Marth, Lena; Martinez-Murcia, Francisco J; Górriz-Sáez, Juan-Manuel; et al. Neurology Vol. 106, no. 4, p. e214510

Introduction Prior studies1,2 of postacute dengue sequelae report its association with subsequent cardiovascular, neuropsychiatric, and gastrointestinal complications, but follow-up in those studies was short, and estimates of the disability-adjusted life-year (DALY) burden were limited. We estimated the 2-year risks, rates, and DALY burden of postacute, multisystemic sequelae following dengue infection in Singapore, where dengue is endemic with recurrent outbreaks. Methods We conducted a retrospective cohort study using Singapore’s linked national dengue surveillance and health care claims data (eAppendix 1 and eFigure in Supplement 1). Institutional review board approval and patient consent were not required as this study was conducted under the Infectious Diseases Act, Singapore. Reporting followed the STROBE reporting guidelines for cohort studies. Adults aged 18 years and older with dengue first notified as of time 0 (T0) between January 1, 2013, and June 30, 2022 were included. Individuals who died 30 days or less after T0, had another dengue infection 30 to 730 days after T0, or SARS-CoV-2 infection 365 days before T0 or 30 to 730 days after T0 were excluded. Controls had no recorded dengue and were alive 30 days after an assigned enrollment date sampled from the distribution of case enrollment times, yielding 42 controls per case by exact matching. Primary outcomes from T0 plus 30 days to T0 plus 730 days were all-cause mortality, hospitalization, and incident cardiovascular, neuropsychiatric, autoimmune, kidney, endocrine, and gastrointestinal sequelae defined by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes, recorded in national health care claims data (eAppendix 2 in Supplement 1). Covariates included age, sex, ethnicity (from national registration records), Charlson Comorbidity Index, prior admissions, and housing-based socioeconomic status. Propensity scores were estimated using logistic regression with overlap weighting, and standardized mean differences (SMDs) assessed covariate balance. Competing-risks regression (death as competing event) and Cox models were used to estimate hazard ratios (HRs); negative-binomial regression was used to estimate incidence rate ratios (IRRs) and excess burdens (weighted incidence rate differences). Excess DALYs were derived by multiplying excess burdens by Global Burden of Disease 2021 Level-3 DALYs per case. Subgroup analyses included age, sex, ethnicity, socioeconomic status, and comorbidity to examine potential effect modification. Sensitivity analyses applied alternative weighting strategies, DALY specifications, negative-outcome control (asthma), and temporal incidence assessments. All statistical tests reported 95% CIs, with statistical significance defined as a 95% CI that did not include 1. Analyses were implemented in R statistical version 4.3.1 (R Project for