Cross-reactivity among drugs: clinical problems

Toxicology 209 (2005) 169–179

Cross-reactivity among drugs: clinical problems Antonino Romano a, b, ∗ , Rosa-Maria Gu´eant-Rodriguez c, d , Marinella Viola a , Francesco Gaeta a , Cristiano Caruso a , Jean-Louis Gu´eant c a

c

Department of Internal Medicine and Geriatrics, UCSC-Allergy Unit, Unit`a di Allergologia, Complesso Integrato Columbus, Via G. Moscati 31, 00168 Rome, Italy b IRCCS Oasi Maria S.S., Troina, Italy Laboratoire de Pathologie Cellulaire et Mol´eculaire en Nutrition, EMI INSERM 0014 et IFREMER 20, Facult´e de M´edecine, BP 184, F-54500 Vandoeuvre, France d Service de Cardiologie, CHU de Nancy-Brabois, F-54500 Vandoeuvre, France

Abstract Cross-reactivity among drugs is either mediated by immunologic mechanisms or not. The former kind is usually explained by the presence of common antigenic determinants in the cross-reacting drugs. In the case of compounds provoking non-allergic hypersensitivity reactions, cross-reactivity is explained by a common pharmacological characteristic, such as the inhibitory effect of non-steroidal anti-inflammatory drugs on cyclooxygenase-1 and the capability of muscle relaxants or contrast media to release histamine through a non-immunologic mechanism. The main clinical problem deriving from cross-reactivity among drugs is the compelling need to choose a potentially crossreactive compound and, therefore, to assess cross-reactivity by diagnostic tests. In choosing alternative compounds, skin testing has been used in evaluating IgE-mediated cross-reactivity between penicillins and cephalosporins, as well as among muscle relaxants. In assessing T cell-mediated cross-reactivity among contrast media, corticosteroids, anticonvulsants and heparins, delayedreading intradermal tests and patch tests, together with lymphocyte transformation tests, can be performed. Because of the limited sensitivity of in vivo and in vitro testing, the most prudent way of establishing the tolerability of a compound of the same group in patients who especially require one is a graded challenge when other allergologic tests are negative. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Beta-lactam antibiotics; Quinolones; Radio contrast media; IgE; T cells; Cross-reactivity; Drugs; Hypersensitivity reactions

1. Introduction ∗

Corresponding author. Tel.: +39 06 3503782; fax: +39 06 3503235. E-mail address: [email protected] (A. Romano).

Cross-reactivity among drugs becomes clinically manifest when a drug not previously administered elicits hypersensitivity reactions because of a preexisting

0300-483X/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.tox.2004.12.016

170

A. Romano et al. / Toxicology 209 (2005) 169–179

Fig. 1. Chemical structures of some cross-reacting drugs.

A. Romano et al. / Toxicology 209 (2005) 169–179

sensitisation to a structurally related compound or because of a common pharmacological characteristic. The revised nomenclature for allergies classifies hypersensitivity reactions to drugs as either allergic or non-allergic (Johansson et al., 2001). The former are mediated by immunologic mechanisms, either antibodies or cells; all other reactions should be referred to as non-allergic drug hypersensitivity. In addition, allergic reactions to drugs are classified as IgE-mediated or non-IgE-mediated. Cross-reactivity mediated by immunologic mechanisms is usually explained by the presence of a common antigenic determinant in the cross-reacting drugs (Fig. 1). T cell cross-reactivity differs from that of IgEmediated reactions. In vitro data suggest that T cells recognise the complete structure, mainly the core, and, to a lesser extent, the side-chain (Depta et al., 2004; Depta and Pichler, 2003; Pichler, 2003). In the sulfamethoxazole hypersensitivity model, the complete sulfanilamide core structure must always be present to elicit cross-reactivity to other sulfonamides (Depta and Pichler, 2003; Pichler, 2003). On the other hand, B cells may recognise smaller structures (Fernandez et al., 1995). In effect, an exclusive side-chain reactivity has been reported for IgE in subjects with immediate reactions to penicillins and cephalosporins (Blanca et al., 2002). Cross-reactivity can also derive from a non-specific binding of drugs to IgE (Gu´eant et al., 1995). For example, most allergenic drugs, such as penicillin, are hydrophobic compounds containing a C6 H5 phenyl ring (cyclohexenyl derivatives). These compounds can strongly bind to external hydrophobic areas of globular proteins and therefore non-specifically bind IgE. A high level of hydrophobic IgE in the serum of a patient allergic to a hydrophobic drug seems to be a risk factor for IgE cross-reactivity to another drug (Gu´eant et al., 1995). In the case of compounds provoking non-allergic hypersensitivity reactions, cross-reactivity is explained by common pharmacological characteristics. Crossreactivity among anti-inflammatory agents has been attributed to their inhibitory effect on cyclooxygenase (COX)-1 (Szczeklik and Stevenson, 2003), while that among muscle relaxants or contrast media to their capability of releasing histamine through a nonimmunologic mechanism (Laroche et al., 1998; Mertes et al., 2003).

171

The question of whether some subjects develop a response to a drug because of cross-reactivity with another one or because of a coexisting sensitivity is often difficult to answer. An irrefutable proof of the existence of a true cross-reactivity is provided by reactions to compounds to which sensitive patients have not been previously exposed. With regard to IgE-mediated hypersensitivity reactions, this has been clearly demonstrated with muscle relaxants (Laxenaire et al., 1995). In addition, patients allergic to benzylpenicillin who have never been administered cephalosporins may have antibodies specific for the latter, indicating a crosssensitivity (Grieco, 1967; Shepherd, 1991). However, there is some evidence (Ong and Sullivan, 1988) that coexisting sensitivities may occur. The following drugs are frequently involved in cross-reactivity.

