Elevated Liver Enzyme (AST and ALT) as Biomarkers for Severe Dengue in Nepalese Patients: A Cross-Sectional Study

Elevated Liver Enzyme (AST and ALT) as Biomarkers for Severe Dengue in Nepalese Patients: A Cross-Sectional Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Elevated Liver Enzyme (AST and ALT) as Biomarkers for Severe Dengue in Nepalese Patients: A Cross-Sectional Study Chandramani Wagle, Dinesh Prasad Ghimire, Ajay Kumar Sah, Abhay Kumar Sah, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7021918/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Sep, 2025 Read the published version in BMC Infectious Diseases → Version 1 posted 15 You are reading this latest preprint version Abstract Introduction Dengue remains a major global health concern, with rising incidence and severity in endemic regions. Liver involvement, particularly elevated transaminases such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT), is frequently observed during infection. Prior research has reported inconsistent associations between AST/ALT elevation and severe dengue, particularly in diverse geographical settings. This study addresses these gaps by investigating the relationship between liver enzyme elevation and dengue severity in Nepalese patients, leveraging a pre-existing dataset to evaluate their potential as biomarkers for severe disease. Methods A cross-sectional study was conducted among 325 laboratory-confirmed dengue patients at a tertiary care hospital in Koshi province Nepal. Liver enzyme levels (AST and ALT) were categorized based on upper limit of normal (AST > 48 U/L, ALT > 55 U/L), and dengue severity was classified according to the WHO 2009 guidelines. Elevated AST & ALT were assessed for associations with DWS using Chi-square tests and multivariable logistic regression, adjusting for age and sex. Spearman’s correlations were performed to assess associations between liver enzyme elevations, clinical features, and disease severity. Variance inflation factor (VIF) was used to check for multicollinearity. Results Among the 325 dengue patients, 40.0% had dengue with warning signs (DWS). Elevated AST was significantly associated with DWS (aOR = 2.40, 95% CI: 1.49–3.86, p = 0.0003), while elevated ALT showed no significant association. AST elevation also correlated with gastrointestinal symptoms, such as nausea (ρ = 0.243, p < 0.0001) and vomiting (ρ = 0.151, p = 0.0064), and with key laboratory markers including hemoglobin (ρ = 0.407, p < 0.0001) and platelet count (ρ = 0.277, p < 0.0001). ALT showed weaker and inconsistent correlations. Adjusted analyses confirmed AST as an independent predictor of severe dengue. Female identified as a novel risk factor for DWS, independent of age and AST levels. The logistic regression model demonstrated good fit (McFadden’s R² = 0.074), with no multicollinearity detected. Conclusion This study establishes elevated AST as a significant predictor of severe dengue, offering a valuable biomarker for early risk stratification. The findings highlight the importance of liver function monitoring in dengue management. While the study's strengths include its structured assessment and comprehensive analysis, limitations such as its cross-sectional design, convenience sampling and reliance on a few centers’ dataset limit causal inference and generalizability. Future research should validate these findings in prospective, multi-center studies and assess gender-specific risks along with prognostic value of dynamic liver enzyme monitoring throughout the disease course. Dengue severity Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Liver Enzyme Nepal Figures Figure 1 Figure 2 Introduction Dengue fever, a mosquito-borne viral disease, remains a major public health threat worldwide, with increasing incidence and geographic expansion in recent years [ 1 ]. The clinical spectrum ranges from mild illness to more severe forms, such as dengue with warning signs (DWS) and severe dengue (SD), which can involve complications like persistent vomiting, mucosal bleeding, or plasma leakage [ 2 ]. Hepatic involvement is frequently observed and may present as elevated liver enzymes particularly AST and ALT ranging from mild elevations to fulminant liver failure in rare cases [ 3 ]. Several studies have indicated that the degree of enzyme elevation may correlate with disease severity, suggesting a potential role for AST and ALT as early markers of clinical deterioration in dengue infection [ 4 , 5 ]. Although liver involvement in dengue is widely recognized, the predictive role of transaminase elevations AST and ALT in determining disease severity remains inadequately defined. Meta-analyses have shown that AST elevations are more common and pronounced in severe dengue compared to ALT, with AST abnormalities reported in up to 80% of dengue hemorrhagic fever (DHF) cases versus 54% for ALT [ 6 ]. Furthermore, a systematic review highlighted that AST levels exceeding three times the upper limit of normal (ULN) during early illness may serve as an early warning marker for disease progression [ 7 ]. However, inconsistencies in the timing of liver function testing, varied ULN cut-offs, and the presence of comorbid hepatic conditions complicate interpretation across studies. Importantly, most of the existing evidence is derived from studies in Southeast Asia and Latin America, with little population-specific data from Nepal, where dengue is now endemic and expanding [ 8 , 9 ]. This lack of localized evidence limits the application of liver enzymes in clinical triage, particularly under the WHO 2009 classification system. This study addresses these gaps through a secondary analysis of a previously published dataset from Nepal, utilizing the same cohort of laboratory-confirmed dengue patients [ 10 ]. By leveraging this existing data, we aim to evaluate the association between elevated AST and ALT levels and dengue severity, comparing their effectiveness as biomarkers for identifying patients at risk of severe disease. Additionally, we explore the correlation between liver enzyme levels and clinical features to elucidate the pathophysiological mechanisms of hepatic involvement in dengue. The findings of this study will provide critical insights for early risk stratification and improved clinical management of dengue patients, particularly in resource-limited settings where cost-effective biomarkers are urgently needed. Methods Study Design and Setting This study is a secondary analysis of a previously published cross-sectional study conducted by Gupta et al. (2025) which investigated hematological abnormalities (Leukopenia & Thrombocytopenia) in dengue patients [ 10 ]. The parent study was conducted during a seasonal dengue outbreak (September–December 2022) across four tertiary hospitals in Sunsari District, Koshi Province, Nepal: Bijayapur Hospital, Sunkoshi Laboratory, B.P. Koirala Institute of Health Sciences, and Itahari Municipal Hospital. Study Population and Patient Enrollment The cohort comprised 325 laboratory-confirmed dengue patients enrolled via convenience sampling during hospital visits. Inclusion/exclusion criteria were identical to parent study [ 10 ]. Patients presenting to the Outpatient Department (OPD) of participating hospitals with fever for ≤ 72 hours and clinical symptoms suggestive of dengue were confirmed via NS1 antigen or IgM/IgG positivity using rapid diagnostic tests. Patients with suspected dengue who did not have upper respiratory symptoms were considered eligible. Exclusion criteria included localizing symptoms suggesting alternative diagnoses (e.g., pneumonia, otitis), known HIV infection, chronic illnesses (e.g., liver or kidney disease, malignancy), immunosuppressive therapy, or pregnancy. This secondary analysis did not include a separate sample size or power calculation specific to liver enzyme elevations. The analysis utilized all eligible patients with complete AST and ALT data from the original dataset, which enrolled patients consecutively during the study period using convenience sampling. A convenience sampling approach may introduce selection bias by primarily capturing patients with moderate to severe symptoms seeking hospital care, potentially underrepresenting mild or asymptomatic cases. Written informed consent was obtained from patients or their guardians. Ethical approval was obtained from the Nepal Health Research Council (Ref: 678), and data were anonymized using sample codes to preserve participant confidentiality. Data Collection and Laboratory Procedures Data were collected using a structured case report form (CRF) that included demographic details, clinical features, medical history, dengue confirmation tests, and laboratory results such as CBC and liver function tests (Supplementary File 1). Dengue diagnosis was confirmed using rapid diagnostic test (RDT) kits, primarily SD BIOLINE Dengue Duo NS1 Ag + Ab Combo, with Dengucheck Combo used in some settings, as described in parent article [ 10 ]. Liver function tests, specifically aspartate aminotransferase (AST) and alanine aminotransferase (ALT), were measured using the DIASYS Response 910 automated biochemistry analyzer. All participating hospitals followed standardized protocols for blood sample collection, handling, and analysis, with regular equipment calibration and reagent validation per hospital laboratory standards. Variables and Classification AST and ALT levels were measured at enrollment as part of routine clinical chemistry analysis. The upper limit of normal (ULN) was defined as 48 U/L for AST and 55 U/L for ALT, based on laboratory reference values provided by the Mayo Clinic [ 11 ]. Dengue severity was classified using the 2009 WHO dengue case classification system into dengue without warning signs (DWWS) and dengue with warning signs (DWS) aligned with Nepal’s national clinical guidelines [ 12 , 13 ]. DWWS was defined by fever with at least two additional features (e.g., nausea, vomiting, rash, aches, leukopenia, positive tourniquet test) and laboratory-confirmed dengue, with adequate oral intake and urine output. DWS was characterized by at least one warning sign, such as abdominal pain, persistent vomiting, clinical fluid accumulation, mucosal bleeding, lethargy, liver enlargement (> 2 cm), or hematological changes (e.g., increased hematocrit with platelet count ≤ 100,000/mm³). Comorbidities (e.g., diabetes, renal failure) or social factors (e.g., living alone) also qualified patients for DWS classification [ 12 ]. Data management and analysis Data were entered into Microsoft Excel and analyzed using Python (v3.9) with libraries including pandas, SciPy, and statsmodels. Patients with missing laboratory results were excluded to ensure data completeness. Continuous variables, such as AST and ALT levels, were tested for normality using the Shapiro-Wilk test and were found to be non-normally distributed; hence, they were reported as medians with interquartile ranges (IQR). Categorical variables, including disease severity classification and demographic characteristics, were presented as frequencies and percentages. The association between liver enzyme elevation (AST and ALT) and disease severity was assessed using chi-square tests or Fisher’s exact tests, as appropriate. Multivariable logistic regression was performed to evaluate the independent association of AST and ALT elevation with dengue severity (DWS vs. DWWS), adjusting for potential confounders such as age and gender. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Spearman’s rank correlation was used to assess the strength and direction of the relationship between liver enzyme levels and other clinical/laboratory parameters. Correlation results were presented with corresponding p-values, and statistically significant associations were highlighted. Model fit was evaluated using McFadden’s pseudo R² and Akaike Information Criterion (AIC). Variance inflation factors (VIFs) were calculated to check for multicollinearity among predictor variables. A p-value of less than 0.05 was considered statistically significant throughout the analysis. Results Patients’ Demographics Characteristics Among the 325 patients enrolled with laboratory-confirmed dengue, 130 (40.0%) were classified as having dengue with warning signs (DWS) and 195 (60.0%) as dengue without warning signs (DWWS) according to the WHO 2009 classification. Notably, no cases of severe dengue were identified among the enrolled participants. Table 1 presents the sociodemographic distribution of patients stratified by dengue severity. The median age of patients in the DWS group was 40 years (IQR 29–52), significantly higher than the 33 years (IQR 21–48) observed in the DWWS group. However, age group distribution did not differ significantly between the two severity groups (p = 0.9168), with children, adults, and elderly individuals represented similarly in both groups. Table 1 Sociodemographic characteristics of dengue patients by severity classification (N = 325) Characteristic DWS (n, %) DWWS (n, %) p-value Age: Median (IQR) 40 (29–52) 33 (21–48) Age Group 0.9168 Child (≤ 14 years) 17 (41.5%) 24 (58.5%) Adult (15–59 years) 94 (39.3%) 145 (60.7%) Elderly (≥ 60 years) 19 (42.2%) 26 (57.8%) Gender 0.0004 Male 77 (50.3%) 76 (49.7%) Female 53 (30.8%) 119 (69.2%) BMI (≥ 20 years) 0.2936 Underweight (< 18.5) 5 (27.8%) 13 (72.2%) Healthy weight (18.5–24.9) 67 (40.6%) 98 (59.4%) Overweight (25–29.9) 33 (49.3%) 34 (50.7%) Obese (30 ≤) 5 (55.6%) 4 (44.4%) BMI categorization was restricted to participants aged ≥ 20 years. P-values were calculated using Chi-square or Fisher’s exact test, as appropriate. P-values less than 0.05 are indicated in bold to denote statistical significance. A significant gender disparity was noted, with females comprising 69.2% of the DWWS group compared to 30.8% in the DWS group (p = 0.0004). Among adults aged ≥ 20 years, BMI distribution showed no significant association with disease severity (p = 0.2936), although overweight and obese individuals were slightly more prevalent in the DWS group (Table 1 ). Liver Enzyme Elevation and Disease Severity We further examined the association between liver enzyme elevation and disease severity among the 325 dengue patients analyzed. AST elevation was found more common than ALT elevation. AST levels showed marked stratification by disease severity, with 25.5% of DWS patients exhibiting > 1–3× upper limit of normal (ULN) elevations versus 29.5% in DWWS. Notably, 3.1% of DWS patients demonstrated > 3–10× ULN AST elevations (vs 2.5% DWWS), while no cases exceeded 10× ULN. ALT elevations were less pronounced, with only 5.5% of DWS patients showing > 1–3× ULN increases and no DWS cases exceeding 3× ULN (Fig. 1 ). Violin plots (Fig. 2 ) demonstrate significantly elevated AST levels in DWS patients (median: 61.5 U/L, IQR: 36.3–90.9) compared to DWWS (median: 44.0 U/L, IQR: 24.6–75.8), with wider dispersion and a pronounced right-skewed density peak above 80 U/L. While ALT medians were comparable between groups (DWS: 27.1 U/L vs DWWS: 28.2 U/L), DWWS patients exhibited greater variability including an outlier at 182.0 U/L (4.6× ULN) (Fig. 2 ). The Chi square analysis revealed a significant association between elevated AST levels and dengue with warning signs (DWS). Specifically, patients with elevated AST were more likely to be in the DWS group compared to those with normal AST levels (48.9% vs. 29.8%), with a statistically significant p-value of 0.0006 and an odds ratio (OR) of 0.44 (95% CI: 0.28–0.70). This suggests that elevated AST may serve as a notable biomarker for more severe disease manifestations. In contrast, ALT levels showed a non-significant trend toward association with DWS, with a p-value of 0.1809 and an OR of 1.56 (95% CI: 0.85–2.86), indicating ALT may be less specific for disease severity in this context (Table 2 ). Table 2 Association of liver enzyme elevation with dengue severity (N = 325) Liver Enzyme Total n (%) DWS n (%) DWWS n (%) p-value OR (95% CI) Aspartate Aminotransferase (AST) Normal 151 (46.5%) 45 (29.8%) 106 (70.2%) 0.0006 0.44 (0.28–0.70) Elevated 174 (53.5%) 85 (48.9%) 89 (51.1%) Alanine Aminotransferase (ALT) Normal 268 (82.5%) 112 (41.8%) 156 (58.2%) 0.1809 1.56 (0.85–2.86 Elevated 57 (17.5%) 18 (31.6%) 39 (68.4%) P-values were calculated using Chi-square or Fisher’s exact test, as appropriate. P-values less than 0.05 are indicated in bold to denote statistical significance.. Clinical Characteristics by Dengue Severity To establish the clinical context of dengue severity, we analyzed key symptoms among the 325 patients, stratified by DWWS (n = 195, 60.0%) and DWS (n = 130, 40.0%), as shown in Table 3 . Fever was nearly universal (99.1%), with no significant difference between severity groups (p = 1.000). Gastrointestinal symptoms, particularly nausea (33.8% in DWS vs. 14.9% in DWWS, p < 0.0001), vomiting (21.5% vs. 7.7%, p = 0.0004), and abdominal pain (16.9% vs. 0.0%, p < 0.0001), were significantly more prevalent in DWS, suggesting a link to severe disease manifestations. Notably, joint pain emerged as another discriminating feature, present in nearly half of DWS patients (47.7%) versus 34.4% in DWWS (p = 0.021), suggesting systemic inflammatory responses may parallel hepatic injury (Table 3 ). Table 3 Clinical features of dengue patients by severity classification (N = 325) Clinical Feature Overall (n = 325) DWWS (n = 195) DWS (n = 130) p-value Fever 322 (99.1%) 193 (99.0%) 129 (99.2%) 1.000 Headache 175 (53.8%) 98 (50.3%) 77 (59.2%) 0.1397 Malaise 108 (33.2%) 65 (33.3%) 43 (33.1%) 1.000 Muscle Pain 183 (56.3%) 101 (51.8%) 82 (63.1%) 0.0524 Joint Pain 129 (39.7%) 67 (34.4%) 62 (47.7%) 0.0205 Retro-orbital Pain 76 (23.4%) 46 (23.6%) 30 (23.1%) 1.000 Rash 18 (5.5%) 11 (5.6%) 7 (5.4%) 1.000 Nausea 73 (22.5%) 29 (14.9%) 44 (33.8%) < 0.0001 Vomiting 43 (13.2%) 15 (7.7%) 28 (21.5%) 0.0004 Diarrhea 31 (9.5%) 16 (8.2%) 15 (11.5%) 0.3394 Abdominal Pain 22 (6.8%) 0 (0.0%) 22 (16.9%) < 0.0001 Chest Pain 19 (5.8%) 9 (4.6%) 10 (7.7%) 0.3344 This table summarizes the presence of clinical features among all enrolled patients, and stratifies by severity classification DWS and DWWS. P-values were calculated using Chi-square or Fisher’s exact test as appropriate. P-values less than 0.05 are bolded. In cases with zero cell counts, Fisher’s exact test was used and p-values interpreted with caution. Clinical Characteristics by Liver Enzyme Elevation Status Clinical features were analyzed in relation to liver enzyme status to identify symptoms associated with elevated AST or ALT levels (Table 4 ). Patients with elevated AST demonstrated significantly higher rates of gastrointestinal symptoms, including nausea (33.3% vs 9.9%, p < 0.0001) and vomiting (18.4% vs 7.3%, p = 0.003), aligning with our earlier observation that these symptoms cluster in severe dengue cases (Table 3 ). Unexpectedly, malaise was 2× less prevalent in elevated AST patients (23.0% vs 45.0%, p < 0.0001), suggesting potential pathophysiological differences in energy metabolism during hepatic injury. 100% of patients with elevated AST/ALT reported fever, reinforcing fever as a universal marker of dengue-associated liver injury. Rash was less frequent in patients with elevated AST (p = 0.0289). For ALT abnormalities, a paradoxical pattern emerged: elevated ALT was associated with absence of abdominal pain (0% vs 8.2%, p = 0.019) and reduced headache prevalence (33.3% vs 58.2%, p < 0.0001) (Table 4 ). Table 4 Clinical features by liver enzyme status (AST and ALT) (N = 325) Clinical Feature AST Normal AST Elevated AST p-value ALT Normal ALT Elevated ALT p-value Fever 149 (98.7%) 173 (99.4%) 0.5991 267 (99.6%) 55 (96.5%) 0.0806 Headache 85 (56.3%) 90 (51.7%) 0.4360 156 (58.2%) 19 (33.3%) < 0.0001 Malaise 68 (45.0%) 40 (23.0%) < 0.0001 100 (37.3%) 8 (14.0%) < 0.0001 Muscle Pain 80 (53.0%) 103 (59.2%) 0.2649 155 (57.8%) 28 (49.1%) 0.2422 Joint Pain 58 (38.4%) 71 (40.8%) 0.7332 113 (42.2%) 16 (28.1%) 0.0533 Retro-orbital Pain 37 (24.5%) 39 (22.4%) 0.6945 68 (25.4%) 8 (14.0%) 0.0840 Rash 13 (8.6%) 5 (2.9%) 0.0289 17 (6.3%) 1 (1.8%) 0.2169 Nausea 15 (9.9%) 58 (33.3%) < 0.0001 60 (22.4%) 13 (22.8%) 1.0000 Vomiting 11 (7.3%) 32 (18.4%) 0.0031 39 (14.6%) 4 (7.0%) 0.1940 Diarrhea 8 (5.3%) 23 (13.2%) 0.0219 25 (9.3%) 6 (10.5%) 0.8041 Abdominal Pain 14 (9.3%) 8 (4.6%) 0.1212 22 (8.2%) 0 (0.0%) 0.0188 Chest Pain 4 (2.6%) 15 (8.6%) 0.0309 14 (5.2%) 5 (8.8%) 0.3468 P-values were calculated using Chi-square or Fisher’s exact test, as appropriate. P-values < 0.05 are bolded to indicate statistical significance. In cases with zero cell counts, Fisher’s exact test was used and p-values interpreted with caution. These findings reinforce the clinical relevance of liver enzyme monitoring, particularly AST, in the assessment of dengue patients, not only as a marker of hepatic involvement but also in predicting symptom patterns linked to more severe or systemic disease. The clinical symptom burden appears more pronounced among individuals with elevated AST than ALT, aligning with earlier findings that AST had a stronger association with disease severity (Table 2 ). Diagnostic and Treatment Profiles In alignment with earlier findings that associated AST elevation with dengue severity, Table 5 reveals critical diagnostic and management differences among dengue patients with liver injury. Elevated AST showed a striking association with NS1 antigen positivity (83.3% vs. 44.4%, p = < 0.0001), suggesting enhanced early viral detection in hepatic-involved cases, a finding that aligns with our earlier observation of more frequent vomiting and fever in this group (Table 4 ). Conversely, IgM positivity was paradoxically lower in AST-elevated patients (18.4% vs. 63.6%, p = < 0.0001), potentially reflecting delayed seroconversion due to immune modulation during severe hepatic injury. Table 5 Diagnostic and treatment patterns stratified by liver enzyme elevation (N = 325) Parameter AST Normal AST Elevated p-value (AST) ALT Normal ALT Elevated p-value (ALT) NS1 Positive 67 (44.4%) 145 (83.3%) < 0.0001 175 (65.3%) 37 (64.9%) 1.0000 IgG Positive 1 (0.7%) 1 (0.6%) 1.0000 1 (0.4%) 1 (1.8%) 0.3205 IgM Positive 96 (63.6%) 32 (18.4%) < 0.0001 104 (38.8%) 24 (42.1%) 0.6566 Antipyretics/Analgesics 142 (94.0%) 171 (98.3%) 0.0729 260 (97.0%) 53 (93.0%) 0.2351 Intravenous (IV) Fluids 1 (0.7%) 17 (9.8%) 0.0003 16 (6.0%) 2 (3.5%) 0.7493 P-values were calculated using Chi-square or Fisher’s exact test, as appropriate. Bold values indicate statistical significance (p < 0.05). In cases with zero cell counts, p-values interpreted with caution. The need for intravenous (IV) fluid support was significantly greater among those with elevated AST (9.8% vs. 0.7%, p = 0.0003), consistent with a more severe clinical presentation and previously noted associations between elevated AST and gastrointestinal symptoms such as nausea and vomiting (Table 4 ). No statistically significant differences were observed in treatment or diagnostic patterns when stratified by ALT status (Table 5 ). Adjusted Associations and Exploratory Analyses In multivariable logistic regression analysis, elevated AST was significantly associated with increased odds of developing dengue with warning signs (DWS), with an adjusted odds ratio (aOR) of 2.40 (95% CI: 1.49–3.86, p = 0.0003). Female gender was also independently associated with higher odds of DWS (aOR = 2.31, 95% CI: 1.45–3.70, p = 0.0005). Age demonstrated a modest but statistically significant association with severity (aOR = 1.01 per year increase, 95% CI: 1.00–1.03, p = 0.0299). Although elevated ALT showed a trend toward a protective effect, the association did not reach statistical significance (aOR = 0.57, 95% CI: 0.30–1.09, p = 0.0900). The logistic regression model demonstrated an acceptable fit, with a McFadden's pseudo R² of 0.074 and an AIC of 414.9 (Table 6 ). Multicollinearity diagnostics using Variance Inflation Factor (VIF) indicated no concerning collinearity among predictors (VIFs ranged from 1.003 to 1.014 for all variables), confirming the model's internal consistency and robustness. Table 6 Adjusted odds ratios for dengue severity (DWS vs DWWS) (N = 325) Variable aOR 95% CI p-value Elevated AST 2.40 1.49–3.86 0.0003 Elevated ALT 0.57 0.30–1.09 0.0900 Age (year) 1.01 1.00–1.03 0.0299 Female gender 2.31 1.45–3.70 0.0005 Model fit: McFadden’s pseudo R² = 0.074, AIC = 414.9, log-likelihood = − 202.5. Spearman’s correlation analysis was conducted to explore the relationships between liver enzyme levels (AST and ALT) and various clinical and laboratory parameters (Table 7 ). The selected parameters were chosen based on their clinical relevance and previously documented associations with dengue severity or hepatic involvement. For instance, WBC count, platelet count, and hemoglobin are commonly monitored in dengue management due to their relevance in assessing disease progression. Serum creatinine and hematocrit were included to evaluate renal function and hydration status, respectively. Clinical features such as headache, malaise, nausea, vomiting, and abdominal pain were included as they are frequently reported symptoms in dengue patients and may correlate with systemic inflammation or hepatic dysfunction. The analysis revealed several significant associations. AST showed strong positive correlations with hemoglobin (ρ = 0.407, p < 0.0001) and platelet count (ρ = 0.277, p < 0.0001), suggesting potential interactions between liver function and hematological parameters. AST also correlated with nausea (ρ = 0.243, p < 0.0001) and vomiting (ρ = 0.151, p = 0.0064), linking elevated AST to gastrointestinal symptoms (Table 7 ). Table 7 Spearman’s Correlation Between Liver Enzyme Levels and Clinical/Laboratory Parameters (N = 325) Parameter AST (ρ) p-value ALT (ρ) p-value WBC count –0.140 0.0118 –0.115 0.0379 Serum Creatinine –0.134 0.0157 –0.137 0.0131 Hemoglobin 0.407 < 0.0001 –0.003 0.9577 Platelet Count 0.277 < 0.0001 0.020 0.7245 Hematocrit 0.194 0.0004 0.072 0.1933 Headache 0.003 0.9604 –0.177 0.0013 Malaise –0.265 < 0.0001 –0.149 0.0072 Nausea 0.243 < 0.0001 0.037 0.5020 Vomiting 0.151 0.0064 –0.024 0.6631 Abdominal Pain –0.100 0.0725 –0.048 0.3873 Spearman’s rank correlation coefficients between aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels and selected clinical and laboratory parameters in patients with dengue. Statistically significant correlations (p < 0.05) are indicated in bold. ALT demonstrated a significant negative correlation with headache (ρ = -0.177, p = 0.0013) and a weaker negative correlation with malaise (ρ = -0.149, p = 0.0072). No significant association was found between ALT and hemoglobin (ρ = -0.003, p = 0.9577) or platelet count (ρ = 0.020, p = 0.7245) (Table 7 ). Both enzymes showed weak negative correlations with WBC count and serum creatinine, though these associations were only marginally significant for AST. These findings highlight distinct patterns of correlation