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Background Unusually high snowfall in western Washington State in February 2019 led to widespread school and workplace closures. We assessed the impact of social distancing caused by this extreme weather event on the transmission of respiratory viruses. Methods Residual specimens from patients evaluated for acute respiratory illness at hospitals in the Seattle metropolitan area were screened for a panel of respiratory viruses. Transmission models were fit to each virus to estimate the magnitude reduction in transmission due to weather-related disruptions. Changes in contact rates and care-seeking were informed by data on local traffic volumes and hospital visits. Results Disruption in contact patterns reduced effective contact rates during the intervention period by 16 to 95%, and cumulative disease incidence through the remainder of the season by 3 to 9%. Incidence reductions were greatest for viruses that were peaking when the disruption occurred and least for viruses in an early epidemic phase. Conclusion High-intensity, short-duration social distancing measures may substantially reduce total incidence in a respiratory virus epidemic if implemented near the epidemic peak. For SARS-CoV-2, this suggests that, even when SARS-CoV-2 spread is out of control, implementing short-term disruptions can prevent COVID-19 deaths.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection elicits an antibody response that targets several viral proteins including spike (S) and nucleocapsid (N); S is the major target of neutralizing antibodies. Here, we assess levels of anti-N binding antibodies and anti-S neutralizing antibodies in unvaccinated children compared with unvaccinated older adults following infection. Specifically, we examine neutralization and anti-N binding by sera collected up to 52 weeks following SARS-CoV-2 infection in children and compare these to a cohort of adults, including older adults, most of whom had mild infections that did not require hospitalization. Neutralizing antibody titers were lower in children than adults early after infection, but by 6 months titers were similar between age groups. The neutralizing activity of the children’s sera decreased modestly from one to six months; a pattern that was not significantly different from that observed in adults. However, infection of children induced much lower levels of anti-N antibodies than in adults, and levels of these anti-N antibodies decreased more rapidly in children than in adults, including older adults. These results highlight age-related differences in the antibody responses to SARS-CoV-2 proteins and, as vaccines for children are introduced, may provide comparator data for the longevity of infection-elicited and vaccination-induced neutralizing antibody responses.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection elicits antibodies (Abs) that bind several viral proteins such as the spike entry protein and the abundant nucleocapsid (N) protein. We examined convalescent sera collected through 6 months (~24wks) post-SARS-CoV-2 infection in children to evaluate changes in neutralization potency and N-binding. Methods Outpatient, hospitalized, and community recruited volunteers < 18 years with COVID-19 were enrolled in a longitudinal study at Seattle Children’s Hospital. Analysis includes symptomatic and asymptomatic children with laboratory-confirmed SARS-CoV-2 infection who provided blood samples at approximately 4wks (range: 2-18wks, IQR:4-8wks) and 24 wks (range: 23-35wks, IQR:25-27wks) after diagnosis. We measured neutralizing Ab using an in-house pseudoneutralization assay and anti-N binding Ab using the Abbott Architect assay. Results Of 32 children enrolled between April 2020 and January 2021, 27 had no underlying immunocompromised state and 25 of these 27 children had symptomatic disease. Ten of 27 had a > 2-fold decrease neutralization titers between 4 and 24wks (most were < 10-fold); 12 had < 2-fold change; and 5 had neutralization titers that increased > 2-fold over time (Fig. 1A). All but one of these 27 children had detectable neutralizing activity at 24wks. Anti-N Abs were assessed for 25 children at 4wks and 17 children at 24wks (data pending for 14 samples); all children with paired samples had a > 1.75-fold Abbott index reduction at 24wks, and 5 children had no detectable anti-N Abs by 24wks (Fig. 2A). An additional 5 children with symptomatic disease had complicating immunosuppression or multiple blood transfusions; 2 had decreasing neutralizing titers, 2 increased, and 1 had no change (Fig. 1B). Anti-N Abs were undetectable for one child by 24wks (data pending for 4 samples) (Fig. 2B). No participants received COVID-19 vaccine. Figure 1. Pseusoneutralization titers in children over time. Figure 2. Nucleocapsid-binding antibody titers in children over time. Conclusion We show neutralizing Abs wane to a small degree over 24wks post-SARS-CoV-2 infection and remain detectable in most children. In contrast, anti-N Abs decreased, becoming undetectable in some children by 24wks. These findings add to understanding of the natural history of SARS-CoV-2 immunity in children. * This study was supported by CDC BAA75D301-20-R-67897 Disclosures Jesse Bloom, PhD, Flagship Labs 77 (Consultant)Moderna (Consultant) Janet A. Englund, MD, AstraZeneca (Consultant, Grant/Research Support)GlaxoSmithKline (Research Grant or Support)Meissa Vaccines (Consultant)Pfizer (Research Grant or Support)Sanofi Pasteur (Consultant)Teva Pharmaceuticals (Consultant)

