Underreporting of Dengue-4 in Brazil Due to Low Sensitivity of the NS1 Ag Test in Routine Control Programs

Sea, Vanessa Ramos Faria; Cruz, Ana Cecília Ribeiro; Gurgel, Ricardo Queiróz; Nunes, Bruno Tardelli Diniz; Silva, Eliana Vieira Pinto; Dolabella, Silvio Santana; Santos, Roseli La Corte dos

doi:10.1371/journal.pone.0064056

Cited by 23 publications

(26 citation statements)

References 11 publications

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“…However, some studies have also reported a lower sensitivity for Platelia for DENV2 [30], [35], [36], [47], [50]. The low accuracy of the Panbio during an epidemic of DENV4 and Platelia were recently analyzed by Colombo et al [52] and Sea et al [54], who observed the occurrence of false negatives. It is not yet known why the NS1 ELISA has a lower sensitivity in the patients infected with DENV4, but some hypotheses can be postulated: (i) there could be quantitative differences in the secreted NS1 form, depending on the viral serotype, which may lead to less availability of NS1 and reduced chances of detection, (ii) the higher incidence of DENV4 in secondary infections, and (iii) there could be presence of polymorphism in the NS1 gene associated with immune epitopes.…”

Section: Discussionmentioning

confidence: 99%

A Meta-Analysis of the Diagnostic Accuracy of Two Commercial NS1 Antigen ELISA Tests for Early Dengue Virus Detection

2014

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BackgroundDengue virus (DENV) NS1 antigen detection is regarded as an early diagnostic marker. Accordingly, several studies have evaluated the performance of tests that utilize NS1 capture, but the results of individual studies may be limited due to the restricted sample size of the patients recruited. Therefore, our objective was to perform a meta-analysis of the diagnostic accuracy of two commercial NS1 ELISAs (Panbio and Platelia).Methods and ResultsStudies of interest were found in PubMed, Embase and Google Scholar databases using defined inclusion/exclusion criteria. A total of 30 studies containing 12,105 total enrolled patients were included. The results were as follows: 1) Panbio assays showed low overall performance, sensitivity 66% (95% confidence interval (CI) 61–71), specificity 99% (95% CI 96–100), positive likelihood ratio (LR+) 98 (95% CI 20–464), negative likelihood ratio (LR-) 0.3 (95% CI 0.2–0.4), diagnostic odds ratio (DOR) 289 (95% CI 59–1412); 2) Platelia assays showed high overall performance, sensitivity 74% (95% CI 63–82), specificity 99% (95% CI 97–100), LR+ 175 (95% CI 28–1099), LR- 0.3 (95% CI 0.2–0.4), DOR 663 (95% CI 98–4478). The lowest sensitivity values were for secondary infections (57% [95% CI 47–67] and 66% [95% CI 53–77] for Panbio and Platelia, respectively) and for the detection of DENV4. Regarding clinical manifestations, the sensitivity of Platelia was 69% (95% CI 43–86) and 60% (95% CI 48–70) for fever and dengue hemorrhagic fever, respectively. In addition, the sensitivity of both tests was slightly lower for samples from Southeast Asia and Oceania.ConclusionDENV1 samples gave higher sensitivity results for both tests. We observed that factors negatively influencing the tests, such as the type of infection, geographical origins of samples and viral serotypes, require further investigation to optimize the diagnostic accuracy.

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Section: Discussionmentioning

confidence: 99%

A Meta-Analysis of the Diagnostic Accuracy of Two Commercial NS1 Antigen ELISA Tests for Early Dengue Virus Detection

2014

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“…However, in our study, fever was not reported in 13% of dengue deaths, as reported previously. 4,25 Cough not has been reported to be a symptom of dengue, but it was observed in 76.1% of fatal cases in this study. Convulsion was observed in 34.9% of the dengue deaths, confirming the findings of Araújo and others 26 and warning of the importance of this clinical manifestation in severe cases.…”

Section: Discussionmentioning

confidence: 44%

“…This study showed the importance of using all available techniques for dengue diagnosis in postmortem cases, as demonstrated in other studies. [22][23][24] The most common signs and symptoms were fever, respiratory distress, dyspnea, cough, vomiting, abdominal pain, headache, and prostration. Dengue is traditionally defined as an acute febrile illness.…”

