Clinical Associations and Trajectory of “Long COVID”

Background Persistent symptoms after acute COVID-19 are being increasingly reported. To date, little is known about the cause, clinical associations, and trajectory of “Long COVID”. Methods Participants of an outpatient clinical trial of Peginterferon-Lambda as treatment for uncomplicated SARS-CoV-2 infection were invited to long term follow-up visits 4, 7, and 10 months after initial COVID-19 diagnosis. Ongoing symptoms and functional impairment measures (work productivity and activity index (WPAI), NIH toolbox smell test, 6-minute walk test) were assessed and blood samples obtained. “Long COVID” was defined as presence of 2 or more typical symptoms (fatigue, hyposmia/hypogeusia, dyspnea, cough, palpitations, memory problems, joint pain) at follow up. Associations between baseline characteristics, initial COVID-19 clinical course, and presence of “Long COVID” during follow-up were assessed using generalized estimating equations accounting for repeated measurements within individuals. Results Eighty-seven participants returned for at least one follow-up visit. At four months, 29 (34.1%) had “Long COVID”;19 (24.7%) met criteria at 7 months and 18 (23.4%) at 10 months (Figure 1). Presence of “Long COVID” symptoms did not correlate significantly with functional impairment measures. Female gender (OR 3.01, 95% CI 1.37-6.61) and having gastrointestinal symptoms during acute COVID-19 illness (OR 5.37, 95% CI 1.02-28.18) were associated with “Long COVID” during follow-up (Figure 2). No significant associations with baseline immunologic signatures were observed. Figure 1. Alluvial plot of long term follow-up participants showing outcomes of symptoms at each visit. Figure 2. Generalized Estimating Equations Model showing associations with “Long COVID” (presence of 2+ symptoms) at month 4, 7, and 10 following acute infection using unstructured correlation matrix. Conclusion “Long COVID” was prevalent in this outpatient trial cohort and had low rates of resolution over 10 months of follow up. Female sex and gastrointestinal symptoms during acute illness were associated with “Long COVID”. Identifying modifiable risk factors associated with the development of persistent symptoms following SARS-CoV-2 infection remains a critical need. Disclosures All Authors: No reported disclosures

Inflammatory but not respiratory symptoms are associated with ongoing upper airway viral shedding in outpatients with uncomplicated COVID-19.

Although the vast majority of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections are uncomplicated, our understanding of predictors of symptom resolution and viral shedding cessation remains limited. We characterized symptom trajectories and oropharyngeal viral shedding among 120 outpatients with uncomplicated Coronavirus Disease of 2019 (COVID-19) enrolled in a clinical trial of Peginterferon Lambda, which demonstrated no clinical or virologic benefit compared with placebo. In the combined trial cohort, objective fever was uncommon, inflammatory symptoms (myalgias, fatigue) peaked at 4 to 5 days postsymptom onset, and cough peaked at 9 days. The median time to symptom resolution from earliest symptom onset was 17 days (95% confidence interval 14-18). SARS-CoV-2 IgG seropositivity at enrollment was associated with hastened resolution of viral shedding (hazard ratio 1.80, 95% confidence interval 1.05-3.1, P = 0.03), but not with symptom resolution. Inflammatory symptoms were associated with a significantly greater odds of oropharyngeal SARS-CoV-2 RNA detection; respiratory symptoms were not. These findings have important implications for COVID-19 screening approaches and trial design.

Peginterferon Lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized placebo-controlled trial.

Type III interferons have been touted as promising therapeutics in outpatients with coronavirus disease 2019 (COVID-19). We conducted a randomized, single-blind, placebo-controlled trial (NCT04331899) in 120 outpatients with mild to moderate COVID-19 to determine whether a single, 180 mcg subcutaneous dose of Peginterferon Lambda-1a (Lambda) within 72 hours of diagnosis could shorten the duration of viral shedding (primary endpoint) or symptoms (secondary endpoint). In both the 60 patients receiving Lambda and 60 receiving placebo, the median time to cessation of viral shedding was 7 days (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.56 to 1.19). Symptoms resolved in 8 and 9 days in Lambda and placebo, respectively, and symptom duration did not differ significantly between groups (HR 0.94; 95% CI 0.64 to 1.39). Both Lambda and placebo were well-tolerated, though liver transaminase elevations were more common in the Lambda vs. placebo arm (15/60 vs 5/60; p = 0.027). In this study, a single dose of subcutaneous Peginterferon Lambda-1a neither shortened the duration of SARS-CoV-2 viral shedding nor improved symptoms in outpatients with uncomplicated COVID-19.

Clinical trials in a COVID-19 pandemic: Shared infrastructure for continuous learning in a rapidly changing landscape.

BACKGROUND: Clinical trials, conducted efficiently and with the utmost integrity, are a key component in identifying effective vaccines, therapies, and other interventions urgently needed to solve the COVID-19 crisis. Yet launching and implementing trials with the rigor necessary to produce convincing results is a complicated and time-consuming process. Balancing rigor and efficiency involves relying on designs that employ flexible features to respond to a fast-changing landscape, measuring valid endpoints that result in translational actions and disseminating findings in a timely manner. We describe the challenges involved in creating infrastructure with potential utility for shared learning. METHODS: We have established a shared infrastructure that borrows strength across multiple trials. The infrastructure includes an endpoint registry to aid in selecting appropriate endpoints, a registry to facilitate establishing a Data & Safety Monitoring Board, common data collection instruments, a COVID-19 dedicated design and analysis team, and a pragmatic platform protocol, among other elements. RESULTS: The authors have relied on the shared infrastructure for six clinical trials for which they serve as the Data Coordinating Center and have a design and analysis team comprising 15 members who are dedicated to COVID-19. The authors established a pragmatic platform to simultaneously investigate multiple treatments for the outpatient with adaptive features to add or drop treatment arms. CONCLUSION: The shared infrastructure provides appealing opportunities to evaluate disease in a more robust manner with fewer resources and is especially valued during a pandemic where efficiency in time and resources is crucial. The most important element of the shared infrastructure is the pragmatic platform. While it may be the most challenging of the elements to establish, it may provide the greatest benefit to both patients and researchers.