Contrast media hypersensitivity

Contrast MediaHypersensitivity

Thitima Kantachatvanich, M.D.

Division of Allergy and Clinical ImmunologyFaculty Medicine, Chulalongkorn University

Chemical Structure

• Ionic contrast media

• Nonionic contrast media

CONTRAST MEDIA TUTORIAL ;Jessica B. Robbins, MD 2010

Tri-iodinated benzene ring

U. Speck (ed.), Contrast Media Springer-Verlag Berlin Heidelberg 1999

Clinical Practice Guidelines for Diagnosis and Management of HypersensitivityReactions to Contrast Media: J Investig Allergol Clin Immunol 2016; Vol. 26(3): 144-155

Contrast Medium Reactions : medscape.com, Nasir H Siddiqi ; Jul 22, 2017

Osmolarity of Contrast Media

• High-osmolar contrast media (HOCM) : >900mOsm

– Ionic monomer

either sodium or meglumine is cation



• Low-osmolar contrast media (LOCM) : 500-900 mOsm/kg H2O

– Nonionic monomer : Iopamidol(Isovue), Iohexol(Omipaque)

– Ionic dimer : Ioxaglate(Hexabrix)



• Iso-osmolar contrast media (IOCM) : 290 mOsm/kg H2O– Nonionic dimer : Iodixanol 320 (Visipaque)



Ratio of iodine atoms to particlesHOCM–0.5 LOCM–3.0 IOCM –6.0


Osmolarity & Immunogenicity

• Nonionic CM has lower osmolarity than ionic CM

• High osmolarity CM ↑Immediate reaction

– The overall prevalence of mild immediate CM reactions : 3.8% to 12.7% in ionic iodinated CM and 0.7% to 3.1% for non-ionic iodinated CM,

Wolf GL, Arenson RL, Cross AP. A prospective trial of ionic vs nonionic contrast agents in routine clinical practice: comparison of adverse effects. AJR Am J Roentgenol. 1989;152:939-44.

Ionic Charge & Immunogenicity

• Nonionic contrast media

– Low osmolarity (at 37 C : can be at least 2.5X lower than ionic CM)

– No electrical charges

– No cations : sodium or meglumine

– Better shielded by hydrophilic side chains

Nonionic CM

• Less protein binding & enzyme inhibition • Less impairment of the function of biological membranes

U. Speck (ed.), Contrast Media Springer-Verlag Berlin Heidelberg 1999

Viscosity & Immunogenicity

• Directly associated with the molecular size, iodine concentration

• ↑frequency of non-immediate reaction

• ↑Temperature ↓viscosity– Heating the ICM to body temperature (37°C)

before administration

• Nonionic dimers > Nonionic monomers : as the cause of nonimmediate reactions– Contrary to immediate reactions


Extrinsic Warming of ICM to 37°C

– For high-rate (> 5 mL/second) IV LOCM power injections

– For injections of viscous iodinated contrast (e.g., iopamidol 370, other similar or higher viscosity)

– For direct arterial injections through small-caliber catheters (5 French or smaller)

– For intravenously injected arterial studies in which timing and peak enhancement are critical features

ACR Manual on Contrast Media – Version 10.3 / May 31, 2017

Management of hypersensitivity reactions to iodinated contrast media; Brockow et al. : Allergy 2005: 60: 150–158

Management of hypersensitivity reactions to iodinated contrast media; Brockow et al. : Allergy 2005: 60: 150–158

Prevalence of Immediate Reactions in Asia Pacific Region

• Since 1988 to 2014

• From Korea, Japan, Australia, India, Thailand, Turkey, and Qatar

• Overall prevalence

– 6.4–31.2% with ionic RCM

– 0.16–7.7% with nonionic RCM

• In 21st century, the overall prevalence was 0.16–2.21%

Radiocontrast media hypersensitivity in the Asia Pacific region.Lee SY, Lim KW, Chang YS.Asia Pac Allergy. 2014 Apr;4(2):119-25

