Comparison of incidence, causes and prognosis of adult and pediatric epidermal necrolysis: a population-based study in France.

BACKGROUND: Epidermal necrolysis (EN), comprising Stevens Johnson syndrome and toxic epidermal necrolysis is a rare and severe blistering reaction, mainly induced by drugs. Differences have been discussed between pediatric and adult patients regarding incidence, causes, and outcomes, but only based on a limited number of patients, in small case-series. OBJECTIVES: To directly compare incidence, causes and prognosis between adult and pediatric EN patients. METHODS: We used the French Health System Database from January 1st 2013 to December 31st 2022. We included adult and pediatric patients hospitalized for EN using the international classification of diseases, 10th revision codes combined with validated algorithms. The outcomes were incidence of EN; presence of a suspected drug before EN onset, defined by a new drug dispensation from 5 to 56 days before hospitalization; and in-hospital mortality. To estimate the association between pediatric EN and the presence of a suspected drug, we computed a multivariable logistic regression with odd ratios (OR). To estimate the association with mortality, we computed a multivariable Cox proportional hazard ratio (HR) model. RESULTS: A total of 1440 EN patients were included, with 799 (55.5%) females, comprising 219 children and 1221 adults. Among children, EN incidence was 1.5 cases (95%CI: 1.3-1.7) per million people year compared with 2.6 cases (95%CI: 2.5-2.7) in adults. Moreover, children had less chances to have a culprit drug before EN onset (93/219 (42.5%) versus 829/1221 (67.9%)), with an adjusted OR of 0.43 (95%CI: 0.32-0.59), p < 0.0001, together with a better prognosis, with death rates of 1.4% (95%CI: 0.4%-3.7%) in pediatric patients compared with 19.4% (95%CI: 17.3%-21.7%) in adult patients, and an adjusted HR of 0.12 (95%CI: 0.04-0.38), p = 0.0003 for in-hospital mortality. CONCLUSION: Pediatric EN seems to be rarer, with less chances to be caused by drugs, together with a better prognosis than adult EN. These results suggest the existence of different underlying pathophysiological mechanisms and clinical particularities between adult and pediatric patients.

Drugs associated with epidermal necrolysis in children: A World Health Organization pharmacovigilance database analysis.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare life-threatening mucocutaneous reactions most often induced by drugs. To date, no large pharmacovigilance study has been conducted in the paediatric population. OBJECTIVES: To describe the spectrum of drugs associated with SJS-TEN in children through the analysis of cases reported in the WHO pharmacovigilance database (VigiBase). METHODS: Disproportionality study using data from VigiBase. All paediatric (age under 18 years) cases reported between January 1, 1967, and July 6, 2022, were included. For each molecule, a case-non-case study was performed to assess a potential pharmacovigilance signal by computing the lower end of the 95% credibility interval for the information component (IC025). We performed sensitivity analyses, (i) taking into account only cases reported by physicians and (ii) taking into account only cases reported in the last 10 years. RESULTS: Among 31,376,783 adverse drug reactions reported in VigiBase, 2,248,727 were paediatric cases and 7342 were encoded as paediatric SJS-TEN. Significant statistical pharmacovigilance signals were observed for 165 drugs. The two most represented drug classes were antiepileptics and anti-infectious drugs. The five drugs with the highest IC025 were lamotrigine (IC025 4.99), carbamazepine (IC025 4.88), phenobarbital (IC025 4.67), phenytoin (IC025 4.52) and nimesulide (IC025 4.23). Acetaminophen was significantly associated with paediatric SJS-TEN (IC025 2.85) and we also described various new suspected drugs. Vaccines had no significant pharmacovigilance signal. These results were confirmed with the sensitivity analyses. CONCLUSIONS: This study updates the spectrum of drugs potentially associated with paediatric SJS-TEN.