for AST and ALT with clinical and laboratory parameters, providing further insight into the pathophysiology of dengue-associated liver injury. Discussion This follows up analysis of cross-sectional study establishes AST as a consistent marker of disease severity, with patients exhibiting significantly higher odds of dengue with warning signs (DWS) (aOR 2.40, 95% CI: 1.49–3.86) after adjusting for age and gender. The identification of female gender as an independent risk factor for DWS introduces a new dimension to severity risk stratification. The positive correlations of AST with hemoglobin and platelet count, despite expectations of thrombocytopenia in severe dengue, suggest complex hematological interactions unique to this population. Elevated AST was also associated with gastrointestinal manifestations (nausea and vomiting), increased need for intravenous fluids, and diagnostic positivity for NS1 antigen, suggesting a broader systemic burden in these patients. In contrast, ALT showed minimal discriminative capacity in severity prediction or symptom association. The distinct behavior of AST as a hepatic and systemic marker highlights its potential utility in clinical triage and risk stratification in dengue, particularly in resource-limited endemic settings where early markers of severe progression are critically needed. The findings of this study align with and extend previous research in the field. Prior meta-analyses have consistently shown that AST elevations are more prevalent and pronounced than ALT in both dengue fever and dengue hemorrhagic fever [ 14 ]. A 2016 meta-analysis reported AST abnormalities in approximately 75–80% of dengue cases versus 50–55% for ALT. Similarly, studies from Southeast Asia, including one in Vietnam, observed stronger associations between AST and severe dengue compared to ALT [ 15 ]. Our findings mirror this pattern in a Nepalese cohort: elevated AST, but not ALT was independently associated with warning-sign dengue (DWS) and correlated with critical clinical features like gastrointestinal symptoms and IV fluid need. This differential association aligns with previous adult and pediatric studies, reinforcing AST’s diagnostic value over ALT across diverse demographics [ 16 ]. Additional studies further support the prognostic relevance of liver enzyme abnormalities. For instance, a hospital-based study in Rawalpindi demonstrated that derangements in liver function tests, including AST and ALT, were significantly associated with WHO-classified dengue severity [ 17 ]. A tertiary center study in Punjab similarly observed that AST was preferentially elevated over ALT and served as an early indicator of infection and severity, corroborating our findings [ 18 ]. In Nepal, a study noted significantly elevated AST and ALT values in patients with DSS and DHF compared to those with DF, highlighting the clinical utility of early liver function monitoring [ 19 ]. This study contributes to the existing body of research by offering a more detailed analysis of liver enzyme elevation in dengue patients. Unlike previous studies that have primarily focused on the presence of elevated liver enzymes, this research delves deeper into the correlation between AST levels and specific clinical symptoms like nausea and vomiting. While ALT elevation coincides with symptom resolution (reduced headache/malaise), indicating convalescence. This temporal dichotomy resolves conflicting literature on enzyme roles. This study document previously unrecognized female vulnerability, with women facing 2.3× higher severity risk, a pattern unseen in prior Nepalese studies, potentially linked to hormonal-immune interactions. This study offers a comprehensive analysis of hepatic involvement in Nepalese dengue patients, addressing a critical knowledge gap in a high-burden region. This study has several notable strengths. Strengths include the use of a structured assessment of liver enzymes alongside detailed clinical and laboratory data, enhancing the comprehensiveness of the analysis. The use of WHO 2009 classification ensured standardized severity assessment, enhancing global comparability. Comprehensive analyses, including unadjusted associations, adjusted logistic regression, and continuous correlations, offered a multi-faceted understanding of AST’s role in dengue severity. However, limitations include the further analysis of cross-sectional design, which precludes causality inferences between AST elevation and DWS. The absence of data on comorbidities, such as pre-existing liver disease, or hepatotoxic medications may confound enzyme levels. The lower prevalence of elevated ALT (n = 57) likely limited statistical power for ALT associations. Binary or ordinal symptom scoring may have reduced sensitivity compared to continuous measures. Unmeasured viral serotypes and cytokines represent additional constraints. Additionally, the convenience sampling method could introduce selection bias and the absence of patients with severe dengue (SD) precluded evaluation across the full clinical spectrum. This study underscores the critical role of AST as a practical biomarker for identifying severe dengue (dengue with warning signs, DWS) in resource-limited settings like Nepal, where accessible tools are essential for effective patient triage. By demonstrating AST’s strong association with severe clinical presentations, including gastrointestinal symptoms and NS1 positivity, and its unexpected correlations with hematological markers, our findings advocate for routine AST monitoring to guide early intervention, such as intravenous fluid administration. The novel identification of female as a risk factor further highlights the need for tailored clinical approaches. Future research should explore longitudinal designs to establish causality and investigate gender-specific and serotype-related factors to refine dengue management strategies. Incorporate additional hepatic markers such as bilirubin and albumin and validate these findings in multi-center cohorts that include cases of severe dengue. Conclusion Elevated AST levels in dengue patients were found to be significantly associated with disease severity and symptom burden, reinforcing its clinical utility as an early marker of hepatic involvement. Unlike ALT, which showed limited predictive value, AST demonstrated consistent correlations with gastrointestinal manifestations and treatment intensity. These findings contribute to a better understanding of the hepatic profile in dengue and support the incorporation of AST monitoring into routine clinical assessments. New contributions to the literature include the adjusted confirmation of AST’s predictive role, the novel identification of female as a risk factor, and unexpected positive correlations with hemoglobin and platelet count, suggesting unique pathophysiological dynamics. Further prospective studies are warranted to validate these associations and explore the integration of liver enzyme trends into predictive models for early risk stratification and management in dengue-endemic regions. Abbreviations ALT Alanine Aminotransferase AST Aspartate Aminotransferase DWWS Dengue Without Warning Signs DWS Dengue with Warning Signs AR Adjusted Residual CI Confidence Interval. Declarations Author contributions BPG, SU designed the study, review and finalize the manuscript. CW analyzed, interpreted the data and draft the manuscript. DPG, VPG, AKS, and AKS review the manuscript. Acknowledgments We extend our sincere gratitude to the hospital staff and laboratory professionals at study site. We also thank the research assistants involved in the parent study for their diligent efforts in ensuring data completeness and quality. Funding Part of funding for laboratory investigation of biochemical test was received from Virology Society Nepal and Global Clinical Research Nepal. Data availability The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate The study was approved by the Ethics committee of Nepal Health Research Council, Kathmandu, Nepal (Approval No. 678). Informed consent was obtained from all participants or their guardians, and patient confidentiality was maintained through data anonymization. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Clinical trial registration details Clinical trial number: not applicable. References World Health Organization. Disease Outbreak News; Dengue – Global Situation. 2024. https://www.who.int/emergencies/disease-outbreak-news/item/2023-DON518 . Accessed 1 Jul 2025. US Center for Disease Control and Prevention. Severe Dengue: Know the Warning Signs. 2025. https://www.cdc.gov/dengue/stories/severe-dengue.html . Accessed 1 Jul 2025. Samanta J, Sharma V. Dengue and its effects on liver. World J Clin Cases. 2015;3:125–31. Campana V, Inizan C, Pommier JD, Menudier LY, Vincent M, Lecuit M et al. Liver involvement in dengue: A systematic review. Rev Med Virol. 2024;34. Swamy AM, Mahesh PY, Rajashekar ST. Liver function in dengue and its correlation with disease severity: a retrospective cross-sectional observational study in a tertiary care center in Coastal India. Pan Afr Med J. 2021;40. Thach TQ, Eisa HG, Hmeda A, Ben, Faraj H, Thuan TM, Abdelrahman MM et al. Predictive markers for the early prognosis of dengue severity: A systematic review and meta-analysis. PLoS Negl Trop Dis. 2021;15. Sangkaew S, Ming D, Boonyasiri A, Honeyford K, Kalayanarooj S, Yacoub S, et al. Risk predictors of progression to severe disease during the febrile phase of dengue: a systematic review and meta-analysis. Lancet Infect Dis. 2021;21:1014–26. Epidemiology and Disease Control Division D of HSM of H. and P. Situation Report on Dengue in Nepal – 2024. 2024. Rayamajhi RJ, Thapa S, Rayamajhi P, Maharjan S, Yadav RKR, Roka K. Transaminitis among Patients with Dengue Fever Visiting a Tertiary Care Centre. J Nepal Med Association. 2023;61:683–6. Gupta BP, Uranw S, Gupta VP, Deuba E, Sah AK, Chaudhary S et al. Leukopenia and thrombocytopenia in dengue patients: a cross-sectional study from a tertiary hospitals in Koshi Province, Nepal. BMC Infect Dis. 2025;25. Liver function tests. Mayo Clinic. 2025. https://www.mayoclinic.org/tests-procedures/liver-function-tests/about/pac-20394595 . Accessed 1 Jul 2025. World Health Organization. Dengue guidelines for diagnosis, treatment, prevention and control: new edition. World Health Organization; 2009. Epidemiology and Disease Control Division. Prevention, Management and Control of Dengue in Nepal 2019. Kathmandu. Wang XJ, Wei HX, Jiang SC, He C, Xu XJ, Peng HJ. Evaluation of aminotransferase abnormality in dengue patients: A meta analysis. Acta Trop. 2016;156:130–6. Nguyen RN, Lam HT, Phan HV. Liver Impairment and Elevated Aminotransferase Levels Predict Severe Dengue in Vietnamese Children. Cureus. 2023;15:e47606. Kittitrakul C, Silachamroon U, Phumratanaprapin W, Krudsood S, Wilairatana P, Treeprasertsuk S. Liver function tests abnormality and clinical severity of dengue infection in adult patients. J Med Assoc Thai. 2015;98:S1–8. Rehman WU, Ali MZ, Arshad AR, Iqbal M, Karim N, Abbas M, et al. Correlation Between Liver Function Test and Severity of Dengue Fever at a Tertiary Care Hospital, Rawalpindi. Life Sci. 2025;6:07. Malhi NS. Spectrum of Liver Dysfunction in Patients with Dengue Infection and the Markers of Severe Disease: Study from a Tertiary Care Centre in Punjab. J Liver Res Disord Ther. 2017;3. Chaudhary RD, Jha SD, Sah VK, Mandal RN, Pandey M, Yadav BK, et al. Derangement of liver function tests in dengue patients. Int J Res Med Sci. 2023;12:32–6. Supplementary File Supplementary file 1 is not available with this version. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 24 Sep, 2025 Read the published version in BMC Infectious Diseases → Version 1 posted Editorial decision: Revision requested 29 Jul, 2025 Reviews received at journal 28 Jul, 2025 Reviews received at journal 28 Jul, 2025 Reviewers agreed at journal 27 Jul, 2025 Reviews received at journal 24 Jul, 2025 Reviewers agreed at journal 23 Jul, 2025 Reviewers agreed at journal 23 Jul, 2025 Reviews received at journal 23 Jul, 2025 Reviewers agreed at journal 22 Jul, 2025 Reviewers agreed at journal 22 Jul, 2025 Reviewers invited by journal 22 Jul, 2025 Editor invited by journal 03 Jul, 2025 Editor assigned by journal 01 Jul, 2025 Submission checks completed at journal 01 Jul, 2025 First submitted to journal 01 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7021918","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":489755928,"identity":"dcf14f5d-0114-4a32-a98c-f91f887db440","order_by":0,"name":"Chandramani Wagle","email":"","orcid":"","institution":"Global Clinical Research","correspondingAuthor":false,"prefix":"","firstName":"Chandramani","middleName":"","lastName":"Wagle","suffix":""},{"id":489755929,"identity":"6dd4ef16-515a-4c8f-9ee3-263e3bb20535","order_by":1,"name":"Dinesh Prasad Ghimire","email":"","orcid":"","institution":"Virology Society Nepal","correspondingAuthor":false,"prefix":"","firstName":"Dinesh","middleName":"Prasad","lastName":"Ghimire","suffix":""},{"id":489755930,"identity":"64863172-dc10-491a-a0df-642bae45fece","order_by":2,"name":"Ajay Kumar Sah","email":"","orcid":"","institution":"Global Clinical Research","correspondingAuthor":false,"prefix":"","firstName":"Ajay","middleName":"Kumar","lastName":"Sah","suffix":""},{"id":489755931,"identity":"31b92093-4530-4227-a73b-31d0f58bf1ab","order_by":3,"name":"Abhay Kumar Sah","email":"","orcid":"","institution":"Virology Society Nepal","correspondingAuthor":false,"prefix":"","firstName":"Abhay","middleName":"Kumar","lastName":"Sah","suffix":""},{"id":489755932,"identity":"dafa7eea-a8c4-4450-817e-627537932817","order_by":4,"name":"Vivek Prasad Gupta","email":"","orcid":"","institution":"Virology Society 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Gupta","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5ElEQVRIiWNgGAWjYBACA2YQyQbEEgyGD4AUDx8pWowNQFrYCGphQGgxk4Cx8QJzdt6HjwvK7smbSzdvq/yaYyfDxsD88NENPFosm9mNjWecKzbcOedY2W3ZbclAh7EZG+fgc9hhNjZp3rYExg03csxuS25jBmrhYZMmoIX9N1CLPUhLseS2eqK0sDEDtSSCtDB+3HaYsBbLZjZmaZ5zCck7Z6QVSzNuO87DxkzAL+b8xxg/85Ql2G6XSN748ee2ant+9uaHj/FpQbgQiJl5QCxmYpTDtDD+IFb1KBgFo2AUjCgAAGFtP5/1rQ1pAAAAAElFTkSuQmCC","orcid":"","institution":"Virology Society Nepal","correspondingAuthor":true,"prefix":"","firstName":"Birendra","middleName":"Prasad","lastName":"Gupta","suffix":""}],"badges":[],"createdAt":"2025-07-01 15:38:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7021918/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7021918/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12879-025-11549-3","type":"published","date":"2025-09-24T15:56:53+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":87724342,"identity":"8c9cdfc3-c3c6-4675-96f1-fbe27647280d","added_by":"auto","created_at":"2025-07-28 10:23:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":61512,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of liver enzyme elevation by dengue severity\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7021918/v1/a2f8fa1cce04a3d082562bb4.png"},{"id":87724343,"identity":"f67b4c1b-e35a-4033-a030-69a256a6be4b","added_by":"auto","created_at":"2025-07-28 10:23:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":100326,"visible":true,"origin":"","legend":"\u003cp\u003eViolin plots of liver enzyme distributions by dengue severity\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7021918/v1/3a7ea75c868008c08ea6cca5.png"},{"id":92431188,"identity":"6e01c6cf-d52b-4222-bba3-c29591dbe0a2","added_by":"auto","created_at":"2025-09-29 16:08:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1324985,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7021918/v1/28bd653e-c762-4f5b-af75-8c915d8adbb4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Elevated Liver Enzyme (AST and ALT) as Biomarkers for Severe Dengue in Nepalese Patients: A Cross-Sectional Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDengue fever, a mosquito-borne viral disease, remains a major public health threat worldwide, with increasing incidence and geographic expansion in recent years [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The clinical spectrum ranges from mild illness to more severe forms, such as dengue with warning signs (DWS) and severe dengue (SD), which can involve complications like persistent vomiting, mucosal bleeding, or plasma leakage [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Hepatic involvement is frequently observed and may present as elevated liver enzymes particularly AST and ALT ranging from mild elevations to fulminant liver failure in rare cases [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Several studies have indicated that the degree of enzyme elevation may correlate with disease severity, suggesting a potential role for AST and ALT as early markers of clinical deterioration in dengue infection [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAlthough liver involvement in dengue is widely recognized, the predictive role of transaminase elevations AST and ALT in determining disease severity remains inadequately defined. Meta-analyses have shown that AST elevations are more common and pronounced in severe dengue compared to ALT, with AST abnormalities reported in up to 80% of dengue hemorrhagic fever (DHF) cases versus 54% for ALT [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Furthermore, a systematic review highlighted that AST levels exceeding three times the upper limit of normal (ULN) during early illness may serve as an early warning marker for disease progression [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, inconsistencies in the timing of liver function testing, varied ULN cut-offs, and the presence of comorbid hepatic conditions complicate interpretation across studies. Importantly, most of the existing evidence is derived from studies in Southeast Asia and Latin America, with little population-specific data from Nepal, where dengue is now endemic and expanding [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. This lack of localized evidence limits the application of liver enzymes in clinical triage, particularly under the WHO 2009 classification system.\u003c/p\u003e\u003cp\u003eThis study addresses these gaps through a secondary analysis of a previously published dataset from Nepal, utilizing the same cohort of laboratory-confirmed dengue patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. By leveraging this existing data, we aim to evaluate the association between elevated AST and ALT levels and dengue severity, comparing their effectiveness as biomarkers for identifying patients at risk of severe disease. Additionally, we explore the correlation between liver enzyme levels and clinical features to elucidate the pathophysiological mechanisms of hepatic involvement in dengue. The findings of this study will provide critical insights for early risk stratification and improved clinical management of dengue patients, particularly in resource-limited settings where cost-effective biomarkers are urgently needed.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cb\u003eStudy Design and Setting\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis study is a secondary analysis of a previously published cross-sectional study conducted by Gupta et al. (2025) which investigated hematological abnormalities (Leukopenia \u0026amp; Thrombocytopenia) in dengue patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The parent study was conducted during a seasonal dengue outbreak (September–December 2022) across four tertiary hospitals in Sunsari District, Koshi Province, Nepal: Bijayapur Hospital, Sunkoshi Laboratory, B.P. Koirala Institute of Health Sciences, and Itahari Municipal Hospital.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStudy Population and Patient Enrollment\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe cohort comprised 325 laboratory-confirmed dengue patients enrolled via convenience sampling during hospital visits. Inclusion/exclusion criteria were identical to parent study [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Patients presenting to the Outpatient Department (OPD) of participating hospitals with fever for ≤ 72 hours and clinical symptoms suggestive of dengue were confirmed via NS1 antigen or IgM/IgG positivity using rapid diagnostic tests. Patients with suspected dengue who did not have upper respiratory symptoms were considered eligible. Exclusion criteria included localizing symptoms suggesting alternative diagnoses (e.g., pneumonia, otitis), known HIV infection, chronic illnesses (e.g., liver or kidney disease, malignancy), immunosuppressive therapy, or pregnancy.\u003c/p\u003e\u003cp\u003eThis secondary analysis did not include a separate sample size or power calculation specific to liver enzyme elevations. The analysis utilized all eligible patients with complete AST and ALT data from the original dataset, which enrolled patients consecutively during the study period using convenience sampling. A convenience sampling approach may introduce selection bias by primarily capturing patients with moderate to severe symptoms seeking hospital care, potentially underrepresenting mild or asymptomatic cases. Written informed consent was obtained from patients or their guardians. Ethical approval was obtained from the Nepal Health Research Council (Ref: 678), and data were anonymized using sample codes to preserve participant confidentiality.\u003c/p\u003e\u003cp\u003e\u003cb\u003eData Collection and Laboratory Procedures\u003c/b\u003e\u003c/p\u003e\u003cp\u003eData were collected using a structured case report form (CRF) that included demographic details, clinical features, medical history, dengue confirmation tests, and laboratory results such as CBC and liver function tests (Supplementary File 1).\u003c/p\u003e\u003cp\u003eDengue diagnosis was confirmed using rapid diagnostic test (RDT) kits, primarily SD BIOLINE Dengue Duo NS1 Ag + Ab Combo, with Dengucheck Combo used in some settings, as described in parent article [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Liver function tests, specifically aspartate aminotransferase (AST) and alanine aminotransferase (ALT), were measured using the DIASYS Response 910 automated biochemistry analyzer. All participating hospitals followed standardized protocols for blood sample collection, handling, and analysis, with regular equipment calibration and reagent validation per hospital laboratory standards.\u003c/p\u003e\u003cp\u003e\u003cb\u003eVariables and Classification\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAST and ALT levels were measured at enrollment as part of routine clinical chemistry analysis. The upper limit of normal (ULN) was defined as 48 U/L for AST and 55 U/L for ALT, based on laboratory reference values provided by the Mayo Clinic [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Dengue severity was classified using the 2009 WHO dengue case classification system into dengue without warning signs (DWWS) and dengue with warning signs (DWS) aligned with Nepal’s national clinical guidelines [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. DWWS was defined by fever with at least two additional features (e.g., nausea, vomiting, rash, aches, leukopenia, positive tourniquet test) and laboratory-confirmed dengue, with adequate oral intake and urine output. DWS was characterized by at least one warning sign, such as abdominal pain, persistent vomiting, clinical fluid accumulation, mucosal bleeding, lethargy, liver enlargement (\u0026gt; 2 cm), or hematological changes (e.g., increased hematocrit with platelet count ≤ 100,000/mm³). Comorbidities (e.g., diabetes, renal failure) or social factors (e.g., living alone) also qualified patients for DWS classification [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cb\u003eData management and analysis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eData were entered into Microsoft Excel and analyzed using Python (v3.9) with libraries including pandas, SciPy, and statsmodels. Patients with missing laboratory results were excluded to ensure data completeness. Continuous variables, such as AST and ALT levels, were tested for normality using the Shapiro-Wilk test and were found to be non-normally distributed; hence, they were reported as medians with interquartile ranges (IQR). Categorical variables, including disease severity classification and demographic characteristics, were presented as frequencies and percentages.\u003c/p\u003e\u003cp\u003eThe association between liver enzyme elevation (AST and ALT) and disease severity was assessed using chi-square tests or Fisher’s exact tests, as appropriate. Multivariable logistic regression was performed to evaluate the independent association of AST and ALT elevation with dengue severity (DWS vs. DWWS), adjusting for potential confounders such as age and gender. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Spearman’s rank correlation was used to assess the strength and direction of the relationship between liver enzyme levels and other clinical/laboratory parameters. Correlation results were presented with corresponding p-values, and statistically significant associations were highlighted. Model fit was evaluated using McFadden’s pseudo R² and Akaike Information Criterion (AIC). Variance inflation factors (VIFs) were calculated to check for multicollinearity among predictor variables. A p-value of less than 0.05 was considered statistically significant throughout the analysis.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003ePatients\u0026rsquo; Demographics Characteristics\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAmong the 325 patients enrolled with laboratory-confirmed dengue, 130 (40.0%) were classified as having dengue with warning signs (DWS) and 195 (60.0%) as dengue without warning signs (DWWS) according to the WHO 2009 classification. Notably, no cases of severe dengue were identified among the enrolled participants. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the sociodemographic distribution of patients stratified by dengue severity. The median age of patients in the DWS group was 40 years (IQR 29\u0026ndash;52), significantly higher than the 33 years (IQR 21\u0026ndash;48) observed in the DWWS group. However, age group distribution did not differ significantly between the two severity groups (p\u0026thinsp;=\u0026thinsp;0.9168), with children, adults, and elderly individuals represented similarly in both groups.