Immediate Reactions


Prevalence of Nonimmediate Reactions in Asia Pacific Region

• Since 1982 to 2014

• Delayed type hypersensitivity reactions

• From Japan, Korea, Thailand, and Turkey

• Overall prevalence was 0.03–16.5%

• In 21st century, the overall prevalence was 0.03–1.95%


Nonimmediate Reactions


Prevalence in Thailand

• Overall prevalence of CM adverse reaction : 1.05%

• The prevalence of repeated reactions : 0.12%

• The prevalence of breakthrough reactions (despite premedication) : 0.11%

• The prevalence of serious reactions : 0.03%• The prevalence of fatal reactions : 0.002%

Adverse reactions to iodinated contrast media: prevalence, risk factors and outcome-the results of a 3-year period.Pradubpongsa P.Asian Pac J Allergy Immunol. 2013

Immediate(96.9%) & Non-immediate(3.1%) Reactionin Siriraj Hospital, from January 1,2008 – December 31, 2010


Immediate(96.9%,561/579) & Non-immediate Reaction(3.1%,18/579)in Siriraj Hospital, from January 1,2008 – December 31, 2010


In a multivariate analysis, Hx of previous CM reactions, female and Hx of seafood allergy : significant risk factors for CM reactions


In a multivariate analysis, the most significant risk factor of serious CM reactions was asthma, when compared to mild reactions (p =0.013) and controls(p =0.003)

Allergic Disease vsRCM Hypersensitivity


Hx of allergic disease : controversy in other studies

Risk factor of immediate reaction

• Female sex

• Atopy

• History of previous reactions to RCM

• Concomitant use of beta-blocking drugs

Practice Parameter 2010

Risk Factor for Nonimmediate Reaction

• Female sex

• Previous reaction to iodinated contrast media

• Atopy, a history of drug and contact allergy

• Interleukin-2 treatment

• Other diseases such as diabetes mellitus, and heart, liver or kidney diseases

Gomez E, Ariza A, Blanca-Lopez N, Torres MJ.Nonimmediate hypersensitivity reactions to iodinated contrast media. Curr Opin Allergy Clin Immunol. 2013;13:345-53.

Mechanism

• Immediate reaction : within 1 hr after administration (70% within 5 min)

– IgE mediated

– Non IgE mediated

• Direct membrane effect : osmolarity

• Complement activation

*Genetic variation : metabolism of mediator

• Non Immediate reaction : 1 hour to 7 days– Mainly T cell mediated


• 16/27 patients : significant basophil activation

– 2 : ↑IgE and HSC5b-9( human terminal complement complex SC5b-9)

– 2 : ↑IgE alone

– 9 : ↑ HSC5b-9 alone

– 3 : neither increased IgE nor HSC5b-9.

Zhai L, Guo X, Zhang H, Jin Q, Zeng Q, Tang X, et al. Non-ionic iodinated contrast media related immediate reactions: A mechanism study of 27 patients. Legal medicine (Tokyo, Japan). 2017;24:56-62.

IgE vs Non-IgE mediated Immediate Reaction

• Most cases, the reactions occur in patients exposed to ICM first time

• Severity does not increase with subsequent exposure to ICM

• Difficult to bind to protein(form a hapten-protein conjugate) because being highly hydrophilic

…. Later, a multicenter study conducted in Europe : up to 50% of immediate reactors were skin test-positive

Zhai L, Guo X, Zhang H, Jin Q, Zeng Q, Tang X, et al. Non-ionic iodinated contrast media related immediate reactions: A mechanism study of 27 patients. Legal medicine (Tokyo, Japan). 2017;24:56-62.

Immediate Reaction

Morales-Cabeza C, Roa-Medellin D, Torrado I, De Barrio M, Fernandez-Alvarez C, Montes-Acenero JF, et al. Immediate reactions to iodinated contrast media. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2017;119(6):553-7

From Spanish tertiary hospital during a 7-year period

Immediate Reaction


The mean (SD) time between reaction and testing was 3.9 (5.0) months, constituting 1-6 months in 88%

Suggesting that IgE-mediated reactions to ICMs are more severe

Immediate Reaction

Brown SG. Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol. 2004;114:371e376.