Section: Discussionmentioning

confidence: 99%

Postmortem Diagnosis of Dengue as an Epidemiological Surveillance Tool

Cavalcanti

Braga

Silva

et al. 2016

The American Journal of Tropical Medicine and Hygiene

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Abstract. Dengue remains a problem in Brazil, and a substantial number of cases that progress to death are not diagnosed by health services. We evaluated the impact of a protocol adopted by the Coroner's Office Rocha Furtado (CO-RF) for the detection of unreported deaths from dengue in Brazil. We evaluated prospectively cases of deaths referred to the CO-RF with suspicion of dengue and those referred with other diagnosis in which the pathologists suspected dengue as the cause of death. Biological material was collected from all bodies autopsied, for which the suspected cause of death was dengue, between January 2011 and December 2012. Of the 214 bodies autopsied, 134 (62.6%) tested positive for dengue; of these cases, 121 were classified as dengue according to the World Health Organization's case definition (1997 or 2009, as appropriate). Thus, CO-RF detected 90 deaths from dengue, which were not suspected during disease progression. This CO-RF protocol, through a combined effort of the surveillance and laboratory teams, increased the detection of fatal dengue cases by 5-fold. This is the largest series of autopsies performed in cases of death related to dengue in the world to date.

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“…Commercially available NS1 antigen (Ag) tests manufactured by BioRad (Platelia) and Panbio (Dengue Early) both have low sensitivity to DENV-4 infections [8,[10][11][12]. Previous evaluations of Dengue Early test showed a sensitivity as low as 19% for DENV4 [6,8,[13][14][15]. Although the overall sensitivity of Platelia test was good however when comparing the sensitivities between all DENV serotypes, the BioRad test had the lowest sensitivity for DENV-4 (58.3%) [10].…”

Section: Introductionmentioning

confidence: 99%

Development and characterization of serotype-specific monoclonal antibodies against the dengue virus-4 (DENV-4) non-structural protein (NS1)

Gelanew¹,

Hunsperger²

2018

Virol J

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BackgroundDengue, caused by one of the four serologically distinct dengue viruses (DENV-1 to − 4), is a mosquito-borne disease of serious global health significance. Reliable and cost-effective diagnostic tests, along with effective vaccines and vector-control strategies, are highly required to reduce dengue morbidity and mortality. Evaluation studies revealed that many commercially available NS1 antigen (Ag) tests have limited sensitivity to DENV-4 serotype compared to the other three serotypes. These studies indicated the need for development of new NS1 Ag detection test with improved sensitivity to DENV-4. An NS1 capture enzyme linked immunoassay (ELISA) specific to DENV-4 may improve the detection of DENV-4 cases worldwide. In addition, a serotype-specific NS1 Ag test identifies both DENV and the infecting serotype.MethodsIn this study, we used a small-ubiquitin-like modifier (SUMO*) cloning vector to express a SUMO*-DENV-4 rNS1 fusion protein to develop NS1 DENV-4 specific monoclonal antibodies (MAbs). These newly developed MAbs were then optimized for use in an anti-NS1 DENV-4 capture ELISA. The serotype specificity and sensitivity of this ELISA was evaluated using (i) supernatants from DENV (1–4)-infected Vero cell cultures, (ii) rNS1s from all the four DENV (1–4) and, (iii) rNS1s of related flaviviruses (yellow fever virus; YFV and West Nile virus; WNV).ResultsFrom the evaluation studies of the newly developed MAbs, we identified three DENV-4 specific anti-NS1 MAbs: 3H7A9, 8A6F2 and 6D4B10. Two of these MAbs were optimal for use in a DENV-4 serotype-specific NS1 capture ELISA: MAb 8A6F2 as the capture antibody and 6D4B10 as a detection antibody.ConclusionThis ELISA was sensitive and specific to DENV-4 with no cross-reactivity to other three DENV (1–3) serotypes and other heterologous flaviviruses. Taken together these data indicated that our MAbs are useful reagents for the development of DENV-4 immunodiagnostic tests.Electronic supplementary materialThe online version of this article (doi: 10.1186/s12985-018-0925-7) contains supplementary material, which is available to authorized users.

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Underreporting of Dengue-4 in Brazil Due to Low Sensitivity of the NS1 Ag Test in Routine Control Programs

Cited by 23 publications

References 11 publications

A Meta-Analysis of the Diagnostic Accuracy of Two Commercial NS1 Antigen ELISA Tests for Early Dengue Virus Detection

A Meta-Analysis of the Diagnostic Accuracy of Two Commercial NS1 Antigen ELISA Tests for Early Dengue Virus Detection

Postmortem Diagnosis of Dengue as an Epidemiological Surveillance Tool

Development and characterization of serotype-specific monoclonal antibodies against the dengue virus-4 (DENV-4) non-structural protein (NS1)

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