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSociodemographic characteristics of dengue patients by severity classification (N\u0026thinsp;=\u0026thinsp;325)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristic\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDWS (n, %)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDWWS (n, %)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge: Median (IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e40 (29\u0026ndash;52)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e33 (21\u0026ndash;48)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge Group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.9168\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChild (\u0026le;\u0026thinsp;14 years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17 (41.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24 (58.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdult (15\u0026ndash;59 years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e94 (39.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e145 (60.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElderly (\u0026ge;\u0026thinsp;60 years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19 (42.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26 (57.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.0004\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e77 (50.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e76 (49.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e53 (30.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e119 (69.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI (\u0026ge;\u0026thinsp;20 years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.2936\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnderweight (\u0026lt;\u0026thinsp;18.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (27.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (72.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHealthy weight (18.5\u0026ndash;24.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e67 (40.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e98 (59.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOverweight (25\u0026ndash;29.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e33 (49.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e34 (50.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eObese (30 \u0026le;)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (55.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (44.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eBMI categorization was restricted to participants aged\u0026thinsp;\u0026ge;\u0026thinsp;20 years. P-values were calculated using Chi-square or Fisher\u0026rsquo;s exact test, as appropriate. P-values less than 0.05 are indicated in bold to denote statistical significance.\u003c/em\u003e\u003c/p\u003e\u003cp\u003eA significant gender disparity was noted, with females comprising 69.2% of the DWWS group compared to 30.8% in the DWS group (p\u0026thinsp;=\u0026thinsp;0.0004). Among adults aged\u0026thinsp;\u0026ge;\u0026thinsp;20 years, BMI distribution showed no significant association with disease severity (p\u0026thinsp;=\u0026thinsp;0.2936), although overweight and obese individuals were slightly more prevalent in the DWS group (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cb\u003eLiver Enzyme Elevation and Disease Severity\u003c/b\u003e\u003c/p\u003e\u003cp\u003eWe further examined the association between liver enzyme elevation and disease severity among the 325 dengue patients analyzed. AST elevation was found more common than ALT elevation. AST levels showed marked stratification by disease severity, with 25.5% of DWS patients exhibiting\u0026thinsp;\u0026gt;\u0026thinsp;1\u0026ndash;3\u0026times; upper limit of normal (ULN) elevations versus 29.5% in DWWS. Notably, 3.1% of DWS patients demonstrated\u0026thinsp;\u0026gt;\u0026thinsp;3\u0026ndash;10\u0026times; ULN AST elevations (vs 2.5% DWWS), while no cases exceeded 10\u0026times; ULN. ALT elevations were less pronounced, with only 5.5% of DWS patients showing\u0026thinsp;\u0026gt;\u0026thinsp;1\u0026ndash;3\u0026times; ULN increases and no DWS cases exceeding 3\u0026times; ULN (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eViolin plots (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e) demonstrate significantly elevated AST levels in DWS patients (median: 61.5 U/L, IQR: 36.3\u0026ndash;90.9) compared to DWWS (median: 44.0 U/L, IQR: 24.6\u0026ndash;75.8), with wider dispersion and a pronounced right-skewed density peak above 80 U/L. While ALT medians were comparable between groups (DWS: 27.1 U/L vs DWWS: 28.2 U/L), DWWS patients exhibited greater variability including an outlier at 182.0 U/L (4.6\u0026times; ULN) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe Chi square analysis revealed a significant association between elevated AST levels and dengue with warning signs (DWS). Specifically, patients with elevated AST were more likely to be in the DWS group compared to those with normal AST levels (48.9% vs. 29.8%), with a statistically significant p-value of 0.0006 and an odds ratio (OR) of 0.44 (95% CI: 0.28\u0026ndash;0.70). This suggests that elevated AST may serve as a notable biomarker for more severe disease manifestations. In contrast, ALT levels showed a non-significant trend toward association with DWS, with a p-value of 0.1809 and an OR of 1.56 (95% CI: 0.85\u0026ndash;2.86), indicating ALT may be less specific for disease severity in this context (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAssociation of liver enzyme elevation with dengue severity (N\u0026thinsp;=\u0026thinsp;325)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiver Enzyme\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTotal n (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDWS n (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDWWS n (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eOR (95% CI)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eAspartate Aminotransferase (AST)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e151 (46.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e45 (29.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e106 (70.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.0006\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0.44 (0.28\u0026ndash;0.70)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e174 (53.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e85 (48.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e89 (51.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAlanine Aminotransferase (ALT)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e268 (82.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e112 (41.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e156 (58.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.1809\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.56 (0.85\u0026ndash;2.86\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e57 (17.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e18 (31.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e39 (68.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eP-values were calculated using Chi-square or Fisher\u0026rsquo;s exact test, as appropriate. P-values less than 0.05 are indicated in bold to denote statistical significance..\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eClinical Characteristics by Dengue Severity\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTo establish the clinical context of dengue severity, we analyzed key symptoms among the 325 patients, stratified by DWWS (n\u0026thinsp;=\u0026thinsp;195, 60.0%) and DWS (n\u0026thinsp;=\u0026thinsp;130, 40.0%), as shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Fever was nearly universal (99.1%), with no significant difference between severity groups (p\u0026thinsp;=\u0026thinsp;1.000). Gastrointestinal symptoms, particularly nausea (33.8% in DWS vs. 14.9% in DWWS, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), vomiting (21.5% vs. 7.7%, p\u0026thinsp;=\u0026thinsp;0.0004), and abdominal pain (16.9% vs. 0.0%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), were significantly more prevalent in DWS, suggesting a link to severe disease manifestations. Notably, joint pain emerged as another discriminating feature, present in nearly half of DWS patients (47.7%) versus 34.4% in DWWS (p\u0026thinsp;=\u0026thinsp;0.021), suggesting systemic inflammatory responses may parallel hepatic injury (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eClinical features of dengue patients by severity classification (N\u0026thinsp;=\u0026thinsp;325)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClinical Feature\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOverall (n\u0026thinsp;=\u0026thinsp;325)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDWWS (n\u0026thinsp;=\u0026thinsp;195)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDWS (n\u0026thinsp;=\u0026thinsp;130)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFever\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e322 (99.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e193 (99.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e129 (99.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHeadache\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e175 (53.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e98 (50.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e77 (59.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.1397\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMalaise\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e108 (33.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e65 (33.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e43 (33.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMuscle Pain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e183 (56.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e101 (51.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e82 (63.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.0524\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJoint Pain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e129 (39.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e67 (34.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e62 (47.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.0205\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRetro-orbital Pain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e76 (23.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e46 (23.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e30 (23.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRash\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e18 (5.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e11 (5.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e7 (5.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNausea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e73 (22.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e29 (14.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e44 (33.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVomiting\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e43 (13.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e15 (7.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e28 (21.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.0004\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiarrhea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e31 (9.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e16 (8.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e15 (11.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.3394\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbdominal Pain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e22 (6.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0 (0.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e22 (16.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChest Pain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e19 (5.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e9 (4.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e10 (7.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.3344\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eThis table summarizes the presence of clinical features among all enrolled patients, and stratifies by severity classification DWS and DWWS. P-values were calculated using Chi-square or Fisher\u0026rsquo;s exact test as appropriate. P-values less than 0.05 are bolded. In cases with zero cell counts, Fisher\u0026rsquo;s exact test was used and p-values interpreted with caution.\u003c/em\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eClinical Characteristics by Liver Enzyme Elevation Status\u003c/b\u003e\u003c/p\u003e\u003cp\u003eClinical features were analyzed in relation to liver enzyme status to identify symptoms associated with elevated AST or ALT levels (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Patients with elevated AST demonstrated significantly higher rates of gastrointestinal symptoms, including nausea (33.3% vs 9.9%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and vomiting (18.4% vs 7.3%, p\u0026thinsp;=\u0026thinsp;0.003), aligning with our earlier observation that these symptoms cluster in severe dengue cases (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Unexpectedly, malaise was 2\u0026times; less prevalent in elevated AST patients (23.0% vs 45.0%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), suggesting potential pathophysiological differences in energy metabolism during hepatic injury. 