Immediate Reaction

• Reactions to RCM frequently occur on first exposure(49.5%; 99 of 200)

– Also high in a European retrospective multicenter study

– Suggesting previous sensitization through an unknown molecule or non-IgE mediated

• Reactivity to RCM might be induced by earlier exposure to molecules containing carbamoyl side chains(found in buzepide metiodure, cefuroxime)


Anaphylaxis from RCM


• Biphasic reaction : recurrence of anaphylaxis within 72 h of the initial anaphylactic event after asymptomatic period of 1 h with no re-exposure to the trigger

• Protracted reaction : anaphylaxis lasting ≥ 5 h without clearly resolving completely

• Uniphasic reaction : anaphylaxis lasting < 5 h without recurrence after its complete resolution

Kim TH, Yoon SH, Lee SY, Choi YH, Park CM, Kang HR, et al. Biphasic and protracted anaphylaxis to iodinated contrast media. Eur Radiol. 2017.


No significant differences in the administration of steroids and H1-antihistamine medications among the groups


Multivariate logistic regression analysis


Longer duration of initial anaphylaxis(defined as 40 min or longer based on ROC analysis

sensitivity, 93.3%; specificity, 43.1%, P=0.011

The First-hour Event

• The first-hour events during initial anaphylaxis predict biphasic, protracted reactions– Initial anaphylaxis >40 min Biphasic anaphylaxis

OR: 8.65,95 % CI 1.05–70.71, P=0.044– Additional epinephrine administration within 1 h after

the initial dosing Protracted reaction OR: 102.00,95 % CI 3.40–3057.25, P=0.008

– At least 1 h of post anaphylactic observation is necessary : protracted anaphylaxis can experience transient relief• 5/6 patients : transient relief from anaphylaxis lasting < 30

min (median : 24 min, range : 3–26 min)


Duration of post-anaphylaxis observation


6 h : practical for detecting a biphasic reaction to ICM (for resource limited or patient preference)

12 h in total : NPV ↑1 % 24 h in total : NPV = 100 %

↑≥4X person-hours required to detect 1 case

Duration of post-anaphylaxis observation

• USA current guidelines : recommend 6 h of observation after the initial anaphylaxis resolves

• Secondary reactions were similar or milder in intensity than initial reactions

– Fatalities from secondary reactions have rarely been reported




• Incidence of biphasic anaphylaxis in iodinated contrast media anaphylaxis is 10.3 %.– The median duration between the resolution of initial

anaphylaxis and onset of the secondary reaction was 4 h 52 min (range : 1 h 7 min – 20 h 50 min)

• Incidence of protracted anaphylaxis in iodinated contrast media anaphylaxis is 4.1 %.– 5/6 patients : transient relief from anaphylaxis lasting < 30 min

(median : 24 min, range : 3–26 min)

• Initial anaphylaxis >40 min can predict for biphasic anaphylaxis development.

• 6-h post-anaphylactic observation in ICM-related anaphylaxis seems practical.



• Rate of protracted, biphasic reaction to ICM

: consistent with anaphylaxis to triggers other than ICM

• History of allergic diseases & biphasic anaphylaxis– Uniphasic vs biphasic : 9.6 % vs. 33.3%, P=0.020

– Lertnawapan et al., Smit et al. and Rohacek et al. : previous allergic diseases did not contribute to the development of biphasic reactions

– Ko et al. and Lee et al. : history of previous anaphylaxis was associated with biphasic reactions



• Higher proportion of cardiovascular symptoms in this study (CVS>mucocutaneous>RS)– CVS : 88.2% (128/145)

– Similar trends were reported by Kim et al.


Prescreening Skin Test in Immediate Reaction

• Not routinely skin test all patients with a past reaction to RCM– Severe anaphylaxis, could consider to do

• Salas et al in Spain, 90 patients with symptoms

: positive skin testing only 5 patients

• A large prospective study (n=1048) done intradermal skin : positive reaction only 1 patient

• Protocol– Undiluted SPT 1:10 IDT

J Allergy Clin Immunol Pract 2017;5:587-92

Skin Test for Diagnosisin Immediate Reaction

• May be helpful for identifying nontolerated RCM

• Duration 2-6 months after reaction(both immediate, non immediate)

– > 6 month lower sensitivity

• Skin test in immediate reaction

– Sensitivity 4.2-73%


Basophil Activation Test (BAT)

• Good correlation with in vivo test(skin test)• Detect both IgE, non-IgE mediated immediate

reaction• Sensitivity : 46.2–61.5% • Specificity : 88.4–100%• Need to be validated in various population

Song WJ, Chang YS. Recent applications of basophil activation tests in

the diagnosis of drug hypersensitivity. Asia Pac Allergy 2013;3:266-80.

