Timing of seasonal influenza epidemics for 25 countries in Africa during 2010-19: a retrospective analysis.

BACKGROUND: Using country-specific surveillance data to describe influenza epidemic activity could inform decisions on the timing of influenza vaccination. We analysed surveillance data from African countries to characterise the timing of seasonal influenza epidemics to inform national vaccination strategies. METHODS: We used publicly available sentinel data from African countries reporting to the WHO Global Influenza Surveillance and Response FluNet platform that had 3-10 years of data collected during 2010-19. We calculated a 3-week moving proportion of samples positive for influenza virus and assessed epidemic timing using an aggregate average method. The start and end of each epidemic were defined as the first week when the proportion of positive samples exceeded or went below the annual mean, respectively, for at least 3 consecutive weeks. We categorised countries into five epidemic patterns: northern hemisphere-dominant, with epidemics occurring in October-March; southern hemisphere-dominant, with epidemics occurring in April-September; primarily northern hemisphere with some epidemic activity in southern hemisphere months; primarily southern hemisphere with some epidemic activity in northern hemisphere months; and year-round influenza transmission without a discernible northern hemisphere or southern hemisphere predominance (no clear pattern). FINDINGS: Of the 34 countries reporting data to FluNet, 25 had at least 3 years of data, representing 46% of the countries in Africa and 89% of Africa's population. Study countries reported RT-PCR respiratory virus results for a total of 503 609 specimens (median 12 971 [IQR 9607-20 960] per country-year), of which 74 001 (15%; median 2078 [IQR 1087-3008] per country-year) were positive for influenza viruses. 248 epidemics occurred across 236 country-years of data (median 10 [range 7-10] per country). Six (24%) countries had a northern hemisphere pattern (Algeria, Burkina Faso, Egypt, Morocco, Niger, and Tunisia). Eight (32%) had a primarily northern hemisphere pattern with some southern hemisphere epidemics (Cameroon, Ethiopia, Mali, Mozambique, Nigeria, Senegal, Tanzania, and Togo). Three (12%) had a primarily southern hemisphere pattern with some northern hemisphere epidemics (Ghana, Kenya, and Uganda). Three (12%) had a southern hemisphere pattern (Central African Republic, South Africa, and Zambia). Five (20%) had no clear pattern (Côte d'Ivoire, DR Congo, Madagascar, Mauritius, and Rwanda). INTERPRETATION: Most countries had identifiable influenza epidemic periods that could be used to inform authorities of non-seasonal and seasonal influenza activity, guide vaccine timing, and promote timely interventions. FUNDING: None. TRANSLATIONS: For the Berber, Luganda, Xhosa, Chewa, Yoruba, Igbo, Hausa and Afan Oromo translations of the abstract see Supplementary Materials section.

Results from the second WHO external quality assessment for the molecular detection of respiratory syncytial virus, 2019-2020.

Background: External quality assessments (EQAs) for the molecular detection of human respiratory syncytial virus (RSV) are necessary to ensure the standardisation of reliable results. The Phase II, 2019-2020 World Health Organization (WHO) RSV EQA included 28 laboratories in 26 countries. The EQA panel evaluated performance in the molecular detection and subtyping of RSV-A and RSV-B. This manuscript describes the preparation, distribution, and analysis of the 2019-2020 WHO RSV EQA. Methods: Panel isolates underwent whole genome sequencing and in silico primer matching. The final panel included nine contemporary, one historical virus and two negative controls. The EQA panel was manufactured and distributed by the UK National External Quality Assessment Service (UK NEQAS). National laboratories used WHO reference assays developed by the United States Centers for Disease Control and Prevention, an RSV subtyping assay developed by the Victorian Infectious Diseases Reference Laboratory (Australia), or other in-house or commercial assays already in use at their laboratories. Results: An in silico analysis of isolates showed a good match to assay primer/probes. The panel was distributed to 28 laboratories. Isolates were correctly identified in 98% of samples for detection and 99.6% for subtyping. Conclusions: The WHO RSV EQA 2019-2020 showed that laboratories performed at high standards. Updating the composition of RSV molecular EQAs with contemporary strains to ensure representation of circulating strains, and ensuring primer matching with EQA panel viruses, is advantageous in assessing diagnostic competencies of laboratories. Ongoing EQAs are recommended because of continued evolution of mismatches between current circulating strains and existing primer sets.

