Delayed skin testing for systemic medications: helpful or not?

Cutaneous adverse drug reactions (CADR) collectively are delayed drug reactions such as morbilliform drug eruption (MDE) and severe cutaneous adverse reactions (SCAR). Whereas MDE may wane over time, be the result of drug viral interactions and be amenable to slow reintroduction or rechallenge, SCAR are HLA class I restricted, T-cell mediated reactions that demonstrate durable immunity and warrant lifelong avoidance. SCAR such as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP) and generalized bullous fixed drug eruption (GBFDE) often occur in the setting of multiple drugs dosed together. Collectively, they lead to significant morbidity, mortality and drug safety concerns that could severely limit future treatment options. Currently, no single or combination of diagnostic tests for SCAR such as ex vivo or in vitro testing, in vivo (skin testing) or other adjunctive tests such as HLA typing have 100% negative predictive value. In this "Controversies in Allergy Review Article", we review the current literature on delayed skin testing (patch and delayed prick/intradermal test) and critically assess the evidence base of its utility across different drugs and clinical phenotypes of delayed hypersensitivity reactions.

[Reproducibilidad clínica de reacciones de hipersensibilidad a fármacos en pruebas de exposición controlada].

Objective: To assess the reproducibility of symptoms in drug challenge tests. Methods: The study included patients with positive cutaneous or challenge test throughout 2019. For each patient, clinical suspicion according to Karch-Lasagna algorithm was registered. Primary outcome was the reproducibility of symptoms in the provocation tests using a paired analysis of data with McNemar test. Results: Eighty-nine patients were included, 16 of them presented more than one positive test. Thirty were skin tests positive and 75 reacted to provocation tests. Eighty nine percent of patients who reacted in challenge test were probably or possibly reactors according to Karch-Lasagna scale. Symptoms of initial reaction did not differ from those triggered in challenge tests. Conclusions: Karch-Lasagna scale is useful in predicting the response to drug provocation tests. In most of the positive studies, results were suggested by clinical history and no differences were found between symptoms triggered in challenge test and that referred to in the previous reaction.

Objetivo: Evaluar la reproducibilidad de los síntomas en pruebas de exposición con fármacos. Métodos: Estudio retrospectivo, efectuado en pacientes con prueba cutánea o exposición positiva, atendidos en 2019. De cada paciente se registró la sospecha clínica según el algoritmo de Karch-Lasagna. El resultado principal fue la reproducibilidad de síntomas en las pruebas de exposición, mediante el análisis de datos emparejado con prueba de McNemar. Resultados: Se incluyeron 89 pacientes, y de estos 16 reportaron varias pruebas positivas. Se obtuvieron 30 pruebas cutáneas y 75 de exposición positivas. En el 89% de las pruebas de exposición positivas, las reacciones iniciales se clasificaron en probables o posibles, según la escala de Karch-Lasagna. Los síntomas reportados en la reacción inicial no difirieron de los de las pruebas de exposición. Conclusiones: La escala de Karch-Lasagna es un método útil para predecir la respuesta en las pruebas de exposición con fármacos. En la mayor parte de las pruebas positivas, los resultados fueron sugeridos por la historia clínica, sin diferencias entre la manifestación de síntomas en la prueba de exposición versus los referidos en la reacción inicial.

Comparison of Skin Prick Tests (SPT), Intradermal Tests (IDT) and In Vitro Tests in the Characterization of Insect Bite Hypersensitivity (IBH) in a Population of Lusitano Horses: Contribution for Future Implementation of SPT in IBH Diagnosis.

Thirty controls (C) and 30 IBH-affected (T) Lusitano horses were evaluated. T horses were included based on anamnesis and physical examination, supported by questionnaires. All horses were submitted to skin tests, Intrademal (IDT) and Skin Prick Tests (SPT), on the neck with 14 specific allergens, 13 recombinant proteins (r-proteins) from Culicoides nubeculosus (Cul n) and Culicoides obsoletus (Cul o) salivary glands and Culicoides nubeculosus Whole Body Extract (Cul n WBE). Addicionally, a cluster of six T and six C horses were also tested with Cul n 3 and Cul n 4 produced in insect cells and barley, as well as E. coli produced Cul o 3 and Cul o WBE. Allergen concentrations were 10 µg/mL for IDT and 100 µg/mL for SPT, and wheal diameters assessed at 20 min, 6 and 48 h. IDTs were considered positive when wheal diameter was ≥50% of the histamine wheal and SPT's ≥ 0.9 cm. In vitro tests, allergen-specific serum IgE and sulfidoleukotriene (sLT) release assay were also carried out. Results showed that Cul n WBE, Cul n 7, 8, 9, Cul o1P and Cul o 2P were the best performing allergens for SPTs (p ≤ 0.0001) for the 1st allergen panel and Cul o WBE, Cul n 3 Bar and Cul n 4 Bac (p ≤ 0.05) for the 2nd, presenting a higher discriminatory diagnostic potential than IDTs, at a concentration of 100 µg/mL, with readings assessed at 20 min. Regarding in vitro tests overall, the sLT release assay performed best.

