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

Abstract 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.


| INTRODUC TI ON
(UR 94 600-149 400). During the neonatal period, 6.5% (95% CI 5. 8-7.6) RSV infection can present as apnea or sepsis. 2,3 RSV disease among young children may be associated with long-term sequelae, including recurrent wheezing and asthma, though whether these associations are causal or due to shared susceptibility is unclear. RSV not only affects children but also causes annual outbreaks of respiratory illnesses among all age groups 4,5 particularly affecting the elderly and adults with comorbidities such as diabetes, heart and lung disease. 6,7 Given the high RSV disease burden, the development of effective preventive and therapeutic strategies are of high priority.
Currently, 19 RSV vaccine candidates and monoclonal antibodies are in various stages of development as prophylactic interventions. 8 To formulate appropriate intervention strategies, a standardized global RSV surveillance system is needed to better describe the epidemiological characteristics of RSV disease, including seasonal variations in incidence in different geographic settings. In several high-income countries, surveillance of RSV has been integrated within their routine influenza surveillance 9 ; however, there is a paucity of data from low-and middle-income countries (LMICs), where the RSV disease burden is likely the highest.

The World Health Organization (WHO) Global Influenza
Surveillance and Response System (GISRS) has been monitoring influenza viruses for over six decades. GISRS operates through a worldwide network of laboratories that provides real-time surveillance information on the circulation and evolution of influenza viruses. Most of the countries participating in GISRS use a case definition of severe acute respiratory infection (SARI), influenza-like illness(ILI), and/or acute respiratory infection (ARI), to identify potential influenza cases for laboratory testing, a surveillance system which could be leveraged to build global RSV surveillance. Following several meetings with influenza and RSV experts from different countries, it was agreed to assess the feasibility of establishing RSV surveillance as a pilot using the existing GISRS platform. The pilot would also assess the possibility of compromise to influenza surveillance resulting from the integration of RSV through GISRS. 10 One of the primary objectives of the RSV pilot was to analyze the seasonal patterns of RSV disease in different countries in varied geographical regions. Fourteen countries, in six WHO regions, which were already members of GISRS, were selected and invited for the pilot.
This paper aims to describe RSV seasonality in countries participating in the WHO RSV pilot surveillance programme during the period January 2017 to April 2019, compared to the seasonality of influenza. Other aspects of the pilot initiative are being published in separate papers.

| Study sites
Fourteen countries, in six WHO regions, which were already participating in GISRS, were invited to participate in the pilot (Figure 1). In each of these countries, there was a recognized National Influenza Center and/or a national public health laboratory with ongoing influenza surveillance and laboratory capacity for RSV testing using 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.

K E Y W O R D S
Global Influenza Surveillance and Response network, human respiratory syncytial virus, influenza, seasonality molecular methods and a history of successful past performance in the WHO EQA for the molecular detection of influenza. All these laboratories/countries regularly provide influenza surveillance data to WHO via the FluNet platform.

| Selection of sentinel sites and case definition
The number and type of sentinel hospitals (secondary-and tertiary-level care) and clinics included in the RSV Surveillance Pilot varied among the countries ( Table 1). The selection of sentinel hospitals and clinics was largely based on patient load and convenience. These sites were not necessarily nationally representative. For clinic-and hospital-based surveillance, countries chose sentinel sites that were able to comply with the required minimum sample size. Hospitals with inpatient care and intensive care units providing adult and pediatric care were preferentially selected. At these sites, patients across all ages who presented with extended SARI were eligible for inclusion. The SARI case definition requires cough and hospitalization plus the presence, or a history, of fever, whereas the extended SARI definition does not require fever. In addition, infants less than 6 months presenting with sepsis or apnea were also eligible for inclusion, as RSV illness frequently presents with these conditions in this age group. 10 For outpatientbased surveillance, the WHO ARI case definition was used at these sites.

| Duration of surveillance
During the pilot, RSV surveillance was conducted year-round by all countries even though seasonality was already well-established in some temperate countries, except for Canada where the RSV pilot ran within the timeframe of well-established seasonality from the beginning of November (epidemiological week 44) through to the end of May (epidemiological week 22; Table 1).