Respiratory syncytial virus prevention within reach: the vaccine and monoclonal antibody landscape.

Respiratory syncytial virus is the second most common cause of infant mortality and a major cause of morbidity and mortality in older adults (aged >60 years). Efforts to develop a respiratory syncytial virus vaccine or immunoprophylaxis remain highly active. 33 respiratory syncytial virus prevention candidates are in clinical development using six different approaches: recombinant vector, subunit, particle-based, live attenuated, chimeric, and nucleic acid vaccines; and monoclonal antibodies. Nine candidates are in phase 3 clinical trials. Understanding the epitopes targeted by highly neutralising antibodies has resulted in a shift from empirical to rational and structure-based vaccine and monoclonal antibody design. An extended half-life monoclonal antibody for all infants is likely to be within 1 year of regulatory approval (from August, 2022) for high-income countries. Live-attenuated vaccines are in development for older infants (aged >6 months). Subunit vaccines are in late-stage trials for pregnant women to protect infants, whereas vector, subunit, and nucleic acid approaches are being developed for older adults. Urgent next steps include ensuring access and affordability of a respiratory syncytial virus vaccine globally. This review gives an overview of respiratory syncytial virus vaccines and monoclonal antibodies in clinical development highlighting different target populations, antigens, and trial results.

Assembling a global database of child pneumonia studies to inform WHO pneumonia management algorithm: Methodology and applications.

Background: The existing World Health Organization (WHO) pneumonia case management guidelines rely on clinical symptoms and signs for identifying, classifying, and treating pneumonia in children up to 5 years old. We aimed to collate an individual patient-level data set from large, high-quality pre-existing studies on pneumonia in children to identify a set of signs and symptoms with greater validity in the diagnosis, prognosis, and possible treatment of childhood pneumonia for the improvement of current pneumonia case management guidelines. Methods: Using data from a published systematic review and expert knowledge, we identified studies meeting our eligibility criteria and invited investigators to share individual-level patient data. We collected data on demographic information, general medical history, and current illness episode, including history, clinical presentation, chest radiograph findings when available, treatment, and outcome. Data were gathered separately from hospital-based and community-based cases. We performed a narrative synthesis to describe the final data set. Results: Forty-one separate data sets were included in the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) database, 26 of which were hospital-based and 15 were community-based. The PREPARE database includes 285 839 children with pneumonia (244 323 in the hospital and 41 516 in the community), with detailed descriptions of clinical presentation, clinical progression, and outcome. Of 9185 pneumonia-related deaths, 6836 (74%) occurred in children <1 year of age and 1317 (14%) in children aged 1-2 years. Of the 285 839 episodes, 280 998 occurred in children 0-59 months old, of which 129 584 (46%) were 2-11 months of age and 152 730 (54%) were males. Conclusions: This data set could identify an improved specific, sensitive set of criteria for diagnosing clinical pneumonia and help identify sick children in need of referral to a higher level of care or a change of therapy. Field studies could be designed based on insights from PREPARE analyses to validate a potential revised pneumonia algorithm. The PREPARE methodology can also act as a model for disease database assembly.

Evaluation of post-introduction COVID-19 vaccine effectiveness: Summary of interim guidance of the World Health Organization.