Pilot study to determine the concordance between skin prick and intradermal test (IDT) reactivity to environmental allergens in atopic dogs using IDT as the gold standard.

BACKGROUND: Prick testing is widely used as the first-line in vivo test for environmental allergens in people owing to its noninvasive nature and speed of performance. OBJECTIVES: To determine concordance between skin prick testing (SPT) and intradermal testing (IDT) reactivity to environmental allergen mixes in dogs with atopic dermatitis (cAD). ANIMALS: Forty client-owned dogs with cAD. MATERIALS AND METHODS: Skin prick testing (GREER Pick System; Stallergenes Greer) and IDT were performed on 40 dogs using seven glycerinated and aqueous environmental allergen mixes, respectively (tree, grass and weed pollens, house dust mites and three mould mixes). Reactions for IDT and SPT were evaluated both subjectively and objectively (mean wheal diameter; MWD) and compared to saline and histamine controls. RESULTS: Using IDT as the gold standard, with subjective scoring, SPT was 47.0% sensitive [95% confidence interval (CI) 36.0%-58.7%], 92.1% specific (95% CI 87.6%-95.3%) and agreement was moderate (79%, Cohen's kappa = 0.424). The positive predictive value of SPT was 36% and negative predictive value was 95%. Objective and subjective scores had only fair agreement. CONCLUSIONS AND CLINICAL RELEVANCE: Skin prick testing with allergen mixes was specific yet poorly sensitive as compared to IDT. For both IDT and SPT, 95% (38 of 40) dogs failed to react to an allergen mix, despite showing a positive reaction to at least one component. Future studies comparing SPT and IDT should test individual allergens rather than mixes to prevent the dilution of individual components, which may have resulted in false negatives.

Alfaxalone provides reliable sedation for intradermal allergen testing in dogs and does not significantly affect results when compared to dexmedetomidine.

BACKGROUND: Dexmedetomidine (Dexmedetomidine hydrochloride-Dexdomitor; Zoetis) is the preferred sedative used for canine intradermal allergen testing (IDT) in the United States. Alfaxalone (Alfaxan Multidose; Jurox Animal Health) is a neuroactive steroid, and its effect on sedation and allergen reactivity scores is unknown. HYPOTHESIS/OBJECTIVES: We hypothesised that alfaxalone would produce an adequate level of sedation with fewer cardiovascular adverse effects and would not affect allergen reactivity scores or histamine wheal size compared to dexmedetomidine. MATERIALS AND METHODS: Twenty client-owned dogs were included in two groups: 10 atopic and 10 nonatopic. In a randomised, controlled, blinded, cross-over design all dogs underwent two modified IDT, 1-4 weeks apart, using intravenous dexmedetomidine (2.87-5.22 µg/kg) or alfaxalone (1.8-2.4 mg/kg). Anaesthetic parameters and sedation level were recorded over 25 min using a validated canine sedation scale described by Grint et al. (Small Anim Pract, 2009, 50, 62). Simultaneously, both objective and subjective reactivity scores were measured in technical triplicates at 10, 15 and 20 min. The modified IDT included eight allergens, histamine-positive and saline-negative controls. RESULTS: Alfaxalone produced a significantly higher sedation score across all time points (p < 0.05). All objective scores were significantly correlated to the corresponding subjective scores (Spearman R = 0.859, p < 0.0001). Sedative used did not significantly affect subjective allergen scores for nine atopic dogs (p > 0.05, 15 min). Sedative used did not affect the diameter of objective scores for individual allergens and histamine wheals (p > 0.05, 15 min). CONCLUSIONS AND CLINICAL RELEVANCE: Intravascular alfaxalone is an alternative sedative for IDT in dogs. Alfaxalone may be preferred to dexmedetomidine in some clinical scenarios as a result of having fewer cardiovascular adverse effects.

DRESS syndrome due to iodinated contrast media. A case report.

