Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 11 de 11
Filter
1.
Acs Es&T Water ; : 12, 2022.
Article in English | Web of Science | ID: covidwho-1927042

ABSTRACT

Wastewater based epidemiology (WBE) has emerged as a tool to track the spread of SARS-CoV-2. However, sampling at wastewater treatment plants (WWTPs) cannot identify transmission hotspots within a city. Here, we sought to understand the diurnal variations (24 h) in SARS-CoV-2 RNA titers at the m A neighborhood level, using pump stations that serve vulnerable communities (e.g., essential workers, more diverse communities). Hourly composite samples were collected from wastewater pump stations located in (i) a residential area and (ii) a shopping district. In the residential area, SARS-CoV-2 RNA concentration (N1, N2, and E assays) varied by up to 42-fold within a 24 h period. The highest viral load was observed between 5 and 7 am, when viral RNA was not diluted by stormwater. Normalizing peak concentrations during this time window with nutrient concentrations (N and P) enabled correcting for rainfall to connect sewage to clinical cases reported in the sewershed. Data from the shopping district pump station were inconsistent, probably due to the fluctuation of customers shopping at the mall. This work indicates pump stations serving the residential area offer a narrow time period of high signal intensity that could improve the sensitivity of WBE, and tracer compounds (N, P concentration) can be used to normalize SARS-CoV-2 signals during rainfall.

2.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-333859

ABSTRACT

INTRODUCTION: Since March of 2020, over 210 million SARS-CoV-2 cases have been reported and roughly five billion doses of a SARS-CoV-2 vaccine have been delivered. The rise of the more infectious delta variant has recently indicated the value of reinstating previously relaxed non-pharmacological and test-driven preventative measures. These efforts have been met with resistance, due, in part, to a lack of site-specific quantitative evidence which can justify their value. As vaccination rates continue to increase, a gap in knowledge exists regarding appropriate thresholds for escalation and de-escalation of COVID-19 preventative measures. METHODS: We conducted a series of simulation experiments, trialing the spread of SARS-CoV-2 virus in a hypothesized working environment that is subject to COVID-19 infections from the surrounding community. We established cohorts of individuals who would, in simulation, work together for a set period of time. With these cohorts, we tested the rates of workplace and community acquired infections based on applied isolation strategies, community infection rates (CIR), scales of testing, non-pharmaceutical interventions, variant predominancea TMs and testing strategies, vaccination coverages, and vaccination efficacies of the members included. Permuting through each combination of these variables, we estimated expected case counts for 33,462 unique workplace scenarios. RESULTS: When the CIR is 5 new confirmed cases per 100,000 or fewer, and at 50% of the workforce is vaccinated with a 95% efficacious vaccine, then testing daily with an antigen-based or PCR based test in only unvaccinated workers will result in less than one infection through 4,800 person weeks. When the community infection rate per 100,000 persons is less than or equal to 60, and the vaccination coverage of the workforce is 100% with 95% vaccine efficacy then no masking or routine testing + isolation strategies are needed to prevent workplace acquired infections regardless of variant predominance. Identifying and isolating workers with antigen-based SARS-CoV-2 testing methods results in the same or fewer workplace acquired infections than testing with polymerase chain reaction (PCR) methods. CONCLUSIONS: Specific scenarios exist in which preventative measures taken to prevent SARS-CoV-2 spread, including masking, and testing plus isolation strategies can safely be relaxed. Further, efficacious testing with quarantine strategies exist for implementation in only unvaccinated cohorts in a workplace. Due to shorter turnaround time, antigen-based testing with lower sensitivity is more effective than PCR testing with higher sensitivities in comparable testing strategies. The general reference interactive heatmap we provide can be used for site specific, immediate, parameter-based case count predictions to inform appropriate institutional policy making.

