Meta-analysis of ACE inhibitor-induced angioedema identifies novel risk locus.

BACKGROUND: Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited. OBJECTIVE: We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology. METHODS: By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE. RESULTS: Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort. CONCLUSIONS: The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries.

Identification and comparison of sex-specific serious adverse drug reactions in spontaneous reports and systematically collected reports (ADRED).

AIMS: Adverse drug reactions (ADRs) are known to show sex-specific differences in occurrence and phenotype. The aim of this study was to analyse sex-specific differences in ADR-drug combinations that required hospitalization based on two different datasets. METHODS: We performed a complementary analysis of (i) spontaneously reported (n = 12 564, female = 51.7%) and (ii) systematically collected ADR reports from a prospective multicentre observational study (ADRED, n = 2355, female = 48.2%) from Germany in the ADR database EudraVigilance (EV). Both datasets were analysed separately concerning the suspected drugs, ADRs and ADR-drug combinations more frequently reported for females or males by calculating reporting odds ratios (ROR) with 95% confidence intervals. ADR-drug combinations more frequently reported for either females or males in EV reports were related to prescription data. Finally, the results from both datasets were discussed with regard to their (dis-)concordance. RESULTS: In both datasets, some antineoplastic agents and nervous system drugs were found to be reported more often for females than males (RORs ranging from 1.5 [1.1-2.1] for quetiapine in spontaneous reports to 41.3 [13.1-130.0] for trastuzumab in spontaneous reports). ADRs of the respiratory system, and haemorrhages were described predominantly for males in both datasets. In spontaneous reports the ADR-drug combination self-injurious behaviour-quetiapine was more often reported for females without and with consideration of drug prescriptions (ROR: 3.8 [1.3-11.0]). Quetiapine and psychiatric disorders (superordinate level) was exclusively reported for females in ADRED reports. CONCLUSIONS: Our results can contribute to raise awareness and further knowledge regarding sex-specific ADRs. The findings require further in-depth investigation.

Comparative Analysis of Information Provided in German Adverse Drug Reaction Reports Sent by Physicians, Pharmacists and Consumers.

INTRODUCTION: Adverse drug reactions (ADRs) can be reported by Health Care Professionals (HCPs; e.g., physicians, pharmacists) and non-Health Care Professionals (non-HCPs; e.g., consumers). Previous studies investigating differences between reports from HCPs and non-HCPs rarely considered the completeness of information provided. In addition, they mostly did not distinguish between physicians and pharmacists or were performed years ago. The aim of our study was to analyse and compare the completeness of information provided in reports from physicians, pharmacists and consumers from Germany in a more recent dataset. MATERIALS AND METHODS: We analysed all spontaneous reports from Germany received between 2018 and 2021 in the ADR database EudraVigilance exclusively reported by physicians (n = 69,976), pharmacists (n = 42,396) or consumers (n = 121,144). Demographical parameters of the patients were analysed descriptively. Completeness of reports was evaluated applying an established score (vigiGrade). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using logistic regression analysis in order to identify report, patient, drug or ADR-specific information provided more often in reports from physicians, pharmacists or consumers. RESULTS: Within the study period the number of reports per year by physicians and pharmacists decreased steadily, while an opposite trend was observed for consumer reports. The proportion of female patients was higher in reports from pharmacists (64.4%) and consumers (64.8%) compared to those from physicians (55.3%). On average, patients in reports from pharmacists (58.7) were older compared to those from physicians (53.5) and consumers (52.6). As an example for the presence of specific information, the time to onset of the ADR could be calculated more often in consumer compared to physician (OR 1.9 [1.8-1.9]) and pharmacist reports (OR 1.7 [1.6-1.7]). In contrast, pharmacist (OR 0.5 [0.4-0.5]) and consumer (OR 0.5 [0.5-0.5]) reports included the indication of the suspected drug less often than physician reports. Physician reports on average (mean = 0.5) were slightly more complete according to the vigiGrade score compared to reports from consumers (mean = 0.4) and pharmacists (mean = 0.4). CONCLUSION: The ADR reports from consumers were comparable with regard to the completeness score with those from physicians and pharmacists underlining their value. Differences in completeness of specific information between the reporter types were found, suggesting that a common reporting of interactions between the three reporters may further improve the completeness of ADR reports. Furthermore, stratified analysis of ADR reports per reporter type may be helpful for certain objectives in scientific research.

