Polymyalgia rheumatica and giant cell arteritis following COVID-19 vaccination: Results from a nationwide survey.

We conducted a national in-depth analysis including pharmacovigilance reports and clinical study to assess the reporting rate (RR) and to determine the clinical profile of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) in COVID-19-vaccinated individuals. First, based on the French pharmacovigilance database, we estimated the RR of PMR and GCA cases in individuals aged over 50 who developed their initial symptoms within one month of receiving the BNT162b2 mRNA, mRNA-1273, ChAdOx1 nCoV-19, and Ad26.COV2.S vaccines. We then conducted a nationwide survey to gather clinical profiles, therapeutic management, and follow-up data from individuals registered in the pharmacovigilance study. A total of 70 854 684 COVID-19 vaccine doses were administered to 25 260 485 adults, among which, 179 cases of PMR (RR 7. 1 cases/1 000 000 persons) and 54 cases of GCA (RR 2. 1 cases/1 000 000 persons) have been reported. The nationwide survey allowed the characterization of 60 PMR and 35 GCA cases. Median time to the onset of first symptoms was 10 (range 2-30) and 7 (range 2-25) days for PMR and GCA, respectively. Phenotype, GCA-related ischemic complications and -large vessel vasculitis as well as therapeutic management and follow-up seemed similar according to the number of vaccine shots received and when compared to the literature data of unvaccinated population. Although rare, the short time between immunization and the onset of first symptoms of PMR and GCA suggests a temporal association. Physician should be aware of this potential vaccine-related phenomenon.

Management and outcomes of pregnant women with cardiovascular diseases in a cardio-obstetric team.

BACKGROUND: Cardiovascular diseases (CVDs) are currently the leading cause of maternal death in Western countries. Although multidisciplinary cardio-obstetric teams are recommended to improve the management of pregnant women with CVD, data supporting this approach are scarce. AIMS: To describe the characteristics and outcomes of pregnant patients with CVD managed within the cardio-obstetric programme of a tertiary centre. METHODS: We included every pregnant patient with history of CVD managed by our cardio-obstetric team between June 2017 and December 2019, and collected all major cardiovascular events (death, heart failure, acute coronary syndromes, stroke, endocarditis and aortic dissection) that occurred during pregnancy, peripartum and the following year. RESULTS: We included 209 consecutive pregnancies in 202 patients. CVDs were predominantly valvular heart diseases (37.8%), rhythm disorders (26.8%), and adult congenital heart diseases (22.5%). Altogether, 47.4% were classified modified World Health Organization (mWHO)>II, 66.5% had CARdiac disease in PREGnancy score (CARPREG II)≥2 and 80 pregnancies (38.3%) were delivered by caesarean section. Major cardiovascular events occurred in 16 pregnancies (7.7%, 95% confidence interval [CI] 4.5-12.2) during pregnancy and in three others (1.5%, 95% CI 0.3-4.1) during 1-year follow-up. Most events (63.1%) occurred in the 16.3% of patients with unknown CVD before pregnancy. CONCLUSIONS: The management of pregnant patients with CVD within a cardio-obstetric team seems encouraging as we found a relatively low rate of cardiovascular events compared to the high-risk profile of our population. However, most of the remaining events occurred in patients without cardiac monitoring before pregnancy.

Adverse drug effect in the context of drug shortage: the CIRUPT prospective study from the French pharmacovigilance network.

