Hypersensitivity reaction to iodinated contrast media

Thatchai Kampitak20 May 2009

Scope

• Contrast media• hypersensitivity reaction (immediate &

delayed)o Prevalenceo Clinical manifestationo Pathophysiologyo Diagnosiso Treatmento Prevention

Introduction

• Iodinated contrast media (ICM) are one of the most common prescribed drugs in the world

• More than 75 million CM-enhanced X-ray procedures are conducted yearly worldwide

• Hypersensitivity reactions, although uncommon, may occur and can be fatal

• Pathophysiology still remains unclear• Diagnosis is mainly based on clinical

history due to lack of reliable diagnostic methods

• Premedication remains controversial

Iodinated contrast media

• ICM were introduced for radiographic image enhancement since 1920 in bi-iodinated form

• ICM containing tri-iodinated compound were introduced in 1950

• Low osmolar ICM were developed in 1960• Non-ionic low osmolar ICM were

developed in 1980Idee JM et al. Fundam Clin Pharmacol 2005;19:263-81

Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72

Idee JM et al. Fundam Clin Pharmacol 2005;19:263-81

Christensen C In Pichler WJ Drug hypersensitivity 2007

Pharmacokinetic

• MW of ICM range between 750-850 for monomers and twice higher for dimers

• ICM usually contain 270-400 mg iodine/mL

• 70% of ICM is cleared from plasma within 2-5 minutes after injection

• Half life is about 1-2 hours and 75% is excreted in urine within 4 hours

Idee JM et al. Fundam Clin Pharmacol 2005;19:263-81Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72

Brockow K et al. Allergy 2005;60:150-8

Immediate hypersensitivity reaction

Prevalence

• Death rates are not different between ionic and non-ionic ICM

• Estimated mortality rate is 1-3/100,000 examinations

Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72

Clinical manifestations

• Most symptoms are apparent within 5-15 minutes after ICM administration and disappear within 30-60 minutes

• Severe and fatal reactions are reported to occur immediately to 30 minutes

Brockow K et al. Allergy 2005;60:150-8Idee JM et al. Fundam Clin Pharmacol 2005;19:263-81

Christensen C In Pichler WJ Drug hypersensitivity 2007

Brockow K et al. Allergy 2005;60:150-8

Risk factors

• History of previous reaction to ICMo OR 2.04o 21-60% risk of a repeat reaction when re-

exposed to the same or a similar ionic CM• History of allergy

o Asthma is the most important predisposing factor for severe reaction (OR 5.1)

o No evidence that seafood allergy predispose to the reactions

Idee JM et al. Fundam Clin Pharmacol 2005;19:263-81Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72

• Ageo Higher prevalence in younger age groups but

predominant of severe reactions in the older age groups

• Concomitant treatment with IL-2 or -blocker

• History of cardiac diseases• Female gender• Dose and rate• Route

o Intravenous > intraarterial• Anxiety Idee JM et al. Fundam Clin Pharmacol 2005;19:263-81

Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72

Pathophysiology

• Unclear• Multifactorial• Associated with histamine release from

mast cells and basophilso Direct membrane effect related to the

osmolarity or chemical structure of ICMo Activation of the complement systemo IgE-mediated mechanism

Brockow K et al. Allergy 2005;60:150-8

Szebeni J. Curr Allergy Asthma Rep 2004;4:25-30

Chemotoxic effect

• Histamine release may be resulted from NHCO group, size, complexity and iodine concentration of ICM

• ICM might inhibit acetylcholinesterase enzyme which leads to side effects such as flushing, bronchospasm, urticaria and abdominal pain

Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72

Osmolality

• Discrepant results have been shown in histamine release

• ICM with comparable osmolalities can induce different levels of histamine release

Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72

Complement activation

• Decrease in CH50 have been shown after ICM exposure

• Increase of blood histamine and complement activation have been shown in both reactors and non-reactors to ICM without any difference

• ICM may induce activation of coagulation and kinin-kallikrein system

Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72

IgE-mediated mechanism

Idee JM et al. Fundam Clin Pharmacol 2005;19:263-81

Diagnosis

• During of immediate after the reactiono Serum histamine and tryptase

Elevate in some patients with severe or fatal reactions

Brockow K et al. Allergy 2005;60:150-8

• After recoveryo Skin test

Positive tests were rarely reported and only in patients with severe reactions

Standardization is not yet establishedo Specific IgE

No commercial assay is availableo Basophil activation test

Not widely available and no defined standardizationo Provocation test

May induce severe reactions in high risk patients

Brockow K et al. Allergy 2005;60:150-8

Skin test was positive in 50% of patients who were skin tested within 2-6 months

Specificity of skin test was 96.3%

32 (26%) (4 by SPT, 30 by IDT)

122Brockow K et al (Allergy 2009)

BAT was positive in 3 patients4 (4%) by IDT96Trcka J et al (Am J Roentgenol 2008)

Median time to skin test was 3 and 48 months in positive and negative skin test patients (p

<0.05) Respiratory allergy was more frequent in the positive skin

test patient

9 (28%) (1 by SPT, 8 by IDT)