Guideline for allergological diagnosis of drug hypersensitivity reactions: S2k Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) in cooperation with the German Dermatological Society (DDG), the Association of German Allergologists (ÄDA), the German Society for Pediatric Allergology (GPA), the German Contact Dermatitis Research Group (DKG), the German Society for Pneumology (DGP), the German Society of Otorhinolaryngology, Head and Neck Surgery, the Austrian Society of Allergology and Immunology (ÖGAI), the Austrian Society of Dermatology and Venereology (ÖGDV), the German Academy of Allergology and Environmental Medicine (DAAU), and the German Documentation Center for Severe Skin Reactions (dZh).

Not available.

A Complex Intervention to Prevent Medication-Related Hospital Admissions.

BACKGROUND: Children are often treated off-label and are at a disadvantage in pharmacotherapy. The aim of this study was to implement and evaluate a quality assurance measure (PaedPharm) for pediatric pharmacotherapy whose purpose is to reduce medication-related hospitalizations among children and adolescents. METHODS: PaedPharm consisted of the digital pediatric drug information system PaedAMIS, pediatric pharmaceutical quality circles (PaedZirk), and an adverse drug event (ADE) reporting system (PaedReport). The intervention was implemented in a cluster-randomized trial (DRKS 00013924) in 12 regions, with a pediatric and adolescent medicine clinic in each and a total of 152 surrounding private practitioners, in 6 sequences over 8 quarters. In addition to the proportion of ADE-related hospital admissions (primary endpoint), comprehensive process evaluation included other endpoints such as coverage, user acceptance, and relevance to practice. RESULTS: 41 829 inpatient admissions were recorded, of which 5101 were patients of physicians who participated in our study. 4.1% of admissions were ADE-related under control conditions, and 3.1% under intervention conditions (95% CI: [2.3; 5.9] and [1.8; 4.5], respectively). A model-based comparison yielded an intervention effect of 0.73 (population-based odds ratio; [0.39; 1.37]; p = 0.33). PaedAMIS achieved moderate user acceptance and PaedZirk achieved high user acceptance. CONCLUSION: The introduction of PaedPharm was associated with a decrease in medication-related hospitalizations that did not reach statistical significance. The process evaluation revealed broad acceptance of the intervention in outpatient pediatrics and adolescent medicine.

IFN-γ secretion of PBMC from non-drug-allergic control persons: Considerations for the validity of a positive lymphocyte transformation test.

BACKGROUND: The lymphocyte transformation test (LTT) is used for the in vitro detection of a drug sensitization in assumed drug allergic patients. It is based on the detection of antigen (drug)-specific activation of T cells indicated by e.g. proliferation or cytokine secretion. However, occasional stimulatory effects of the drug unrelated to specific drug-allergic mechanisms can only be detected if a larger number of non-drug allergic control persons are tested with this specific drug. In this respect, the overall specificity of the LTT with ELISA read-out is summarized in several review articles, but the impact of a specific drug on the specificity has not yet been analyzed in a larger set of control persons. OBJECTIVE: Do amoxicillin, cefuroxime and clindamycin induce an interferon (IFN)-y or interleukin (IL)-5 secretion of PBMC from control persons using the LTT with ELISA read-out? METHODS: We performed LTTs with amoxicillin, cefuroxime and clindamycin and determined drug-specific IFN-γ and IL-5 secretion measured by ELISA read-out. We included PBMC from 60 non-drug allergic control persons, who were unexposed to the tested drug at the time of blood donation. RESULTS: PBMC from 12 out of 23 control persons tested with amoxicillin gave a positive stimulation index (SI > 3.0) for IFN-γ resulting in a specificity of 47.8%. The corresponding specificity was 75% for cefuroxime (5/20 if SI > 3.0) and 58.8% for clindamycin (7/17, if SI > 2.0), respectively. In a next step, we calculated the Δ IFN-γ concentration by subtracting the background IFN-γ concentration in the unstimulated sample from the stimulated sample. After stimulation with amoxicillin, a mean concentration of 21.0 pg/mL IFN-γ was secreted. The less outlier prone median concentration was 7.4 pg/mL and much higher than for cefuroxime (1.7 pg/mL) and clindamycin (1.0 pg/mL). Remarkably, IL-5 concentrations were below the detection limit (< 1 pg/mL) for all drugs in all control persons who responded to TT. CONCLUSION: Consideration of these observations may be helpful since a positive LTT result in a control patient may challenge the validity of a positive LTT result in the same experiment for a patient with assumed drug allergy.