BACKGROUND: The most frequent non-immediate reactions described with iodinated contrast media (ICM) are mild to moderate, however, some cases of patients with severe non-immediate reactions, such as drug eruption with eosinophilia and systemic symptoms (DRESS) have been described. CASE PRESENTATION: An 84-year-old patient developed DRESS syndrome after administration of ICM ioversol. The patient fullfilled the RegiSCAR diagnostic criteria for DRESS (definite score = 6). He underwent intradermal skin testing (IDT) with the widest panel of ICM available at our center. IDT was positive with ioversol and iomeprol. A punch biopsy was performed on the positive IDT with the culprit drug (ioversol) and histopathology was compatible with a T-cell mediated mechanism. CONCLUSION: In this case, the IDT-positive biopsy was consistent with DRESS syndrome caused by T-lymphocyte activation, supporting the clinical diagnosis.

Skin Testing and Drug Provocation Tests in Epidermal Necrolysis: A French Experience.

BACKGROUND: There are limited data on the use of skin testing, other than patch testing, and challenges in the evaluation of epidermal necrolysis (EN), including Stevens-Johnson syndrome and toxic epidermal necrolysis. OBJECTIVE: To report a French multicenter experience in skin testing and challenges in EN, and investigate the factors associated with tests' positivity. METHODS: All patients who were evaluated by patch tests (PTs), skin prick tests, intradermal tests (IDTs), or drug provocation tests (DPTs) for EN between 2010 and 2020 were retrospectively included through 2 French drug reaction networks. RESULTS: In total, 113 patients were included from 8 centers. Median (interquartile range) time from EN to hypersensitivity workup was 7.9 months (5.1-15 months). All patients had PTs, 17 (15%) had skin prick tests or IDTs with delayed readings and 32 (28.3%) had DPTs. One mild reaction occurred after a DPT. Overall, 22 patients (19.5%) had positive PTs, and the only factors associated with positivity were Algorithm of Drug Causality for Epidermal Necrolysis (ALDEN) score and drug class. Only 1 IDT was positive but considered irrelevant. The DPTs were never performed to prove responsibility of a highly suspected drug but were used to confirm current tolerance of needed medications. CONCLUSIONS: Allergological workup in EN, performed by specialists involved in EN, seems safe. Skin tests, although of limited sensitivity, can be helpful for considering the reintroduction of essential drugs according to a benefit-to-risk decision. We propose an algorithm for approaching hypersensitivity testing in patients with EN, to be adapted to each patient.

NTRK1-related Hereditary Sensory and Autonomic Neuropathy Type 4: The Role of the Histamine Challenge Test.

Hereditary sensory and autonomic neuropathies (HSAN) are rare, genetically inherited disorders characterized by impaired unmyelinated nerve fiber function. Here we report a patient with self-mutilation behavior and decreased response to pain, suggestive of an underlying small fiber neuropathy. Nerve conduction studies were normal but sympathetic skin response was absent at the left arm. Intradermal histamine challenge test was performed to evaluate the function of small unmyelinated nerve fibers and revealed absence of a flare response. Using whole genome sequencing, a novel variant in the neurotrophic tyrosine kinase type 1 gene was identified, expanding the known disease-causing variants associated with HSAN type 4. Through this case, we demonstrate the role of the histamine challenge test in patients suspected to have a small fiber neuropathy where electrophysiological testing may be normal and who may present with non-specific symptoms including hypotonia and failure to thrive. The information gained can guide genetic testing and contribute to interpretation of new variants identified.

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.

Skin tests in the work-up of cutaneous adverse drug reactions: A review and update.

Skin tests, including patch tests (PTs), prick tests, and intradermal tests (IDTs), are useful in identifying the culprits of cutaneous adverse drug reactions (CADRs), and determining safer, alternative drugs. PTs have a low sensitivity but are valuable in investigating maculopapular exanthema (MPE), as well as severe CADR, including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and in particular, acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS). To ensure their specificity, at least 10 control tests should be performed. Prick tests are mainly used in the evaluation of immediate-type hypersensitivity and can be performed with all drugs, except opiates. IDTs can be used to explore immediate and delayed-type hypersensitivity, if an injectable form of the drug exists. Except for SJS/TEN, IDTs should be performed by injecting 0.02 mL of the drug. We here provide a practical, up-to-date review on the use of these skin tests in the work-up of CADRs. Numerous negative controls for drug PTs, as well as criteria for the immediate and delayed positivity of prick tests and IDT, are included. It should be emphasized that a negative result never excludes the potential responsibility of a drug in a CADR.

