Management of pharmacovigilance during the COVID-19 pandemic crisis by the safety department of an academic sponsor: Lessons learnt and challenges from the EU DisCoVeRy clinical trial.

The current COVID-19 pandemic was an exceptional health situation, including for drug use. As there was no known effective drug for COVID-19 at the beginning of the pandemic, different drug candidates were proposed. In this article, we present the challenges for an academic Safety Department to manage the global safety of a European trial during the pandemic. The National Institute for Health and Medical Research (Inserm) conducted a European multicenter, open-label, randomized, controlled trial involving three repurposed and one-in development drugs (lopinavir/ritonavir, IFN-ß1a, hydroxychloroquine, and remdesivir) in adults hospitalized with COVID-19. From 25 March 2020 to 29 May 2020, the Inserm Safety Department had to manage 585 Serious Adverse Events (SAEs) initial notification and 396 follow-up reports. The Inserm Safety Department's staff was mobilized to manage these SAEs and to report Expedited safety reports to the competent authorities within the legal timeframes. More than 500 queries were sent to the investigators due to a lack of or incoherent information on SAE forms. At the same time, the investigators were overwhelmed by the management of patients suffering from COVID-19 infection. These particular conditions of missing data and lack of accurate description of adverse events made evaluation of the SAEs very difficult, particularly the assessment of the causal role of each investigational medicinal product. In parallel, working difficulties were accentuated by the national lockdown, frequent IT tool dysfunctions, delayed implementation of monitoring and the absence of automatic alerts for SAE form modification. Although COVID-19 is a confounding factor per se, the delay in and quality of SAE form completion and the real-time medical analysis by the Inserm Safety Department were major issues in the quick identification of potential safety signals. To conduct a high-quality clinical trial and ensure patient safety, all stakeholders must take their roles and responsibilities.

Respiratory recovery trajectories after severe-to-critical COVID-19: a 1-year prospective multicentre study.

BACKGROUND: Survivors of severe-to-critical coronavirus disease 2019 (COVID-19) may have functional impairment, radiological sequelae and persistent symptoms requiring prolonged follow-up. This pragmatic study aimed to describe their clinical follow-up and determine their respiratory recovery trajectories, and the factors that could influence them and their health-related quality of life. METHODS: Adults hospitalised for severe-to-critical COVID-19 were evaluated at 3 months and up to 12 months post-hospital discharge in this prospective, multicentre, cohort study. RESULTS: Among 485 enrolled participants, 293 (60%) were reassessed at 6 months and 163 (35%) at 12 months; 89 (51%) and 47 (27%) of the 173 participants initially managed with standard oxygen were reassessed at 6 and 12 months, respectively. At 3 months, 34%, 70% and 56% of the participants had a restrictive lung defect, impaired diffusing capacity of the lung for carbon monoxide (D LCO) and significant radiological sequelae, respectively. During extended follow-up, both D LCO and forced vital capacity percentage predicted increased by means of +4 points at 6 months and +6 points at 12 months. Sex, body mass index, chronic respiratory disease, immunosuppression, pneumonia extent or corticosteroid use during acute COVID-19 and prolonged invasive mechanical ventilation (IMV) were associated with D LCO at 3 months, but not its trajectory thereafter. Among 475 (98%) patients with at least one chest computed tomography scan during follow-up, 196 (41%) had significant sequelae on their last images. CONCLUSIONS: Although pulmonary function and radiological abnormalities improved up to 1 year post-acute COVID-19, high percentages of severe-to-critical disease survivors, including a notable proportion of those managed with standard oxygen, had significant lung sequelae and residual symptoms justifying prolonged follow-up.

Thyrotropin Levels in Patients with Coronavirus Disease 2019: Assessment during Hospitalization and in the Medium Term after Discharge.

