Showing papers by "Timothy M. Uyeki published in 2021"
TL;DR: In this article, the authors identified cellular targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tropism and replication in various tissues and demonstrated its direct infection in vascular endothelium.
Abstract: BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic continues to produce substantial morbidity and mortality. To understand the reasons for the wide-spectrum complications and severe outcomes of COVID-19, we aimed to identify cellular targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tropism and replication in various tissues. METHODS: We evaluated RNA extracted from formalin-fixed, paraffin-embedded autopsy tissues from 64 case patients (age range, 1 month to 84 years; 21 COVID-19 confirmed, 43 suspected COVID-19) by SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR). For cellular localization of SARS-CoV-2 RNA and viral characterization, we performed in situ hybridization (ISH), subgenomic RNA RT-PCR, and whole-genome sequencing. RESULTS: SARS-CoV-2 was identified by RT-PCR in 32 case patients (21 COVID-19 confirmed, 11 suspected). ISH was positive in 20 and subgenomic RNA RT-PCR was positive in 17 of 32 RT-PCR-positive case patients. SARS-CoV-2 RNA was localized by ISH in hyaline membranes, pneumocytes, and macrophages of lungs; epithelial cells of airways; and endothelial cells and vessel walls of brain stem, leptomeninges, lung, heart, liver, kidney, and pancreas. The D614G variant was detected in 9 RT-PCR-positive case patients. CONCLUSIONS: We identified cellular targets of SARS-CoV-2 tropism and replication in the lungs and airways and demonstrated its direct infection in vascular endothelium. This work provides important insights into COVID-19 pathogenesis and mechanisms of severe outcomes.
73 citations
TL;DR: In this paper, the authors investigated whether bacterial respiratory infections were associated with poor clinical outcome of COVID-19 in a prospective, observational cohort of 589 critically ill adults, all of whom required mechanical ventilation.
Abstract: Respiratory failure is associated with increased mortality in COVID-19 patients. There are no validated lower airway biomarkers to predict clinical outcome. We investigated whether bacterial respiratory infections were associated with poor clinical outcome of COVID-19 in a prospective, observational cohort of 589 critically ill adults, all of whom required mechanical ventilation. For a subset of 142 patients who underwent bronchoscopy, we quantified SARS-CoV-2 viral load, analysed the lower respiratory tract microbiome using metagenomics and metatranscriptomics and profiled the host immune response. Acquisition of a hospital-acquired respiratory pathogen was not associated with fatal outcome. Poor clinical outcome was associated with lower airway enrichment with an oral commensal (Mycoplasma salivarium). Increased SARS-CoV-2 abundance, low anti-SARS-CoV-2 antibody response and a distinct host transcriptome profile of the lower airways were most predictive of mortality. Our data provide evidence that secondary respiratory infections do not drive mortality in COVID-19 and clinical management strategies should prioritize reducing viral replication and maximizing host responses to SARS-CoV-2.
71 citations
TL;DR: In this paper, a cross-sectional study used a respiratory virus surveillance platform in persons of all ages to detect community COVID-19 cases from March 23 to November 9, 2020.
Abstract: Importance The association between COVID-19 symptoms and SARS-CoV-2 viral levels in children living in the community is not well understood. Objective To characterize symptoms of pediatric COVID-19 in the community and analyze the association between symptoms and SARS-CoV-2 RNA levels, as approximated by cycle threshold (Ct) values, in children and adults. Design, Setting, and Participants This cross-sectional study used a respiratory virus surveillance platform in persons of all ages to detect community COVID-19 cases from March 23 to November 9, 2020. A population-based convenience sample of children younger than 18 years and adults in King County, Washington, who enrolled online for home self-collection of upper respiratory samples for SARS-CoV-2 testing were included. Exposures Detection of SARS-CoV-2 RNA by reverse transcription–polymerase chain reaction (RT-PCR) from participant-collected samples. Main Outcomes and Measures RT-PCR–confirmed SARS-CoV-2 infection, with Ct values stratified by age and symptoms. Results Among 555 SARS-CoV-2–positive participants (mean [SD] age, 33.7 [20.1] years; 320 were female [57.7%]), 47 of 123 children (38.2%) were asymptomatic compared with 31 of 432 adults (7.2%). When symptomatic, fewer symptoms were reported in children compared with adults (mean [SD], 1.6 [2.0] vs 4.5 [3.1]). Symptomatic individuals had lower Ct values (which corresponded to higher viral RNA levels) than asymptomatic individuals (adjusted estimate for children, −3.0; 95% CI, −5.5 to −0.6;P = .02; adjusted estimate for adults, −2.9; 95% CI, −5.2 to −0.6;P = .01). The difference in mean Ct values was neither statistically significant between symptomatic children and symptomatic adults (adjusted estimate, −0.7; 95% CI, −2.2 to 0.9;P = .41) nor between asymptomatic children and asymptomatic adults (adjusted estimate, −0.6; 95% CI, −4.0 to 2.8;P = .74). Conclusions and Relevance In this community-based cross-sectional study, SARS-CoV-2 RNA levels, as determined by Ct values, were significantly higher in symptomatic individuals than in asymptomatic individuals and no significant age-related differences were found. Further research is needed to understand the role of SARS-CoV-2 RNA levels and viral transmission.