Selective serotonin reuptake inhibitors and suicidality in children and young adults: analyses of pharmacovigilance databases.

BACKGROUND: Since the warnings by the United States (US) and European regulatory authorities in 2004 and 2005 it had been discussed whether there is some link between selective serotonin reuptake inhibitors (SSRIs) and suicidality in the pediatric population. The aim of our study was to describe trends and patterns in spontaneous reporting data referring to suicidality in children, adolescents and young adults treated with SSRI after the warnings. METHODS: Descriptive analyses of reports for 0-24 year olds referring to suicide/suicidal ideations, self-harms and overdoses with SSRIs reported as suspected submitted to the US (FAERS) and the European (EudraVigilance) adverse drug reaction databases until 2019 were performed. The causal relationship was assessed in accordance with the WHO criteria for the European reports. For Germany, prescription data for SSRIs were provided and reporting rates (number of reports/number of prescriptions) were calculated for the reports with possible causal relationship (so called "confirmed reports"). RESULTS: Since 2004, the number of reports referring to suicide/suicidal ideations, self-harm and overdoses increased steadily in the US and EU. However, only a slight increase was seen for the confirmed EU reports. After 2008, the proportion of reports informing about suicidal ideations increased, while the proportion of fatal suicide attempts decreased. Reporting rates were higher for females and adolescents (12-18 years). CONCLUSIONS: Our results demonstrate the importance of further monitoring suicidality in 0-24 year olds treated with SSRI in order to recognize suicidality early avoiding fatal suicide attempts. The higher reporting rates for females and adolescents should be further investigated.

Adverse Drug Reactions in Children: Comparison of Reports Collected in a Pharmacovigilance Project Versus Spontaneously Collected ADR Reports.

BACKGROUND: Adverse drug reactions (ADRs) and medication errors in children may result from a lack of appropriate drugs, dosages, and pharmaceutical forms. In addition, children may respond differently to drugs than adults. Reporting of ADRs in the pediatric population is therefore of importance in order to increase the amount of safety data. However, different methodological approaches are used to collect ADRs. OBJECTIVE: The aim of the present study was to analyze whether there were differences in the ADRs collected in the KiDSafe project (845 ADR reports) compared with the spontaneous ADR reports sent to EudraVigilance (697 reports) in the same time period. The strengths and limitations of these two different approaches should be discussed. METHODS: The same inclusion criteria were applied for the systematically collected ADRs in the KiDSafe project and the spontaneous reports from EudraVigilance, and only reports of ADRs coded with hospitalization were considered. In both datasets, the number of reports (related to number of hospitals), their documentation quality (VigiGrade), causal relationship (World Health Organization-Uppsala Monitoring Centre [WHO-UMC] criteria), most frequently reported drugs and ADRs, demographical parameters of the patients, reported medical histories, and the seriousness of ADR reports were analyzed descriptively. The results of the two analyses were compared. RESULTS: There was considerable underreporting of ADRs via the spontaneous reports (0.4 reports per hospital; 697/1902) compared with 70.4 reports per hospital (845/12) in the systematically collected KiDSafe reports. Documentation quality assessment yielded similar results in both datasets. Among the 10 most frequently reported drugs, anticonvulsants such as levetiracetam (6.6%), valproic acid (5.6%), oxcarbazepine (3.6%), and lamotrigine (3.4%) were mainly reported in the KiDSafe reports, while in the EudraVigilance reports, mite allergen extract (4.4%) and allergens (3.6%) were preferentially reported. Seizures were the most frequently reported clinically specific ADRs in the KiDSafe reports, whereas anaphylactic reactions and urticaria were prominent in the spontaneous reports from EudraVigilance. Notably, the proportion of reports referring to medication errors and other medication safety related issues were more prominent in KiDSafe than in the spontaneous reports (27.8% vs. 12.6% and 46.0% vs. 29.0%, respectively). CONCLUSION: In general, reports from both data sources contributed to the identification of ADRs and dedicated issues related to drug therapy. However, these differed by nature and strength of the signal, likely due to the characteristics of the individual method. A combined approach could likely compensate for limitations inherent to the single approaches, but will most likely only be applied to dedicated pharmacovigilance topics or research objectives.