BACKGROUND: The objectives of this study were (1) to compare TSH levels between inpatients with critical versus non-critical coronavirus disease 19 (COVID-19), and (2) to describe the status of TSH levels three months after hospitalization. METHODS: We collected data on adult patients hospitalized with COVID-19 at Amiens University Hospital. We compared TSH levels between inpatients with critical (intensive care unit admission and/or death) versus non-critical COVID-19. Thereafter, survivors were invited to return for a three-month post-discharge visit where thyroid function tests were performed, regardless of the availability of TSH measurement during hospitalization. RESULTS: Among 448 inpatients with COVID-19, TSH assay data during hospitalization were available for 139 patients without prior thyroid disease. Patients with critical and non-critical forms of COVID-19 did not differ significantly with regard to the median (interquartile range) TSH level (0.96 (0.68-1.71) vs. 1.27 mIU/L (0.75-1.79), p = 0.40). Abnormal TSH level was encountered in 17 patients (12.2%); most of them had subclinical thyroid disease. TSH assay data at the three-month post-discharge visit were available for 151 patients without prior thyroid disease. Only seven of them (4.6%) had abnormal TSH levels. Median TSH level at the post-discharge visit was significantly higher than median TSH level during hospitalization. CONCLUSIONS: Our findings suggest that COVID-19 is associated with a transient suppression of TSH in a minority of patients regardless of the clinical form. The higher TSH levels three months after COVID-19 might suggest recovery from non-thyroidal illness syndrome.

No Impact of Corticosteroid Use During the Acute Phase on Persistent Symptoms Post-COVID-19.

Persistent COVID-19 symptoms may be related to residual inflammation, but no preventive treatment has been evaluated. This study aimed to analyze, in a prospective cohort, whether corticosteroid use in the acute phase of COVID-19 in hospitalized patients may reduce the risk of persistent COVID-19 symptoms. A total of 306 discharged patients, including 112 (36.6%) from the ICU, completed a structured face-to-face assessment 4 months after admission. Of these, 193 patients (63.1%) had at least one persistent symptom, mostly dyspnea (38.9%) and asthenia (37.6%). One-hundred and four patients have received corticosteroids. In multivariable adjusted regression analysis, corticosteroid use was not associated with the presence of at least one symptom (OR=1.00, 95% CI: 0.58-1.71, p=0.99) or with the number of persistent symptoms (p=0.74). Corticosteroid use remained ineffective when analyzing the ICU subpopulation separately. Our study suggests that corticosteroid use had no impact on persistent symptoms after COVID-19 in discharged patients.

Clinical and Imaging Determinants of Neurocognitive Disorders in Post-Acute COVID-19 Patients with Cognitive Complaints.

BACKGROUND: Neurocognitive disorders (NCDs) are a part of the post-acute coronavirus disease (COVID-19) syndrome. No study has specifically evaluated NCDs in post-acute COVID-19 patients with cognitive complaints or their MRI determinants. OBJECTIVE: To characterize NCDs in post-acute COVID-19 patients with cognitive complaints. The secondary objectives were to assess their clinical and MRI determinants. METHODS: We included 46 patients with a post-acute COVID-19 cognitive complaint referred to the Amiens University Hospital Memory Center. They underwent a neuropsychological assessment and 36 had cerebral MRI. The G3 overall summary score was the sum of the mean z scores for the executive function, language, and action speed domains. Neuropsychological profiles were compared in a general linear model. Clinical determinants were analyzed by stepwise linear regression. White matter hyperintensities (WMH) masks were analyzed using parcel-based WMH symptom mapping to identify the locations of WMHs associated with cognitive performance. RESULTS: Repeated ANOVA showed a group effect (p = 0.0001) due to overall lower performance for patients and a domain effect (p = 0.0001) due to a lower (p = 0.007) action speed score. The G3 overall summary score was significantly associated with solely the requirement for oxygen (R2 = 0.319, p = 0.031). WHMs were associated with the G3 overall summary score in the following structures, all right-sided (p < 0.01): superior frontal region, postcentral region, cingulum, cortico-spinal tract, inferior longitudinal fasciculus, internal capsule, and posterior segment of the arcuate fasciculus. CONCLUSION: Post-acute COVID-19 patients with cognitive complaints had NCD, with prominent action slowing, significantly associated with the acute phase oxygen requirement and a right-sided WMH structure pattern.

