Drug-induced urticaria and angioedema caused by non-IgE mediated pathomechanisms

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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