2. Antimicrobial drugs 2.1. Beta-lactam antibiotics Beta-lactam antibiotics constitute a classic example of compounds provoking both IgE- and cell-mediated allergic reactions. Cross-reactions are frequent among penicillins as well as among cephalosporins; they can also occur among classes, particularly between penicillins and cephalosporins (Blanca et al., 2002); in fact, in addition to the beta-lactam ring, the side-chain groups sometimes present structural features common to penicillins and cephalosporins (for example, ampicillin and cefaclor have an identical R1 side-chain) (Fig. 1). In patients with documented IgE-mediated immediate hypersensitivity to penicillins, the data regarding a true allergic cross-reactivity to cephalosporins—diagnosed on the basis of positive responses to challenges carried out without performing prophylactic skin tests with the cephalosporin concerned—are variable (Assem and Vickers, 1974; Blanca et al., 1989; Macy, 1998; Saxon et al., 1987; Shepherd and Burton, 1993; Solley et al., 1982). In fact, such cross-reactivity varies between 0% (Shepherd and Burton, 1993) and 100% (Assem and Vickers, 1974), the most recent review estimating the rate of positivity at 4.4% (Kelkar and Li, 2001). Such variability has caused confusion concerning the

172

A. Romano et al. / Toxicology 209 (2005) 169–179

administration of cephalosporins to penicillin-allergic patients, which may lead to the risk of cross-reactivity being either under- or overestimated. In both cases, there may be negative consequences, such as fatal anaphylactic reactions in penicillin-allergic patients to whom cephalosporins had been administered (Pumphrey and Davis, 1999) or decreased effectiveness and increased antimicrobial resistance due to excessive use of non-beta-lactam antibiotics (Kelkar and Li, 2001). A recent study by our group (Romano et al., 2004), as well as previous ones assessing subjects with IgE-mediated allergy to penicillins (Audicana et al., 1994; Novalbos et al., 2001; Warrington et al., 1978), demonstrate that negative results in skin testing with cephalosporins are a useful indicator of tolerability. There were no adverse reactions to cephalosporins in a total of 174 challenged patients with negative skin tests to cephalosporins: our 101 patients (Romano et al., 2004) plus the 73 from the previous smaller series (Audicana et al., 1994; Novalbos et al., 2001; Warrington et al., 1978). In contrast, 7 of the 145 (4.8%) penicillin-allergic subjects from all the aforesaid studies (Assem and Vickers, 1974; Blanca et al., 1989; Macy, 1998; Saxon et al., 1987; Shepherd and Burton, 1993; Solley et al., 1982)—who were not administered cephalosporin skin tests—suffered adverse reactions. The difference in adverse reactions to cephalosporins between the two groups supports the advisability of performing skin tests with cephalosporins before their administration to penicillin-allergic patients. With regard to cell-mediated cross-reactivity, it has been described among penicillins in patients with this kind of hypersensitivity (de Haan et al., 1986; Romano et al., 1999). In delayed allergy to aminopenicillins, both the beta-lactam core structure and the whole molecule (core structure and the amino-benzyl group of the side-chain) are recognised by T cells (MauriHellweg et al., 1996; Padovan et al., 1996). However, the amino-benzyl group plays a predominant role: more than 70% of patients with such hypersensitivity display negative responses to benzylpenicillin (Romano et al., 1999). Cross-reactivity of penicillin-specific T cell clones with various cephalosporins has never been observed in vitro, even if the same side-chain was present (Mauri-Hellweg et al., 1996). This does not mean only that alterations of side-chain affect recogni-

tion, but also that the same side-chain presented by cephalosporin core structures are not recognised. Thus, cell-mediated cross-reactivity between cephalosporins and penicillins seems to be very rare. However, crossreactivity with cephalosporins has been demonstrated by challenges or patch tests in patients with this kind of hypersensitivity to penicillins (Patriarca et al., 1999). There are few published data concerning crossreactivity between penicillins and carbapenems (McConnell et al., 2000; Saxon et al., 1988). One study demonstrated a 50% rate of cross-reactivity with imipenem in patients with IgE-mediated hypersensitivity to penicillin, but skin tested only 20 subjects (Saxon et al., 1988). In another retrospective study of patients who had undergone bone marrow transplant, about 10% of cross-reactivity with imipem was observed in those with a self-reported or confirmed penicillin allergy (McConnell et al., 2000). On the other hand, the monobactam prototype aztreonam seems to have a very weak cross-reactivity with other classes of beta-lactams and to be well tolerated by patients with IgE-mediated hypersensitivity to penicillins (Adkinson, 1990; Saxon et al., 1984; Vega et al., 1991). In addition, a case of sensitisation to aztreonam with cross-reactivity to ceftazidime (a third-generation cephalosporin, which shares the same side-chain with aztreonam) diagnosed by skin tests has been described (P´erez Pimiento et al., 1998). With regard to patients allergic to cephalosporins, the principles of allergenic cross-reactions among these beta-lactams are similar to those among penicillins, i.e., recognition of the core ring structures may result in cross-reactivity with all cephalosporins, regardless of side-chain structure. However, because the R2 as well as the R1 side-chain group may differ among different cephalosporins, the situation is more complex. Cross-reactivity may occur via R1 recognition, where side-chain groups are the same (for example, cefaclor and cephalexin, cefotaxime and ceftriaxone) or similar (cefaclor and cefadroxil, cefuroxime and ceftriaxone), or it may be affected by R2 recognition (cephalexin and cephadrine, cephalothin and cefotaxime) (Baldo, 1999). We recently examined 30 patients with an IgEmediated hypersensitivity to injectable cephalosporins (cefuroxime, ceftazidime, ceftriaxone and cefotaxime) (Romano et al., 2000). Four subjects (group B, 13.3%) were positive to penicillin determinants. Twenty-six re-

