In the context of the COVID-19 health emergency, several drugs are currently being tested or used for the treatment of COVID-19 patients. While there are some data to evaluate the efficacy of drugs (from clinical trials), there are no specific data on the risks associated with the drugs prescribed in the treatment of covid-19. In the VigiDrugs COVID-19 project, we will review and characterize main adverse effects with the drugs used and/or approved in the treatment of COVID-19 patients in France. To assess the risks with COVID-19 drugs, we will conduct a weekly analysis of the WHO global pharmacovigilance database VigiBase®. VigiBase® contained more than 22 million spontaneously generated adverse drug reactions, from 136 countries and covering more than 90% of the world’s population. All reports with drugs of interest (for example remdesivir, dexamethasone, tocilizumab, lopinavir/ritonavir…) will be screened to exclude those not related to a COVID-19 indication. We will select and evaluate the most frequent and the most clinically relevant adverse drug reactions reported in VigiBase. In order to complete our pharmacovigilance review, we will perform disproportionality analyses to compare reports of adverse drug reaction of interest in COVID-19 patients exposed to one drug with those reported in COVID-19 patients exposed to other drugs used for COVD-19. This approach has already made it possible to identify several risks with the COVID-19 drugs used in France. In May 2020, we alerted about the potential risk of psychiatric disorders (including suicide) with the use of hydroxychloroquine for COVID-19 (publication in Drug Safety 2020). In July 2020, we published the first descriptions of hepatic disorders with remdesivir (Clin Gastroenterol Hepatol 2020). We want to improve our approach by using best statistical approaches that will take into account confounding factors and by speeding up analyses. Several other risks need to be assessed with these drugs. For example, risks of kidney failure or rhythm disturbances with remdesivir need to be explored.

The number of people with dementia worldwide is expected to rise to 150 million in 2050. Prevention of dementia is a major public health challenge and a research priority has been the identification of potentially modifiable risk factors. Among them, hypertension (HTN) in midlife is associated with higher risk of cognitive decline and dementia in later life but data on late-life HTN and cognitive health remain inconsistent. HTN may be protective on dementia risk among the oldest old, possibly due to higher brain perfusion. Whether high blood pressure (BP) prior to midlife affects risk of late-onset dementia is unclear. In addition, young patients with early-onset HTN are paradoxically less likely to receive aggressive BP treatment. Studies with a life-course approach are needed to characterize the effects of HTN and BP lowering strategies, which optimal timing to optimize cognitive health is still under investigation. Identifying optimal BP levels in patients with HTN to preserve brain health is an added challenge. Independently of cognitive impairment and dementia prevention, controversies exist regarding HTN treatment guidelines for optimal BP targets, including in older adults where American guidelines recommend a systolic BP (SBP) goal < 130 mmHg and European guidelines 130-139 mmHg. These controversies might influence primary prevention of a large group of HTN-related diseases, including cognitive impairment and dementia. The question of whether BP lowering strategies could benefit cognitive health has been tested in randomized controlled trials (RCT) with inconclusive results. Although the SPRINT-MIND trial has suggested that intensive (SBP goal < 120 mmHg) compared to standard treatment (SBP goal < 140 mmHg), could significantly reduce the risk of mild cognitive impairment (MCI), a recent meta-analysis of RCT was unable to identify an optimal BP range for dementia prevention. Further research is also needed to assess whether age-specific BP thresholds and treatment effects differ across population subgroups and comorbidities, and which individuals could benefit most from BP lowering. Higher midlife SBP could be associated with greater risk of dementia in women, compared to men. Similar to dementia, HTN disproportionally affects Black individuals, whose higher cumulative BP levels could contribute to racial differences in later-life cognitive decline. To date, target SBP guidelines have not addressed the potential that Black patients may have greater morbidity from HTN, especially with regard to cognitive outcomes. ApoE ε4 genotype may potentiate cognitive decline in individuals with HTN; whether ApoE ε4 carriers would benefit more for cognitive health from an intensive BP control is unknown. As patients with high enough cardiovascular risk were excluded from SPRINT-MIND, whether individualized SBP targets in patients with cardiometabolic comorbidities impacts cognitive health needs further investigation. Finally, clinical guidelines on HTN recommend considering frailty in individual HTN management; however, to what extent BP lowering treatment benefits very frail patients remains to be determined. Our research aims to (1) investigate the association of age-specific SBP targets across the life-course with domain-specific cognitive trajectories and incident dementia in treated hypertensive patients and (2) to investigate whether these associations differ by (a) sex, race, ApoE ε4 genotype and (b) diabetes, chronic kidney disease, cardiovascular disease, and frailty. We will use data from 3 longitudinal cohort studies, each one focusing on specific life stages (CARDIA: early to midlife, Whitehall II Study: mid to latelife, Health ABC: latelife) and covering the entire adult lifespan. Our project will fill an important gap in the literature and be innovative with an age-specific and life-course approach, inclusion of mid-to-latelife transition often underestimated, and a personalized medicine approach.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARScov2) is a new coronavirus discovered in December 2019 in Wuhan, China and currently responsible of a worldwide outbreak and the death of more than 25,000 patients in France. The more severe form of COVID-19 disease induces a pneumonia with profound hypoxemia which may require invasive mechanical ventilation. It is estimated that 5% of COVID-19 patients are admitted to the Intensive Care Unit (ICU) for management. Hospital mortality in patients who develop severe acute respiratory distress syndrome (ARDS) ranges between 40% and 60%. The exact pathophysiology of the disease and the lesions of the lungs are poorly understood and characterised. Indeed, pathological data of SARScov2-induced ARDS are very limited. A better knowledge of the cause death by SARScov2-induced acute respiratory failure is fundamental to guide clinicians in the management of critically-ill COVID-19 patients and help developing new therapeutic strategies. Our purpose is to investigate the pathological findings of COVID-19 patients who died from ARDS in the ICU by doing post-mortem lung biopsies. Forty-six French ICUs participate to this study with the aim to perform 200 lung biopsies in 100 patients over a 12-month period. This cohort will be the largest pathological database of COVID-19 patients who developed ARDS. In accordance with the French law, this study has been approved and registered by the French Agency of Biomedicine and the French Ministry of Education and Research (#PFS 20-016). Two transcutaneous lung biopsies per patient will be performed using a 14G needle and anatomical landmarks (1 anterior biopsy and 1 posterior biopsy). All biopsies will be referred to the Department of Pathology of Nantes university hospital and analysed by two pathologists specialized in lung tissue. The primary objective is to describe and characterize the lesions of the lung induced by the SARScov2 infection. The secondary objectives are to correlate the pathological findings with the patients’ demographics, the treatments administered during the ICU stay, the ventilator settings, to document the percentage of co-infections and their types, compare the radiographic findings (Chest X-ray and CT-scan of the chest) with the pathological findings, to compare the pathological findings of early deaths (1 week). These pathological findings will undoubtedly help to better understand the pathophysiology of SARScov2 pneumonia and pave the way to the development of new therapeutic strategies.