70 citations
19 citations
TL;DR: In this paper, the authors investigated whether virus-containing aerosols were present in nursing stations and patient room hallways in a referral center with critically ill COVID-19 patients and found that none were positive for SARS-CoV-2 RNA by the estimated limit of detection of 8 viral copies/m3 of air.
Abstract: Background Previous research has shown that rooms of patients with coronavirus disease 2019 (COVID-19) present the potential for healthcare-associated transmission through aerosols containing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). However, data on the presence of these aerosols outside of patient rooms are limited. We investigated whether virus-containing aerosols were present in nursing stations and patient room hallways in a referral center with critically ill COVID-19 patients. Methods Eight National Institute for Occupational Safety and Health BC 251 2-stage cyclone samplers were set up throughout 6 units, including nursing stations and visitor corridors in intensive care units and general medical units, for 6 h each sampling period. Samplers were placed on tripods which held 2 samplers positioned 102 cm and 152 cm above the floor. Units were sampled for 3 days. Extracted samples underwent reverse transcription polymerase chain reaction for selected gene regions of the SARS-CoV-2 virus nucleocapsid and the housekeeping gene human RNase P as an internal control. Results The units sampled varied in the number of laboratory-confirmed COVID-19 patients present on the days of sampling. Some of the units included patient rooms under negative pressure, while most were maintained at a neutral pressure. Of 528 aerosol samples collected, none were positive for SARS-CoV-2 RNA by the estimated limit of detection of 8 viral copies/m3 of air. Conclusions Aerosolized SARS-CoV-2 outside of patient rooms was undetectable. While healthcare personnel should avoid unmasked close contact with each other, these findings may provide reassurance for the use of alternatives to tight-fitting respirators in areas outside of patient rooms during the current pandemic.
16 citations
TL;DR: In this article, the authors investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone, and found that poor clinical outcomes was associated with enrichment of the lower airway microbiota with an oral commensal (Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-coV2 antibody response, together with a unique host transcriptome profile of lower airways were most predictive of mortality.
Abstract: Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.
15 citations
TL;DR: In this article, the authors assessed surveyed COVID-19 vaccination intent among adult homeless shelter residents and staff and identified factors associated with vaccine deliberation (responded "undecided" or "no"), including time trends.
15 citations
13 citations
TL;DR: The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force as discussed by the authors.
Abstract: The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.
12 citations
TL;DR: Improved understanding of clinical phenotypes and risk factors for their development could help inform prognosis and tailored clinical management for COVID-19, and need to be validated in other cohorts.
Abstract: Background The epidemiological features and outcomes of hospitalized adults with coronavirus disease 2019 (COVID-19) have been described; however, the temporal progression and medical complications of disease among hospitalized patients require further study. Detailed descriptions of the natural history of COVID-19 among hospitalized patients are paramount to optimize health care resource utilization, and the detection of different clinical phenotypes may allow tailored clinical management strategies. Methods This was a retrospective cohort study of 305 adult patients hospitalized with COVID-19 in 8 academic and community hospitals. Patient characteristics included demographics, comorbidities, medication use, medical complications, intensive care utilization, and longitudinal vital sign and laboratory test values. We examined laboratory and vital sign trends by mortality status and length of stay. To identify clinical phenotypes, we calculated Gower's dissimilarity matrix between each patient's clinical characteristics and clustered similar patients using the partitioning around medoids algorithm. Results One phenotype of 6 identified was characterized by high mortality (49%), older age, male sex, elevated inflammatory markers, high prevalence of cardiovascular disease, and shock. Patients with this severe phenotype had significantly elevated peak C-reactive protein creatinine, D-dimer, and white blood cell count and lower minimum lymphocyte count compared with other phenotypes (P < .01, all comparisons). Conclusions Among a cohort of hospitalized adults, we identified a severe phenotype of COVID-19 based on the characteristics of its clinical course and poor prognosis. These findings need to be validated in other cohorts, as improved understanding of clinical phenotypes and risk factors for their development could help inform prognosis and tailored clinical management for COVID-19.