A. Romano et al. / Toxicology 209 (2005) 169–179

acted only to cephalosporins (group A, 86.7%), displaying two patterns of skin test reactivity: one (n = 15, 57.7%) characterised by selective responses to the responsible cephalosporins and the other (n = 11, 42.3%) by positive responses to different cephalosporins, particularly to cefuroxime, ceftriaxone and cefotaxime. 2.2. Non-beta-lactam antibiotics Cross-reactivity among other antimicrobial drugs, like sulfonamides and quinolones (Fig. 1), has also been diagnosed on the basis of skin test and/or serumspecific IgE assay responses. An important clinical problem with respect to sulfonamide antibiotics is the degree of cross-reactivity between these compounds, which have an arylamine group at the N4 position of the benzene ring, and other sulfonamide derivatives (diuretics, carbonic anhydrase inhibitors, sulfonylureas, celecoxib, etc.), which do not have this group. However, few studies have addressed this problem. In vitro studies have demonstrated that a sulfonamide (SO2 –NH2 ) structure present in furosemide or celecoxib is never sufficient by itself to stimulate T cell clones originally stimulated by sulfamethoxazole; on the other hand, celecoxibstimulated T cells do not recognise sulfamethoxazole (Britschgi et al., 2001; Depta and Pichler, 2003; von Greyerz et al., 1999). Therefore, the complete sulfanilamide core structure is always required to elicit in vitro cross-reactivity to other sulfonamides with antibacterial activity (Depta and Pichler, 2003; Pichler, 2003). As far as IgE-mediated reactions are concerned, Harle et al. (1988) demonstrated that the substituted sulfonamide region of sulfonamide antibiotics is a strong determinant of recognition by specific IgE. The attachment of a five- or six-member aromatic heterocyclic ring with at least one nitrogen to the sulfonamido-N1 and the presence of a single methyl group on the second carbon atom (␤ position) from the sulfonamido substitution are important allergenic determinants. Unlike sulfonamide nonantibiotics, sulfamethoxazole, sulfamerazine, and sulfamethizole contain such determinants and have a greater potential for cross-reactivity. These data have been confirmed by a recent study on cross-reactivity among sulfonamide drugs which used the solutionaffinity analysis technique and the BIACORE 3000 biosensor, showing that the sulfonamide containing

173

moiety is not an especially reliable indicator of drug cross-reactivity and antigenic potency (Ahmad et al., 2002). Furthermore, Carrington et al. (1987) developed an in vitro assay, which detected IgE to sulfamethoxazole in 7 out of 10 patients with immediate reactions. Binding of one reactive serum was significantly inhibited by sulfamethoxazole, sulfamerazine, and sulfamethizole, but not by sulfanilic acid, suggesting that the N4 -sulfonamidoyl group was a major determinant recognised by IgE to sulfamethoxazole. In the study by Shapiro et al. (2000), six patients with sulfonamide allergy diagnosed by intradermal or in vitro testing tolerated celecoxib, confirming Cribb et al.’s meta-analysis (1996) of data from clinical trials of celecoxib, which found no increased risk of an allergic reaction related to sulfonamide hypersensitivity. However, there are subjects with adverse reactions to both sulfonamide antibiotics and sulfonamide non-antibiotics, such as celecoxib (Kaur et al., 2001; Schuster and W¨uthrich, 2003). These could be cases of double sensitisations (Ong and Sullivan, 1988). Further studies are required to clarify this issue. With regard to quinolones, a recent study by Manfredi et al. (2004) demonstrated an IgE-mediated cross-reactivity among these antimicrobial agents. In fact, 16% of the patients assessed (9 out of 55) had reported reactions to more than one quinolone, and the majority of patients (24 out of 30) with positive radioimmunoassays revealed specific IgE to several quinolones.

3. Non-antimicrobial drugs 3.1. Muscle relaxants Muscle relaxants are responsible for about 60% of anaphylactic reactions occurring during anaesthesia (Mertes et al., 2003). Such manifestations are due to a pharmacological effect on mast cells and basophils in 30% of cases, while they are based on an allergic hypersensitivity in the other 70%, with specific IgE antibodies directed against the quaternary ammonium radicals, which are shared by all muscle relaxants (Baldo and Fisher, 1983). This explains the high rate of crossreactivity among these drugs observed by skin testing, serum IgE-radioimmunoassays, and, to a lesser extent, in vitro leukocyte histamine release (Gu´eant et al.,

174

A. Romano et al. / Toxicology 209 (2005) 169–179

1991; Mata et al., 1992; Mertes and Laxenaire, 2002; Mertes et al., 2003). Recently, such cross-reactivity was diagnosed in 220 out of 293 (75.1%) patients who had experienced IgE-mediated anaphylactic reactions during anaesthesia (Mertes et al., 2003). Nevertheless, cross-reactivity is not found in all patients who have experienced IgE-mediated anaphylaxis provoked by a muscle relaxant (Laxenaire et al., 1995). This is because specific IgE can recognise structures adjacent to the ammonium groups. An allergologic exam is mandatory in patients with a documented allergy to a muscle relaxant in view of future anaesthesia. The best way of looking for cross-reactivity in such subjects is to perform intradermal tests with all the new muscle relaxants available. Prick tests are not appropriate when looking for crossreactivity. Non-irritant dilutions must be precisely defined for each agent tested in order to avoid falsepositive results due to direct histamine releasing properties, such as those of mivacurium, atracurium, and tubocurarine. In dubious cases, the leukocyte histamine release test could be useful. If the new agent does not cause positive results to these tests, it could be chosen as an alternative drug for future anaesthesia (Laxenaire et al., 1995; Mertes and Laxenaire, 2002). In patients with negative results in allergologic tests, a muscle relaxant different from the responsible agent should be selected, and a preoperative preparation of corticosteroids and antihistamines could be administered (Patterson et al., 1995). 3.2. Hypnotics Life-threatening anaphylactic reactions have been reported, with serum IgE antibodies that cross-react with thiopentone via substituted ammonium groups (Harle et al., 1990). This could explain the frequency of reactions to thiopentone in patients allergic to muscle relaxants (Moneret-Vautrin et al., 1990). Several cases of anaphylactic reactions to propofol have been also observed (Laxenaire et al., 1988, 1992), with evidence of specific in vitro histamine release and detection of serum specific IgE (Gu´eant et al., 1993, 1998). These IgE have a very low affinity for propofol and, in some cases, may cross-react with the quaternary ammoniums of lecithins, used for dissolving propofol in micelles, and may increase the release of histamine observed in vitro (Gu´eant et al., 1998).