32Kvedariene V et al (Clin Exp Allergy 2006)

9.3% cross-reactivity rate19 (73%) by IDT26Laroche D et al (Contrast Mol Med

Imaging 2006)

NotePositive results

Number of patients

References

• Skin tests were positive in 14/28 (50%) of patients tested within 2-6 months while only 17/92 (18%) of patients tested at other time were positive skin test (p = 0.0003)

• 43% of positive skin tested patients had reacted to a ICM on first exposure

Treatment

• Majority of patients recover if they are treated quickly and appropriately

• The proper training personnel, first line drugs and equipments should be readily available

• Patients should never be left alone for at least 30 minutes after ICM administration

• Patients should be given a MedicAlert bracelet

Christensen C. in Pichler WJ Drug hypersensitivity 2007

Prevention

• Contrast media selectiono 10 fold reduction in severe repeat reactions with

non-ionic ICM in patients with a previous reaction to ionic ICM

o No available data of repeat reactions to non-ionic ICM

o Patients with previous severe reactions should avoid re-exposure to ICM

o Role of skin testing and in vitro tests to prevent repeat reactions remains to be established

Brockow K et al. Allergy 2005;60:150-8

• Premedicationo Remains controversial o Marked variable prophylactic protocolo The estimated recurrence rate despite steroid

administration is almost 10%o Severe reactions have been reported despite

optimal premedication

Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72

Idee JM et al. Fundam Clin Pharmacol 2005;19:263-81

Idee JM et al. Fundam Clin Pharmacol 2005;19:263-81

• Premedication may help to lessen reactions caused by non-specific histamine release, but may not be as effective in preventing IgE-mediated reactions

• ANDEM-ANAES stated that ‘the limited number of relevant information in humans does not allow to establish the efficacy of a systemic premedication intended to prevent anaphylactoid reactions’Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72

Christensen C. in Pichler WJ Drug hypersensitivity 2007

Delayed hypersensitivity reaction

Prevalence

• The frequency of delayed reactions varies from 0.5-23%

• There seems to be a higher incidence of delayed reactions associated with non-ionic dimer

• Severe delayed reactions are extremely rare

• Only 6 cases have been reported

Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72

Idee JM et al. Fundam Clin Pharmacol 2005;19:263-81

Clinical manifestations

• MP rash is the most frequent presentations (> 50%)

• Usually mild to moderate in severity, transient and self-limiting

• Most reactions occurs between 3 hr-2 days and disappear after 1-7 days

• Immediate type symptoms and biphasic reactions have been reported

Brockow K et al. Allergy 2005;60:150-8

Risk factors

• Previous reactions to ICMo The most important risk factor

• IL-2 treatment• Serum Cr > 2 mg/dl• History of drug and contact allergy

Brockow K et al. Allergy 2005;60:150-8

Pathophysiology

• T-cell mediated reactionso The frequently reported positive patch tests

and delayed IDTs to the culprit CM in previous reactors

o The presence of dermal infiltrates of T cells in affected skin and positive skin test sites

o The reappearance of the eruption after provocation testing

o The ability of CM to simulate proliferation of peripheral T cells from patients with CM-induced skin eruptions

Brockow K et al. Allergy 2005;60:150-8 Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72

• ICM might stimulate memory T cells directly via their TCR, in absence of a peptide antigen (direct metabolism-independent T-cell stimulation)

Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72

Diagnosis

• During or immediately after the reactiono CBC (eosinophilia)o Liver and renal function testso Presence of lymphocyte activation markers

(CD25, CD69, HLA-DR by flow cytometry or soluble CD25 by enzyme immunoassay)

o Skin biopsy

Brockow K et al. Allergy 2005;60:150-8Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72

• After recoveryo Patch tests with undiluted ICM and IDT with

diluted ICM appear to be specific and useful for diagnosis

o Frequent cross-reactivity has been observedo The sensitivity of both PT and IDT has to be

investigatedo LTT cannot be recommended for routine use

Brockow K et al. Allergy 2005;60:150-8Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72

• Delayed skin tests were positive in 37/98 (38%)• 32% had positive delayed IDTs and 28% were positive to patch tests• 47% (29/62) were skin test positive when tested within 6 months after

reactions while 22% (8/36) were positive when tested at other time (p = 0.02)

• 33% of positive skin tested patients had reacted on first ICM exposure

Prevention

• Contrast medium selectiono Change of ICM is no guarantee against repeat

reactions due to frequent cross-reactivityo The value of skin testing to selective an

alternative ICM remains to be established• Premedication

o Delayed reactions have been reported despite steroid premedication

Brockow K et al. Allergy 2005;60:150-8Gueant-Rodriguez RM et al. Curr Pharm Des 2006;12:3359-72

Conclusion

• Hypersensitivity reactions to ICM remain a significant problem for both the patients and physicians involved

• Most delayed reactions are T-cell mediated while new data indicate that many of immediate reactions are IgE-mediated

• Skin testing may be a useful tool for diagnosis and selection of an alternative ICM to prevent repeat reaction

Thank You