RESUMEN
The Eyes Absent family (EYA1-4) are a group of dual function proteins that act as both tyrosine phosphatases and transcriptional co-activators. EYA proteins play a vital role in development, but are also aberrantly overexpressed in cancers, where they often confer an oncogenic effect. Precisely how the EYAs impact cell biology is of growing interest, fuelled by the therapeutic potential of an expanding repertoire of EYA inhibitors. Recent functional studies suggest that the EYAs are important players in the regulation of genome maintenance pathways including DNA repair, mitosis, and DNA replication. While the characterized molecular mechanisms have predominantly been ascribed to EYA phosphatase activities, EYA co-transcriptional activity has also been found to impact the expression of genes that support these pathways. This indicates functional convergence of EYA phosphatase and co-transcriptional activities, highlighting the emerging importance of the EYA protein family at the intersection of genome maintenance mechanisms. In this review, we discuss recent progress in defining EYA protein substrates and transcriptional effects, specifically in the context of genome maintenance. We then outline future directions relevant to the field and discuss the clinical utility of EYA inhibitors.
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Reparación del ADN , Replicación del ADN , Mitosis , Proteínas Tirosina Fosfatasas , Humanos , Proteínas Tirosina Fosfatasas/metabolismo , Proteínas Tirosina Fosfatasas/genética , Animales , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Proteínas del Ojo/metabolismo , Proteínas del Ojo/genética , Neoplasias/genética , Neoplasias/metabolismoRESUMEN
Telomeres are repetitive nucleoprotein complexes at chromosomal termini essential for maintaining genome stability. Telomeric RNA, or TERRA, is a previously presumed long noncoding RNA of heterogeneous lengths that contributes to end-capping structure and function, and facilitates telomeric recombination in tumors that maintain telomere length via the telomerase-independent Alternative Lengthening of Telomeres (ALT) pathway. Here, we investigated TERRA in the radiation-induced DNA damage response (DDR) across astronauts, high-altitude climbers, healthy donors, and cellular models. Similar to astronauts in the space radiation environment and climbers of Mt. Everest, in vitro radiation exposure prompted increased transcription of TERRA, while simulated microgravity did not. Data suggest a specific TERRA DDR to telomeric double-strand breaks (DSBs), and provide direct demonstration of hybridized TERRA at telomere-specific DSB sites, indicative of protective TERRA:telomeric DNA hybrid formation. Targeted telomeric DSBs also resulted in accumulation of TERRA foci in G2-phase, supportive of TERRA's role in facilitating recombination-mediated telomere elongation. Results have important implications for scenarios involving persistent telomeric DNA damage, such as those associated with chronic oxidative stress (e.g., aging, systemic inflammation, environmental and occupational radiation exposures), which can trigger transient ALT in normal human cells, as well as for targeting TERRA as a therapeutic strategy against ALT-positive tumors.
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Altitud , Vuelo Espacial , Telómero , Humanos , Telómero/metabolismo , Telómero/genética , Masculino , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Adulto , Persona de Mediana Edad , Roturas del ADN de Doble Cadena , Femenino , Daño del ADN , Montañismo , Homeostasis del TelómeroRESUMEN
BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of morbidity and mortality among US infants. A child's calendar birth month determines their age at first exposure(s) to RSV. We estimated birth month-specific risk of medically attended (MA) RSV lower respiratory tract infection (LRTI) among infants during their first RSV season and first year of life (FYOL). METHODS: We analyzed infants born in the USA between July 2016 and February 2020 using three insurance claims databases (two commercial, one Medicaid). We classified infants' first MA RSV LRTI episode by the highest level of care incurred (outpatient, emergency department, or inpatient), employing specific and sensitive diagnostic coding algorithms to define index RSV diagnoses. In our main analysis, we focused on infants' first RSV season. In our secondary analysis, we compared the risk of MA RSV LRTI during infants' first RSV season to that of their FYOL. RESULTS: Infants born from May through September generally had the highest risk of first-season MA RSV LRTI-approximately 6-10% under the specific RSV index diagnosis definition and 16-26% under the sensitive. Infants born between October and December had the highest risk of RSV-related hospitalization during their first season. The proportion of MA RSV LRTI events classified as inpatient ranged from 9% to 54% (specific) and 5% to 33% (sensitive) across birth month and comorbidity group. Through the FYOL, the overall risk of MA RSV LRTI is comparable across birth months within each claims database (6-11% under the specific definition, 17-30% under the sensitive), with additional cases progressing to care at outpatient or ED settings. CONCLUSIONS: Our data support recent national recommendations for the use of nirsevimab in the USA. For infants born at the tail end of an RSV season who do not receive nirsevimab, a dose administered prior to the onset of their second RSV season could reduce the incidence of outpatient- and ED-related events.