Statistical Computing) (eAppendix 3 in Supplement 1). Results After exclusions, 68 145 dengue-infected adults and 2 886 119 controls were included. SMDs were below 0.1 after weighting (Table 1). Over 2 years, dengue infection was associated with increased risks of all-cause hospitalization (HR, 1.12; 95% CI, 1.10-1.14) and any prespecified sequelae (HR, 1.06; 95% CI, 1.01-1.11) (Table 2). We estimated 1670 excess DALYs (95% CI, 850-2492 excess DALYs) (Table 2) due to sequelae, equivalent to 2.52 DALYs per 100 infections. Neuropsychiatric sequelae contributed most of the burden (1589 DALYs), followed by endocrine (53 DALYs), kidney (16 DALYs), and gastrointestinal (4 DALYs) sequelae. Although risks for postacute sequelae declined across most organ systems in the second year, elevated risks for all-cause hospitalization and for neuropsychiatric, kidney, and gastrointestinal complications persisted. Excess DALYs were higher among older adults (aged ≥61 years), individuals with comorbidities, public housing residents, male individuals, and those of Chinese ethnicity. Table 1.  Baseline Characteristics Before and After Overlap Weighting View LargeDownload (opens in new tab)Go to Figure in ArticleCharacteristicUnweightedWeightedSMDaControls (n = 2 886 119)Dengue positive (n = 68 145)ControlsDengue positiveAge, mean (SD), y45.87 (16.96)44.6 (16.42)44.62 (17.00)44.62 (16.41)<.01Ethnicity Chinese2 179 522 (75.52)53 916 (79.12)52 094 (78.99)52 094 (78.99)<.01 Indian262 614 (9.10)5536 (8.12)5379 (8.16)5379 (8.16)<.01 Malay339 319 (11.76)6833 (10.03)6663 (10.10)6663 (10.10)<.01 Othersb104 664 (3.63)1860 (2.73)1812 (2.75)1812 (2.75)<.01Sex Female1 505 634 (52.17)31 588 (46.35)30 670 (46.51)30 670 (46.51)<.01 Male1 380 485 (47.83)36 557 (53.65)35 273 (53.49)35 273 (53.49)Apartment typec 1-2 Rooms public134 812 (4.67)2346 (3.44)2296 (3.48)2296 (3.48)<.01 3 Rooms public439 230 (15.22)8286 (12.16)8096 (12.28)8096 (12.28)<.01 4 Rooms public915 902 (31.73)17 949 (26.34)17 538 (26.59)17 538 (26.59)<.01 5 Rooms or executive public1 119 839 (38.80)26 635 (39.09)25 916 (39.30)25 916 (39.30)<.01 Others66 511 (2.30)468 (0.69)463 (0.70)463 (0.70)<.01 Private209 825 (7.27)12 461 (18.29)11 638 (17.65)11 638 (17.65)<.01Charleson Comorbidity Index ≥1299 715 (10.38)7577 (11.12)7345 (11.14)7345 (11.14)<.01Previous hospitalizations (≥1)975 746 (33.81)35 994 (52.82)34 455 (52.25)34 455 (52.25)<.01 Table 2.  Postacute Sequelae 2 Years After Dengue Infection Among Patients and Control Groups View LargeDownload (opens in new tab)Go to Figure in ArticleOutcome30-365 d After infectiona365-730 d After infectionaHR (95% CI)IRR (95% CI)Excess DALYs (95% CI)HR (95% CI)IRR (95% CI)Excess DALYs (95% CI)Death1.93 (1.68 to 2.21)b1.81 (0.69 to 4.76)NEc0.89 (0.77 to 1.03)1.04 (0.25 to 4.41)NEcAll-cause hospitalization1.13 (1.11 to 1.15)b1.18 (1.14 to 1.22)bNEc1.12 (1.10 to 1.14)b1.14 (1.11 to 1.17)bNEcComposite outcomes Any sequelae1.12 (1.07 to 1.17)b1.18 (1.08 to 1.29)bNEc1.06 (1.01 to 