HLA-DRB1 is associated with cefaclor-induced immediate hypersensitivity.

Background: Drug-induced hypersensitivity such as anaphylaxis is an important cause of drug-related morbidity and mortality. Cefaclor is a leading cause of drug induced type I hypersensitivity in Korea, but little is yet known about genetic biomarkers to predict this hypersensitivity reaction. We aimed to evaluate the possible involvement of genes in cefaclor induced type I hypersensitivity. Methods: Whole exome sequencing (WES) and HLA genotyping were performed in 43 patients with cefaclor induced type I hypersensitivity. In addition, homology modeling was performed to identify the binding forms of cefaclor to HLA site. Results: Anaphylaxis was the most common phenotype of cefaclor hypersensitivity (90.69%). WES results show that rs62242177 and rs62242178 located in LIMD1 region were genome-wide significant at the 5 × 10-8 significance level. Cefaclor induced type I hypersensitivity was significantly associated with HLA-DRB1∗04:03 (OR 4.61 [95% CI 1.51-14.09], P < 0.002) and HLA-DRB1∗14:54 (OR 3.86 [95% CI 1.09-13.67], P < 0.002). Conclusion: LIMD1, HLA-DRB1∗04:03 and HLA-DRB1∗14:54 may affect susceptibility to cefaclor induced type I hypersensitivity. Further confirmative studies with a larger patient population should be performed to ascertain the role of HLA-DRB1 and LIMD1 in the development of cefaclor induced hypersensitivity.

[Prehospital care of anaphylactic reactions by the air rescue and ground-based emergency services Dresden : An analysis of treatment and outcome]. / Präklinische Versorgung von anaphylaktischen Reaktionen durch die Dresdner Luft- und Bodenrettung : Analyse von Therapie und Outcome.

BACKGROUND: Anaphylaxis can lead to a life-threatening situation. Therefore, rapid diagnosis and emergency treatment is indicated. Immediate treatment with intramuscular adrenaline (or intravascularly with sufficient medical expertise) in anaphylaxis with cardiovascular and/or respiratory symptoms is recommended by various guidelines. Previous studies have shown that anaphylaxis is often not treated according to guidelines and that adrenaline in particular is rarely administered. OBJECTIVE: The aim of the study was to investigate the data on emergency treatment and outcomes of patients with anaphylaxis by the air rescue and ground-based emergency services Dresden. Moreover, the results of the air- and ground-based services were compared. The focus was on administration of adrenaline and outcomes. MATERIALS AND METHODS: Data from the ground-based emergency service Dresden (from 2012 to 2016) and the air rescue service Dresden (from 2008 to 2015) related to anaphylactic reactions were analyzed retrospectively. The severity of the anaphylaxis, the emergency medication administered, further monitoring, and outcomes were analyzed. RESULTS: Data from 152 adults/29 children were analyzed for air rescue and 1131 adults/223 children for the ground-based emergency service. Adults with grade II-IV anaphylaxis received adrenaline in 19% (air rescue) and 7% (ground rescue) of cases. Children with grade II-IV anaphylaxis received adrenaline in 7% (air rescue) and 8% (ground rescue) of cases. Immediate drug therapy led to an improvement in general condition in 96-98% (air rescue) and 72-77% (ground-based emergency service) of cases. A significant correlation was found between the administration of adrenaline and the improvement in outcome in the ground-based emergency cohort. CONCLUSION: Guideline-compliant first-line therapy with adrenaline was not performed in the majority of the cases analyzed in this study. The significant effect of adrenaline on outcome demonstrated in this study emphases the need to improve the emergency treatment of anaphylactic reactions.

Radiographers' confidence in handling iodine based contrast media hypersensitivity reactions.

