Impact of the COVID-19 pandemic on antiviral drug development for other community-acquired respiratory viruses' infections.

The coronavirus disease 2019 (COVID-19) pandemic indirectly resulted in missed therapeutic opportunities for many diseases. Here we focus on community-acquired respiratory viruses other than severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) [respiratory syncytial virus, parainfluenza and influenza A], and highlight the pandemics impact on clinical trials to develop novel therapies for other severe respiratory viral infections. We retrospectively reviewed inclusion rates within respiratory antiviral clinical trials in comparison with all other clinical trials in our clinical investigations center, before and during the COVID-19 pandemic. As opposed to the remaining clinical trials developed within our unit, respiratory antiviral trials inclusion rates did not recover after the initial recruitment decrease observed across all trials during the first pandemic wave. These results were discussed in the context of non-COVID-19 respiratory viral infection rates within our center, showing a general decline in seasonal respiratory viruses spread since the COVID-19 pandemic onset. Virus epidemiology changes upon the wide SARS-CoV-2 expansion as well as the lifestyle changes globally adopted to prevent SARS-CoV-2 transmission could have therefore contributed to the negative impact of the COVID-19 pandemic on antiviral drug development. Our study highlights the peculiarity of respiratory antiviral drug development during the COVID-19 pandemic era and describes potential explanations for such drug development halting.

Bronchiolitis obliterans syndrome following SARS-CoV-2 infection in an allogeneic hematopoietic stem cell recipient.

Peripheral allogeneic hematopoietic stem cell transplant recipients are the most vulnerable patients to community-acquired respiratory viruses such as respiratory syncytial virus, influenza virus, or others. These patients are likely to develop severe acute viral infections; community-acquired respiratory viruses have also been identified as triggers of bronchiolitis obliterans (BO). BO is a manifestation of pulmonary graft-versus-host disease, most often leading to irreversible ventilatory impairment. To date, there are no data on whether Severe acute respiratory syndrome â€‹coronavirus 2 (SARS-CoV-2) could be a trigger for BO. Here, we report the first report of a case of bronchiolitis obliterans syndrome following SARS-CoV-2 infection occurring 10 months after allogeneic hematopoietic stem cell transplant with a flare of underlying extra thoracic graft-versus-host disease. This observation provides a new perspective and should be of particular interest to clinicians, suggesting the need for close monitoring of pulmonary function test (PFTs) after SARS-CoV-2 infection. The mechanisms leading to bronchiolitis obliterans syndrome after SARS-CoV-2 infection require further investigation.

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.

Severe COVID-19 is associated with hyperactivation of the alternative complement pathway

Background Severe coronavirus disease 2019 (COVID-19) is characterized by impaired type I interferon activity and a state of hyperinflammation leading to acute respiratory distress syndrome. The complement system has recently emerged as a key player in triggering and maintaining the inflammatory state, but the role of this molecular cascade in severe COVID-19 is still poorly characterized. Objective We aimed at assessing the contribution of complement pathways at both protein and transcriptomic levels. Methods To this end, we systematically assessed RNA levels of 28 complement genes in circulating whole blood of COVID-19 patients and healthy controls, including genes of the alternative pathway, for which data remain scarce. Results We found differential expression of genes involved in the complement system, yet with various expression patterns: while patients displaying moderate disease had elevated expression of classical pathway genes, severe disease was associated with increased lectin and alternative pathway activation, which correlated with inflammation and coagulopathy markers. Additionally, properdin, a pivotal positive regulator of the alternative pathway, showed high RNA expression but was found at low protein concentrations in severe and critical patients, suggesting its deposition at the sites of complement activation. Notably, low properdin levels were significantly associated with the use of mechanical ventilation (AUC = 0.82, p = 0.002). Conclusion This study sheds light on the role of the alternative pathway in severe COVID-19 and provides additional rationale for the testing of drugs inhibiting the alternative pathway of the complement system. We show that activation of the alternative complement pathway characterizes COVID-19 severity. Specifically, low properdin levels were associated with use of mechanical ventilation. This work provides a rationale for the specific inhibition of the alternative complement pathway.