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Hospitalización , Infecciones por Virus Sincitial Respiratorio , Estaciones del Año , Humanos , Infecciones por Virus Sincitial Respiratorio/epidemiología , Infecciones por Virus Sincitial Respiratorio/diagnóstico , Estados Unidos/epidemiología , Lactante , Hospitalización/estadística & datos numéricos , Recién Nacido , Medición de Riesgo , Masculino , Femenino , Virus Sincitial Respiratorio Humano , Bases de Datos FactualesRESUMEN
BACKGROUND: Respiratory syncytial virus (RSV) is a substantial cause of infant morbidity and mortality due to seasonal peaks of bronchiolitis across the United States. Clinical and viral surveillance plays a pivotal role in helping hospital systems prepare for expected surges in RSV bronchiolitis. Existing surveillance efforts have shown a geographic pattern of RSV positivity across the United States, with cases typically starting in the southeast and spreading north and west. Public health measures implemented due to the COVID-19 pandemic disrupted viral transmission across the nation and altered the expected seasonality of RSV. The impact of these changes on the geographic progression of infant RSV bronchiolitis across the United States has not been described. METHODS: Here, we used clinical and viral surveillance data from four health care systems located in different regions of the United States to describe the geographic progression of infant RSV bronchiolitis across the country from 2015 to 2023. RESULTS: Prior to widespread circulation of SARS-CoV-2, infant RSV bronchiolitis followed an established geographic pattern associated with seasonal epidemics originating in Florida and spreading north (North Carolina and New York) and later westward (Nevada). Although public health and social measures implemented during the COVID-19 pandemic disrupted the seasonality of RSV disease, infant RSV bronchiolitis epidemics progressed across the nation in a pattern identical to the prepandemic era. CONCLUSIONS: Our findings highlight the importance of ongoing clinical and viral surveillance to optimally track the onset of RSV epidemics and allow health care systems to prepare for expected RSV bronchiolitis surges.
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Bronquiolitis , COVID-19 , Infecciones por Virus Sincitial Respiratorio , Humanos , COVID-19/epidemiología , COVID-19/transmisión , Estados Unidos/epidemiología , Lactante , Infecciones por Virus Sincitial Respiratorio/epidemiología , Bronquiolitis/epidemiología , Bronquiolitis/virología , Virus Sincitial Respiratorio Humano/aislamiento & purificación , Estaciones del Año , SARS-CoV-2 , Recién Nacido , Femenino , MasculinoRESUMEN
BACKGROUND: Bronchiolitis due to respiratory syncytial virus (RSV) is the leading cause of hospitalization among American infants. The overall burden of RSV among infants has been historically under-estimated due to variable testing practices, particularly in the outpatient setting. Universal masking and social distancing implemented during the coronavirus disease 2019 (COVID-19) pandemic altered RSV seasonality, however potential consequences on RSV testing practices across different healthcare settings and sociodemographic groups have not been described. Variable testing practices could also affect accurate assessment of the effects of two recently approved RSV preventative agents targeting infants. METHODS: Utilizing real-time clinical and viral surveillance, we examined RSV testing practices among infants with bronchiolitis within four United States healthcare systems across different healthcare settings and sociodemographic groups pre- and post-COVID-19. RESULTS: RSV testing among infants with bronchiolitis increased since 2015 within each healthcare system across all healthcare settings and sociodemographic groups, with a more dramatic increase since the COVID-19 pandemic. Outpatient testing remained disproportionately low compared to hospital-based testing, although there were no major differences in testing frequency among sociodemographic groups in either setting. CONCLUSIONS: Although RSV testing increased among infants with bronchiolitis, relatively low outpatient testing rates remain a key barrier to accurate RSV surveillance.
