Management of Adult Patients With Drug Reaction With Eosinophilia and Systemic Symptoms: A Delphi-Based International Consensus.

Importance: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but potentially fatal drug hypersensitivity reaction. To our knowledge, there is no international consensus on its severity assessment and treatment. Objective: To reach an international, Delphi-based multinational expert consensus on the diagnostic workup, severity assessment, and treatment of patients with DRESS. Design, Setting, and Participants: The Delphi method was used to assess 100 statements related to baseline workup, evaluation of severity, acute phase, and postacute management of DRESS. Fifty-seven international experts in DRESS were invited, and 54 participated in the survey, which took place from July to September 2022. Main Outcomes/Measures: The degree of agreement was calculated with the RAND-UCLA Appropriateness Method. Consensus was defined as a statement with a median appropriateness value of 7 or higher (appropriate) and a disagreement index of lower than 1. Results: In the first Delphi round, consensus was reached on 82 statements. Thirteen statements were revised and assessed in a second round. A consensus was reached for 93 statements overall. The experts agreed on a set of basic diagnostic workup procedures as well as severity- and organ-specific further investigations. They reached a consensus on severity assessment (mild, moderate, and severe) based on the extent of liver, kidney, and blood involvement and the damage of other organs. The panel agreed on the main lines of DRESS management according to these severity grades. General recommendations were generated on the postacute phase follow-up of patients with DRESS and the allergological workup. Conclusions and Relevance: This Delphi exercise represents, to our knowledge, the first international expert consensus on diagnostic workup, severity assessment, and management of DRESS. This should support clinicians in the diagnosis and management of DRESS and constitute the basis for development of future guidelines.

Tools for Etiologic Diagnosis of Drug-Induced Allergic Conditions.

Drug hypersensitivity reactions are a serious concern in clinical practice because they can be severe and result in lifelong sequelae. An accurate diagnosis and identification of the culprit drug is essential to prevent future reactions as well as for the identification of safe treatment alternatives. Nonetheless, the diagnosis can be challenging. In vivo and in vitro tests can be helpful, although none are conclusive; therefore, the tests are not usually performed in isolation but as part of a diagnostic algorithm. In addition, some in vitro tests are only available in research laboratories, and standardization has not been fully accomplished. Collaborating research is needed to improve drug hypersensitivity reaction diagnosis. In this review, we update the current available in vivo and in vitro tools with their pros and cons and propose an algorithm to integrate them into clinical practice.

Long-Term Omalizumab in Elderly Patients with Chronic Urticaria: Is It a Safe Therapy?

BACKGROUND: Biologics have revolutionized the treatment of many diseases. In this regard, omalizumab (OMA), an anti-IgE monoclonal antibody, is the recommended therapeutic option for patients with chronic spontaneous urticaria (CSU) refractory to second-generation H1-antihistamines. Several studies confirm the efficacy and safety of the drug. However, the literature focusing on the elderly population is scarce, as this age group is often excluded from clinical trials. Therefore, the pharmacological treatment of CSU in elderly patients is a challenge that is increased by their comorbidities and consequent polypharmacy. OBJECTIVES: We describe the real-life safety profile of OMA in elderly patients (≥70 years) with CSU and chronic inducible urticaria (CIndU). We aimed to provide data for daily clinical practice in this vulnerable patient group. METHOD: A retrospective review was performed of the records of patients with CSU/CIndU from May 2003 to December 2019 in the Hospital Universitario La Paz. We describe qualitative and quantitative data according to measures of central tendency. Comparisons between qualitative and quantitative data were performed with the Mann-Whitney U test and the Fisher's test for qualitative variables. A p value <0.05 was considered statistically significant. RESULTS AND CONCLUSIONS: Eighty-nine patients were included, divided into two groups (<70 vs. ≥70 years). The overall rate of adverse events (AEs) was 48%, mainly mild. No association between age and AE was found (p = 0.789). No serious AE such as anaphylaxis was detected. CSU predominated in both groups. CIndU was less prevalent in the elderly (p = 0.017). There was no association between age and the other variables. Although the frequency of neoplasms was slightly higher in the elderly with OMA, we found no difference compared to the incidence of neoplasms in the general population. Therefore, our data suggest that OMA may be a safe treatment in elderly people with CSU/CIndU for prolonged periods of treatment, although further studies with larger samples are needed to corroborate our observations.

