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Fisetin for COVID-19 in skilled nursing facilities: Senolytic trials in the COVID era.

ABSTRACT: The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS-CoV-2 infection. SARS-CoV-2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence-associated secretory phenotype (SASP). The SASP can be amplified by infection-related pathogen-associated molecular profile factors. Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS-CoV-2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS-CoV-2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health-funded, multicenter, placebo-controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS-CoV-2 rtPCR-positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long-term care settings in the SARS-CoV-2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials.

SUBMITTER: Verdoorn BP

PROVIDER: S-EPMC8447437 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Fisetin for COVID-19 in skilled nursing facilities: Senolytic trials in the COVID era.

Verdoorn Brandon P BP Evans Tamara K TK Hanson Gregory J GJ Zhu Yi Y Langhi Prata Larissa G P LGP Pignolo Robert J RJ Atkinson Elizabeth J EJ Wissler-Gerdes Erin O EO Kuchel George A GA Mannick Joan B JB Kritchevsky Stephen B SB Khosla Sundeep S Rizza Stacey A SA Walston Jeremy D JD Musi Nicolas N Lipsitz Lewis A LA Kiel Douglas P DP Yung Raymond R LeBrasseur Nathan K NK Singh Ravinder J RJ McCarthy Teresa T Puskarich Michael A MA Niedernhofer Laura J LJ Robbins Paul D PD Sorenson Matthew M Tchkonia Tamara T Kirkland James L JL

Journal of the American Geriatrics Society 20210820 11

The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS-CoV-2 infection. SARS-CoV-2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence-associated secretory phenotype (SASP). The SASP can be ampli ...[more]

PMID: 34375437

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Project description:ImportanceSkilled nursing facilities (SNFs) experienced high mortality during the COVID-19 pandemic, leading them to adopt preventive measures to counteract viral spread. A critical appraisal of these measures is essential to support SNFs in managing future infectious disease outbreaks.ObjectiveTo perform a scoping review of data and evidence on the use and effectiveness of preventive measures implemented from 2020 to 2024 to prevent COVID-19 infection in SNFs in the US.Evidence reviewTwo analyses were performed. First, an analysis of the federal COVID-19 SNF Database was conducted to describe time trends in COVID-19 incidence, deaths, testing, vaccination, and treatment among SNF residents and staff, as well as shortages in staff and personal protective equipment (PPE). Then, a comprehensive literature search was conducted from May 2023 to April 2024 to identify high-quality evidence on the use and effectiveness of modifiable preventive measures used among SNF residents. Both nonpharmacologic (facility characteristics, PPE, cohorting, and isolation, visitation, staffing, testing) and pharmacologic (vaccination, treatment) measures were reviewed.FindingsNationwide data indicated early shortages of PPE, infrequent testing, and persistent staff shortages in SNFs. Other nonpharmacologic measures, such as visitor restrictions or ventilation modifications, were widely adopted but there were no available national data to quantify their effectiveness. These nonpharmacologic measures lacked high-quality studies to verify effectiveness. In contrast, the effectiveness of vaccination and antiviral treatment was shown in multiple studies. Evidence also showed associations between COVID-19 outcomes in residents and crowding, staff size, hours per residents and networks, and surveillance testing of residents and staff. Despite high initial uptake, up-to-date vaccination status was suboptimal in residents and staff from 2022 to 2024. Only a minority of infected residents received antiviral treatment.Conclusions and relevanceThis scoping review found that although many preventive measures were implemented in SNFs in the US throughout the COVID-19 pandemic, few were based on clear evidence of their effectiveness. Pharmacologic measures, such as vaccination and antiviral treatment, had more robust evidence supporting their efficacy than nonpharmacologic interventions. Using the scarce resources and staff of SNFs on measures of questionable effectiveness could distract from known effective ones such as vaccination and antiviral treatment. When possible, implementation efforts should be commensurate with the demonstrated effectiveness of available preventive measures.