3.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-333772

ABSTRACT

BACKGROUND: The first confirmed case of SARS-CoV-2 in North America was identified in Washington state on January 21, 2020. We aimed to quantify the number and temporal trends of out-of-state introductions of SARS-CoV-2 into Washington. METHODS: We conducted a phylogenetic analysis of 11,422 publicly available whole genome SARS-CoV-2 sequences from GISAID sampled between December 2019 and September 2020. We used maximum parsimony ancestral state reconstruction methods on time-calibrated phylogenies to enumerate introductions/exports, their likely geographic source (e.g. US, non-US, and between eastern and western Washington), and estimated date of introduction. To incorporate phylogenetic uncertainty into our estimates, we conducted 5,000 replicate analyses by generating 25 random time-stratified samples of non-Washington reference sequences, 20 random polytomy resolutions, and 10 random resolutions of the reconstructed ancestral state. RESULTS: We estimated a minimum 287 separate introductions (median, range 244-320) into Washington and 204 exported lineages (range 188-227) of SARS-CoV-2 out of Washington. Introductions began in mid-January and peaked on March 29, 2020. Lineages with the Spike D614G variant accounted for the majority (88%) of introductions. Overall, 61% (range 55-65%) of introductions into Washington likely originated from a source elsewhere within the US, while the remaining 39% (range 35-45%) likely originated from outside of the US. Intra-state transmission accounted for 65% and 28% of introductions into eastern and western Washington, respectively. CONCLUSIONS: There is phylogenetic evidence that the SARS-CoV-2 epidemic in Washington is continually seeded by a large number of introductions, and that there was significant inter- and intra-state transmission. Due to incomplete sampling our data underestimate the true number of introductions.

4.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-333599

ABSTRACT

OBJECTIVE: To evaluate the effectiveness of SARS-CoV-2 testing on shortening the duration of quarantines for COVID-19 and to identify the most effective choices of testing schedules. DESIGN: We performed extensive simulations to evaluate the performance of quarantine strategies when one or more SARS-CoV-2 tests were administered during the quarantine. Simulations were based on statistical models for the transmissibility and viral loads of SARS-CoV-2 infections and the sensitivities of available testing methods. Sensitivity analyses were performed to evaluate the impact of perturbations in model assumptions on the outcomes of optimal strategies. RESULTS: We found that SARS-CoV-2 testing can effectively reduce the length of a quarantine without compromising safety. A single RT-PCR test performed before the end of quarantine can reduce quarantine duration to 10 days. Two tests can reduce the duration to 8 days, and three highly sensitive RT-PCR tests can justify a 6-day quarantine. More strategic testing schedules and longer quarantines are needed if tests are administered with less sensitive RT-PCR tests or antigen tests. Shorter quarantines can be utilized for applications that tolerate a residual post-quarantine transmission risk comparable to a 10-day quarantine. CONCLUSIONS: Testing could substantially reduce the length of isolation, reducing the physical and mental stress caused by lengthy quarantines. With increasing capacity and lowered costs of SARS-CoV-2 tests, test-assisted quarantines could be safer and more cost-effective than 14-day quarantines and warrant more widespread use. RESEARCH IN CONTEXT: What is already known on this topic?: Recommendations for quarantining individuals who could have been infected with COVID-19 are based on limited evidence.Despite recent theoretical and case studies of test-assisted quarantines, there has been no substantive investigation to quantify the safety and efficacy of, nor an exhaustive search for, optimal test-assisted quarantine strategies. WHAT THIS STUDY ADDS: Our simulations indicate that the 14-day quarantine approach is overly conservative and can be safely shortened if testing is performed.Our recommendations include testing schedules that could be immediately adopted and implemented as government and industry policies. ROLE OF THE FUNDING SOURCE: A major technology company asked that we perform simulations to understand the optimal strategy for managing personnel quarantining before forming cohorts of individuals who would work closely together. The funding entity did not influence the scope or output of the study but requested that we include antigen testing as a component of the quarantining process. Patrick Yu and Peter Matos are employees of Corporate Medical Advisors, and International S.O.S employs Julie McCashin. Other funding sources are research grants and did not influence the investigation.

