Radiocontrast hypersensitivity: Nonimmediate (delayed) reactions

INTRODUCTION — Hypersensitivity reactions to both iodinated contrast used in computed tomography (CT), angiography, and urography and gadolinium-based contrast agents (GBCAs) used in magnetic resonance imaging (MRI) are well described. They can be divided into immediate (occurring within minutes to an hour of administration) or nonimmediate (delayed; occurring after hours to days). Nonimmediate reactions are discussed in this topic review. Immediate reactions are reviewed in detail separately:

●(See "Diagnosis and treatment of an acute reaction to a radiologic contrast agent".)

●(See "Allergy evaluation of immediate hypersensitivity reactions to radiocontrast media".)

DEFINITION — Nonimmediate hypersensitivity reactions (NIHR), also called delayed hypersensitivity reactions (DHRs), are defined as reactions occurring more than one hour and up to 10 days after contrast administration [1,2]. Understanding of these reactions has been evolving since the earlier reports more than 15 years ago [3].

DELAYED REACTIONS TO IODINATED CONTRAST

Prevalence — The frequency of DHRs to iodinated contrast agents is not well defined. Reported frequencies range from 0.52 to 51 percent for all types and severities of delayed reactions to nonionic monomers [4,5]. However, the majority of studies report delayed cutaneous reaction rates below 4 percent [6]. A prospective comparison of the manifestations observed after enhanced versus unenhanced computed tomography (CT) showed that patients who received contrast reported more skin rashes and redness in the days following the radiologic examination [5-8].

It is possible that these reactions are underreported because many patients are in the radiology facility only for the procedure and, if the reaction is mild, the patient may not seek medical attention. On the other hand, unrelated events may be incorrectly counted as a DHR if too long a period of time is evaluated by questionnaire.

Risk factors — A previous DHR to contrast is the greatest predisposing factor for a subsequent DHR [8]. In contrast, a previous immediate reaction to contrast has no bearing on the risk of DHR. Further risk factors for DHR are a history of allergy, particularly another drug allergy or contact allergy [4,9,10]. DHRs can develop after a patient's first exposure to radiocontrast; previous exposure is not required [9].

Types of reactions — The two most common forms of delayed hypersensitivity to radiocontrast are maculopapular exanthema (MPE) [11] and delayed-onset urticaria or angioedema. Both are generally mild and self-limited.

There are other nonspecific symptoms that can develop in the hours after administration of radiocontrast, including local pain or a wheal at the injection site, generalized pruritus only, transient erythema, headache, dizziness, fever, and/or nausea. These are considered nonspecific reactions, and allergy evaluation is not indicated [12].

Maculopapular exanthema — DHRs most commonly present as macular or maculopapular exanthems occurring >6 hours (and typically approximately 12 hours) to days after contrast administration (picture 1A-B). Ten days is generally considered the outer limit of the period in which DHRs to contrast can develop. Symptoms can develop more quickly with subsequent exposures [13].

●Pathogenesis – These reactions are believed to be T cell mediated, and perivascular infiltrates of CD4+ and CD8+ T cells have been demonstrated [1,14]. In the vast majority of patients, the DHR is directed against the structure of the contrast and only rarely to the iodine ion [15]. However, iodine reactions do occur and usually present with delayed exanthems as well [15,16]. (See 'Testing for rare iodine sensitivity' below.)

●Treatment – Often, only topical corticosteroid treatment is required because the reactions are generally mild and resolve spontaneously. Minimally sedating antihistamines can be given to relieve pruritus (eg, cetirizine 10 mg twice daily), and a brief course of oral glucocorticoids can be given for severe exanthema.

●Evaluation and diagnosis – The diagnosis of MPE can be made simply based on signs, symptoms, and proximity to radiocontrast administration (picture 1A-B). The differential diagnosis includes an exanthem induced by another drug or viral infection, as well as erythema multiforme and pityriasis rosea. Referral to an allergy or dermatology specialist is indicated if additional evaluation is desired. The purpose of an allergy evaluation for MPE is to confirm that the exanthem was related to the contrast and to identify an alternative contrast agent for future use because many patients will be reactive to multiple agents [17]. (See 'Allergy evaluation (skin testing and patch testing)' below.)