IntroductionInfluenza epidemics and pandemics cause significant morbidity and mortality. An effective response to a potential pandemic requires the infrastructure to rapidly detect, characterize, and potentially contain new and emerging influenza strains at a population level. The objective of this study is to use data gathered simultaneously from community and hospital sites to develop a model of how influenza enters and spreads in a population.Methods and AnalysisStarting in the 2018-19 season, we have been enrolling individuals with acute respiratory illness from community sites throughout the Seattle metropolitan area, including clinics, childcare facilities, Seattle-Tacoma International Airport, workplaces, college campuses, and homeless shelters. At these sites, we collect clinical data and mid-nasal swabs from individuals with at least two acute respiratory symptoms. Additionally, we collect residual nasal swabs and data from individuals who seek care for respiratory symptoms at four regional hospitals. Samples are tested using a multiplex molecular assay, and influenza whole genome sequencing is performed for samples with influenza detected. Geospatial mapping and computational modeling platforms are in development to characterize the regional spread of influenza and other respiratory pathogens.Ethics and DisseminationThe study was approved by the University of Washington’s Institutional Review Board. Results will be disseminated through talks at conferences, peer-reviewed publications, and on the study website (www.seattleflu.org).Article SummaryStrengths and limitations of this study-Large-scale multiple-arm study of respiratory illness characterization with collection of samples from individuals in the community as well as in ambulatory care and hospital settings-Integration of sociodemographic, clinical, and geospatial data on a regional level-Multiplex molecular testing for multiple viral and bacterial pathogens and whole genome sequencing of influenza for detailed molecular epidemiologic characterization and transmission mapping-Geographically and socioeconomically diverse sampling of community-based acute respiratory illnesses

Detection of Covid-19 through a Citywide Surveillance Platform The Seattle Flu study, initiated in 2018, mailed kits for home collection of midnasal swabs to people reporting respiratory symptoms. ...

Children are strikingly underrepresented in COVID-19 case counts. In the United States, children represent 22% of the population but only 1.7% of confirmed SARS-CoV-2 cases as of April 2, 2020. One possibility is that symptom-based viral testing is less likely to identify infected children, since they often experience milder disease than adults. Here, to better assess the frequency of pediatric SARS-CoV-2 infection, we serologically screen 1,775 residual samples from Seattle Children’s Hospital collected from 1,076 children seeking medical care during March and April of 2020. Only one child was seropositive in March, but seven were seropositive in April for a period seroprevalence of ≈1%. Most seropositive children (6/8) were not suspected of having had COVID-19. The sera of seropositive children have neutralizing activity, including one that neutralized at a dilution > 1:18,000. Therefore, an increasing number of children seeking medical care were infected by SARS-CoV-2 during the early Seattle outbreak despite few positive viral tests., COVID-19 disease is less common in children than adults, but the extent to which SARS-CoV-2 infections are missed through symptom-driven testing is not well understood. In this study, the authors show that approximately 1% of children seeking care for reasons other than COVID-19 at a Seattle hospital in March/April 2020 were seropositive for SARS-CoV-2.

A series of unfortunate events The history of how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread around the planet has been far from clear. Several narratives have been propagated by social media and, in some cases, national policies were forged in response. Now that many thousands of virus sequences are available, two studies analyzed some of the key early events in the spread of SARS-CoV-2. Bedford et al. found that the virus arrived in Washington state in late January or early February. The viral genome from the first case detected had mutations similar to those found in Chinese samples and rapidly spread and dominated subsequent undetected community transmission. The other viruses detected had origins in Europe. Worobey et al. found that early introductions into Germany and the west coast of the United States were extinguished by vigorous public health efforts, but these successes were largely unrecognized. Unfortunately, several major travel events occurred in February, including repatriations from China, with lax public health follow-up. Serial, independent introductions triggered the major outbreaks in the United States and Europe that still hold us in the grip of control measures. Science, this issue p. 571, p. 564, The first case of SARS-CoV-2 in Washington state occurred at the end of January and, by going undetected, sparked community transmission., After its emergence in Wuhan, China, in late November or early December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus rapidly spread globally. Genome sequencing of SARS-CoV-2 allows the reconstruction of its transmission history, although this is contingent on sampling. We analyzed 453 SARS-CoV-2 genomes collected between 20 February and 15 March 2020 from infected patients in Washington state in the United States. We find that most SARS-CoV-2 infections sampled during this time derive from a single introduction in late January or early February 2020, which subsequently spread locally before active community surveillance was implemented.