Phase 3 randomized-controlled trials have provided promising results of COVID-19 vaccine efficacy, ranging from 50 to 95% against symptomatic disease as the primary endpoints, resulting in emergency use authorization/listing for several vaccines. However, given the short duration of follow-up during the clinical trials, strict eligibility criteria, emerging variants of concern, and the changing epidemiology of the pandemic, many questions still remain unanswered regarding vaccine performance. Post-introduction vaccine effectiveness evaluations can help us to understand the vaccine's effect on reducing infection and disease when used in real-world conditions. They can also address important questions that were either not studied or were incompletely studied in the trials and that will inform evolving vaccine policy, including assessment of the duration of effectiveness; effectiveness in key subpopulations, such as the very old or immunocompromised; against severe disease and death due to COVID-19; against emerging SARS-CoV-2 variants of concern; and with different vaccination schedules, such as number of doses and varying dosing intervals. WHO convened an expert panel to develop interim best practice guidance for COVID-19 vaccine effectiveness evaluations. We present a summary of the interim guidance, including discussion of different study designs, priority outcomes to evaluate, potential biases, existing surveillance platforms that can be used, and recommendations for reporting results.

Proposal for Human Respiratory Syncytial Virus Nomenclature below the Species Level.

Human respiratory syncytial virus (HRSV) is the leading viral cause of serious pediatric respiratory disease, and lifelong reinfections are common. Its 2 major subgroups, A and B, exhibit some antigenic variability, enabling HRSV to circulate annually. Globally, research has increased the number of HRSV genomic sequences available. To ensure accurate molecular epidemiology analyses, we propose a uniform nomenclature for HRSV-positive samples and isolates, and HRSV sequences, namely: HRSV/subgroup identifier/geographic identifier/unique sequence identifier/year of sampling. We also propose a template for submitting associated metadata. Universal nomenclature would help researchers retrieve and analyze sequence data to better understand the evolution of this virus.

Recommendations for respiratory syncytial virus surveillance at the national level.

Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infections and hospitalisations among young children and is globally responsible for many deaths in young children, especially in infants aged <6 months. Furthermore, RSV is a common cause of severe respiratory disease and hospitalisation among older adults. The development of new candidate vaccines and monoclonal antibodies highlights the need for reliable surveillance of RSV. In the European Union (EU), no up-to-date general recommendations on RSV surveillance are currently available. Based on outcomes of a workshop with 29 European experts in the field of RSV virology, epidemiology and public health, we provide recommendations for developing a feasible and sustainable national surveillance strategy for RSV that will enable harmonisation and data comparison at the European level. We discuss three surveillance components: active sentinel community surveillance, active sentinel hospital surveillance and passive laboratory surveillance, using the EU acute respiratory infection and World Health Organization (WHO) extended severe acute respiratory infection case definitions. Furthermore, we recommend the use of quantitative reverse transcriptase PCR-based assays as the standard detection method for RSV and virus genetic characterisation, if possible, to monitor genetic evolution. These guidelines provide a basis for good quality, feasible and affordable surveillance of RSV. Harmonisation of surveillance standards at the European and global level will contribute to the wider availability of national level RSV surveillance data for regional and global analysis, and for estimation of RSV burden and the impact of future immunisation programmes.

Global burden of acute lower respiratory infection associated with human metapneumovirus in children under 5 years in 2018: a systematic review and modelling study.