Delayed-onset urticaria/angioedema — Delayed-onset urticaria or angioedema has been described, especially within the first hours after contrast administration.

●Pathogenesis – It remains unclear whether these are nonallergic or allergic (late-phase reaction) forms of contrast hypersensitivity. Other possible explanations include incorrectly labeled MPE with some features of urticaria (since the two can be difficult to differentiate in the first hours) or acute urticaria unrelated to contrast media [12].

●Treatment – These reactions resolve spontaneously. Minimally sedating antihistamines can be given to relieve pruritus (eg, cetirizine 10 mg twice daily).

●Evaluation and diagnosis – Detailed evaluation of this uncommon clinical presentation has not been performed. In our clinic, we perform skin prick testing (SPT) and intradermal testing (IDT) with immediate and delayed readings, as well as patch testing. In many cases, testing is negative, and the radiocontrast agent cannot be confirmed as the culprit. However, in some cases, the reaction was actually an MPE with an urticaria-like appearance, and these reactions can be detected. (See 'Allergy evaluation (skin testing and patch testing)' below.)

Other reactions — Other rare forms of DHRs to radiocontrast have been reported, including the following [1,13,18,19]:

●Fixed drug eruption (FDE) including generalized bullous FDE [18,20,21]. In most cases, the eruptions resolved spontaneously within seven days of onset [13]. (See "Fixed drug eruption".)

●Symmetrical drug-related intertriginous and flexural exanthema [22,23]. (See "Drug eruptions", section on 'Symmetrical drug-related intertriginous and flexural exanthema'.)

●Acute generalized exanthematous pustulosis [24-27]. (See "Acute generalized exanthematous pustulosis (AGEP)".)

●Vasculitis [28,29].

●Iododerma, a rare and potentially serious neutrophilic dermatosis that can develop after exposure to iodinated contrast media, oral iodide supplements, amiodarone, or irrigation of wounds with povidone iodine [13,30,31]. Extracutaneous signs and symptoms can include conjunctivitis, salivary gland swelling, and respiratory compromise [13].

●Transient angioedema of the small bowel may result in self-limited, mild abdominal discomfort [32].

●Drug reaction with eosinophilia and systemic symptoms (DRESS) [33-35]. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

●Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) [36,37]. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae".)

These reactions range in severity from relatively mild (FDE) to potentially life threatening (TEN). The evaluation and management of these reactions are discussed in the linked topic reviews.

Causative agents — Many agents have been associated with DHRs. The dimeric nonionic agent iodixanol is associated with more DHRs than other contrast agents, although this is based on limited evidence [5,8,38-40].

Allergy evaluation (skin testing and patch testing) — Skin testing with late readings of intradermal sites and patch testing are the two forms of testing that have proven helpful in identifying the responsible contrast agent in DHRs and in choosing alternative agents for future use [9,14,16,17,40-46].

Whom to test and timing — Testing is most useful in patients with delayed-onset (ie, from approximately 6 hours to 10 days) MPE that developed after the administration of radiocontrast. We also perform these tests in patients with delayed-onset urticaria/angioedema, but the positivity rate is much lower. Testing takes several days to perform. Patients whose reactions were uncomfortable and who will likely need future radiologic examinations are generally the most motivated to undergo testing.

Testing should be performed within six months of the index reaction because of a higher sensitivity during this time period [9,47,48]. In a European multicenter study, intradermal tests performed within the first six months after the resolution of DHR showed positive reactions in 48 percent of patients, as opposed to 23 percent in those in whom the time interval between the reaction and IDT was more than six months [9].

What to include in testing — In the evaluation of patients with past DHRs, we suggest testing with the suspected culprit and some alternatives that are available at the facility where the patient receives care. Iobitridol is often included as a possible alternative because it shows a low cross-reactivity with other agents in patients with DHRs [46].