Perspectives post-COVID-19 : le point de vue des pneumologues Post-COVID-19 perspectives: Pulmonologists’ point of view

Plus de 5 millions de personnes en France ont présenté une infection par le SARS-CoV-2. Lors des précédentes épidémies de coronavirus (SARS-CoV, Mers-CoV), les patients ont développé des séquelles pulmonaires avec une dyspnée, une diminution de la capacité de diffusion du monoxyde de carbone et/ou des lésions de fibrose. Le but de cette revue était d’évaluer les séquelles respiratoires et de faire une synthèse des principaux symptômes respiratoires après une infection au COVID-19 et de leurs étiologies. Les quatre principales causes de dyspnée sont les séquelles respiratoires, le déconditionnement, l’hyperventilation et les causes classiques de dyspnée. Les principales séquelles respiratoires étaient l’altération de la capacité de diffusion du monoxyde de carbone et le schéma de fibrose. La prévalence de ces séquelles respiratoires est actuellement inconnue.

Perspectives post-COVID-19 : le point de vue des pneumologues

Résumé Plus de 5 millions de personnes en France ont présenté une infection par le SARS-CoV-2. Lors des précédentes épidémies de coronavirus (SARS-CoV, Mers-CoV), les patients ont développé des séquelles pulmonaires avec une dyspnée, une diminution de la capacité de diffusion du monoxyde de carbone et/ou des lésions de fibrose. Le but de cette revue était d’évaluer les séquelles respiratoires et de faire une synthèse des principaux symptômes respiratoires après une infection au COVID-19 et de leurs étiologies. Les quatre principales causes de dyspnée sont les séquelles respiratoires, le déconditionnement, l’hyperventilation et les causes classiques de dyspnée. Les principales séquelles respiratoires étaient l’altération de la capacité de diffusion du monoxyde de carbone et le schéma de fibrose. La prévalence de ces séquelles respiratoires est actuellement inconnue. Summary More than 5 millions of people in France have presented a SARS-CoV-2 infection. In the previous coronavirus epidemics (SARS-CoV, Mers-CoV), patients have developed pulmonary sequelae with dyspnoea, DLCO decrease and/or fibrosis lesions. The purpose of this review was to evaluate the respiratory sequelae and to do a summary of the main respiratory symptoms after a COVID-19 infection and their aetiologies. The four main causes of dyspnoea are respiratory sequelae, deconditioning, hyperventilation and classical causes of dyspnoea. The main respiratory sequelae were DLCO alteration and fibrosis pattern. Actually, the prevalence of these respiratory sequelae is unknown.

Number of initial symptoms is more related to long COVID-19 than acute severity of infection: a prospective cohort of hospitalized patients.

OBJECTIVES: Post-COVID-19 symptoms experienced by many survivors have a further devastating effect. This study aimed to analyze the risk factors associated with long COVID-19 in a prospective cohort of hospitalized patients including those requiring intensive care unit (ICU) transfer, taking into account objective measures of COVID-19 severity. METHODS: Hospitalized patients with confirmed COVID-19 were enrolled. A structured follow-up visit was performed 4 months after hospital admission. Multivariable adjusted regression models were used to analyse the association between parameters at the acute phase and persistent symptoms. RESULTS: A follow-up visit was performed in 316 patients including 115 (36.4%) discharged from the ICU. Mean age was 64.1 years, and 201 patients (58.3%) were men. Female sex (odds ratio [OR], 1.94; 95% confidence interval [CI], 1.17-3.22; P =.01), hypertension (OR, 2.01; 95% CI, 1.22-3.31; P <.01), and the number of initial symptoms (NIS) (OR, 1.35; 95% CI, 1.17-1.54; P <.001) were significantly associated with long COVID-19. Number of persistent symptoms was significantly associated with NIS (adjusted incidence rate ratio [aIRR], 1.16; 95% CI, 1.11-1.22; P <.001), female sex (aIRR, 1.56; 95% CI 1.29-1.87; P <.001), hypertension (aIRR, 1.23; 95% CI, 1.02-1.50; P =.03), and length of stay in hospital (aIRR, 1.01; 95% CI, 1.005-1.017; P <.001). CONCLUSION: Our study suggested that female sex, hypertension, and NIS had a significant impact on persistent symptoms in hospitalized patients in contrast to severity of acute COVID-19 infection.