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Bronquiolitis , COVID-19 , Infecciones por Virus Sincitial Respiratorio , SARS-CoV-2 , Humanos , Lactante , Infecciones por Virus Sincitial Respiratorio/diagnóstico , Infecciones por Virus Sincitial Respiratorio/epidemiología , Estados Unidos/epidemiología , COVID-19/epidemiología , COVID-19/diagnóstico , Femenino , Masculino , Bronquiolitis/diagnóstico , Bronquiolitis/epidemiología , Hospitalización/estadística & datos numéricos , Virus Sincitial Respiratorio Humano/aislamiento & purificación , Recién NacidoRESUMEN
The ATR-CHK1 DNA damage response pathway becomes activated by the exposure of RPA-coated single-stranded DNA (ssDNA) that forms as an intermediate during DNA damage and repair, and as a part of the replication stress response. Here, we identify ZNF827 as a component of the ATR-CHK1 kinase pathway. We demonstrate that ZNF827 is a ssDNA binding protein that associates with RPA through concurrent binding to ssDNA intermediates. These interactions are dependent on two clusters of C2H2 zinc finger motifs within ZNF827. We find that ZNF827 accumulates at stalled forks and DNA damage sites, where it activates ATR and promotes the engagement of homologous recombination-mediated DNA repair. Additionally, we demonstrate that ZNF827 depletion inhibits replication initiation and sensitizes cancer cells to the topoisomerase inhibitor topotecan, revealing ZNF827 as a therapeutic target within the DNA damage response pathway.
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Proteínas Quinasas , Transducción de Señal , Proteínas Quinasas/metabolismo , Fosforilación , Proteína de Replicación A/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Proteínas de Unión al ADN/metabolismo , Replicación del ADN , Daño del ADN , ADN de Cadena Simple , Reparación del ADNRESUMEN
The Eyes Absent proteins (EYA1-4) are a biochemically unique group of tyrosine phosphatases known to be tumour-promoting across a range of cancer types. To date, the targets of EYA phosphatase activity remain largely uncharacterised. Here, we identify Polo-like kinase 1 (PLK1) as an interactor and phosphatase substrate of EYA4 and EYA1, with pY445 on PLK1 being the primary target site. Dephosphorylation of pY445 in the G2 phase of the cell cycle is required for centrosome maturation, PLK1 localization to centrosomes, and polo-box domain (PBD) dependent interactions between PLK1 and PLK1-activation complexes. Molecular dynamics simulations support the rationale that pY445 confers a structural impairment to PBD-substrate interactions that is relieved by EYA-mediated dephosphorylation. Depletion of EYA4 or EYA1, or chemical inhibition of EYA phosphatase activity, dramatically reduces PLK1 activation, causing mitotic defects and cell death. Overall, we have characterized a phosphotyrosine signalling network governing PLK1 and mitosis.
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Proteínas de Ciclo Celular , Proteínas Serina-Treonina Quinasas , Humanos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Tirosina/metabolismo , Mitosis , Centrosoma/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Células HeLa , Proteínas Nucleares/metabolismo , Proteínas Tirosina Fosfatasas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Transactivadores/metabolismoRESUMEN
Alternative lengthening of telomeres (ALT) is a homology-directed repair mechanism that becomes activated in a subset of cancers to maintain telomere length. One of the defining features of ALT cells is the prevalence of extrachromosomal telomeric repeat (ECTR) DNA. Here, we identify that ALT cells engage in two modes of telomere synthesis. Non-productive telomere synthesis occurs during the G2 phase of the cell cycle and is characterized by newly synthesized internal telomeric regions that are not retained in the subsequent G1, coinciding with an induction of ECTR DNA. Productive telomere synthesis occurs specifically during the transition from G2 to mitosis and is defined as the extension of the telomere termini. While many proteins associated with break-induced telomere synthesis function in both non-productive and productive telomere synthesis, POLH specifically promotes productive telomere lengthening and suppresses non-productive telomere synthesis. These findings delineate the mechanism and cell cycle regulation of ALT-mediated telomere synthesis and extension.
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Following prolonged cell division, mesenchymal stem cells enter replicative senescence, a state of permanent cell cycle arrest that constrains the use of this cell type in regenerative medicine applications and that in vivo substantially contributes to organismal ageing. Multiple cellular processes such as telomere dysfunction, DNA damage and oncogene activation are implicated in promoting replicative senescence, but whether mesenchymal stem cells enter different pre-senescent and senescent states has remained unclear. To address this knowledge gap, we subjected serially passaged human ESC-derived mesenchymal stem cells (esMSCs) to single cell profiling and single cell RNA-sequencing during their progressive entry into replicative senescence. We found that esMSC transitioned through newly identified pre-senescent cell states before entering into three different senescent cell states. By deconstructing this heterogeneity and temporally ordering these pre-senescent and senescent esMSC subpopulations into developmental trajectories, we identified markers and predicted drivers of these cell states. Regulatory networks that capture connections between genes at each timepoint demonstrated a loss of connectivity, and specific genes altered their gene expression distributions as cells entered senescence. Collectively, this data reconciles previous observations that identified different senescence programs within an individual cell type and should enable the design of novel senotherapeutic regimes that can overcome in vitro MSC expansion constraints or that can perhaps slow organismal ageing.