3.3. Anticonvulsants Cross-reactivity has been reported among aromatic anticonvulsant drugs such as phenytoin, phenobarbital, and carbamazepine, which are known to cause cutaneous eruptions as well as a severe hypersensitivity syndrome (HS) consisting of fever, rash, lymphadenopathy, and differing degrees of internal organ involvement. Such cross-reactivity may be as high as 75% and has been explained by the fact that these drugs are metabolised into reactive intermediates, such as toxic arene oxides. Under certain circumstances, these intermediates may accumulate and bind covalently to cellular macromolecules, directly causing cell damage or initiating immune responses (Shear and Spielberg, 1988). Use of the in vitro lymphocyte toxicity assay in patients with HS demonstrated increased cytotoxicity in them compared with controls. Moreover, 40 out of 50 patients with HS to one aromatic anticonvulsant showed cross-reactivity to the other two, as evaluated by in vitro toxicity tests. Seven out of the 10 of them who had received the three drugs had adverse reactions to each (Shear and Spielberg, 1988). Immune responses have been shown to be T cellmediated, with the involvement of both CD4+ and CD8+ T cell subsets (Mauri-Hellweg et al., 1995). Moreover, in patients with anticonvulsant-associated HS, drug-specific T cells that express cutaneous lymphocyte antigen and type-1 cytokines have been identified (Naisbitt et al., 2003). Because of this immune response, both patch tests and delayed-reading intradermal tests can be useful tools for diagnosing such hypersensitivity reactions. In some studies (Galindo et al., 2002; Maquiera et al., 1996), subjects with HS associated with carbamazepine and/or phenytoin displayed positive patch tests to both drugs, suggesting a cell-mediated cross-reactivity or, more likely, coexisting sensitisations. Patients who have suffered a HS should avoid all aromatic anticonvulsants; potential alternatives are valproic acid (but not in the acute phase, because of the risk of hepatitis), gabapentin, vigabatrin, topiramate and benzodiazepines, while oxcarbazepine should be considered potentially cross-reactive with carbamazepine. However, HS patients often relapse with fever and rash after administration of other drugs unrelated to the offending ones. Some studies (Kano et al., 2004; Shiohara, 2004) suggest an intimate relationship be-

A. Romano et al. / Toxicology 209 (2005) 169–179

tween human herpes virus 6 (HHV-6) reactivation associated with decreased serum IgG levels and decreased B cell counts and the development of a severe hypersensitivity reaction. According to Shiohara (2004), a massive expansion of HHV-6 specific and non-specific bystander CD8+ and CD4+ T cells in response to HHV6 reactivation occurs, and these cells might be crossreactive to drugs and thus be able to recognise multiple antigens, thereby causing severe clinical illness involving multiple organs. 3.4. Heparins Heparins can be classified according to their molecular weight as un-fractionated heparins (UFHs, 10–20 kDa: heparin calcium, heparin sodium), low molecular weight heparins (LMWHs, 4–6 kDa: enoxaparin, dalteparin, centoparin, repivarin, nadroparin, tinzaparin), and ultra low molecular weight heparins (ULMWHs, 1.7 kDa: fondaparinux). Delayed-type hypersensitivity reactions have been reported with UFH, LMWHs and heparinoids (danaparoid sodium, glycosaminoglycane polysulfate, and pentosanpolysulfate). Such reactions usually consist of erythematous, infiltrated, or vesicular (eczema-like) itchy plaques usually confined to the injection sites, but sometimes accompanied by a maculopapular rash (Koch et al., 2000; W¨utschert et al., 1999). A cell-mediated pathogenic mechanism has been demonstrated in patients who have delayed-type hypersensitivity reactions. 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. Subcutaneous provocation tests are performed with 0.1 ml of an undiluted compound, and must be read until the fifth day (W¨utschert et al., 1999). Delayed-type hypersensitivity reactions to UFHs, LMWHs, and heparinoids following subcutaneous tests show a high degree of cross-reactivity. However, some patients can tolerate LMWHs, even though they present hypersensitivity to UFHs, and vice versa. This finding is important, since the use of UFHs may be necessary in severe thromboembolic diseases or in the context of vascular surgery. Heparin preparations found to be negative in subcutaneous testing may be selected

175

for further treatments. Argatroban, a direct thrombin inhibitor, and recombinant hirudins are recommended for those patients with hypersensitivity to most or all heparins and heparinoid preparations (Grassegger et al., 2001). Specifically, recombinant hirudins may be administered by intravenous (lepirudin) or subcutaneous (desirudin) routes, and have proved to be effective in preventing thrombotic disorders. However, recombinant hirudins may also induce immediate- and delayed-type hypersensitivity reactions (Koch et al., 2000). Moreover, hirudins and oral anticoagulants are contra-indicated during pregnancy for thromboprophylaxis, which is usually carried out with LMWHs. In case of delayed hypersensitivity to the latter, single case studies have shown that fondaparinux, a ULMWH, can be a safe alternative (Borch and Bindslev-Jensen, 2004; Maetzke et al., 2004). The entire allergologic work-up with a panel of different UFHs, LMWHs and heparinoids is very timeconsuming. Because reactions are not life-threatening, in patients urgently requiring anticoagulation the therapy can be changed immediately to lepirudin, and specific symptomatic treatment can be initiated (Koch et al., 2000). 3.5. Contrast media (CM) CM can provoke both non-allergic and allergic hypersensitivity reactions. Non-allergic immediate reactions (i.e., occurring within 1 h after administration), such as itching and urticaria, could be associated with non-specific histamine release from basophils and mast cells due to a direct membrane effect related to the osmolality of the CM solution (Laroche et al., 1998). Therefore, cross-reactivity among CM can be explained by their common characteristic of hypertonicity. However, in some severe immediate reactions, like anaphylactic shock, an IgE-mediated pathogenic mechanism has been demonstrated on the basis of positive results of skin tests and serum specific IgE assays (Laroche et al., 1998; Mita et al., 1998). Laroche et al. (1998) observed IgE-mediated cross-reactivity among ionic CM, but not with iopamidol, a non-ionic CM, in two patients who had experienced severe reactions respectively to amidotrizoate and ioxithalamate. Furthermore, the affinity of IgE for CM is extremely low and suggests a non-specific rather than a specific bind-

