Abstract
This cohort study investigates the association between dengue fever and risk of neurological and psychiatric disorders among adults in Taiwan.
Introduction
Dengue fever, which has an estimated annual infection rate of up to 390 million, mainly affects Central and South America and Southeast Asia.1,2 Apart from possible direct invasion of dengue fever virus to the neurological system, the disease has been reported to be associated with neurological complications probably attributable to autoimmune reactions and metabolic alterations.3 Several studies4,5 have found an association between dengue fever and neurologic and psychiatric disorders, including anxiety and depression symptoms. This retrospective nationwide cohort study attempted to further scrutinize the association between dengue fever and risk of subsequent neurological or psychiatric complications.
Methods
This cohort study, conducted in 2022, adhered to the STROBE reporting guidelines. Institutional review board approval was secured from the E-Da Hospital of Taiwan, which waived informed consent requisites owing to the anonymization of personal information.
Using data from the National Health Insurance Research Database, which covers 99% of the Taiwanese population, the research enrolled patients diagnosed with dengue fever from 2000 to 2015 who were propensity score matched at a 1:4 ratio with a comparator group without dengue fever based on various demographic and health factors. End points were the appearance of any outcome of interest, end of the study (ie, end of 2017), and death. The primary objective was to investigate whether dengue fever was associated with increased risk of neurological or psychiatric disorders. We excluded patients with preexisting conditions or who were younger than 18 years. The study used International Classification of Diseases, Ninth Revision (ICD-9) and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes to identify relevant diagnoses and Cox proportional hazards regression models for analysis.
Results
A total of 48 884 adults with dengue fever (26 415 male [54.04%]; mean [SD] age, 43.08 [16.54] years) and 195 536 individuals without the diagnosis (105 660 male [54.04%]; mean [SD] age, 43.08 [16.54] years) were identified (Table 1). Adjusted hazard ratios (aHRs) showed an increased risk for neurological and psychiatric disorders in the group with vs without dengue fever, including Guillain-Barré syndrome (1.10; 95% Cl, 1.03-1.18), myoneural junction disease (1.15; 95% CI, 1.08-1.23); Parkinson disease (1.44; 95% CI, 1.12-1.86); dementia (1.23; 95% CI, 1.07-1.41), and psychotic, mood, and anxiety disorders (1.13; 95% CI, 1.08-1.19). No significant difference was observed in the risk of intracranial hemorrhage or ischemic stroke (Table 2). Subgroup analysis based on age reinforced main findings, with aHRs showing an increased risk of composite psychiatric disorders after dengue infection for all age groups (18 to 30 years: 1.14; 95% CI, 1.05-1.24; >30 to 60 years: 1.07; 95% CI, 1.02-1.12; >60 years: 1.22; 95% CI, 1.13-1.31), while a significantly increased risk of neurological disorders was observed in individuals older than 60 years (aHR, 1.17; 95% CI, 1.07-1.28). Sex subgroup analysis revealed a universally higher risk of neurological and psychiatric disorders in the dengue fever group (Table 2).
Table 1. Baseline Characteristics of the Study Population.
| Characteristic | Patients, No. (%) (N = 244 420) | |
|---|---|---|
| No dengue (n = 195 536) | Dengue (n = 48 884) | |
| Age, y | ||
| Mean (SD) | 43.08 (16.54) | 43.08 (16.54) |
| 18 to 30 | 53 208 (27.21) | 13 302 (27.21) |
| >30 to 60 | 105 986 (54.20) | 26 497 (54.20) |
| >60 | 36 342 (18.59) | 9085 (18.58) |
| Sex | ||
| Female | 89 876 (45.96) | 22 469 (45.96) |
| Male | 105 660 (54.04) | 26 415 (54.04) |
| Medication | ||
| Aspirin | 5756 (2.94) | 1601 (3.28) |
| Colchicine | 1842 (0.94) | 574 (1.17) |
| Metformin | 7115 (3.64) | 2086 (4.27) |
| Plavix | 524 (0.27) | 170 (0.35) |
| Statin | 9301 (4.76) | 2657 (5.44) |
| Ticlopidine | 184 (0.09) | 51 (0.10) |
| Warfarin | 341 (0.17) | 91 (0.19) |
| Follow-ups per year, mean (SD) | ||
| Neurology outpatient department visit | 0.49 (3.99) | 0.53 (3.98) |
| Psychiatry outpatient department visit | 0.05 (0.99) | 0.09 (2.52) |
| Comorbidity | ||
| Cancer | 7513 (3.84) | 1652 (3.38) |
| Chronic kidney disease | 2994 (1.53) | 786 (1.61) |
| Coronary artery disease | 12 282 (6.28) | 2983 (6.10) |
| COPD | 11 484 (5.87) | 2764 (5.65) |
| Diabetes | 19 095 (9.77) | 4900 (10.02) |
| Heart failure | 3001 (1.53) | 643 (1.32) |
| Hyperlipidemia | 30 449 (15.57) | 7755 (15.86) |
| Hypertension | 36 279 (18.55) | 8926 (18.26) |
| PAOD | 1199 (0.61) | 299 (0.61) |
| Sleep apnea | 875 (0.45) | 207 (0.42) |
| Neurological or psychiatric condition | 20 447 (10.46) | 5218 (10.67) |
| Neurological condition | 7004 (3.58) | 1759 (3.60) |
| Encephalitis | 73 (0.04) | 22 (0.05) |
| Guillain-Barré syndrome | 20 (0.01) | 4 (0.01) |
| Intracranial hemorrhage | 437 (0.22) | 116 (0.24) |
| Ischemic stroke | 1878 (0.96) | 391 (0.80) |
| Myoneural junction and muscle disease | 205 (0.1) | 61 (0.12) |
| Nerve, nerve root, or plexus disorder | 4122 (2.11) | 1085 (2.22) |
| Parkinson disease or parkinsonism | 269 (0.14) | 80 (0.16) |
| Psychiatric condition | 13 443 (6.87) | 3459 (7.08) |
| Dementia | 1032 (0.53) | 245 (0.50) |
| Insomnia | 4066 (2.08) | 1030 (2.11) |
| Psychotic, mood, or anxiety disorder | 7317 (3.74) | 1902 (3.89) |
| Substance use disorder | 1028 (0.53) | 282 (0.58) |
Abbreviations: COPD, chronic obstructive pulmonary disease; PAOD, peripheral arterial occlusion disease.
