Diagnostic accuracy of the WHO clinical definitions for dengue and implications for surveillance: A systematic review and meta-analysis

Abstract

Background: Dengue is the world's most common mosquito-borne virus but remains diagnostically challenging due to its nonspecific presentation. Access to laboratory confirmation is limited and thus most reported figures are based on clinical diagnosis alone, the accuracy of which is uncertain. This systematic review assesses the diagnostic accuracy of the traditional (1997) and revised (2009) WHO clinical case definitions for dengue fever, the basis for most national guidelines.

Methodology/principal findings: PubMed, EMBASE, Scopus, OpenGrey, and the annual Dengue Bulletin were searched for studies assessing the diagnostic accuracy of the unmodified clinical criteria. Two reviewers (NR/SL) independently assessed eligibility, extracted data, and evaluated risk of bias using a modified QUADAS-2. Additional records were found by citation network analysis. A meta-analysis was done using a bivariate mixed-effects regression model. Studies that modified criteria were analysed separately. This systematic review protocol was registered on PROSPERO (CRD42020165998). We identified 11 and 12 datasets assessing the 1997 and 2009 definition, respectively, and 6 using modified criteria. Sensitivity was 93% (95% CI: 77-98) and 93% (95% CI: 86-96) for the 1997 and 2009 definitions, respectively. Specificity was 29% (95% CI: 8-65) and 31% (95% CI: 18-48) for the 1997 and 2009 definitions, respectively. Diagnostic performance suffered at the extremes of age. No modification significantly improved accuracy.

Conclusions/significance: Diagnostic accuracy of clinical criteria is poor, with significant implications for surveillance and public health responses for dengue control. As the basis for most reported figures, this has relevance to policymakers planning resource allocation and researchers modelling transmission, particularly during COVID-19.

Fig 1. PRISMA flow diagram for systematic review search results.

AFI: Acute febrile illness. PubMed, EMBASE, Scopus, and OpenGrey were searched for articles assessing the diagnostic accuracy of clinical criteria for dengue diagnosis, Dengue Bulletin articles and short notes were also included. The additional record was identified from previous work but did not mention WHO criteria in the title or abstract. Citation network analysis used Web of Science, Google Scholar, and reference lists. Articles assessing the diagnostic accuracy of unmodified WHO clinical criteria (1997 or 2009) for dengue were included in the meta-analysis, articles using modified criteria were included in qualitative analysis only.

Fig 2. Risk of bias analysis for included studies assessing the diagnostic accuracy of clinical criteria for dengue fever.

+ (green): Low risk; +* (green): Withdrawals/indeterminate results not mentioned, assumed none and thus low risk;? (amber): unclear risk;—(red): high risk; CS: cohort study; HS: Hospital study; AN: Aedes Network study; PHS: Public Health Surveillance study. Modified refers to modifications from the 1997 or 2009 WHO criteria. The assessment was carried out by two independent reviewers (NR/SL) using a modified version of QUADAS-2 (S2 Table). A study was deemed to be at high risk of bias if any domain was at high risk of bias.

Fig 3. Forest plot for sensitivity and specificity of the WHO 1997 case definition for probable dengue.

Meta-analysis carried out in Stata/IC 14 using the MIDAS statistical package. 95% confidence intervals given in parentheses. HS: hospital study; CS: cohort study; AN: Aedes Network Study; PHS: Public Health Surveillance Network Study. a: Calculated specificity differs from the reported value (0.2121); b: Calculated sensitivity differs from the reported value (0.98).

Fig 4. Forest plot for sensitivity and specificity of the WHO 2009 case definition for probable dengue.

Meta-analysis carried out in Stata/IC 14 using the MIDAS statistical package. 95% confidence intervals given in parentheses. HS: hospital study; CS: cohort study; AN: Aedes Network Study; PHS: Public Health Surveillance Network Study. a: Calculated sensitivity differs from the reported value (0.909).