OBJECTIVES: Drug shortages are of increasing concern to worldwide public health. The consequences of drug shortages for patient safety have been little studied, especially from a pharmacovigilance point of view. In this context, the network of French pharmacovigilance centres conducted the CIRUPT study (Conséquences Iatrogènes des RUPTures de stock/iatrogenic consequences of drug shortages) based on a prospective campaign of adverse effects occurring in the context of drug shortage notifications. METHODS: All notifications involving a shortage drug submitted to the French pharmacovigilance centres between 1 January 2020 and 30 June 2021 were collected and registered in the French national pharmacovigilance database with the standardised high level term 'product supply and availability issues' and with predefined keywords in the narrative section. RESULTS: 224 cases were included, involving mainly adverse drug reactions (ADRs) (n=131/224, 59%) and medication errors (n=51/224, 23%); 29% of the cases were serious. The most represented classes of shortage drugs were: vaccines (n=78/224, 35%); drugs for acid-related disorders (H2-receptor antagonists) (n=27/224, 12%); antineoplastic agents (n=17/224, 8%); and antiepileptics (n=15/224, 7%). In 82% of cases, the involved shortage drug was the subject of information delivered to health professionals by the National Agency for the Safety of Medicines and Health Products. Drug shortages were associated with an ADR related to replacement drugs in 59% (n=131/224) of the cases, drug inefficacy in 18% (n=41/224), and/or an aggravation of the underlying disease in 11% (n=25/224). CONCLUSIONS: From a pharmacovigilance point of view, a large diversity of anatomical therapeutic classes is involved and the risk related to drug shortages is not limited to drugs registered on 'major therapeutic interest or essential drug' lists. Information from health agencies is not sufficient to avoid the risks, and further strategies should be developed.

Could psychostimulant drug use among university students be related to ADHD symptoms? A preliminary study.

We aimed to explore if psychostimulant use among student could be linked to attention deficit-hyperactivity disorder (ADHD) symptoms using a self-administered questionnaire sent by email to French students in 2021. Participants were asked about their psychostimulant use and the presence of ADHD symptoms using the Wender Utah Rating Scale and the Adult Self-Report Scale. Among the 4431 respondents, the prevalence of psychostimulant use was concerning and significantly associated with ADHD symptoms. This association could be related to undiagnosed ADHD or to psychobehavioral impairments induced by psychostimulant use underlining the need of ADHD screening and targeted prevention measures.

Experimental Models of Posterior Reversible Encephalopathy Syndrome: A Review From Pathophysiology to Therapeutic Targets.

Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiological entity characterized by nonspecific symptomatology (eg, headache, visual disturbances, encephalopathy, and seizures) and classically cortical and subcortical vasogenic edema predominantly affecting the parietooccipital region. PRES etiologies are usually dichotomized into toxic PRES (eg, antineoplastic drugs, illicit drugs) and clinical condition-associated PRES (eg, acute hypertension, dysimmune disorders). Although the pathophysiology of PRES remains elusive, 2 main pathogenic hypotheses have been suggested: cerebral hyperperfusion due to acute hypertension and cerebral hypoperfusion related to endothelial dysfunction. Research into the pathogenesis of PRES has emerged through the development of animal models in the last decade. The motivation for developing a suitable PRES model is 2-fold: to fill in knowledge gaps of the pathophysiological mechanisms involved, and to open new perspectives for clinical assessment of pharmacological targets to improve therapeutic management of PRES. All current models of PRES have a hypertensive background, on which other triggers (acute hypertension, inflammatory, drug toxicity) have been added to address specific facets of PRES (eg, seizures). The initial model consisted in inducing a reduced uterine perfusion pressure that mimics preeclampsia, a leading cause of PRES. More recently, a model of stroke-prone spontaneously hypertensive rats on high-salt diet, originally developed for hypertensive small vessel disease and vascular cognitive impairment, has been studied in PRES. This review aims to discuss, depending on the research objective, the benefits and limitations of current experimental approaches and thus to define the desirable characteristics for studying the pathophysiology of PRES and developing new therapies.

An overview of the use of psychoactive substances among students at the University of Lille during the COVID-19 health crisis: Results of the PETRA study.