Techniques and interpretation — For both delayed exanthema and delayed urticaria/angioedema, we perform SPT with immediate readings and IDT with both immediate and late readings, as well as patch testing.

We start with SPT with undiluted contrast, primarily to screen for immediate reactivity. SPT is read at 20 minutes and is negative in nearly all cases. If SPT is negative, we perform IDT with a 1:10 dilution [49]. If undiluted contrast is used for IDT, there are more nonspecific irritant reactions at the 20 minute reading, although the sensitivity of late readings in DHRs appears to be higher [50]. Additional data are needed before IDT with undiluted contrast can be recommended as routine practice. IDT is read at 20 minutes and again after 24 or 48 hours and after 72 hours. Any induration with erythema developing after more than six hours is considered to be a positive delayed reaction [1,51]. Patients should also report any later-appearing skin changes at the test site, up to a week later. A more detailed discussion of skin testing is found separately. (See "Overview of skin testing for IgE-mediated allergic disease".)

Concomitantly, patch testing is performed with small pieces of filter paper soaked in undiluted contrast and placed in a 12 mm aluminum Finn chamber, fixed with adhesive tape on the back for 48 hours (two days). The chambers are removed and the test sites read after 48 hours and again after 72 hours [51]. Positives are interpreted using the standard scoring system (table 1). A more detailed discussion of patch testing techniques and interpretation is found separately. (See "Patch testing".)

Test performance

●In a 2015 meta-analysis of studies evaluating skin testing for hypersensitivity reactions to radiocontrast media, the overall positive rate in patients with delayed reactions (any type) on either delayed reading of IDT or patch testing was 26 percent (95% CI 15-41 percent) [52]. The pooled positive rates of SPTs, delayed reading of IDTs, and patch tests were 7, 22, and 16 percent, respectively. The timepoints for delayed readings of IDT differed among studies, but eight studies included at least one or two delayed reading at 24 to 72 hours, sometimes with additional readings out to one week.

In six studies on delayed reactions included in the meta-analysis, none reported any false-positive skin test results in 83 exposed and tolerant controls [52].

Estimates of the negative predictive value in patients who were subsequently given the contrast to which they tested negative on delayed reading of IDT have varied across studies, ranging from approximately 53 to 100 percent [17,18,40,41,44-46,53].

●One of the studies included in the meta-analysis was a 2009 European multicenter prospective study, which included 98 patients with DHRs to contrast [9]. Methods were uniform across all centers and followed the protocols describe above. Patients were evaluated at a median time interval of six months after the clinical reaction and were tested with the suspected culprit contrast agent and a variety of other agents, including ionic monomers, ionic dimers, nonionic monomers, and nonionic dimers [9,12].

Results of either delayed IDT or patch testing, or both, were positive in 37 of 98 patients (38 percent), with 32 percent of patients testing positive on the late intradermal reading and 28 percent on the patch test [9]. Skin tests of either type were more often positive when patients were tested within the first six months after the clinical reaction (48 percent) than when tested later (22 percent).

The specificity was 100 percent for both IDT with late reading and for patch testing. There were no false-positive tests in 82 healthy controls (71 who had never received contrast and 11 who had tolerated contrast in the past).

Cross-reactivity — There appears to be extensive cross-reactivity based on skin testing results (IDT with delayed readings) among contrast agents in patients with past DHRs [9,41,52]. Most patients test positive to several contrast agents. In the multicenter European study, 25 of the 37 skin test-positive patients were tested with at least seven other agents, and 22 tested positive to several agents [9]. Cross-reactivity is commonly reported between iodixanol and iohexol and between ioversol or iopamidol [53] and iomeprol [9,16,41,44-46]. Iobitridol appears to have minimal cross-reactivity with other agents [46,54].

