Risk of death following chikungunya virus disease in the 100 Million Brazilian Cohort, 2015–18: a matched cohort study and self-controlled case series

Background Chikungunya virus outbreaks have been associated with excess deaths at the ecological level. Previous studies have assessed the risk factors for severe versus mild chikungunya virus disease. However, the risk of death following chikungunya virus disease compared with the risk of death in individuals without the disease remains unexplored. We aimed to investigate the risk of death in the 2 years following chikungunya virus disease. Methods We used a population-based cohort study and a self-controlled case series to estimate mortality risks associated with chikungunya virus disease between Jan 1, 2015, and Dec 31, 2018, in Brazil. The dataset was created by linking national databases for social programmes, notifiable diseases, and mortality. For the matched cohort design, individuals with chikungunya virus disease recorded between Jan 1, 2015, and Dec 31, 2018, were considered as exposed and those who were arbovirus disease-free and alive during the study period were considered as unexposed. For the self-controlled case series, we included all deaths from individuals with a chikungunya virus disease record, and each individual acted as their own control according to different study periods relative to the date of disease. The primary outcome was all-cause natural mortality up to 728 days after onset of chikungunya virus disease symptoms, and secondary outcomes were cause-specific deaths, including ischaemic heart diseases, diabetes, and cerebrovascular diseases. Findings In the matched cohort study, we included 143 787 individuals with chikungunya virus disease who were matched, at the day of symptom onset, to unexposed individuals using sociodemographic factors. The incidence rate ratio (IRR) of death within 7 days of chikungunya symptom onset was 8·40 (95% CI 4·83–20·09) as compared with the unexposed group and decreased to 2·26 (1·50–3·77) at 57–84 days and 1·05 (0·82–1·35) at 85–168 days, with IRR close to 1 and wide CI in the subsequent periods. For the secondary outcomes, the IRR of deaths within 28 days after disease onset were: 1·80 (0·58–7·00) for cerebrovascular diseases, 3·75 (1·33–17·00) for diabetes, and 3·67 (1·25–14·00) for ischaemic heart disease, and there was no evidence of increased risk in the subsequent periods. For the self-controlled case series study, 1933 individuals died after having had chikungunya virus disease and were included in the analysis. The IRR of all-cause natural death within 7 days of symptom onset of chikungunya virus disease was 8·75 (7·18–10·66) and decreased to 1·59 (1·26–2·00) at 57–84 days and 1·09 (0·92–1·29) at 85–168 days. For the secondary outcomes, the IRRs of deaths within 28 days after disease onset were: 2·73 (1·50–4·96) for cerebrovascular diseases, 8·43 (5·00–14·21) for diabetes, and 2·38 (1·33–4·26) for ischaemic heart disease, and there was no evidence of increased risk at 85–168 days. Interpretation Chikungunya virus disease is associated with an increased risk of death for up to 84 days after symptom onset, including deaths from cerebrovascular diseases, ischaemic heart diseases, and diabetes. This study highlights the need for equitable access to approved vaccines and effective anti-chikungunya virus therapeutics and reinforces the importance of robust vector-control efforts to reduce viral transmission. Funding Brazilian National Research Council (CNPq), Fundação de Amparo à Pesquisa do Estado da Bahia, Wellcome Trust, and UK Medical Research Council. Translation For the Portuguese translation of the abstract see Supplementary Materials section.