Effect of the topical administration of corticosteroids and tuberculin pre-sensitisation on the diagnosis of tuberculosis in goats.

BACKGROUND: Caprine tuberculosis (TB) is a zoonosis caused by members of the Mycobacterium tuberculosis complex (MTBC). Caprine TB control and eradication programmes have traditionally been based on intradermal tuberculin tests and slaughterhouse surveillance. However, this strategy has limitations in terms of sensitivity and specificity. Different factors may affect the performance of the TB diagnostic tests used in goats and, subsequently, the detection of TB-infected animals. In the present study, the effect of two of the factors that may affect the performance of the techniques used to diagnose TB in goats, the topical administration of corticosteroids and a recent pre-sensitisation with tuberculin, was analysed. METHODS: The animals (n = 151) were distributed into three groups: (1) a group topically treated with corticosteroids 48 h after intradermal tuberculin tests (n = 53); (2) a group pre-sensitised with bovine and avian purified protein derivatives (PPDs) 3 days before the intradermal tuberculin test used for TB diagnosis (n = 48); and (3) a control group (n = 50). All the animals were tested using single and comparative intradermal tuberculin (SIT and CIT, respectively) tests, an interferon-gamma release assay (IGRA) and a P22 ELISA. RESULTS: The number of SIT test reactors was significantly lower in the group treated with corticosteroids when compared to the pre-sensitised (p < 0.001) and control (p = 0.036) groups. In contrast, pre-sensitisation with bovine and avian PPDs did not cause a significant reduction in the number of SIT and CIT test reactors compared with the control group. In fact, a higher number of reactors was observed after the prior tuberculin injection in the pre-sensitised group (p > 0.05). No significant effect was observed on IGRA and P22 ELISA due to corticosteroids administration. Nevertheless, a previous PPD injection affected the IGRA performance in some groups. CONCLUSIONS: The application of topical corticosteroid 24 h before reading the SIT and CIT tests can reduce the increase in skin fold thickness and subsequently significantly decrease the number of positive reactors. Corticosteroids used can be detected in hair samples. A previous pre-sensitisation with bovine and avian PPDs does not lead to a significant reduction in the number of intradermal tests reactors. These results are valuable in order to improve diagnosis of caprine TB and detect fraudulent activities in the context of eradication programs.

Skin Tests for the Exploration of Hypersensitivity Reactions Associated with Iodinated Contrast Media.

BACKGROUND: Iodinated contrast media (ICM) are responsible for multiple side effects, especially hypersensitivity reactions. These reactions can either be authentic allergies or non-allergic hypersensitivity reactions. Skin tests (prick and intradermal tests) are simple to perform and can be of great help, especially if the ICM needs to be re-used. The aim of the study was to assess the characteristics of the patients in whom skin tests were performed and the results of these tests. METHODS: This is a retrospective study from June 2014 to June 2019. All included patients had at least one episode of hypersensitivity reaction to ICM and underwent skin tests. RESULTS: We included 35 patients aged 18 to 85 years. The iopromide was the most implicated ICM. The reactions were mainly cutaneous (n=30) and immediate (n=27). The skin tests were negative, except for two patients. The re-use of ICM occurred in 11 patients: 9 with an ICM other than the one suspected and two patients with the same ICM. Among these patients, 5 did not have any premedication. Two of them had a second hypersensitivity reaction, the first with another ICM and the second with the same ICM. CONCLUSION: One of the main pillars of allergic exploration is ICM skin testing, not only to prevent a recurrence, but also to allow patients to benefit from ICM re-use, which are sometimes essential.

Management of patients with allergy to local anesthetics: two case reports.

Lidocaine is the most commonly used local anesthetic (LA) agent in various dental as well as oral and maxillofacial procedures. Although rare, adverse effects and allergic reactions to lidocaine have been reported. In patients with suspected allergy to LA or a history of such reaction, careful history-taking and allergy testing should be performed to choose an alternative LA agent to avoid any adverse effects. Here, we present two cases of delayed hypersensitivity reaction to lidocaine, wherein the patients presented with erythema, edema, and itching. Intradermal testing confirmed allergic reaction to lidocaine, and the patients underwent successful dental treatment using an alternative LA agent. This report highlights the importance of allergy testing prior to LA use considering the serious consequences of allergy to these agents and describes the management of such patients using an alternative LA agent.

Effect of the Inoculation Site of Bovine and Avian Purified Protein Derivatives (PPDs) on the Performance of the Intradermal Tuberculin Test in Goats From Tuberculosis-Free and Infected Herds.

