cross-reactivity among drugs: clinical problems

Toxicology 209 (2005) 169–179

Cross-reactivity among drugs: clinical problems

Antonino Romanoa, b, ∗, Rosa-Maria Gueant-Rodriguezc, d, Marinella Violaa,Francesco Gaetaa, Cristiano Carusoa, Jean-Louis Gueantc

a Department of Internal Medicine and Geriatrics, UCSC-Allergy Unit, Unità di Allergologia, Complesso Integrato Columbus,Via G. Moscati 31, 00168 Rome, Italy

b IRCCS Oasi Maria S.S., Troina, Italyc Laboratoire de Pathologie Cellulaire et Moléculaire en Nutrition, EMI INSERM 0014 et IFREMER 20, Faculté de Medecine,

BP 184, F-54500 Vandoeuvre, Franced 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 explainedby 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 commonpharmacological characteristic, such as the inhibitory effect of non-steroidal anti-inflammatory drugs on cyclooxygenase-1 andthe 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 cross-skin testingng muscle

, delayed-

ity of atests are

s

llylic-ting

reactive compound and, therefore, to assess cross-reactivity by diagnostic tests. In choosing alternative compounds,has been used in evaluating IgE-mediated cross-reactivity between penicillins and cephalosporins, as well as amorelaxants.

In assessing T cell-mediated cross-reactivity among contrast media, corticosteroids, anticonvulsants and heparinsreading 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 tolerabilcompound of the same group in patients who especially require one is a graded challenge when other allergologicnegative.© 2004 Elsevier Ireland Ltd. All rights reserved.

Keywords:Beta-lactam antibiotics; Quinolones; Radio contrast media; IgE; T cells; Cross-reactivity; Drugs; Hypersensitivity reaction

∗ Corresponding author. Tel.: +39 06 3503782;fax: +39 06 3503235.

E-mail address:[email protected] (A. Romano).

1. Introduction

Cross-reactivity among drugs becomes clinicamanifest when a drug not previously administered eits hypersensitivity reactions because of a preexis

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) 169–179 171

sensitisation to a structurally related compound or be-cause of a common pharmacological characteristic.

The revised nomenclature for allergies classifies hy-persensitivity reactions to drugs as either allergic ornon-allergic (Johansson et al., 2001). The former aremediated by immunologic mechanisms, either antibod-ies or cells; all other reactions should be referred to asnon-allergic drug hypersensitivity. In addition, aller-gic reactions to drugs are classified as IgE-mediated ornon-IgE-mediated.

Cross-reactivity mediated by immunologic mecha-nisms is usually explained by the presence of a com-mon antigenic determinant in the cross-reacting drugs(Fig. 1). T cell cross-reactivity differs from that of IgE-mediated reactions. In vitro data suggest that T cellsrecognise 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 sul-famethoxazole hypersensitivity model, the completesulfanilamide core structure must always be presentto elicit cross-reactivity to other sulfonamides (Deptaand Pichler, 2003; Pichler, 2003). On the other hand,B cells may recognise smaller structures (Fernandez etal., 1995). In effect, an exclusive side-chain reactivityhas been reported for IgE in subjects with immediatereactions to penicillins and cephalosporins (Blanca etal., 2002).

Cross-reactivity can also derive from a non-specificbinding of drugs to IgE (Gueant et al., 1995). For ex-ample, most allergenic drugs, such as penicillin, arehr cans bu-l . Ah enta ctorf ,1

rgich nedb oss-r eena e-nt a tot on-i se

The question of whether some subjects develop aresponse to a drug because of cross-reactivity with an-other one or because of a coexisting sensitivity is oftendifficult to answer. An irrefutable proof of the exis-tence of a true cross-reactivity is provided by reactionsto compounds to which sensitive patients have not beenpreviously exposed. With regard to IgE-mediated hy-persensitivity reactions, this has been clearly demon-strated with muscle relaxants (Laxenaire et al., 1995).In addition, patients allergic to benzylpenicillin whohave never been administered cephalosporins may haveantibodies specific for the latter, indicating a cross-sensitivity (Grieco, 1967; Shepherd, 1991). However,there is some evidence (Ong and Sullivan, 1988) thatcoexisting sensitivities may occur.

The following drugs are frequently involved incross-reactivity.