BACKGROUND: Human metapneumovirus is a common virus associated with acute lower respiratory infections (ALRIs) in children. No global burden estimates are available for ALRIs associated with human metapneumovirus in children, and no licensed vaccines or drugs exist for human metapneumovirus infections. We aimed to estimate the age-stratified human metapneumovirus-associated ALRI global incidence, hospital admissions, and mortality burden in children younger than 5 years. METHODS: We estimated the global burden of human metapneumovirus-associated ALRIs in children younger than 5 years from a systematic review of 119 studies published between Jan 1, 2001, and Dec 31, 2019, and a further 40 high quality unpublished studies. We assessed risk of bias using a modified Newcastle-Ottawa Scale. We estimated incidence, hospital admission rates, and in-hospital case-fatality ratios (hCFRs) of human metapneumovirus-associated ALRI using a generalised linear mixed model. We applied incidence and hospital admission rates of human metapneumovirus-associated ALRI to population estimates to yield the morbidity burden estimates by age bands and World Bank income levels. We also estimated human metapneumovirus-associated ALRI in-hospital deaths and overall human metapneumovirus-associated ALRI deaths (both in-hospital and non-hospital deaths). Additionally, we estimated human metapneumovirus-attributable ALRI cases, hospital admissions, and deaths by combining human metapneumovirus-associated burden estimates and attributable fractions of human metapneumovirus in laboratory-confirmed human metapneumovirus cases and deaths. FINDINGS: In 2018, among children younger than 5 years globally, there were an estimated 14·2 million human metapneumovirus-associated ALRI cases (uncertainty range [UR] 10·2 million to 20·1 million), 643 000 human metapneumovirus-associated hospital admissions (UR 425 000 to 977 000), 7700 human metapneumovirus-associated in-hospital deaths (2600 to 48 800), and 16 100 overall (hospital and community) human metapneumovirus-associated ALRI deaths (5700 to 88 000). An estimated 11·1 million ALRI cases (UR 8·0 million to 15·7 million), 502 000 ALRI hospital admissions (UR 332 000 to 762 000), and 11 300 ALRI deaths (4000 to 61 600) could be causally attributed to human metapneumovirus in 2018. Around 58% of the hospital admissions were in infants under 12 months, and 64% of in-hospital deaths occurred in infants younger than 6 months, of which 79% occurred in low-income and lower-middle-income countries. INTERPRETATION: Infants younger than 1 year have disproportionately high risks of severe human metapneumovirus infections across all World Bank income regions and all child mortality settings, similar to respiratory syncytial virus and influenza virus. Infants younger than 6 months in low-income and lower-middle-income countries are at greater risk of death from human metapneumovirus-associated ALRI than older children and those in upper-middle-income and high-income countries. Our mortality estimates demonstrate the importance of intervention strategies for infants across all settings, and warrant continued efforts to improve the outcome of human metapneumovirus-associated ALRI among young infants in low-income and lower-middle-income countries. FUNDING: Bill & Melinda Gates Foundation.

Results from the WHO external quality assessment for the respiratory syncytial virus pilot, 2016-17.

BACKGROUND: External quality assessments (EQAs) for the molecular detection of respiratory syncytial virus (RSV) are necessary to ensure the provision of reliable and accurate results. One of the objectives of the pilot of the World Health Organization (WHO) Global RSV Surveillance, 2016-2017, was to evaluate and standardize RSV molecular tests used by participating countries. This paper describes the first WHO RSV EQA for the molecular detection of RSV. METHODS: The WHO implemented the pilot of Global RSV Surveillance based on the WHO Global Influenza Surveillance and Response System (GISRS) from 2016 to 2018 in 14 countries. To ensure standardization of tests, 13 participating laboratories were required to complete a 12 panel RSV EQA prepared and distributed by the Centers for Disease Control and Prevention (CDC), USA. The 14th laboratory joined the pilot late and participated in a separate EQA. Laboratories evaluated a RSV rRT-PCR assay developed by CDC and compared where applicable, other Laboratory Developed Tests (LDTs) or commercial assays already in use at their laboratories. RESULTS: Laboratories performed well using the CDC RSV rRT-PCR in comparison with LDTs and commercial assays. Using the CDC assay, 11 of 13 laboratories reported correct results. Two laboratories each reported one false-positive finding. Of the laboratories using LDTs or commercial assays, results as assessed by Ct values were 100% correct for 1/5 (20%). With corrective actions, all laboratories achieved satisfactory outputs. CONCLUSIONS: These findings indicate that reliable results can be expected from this pilot. Continued participation in EQAs for the molecular detection of RSV is recommended.

Validating a GPS-based approach to detect health facility visits against maternal response to prompted recall survey.