176

A. Romano et al. / Toxicology 209 (2005) 169–179

ing, which occurs only at a high concentration of the compound (Rodriguez et al., 2002). Pretreatment with corticosteroids and antihistamines may be indicated for some patients who have had immediate reactions to CM and display negative results in allergologic tests (Patterson et al., 1995). Non-immediate (i.e., occurring more than 1 h after administration) allergy-like reactions to CM consist mainly of cutaneous manifestations, such as maculopapular rashes, fixed eruptions, erythema multiforme, and urticarial eruptions. The most frequently involved agents are iopamidol, iohexol, iopentol, and ioversol, among non-ionic CM, and ioxaglate and ioxithalamate, among ionic CM. Recent data strongly indicate that most of these manifestations are T cell-mediated hypersensitivity reactions. This concept is supported by the presence of T cell infiltrates in the affected skin, the frequently positive skin tests and lymphocyte transformation tests for the culprit CM in previous reactors, and the reappearance of the eruption after provocation testing. In particular, positive delayed-reading skin tests and/or patch tests for the responsible compound have been found in about 100 patients with CM-induced late-onset skin reactions. Approximately 50% of the patients presented positive responses not only to the culprit CM, but also to other, structurally similar compounds (Christiansen, 2002). Corticosteroids, when administered with appropriate lead-time before exams with CM, appear to confer protection against delayed systemic reactions to ionic and non-ionic CM (Lasser et al., 1994). However, in the only patient with a true delayed allergic reaction to iopamidol—diagnosed on the basis of patch test positivity—a pretreatment regimen with prednisone and cetirizine, started 3 days before the exam, was not effective (Courvoisier and Bircher, 1998). In such patients, administration of 6-methylprednisolone and cyclosporine 1 week before and 2 weeks after the exam could be effective. Recently, we evaluated a patient with maculopapular reactions to iopamidol who needed angiographies for a cerebral arteriovenous malformation. In vivo and in vitro tests were performed with ionic and non-ionic CM, including iopamidol and iobitridol. All results were positive, demonstrating delayed hypersensitivity. Our subject received this prophylactic protocol before four angiograms with iobitridol, which were well tolerated (Romano et al., 2002).

3.6. Corticosteroids Cell-mediated hypersensitivity to corticosteroids is a frequent cause of contact dermatitis; a persistent skin disease that fails to respond to locally applied corticosteroids (Matura and Goossens, 2000). Most patients with this kind of hypersensitivity react to several corticosteroids. Clinical studies have led to the classification of corticosteroids into four groups according to their allergenicity (Coopman et al., 1989; Scheuer and Warshaw, 2003). In general, many positive reactions are observed to group A (e.g., hydrocortisone, prednisolone and methylprednisolone), group B (e.g., triamcinolone acetonide, amcinonide and budesonide), and those compounds belonging to group D2, which lack both a C16 methyl and halogen substitute (e.g., hydrocortisone-17-butyrate, -aceponate, buteprate, methylprednisolone aceponate and prednicarbate). Group D2 steroids show significant crossreactivity within their own group as well as to group A compounds and budesonide (group B). On the other hand, group C and those of group D1 that are C16 methyl and halogen substituted (e.g., betamethasone and its esters, clobetasone and its esters, mometasone furoate, and fluticasone propionate) produce very few allergic contact reactions (Matura and Goossens, 2000). Group D1 compounds exhibit minimal crossreactivity with other steroid groups. Tixocortol pivalate and budesonide have proved to be very useful screening markers of corticosteroid hypersensitivity. Tixocortol pivalate and hydrocortisone contact allergy are definitely associated; therefore, the former is used to test for allergies to the group A compounds. Budesonide detects a different pattern of corticosteroid hypersensitivity. It is involved in crossreactions not only with acetonides (group B, to which it theoretically belongs), but also with some of the esters of group D (Lepoittevin et al., 1995). Less is known about the classification and crossreactivity patterns of systemic steroid preparations than those of topical preparations. It is generally accepted, however, that the same cross-reactivity patterns observed for topical preparations occur when they are used systemically. As with their topical counterparts, there will be exceptions to systemic steroid cross-reactivity patterns. Thus, there are no adequate substitutes for direct patch testing the corticos-

A. Romano et al. / Toxicology 209 (2005) 169–179

teroid compound in question (Scheuer and Warshaw, 2003).

4. Conclusions The main clinical problem that can derive from cross-reactivity among drugs is the compelling need to choose a potentially cross-reactive compound, and, therefore, to assess cross-reactivity by diagnostic tests. Even if infrequently, it may be also necessary to use a drug found to cross-react. Generally, because of the limited sensitivity of in vivo and in vitro tests, a graded challenge is advisable to establish the tolerability of a compound of the same group in those patients who especially require one, when other allergologic tests are negative. Pretreatments may be indicated for some patients who have had immediate reactions to CM or muscle relaxants and display negative results in allergologic tests. Desensitisation is sometimes indicated when it is necessary to use a drug found to cross-react and no alternative compounds are available. Both graded challenges and desensitisation procedures should be performed by specialists experienced with these protocols and the possible adverse events associated with them (Patterson et al., 1995).

References Adkinson Jr., N.F., 1990. Immunogenicity and cross-allergenicity of aztreonam. Am. J. Med. 88 (Suppl. 3C), 12S–15S. Ahmad, A., Ramakrishnan, A., McLean, M.A., Li, D., Rock, M.T., Karim, A., Breu, A.P., 2002. Use of optical biosensor technology to study immunological cross-reactivity between different sulfonamide drugs. Anal. Biochem. 300, 177– 184. Assem, E.S., Vickers, M.R., 1974. Tests for penicillin allergy in man. II. The immunological cross-reaction between penicillins and cephalosporins. Immunology 27, 255–269. Audicana, M., Bernaola, G., Urrutia, I., Echechipia, S., Gastaminza, G., Mu˜noz, D., Fern´andez, E., Fern´andez de Corres, L., 1994. Allergic reactions to betalactams: studies in a group of patients allergic to penicillin and evaluation of cross-reactivity with cephalosporin. Allergy 49, 108–113. Baldo, B.A., 1999. Penicillins and cephalosporins as allergens—structural aspects of recognition and cross-reactions. Clin. Exp. Allergy 29, 744–749. Baldo, B.A., Fisher, M.M., 1983. Substituted ammonium ions as allergenic determinants in drug allergy. Nature 306, 262–264.