OBJECTIVES: Students represent a population at risk for substance abuse. That risk may have been exacerbated by the COVID-19 pandemic. We aimed to describe substance abuse among students and to compare consumption according to the university field. METHODS: A self-administered questionnaire was sent by email to all students at the University of Lille, France, between March and July 2021. This anonymous questionnaire included questions about sociodemographic characteristics, university courses and the use of psychoactive substances (frequency, reasons, routes of administration) since the first university year. RESULTS: Among the 4431 students who responded (response rate 6.1%), eighty percent declared having used alcohol since the first university year, 34% cannabis, 15.4% benzodiazepines, 14.7% opioid drugs, 7.5% cocaine, 6.8% nitrous oxide and 6.5% MDMA. More than 20% of the users of cannabis, benzodiazepines, amphetamines and cocaine reported having already felt dependent. Recreational use was described by more than 10% of benzodiazepine or opioid drug users. Nitrous oxide use was significantly more frequent in the health and sport field (p < 0.001). Tobacco, benzodiazepine, cannabis and MDMA uses were significantly more frequent in the humanities and social sciences/art, language and literature fields (p < 0.001). CONCLUSION: Prevention measures focusing on alcohol, cannabis, illicit psychostimulants, nitrous oxide and prescription drugs are required in the student population.

Fosfomycin-induced agranulocytosis: a case report and review of the literature.

BACKGROUND: The intravenous form of fosfomycin, a bactericide antibiotic used to treat multiresistant bacterial infections is little prescribed. The most common reported adverse effects are hypokaliemia and hypernatremia. We describe a case of agranulocytosis, a rarely described side effect that may be fatal. CASE PRESENTATION: A 45 year-old woman was admitted to the intensive care unit for post-surgical meningitis following meningioma resection. Meropenem and vancomycin were first introduced. A DRESS-syndrom with meropenem was suspected. Neutropenia was diagnosed three days after the introduction of parenteral fosfomycin and agranulocytosis four days later. Eosinophilia was also observed. A bone marrow aspiration was performed showing a disappearance of the neutrophil granulocyte line and a significant eosinophilia. Meropenem was discontinued. Fosfomycin was maintained and filgrastim was added. As filgrastim had no effect, the relationship with fosfomycin was suspected, so it was then withheld. An increase of the neutrophil count was observed. Because of the complexity of the case, the unfavorable course of the illness and the urgent need for revision surgery, a rechallenge with fosfomycin was done followed by a decrease of the neutrophil count. CONCLUSION: This is the third paper reporting agranulocytosis induced by fosfomycin, and the first detailed description of a case. Based on chronological and semiological criteria and bibliographic data, the event was qualified as probable with the Naranjo adverse drug probability scale. Literature data is scarce. The summary of product characteristics mentions that only a few cases of transient neutropenia and agranulocytosis have been reported. An analysis of the FDA Adverse Event Reporting System Database highlighted a higher than expected frequency of agranulocytosis in patients treated with fosfomycin. Parenteral fosfomycin is often used in patients receiving other medications, so that it is rarely the only suspect. In our case, the results of the bone marrow aspiration, the sudden drop of the neutrophil count with concomitant eosinophilia and the absence of improvement despite the dose decrease, point towards an immuno-allergic mechanism. However, the overlap between the suspected DRESS induced by meropenem and the agranulocytosis do not allow to conclude with certainty on the causality. Awareness should be raised about this side effect.

Acute stroke in patients taking an oral anticoagulant: impact of clinical pharmacist's intervention on pharmacovigilance reporting.

INTRODUCTION: Ischemic or hemorrhagic stroke can occur to patients treated with oral anticoagulants (OAC), through lack of effectiveness or overdosing. OBJECTIVE: To evaluate the impact of clinical pharmacist's intervention on pharmacovigilance (PV) reporting for OAC-treated patients hospitalized for stroke. METHODS: Monocentric prospective study in which a clinical pharmacist's intervention was performed in a stroke unit, with a focus on patients treated by OAC prior admission. A PV report was made with all data collected for cases of stroke suspected to be related to OAC therapy. Data provided by pharmacist were compared with data initially available in the patient's electronic medical records. PV reports with pharmacist intervention were compared to those without. RESULTS: During the study period, 48 patients were included in the study: 43 (89.6%) ischemic strokes with an embolic or unknown etiology, four hemorrhage strokes (8.33%), and one medication error (2.08%). A clinical pharmacist intervention was performed for 19 patients (39.6%) and provided significant additional data in all of them (100%). The information was related to adherence to treatment for 17 cases (89.5%), OAC's initial prescription date for 11 cases (57.9%) and identifying event(s) that could have interfered with the efficacy of the OAC in five cases (26.3%). For patients with pharmacist intervention, PV reports were significantly more informative in terms of date's introduction of anticoagulant, adherence to treatment, reference to weight change or concomitant event. CONCLUSIONS: clinical pharmacist's intervention with patients taking oral anticoagulants and hospitalized for acute stroke contributes to collect high-quality data for pharmacovigilance reporting.

