Risk Predictors of Dengue Disease Progression During the Febrile Phase

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Study authors searched medical databases to identify factors that could be detected in the febrile phase associated with progression to severe dengue disease.

Monitoring liver aminotransferases and serum albumin during the febrile phase of dengue could enhance the ability to predict the risk of progression to severe dengue disease in patients, according to findings published in the Lancet Infectious Diseases. This analysis supports the warning signs described in the 2009 World Health Organization guidelines.

The study authors examined 25 factors associated with the disease progression of dengue grouped into 4 domains: demographics and comorbidities (9 factors), clinical signs and symptoms (7 factors), laboratory parameters (7 factors), and viral-related biomarkers (2 factors).

In this systematic review and meta-analysis, study authors searched 6 various medical databases for publications on predictors of severe dengue hemorrhagic fever between January 1, 1997, and January 31, 2020. They included 150 studies in the systematic review, of which 122 studies were included in the meta-analysis.

Investigators found the following demographic and comorbidity predictors to be associated with progression to severe dengue:

  • Older adults (standardized mean differences [SMD], 0.1; 95% CI, 0.02%-0.18%)
  • Female sex (pooled odds ratio [OR], 0.95; 95% CI, 0.84%-1.08%)
  • Diabetes (OR, 4.38; 95% CI, 2.58%-7.43%)
  • Renal disease (OR, 4.67; 95% CI, 2.21%-9.88%)

Younger children had higher risk of disease progression compared with older children, with odds of progression reduced by 8% (95% CI, 2%-14%) for every year of increase in age.

The following are clinical signs and symptoms positively associated with disease progression:

  • Vomiting (OR, 2.25; 95% CI, 1.87%-2.71%)
  • Abdominal pain and tenderness (OR, 1.92; 95% CI, 1.35%-2.74%)
  • Bleeding, mucosal or spontaneous (OR, 1.57; 95% CI, 1.13%-2.19%)
  • Clinical fluid accumulation (OR, 4.61; 95% CI, 2.29%-9.26%)

Patient laboratory parameters associated with progression include the following:

  • Platelet count (SMD, -0.34; 95% CI, -0.54% to -0.15%)
  • Aspartate aminotransferase (SMD, 1.06; 95% CI, 0.54%-1.57%)
  • Alanine aminotransferase (SMD, 0.73; 95% CI, 0.36%-1.09%)
  • Serum albumin (SMD, -0.5; 95% CI, -0.86% to -0.15%)

Study authors found secondary infection with dengue virus was associated with progression (OR, 2.26; 95% CI, 1.65%-3.09%). Additionally, children with dengue virus serotype 2 infection had increased risk of disease progression compared with children with dengue virus serotype 1 (OR, 1.81; 95% CI, 1.24%-2.65%) or dengue virus serotype 3 (OR, 2.24; 95% CI, 1.48%-3.38%) infections.

Some limitations of this study include failure to address high risk of bias regarding potential confounders and failure to appropriately adjust for the confounders.

“Further prospective studies focusing on the febrile phase of illness will allow investigation of the role of novel biomarkers and non-invasive methods, such as ultrasonography, in predicting the early onset of severe dengue, with the ultimate objective of improving patient triage and allocation of resources, and reducing hospital morbidity, mortality, and the health and economic impact of dengue worldwide,” the study authors concluded.


Sangkaew S, Ming D, Boonyasiri A, et al. Risk predictors of progression to severe disease during the febrile phase of dengue: a systematic review and meta-analysis. Lancet Infect Dis. Published online February 25, 2021. doi:10.1016/S1473-3099(20)30601-0