Non immediate Reaction

• Skin is the most affected organ

• Generally mild reaction : MPE

• Maculopapular exanthema (MPE) : most often reported in the different studies(37.5–91% of all reactions)

• Urticaria and angioedema (40-62.4%)

• Fixed drug eruptions, contact dermatitis, Stevens–Johnson syndrome, toxic epidermal necrolysis, and AGEP


Non immediate Reaction

• Mainly T-cell mediated (but still being debated)

• Most accepted mechanism proposed by Landsteiner : Hapten concept

– CD4+ T cell and APCs : key players

• ↑Production of IFN-g and IL-2 when compared with tolerant individuals

Landsteiner K, Jacobs J. Studies on the sensitization of animals with simplechemical compounds. J Exp Med 1935; 61:643–656.


• Perivascular mononuclear cell infiltrate composed mainly of CD45RO+ CD3+ T cells

• Higher frequency of CD4+ T cells mainly in the dermis

• Moderate expression of CD25 and perforin

• High expression of HLA-DR and CLA, accompanied by an ↑influx of eosinophils


Skin biopsy : MPE from Iodixanol

Antunez C, Barbaud A, Gomez E, et al. Recognition of iodixanol by dendritic cells increases the cellular response in delayed allergic reactions to contrast media. Clin Exp Allergy 2011; 41:657–664.

Diagnostic Test for Non immediate Reaction

• Skin patch testing or delayed reading IDT(higher sensitivity than patch test) : in-vivo test– Only 37%(18.7-66.7%) of patients with delayed reaction

: positive in delayed IDT or patch tests (done within 2–6 months)

– Not good NPV (58.3-83%)

– Multiple factors : timing, type of CM(Iodixanol positive rate < iomeprol), phenotype of reaction

– Protocol : SPT(undiluted) IDT(1:10) PT(undiluted) ;delayed reading at 24, 48, 72, 96 hr (Reading 15 minutes after removal of the strips) DPT• IDT undiluted : false positive 70%



• A multicenter study had positive patch tests for 58% of patients with AGEP

– Nonimmediate reactions from ICM, both delayed IDT and patch tests are recommended to enhance test sensitivity

Grandvuillemin A, Ripert C, Sgro C, Collet E. Iodinated contrast media-induced acute generalized exanthematous pustulosisconfirmed by delayed skin tests. The journal of allergy and clinical immunology In practice. 2014;2(6):805-6.


• LTT : in-vitro test

– Classic LTT(B cell, monocyte = APC) stimulate memory T cell (low frequency of drug specific T cell repertoire 0.05-0.6%)

• Limitation : inconsistent result (sensitivity =13-75%)

– Inclusion of autologous dendritic cells, T cell lines from allergic individual can improve its sensitivity (Autologous DC = APC)

stimulate both naïve, memory T cell

Antunez C, Barbaud A, Gomez E, et al. Recognition of iodixanol by dendritic cells increases the cellular response in delayed allergic reactions to contrast media. Clin Exp Allergy 2011; 41:657–664.

Sensitivity improved from 16%(1/6)83%(5/6)


• Drug Provocation Test

– After careful analysis, base on negative skin test

– Single blind placebo control

– Absolutely contraindicated if SCARs or organ-specific reactions (eg, ICM-induced hepatitis)



Drug Provocation Test

• DPT in immediate reaction : 5, 15, 30, and 50 ml every 30-45 minutes

• DPT in non-immediate reaction : 5, 15, 30, and 50 ml every 60 minutes– Severe non-immediate : 2 separate sessions with a

gap of at least 1 week between sessions

“5, 10, and 15 ml on the first day (cumulative total of 30 ml) and 20, 30, and 50 ml on the second day, a week later (cumulative total of 100 ml)”by Torres et al, 2012– Cumulative dose 100 ml 40% of cases positive


Diagnostic Algorithm


Cross-reactivity

• Iodine is not the eliciting agent

– No cross-reactivity between RCM and iodized antiseptics

• Cross-reactions among RCM do not follow the current chemical classification

Cross-reactivity

• Nonionic dimers > Nonionic monomers

– Contrary to immediate reactions


Lerondeau B, Trechot P, Waton J, Poreaux C, Luc A, Schmutz JL, et al. Analysis of cross-reactivity among radiocontrast media in 97 hypersensitivity reactions. The Journal of allergy and clinical immunology. 2016;137(2):633-5.e4.