177

Blanca, M., Fernandez, J., Miranda, A., Terrados, S., Torres, M.J., Vega, J.M., Avila, M.J., Perez, E., Garcia, J.J., Suau, R., 1989. Cross-reactivity between penicillins and cephalosporins: clinical and immunologic studies. J. Allergy Clin. Immunol. 83, 381–385. Blanca, M., Mayorga, C., Torres, M.J., Warrington, R., Romano, A., Demoly, P., Silviu-Dan, F., Moya, M., Fernandez, J., Juarez, C., 2002. Side-chain-specific reactions to betalactams: 14 years later. Clin. Exp. Allergy 32, 192–197. Borch, J.E., Bindslev-Jensen, C., 2004. Delayed-type hypersensitivity to heparins. Allergy 59, 118–119. Britschgi, M., Steiner, U.C., Schmid, S., Depta, J.P.H., Senti, G., Bircher, A., Burkhart, C., Yawalkar, N., Pichler, W.J., 2001. T-cell involvement in drug-induced acute generalized exanthematous pustolosis. J. Clin. Invest. 107, 1433–1441. Carrington, D.M., Earl, H.S., Sullivan, T.J., 1987. Studies of human IgE to a sulfonamide determinant. J. Allergy Clin. Immunol. 79, 442–447. Christiansen, C., 2002. Late-onset allergy-like reactions to X-ray contrast media. Curr. Opin. Allergy Clin. Immunol. 2, 333–339. Coopman, S., Degreef, H., Dooms-Goossens, A., 1989. Identification of cross-reaction patterns in allergic contact dermatitis from topical corticosteroids. Br. J. Dermatol. 121, 27–34. Courvoisier, S., Bircher, A.J., 1998. Delayed-type hypersensitivity to a nonionic, radiopaque contrast medium. Allergy 53, 1221– 1224. Cribb, A.E., Lee, B.L., Trepanier, L.A., Spielberg, S.P., 1996. Adverse reactions to sulphonamide and sulphonamide–trimethoprim antimicrobials: clinical syndromes and pathogenesis. Adverse Drug React. Toxicol. Rev. 15, 9–50. de Haan, P., Bruynzeel, D.P., Van Ketel, W.G., 1986. Onset of penicillin rashes: relation between type of penicillin administered and type of immune reactivity. Allergy 41, 75–78. Depta, J.P.H., Altznauer, F., Gamerdinger, K., Burkhart, C., Weltzien, H.U., Pichler, W.J., 2004. Drug interaction with T-cell receptors: T-cell receptor density determines degree of cross-reactivity. J. Allergy Clin. Immunol. 113, 519–527. Depta, J.P.H., Pichler, W.J., 2003. Cross-reactivity with drugs at the T cell level. Curr. Opin. Allergy Clin. Immunol. 3, 261– 267. Fernandez, M., Warbrick, E.V., Blanca, M., Coleman, J.W., 1995. Activation and hapten inhibition of mast cells sensitized with monoclonal IgE anti-penicillin antibodies: evidence for two-site recognition of the penicillin derived determinant. Eur. J. Immunol. 25, 2486–2491. Galindo, P.A., Borja, J., G´omez, E., Mur, P., Gud´ın, M., Garc´ı, R., Encinas, C., Romero, G., Garrido, J.A., Cortina, P., Feo, F., 2002. Anticonvulsant drug hypersensitivity. J. Invest. Allergol. Clin. Immunol. 12, 299–304. Grassegger, A., Fritsch, P., Reider, N., 2001. Delayed-type hypersensitivity and cross-reactivity to heparins and danaparoid: a prospective study. Dermatol. Surg. 27, 47–52. Grieco, M.H., 1967. Cross-allergenicity of the penicillin and the cephalosporins. Arch. Intern. Med. 119, 141–145. Gu´eant, J.L., Aimone-Gastin, I., Namour, F., Laroche, D., Bellou, A., Laxenaire, M.C., 1998. Diagnosis and pathogenesis of the anaphylactic and anaphylactoid reactions to anaesthetics. Clin. Exp. Allergy 28 (Suppl. 4), 65–70.

178

A. Romano et al. / Toxicology 209 (2005) 169–179

Gu´eant, J.L., Mata, E., Masson, C., G´erard, P., Moneret-Vautrin, D.A., Mouton-Faivre, C., Laxenaire, M.C., 1995. Non-specific cross-reactivity of hydrophobic serum IgE to hydrophobic drugs. Mol. Immunol. 32, 259–266. Gu´eant, J.L., Mata, E., Masson, C., Moneret-Vautrin, D.A., Laxenaire, M.C., 1993. Nonspecific interactions in anti-agent IgERIA to anesthetic agents. Ann. Fr. Anesth. Reanim. 12, 141–146. Gu´eant, J.L., Mata, E., Monin, B., Moneret-Vautrin, D.A., Kamel, L., Nicolas, J.P., Laxenaire, M.C., 1991. Evaluation of a new reactive solid phase for radioimmunoassay of serum specific IgE against muscle relaxant drugs. Allergy 46, 452–458. Harle, D.G., Baldo, B.A., Fisher, M.M., 1990. The molecular basis of IgE antibody binding to thiopentone. Binding of IgE from thiopentone-allergic and non-allergic subjects. Mol. Immunol. 27, 853–858. Harle, D.G., Baldo, B.A., Wells, J.V., 1988. Drugs as allergens: detection and combining site specificities of IgE antibodies to sulfamethoxazole. Mol. Immunol. 25, 1347–1354. Johansson, S.G., Hourihane, J.O., Bousquet, J., Bruijnzeel-Koomen, C., Dreborg, S., Haahtela, T., Kowalski, M.L., Mygind, N., Ring, J., van Cauwenberge, P., van Hage-Hamsten, M., W¨uthrich, B., 2001. A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force. Allergy 56, 813–824. Kano, Y., Inaoka, M., Shiohara, T., 2004. Association between anticonvulsant hypersensitivity syndrome and human herpesvirus 6 reactivation and hypogammaglobulinemia. Arch. Dermatol. 140, 183–188. Kaur, C., Sarkar, R., Kanwar, A.J., 2001. Fixed drug eruption to rofecoxib with cross-reactivity to sulfonamides. Dermatology 203, 351. Kelkar, P.S., Li, J.T., 2001. Cephalosporin allergy. N. Engl. J. Med. 345, 804–809. Koch, P., M¨unßinger, T., Rupp-John, C., Uhl, K., 2000. Delayedtype hypersensitivity skin reactions caused by subcutaneous unfractioned and low-molecular weight heparins: Tolerance of a new recombinant hirudins. J. Am. Acad. Dermatol. 42, 612–619. Laroche, D., Aimone-Gastin, I., Dubois, F., Huet, H., G´erard, P., Vergnaud, M.C., Mouton-Faivre, C., Gu´eant, J.L., Laxenaire, M.C., Bricard, H., 1998. Mechanisms of severe, immediate reactions to iodinated contrast material. Radiology 209, 183–190. Lasser, E.C., Berry, C.C., Mishkin, M.M., Williamson, B., Zheutlin, N., Silverman, J.M., 1994. Pretreatment with corticosteroids to prevent adverse reactions to nonionic contrast media. Am. J. Roentgenol. 162, 523–526. Laxenaire, M.C., Gastin, I., Moneret-Vautrin, D.A., Widmer, S., Gu´eant, J.L., 1995. Cross-reactivity of rocuronium with other neuromuscular blocking agents. Eur. J. Anaesthesiol. 12 (Suppl. 11), 55–64. Laxenaire, M.C., Gu´eant, J.L., Bermejo, E., Mouton, C., Navez, M.T., 1988. Anaphylactic shock due to propofol. Lancet 24, 739–740. Laxenaire, M.C., Mata-Bermejo, E., Moneret-Vautrin, D.A., Gu´eant, J.L., 1992. Life-threatening anaphylactoid reactions to propofol (Diprivan). Anesthesiology 77, 275–280. Lepoittevin, J.P., Drieghe, J., Dooms-Goossens, A., 1995. Studies in patients with corticosteroids contact allergy. Understanding

