REVIEW

CURRENTOPINION Nonimmediate hypersensitivity reactions to

iodinated contrast media

Copyright © Lippincott W

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´ a a ´ b c

Enrique Gomez , Adriana Ariza , Natalia Blanca-Lopez , and Maria J. Torres

Purpose of review

To provide a detailed analysis of the latest findings on the mechanisms underlying the nonimmediatereactions to iodinated contrast media and comment on the recent advances in diagnosis, focusing on theroles of the skin test, drug provocation test (DPT), and lymphocyte transformation test (LTT).

Recent findings

Several studies have reported new findings supporting an important role for T-lymphocytes in thenonimmediate reactions to iodinated contrast media. The LTT has been used as an in-vitro tool fordiagnosis, but with variable results. However, the inclusion of autologous monocyte-derived dendritic cellsas professional antigen-presenting cells has improved the sensitivity of this test. Regarding in-vivo diagnosis,although skin testing has been routine, it has now been shown that its sensitivity and negative predictive valueare low. Recent studies have demonstrated that the DPT is a well tolerated and useful procedure that isnecessary to confirm the diagnosis of nonimmediate hypersensitivity reactions to iodinated contrast media.

Summary

Nonimmediate reactions to contrast media are usually T-cell mediated. Diagnosis is based on skin testing,although its sensitivity and negative predictive value are not optimal. Consequently, drug provocationtesting is often needed to confirm the diagnosis and also to seek alternative contrast media that can betolerated.

Keywords

drug provocation test, hypersensitivity, iodine contrast media, lymphocyte transformation test,nonimmediate reactions, skin test

aResearch Laboratory for Allergic Diseases, Carlos Haya Hospital,Malaga, bAllergy Service, Infanta Leonor Hospital, Madrid and cAllergyService, Carlos Haya Hospital, Malaga, Spain

Correspondence to M.J. Torres, MD, PhD, Allergy Service, Pabellon 6,Primera planta, Carlos Haya Hospital (Pabellon C), Plaza del HospitalCivil, 29009Malaga, Spain. Tel: +34 951290346; fax: +34 951290302;e-mail: mjtorresj@gmail.com

Curr Opin Allergy Clin Immunol 2013, 13:345–353

DOI:10.1097/ACI.0b013e328362b926

INTRODUCTION

Iodinated contrast media are used to enhance theimaging of different organs and vessels, with morethan 70 million injections administered each yearworldwide [1]. Iodinated contrast media are highlyconcentrated solutions sharing a tri-iodinatedbenzene ring, but differing in the side chain in 1,3, and 5 positions and in the number of benzenerings. Iodinated contrast media are classified intofour groups depending on their chemical structure,osmolarity, iodine content, and ionization degree insolution: high osmolarity ionic monomers, lowosmolarity nonionic monomers, low osmolarityionic dimers, and low osmolarity nonionic dimers[2] (Table 1).

Although iodinated contrast media are usuallywell tolerated, hypersensitivity reactions neverthe-less occur. These reactions are classified accordingto the time interval between drug administrationand symptom appearance as immediate or non-immediate reactions. Immediate reactions are those

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appearing within 1 h of iodinated contrast mediaadministration, and nonimmediate reactions arethose occurring after at least 1 h, although mostappear 6–12 h after iodinated contrast mediaadministration [3]. Because of this delayed appear-ance and because many physicians are unaware thatsuch reactions can occur, nonimmediate reactionsto iodinated contrast media are often attributed toother agents, thus hampering the diagnosis andmanagement of these patients. This review focuseson the recent advances in the understanding of the

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KEY POINTS

� Nonimmediate allergic reactions to contrast media aremainly T-cell mediated.

� Diagnosis on nonimmediate allergic reactions tocontrast media may be difficult.

� Skin testing is routinely used; however, sensitivity andnegative predictive value are not optimal.

� Drug provocation testing may be necessary to confirmskin-test results and are useful for testing alternativeiodinated contrast media.

� LTT is frequently used as an in-vitro test; however,results are inconsistent. Inclusion of autologous dendriticcells can improve its sensitivity.

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mechanisms involved and in the diagnosis ofpatients with nonimmediate reactions to iodinatedcontrast media.