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Senescencia Celular , Células Madre Mesenquimatosas , Humanos , Senescencia Celular/fisiología , Células Madre Mesenquimatosas/metabolismoRESUMEN
BACKGROUND: Respiratory syncytial virus (RSV) bronchiolitis is the leading cause of hospitalizations among infants in the United States. Unpredictability in RSV seasonality has occurred following the onset of the coronavirus disease 2019 (COVID-19) pandemic. Local surveillance networks can enhance the ability to appropriately time prophylaxis when exposure risk is highest. METHODS: A retrospective, cohort study was conducted to describe the epidemiologic patterns of RSV disease among outpatient, emergency department and inpatient encounters in children <5 years in Central New York before and after the onset of the COVID-19 pandemic. Local data were collected from October 2015 to January 2023 and compared to state-level data. Linear regression models were used to identify clinical and sociodemographic differences before and after the pandemic. RESULTS: Local variation in RSV seasonality was noted prior to the COVID-19 pandemic, however highly atypical circulation patterns appeared in the post-COVID-19 era. Since March 2020, patterns for local and state-defined RSV seasons have remained atypical (local season onset in 2021: week 27 and 2022: week 27; state season onset in 2021: week 31 and 2022: week 38). After adjusting for increases in testing, RSV bronchiolitis cases were not significantly different during pre- and post-pandemic eras. In comparison to the 2021 bronchiolitis season, the 2022 season had a higher proportion of RSV cases despite decreased testing. CONCLUSIONS: Temporal patterns for RSV have shifted during the COVID-19 pandemic. Local surveillance networks may be advantageous in trending community-level RSV activity to optimize prophylaxis administration. Changes in RSV testing patterns occurred throughout the study period and should be accounted for when describing infant and childhood RSV disease.
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Bronquiolitis , COVID-19 , Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Lactante , Niño , Humanos , Estados Unidos , Preescolar , Pandemias , New York/epidemiología , Estudios Retrospectivos , Estudios de Cohortes , COVID-19/epidemiología , Infecciones por Virus Sincitial Respiratorio/epidemiología , Infecciones por Virus Sincitial Respiratorio/prevención & control , Bronquiolitis/epidemiología , Estaciones del Año , HospitalizaciónRESUMEN
INTRODUCTION: New extended half-life antibodies for the single-dose prevention of medically attended (MA) respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) have been developed for administration to all infants before or during their first RSV season. For infants born during the season, administration as soon as feasible after birth would provide optimal protection and minimize access disparities. The objective of this study was to assess the time from birth hospitalization discharge to the first outpatient visit (FOV) among US infants in order to determine optimal site of administration for the extended half-life antibody. MATERIAL AND METHODS: This retrospective, observational, time-to-event analysis uses the Merative™ MarketScan® Commercial and Multi-State Medicaid Databases. Time to FOV is reported separately for the COVID-19 and recent pre-COVID-19 eras and for commercially insured and Medicaid infants. RESULTS: Overall, 73.8 % of Medicaid infants had an FOV within 5 days as compared to 84.7 % of commercially insured infants. Estimates were higher during the COVID-19 era. Urban commercially insured infants had much higher FOV completion than their counterparts. Among Medicaid infants, urban Black and rural White infants were least likely to complete their FOV within 5 days of birth hospitalization discharge. DISCUSSION AND CONCLUSION: FOV within 5 days after birth hospitalization discharge for Medicaid infants is substantially lower than that of commercially insured infants. Approximately 1 in 4 Medicaid infants and 1 in 8 infants with commercial insurance did not have an outpatient visit within 5 days of birth hospitalization discharge. For US infants born during the RSV season, administration of extended half-life RSV antibodies in the newborn nursery prior to discharge would ensure optimal uptake and minimize access disparities.