LTT and HLA testing as diagnostic tools in Spanish vancomycin-induced DRESS cases: A case-control study.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe T-cell-mediated off-target adverse reaction. DRESS cases caused by vancomycin have often been reported. The HLA-A*32:01 allele has been associated with genetic susceptibility to vancomycin-induced DRESS in US citizens of European descent. We have analyzed the association of the HLA-A*32:01 allele in 14 Spanish DRESS cases in which vancomycin was suspected as the culprit drug, and the lymphocyte transformation test (LTT) as an in vitro assay to evaluate vancomycin sensitization. The results were compared to vancomycin-tolerant control donors. LTT was performed in 12 DRESS cases with PBMCs from resolution samples available and in a group of 12 tolerant donors. ROC curves determined that LTT is a suitable tool to identify patients sensitized to vancomycin (AUC = 0.9646; p < 0.0001). When a stimulation index >3 was regarded as a positive result, contingency tables determined 91% sensitivity, 91.67% specificity, 91% positive predictive value, and 91.67% negative predictive value (p = 0.0001, Fisher's exact test). The HLA A*32:01 allele was determined by an allele-specific PCR assay in 14 cases and 25 tolerant controls. Among the DRESS cases, five carriers were identified (35.7%), while it was detected in only one (4%) of the tolerant donors, [odds ratio (OR) = 13.33; 95% CI: 1.364-130.3; p = 0.016]. The strength of the association increased when only cases with positive LTT to vancomycin were considered (OR = 24.0; 95% CI: 2.28-252.6; p = 4.0 × 10-3). Our results confirm the association of the risk allele HLA-A*32:01 with vancomycin-induced DRESS in Spanish cases, and support LTT as a reliable tool to determine vancomycin sensitization.

IL-15/IL-15Rα in SJS/TEN: Relevant Expression of IL15 and IL15RA in Affected Skin.

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a life-threatening hypersensitivity reaction to medications characterized by keratinocyte apoptosis and skin detachment. IL-15 serum levels have been associated with severity and prognosis of SJS/TEN. We have measured IL-15 concentrations in serum and blister fluid (BF) from patients with SJS/TEN by ELISA and used quantitative RT-PCR to analyze the expression of IL15 and IL15RA (encoding for IL-15 Receptor-α chain) genes in peripheral blood and BF cells, including isolated monocytes, and in affected skin. A positive correlation was found between IL-15 serum levels and a percent of detached skin. BF concentrations were higher, but no correlation was found. Higher IL15 and IL15RA gene expression levels were found in skin-infiltrating blister fluid cells compared to peripheral mononuclear cells. Moreover, IL15RA transcripts were barely detected in healthy skin, being the highest expression levels found in samples from two SJS/TEN patients who did not survive. The cutaneous expression of IL-15Rα in SJS/TEN may provide an explanation to the tissue-specific immune cytotoxic response in this clinical entity, and the results suggest that the effects of IL-15 in SJS/TEN patients may be dependent on the expression of its private receptor IL-15Rα in affected skin.

Hereditary angioedema due to C1 inhibitor deficiency: real-world experience from the Icatibant Outcome Survey in Spain.

