A study of proteinuria and urine protein-creatinine ratio as a tool in predicting disease severity and adverse outcome in paediatric dengue fever

INTRODUCTION

Dengue fever (DF) is a benign syndrome caused by several arthropod-borne viruses and is characterised by biphasic fever, myalgia or arthralgia, rash, leucopenia and lymphadenopathy.^[1] Most dengue infections remain asymptomatic or present as a mild febrile illness; however, the virus can also lead to severe, life-threatening complications. Dengue illness can be divided into three phases: Febrile phase followed by critical phase and the recovery phase. During the critical phase, the condition of patients can worsen or improve rapidly, requiring careful monitoring by caregivers. The incubation period of dengue virus infection is 3–14 days with a variety of clinical manifestations including asymptomatic infection, undifferentiated fever, DF, dengue haemorrhagic fever and life-threatening dengue shock syndrome (DSS).^[2] Mortality in dengue is due to abnormal capillary permeability, abnormalities of haemostasis and in severe cases, DSS. Therefore, improvements in early diagnosis and risk prediction for severe disease are urgently needed. This would enable appropriate and early intervention. The risk factors for the development of severe disease are poorly characterised, and consequently, uncomplicated cases are frequently hospitalised for observation during the critical phase for capillary leakage syndrome, thereby increasing the financial cost to the patients.^[3] Significant proteinuria occurs in DSS, and it is possible that proteinuria in the early phase may be helpful for the identification of patients who are likely to develop severe complications in dengue.^[4] Very few literatures of this study are available in North Karnataka. Hence, the present study was undertaken to establish proteinuria and urine protein-creatinine ratio (UPCR) as an indicator to predict disease severity and adverse outcome as well as enable management in paediatric patients with DF.

MATERIAL AND METHODS

Methodology

Patients with dengue were classified according to the World Health Organization (WHO) dengue guidelines into DF without warning signs, which was Category A; DF with warning signs included Category B and severe dengue was classified as Category C,^[6.7] [Figure 1]. Dengue diagnosis was confirmed using non-structural protein 1 antigen or immunoglobulin M antibody assays.^[8] Proteinuria was assessed using a urine dipstick.^[9] UPCR estimation was performed using the standard biochemical methods, including the pyrogallol red method for the estimation of urine protein and the modified Jaffe method for creatinine estimation.^[10] Patient vitals were recorded from day 1 of admission up to 5 days. Peak value of UPCR and degree of proteinuria in patients with dengue belonging to the various categories were compared with their clinical and laboratory parameters. Peak UPCR values were categorised for severity into <0.5, 0.5–1, 1–3 and >3.^[5]

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Figure 1: World Health Organization classification of dengue fever.

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RESULTS

The data were collected from 90 serologically confirmed dengue cases aged 1 month to 18 years. The mean age was 7.9 ± 4.5 years, with no significant association between age and severity (p = 0.698). Males constituted 55.6% of cases, and gender had no correlation with severity (p = 0.479).

Based on the WHO classification, 47.78% belonged to Category A, 24.44% to Category B and 27.78% to Category C [Figure 2].

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Figure 2: Category-wise distribution of dengue cases.

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Proteinuria was absent in 38.89% of children and was predominantly seen in Category A. Higher grades (2+ and 3+) were largely confined to Category C and showed a significant positive correlation with disease severity (r = 0.35, p = 0.001) [Table 1]. The mean peak UPCR occurred on day 4.04 ± 1.34 of illness, which is the critical phase of DF.

Elevated UPCR (>3) was mainly observed in Category C, and the association between peak UPCR and severity was highly significant (p < 0.001) [Figure 3].

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Figure 3: Comparison of peak urine protein-creatinine ratio (UPCR) values with the category.

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Higher peak UPCR was significantly associated with warning signs (χ² = 29.8, p < 0.001), hypotension (χ² = 32.86, p < 0.001), bleeding (χ² = 18, p < 0.001) [Figure 4], inotropic requirement (χ² = 33.56, p < 0.001) and paediatric intensive care unit admission (p < 0.001). All children requiring inotropes had UPCR >3.

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Figure 4: Box plot representing the correlation of peak urine protein-creatinine ratio (UPCR) with bleeding manifestations.

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Mortality (4.44%) occurred only in children with ≥2+ proteinuria and UPCR ≥1, with the highest deaths in the >3 UPCR group (3.33%). Logistic regression confirmed peak UPCR as a significant predictor of mortality (Chi-square = 15.85, p < 0.001) [Table 2]. Peak UPCR was a significant predictor of mortality, with each unit increase associated with a 2.77-fold increase in the odds of death [Table 3].