Analyses of Basal and Squamous Cell Carcinoma Reported as an Adverse Drug Reaction and Comparison with Cases from the Cancer Registry from Germany.

INTRODUCTION: In Germany, incidence rates of basal cell (BCC) and squamous cell carcinoma (SCC) rose significantly from 1998 to 2010. Ultraviolet (UV) light exposure, immunosuppressants and drugs with photosensitising potential are known to increase the risk to develop BCC and SCC. The aim of our study was to analyse the adverse drug reaction (ADR) reports from Germany referring to BCC and SCC and to compare them to BCC and SCC occurring in the general population. METHODS: We analysed all validated spontaneous ADR reports referring to BCC (n = 191) and SCC (n = 75) from Germany contained in the European ADR database EudraVigilance prior to 6 March 2019. These reports were compared to 1,267,210 BCC and 476,903 SCC cases from the German Centre for Cancer Registry Data recorded from 2006 to 2018. RESULTS: The number of BCC and SCC reports as well as the BCC and SCC incidences in the registry increased in the analysed time period. Patients with drug-associated BCC (60 years) and SCC (64 years) were younger than patients with BCC (72 years) and SCC (76 years) in the registry. In 57.1 and 60.0% of BCC and SCC reports immunosuppressants were reported as suspected. The reported suspected drug was assumed to possess a photosensitising potential in 41.9 and 44.0% of BCC and SCC reports. CONCLUSIONS: In Germany, drug-associated BCC and SCC occurred at a younger age than in the general population. The results underline the necessity for skin cancer screening of patients treated with immunosuppressants or with drugs with photosensitising potential.

Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes.

Angioedema is a relatively rare but potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs). As with hereditary forms of angioedema (HAE), this adverse reaction is mediated by bradykinin. Research suggests that ACEi/ARB-induced angioedema has a multifactorial etiology. In addition, recent case reports suggest that some ACEi/ARB-induced angioedema patients may carry pathogenic HAE variants. The aim of the present study was to investigate the possible association between ACEi/ARB-induced angioedema and HAE genes via systematic molecular genetic screening in a large cohort of ACEi/ARB-induced angioedema cases. Targeted re-sequencing of five HAE-associated genes (SERPING1, F12, PLG, ANGPT1, and KNG1) was performed in 212 ACEi/ARB-induced angioedema patients recruited in Germany/Austria, Sweden, and Denmark, and in 352 controls from a German cohort. Among patients, none of the identified variants represented a known pathogenic variant for HAE. Moreover, no significant association with ACEi/ARB-induced angioedema was found for any of the identified common [minor allele frequency (MAF) >5%] or rare (MAF < 5%) variants. However, several non-significant trends suggestive of possible protective effects were observed. The lowest p-value for an individual variant was found in PLG (rs4252129, p.R523W, p = 0.057, p.adjust > 0.999, Fisher's exact test). Variant p.R523W was found exclusively in controls and has previously been associated with decreased levels of plasminogen, a precursor of plasmin which is part of a pathway directly involved in bradykinin production. In addition, rare, potentially functional variants (MAF < 5%, Phred-scaled combined annotation dependent depletion score >10) showed a nominally significant enrichment in controls both: 1) across all five genes; and 2) in the F12 gene alone. However, these results did not withstand correction for multiple testing. In conclusion, our results suggest that HAE-associated mutations are, at best, a rare cause of ACEi/ARB-induced angioedema. Furthermore, we were unable to identify a significant association between ACEi/ARB-induced angioedema and other variants in the investigated genes. Further studies with larger sample sizes are warranted to draw more definite conclusions concerning variants with limited effect sizes, including protective variants.