INTRODUCTION: Adverse reactions to iodinated contrast media, which is used during computed tomography (CT) examinations, are rare. As a result, radiographers have limited experience handling those situations and may feel uncertainty and a lack of confidence. The aim of this study was to investigate radiographers' confidence in handling hypersensitivity reactions to contrast media during CT examinations. METHODS: A survey in the form of a questionnaire was conducted to gather both quantitative and qualitative data. There were 31 clinics that participated in this study, of which four were university hospitals, 17 were medium-sized hospitals and 10 were small hospitals. In total, the questionnaires were distributed to 700 radiographers. The questionnaire contained 12 questions and was distributed via email with a link to the questionnaire. RESULTS: Two hundred-ninety radiographers participated in the survey. 72% of the respondents answered in the middle of the four-point scale (2-3) in response to the statement "I feel confident in handling hypersensitivity reactions". 65% answered that they did not have routines for training regularly regarding hypersensitivity reactions. Qualitative data showed that many of the respondents wished to receive education and training regularly. CONCLUSIONS: The confidence of radiographers regarding the management of hypersensitivity reactions was deficient and most of the respondents wished they felt more confident. IMPLICATION FOR PRACTICE: To increase radiographers' confidence in handling hypersensitivity reactions, it is recommended that the radiology clinics review their routines and the possibility to implement regular training.

Skin Test-Guided Strategy to Select Alternative Iodinated Contrast Media in Patients With Immediate Hypersensitivity Reaction: A Prospective Confirmative Study.

BACKGROUND: Iodinated contrast media (ICM) are a common cause of drug-induced immediate hypersensitivity reaction (IHR). Repeated use of ICM is often necessary; therefore, a standardized protocol to prevent recurrence of IHR is required. OBJECTIVE: We aimed to propose an intradermal skin test (IDT)-guided strategy for previous reactors to prevent recurrence of IHR. METHODS: We conducted a prospective multicenter study from May 2018 to December 2020 and recruited patients who had experienced IHR to ICM. Once enrolled, the participants underwent IDT with a causative ICM. The alternatives for reexposure were selected using the following protocol: (1) if the IDT with the culprit ICM was positive, further skin tests with other available ICM were conducted to choose IDT-negative agents as alternatives, and (2) if the IDT with the culprit ICM was negative, a randomly changed ICM was used without additional skin tests. The recurrence and severity of hypersensitivity were assessed in subsequent computed tomography examinations. Premedication was administered according to the severity of the index event in all cases. RESULTS: A total of 496 participants were enrolled, and 299 were reexposed to ICM. Among 269 participants who followed the protocol, 228 (84.8%) completed computed tomography examinations without adverse reactions, and IHR recurred in 16 of 30 participants (53.3%) who did not follow the protocol (P < .001). In addition, application of the protocol reduced the severity of IHR in recurred cases (P = 0.003). CONCLUSIONS: Our IDT-guided strategy not only reduced recurrence of IHR to ICM but also mitigated the severity in recurred cases. This provides evidence for recommending an IDT to diagnose ICM allergy and find safe alternatives.

United States Drug Allergy Registry (USDAR) grading scale for immediate drug reactions.

BACKGROUND: There is no accepted grading system classifying the severity of immediate reactions to drugs. OBJECTIVE: The purpose of this article is to present a proposed grading system developed through the consensus of drug allergy experts from the United States Drug Allergy Registry (USDAR) Consortium. METHODS: The USDAR investigators sought to develop a consensus severity grading system for immediate drug reactions that is applicable to clinical care and research. RESULTS: The USDAR grading scale scores severity levels on a scale of 0 to 4. A grade of no reaction (NR) is used for patients who undergo challenge without any symptoms or signs, and it would confirm a negative challenge result. A grade 0 reaction is indicative of primarily subjective complaints that are commonly seen with both historical drug reactions and during drug challenges, and it would suggest a low likelihood of a true drug allergic reaction. Grades 1 to 4 meet the criteria for a positive challenge result and may be considered indicative of a drug allergy. Grade 1 reactions are suggestive of a potential immediate drug reaction with mild symptoms. Grade 2 reactions are more likely to be immediate drug reactions of moderate severity. Grade 3 reactions have features suggestive of a severe allergic reaction, whereas grade 4 reactions are life-threatening reactions such as anaphylactic shock and fatal anaphylaxis. CONCLUSION: This proposed grading schema for immediate drug reactions improves on prior schemata by being developed specifically for immediate drug reactions and being easy to implement in clinical and research practice.

Clinical validation of the basophil activation test in immediate hypersensitivity reactions to gadolinium-based contrast agents.

