Characterization of post-acute multi-organ sequelae following dengue infection.

Abstract

Objectives: Population-based cohort studies on long-term sequelae post-dengue are lacking, given dengue's disproportionate burden in tropical low-and-middle-income countries (LMICs) with limited access to diagnostic testing and follow-up. We estimated the 300-day post-acute risk of new-incident multi-systemic complications following dengue infection.

Methods: National dengue registries and healthcare-claims databases in Singapore were utilised to build a retrospective population-based adult cohort with laboratory-confirmed dengue infection (1 Jan 2017-30 Jun 2023) and a cohort of uninfected controls. Differences in baseline characteristics were adjusted using overlap weighting. Risks of new-incident complications across multiple organ systems, all-cause hospitalisation and death up to 300 days post-dengue infection were systematically contrasted against population-based-controls, using competing risk regression.

Results: 55,870 dengue-infected individuals and 3,072,309 uninfected controls were included; the majority had mild initial infection not requiring hospitalisation. In the post-acute period, there was 19.0% (aHR=1.19[1.13,1.26]) increased risk of any post-acute sequelae, with an 46.0% increase in risk of cardiovascular sequelae (aHR=1.46[1.01,2.10]) and 29.0% increase in risk of neuropsychiatric sequelae (aHR=1.29[1.14,1.45]) in dengue-infected individuals versus controls. There was also a 37.0% increase in risk of autoimmune disorders (aHR=1.37 [1.24,1.52]), a 19% increase in risk of endocrine disorders (aHR=1.19[1.12,1.25]), a 42.0% increase in risk of gastrointestinal sequelae (aHR=1.42[1.17,1.72]). and 230.0% increase in risk of renal sequelae (aHR=2.30[1.69,3.12]). Post-acute risk of all-cause hospitalisation (aHR= 1.22[1.20,1.25]) and death (aHR= 2.08[1.85,2.33]) were also elevated in dengue-infected cases. The cumulative number of post-acute outcomes amongs dengue-infected cases increased over the 31-300 day follow-up period, versus uninfected controls. Risks of post-acute sequelae were increased in hospitalised dengue patients, older age groups (61+ years), those with comorbidities and across DENV-2/DENV-3 predominant transmission.

Conclusions: Increased post-acute risk of multi-organ complications, all-cause hospitalisations and death was observed in dengue survivors, versus uninfected population-based-controls. Development of multidisciplinary care strategies to reduce chronic health loss post-dengue infection is crucial.