BACKGROUNDUnusually high snowfall in western Washington State in February 2019 led to widespread school and workplace closures. We assessed the impact of social distancing caused by this extreme weather event on the transmission of respiratory viruses.METHODSResidual specimens from patients evaluated for acute respiratory illness at hospitals in the Seattle metropolitan area were screened for a panel of respiratory viruses. Transmission models were fit to each virus, with disruption of contact rates and care-seeking informed by data on local traffic volumes and hospital admissions.RESULTSDisruption in contact patterns reduced effective contact rates during the intervention period by 16% to 95%, and cumulative disease incidence through the remainder of the season by 3% to 9%. Incidence reductions were greatest for viruses that were peaking when the disruption occurred and least for viruses in early epidemic phase.CONCLUSIONHigh-intensity, short-duration social distancing measures may substantially reduce total incidence in a respiratory virus epidemic if implemented near the epidemic peak.One sentence summaryDisruptions of school and work due to heavy snowfall in the Seattle metro area reduced the total size of respiratory virus epidemics by up to 9%.

Background Alaska Native (AN) infants are at risk for severe disease due to respiratory syncytial virus (RSV) and influenza. Maternal immunization protects young infants through transplacental antibody transfer. RSV- and influenza-specific transplacental antibody transfer in mother–infant pairs has not previously been evaluated in the AN population. Methods Serum samples collected during pregnancy and at birth from AN mother–infant pairs in the Yukon-Kuskokwim Delta region (YKD) of Alaska (2000–2011; n = 75) and predominantly white pairs in Seattle, Washington (2014–2016; n = 57), were tested for RSV and influenza antibody using a microneutralization and hemagglutination inhibition assay, respectively, and compared between sites. Results Mean RSV antibody concentrations in pregnant women in YKD and Seattle were similar (log2 RSV antibody 10.6 vs 10.7, P = .86), but cord blood RSV antibody concentrations were significantly lower in infants born to mothers in YKD compared with Seattle (log2 RSV antibody 11.0 vs 12.2, P < .001). Maternal and cord blood influenza antibody concentrations were lower for women and infants in YKD compared with Seattle for all 4 influenza antigens tested (all P < .05). The mean cord to maternal RSV antibody transfer ratio was 1.15 (standard deviation [SD], 0.13) in mother–infant pairs in Seattle compared with 1.04 (SD, 0.08) in YKD. Mean cord blood to maternal antibody transfer ratios for influenza antigens ranged from 1.22 to 1.42 in Seattle and from 1.05 to 1.59 in YKD. Conclusions Though the transplacental antibody transfer ratio was high (>1.0) for both groups, transfer ratios for RSV antibody were significantly lower in AN mother–infant pairs. Further studies are needed to elucidate the impact of lower transplacental antibody transfer on infant disease risk in rural Alaska. Alaska Native and continental US mother-infant pairs have high transplacental antibody transfer ratios (>1.0) for influenza and respiratory syncytial virus, but anti-respiratory syncytial virus antibody levels are significantly lower in Alaska Native pairs than in those from the continental US.

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.