Table 2. Risk of Disorders Among Patients With Dengue Fever.
| Disorder | Risk in dengue group, aHR (95% CI)a | P value |
|---|---|---|
| Neurological or psychiatric disorder | 1.12 (1.09-1.15) | <.001 |
| Neurological disorder | 1.12 (1.06-1.18) | <.001 |
| Encephalitis | 1.29 (0.97-1.72) | .08 |
| Guillain-Barré syndrome | 1.10 (1.03-1.18) | <.001 |
| Intracranial hemorrhage | 1.19 (0.97-1.46) | .10 |
| Ischemic stroke | 0.96 (0.86-1.07) | .48 |
| Myoneural junction and muscle disease | 1.15 (1.08-1.23) | <.001 |
| Nerve, nerve root, or plexus disorder | 0.88 (0.30-2.59) | .82 |
| Parkinson disease and parkinsonism | 1.44 (1.12-1.86) | <.001 |
| Psychiatric disorder | 1.12 (1.08-1.17) | <.001 |
| Dementia | 1.23 (1.07-1.41) | <.001 |
| Psychotic, mood, and anxiety disorders | 1.13 (1.08-1.19) | <.001 |
| Insomnia | 1.10 (1.03-1.18) | <.001 |
| Substance use disorder | 1.14 (1.00-1.30) | .05 |
| Subgroup analyses | ||
| Ages 18 to 30 y | ||
| Neurological disorder | 1.08 (0.91-1.27) | NAb |
| Psychiatric disorder | 1.14 (1.05-1.24) | NAb |
| Ages >30 to 60 y | ||
| Neurological disorder | 1.07 (0.99-1.14) | NAb |
| Psychiatric disorder | 1.07 (1.02-1.12) | NAb |
| Age >60 y | ||
| Neurological disorder | 1.17 (1.07-1.28) | NAb |
| Psychiatric disorder | 1.22 (1.13-1.31) | NAb |
| Female | ||
| Neurological disorder | 1.10 (1.03-1.19) | NAb |
| Psychiatric disorder | 1.12 (1.06-1.18) | NAb |
| Male | ||
| Neurological disorder | 1.13 (1.05-1.22) | NAb |
| Psychiatric disorder | 1.12 (1.07-1.18) | NAb |
Abbreviations: aHR, adjusted hazard ratio; NA, not applicable.
The reference group for all outcomes is patients without dengue fever. Adjusted for age, sex, cancer, chronic kidney disease, coronary artery disease, chronic obstructive pulmonary disease, diabetes, heart failure, hyperlipidemia, hypertension, peripheral arterial occlusion disease, and sleep apnea.
According to the guidelines of Taiwan's National Health Insurance and Research Database, information will be deleted if it has not been assessed within a 2-year time frame, so these data were inaccessible.
Discussion
This cohort study’s findings support those of previous research suggesting a potential association between dengue fever and neurological and psychiatric complications, especially in individuals older than 60 years. Although prior case reports and smaller studies4,5 noted the neurotropic nature of the dengue fever virus, this study stands out due to its extensive scale and use of long-term, comprehensive national health data, which may avoid selection bias inherent in smaller datasets.6 The study has several limitations. Diagnoses were based on ICD codes, which may be prone to misclassification. The lack of detailed patient information (eg, lifestyle factors and severity of dengue fever) may have influenced results. Furthermore, our findings may not be generalized beyond the Taiwanese population.
This population-based retrospective study provides updated epidemiological evidence for the association of dengue fever with increased risk of neurological and psychiatric disorders. Findings may highlight the need for awareness and monitoring of neuropsychiatric complications in this patient population. However, further research is necessary to understand mechanisms behind these associations.
Data Sharing Statement
References
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Associated Data
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Supplementary Materials
Data Sharing Statement