1.11)b1.03 (0.94 to 1.13)NEc Major adverse cardiovascular event1.20 (1.05 to 1.37)b1.17 (0.94 to 1.46)22.64 (−3.40 to 48.68)1.05 (0.91 to 1.21)0.99 (0.79 to 1.24)−1.72 (−26.19 to 22.74) Autoimmune outcomes1.22 (0.86 to 1.73)1.02 (0.42 to 2.48)2.07 (−20.64 to 24.79)0.91 (0.63 to 1.33)0.54 (0.24 to 1.18)−35.16 (−55.79 to −14.53) Cardiovascular and thrombotic outcomes1.12 (1.00 to 1.25)1.33 (0.54 to 3.31)25.26 (−0.73 to 51.25)1.05 (0.94 to 1.18)0.99 (0.82 to 1.18)−2.72 (−27.80 to 22.36) Neurological and psychiatric outcomes1.21 (1.09 to 1.33)b1.30 (1.09 to 1.55)b939.49 (499.68 to 1379.30)b1.09 (0.99 to 1.21)1.18 (0.99 to 1.40)572.98 (129.89 to 1016.06)b Endocrine outcomes1.12 (1.06 to 1.18)b1.21 (1.09 to 1.34)b27.23 (19.40 to 35.060)b1.07 (1.01 to 1.13)b1.05 (0.95 to 1.16)7.61 (−0.49 to 15.71) Gastrointestinal outcomes1.24 (1.04 to 1.47)b1.21 (0.92 to 1.58)1.29 (−0.41 to 2.99)1.24 (1.05 to 1.47)b1.38 (1.05 to 1.81)b2.41 (0.60 to 4.22)b Kidney outcomes1.98 (1.46 to 2.68)b2.14 (0.77 to 6.03)7.84 (3.64 to 12.04)b1.05 (0.72 to 1.54)1.39 (0.59 to 3.28)4.86 (0.69 to 9.02)bIndividual diagnoses Autoimmune Connective tissue disorders1.84 (1.05 to 3.21)b1.96 (0.54 to 7.17)1.29 (0.14 to 2.44)b0.82 (0.39 to 1.74)0.60 (0.14 to 2.50)−0.67 (−1.64 to 0.29) Cardiovascular Dysrhythmias1.23 (1.03 to 1.47)b1.95 (0.27 to 14.55)4.50 (0.77 to 8.24)b1.06 (0.88 to 1.27)1.03 (0.32 to 3.30)0.61 (−3.03 to 4.24) Ischemic heart disease1.16 (1.01 to 1.34)b1.15 (0.91 to 1.44)21.44 (−7.79 to 50.68)1.05 (0.91 to 1.22)0.99 (0.79 to 1.25)−1.51 (−29.33 to 26.31) Inflammatory heart diseasesNEcNEcNEcNEcNEcNEc Other heart diseases1.69 (0.69 to 4.15)15.18 (0.01 to 23301.99)0.14 (−0.27 to 0.56)0.66 (0.21 to 2.09)0.68 (0.01 to 81.37)−0.15 (−0.56 to 0.27) Thrombotic disorders1.21 (0.80 to 1.83)1.22 (0.48 to 3.13)0.28 (−0.72 to 1.28)0.86 (0.54 to 1.37)0.65 (0.05 to 7.74)−0.43 (−1.37 to 0.52) Neurological Cerebrovascular disease1.51 (0.97 to 2.34)1.22 (0.47 to 3.19)1.66 (−4.19 to 7.50)1.03 (0.59 to 1.79)0.92 (0.32 to 2.62)−0.58 (−5.50 to 4.34) Movement disorders1.21 (0.83 to 1.77)1.07 (0.47 to 2.42)1.58 (−10.34 to 13.50)0.81 (0.53 to 1.22)0.98 (0.46 to 2.08)−0.49 (−13.24 to 12.26) Cognitive disorders1.53 (1.22 to 1.92)b1.65 (1.02 to 2.65)b33.03 (14.65 to 51.41)b1.14 (0.89 to 1.46)1.30 (0.78 to 2.18)14.35 (−4.04 to 32.73) Episodic disorders1.31 (0.93 to 1.82)1.22 (0.69 to 2.15)2.26 (−2.81 to 7.32)0.95 (0.65 to 1.38)0.75 (0.42 to 1.33)−2.81 (−7.49 to 1.86) Other neurological disorders1.23 (1.04 to 1.47)b1.25 (0.96 to 1.64)486.09 (−52.92 to 1025.10)1.03 (0.86 to 1.24)1.08 (0.82 to 1.42)162.04 (−367.10 to 691.18) Peripheral neuropathies0.79 (0.35 to 1.77)0.70 (0.14 to 3.27)−40.80 (−166.44 to 84.84)1.04 (0.53 to 2.02)0.94 (0.27 to 3.24)−9.78 (−151.88 to 132.32) Sensory disorders1.10 (0.79 to 1.54)1.18 (0.71 to 1.97)0.14 (−0.25 to 0.53)1.13 (0.82 to 1.56)1.06 (0.66 to 1.71)0.05 (−0.34 to 0.44) Psychiatric Mood disorders0.59 (0.22 to 1.59)0.71 (0.14 to 3.49)−0.20 (−0.79 to 0.39)1.12 (0.52 to 2.36)1.51 (0.35 to 6.67)0.30 (−0.34 to 0.94) Stress and anxiety disorders1.23 (0.98 to 1.54)1.28 (0.83 to 1.98)3.77 (0.05 to 7.49)b1.17 (0.93 to 1.46)1.31 (0.84 to 2.03)4.40 (0.53 to 8.27)b Psychotic disorders0.98 (0.54 to 1.79)1.59 (0.51 to 5.05)0.65 (−0.25 to 1.56)1.08 (0.63 to 1.83)1.21 (0.44 to 3.36)0.29 (−0.64 to 1.22) Endocrine Diabetes1.09 (0.89 to 1.33)0.98 (0.67 to 1.43)−0.43 (−3.41 to 2.55)1.00 (0.80 to 1.24)0.93 (0.63 to 1.37)−0.76 (−3.34 to 1.82) Dyslipidemia1.12 (1.06 to 1.18)b1.20 (1.09 to 1.33)b13.14 (9.23 to 17.04)b1.07 (1.02 to 1.13)b1.06 (0.96 to 1.17)4.35 (0.29 to 8.42)b Gastrointestinal Gastritis1.23 (0.93 to 1.62)1.20 (0.78 to 1.84)0.09 (−0.11 to 0.28)1.06 (0.79 to 1.43)1.15 (0.73 to 1.81)0.06 (−0.13 to 0.25) Irritable bowel syndrome1.00 (0.69 to 1.43)0.99 (0.59 to 1.64)NEc1.37 (1.01 to 1.85)b1.35 (0.85 to 2.17)NEc Acute pancreatitis1.28 (0.81 to 2.02)1.12 (0.46 to 2.73)0.35 (−1.47 to 2.16)1.05 (0.66 to 1.68)1.03 (0.36 to 2.94)−0.06 (−1.93 to 1.82) Biliary tract disease1.21 (0.82 to 1.77)1.18 (0.64 to 2.17)0.11 (−0.25 to 0.47)1.44 (1.03 to 2.01)b1.67 (0.73 to 3.87)0.47 (0.05 to 0.89)b Noninfectious hepatitis and cirrhosis2.30 (1.12 to 4.72)b2.77 (0.51 to 16.62)0.03 (−0.00 to 0.05)2.66 (1.29 to 5.47)b3.99 (0.73 to 25.60)0.03 (0.00 to 0.06)b Discussion This nationwide cohort study found that dengue infection is followed by sustained multisystem morbidity and mortality extending well beyond the febrile phase. Benchmarking against prior acute dengue DALY estimates suggests dengue’s burden in Singapore has been underestimated by 13% to 37%,3 consistent with data from Mexico, where persistent symptoms contributed 13% to 43% additional burden.2 Given the high incidence of dengue in endemic settings, this postacute disability represents a substantial population health impact. Although these sequelae are proposed to be mediated by persistent immune dysregulation and inflammation, the underlying pathophysiology remains incompletely understood.1,4-6 Limitations include restriction to adults, reliance on claims-based diagnoses, ecological assignment of dengue serotypes, and exclusion of asymptomatic infections, which likely bias estimates toward the null. Nonetheless, sensitivity analyses yielded consistent conclusions. These results support comprehensive incorporation of long-term postacute complications into dengue burden assessments and argue for postdischarge surveillance in high-risk groups. Back to top Article Information Accepted for Publication: December 18, 2025.Published: February 12, 2026. doi:10.1001/jamanetworkopen.2025.59108Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2026 Chow JY et al. JAMA Network Open.Corresponding Author: Liang En Wee, MPH, Singapore General Hospital, Outram Rd, Singapore 169608, Singapore (ian.wee.l.e@singhealth.com.sg).Author Contributions: Ms Chow and Dr Lim had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Ms Chow, Mr W. Z. Tan, and Dr Wee contributed equally to this work.Concept and