BACKGROUND: The Icatibant Outcome Survey (IOS) is an international registry monitoring the use of icatibant, a bradykinin B2 receptor antagonist indicated for the acute treatment of hereditary angioedema (HAE) attacks. Our goal was to assess disease characteristics and icatibant treatment outcomes in patients with HAE due to C1 inhibitor deficiency (HAE type 1 or 2 (HAE-1/2)) from Spain relative to other countries participating in IOS. METHODS: Descriptive retrospective analyses of data are reported from 10 centers in Spain vs 51 centers in 12 other participating countries (July 2009 to January 2019). RESULTS: No meaningful differences were identified between patients in Spain (n = 119) and patients across other countries (n = 907) regarding median age at symptom onset (15.0 vs 12.0 years) or diagnosis (22.3 vs 20.5 years). Overall HAE attack rates (total attacks/total years of follow-up) were 2.66 in Spain and 1.46 across other countries. Patients in Spain reported fewer severe/very severe HAE attacks before treatment (41.0% vs 45.9%; P < 0.0001) and, for icatibant-treated attacks, longer median time to treatment (2.9 vs 1.0 h), time to attack resolution (18.0 vs 5.5 h), and total attack duration (24.6 vs 8.0 h). Use of androgens for long-term prophylaxis was higher in Spain (51.2% vs 26.7%). CONCLUSION: Patients with HAE-1/2 in Spain reported fewer severe/very severe attacks, administered icatibant later, and had longer-lasting attacks than did patients across other countries in IOS. These differences may indicate varying disease management practices (e.g., delayed icatibant treatment) and reporting. Efforts to raise awareness on the benefits of early on-demand treatment may be warranted. TRIAL REGISTRATION: NCT01034969.

In Search of an Association Between Genotype and Phenotype in Hereditary Angioedema due to C1-INH Deficiency.

Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is caused by mutations affecting the SERPING1 gene. Adult patients (≥ 18 years old) diagnosed with C1-INH-HAE were clustered according to a modified SERPING1 gene mutation classification [5]. Demographic, clinical, and laboratory data were studied. Published manuscripts on the genotype/phenotype relationship were reviewed. Eighty-eight patients participated in the study, with 78 having a classifiable mutation. We compared the data in the 3 largest groups: class 0 only (n = 32), class II only (n = 18), class III only (n = 22). Antigenic C4 and C1 inhibitors were higher in class II (p = 0.008 and p = 0.02, respectively), and facial attacks in the last 6 months were more frequent in class III (p = 0.04)). All the other differences were non-significant. Twelve manuscripts on phenotype/genotype correlation were found: missense mutations in SERPING1 gene were associated with delay in disease onset and lower severity score in some studies, whereas the CC F12-C46T/C polymorphism produced earlier disease onset. Our study shows minimal differences regarding clinical phenotype in patients with class 0, II, and III SERPING1 gene mutations, with a tendency to class III having a more severe phenotype. The study should be performed in a larger sample to confirm if they are significant.We propose that larger multicenter, international studies are performed, comparing different SERPING1 gene mutation classifications, combining polymorphisms in other involved genes (kallikrein-kinin system, regulation of vasculature, plasminogen activation) and using different variables and clinical scores to assess C1-INH-HAE disease activity and/or severity in order to study possible genotype/phenotype relationships.

Spanish guidelines for diagnosis, management, treatment, and prevention of DRESS syndrome

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a complex multisystemic severe drug hypersensitivity reaction whose diagnosis and management are troublesome. DRESS syndrome requires management by various specialists. The correct identification of the culprit drug is essential to ensure safe future therapeutic options for the patient. There are no previous Spanish guidelines or consensus statements on DRESS syndrome. OBJECTIVE: To draft a review and guidelines on the clinical diagnosis, allergy work-up, management, treatment, and prevention of DRESS syndrome in light of currently available scientific evidence and the experience of experts from multiple disciplines. METHODS: These guidelines were drafted by a panel of allergy specialists from the Drug Allergy Committee of the Spanish Society of Allergy and Clinical Immunology (SEAIC), together with other medical specialists involved in the management of DRESS syndrome and researchers from the PIELenRed consortium. A review was conducted of scientific papers on DRESS syndrome, and the expert panel evaluated the quality of the evidence of the literature and provided grades of recommendation. Whenever evidence was lacking, a consensus was reached among the experts. RESULTS: The first Spanish guidelines on DRESS syndrome are now being published. Important aspects have been addressed, including practical recommendations about clinical diagnosis, identification of the culprit drug through the Spanish pharmacovigilance system algorithm, and the allergy work-up. Recommendations are provided on management, treatment, and prevention. Algorithms for the management of DRESS in the acute and recovery phases have been drawn up. Expert consensus-based stepwise guidelines for the management and treatment of DRESS syndrome are provided