Cross-reactivity

• Group A,

– Nonionic dimer : Iodixanol, Iohexol, Iopamidol, Iomeprol, Ioversol

– Ionic monomer : Ioxitalamate

– Shared 2 identical N-(2,3-dihydroxypropyl) carbamoyl side chains except for ioxitalamate

– Iobitridol does not belong to group A; it has a methyl group on its side chain [N-methyl-(2,3-dihydroxypropyl) carbamoyl]


Cross-reactivity

• Group B – Ioxaglate(ionic dimer) and iobitridol(nonionic

monomer) • could not establish a chemical link between these

• Group C – Amidotrizoate(ionic monomer)

• Statistically significant among patients

• Belonging to the ‘‘delayed’’ subgroup but less robust for those in the ‘‘immediate reactions’’ group


Yoon SH, Lee SY, Kang HR, Kim JY, Hahn S, Park CM, et al. Skin tests in patients with hypersensitivity reaction to iodinated contrast media: a meta-analysis. Allergy. 2015;70(6):625-37.

• White : ≤10%• Light gray :11-15%• Gray : 16-25% • Dark gray : 26-50%• Black : >50%

Cross-reactivity

• Non immediate reaction > immediate reactions

• Iobitridol and Iotrolan to be the least stimulatory ICM among nonionic ICM in non-immediate reaction

• Skin test-negative ICM were more tolerable in immediate HSR than in nonimmediate HSR



• White : ≤10%• Light gray :11-15%• Gray : 16-25% • Dark gray : 26-50%• Black : >50%

Cross-reactivity in Immediate Reaction from Another Study

(15 cases cross reactivity)• Iomeprol and ioversol were cross-reactive(by

skin test, challenge test)

• No cross-reactivity was detected between iopamidol and ioversol in 14 of 15 tested patients, with cross-reactivity challenge tests performed in 10 of these patients


• 453 subjects with history of mild RCM-induced HRs.

• All nonionic low osmolar iodinated media

• CPM 4 mg injected according to the physician’s judgment (273 subjects)

• Antihistamines injection before RCM : 30-60 minutes

Lee SH, Park HW, Cho SH, Kim SS.The efficacy of single premedication with antihistamines for radiocontrast media hypersensitivity. Asia Pac Allergy. 2016 Jul;6(3):164-7.


• No difference in RCM-induced HRs between premedication and non-premedication groups (10.6% vs. 11.7%, p = 0.729)

• No any significant differences between

– the severity (mild vs. moderate, p = 1.000)

– time interval (immediate vs. nonimmediate, p = 1.000)


Benefit of Premedication

• Average-risk patients & HOCM :↓ immediate events of all severity (RCT)

• Average-risk patients & modern LOCM : ↓mild and aggregate immediate adverse events, underpowered to on moderate and severe reactions (RCT)

• NNT to prevent a reaction is high

• One study : NNT to prevent 1 reaction in high-risk patients = 69 (any severity), NNT = 569 for a severe reaction

• Another study : NNT to prevent a lethal reaction in high-risk patients to be 50,000

ACR Manual on Contrast Media – Version 10.3 / May 31, 2017

Premedication Regimen by Greenberger & Patterson


Greenberger PA, Patterson R. Adverse reactions to radiocontrast media. Prog Cardiovasc Dis 1988;31:239-48.