Testing for rare iodine sensitivity — In rare cases of MPE to contrast agents, the reaction can be triggered by free iodine or iodide rather than by the radiocontrast media molecule itself. In these cases, prick and patch tests with iodine in petrolatum (0.5 and 1%), iodine in ethanol (0.5%), or iodine dissolved in a mixture of ethanol and water has been performed [15,18]. The optimal testing and challenge strategy has not been determined, and the methods outlined here should be considered preliminary.

●In one publication that included 9 patients with immediate reactions and 10 with delayed reactions, three reactions (one immediate urticaria and two delayed MPEs) were ultimately reproduced with oral challenge to a 5% Lugol's solution (ie, a solution of 5% elemental iodine and 10% potassium iodide in distilled water) [15]. However, Lugol's solution is quite unpalatable.

●In another report, skin tests in two patients were positive to the majority of contrast agents tested and also to iodine tincture (iodine dissolved in a mixture of ethanol and water, resulting in a solution containing 18 to 22 mg/mL iodine and 21 to 26 mg/mL sodium iodide) but negative to Lugol's solution [18]. The clinical relevance of the skin test reaction was tested by repeated topical application (ie, repeated open application testing) of the iodine solutions twice daily for five days onto the outer upper arm or by oral provocation test with 2% Lugol's solution (after excluding thyroid contraindications). In these patients, topical application of iodine tincture resulted in acute allergic contact dermatitis, whereas application of 2% Lugol's solution did not. Patients refused oral challenge with Lugol's solution.

Investigational tests — The lymphocyte transformation test (LTT) measures the proliferation of T cells after stimulation with a drug in vitro. LTT results in DHRs to contrast agents are heterogeneous, and the sensitivity is considered to be moderate [14,44,55-57]. Because of these limitations, the LTT is considered to be an additional diagnostic tool for selected cases but not for routine use.

Challenge procedures (rarely needed) — In patients with past DHRs, challenge procedures with contrast, although rarely needed, can be used to identify alternative agents that are tolerated [16,40,43-46,58-61]. In patients sensitized to several contrast agents, challenge may be advisable to prove that a certain skin test-negative agent is indeed tolerated [44]. A maximum single challenge dose of 20 to 50 mL appears to be sufficient for excluding recurrent exanthema reactions in response to a future radiologic examination that requires 100 to 150 mL of contrast (the volume considered adequate for a basic radiologic examination).

The literature contains several approaches to challenges, and consensus regarding the total dose or time intervals used is lacking. Total doses between one-tenth of the required dose up to 100 mL per day and at one hour to one day intervals have been used [17,44-46]. In one study, five patients reacted only after the administration of 25 mL of contrast and six patients after the administration of two doses of 50 mL given within an hourly interval [46].

FUTURE ADMINISTRATION OF CONTRAST — Patients with past delayed hypersensitivity reactions (DHRs) who have been evaluated by an allergist should receive contrast agents to which they tested negative [62,63]. In patients with past DHRs, premedication is unlikely to be effective in preventing recurrence in most cases and therefore not recommended [41,64,65]. However, it may reduce the severity of a subsequent reaction and thus might have a role in certain situations. For example, a case report described a patient with a severe past delayed maculopapular exanthem and positive skin tests to multiple contrast agents in whom glucocorticoids and cyclosporine were given prior to administration of a contrast agent to which the patient tested positive, with no recurrence [66].

Urgent cases (no time for testing) — In cases of urgent need when there is inadequate time to test, using a structurally unrelated contrast medium is associated with a moderately increased risk for a repeat occurrence of exanthema [16,62,63]. There is some evidence that using iobitridol has a very low risk of a repeat reaction, provided that it was not the cause of the patient's index reaction [16,46]. Thus, iobitridol would be the best choice in this situation, if it is available [54].