EPIDEMIOLOGY

The incidence of adverse reactions to iodinatedcontrast media has been estimated to be between0.6 and 12.7% [4,5], though since 2000 thereappears to have been a decrease in their incidencein Japan [6]. A recent retrospective study [4] of84 928 patients receiving iodinated contrast mediafound the frequency of hypersensitivity reactions tobe 0.6%, with 77% mild, 21% moderate, and 2%severe. A recent evaluation of drug hypersensitivityreactions seen in a Spanish Allergy unit from 2005 to2010 found an increase in the percentage of reac-tions attributed to iodinated contrast media rosefrom 2.1 to 4.07%, and in those finally confirmedas having iodinated contrast media hypersensitivityfrom 1.08 to 5.9%; this is now the leading cause ofnonimmediate reactions in this Spanish population[7]. Similar results have been reported by others,with iodinated contrast media being the thirdleading cause of all cutaneous drug reactions inves-tigated, after antibiotics and nonsteroidal anti-inflammatory drugs [8].

The frequency of nonimmediate reactions variesfrom 0.5 to 23% [9]. In this type of reaction, the skinis the most affected organ, with an average inci-dence of cutaneous symptoms between 1 and 3%[1]. These reactions are generally mild, and althoughrarely severe, they can nevertheless still be life-threatening [10]. Nonionic dimers seem to be moreoften implicated than nonionic monomers as thecause of nonimmediate reactions, contrary to thesituation with immediate reactions [11]. However, arecent study [12] evaluating a large group of patients

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receiving the nonionic monomer iohexol foundhypersensitivity reactions in 14.3% of the patientscompared with 2.5% in the control group. Thesestudies thus suggest that the reporting of non-immediate hypersensitivity reactions to iodinatedcontrast media seems to be increasing, which there-fore requires diagnostic workups to be established.Risk factors identified for nonimmediate reactions toiodinated contrast media are female sex, a previousreaction to iodinated contrast media, atopy, a historyof drug and contact allergy, interleukin-2 treatmentand other diseases such as diabetes mellitus, andheart, liver or kidney diseases [13,14].

MECHANISMS INVOLVED

The pathogenesis of nonimmediate reactions toiodinated contrast media is becoming clearer andT-cell involvement has been postulated. Argumentsin favor of this idea include the presence of a clinicalpicture of nonimmediate iodinated contrast mediareactions that resembles other drug-allergic T-cell-mediated reactions or the fact that re-exposure tothe culprit drug increases the incidence of theseallergic reactions [14]. Several reports have describedpositive results with skin patch testing or delayed-reading intradermal tests, tests that are typicallyused to diagnose nonimmediate reactions[10,14,15], as well as to monitor the immuneresponse during the acute and resolution phases,showing T-cell participation [10]. Immunohistolog-ical studies [10,15–17] on affected skin after a non-immediate reaction induced by iodinated contrastmedia have revealed the presence of a perivascularmononuclear cell infiltrate composed mainly ofCD45ROþ CD3þ T cells, with a higher frequencyof CD4þ T cells mainly in the dermis, a moderateexpression of CD25 and perforin, and a high expres-sion of HLA-DR and CLA, accompanied by anincreased influx of eosinophils (Fig. 1). These resultshave been confirmed by flow cytometry in whichanalysis of CD4þ and CD8þ T cells showed a higherexpression of the early activation marker CD69during the acute phase, whereas analysis of samples15 days after the reaction disclosed a significantincrease in the late activation marker CD25[10,18]. The pattern of these T-cell responses hasalso been evaluated by cytokine assays, whichshowed an increased production of IFN-g and IL-2in patients when compared with tolerant individ-uals [19]. The mechanisms by which iodinated con-trast media are recognized by T cells are still beingdebated. Although a direct interaction of drugs withthe T-cell receptor has been shown [20], the mostaccepted mechanism was proposed by Landsteiner[21] who described how a chemical compound has

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Table 1. Chemical structures of commonly used iodinated contrast media (CM)

ype of CM Name Chemical structure Type of CM Name Chemical structure

onic monomeric Meglumine Iothalamate Ionic dimeric Ioxaglate

Meglumine Ioxithalamate

Sodium amidotrizoate

on-ionic monomeric Iohexol Non-ionic dimeric Iotrolan

Iopentol

Ioxitol

Iomeprol

Iopromide Iodixanol

Iobitridol

Iopamidol

Ioversol

Nonimmediate hypersensitivity reactions to ICM Gomez et al.