European Respiratory Society statement on long COVID follow-up.

Patients diagnosed with coronavirus disease 2019 (COVID-19) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection frequently experience symptom burden post-acute infection or post-hospitalisation. We aimed to identify optimal strategies for follow-up care that may positively impact the patient's quality of life (QoL). A European Respiratory Society (ERS) Task Force convened and prioritised eight clinical questions. A targeted search of the literature defined the timeline of "long COVID" as 1-6 months post-infection and identified clinical evidence in the follow-up of patients. Studies meeting the inclusion criteria report an association of characteristics of acute infection with persistent symptoms, thromboembolic events in the follow-up period, and evaluations of pulmonary physiology and imaging. Importantly, this statement reviews QoL consequences, symptom burden, disability and home care follow-up. Overall, the evidence for follow-up care for patients with long COVID is limited.

Case Reports: Bronchial Mucosal Vasculature Is Also Involved in the Acute Vascular Distress Syndrome of COVID-19.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which targets the pulmonary vasculature is supposed to induce an intrapulmonary right to left shunt with an increased pulmonary blood flow. We report here what may be, to the best of our knowledge, the first videoendoscopic descriptions of an hypervascularization of the bronchial mucosa in two patients hospitalized for coronavirus disease 2019 (COVID-19) pneumonia. Cases Presentation: Two patients, 27- and 37-year-old, were addressed to our Pneumology department for suspicion of COVID-19 pneumonia. Their symptoms (fever, dry cough, and dyspnoea), associated to pulmonary ground glass opacities on thoracic CT, were highly suggestive of a COVID-19 disease despite repeated negative pharyngeal swabs RT-PCR. In both patients, bronchoscopy examination using white light was unremarkable but NBI bronchoscopy revealed a diffuse hypervascularization of the mucosa from the trachea to the sub-segmental bronchi, associated with dilated submucosal vessels. RT-PCR performed in bronchoalveolar lavage (BAL) confirmed the presence of Sars-CoV-2. Conclusions: These two case reports highlight the crucial importance of the vascular component of the viral disease. We suggest that such bronchial hypervascularization with dilated vessels contributes, at least in part, to the intrapulmonary right to left shunt that characterizes the COVID-19 related Acute Vascular Distress Syndrome (AVDS). The presence of diffuse bronchial hypervascularization in the context of COVID-19 pandemic should prompt the search for Sars-CoV-2 in BAL samples.

Dissociation between the clinical course and chest imaging in severe COVID-19 pneumonia: A series of five cases.

BACKGROUND: Although an RT-PCR test is the "gold standard" tool for diagnosing an infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), chest imaging can be used to support a diagnosis of coronavirus disease 2019 (COVID-19) - albeit with fairly low specificity. However, if the chest imaging findings do not faithfully reflect the patient's clinical course, one can question the rationale for relying on these imaging data in the diagnosis of COVID-19. AIMS: To compare clinical courses with changes over time in chest imaging findings among patients admitted to an ICU for severe COVID-19 pneumonia. METHODS: We retrospectively reviewed the medical charts of all adult patients admitted to our intensive care unit (ICU) between March 1, 2020, and April 15, 2020, for a severe COVID-19 lung infection and who had a positive RT-PCR test. Changes in clinical, laboratory and radiological variables were compared, and patients with discordant changes over time (e.g. a clinical improvement with stable or worse radiological findings) were analyzed further. RESULTS: Of the 46 included patients, 5 showed an improvement in their clinical status but not in their chest imaging findings. On admission to the ICU, three of the five were mechanically ventilated and the two others received high-flow oxygen therapy or a non-rebreather mask. Even though the five patients' radiological findings worsened or remained stable, the mean ± standard deviation partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2:FiO2) ratio increased significantly in all cases (from 113.2 ± 59.7 mmHg at admission to 259.8 ± 59.7 mmHg at a follow-up evaluation; p=0.043). INTERPRETATION: Our results suggest that in cases of clinical improvement with worsened or stable chest imaging variables, the PaO2:FiO2 ratio might be a good marker of the resolution of COVID-19-specific pulmonary vascular insult.