INTRODUCTION: Common approaches to measure health behaviors rely on participant responses and are subject to bias. Technology-based alternatives, particularly using GPS, address these biases while opening new channels for research. This study describes the development and implementation of a GPS-based approach to detect health facility visits in rural Pune district, India. METHODS: Participants were mothers of under-five year old children within the Vadu Demographic Surveillance area. Participants received GPS-enabled smartphones pre-installed with a location-aware application to continuously record and transmit participant location data to a central server. Data were analyzed to identify health facility visits according to a parameter-based approach, optimal thresholds of which were calibrated through a simulation exercise. Lists of GPS-detected health facility visits were generated at each of six follow-up home visits and reviewed with participants through prompted recall survey, confirming visits which were correctly identified. Detected visits were analyzed using logistic regression to explore factors associated with the identification of false positive GPS-detected visits. RESULTS: We enrolled 200 participants and completed 1098 follow-up visits over the six-month study period. Prompted recall surveys were completed for 694 follow-up visits with one or more GPS-detected health facility visits. While the approach performed well during calibration (positive predictive value (PPV) 78%), performance was poor when applied to participant data. Only 440 of 22 251 detected visits were confirmed (PPV 2%). False positives increased as participants spent more time in areas of high health facility density (odds ratio (OR) = 2.29, 95% confidence interval (CI) = 1.62-3.25). Visits detected at facilities other than hospitals and clinics were also more likely to be false positives (OR = 2.78, 95% CI = 1.65-4.67) as were visits detected to facilities nearby participant homes, with the likelihood decreasing as distance increased (OR = 0.89, 95% CI = 0.82-0.97). Visit duration was not associated with confirmation status. CONCLUSIONS: The optimal parameter combination for health facility visits simulated by field workers substantially overestimated health visits from participant GPS data. This study provides useful insights into the challenges in detecting health facility visits where providers are numerous, highly clustered within urban centers and located near residential areas of the population which they serve.

Human respiratory syncytial virus and influenza seasonality patterns-Early findings from the WHO global respiratory syncytial virus surveillance.

BACKGROUND: Human respiratory syncytial virus (RSV) causes illnesses among all age groups and presents a burden to healthcare services. To better understand the epidemiology and seasonality of RSV in different geographical areas, the World Health Organization (WHO) coordinated a pilot initiative to access the feasibility of establishing RSV surveillance using the existing Global Influenza Surveillance and Response System (GISRS) platform. OBJECTIVES: To describe and compare RSV and influenza seasonality in countries in the northern andsouthern temperate, and tropics during the period January 2017 to April 2019. METHODS: Fourteen countries in six WHO regions participating in the GISRS were invited for the pilot. Hospitalized patients presenting with severe acute respiratory illness (SARI), SARI without fever and outpatients presenting with acute respiratory illness (ARI) were enrolled from January 2017 to April 2019. The expected minimum sample size was 20 samples per week, year-round, per country. Real-time RT-PCR was used to detect RSV and influenza viruses. Results were uploaded to the WHO FluMart platform. RESULTS: Annual seasonality of RSV was observed in all countries, which overlapped to a large extent with the influenza activity. In countries, in temperate regions RSV peaked in the autumn/winter months. In Egypt, a subtropical country, RSV activity peaked in the cooler season. In the tropical regions, RSV peaked during the rainy seasons. CONCLUSION: Early findings from the WHO RSV surveillance pilot based on the GISRS suggest annual seasonal patterns for of RSV circulation that overlap with influenza. RSV surveillance needs to be continued for several more seasons to establish seasonality patterns to inform prevention and control strategies.

Determinants and patterns of care-seeking for childhood illness in rural Pune District, India.