Profiles and outcomes in patients with COVID-19 admitted to wards of a French oncohematological hospital: A clustering approach.

OBJECTIVES: Although some prognostic factors for COVID-19 were consistently identified across the studies, differences were found for other factors that could be due to the characteristics of the study populations and the variables incorporated into the statistical model. We aimed to a priori identify specific patient profiles and then assess their association with the outcomes in COVID-19 patients with respiratory symptoms admitted specifically to hospital wards. METHODS: We conducted a retrospective single-center study from February 2020 to April 2020. A non-supervised cluster analysis was first used to detect patient profiles based on characteristics at admission of 220 consecutive patients admitted to our institution. Then, we assessed the prognostic value using Cox regression analyses to predict survival. RESULTS: Three clusters were identified, with 47 patients in cluster 1, 87 in cluster 2, and 86 in cluster 3; the presentation of the patients differed among the clusters. Cluster 1 mostly included sexagenarian patients with active malignancies who were admitted early after the onset of COVID-19. Cluster 2 included the oldest patients, who were generally overweight and had hypertension and renal insufficiency, while cluster 3 included the youngest patients, who had gastrointestinal symptoms and delayed admission. Sixty-day survival rates were 74.3%, 50.6% and 96.5% in clusters 1, 2, and 3, respectively. This was confirmed by the multivariable Cox analyses that showed the prognostic value of these patterns. CONCLUSION: The cluster approach seems appropriate and pragmatic for the early identification of patient profiles that could help physicians segregate patients according to their prognosis.

[An example of Clinical Investigations Center reorganization during the COVID-19 pandemic French national lockdown]. / Un exemple de réorganisation dans le fonctionnement d'un Centre d'investigations cliniques en période de confinement national suite à la pandémie COVID-19.

BACKGROUND: The Clinical Investigations Center of Saint-Louis Hospital (CIC-1427) is a structure dedicated to clinical trials and mainly early phase trials (first-in-man administration, phase 1 and 2). These trials are conducted in a French Regional Health Agency (ARS) authorized structure. In March 2020, faced to the global COVID-19 pandemic and the French national lockdown measures, the CIC-1427 had to rapidly adapt its operating procedures to ensure the safety of both patients and staff. STUDY OBJECTIVE: Ensuring optimal management of patients included in early phase clinical trials, while respecting the good clinical and professional practices (GCP/GPP) of the CICs protocol sponsors' requirements, patients' safety and clinical research multidisciplinary staff safety (nurses, caregivers' assistants (AS), clinical research assistants (CRA), clinical trial coordinators (CTC), project leaders, health executive and investigating physicians), in the context of the health crisis related to COVID-19. METHODS AND RESULTS: Due to their activity, requiring on-site presence, each staff member of the CIC-1427 clinical research team had to adapt their daily activity to the constraints of the health crisis. New specific procedures were quickly developed to deal with the pandemic. Most of the on-site medical visits were replaced by virtual consults with biological assessments in the local laboratories. "Remote monitoring" replaced on-site monitoring visits. Treatments were sent to each patient's home via couriers after agreement of the CPPs of each protocol (Committee for the Protection of Persons). The essential visits were maintained on site thanks to the unfailing involvement of our clinical care team, with implementation of a specific sanitary protocol. CONCLUSION: The involvement of our entire multidisciplinary research team ensured that each patient was able to benefit from a personalized follow-up and to continue the treatment on-trial. The newly introduced procedures also allowed collection of a maximum of safety and efficacy data for clinical trial sponsors while complying with good regulatory practices. This set of procedures developed during the first epidemic wave, fundamentally helped setting the frame for a better coping during the subsequent pandemic waves.