Project description:ImportanceTelemedicine in skilled nursing facilities (SNFs) has the potential to improve access and timeliness of care. During the COVID-19 pandemic in 2020 to 2022, telemedicine coverage expanded, but little is known about patterns of use in SNFs.ObjectiveTo describe patterns of telemedicine use in SNFs.Design, setting, and participantsThis cohort study used 2018 to 2022 Medicare fee-for-service claims and Minimum Data Set 3.0 records to identify short- and long-term care SNF residents. Clinician visits were grouped into routine SNF visits (ie, regular primary care within SNF) and other outpatient visits (ie, with non-SNF affiliated primary and specialty care clinicians). Using a difference-in-differences approach, assessments included whether off-hours visits (measured as weekend visits), new specialist visits, psychiatrist visits, or visits for residents with limited mobility changed differentially between 2018 to 2019 and 2020 to 2021 for SNFs with high compared with low telemedicine use in 2020.ExposureTelemedicine adoption at SNF after 2020.Main outcomes and measuresNumber and proportion of telemedicine SNF and outpatient visits.ResultsAcross 15 434 SNFs and 4 463 591 residents from the period January 2019 through June 2022 (mean [SD] age, 79.7 [11.6] years; 61% female in 2020), telemedicine visits increased from 0.15% in January 2019 to February 2020 to 15% SNF visits and 25% outpatient visits in May 2020. By 2022, telemedicine dropped to 2% of SNF visits and 8% of outpatient visits. The proportion of SNFs with any telemedicine visits annually dropped from 91% in 2020 to 61% in 2022. The facilities with high telemedicine use were more likely to be rural (adjusted odds ratio vs urban, 2.06; 95% CI, 1.77 to 2.40). Psychiatry visits differentially increased in high vs low telemedicine-use SNFs (20.2% relative increase; 95% CI, 1.2% to 39.2%). In contrast, there was little change in outpatient visits for residents with limited mobility (7.2%; 95% CI, -0.1% to 14.6%) or new specialist visits (-0.7%; 95% CI, -2.5% to 1.2%).Conclusions and relevanceIn this cohort study of SNF residents, telemedicine was rapidly adopted in early 2020 but subsequently stabilized at a low use rate that was nonetheless higher than before 2020. Higher telemedicine use in SNFs was associated with improved access to psychiatry visits in SNFs. A policy to encourage continued telemedicine use may facilitate further access to important services as the technology matures.

Project description:ImportanceDuring the COVID-19 pandemic, the US federal government required that skilled nursing facilities (SNFs) close to visitors and eliminate communal activities. Although these policies were intended to protect residents, they may have had unintended negative effects.ObjectiveTo assess health outcomes among SNFs with and without known COVID-19 cases.Design, setting, and participantsThis retrospective observational study used US Medicare claims and Minimum Data Set 3.0 for January through November in each year beginning in 2018 and ending in 2020 including 15 477 US SNFs with 2 985 864 resident-years.ExposuresJanuary through November of calendar years 2018, 2019, and 2020. COVID-19 diagnoses were used to assign SNFs into 2 mutually exclusive groups with varying membership by month in 2020: active COVID-19 (≥1 COVID-19 diagnosis in the current or past month) or no-known COVID-19 (no observed diagnosis by that month).Main outcomes and measuresMonthly rates of mortality, hospitalization, emergency department (ED) visits, and monthly changes in activities of daily living (ADLs), body weight, and depressive symptoms. Each SNF in 2018 and 2019 served as its own control for 2020.ResultsIn 2018-2019, mean monthly mortality was 2.2%, hospitalization 3.0%, and ED visit rate 2.9% overall. In 2020, among active COVID-19 SNFs compared with their own 2018-2019 baseline, mortality increased by 1.60% (95% CI, 1.58% to 1.62%), hospitalizations decreased by 0.10% (95% CI, -0.12% to -0.09%), and ED visit rates decreased by 0.57% (95% CI, -0.59% to -0.55%). Among no-known COVID-19 SNFs, mortality decreased by 0.15% (95% CI, -0.16% to -0.13%), hospitalizations by 0.83% (95% CI, -0.85% to -0.81%), and ED visits by 0.79% (95% CI, -0.81% to -0.77%). All changes were statistically significant. In 2018-2019, across all SNFs, residents required assistance with an additional 0.89 ADLs between January and November, and lost 1.9 lb; 27.1% had worsened depressive symptoms. In 2020, residents in active COVID-19 SNFs required assistance with an additional 0.36 ADLs (95% CI, 0.34 to 0.38), lost 3.1 lb (95% CI, -3.2 to -3.0 lb) more weight, and were 4.4% (95% CI, 4.1% to 4.7%) more likely to have worsened depressive symptoms, all statistically significant changes. In 2020, residents in no-known COVID-19 SNFs had no significant change in ADLs (-0.06 [95% CI, -0.12 to 0.01]), but lost 1.8 lb (95% CI, -2.1 to -1.5 lb) more weight and were 3.2% more likely (95% CI, 2.3% to 4.1%) to have worsened depressive symptoms, both statistically significant changes.Conclusions and relevanceAmong skilled nursing facilities in the US during the first year of the COVID-19 pandemic and prior to the availability of COVID-19 vaccination, mortality and functional decline significantly increased at facilities with active COVID-19 cases compared with the prepandemic period, while a modest statistically significant decrease in mortality was observed at facilities that had never had a known COVID-19 case. Weight loss and depressive symptoms significantly increased in skilled nursing facilities in the first year of the pandemic, regardless of COVID-19 status.

