1. Skin testing for acute (immediate) hypersensitivity reactions to contrast media

The diagnostic properties of cutaneous tests for acute (immediate) hypersensitivity reactions (HSR) to Contrast Media (CM) were evaluated in 4 studies (Caimmi, 2010; Kim, 2013; Salas, 2013; Sesé, 2016).

Caimmi (2010) studied 159 patients. Patients were tested with the culprit iodine-based contrast medium (ICM) and a set of other ICM if they were positive for the culprit ICM or if its name was unknown. In order to know which ICM was involved, either patients already knew which drug had supposedly caused the reaction and provided us the name, or we contacted the hospital in which the reaction had occurred. The ICM used were: amidotrizoate, ioxithalamate, iopamidol, iohexol, ioversol, iopromide, iomeprol, iobitridol, iodixanol and ioxaglate. Skin tests were performed firstly as prick tests with the undiluted commercially available solution and then, if negative, by intradermal tests (IDT) at a 1: 10 dilution. Prick tests were considered positive if, after 15 min, the size of the weal was at least 3 mm in diameter. For IDT, positivity was considered when the size of the initial weal increased by at least 3 mm in diameter after 15 to 20 min, considering as non-irritant a maximum dilution of 1/10. The negative predictive value was defined as the proportion of patients with negative skin test results to at least one ICM at first testing who had a further injection with that ICM without reacting. One hundred participated (75.5% participation rate). Seventy-one of them (5 9.2%) were females of a median age of 56 (45–65) years. The majority of the reactions were immediate (101 out of 120, 84.2%), and in two cases, it was not possible to assess whether the reaction was immediate or non-immediate. For immediate reactions, 42 (41.6%) were of grade 1, 34 (33.7%) of grade 2, 20 (19.8%) of grades 3 and five (4.9%) of grade 4. Only one (5.9%) of the 17 non-immediate reactions was moderate, all the others were mild (16 to 94.1%).

Kim (2013) retrospectively included 1048 patients. The mean (SD) age was 55.1 (14.5) years; 501 (47.8%) were male. Intradermal test with the RCM that was to be used in the

pending nonionic CM-enhanced CT was performed just before the CT examinations. The nonionic CM used in our contrast CT scans was iopromide, iomeprol, iohexol, and iodixanol. Intradermal tests were conducted on the volar surface of the forearm with a negative control, saline. A 1:10 solution of contrast medium (0.03 to 0.05 mL), which has been accepted as a non-irritating concentration, was gently injected into the skin to produce a small superficial bleb of 2 to 4 mm. Skin test positivity was determined when the diameter of the wheal increased by at least 3 mm, and surrounding erythema was observed after 15 to 20 minutes. If a patient had a negative response to skin tests, CT was performed as scheduled (provocation). Of the 376 patients previously exposed to CM, 61 (16.2%) had a history of at least 1 mild CM-associated reaction: 56 (91.8%) had immediate and 5 (8.2%) non-immediate reactions.

Salas (2013) included 90 patients with a history of immediate HSR after contrast media (CM). Immediate HSR was classified according to the Ring and Messmer scale.

Skin Test (ST) was carried out using the following CM: iobitridol, iomeprol, iodixanol, iohexol, ioversol, iopromide and ioxaglate. Prick tests were performed using undiluted CM and IDT using 10-fold dilutions. In those with a negative ST, a single-blind placebo-controlled provocation test was performed with the CM involved, as described. In patients with a positive ST and/or provocation test, a basophil activation test (BAT) was performed with iohexol (3; 0.3 mg/ml), iodixanol (3; 0.3 mg/ml), iomeprol (3.5; 0.35 mg/ml) and ioxaglate (5.8; 0.58 mg/ml) (based on dose–response curves and cytotoxicity studies). The median age of the subjects evaluated was 54.50 ± 27 years; 63 (60%) were women. The CM involved in the reaction was iomeprol in 26 cases (28.89%), iodixanol in 19 (21.11%), iohexol in 11 (12.22%), iopromide in 9 (10.00%) and unknown in 25 (27.78%). According to the clinical history, most cases developed reactions with skin involvement (65.65% urticaria/ angioedema and 30% generalized erythema), and only 4.44% had airway or cardiovascular involvement. Regarding symptom severity, 69 cases (76.71%) had grade I reactions, 18 (20%) grade II and 3 (3.33%) grade III. No patients had grade IV reactions.

