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 We also included unpublished data from RSV GEN collaborators.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).

Assessing the Intense Influenza A(H1N1)pdm09 Epidemic and Vaccine Effectiveness in the Post-COVID Season in the Russian Federation.

The COVID-19 pandemic had a profound impact on influenza activity worldwide. However, as the pandemic progressed, influenza activity resumed. Here, we describe the influenza epidemic of high intensity of the 2022-2023 season. The epidemic had an early start and peaked in week 51.2022. The extremely high intensity of the epidemic may have been due to a significant decrease in herd immunity. The results of PCR-testing of 220,067 clinical samples revealed that the influenza A(H1N1)pdm09 virus dominated, causing 56.4% of positive cases, while A(H3N2) influenza subtype accounted for only 0.6%, and influenza B of Victoria lineage-for 34.3%. The influenza vaccine was found to be highly effective, with an estimated effectiveness of 92.7% in preventing admission with laboratory-confirmed influenza severe acute respiratory illness (SARI) cases and 54.7% in preventing influenza-like illness/acute respiratory illness (ILI/ARI) cases due to antigenic matching of circulated viruses with influenza vaccine strains for the season. Full genome next-generation sequencing of 1723 influenza A(H1N1)pdm09 viruses showed that all of them fell within clade 6B.1A.5.a2; nine of them possessed H275Y substitution in the NA gene, a genetic marker of oseltamivir resistance. Influenza A(H3N2) viruses belonged to subclade 3C.2a1b.2a.2 with the genetic group 2b being dominant. All 433 influenza B viruses belonged to subclade V1A.3a.2 encoding HA1 substitutions A127T, P144L, and K203R, which could be further divided into two subgroups. None of the influenza A(H3N2) and B viruses sequenced had markers of resistance to NA inhibitors. Thus, despite the continuing circulation of Omicron descendant lineages, influenza activity has resumed in full force, raising concerns about the intensity of fore coming seasonal epidemics.

A comparative analysis of the epidemiology of influenza and respiratory syncytial virus in Russia, 2013/14 to 2018/19.

BACKGROUND: Influenza and respiratory syncytial virus (RSV) are among the leading causes of lower respiratory tract infections worldwide. We conducted a comparative analysis of the age distribution and spatiotemporal epidemiology of influenza and RSV in Russia using sentinel surveillance data from 2013-14 to 2018-19 in six cities located in the western, central, and eastern regions of the country. METHODS: We calculated the positivity rate for influenza and RSV (by month, season, and overall) in each city, separately for patients seen at the primary and secondary care level (out-patients medical centres housing GP practices and infectious diseases hospitals, respectively). We compared the age distribution of patients infected with the different influenza virus (sub)types and RSV. RESULTS: A total of 17 551 respiratory specimens were included: the overall positivity rate was 13.5% for influenza and 4.4% for RSV. The A(H1N1)pdm09, A(H3N2) and B virus (sub)types caused 31.3%, 44.0% and, respectively, 24.7% of all influenza cases. The median age was older among influenza (15 years) than among RSV patients (3 years); differences across influenza virus (sub)types were seen only at the primary care level, with influenza A(H3N2) patients being significantly older than A(H1N1)pdm09 or B influenza patients. The timing of influenza epidemics was similar across cities, with the peak typically occurring in February or March. In contrast, the typical peak timing of RSV epidemics varied largely across cities, and the virus was often detected also in spring and summer months (unlike influenza). CONCLUSIONS: Influenza and RSV epidemiology differed in many regards in Russia, especially in the timing of epidemics and the age distribution of infected subjects. Health policies aimed at containing the burden of diseases of viral respiratory infections in Russia should take these findings into account.

Resurgence of Influenza Circulation in the Russian Federation during the Delta and Omicron COVID-19 Era.

Influenza circulation was substantially reduced after March 2020 in the European region and globally due to the wide introduction of non-pharmaceutical interventions (NPIs) against COVID-19. The virus, however, has been actively circulating in natural reservoirs. In summer 2021, NPIs were loosened in Russia, and influenza activity resumed shortly thereafter. Here, we summarize the epidemiological and virological data on the influenza epidemic in Russia in 2021-2022 obtained by the two National Influenza Centers. We demonstrate that the commonly used baseline for acute respiratory infection (ARI) is no longer sufficiently sensitive and BL for ILI incidence was more specific for early recognition of the epidemic. We also present the results of PCR detection of influenza, SARS-CoV-2 and other respiratory viruses as well as antigenic and genetic analysis of influenza viruses. Influenza A(H3N2) prevailed this season with influenza B being detected at low levels at the end of the epidemic. The majority of A(H3N2) viruses were antigenically and genetically homogenous and belonged to the clade 3C.2a1b.2a.2 of the vaccine strain A/Darwin/9/2021 for the season 2022-2023. All influenza B viruses belonged to the Victoria lineage and were similar to the influenza B/Austria/1359417/2021 virus. No influenza A(H1N1)pdm09 and influenza B/Yamagata lineage was isolated last season.