100% of patients with elevated AST/ALT reported fever, reinforcing fever as a universal marker of dengue-associated liver injury. Rash was less frequent in patients with elevated AST (p\u0026thinsp;=\u0026thinsp;0.0289). For ALT abnormalities, a paradoxical pattern emerged: elevated ALT was associated with absence of abdominal pain (0% vs 8.2%, p\u0026thinsp;=\u0026thinsp;0.019) and reduced headache prevalence (33.3% vs 58.2%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eClinical features by liver enzyme status (AST and ALT) (N\u0026thinsp;=\u0026thinsp;325)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClinical Feature\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAST Normal\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAST Elevated\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAST p-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eALT Normal\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eALT Elevated\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eALT p-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFever\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e149 (98.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e173 (99.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.5991\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e267 (99.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e55 (96.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.0806\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHeadache\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e85 (56.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e90 (51.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.4360\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e156 (58.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e19 (33.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMalaise\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e68 (45.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e40 (23.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e100 (37.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e8 (14.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMuscle Pain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e80 (53.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e103 (59.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.2649\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e155 (57.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e28 (49.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.2422\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJoint Pain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e58 (38.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e71 (40.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.7332\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e113 (42.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e16 (28.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.0533\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRetro-orbital Pain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e37 (24.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e39 (22.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.6945\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e68 (25.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e8 (14.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.0840\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRash\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e13 (8.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5 (2.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.0289\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e17 (6.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1 (1.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.2169\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNausea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e15 (9.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e58 (33.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e60 (22.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e13 (22.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1.0000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVomiting\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e11 (7.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e32 (18.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.0031\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e39 (14.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e4 (7.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.1940\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiarrhea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8 (5.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e23 (13.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.0219\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e25 (9.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e6 (10.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.8041\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbdominal Pain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e14 (9.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e8 (4.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.1212\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e22 (8.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0 (0.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e0.0188\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChest Pain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4 (2.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e15 (8.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.0309\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e14 (5.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e5 (8.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.3468\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eP-values were calculated using Chi-square or Fisher\u0026rsquo;s exact test, as appropriate. P-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 are bolded to indicate statistical significance. In cases with zero cell counts, Fisher\u0026rsquo;s exact test was used and p-values interpreted with caution.\u003c/em\u003e\u003c/p\u003e\u003cp\u003eThese findings reinforce the clinical relevance of liver enzyme monitoring, particularly AST, in the assessment of dengue patients, not only as a marker of hepatic involvement but also in predicting symptom patterns linked to more severe or systemic disease. The clinical symptom burden appears more pronounced among individuals with elevated AST than ALT, aligning with earlier findings that AST had a stronger association with disease severity (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cb\u003eDiagnostic and Treatment Profiles\u003c/b\u003e\u003c/p\u003e\u003cp\u003eIn alignment with earlier findings that associated AST elevation with dengue severity, Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e reveals critical diagnostic and management differences among dengue patients with liver injury. Elevated AST showed a striking association with NS1 antigen positivity (83.3% vs. 44.4%, p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), suggesting enhanced early viral detection in hepatic-involved cases, a finding that aligns with our earlier observation of more frequent vomiting and fever in this group (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Conversely, IgM positivity was paradoxically lower in AST-elevated patients (18.4% vs. 63.6%, p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), potentially reflecting delayed seroconversion due to immune modulation during severe hepatic injury.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDiagnostic and treatment patterns stratified by liver enzyme elevation (N\u0026thinsp;=\u0026thinsp;325)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParameter\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAST Normal\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAST Elevated\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value (AST)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eALT Normal\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eALT Elevated\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep-value (ALT)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNS1 Positive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e67 (44.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e145 (83.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e175 (65.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e37 (64.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1.0000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIgG Positive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1 (0.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1 (0.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.0000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1 (0.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1 (1.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.3205\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIgM Positive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e96 (63.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e32 (18.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e104 (38.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e24 (42.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.6566\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAntipyretics/Analgesics\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e142 (94.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e171 (98.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.0729\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e260 (97.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e53 (93.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.2351\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIntravenous (IV) Fluids\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1 (0.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e17 (9.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.0003\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e16 (6.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e2 (3.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.7493\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eP-values were calculated using Chi-square or Fisher\u0026rsquo;s exact test, as appropriate. Bold values indicate statistical significance (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). In cases with zero cell counts, p-values interpreted with caution.\u003c/em\u003e\u003c/p\u003e\u003cp\u003eThe need for intravenous (IV) fluid support was significantly greater among those with elevated AST (9.8% vs. 0.7%, p\u0026thinsp;=\u0026thinsp;0.0003), consistent with a more severe clinical presentation and previously noted associations between elevated AST and gastrointestinal symptoms such as nausea and vomiting (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). No statistically significant differences were observed in treatment or diagnostic patterns when stratified by ALT status (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cb\u003eAdjusted Associations and Exploratory Analyses\u003c/b\u003e\u003c/p\u003e\u003cp\u003eIn multivariable logistic regression analysis, elevated AST was significantly associated with increased odds of developing dengue with warning signs (DWS), with an adjusted odds ratio (aOR) of 2.40 (95% CI: 1.49\u0026ndash;3.86, p\u0026thinsp;=\u0026thinsp;0.0003). Female gender was also independently associated with higher odds of DWS (aOR\u0026thinsp;=\u0026thinsp;2.31, 95% CI: 1.45\u0026ndash;3.70, p\u0026thinsp;=\u0026thinsp;0.0005). Age demonstrated a modest but statistically significant association with severity (aOR\u0026thinsp;=\u0026thinsp;1.01 per year increase, 95% CI: 1.00\u0026ndash;1.03, p\u0026thinsp;=\u0026thinsp;0.0299). Although elevated ALT showed a trend toward a protective effect, the association did not reach statistical significance (aOR\u0026thinsp;=\u0026thinsp;0.57, 95% CI: 0.30\u0026ndash;1.09, p\u0026thinsp;=\u0026thinsp;0.0900). The logistic regression model demonstrated an acceptable fit, with a McFadden's pseudo R\u0026sup2; of 0.074 and an AIC of 414.9 (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). Multicollinearity diagnostics using Variance Inflation Factor (VIF) indicated no concerning collinearity among predictors (VIFs ranged from 1.003 to 1.014 for all variables), confirming the model's internal consistency and robustness.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAdjusted odds ratios for dengue severity (DWS vs DWWS) (N\u0026thinsp;=\u0026thinsp;325)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eaOR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated AST\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.49\u0026ndash;3.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.0003\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated ALT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.30\u0026ndash;1.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.0900\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (year)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.00\u0026ndash;1.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.0299\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale gender\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.45\u0026ndash;3.