Multiple linear regression analysis was performed, which showed that warning signs, bleeding and inotrope use significantly influenced peak UPCR (R² = 0.62, p < 0.001). Overall, both increasing proteinuria and elevated UPCR were strongly associated with the severity of dengue, plasma leakage, haemodynamic instability, intensive care requirement and mortality, establishing proteinuria and UPCR as important prognostic markers in paediatric dengue.

DISCUSSION

Proteinuria in dengue is usually transient and reflects the extent of systemic involvement. Dengue non-structural protein 1 (NS1), a secreted viral glycoprotein, plays a significant role in the pathogenesis of vascular permeability in dengue infection. The circulating NS1 can directly interact with endothelial cells and disrupt the endothelial glycocalyx layer, a critical barrier regulating vascular integrity. This disruption results in increased endothelial permeability and contributes to plasma leakage, a hallmark of severe dengue.^[5] Proteinuria is observed in a significant proportion of patients with dengue infection, while hypoalbuminaemia is believed to result from altered glomerular filtration. The dengue virus and its non-structural protein NS1 have been shown to bind to heparan sulphate, a key component of the glomerular endothelial glycocalyx. This interaction disrupts the integrity of the glomerular basement membrane, leading to increased permeability and subsequent proteinuria, which contributes to hypoalbuminaemia.^[4] While urine dipstick testing is simple, it is semi-quantitative and affected by urine concentration; in contrast, UPCR provides a reliable, non-invasive and cost-effective quantitative estimate, correlating well with 24-h urinary protein. Early identification of severe dengue is crucial, particularly in resource-limited settings and paediatric data remain limited. In the present study, the mean age of children with dengue infection was 7.9 ± 4.5 years, with ages ranging from 9 months to 18 years. However, no statistically significant association was observed between age and severity of dengue (p = 0.698). This suggests that disease severity in our study population was independent of age, indicating that children across all age groups are equally susceptible to developing severe manifestations.

In the present study, the mean age was 7.9 ± 4.5 years, with no significant association between age and disease severity (p = 0.698), indicating that severity is independent of age. Males constituted 55.6% of cases; however, gender was not significantly associated with severity (p = 0.479), consistent with findings by Joseph et al.,^[10] Bhavani Shankar et al.^[4] and Venkataramanan et al.,^[5] all of whom reported male predominance without correlation to severity.

Most cases in our study belonged to Category A, whereas Bhavani Shankar et al.^[4] and Venkataramanan et al.^[5] reported a predominance of Category B and Datla et al.^[11] observed more Category C cases, likely reflecting differences in referral patterns.

Higher grades of proteinuria were predominantly seen in severe dengue (Category C), showing a significant positive correlation with severity (r = 0.35, p = 0.001). This contrasts with Datla et al.,^[11] who found no significant association. Peak UPCR showed a strong association with severity (p < 0.001), consistent with studies by Venkataramanan et al.,^[5] Joseph et al.,^[10] Jarutunyaluk et al.^[12] and Datla et al.^[11] [Table 4].

Proteinuria ≥2+ was significantly associated with mortality (p = 0.001), similar to Datla et al.,^[11] whereas Andries et al.^[13] did not find a significant association. Peak UPCR also predicted adverse outcomes (p < 0.001). In addition, proteinuria correlated with warning signs (p < 0.001), unlike Andries et al.,^[13] and higher UPCR values were significantly associated in patients with bleeding manifestations, as reported by Venkataramanan et al.,^[5] Bhavani Shankar et al.^[4] and Datla et al.^[11]

Thus, proteinuria and UPCR serve as useful early predictors of severity and adverse outcomes in paediatric dengue.

CONCLUSION

Proteinuria and UPCR showed a significant association with dengue severity in children. Increasing proteinuria and higher UPCR correlated with warning signs, bleeding, third-space loss and progression to severe dengue. Children with minimal proteinuria had favourable outcomes, whereas ≥2+ proteinuria and elevated UPCR were linked to complications and mortality. Peak UPCR was a strong predictor of severity and adverse outcomes, reflecting capillary leak and endothelial dysfunction. As a simple, rapid, non-invasive and cost-effective test, UPCR can be used for early risk stratification, helping identify high-risk patients requiring close monitoring and timely intervention, thereby improving clinical outcomes in paediatric dengue. Proteinuria and UPCR appear to be associated with disease severity and outcomes in paediatric dengue; however, their predictive value should be interpreted with caution due to possible confounding factors, and further validation in larger studies is required.