High Clinical Burden of Influenza Disease in Adults Aged ≥ 65 Years: Can We Do Better? A Systematic Literature Review

Abstract

Introduction: Influenza is a respiratory infection associated with a significant clinical burden globally. Adults aged ≥ 65 years are at increased risk of severe influenza-related symptoms and complications due to chronic comorbidity and immunosenescence. Annual influenza vaccination is recommended; however, current influenza vaccines confer suboptimal protection, in part due to antigen mismatch and poor durability. This systematic literature review characterizes the global clinical burden of seasonal influenza among adults aged ≥ 65 years.

Methods: An electronic database search was conducted and supplemented with a conference abstract search. Included studies described clinical outcomes in the ≥ 65 years population across several global regions and were published in English between January 1, 2012 and February 9, 2022.

Results: Ninety-nine publications were included (accounting for > 156,198,287 total participants globally). Clinical burden was evident across regions, with most studies conducted in the USA and Europe. Risk of influenza-associated hospitalization increased with age, particularly in those aged ≥ 65 years living in long-term care facilities, with underlying comorbidities, and infected with A(H3N2) strains. Seasons dominated by circulating A(H3N2) strains saw increased risk of influenza-associated hospitalization, intensive care unit admission, and mortality within the ≥ 65 years population. Seasonal differences in clinical burden were linked to differences in circulating strains.

Conclusions: Influenza exerts a considerable burden on adults aged ≥ 65 years and healthcare systems, with high incidence of hospitalization and mortality. Substantial influenza-associated clinical burden persists despite increasing vaccination coverage among adults aged ≥ 65 years across regions included in this review, which suggests limited effectiveness of currently available seasonal influenza vaccines. To reduce influenza-associated clinical burden, influenza vaccine effectiveness must be improved. Next generation vaccine production using mRNA technology has demonstrated high effectiveness against another respiratory virus-SARS-CoV-2-and may overcome the practical limitations associated with traditional influenza vaccine production.

Keywords: Burden of disease; Hospitalization; Mortality; Older adults; Strain; Vaccination; mRNA vaccine.

Fig. 1

PRISMA flowchart of publications included in the SLR. *SLRs and cost-effectiveness models captured in the database search that met inclusion criteria underwent a manual bibliography check, and data was extracted from studies that met inclusion criteria and were not already captured. ^†Search was designed to capture studies reporting the clinical, humanistic, and economic burdens of influenza. For this publication only studies reporting relevant clinical outcomes were included. CEM cost-effectiveness model, PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses, SLR systematic literature review

Fig. 2

Included study characteristics. Breakdown of included studies by i. WHO region, ii. country, iii. type of study design, iv. study setting, and v. study outcome. ICU intensive care unit, RCT randomized controlled study, WHO World Health Organization

Fig. 3

Studies reporting the burden of influenza-associated hospitalization by country. USA [24, 25, 26, 27, 28, 29, 30, 31, 32, 33], China [34, 35, 36, 37, 38, 39, 40], Spain [41, 42, 43, 44, 45, 46, 47], France [48, 49, 50, 51, 52], Canada [52, 53, 54], Japan [55, 56], UK [57, 58], Germany [59], Multinational (Brazil, Canada, and the USA) [60]

Fig. 4

Trends in hospitalization for influenza in patients aged ≥ 65 years by season, reported by three publications [26, 41, 50], and national census data for population aged ≥ 65 years. i. Number of influenza-related hospitalizations among those aged ≥ 65 years by Reed et al. (US-study). Dominant strains not reported, US census data over study period [62]. ii. Number of severe hospitalized confirmed influenza cases among those aged ≥ 65 years reported by Oliva et al. (Spanish study, n of age subgroup not reported). Dominant strains [41], and Spanish census data over the same period [63]. iii. Number of influenza-related hospitalizations; average number of cases reported for ≥ 65 years subgroups (French study) (n of age subgroup not reported). Dominant strains [50] and French census data over the same period [64]

Fig. 5

Studies reporting the burden of influenza-associated mortality by country

Fig. 6

Patient comorbidities in studies reporting clinical burden of influenza among patients with underlying conditions. COPD chronic obstructive pulmonary disease, CVD cardiovascular disease. COPD [24, 71, 72, 77], diabetes mellitus [24, 71, 75, 84], respiratory disease [71, 75, 76, 84], ischemic stroke [77], CVD [75, 76, 85], heart failure [24], ischemic heart disease [72, 77, 85]