T

I

N

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H-E CD3 CD4

HLA-DR Perforin

CD8 CD25

CD45RO CD69 CLA

FIGURE 1. Hematoxylin–eosin and immunohistochemical analysis of different markers, CD3, CD4, CD8, CD25, CD45RO,CD69, human leukocyte antigen D-related (HLA-DR), cutaneous lymphocyte-associated antigen (CLA), and perforin in a skinbiopsy obtained after a drug provocation test with CM. CM, iodinated contrast media.

Drug allergy

to be bound to a protein (Hapten concept), thusbecoming accessible to the immune system and tobeing recognized by antigen-presenting cells (APCs),which in turn process and present the iodinatedcontrast media on MHC type II molecules to T-lymphocytes. Several cellular compounds are thusinvolved in nonimmediate iodinated contrastmedia reactions, with CD4þ T cells and APCs beingkey players in their development.

CLINICAL SYMPTOMS

As mentioned earlier, the skin is the organ mostfrequently involved in nonimmediate reactions toiodinated contrast media, with maculopapularexanthema (MPE) being the clinical entity mostoften reported in the different studies, accountingfor 37.5–91% of all reactions evaluated [10,22

&

,23–28], followed by urticaria and angioedema fromaround 40% of cases diagnosed [22

&

,23] to up to62.4% of patients [28]. Regarding the severity of thereactions, most were mild or moderate, with figuresranging from 76.4 to 98.7% in the studies[22

&

,23,25] that evaluated larger series of patients.Although less frequent, reports also exist of

other skin disorders such as fixed drug eruptions[29] and contact dermatitis [30], as well as a fewsevere reactions such as Stevens–Johnson syndrome[31], toxic epidermal necrolysis [32], and acutegeneralized exanthematic pustulosis [33–35].

DIAGNOSTIC APPROACH

The diagnosis of nonimmediate reactions to iodi-nated contrast media is a complex issue that has

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been attracting increased attention over the recentyears, with diagnostic guidelines now available [3].The allergological workup is based on the clinicalhistory and skin tests, though more recently thedrug provocation test (DPT) has been shown tobe a necessary tool for the diagnosis of a nonnegliblepercentage of cases. In-vitro tests such as thelymphocyte transformation test (LTT) have alsobeen used for diagnosis. These methods will bediscussed in detail below.

Clinical history

In daily practice, the clinical history can be particu-larly difficult in nonimmediate reactions because inmany cases it is not easy to establish a temporalassociation between drug administration and onsetof symptoms, especially in those cases in which thereactions appear more than 24 h after the drugintake. Moreover, in many cases, it is difficult toidentify the iodinated contrast media administeredand reactions can be attributed to other drugs, suchas acetylsalicylic acid, used during coronary angiog-raphy. It is also important to record the type ofreaction (which in some cases can be confused withother skin disorders), the time interval between thereaction and the study, and the severity. Thesedifficulties therefore necessitate the use of otherdiagnostic tests.

Skin test

Skin tests are useful tools in the allergologicalworkup of nonimmediate hypersensitivity reac-tions to iodinated contrast media. It has been

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Nonimmediate hypersensitivity reactions to ICM Gomez et al.

recommended to perform prick and intradermaltesting at 1/10 dilution, and patch testing undilutedwith readings at 24, 48, 72, and 96 h [6,15,22

&

,23–25,27,28,36–38]. Intradermal tests have also beencarried out undiluted without false-positive results,with nearly 70% reacting to the undiluted concen-tration and 30% to the 1/10 dilution, thus reinforc-ing the need to perform skin tests undiluted innonimmediate reactions [22

&

]. These tests are quitesafe and no systemic symptoms have beendescribed. Even patch testing has been used in moresevere reactions such as toxic epidermal necrolysiswith positive results [32].

