Dengue versus COVID-19: comparing the incidence of cardiovascular, neuropsychiatric and autoimmune complications
Authors: Wee Liang En , Lim Jue Tao , Tan Janice Yu Jin , Malek Muhammed Ismail Bin Abdul , Chiew Calvin , Ng Lee Ching , Chia Po Ying , Leo Yee Sin , Lye David Chien Boon , Tan Kelvin Bryan 
Published: June 2024

Abstract

Background
While persistence of chronic symptoms following dengue infection has been documented in small prospective cohorts, population-based studies are limited. The post-acute risk of new-incident multi-systemic complications following dengue infection was contrasted against that following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a multi-ethnic adult Asian population.

Methods
National testing and healthcare claims that databases in Singapore were utilized to build a retrospective population-based adult cohort with laboratory-confirmed infection during overlapping waves of SARS-CoV-2 and dengue transmission (1 July 2021 to 31 October 2022). Risks of new-incident cardiovascular/neuropsychiatric/autoimmune complications 31–300 days of post-dengue infection, contrasted with SARS-CoV-2 infection, were estimated using Cox regression with overlap weights. Risks were reported in terms of adjusted hazard ratio (aHR) and excess burden per 1000 persons.

Results
11 707 dengue-infected individuals and 1 248 326 contemporaneous coronavirus disease 2019 (COVID-19) cases were included; the majority had mild initial infection not requiring hospitalization. Amongst dengue-infected individuals, there was 21% [aHR = 1.21 (1.06–1.38)] increased risk of any sequelae, with 55% [aHR = 1.55 (1.27–1.89)] increased risk of cardiovascular sequelae. Specifically, increased risk of dysrhythmias [aHR = 1.79(1.35–2.37)], ischemic heart disease [aHR = 1.45(1.12–1.89)], other cardiac disorders [aHR = 2.21(1.54–3.16)] and thrombotic disorders [aHR = 2.55(1.50–4.35)] was noted. Elevated risk of individual neuropsychiatric sequelae, including cerebrovascular disorders [aHR = 1.49(1.09–2.13)], cognition/memory disorders [aHR = 2.13(1.55–2.93)], extrapyramidal/movement disorders [aHR = 1.98(1.33–2.94)] and anxiety disorders [aHR = 1.61(1.01–2.56)], was observed in dengue-infected individuals compared to COVID-19 cases. Elevated risks of post-acute sequelae in dengue survivors were observed when contrasted against COVID-19 survivors infected during Delta/Omicron predominance, as well as across vaccination strata.

Conclusion
Increased risk of post-acute cardiovascular/neuropsychiatric complications was observed in dengue survivors, when contrasted against COVID-19 survivors infected during Delta/Omicron predominance.

Research in context

Evidence before this study
Post-acute sequelae following SARS-CoV-2 infection has been extensively reported; however, long-term sequelae may also occur after other acute infections, such as dengue. While chronic symptom persistence has been reported in small cohorts of dengue survivors, population-based cohort studies are lacking, given dengue’s disproportionate burden in tropical low-and-middle-income countries (LMICs) where access to diagnostic testing and follow-up is limited. We searched PubMed for studies published until 1 March 2024, using search terms ‘dengue’, ‘chronic’, ‘long term’, “with search terms found in abstract, title or MESH headings. Current research on post-acute sequelae following dengue is limited to small prospectively recruited cohorts, impairing generalizability to the population at-large. We only found four population-based retrospective cohort studies from a single country, Taiwan, which examined long-term risk of a limited set of autoimmune and cognitive sequelae following dengue infection. Evidence for post-acute sequelae was mixed, particularly when milder non-hospitalized cases were included. There are no reports on the risk of post-acute sequelae across multiple organ systems following dengue infection, and no reports contrasting the risk of post-acute sequelae in dengue versus SARS-CoV-2 infection.

Added value of this study
National testing and healthcare claims that databases in Singapore were utilized to build a retrospective population-based adult cohort of laboratory-confirmed dengue and SARS-CoV-2 infections during overlapping waves of COVID-19/dengue transmission. Increased overall risk of any post-acute sequelae and individual cardiovascular/neurological sequelae in dengue-infected adults was observed up to 300 days postinfection, compared against COVID-19 cases infected during Delta/Omicron predominance. While other studies have compared the risk of post-acute sequelae across different respiratory viral infections, such as influenza and SARS-CoV-2, to the best of our knowledge no prior studies have contrasted the potential risks of post-acute sequelae following dengue with that arising after SARS-CoV-2 infection.

Implication of all the available evidence
Risk of chronic multi-systemic sequelae arising post-dengue infection was significantly elevated when contrasted against post-acute sequelae following COVID-19. Post-acute sequelae may increase the burden of disease attributable to dengue in tropical countries where seasonal outbreaks occur; this is increasingly relevant, given that climate change has broadened the list of countries at risk of dengue endemicity.