BACKGROUND: An estimated 1.2 million children under five years of age die each year in India, with pneumonia and diarrhea among the leading causes. Increasing care-seeking is important to reduce mortality and morbidity from these causes. This paper explores the determinants and patterns of care-seeking for childhood illness in rural Pune district, India. METHODS: Mothers having at least one child <5 years from the study area of the Vadu Health and Demographic Surveillance System were enrolled in a prospective cohort study. Household sociodemographic information was collected through a baseline questionnaire administered at enrollment. Participants were visited up to six times between July 2015 and February 2016 to collect information on recent childhood acute illness and associated care-seeking behavior. Multivariate logistic regression explored the associations between care-seeking and child, participant, and household characteristics. RESULTS: We enrolled 743 mothers with 1066 eligible children, completing 2585 follow-up interviews (90% completion). Overall acute illness prevalence in children was 26% with care sought from a health facility during 71% of episodes. Multivariable logistic regression showed care-seeking was associated with the number of reported symptoms (Odds ratio (OR) = 2.4, 95% confidence interval (CI) = 1.5-3.9) and household insurance coverage (OR = 2.2, 95% CI = 1.1-4.3). We observed an interaction between the associations of illness severity and maternal employment on care-seeking. Somewhat-to-very severe illness was associated with increased care-seeking among both employed (OR = 5.0, 95% CI = 2.2-11.1) and currently unemployed mothers (OR = 7.0, 95% CI = 3.9-12.6). Maternal employment was associated with reduced care-seeking for non-severe illness (OR = 0.3, 95% CI = 0.1-0.7), but not associated with care-seeking for somewhat-to-very severe illness. Child sex was not associated with care-seeking. CONCLUSIONS: This study demonstrates the importance of illness characteristics in determining facility-based care-seeking while also suggesting that maternal employment resulted in decreased care-seeking among non-severe illness episodes. The nature of the association between maternal employment and care-seeking is unclear and should be explored through additional studies. Similarly, the absence of male bias in care-seeking should be examined to assess for potential bias at other stages in the management of childhood illness.

Risk factors for hospitalized respiratory syncytial virus disease and its severe outcomes.

INTRODUCTION: Respiratory syncytial virus (RSV) is a major cause of hospital admission for acute lower respiratory tract infection in young children. OBJECTIVES: We aimed to identify risk factors for hospitalized RSV disease and its severe outcomes. METHODS: We conducted a retrospective cohort study analyzing data of a ICD-10-code-based hospital surveillance for severe acute respiratory infections (SARI). Using univariable and multivariable logistic regression analysis, we assessed age-group, gender, season, and underlying medical conditions as possible risk factors for RSV and its severe outcomes including ICU admission, application of ventilator support, and death, respectively. RESULTS: Of the 413 552 patients hospitalized with SARI in the database, 8761 were diagnosed with RSV from week 01/2009 to 20/2018 with 97% (8521) aged <5 years. Among children aged <5 years, age-groups 0-5 months (OR: 20.29, 95% CI: 18.37-22.41) and 6 months-1 year (OR: 4.59, 95% CI: 4.16-5.06), and underlying respiratory and cardiovascular disorders specific to the perinatal period (OR: 1.32, 95% CI: 1.11-1.57) were risk factors for being diagnosed with RSV. Age-group 0-5 months (OR: 2.39, 95% CI: 1.45-3.94), low birth weight (OR: 6.77, 95% CI: 1.28-35.71), preterm newborn (OR: 6.71, 95% CI: 2.19-20.61), underlying respiratory and cardiovascular disorders specific to the perinatal period (OR: 4.97, 95% CI: 3.36-7.34), congenital malformation of the heart (OR: 3.65, 95% CI: 1.90-7.02), congenital malformation of the great vessels (OR: 3.50, 95% CI: 1.10-11.18), congenital defect originating in perinatal period (OR: 4.07, 95% CI: 1.71-9.70), cardiovascular disease (OR: 5.19, 95% CI: 2.77-9.72), neurological disorders (OR: 6.48, 95% CI: 3.76-11.18), blood disease (OR: 3.67, 95% CI: 1.98-6.79), and liver disease (OR: 14.99, 95% CI: 1.49-150.82) contributed to ICU admission in RSV cases. CONCLUSIONS: Using ICD-10-based surveillance data allows to identify risk factors for hospitalized RSV disease and its severe outcomes, and quantify the risk in different age-groups.

Global burden of respiratory infections associated with seasonal influenza in children under 5 years in 2018: a systematic review and modelling study.