Gadolinium based contrast agents (GBCAs) are safe compounds globally used in magnetic resonance imaging (MRI). However, in last years it has been detected an increase of immediate hypersensitivity reactions (IHRs) to them. Diagnosis of IHRs to GBCAs is based on clinical symptoms, skin tests (STs) and drug provocation test (DPT). But DPTs are not without risks, thus it is important to implement an in vitro alternative method such as the basophil activation test (BAT). We described the clinical validation of the BAT using ROC curves from a control population formed by 40 healthy individuals without previous reactions to any contrast agents and 5 patients suffering from IHRs to GBCAs. Four patients presented IHRs to gadoteric acid (GA) as the culprit agent and another one to gadobutrol (G). Basophil reactivity was measured in percentage of CD63 expression and in stimulation index (SI). The optimal cut-off with the highest sensitivity (S) and specificity (E) for the GA was of 4.6% at 1:100 dilution (S = 80% and E = 85%; AUC = 0.880, p = 0.006). For the SI with GA, the cut-off of highest sensitivity and specificity was of 2.79 at 1:100 dilution (S = 80% and E = 100%; AUC = 0.920, p = 0.002). Sensitivity did not show differences between STs regarding the BAT (p < 0.05). Moreover, the BAT was able to detect one case with IHR to GA which had negative STs. Therefore, the BAT is a useful method in diagnosis of IHRs to GBCAs.

Immediate hypersensitivity reactions to antineoplastic agents - A practical guide for the oncologist.

Immediate hypersensitivity reactions (IHRs) to antineoplastic agents occur frequently, and every oncologist will encounter these reactions in their clinical practice at some point. The clinical signature of IHRs can range from mild to life-threatening, and their occurrence can substantially impede the treatment course of patients with cancer. Yet, clear guidelines regarding the diagnosis and management are scarce, especially from an oncologic point of view. Therefore, herein, we review the definition, pathophysiology, epidemiology, diagnosis and management of IHRs to chemotherapeutic agents and monoclonal antibodies. First, we focus on defining the specific entities that comprise IHRs and discuss their underlying mechanisms. Then, we summarize the epidemiology for the antineoplastic agents that represent the most common causes of IHRs, i.e., platinum compounds, taxanes and monoclonal antibodies (mAbs). Next, we describe the possible clinical pictures and the comprehensive diagnostic work-up that should be executed to identify the culprit and safe alternatives for the future. Finally, we finish with reviewing the treatment options in both the acute phase and after recovery, with the aim to improve the oncologic care of patients with cancer.

Allergic Rhinitis in Preschoolers: A Systematic Review of Diagnostics.

BACKGROUND: Most studies that seek to analyze the prevalence of allergic rhinitis do not include preschool children and the diagnosis in this age group is difficult. OBJECTIVE: Identify complementary tests to the diagnosis of allergic rhinitis in preschool children and verify if there is scientific robustness to propose a diagnostic algorithm for this condition in this age group. METHODS: Systematic review of the literature in four databases: SCIELO, PubMed/MEDLINE, LILACS and SCOPUS. Each article was initially chosen by title, abstract and by the keywords "allergic rhinitis," "diagnosis" and "preschool." Those articles selected entered the complete reading and data extraction phase. The study was registered in the International Prospective Register of Systematic Reviews under number CRD42020207053. RESULTS: Fourteen articles were suitable for analysis. In the assessment using Quality Assessment of Diagnostic Accuracy Studies - 2, all studies had at least one domain considered "high risk" or "undetermined risk." Seven reports of nasal cytology, seven of specific IgE, four of immediate hypersensitivity skin test, one of nasal nitric oxide, three of total IgE and one of urinary leukotriene E4 were found. Eight articles evaluated more than one diagnostic test. CONCLUSION: There are no defined criteria for the diagnosis of allergic rhinitis in preschool children. Nasal cytology, serum specific IgE and immediate hypersensitivity skin test were the most used tests. A reliable diagnostic criterion in this age group is necessary so that in the future it is possible to propose a diagnostic algorithm for allergic rhinitis in preschool children.

Agreement of a clinical scoring system with allergic anaphylaxis in suspected perioperative hypersensitivity reactions: prospective validation of a new tool.

