Background Radiocontrast media (RCM) are intravenous agents widely used in diagnostic imaging. While generally well-tolerated, a small proportion of patients experience adverse reactions (ARs). These can range from mild symptoms to severe systemic reactions 1. Conventional ionic, high-osmolar iterations of RCM were associated with frequent rates of ARs because of their physicochemical properties. These have since been replaced by nonionic, low-osmolar iodinated agents, such as iohexol (Omnipaque), iodixanol (Visipaque), and iopromide (Ultravist). The rates of ARs to these newer RCMs are significantly lower, estimated to be <1%, resulting from either an immunoglobulin E (IgE)-dependent or an independent mechanism 2. RCM allergy labels influence clinical decision-making across all specialties of medicine, leading to either the avoidance of recommended imaging modalities or reliance on inferior, alternative imaging. These have several negative implications, including delays in clinical diagnoses and treatment guidance. Until recently, consensus guidelines in RCM allergy assessment recommended history-based risk stratification, followed by in vivo testing (including skin prick and intradermal tests), and graded challenge (GC). While comprehensive, this approach is resource-intensive, costly, and demands significant healthcare capacity. RCM dilutions with several agents need to be prepared on the day, impacting resources in an allergy day unit. This is particularly relevant in our centre, where we have previously reported prolonged outpatient drug allergy waitlists 3, highlighting delays in timely evaluation. Recent consensus guidelines from the American Academy of Allergy, Asthma intervals <5 years were considered high risk. A tryptase level obtained 1–4 hours after symptom onset was considered reflective of the acute episode, and a dynamic tryptase rise was defined as an acute level exceeding the baseline by ≥20% + 2 μg/L 7. Local testing is performed by Phadia ImmunoCAP immunoassay (Thermo Fisher Scientific, Uppsala, Sweden) with reference range ≤11.9 μg/L. Patients who underwent opportunistic testing during inpatient hospitalisation were excluded, as these data were not routinely entered into a formal database until after the conclusion of the study period. Results Twenty-three patients were identified; 1 patient with a delayed reaction was excluded after declining follow-up GC. The median age was 62 years (interquartile range IQR, 49.5–70.5), and the majority were female (n = 17, 77%). In half of referrals (n = 11, 50%), triage was urgent (category 1, clinically indicated <30 days). Five were semi-urgent (category 2, <90 days), and 6 were not assigned a triage category. Despite category 1 triage, the total median wait time from primary care referral to testing in this group was 17 weeks. Before review or challenge, 9 (41%) patients underwent second-line imaging because of RCM allergy label. The index RCM was identified in 14 (64%) patients; iohexol was most frequently implicated, reflecting local availability. Five (23%) patients had a history of grade 2 anaphylaxis, and 3 (14%) patients had a history of grade 3 anaphylaxis (Table 1). Five (23%) patients had episodic and baseline tryptase levels measured; of these, 3 showed a dynamic rise in tryptase levels. No patient had an elevated baseline tryptase level. Table 1. - Summary of patients with a history of moderate or severe anaphylaxis to RCM Patients Age/sex Index RCM Brown grade of anaphylaxis Dynamic rise in event tryptase Elevated baseline tryptase Time from event to challenge IDT agents (conc) IDT result Challenge agent (volume in mL) Challenge outcome Postchallenge exposure 1 61/F Iohexol 2 Yes No 1 y Iodixanol (1:10) Negative Iodixanol (0.02, 0.2, 2, 20) Tolerated Yes, tolerated iodixanol 2 64/M Iodixanol 2 Yes No 6 y Iodixanol, iopromide (NR) Negative Iopromide (0.1, 1, 5) Tolerated Nil 3 66/F Iohexol 2 No No 1 y Iohexol, iodixanol, iopromide (1:10) Negative Iodixanol (0.2, 2, 20) Tolerated Nil 4 39/F Iohexol 2 Not tested Not tested 8 y Iohexol, iodixanol, iopromide (1:10) Negative Iodixanol (0.2, 2, 20) Tolerated Nil 5 68/F Unknown iodinated RCM 2 Not tested Not tested 41 y Iohexol, iodixanol, iopromide (1:10) Negative Iohexol (2, 20) Tolerated Nil 6 57/F Iohexol 3 No No 3 y Iohexol, iodixanol, iopromide, Optiray (1:100, 1:10) Negative Iodixanol (0.2, 2, 20) Tolerated Nil 7 45/F Iohexol 3 Yes No 2 y Iohexol, iodixanol, iopromide (1:100, 1:10) Iohexol positive (1:100); iodixanol NR, not recorded; RCM, radiocontrast media. Intradermal testing (IDT) was performed in 20 (91%) patients, of whom 14 (70%) were tested with a single 1:10 dilution and the remainder (n = 6) with several dilutions (1:100 and 1:10, or 1:10 and neat). Two patients had a positive IDT: 1 patient with hypotensive anaphylaxis to iohexol who tested positive to the index agent at 1:100 and negative to the remainder; the second patient with a remote history of cutaneous reaction to iohexol and who tested positive to the index agent at 1:10 and iopromide at neat dilution. Two patients proceeded directly to GC bypassing in vivo testing, and 2 were delabelled after negative IDT alone, performed opportunistically during unrelated immunology admissions. All 4 patients had low-risk histories of distant reactions. All patients safely tolerated the RCM challenge, whether to the index agent (when history was low/negligible risk) or to an alternative (Fig. 1). Two-, three-, or four-step challenge protocols were used at the discretion of the treating clinician at the time of the challenge. All GCs had 30-minute intervals between intravenous RCM doses. Many patients underwent a 3-step challenge (n = 13, 65%), which comprised variable volumes: 8/13 received 0.2, 2, and 20 mL. Four patients (20%) received a 2-step RCM challenge, all with 2 mL followed by 20 mL. The remaining 3 patients (15%) underwent a 4-step challenge with incremental increases in administered volume of RCM. Since 2022, the department has standardised volumes for such challenges: 0.02 and 0.2 mL, 2 and 