Human Epidemiology and RespOnse to SARS-CoV-2 (HEROS): Objectives, Design and Enrollment Results of a 12-City Remote Observational Surveillance Study of Households with Children using Direct-to-Participant Methods (preprint)

The Human Epidemiology and Response to SARS-CoV-2 (HEROS) is a prospective multi-city 6-month incidence study which was conducted from May 2020-February 2021. The objectives were to identify risk factors for SARS-CoV-2 infection and household transmission among children and people with asthma and allergic diseases, and to use the host nasal transcriptome sampled longitudinally to understand infection risk and sequelae at the molecular level. To overcome challenges of clinical study implementation due to the coronavirus pandemic, this surveillance study used direct-to-participant methods to remotely enroll and prospectively follow eligible children who are participants in other NIH-funded pediatric research studies and their household members. Households participated in weekly surveys and biweekly nasal sampling regardless of symptoms. The aim of this report is to widely share the methods and study instruments and to describe the rationale, design, execution, logistics and characteristics of a large, observational, household-based, remote cohort study of SARS-CoV-2 infection and transmission in households with children. The study enrolled a total of 5,598 individuals, including 1,913 principal participants (children), 1,913 primary caregivers, 729 secondary caregivers and 1,043 other household children. This study was successfully implemented without necessitating any in-person research visits and provides an approach for rapid execution of clinical research.

A randomized controlled trial of inhaled ciclesonide for outpatient treatment of symptomatic COVID-19 infections (preprint)

ImportanceSystemic corticosteroids are commonly used in the treatment of severe COVID-19. However, their role in the treatment of patients with mild to moderate disease is less clear. The inhaled corticosteroid ciclesonide has shown early promise as a potential treatment for COVID-19. ObjectiveTo determine whether the inhaled steroid ciclesonide is efficacious in patients with high risk for disease progression and can reduce the incidence of long-term COVID-19 symptoms or post-acute sequelae of SARS-CoV-2. DesignThis was a phase III, multicenter, double-blind, randomized controlled trial to assess the safety and efficacy of ciclesonide metered-dose inhaler (MDI) for the treatment of non-hospitalized participants with symptomatic COVID-19 infection. Patients were screened from June 11, 2020 to November 3, 2020. SettingThe study was conducted at 10 centers throughout the U.S. public and private, academic and non-academic sites were represented among the centers. ParticipantsParticipants were randomly assigned to ciclesonide MDI 160 {micro}g per actuation, two actuations twice a day (total daily dose 640 {micro}g) or placebo for 30 days. Main Outcomes and MeasuresThe primary endpoint was time to alleviation of all COVID-19 related symptoms (cough, dyspnea, chills, feeling feverish, repeated shaking with chills, muscle pain, headache, sore throat, and new loss of taste or smell) by Day 30. Secondary endpoints included subsequent emergency department visits or hospital admissions for reasons attributable to COVID-19. Results413 participants were screened and 400 (96.9%) were enrolled and randomized (197 in the ciclesonide arm and 203 in the placebo arm). The median time to alleviation of all COVID-19-related symptoms was 19.0 days (95% CI: 14.0, 21.0) in the ciclesonide arm and 19.0 days (95% CI: 16.0, 23.0) in the placebo arm. There was no difference in resolution of all symptoms by Day 30 (odds ratio [OR] 1.28, 95% CI: 0.84, 1.97). Participants treated with ciclesonide had fewer subsequent emergency department visits or hospital admissions for reasons attributable to COVID-19 (OR 0.18, 95% CI: 0.04 - 0.85). No subjects died during the study. Conclusions and RelevanceCiclesonide did not achieve the primary efficacy endpoint of time to alleviation of all COVID-19-related symptoms. Future studies of inhaled steroids are needed to explore their efficacy in patients with high risk for disease progression and in reducing the incidence of long-term COVID-19 symptoms or post-acute sequelae of SARS-CoV-2. Trial RegistrationClinicalTrials.gov NCT04377711 https://clinicaltrials.gov/ct2/show/NCT04377711 Key PointsO_ST_ABSQuestionC_ST_ABSCan the inhaled steroid ciclesonide be efficacious in patients with high risk for disease progression and reduce the incidence of long-term COVID-19 symptoms or post-acute sequelae of SARS-CoV-2? FindingsIn this randomized clinical trial of 413 patients, ciclesonide did not reduce the time to alleviation of all COVID-19-related symptoms. However, patients treated with ciclesonide had fewer subsequent emergency department visits or hospital admissions for reasons attributable to COVID-19. MeaningFuture studies of inhaled steroids are needed to explore their efficacy in patients with high risk for disease progression and in reducing the incidence of long-term COVID-19 symptoms or post-acute sequelae of SARS-CoV-2.

Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study: Study Design (preprint)

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults at risk for coronavirus disease 2019 (COVID-19) comprising 14 established United States (US) prospective cohort studies. For decades, C4R cohorts have collected extensive data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R will link this pre-COVID phenotyping to information on SARS-CoV-2 infection and acute and post-acute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and broadly reflects the racial, ethnic, socioeconomic, and geographic diversity of the US. C4R is ascertaining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations, and high-quality events surveillance. Extensive pre-pandemic data minimize referral, survival, and recall bias. Data are being harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these will be pooled and shared widely to expedite collaboration and scientific findings. This unique resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including post-acute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term trajectories of health and aging.

Childhood asthma outcomes during the COVID-19 pandemic: Findings from the PeARL multi-national cohort. (preprint)

ImportanceImportance: The interplay between COVID-19 pandemic and asthma in children is still unclear. ObjectiveWe evaluated the impact of COVID-19 pandemic on childhood asthma outcomes. DesignThe PeARL multinational cohort included children with asthma and non-asthmatic controls recruited during the COVID-19 pandemic and compared current disease activity with data available from the previous year. SettingPediatric outpatient clinics. ParticipantsThe study included 1,054 children with asthma and 505 non-asthmatic controls, aged between 4-18 years, from 25 pediatric departments, from 15 countries globally. ExposuresCOVID-19 pandemic first wave, starting from the date of the first fatality in the respective country. Main outcomes and measuresWe assessed the pandemics impact on the frequency of respiratory infections, emergency presentations and hospital admissions in asthmatic versus non-asthmatic participants, controlling for confounding factors including the pandemics duration and the frequency of such acute events during 2019. Using paired analyses, we evaluated the impact of the pandemic on the annualized frequency of asthma attacks and the previously mentioned acute events, asthma control, and pulmonary function in children with asthma, compared to their baseline disease activity, during the preceding year. ResultsDuring the pandemic, children with asthma experienced fewer upper respiratory tract infections, episodes of pyrexia, emergency visits, hospital admissions, asthma attacks and hospitalizations due to asthma, in comparison to the preceding year. Sixty-six percent of asthmatic children had improved asthma control while in 33% the improvement exceeded the minimally clinically important difference. Pre-bronchodilatation FEV1 and peak expiratory flow rate were also improved during the pandemic. When compared to non-asthmatic controls, children with asthma were not found to be at increased risk of LRTIs, episodes of pyrexia, emergency visits or hospitalizations during the pandemic. However, an increased risk of URTIs emerged. Conclusions and relevanceChildhood asthma outcomes, including control, were improved during the first wave of the COVID-19 pandemic, probably because of reduced exposure to asthma triggers and increased treatment adherence. The decreased frequency of acute episodes does not support the notion that childhood asthma may be a risk factor for COVID-19. Furthermore, the potential for improving childhood asthma outcomes through environmental control becomes apparent. Key PointsO_ST_ABSQuestionC_ST_ABSWhat was the impact of COVID-19 pandemic on childhood asthma outcomes? FindingsDuring the first wave of the pandemic, children with asthma have experienced improved outcomes, as evidenced by fewer asthma attachks, hospitalizations, improved scores in validated asthma control measures and improved pulmonary function. MeaningThis is the first study to show a positive impact of COVID-19 pandemic on childhood asthma activity. This is probably the result of reduced exposure to asthma triggers and increased treatment adherence. The decreased frequency of acute episodes does not support the hypothesis that childhood asthma may be a risk factor for COVID-19.