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COVID-19 , Virus Sincitial Respiratorio Humano , Estados Unidos/epidemiología , Recién Nacido , Humanos , Lactante , Semivida , Estudios Retrospectivos , Anticuerpos AntiviralesRESUMEN
Background and Aims: Policymakers need data about the burden of respiratory syncytial virus (RSV) lower respiratory tract infections (LRTI) among infants. This study estimates quality of life (QoL) for otherwise healthy term US infants with RSV-LRTI and their caregivers, previously limited to premature and hospitalized infants, and corrects for selective testing. Methods: The study enrolled infants <1 year with a clinically diagnosed LRTI encounter between January and May 2021. Using an established 0-100 scale, the 36 infants' and caregivers' QoL at enrollment and quality-adjusted life year losses per 1000 LRTI episodes (quality-adjusted life years [QALYs]/1000) were validated and analyzed. Regression analyses examined predictors of RSV-testing and RSV-positivity, creating modeled positives. Results: Mean QoL at enrollment in outpatient (n = 11) LRTI-tested infants (66.4) was lower than that in not-tested LRTI infants (79.6, p = 0.096). For outpatient LRTI infants (n = 23), median QALYs/1000 losses were 9.8 and 0.25 for their caregivers. RSV-positive outpatient LRTI infants (n = 6) had significantly milder QALYs/1000 losses (7.0) than other LRTI-tested infants (n = 5)(21.8, p = 0.030). Visits earlier in the year were more likely to be RSV-positive than later visits (p = 0.023). Modeled RSV-positivity (51.9%) was lower than the observed rate (55.0%). Infants' and caregivers' QALYs/1000 loss were positively correlated (rho = 0.34, p = 0.046), indicating that infants perceived as sicker imposed greater burdens on caregivers. Conclusions: The overall median QALYs/1000 losses for LRTI (9.0) and RSV-LRTI (5.6) in US infants are substantial, with additional losses for their caregivers (0.25 and 0.20, respectively). These losses extend equally to outpatient episodes. This study is the first reporting QALY losses for infants with LRTI born at term or presenting in nonhospitalized settings, and their caregivers.
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BACKGROUND: The World Health Organization (WHO) recommended 'pre-vaccination screening' as its preferred implementation strategy when using the licensed dengue vaccine (CYD-TDV; Dengvaxia, Sanofi), so that only individuals with previous dengue infection are vaccinated. The US Centers for Disease Control and Prevention (CDC) recommended use of CYD-TDV to prevent dengue in children with previous laboratory-confirmed dengue infection in regions where dengue is endemic. Here, we evaluate the public health impact and cost-effectiveness of a 'pre-vaccination screening' strategy in Puerto Rico. METHODS: The current analysis builds upon a previously published transmission model used to assess the benefits/risks associated with dengue vaccination. For 'pre-vaccination screening', three alternative testing methods were assessed: one using an immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) dengue serotest, another with dengue serotesting using a rapid diagnostic test (RDT), and one using both sequentially (as recommended in Puerto Rico). The time horizon considered was 10 years. RESULTS: In Puerto Rico, the disability-adjusted life years (DALYs) averted for 'pre-vaccination screening' with an ELISA-based program, RDT-based program, and both sequentially would be a median 1,192 (95% CI: 716-2,232), 2,812 (95% CI: 1,579-5,019), and 1,017 (95% CI: 561-1,738), respectively. These benefits would arise from the reduction in cases: median 24,961 (95% CI: 17,480-36,782), 58,273 (95% CI: 40,729-84,796), 20,775 (95% CI: 14,637-30,374) fewer cases, respectively. The cost per DALY averted from a payer perspective would be US$12,518 (95 %CI: US$4,749-26,922), US$10,047 (95% CI: US$3,350-23,852), and US$12,334 (95% CI: US$4,965-26,444), respectively. All three strategies would be cost saving from a societal perspective. CONCLUSIONS: Our study supports the WHO and CDC 'pre-vaccination screening' guidance for CYD-TDV implementation. In Puerto Rico, regardless of the testing strategy and even with a relatively low rate of testing, it would be cost-effective from a payer perspective and cost saving from a societal perspective.