5.
Blood ; 138(SUPPL 1):1363, 2021.
Article in English | EMBASE | ID: covidwho-1770425

ABSTRACT

Background: Standard chemoimmunotherapy for first-line treatment of follicular lymphoma (FL) achieves high rates of disease control but is not curative and carries significant toxicities including prolonged immunosuppression that may attenuate response to vaccinations (Marcus et al., NEJM 2017). While proteasome inhibitors have shown modest activity in R/R FL (Goy et al., JCO 2005), limited data address their use frontline. The comparatively favorable toxicity profile and convenient oral dosing of ixazomib support its investigation in this space. Methods: We evaluated ixazomib and its combination with short-course rituximab (R) for FL as part of an open-label, phase II investigator-initiated trial at the University of Washington / Fred Hutch Cancer Research Center / Seattle Cancer Care Alliance (NCT 02339922). Eligibility included an indication for treatment per NCCN guidelines and no prior standard systemic FL therapy. Ixazomib was administered at 4 mg orally once a week until disease progression or unmanageable toxicity. One course of R at 4 weekly doses of 375 mg/m2 was added during the 7th 28-day cycle, after an initial 6-cycle “window” on ixazomib alone. Available pretreatment formalin-fixed, paraffin-embedded tissue biopsies were subjected to RNA extraction by standard methods and gene expression profiling (GEP) using the NanoString™ PanCancer IO 360 panel to query pathways in proteasomal degradation and lymphomagenesis. Standard GEP quality control and data processing were performed with the ROSALIND® platform. Patients vaccinated per standard of care for COVID-19 while actively receiving ixazomib and ≥ 6 mo after completing R were evaluated for serologic response ≥ 2 weeks after the final dose of vaccine using the Roche Elecsys® Anti-SARS-CoV-2 S assay against the spike protein receptor binding domain. Results: Twenty pts began therapy between Feb 2017 and January 2020. All had grade I/II FL and FLIPI score was 2 in 20% and ≥ 3 in 20%;FLIPI score in all other patients was 0 or 1. Eleven (55%) pts met GELF criteria for high tumor burden disease including 6 (30%) pts with a tumor mass ≥ 7 cm. Median follow-up was 32.1 months (range 5.7 - 51.6). The ORR by Lugano criteria was 35% (CR 5%) during the ixazomib window and 65% (CR 45%) overall. At data cut (June 15, 2021) all patients were alive and 8 (40%) remained progression-free on treatment (Figure 1). By KM estimate, median PFS was 25.8 mo and median DOR was not reached at a median follow-up of 29.6 mo. As expected, high-grade treatment-related AEs were infrequent for ixazomib and R, including grade ≥ 3 events in 3 unique pts (15%;diarrhea, transaminitis, and cytopenias). No grade ≥ 4 or serious AEs were observed. Toxicities led to study-directed drug interruptions in 4 (20%) pts and dose reduction to ixazomib 3 mg weekly in 2 pts (10%). Higher ORR to ixazomib monotherapy was associated with FLIPI > 1 (p = 0.04) and, by exploratory GEP, downregulation of components of proteasomal degradation and upregulation of NF-KB and chemokine signaling (Figure 2). High tumor burden by GELF (p = 0.89) and tumor mass ≥ 7 cm (p = 0.26) were not associated with ORR to ixazomib. All 6 of 6 patients evaluated to date for response to COVID-19 vaccination, administered at a median of 32.5 mo (range 7.0 - 41.0) after last dose of R, achieved positive anti-spike protein antibodies (median anti-S 163.8 AU/mL, range 13.3 - 1139);none was diagnosed with COVID-19. Conclusions: The simple outpatient regimen of weekly oral ixazomib and the addition of 4 doses of R shows significant long-term activity with low toxicity in untreated FL. Extended DOR is achievable especially in patients who respond to ixazomib monotherapy. Ixazomib efficacy was associated with higher FLIPI scores and gene expression signatures implicated in proteasomal degradation and B-cell signaling pathways. Ixazomib deserves further investigation as a biomarker-driven therapeutic in untreated FL, particularly as an option that prioritizes outpatient management and serologic responsiveness to im unization. (Figure Presented).