2. Antimicrobial drugs

2.1. Beta-lactam antibiotics

Beta-lactam antibiotics constitute a classic exampleof compounds provoking both IgE- and cell-mediatedallergic reactions. Cross-reactions are frequent amongpenicillins as well as among cephalosporins; they canalso occur among classes, particularly between peni-cillins and cephalosporins (Blanca et al., 2002); infact, in addition to the beta-lactam ring, the side-chaing mont pi-c )(

tedi hed toc itiver orm-i rinc 4;B 87;S 82I 0%(V ngtS the

ydrophobic compounds containing a C6H5 phenyling (cyclohexenyl derivatives). These compoundstrongly bind to external hydrophobic areas of gloar proteins and therefore non-specifically bind IgEigh level of hydrophobic IgE in the serum of a patillergic to a hydrophobic drug seems to be a risk fa

or IgE cross-reactivity to another drug (Gueant et al.995).

In the case of compounds provoking non-alleypersensitivity reactions, cross-reactivity is explaiy common pharmacological characteristics. Creactivity among anti-inflammatory agents has bttributed to their inhibitory effect on cyclooxygase (COX)-1 (Szczeklik and Stevenson, 2003), while

hat among muscle relaxants or contrast mediheir capability of releasing histamine through a nmmunologic mechanism (Laroche et al., 1998; Mertet al., 2003).

roups sometimes present structural features como penicillins and cephalosporins (for example, amillin and cefaclor have an identical R1 side-chainFig. 1).

In patients with documented IgE-mediammediate hypersensitivity to penicillins, tata regarding a true allergic cross-reactivityephalosporins—diagnosed on the basis of posesponses to challenges carried out without perfng prophylactic skin tests with the cephalospooncerned—are variable (Assem and Vickers, 197lanca et al., 1989; Macy, 1998; Saxon et al., 19hepherd and Burton, 1993; Solley et al., 19).

n fact, such cross-reactivity varies betweenShepherd and Burton, 1993) and 100% (Assem andickers, 1974), the most recent review estimati

he rate of positivity at 4.4% (Kelkar and Li, 2001).uch variability has caused confusion concerning


administration of cephalosporins to penicillin-allergicpatients, which may lead to the risk of cross-reactivitybeing either under- or overestimated. In both cases,there may be negative consequences, such as fatalanaphylactic reactions in penicillin-allergic patientsto whom cephalosporins had been administered(Pumphrey and Davis, 1999) or decreased effective-ness and increased antimicrobial resistance due toexcessive use of non-beta-lactam antibiotics (Kelkarand Li, 2001).

A recent study by our group (Romano et al.,2004), as well as previous ones assessing subjects withIgE-mediated allergy to penicillins (Audicana et al.,1994; Novalbos et al., 2001; Warrington et al., 1978),demonstrate that negative results in skin testing withcephalosporins are a useful indicator of tolerability.There were no adverse reactions to cephalosporins ina total of 174 challenged patients with negative skintests to cephalosporins: our 101 patients (Romano etal., 2004) plus the 73 from the previous smaller se-ries (Audicana et al., 1994; Novalbos et al., 2001; War-rington et al., 1978). In contrast, 7 of the 145 (4.8%)penicillin-allergic subjects from all the aforesaid stud-ies (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 administeredcephalosporin skin tests—suffered adverse reactions.The difference in adverse reactions to cephalosporinsbetween the two groups supports the advisability ofperforming skin tests with cephalosporins before theira

hasb thisk noe s,b holem oupoH ,t oret layn .,1

esw rvedi ent( no ni-

tion, but also that the same side-chain presented bycephalosporin core structures are not recognised. Thus,cell-mediated cross-reactivity between cephalosporinsand penicillins seems to be very rare. However, cross-reactivity with cephalosporins has been demonstratedby challenges or patch tests in patients with this kind ofhypersensitivity to penicillins (Patriarca et al., 1999).

