Clinical characteristics with inflammation profiling of Long-COVID and association with one-year recovery following hospitalisation in the UK: a prospective observational study (preprint)

Background There are currently no effective pharmacological or non-pharmacological interventions for Long-COVID. To identify potential therapeutic targets, we focussed on previously described four recovery clusters five months after hospital discharge, their underlying inflammatory profiles and relationship with clinical outcomes at one year. Methods PHOSP-COVID is a prospective longitudinal cohort study, recruiting adults hospitalised with COVID-19 across the UK. Recovery was assessed using patient reported outcomes measures (PROMs), physical performance, and organ function at five-months and one-year after hospital discharge. Hierarchical logistic regression modelling was performed for patient-perceived recovery at one-year. Cluster analysis was performed using clustering large applications (CLARA) k-medoids approach using clinical outcomes at five-months. Inflammatory protein profiling from plasma at the five-month visit was performed. Findings 2320 participants have been assessed at five months after discharge and 807 participants have completed both five-month and one-year visits. Of these, 35.6% were female, mean age 58.7 (SD 12.5) years, and 27.8% received invasive mechanical ventilation (IMV). The proportion of patients reporting full recovery was unchanged between five months 501/165 (25.6%) and one year 232/804 (28.9%). Factors associated with being less likely to report full recovery at one year were: female sex OR 0.68 (95% CI 0.46-0.99), obesity OR 0.50 (95%CI 0.34-0.74) and IMV OR 0.42 (95%CI 0.23-0.76). Cluster analysis (n=1636) corroborated the previously reported four clusters: very severe, severe, moderate/cognitive, mild relating to the severity of physical, mental health and cognitive impairments at five months in a larger sample. There was elevation of inflammatory mediators of tissue damage and repair in both the very severe and the moderate/cognitive clusters compared to the mild cluster including interleukin-6 which was elevated in both comparisons. Overall, there was a substantial deficit in median (IQR) EQ5D-5L utility index from pre-COVID (retrospective assessment) 0.88 (0.74-1.00), five months 0.74 (0.60-0.88) to one year: 0.74 (0.59-0.88), with minimal improvements across all outcome measures at one-year after discharge in the whole cohort and within each of the four clusters. Interpretation The sequelae of a hospital admission with COVID-19 remain substantial one year after discharge across a range of health domains with the minority in our cohort feeling fully recovered. Patient perceived health-related quality of life remains reduced at one year compared to pre-hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials.

ASCOT ADAPT study of COVID-19 therapeutics in hospitalised patients: an international multicentre adaptive platform trial (preprint)

Background SARS-CoV-2 infection is associated with a significant risk of hospitalisation, death, and prolonged impact on quality of life. Evaluation of new treatment options and optimising therapeutic management of people hospitalised with SARS-CoV-2 infection remains essential, but rapid changes in pandemic conditions and potential therapies have limited the utility of traditional approaches to randomised controlled trials.Methods ASCOT ADAPT is an international, investigator-initiated, adaptive platform, randomised controlled trial of therapeutics for non-critically ill patients hospitalised with COVID-19. The study design is open label and pragmatic. Potential participants are hospitalised adults with PCR confirmed, symptomatic, SARS-CoV-2 infection, within 14 days of symptom onset. Domains include antiviral, antibody and anticoagulant interventions, with a composite primary outcome of 28-day mortality or progression to intensive-care level respiratory or haemodynamic support. Initial interventions include intravenous nafamostat and variable dose anticoagulation. A range of secondary endpoints, and substudies for specific domains and interventions are outlined.Discussion This paper presents the trial protocol and management structure, including international governance, remote site monitoring and biobanking activities, and provides commentary on ethical and pragmatic considerations in establishing the ASCOT ADAPT trial under pandemic conditions.

Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY disease (CLARITY): Statistical analysis plan for a randomised controlled Bayesian adaptive sample size trial (preprint)

The CLARITY trial (Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY Disease) investigates the effectiveness of angiotensin receptor blockers in addition to standard care compared to placebo (in Indian sites) with standard care in reducing the duration and severity of lung failure in patients with COVID-19. The CLARITY trial is a multi-centre, randomised controlled Bayesian adaptive trial with regular planned analyses where pre-specified decision rules will be assessed to determine whether the trial should be stopped due to sufficient evidence of treatment effectiveness or futility. Here we describe the statistical analysis plan for the trial, and define the pre-specified decision rules, including those that could lead to the trial being halted. The primary outcome is clinical status on a 7-point ordinal scale adapted from the WHO Clinical Progression scale assessed at Day 14. The primary analysis will follow the intention-to-treat principle. A Bayesian adaptive trial design was selected because there is considerable uncertainty about the extent of potential benefit of this treatment. Trial registrationClinicalTrials.gov, NCT04394117. Registered on 19 May 2020. https://clinicaltrials.gov/ct2/show/NCT04394117 Clinical Trial Registry of India: CTRI/2020/07/026831 Version and revisionsVersion 1.0. No revisions.

Pandemic impacts on healthcare utilisation: a systematic review (preprint)

Objectives: To determine the extent and nature of changes in utilisation of healthcare services during COVID-19 pandemic. Design: Systematic review Eligibility: Eligible studies compared utilisation of services during COVID-19 pandemic to at least one comparable period in prior years. Services included visits, admissions, diagnostics, and therapeutics. Studies were excluded if from single-centres or studied only COVID-19 patients. Data sources: PubMed, Embase, Cochrane COVID-19 Study Register, and pre-prints were searched, without language restrictions, until August 10, using detailed searches with key concepts including COVID-19, health services and impact. Data analysis: Risk of bias was assessed by adapting ROBINS-I and Cochrane Effective Practice and Organization of Care tool. Results were analysed using descriptive statistics, graphical figures, and narrative synthesis. Outcome measures: Primary outcome was change in service utilisation between pre-pandemic and pandemic periods. Secondary outcome was the change in proportions of users of healthcare services with milder or more severe illness (e.g. triage scores). Results: 3097 unique references were identified, and 81 studies across 20 countries included, reporting on >11 million services pre-pandemic and 6.9 million during pandemic. For the primary outcome, there were 143 estimates of changes, with a median 37% reduction in services overall (interquartile range -51% to -20%), comprising median reductions for visits of 42%(-53% to -32%), admissions, 28%(-40% to -17%), diagnostics, 31%(-53% to -24%), and for therapeutics, 30%(-57% to -19%). Among 35 studies reporting secondary outcomes, there were 60 estimates, with 27(45%) reporting larger reductions in utilisation among people with a milder spectrum of illness, and 33 (55%) reporting no change. Conclusions: Healthcare utilisation decreased by about a third during the pandemic, with considerable variation, and with greater reductions among people with less severe illness. While addressing unmet need remains a priority, studies of health impacts of reductions may help health-systems prioritise higher-value care in the post-pandemic recovery. Funding, Study registration: No funding was required. PROSPERO: CRD42020203729

It’s Alright, Ma, It’s Life and Life Only: Are Colleges and Universities Legally Obligated during the Coronavirus Pandemic to Exempt High-Risk Faculty from In-Person Teaching Requirements? (preprint)

Because there is no law specifically addressing colleges’ and universities’ legal obligations to allow faculty for health reasons to opt for online, rather than in-person, teaching during the coronavirus pandemic, colleges, universities, and their faculties generally seem to be proceeding on the assumption that any such legal obligations are no more than minimal. This Article challenges that widespread assumption and argues that colleges and universities in fact have very substantial legal obligations in this regard. We focus on the group of faculty whom we believe colleges and universities have the clearest legal obligation to protect -- those who, according to the Centers for Disease Control and Prevention, appear to be most vulnerable to getting seriously ill or even dying if they contract the coronavirus. In the language of the CDC, our focus is faculty members “at increased risk of severe illness from COVID-19,” which, according to the CDC, means anyone who has reached age 65 or who has one of various “medical conditions,” including cancer, chronic kidney disease, diabetes, hypertension, pregnancy, and more. We argue that four separate legal sources are best understood as requiring colleges and universities to exempt high-risk faculty from any in-person teaching requirement. Two of the four sources are federal statutes that qualify as major statements of national policy – the Americans with Disabilities Act and the Age Discrimination in Employment Act. The other two sources are important state-law doctrines with strong support in the American Law Institute’s most recent restatement of the law of torts – protection from intentional infliction of physical harm, and protection from intentional infliction of emotional distress. We hope our arguments will provide college and university leaders with a perspective that will prompt them to recognize the great importance of adopting an exemption policy that at a minimum covers high-risk faculty. Perhaps they would adopt such a policy simply to avoid possible legal liability. Ideally, however, they would do so at least in part out of a recognition that a college or university policy at odds with legal sources as weighty as the four discussed speaks very poorly for their institution.

