Researching COVID to enhance recovery (RECOVER) adult study protocol: Rationale, objectives and design (preprint)

Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. Methods: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged [≥]18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms. Discussion: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.

Point-of-Care Ultrasound (POCUS) Predicts Clinical Outcomes in Patients with COVID-19 (preprint)

Introduction Point-of-care ultrasound (POCUS) may detect the cardiopulmonary manifestations of COVID-19 and expediently predict patient outcomes. Methods We conducted a prospective cohort study at four medical centers from 3/2020-1/2021 to evaluate POCUS findings and clinical outcomes with COVID-19. Our inclusion criteria included adult patients hospitalized for COVID-19 who received cardiac or lung POCUS with a 12-zone protocol. Images were interpreted by two reviewers blinded to clinical outcomes. Our primary outcome was ICU admission incidence. Secondary outcomes included intubation and supplemental oxygen usage. Results N=160 patients (N=201 scans) were included. Scans were collected a median 23 hours (IQR:7-80) from emergency department triage. Triage POCUS findings associated with ICU admission included B-lines (OR 4.41 [95% CI:1.71-14.30]; p<0.01) or consolidation (OR 2.49 [95% CI:1.35-4.86]; p<0.01). B-lines were associated with intubation (OR 3.10 [95% CI:1.15-10.27]; p=0.02) and supplemental oxygen usage (OR 3.74 [95% CI:1.63-8.63; p<0.01). Consolidations present on triage were associated with the need for oxygen at discharge (OR 2.16 [95% CI: 1.01-4.70]; p=0.047). A normal lung triage scan was protective for ICU admission (OR 0.28 [95% CI:0.09-0.75; p<0.01) or need for supplemental oxygen during the hospitalization (OR 0.26 [95% CI:0.11-0.61]; p<0.01). Triage cardiac POCUS scans were not associated with any outcomes. Discussion Lung POCUS findings detected early in the hospitalization may provide expedient risk stratification for important COVID-19 clinical outcomes, including ICU admission, intubation, or need for oxygen on discharge. A normal admission scan appears protective against adverse outcomes, which may aid in triage decisions of patients.

Point of Care Ultrasonography Findings and Clinical Outcomes in Hospitalized Patients with SARS-CoV-2 (preprint)

Introduction: Point-of-care ultrasound (POCUS) can detect the cardiopulmonary manifestations of COVID-19 and may predict patient outcomes in an expedient and cost-effective manner.Methods: We conducted a prospective cohort study at four medical centers from 3/2020 to 9/2020 to evaluate the relationship between POCUS findings and clinical outcomes with COVID-19. Our inclusion criteria included adult patients hospitalized for COVID-19 who received lung ultrasound (LUS) examinations at the bedside with a 12-zone protocol. All images were interpreted by at least two reviewers who were blinded to clinical outcomes.Results: N=99 patients met inclusion criteria. The median time from ED triage to LUS was 0.9 days (IQR: 0.1-2.9). LUS was rarely normal (11% of patients), with B-lines (90%) and subpleural consolidations (62%) representing the most prevalent findings. Findings associated with ICU admission included anterior B-lines (OR: 3.1 [95% CI: 1.2-9.7]), anterior consolidations (OR: 3.1 [95% CI: 1.1-9.9]) and lateral consolidations (OR: 4.1 [95% CI: 1.3-15.5]), while a normal scan was strongly protective against ICU admission (OR 0.08 [95% CI: 0.00-0.68]). LUS findings remained stable over a period of 28 days from symptom onset.Discussion: Anterior and/or lateral lung involvement on POCUS may portend a three to four-fold risk of critical illness among COVID-19 patients. The location, rather than the absolute appearance of POCUS findings, may be important harbingers of severe disease. POCUS findings did not change over a 28-day scanning period, suggesting that their detection at any time point may be clinically important.Funding Statement: None to declareDeclaration of Interests: None to declare. Ethics Approval Statement: This study was approved by the Institutional Review Boards of Stanford University and the University of California, San Francisco. A waiver of consent was obtained by both institutions.