BACKGROUND: Seasonal influenza virus is a common cause of acute lower respiratory infection (ALRI) in young children. In 2008, we estimated that 20 million influenza-virus-associated ALRI and 1 million influenza-virus-associated severe ALRI occurred in children under 5 years globally. Despite this substantial burden, only a few low-income and middle-income countries have adopted routine influenza vaccination policies for children and, where present, these have achieved only low or unknown levels of vaccine uptake. Moreover, the influenza burden might have changed due to the emergence and circulation of influenza A/H1N1pdm09. We aimed to incorporate new data to update estimates of the global number of cases, hospital admissions, and mortality from influenza-virus-associated respiratory infections in children under 5 years in 2018. METHODS: We estimated the regional and global burden of influenza-associated respiratory infections in children under 5 years from a systematic review of 100 studies published between Jan 1, 1995, and Dec 31, 2018, and a further 57 high-quality unpublished studies. We adapted the Newcastle-Ottawa Scale to assess the risk of bias. We estimated incidence and hospitalisation rates of influenza-virus-associated respiratory infections by severity, case ascertainment, region, and age. We estimated in-hospital deaths from influenza virus ALRI by combining hospital admissions and in-hospital case-fatality ratios of influenza virus ALRI. We estimated the upper bound of influenza virus-associated ALRI deaths based on the number of in-hospital deaths, US paediatric influenza-associated death data, and population-based childhood all-cause pneumonia mortality data in six sites in low-income and lower-middle-income countries. FINDINGS: In 2018, among children under 5 years globally, there were an estimated 109·5 million influenza virus episodes (uncertainty range [UR] 63·1-190·6), 10·1 million influenza-virus-associated ALRI cases (6·8-15·1); 870 000 influenza-virus-associated ALRI hospital admissions (543 000-1 415 000), 15 300 in-hospital deaths (5800-43 800), and up to 34 800 (13 200-97 200) overall influenza-virus-associated ALRI deaths. Influenza virus accounted for 7% of ALRI cases, 5% of ALRI hospital admissions, and 4% of ALRI deaths in children under 5 years. About 23% of the hospital admissions and 36% of the in-hospital deaths were in infants under 6 months. About 82% of the in-hospital deaths occurred in low-income and lower-middle-income countries. INTERPRETATION: A large proportion of the influenza-associated burden occurs among young infants and in low-income and lower middle-income countries. Our findings provide new and important evidence for maternal and paediatric influenza immunisation, and should inform future immunisation policy particularly in low-income and middle-income countries. FUNDING: WHO; Bill & Melinda Gates Foundation.

Evaluation of using ICD-10 code data for respiratory syncytial virus surveillance.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory tract infection (ALRI) in young children. ICD-10-based syndromic surveillance can transmit data rapidly in a standardized way. OBJECTIVES: We investigated the use of RSV-specific ICD-10 codes for RSV surveillance. METHODS: We performed a retrospective descriptive data analysis based on existing ICD-10-based surveillance systems for ALRI in primary and secondary care and a linked virological surveillance in Germany. We described RSV epidemiology and compared the epidemiological findings based on ICD-10 and virological data. We calculated sensitivity and specificity of RSV-specific ICD-10 codes and in combination with ICD-10 codes for acute respiratory infections (ARI) for the identification of laboratory-confirmed RSV infections. RESULTS: Based on the ICD-10 and virological data, epidemiology of RSV was described, and common findings were found. The RSV-specific ICD-10 codes had poor sensitivity 6% (95%-CI: 3%-12%) and high specificity 99.8% (95%-CI: 99.6%-99.9%). In children <5 years and in RSV seasons, the sensitivities of RSV-specific ICD-10 codes combined with general ALRI ICD-10 codes J18.-, J20.- and with J12.-, J18.-, J20.-, J21.-, J22 were moderate (44%, 95%-CI: 30%-59%). The specificities of both combinations remained high (91%, 95%-CI: 86%-94%; 90%, 95%-CI: 85%-94%). CONCLUSIONS: The use of RSV-specific ICD-10 codes may be a useful indicator to describe RSV epidemiology. However, RSV-specific ICD-10 codes underestimate the number of actual RSV infections. This can be overcome by combining RSV-specific and general ALRI ICD-10 codes. Further investigations are required to validate this approach in other settings.