20 mL for the 4-step; 0.2, 2, and 20 mL for the 3-step; and 2 and 20 mL for the 2-step challenge. All steps are separated by 30-minute intervals, and a 2-hour observation after the final 20 mL volume.Figure 1.: Flow diagram summarising testing outcomes. IDT, intradermal test; RCM, radiocontrast media.Real-world clinical use was safe—7 (32%) patients had subsequent clinical re-exposure, and importantly, no patients were relabelled with RCM allergy on their medical records. Discussion Our finding of low in vivo testing yield aligns with international cohort data demonstrating wide variability in RCM IDT positivity, ranging from 10.2% 8 to 25.9% 9 even when testing is performed early (within 6 months of index reaction). In addition, performance is further impacted by delays in testing because of long waitlists in our allergy department 3. The highest diagnostic yield is consistently observed in patients with severe IHR, in whom pooled positivity reaches 52% and the likelihood of a positive test is increased 6.8-fold, compared with markedly lower rates across all IHR (17%) and delayed reactions (26%) 10. Evidence for structural cross-reactivity remains conflicting, with reported rates ranging from 0% to 100% 11, and higher rates of in vivo testing positivity in delayed reactions 10,11 suggesting that nonspecific or polyvalent reactivity, rather than true structure-based cross-reactivity, may also contribute. Notably, a prospective cohort study performed a 1:10 dilution IDT to the index agent before administration of an alternative RCM and demonstrated similar rates of breakthrough reactions between IDT-positive and IDT-negative groups 12. The excellent safety profile observed in our RCM challenges is consistent with existing literature, which similarly reports that following risk stratification, supervised GCs are generally well-tolerated. Even studies employing rapid, full-dose parenteral challenges (without premedication) guided by history and skin testing have reported low rates of severe reactions and effective identification of tolerated alternatives 13. While use of an alternative RCM remains the most effective strategy to prevent recurrent reactions, a low but persistent rate of breakthrough reactions (~10% 5) persists. Accordingly, IDT has a limited adjunctive role in RCM allergy assessment because of its low sensitivity and negative predictive value, with greatest utility in patients with recent, severe IHR, in whom further RCM exposure is unavoidable. Beyond diagnostic considerations, our findings highlight the significant clinical consequences of carrying an unverified RCM allergy label. Despite high-priority triage, patients in our cohort experienced prolonged wait times, with 41% requiring second-line imaging before assessment. This reflects broader national and international system-level pressures that contribute to postponement or avoidance of essential imaging 14 with downstream effects reduced diagnostic accuracy, inappropriate premedication, and delays in care. These findings reinforce the importance of timely, structured assessment to confirm or remove RCM allergy labels. Such pathways can be streamlined through proactive radiology-led risk assessment (eg, using the framework proposed by Wang et al. 1), use of an alternative agent when appropriate, and assessment by clinical immunologists and allergists for severe or uncertain cases, without compromising patient safety 14. This study contributes to the limited international literature on the long-term, real-world outcomes of RCM use following evaluation. Reported rates of allergy relabelling after re-exposure to an alternative RCM are low, ranging from 4.4% (6 of 137 re-exposed patients; severity not reported 15) to 10.5% (4 of 39 re-exposed patients 8), with the latter reactions uniformly mild and not requiring adrenaline or hospitalisation. Several limitations should be acknowledged. Testing for antibiotics and nonsteroidal anti-inflammatory drugs predominates in our allergy day unit, which may partially explain the low numbers of RCM tests performed. In addition, given the absence of database recording of inpatients assessed during acute hospitalisation, the data are limited to only those in which RCM testing was performed in the allergy day unit. The retrospective design, variability in IDT and GC protocols over the study period, and small sample size, limit further subgroup analysis and constrain comparability, particularly for patients with severe reactions and complex comorbidities. A prospective evaluation of RCM allergy labels and testing in accordance with the new guidelines is currently underway in both the allergy day unit and inpatient setting. Overall, implementation of these streamlined protocols may reduce unnecessary investigations, relieve service pressures, and improve access to essential imaging. Finally, larger, multicentre, prospective studies are needed in RCM allergy assessment for the application of the current guidelines. Conclusion This longitudinal study, one of the very first from Australia, confirms findings that align with the recently published international guidelines advocating history-based risk stratification and agent switching, with targeted testing reserved for high-risk cases. Among patients who underwent evaluation, testing was safe, and importantly, all patients tolerated GC. Notably, positive IDTs were rare and did not alter management, supporting evidence that routine in vivo testing is of limited benefit for those deemed low-risk. Acknowledgments We wish to acknowledge the Department of Clinical Immunology and Allergy at Flinders Medical Centre. Conflicts of interest The authors have no financial conflicts of interest. Author contributions Data collection, analysis, writing manuscript: Dariel A. Roper. Study design, manuscript reviewing and supervision: Syed B. Ali. Ethical statement This study was registered as a quality improvement project with the Southern Adelaide Clinical Human Research Ethics Committee (reference 113.25).
Roper et al. (Wed,) studied this question.