Pharmacovigilance signals from active surveillance of mRNA platform vaccines (tozinameran and elasomeran).

INTRODUCTION: Two severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines, tozinameran/BNT162b2 (Comirnaty®, Pfizer-BioNTech) and elasomeran/mRNA-1273 (Spikevax®, Moderna), were approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) at the end of 2020, less than a year after the start of the coronavirus disease 2019 (COVID-19) pandemic. In France, the health authorities have requested an intensive vaccination campaign, accompanied by a reinforced and active pharmacovigilance surveillance. This surveillance and analysis of real-life data, based on spontaneous reports received by the French Network of Regional PharmacoVigilance Centers (RFCRPV), has enabled to identify numerous pharmacovigilance signals. Some of them, such as myocarditis and heavy menstrual bleeding, have been confirmed as adverse effects of these vaccines. METHOD: We propose a descriptive review of the main pharmacovigilance signals identified by the RFCRPV concerning vaccines from the mRNA platform. RESULTS: Most pharmacovigilance signals were common to both mRNA vaccines: myocarditis, menstrual disorders, acquired haemophilia, Parsonage-Turner syndrome, rhizomelic pseudo-polyarthritis and hearing disorders. Other signals were more specific, such as arterial hypertension with tozinameran or delayed reaction site injection with elasomeran. CONCLUSION: This non-exhaustive review illustrates the experience of RFCRPV in identifying and monitoring pharmacovigilance signals related to mRNA vaccines in France during the COVID-19 pandemics, and the crucial role of pharmacological and clinical expertise in this area. It also highlights the predominant contribution of spontaneous reporting in the generation of pharmacovigilance signals, particularly for serious and rare adverse events not detected before marketing.

Role of spontaneous reporting in investigating the relationship between mRNA COVID-19 vaccines and myocarditis: The French perspective.

AIM OF THE STUDY: Post-mRNA coronavirus diseases 2019 (COVID-19) vaccines myocarditis emerged as a rare adverse effect, particularly in adolescents and young adults, and was labeled as such for both vaccines in the summer of 2021. This study aims to summarize the timeline and process of signal detection, substantiation, and quantification of myocarditis cases related to mRNA vaccines in France. METHODS: The intensive monitoring plan for COVID-19 vaccine safety was based on case-by-case analysis of all cases collected in the French spontaneous reporting database (Base nationale de pharmacovigilance, BNPV). Cases were evaluated by drug safety medical professionals and discussed at a national level for signal detection purposes. Reported cases were compared to the number of vaccine-exposed persons up to September 30th, 2021. Reporting rates (Rr) of myocarditis per 100,000 injections were calculated and stratified according to age, gender, and injection rank of BNT162b2 and mRNA-1273 vaccines. Poisson distribution was used to compute Rrs 95% Confidence Interval (95% CI). RESULTS: The case-by-case analysis detected a possible cluster of myocarditis in April 2021 (5 cases, 4 after the 2nd injection). In June 2021, the signal was substantiated with 12 cases (9 related to BNT162b2, and 3 to mRNA-1273). As of September 2021, almost 73 million BNT162b2 and 10 million mRNA-1273 doses had been injected. The Rr per 100,000 injections was 0.5 (0.5-0.6) for BNT162b2 and 1.1 (95% CI 0.9-1.3) for mRNA-1273. The difference among vaccines was more pronounced after the second injection, particularly in men aged 18-24 years (4.3 [3.4-5.5] for BNT162b2 vs. 13.9 [9.2-20.1] for mRNA-1273) and aged 25-29 years (1.9 [1.2-2.9] vs. 7.0 [3.4-12.9]). CONCLUSION: The study highlighted the role of the spontaneous reporting system in the detection, assessment, and quantification of myocarditis related to m-RNA vaccines. It suggested from September 2021 that mRNA-1273 was reasonably related to a higher risk of myocarditis than BNT162b2 in people under 30, particularly after the second injection.