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Vacunas contra el Dengue , Dengue , Humanos , Estados Unidos , Niño , Salud Pública , Análisis Costo-Beneficio , Puerto Rico , Vacunación , Dengue/prevención & controlRESUMEN
The target populations and financing mechanisms for a new health technology may affect health inequalities in access and impact. We projected the distributional consequences of introducing nirsevimab for prevention of respiratory syncytial virus in a US birth cohort of infants through alternative reimbursement pathway scenarios. Using the RSV immunization impact model, we estimated that a vaccine-like reimbursement pathway would cover 32% more infants than a pharmaceutical pathway. The vaccine pathway would avert 30% more hospitalizations and 39% more emergency room visits overall, and 44% and 44%, respectively, in publicly insured infants. The vaccine pathway would benefit infants from poorer households.
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Infecciones por Virus Sincitial Respiratorio , Vacunas contra Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Anticuerpos Monoclonales Humanizados , Humanos , Lactante , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Infecciones por Virus Sincitial Respiratorio/prevención & control , Factores Socioeconómicos , Estados UnidosRESUMEN
BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of infant hospitalization in the United States. Preterm infants and those with select comorbidities are at highest risk of RSV-related complications. However, morbidity due to RSV infection is not confined to high-risk infants. We estimated the burden of medically attended (MA) RSV-associated lower respiratory tract infection (LRTI) among infants in the United States. METHODS: We analyzed commercial (MarketScan Commercial [MSC], Optum Clinformatics [OC]), and Medicaid (MarketScan Medicaid [MSM]) insurance claims data for infants born between April 2016 and February 2020. Using both specific and sensitive definitions of MA RSV LRTI, we estimated the burden of MA RSV LRTI during infants' first RSV season, stratified by gestational age, comorbidity status, and highest level of medical care associated with the MA RSV LRTI diagnosis. RESULTS: According to the specific definition 75.0% (MSC), 78.6% (MSM), and 79.6% (OC) of MA RSV LRTI events during infants' first RSV season occurred among term infants without known comorbidities. CONCLUSIONS: Term infants without known comorbidities account for up to 80% of the MA RSV LRTI burden in the United States during infants' first RSV season. Future prevention efforts should consider all infants.
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Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Infecciones del Sistema Respiratorio , Femenino , Hospitalización , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Estados Unidos/epidemiologíaAsunto(s)
Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Infecciones del Sistema Respiratorio , Humanos , Lactante , Infecciones por Virus Sincitial Respiratorio/epidemiología , Infecciones por Virus Sincitial Respiratorio/prevención & control , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/prevención & controlRESUMEN
BACKGROUND: Surveillance in 2020-2021 showed that seasonal respiratory illnesses were below levels seen during prior seasons, with the exception of interseasonal respiratory syncytial virus (RSV). METHODS: Electronic health record data of infants aged <1 year visiting the Duke University Health System from 4 October 2015 to 28 March 2020 (pre-COVID-19) and 29 March 2020 to 30 October 2021 (COVID-19) were assessed. International Classification of Diseases-Tenth Revision (ICD-10) codes for RSV (B97.4, J12.1, J20.5, J21.0) and bronchiolitis (RSV codes plus J21.8, J21.9) were used to detail encounters in the inpatient (IP), emergency department (ED), outpatient (OP), urgent care (UC), and telemedicine (TM) settings. RESULTS: Pre-COVID-19, 88% of RSV and 92% of bronchiolitis encounters were seen in ambulatory settings. During COVID-19, 94% and 93%, respectively, occurred in ambulatory settings. Pre-COVID-19, the highest RSV proportion was observed in December-January (up to 38% in ED), while the peaks during COVID-19 were seen in July-September (up to 41% in ED) across all settings. RSV laboratory testing among RSV encounters was low during pre-COVID-19 (IP, 51%; ED, 51%; OP, 41%; UC, 84%) and COVID-19 outside of UC (IP, 33%; ED, 47%; OP, 47%; UC, 87%). Full-term, otherwise healthy infants comprised most RSV encounters (pre-COVID-19, up to 57% in OP; COVID-19, up to 82% in TM). CONCLUSIONS: With the interruption of historical RSV epidemiologic trends and the emergence of interseasonal disease during COVID-19, continued monitoring of RSV is warranted across all settings as the changing RSV epidemiology could affect the distribution of health care resources and public health policy.