Characteristics and outcomes of COVID-19 in hospitalized patients with and without diabetes.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a rapidly progressing pandemic, with four million confirmed cases and 280 000 deaths at the time of writing. Some studies have suggested that diabetes is associated with a greater risk of developing severe forms of COVID-19. The primary objective of the present study was to compare the clinical features and outcomes in hospitalized COVID-19 patients with vs without diabetes. METHODS: All consecutive adult patients admitted to Amiens University Hospital (Amiens, France) with confirmed COVID-19 up until April 21st, 2020, were included. The composite primary endpoint comprised admission to the intensive care unit (ICU) and death. Both components were also analysed separately in a logistic regression analysis and a Cox proportional hazards model. RESULTS: A total of 433 patients (median age: 72; 238 (55%) men; diabetes: 115 (26.6%)) were included. Most of the deaths occurred in non-ICU units and among older adults. Multivariate analyses showed that diabetes was associated neither with the primary endpoint (odds ratio (OR): 1.12; 95% confidence interval (CI): 0.66-1.90) nor with mortality (hazard ratio: 0.73; 95%CI: 0.40-1.34) but was associated with ICU admission (OR: 2.06; 95%CI 1.09-3.92, P = .027) and a longer length of hospital stay. Age was negatively associated with ICU admission and positively associated with death. CONCLUSIONS: Diabetes was prevalent in a quarter of the patients hospitalized with COVID-19; it was associated with a greater risk of ICU admission but not with a significant elevation in mortality. Further investigation of the relationship between COVID-19 severity and diabetes is warranted.

Pure SARS-CoV-2 related AVDS (Acute Vascular Distress Syndrome).

BACKGROUND: SARS-CoV-2 virus which targets the pulmonary vasculature is supposed to induce an intrapulmonary right to left shunt with an increased pulmonary blood flow. Such vascular injury is difficult to observe because it is hidden by the concomitant lung injury. We report here what may be, to the best of our knowledge, the first case of a pure Covid-19 related Acute Vascular Distress Syndrome (AVDS). CASE PRESENTATION: A 43-year-old physician, tested positive for Covid-19, was addressed to the emergency unit for severe dyspnoea and dizziness. Explorations were non informative with only a doubt regarding a sub-segmental pulmonary embolism (no ground-glass lesions or consolidations related to Covid-19 disease). Dyspnoea persisted despite anticoagulation therapy and normal pulmonary function tests. Contrast-enhanced transthoracic echocardiography was performed which revealed a moderate late right-to-left shunt. CONCLUSIONS: This case report highlights the crucial importance of the vascular component of the viral disease. The intrapulmonary shunt induced by Covid-19 which remains unrecognized because generally hidden by the concomitant lung injury, can persist for a long time. Contrast-enhanced transthoracic echocardiography is the most appropriate test to propose in case of persistent dyspnoea in Covid-19 patients.

The association between body mass index class and coronavirus disease 2019 outcomes.