Project description:ImportanceIdentifying successful strategies to increase COVID-19 vaccination among skilled nursing facility (SNF) residents and staff is integral to preventing future outbreaks in a continually overwhelmed system.ObjectiveTo determine whether a multicomponent vaccine campaign would increase vaccine rates among SNF residents and staff.Design, setting, and participantsThis was a cluster randomized trial with a rapid timeline (December 2020-March 2021) coinciding with the Pharmacy Partnership Program (PPP). It included 133 SNFs in 4 health care systems across 16 states: 63 and 70 facilities in the intervention and control arms, respectively, and participants included 7496 long-stay residents (>100 days) and 17 963 staff.InterventionsMulticomponent interventions were introduced at the facility level that included: (1) educational material and electronic messaging for staff; (2) town hall meetings with frontline staff (nurses, nurse aides, dietary, housekeeping); (3) messaging from community leaders; (4) gifts (eg, T-shirts) with socially concerned messaging; (5) use of a specialist to facilitate consent with residents' proxies; and (6) funds for additional COVID-19 testing of staff/residents.Main outcomes and measuresThe primary outcomes of this study were the proportion of residents (from electronic medical records) and staff (from facility logs) who received a COVID-19 vaccine (any), examined as 2 separate outcomes. Mixed-effects generalized linear models with a binomial distribution were used to compare outcomes between arms, using intent-to-treat approach. Race was examined as an effect modifier in the resident outcome model.ResultsMost facilities were for-profit (95; 71.4%), and 1973 (26.3%) of residents were Black. Among residents, 82.5% (95% CI, 81.2%-83.7%) were vaccinated in the intervention arm, compared with 79.8% (95% CI, 78.5%-81.0%) in the usual care arm (marginal difference 0.8%; 95% CI, -1.9% to 3.7%). Among staff, 49.5% (95% CI, 48.4%-50.6%) were vaccinated in the intervention arm, compared with 47.9% (95% CI, 46.9%-48.9%) in usual care arm (marginal difference: -0.4%; 95% CI, -4.2% to 3.1%). There was no association of race with the outcome among residents.Conclusions and relevanceA multicomponent vaccine campaign did not have a significant effect on vaccination rates among SNF residents or staff. Among residents, vaccination rates were high. However, half the staff remained unvaccinated despite these efforts. Vaccination campaigns to target SNF staff will likely need to use additional approaches.Trial registrationClinicalTrials.gov Identifier: NCT04732819.

Dataset Information

Fisetin for COVID-19 in skilled nursing facilities: Senolytic trials in the COVID era.

Publications

Fisetin for COVID-19 in skilled nursing facilities: Senolytic trials in the COVID era.

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