A number of studies [6,10,15,22&

,23–25,27,28,36–38,39

&

] have shown the value of skin testing inthe diagnosis of nonimmediate reactions to drugs,with positive results ranging from 18.7 to 66.7%(Table 2). Variables associated with the presenceof positive skin testing include the type of skin test,the time interval between the reaction and thestudy, the history of allergy to other drugs, andthe type of iodinated contrast media. In fact, aconsensus exists that the sensitivity of intradermaltests is higher than that of patch testing. In theallergological workup, therefore, it is recommendedto begin with intradermal tests with delayed read-ings and if negative continue with patch testing.Skin testing is more likely to be positive if conductedbetween 2 and 6 months after the reaction [23] andin patients with a confirmed allergy to other drugs[22

&

,24,27,38]. In addition, the type of iodinatedcontrast media influences skin test results, the per-centage of positivity being lower with iodixanolthan with iomeprol [22

&

].A detailed analysis of two studies [22

&

,23] whichincluded a large number of patients showed con-trasting results. Whereas one study [22

&

] found that21.1% of the patients with a consistent clinicalhistory were skin-test positive, in the other [23], amulticenter study, 38% of the patients with aclinical history of nonimmediate reactions to iodi-nated contrast media were skin-test positive.Reasons for these differences could include thetime interval between the reaction and the study,the skin-test procedures, the interpretation of theresults, and the criteria to consider cases as positive,although the more plausible explanation is selectionbias in the multicenter study. Nevertheless, thesedata indicate that although useful, skin-test sensi-tivity with iodinated contrast media is still low,although agreement exists about the high specificityof skin testing.

The negative predictive value of skin testing innonimmediate reactions to iodinated contrastmedia has not been sufficiently established. In somestudies [10,24,37] performed in a limited number of

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patients with negative delayed reading intradermaland patch tests, a DPT with the culprit iodinatedcontrast media, mainly iodixanol, was done, givingpositive results ranging from 17 to 41.67%. Caimmiet al. [36] performed DPT in patients with initialnegative skin tests, and found that one in four with ahistory of nonimmediate reactions presented withmild reactions upon DPT. However, the DPT wasdone with the culprit iodinated contrast media injust one case. A recent study [22

&

] in 127 cases withnegative skin tests found that DPT with the culpritiodinated contrast media was positive in 44 (34.6%).This indicates that the predictive value of skin test-ing is low and that DPT is often needed to confirmthe diagnosis.

DPT can also be used to seek an alternativeiodinated contrast media in patients with confirmedhypersensitivity to one or several iodinated contrastmedia. In these cases, the iodinated contrast mediaused for DPT is selected based on negative skin-testresults. Some authors [25,27] believe that skin test-ing alone is a suitable tool for selecting an alterna-tive iodinated contrast media safely and DPT is notnecessary. However, controversy exists as a recentstudy [22

&

] found that 32.3% of patients developed apositive DPT (nine to one iodinated contrast mediaand two to two iodinated contrast media) with aiodinated contrast media that produced a negativeskin test. A similar situation was seen in a patientwith a positive DPT despite a negative skin test forthe iodinated contrast media [39

&

].

Drug provocation test

As stated above, the negative predictive value of skintesting in nonimmediate reactions to iodinated con-trast media is not sensitive enough, and DPT may benecessary to confirm a negative skin test result andalso to search for an alternative in those who areskin-test positive. A single-blind, placebo-controlledprocedure is recommended, administering the iodi-nated contrast media intravenously diluted in salineat different doses at 1-h intervals, in two runs sep-arated unless 1 week time to detect reactions appear-ing over 48 h later. In the first run, 5, 10, and 15 cc ofiodinated contrast media are administered and, ifthis is well tolerated, 1 week later iodinated contrastmedia is administered at 20, 30, and 50 cc (cumu-lative dose¼100 cc) [22

&

]. This high cumulativedose is important because nearly 40% of casesresponded to 100 cc. By using this methodology,these authors diagnosed 59.4% of the total casesfinally confirmed as allergic. They also found that40% of the cases with a positive skin test had apositive DPT when a skin-test negative iodinatedcontrast media was used. These data are in

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Table 2. CM involved in the reaction, skin tests and drug provocation test results

Culprit CM Skin testDPT culprit withnegative skin test

DPT alternative withnegative skin test Reference

Iomeprol (n¼4) Iomeprol (n¼4) Iomeprol (n¼2) Not done [10]

Iodixanol (n¼2) Iodixanol (n¼4) Not done (n¼4)

Ioversol (n¼4) Negative (n¼0)

Iopramide (n¼3)

Negative (n¼2)

Iomeprol (n¼53) Iodixanol (n¼38) Iodixanol (n¼9) [22&]