Age-Specific Etiology of Severe Acute Respiratory Infections and Influenza Vaccine Effectivity in Prevention of Hospitalization in Russia, 2018-2019 Season.

The expansion and standardization of clinical trials, as well as the use of sensitive and specific molecular diagnostics methods, provide new information on the age-specific roles of influenza and other respiratory viruses in development of severe acute respiratory infections (SARI). Here, we present the results of the multicenter hospital-based study aimed to detect age-specific impact of influenza and other respiratory viruses (ORV). The 2018-2019 influenza season in Russia was characterized by co-circulation of influenza A(H1N1)pdm09 and A(H3N2) virus subtypes which were detected among hospitalized patients with SARI in 19.3% and 16.4%, respectively. RSV dominated among ORV (15.1% of total cases and 26.8% in infants aged ≤ 2 years). The most significant SARI agents in intensive care units were RSV and influenza A(H1N1)pdm09 virus, (37.3% and 25.4%, respectively, of PCR-positive cases). Hyperthermia was the most frequently registered symptom for influenza cases. In contrast, hypoxia, decreased blood O2 concentration, and dyspnea were registered more often in RSV, rhinovirus, and metapneumovirus infection in young children. Influenza vaccine effectiveness (IVE) against hospitalization of patients with PCR-confirmed influenza was evaluated using test-negative case-control design. IVE for children and adults was estimated to be 57.0% and 62.0%, respectively. Subtype specific IVE was higher against influenza A(H1N1)pdm09, compared to influenza A(H3N2) (60.3% and 45.8%, respectively). This correlates with delayed antigenic drift of the influenza A(H1N1)pdm09 virus and genetic heterogeneity of the influenza A(H3N2) population. These studies demonstrate the need to improve seasonal influenza prevention and control in all countries as states by the WHO Global Influenza Strategy for 2019-2030 initiative.

The Global Epidemiology of RSV in Community and Hospitalized Care: Findings From 15 Countries.

BACKGROUND: Respiratory syncytial virus (RSV) is one of the leading causes of acute respiratory tract infections. To optimize control strategies, a better understanding of the global epidemiology of RSV is critical. To this end, we initiated the Global Epidemiology of RSV in Hospitalized and Community care study (GERi). METHODS: Focal points from 44 countries were approached to join GERi and share detailed RSV surveillance data. Countries completed a questionnaire on the characteristics of their surveillance system. RESULTS: Fifteen countries provided granular surveillance data and information on their surveillance system. A median (interquartile range) of 1641 (552-2415) RSV cases per season were reported from 2000 and 2020. The majority (55%) of RSV cases occurred in the <1-year-olds, with 8% of cases reported in those aged ≥65 years. Hospitalized cases were younger than those in community care. We found no age difference between RSV subtypes and no clear pattern of dominant subtypes. CONCLUSIONS: The high number of cases in the <1-year-olds indicates a need to focus prevention efforts in this group. The minimal differences between RSV subtypes and their co-circulation implies that prevention needs to target both subtypes. Importantly, there appears to be a lack of RSV surveillance data in the elderly.

Rapid spread of influenza A(H1N1)pdm09 viruses with a new set of specific mutations in the internal genes in the beginning of 2015/2016 epidemic season in Moscow and Saint Petersburg (Russian Federation).

A dramatic increase of influenza activity in Russia since week 3 of 2016 significantly differs from previous seasons in terms of the incidence of influenza and acute respiratory infection (ARI) and in number of lethal cases. We performed antigenic analysis of 108 and whole-genome sequencing of 77 influenza A(H1N1)pdm09 viruses from Moscow and Saint Petersburg. Most of the viruses were antigenically related to the vaccine strain. Whole-genome analysis revealed a composition of specific mutations in the internal genes (D2E and M83I in NEP, E125D in NS1, M105T in NP, Q208K in M1, and N204S in PA-X) that probably emerged before the beginning of 2015/2016 epidemic season.