BACKGROUND: A clinical scoring system to estimate the likelihood that a reaction represents a perioperative immediate hypersensitivity reaction has been devised using a Delphi consensus process. Agreement of this clinical scoring system with the outcome of allergological assessment would allow the use of this tool in post-resuscitation and subsequent management of suspected perioperative immediate hypersensitivity reaction and potentially as a new standard reference for clinical investigations. METHODS: We prospectively scored 301 cases of suspected perioperative immediate hypersensitivity reaction according to the Hypersensitivity Clinical Scoring Scheme. Classification of cases was by allergological workup based on immediate and delayed investigations. The discrimination and calibration of the Hypersensitivity Clinical Scoring Scheme was compared with results from an expert panel of allergologists, skin testing, mast cell tryptase ratios, and specific IgE assays, as was agreement by Cohen's kappa coefficient. RESULTS: The Hypersensitivity Clinical Scoring Scheme predicted cases of allergic perioperative immediate hypersensitivity reaction with comparable discrimination to an expert panel, mast cell tryptase formula, and specific IgE assays in anaphylaxis to neuromuscular blocking drugs. Using a score threshold of 15 or greater to indicate allergic perioperative immediate hypersensitivity reaction, the sensitivity was 88.9%, with a specificity of 79.4%. Prospectively, the Hypersensitivity Clinical Scoring Scheme correctly classified a greater number of subjects than the expert panel and the optimal post hoc binary logistic regression model (86% vs 85% vs 84%), however it was inferior to skin testing. CONCLUSION: The Hypersensitivity Clinical Scoring Scheme predicts allergic perioperative immediate hypersensitivity using features of the acute syndrome. This approach could guide algorithms for the post-resuscitative management of suspected perioperative immediate hypersensitivity, and identify patients requiring drug provocation challenge.

Basophil Activation Test as a Biomarker for Taxanes Anaphylaxis.

Introduction: Taxanes are widely used chemotherapy agents, and their administration, despite premedication, is associated with hypersensitivity reactions (HR) in up to 9% of patients, 1% of which are severe. The mechanisms of these reactions are not fully understood. Finding biomarkers for early diagnosis and better understanding the underlying mechanisms of these reactions are key to defining the best treatment strategy for patients. Methods: The purpose of this study was to evaluate the effectiveness of the basophil activation test (BAT) to diagnose patients with anaphylactic reactions to taxanes. Patients with anaphylaxis to taxane compounds (n = 15) were assessed through clinical history, skin testing (when possible), and BAT. BAT was performed immediately before rapid drug desensitization or before skin testing using anti-CD123 conjugated (APC-Biolegend), anti-HLADR conjugated (FITC-Biolegend) to gate Basophils and anti-CD63 conjugated (PE-Biolegend), and anti-CD203c conjugated (BV-Biolegend) to assess CD203c and CD63 expression on basophils under taxane stimulation. BAT was also performed in eight healthy volunteers. Results: BAT was positive for CD203c in eight out of 15 patients and for CD63 in four out of 15 patients and in two out of eight controls. The sensitivity for CD203c was 53%, the specificity was 87%, and the area under the curve was 0.66 (p = 0.19%). For CD63, these rates were 33%, 87%, and 0.6 (p = 0.4). In a subgroup analysis of patients with positive skin tests (11 patients), CD203c was positive in six patients (sensitivity of 54.5% and specificity of 87.5%), and CD63 was positive in five patients (sensitivity of 45% and specificity of 75%). Conclusions: BAT as a diagnostic tool for immediate hypersensitivity reactions to taxanes may be relevant in patients with selected phenotypes and endotypes, especially those with severe reactions or when the diagnosis cannot be established by the skin test. Increased expression of CD203c was more frequent than of CD63 in patients with positive results, and the sensitivity of this biomarker was higher in patient sub-group with positive skin tests, i.e., patients with IgE-mediated endotypes.

Incidence and Risk Factors of Immediate Hypersensitivity Reactions and Immunization Stress-Related Responses With COVID-19 mRNA Vaccine.