There are few published data concerning cross-reactivity between penicillins and carbapenems(McConnell et al., 2000; Saxon et al., 1988). Onestudy demonstrated a 50% rate of cross-reactivity withimipenem in patients with IgE-mediated hypersensitiv-ity to penicillin, but skin tested only 20 subjects (Saxonet al., 1988). In another retrospective study of patientswho had undergone bone marrow transplant, about10% of cross-reactivity with imipem was observed inthose with a self-reported or confirmed penicillin al-lergy (McConnell et al., 2000). On the other hand, themonobactam prototype aztreonam seems to have a veryweak cross-reactivity with other classes of beta-lactamsand to be well tolerated by patients with IgE-mediatedhypersensitivity to penicillins (Adkinson, 1990; Saxonet al., 1984; Vega et al., 1991). In addition, a caseof sensitisation to aztreonam with cross-reactivity toceftazidime (a third-generation cephalosporin, whichshares the same side-chain with aztreonam) diagnosedby skin tests has been described (Perez Pimiento et al.,1998).

With regard to patients allergic to cephalosporins,the principles of allergenic cross-reactions among theseb lins,i sulti lessow if-f lex.C es aclora ilar( ne),o na1

E-m rins( me)( )w re-

dministration to penicillin-allergic patients.With regard to cell-mediated cross-reactivity, it

een described among penicillins in patients withind of hypersensitivity (de Haan et al., 1986; Romat al., 1999). In delayed allergy to aminopenicillinoth the beta-lactam core structure and the wolecule (core structure and the amino-benzyl grf the side-chain) are recognised by T cells (Mauri-ellweg et al., 1996; Padovan et al., 1996). However

he amino-benzyl group plays a predominant role: mhan 70% of patients with such hypersensitivity dispegative responses to benzylpenicillin (Romano et al999).

Cross-reactivity of penicillin-specific T cell clonith various cephalosporins has never been obse

n vitro, even if the same side-chain was presMauri-Hellweg et al., 1996). This does not meanly that alterations of side-chain affect recog

eta-lactams are similar to those among penicil.e., recognition of the core ring structures may ren cross-reactivity with all cephalosporins, regardf side-chain structure. However, because the R2 asell as the R1 side-chain group may differ among d

erent cephalosporins, the situation is more compross-reactivity may occur via R1 recognition, wheride-chain groups are the same (for example, cefnd cephalexin, cefotaxime and ceftriaxone) or simcefaclor and cefadroxil, cefuroxime and ceftriaxor it may be affected by R2 recognition (cephalexind cephadrine, cephalothin and cefotaxime) (Baldo,999).

We recently examined 30 patients with an Igediated hypersensitivity to injectable cephalospo

cefuroxime, ceftazidime, ceftriaxone and cefotaxiRomano et al., 2000). Four subjects (group B, 13.3%ere positive to penicillin determinants. Twenty-six


acted only to cephalosporins (group A, 86.7%), dis-playing two patterns of skin test reactivity: one (n= 15,57.7%) characterised by selective responses to the re-sponsible cephalosporins and the other (n= 11, 42.3%)by positive responses to different cephalosporins, par-ticularly to cefuroxime, ceftriaxone and cefotaxime.

2.2. Non-beta-lactam antibiotics

Cross-reactivity among other antimicrobial drugs,like sulfonamides and quinolones (Fig. 1), has alsobeen diagnosed on the basis of skin test and/or serum-specific IgE assay responses.

An important clinical problem with respect to sul-fonamide antibiotics is the degree of cross-reactivitybetween these compounds, which have an arylaminegroup at theN4 position of the benzene ring, and othersulfonamide derivatives (diuretics, carbonic anhydraseinhibitors, sulfonylureas, celecoxib, etc.), which donot have this group. However, few studies have ad-dressed this problem. In vitro studies have demon-strated that a sulfonamide (SO2–NH2) structure presentin furosemide or celecoxib is never sufficient by it-self to stimulate T cell clones originally stimulatedby sulfamethoxazole; on the other hand, celecoxib-stimulated T cells do not recognise sulfamethoxazole(Britschgi et al., 2001; Depta and Pichler, 2003; vonGreyerz et al., 1999). Therefore, the complete sulfanil-amide core structure is always required to elicit in vitrocross-reactivity to other sulfonamides with antibacte-r

ned,H ti-t ticsi ificI ro-m ent lemt or-t on-a sul-f ve ag haveb tivitya ion-a 00b ning