cross-reactivity among different steroids. Arch. Dermatol. 131, 31–37. Macy, E., 1998. Elective penicillin skin testing and amoxicillin challenge: effect on outpatient antibiotic use, cost, and clinical outcomes. J. Allergy Clin. Immunol. 102, 281–285. Maetzke, J., Hinrichs, R., Staib, G., Scharffetter-Kochanekm, K., 2004. Fondaparinux as a novel therapeutic alternative in a patient with heparin allergy. Allergy 59, 237–238. Manfredi, M., Severino, M., Testi, S., Macchia, D., Ermini, G., Pichler, W.J., Campi, P., 2004. Detection of specific IgE to quinolones. J. Allergy Clin. Immunol. 113, 155–160. Maquiera, E., Yanez, S., Fernandez, L., Rodriguez, F., Picans, I., Sanchez, I., Jerez, J., 1996. Mononucleosis-like illness as a manifestation of carbamazepine-induced anticonvulsant hypersensitivity syndrome. Allergol. Immunopathol. 24, 87–88. Mata, E., Gu´eant, J.L., Moneret-Vautrin, D.A., Bermejo, N., G´erard, P., Nicolas, J.P., Laxenaire, M.C., 1992. Clinical evaluation of in vitro leukocyte histamine release in allergy to muscle relaxant drugs. Allergy 47, 471–476. Matura, M., Goossens, A., 2000. Contact allergy to corticosteroids. Allergy 55, 698–704. Mauri-Hellweg, D., Bettens, F., Mauri, D., Brander, C., Hunziker, T., Pichler, W.J., 1995. Activation of drug-specific CD4+ and CD8+ T cells in individuals allergic to sulfonamides, phenytoin, and carbamazepine. J. Immunol. 155, 462–472. Mauri-Hellweg, D., Zanni, M., Frei, E., Bettens, F., Brander, C., Mauri, D., Padovan, E., Weltzien, H.U., Pichler, W.J., 1996. Cross-reactivity of T cell lines and clones to ␤-lactam antibiotics. J. Immunol. 157, 1071–1079. McConnell, S.A., Penzak, S.R., Warmack, T.S., Anaissie, E.J., Gubbins, P.O., 2000. Incidence of imipenem hypersensitivity reactions in febrile neutropenic bone marrow transplant patients with a history of penicillin allergy. Clin. Infect. Dis. 31, 1512–1514. Mertes, P.M., Laxenaire, M.C., 2002. Allergic reactions occurring during anaesthesia. Eur. J. Anaesthesiol. 19, 240–262. Mertes, P.M., Laxenaire, M.C., Alla, F., Groupe d’Etudes des R´eactions Anaphylacto¨ıdes Peranesth´esiques, 2003. Anaphylactic and anaphylactoid reactions occurring during anesthesia in France in 1999–2000. Anesthesiology 99, 536–545. Mita, H., Tadokoro, K., Akiyama, K., 1998. Detection of IgE antibody to a radiocontrast medium. Allergy 53, 1133–1140. Moneret-Vautrin, D.A., Widmer, S., Gu´eant, J.L., Kamel, L., Laxenaire, M.C., Mouton, C., Gerard, H., 1990. Simultaneous anaphylaxis to thiopentone and a neuromuscular blocker: a study of two cases. Br. J. Anaesth. 64, 743–745. Naisbitt, D.J., Farrel, J., Wong, G., Depta, J.P.H., Dodd, C.C., Hopkins, J.E., Gibney, C.A., Chadwick, D.W., Pichler, W.J., Pirmohamed, M., Park, K., 2003. Characterization of drug-specific T cells in lamotrigine hypersensitivity. J. Allergy Clin. Immunol. 111, 1393–1403. Novalbos, A., Sastre, J., Cuesta, J., De Las Heras, M., LluchBernal, M., Bomb´ın, C., Quirce, S., 2001. Lack of allergic crossreactivity to cephalosporins among patients allergic to penicillins. Clin. Exp. Allergy 31, 438–443. Ong, R., Sullivan, T., 1988. Detection and characterization of human IgE to cephalosporin determinants. J. Allergy Clin. Immunol. 81, 222 (abstract).