ANTECEDENTES: El síndrome DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) es una reacción cutánea grave inducida por hipersensibilidad a fármacos, compleja y multisistémica. Su diagnóstico y manejo es difícil e implica a diferentes especialistas. Es muy importante una correcta identificación del fármaco responsable para que el paciente disponga de opciones terapéuticas seguras en el futuro. No hay guías ni documentos de consenso españoles previos sobre el síndrome DRESS. OBJETIVO: Realizar una revisión y guía sobre el diagnóstico clínico y alergológico, manejo, tratamiento y prevención del DRESS según la evidencia científica disponible y la experiencia de expertos de diferentes especialidades médicas. MÉTODOS: Esta guía ha sido elaborada por un grupo de alergólogos del Comité de Alergia a Fármacos de la SEAIC, junto a otros especialistas involucrados en el manejo del DRESS e investigadores del Consorcio PIELenRed. Se realizó una búsqueda de publicaciones científicas sobre DRESS y el grupo de expertos evaluó la evidencia científica de la literatura y aportaron grados de recomendación. Cuando no existía evidencia se alcanzó un consenso entre expertos. RESULTADOS: Se publica la guía española sobre DRESS. Incluye aspectos prácticos importantes sobre el diagnóstico clínico, la identificación de fármacos causales a través del algoritmo del Sistema Español de Farmacovigilancia y guía para el diagnóstico alergológico. Se realizan recomendaciones sobre el manejo, tratamiento y prevención del DRESS. Se aportan algoritmos sobre el manejo en la fase aguda y en la de recuperación. Se ha elaborado una guía terapéutica escalonada consensuada por expertos especialistas implicados en el tratamiento del DRESS

[Delayed allergic reaction to furosemide with a positive lymphocyte transformation test]. / Reacción alérgica tardía a furosemida con positividad de la prueba de transformación de linfocitos.

BACKGROUND: Furosemide is the most commonly prescribed loop diuretic worldwide. Although, its extended use, furosemide rarely induces allergic reactions. Until 2013, only 49 cases of furosemide allergy had been described. CLINICAL CASE: We have reported on a patient who developed a delayed, erythematous and pruritic skin eruption after the ingestion of furosemide. The implication of furosemide in the reaction was established by a positive lymphocyte transformation test (LTT). CONCLUSION: This is the first reported case of hypersensitivity to furosemide in which this drug was confirmed as the trigger by a positive LTT. LTT could become a decent diagnostic alternative for patients who experience delayed reactions to furosemide.

Antecedentes: La furosemida es el diurético de asa más comúnmente prescrito en todo el mundo. A pesar de su amplio uso, rara vez induce reacciones alérgicas. Hasta 2013 solo se habían descrito 49 casos de alergia a la furosemida. Caso clínico: Mujer de 68 años con hipertensión tratada con amlodipina, así como rinoconjuntivitis alérgica. Después del consumo de 40 mg de furosemida por cinco días debido a edema bilateral maleolar presentó exantema cutáneo maculopapular, eritematoso y pruriginoso. Los resultados positivos en la prueba de transformación de linfocitos confirmaron la implicación de la furosemida en la reacción. Conclusión: El caso que se reporta es el primero de hipersensibilidad a la furosemida en el que se confirma la implicación del fármaco por medio de una prueba de transformación de linfocitos positiva, la cual podría convertirse en una alternativa diagnóstica para los pacientes que experimentan reacciones adversas tardías a la furosemida.

Lymphocyte Transformation Test (LTT) in Allergy to Benznidazole: A Promising Approach.