| Data collection and analysis
Data from surveillance sites were uploaded to the WHO's web-based FluMart data platform by the respective countries. To analyze RSV seasonality, the date of specimen collection was used to aggregate by epidemiologic week (EW). When the date of specimen collection was missing, the date of onset of symptoms was used instead. Since date of onset was missing in 6560 cases and date of specimen collection was most definitive, it was used for construction of the epi curve. All specimens collected using the SARI, extended SARI and ARI/ILI case definition were pooled per country for the RSV seasonality graphs.
Temporal plots of RSV and influenza activity were smoothed using the For analyzing seasonality, a threshold of 10% RSV positivity for two consecutive weeks was used to indicate the onset of the RSV season and similarly a percent positivity of <10% for two consecutive weeks was used to indicate the end of the season. For Canada, the number of RSV-positive cases was used to analyze seasonality as the total number of specimens tested was not reported. In countries with multiple sentinel sites, data were pooled for each country's seasonality analysis. For countries which typed RSV cases (Argentina, Australia, Canada, India, Thailand, South Africa, and the UK), data were also analyzed by RSV subtypes.

| RE SULTS
Fourteen countries provided data for the seasonality analysis ( Table 1). which was not the coldest period of the year. This temperature-dependent pattern appears to be independent of precipitation patterns. 22 [25][26][27] This could support the hypothesis that due to increased precipitation there is more indoor crowding, facilitating RSV transmission in the tropics. 28 The timing of the RSV season was not dependent on subtype (type A or type B) that occurred, or the proportions of A/B seen in that season in countries that performed this typing. This aspect will be further studied in the next phase of the WHO RSV surveillance program.

Nine of 14 countries initiated surveillance from EW
Respiratory syncytial virus had broader distribution of peak timings, relative to that of influenza, even within the temperate zone. Although most countries in our study experienced distinct respiratory virus seasons, it is noteworthy that there was a bi-annual influenza peak in Chile in 2017. Although distinct RSV seasonality was observed in tropical countries, that is, Brazil, Côte d'Ivoire, India, Mozambique, and Thailand, Influenza activity was observed year-round, which is consistent with previous reports. 29,30 This could influence the country-specific RSV vaccination strategies and timing in relation to influenza vaccination.
However, additional years of surveillance data are required for better understanding of the variability in the distribution of RSV timing relative to influenza and whether RSV-A and RSV-B subtypes have any role to play in multi-year periodicity of RSV compared to Influenza.
There are several limitations to be noted. First, the duration of surveillance varied between countries and covered only two seasons. It is not possible to establish reliably the consistency of seasonal patterns of RSV from year-to-year in these countries.
Second, we did not consider detailed meteorological data for each country during the actual period of surveillance and, as such, seasons were used descriptively for our assessment based on usual patterns. Third, RSV activity observed was limited to the catchment areas of participating surveillance sites within the countries and may not be representative of the whole country, especially in countries with a large latitudinal spread with multiple climate zones. Some of these limitations will be addressed in the second phase of global RSV surveillance initiative. Surveillance needs to be conducted over a longer period, using uniform case definition and sampling strategies and ensuring geographical representativeness in larger countries. It would also be useful to evaluate the threshold of 10% RSV positivity to describe onset and offset of the seasonal RSV epidemic. With more data available other methods of analyzing seasonal data may be used. 16 Despite its limitations, this pilot provides a better understanding of the seasonality of RSV circulation globally. Additional years of RSV surveillance data from different geographical regions within the same country will provide more robust RSV seasonality patterns.
In conclusion, we observed distinct annual peak activity of RSV in different regions of the world. Timing of RSV epidemics varied among participating countries, and it generally overlapped with seasonal influenza epidemics in most countries. The GISRS platform can be leveraged for generating standardized and quality data on RSV circulation. These data will be useful for deciding the best time for targeting interventions such as future RSV vaccination and the use of monoclonal antibodies.