DELAYED REACTIONS TO GADOLINIUM-BASED CONTRAST — Very few cases of delayed reactions following gadolinium-based contrast agent (GBCA) administration have been described [60]. In a case report, a 64-year-old woman with a history of past immediate hypersensitivity reactions to iodinated contrast was premedicated with methylprednisolone and clemastine and given 12 mL of gadobutrol 1 mmol/mL prior to undergoing magnetic resonance imaging (MRI) [67]. She was readmitted two days later because of symptoms that began several hours after the GBCA injection, which consisted of exanthema of the face and trunk, palpitations, arrhythmia, and hypertensive episodes (with blood pressure readings up to 220/120 mmHg). The reaction persisted for approximately 12 hours and then resolved without treatment.

In another case report, a 53-year-old woman developed a generalized eruption of pustules and erythema on intertriginous areas together with mild kidney impairment, malaise, fever, and leukocytosis three days after MRI with a GBCA [68]. Patch tests with undiluted GBCA showed a positive reaction with indurated erythema and pustules to gadobutrol and negative skin test results with gadoteric acid.

Subsequent case reports of patients with maculopapular exanthems have appeared, with and without positive skin tests to GBCA [69-71]. One pediatric case described drug reaction with eosinophilia with systemic symptoms (DRESS) that was attributed to GBCA and which recurred upon reexposure [70].

In subjects with kidney disease, GBCAs have been associated with nephrogenic systemic fibrosis, a disease resembling scleromyxedema or scleroderma. There is no evidence for an allergic pathogenesis underlying this disease entity. Diagnosis and management are discussed separately. (See "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease" and "Patient evaluation before gadolinium contrast administration for magnetic resonance imaging".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypersensitivity to iodinated and gadolinium-based contrast agents".)

SUMMARY AND RECOMMENDATIONS

●Delayed reactions to iodinated contrast – Nonimmediate hypersensitivity reactions, also called delayed hypersensitivity reactions (DHRs), are defined as reactions that appear later than one hour and up to 10 days after contrast administration. The frequency of all reported DHRs to iodinated contrast is unclear, but most studies suggest that DHRs occur in less than 4 percent of patients. (See 'Definition' above and 'Prevalence' above.)

•Signs, symptoms, and timing – The most common presentation is a macular or maculopapular exanthem (MPE) appearing between six hours and several days after contrast administration. Delayed-onset urticaria or angioedema can also occur. There are also some rare but serious delayed reactions reported to contrast media, including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and others. (See 'Types of reactions' above.)

•Utility of allergy evaluation – For patients with a history of an MPE up to 10 days after the administration of radiocontrast, an allergy evaluation can be helpful in confirming that the exanthem was related to the contrast (rather than a viral exanthem, erythema multiforme, or pityriasis rosea). Testing can also identify an alternative contrast agent that is likely to be tolerated for future use because contrast agents show extensive cross-reactivity in their ability to cause DHRs and premedication is generally not effective in preventing recurrent reactions. (See 'Maculopapular exanthema' above.)

•Components of the evaluation – Allergy evaluation for a DHR consists of skin testing with late readings and patch testing, which yield positive results in nearly 50 percent of patients when performed within six months of the index reaction. The contrast agent involved in the past reaction should be tested, if known, as well as several possible alternative agents. Iobitridol is often included as a possible alternative because it has low cross-reactivity with other agents. Skin prick testing (SPT) and patch testing are performed with undiluted contrast, and a 1:10 dilution is used for intradermal testing (IDT). IDT sites are examined after 48 and 72 hours, with any induration with erythema developing after 24 hours considered to be a positive reaction.

•Rare iodine/iodide reactions – In rare cases of MPE to contrast agents, the reaction can be triggered by free iodine or iodide rather than by the radiocontrast media molecule itself. The optimal testing strategy for this is uncertain. (See 'Testing for rare iodine sensitivity' above.)

●Rare reactions to gadolinium-based contrast – Very few cases of DHRs following gadolinium-based contrast agent (GBCA) administration have been described. Allergy evaluation has been performed as described for iodinated contrast media and has elicited a positive skin test in some cases. (See 'Delayed reactions to gadolinium-based contrast' above.)