Sesé (2016) included 37 patients with a definite history of immediate HSR due to Iodine-based Contrast Media (ICM). Immediate HSR was classified according to the Ring and Messmer scale. Skin tests were performed at least 6 weeks after the HSR on the volar forearm with the suspected ICM and with four other ICM. Skin prick tests (SPTs) involved freshly prepared undiluted ICM commercial solutions, and intradermal tests (IDTs) were performed successively with 100-fold and then 10-fold solution diluted in 0.9% sterile saline. Saline and chlorhydrate histamine were negative and positive controls, respectively. In total, 37 patients (24 women, mean age 49.3 years at the time of the reaction) completed the tests. The clinical severity of the reaction was grade I for 26 (70%), grade II for 4 (11%), and grade III for 7 (19%); 35 (95%) reported skin or mucosal symptoms, including pruritus (n = 11), facial erythema (n = 6), generalized erythema (n = 20), urticaria (n = 7), and angioedema (n = 5).

2. Skin testing for late (delayed) hypersensitivity reactions to contrast media

The diagnostic property of cutaneous tests for late (non-immediate) hypersensitivity reactions (HSR) to Iodinated Contrast Media (ICM) was evaluated in one study (Torres, 2012). Torres included a total of 161 subjects with a history of a non-immediate reaction imputable to at least one CM was evaluated. One patient who developed Stevens–Johnson syndrome was not included. The median age was 58.5 years (IR: 48.85 to 66.5) with 82 men (50.9%). According to the information obtained from the clinical history, the CM involved in the reaction were iomeprol in 53 (32.9%), iodixanol in 46 (28.6%), iohexol in 27 (16.8%), iobitridol in 4 (2.5%), ioversol in 3 (1.9%), iopromide in 3 (1.9%), ioxaglate in 2 (1.2%) and unknown in 23 (14.3%). According to the clinical history, 108 cases (67.1%) developed symptoms compatible with exanthema and 53 (32.9%) with delayed urticaria. Regarding symptom severity, 16 cases (9.9%) had mild reactions, 143 (88.8%) moderate reactions, and 2 severe reactions (1.2%) consisting of desquamative exanthema. Concerning the number of episodes, 132 cases (82%) had one episode and 29 cases (18%) two episodes.

Results

1. Skin testing for acute hypersensitivity reactions

Negative predictive value

The rate of a positive skin test in the study of Sesé (2016) was 13.5% (95% CI 4 to 29%) and increased to 20% (95% CI 4 to 48%) for patients who consulted during the year after the HSR. Among the 32 patients with negative skin test results, 31 were challenged successfully, 15 with the culprit ICM. One grade I reaction occurred 2 h after challenge (generalized pruritus, erythema, and eyelid oedema lasting < 1 h) and was considered a positive intravenous challenge result. At 2 h after provocation test, two patients reported generalized and isolated pruritus that regressed with antihistamine therapy and was not considered a positive IPT result. None of five patients with positive skin test to ICM were re-exposed to contrast media during radiologic examination, positive predictive could not be calculated. For an immediate HSR to ICM, the negative predictive value for skin tests with low dose was 80% (95% CI 44 to 97%).

Kim (2013) showed that among the 1046 patients who had negative responses on skin tests, 52 (5.0%) showed immediate-type adverse reactions after CT using radio contrast media. However, most reactions were mild and cutaneous, such as pruritus, urticaria, and mild angioedema. Only 1 patient (0.1%) had a grade II moderate immediate reaction accompanied by breathing difficulty and mild laryngeal oedema, which were relieved with an antihistamine. The negative predictive value of the pre-screening skin test for immediate hypersensitivity reactions before contrast media administration was 95.0%. The negative predictive value of the skin test for immediate hypersensitivity reactions in patients with a history of contrast media hypersensitivity reactions was 80.3% (n= 49/61) and that in patients without a history was 95.9% (n= 945/985).

Results of Salas (2013) showed that five subjects (5.56%) had a positive skin test: three by prick test (one to iodixanol, one to iomeprol and one to iohexol) and five by intradermal testing (four to iohexol, three iodixanol and two to iomeprol). In cases with a negative skin test to all CM tested (N = 74), provocation test was carried out with the culprit CM if known, being positive in three cases; one to iodixanol, one to iomeprol and one to iodixanol, iohexol plus iomeprol. In total, 11 patients with a negative ST refused to undergo a provocation test, resulting in a negative predictive value to immediate hypersensitivity reactions of 95.26%. Eight (8.9%) cases were confirmed as having IHR, 5 (62.5%) by ST and 3 (37.5%) by provocation test. Five from those confirmed as IHR (62.5%) had a positive BAT.

The results of Caimmi (2010) revealed that ICM skin tests were positive in 21 patients (17.5%). Seventeen of them (80.9%) had a history of immediate reaction (four with grade 1, eight grade 2, four grade 3 and one grade 4). Prick tests were all negative. IDT were positive at 20 min for 15 patients with an immediate history and for the patient with unknown chronology. Caimmi (2010) found one single false negative; the negative predictive value of ICM skin tests was 96.6% (95% CI: 89.9 to 103.2).

Quality of evidence

The quality of certainty of evidence was graded as very low due to high risk of bias (see Tab Rob assessment, downgraded by two points) and low number of patients (imprecision downgraded by one point).

