Influenza-Associated Excess Mortality by Age, Sex, and Subtype/Lineage: Population-Based Time-Series Study With a Distributed-Lag Nonlinear Model
Authors: Li Li , Yan Ze-Lin , Luo Lei , Liu Wenhui , Yang Zhou , Shi Chen , Ming Bo-Wen , Yang Jun , Cao Peihua , Ou Chun-Quan 
Published: November 2022

Background
Accurate estimation of the influenza death burden is of great significance for influenza prevention and control. However, few studies have considered the short-term harvesting effects of influenza on mortality when estimating influenza-associated excess deaths by cause of death, age, sex, and subtype/lineage.

Objective
This study aimed to estimate the cause-, age-, and sex-specific excess mortality associated with influenza and its subtypes and lineages in Guangzhou from 2015 to 2018.

Methods
Distributed-lag nonlinear models were fitted to estimate the excess mortality related to influenza subtypes or lineages for different causes of death, age groups, and sex based on daily time-series data for mortality, influenza, and meteorological factors.

Results
A total of 199,777 death certificates were included in the study. The average annual influenza-associated excess mortality rate (EMR) was 25.06 (95% empirical CI [eCI] 19.85-30.16) per 100,000 persons; 7142 of 8791 (81.2%) deaths were due to respiratory or cardiovascular mortality (EMR 20.36, 95% eCI 16.75-23.74). Excess respiratory and cardiovascular deaths in people aged 60 to 79 years and those aged ≥80 years accounted for 32.9% (2346/7142) and 63.7% (4549/7142) of deaths, respectively. The male to female ratio (MFR) of excess death from respiratory diseases was 1.34 (95% CI 1.17-1.54), while the MFR for excess death from cardiovascular disease was 0.72 (95% CI 0.63-0.82). The average annual excess respiratory and cardiovascular mortality rates attributed to influenza A (H3N2), B/Yamagata, B/Victoria, and A (H1N1) were 8.47 (95% eCI 6.60-10.30), 5.81 (95% eCI 3.35-8.25), 3.68 (95% eCI 0.81-6.49), and 2.83 (95% eCI –1.26 to 6.71), respectively. Among these influenza subtypes/lineages, A (H3N2) had the highest excess respiratory and cardiovascular mortality rates for people aged 60 to 79 years (20.22, 95% eCI 14.56-25.63) and ≥80 years (180.15, 95% eCI 130.75-227.38), while younger people were more affected by A (H1N1), with an EMR of 1.29 (95% eCI 0.07-2.32). The mortality displacement of influenza A (H1N1), A (H3N2), and B/Yamagata was 2 to 5 days, but 5 to 13 days for B/Victoria.

Conclusions
Influenza was associated with substantial mortality in Guangzhou, occurring predominantly in the elderly, even after considering mortality displacement. The mortality burden of influenza B, particularly B/Yamagata, cannot be ignored. Contrasting sex differences were found in influenza-associated excess mortality from respiratory diseases and from cardiovascular diseases; the underlying mechanisms need to be investigated in future studies. Our findings can help us better understand the magnitude and time-course of the effect of influenza on mortality and inform targeted interventions for mitigating the influenza mortality burden, such as immunizations with quadrivalent vaccines (especially for older people), behavioral campaigns, and treatment strategies.