moiety is not an especially reliable indicator of drugcross-reactivity and antigenic potency (Ahmad et al.,2002). Furthermore,Carrington et al. (1987)developedan in vitro assay, which detected IgE to sulfamethoxa-zole in 7 out of 10 patients with immediate reactions.Binding of one reactive serum was significantly in-hibited by sulfamethoxazole, sulfamerazine, and sul-famethizole, but not by sulfanilic acid, suggesting thattheN4-sulfonamidoyl group was a major determinantrecognised by IgE to sulfamethoxazole. In the study byShapiro et al. (2000), six patients with sulfonamide al-lergy diagnosed by intradermal or in vitro testing toler-ated celecoxib, confirmingCribb et al.’s meta-analysis(1996)of data from clinical trials of celecoxib, whichfound no increased risk of an allergic reaction related tosulfonamide hypersensitivity. However, there are sub-jects with adverse reactions to both sulfonamide an-tibiotics and sulfonamide non-antibiotics, such as cele-coxib (Kaur et al., 2001; Schuster and Wuthrich, 2003).These could be cases of double sensitisations (Ong andSullivan, 1988). Further studies are required to clarifythis issue.

With regard to quinolones, a recent study byManfredi et al. (2004)demonstrated an IgE-mediatedcross-reactivity among these antimicrobial agents. Infact, 16% of the patients assessed (9 out of 55) hadreported reactions to more than one quinolone, andthe majority of patients (24 out of 30) with positiveradioimmunoassays revealed specific IgE to severalquinolones.

3

3

0%o the-s uet philsi c hy-p nti-b rad-ia s-r test-i r ex-t ,

ial activity (Depta and Pichler, 2003; Pichler, 2003).As far as IgE-mediated reactions are concer

arle et al. (1988)demonstrated that the subsuted sulfonamide region of sulfonamide antibios a strong determinant of recognition by specgE. The attachment of a five- or six-member aatic heterocyclic ring with at least one nitrog

o the sulfonamido-N1 and the presence of a singethyl group on the second carbon atom (� posi-

ion) from the sulfonamido substitution are impant allergenic determinants. Unlike sulfonamide nntibiotics, sulfamethoxazole, sulfamerazine, and

amethizole contain such determinants and hareater potential for cross-reactivity. These dataeen confirmed by a recent study on cross-reacmong sulfonamide drugs which used the solutffinity analysis technique and the BIACORE 30iosensor, showing that the sulfonamide contai

. Non-antimicrobial drugs

.1. Muscle relaxants

Muscle relaxants are responsible for about 6f anaphylactic reactions occurring during anaesia (Mertes et al., 2003). Such manifestations are do a pharmacological effect on mast cells and bason 30% of cases, while they are based on an allergiersensitivity in the other 70%, with specific IgE aodies directed against the quaternary ammonium

cals, which are shared by all muscle relaxants (Baldond Fisher, 1983). This explains the high rate of croseactivity among these drugs observed by skinng, serum IgE-radioimmunoassays, and, to a lesseent, in vitro leukocyte histamine release (Gueant et al.


1991; Mata et al., 1992; Mertes and Laxenaire, 2002;Mertes et al., 2003). Recently, such cross-reactivitywas diagnosed in 220 out of 293 (75.1%) patients whohad experienced IgE-mediated anaphylactic reactionsduring anaesthesia (Mertes et al., 2003). Nevertheless,cross-reactivity is not found in all patients who haveexperienced IgE-mediated anaphylaxis provoked by amuscle relaxant (Laxenaire et al., 1995). This is be-cause specific IgE can recognise structures adjacent tothe ammonium groups.

An allergologic exam is mandatory in patients witha documented allergy to a muscle relaxant in viewof future anaesthesia. The best way of looking forcross-reactivity in such subjects is to perform intrader-mal tests with all the new muscle relaxants available.Prick tests are not appropriate when looking for cross-reactivity. Non-irritant dilutions must be precisely de-fined for each agent tested in order to avoid false-positive results due to direct histamine releasing prop-erties, such as those of mivacurium, atracurium, andtubocurarine. In dubious cases, the leukocyte histaminerelease test could be useful. If the new agent does notcause positive results to these tests, it could be chosenas an alternative drug for future anaesthesia (Laxenaireet al., 1995; Mertes and Laxenaire, 2002).

In patients with negative results in allergologic tests,a muscle relaxant different from the responsible agentshould be selected, and a preoperative preparation ofcorticosteroids and antihistamines could be adminis-tered (Patterson et al., 1995).

