Distinct patterns of within-host virus populations between two subgroups of human respiratory syncytial virus

Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in young children globally, but little is known about within-host RSV diversity. Here, we characterised within-host RSV populations using deep-sequencing data from 319 nasopharyngeal swabs collected during 2017–2020. RSV-B had lower consensus diversity than RSV-A at the population level, while exhibiting greater within-host diversity. Two RSV-B consensus sequences had an amino acid alteration (K68N) in the fusion (F) protein, which has been associated with reduced susceptibility to nirsevimab (MEDI8897), a novel RSV monoclonal antibody under development. In addition, several minor variants were identified in the antigenic sites of the F protein, one of which may confer resistance to palivizumab, the only licensed RSV monoclonal antibody. The differences in within-host virus populations emphasise the importance of monitoring for vaccine efficacy and may help to explain the different prevalences of monoclonal antibody-escape mutants between the two subgroups

Publisher Correction:: Distinct patterns of within-host virus populations between two subgroups of human respiratory syncytial virus

Correction to: Nature Communications https://doi.org/10.1038/s41467-021-25265-4, published online 26 August 2021. The original HTML version of this Article contained errors in the author affiliations, which were correct in the PDF version. Specifically, affiliations after number 14 in the PDF version were displaying incorrectly in the online version of the paper. This has been updated so that all affiliations are accurate in the HTML version of the Article

Year-to-year variation in attack rates could result in underpowered respiratory syncytial virus vaccine efficacy trials

Objectives: Year-to-year variation in respiratory viruses may result in lower attack rates than expected. We aimed to illustrate the impact of year-to-year variation in attack rates on the likelihood of demonstrating vaccine efficacy (VE). Study Design and Setting: We considered an individually randomized maternal vaccine trial against respiratory syncytial virus (RSV)-associated hospitalizations. For 10 RSV-associated hospitalizations per 1,000 infants, sample size to have 80% power for true VE of 50% and 70% was 9,846 and 4,424 participants. We reported power to show VE for varying attack rates, selected to reflect realistic year-to-year variation using observational studies. Eight scenarios including varying number of countries and seasons were developed to assess the influence of these trial parameters. Results: Including up to three seasons decreased the width of the interquartile range for power. Including more seasons concentrated statistical power closer to 80%. Least powered trials had higher statistical power with more seasons. In all scenarios, at least half of the trials had <80% power. For three-season trials, increasing the sample size by 10% reduced the percentage of underpowered trials to less than one-quarter of trials. Conclusion: Year-to-year variation in RSV attack rates should be accounted for during trial design. Mitigation strategies include recruiting over more seasons, or adaptive trial designs

World Health Organization Influenza-Like Illness Underestimates the Burden of Respiratory Syncytial Virus Infection in Community-Dwelling Older Adults

BACKGROUND: Respiratory syncytial virus (RSV) surveillance is heavily dependent on the influenza-like illness (ILI) case definition from the World Health Organization (WHO). Because ILI includes fever in its syndromic case definition, its ability to accurately identify acute respiratory tract infections (ARTI) caused by RSV in older adults is uncertain. METHODS: The accuracy of the WHO ILI and a modified ILI (requiring only self-reported fever) case definitions in identifying patients with PCR-confirmed RSV-ARTI was evaluated in community-dwelling older adults (≥60 years) from the prospective European RESCEU cohort study. RESULTS: Among 1040 participants, 750 ARTI episodes were analyzed including 36 confirmed RSV-ARTI. Due to a general lack of fever, sensitivity for RSV-ARTI was 33% for modified ILI and 11% for ILI. The area under the curve for both ILI definitions was 0.52 indicating poor discrimination for RSV. RSV-ARTI could not be distinguished from all other ARTI based on clinical symptoms. CONCLUSIONS: The use of ILI underestimated the occurrence of RSV-ARTI in community-dwelling older adults up to 9-fold (11% sensitivity). Because worldwide RSV surveillance depends largely on ILI, there is an urgent need for a better approach to measure the occurrence of RSV disease and the impact of future RSV vaccine introduction. Clinical Trials Registration. NCT03621930