Benznidazole (Bzn) from the nitroimidazole family and nifurtimox from nitrofurans family, are drugs used as first and second line treatment for acute and chronic phases of Chagas disease (CD). Even though skin reactions are frequent, confirmed allergy to Bzn is rare, and there are few cases reported in the literature. Since CD treatment is very restrained, the possibility of cross-reactivity between members of the same and other pharmacological families highlights the importance of an adequate diagnosis that allows alternative treatments in CD and other diseases. We report a series of 31 patients (69% women) referred to our Allergy unit with suspected hypersensitivity to Bzn, twenty three of them with mild reactions and eight of them with severe reactions. LTT with Bzn was performed in 31 patients and in 8 negative controls. LTT was also performed in 25 and 20 of these patients with nifurtimox and Mtn, respectively. Twenty-one out of thirty-one patients were Bzn prick tested, and all were negative. We obtained 2/19 positive results on patch tests to Bzn. LTT with Bzn was positive in 22/31 patients (Sensitivity 75.9% and specificity 100%). The test was considered positive with a stimulation index ≥2. There was a positive result in 7/25 patients for nifurtimox and in 7/20 patients with Mtn. After negative LTT and skin tests, oral provocation was performed in 4/9 patients, all negative. LTT is a safe test that seems to be more useful than skin tests (prick and patch test), particularly in severe reactions, in confirming delayed hypersensitivity to Bzn and detecting cross reactivity with other imidazoles such as Mtn and reactivity to other drugs like nifurtimox. Tests for these drugs need to be included in the workup of patients with hypersensitivity to Bzn in case they are needed as an alternative treatment for CD or to treat other frequent infectious diseases.

Quality of Life in Patients with Allergic Reactions to Medications: Influence of a Drug Allergy Evaluation.

BACKGROUND: Suspicion of allergic drug reaction can cause important disturbances in the patient's life. OBJECTIVE: We evaluated in a prospective multicenter study the quality of life of patients who suffered a possible allergic drug reaction, and analyzed the effect of a drug allergy evaluation. METHODS: Patients (>18 years old) answered the specific questionnaire twice: before the drug allergy evaluation, and 1 month after it was completed. Statistics were performed using STATA. RESULTS: A total of 360 patients (240, 66.6% female; mean age, 45.4 years; standard deviation [SD], 15.6 years) completed the first questionnaire. After the evaluation, 150 of 346 patients (43.4%) were diagnosed as allergic to the drug (115 of 150 immediate; 35 of 150 delayed) and 196 of 346 patients (56.6%) as nonallergic. The mean value of the first questionnaire was 32.14 (SD, 11.84); patients with anaphylaxis, nonanaphylactic immediate reaction, with more than 1 drug reaction, or a chronic osteoarticular disease, had a statistically significant higher score in Q0 (worse quality of life). After the allergy study, the mean of the second questionnaire was 27.27 (SD, 9.96), showing a global improvement (P < .001). No statistically significant difference was found between drug allergic and non-drug allergic patients (P = .340); however, being >40 years old (P = .030), having a chronic osteoarticular disease (P = .003) and having more than 1 reaction to drugs (P < .001) were associated with a statistically significant worse quality of life after the evaluation. CONCLUSIONS: Having suffered anaphylaxis, more than 1 reported drug allergy or presenting a musculoskeletal disease are factors that worsen the quality of life. Quality of life improved significantly after completing a drug allergy evaluation.

The lymphocyte transformation test is useful in the diagnosis of fixed drug eruption induced by etoricoxib

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Aspirin desensitization in aspirin-exacerbated respiratory disease: New insights into the molecular mechanisms.

BACKGROUND: Aspirin desensitization (AD) has been the only available modifying treatment in aspirin-exacerbated respiratory disease (AERD). The mechanisms of AD are nonetheless poorly understood. Though very effective, AD is limited by its risks and side-effects. OBJECTIVE: Moving forward to the targeted biologicals era, the aim of this study was to characterize the airway inflammatory response to long-term AD, including TSLP dynamics, in order to assess potential new targets in AERD. PATIENTS AND METHODS: Adult patients with aspirin challenge-confirmed AERD underwent an oral AD followed by daily ingestion of aspirin for at least 6 months. Clinical data and inflammatory biomarkers were measured and compared, before and after AD. Induced sputum analyses were performed at baseline, one and six months after AD (differential cell count and levels of sputum supernatant leukotriene C4, prostaglandin D2 and E2, and TSLP). RESULTS: AD was followed by significant clinical improvement, as quantified by all monitored parameters. The good clinical outcomes of AD in our study are supported by overall changes observed in the arachidonic acid metabolites (decreased PGD2 over a constant LTC4/PGE2). TSLP increased (mean baseline 0.1 ±â€¯0.03; 1 month 3.68 ±â€¯7; 6 months 212.2 ±â€¯44 pg/ml; p < 0.01). CONCLUSIONS: Our findings suggest that new biologicals blocking TSLP might have a clinical benefit in AERD, by cutting down the TSLP-induced PGD2 generation.