3

eenr eactw ups( ofr scler so alsooo n ofsI ec iumso s,a ed inv

3.3. Anticonvulsants

Cross-reactivity has been reported among aromaticanticonvulsant drugs such as phenytoin, phenobarbi-tal, and carbamazepine, which are known to causecutaneous eruptions as well as a severe hypersensi-tivity syndrome (HS) consisting of fever, rash, lym-phadenopathy, and differing degrees of internal organinvolvement. Such cross-reactivity may be as high as75% and has been explained by the fact that these drugsare metabolised into reactive intermediates, such astoxic arene oxides. Under certain circumstances, theseintermediates may accumulate and bind covalently tocellular macromolecules, directly causing cell damageor initiating immune responses (Shear and Spielberg,1988). Use of the in vitro lymphocyte toxicity assayin patients with HS demonstrated increased cytotoxic-ity in them compared with controls. Moreover, 40 outof 50 patients with HS to one aromatic anticonvulsantshowed cross-reactivity to the other two, as evaluatedby in vitro toxicity tests. Seven out of the 10 of themwho had received the three drugs had adverse reactionsto each (Shear and Spielberg, 1988).

Immune responses have been shown to be T cell-mediated, with the involvement of both CD4+ andCD8+ T cell subsets (Mauri-Hellweg et al., 1995).Moreover, in patients with anticonvulsant-associatedHS, drug-specific T cells that express cutaneous lym-phocyte antigen and type-1 cytokines have been iden-tified (Naisbitt et al., 2003). Because of this immuner intra-d uchhea dis-p ing ac ist-i

alla val-p e risko andb con-s ine.

andr d tot ;S e-

.2. Hypnotics

Life-threatening anaphylactic reactions have beported, with serum IgE antibodies that cross-rith thiopentone via substituted ammonium gro

Harle et al., 1990). This could explain the frequencyeactions to thiopentone in patients allergic to muelaxants (Moneret-Vautrin et al., 1990). Several casef anaphylactic reactions to propofol have beenbserved (Laxenaire et al., 1988, 1992), with evidencef specific in vitro histamine release and detectioerum specific IgE (Gueant et al., 1993, 1998). ThesegE have a very low affinity for propofol and, in somases, may cross-react with the quaternary ammonf lecithins, used for dissolving propofol in micellend may increase the release of histamine observitro (Gueant et al., 1998).

esponse, both patch tests and delayed-readingermal tests can be useful tools for diagnosing sypersensitivity reactions. In some studies (Galindot al., 2002; Maquiera et al., 1996), subjects with HSssociated with carbamazepine and/or phenytoinlayed positive patch tests to both drugs, suggestell-mediated cross-reactivity or, more likely, coexng sensitisations.

Patients who have suffered a HS should avoidromatic anticonvulsants; potential alternatives areroic acid (but not in the acute phase, because of thf hepatitis), gabapentin, vigabatrin, topiramateenzodiazepines, while oxcarbazepine should beidered potentially cross-reactive with carbamazep

However, HS patients often relapse with feverash after administration of other drugs unrelatehe offending ones. Some studies (Kano et al., 2004hiohara, 2004) suggest an intimate relationship b


tween human herpes virus 6 (HHV-6) reactivation asso-ciated with decreased serum IgG levels and decreasedB cell counts and the development of a severe hyper-sensitivity reaction. According toShiohara (2004), amassive expansion of HHV-6 specific and non-specificbystander CD8+ and CD4+ T cells in response to HHV-6 reactivation occurs, and these cells might be cross-reactive to drugs and thus be able to recognise multipleantigens, thereby causing severe clinical illness involv-ing multiple organs.

3.4. Heparins

Heparins can be classified according to theirmolecular weight as un-fractionated heparins (UFHs,10–20 kDa: heparin calcium, heparin sodium), lowmolecular weight heparins (LMWHs, 4–6 kDa: enoxa-parin, dalteparin, centoparin, repivarin, nadroparin, tin-zaparin), and ultra low molecular weight heparins(ULMWHs, 1.7 kDa: fondaparinux). Delayed-type hy-persensitivity reactions have been reported with UFH,LMWHs and heparinoids (danaparoid sodium, gly-cosaminoglycane polysulfate, and pentosanpolysul-fate). Such reactions usually consist of erythematous,infiltrated, or vesicular (eczema-like) itchy plaquesusually confined to the injection sites, but sometimesaccompanied by a maculopapular rash (Koch et al.,2000; Wutschert et al., 1999).