9 citations
TL;DR: A standardized literature review was conducted on the clinical, pathological, vaccine, and treatment factors for South American Hemorrhagic fevers as a group and for each individual virus/disease.
TL;DR: Observational data show a reduction of severe outcomes when pregnant and postpartum women are treated with oseltamivir and other neuraminidase inhibitors without increased risk of adverse maternal, fetal, or neonatal outcomes.
Abstract: Seasonal influenza epidemics result in substantial health care burden annually. Early initiation of antiviral treatment of influenza has been shown to reduce the risk of complications and duration of illness. Pregnant and postpartum women may be at increased risk for influenza-associated complications; however, pregnant women have been generally excluded from clinical trials of antiviral treatment of influenza. In this review, we summarize the available evidence on the clinical effectiveness and safety of antiviral treatment of pregnant women with influenza. Observational data show a reduction of severe outcomes when pregnant and postpartum women are treated with oseltamivir and other neuraminidase inhibitors without increased risk of adverse maternal, fetal, or neonatal outcomes. Due to lack of safety and efficacy data for baloxavir treatment of pregnant and postpartum women, baloxavir is currently not recommended for use in these populations.
29 Mar 2021
TL;DR: In this paper, the authors investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone, and found that poor clinical outcomes was associated with enrichment of the lower airway microbiota with an oral commensal (Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-coV2 antibody response, together with a unique host transcriptome profile of lower airways were most predictive of mortality.
Abstract: Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.
TL;DR: In this article, a pilot interventional study of remote influenza diagnosis and treatment in Seattle-area households with children during the 2019-2020 influenza season using pre-positioned nasal swabs and home influenza tests was conducted.
Abstract: Background Households represent important settings for transmission of influenza and other respiratory viruses Current influenza diagnosis and treatment relies upon patient visits to healthcare facilities, which may lead to under-diagnosis and treatment delays This study aimed to assess the feasibility of an at-home approach to influenza diagnosis and treatment via home testing, telehealth care, and rapid antiviral home delivery Methods We conducted a pilot interventional study of remote influenza diagnosis and treatment in Seattle-area households with children during the 2019-2020 influenza season using pre-positioned nasal swabs and home influenza tests Home monitoring for respiratory symptoms occurred weekly; if symptoms were reported within 48 hours of onset, participants collected mid-nasal swabs and used a rapid home-based influenza immunoassay An additional home-collected swab was returned to a laboratory for confirmatory influenza RT-PCR testing Baloxavir antiviral treatment was prescribed and delivered to symptomatic and age-eligible participants, following a telehealth encounter Results 124 households comprising 481 individuals self-monitored for respiratory symptoms, with 58 home tests administered 12 home tests were positive for influenza, of which eight were true positives confirmed by RT-PCR The sensitivity and specificity of the home influenza test were 727% and 962%, respectively There were eight home deliveries of baloxavir, with 7 (875%) occurring within 3 hours of prescription and all within 48 hours of symptom onset Conclusions We demonstrate the feasibility of self-testing combined with rapid home delivery of influenza antiviral treatment This approach may be an important control strategy for influenza epidemics and pandemics
TL;DR: In this article, the authors investigated the presence of aerosols containing SARS-CoV-2 inside of dedicated COVID-19 patient rooms and found that three National Institute for Occupational Safety and Health BC 251 samplers were set up in each patient room for a six-hour sampling period.
Abstract: Evidence varies as to how far aerosols spread from individuals infected with SARS-CoV-2 in hospital rooms. We investigated the presence of aerosols containing SARS-CoV-2 inside of dedicated COVID-19 patient rooms. Three National Institute for Occupational Safety and Health BC 251 two-stage cyclone samplers were set up in each patient room for a six-hour sampling period. Samplers were place on tripods, which each held two samplers at various heights above the floor. Extracted samples underwent reverse transcription polymerase chain reaction for selected gene regions of the SARS-CoV-2 virus nucleocapsid. Patient medical data were compared between participants in rooms where virus-containing aerosols were detected and those where they were not. Of 576 aerosols samples collected from 19 different rooms across 32 participants, 3% (19) were positive for SARS-CoV-2, the majority from near the head and foot of the bed. Seven of the positive samples were collected inside a single patient room. No significant differences in participant clinical characteristics were found between patients in rooms with positive and negative aerosol samples. SARS-CoV-2 viral aerosols were detected from the patient rooms of nine participants (28%). These findings provide reassurance that personal protective equipment that was recommended for this virus is appropriate given its spread in hospital rooms.
TL;DR: In this paper, the authors describe the methodology for study implementation, challenges encountered, and key issues that impacted EVD vision care in the immediate aftermath of the 2014-2016 West African Ebola virus disease (EVD) outbreak in Sierra Leone.