Iodixanol (n¼46) Iomeprol (n¼21) Iomeprol (n¼8) Iohexol (n¼4)

Iohexol (n¼27) Iodixanol (n¼7) Iohexol (n¼4) Negative (n¼23)

Iobitridol (n¼4) Iobitridol (n¼5) Negative (n¼83)

Ioversol (n¼3) Ioxaglate (n¼4)

Iopramide (n¼3) Iohexol (n¼3)

Ioxaglate (n¼3) Iopramide (n¼1)

Unknown (n¼33) Negative (n¼127)

Iodixanol (n¼9) Not done Not done [23]

Iobitridol (n¼4) Iohexol (n¼10)

Iohexol (n¼5) Iopentol (n¼7)

Iomeprol (n¼12) Ioversol (n¼10)

Iopamidol (n¼3) Iomeprol (n¼11)

Iopentol (n¼7) Iopamidol (n¼11)

Iopromide (n¼8) Iopromide (n¼10)

Ioversol (n¼2) Iobitridol (n¼10)

Iodixanol (n¼26) Iotrolan (n¼6)

Ioxithalamate (n¼4) Ioxaglate (n¼11)

Amidotrizoate (n¼1) Ioxithalamate (n¼9)

Others (n¼5) Amidotrizoate (n¼8)

Unknown (n¼24) Iodamide (n¼1)

Negative (n¼61)

Iodixanol (n¼14) Iodixanol (n¼3) Iodixanol (n¼4) Ioxaglate (n¼1) [24]

Unknown (n¼1) Ioxaglate (n¼1) Not done (n¼11) Negative (n¼10)

Ioxithalamate (n¼4)

Iobitridol (n¼2)

Iomeprol (n¼3)

Iohexol (n¼3)

Iopamidol (n¼5)

Negative (n¼12)

Iopamidol (n¼5) Iopamidol (n¼5) Not done Not done (n¼2) [25]

Iopromide (n¼12) Iopromide (n¼4) Negative (n¼4)

Iomeprol (n¼10) Iomeprol (n¼5)

Iopentol (n¼2) Iopentol (n¼3)

Iohexol (n¼1) Ioversol (n¼2)

Iotrolan (n¼1) Iobitridol (n¼1)

Iodixanol (n¼1) Iotrolan (n¼1)

Iodixanol (n¼2)

Negative (n¼26)

Iodixanol (n¼22) Iodixanol (n¼11) Not done Negative (n¼11) [27]

Iohexol (n¼6)

Ioversol (n¼4)

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Table 2 (Continued)

Culprit CM Skin testDPT culprit withnegative skin test

DPT alternative withnegative skin test Reference

Iopentol (n¼3)

Iomeprol (n¼2)

Iopamidol (n¼2)

Iobitridol (n¼1)

Negative (n¼11)

Iohexol (n¼7) Iohexol (n¼1) Not done Not done [28]

Iopramide (n¼1) Iodixanol (n¼1)

Unknown (n¼2) Iomeprol (n¼1)

Negative (n¼8)

Iopamidol (n¼1) Negative (n¼4) Iobitridol (n¼1) Negative (n¼2) [36]

Iomeprol (n¼1) Negative (n¼1)

Unknown (n¼2)

Iodixanol (n¼12) Iodixanol (n¼3) Iodixanol (n¼2) Not done [37]

Negative (n¼9)

Unknown (n¼11) Iopamidol (n¼1) Not done Not done [38]

Iohexol (n¼1)

Ioversol (n¼1)

Iopromide (n¼1)

Iomeprol (n¼1)

Iopentol (n¼1)

Iodixanol (n¼1)

Ioxaglate (n¼1)

Negative (n¼10)

Iodixanol (n¼1) Iodixanol (n¼1) Not done Iobitridol (n¼1) [39&]

Iohexol (n¼1) Negative (n¼0)

Ioversol (n¼1)

CM, iodinated contrast media; DPT, drug provocation test.

Nonimmediate hypersensitivity reactions to ICM Gomez et al.

agreement with others who found that 41.7% ofpatients with negative skin tests developed apositive DPT [24]. Furthermore, a recent case reportshowed that patients can react to iodinated contrastmedia after a negative skin test [28] (Table 2).

