ARTICLE
Urticaria and angioedema are common disorders which may affect between
1 to 25% of the population according to the definitions used. A commonly
accepted definition defines an acute urticaria as lasting up to six weeks,
the chronic form is typically present or recurs for weeks, months or even
up to years. Drugs are among one of many triggers that may induce urticaria
and/or angioedema. Apart from the well established IgE-mediated immediate
type hypersensitivity reactions, the pathogenesis of drug-induced urticaria
and angioedema is often not clear. IgE-mediated reactions to penicillins
have been extensively investigated and appropriate diagnostic tests such
as skin tests and determination of specific IgE with standardized allergens
are available [1]. Studies on sensitivity, specificity and predictive
value have been performed [2, 3]. In this article the main emphasis is
on pseudoallergic and idiosyncratic reactions to two important drug groups,
the nonsteroidal antiinflammatory drugs (NSAIDs, cyclo-oxygenase inhibitors)
and the angiotensin-converting-enzyme (ACE) inhibitors.
Pathogenesis
Pseudoallergy
In pseudoallergic reactions, sometimes also called drug intolerance,
the pathomechanism is not clear. The clinical symptoms are practically
identical to IgE-mediated immediate type symptoms and include angioedema,
urticaria, bronchospasm, gastrointestinal signs and anaphylaxis (then
termed anaphylactoid reactions). It is likely that the same effector mechanisms
and cells (basophils and mast cells) are involved. However, since no induction
of specific immunological parameters occurs, skin tests and antibody determinations
are typically negative.
Idiosyncrasy
In idiosyncratic reactions the pathomechanism is also not clearly elucidated.
In some reactions to drugs an enzyme defect or deficiency is thought to
be involved as e.g. in severe hypersensitivity reactions to sulfonamides
[4, 5] and aromatic anticonvulsant drugs [6]. In drug-induced angioedema
associated with angiotensin-converting-enzyme (ACE)-inhibitors, an enzyme
deficiency or imbalance may be involved.
Clinical presentation
Clinically urticaria and angioedema are usually easy to distinguish
from other skin disorders such as maculo-papular exanthemas or perifocal
swellings due to infections in the case of angioedema. Urticaria manifests
with weals and flares ranging from pinpoint to gigantic sizes. It typically
lasts from a few minutes up to 24 hours and affects the trunk and the
proximal extremities, more rarely also the head, palms or feet. Angioedema
is characterized by an often asymmetric, slightly erythematous swelling
of the deeper skin and mucosa, mainly affecting the face, the lips, more
rarely the oral cavity or the male genitals. It may take several days
to completely resolve. Urticaria is associated with pruritus whereas angioedema
causes a feeling of pressure or pain in the affected areas. Both may occur
isolated or combined, and both may be the initial cutaneous signs of a
more severe immediate type allergic reaction such as anaphylaxis.
Etiology
The causes of acute and chronic urticaria and angioedema are manifold
including infections and parasitic infestations, drugs, food additives,
allergens such as food proteins, bee and wasp venom, and more rarely autoimmune
and malignant diseases. Up to 60% of the chronic-recurrent forms remain
etiologically unexplained, i.e. that not one single eliciting factor
can be identified. As outlined below, some drugs are well known elicitors
of urticaria or angioedema.
Nonsteroidal antiinflammatory
drugs (NSAIDs)
Patient groups
Based on clinical criteria, three distinct groups of patients can be
separated who may suffer from pseudoallergic reactions to NSAIDs.
A) Patients with the aspirin or salicylate triad (Widal's syndrome)
which includes intrinsic asthma, nasal polyps, often serum and tissue
eosinophilia and sometimes chronic rhinosinusitis. They typically suffer
an occasionally life threatening aggravation of their rhinitic and asthmatic
symptoms from acetylsalicylic acid and often a broad range of other NSAIDs.
Usually they have no cutaneous symptoms and signs [7].
B) Patients with chronic or chronic recurrent urticaria or angioedema
may react with an aggravation of either disorder. Some individuals have
an oppressive feeling or dyspnoe, but usually there is no evidence of
bronchial hyperreactivity or asthma. They typically react to acetylsalicylic
acid and other NSAIDs.
C) Otherwise healthy individuals may suffer typically from anaphylactoid
reactions to only one chemically distinct group of NSAIDs such as a pyrazolone
derivative, diclofenac or others [8-11] (Table
I).