BACKGROUND/OBJECTIVES: A growing body of data suggests that obesity influences coronavirus disease 2019 (COVID-19). Our study's primary objective was to assess the association between body mass index (BMI) categories and critical forms of COVID-19. SUBJECTS/METHODS: Data on consecutive adult patients hospitalized with laboratory-confirmed COVID-19 at Amiens University Hospital (Amiens, France) were extracted retrospectively. The association between BMI categories and the composite primary endpoint (admission to the intensive care unit or death) was probed in a logistic regression analysis. RESULTS: In total, 433 patients were included, and BMI data were available for 329: 20 were underweight (6.1%), 95 have a normal weight (28.9%), 90 were overweight (27.4%), and 124 were obese (37.7%). The BMI category was associated with the primary endpoint in the fully adjusted model; the odds ratio (OR) [95% confidence interval (CI)] for overweight and obesity were respectively 1.58 [0.77-3.24] and 2.58 [1.28-5.31]. The ORs [95% CI] for ICU admission were similar for overweight (3.16 [1.29-8.06]) and obesity (3.05 [1.25-7.82]) in the fully adjusted model. The unadjusted ORs for death were similar in all BMI categories while obesity only was associated with higher risk after adjustment. CONCLUSIONS: Our results suggest that overweight (and not only obesity) is associated with ICU admission, but overweight is not associated with death.

Abnormal laboratory findings and plasma concentration monitoring of lopinavir and ritonavir in COVID-19.

It is not known whether the adverse events (AEs) associated with the administration of lopinavir and ritonavir (LPV/r) in the treatment of COVID-19 are concentration-dependent. In a retrospective study of 65 patients treated with LPV/r and therapeutic drug monitoring (TDM) for severe forms of COVID-19 (median age: 67; males: 41 [63.1%]), 33 (50.8%) displayed a grade ≥2 increase in plasma levels of hepatobiliary markers, lipase and/or triglycerides. A causal relationship between LPV/r and the AE was suspected in 9 of the 65 patients (13.8%). At 400 mg b.i.d., the plasma trough concentrations of LPV/r were high and showed marked interindividual variability (median [interquartile range]: 16,600 [11,430-20,842] ng/ml for lopinavir and 501 [247-891] ng/ml for ritonavir). The trough lopinavir concentration was negatively correlated with body mass index, while the trough ritonavir concentration was positively correlated with age and negatively correlated with prothrombin activity. However, the occurrence of abnormal laboratory values was not associated with higher trough plasma concentrations of LPV/r. Further studies will be needed to determine the value of TDM in LPV/r-treated patients with COVID-19.

Association between renin-angiotensin system inhibitors and COVID-19 complications.

AIMS: To describe the characteristics of patients hospitalized with COVID-19 (including their long-term at-home medication use), and compare them with regard to the course of the disease. To assess the association between renin-angiotensin system inhibitors (RASIs) and disease progression and critical outcomes. METHODS AND RESULTS: All consecutive hospitalized patients with laboratory-confirmed COVID-19 in a university hospital in Amiens (France) were included in this study. The primary composite endpoint was admission to an intensive care unit (ICU) or death before ICU admission. Univariable and multivariable logistic regression models were used to identify factors associated with the composite endpoint. Between 28 February 2020 and 30 March 2020, a total of 499 local patients tested positive for SARS-CoV-2. Of these, 231 were not hospitalized {males 33%; median [interquartile range (IQR)] age: 44 (32-54)}, and 268 were hospitalized [males 58%; median (IQR) age: 73 (61-84)]. A total of 116 patients met the primary endpoint: 47 died before ICU admission, and 69 were admitted to the ICU. Patients meeting the primary endpoint were more likely than patients not meeting the primary endpoint to have coronary heart disease and to have been taking RASIs; however, the two subsets of patients did not differ with regard to median age. After adjustment for other associated variables, the risk of meeting the composite endpoint was 1.73 times higher (odds ratio 1.73, 95% confidence interval 1.02-2.93) in patients treated at baseline with a RASI than in patients not treated with this drug class. This association was confirmed when the analysis was restricted to patients treated with antihypertensive agents. CONCLUSIONS: We highlighted a potential safety signal for RASIs, the long-term use of which was independently associated with a higher risk of severe COVID-19 and a poor outcome. Due to the widespread use of this important drug class, formal proof based on clinical trials is needed to better understand the association between RASIs and complications of COVID-19.