design: Wee, Ng, Lye, K. B. Tan, Lim.Acquisition, analysis, or interpretation of data: Chow, W. Z. Tan, Guo, Choo, Chiew, Kurupatham, Chia, K. B. Tan, Lim.Drafting of the manuscript: Chow, W. Z. Tan, Wee, Choo, K. B. Tan, Lim.Critical review of the manuscript for important intellectual content: Chow, Wee, Guo, Chiew, Kurupatham, Ng, Chia, Lye, Lim.Statistical analysis: Chow, W. Z. Tan, Wee, K. B. Tan, Lim.Obtained funding: Lye, Lim.Administrative, technical, or material support: W. Z. Tan, Chiew, Kurupatham, Lye, Lim.Supervision: Chia, Lye, K. B. Tan, Lim.Conflict of Interest Disclosures: Dr Chia reported receiving support from Merck, Sharp, & Dohme, AstraZeneca, and Novartis as the principal investigator for sponsored trials, and speaker’s fees from Takeda paid to institution outside the submitted work. No other disclosures were reported.Funding/Support: This research is supported by the Ministry of Health (MOH), Government of Singapore through the National Medical Research Council Office, MOH Holdings Pte Ltd under the National Epidemic Preparedness and Response R&D Programme Funding Initiative (MOH-001041/MOH-001073/MOH-001446), as well as the National Research Foundation Singapore under its Clinician-Scientist Individual Research Grant (MOH-001572). Dr Lim is supported by the Ministry of Education, Singapore’s Start-up Grant. Dr Wee is supported by the National Medical Research Council through the Clinician Scientist New Investigator Award.Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.Data Sharing Statement: See Supplement 2. References 1.Lim  JT, Wee  LE, Tan  WZ,  et al.  Characterization of post-acute multi-organ sequelae following dengue infection.   Clin Microbiol Infect. 2025;31(11):1865-1872. doi:10.1016/j.cmi.2025.06.012PubMedGoogle ScholarCrossref2.Tiga  DC, Undurraga  EA, Ramos-Castañeda  J, Martínez-Vega  RA, Tschampl  CA, Shepard  DS.  Persistent symptoms of dengue: estimates of the incremental disease and economic burden in Mexico.   Am J Trop Med Hyg. 2016;94(5):1085-1089. doi:10.4269/ajtmh.15-0896PubMedGoogle ScholarCrossref3.Carrasco  LR, Lee  LK, Lee  VJ,  et al.  Economic impact of dengue illness and the cost-effectiveness of future vaccination programs in Singapore.   PLoS Negl Trop Dis. 2011;5(12):e1426. doi:10.1371/journal.pntd.0001426PubMedGoogle ScholarCrossref4.Dinakaran  D, Sreeraj  VS, Venkatasubramanian  G.  Dengue and psychiatry: manifestations, mechanisms, and management options.   Indian J Psychol Med. 2022;44(5):429-435. doi:10.1177/02537176211022571PubMedGoogle ScholarCrossref5.Samanta  J, Sharma  V.  Dengue and its effects on liver.   World J Clin Cases. 2015;3(2):125-131. doi:10.12998/wjcc.v3.i2.125PubMedGoogle ScholarCrossref6.Yacoub  S, Wertheim  H, Simmons  CP, Screaton  G, Wills  B.  Cardiovascular manifestations of the emerging dengue pandemic.   Nat Rev Cardiol. 2014;11(6):335-345. doi:10.1038/nrcardio.2014.40PubMedGoogle ScholarCrossref

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