[Delayed allergic reaction to amlodipine with a positive lymphocyte transformation test]. / Reacción alérgica tardía a amlodipino con positividad de la prueba de transformación de linfocitos.

BACKGROUND: Amlodipine is one of the third generation dihydropyridine calcium channel blockers used for hypertension. Mild, moderate and severe reactions have been reported with calcium channel blockers. Cross-reactivity among these drugs has not been established. CLINICAL REPORT: We have presented the case of a patient who developed a delayed pruritic, and erythematous maculopapular skin exanthema after the intake of amlodipine. A positive lymphocyte transformation test (LTT) confirmed the implication of amlodipine in the reaction and showed positivity to another calcium channel blocker, nifedipine, demonstrating cross reactivity. CONCLUSION: This is the first reported case of hypersensitivity to amlodipine in which the involvement of the drug is confirmed by a positive TTL. TTL could become a good diagnostic alternative for patients who experience late reactions to amlodipine and possibly cross-reactivity with nifedipine.

Antecedentes: el amlodipino es uno de los bloqueadores de los canales de calcio de dihidropiridinas de tercera generación utilizado para la hipertensión. Se han notificado reacciones leves, moderadas y graves con bloqueadores de los canales de calcio. No se ha establecido la reactividad cruzada entre estos fármacos. Caso clínico: se presenta el caso de una paciente con exantema cutáneo maculopapular, eritematoso y pruriginoso tardío tras la ingestión de amlodipino. La prueba de transformación de linfocitos mostró positividad al amlodipino, lo que confirmó la implicación de este fármaco en la reacción; también mostró positividad al nifedipino, lo que demostró la presencia de reactividad cruzada. Conclusión: este es el primer caso reportado de hipersensibilidad a amlodipino en el que se confirma la implicación del fármaco por medio de una prueba positiva de transformación de linfocitos, la cual podría convertirse en una buena opción diagnóstica en aquellos pacientes que experimentan reacciones tardías al amlodipino, así como posible reactividad cruzada con nifedipino.

Eosinophilic drug reactions detected by a prospective pharmacovigilance programme in a tertiary hospital.

AIM: We conducted a prospective evaluation of all eosinophilic drug reactions (EDRs) through the Prospective Pharmacovigilance Program from Laboratory Signals at Hospital to find out the incidence and distribution of these entities in our hospital, their causative drugs, and predictors. METHODS: All peripheral eosinophilia >700 × 106  cells l-1 detected at admission or during hospitalisation, were prospectively monitored over 42 months. The spectrum of the localised or systemic manifestation of EDR, the incidence, the distribution of causative drugs, and the predictors were analysed. RESULTS: The incidence of EDR was 16.67 (95% Poisson confidence interval [CI]: 9.90-25.98) per 10 000 admissions. Of 274 cases of EDR, 154 (56.2%) cases in 148 patients were asymptomatic hypereosinophilia. In the remaining 120 (43.8%) cases, there was other involvement. Skin and soft tissue reactions were detected in 36 (13.1%) cases; visceral EDRs in 19(7.0%) cases; and drug-induced eosinophilic cutaneous and visceral manifestations were detected in the remaining 65 (23.7%) cases, 64 of which were potential drug reaction with eosinophilia and systemic symptoms (DRESS). After adjusting for age, sex, and hospitalisation wards, predictors of symptomatic eosinophilia were earlier onset of eosinophilia (hazard ratio [HR], 10.49; 95%CI: 3.13-35.16) higher eosinophil count (HR, 8.51; 95%CI: 3.28-22.08), and a delayed onset of corticosteroids (HR, 1.34; 95%CI: 1.01-1.73). A higher eosinophil count in patients with DRESS was significantly associated with greater impairment of liver function, prolonged hospitalisation, higher cumulative doses of corticosteroids, and if hypogammaglobinaemia was detected, a reactivation of human-herpesvirus 6 was subsequently detected. CONCLUSIONS: Half (53.3%, 64/120 cases) of symptomatic EDRs were potential DRESS. The main predictor of severity of EDR was an early severe eosinophilia.