Outcome of hospitalisation for COVID-19 in patients with Interstitial Lung Disease: An international multicentre study. (preprint)

Rationale: The impact of COVID-19 on patients with Interstitial Lung Disease (ILD) has not been established. Objectives: To assess outcomes following COVID-19 in patients with ILD versus those without in a contemporaneous age, sex and comorbidity matched population. Methods: An international multicentre audit of patients with a prior diagnosis of ILD admitted to hospital with COVID-19 between 1 March and 1 May 2020 was undertaken and compared with patients, without ILD obtained from the ISARIC 4C cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished IPF from non-IPF ILD and used lung function to determine the greatest risks of death. Measurements and Main Results: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity-score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching ILD patients with COVID-19 had higher mortality (HR 1.60, Confidence Intervals 1.17-2.18 p=0.003) compared with age, sex and co-morbidity matched controls without ILD. Patients with a Forced Vital Capacity (FVC) of <80% had an increased risk of death versus patients with FVC [≥]80% (HR 1.72, 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR 1.98, 1.13-3.46). Conclusions: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.

Physical interventions to interrupt or reduce the spread of respiratory viruses. Part 1 - Face masks, eye protection and person distancing: systematic review and meta-analysis (preprint)

Abstract OBJECTIVE: To examine the effectiveness of eye protection, face masks, or person distancing on interrupting or reducing the spread of respiratory viruses. DESIGN: Update of a Cochrane review that included a meta-analysis of observational studies during the SARS outbreak of 2003. DATA SOURCES: Eligible trials from the previous review; search of Cochrane Central Register of Controlled Trials, PubMed, Embase and CINAHL from October 2010 up to 1 April 2020; and forward and backward citation analysis. DATA SELECTION: Randomised and cluster-randomised trials of people of any age, testing the use of eye protection, face masks, or person distancing against standard practice, or a similar physical barrier. Outcomes included any acute respiratory illness and its related consequences. DATA EXTRACTION AND ANALYSIS: Six authors independently assessed risk of bias using the Cochrane tool and extracted data. We used a generalised inverse variance method for pooling using a random-effects model and reported results with risk ratios and 95% Confidence Intervals (CI). RESULTS: We included 15 randomised trials investigating the effect of masks (14 trials) in healthcare workers and the general population and of quarantine (1 trial). We found no trials testing eye protection. Compared to no masks there was no reduction of influenza-like illness (ILI) cases (Risk Ratio 0.93, 95%CI 0.83 to 1.05) or influenza (Risk Ratio 0.84, 95%CI 0.61-1.17) for masks in the general population, nor in healthcare workers (Risk Ratio 0.37, 95%CI 0.05 to 2.50). There was no difference between surgical masks and N95 respirators: for ILI (Risk Ratio 0.83, 95%CI 0.63 to 1.08), for influenza (Risk Ratio 1.02, 95%CI 0.73 to 1.43). Harms were poorly reported and limited to discomfort with lower compliance. The only trial testing quarantining workers with household ILI contacts found a reduction in ILI cases, but increased risk of quarantined workers contracting influenza. All trials were conducted during seasonal ILI activity. CONCLUSIONS: Most included trials had poor design, reporting and sparse events. There was insufficient evidence to provide a recommendation on the use of facial barriers without other measures. We found insufficient evidence for a difference between surgical masks and N95 respirators and limited evidence to support effectiveness of quarantine. Based on observational evidence from the previous SARS epidemic included in the previous version of our Cochrane review we recommend the use of masks combined with other measures.