6.
Open Forum Infectious Diseases ; 8(SUPPL 1):S345, 2021.
Article in English | EMBASE | ID: covidwho-1746508

ABSTRACT

Background. Antenatal care is a unique opportunity to assess SARS-CoV-2 seroprevalence and antibody response in pregnant people, including those with previously unknown infection. Methods. Pregnant people were screened for SARS-CoV-2 IgG during antenatal care or delivery in Seattle, Washington with Abbott Architect chemiluminescent immunoassay which provides quantitative index (positive ≥1.4). Participants with IgG+ results or identified with RT-PCR+ results via medical records were invited to enroll in a longitudinal evaluation of antibody responses. We report preliminary results of an ongoing seroprevalence and longitudinal study with planned 18-month follow-up. Results. Between September 9, 2020-May 7, 2021, we screened 1304 pregnant people;62 (4.8%) tested SARS-CoV-2 IgG+, including 28 (45%) with known prior SARS-CoV-2 infection. Among participants testing IgG+, median age was 32 years (interquartile range [IQR] 26-35) and median gestational age was 21 weeks (IQR 12-38) at screening;median IgG index was 3.2 (IQR 2.1-4.9, range 1.4-9.9), including 3.9 (IQR 2.3-5.8) among those with vs. 2.7 (IQR 1.9-4.2) among those without prior RT-PCR+ results (p=0.05 by Wilcoxon rank-sum). Of 30 longitudinal study participants enrolled, 24 tested IgG+ at baseline (75% with prior RT-PCR+ result) and 6 tested IgG- on enrollment but were identified as previously RT-PCR+ via medical records;24/30 (80%) reported previous symptoms. Of 24 participants testing IgG+ at baseline, 14 (58%) had first follow-up IgG results at median of 66 days (IQR 42-104) since initial testing, with median IgG index of 2.0 (IQR 1.0-3.8). 9/14 (64%) participants with repeat IgG testing remained IgG+ at first follow-up (≤280 days after first RT-PCR+ result for those with and ≥104 days after first IgG detection for those without prior RT-PCR+ results), while 5/14 (26%) had a negative Abbott IgG test at a median of 81 days (IQR 75-112) since initial testing. Conclusion. Nearly half of pregnant people testing SARS-CoV-2 IgG+ reported no known prior SARS-CoV-2 diagnosis or symptoms. SARS-CoV-2 IgG antibody response and durability in pregnancy has implications for maternal and neonatal protection and susceptibility and highlights potential benefits of vaccination in this population.

7.
Morbidity and Mortality Weekly Report ; 69(14):416-418, 2020.
Article in English | GIM | ID: covidwho-1717418

ABSTRACT

Community transmission of COVID-19 has been associated with rapid spread and high morbidity and mortality among older adults in long-term skilled nursing facilities. COVID-19 transmission in other types of senior living communities has not been described. Following identification of two COVID-19 cases in a Seattle independent and assisted living facility, stringent preventive measures were implemented. Testing of all residents and staff members found few cases of COVID-19. Three of four residents who had positive test results were asymptomatic. Symptom-based screening might not identify SARS-CoV-2 infections in independent and assisted living facility residents, underscoring the importance of adhering to CDC guidance to prevent COVID-19 transmission in senior living communities.

8.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-329485

ABSTRACT

Background: Novel SARS-CoV-2 Variants of Concern (VoC) pose a challenge to controlling the COVID-19 pandemic. Previous studies indicate that clinical samples collected from individuals infected with the Delta variant may contain higher levels of RNA than previous variants, but the relationship between viral RNA and infectious virus for individual variants is unknown. Methods: We measured infectious viral titer (using a micro-focus forming assay) as well as total and subgenomic viral RNA levels (using RT-PCR) in a set of 165 clinical samples containing SARS-CoV-2 Alpha, Delta and Epsilon variants that were processed within two days of collection from the patient. Results: We observed a high degree of variation in the relationship between viral titers and RNA levels. Despite the variability we observed for individual samples the overall infectivity differed among the three variants. Both Delta and Epsilon had significantly higher infectivity than Alpha, as measured by the number of infectious units per quantity of viral E gene RNA (6 and 4 times as much, p=0.0002 and 0.009 respectively) or subgenomic E RNA (11 and 7 times as much, p<0.0001 and 0.006 respectively). Conclusion: In addition to higher viral RNA levels reported for the Delta variant, the infectivity (amount of replication competent virus per viral genome copy) may also be increased compared to Alpha. Measuring the relationship between live virus and viral RNA is an important step in assessing the infectivity of novel SARS-CoV-2 variants. An increase in the infectivity of the Delta variant may further explain increased spread and suggests a need for increased measures to prevent viral transmission. SIGNIFICANCE STATEMENT: Current and future SARS-CoV-2 variants threaten our ability to control the COVID-19 pandemic. Variants with increased transmission, higher viral loads, or greater immune evasion are of particular concern. Viral loads are currently measured by the amount of viral RNA in a clinical sample rather than the amount of infectious virus. We measured both RNA and infectious virus levels directly in a set of 165 clinical specimens from Alpha, Epsilon or Delta variants. Our data shows that Delta is more infectious compared to Alpha, with a