Abstract: Background Following the West African Ebola virus disease (EVD) outbreak of 2013-2016 and more recent EVD outbreaks in the Democratic Republic of Congo, thousands of EVD survivors are at-risk for sequelae including uveitis, which can lead to unremitting inflammation and vision loss from cataract. Because of the known risk of Ebola virus persistence in ocular fluid and the need to provide vision-restorative, safe cataract surgery, the Ebola Virus Persistence in Ocular Tissues and Fluids (EVICT) Study was implemented in Sierra Leone. During implementation of this multi-national study, challenges included regulatory approvals, mobilization, community engagement, infection prevention and control, and collaboration between multiple disciplines. In this report, we address the multifacted approach to address these challenges and the impact of implementation science research to address an urgent clinical subspecialty need in an outbreak setting. Methodology/principal findings Given the patient care need to develop a protocol to evaluate ocular fluid for Ebola virus RNA persistence prior to cataract surgery, as well as protocols to provide reassurance to ophthalmologists caring for EVD survivors with cataracts, the EVICT study was designed and implemented through the work of the Ministry of Health, Sierra Leone National Eye Programme, and international partnerships. The EVICT study showed that all 50 patients who underwent ocular fluid sampling at 19 and 34 months, respectively, tested negative for Ebola virus RNA. Thirty-four patients underwent successful cataract surgery with visual acuity improvement. Here we describe the methodology for study implementation, challenges encountered, and key issues that impacted EVD vision care in the immediate aftermath of the EVD outbreak. Key aspects of the EVICT study included defining the pertinent questions and clinical need, partnership alignment with key stakeholders, community engagement with EVD survivor associations, in-country and international regulatory approvals, study site design for infection prevention and control, and thorough plans for EVD survivor follow-up care and monitoring. Challenges encountered included patient mobilization owing to transportation routes and distance of patients in rural districts. Strong in-country partnerships and multiple international organizations overcame these challenges so that lessons learned could be applied for future EVD outbreaks in West and Central Africa including EVD outbreaks that are ongoing in Guinea and Democratic Republic of Congo. Conclusions/significance The EVICT Study showed that cataract surgery with a protocol-driven approach was safe and vision-restorative for EVD survivors, which provided guidance for EVD ophthalmic surgical care. Ophthalmologic care remains a key aspect of the public health response for EVD outbreaks but requires a meticulous, yet partnered approach with international and local in-country partners. Future efforts may build on this framework for clinical care and to improve our understanding of ophthalmic sequelae, develop treatment paradigms for EVD survivors, and strengthen vision health systems in resource-limited settings.
TL;DR: Findings from the INVESTED trial compared the relative efficacy of 2 influenza vaccines on outcomes of relevance to the global public health community: death from all causes and cardiopulmonary hospitalizations are compared.
01 Jan 2021
TL;DR: In this paper, a pilot interventional study of remote influenza diagnosis and treatment in Seattle-area households with children during the 2019-2020 influenza season using pre-positioned nasal swabs and home influenza tests was conducted.
Abstract: Background Households represent important settings for transmission of influenza and other respiratory viruses Current influenza diagnosis and treatment relies upon patient visits to healthcare facilities, which may lead to under-diagnosis and treatment delays This study aimed to assess the feasibility of an at-home approach to influenza diagnosis and treatment via home testing, telehealth care, and rapid antiviral home delivery Methods We conducted a pilot interventional study of remote influenza diagnosis and treatment in Seattle-area households with children during the 2019-2020 influenza season using pre-positioned nasal swabs and home influenza tests Home monitoring for respiratory symptoms occurred weekly; if symptoms were reported within 48 hours of onset, participants collected mid-nasal swabs and used a rapid home-based influenza immunoassay An additional home-collected swab was returned to a laboratory for confirmatory influenza RT-PCR testing Baloxavir antiviral treatment was prescribed and delivered to symptomatic and age-eligible participants, following a telehealth encounter Results 124 households comprising 481 individuals self-monitored for respiratory symptoms, with 58 home tests administered 12 home tests were positive for influenza, of which 8 were true positives confirmed by RT-PCR The sensitivity and specificity of the home influenza test was 727% and 962%, respectively There were 8 home deliveries of baloxavir, with 7 (875%) occurring within 3 hours of prescription, and all within 48 hours of symptom onset Conclusions We demonstrate the feasibility of self-testing combined with rapid home delivery of influenza antiviral treatment This approach may be an important control strategy for influenza epidemics and pandemics Summary In this pilot study, 481 individuals self-monitored for respiratory symptoms Of 58 home tests, 12 were influenza-positive There were 8 baloxavir home deliveries within 48 hours of illness onset A home-based approach to influenza diagnosis and treatment could be feasible