Premedication Regimen by Lasser et al(primary prevention in ionic CM)

• Multicenter (27 centers)

• 32 mg methylprednisolone given orally 12, 2 hours before (ionic CM) vs 32 mg methylprednisolone given orally 2 hours before (ionic CM) vs placebo (nonionic CM)

• 32 mg oral methylprednisolone 2 hours(single dose) prior to IV high-osmolality ICM in average-risk patients was not effective– while 2 doses at 2- and 12-hours before contrast medium

administration were effective

J Allergy Clin Immunol Pract 2017;5:587-92Lasser EC, Berry CC, Talner LB, Santini LC, Lang LC, Gerber FH, et al. Pretreatment with corticosteroids to alleviate reactions to intravenous contrast material. N Engl J Med 1987;317:845-9.

Premedication Regimen by Lasser et al(primary prevention in ionic CM)

Lasser EC, Berry CC, Talner LB, Santini LC, Lang LC, Gerber FH, et al. Pretreatment with corticosteroids to alleviate reactions to intravenous contrast material. N Engl J Med 1987;317:845-9.

Premedication Regimen

• Prednisone 50 mg or IVMP 40 mg 13, 7, and 1 hr before injection of ICM + IV dexchlorpheniramine 5 mg 1 hour before

• Urgent radiological examination with ICM

– IV hydrocortisone 200 mg + IV dexchlorpheniramine 5 mg 1 hour before


Adverse Reactions to Contrast Material: A Canadian Can Assoc Radiol J. 2017 May;68(2):187-193.

Clinical practice guideline for anaphylaxis (Thai) 2017

Guidelines from European Society of Urogenital Radiology

• Prednisolone (30 mg) or methylprednisolone (32 mg) orally 12 and 2 h before contrast medium exposure was recommended in high risk patients

Practice Parameter 2010

• Previous anaphylactoid reactions to RCM should receive nonionic,iso-osmolar agentsand be treated with a premedication regimen,

– Systemic corticosteroids and histamine1 receptor antihistamines

– 50 mg prednisolone 13,7,1 hour before and 50 mg diphenhydramine 1 hour before

Stratified Premedication Strategy

• 850 patients with a history of immediate reaction• 5 kinds of LOCM for CT: iobitridol, iohexol, iomeprol,

iopamidol, and iopromide(1) 50 mg of diphenhydramine 1 hr before for mild

reactions(2) Adding 40 mg of methylprednisolone 1 hr before for

moderate reactions(3) Adding 40 mg of methylprednisolone 4,1 hr before for severe index reactions• 4 mg of intravenous CPM was used instead of 50 mg of

diphenhydramine because of unavailability in Korea

Lee SY, Yang MS, Choi YH, Park CM, Park HW, Cho SH, et al. Stratified premedication strategy for the prevention of contrast media hypersensitivity in high-risk patients. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2017;118(3):339-44.e1.


• Mild reactions : limited urticaria, pruritus, cutaneousedema, nasal congestion, rhinorrhea, and conjunctivitis

• Moderate reactions : diffuse urticaria, erythema, facialedema without dyspnea, laryngeal edema, and mildwheezing without hypoxia

• Severe reactions : life-threatening, diffuse erythemaand edema with dyspnea, hypotension (defined as SBP<90 mm Hg), laryngeal edema with hypoxia, wheezingwith hypoxia, unresponsiveness, cardiopulmonaryarrest, arrhythmias



• Near-fatal anaphylactic shock, life-threatening reactions, including hypotension that requires epinephrine injection in the previous exposure

– Skin test

– Admission for close monitoring

– Alternative ICM were determined (negative skin test)



• Underpremedicated : lower dose or fewer kinds of premedication drugs

• Overpremedicated : higher dose or more kinds of premedication compared with the stratified recommendation




• 850 patients– breakthrough reactions 17.1%, but most (89.0%)

were mild, not require medical treatment

• Additional corticosteroid use did not reducethe breakthrough reaction rate in cases with amild index reaction

• Most moderate ICM hypersensitivity cases arepreventable through regimen with a singledose of systemic steroids



• Single dose steroid : significantly higher BTR than did double doses steroid in severe index reaction (55.6% vs 17.4%, P = 0.02)

• Changing the iodinated contrast media ↓BTR overall (14.9% vs 32.1%, P=0.001) and the BTR rate in mild reaction (15.6% vs 32.5%, P = .002)