Monitoring the safety of drugs and COVID-19 vaccines by the French Pharmacovigilance Centers during the pandemic: A win-win bet with Health Authorities!

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) pandemic virus was a "health crisis" and a significant burden also for the French pharmacovigilance system. It took its toll in 2 phases, the first being in early 2020 when very little was known, and during which the missions of the 31 Regional Pharmacovigilance Centers (RPVCs) from university hospitals were to detect adverse reactions of drugs used in the context of the disease. Whether as a possible aggravating role on COVID-19, or displaying a different safety profile during its course, or to assess safety of curative treatment, this phase preceded that of the arrival of dedicated vaccines. Then the RPVCs' missions were to detect, as early as possible, any new serious adverse effect leading to a potential signal that would modify the benefit/risk ratio of a vaccine and require the implementation of health safety measures. During these two distinct periods, signal detection remained the core business of the RPVCs. Each RPVC had to organize itself to handle an unprecedented surge of declarations and requests for advice, from health care professionals and patients alike. "Leading" RPVCs, who were in charge of monitoring vaccines, had to deal with an extraordinary workload (still going on to this date), to generate in real-time and on a weekly basis, a summary of all the adverse drug reaction (ADR) reports as well as an extended analysis of the different safety signals. The organization put in place at the beginning of the health crisis, adapted to the context of the vaccines, allowed to meet the challenge of real-time pharmacovigilance monitoring, and to identify many safety signals. Efficient "short-circuits exchanges" with the French Regional Pharmacovigilance Centers Network (RPVCN) were paramount to the National Agency for the Safety of Medicines and Health Products (ANSM) to develop an optimal collaborative partnership. The French RPVCN has shown at this occasion both agility and flexibility, swiftly adapting to vaccine- and media-related unrest, and demonstrated its effectiveness in the early detection of safety signals. This crisis also confirmed the superiority of manual/human signal detection over automated ones, as the most effective and powerful tool to date to rapidly detect and validate a new ADR and enable to elaborate rapid risk reduction measures. To maintain the performance of French RPVCN in signal detection and to monitor all drugs as they should, and as expected by our fellow citizens, a new funding model should be considered.

[Monitoring the safety of drugs and COVID-19 vaccines by the French Pharmacovigilance Centers during the pandemic: a win-win bet with Health Authorities!] / Pharmacovigilance des médicaments et des vaccins contre la COVID-19 durant la pandémie : comment le Réseau français des centres régionaux de pharmacovigilance a relevé le défi ?