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.0005\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eModel fit: McFadden\u0026rsquo;s pseudo R\u0026sup2; = 0.074, AIC\u0026thinsp;=\u0026thinsp;414.9, log-likelihood = \u0026minus;\u0026thinsp;202.5.\u003c/em\u003e\u003c/p\u003e\u003cp\u003eSpearman\u0026rsquo;s correlation analysis was conducted to explore the relationships between liver enzyme levels (AST and ALT) and various clinical and laboratory parameters (Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). The selected parameters were chosen based on their clinical relevance and previously documented associations with dengue severity or hepatic involvement. For instance, WBC count, platelet count, and hemoglobin are commonly monitored in dengue management due to their relevance in assessing disease progression. Serum creatinine and hematocrit were included to evaluate renal function and hydration status, respectively. Clinical features such as headache, malaise, nausea, vomiting, and abdominal pain were included as they are frequently reported symptoms in dengue patients and may correlate with systemic inflammation or hepatic dysfunction. The analysis revealed several significant associations.\u003c/p\u003e\u003cp\u003eAST showed strong positive correlations with hemoglobin (ρ\u0026thinsp;=\u0026thinsp;0.407, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and platelet count (ρ\u0026thinsp;=\u0026thinsp;0.277, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), suggesting potential interactions between liver function and hematological parameters. AST also correlated with nausea (ρ\u0026thinsp;=\u0026thinsp;0.243, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and vomiting (ρ\u0026thinsp;=\u0026thinsp;0.151, p\u0026thinsp;=\u0026thinsp;0.0064), linking elevated AST to gastrointestinal symptoms (Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab7\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 7\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSpearman\u0026rsquo;s Correlation Between Liver Enzyme Levels and Clinical/Laboratory Parameters (N\u0026thinsp;=\u0026thinsp;325)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParameter\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAST (ρ)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eALT (ρ)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWBC count\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u0026ndash;0.140\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e0.0118\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.115\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.0379\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSerum Creatinine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u0026ndash;0.134\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e0.0157\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.137\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.0131\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHemoglobin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.407\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.003\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.9577\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePlatelet Count\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.277\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.7245\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHematocrit\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.194\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e0.0004\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.072\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.1933\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHeadache\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.003\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.9604\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.177\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.0013\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMalaise\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u0026ndash;0.265\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.149\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.0072\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNausea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.243\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.037\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.5020\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVomiting\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.151\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e0.0064\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.6631\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbdominal Pain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u0026ndash;0.100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.0725\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026ndash;0.048\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.3873\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eSpearman\u0026rsquo;s rank correlation coefficients between aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels and selected clinical and laboratory parameters in patients with dengue. Statistically significant correlations (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) are indicated in bold.\u003c/em\u003e\u003c/p\u003e\u003cp\u003eALT demonstrated a significant negative correlation with headache (ρ = -0.177, p\u0026thinsp;=\u0026thinsp;0.0013) and a weaker negative correlation with malaise (ρ = -0.149, p\u0026thinsp;=\u0026thinsp;0.0072). No significant association was found between ALT and hemoglobin (ρ = -0.003, p\u0026thinsp;=\u0026thinsp;0.9577) or platelet count (ρ\u0026thinsp;=\u0026thinsp;0.020, p\u0026thinsp;=\u0026thinsp;0.7245) (Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eBoth enzymes showed weak negative correlations with WBC count and serum creatinine, though these associations were only marginally significant for AST. These findings highlight distinct patterns of correlation for AST and ALT with clinical and laboratory parameters, providing further insight into the pathophysiology of dengue-associated liver injury.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis follows up analysis of cross-sectional study establishes AST as a consistent marker of disease severity, with patients exhibiting significantly higher odds of dengue with warning signs (DWS) (aOR 2.40, 95% CI: 1.49\u0026ndash;3.86) after adjusting for age and gender. The identification of female gender as an independent risk factor for DWS introduces a new dimension to severity risk stratification. The positive correlations of AST with hemoglobin and platelet count, despite expectations of thrombocytopenia in severe dengue, suggest complex hematological interactions unique to this population. Elevated AST was also associated with gastrointestinal manifestations (nausea and vomiting), increased need for intravenous fluids, and diagnostic positivity for NS1 antigen, suggesting a broader systemic burden in these patients. In contrast, ALT showed minimal discriminative capacity in severity prediction or symptom association. The distinct behavior of AST as a hepatic and systemic marker highlights its potential utility in clinical triage and risk stratification in dengue, particularly in resource-limited endemic settings where early markers of severe progression are critically needed.\u003c/p\u003e\u003cp\u003eThe findings of this study align with and extend previous research in the field. Prior meta-analyses have consistently shown that AST elevations are more prevalent and pronounced than ALT in both dengue fever and dengue hemorrhagic fever [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. A 2016 meta-analysis reported AST abnormalities in approximately 75\u0026ndash;80% of dengue cases versus 50\u0026ndash;55% for ALT. Similarly, studies from Southeast Asia, including one in Vietnam, observed stronger associations between AST and severe dengue compared to ALT [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Our findings mirror this pattern in a Nepalese cohort: elevated AST, but not ALT was independently associated with warning-sign dengue (DWS) and correlated with critical clinical features like gastrointestinal symptoms and IV fluid need. This differential association aligns with previous adult and pediatric studies, reinforcing AST\u0026rsquo;s diagnostic value over ALT across diverse demographics [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAdditional studies further support the prognostic relevance of liver enzyme abnormalities. For instance, a hospital-based study in Rawalpindi demonstrated that derangements in liver function tests, including AST and ALT, were significantly associated with WHO-classified dengue severity [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. A tertiary center study in Punjab similarly observed that AST was preferentially elevated over ALT and served as an early indicator of infection and severity, corroborating our findings [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In Nepal, a study noted significantly elevated AST and ALT values in patients with DSS and DHF compared to those with DF, highlighting the clinical utility of early liver function monitoring [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThis study contributes to the existing body of research by offering a more detailed analysis of liver enzyme elevation in dengue patients. Unlike previous studies that have primarily focused on the presence of elevated liver enzymes, this research delves deeper into the correlation between AST levels and specific clinical symptoms like nausea and vomiting. While ALT elevation coincides with symptom resolution (reduced headache/malaise), indicating convalescence. This temporal dichotomy resolves conflicting literature on enzyme roles. This study document previously unrecognized female vulnerability, with women facing 2.3\u0026times; higher severity risk, a pattern unseen in prior Nepalese studies, potentially linked to hormonal-immune interactions.\u003c/p\u003e\u003cp\u003eThis study offers a comprehensive analysis of hepatic involvement in Nepalese dengue patients, addressing a critical knowledge gap in a high-burden region. This study has several notable strengths. Strengths include the use of a structured assessment of liver enzymes alongside detailed clinical and laboratory data, enhancing the comprehensiveness of the analysis. The use of WHO 2009 classification ensured standardized severity assessment, enhancing global comparability. Comprehensive analyses, including unadjusted associations, adjusted logistic regression, and continuous correlations, offered a multi-faceted understanding of AST\u0026rsquo;s role in dengue severity. However, limitations include the further analysis of cross-sectional design, which precludes causality inferences between AST elevation and DWS. The absence of data on comorbidities, such as pre-existing liver disease, or hepatotoxic medications may confound enzyme levels. The lower prevalence of elevated ALT (n\u0026thinsp;=\u0026thinsp;57) likely limited statistical power for ALT associations. Binary or ordinal symptom scoring may have reduced sensitivity compared to continuous measures. Unmeasured viral serotypes and cytokines represent additional constraints. Additionally, the convenience sampling method could introduce selection bias and the absence of patients with severe dengue (SD) precluded evaluation across the full clinical spectrum.\u003c/p\u003e\u003cp\u003eThis study underscores the critical role of AST as a practical biomarker for identifying severe dengue (dengue with warning signs, DWS) in resource-limited settings like Nepal, where accessible tools are essential for effective patient triage. By demonstrating AST\u0026rsquo;s strong association with severe clinical presentations, including gastrointestinal symptoms and NS1 positivity, and its unexpected correlations with hematological markers, our findings advocate for routine AST monitoring to guide early intervention, such as intravenous fluid administration. The novel identification of female as a risk factor further highlights the need for tailored clinical approaches. Future research should explore longitudinal designs to establish causality and investigate gender-specific and serotype-related factors to refine dengue management strategies. Incorporate additional hepatic markers such as bilirubin and albumin and validate these findings in multi-center cohorts that include cases of severe dengue.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eElevated AST levels in dengue patients were found to be significantly associated with disease severity and symptom burden, reinforcing its clinical utility as an early marker of hepatic involvement. Unlike ALT, which showed limited predictive value, AST demonstrated consistent correlations with gastrointestinal manifestations and treatment intensity. These findings contribute to a better understanding of the hepatic profile in dengue and support the incorporation of AST monitoring into routine clinical assessments. New contributions to the literature include the adjusted confirmation of AST\u0026rsquo;s predictive role, the novel identification of female as a risk factor, and unexpected positive correlations with hemoglobin and platelet count, suggesting unique pathophysiological dynamics. Further prospective studies are warranted to validate these associations and explore the integration of liver enzyme trends into predictive models for early risk stratification and management in dengue-endemic regions.