Background Rhinovirus (RV) quantitation by reverse transcription-quantitative PCR is limited by variable amplification efficiency across genotypes. We used a precise viral quantitation method, reverse transcription-digital PCR (RT-dPCR), to characterize the role of viral load in clinical outcomes and in viral co-infections in children presenting to a tertiary hospital emergency department (ED). Methods Children < 18 years with respiratory symptoms for ≤ 14 days were enrolled from December 1, 2016 to December 31, 2018. Participants had nasal and throat specimens obtained and multiplex PCR testing with a commercial assay (FilmArray; bioMerieux). RV positive samples were quantified using RT-dPCR. Samples with sufficient viral load were sequenced at a 543 bp fragment of the RV VP4/VP2 region. RV species were assigned by comparison to RV sequences in GenBank using BLAST. Clinical data were collected into REDCap. T-tests were used to compare mean viral loads between groups. Results Of 1703 children enrolled in the ED, 697 were RV/enterovirus positive by FilmArray [median age 18 months (interquartile range 9–39 months)]. Of 590 subjects with viral load available, 276 (47%) were admitted to the hospital. Among RV mono-infections (N = 434), mean viral load did not differ between subjects admitted vs. discharged from the ED (7.03 log copies/mL for both, P = 0.97). Among admitted subjects with RV mono-infection, viral load also did not differ between subjects requiring supplemental oxygen vs. not (7.01 vs. 7.10 log copies/mL, P = 0.6). Subjects with viral co-infections had lower mean RV viral loads (6.31 log copies/mL) compared with those with RV only (7.03 log copies/mL; P < 0.001) (figure). Significantly different RV viral loads were seen with co-infections with respiratory syncytial virus (RSV), metapneumovirus (MPV) and parainfluenza (PIV), but not with influenza, adenovirus or coronavirus. In 525 sequenced samples (46% RV-A, 4% RV-B, 50% RV-C), viral load did not vary between RV viral species (P = 0.09). Conclusion Precise viral quantitation demonstrates children co-infected with RV and RSV, MPV or PIV have lower nasal viral loads than those with RV alone. Among RV mono-infections, RV viral load was not associated with admission or need for supplemental oxygen. Disclosures All authors: No reported disclosures.

Background Human rhinovirus (HRV) infections are highly prevalent, genetically diverse, and associated with both mild upper respiratory tract and more severe lower tract illnesses (LRTI).

BACKGROUND: Infants born prematurely or with underlying conditions are at increased risk of severe rotavirus disease and associated complications. Given the theoretical risk of nosocomial transmission of vaccine-type rotavirus, rotavirus vaccination is recommended for infants at or after discharge from neonatal care settings. Because the first dose should be administered by 104 days of age, some infants may be age-ineligible for vaccination if delayed until discharge. METHODS: This prospective cohort included infants admitted to an urban academic medical center between birth and 104 days who received care in intensive care settings. Pentavalent human-bovine reassortant rotavirus vaccine (RV5) was used, per routine clinical care. Stool specimens were collected weekly (February 2013–April 2014) and analyzed for rotavirus strains using real-time reverse transcription–polymerase chain reaction. Demographic and vaccine data were collected. RV5 safety was not assessed. RESULTS: Of 385 study infants, 127 were age-eligible for routine vaccinations during hospitalization. At discharge, 32.7% were up-to-date for rotavirus vaccination, compared with 82.7% for other vaccinations. Of rotavirus-unvaccinated infants, 42.6% were discharged at age >104 days and thus vaccination-ineligible. Of 1192 stool specimens collected, rotavirus was detected in 13 (1.1%): 1 wild-type strain from an unvaccinated infant; 12 vaccine-type strains from 9 RV5-vaccinated infants. No vaccine-type rotavirus cases were observed among unvaccinated infants (incidence rate: 0.0 [95% confidence interval: 0.0–1.5] cases per 1000 patient days at risk). CONCLUSIONS: These data suggest that delaying rotavirus vaccination until discharge from the hospital could lead to missed vaccination opportunities and may be unnecessary in institutions using RV5 with comparable infection control standards.