However, cases with bronchial and cutaneous symptoms and full blown
anaphylaxis have been described and patients have reacted to different
NSAIDs including paracetamol [acetaminophen) [11-13]. In patients with
anaphylaxis to pyrazolones a significantly higher frequency of HLA-DQ7
as compared to atopic and non-atopic controls has been observed [14].
In patients with anaphylactoid reactions to different classes of NSAID,
such as pyrazolones, aspirin and others, an association with HLA-DR11
has been found, as compared to subjects tolerant to the respective drugs
[15]. This indicates a genetic predisposition at least for this drug class.
Also exercise-induced drug-dependent anaphylaxis to nafylpropion acid
has been confirmed by controlled challenges [16], indicating that in some
cases cofactors such as concurrent exercise may play a role.
Recently, an apparently distinct entity of NSAID intolerance has been
postulated in atopic patients sensitized to house dust mites. They suffer
from a) allergic rhinitis, b) severe anaphylactic reactions upon ingestion
of mite-contaminated flour, and c) mostly periorbital angioedema to several
NSAIDs [17, 18].
Pathogenesis
As mentioned, the pathogenesis is not clear for all entities, however,
it is thought that an imbalance in the arachidonic acid cascade, i.e.
inhibition of prostaglandin synthesis and increase of leukotrienes may
play a crucial role (Fig. 1).
In respiratory symptoms to NSAIDs the stimulation of the cysteinyl (sulfido)
-leukotrienes LTC4, LTD4 and LTE4 appears to be specific for this group
of patients [19]. In severe cases there is a broad crossreactivity between
all cyclo-oxygenase (COX) inhibitors dependent on individual factors,
dosage and the potency of COX-inhibition. In patient group C with anaphylactoid
cutaneous reactions which mimic IgE-mediated symptoms, there is often
only intolerance to one chemical group of NSAIDs. In the future new interesting
insights into the pathogenesis of these pseudoallergic reactions to NSAIDs
may be obtained by the use of two new agents, the leukotriene and the
COX-2 antagonists.
In aspirin-induced asthma it has been shown that leukotriene antagonists
(e.g. montelukast, zafirlukast) may prevent aspirin-induced bronchospasm
[20]. On the contrary the leukotriene antagonist zafirlukast did not prevent
anaphylaxis to ibuprofen in one patient [21], and a patient with aspirin
triad treated with montelukast, developed a life-threatening bronchospasm
to diclofenac [22]. Two patients with aspirin-sensitive urticaria had
a severe exacerbation of urticaria to pranlukast [23]. On the other hand
two patients with chronic urticaria resistant to standard therapy were
reported, one who responded favorably to zafirlukast, the other to zileuton,
a 5-lipoxygenase inhibitor, in combination with antihistaminic drugs [24].
These cases illustrate that controlled trials are needed, on the one hand
to establish the potential value or problems with leukotriene antagonists
in NSAID intolerant patients and on the other hand to be able to identify
pathogenic differences between the clinical entities.
Action of COX involves two isoenzymes, COX-1 and COX-2 (Fig.
1). COX-1, a "housekeeping" enzyme, is constitutionally expressed
in most tissues such as kidneys and gastrointestinal tract and is held
responsible for the classical pharmacological side effects of NSAIDs such
as renal failure, bleeding and gastric ulcers. COX-2 is constitutionally
present in brain tissue and is induced by proinflammatory factors such
as cytokines and endotoxins. The COX-2 inhibitors may be of value as replacement
antiinflammatory drugs in patients intolerant to COX-1 inhibitors as it
has been shown for nimesulide [11, 25]. However, there is a considerable
variability of COX-1 and COX-2 inhibition of the different NSAIDs partially
depending on the determination techniques used [25]. The relatively selective
COX-2 inhibitor meloxicam and the highly selective COX-2 inhibitors (celecoxib
and rifecoxib) offer interesting advantages for antiinflammatory treatment,
so far there is limited experience in patients with pseudoallergic reactions
to NSAIDs. Four patients with angioedema or urticaria to aspirin tolerated
meloxicam, while one female with intrinsic asthma and high sensitivity
to aspirin experienced rhinorrhea and a decrease in peak flow to meloxicam
[26].