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Bronquiolitis , COVID-19 , Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Bronquiolitis/epidemiología , COVID-19/epidemiología , Humanos , Lactante , Pandemias , Infecciones por Virus Sincitial Respiratorio/epidemiología , Estudios RetrospectivosRESUMEN
BACKGROUND: Respiratory syncytial virus (RSV), a leading cause of lower respiratory tract infection in US children, reduces quality of life (QOL) of children, their caregivers, and families. METHODS: We conducted a systematic literature review in PubMed, EconLit, and other databases in the United States of articles published since 2000, derived utility lost per RSV episode from cohort studies, and performed a systematic analysis. RESULTS: From 2262 unique citations, 35 received full-text review and 7 met the inclusion criteria (2 cohort studies, 4 modeling studies, and 1 synthesis). Pooled data from the 2 cohort studies (both containing only hospitalized premature infants) gave quality-adjusted life-year (QALY) losses per episode of 0.0173 at day 38. From the cohort study that also assessed caregivers' QOL, we calculated net QALYs lost directly attributable to RSV per nonfatal episode from onset to 60 days after onset for the child, caregiver, child-and-caregiver dyad of 0.0169 (167% over prematurity alone), 0.0031, and 0.0200, respectively. CONCLUSION: Published data on QOL of children in the United States with RSV are scarce and consider only premature hospitalized infants, whereas most RSV episodes occur in children who were born at term and were otherwise healthy. QOL studies are needed beyond hospitalized premature infants.
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Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Cuidadores , Estudios de Cohortes , Humanos , Lactante , Calidad de Vida , Infecciones por Virus Sincitial Respiratorio/epidemiología , Infecciones por Virus Sincitial Respiratorio/etiología , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: A systematic literature review was conducted to summarize the mortality (overall and by disease severity factors) of US infants and children aged <5 years with respiratory syncytial virus (RSV) or all-cause bronchiolitis (ACB). METHODS: Comprehensive, systematic literature searches were conducted; articles were screened using prespecified eligibility criteria. A standard risk of bias tool was used to evaluate studies. Mortality was extracted as the rate per 100 000 or the case fatality ratio (CFR; proportion of deaths among RSV/ACB cases). RESULTS: Among 42 included studies, 36 evaluated inpatient deaths; 10 used nationally representative populations updated through 2013, and only 2 included late-preterm/full-term otherwise healthy infants and children. The RSV/ACB definition varied across studies (multiple International Classification of Diseases [ICD] codes; laboratory confirmation); no study reported systematic testing for RSV. No studies reported RSV mortality rates, while 3 studies provided ACB mortality rates (0.57-9.4 per 100 000). CFRs ranged from 0% to 1.7% for RSV (n = 15) and from 0% to 0.17% for ACB (n = 6); higher CFRs were reported among premature, intensive care unit-admitted, and publicly insured infants and children. CONCLUSIONS: RSV mortality reported among US infants and children is variable. Current, nationally representative estimates are needed for otherwise healthy, late-preterm to full-term infants and children.
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Bronquiolitis , Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Niño , Preescolar , Recolección de Datos , Hospitalización , Humanos , Lactante , Recién NacidoRESUMEN
BACKGROUND: Respiratory syncytial virus (RSV) can cause serious illness in those aged <5 years in the United States, but uncertainty remains around which populations receive RSV testing. We conducted a systematic literature review of RSV testing patterns in studies published from 2000 to 2021. METHODS: Studies of RSV, medically attended RSV lower respiratory tract infections (LRTIs), and bronchiolitis were identified using standard methodology. Outcomes were clinical decisions to test for RSV, testing frequency, and testing incidence proportions in inpatient (IP), emergency department (ED), outpatient (OP), and urgent care settings. RESULTS: Eighty good-/fair-quality studies, which reported data from the period 1988-2020, were identified. Twenty-seven described the clinical decision to test, which varied across and within settings. Two studies reported RSV testing frequency for multiple settings, with higher testing proportions in IP (n = 2, range: 83%-85%, 1996-2009) compared with ED (n = 1, 25%, 2006-2009) and OP (n = 2, 15%-25%, 1996-2009). Higher RSV testing incidence proportions were observed among LRTI infant populations in the ED (n = 1, 74%, 2007-2008) and OP (n = 2, 54%-69%, 1995-2008). Incidence proportions in LRTI populations were not consistently higher in the IP setting (n = 13). Across studies and time, there was heterogeneity in RSV testing patterns, which may reflect varying detection methods, populations, locations, time periods, and healthcare settings. CONCLUSIONS: Not all infants and children with LRTI are tested for RSV, highlighting underestimation of RSV burden across all settings.