Background. Rhinovirus is the most common cause of viral respiratory tract infections in children. Virologicpredictors of lower respiratory tract infection (LRTI), such as viral load and the presence of another respiratoryvirus (coinfection), are not well characterized in pediatric outpatients.Methods. Mid-nasal turbinate samples were collected from children presenting for care to the SeattleChildren’s Hospital emergency department (ED) or urgent care with a symptomatic respiratory infectionbetween December 2011 and May 2013. A subset of samples was tested for rhinovirus viral load by real-timepolymerase chain reaction. Clinical data were collected by chart reviews. Multivariate logistic regression wasused to evaluate the relationship between viral load and coinfection and the risk for LRTI.Results. Rhinovirus wasthe most frequent respiratory virus detected in children younger than 3 years. Of 445patients with rhinovirus infection, 262 (58.9%) had LRTIs, 231 (51.9%) required hospital admission and 52(22.5%)werehospitalizedfor3 daysorlonger.Childrenwithnocomorbiditiesaccountedfor142(54%)of262rhinovirus LRTIs. Higher viral load was significantly associated with LRTI among illness episodes withrhinovirus alone (OR, 2.11; 95% confidence interval [CI], 1.24–3.58). Coinfection increased the risk of LRTI(OR, 1.83; 95% CI, 1.01–3.32).Conclusions. Rhinovirus was the most common pathogen detected among symptomatic young children in apediatric ED who had respiratory viral testing performed, with the majority requiring hospitalization. Higherrhinovirus viral load and coinfection increased disease severity. Virologic data may assist clinical decisionmaking for children with rhinovirus infections in the pediatric ED.Key words. rhinovirus; viral load; disease severity; coinfection; emergency department.Human rhinovirus (HRV) is the most common etiology ofviral upper respiratory tract infections (URTIs) in childrenworldwide and causes primarily mild self-limited infec-tions with rhinorrhea, cough, sore throat, and nasal con-gestion [1, 2]. HRV also causes lower respiratory tractinfections (LRTIs), particularly in young infants, theelderly, and patients with immunocompromising condi-tionssuchasasthma,malignancy,cysticfibrosis,orchronicobstructive pulmonary disease [3, 4]. Among outpatientspresenting forevaluation in the clinic setting, HRV is asso-ciated with a burden of disease similar to that of influenza[5]. However, frequent detection of HRV among asymp-tomatic children or in the presence of respiratory viralcoinfections, such as respiratory syncytial virus (RSV),makes it difficult to define its true etiologic role [4,6,7].Recentimprovementsinmoleculartechniques,includingreal-time quantitative polymerase chain reaction (qPCR)assays, have permitted increased identification of HRV asthecause ofrespiratorytractinfections [8].Anunderstand-ing of how to interpret virologic data is increasingly rele-vant to outpatient clinical care, because rapid multiplexPCR assays are used for the point-of-care diagnosis of re-spiratory viruses in emergency department (ED) and ur-gent care (UC) settings [9, 10]. Rapid tests can provideresults, including a semiquantitative measure of viral load(VL), in lessthan 1 hour [11].Rapid diagnosis of influenzain a pediatric ED has been shown to decrease antiviral use

Background Influenza epidemics and pandemics cause significant morbidity and mortality. An effective response to a potential pandemic requires the infrastructure to rapidly detect and contain new and emerging flu strains at a population level. The objective of this study was to use data gathered simultaneously from community and hospital sites to develop a model of how flu enters and spreads in a population. Methods In the 2018–2019 season, we enrolled individuals with respiratory illness from community sites throughout the Seattle area, including homeless shelters, childcare facilities, Seattle-Tacoma International Airport, workplaces, college campuses, clinics, and at home (Figure 1). We collected data and nasal swabs from individuals with at least two respiratory symptoms. Additionally, we collected residual nasal swabs and data from individuals who sought care at four regional hospitals. Home-based self-testing for influenza and prediction models for influenza were piloted. Swabs were tested with a multiplex molecular assay, and influenza whole-genome sequencing was performed. Geospatial mapping and computational modeling platforms were developed to characterize regional spread of respiratory pathogens. Results A total of 18,847 samples were collected in the 2018–2019 season. Of those tested to date, 291/3,653 (8%) community and 2,393/11,273 (21%) hospital samples have influenza detected. Of the community enrollments, 39% had influenza-like illness. Community enrollees were in age groups not well-represented from hospitals. Influenza A/H3N2 activity peaked on college campuses and homeless shelters 2 weeks before the peak in hospitals. We observed multiple independent introductions of influenza strains into the city and evidence of sustained transmission chains within the city (Figures 2 and 3). Conclusion Utilizing the city-wide infrastructure we developed, we observed the introduction of influenza A/H3N2 into the community before the hospital and evidence of transmissions of unique strains into and within the Seattle area. These data provide the blueprint for implementing city-wide, community-based surveillance systems for rapid detection, real-time assessment of transmission patterns, and interruption of spread of seasonal or pandemic strains. Disclosures Helen Y. Chu, MD MPH, Merck (Advisor or Review Panel member), Michael Boeckh, MD PhD, Ablynx (Consultant, Grant/Research Support), Ansun Biopharma (Consultant, Grant/Research Support), Bavarian Nordic (Consultant), Gilead (Consultant, Grant/Research Support), GlaxoSmithKline (Consultant), Vir Bio (Consultant, Grant/Research Support), Janet A. Englund, MD, Chimerix (Grant/Research Support), GlaxoSmithKline (Grant/Research Support), MedImmune/Astrazeneca (Grant/Research Support), Meissa Vaccines (Consultant), Merck (Grant/Research Support),Novavax (Grant/Research Support), Sanofi Pastuer (Consultant), Matthew Thompson, MD, Alere Inc. (Research Grant or Support), Roche Molecular Diagnostics (Consultant, Research Grant or Support, Speaker’s Bureau), . Other Authors: No reported disclosures.

Background. Children