Lymphocyte transformation test for drug allergy detection: When does it work?

BACKGROUND: The lymphocyte transformation test (LTT) is an in vitro test system for the detection of a sensitization in the context of allergies to drugs. Its reported sensitivity varies largely and seems to be affected by different parameters. In review articles, the average LTT performance was often calculated by combining overall mean sensitivities of various published studies, but without considering different patient characteristics or varying patient numbers per publication. OBJECTIVE: To investigate the impact of different patient-specific and methodological parameters on the sensitivity of the LTT based on data on the level of the individual patient extracted from single studies. METHODS: We performed an advanced literature search in PubMed and screened the identified publications according to previously defined inclusion criteria. In total, individual patient data from 721 patients were extracted from 30 studies. Random-effects meta-regression analyses were performed. RESULTS: The analysis indicate that the enzyme-linked immunosorbent assay-based read-out is more sensitive compared with the classical radioactivity method (enzyme-linked immunosorbent assay: 80% vs radioactivity: 66%; P = .08). Interestingly, drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome is associated with a higher probability of a positive LTT test result compared with other investigated clinical phenotypes ("drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome" vs "bullous reaction"; odds ratio, 2.52; P value = .003). Our analysis also revealed an impact of the time to testing period after the occurrence of the allergic event ("< 2 weeks" vs "2 weeks-2 months"; odds ratio, 2.12; P value = .03). CONCLUSION: The read-out method and relevant clinical parameters affect the sensitivity of the LTT. These findings are based on a meta-analysis providing a higher level of evidence than a single study or previous reviews not considering individual patient data.

Descriptive analysis of adverse drug reaction reports for hypersensitivity reactions stratified in relation to different beta-lactam antibiotics.

ß-lactam antibiotics (BLA) are commonly reported to induce hypersensitivity reactions. However, ß-lactam antibiotic-stratified analyses are rare. In the presented study, ß-lactam antibiotic associated hypersensitivity reactions were analyzed in the European adverse drug reaction (ADR) database. 923, 38, 222, and 99 hypersensitivity reports for penicillins and first-, second- and third-generation cephalosporins were reported. Differences with regard to demographical parameters, seriousness and types of hypersensitivity reactions, as well as in the number of hypersensitivity reports per outpatient prescriptions were observed between the different ß-lactam antibiotics. The number of ADR reports classified as serious was higher for all generations of cephalosporins compared to penicillins. Additionally, anaphylactic reactions were more often reported for first- and second-generation cephalosporins compared to third-generation cephalosporins and penicillins, while bullous reactions were more often reported for first- and third-generation cephalosporins as opposed to second-generation cephalosporins and penicillins. The observed differences may be caused by differences between ß-lactam antibiotics and their routes of administration (oral, intravenous), the patient populations, or the reporting of ADRs. Due to the methodological limitations of ADR database analysis, no conclusions can be drawn whether and to what extent the aforementioned factors influenced our results.

Descriptive analysis of 179 German reports of melanoma reported to an adverse drug reaction database as a drug-related adverse effect, and comparison with melanoma cases contained in German cancer registries.

BACKGROUND: Malignant melanoma (MM) is one of the most aggressive forms of skin cancer. The occurrence of MM associated with drug therapy has been described in the literature. However, there is no analysis of a substantial number of validated reports of drug-associated MM. AIM: To analyse a substantial number of validated spontaneous reports of drug-associated MM with regard to the suspected drug and the reported characteristics, and to compare these analyses with those of MM cases occurring in the general population in Germany. METHODS: Spontaneous reports of MM associated with drug therapy in Germany were identified in a large adverse drug reaction database (EudraVigilance). These results were then compared with analyses of MMs in the pooled data from a population-based German cancer registry. RESULTS: The 10 most frequently suspected drugs in the MM reports all target the immune system, with 7 of these being immunosuppressants. The median time to onset to MM diagnosis was 2.0 years. Patients with drug-associated MM were 11 years (median) younger than patients with MM in the cancer registry, and this age difference was greater for female than for male patients. CONCLUSIONS: Our results emphasize the importance of regular dermatological examinations of patients being treated with immunosuppressants. Physicians should be aware that in these patients, MM might be detected at younger ages and even within 2 years after initiating therapy.