BACKGROUND: With the implementation of mass vaccination campaigns against COVID-19, the safety of vaccine needs to be evaluated. OBJECTIVE: We aimed to assess the incidence and risk factors for immediate hypersensitivity reactions (IHSR) and immunization stress-related responses (ISRR) with the Moderna COVID-19 vaccine. METHODS: This nested case-control study included recipients who received the Moderna vaccine at a mass vaccination center, Japan. Recipients with IHSR and ISRR were designated as cases 1 and 2, respectively. Controls 1 and 2 were selected from recipients without IHSR or ISRR and matched (1 case: 4 controls) with cases 1 and cases 2, respectively. Conditional logistic regression analysis was used to identify risk factors associated with IHSR and ISRR. RESULTS: Of the 614,151 vaccine recipients who received 1,201,688 vaccine doses, 306 recipients (cases 1) and 2478 recipients (cases 2) showed 318 events of IHSR and 2558 events of ISRR, respectively. The incidence rates per million doses were estimated as IHSR: 266 cases, ISRR: 2129 cases, anaphylaxis: 2 cases, and vasovagal syncope: 72 cases. Risk factors associated with IHSR included female, asthma, atopic dermatitis, thyroid diseases, and a history of allergy; for ISRR, the risk factors were younger age, female, asthma, thyroid diseases, mental disorders, and a history of allergy and vasovagal reflex. CONCLUSION: In the mass vaccination settings, the Moderna vaccine can be used safely owing to the low incidence rates of IHSR and anaphylaxis. However, providers should be aware of the occurrence of ISRR. Although recipients with risk factors are associated with slightly increased risks of IHSR and ISRR, this is not of sufficient magnitude to warrant special measures regarding their vaccination.

Non-immediate hypersensitivity reactions to iomeprol: Diagnostic value of skin tests and cross-reactivity with other iodinated contrast media.

BACKGROUND: Iodinated contrast media produce non-immediate hypersensitivity reactions (NIHR). The goal of this prospective study was to determine the utility of skin tests and the subsequent tolerance to negative skin-tested iodinated contrasts in patients with NIHR caused by iomeprol. METHODS: Prick and intradermal tests with iomeprol, iopamidol, iopromide, and iobitridol were performed in all patients. IV challenge with the causative contrast (iomeprol in 90%) was made if skin tests were negative. In case of a positive skin test with the causal contrast, or a positive challenge test with it, IV challenge test with an alternative, negative skin-tested contrast was performed in all patients. RESULTS: Skin tests were positive in 47.6% (20/42) of patients with NIHR induced by iomeprol. Of the 66 challenge tests performed with negative skin-tested iodinated contrasts, tolerance was confirmed in 35 (53%): 32 iomeron, 2 iobitridol, 1 iopamidol. Cross-reactivity between iomeprol and iopamidol was 22% (4/20 in patients with positive skin tests and 5/21 in patients with negative skin tests). CONCLUSIONS: Sensitivity of the skin tests was less than 50% NIHRs due to iomeprol, while the negative predictive value of skin tests in patients who tolerated challenges with alternative contrasts (mainly iopamidol) was 53% (35 tolerated out of 66 performed). The cross-reactivity between iomeprol and iopamidol is high.

Changes in Sensitization Patterns in the Last 25 Years in 619 Patients with Confirmed Diagnoses of Immediate Hypersensitivity Reactions to Beta-Lactams.

Beta-lactam (BL) drugs are the antibiotics most prescribed worldwide due to their broad spectrum of action. They are also the most frequently implied in hypersensitivity reactions with a known specific immunological mechanism. Since the commercialization of benzylpenicillin, allergic reactions have been described; over the years, other new BL drugs provided alternative treatments to penicillin, and amoxicillin is now the most prescribed BL in Europe. Diagnosis of BL allergy is mainly based on skin tests and drug provocation tests, defining different sensitization patterns or phenotypes. In this study, we evaluated 619 patients with a confirmed diagnosis of BL-immediate allergy during the last 25 years, using the same diagnostic procedures with minor adaptations to the successive guidelines. The initial eliciting drug was benzylpenicillin, which changed to amoxicillin with or without clavulanic acid and cephalosporins in recent years. In skin tests, we found a decrease in sensitivity to major and minor penicillin determinants and an increase in sensitivity to amoxicillin and others; this might reflect that the changes in prescription could have influenced the sensitization patterns, thus increasing the incidence of specific reactions to side-chain selective reactions.

Immediate Hypersensitivity Reactions Induced by COVID-19 Vaccines: Current Trends, Potential Mechanisms and Prevention Strategies.

