Increased severity of influenza-associated hospitalizations in resource-limited settings: Results from the Global Influenza Hospital Surveillance Network (GIHSN)

Background Influenza disease data remain scarce in middle and lower-income countries. We used data from the Global Influenza Hospital Surveillance Network (GIHSN), a prospective multi-country surveillance system from 2012-2019, to assess differences in the epidemiology and severity of influenza hospitalizations by country income level. Methods We compiled individual-level data on acute respiratory hospitalizations, with standardized clinical reporting and testing for influenza. Adjusted odds ratios (aORs) for influenza-associated intensive care unit (ICU) admission and in-hospital death were estimated with multivariable logistic regression that included country income group (World Bank designation: high-income countries: HIC; upper middle-income countries: UMIC; lower middle-income countries: LMIC), age, sex, number of comorbidities, influenza subtype and lineage, and season as covariates. Findings From 73,121 patients hospitalized with respiratory illness in 22 countries, 15,660 were laboratory-confirmed for influenza. After adjustment for patient-level covariates, there was a two-fold increased risk of ICU admission for patients in UMIC (aOR 2.31; 95% confidence interval (CI) 1.85-2.88, p < 0.001), and a 5-fold increase in LMIC (aOR 5.35; 95% CI 3.98-7.17, p < 0.001), compared to HIC. The risk of in-hospital death in HIC and UMIC was comparable (UMIC: aOR 1.14; 95% 0.87-1.50; p > 0.05), though substantially lower than that in LMIC (aOR 5.05; 95% 3.61-7.03; p < 0.001 relative to HIC). A similar severity increase linked to country income was found in influenza-negative patients. Interpretation We found significant disparities in influenza severity among hospitalized patients in countries with limited resources, supporting global efforts to implement public health interventions. Funding The GIHSN is partially funded by the Foundation for Influenza Epidemiology (France). This analysis was funded by Ready2Respond under Wellcome Trust grant 224690/Z/21/Z. Evidence before this study In the past 35 years, fewer than 10% of peer-reviewed articles on influenza burden of disease have reported analyses from lower middle- or lower-income settings. Whereas the impact of influenza in upper middle- and high-income countries – regions where influenza seasonality is well-defined and where high numbers of influenza-related clinic visits, hospital admissions, and deaths are well-documented – has been clearly quantified, data scarcity has challenged our ability to ascertain influenza burden in resource-limited settings. As a result, policy decisions on vaccine use in lower-income countries have been made with limited data, slowing the development of influenza vaccine recommendations in these settings. In this study, we have conducted prospective influenza surveillance in the hospital setting in multiple countries to assess potential geographic differences in the severity of influenza admissions and have shown that influenza is a global concern, and report poorer clinical outcomes among patients admitted to hospitals in resource-limited settings. In these settings, it is especially important to consider the role of preventive measures, such as vaccines, in providing protection against severe disease. Added value of this study Since 2012, in collaboration with over 100 clinical sites worldwide, the Global Influenza Hospital Surveillance Network (GIHSN) has provided patient-level data on severe influenza-like illnesses based on a core protocol and consistent case definitions. To our knowledge, this is the first study to analyze multiple years of global, patient-level data generated by prospective, hospital-based surveillance across a large number of countries to investigate geographic differences in both influenza morbidity and mortality. Our study provides information on influenza burden in under-researched populations, particularly those in lower middle-income countries, and highlights the need for continued global collaboration and unified protocols to better understand the relationships between socio-economic development, healthcare, access to care, and influenza morbidity and mortality. After adjustment for differences in the characteristics of individual patients admitted to the hospital for influenza, we find an increased severity of disease in lower-income settings. In particular, the risk of ICU admissions increases two- and five-fold in upper middle- and lower-middle income countries, compared to high-income countries. The risk of in-hospital death is five-fold higher in lower-middle income countries, compared to more affluent countries. Implications of all the available evidence We find evidence of increased severity in influenza admissions in lower-income countries, which could point at structural differences in access to care between countries (patients arriving at the hospital later in the disease process) and/or differences in care once in the hospital. Understanding the mechanisms responsible for these disparities will be important to improve management of influenza, optimize vaccine allocation, and mitigate global disease burden. The Global Influenza Hospital Surveillance Network serves as an example of a collaborative platform that can be expanded and leveraged to address geographic differences in the epidemiology and severity of influenza, especially in lower and upper middle-income countries. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The GIHSN is partially funded by the Foundation for Influenza Epidemiology (France). This analysis was funded by Ready2Respond under Wellcome Trust grant 224690/Z/21/Z. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The following ethics committees gave ethical approval for the GIHSN surveillance work: the Research Ethics Board of Nova Scotia Health and of each participating site in Canada; le Comité de Protection des Personnes (CPP) Ile de France IV, Hôpital Saint-Louis, France, as part of the FLUVAC study; the Ethical Committee of the Hospital Na Bulovce, Czech Republic; CEIC Direccion General de Salud Publica/Centro Superior de Investigación en Salud Pública of FISABIO, Spain; the Fudan University School of Public Health Institution Review Board, China; the Institutional Review Board, American University of Beirut, Lebanon; Comité Institucional de ética en Investigación: Instituto de Medicina Tropical DAC Universidad Nacional de San Marcos, Perú; the Bioethics Committee of the National Institute for Infectious Diseases Prof. Dr. Matei Bals, Bucharest, Romania; Comité de Bioética del Hospital Dr. Alejandro Posadas, Argentina; the Research Ethics Committee (Medical) of the University of the Cartagena, the Ethical Committee of the Hospital Universitario del Caribe, the Ethics Committee Hospital children Napoleon Franco Pareja in Cartagena, Colombia; Comitê de ética em Pesquisa - CEP 0097 - Hospital Pequeno Príncipe, Brazil; the Human Research Ethics Committee (Medical) of the University of the Witwatersrand, South Africa; the local Ethic Committee of Hospital 1 for Infectious Diseases of Moscow Health Department of the Federal State Budgetary Healthcare Institution, Moscow, Russia; the Local Ethics Committee at the Federal State Budget Institution Smorodintsev Research Institute of Influenza of the Ministry of Health of the Russian Federation; the Ethical committee of the Institute of Public Health Vojvodina, Serbia; the National Institute of Public Hygiene (INPH), Côte d'Ivoire, as part of the national epidemiological surveillance of influenza; the medical ethics committee of Dr. Abderrahmane Mami, Ariana, Tunisia; KEMRI Scientific and Ethics Review Unit of the Kenya Medical Research Institute, Kenya; the Institute Ethics Committee of the Sher-i Kashmir Institute of Medical Sciences, Srinagar, India; and Hacettepe University Noninterventional Clinical Research Ethics Board, Türkiye. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Anonymized data used for this analysis, along with a data dictionary, are available upon request made to contact{at}gihsn.org. The use of data depends on the approval of an analytical proposal by the Independent Scientific Committee. Investigators from participant sites are informed up front for any planned data analysis and they have the possibility to opt-out.