Descriptive analysis of adverse drug reaction reports in children and adolescents from Germany: frequently reported reactions and suspected drugs.

BACKGROUND: Adverse drug reactions (ADRs) in the pediatric population may differ in types and frequencies compared to other populations. Respective studies analyzing ADR reports referring to children have already been performed for certain countries. However, differences in drug prescriptions, among others, complicate the transferability of the results from other countries to Germany or were rarely considered. Hence, the first aim of our study was to analyze the drugs and ADRs reported most frequently in ADR reports from Germany referring to children contained in the European ADR database (EudraVigilance). The second aim was to set the number of ADR reports in relation to the number of drug prescriptions. These were provided by the Research Institute for Ambulatory Health Care in Germany. METHODS: For patients aged 0-17 years 20,854 spontaneous ADR reports were received between 01/01/2000-28/2/2019. The drugs and ADRs reported most frequently were identified. Stratified analyses with regard to age, sex and drugs used "off-label" were performed. Reporting rates (number of ADR reports/number of drug prescriptions) were calculated. RESULTS: Methylphenidate (5.5%), ibuprofen (2.3%), and palivizumab (2.0%) were most frequently reported as suspected. If related to the number of drug prescriptions, the ranking changed (palivizumab, methylphenidate, ibuprofen). Irrespective of the applied drugs, vomiting (5.4%), urticaria (4.6%) and dyspnea (4.2%) were the ADRs reported most frequently. For children aged 0-1 year, drugs for the treatment of nervous system disorders and foetal exposure during pregnancy were most commonly reported. In contrast, methylphenidate ranked first in children older than 6 years and referred 3.5 times more often to males compared to females. If age- and sex-specific exposure was considered, more ADR reports for methylphenidate referred to children 4-6 years and females 13-17 years. Drugs for the treatment of nervous system disorders ranked first among "off-label" ADR reports. CONCLUSIONS: Our analysis underlines the importance of putting the number of ADR reports of a drug in context with its prescriptions. Additionally, differences in age- and sex-stratified analysis were observed which may be associated with age- and sex-specific diseases and, thus, drug exposure. The drugs most frequently included in "off-label" ADR reports differed from those most often used according to literature.

Future perspectives on in-vitro diagnosis of drug allergy by the lymphocyte transformation test.

This article aims to envisage future perspectives of the lymphocyte transformation test (LTT). We describe the select innovative techniques, which can be integrated at different stages of the LTT to potentially improve the sensitivity, specificity, or practicability of the LTT. We first focus upon the cell sorting techniques comprising immunomagnetic cell separation and flow cytometry, which can be implemented prior and after the LTT culturing step to concentrate and quantify specific immune cell types. Further, we elaborate upon three important omics techniques such as transcriptomics, proteomics, and metabolomics, which can be integrated downstream of the LTT to analyze molecular changes in specific immune cells following drug induced activation and proliferation. We also develop visions, how state of the art techniques used in other scientific fields, can be transferred and applied in the context of in-vitro detection of drug allergy.

Analysis of the reporting of adverse drug reactions in children and adolescents in Germany in the time period from 2000 to 2019.