As the world deals with the COVID-19 pandemic, vaccination remains vital to successfully end this crisis. However, COVID-19-vaccine-induced immediate hypersensitivity reactions presenting with potentially life-threatening systemic anaphylactic reactions are one of the reasons for vaccine hesitancy. Recent studies have suggested that different mechanisms, including IgE-mediated and non-IgE-mediated mast cell activation, may be involved in immediate hypersensitivity. The main culprits triggering hypersensitivity reactions have been suggested to be the excipients of vaccines, including polyethylene glycol and polysorbate 80. Patients with a history of allergic reactions to drugs, foods, or other vaccines may have an increased risk of hypersensitivity reactions to COVID-19 vaccines. Various strategies have been suggested to prevent hypersensitivity reactions, including performing skin tests or in vitro tests before vaccination, administering different vaccines for the primary and following boosters, changing the fractionated doses, or pretreating the anti-IgE antibody. This review discusses the current trends, potential mechanisms, and prevention strategies for COVID-19-vaccine-induced immediate hypersensitivity reactions.

Intradermal testing increases the accuracy of an immediate-type cefaclor hypersensitivity diagnosis.

Background: Hypersensitivity reactions to cefaclor have increased in accordance with its frequent use. However, only limited data are available on the diagnostic value of skin tests for these conditions, particularly intradermal tests (IDTs). Objective: To evaluate the clinical usefulness of IDT compared to the ImmunoCAP test in patients with cefaclor-induced immediate-type hypersensitivity. Methods: We conducted a retrospective chart review from January 2010 to June 2020 of adult subjects from 2 tertiary hospitals in Korea with a history of suspected immediate-type hypersensitivity to cefaclor, and who had undergone ImmunoCAP and IDT. Results: Overall, 131 subjects diagnosed with cefaclor hypersensitivity were included in the analysis. Fifty-nine patients (59/131, 45.04%) were positive in both IDT and ImmunoCAP. Fifty-four (54/131, 41.22%) and 6 (6/131, 4.58%) subjects showed positive results only with IDT or the ImmunoCAP test, respectively. Twelve subjects (12/131, 9.16%) were negative by both tests but reacted positively in a drug provocation test. The frequency of IDT positivity was similar regardless of the severity of reactions. However, positivity of ImmunoCAP was lower in subjects with mild reactions compared to those with anaphylaxis. Regarding the diagnosis of cefaclor hypersensitivity, the overall sensitivity of IDT and ImmunoCAP was 0.863 and 0.496, respectively while the specificity was 1. The combination of IDT and ImmunoCAP further increased this sensitivity to 0.908. Conclusion: IDT was more sensitive than ImmunoCAP for the diagnosis of cefaclor allergy, regardless of the severity of the hypersensitivity reaction. Therefore, we recommend a combination of IDT and ImmunoCAP for the diagnosis of cefaclor hypersensitivity.

Skin Testing Approaches for Immediate and Delayed Hypersensitivity Reactions.

In evaluating adverse drug reactions (ADRs), patch tests (PTs), skin prick tests (SPTs), and intradermal tests (IDTs) are useful tools for identifying responsible drugs and finding safe alternatives. Their diagnostic value depends on the clinical features of the ADR and on the drug tested. PTs have a good sensitivity in assessing acute generalized exanthematous pustulosis and drug rash with eosinophilia and systemic symptoms. SPTs done with all drugs except opiates are used for immediate hypersensitivity reactions. IDTs seem sensitive for immediate hypersensitivity reactions to beta-lactam antibiotics, iodinated contrast media, heparins, general anesthetics, and platinum salts.

Contrast Medium Hypersensitivity: A Large Italian Study with Long-Term Follow-Up.

Hypersensitivity reactions (HRs) to contrast media (CM) are a major problem. We compared differences of HRs to iodinated contrast media (ICM) versus gadolinium-based contrast media (GBCM), collecting data on prevalence, type, latency and severity. Secondly, the predisposition to perform new contrast tests, use of premedication and possible appearance of new reactions were explored in a long-term follow-up of 5 years. Clinical data, comorbidities, skin test (ST) results, re-exposure to CM procedures with any new reactions, premedication and CM used were collected. In a retrospective single-center study, 350 patients with mild to moderate HRs were enrolled. Asthma, food allergy, non-allergic drug hypersensitivity and neurologic disease were significantly more frequent in patients with HRs to GBCM compared to the high evidence of cardiovascular disease and history of cancer in patients with HRs to ICM. A marked delay in performing STs was reported by patients with negative results (66 months, p < 0.01). Iomeprol, iopamidol and gadobenic acid were the culprit CM most involved in HRs in patients with positive STs. During follow-up, 7.1% of responders reported new HRs to CM despite negative STs, premedication and infusion of alternative CM in most cases.