A cell-mediated pathogenic mechanism has beendemonstrated in patients who have delayed-type hy-p ons,d sitivet ationt nos-t ducef testsa nd,a .,1

Hs,L ust ver,s theyp Thisfi ben in thec undt ected

for further treatments. Argatroban, a direct thrombininhibitor, and recombinant hirudins are recommendedfor those patients with hypersensitivity to most or allheparins and heparinoid preparations (Grassegger etal., 2001). Specifically, recombinant hirudins may beadministered by intravenous (lepirudin) or subcuta-neous (desirudin) routes, and have proved to be effec-tive in preventing thrombotic disorders. However, re-combinant hirudins may also induce immediate- anddelayed-type hypersensitivity reactions (Koch et al.,2000). Moreover, hirudins and oral anticoagulants arecontra-indicated during pregnancy for thromboprophy-laxis, which is usually carried out with LMWHs. Incase of delayed hypersensitivity to the latter, single casestudies have shown that fondaparinux, a ULMWH, canbe a safe alternative (Borch and Bindslev-Jensen, 2004;Maetzke et al., 2004).

The entire allergologic work-up with a panel of dif-ferent UFHs, LMWHs and heparinoids is very time-consuming. Because reactions are not life-threatening,in patients urgently requiring anticoagulation the ther-apy can be changed immediately to lepirudin, and spe-cific symptomatic treatment can be initiated (Koch etal., 2000).

3.5. Contrast media (CM)

CM can provoke both non-allergic and allergic hy-persensitivity reactions. Non-allergic immediate re-actions (i.e., occurring within 1 h after administra-t oci-a philsa latedt ,1 bee er-t

ons,l enicm f pos-i says( l.( ongi ,i tionsr ur-t wa bind-

ersensitivity reactions. In evaluating such reactielayed-reading intradermal tests are more sen

han patch tests. However, subcutaneous provocests are considered to be the most reliable diagic method, because intradermal testing may proalse-negative results. Subcutaneous provocationre performed with 0.1 ml of an undiluted compound must be read until the fifth day (Wutschert et al999).

Delayed-type hypersensitivity reactions to UFMWHs, and heparinoids following subcutaneo

ests show a high degree of cross-reactivity. Howeome patients can tolerate LMWHs, even thoughresent hypersensitivity to UFHs, and vice versa.nding is important, since the use of UFHs mayecessary in severe thromboembolic diseases orontext of vascular surgery. Heparin preparations foo be negative in subcutaneous testing may be sel

ion), such as itching and urticaria, could be assted with non-specific histamine release from basond mast cells due to a direct membrane effect re

o the osmolality of the CM solution (Laroche et al.998). Therefore, cross-reactivity among CM canxplained by their common characteristic of hyponicity.

However, in some severe immediate reactiike anaphylactic shock, an IgE-mediated pathog

echanism has been demonstrated on the basis otive results of skin tests and serum specific IgE asLaroche et al., 1998; Mita et al., 1998). Laroche et a1998)observed IgE-mediated cross-reactivity amonic CM, but not with iopamidol, a non-ionic CMn two patients who had experienced severe reacespectively to amidotrizoate and ioxithalamate. Fhermore, the affinity of IgE for CM is extremely lond suggests a non-specific rather than a specific


ing, which occurs only at a high concentration of thecompound (Rodriguez et al., 2002).

Pretreatment with corticosteroids and antihis-tamines may be indicated for some patients who havehad immediate reactions to CM and display negativeresults in allergologic tests (Patterson et al., 1995).

Non-immediate (i.e., occurring more than 1 h af-ter administration) allergy-like reactions to CM con-sist mainly of cutaneous manifestations, such as mac-ulopapular rashes, fixed eruptions, erythema multi-forme, and urticarial eruptions. The most frequentlyinvolved agents are iopamidol, iohexol, iopentol, andioversol, among non-ionic CM, and ioxaglate and iox-ithalamate, among ionic CM.

Recent data strongly indicate that most of these man-ifestations are T cell-mediated hypersensitivity reac-tions. This concept is supported by the presence of Tcell infiltrates in the affected skin, the frequently posi-tive skin tests and lymphocyte transformation tests forthe culprit CM in previous reactors, and the reappear-ance of the eruption after provocation testing. In par-ticular, positive delayed-reading skin tests and/or patchtests for the responsible compound have been found inabout 100 patients with CM-induced late-onset skin re-actions. Approximately 50% of the patients presentedpositive responses not only to the culprit CM, but alsoto other, structurally similar compounds (Christiansen,2002).