Diagnosis of pseudoallergic reactions
A detailed history and exact documentation of the clinical signs is
the first important step. In selected cases diagnostic oral [17, 27, 28],
inhaled or nasal [7] provocation tests may be performed. Identification
of the eliciting drug and the presence of crossreactivity can be reliably
diagnosed by controlled oral provocation tests only. Often, however, it
is advisable to confirm a safe alternative drug by this potentially dangerous
procedure [29]. Skin tests and determination of specific antibodies are
not established and have at present no practical diagnostic value [30].
In the future in vitro tests such as histamine liberation and sulfidoleukotriene
stimulation tests (CAST®) [31] may be more widely available.
Currently they are not well enough established to be used in the clinical
routine [32-34].
Treatment
Standard treatment includes identifying and stopping the drug in question
and initiating an appropriate emergency therapy. In patients with aspirin-induced
asthma and urticaria desensitization has been tried [35-37]. Tolerance
is more easily achieved in patients with asthma than in individuals with
urticaria. In patients with aspirin triad the nasal symptoms respond best
[7]. In both situations, however, the drug has to be continuously administered
otherwise its tolerance is lost within a few days after withdrawal.
ACE-inhibitors
Clinical presentation
ACE-inhibitors may elicit a variety of adverse cutaneous reactions,
particularly captopril, which has a thiol-group has been implicated in
urticarial, exanthematic, bullous and photosensitivity reactions [38,
39]. The most common adverse reactions to ACE-inhibitors are cough and
angioedema, the latter typically without urticaria. It is estimated that
0.1 to 0.5% of the patients suffer from angioedema during ACE-inhibitor
therapy [40, 41], and continuation of treatment after the occurrence of
an angioedema raises this risk by a factor 10 [42]. In patients treated
in emergency wards for angioedema the percentage of ACE-inhibitor induced
cases ranges from 25 [43] to 38% [44]. Onset typically occurs within the
first weeks of treatment, but it may be delayed for months and even years.
The attacks may occur at irregular, unpredictable intervals under ongoing
treatment [45]. As in angioedema of other origins the face and the oral
mucosa are most often affected but isolated visceral angioedema has also
been reported [46-48].
Pathogenesis
ACE-inhibitor associated angioedema is not immunologically mediated,
but appears to be due to the pharmacological effect of ACE inhibition.
Bradykinin is a potent vasodilator and is thought to play a role in the
pathogenesis due to the decreased degradation of bradykinin by ACE-inhibition
(Fig. 2). Recently it
has been found that plasma bradykinin was elevated during an attack of
an ACE-inhibitor induced angioedema, suggesting that this mediator does
play a crucial role [49]. Other factors may also be important since bradykinin
degradation is blocked in all patients receiving ACE-inhibitors and angioedema
does not occur regularly after intake of the drug. Hypothetically a deficiency
of another enzyme degrading bradykinin, namely carboxypeptidase N (Fig.
2) or disturbances in complement metabolism may be involved in
the pathogenesis [50].
Risk factors for ACE-induced angioedema include earlier angioedema of
any origin, narrowing of upper airways and rarely C1 esterase
inhibitor deficiency [51]. A four-fold increase in risk has been reported
in black American patients [52] and an increased sensitivity to bradykinin
has been demonstrated in this ethnic group [53]. ACE-inhibitors may also
aggravate anaphylactic and anaphylactoid reactions, respectively [54,
55]. There is also evidence that in patients under ACE-inhibitor treatment
other drugs such as antibiotics and local anesthetics or surgical trauma
may elicit angioedema [45, 56, 57]. Without ACE-inhibitors these drugs
were well tolerated.
Diagnosis
Since the pathogenesis is not known, diagnostic tests such as skin tests
and determination of antibodies are not available. Oral provocation tests
are difficult to perform and ethically not feasible since the time interval
and the severity of the reaction is not predictable, and fatal outcome
of laryngeal angioedema has been reported [58, 59]. At present the diagnosis
can only be made based on the clinical finding, the typical history and
evolution.
Treatment and prevention
In patients with angioedema under ACE-inhibitor treatment the drug should
be stopped, even when the angioedemas are not severe. We have observed
a sudden life threatening angioedema of the larynx upon continuation of
enalapril after discrete angioedemas of the face and the tongue occurring
monthly for more than eight years. Standard antiallergic treatment may
not be sufficient and in patients with mucosal angioedema intubation should
be considered at an early stage.
Angioedema to ACE-inhibitors is a class effect and, therefore, there
is a complete crossreactivity between all ACE-inhibitors and some patients
had angioedema to more than one ACE-inhibitor [60, 61]. The angiotensin-II
receptor antagonists ("sartanes") do not inhibit ACE (Fig.