Leveraging the Global Influenza Surveillance and Response System for global respiratory syncytial virus surveillance-opportunities and challenges.

BACKGROUND: Respiratory syncytial virus (RSV)-associated acute lower respiratory infection is a common cause for hospitalization and hospital deaths in young children globally. There is urgent need to generate evidence to inform immunization policies when RSV vaccines become available. The WHO piloted a RSV surveillance strategy that leverages the existing capacities of the Global Influenza Surveillance and Response System (GISRS) to better understand RSV seasonality, high-risk groups, validate case definitions, and develop laboratory and surveillance standards for RSV. METHODS: The RSV sentinel surveillance strategy was piloted in 14 countries. Patients across all age groups presenting to sentinel hospitals and clinics were screened all year-round using extended severe acute respiratory infection (SARI) and acute respiratory infection (ARI) case definitions for hospital and primary care settings, respectively. Respiratory specimens were tested for RSV at the National Influenza Centre (NIC) using standardized molecular diagnostics that had been validated by an External Quality Assurance program. The WHO FluMart data platform was adapted to receive case-based RSV data and visualize interactive visualization outputs. RESULTS: Laboratory standards for detecting RSV by RT-PCR were developed. A review assessed the feasibility and the low incremental costs for RSV surveillance. Several challenges were addressed related to case definitions, sampling strategies, the need to focus surveillance on young children, and the data required for burden estimation. CONCLUSIONS: There was no evidence of any significant adverse impact on the functioning of GISRS which is primarily intended for virologic and epidemiological surveillance of influenza.

Clinical characteristics, predictors, and performance of case definition-Interim results from the WHO global respiratory syncytial virus surveillance pilot.

BACKGROUND: The lack of a uniform surveillance case definition poses a challenge to characterize the epidemiology, clinical features, and disease burden of the respiratory syncytial virus (RSV). Global standards for RSV surveillance will inform immunization policy when RSV vaccines become available. METHODS: The WHO RSV surveillance pilot leverages the capacities of the Global Influenza Surveillance and Response System (GISRS). Hospitalized and non-hospitalized medically attended patients of any age were tested for RSV using standardized molecular diagnostics throughout the year in fourteen countries. An extended severe acute respiratory infection (extended SARI) or an acute respiratory infection (ARI) case definition was used that did not require fever as a criterion. RESULTS: Amongst 21 221 patients tested for RSV between January 2017 and September 2018, 15 428 (73%) were hospital admissions. Amongst hospitalized RSV-positive patients, 50% were aged <6 months and 88% <2 years. The percentage of patients testing positive for RSV was 37% in children <6 months and 25% in those aged 6 months to 2 years. Patients with fever were less likely to be RSV positive compared to those without fever (OR 0.74; 95% CI: 0.63-0.86). For infants <6 months, 29% of RSV ARI cases did not have fever. CONCLUSION: Requiring fever in a case definition for RSV lowers the sensitivity to detect cases in young children. Countries should consider ways to leverage the GISRS platform to implement RSV surveillance with an augmented case definition amongst the young pediatric population.

Approaches to use the WHO respiratory syncytial virus surveillance platform to estimate disease burden.

The World Health Organization (WHO) recently completed the first phase of a RSV surveillance pilot study in fourteen countries (two to three in each WHO region) building on the Global Influenza Surveillance and Response System (GISRS). This active surveillance strategy had several objectives including understanding RSV-related health burden in a variety of settings. A range of approaches can be used to estimate disease burden; most approaches could not be applied by participating countries in the WHO surveillance pilot. This article provides the recommendations made by WHO for strengthening and expanding the scope of the RSV surveillance in the next phase to enable burden estimation.