Interobserver Agreement of Lung Ultrasound Findings of COVID-19 (preprint)

Background: Lung ultrasound (LUS) has received considerable interest in the clinical evaluation of patients with COVID-19. Previously described LUS manifestations for COVID-19 include B-lines, consolidations, and pleural thickening. The interrater reliability (IRR) of these findings for COVID-19 is unknown.Methods: This study was conducted at conducted at two academic medical centers between 03/2020-06/2020. Nine physicians (hospitalists: n=4; emergency medicine: n=5) independently evaluated n=20 LUS scans (n=180 independent observations) collected from RT-PCR confirmed COVID-19 patients. These studies were randomly selected from an image database consisting of COVID-19 patients evaluated in the emergency department with portable ultrasound devices. Physicians were blinded to any patient information or previous LUS interpretation. Kappa values (κ) were used to calculate IRR.Findings: There was substantial IRR on the following items: normal LUS scan (κ=0.79 [95% CI: 0.72-0.87]), presence of B-lines (κ=0.79 [95% CI: 0.72-0.87]), >=3 B-lines observed (κ=0.72 [95% CI: 0.64-0.79]). Moderate IRR was observed for the presence of any consolidation (κ=0.57 [95% CI: 0.50-0.64]), subpleural consolidation (κ=0.49 [95% CI: 0.42-0.56]), and presence of effusion (κ=0.49 [95% CI: 0.41-0.56]). Fair IRR was observed for pleural thickening (κ=0.23 [95% CI: 0.15-0.30]).Interpretation: Many LUS manifestations for COVID-19 appear to have moderate to substantial IRR across providers from multiple specialties utilizing differing portable devices.Trial Registration: This analysis was conducted as part of an ongoing study investigating the role of POCUS for COVID-19 that is being conducted at four medical centers in the United States (Clinicaltrials.gov Registration: NCT04384055). Funding Statement: None.Declaration of Interests: Andre Kumar, MD, MEd is a paid consultant for Vave Health, which manufactures one of the ultrasound devices used in this study. His consultant duties include providing feedback on product development. The other authors do not have any items to disclose.Ethics Approval Statement: This study has received institutional review board (IRB) approval at all participating sites.

Interobserver Agreement of Lung Ultrasound Findings of COVID-19 (preprint)

Background: Lung ultrasound (LUS) may be used in the diagnostic evaluation of patients with COVID-19. An abnormal LUS is associated with increased risk for ICU admission in COVID-19. Previously described LUS manifestations for COVID-19 include B-lines, consolidations, and pleural thickening. The interrater reliability (IRR) of these findings for COVID-19 is unknown. Research Question: What is the interrater reliability of lung ultrasound findings in patients with RT-PCR confirmed COVID-19? Study Design and Methods: This study was conducted at conducted at two academic medical centers between 03/2020-06/2020. Nine physicians (hospitalists: n=4; emergency medicine: n=5) independently evaluated n=20 LUS scans (n=180 independent observations) collected from RT-PCR confirmed COVID-19 patients. These studies were randomly selected from an image database consisting of COVID-19 patients evaluated in the emergency department with portable ultrasound devices. Physicians were blinded to any patient information or previous LUS interpretation. Kappa values were used to calculate IRR. Results: There was substantial IRR on the following items: normal LUS scan (K=0.79 [95% CI: 0.72-0.87]), presence of B-lines (K=0.79 [95% CI: 0.72-0.87]), >=3 B-lines observed (K=0.72 [95% CI: 0.64-0.79]). Moderate IRR was observed for the presence of any consolidation (K=0.57 [95% CI: 0.50-0.64]), subpleural consolidation (K=0.49 [95% CI: 0.42-0.56]), and presence of effusion (K=0.49 [95% CI: 0.41-0.56]). Fair IRR was observed for pleural thickening (K=0.23 [95% CI: 0.15-0.30]). Interpretation: Many LUS manifestations for COVID-19 appear to have moderate to substantial IRR across providers from multiple specialties utilizing differing portable devices. The most reliable LUS findings with COVID-19 may include the presence/count of B-lines or determining if a scan is normal. Clinical protocols for LUS with COVID-19 may require additional observers for the confirmation of less reliable findings such as consolidations.