2). Despite this different mechanism angioedema has also been
observed to these drug class [62-66]. Currently as alternative drugs diuretics,
calcium antagonists and ß-blocking agents are recommended. Occasionally,
however, these drugs also elicit angioedema [67].
Other drugs
Some other drug classes have been traditionally classifid as elicitors
of pseudoallergic reactions, e.g. radiocontrast media, muscle relaxants
and local anesthetic agents. In recent years, however, an immunologically-mediated
pathogenesis could be identified for some of these drugs.
Radiocontrast media
Radiocontrast media are typically thought to induce urticaria and angioedema
by a pseudoallergic pathomechanism [68, 69]. Recently, however, in some
patients IgE-antibody-mediated mechanisms have been identified [70, 71].
The so-called "late reactions" include very heterogeneous symptoms such
as cutaneous signs, flu-like diseases, headaches, gastrointestinal disturbances
etc. and are mainly not immunologically mediated [72, 73]. They should
be neither confused with the clearly defined "late phase" of the IgE-mediated
allergy nor with T cell mediated "delayed type" allergy. A few cases with
a documented delayed type hypersensitivity with maculopapular febrile
exanthemas have been described [74].
Muscle relaxants
Apart from latex [75], muscle relaxants are one of the major causes
of anaphylaxis during general anesthesia [76]. IgE-antibodies directed
against quarternary ammonium ions have been identified [77]. Based on
skin tests and IgE determinations crossreactive patterns could be identified
and patients were successfully treated with test-negative agents. Few
attempts have been made to induce tolerance in sensitized patients [78].
Local anesthetics
On the contrary, measurement of specific IgE to amide or ester local
anesthetics has not been successful [79, 80]. There are cases with clearly
positive skin tests to amide or ester local anesthetics in patients with
urticaria or anaphylaxis [81]. But so far the vast majority of the adverse
reactions have a pseudoallergic pathogenesis. Whereas ester local anesthetics
typically induce a delayed type allergy, there are only a few cases with
such reactions to amide derivatives resulting in infiltrated plaques [82].
Dextrans
Dextrans used as plasma volume expanders and in thromboprophylaxis are
another example where the mechanism of a reaction initially classified
as pseudoallergy could be clarified. This has been termed immune complex-mediated
anaphylaxis. Dextran-reactive IgG or IgM antibodies were identified [83]
and hapten-inhibition by a low molecular dextran resulted in a considerable
decrease of severe life-threatening events [84]. Very rarely, severe reactions
occurred despite hapten inhibition [85].
Protamine
Protamine, a protein from fish sperm is used to reverse heparin anticoagulation
and for retarding the absorption of insulin [86]. Some of the reactions,
including urticaria, could be related to the presence of protamine-specific
IgE or IgG antibodies. A significant risk for life-threatening reactions
related to IgE or IgG could be identified in some patients [87].
Thiamine
In a patient with a severe anaphylactic reaction to parenteral vitamin
B1 (thiamine) specific IgE and IgG to thiamine were found. Prick tests
were positive to thiamine hydrochloride, an oral provocation test was
negative [88].
Hirudin
A patient with urticaria to subcutaneous recombinant hirudin, an antithrombotic
agent originally from the leech (Hirudo medicinalis) salivary glands,
has been described. Intradermal tests with hirudin were also positive,
and high titres of hirudin-specific IgG could be measured, which decreased
during the reaction and reached again high titres 48 hours later. These
results suggest an IgG-immune complex mediated reaction with antibody
consumption before and during urticaria [89].
These examples demonstrate that drug-induced urticaria and angioedema
may be elicited by very different pathogenic mechanisms. For commonly
used drug classes such as the NSAIDs and the ACE-inhibitors the pathomechanism
is presently not clear and, therefore, apart from the potentially dangerous
re-exposure, established diagnostic tests are not available. For some
other drugs such as dextrans or muscle relaxants an immunological pathomechanism
has been elucidated. Insight into and a better understanding of the mechanisms
of drug-induced reactions in general enables us to obtain a more precise
diagnosis and e.g. the possibility of introducing preventive measures
such as hapten inhibition.
Abbreviations:
ACE - angiotensin-converting-enzyme
COX - cyclo-oxygenase
NSAID - nonsteroidal antiinflammatory drugs
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