Contact With Young Children Increases the Risk of Respiratory Infection in Older Adults in Europe-the RESCEU Study

BACKGROUND: Knowledge about how older adults get a respiratory infection is crucial for planning preventive strategies. We aimed to determine how contact with young children living outside of the household affects the risk of acute respiratory tract infections (ARTI) in community-dwelling older adults. METHODS: This study is part of the European RESCEU older adult study. Weekly surveillance was performed to detect ARTI throughout 2 winter seasons (2017-2018, 2018-2019). Child exposure, defined as having regular contact with children under 5 living outside of the subject's household, was assessed at baseline. The average attributable fraction was calculated to determine the fraction of ARTI explained by exposure to these children. RESULTS: We prospectively established that 597/1006 (59%) participants experienced at least 1 ARTI. Child exposure increased the risk of all-cause ARTI (adjusted odds ratio [aOR], 1.58; 95% confidence interval [CI], 1.21 -2.08; P = .001). This risk was highest in those with the most frequent contact (aOR, 1.80; 95% CI, 1.23-2.63; P = .003). The average attributable fraction of child exposure explaining ARTI was 10% (95% CI, 5%-15%). CONCLUSIONS: One of 10 ARTI in community-dwelling older adults is attributable to exposure to preschool children living outside of the household. CLINICAL TRIALS REGISTRATION: NCT03621930

Single-cell immune profiling reveals markers of emergency myelopoiesis that distinguish severe from mild respiratory syncytial virus disease in infants

Whereas most infants infected with respiratory syncytial virus (RSV) show no or only mild symptoms, an estimated 3 million children under five are hospitalized annually due to RSV disease. This study aimed to investigate biological mechanisms and associated biomarkers underlying RSV disease heterogeneity in young infants, enabling the potential to objectively categorize RSV-infected infants according to their medical needs. Immunophenotypic and functional profiling demonstrated the emergence of immature and progenitor-like neutrophils, proliferative monocytes (HLA-DR Low , Ki67+), impaired antigen-presenting function, downregulation of T cell response and low abundance of HLA-DR Low B cells in severe RSV disease. HLA-DR Low monocytes were found as a hallmark of RSV-infected infants requiring hospitalization. Complementary transcriptomics identified genes associated with disease severity and pointed to the emergency myelopoiesis response. These results shed new light on mechanisms underlying the pathogenesis and development of severe RSV disease and identified potential new candidate biomarkers for patient stratification

Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis

Background: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0–60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0–60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development. Methods: In this systematic analysis, we expanded our global RSV disease burden dataset by obtaining new data from an updated search for papers published between Jan 1, 2017, and Dec 31, 2020, from MEDLINE, Embase, Global Health, CINAHL, Web of Science, LILACS, OpenGrey, CNKI, Wanfang, and ChongqingVIP. We also included unpublished data from RSV GEN collaborators. Eligible studies reported data for children aged 0–60 months with RSV as primary infection with acute lower respiratory infection in community settings, or acute lower respiratory infection necessitating hospital admission; reported data for at least 12 consecutive months, except for in-hospital case fatality ratio (CFR) or for where RSV seasonality is well-defined; and reported incidence rate, hospital admission rate, RSV positive proportion in acute lower respiratory infection hospital admission, or in-hospital CFR. Studies were excluded if case definition was not clearly defined or not consistently applied, RSV infection was not laboratory confirmed or based on serology alone, or if the report included fewer than 50 cases of acute lower respiratory infection. We applied a generalised linear mixed-effects model (GLMM) to estimate RSV-associated acute lower respiratory infection incidence, hospital admission, and in-hospital mortality both globally and regionally (by country development status and by World Bank Income Classification) in 2019. We estimated country-level RSV-associated acute lower respiratory infection incidence through a risk-factor based model. We developed new models (through GLMM) that incorporated the latest RSV community mortality data for estimating overall RSV mortality. This review was registered in PROSPERO (CRD42021252400). Findings: In addition to 317 studies included in our previous review, we identified and included 113 new eligible studies and unpublished data from 51 studies, for a total of 481 studies. We estimated that globally in 2019, there were 33·0 million RSV-associated acute lower respiratory infection episodes (uncertainty range [UR] 25·4–44·6 million), 3·6 million RSV-associated acute lower respiratory infection hospital admissions (2·9–4·6 million), 26 300 RSV-associated acute lower respiratory infection in-hospital deaths (15 100–49 100), and 101 400 RSV-attributable overall deaths (84 500–125 200) in children aged 0–60 months. In infants aged 0–6 months, we estimated that there were 6·6 million RSV-associated acute lower respiratory infection episodes (4·6–9·7 million), 1·4 million RSV-associated acute lower respiratory infection hospital admissions (1·0–2·0 million), 13 300 RSV-associated acute lower respiratory infection in-hospital deaths (6800–28 100), and 45 700 RSV-attributable overall deaths (38 400–55 900). 2·0% of deaths in children aged 0–60 months (UR 1·6–2·4) and 3·6% of deaths in children aged 28 days to 6 months (3·0–4·4) were attributable to RSV. More than 95% of RSV-associated acute lower respiratory infection episodes and more than 97% of RSV-attributable deaths across all age bands were in low-income and middle-income countries (LMICs). Interpretation: RSV contributes substantially to morbidity and mortality burden globally in children aged 0–60 months, especially during the first 6 months of life and in LMICs. We highlight the striking overall mortality burden of RSV disease worldwide, with one in every 50 deaths in children aged 0–60 months and one in every 28 deaths in children aged 28 days to 6 months attributable to RSV. For every RSV-associated acute lower respiratory infection in-hospital death, we estimate approximately three more deaths attributable to RSV in the community. RSV passive immunisation programmes targeting protection during the first 6 months of life could have a substantial effect on reducing RSV disease burden, although more data are needed to understand the implications of the potential age-shifts in peak RSV burden to older age when these are implemented. Funding: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU)

The age profile of respiratory syncytial virus burden in preschool children of low- and middle-income countries: a semi-parametric, meta-regression approach

BACKGROUND: Respiratory syncytial virus (RSV) infections are among the primary causes of death for children under 5 years of age worldwide. A notable challenge with many of the upcoming prophylactic interventions against RSV is their short duration of protection, making the age profile of key interest to the design of prevention strategies. METHODS AND FINDINGS: We leverage the RSV data collected on cases, hospitalizations, and deaths in a systematic review in combination with flexible generalized additive mixed models (GAMMs) to characterize the age burden of RSV incidence, hospitalization, and hospital-based case fatality rate (hCFR). Due to the flexible nature of GAMMs, we estimate the peak, median, and mean incidence of infection to inform discussions on the ideal "window of protection" of prophylactic interventions. In a secondary analysis, we reestimate the burden of RSV in all low- and middle-income countries. The peak age of community-based incidence is 4.8 months, and the mean and median age of infection is 18.9 and 14.7 months, respectively. Estimating the age profile using the incidence coming from hospital-based studies yields a slightly younger age profile, in which the peak age of infection is 2.6 months and the mean and median age of infection are 15.8 and 11.6 months, respectively. More severe outcomes, such as hospitalization and in-hospital death have a younger age profile. Children under 6 months of age constitute 10% of the population under 5 years of age but bear 20% to 29% of cases, 28% to 39% of hospitalizations, and 38% to 50% of deaths. On an average year, we estimate 28.23 to 31.34 million cases of RSV, between 2.95 to 3.35 million hospitalizations, and 16,835 to 19,909 in-hospital deaths in low, lower- and upper middle-income countries. In addition, we estimate 17,254 to 23,875 deaths in the community, for a total of 34,114 to 46,485 deaths. Globally, evidence shows that community-based incidence may differ by World Bank Income Group, but not hospital-based incidence, probability of hospitalization, or the probability of in-hospital death (p ≤ 0.01, p = 1, p = 0.86, 0.63, respectively). Our study is limited mainly due to the sparsity of the data, especially for low-income countries (LICs). The lack of information for some populations makes detecting heterogeneity between income groups difficult, and differences in access to care may impact the reported burden. CONCLUSIONS: We have demonstrated an approach to synthesize information on RSV outcomes in a statistically principled manner, and we estimate that the age profile of RSV burden depends on whether information on incidence is collected in hospitals or in the community. Our results suggest that the ideal prophylactic strategy may require multiple products to avert the risk among preschool children