The objective of this study was to analyse reports on adverse drug reactions (ADRs) from Germany in the particularly vulnerable patient group of children and adolescents. Reporting characteristics, demographic parameters and off-label use were examined among others. The ratio of ADR reports per number of German inhabitants and the ratio of ADR reports per number of German inhabitants exposed to drugs were calculated and compared. These parameters were examined to derive trends in reporting of ADRs. 20,854 spontaneous ADR reports for the age group 0-17 years were identified in the European ADR database EudraVigilance for the time period 01.01.2000-28.02.2019 and analysed with regard to the aforementioned criteria. 86.5% (18,036/20,854) of the ADR reports originated from Healthcare Professionals and 12.2% (2,546/20,854) from non-Healthcare Professionals. 74.4% (15,522/20,854) of the ADR reports were classified as serious. The proportion of ADR reports per age group was 11.8% (0-1 month), 11.0% (2 months-1 year), 7.4% (2-3 years), 9.3% (4-6 years), 25.8% (7-12 years), and 34.8% (13-17 years) years, respectively. Male sex slightly dominated (51.2% vs. 44.8% females). Only 3.5% of the ADR reports reported off-label use. The annual number of ADR reports increased since 2000, even if set in context with the number of inhabitants and assumed drug-exposed inhabitants. The pediatric population declined in the study period which argues against its prominent role for the increase in the total number of ADR reports. Instead, among others, changes in reporting obligations may apply. The high proportion of serious ADR reports underlines the importance of pediatric drug safety.

Lymphocyte transformation test: History and current approaches.

Drug-induced hypersensitivity reactions encompass a variety of different clinical phenotypes ranging from harmless rashes to fatal reactions. They can be classified into allergic (i.e. drug allergy) and non-allergic reactions (i.e. non-allergic hypersensitivity). Drug allergies in turn can either be antibody (e.g. IgE) or T cell-mediated. One of the diagnostic tools for the in vitro detection of drug allergy is the lymphocyte transformation test (LTT) which is based on the activation and expansion of the drug-specific memory T cells following co-incubation of the patient's peripheral mononuclear cells (PMBC) with the suspected drug in vitro. The read-out parameter in the classical LTT is T cell proliferation which can be measured as counts per minute following the addition of radiolabeled thymidine to the cell culture. However, in the course of time different modifications of the classical LTT with regard to the read-out parameters and methods have been proposed. Likewise, variations of the LTT platform itself have been described in the literature. This review article describes the development of the classical LTT and its use in the context of drug allergy detection and summarizes the modifications which have been published over time.

Do dimethyl fumarate and nicotinic acid elicit common, potentially HCA2 -mediated adverse reactions? A combined epidemiological-experimental approach.

AIM: Dimethyl fumarate and nicotinic acid activate the hydroxy-carboxylic acid receptor 2 (HCA2 ) and induce flushing. It is not known whether HCA2 mediates other adverse drug reactions (ADRs) to these two substances. This study aims to compare ADRs associated with dimethyl fumarate and nicotinic acid, and to discuss whether they are HCA2 -mediated. METHODS: We identified spontaneous reports of suspected ADRs to dimethyl fumarate and nicotinic acid in the European Adverse Drug Reaction Database (EudraVigilance). These reports were analysed at different hierarchical levels of the Medical Dictionary for Regulatory Activities (MedDRA). In addition, we screened murine organs for HCA2 expression. RESULTS: Similarities in the ADR profile of dimethyl fumarate and nicotinic acid included "gastrointestinal signs and symptoms" (odds ratio [OR] 0.8 [0.6-1.1]), "hepatobiliary investigations" (OR 1.3 [0.7-2.5]) and "anxiety disorders and symptoms" (OR 0.9 [0.3-2.2]) in High Level Group Terms; "diarrhoea (excluding infective)" (OR 1.2 [0.7-1.8]) and "liver function analyses" (OR 1.3 [0.7-2.6]) in High Level Terms; and "diarrhoea" (OR 1.2 [0.7-2.0]) and "vomiting" (OR 0.9 [0.4-1.7]) in Preferred Terms. In analogy, HCA2 was expressed in the gastrointestinal tract, liver and central nervous system (CNS) of murine organs. A discrepant ADR profile was seen for "lymphopenia" (n = 777) at the preferred term level (only reported for dimethyl fumarate) and "blood glucose increased" (more often reported for nicotinic acid; OR 0.1 [0.0-0.5]). CONCLUSION: The gastrointestinal ADRs common to both substances may be mediated by HCA2 . Other ADRs not common to both substances are compound or indication-specific reactions and likely do not involve HCA2 .