Epidemiology of Hospital Admissions with Influenza during the 2013/2014 Northern Hemisphere Influenza Season: Results from the Global Influenza Hospital Surveillance Network.

BACKGROUND: The Global Influenza Hospital Surveillance Network was established in 2012 to obtain valid epidemiologic data on hospital admissions with influenza-like illness. Here we describe the epidemiology of admissions with influenza within the Northern Hemisphere sites during the 2013/2014 influenza season, identify risk factors for severe outcomes and complications, and assess the impact of different influenza viruses on clinically relevant outcomes in at-risk populations. METHODS: Eligible consecutive admissions were screened for inclusion at 19 hospitals in Russia, Turkey, China, and Spain using a prospective, active surveillance approach. Patients that fulfilled a common case definition were enrolled and epidemiological data were collected. Risk factors for hospitalization with laboratory-confirmed influenza were identified by multivariable logistic regression. FINDINGS: 5303 of 9507 consecutive admissions were included in the analysis. Of these, 1086 were influenza positive (534 A(H3N2), 362 A(H1N1), 130 B/Yamagata lineage, 3 B/Victoria lineage, 40 untyped A, and 18 untyped B). The risk of hospitalization with influenza (adjusted odds ratio [95% confidence interval]) was elevated for patients with cardiovascular disease (1.63 [1.33-2.02]), asthma (2.25 [1.67-3.03]), immunosuppression (2.25 [1.23-4.11]), renal disease (2.11 [1.48-3.01]), liver disease (1.94 [1.18-3.19], autoimmune disease (2.97 [1.58-5.59]), and pregnancy (3.84 [2.48-5.94]). Patients without comorbidities accounted for 60% of admissions with influenza. The need for intensive care or in-hospital death was not significantly different between patients with or without influenza. Influenza vaccination was associated with a lower risk of confirmed influenza (adjusted odds ratio = 0.61 [0.48-0.77]). CONCLUSIONS: Influenza infection was detected among hospital admissions with and without known risk factors. Pregnancy and underlying comorbidity increased the risk of detecting influenza virus in patients hospitalized with influenza-like illness. Our results support influenza vaccination as a measure for reducing the risk of influenza-associated hospital admission.

INFLUENZA SURVEILLANCE IN RUSSIA BASED ON EPIDEMIOLOGICAL AND LABORATORY DATA FOR THE PERIOD FROM 2005 TO 2012.

Exchange of information on and sharing of influenza viruses through the GISRS network has great significance for understanding influenza virus evolution, recognition of a new pandemic virus emergence and for preparing annual WHO recommendations on influenza vaccine strain composition. Influenza surveillance in Russia is based on collaboration of two NICs with 59 Regional Bases. Most epidemiological and laboratory data are entered through the internet into the electronic database at the Research Institute of Influenza (RII), where they are analyzed and then reported to the Ministry of Public Health of Russia. Simultaneously, data are introduced into WHO's Flu Net and Euro Flu, both electronic databases. Annual influenza epidemics of moderate intensity were registered during four pre-pandemic seasons. Children aged 0-2 and 3-6 years were the most affected groups of the population. Influenza registered clinically among hospitalized patients with respiratory infections for the whole epidemic period varied between 1.3 and 5.4% and up but to 18.5-23.0% during the peak of the two pandemic waves caused by influenza A(H1N1) pdm 09 virus and to lesser extent (2.9 to 8.5%) during usual seasonal epidemics. Most epidemics were associated with influenza A(H1N1), A(H3N2) and B co-circulation. During the two pandemic waves (in 2009-2010 and 2010-2011) influenza A(H1N1) pdm 09 predominated. It was accompanied by a rapid growth of influenza morbidity with a significant increase of both hospitalization and mortality. The new pandemic virus displaced the previous seasonal A(H1N1) virus completely. As a rule, most of the influenza viruses circulating in Russia were antigenic ally related to the strains recommended by WHO for vaccine composition for the Northern hemisphere with the exception of two seasons when an unexpected replacement of the influenza B Victoria lineage by Yamagata lineage (2007-2008) and the following return of Victoria lineage viruses (2008-2009) was registered. Influenza surveillance in Russia was improved as a result of enhancing capacity to international standards and the introduction of new methods in NICs such as rRT-PCR diagnosis, regular testing of influenza viruses for susceptibility to antivirals, phylogenetic analysis as well as organization of sentinel surveillance in a number of Regional Base Laboratories. Improvements promoted rapid recognition of the appearance a new pandemic virus in the country and enhancement of confirmation tests in investigation of influenza related death cases.