The single and comparative intradermal tuberculin (SIT and CIT) tests are used for the ante-mortem diagnosis of caprine tuberculosis (TB). The tuberculin injection site has been associated with a different performance of the test in cattle. In contrast to that required in cattle in Europe (cervical injection), it can be carried out in the scapular region in goats. Nevertheless, there are no previous data concerning the effect of the injection site on the performance of the test in goats. The aim of the present study was to evaluate the effect of two different inoculation sites (cervical and scapular) on the performance of the SIT/CIT tests. This was done by intradermally inoculating 309 goats from two infected herds and one TB-free herd with both avian and bovine PPDs in the mid-cervical and scapular regions. None of the animals from the TB-free herd had positive reactions, and the number of reactors was not significantly higher, regardless of the inoculation site, in the high and low prevalence herds. However, significantly higher increases in skin fold thickness were observed on the cervical site when compared to the scapular site after the avian and bovine PPD inoculations in the TB-free herd (p < 0.001) and after the bovine PPD injection in the high prevalence herd (p = 0.003). The presence of clinical signs was also more evident on the cervical site when using avian and bovine PPDs in the high prevalence herd (p < 0.01). In contrast, increases in higher skin fold thickness were observed on the scapular site when compared to the cervical site after the bovine and avian PPD inoculations were employed in the low prevalence herd (p < 0.01). These results suggest that the cervical injection of PPDs may improve the sensitivity of the intradermal tuberculin test in high TB prevalence caprine herds, mainly owing to the increased presence of local clinical signs and a better performance of the CIT test. Moreover, specificity was not affected when using standard interpretations, although further analyses in a great number of herds are required in order to confirm these findings.

Paracetamol Allergy: A Case of a 9-Year-Old Female with a History of Atopy.

Background: We describe a rare case involving paracetamol, a commonly used drug worldwide. Increased paracetamol consumption increases the risk of adverse drug reactions. Case Presentation: This is a case of a 9-year-old girl who visited the emergency department due to sudden onset sneezing, nasal itching, urticaria, and angioedema after paracetamol ingestion. The diagnostic and etiologic studies revealed an immunoglobulin E (IgE)-mediated hypersensitivity mechanism to paracetamol. Conclusion: Few cases of this phenomenon have been reported in previous literature. As confirmed in this study, a negative skin prick test did not exclude hypersensitivity, and conducting intradermal tests (IDTs) increased diagnostic accuracy. The patient had a positive IDT, confirming the underlying IgE-mediated reaction. The follow-up of a confirmed paracetamol hypersensitivity implies patient education about avoidance of any paracetamol-containing formulation, including combination products and clarification of available alternative drugs. This is likely the first publication documenting IgE-mediated paracetamol allergy in pediatric patients. We intend to underline the clinical benefits of diagnostic confirmation toward suspected drug hypersensitivity reactions in children, a particularly useful topic for pediatricians and pediatric allergists.

Identification of Risk Factors and Cross-Reactivity of Local Anesthetics Hypersensitivity: Analysis of 14-Years' Experience.

PURPOSE: Local anesthetics (LA) are widely used and adverse drug reactions (ADR) occur in 2.5-10%, but hypersensitivity reactions are rare (ranging between 0% and 4.3%). Risk is so overestimated causing too many allergy clinic referrals. There are limited and also conflicting results over the management of LA allergy. We aimed to find out who should be referred to an allergy clinic for a LA allergy testing, to define the subjects with an increased risk of LA allergy and to assess the need for testing for identifying alternative LA. PATIENTS AND METHODS: We performed a retrospective study of patients referred to our clinic for diagnostic workup of LA hypersensitivity from 2006 to 2020. RESULTS: In our cohort of 398 patients, tests were positive in 14 (3.52%) of them. Personal history of ADR with LA was the only independent risk factor for positive test (RR=4.007, p=0.033). Presence of generalized cutaneous symptoms and hypotension during past reaction were independent predictors of positive test (RR=9.043, p=0.021 and RR=10.445, p=0.038, respectively). The negative predictive value of intradermal test at dilution of 1:100 for immediate-type reaction was high (97.56%). Also, we demonstrated cross-reactivity within the amide-group LAs and co-occurrence of immediate- and delayed-type reactions. CONCLUSION: Only patients with an LA-induced ADR should be referred to an allergy clinic. History of generalized cutaneous symptoms and/or hypotension during the reaction may define subjects with an increased risk of LA allergy. A stepwise test procedure may start with skin tests especially for these patients with increased risk factors. In presence of LA allergy, alternative LA should always be confirmed by performing a challenge test.