A. Romano et al. / Toxicology 209 (2005) 169–179 Padovan, E., Mauri-Hellweg, D., Pichler, W.J., Weltzien, H.U., 1996. T cell recognition of penicillin G: structural features determining antigenic specificity. Eur. J. Immunol. 26, 42–48. Patriarca, G., D’Ambrosio, C., Schiavino, D., La Rocca, L.M., Nucera, E., Milani, A., 1999. Clinical usefulness of patch and challenge tests in the diagnosis of cell-mediated allergy to betalactams. Ann. Allergy Asthma Immunol. 83, 257–266. Patterson, R., DeSwarte, R.D., Greenberger, P.A., Grammer, L.C., Brown, J.E., Choy, A.C., 1995. Drug allergy and Protocols for Management of Drug Allergies, second ed. OceanSide Publications, Providence, Rhode Island. P´erez Pimiento, A., G´omez Mart´ınez, M., M´ınguez Mena, A., Trampal Gonz´alez, A., de Paz Arranz, S., Rodr´ıguez, M., 1998. Aztreonam and ceftazidime: evidence of in vivo cross-allergenicity. Allergy 53, 624–625. Pichler, W.J., 2003. Delayed drug hypersensitivity reactions. Ann. Intern. Med. 139, 683–693. Pumphrey, R.S., Davis, S., 1999. Under-reporting of antibiotic anaphylaxis may put patients at risk. Lancet 353, 1157–1158 (letter). Rodriguez, R.M., Gu´eant, J.L., Aimone-Gastin, I., Gerard, P., Amoghly, F., Bellou, A., Julliere, Y., Faure, G., Danchin, N., Romano, A., 2002. The increased histamine release in ischaemic heart disease patients undergoing coronaroangiography is not mediated by specific IgE. Allergy 57 (Suppl. 72), 61–66. Romano, A., Artesani, M.C., Andriolo, M., Viola, M., Pettinato, R., Vecchioli-Scaldazza, A., 2002. Effective prophylactic protocol in delayed hypersensitivity to contrast media: Report of a case involving lymphocyte transformation studies with different compounds. Radiology 225, 466–470. Romano, A., Gu´eant-Rodriguez, R.M., Viola, M., Pettinato, R., Gu´eant, J.L., 2004. Cross-reactivity and tolerability of cephalosporins in patients with immediate hypersensitivity to penicillins. Ann. Intern. Med. 141, 16–22. Romano, A., Mayorga, C., Torres, M.J., Artesani, M.C., Suau, R., S´anchez, F., P´erez, E., Venuti, A., Blanca, M., 2000. Immediate allergic reactions to cephalosporins: Cross-reactivity and selective responses. J. Allergy Clin. Immunol. 106, 1177–1183. Romano, A., Quaratino, D., Di Fonso, M., Papa, G., Venuti, A., Gasbarrini, G., 1999. A diagnostic protocol for evaluating nonimmediate reactions to aminopenicillins. J. Allergy Clin. Immunol. 103, 1186–1190. Saxon, A., Adelman, D.C., Patel, A., Hajdu, R., Calandra, G.B., 1988. Imipenem cross-reactivity with penicillin in humans. J. Allergy Clin. Immunol. 82, 213–217.

179

Saxon, A., Beall, G.N., Rohr, A.S., Adelman, D.C., 1987. Immediate hypersensitivity reactions to beta-lactam antibiotics. Ann. Intern. Med. 107, 204–215. Saxon, A., Hassner, A., Swabb, E.A., Wheeler, B., Adkinson Jr., N.F., 1984. Lack of cross-reactivity between aztreonam, a monobactam antibiotic, and penicillin in penicillin-allergic subjects. J. Infect. Dis. 149, 16–22. Scheuer, E., Warshaw, E., 2003. Allergy to corticosteroids: update and review of epidemiology, clinical characteristics and structural cross-reactivity. Am. J. Contact Dermatol. 14, 179–187. Schuster, C., W¨uthrich, B., 2003. Anaphylactic drug reaction to celecoxib and sulfamethoxazole: cross-reactivity or coincidence? Allergy 58, 1072. Shapiro, L.E., Knowles, S.R., Weber, E., Neuman, M.G., Shear, N.H., 2000. Safety of celecoxib in individuals allergic to sulfonamide: a pilot study. Drug Saf. 26, 187–195. Shear, N.H., Spielberg, S.P., 1988. Anticonvulsant hypersensitivity syndrome, in vitro assessment of risk. J. Clin. Invest. 82, 1826–1832. Shepherd, G.M., 1991. Allergy to ␤-lactam antibiotics. Immunol. Allergy Clin. North Am. 11, 611–633. Shepherd, G.M., Burton, D.A., 1993. Administration of cephalosporin antibiotics to patients with a history of penicillin allergy. J. Allergy Clin. Immunol. 91, 262 (abstract). Shiohara, T., 2004. From viral infection to the development of drug allergy. Allergologie 27 (Suppl. 4), 146. Solley, G.O., Gleich, G.J., Van Dellen, R.G., 1982. Penicillin allergy: clinical experience with a battery of skin-test reagents. J. Allergy Clin. Immunol. 69, 238–244. Szczeklik, A., Stevenson, D.D., 2003. Aspirin-induced asthma: Advances in pathogenesis, diagnosis, and management. J. Allergy Clin. Immunol. 111, 913–921. Vega, J.M., Blanca, M., Garc´ıa, J.J., Mirando, A., Carmona, M.J., Garc´ıa, A., Moya, M.C., Sanchez, F., Terrados, S., 1991. Tolerance to aztreonam in patients allergic to betalactam antibiotics. Allergy 46, 196–202. von Greyerz, S., Zanni, M.P., Frutig, K., Schnyder, B., Burkhart, C., Pichler, W.J., 1999. Interaction of sulfonamide derivatives with TCR of sulfamethoxazole-specific human ␣␤+ T cell clones. J. Immunol. 162, 595–602. Warrington, R.J., Simons, F.E., Ho, H.W., Gorski, B.A., Tse, K.S., 1978. Diagnosis of penicillin allergy by skin testing: the Manitoba experience. Can. Med. Assoc. J. 118, 787–791. W¨utschert, R., Piletta, P., Bounameaux, H., 1999. Adverse skin reactions to low molecular weight heparins. Drug Saf. 20, 515–525.