Corticosteroids, when administered with appropri-ate lead-time before exams with CM, appear to conferp onicat tiont testp nea s note -t cy-c xamc tientw deda ma-t nica ol.A hy-p cticp chw

3.6. Corticosteroids

Cell-mediated hypersensitivity to corticosteroids isa frequent cause of contact dermatitis; a persistent skindisease that fails to respond to locally applied corticos-teroids (Matura and Goossens, 2000). Most patientswith this kind of hypersensitivity react to several cor-ticosteroids.

Clinical studies have led to the classification ofcorticosteroids into four groups according to theirallergenicity (Coopman et al., 1989; Scheuer andWarshaw, 2003). In general, many positive reac-tions are observed to group A (e.g., hydrocorti-sone, prednisolone and methylprednisolone), group B(e.g., triamcinolone acetonide, amcinonide and budes-onide), and those compounds belonging to group D2,which lack both a C16 methyl and halogen substi-tute (e.g., hydrocortisone-17-butyrate, -aceponate, -buteprate, methylprednisolone aceponate and predni-carbate). Group D2 steroids show significant cross-reactivity within their own group as well as to group Acompounds and budesonide (group B). On the otherhand, group C and those of group D1 that are C16methyl and halogen substituted (e.g., betamethasoneand its esters, clobetasone and its esters, mometa-sone furoate, and fluticasone propionate) produce veryfew allergic contact reactions (Matura and Goossens,2000). Group D1 compounds exhibit minimal cross-reactivity with other steroid groups.

Tixocortol pivalate and budesonide have proved tob hy-p nec , thef Ac rn ofc ss-r h itt terso

oss-r ionst ac-c pat-t hent calc mics o ad-e icos-

rotection against delayed systemic reactions to ind non-ionic CM (Lasser et al., 1994). However, in

he only patient with a true delayed allergic reaco iopamidol—diagnosed on the basis of patchositivity—a pretreatment regimen with prednisond cetirizine, started 3 days before the exam, waffective (Courvoisier and Bircher, 1998). In such pa

ients, administration of 6-methylprednisolone andlosporine 1 week before and 2 weeks after the eould be effective. Recently, we evaluated a paith maculopapular reactions to iopamidol who neengiographies for a cerebral arteriovenous malfor

ion. In vivo and in vitro tests were performed with iond non-ionic CM, including iopamidol and iobitridll results were positive, demonstrating delayedersensitivity. Our subject received this prophylarotocol before four angiograms with iobitridol, whiere well tolerated (Romano et al., 2002).

e very useful screening markers of corticosteroidersensitivity. Tixocortol pivalate and hydrocortisoontact allergy are definitely associated; thereforeormer is used to test for allergies to the groupompounds. Budesonide detects a different patteorticosteroid hypersensitivity. It is involved in croeactions not only with acetonides (group B, to whicheoretically belongs), but also with some of the esf group D (Lepoittevin et al., 1995).

Less is known about the classification and creactivity patterns of systemic steroid preparathan those of topical preparations. It is generallyepted, however, that the same cross-reactivityerns observed for topical preparations occur whey are used systemically. As with their topiounterparts, there will be exceptions to systeteroid cross-reactivity patterns. Thus, there are nquate substitutes for direct patch testing the cort


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

4. Conclusions

The main clinical problem that can derive fromcross-reactivity among drugs is the compelling needto 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 adrug found to cross-react.

Generally, because of the limited sensitivity of invivo and in vitro tests, a graded challenge is advis-able to establish the tolerability of a compound of thesame group in those patients who especially requireone, when other allergologic tests are negative.

Pretreatments may be indicated for some patientswho have had immediate reactions to CM or musclerelaxants and display negative results in allergologictests. Desensitisation is sometimes indicated when itis necessary to use a drug found to cross-react and noalternative compounds are available. Both graded chal-lenges and desensitisation procedures should be per-formed by specialists experienced with these protocolsand the possible adverse events associated with them(Patterson et al., 1995).

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cross-reactivity among drugs: clinical problems

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