Impact of the vaccination against SARS-CoV-2 campaign on disproportionality indicator from the WHO pharmacovigilance database: A competition bias study from case/non-case analysis.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) vaccination campaign has resulted in numerous pharmacovigilance's safety reports which were recorded in the World Health Organization (WHO) pharmacovigilance database (VigiBase) and represent in July 2022 more than 10% of cases recorded. The information component (IC) is a statistical disproportionality measure based on the observed and expected numbers of case reports. A positive value of the lower endpoint of a 95% credibility interval for the information component (IC0.25) suggests a possible causal relationship between the drug and the adverse reaction. This study aimed to evaluate the impact of the wave of COVID-19 vaccines safety declarations on IC0.25 from Vigilyze and thus illustrate with a concrete example the competition bias. METHODS: We arbitrarily selected 21 adverse drug reactions using Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs), divided in two types: PTs known to be related to COVID-19 vaccines ("expected") and others (type "unexpected"). Data were extracted from VigiLyze. We created two groups: V+ (the full database, including COVID-19 vaccines reports) and V- (the same extraction without COVID-19 vaccine reports). IC0.25 was recomputed for the group V- and we compared the positive signal evolution in the two settings of selection (V+ and V- groups). RESULTS: The number of positive potential signals was significantly different in the groups V+ and V- for IC0.25. We observed that most of the "unexpected" PTs lost potential signal after the withdrawal of COVID-19 reports. On the contrary, the majority of 'expected' PTs had potential new signals after the withdrawal of COVID-19 reports. DISCUSSION: This study is one of the first to evaluate the effect of COVID-19 vaccines reporting on Automated Signal Detection of Pharmacovigilance. In this study, we observed that a wave of pharmacovigilance reporting can affect disproportionality estimators such as IC0.25 and then have an impact on automated signal detection; some signals disappear (almost with all PTs related to COVID-19 vaccines) and others appear (mostly with PTs not related to COVID-19 vaccines), illustrating the competition bias. CONCLUSION: We show that a health crisis involving a change in drug use can affect adverse drug reactions reporting and pharmacovigilance databases, leading to competition bias and a change in the disproportionality analyses. For health professionals who use quantitative disproportionality analysis, it is important not only to use the crude values of indicators but also the kind of PTs and the evolution of the signal over time (take into account major events such as crises).

Association between direct acting agents used for chronic hepatitis C virus infection and the occurrence of acute leukaemia - A disproportionality analysis.

BACKGROUND AND AIMS: A recent single-center study reported a significant increase in acute myeloid leukaemia (AML) cases, including mixed-phenotype acute leukaemia (MPAL), after exposure to direct acting agents (DAA). We investigated whether DAA use increased the risk of AML in patients with chronic hepatitis C virus (HCV) infection. METHODS: We conducted a disproportionality analysis of the WHO Pharmacovigilance database Vigibase up to 2020. Queries focused on all DAAs, subclasses, combinations or each DAA separately as well as interferon and ribavirin as negative controls. The primary outcome was AML. Secondary outcomes were AML without MPAL, MPAL, acute lymphoid leukemia (ALL) and acute leukemia (AL, high-level term encompassing AML, ALL, MPAL and unspecified acute leukemia [UAL]). The information component (IC0.25) and proportional reporting ratio (PRR0.25) were computed to assess a potential pharmacovigilance signal. RESULTS: We identified 49 notifications reporting any AL occurrence after anti-HCV treatments from June 1997 to December 2020: 23 (47%) involved a DAA, 24 (49%) interferon and 12 (24%) ribavirin. The DAAs sofosbuvir and ledipasvir were suspected in 74% (n = 17) and 39% (n = 9) of cases. The events reported were AML (n = 22), ALL (n = 11), AML and ALL (n = 1) and UAL (n = 15) and no MPAL. DAA, interferon or ribavirin were not significantly associated with AML, ALL or AL. CONCLUSION: This study did not find any association between DAA exposure and the occurrence of AML. Nevertheless, vigilance should remain, particularly for MPAL, which may not have been well captured in our study because of its rareness and high risk of misclassification.

Cross-reactivity among and between macrolides, lincosamides, and streptogramins: Study on the French pharmacovigilance database.