Risk factors for Breakthrough Reaction

• History of long-term steroid use

• Severe allergies, and allergy to multiple allergens

• Younger than 50 years

• Multiple previous exposures to ICM

• Previous severe reaction

• Repeated exposure to the culprit ICM


ACR Guideline 2017

• prior allergic-like or unknown-type contrast reaction to the same class of contrast medium (e.g., iodinated – iodinated)

• IV corticosteroid regimen with a minimum duration of 4-5 hours may be efficacious

• Prednisone-based: 50 mg prednisone at 13, 7, and 1 hour before, plus 50 mg diphenhydramine IV, IM, or oral1 hour before

• Change contrast media

Premedication in Non-immediate Reaction

• Not to be useful for non-immediate reaction, But…

• Case report : 19 years old male without personal or family history of allergic diseases

Romano A, Artesani MC, Andriolo M, et al. Effective prophylactic protocol in delayed hypersensitivity to contrast media: report of a case involving lymphocyte transformation studies with different compounds. Radiology 2002;225:466–470

Cyclosporin 100mg oral bid6 MP 40 mg IM OD 1 wk before + 2 wk after

• LTT before & 6th day after the start of regimen

• Skin test, PT at 9th day after the start of regimen

Case report • Delayed reaction(MPE) after Iopamidol use 3 days for 2 times


SPT, IDT Result (Before)

Before starting regimen• 1: 10, negative in all control subjects• SPT : all negative• IDT : all positive (erythematous, indurated wheals >10 mm)

– After 24 hours, wheal size :• 30 mm for iopamidol• 12 mm for iomeprol• 20 mm for iohexol• 15 mm for iopromide• 15 mm for ioversol

– After 48 hours, wheal size :• 13 mm for ioxaglate• 12 mm for ioxitalamate• 11 mm for iobitridol


Patch Test Result (Before)

Before starting regimen

• Undiluted, negative in all control subjects

• Positive at the 48- and 72-hour

• Iopamidol, Iohexol : positive++ (indurated, erythematous areas 15 mm with vesicles)

• Ioxaglate, Ioxitalamate, Iomeprol, Iobitridol, Iopromide, and ioversol : positive+ (indurated, erythematous lesions >10 mm)


SPT, IDT, PT on 9th day

• Negative for all the reagents tested


Successfully use this regimen 4 times for Premedication before Iobitriol administration

(dose : 300, 35, 50, and 50 mL)

Premedication Recommendation

• History of immediate hypersensitivity to RCM

– Should receive steroid and antihistamine

– Changing the type of contrast agent (nonionic , isoosmolar agent esp. in high risk : CVS disease, asthma, on beta-blocker)

• No evidence to support a premedication duration < 2 hours (oral or IV; corticosteroid-or antihistamine-based)


Cross reactivity with seafood

• Seafood allergen : not related to iodine

– Paralbumin, collagen, gelatin, aldolase, enolase

– Tropomyosin, troponin C, hemacyanin, etc.

http://radiology.ucsf.edu/patient-care/patientsafety/contrast/iodine-allergy

Cross reactivity with iodine antiseptic• Skin irritation rather than allergy

– Irritant reactions to PVP-I preparations are a relatively common condition, but Immediate allergic reaction & allergic contact dermatitis to them is rare

– Not iodine but PVP is thought to be allergenic

Yoshida K, Sakurai Y, Kawahara S, Takeda T, Ishikawa T, Murakami T, et al. Anaphylaxis to polyvinylpyrrolidone in povidone-iodine for impetigo contagiosum in a boy with atopic dermatitis. International archives of allergy and immunology. 2008;146(2):169-73.

PVP : Polyvinylpyrrolidone

• Chemically neutral and cannot be broken down further by enzymes

• Agents containing PVP, besides PVP-I preparations : paramesazone in intraauricularuse, intravenous radiocontrast media and oral analgesic tablets– Rare allergic reaction despite widely use of PVP

containing agent : multiple factors esp. absorption

through the broken skin barrier and made contact with basophils in serum (extravasated blood)



Cross reactivity with those

• Summary Statement 148: Although asthma is associated with an increased risk of a RCM reaction, specific sensitivity to seafood (which is mediated by IgE directed to proteins) does not further increase this risk. There is no evidence that sensitivity to iodine predisposes patients to RCM reactions.

Practice parameter 2010

Health & Medicine

Contrast media hypersensitivity