2. Skin testing for delayed hypersensitivity reactions

Negative predictive value

In the total group of cases evaluated (N = 161), 34 subjects (21.1%) developed a delayed reading of the intradermal tests positive (13 at 1/10 dilution and 29 undiluted). Of these, 27 were skin-test positive to just one CM, 6 to two CM and 1 to three. The immediate reading of the intradermal tests was negative in all cases. The skin test was positive to iomeprol in 21 cases (50%), to iodixanol in 7 (16.7%), to iobitridol in 5 (11.9%), to ioxaglate in 4 (9.5%), to iohexol in 3 (7.1%) and to iopromide in 1 (2.4%). In the 34 cases with a positive intradermal test, 10 also had a positive patch test. No positive patch tests were detected in the patients with negative intradermal results. In the patients with a negative skin test to all the CM tested (N = 127), a provocation test was carried out with the CM involved. Provocation test was positive in 44 cases (34.6%), 19 to one CM and 3 to two CM. Thirty-eight cases (76%) were positive to iodixanol, 8 (16%) to iomeprol and 4 (8%) to iohexol. The time interval between administration and symptom development was: 1 to 6 h (13 cases), 7 to 12 h (27 cases), 13 to 24 h (68 cases), 25 to 48 h (41 cases) and > 48 h (12 cases).

Quality of evidence

The quality of certainty of evidence was graded as very low due to high risk of bias (see Tab Rob assessment, downgraded by two points) and low number of patients (imprecision downgraded by one point).

Positive rates of cutaneous tests

The positive rate of cutaneous tests was reported in 12 studies. Since these studies do not compare cutaneous tests with a provocation test, they are not in line with the PICO. However, studies on positive rates of skin tests in patients with HSR to ICM contain important clinical information. Therefore, we have additionally synthesized literature evaluating positive rates of cutaneous tests in patients with HSR to ICM. Since these studies do not describe comparative research, we did not create risk of bias and evidence tables for these studies.

In patients with immediate HSR to ICM, the pooled positive rate of skin tests was 17% (95% CI, 11–26%; I²= 45%) and was identical to that of IDT (Table 1). The pooled positive rate of SPTs was 3% (95%CI= (1-5%); I²= 0%). The pooled positive rates of IDT were shown to rise as the severity of reactions increased: pooled positive rate for mild HSR is 12% (95%CI= (6 to 23%); I²= 38%); moderate HSR 16% (95%CI= (10 to 24%); I² = 6%) and for severe HSR, 52% (95%CI= (31 to 74%), I²= 42%). Table 1 presents a detailed overview of positive rates across studies. Figure 1 presents an overview of per-test cross-reactivity rates between pairs of ICM in skin test positive patients with HSR to ICM.

A multidisciplinary working group was formed for the development of the guideline in 2016. The working group consisted of representatives from all relevant medical specialization fields that are involved with intravascular contrast administration.

All working group members have been officially delegated for participation in the working group by their scientific societies. The working group has developed a guideline in the period from May 2016 until July 2019.

The working group is responsible for the complete text of this guideline.

Working group

• A.J. van der Molen, radiologist, Leiden University Medical Centre, Leiden (chairman)
• R.W.F. Geenen, radiologist, Noordwest Ziekenhuisgroep (NWZ), Alkmaar
• T. Leiner, radiologist, University Medical Centre Utrecht, Utrecht (until November 2018)
• H.M. Dekker, radiologist, Radboud University Medical Centre, Nijmegen
• I.A. Dekkers, clinical epidemiologist and radiologist in training, Leiden University Medical Centre, Leiden
• K. van der Putten, nephrologist, Tergooi, Hilversum
• J.G.R. de Monchy, allergologist, DC-Klinieken, Amsterdam
• H.R.H. de Geus, internist-intensivist, Erasmus Medical Centre, Rotterdam
• S.W. Zielhuis, hospital pharmacist, Medical Centre Leeuwarden, Leeuwarden
• O.R.M. Wikkeling, vascular surgeon, Heelkunde Friesland Groep, location: Nij Smellinghe Hospital, Drachten
• I. Brummer, emergency physician, Treant Healthcare Group, Emmen
• M. van der Vlugt, cardiologist, Radboud University Medical Centre, Nijmegen (until April 2018)
• M. Gotte, cardiologist, Free University Medical Centre, Amsterdam (from July 2018)
• S.H. Kardaun, dermatologist, University Medical Centre Groningen, Groningen (until March, 2018)

Methodological support

• I.M. Mostovaya, senior advisor, Knowledge Institute of the Federation Medical Specialists
• J. Buddeke, advisor, Knowledge Institute of the Federation Medical Specialists (from April 2018)
• W. Harmsen, advisor, Knowledge Institute of the Federation Medical Specialists (from April 2018)