9.
MEDLINE;
Preprint in English | MEDLINE | ID: ppcovidwho-326686

ABSTRACT

Resistance mutations to monoclonal antibody (mAb) therapy has been reported, but in the non-immunosuppressed population, it is unclear if in vivo emergence of SARS-CoV-2 resistance mutations alters either viral replication dynamics or therapeutic efficacy. In ACTIV-2/A5401, non-hospitalized participants with symptomatic SARS-CoV-2 infection were randomized to bamlanivimab (700mg or 7000mg) or placebo. Treatment-emergent resistance mutations were significantly more likely detected after bamlanivimab 700mg treatment than placebo (7% of 111 vs 0% of 112 participants, P=0.003). There were no treatment-emergent resistance mutations among the 48 participants who received bamlanivimab 7000mg. Participants with emerging mAb resistant virus had significantly higher pre-treatment nasopharyngeal and anterior nasal viral load. Intensive respiratory tract viral sampling revealed the dynamic nature of SARS-CoV-2 evolution, with evidence of rapid and sustained viral rebound after emergence of resistance mutations, and worsened symptom severity. Participants with emerging bamlanivimab resistance often accumulated additional polymorphisms found in current variants of concern/interest and associated with immune escape. These results highlight the potential for rapid emergence of resistance during mAb monotherapy treatment, resulting in prolonged high level respiratory tract viral loads and clinical worsening. Careful virologic assessment should be prioritized during the development and clinical implementation of antiviral treatments for COVID-19.

10.
MEDLINE;
Preprint in English | MEDLINE | ID: ppcovidwho-326567

ABSTRACT

Since its emergence and detection in Wuhan, China in late 2019, the novel coronavirus SARS-CoV-2 has spread to nearly every country around the world, resulting in hundreds of thousands of infections to date. The virus was first detected in the Pacific Northwest region of the United States in January, 2020, with subsequent COVID-19 outbreaks detected in all 50 states by early March. To uncover the sources of SARS-CoV-2 introductions and patterns of spread within the U.S., we sequenced nine viral genomes from early reported COVID-19 patients in Connecticut. Our phylogenetic analysis places the majority of these genomes with viruses sequenced from Washington state. By coupling our genomic data with domestic and international travel patterns, we show that early SARS-CoV-2 transmission in Connecticut was likely driven by domestic introductions. Moreover, the risk of domestic importation to Connecticut exceeded that of international importation by mid-March regardless of our estimated impacts of federal travel restrictions. This study provides evidence for widespread, sustained transmission of SARS-CoV-2 within the U.S. and highlights the critical need for local surveillance.

11.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-296673

ABSTRACT

SARS-CoV-2 remdesivir resistance mutations have been generated in vitro but have not been reported in patients receiving treatment with the antiviral agent. We present a case of an immunocompromised patient with acquired B-cell deficiency who developed an indolent, protracted course of SARS-CoV-2 infection. Remdesivir therapy alleviated symptoms and produced a transient virologic response, but her course was complicated by recrudescence of high-grade viral shedding. Whole genome sequencing identified a mutation, E802D, in the nsp12 RNA-dependent RNA polymerase, which was not present in pre-treatment specimens. In vitro experiments demonstrated that the mutation conferred a ~6-fold increase in remdesivir IC50 but resulted in a fitness cost in the absence of remdesivir. Sustained clinical and virologic response was achieved after treatment with casirivimab-imdevimab. Although the fitness cost observed in vitro may limit the risk posed by E802D, this case illustrates the importance of monitoring for remdesivir resistance and the potential benefit of combinatorial therapies in immunocompromised patients with SARS-CoV-2 infection.

SELECTION OF CITATIONS
SEARCH DETAIL