The pandemic subsequent to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus resulted, for the French institutional pharmacovigilance, in a "health crisis" in 2 phases: the coronavirus disease 2019 - "COVID-19" phase during which the missions of the Regional Pharmacovigilance Centres (RPVC) were to detect a possible impact of drugs on this disease, as whether existed a possible aggravating role of certain drugs, or the safety profile of drugs used for the management of COVID-19 could evolve. The second phase followed the availability of COVID-19 vaccines, during which the RPVCs' missions were to detect as early as possible any new serious adverse effect, source of a potential signal that would modify the benefit/risk ratio of a vaccine and require the implementation of health safety measures. During these two periods, signal detection remained the core business of the RPVCs. The RPVCs had to organize themselves to handle an historical surge of declarations and requests for advice, whereas the RPVCs in charge of monitoring vaccines had to deal with an extraordinary dense activity over a long period of time, in order to produce in real time and on a weekly basis, a summary of all the declarations and an analysis of safety signals. The national organization put in place made it possible to meet the challenge of real-time pharmacovigilance monitoring of 4 vaccines with conditional marketing authorizations. Short-circuit efficient exchanges with the French Regional Pharmacovigilance Centres Network was paramount for the French National Agency for medicines and health products (Agence nationale de sécurité du médicament et des produits de santé) to develop an optimal collaborative partnership. The RPVC network has shown agility and flexibility, has been able to adapt swiftly and demonstrated its effectiveness in the early detection of safety signals. This crisis confirmed the superiority of manual/human signal detection as the most effective and powerful tool to date, to rapidly detect a new adverse drug reaction and enable to elaborate rapid measures of risk reduction. In order to maintain the performance of French RPVCs in signal detection and to monitor all drugs as they should and as expected by our fellow citizens, a new funding model correcting the inadequacy of RPVCs' expertise resources in relation to the volume of reports should be considered.

Detection of Drug-Related Problems through a Clinical Decision Support System Used by a Clinical Pharmacy Team.

Clinical decision support systems (CDSSs) are intended to detect drug-related problems in real time and might be of value in healthcare institutions with a clinical pharmacy team. The objective was to report the detection of drug-related problems through a CDSS used by an existing clinical pharmacy team over 22 months. It was a retrospective single-center study. A CDSS was integrated in the clinical pharmacy team in July 2019. The investigating clinical pharmacists evaluated the pharmaceutical relevance and physician acceptance rates for critical alerts (i.e., alerts for drug-related problems arising during on-call periods) and noncritical alerts (i.e., prevention alerts arising during the pharmacist's normal work day) from the CDSS. Of the 3612 alerts triggered, 1554 (43.0%) were critical, and 594 of these 1554 (38.2%) prompted a pharmacist intervention. Of the 2058 (57.0%) noncritical alerts, 475 of these 2058 (23.1%) prompted a pharmacist intervention. About two-thirds of the total pharmacist interventions (PI) were accepted by physicians; the proportion was 71.2% for critical alerts (i.e., 19 critical alerts per month vs. 12.5 noncritical alerts per month). Some alerts were pharmaceutically irrelevant-mainly due to poor performance by the CDSS. Our results suggest that a CDSS is a useful decision-support tool for a hospital pharmacist's clinical practice. It can help to prioritize drug-related problems by distinguishing critical and noncritical alerts. However, building an appropriate organizational structure around the CDSS is important for correct operation.

Obstetrical outcomes in cases of maternal heart disease with a risk of cardiac decompensation: A retrospective study since the establishment of a multidisciplinary consultation meeting "heart and pregnancy".

BACKGROUND: Pregnant women with chronic heart failure (CHF) are at increased risk for cardiac complications. However, the frequency of obstetrical and neonatal complications in pregnant women with CHF remains unclear. OBJECTIVE: The objective of our study was to describe obstetrical and neonatal outcomes in pregnant with CHF. METHOD: This single-center retrospective cohort study involves pregnant women with a CHF who delivered at Jeanne de Flandre, the Lille's university hospital, from 2017 to 2021. The frequency of obstetrical, neonatal, and cardiovascular complications was collected. RESULT: During this period, we identified 26 pregnant women with a CHF. The main cardiac diseases responsible for CHF were cardiomyopathies (53.8%) and congenital heart disease (46.2%). Acute heart failure occurred in 30.8% of the cases and mainly concerned patients with no follow-up of their heart disease. The main obstetrical complications were fetal growth restriction (38.5%) and premature rupture of fetal membranes (19.2%). The 26 pregnancies comprised 25 live births and 1 stillbirth. Newborn infants were delivered via cesarean in 69.2%. Of the live births, 60% were preterm at a median gestational age of 36 (34-38) weeks. CONCLUSION: Pregnant women with CHF had a higher risk for obstetrical and neonatal outcomes.