In-vitro testing

The LTT is the most used in-vitro test for diagnosingnonimmediate hypersensitivity reactions to drugs.Its usefulness relies on the observation that specificT cells are able to proliferate after recognition of thespecific drug, even several months or years after thereaction. However, the results of the LTT are not100% predictive and the results obtained from somestudies showed how, in a few cases, no proliferationwas detected in allergic patients [16]. Therefore, LTTresults in iodinated contrast media allergic reactionsare heterogeneous and the sensitivity ranges from13 to 75% [15,18,40,41]. Although the causes of thisvariability are unclear, it is probably related to the

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number of patients studied, their clinical character-istics, and the diagnostic approach used. Effortshave been made to improve the sensitivity of thetest. There is a low frequency of the drug-specificT-cell repertoire, ranging from 0.05 to 0.6%, and theuse of T-cell lines and T-cell clones from allergicindividuals could improve the detection not only ofproliferation, but also of cross-reactivity betweendifferent iodinated contrast media drugs [42].However, the time needed and the impossibilityof generating T-cells lines elsewhere make its appli-cation as a routine test difficult. Another alternativebased on the idea that T-cell responses require arecognition and presentation process by APCs andbearing in mind that the classical LTT uses mono-cytes and B cells for this purpose, the use of pro-fessional APCs, like autologous monocyte-deriveddendritic cells (moDCs), could improve the recog-nition of the drugs and induce higher proliferationof specific T cells. This hypothesis has already beenconfirmed with other drugs like amoxicillin [43],

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heparin [44], or budesonide [45], noting an increasein the sensitivity when moDCs were used as APCs.In allergic reactions to iodinated contrast media,Antunez et al. [18] showed that the use of moDCsin LTT from six patients with MPE after iodixanolexposure increased the sensitivity of the test from16 to 83%. Therefore, development of this secondgeneration of LTT could improve the detection ofdrug-specific T-cell activation.

CROSS-REACTIVITY

Different studies [22&

,23,27] have shown thatthe chemical structure seems to be important forcross-reactivity, with the association most fre-quently detected being between iodixanol, iohexol,iopentol, ioversol, and iomeprol, and particularlybetween iodixanol and its monomer iohexol. How-ever, other iodinated contrast media such as ioxa-glate, iopamidol, iopromide, and iobitridol havebeen shown to have limited cross-reactivity [23].

MANAGEMENT

The recommendation in patients with confirmednonimmediate hypersensitivity reactions to iodi-nated contrast media is to use an alternative iodi-nated contrast media that produces a negative skintest and DPT, although a negative skin test alonedoes not guarantee tolerance. Pretreatment withprednisone (50 mg daily) and cetirizine (20 mgdaily), started 3 days before iodinated contrastmedia administration, has been shown not to beuseful in patients with nonimmediate reactions[40]. However, a more aggressive protocol includingmethylprednisolone and cyclosporine 1 week beforeand 2 weeks after iodinated contrast media admin-istration proved useful for the prevention of non-immediate reactions, although just in one patient[46].

All these studies show the complexity of thediagnosis of nonimmediate T-cell reactions to iodi-nated contrast media. The diagnosis is based on skintesting, although the sensitivity and negative pre-dictive values are not optimal. Thus, DPT is oftenneeded to confirm the diagnosis and also to seek analternative iodinated contrast media.

CONCLUSION

More than 70 million iodinated contrast mediainjections per year are administered worldwideand although generally well tolerated, hypersensi-tivity reactions do occur. Nonimmediate reactionsare those occurring after 1 h of iodinated contrastmedia administration and are usually T-cell

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mediated. The diagnosis has been mainly basedon skin testing, although recently it has been dem-onstrated that DPT is useful not only for diagnosis,but also to test for alternative, safer iodinated con-trast media for the patients. Although in-vitro test,mainly lymphocyte transformations test, are devel-oped as a useful diagnostic tool with variable results,the inclusion of new components like autologousmoDCs has been shown to improve the sensitivity ofthis test.

Acknowledgements

The authors thank Ian Johnstone for help with theEnglish language version of this manuscript.

Conflicts of interest

None of the authors has any conflict of interest, nor havethey received any money for the present study. Research ispart of their daily activities. All the authors had fullaccess to all the data and can take responsibility for theintegrity of the data and the accuracy of the dataanalysis. The study was funded by FIS-ThematicNetworks and Co-operative Research Centers (RIRAAF/RD07/0064).

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