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

IMPORTANCE: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults. OBSERVATIONS: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science. CONCLUSIONS AND RELEVANCE: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions. CLINICAL TRIALS.GOV IDENTIFIER: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011.

Researching COVID to enhance recovery (RECOVER) tissue pathology study protocol: Rationale, objectives, and design.

IMPORTANCE: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or organ dysfunction after the acute phase of infection, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are poorly understood. The objectives of the Researching COVID to Enhance Recovery (RECOVER) tissue pathology study (RECOVER-Pathology) are to: (1) characterize prevalence and types of organ injury/disease and pathology occurring with PASC; (2) characterize the association of pathologic findings with clinical and other characteristics; (3) define the pathophysiology and mechanisms of PASC, and possible mediation via viral persistence; and (4) establish a post-mortem tissue biobank and post-mortem brain imaging biorepository. METHODS: RECOVER-Pathology is a cross-sectional study of decedents dying at least 15 days following initial SARS-CoV-2 infection. Eligible decedents must meet WHO criteria for suspected, probable, or confirmed infection and must be aged 18 years or more at the time of death. Enrollment occurs at 7 sites in four U.S. states and Washington, DC. Comprehensive autopsies are conducted according to a standardized protocol within 24 hours of death; tissue samples are sent to the PASC Biorepository for later analyses. Data on clinical history are collected from the medical records and/or next of kin. The primary study outcomes include an array of pathologic features organized by organ system. Causal inference methods will be employed to investigate associations between risk factors and pathologic outcomes. DISCUSSION: RECOVER-Pathology is the largest autopsy study addressing PASC among US adults. Results of this study are intended to elucidate mechanisms of organ injury and disease and enhance our understanding of the pathophysiology of PASC.

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

Importance: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults. Observations: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's RE searching COV ID to E nhance R ecovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of five cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study ( n =10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n=6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n=6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n=600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science. Conclusions and Relevance: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions. Clinical Trialsgov Identifier: Clinical Trial Registration: http://www.clinicaltrials.gov . Unique identifier: NCT05172011.

Outpatient initiation of dofetilide: insights from the complexities of atrial fibrillation management during the COVID-19 lockdown.

BACKGROUND: At peak COVID-19 lockdown, patients with symptomatic atrial fibrillation (AF) were faced with an equipoise between a palliative rate-control versus cautious rhythm-control strategy, including hospitalization for initiation of antiarrhythmic drug/s (AADs) and cardiac procedures which was impossible due to hospitalization restrictions. OBJECTIVES: We aimed to evaluate the efficacy and safety of outpatient initiation of dofetilide in patients with AF using cardiac implantable electronic devices (CIEDs) for rhythm and QTc interval monitoring. METHODS: Adult patients with symptomatic AF with prior failure or intolerance to other AADs were enrolled if they were willing to in-office insertion of implantable loop recorders or already implanted with pacemakers or defibrillators capable of remote monitoring. Exclusion criteria were known medical contraindications of dofetilide and unable to provide consent. After making a shared management decision, dofetilide was initiated in a physician office, and rhythm and QTc intervals were monitored by ECGs and CIEDs. Patients were followed to assess the efficacy and safety of the treatment. RESULTS: The study cohort comprised of 30 patients, age 76 ± 7 years (mean ± standard deviation), 10 female (33%), CHA2DS2-VASc score 3.25 ± 1.3, ejection fraction 63.45% ± 8.52, and QTc interval 431.68 ± 45.09 ms. From 22 (73%) patients in AF at presentation, SR was restored in 14 (64%) patients after 4 doses of dofetilide. At 46 ± 59 days of follow-up, maintenance of SR in total 22 (73%) patients without cardiac adverse effects was accomplished. CONCLUSION: Effective and safe outpatient initiation of dofetilide during the extenuating circumstance of COVID-19 lockdown was possible in patients with AF who had CIEDs.

Outpatient Initiation of Sotalol in Patients with Atrial Fibrillation: Utility of Cardiac Implantable Electronic Devices for Therapy Monitoring.

BACKGROUND: Antiarrhythmic drugs are often used in the management of patients with atrial fibrillation (AF). Sotalol is conventionally initiated in the inpatient setting for monitoring efficacy and adverse effects, including QTc interval prolongation and torsades de pointes (TdP) proarrhythmia. OBJECTIVE: We aimed to evaluate the efficacy and safety of outpatient initiation of sotalol for the treatment of AF in a select group of patients with cardiac implantable electronic devices (CIEDs): permanent pacemakers (PPMs), implantable cardioverter defibrillators (ICDs), and implantable loop recorders (ILRs) capable of continuous rhythm monitoring remotely. METHODS: We conducted our clinical study in a real-world practice setting with longitudinal follow-up of the study cohort. We included adult patients with symptomatic paroxysmal and persistent AF eligible for sotalol for rhythm control strategy and who had CIEDs in our study. Patients with a known contraindication to sotalol were excluded. After making a shared management decision with patients, sotalol was initiated as an outpatient, with regular clinical encounters with patients to assess the efficacy and safety of treatment, and monitoring cardiac rhythm and QTc intervals with CIEDs utilizing their remote monitoring platforms. RESULTS: The study cohort comprised 105 patients; 38 (36%) females, mean age ± standard deviation (SD) 73.9 ± 10.36 years, and with a CHA2DS2-VASc score of 3.26 ± 1.37 and left ventricular ejection fraction of 60.16 ± 9.10%. Twenty-six (24.8%) patients were implanted with PPMs, 10 (9.5%) with dual-chamber ICDs, and 69 (65.7%) with ILRs. Over a follow-up period of 23 ± 15 months, sotalol was continued at a steady median dose of 80 mg twice daily, 105 ± 42 mg (mean ± SD) in 77 (73%) patients who maintained sinus rhythm, and discontinued in 28 (27%) patients because of inefficacy or development of adverse effects. No adverse effects relating to QTc prolongation and TdP or mortality were observed during the study period. CONCLUSIONS: Effective and safe outpatient initiation and maintenance of sotalol therapy is possible in select patients who have CIEDs for continuous remote monitoring and surveillance capabilities.