonal Antibodies for Therapeutic
Use
G. Calogiuri, M.T. Ventura, L. Mason, Á. Valacca,
R. Buquicchio, N. Cassano and G.A. Vena
A new class of drugs, produced with the hybridoma technique,
has been introduced and employed to treat many immunological
diseases. This class consists of recombinant monoclonal antibodies,
which can be chimeric, humanized or human. Predictably, there
has been a rise in adverse hypersensitivity reactions to these
therapeutic agents, whose pathogenic mechanisms are not yet
well understood. Specific IgE has been demonstrated in a very
few cases, and only in some of these recombinant antibodies.
Skin tests are not done as a clinical routine screening. In
the present article the mechanisms underlying hypersensitivity
reactions to these drugs are analyzed, also in the light of
the personal experience and that reported in the literature,
with the aim of identifying potential risk factors and means
of prevention of these reactions. For some drugs, infusion
reactions may be prevented thanks to the the use of premedication.
Moreover, symptoms of acute hypersensitivity during infusion
can be successfully managed in the majority of cases by slowing
the speed of administration. All these findings seem to confirm
that the pathogenesis is not related to a true immediate (IgE-mediated)
hypersensitivity in most cases. When the substitution of the
drug that has triggered a hypersensitivity reaction is required,
this is only possible if such an alternative drug exists (i.e.,
replacement of a chimeric antibody with a humanized or human
antibody sharing the same target). As an alternative, desensitization
protocols have been employed to induce a state of temporary
tolerance to the drug in some cases, yielding successful results
for infliximab and trastuzumab.
[Back to top]
[Purchase
Article]
Hypersensitivity to Antineoplastic Agents
M.C. Castells
The need to offer first line therapy for primary and
recurrent cancers has spurred the clinical development of
rapid desensitizations for chemotherapy and monoclonal antibodies.
Rapid desensitizations allow patients to be treated with medications
to which they have presented with hypersensitivity reactions
(HSRs), including anaphylaxis. Rapid desensitization achieves
temporary tolerization to full therapeutic doses by slow administration
of incremental doses of the drug inducing the HSR. Protocols
are available for most chemotherapy agents, including taxanes,
platins, doxorubicin, monoclonal antibodies, and others. Candidate
patients include those who present with type I HSRs, mast
cell/IgE dependent, including anaphylaxis, and non-IgE mediated
HSRs, during the chemotherapy infusion or shortly after. Idiosyncratic
reactions, erythema multiforme, Stevens-Johnson syndrome and
toxic epidermal necrolysis are not amenable to rapid desensitization.
The recommendation for rapid desensitization can only be made
by allergy and immunology specialists and can only be performed
in settings with one-to-one nurse-patient care and where resuscitation
personnel and resources are readily available. Repeated desensitizations
can be safely performed in outpatient settings with similar
conditions, which allow cancer patients to remain in clinical
studies. We have generated a universal 12-step protocol that
was applied to 413 cases of intravenous and intraperitoneal
rapid desensitizations using taxanes, platins, liposomal doxorubicin,
doxorubicin, rituximab, and other chemotherapy drugs. Under
this protocol all patients were able to complete their target
dose, and 94% of the patients had limited or no reactions.
No deaths or codes were reported, indicating that the procedure
was safe and effective in delivering first line chemotherapy
drugs.
[Back to top]
[Purchase Article]
Antiinflammatory Effects of H1-Antihistamines: Clinical and
Immunological Relevance
G.A. Vena, N. Cassano, R. Buquicchio and M.T. Ventura
Signs supporting antiinflammatory effects of H1-antihistamines
were first reported long ago, but their clinical relevance
remains controversial, especially with respect to their ability
to inhibit the release of histamine and other preformed mediators.
Experimental studies have documented that H1-antihistamines
may affect several inflammatory events, including chemotaxis
and the survival of eosinophils, the expression of adhesion
molecules, and the release of chemokines and cytokines from
different sources, thus highlighting the potential for a modulation
of chronic inflammation and immune responses. Interestingly,
a specific inhibitory effect on Th2-type cytokine secretion
has been demonstrated for some new generation antihistamines.
The mechanisms responsible for the antiinflammatory activity
of H1-antihistamines are still unclear, but are presumed to
be both receptor-dependent and receptor-independent. Recent
findings have indicated the ability of these drugs to down-regulate
intracellular signaling pathways, i.e., NF-κB.
In this article, the current knowledge and novel findings
about the antiinflammatory action and mechanisms of H1-antihistamines
are briefly reviewed and critically analyzed, from the standpoint
of possible clinical implications with special reference to
skin disorders.
|