Performance Assessment of a Rapid Molecular Respiratory Syncytial Virus Point-of-Care Test: A Prospective Community Study in Older Adults

Background. Respiratory syncytial virus (RSV) causes a substantial burden in older adults. Viral load in RSV-infected adults is generally lower compared to young children, which could result in suboptimal sensitivity of RSV diagnostics. Although the Xpert® Xpress Flu/RSV assay has been used in routine clinical care, its sensitivity to diagnose RSV infection in older adults is largely unknown. We aimed to compare the performance of the Xpert® Xpress Flu/RSV assay with real-time reverse-transcription polymerase chain reaction (RT-PCR) in home-dwelling older adults (≥60 years of age). Methods. Nasopharyngeal swabs were tested with Xpert® Xpress Flu/RSV and compared to RSV RT-PCR in older adults with acute respiratory tract infections with different levels of disease severity. Results. We studied 758 respiratory samples from 561 older adults from 2 consecutive RSV seasons. Thirty-five (4.6%) samples tested positive for RSV by at least 1 of the assays, of which 2 samples were negative by Xpert® Xpress Flu/RSV and 3 samples by real-time RT-PCR. The positive percentage agreement (PPA) was 90.9% (95% confidence interval [CI], 76.4%–96.8%) and negative percentage agreement was 99.7% (95% CI, 99.0%–99.9%). Viral loads were low (≤103 copies/mL or cycle threshold value ≥34) in all cases with discordant results for the 2 assays. Conclusions. The PPA of Xpert® Xpress Flu/RSV compared to routine RT-PCR is high for RSV detection in home-dwelling older adults. The assay is fast and easy to use at the point of care

Global and regional burden of hospital admissions for pneumonia in older adults::A systematic review and meta-analysis

Pneumonia constitutes a substantial disease burden among adults overall and those who are elderly. We aimed to identify all studies investigating the disease burden among older adults (age, ≥65 years) admitted to the hospital with pneumonia. We estimated the hospital admission rate and in-hospital case-fatality ratio (CFR) of pneumonia in older adults, stratified by age and economic status (industrialized vs developing), with data from a systematic review of studies published from 1996 through 2017 and from 8 unpublished population-based studies. We applied these rate estimates to population estimates for 2015 to calculate the global and regional burden in older adults who would have been admitted to the hospital with pneumonia that year. We estimated the number of in-hospital pneumonia deaths by combining in-hospital CFRs with hospital admission estimates from hospital-based studies. We identified 109 eligible studies; 73 used clinical pneumonia as the case definition, and 36 used radiologically confirmed pneumonia as the case definition. We estimated that, in 2015, 6.8 million episodes (uncertainty range [UR], 5.8-8.0 episodes) of clinical pneumonia resulted in hospital admissions of older adults worldwide. The hospital admission rate increased with advancing age and was higher in men. The total disease burden was likely underestimated when using the definition of radiologically confirmed pneumonia. Based on data from 52 hospital studies reporting data on pneumonia mortality, we estimated that about 1.1 million in-hospital deaths (UR, 0.9-1.4 in-hospital deaths) occurred among older adults. The burden of pneumonia requiring hospitalization among older adults is substantial. Appropriate prevention and management strategies should be developed to reduce its impact