BACKGROUND: Hypersensitivity reactions (HSR) are reported for the macrolides, lincosamides, and streptogramins (MLS) antibiotic family. Data about cross-reactivity among and between MLS remain scarce or controversial. OBJECTIVES: The aim of this study was to provide an overview of hypersensitivity cross-reactions among MLSs based on data extracted from the French National Pharmacovigilance Database (FPVD). METHODS: Cases of HSR to MLSs reported between January 1985 and December 2019 were extracted from the FPVD using standardized MedDRA queries (SMQ). Cases including an allergological test involving multiple MLSs and giving at least one positive result were included. RESULTS: Of the 8394 cases reviewed, 149 were included. HSR mainly involved pristinamycin (n = 83; 53.2%) and spiramycin (n = 31; 19.9%). HSR to MLS was immediate in 54 cases and delayed in 94 cases. Skin tests represented the majority of the allergological tests performed (n = 728; 84.7%), followed by reintroduction tests (n = 79; 9.2%). Eighty-six cross-reactivities among MLS were identified in 62 cases (41.6%). All the 25 explorations performed for streptogramins showed cross-reactivities, but only 30/253 among macrolides (11.9%). Cross-reactivities between the three MLS were observed in 31/322 (9.6%) of the allergological explorations. CONCLUSION: This study highlights the possibility of cross-reactivity among and between MLSs. Dermatologists and allergologists managing patients with HSR to MLSs should be aware of a risk of cross-reactivity among the macrolides and between the different classes of MLS and to perform MLSs allergological testing before recommending an alternative antibiotic, especially in severe drug hypersensitivity from the MLS family.

Clinical spectrum and evolution of immune-checkpoint inhibitors toxicities over a decade-a worldwide perspective.

Background: Immune-checkpoint inhibitors (ICI) have revolutionized cancer treatment by harnessing the immune system but ICI can induce life-threatening immune-related adverse events (irAE) affecting every organ. Methods: We extracted irAE from VigiBase, the international pharmacovigilance database, first reported in 2008 until 01/2023 to characterize irAE reporting trends, clinical features, risk factors and outcomes. Findings: We distinguished 25 types of irAE (n = 50,347cases, single irAE/case in 84.9%). Cases mainly involved anti-PD1 (programmed-death-1) monotherapy (62.4%) in male (61.7%) aged 64.3 ± 12.6 years. After 2020 vs. prior to 2016, proportion of anti-CTLA4 (Cytotoxic-T-Lymphocyte-Antigen-4) monotherapy prescription almost vanished (1.6% vs. 47%, respectively) contrasting with increased use of anti-PDL1 (PD1-ligand) monotherapy (18% vs. 0.9%) and anti-CTLA4+anti-PD(L)1 combination (20% vs. 8.9%). Anti-LAG3 (Lymphocyte-Activation-Gene-3) prescription was limited (<1%) in the studied timeframe. After 2020, over 14 different cancer types were treated vs. almost exclusively melanoma and lung cancers before 2016. Overall, the most reported irAE were skin reactions (22.9%), pneumonitis (18.5%), enterocolitis (14.4%) and thyroiditis (12.1%). ICI-myotoxicities (6.6%) included myositis, myocarditis and myasthenia-gravis like syndrome and were the most overlapping irAE (up to 30% overlap, vs. <3% in general for other inter-irAE overlap). The top factors associated with specific irAE (odds-ratio>5) were presence of thymic cancer for ICI-myotoxicities or hepatitis; presence of melanoma for vitiligo, uveitis or sarcoidosis; specific types of ICI regimen (anti-LAG3 for meningitis, anti-CTLA4 for hypophysitis); and specific reporting regions (eastern Asia for cholangitis). Median time-to-onset ranged from 31 to 273 days, being shortest for myotoxicities and most delayed for skin-bullous auto-immune reactions. Overall fatality was highest for myocarditis = 27.6%, myasthenia = 23.1%, severe cutaneous adverse reactions (SCAR) = 22.1%, myositis = 21.9%, pneumonitis = 21%, and encephalomyelitis = 18%; generally decreasing after 2020, except for myasthenia and SCAR. When reported, irAE recurrence rate after rechallenge was 28.9% (n = 275/951). Interpretation: This up-to-date comprehensive worldwide pharmacovigilance study defines the spectrum, characteristics, and evolution of irAE reporting summarizing over a decade of use. Multiple risk factors and clinical peculiarities for specific irAE have been identified as signals to guide clinical practice and future research. Funding: Paul Gougis was supported by the academic program: "Contrats ED: Programme blanc Institut Curie PSL" for the conduct of his PhD. Baptiste Abbar was supported by "the Fondation ARC Pour le Rechercher Sur le Cancer". The RT2L research group (Institut Curie) was supported by the academic program "SHS INCa", Sanofi iTech award, and by Monoprix∗.