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eALT\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAlanine Aminotransferase\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eAST\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAspartate Aminotransferase\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eDWWS\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDengue Without Warning Signs\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eDWS\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDengue with Warning Signs\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eAR\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAdjusted Residual\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eCI\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eConfidence Interval.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor contributions\u003c/h2\u003e\n\u003cp\u003eBPG, SU designed the study, review and finalize the manuscript. CW analyzed, interpreted the data and draft the manuscript. DPG, VPG, AKS, and AKS review the manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgments\u003c/h2\u003e\n\u003cp\u003eWe extend our sincere gratitude to the hospital staff and laboratory professionals at study site. We also thank the research assistants involved in the parent study for their diligent efforts in ensuring data completeness and quality.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003ePart of funding for laboratory investigation of biochemical test was received from Virology Society Nepal and Global Clinical Research Nepal.\u003c/p\u003e\n\u003ch2\u003eData availability\u003c/h2\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\n\u003cp\u003eThe study was approved by the Ethics committee of Nepal Health Research Council, Kathmandu, Nepal (Approval No. 678). Informed consent was obtained from all participants or their guardians, and patient confidentiality was maintained through data anonymization.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eConsent for publication\u003c/h2\u003e\n\u003cp\u003e\u0026nbsp;Not applicable.\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003e\u0026nbsp;The authors declare no competing interests.\u003c/p\u003e\n\u003ch2\u003eClinical trial registration details\u003c/h2\u003e\n\u003cp\u003e\u0026nbsp;Clinical trial number: not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWorld Health Organization. Disease Outbreak News; Dengue \u0026ndash; Global Situation. 2024. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.who.int/emergencies/disease-outbreak-news/item/2023-DON518\u003c/span\u003e\u003cspan address=\"https://www.who.int/emergencies/disease-outbreak-news/item/2023-DON518\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed 1 Jul 2025.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUS Center for Disease Control and Prevention. Severe Dengue: Know the Warning Signs. 2025. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.cdc.gov/dengue/stories/severe-dengue.html\u003c/span\u003e\u003cspan address=\"https://www.cdc.gov/dengue/stories/severe-dengue.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed 1 Jul 2025.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSamanta J, Sharma V. Dengue and its effects on liver. World J Clin Cases. 2015;3:125\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCampana V, Inizan C, Pommier JD, Menudier LY, Vincent M, Lecuit M et al. Liver involvement in dengue: A systematic review. Rev Med Virol. 2024;34.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSwamy AM, Mahesh PY, Rajashekar ST. Liver function in dengue and its correlation with disease severity: a retrospective cross-sectional observational study in a tertiary care center in Coastal India. Pan Afr Med J. 2021;40.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eThach TQ, Eisa HG, Hmeda A, Ben, Faraj H, Thuan TM, Abdelrahman MM et al. Predictive markers for the early prognosis of dengue severity: A systematic review and meta-analysis. PLoS Negl Trop Dis. 2021;15.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSangkaew S, Ming D, Boonyasiri A, Honeyford K, Kalayanarooj S, Yacoub S, et al. Risk predictors of progression to severe disease during the febrile phase of dengue: a systematic review and meta-analysis. Lancet Infect Dis. 2021;21:1014\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEpidemiology and Disease Control Division D of HSM of H. and P. Situation Report on Dengue in Nepal \u0026ndash;\u0026thinsp;2024. 2024.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRayamajhi RJ, Thapa S, Rayamajhi P, Maharjan S, Yadav RKR, Roka K. Transaminitis among Patients with Dengue Fever Visiting a Tertiary Care Centre. J Nepal Med Association. 2023;61:683\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGupta BP, Uranw S, Gupta VP, Deuba E, Sah AK, Chaudhary S et al. Leukopenia and thrombocytopenia in dengue patients: a cross-sectional study from a tertiary hospitals in Koshi Province, Nepal. BMC Infect Dis. 2025;25.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiver function tests. Mayo Clinic. 2025. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.mayoclinic.org/tests-procedures/liver-function-tests/about/pac-20394595\u003c/span\u003e\u003cspan address=\"https://www.mayoclinic.org/tests-procedures/liver-function-tests/about/pac-20394595\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed 1 Jul 2025.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWorld Health Organization. Dengue guidelines for diagnosis, treatment, prevention and control: new edition. World Health Organization; 2009.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEpidemiology and Disease Control Division. Prevention, Management and Control of Dengue in Nepal 2019. Kathmandu.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang XJ, Wei HX, Jiang SC, He C, Xu XJ, Peng HJ. Evaluation of aminotransferase abnormality in dengue patients: A meta analysis. Acta Trop. 2016;156:130\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNguyen RN, Lam HT, Phan HV. Liver Impairment and Elevated Aminotransferase Levels Predict Severe Dengue in Vietnamese Children. Cureus. 2023;15:e47606.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKittitrakul C, Silachamroon U, Phumratanaprapin W, Krudsood S, Wilairatana P, Treeprasertsuk S. Liver function tests abnormality and clinical severity of dengue infection in adult patients. J Med Assoc Thai. 2015;98:S1\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRehman WU, Ali MZ, Arshad AR, Iqbal M, Karim N, Abbas M, et al. Correlation Between Liver Function Test and Severity of Dengue Fever at a Tertiary Care Hospital, Rawalpindi. Life Sci. 2025;6:07.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMalhi NS. Spectrum of Liver Dysfunction in Patients with Dengue Infection and the Markers of Severe Disease: Study from a Tertiary Care Centre in Punjab. J Liver Res Disord Ther. 2017;3.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChaudhary RD, Jha SD, Sah VK, Mandal RN, Pandey M, Yadav BK, et al. Derangement of liver function tests in dengue patients. Int J Res Med Sci. 2023;12:32\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Supplementary File","content":"\u003cp\u003eSupplementary file 1 is not available with this version.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Dengue severity, Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Liver Enzyme, Nepal","lastPublishedDoi":"10.21203/rs.3.rs-7021918/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7021918/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction\u003c/h2\u003e\u003cp\u003eDengue remains a major global health concern, with rising incidence and severity in endemic regions. Liver involvement, particularly elevated transaminases such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT), is frequently observed during infection. Prior research has reported inconsistent associations between AST/ALT elevation and severe dengue, particularly in diverse geographical settings. This study addresses these gaps by investigating the relationship between liver enzyme elevation and dengue severity in Nepalese patients, leveraging a pre-existing dataset to evaluate their potential as biomarkers for severe disease.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003e A cross-sectional study was conducted among 325 laboratory-confirmed dengue patients at a tertiary care hospital in Koshi province Nepal. Liver enzyme levels (AST and ALT) were categorized based on upper limit of normal (AST\u0026thinsp;\u0026gt;\u0026thinsp;48 U/L, ALT\u0026thinsp;\u0026gt;\u0026thinsp;55 U/L), and dengue severity was classified according to the WHO 2009 guidelines. Elevated AST \u0026amp; ALT were assessed for associations with DWS using Chi-square tests and multivariable logistic regression, adjusting for age and sex. Spearman\u0026rsquo;s correlations were performed to assess associations between liver enzyme elevations, clinical features, and disease severity. Variance inflation factor (VIF) was used to check for multicollinearity.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAmong the 325 dengue patients, 40.0% had dengue with warning signs (DWS). Elevated AST was significantly associated with DWS (aOR\u0026thinsp;=\u0026thinsp;2.40, 95% CI: 1.49\u0026ndash;3.86, p\u0026thinsp;=\u0026thinsp;0.0003), while elevated ALT showed no significant association. AST elevation also correlated with gastrointestinal symptoms, such as nausea (ρ\u0026thinsp;=\u0026thinsp;0.243, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and vomiting (ρ\u0026thinsp;=\u0026thinsp;0.151, p\u0026thinsp;=\u0026thinsp;0.0064), and with key laboratory markers including hemoglobin (ρ\u0026thinsp;=\u0026thinsp;0.407, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and platelet count (ρ\u0026thinsp;=\u0026thinsp;0.277, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). ALT showed weaker and inconsistent correlations. Adjusted analyses confirmed AST as an independent predictor of severe dengue. Female identified as a novel risk factor for DWS, independent of age and AST levels. The logistic regression model demonstrated good fit (McFadden\u0026rsquo;s R\u0026sup2; = 0.074), with no multicollinearity detected.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThis study establishes elevated AST as a significant predictor of severe dengue, offering a valuable biomarker for early risk stratification. The findings highlight the importance of liver function monitoring in dengue management. While the study's strengths include its structured assessment and comprehensive analysis, limitations such as its cross-sectional design, convenience sampling and reliance on a few centers\u0026rsquo; dataset limit causal inference and generalizability. Future research should validate these findings in prospective, multi-center studies and assess gender-specific risks along with prognostic value of dynamic liver enzyme monitoring throughout the disease course.\u003c/p\u003e","manuscriptTitle":"Elevated Liver Enzyme (AST and ALT) as Biomarkers for Severe Dengue in Nepalese Patients: A Cross-Sectional Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-28 10:15:53","doi":"10.21203/rs.3.rs-7021918/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-07-29T07:51:48+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-28T16:45:40+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-28T10:05:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"240331230658147227819506382290151861776","date":"2025-07-28T00:57:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-24T04:10:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"42976540793154588570926205448099990060","date":"2025-07-24T03:50:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"184681873935157073040444248094369289166","date":"2025-07-23T12:26:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-23T11:44:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"207849280401541433216574502504005404958","date":"2025-07-23T00:58:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"31232710422869493117914573587634127153","date":"2025-07-22T20:03:07+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-22T18:32:12+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-07-03T05:45:47+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-02T02:48:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-02T02:46:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2025-07-01T15:23:19+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c8145060-327a-48f0-a894-afde05a0da52","owner":[],"postedDate":"July 28th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-29T16:07:55+00:00","versionOfRecord":{"articleIdentity":"rs-7021918","link":"https://doi.org/10.1186/s12879-025-11549-3","journal":{"identity":"bmc-infectious-diseases","isVorOnly":false,"title":"BMC Infectious Diseases"},"publishedOn":"2025-09-24 15:56:53","publishedOnDateReadable":"September 24th, 2025"},"versionCreatedAt":"2025-07-28 10:15:53","video":"","vorDoi":"10.1186/s12879-025-11549-3","vorDoiUrl":"https://doi.org/10.1186/s12879-025-11549-3","workflowStages":[]},"version":"v1","identity":"rs-7021918","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7021918","identity":"rs-7021918","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}