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Published in: BMC Infectious Diseases 1/2014

Open Access 01-12-2014 | Research article

Dengue NS1 antigen as a marker of severe clinical disease

Authors: Shiran Ajith Paranavitane, Laksiri Gomes, Achala Kamaladasa, Thiruni N Adikari, Nilanka Wickramasinghe, Chandima Jeewandara, Narangoda Liyanage Ajantha Shyamali, Graham Stuart Ogg, Gathsaurie Neelika Malavige

Published in: BMC Infectious Diseases | Issue 1/2014

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Abstract

Background

Early detection of complications significantly reduces dengue associated mortality and morbidity. We set out to determine if the NS1 rapid antigen detection test could be used as a point of care test to predict severe disease.

Methods

186 adult patients with confirmed dengue were enrolled during day 3-8 of illness. Clinical and laboratory parameters were recorded during the course of the illness and NS1 antigen levels were determined using both the Panbio dengue early ELISA (Panbio, Australia) and a NS1 rapid antigen detection kit (SD Bioline, South Korea).

Results

59.1% of patients presented to hospital on day 5-6 of illness when NS1 antigen positivity was significantly (p = 0.008) associated with severe dengue (odds ratio 3.0, 95% CI 1.39 to 6.47) and the NS1 antigen levels were significantly higher (p = 0.03) in those who went on to develop shock. Serum NS1 antigen levels significantly (p < 0.0001) and inversely correlated with the total white cell counts and lymphocyte counts. The bedside NS1 test showed comparable sensitivity (97.4%) and specificity (93.7%) to the laboratory NS1 test in our setting and cohort.

Conclusion

NS1 antigen positivity is associated with a higher risk of developing severe dengue especially when positive beyond day 5 of illness in our cohort, and while further validation studies are required, the test can therefore potentially be used as a bedside point of care test as a warning sign of severe dengue.
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Literature
1.
go back to reference Callaway E: Dengue fever climbs the social ladder. Nature. 2007, 448: 734-735. 10.1038/448734a.CrossRef Callaway E: Dengue fever climbs the social ladder. Nature. 2007, 448: 734-735. 10.1038/448734a.CrossRef
2.
go back to reference Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O, Myers MF, George DB, Jaenisch T, Wint GR, Simmons CP, Scott TW, Farrar JJ, Hay SI: The global distribution and burden of dengue. Nature. 2013, 496 (7446): 504-507. 10.1038/nature12060.CrossRefPubMedPubMedCentral Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O, Myers MF, George DB, Jaenisch T, Wint GR, Simmons CP, Scott TW, Farrar JJ, Hay SI: The global distribution and burden of dengue. Nature. 2013, 496 (7446): 504-507. 10.1038/nature12060.CrossRefPubMedPubMedCentral
3.
go back to reference WHO: Comprehensive guidelines for prevention and control of dengue fever and dengue haemorrhagic fever. In Geneva, Switzerland: World Health Organization; 2011. WHO: Comprehensive guidelines for prevention and control of dengue fever and dengue haemorrhagic fever. In Geneva, Switzerland: World Health Organization; 2011.
4.
go back to reference Malavige GN, Ogg GS: T cell responses in dengue viral infections. J Clin Virol. 2013, 58 (4): 605-611. 10.1016/j.jcv.2013.10.023.CrossRefPubMed Malavige GN, Ogg GS: T cell responses in dengue viral infections. J Clin Virol. 2013, 58 (4): 605-611. 10.1016/j.jcv.2013.10.023.CrossRefPubMed
5.
go back to reference Ong A, Sandar M, Chen MI, Sin LY: Fatal dengue hemorrhagic fever in adults during a dengue epidemic in Singapore. Int J Infect Dis. 2007, 11 (3): 263-267. 10.1016/j.ijid.2006.02.012.CrossRefPubMed Ong A, Sandar M, Chen MI, Sin LY: Fatal dengue hemorrhagic fever in adults during a dengue epidemic in Singapore. Int J Infect Dis. 2007, 11 (3): 263-267. 10.1016/j.ijid.2006.02.012.CrossRefPubMed
6.
go back to reference Macedo GA, Gonin ML, Pone SM, Cruz OG, Nobre FF, Brasil P: Sensitivity and specificity of the world health organization dengue classification schemes for severe dengue assessment in children in rio de janeiro. PLoS One. 2014, 9 (4): e96314-10.1371/journal.pone.0096314.CrossRefPubMedPubMedCentral Macedo GA, Gonin ML, Pone SM, Cruz OG, Nobre FF, Brasil P: Sensitivity and specificity of the world health organization dengue classification schemes for severe dengue assessment in children in rio de janeiro. PLoS One. 2014, 9 (4): e96314-10.1371/journal.pone.0096314.CrossRefPubMedPubMedCentral
7.
go back to reference Cavalcanti LP, Coelho IC, Vilar DC, Holanda SG, Escossia KN, Souza-Santos R: Clinical and epidemiological characterization of dengue hemorrhagic fever cases in northeastern, Brazil. Rev Soc Bras Med Trop. 2010, 43 (4): 355-358. 10.1590/S0037-86822010000400003.CrossRefPubMed Cavalcanti LP, Coelho IC, Vilar DC, Holanda SG, Escossia KN, Souza-Santos R: Clinical and epidemiological characterization of dengue hemorrhagic fever cases in northeastern, Brazil. Rev Soc Bras Med Trop. 2010, 43 (4): 355-358. 10.1590/S0037-86822010000400003.CrossRefPubMed
8.
go back to reference Leo YS, Thein TL, Fisher DA, Low JG, Oh HM, Narayanan RL, Gan VC, Lee VJ, Lye DC: Confirmed adult dengue deaths in Singapore: 5-year multi-center retrospective study. BMC Infect Dis. 2011, 11: 123-10.1186/1471-2334-11-123.CrossRefPubMedPubMedCentral Leo YS, Thein TL, Fisher DA, Low JG, Oh HM, Narayanan RL, Gan VC, Lee VJ, Lye DC: Confirmed adult dengue deaths in Singapore: 5-year multi-center retrospective study. BMC Infect Dis. 2011, 11: 123-10.1186/1471-2334-11-123.CrossRefPubMedPubMedCentral
9.
go back to reference Magpusao NS, Monteclar A, Deen JL: Slow improvement of clinically-diagnosed dengue haemorrhagic fever case fatality rates. Trop Doct. 2003, 33 (3): 156-159.PubMed Magpusao NS, Monteclar A, Deen JL: Slow improvement of clinically-diagnosed dengue haemorrhagic fever case fatality rates. Trop Doct. 2003, 33 (3): 156-159.PubMed
10.
go back to reference Costa VG, Marques-Silva AC, Moreli ML: A meta-analysis of the diagnostic accuracy of two commercial NS1 antigen ELISA tests for early dengue virus detection. PLoS One. 2014, 9 (4): e94655-10.1371/journal.pone.0094655.CrossRefPubMedPubMedCentral Costa VG, Marques-Silva AC, Moreli ML: A meta-analysis of the diagnostic accuracy of two commercial NS1 antigen ELISA tests for early dengue virus detection. PLoS One. 2014, 9 (4): e94655-10.1371/journal.pone.0094655.CrossRefPubMedPubMedCentral
11.
go back to reference Dussart P, Petit L, Labeau B, Bremand L, Leduc A, Moua D, Matheus S, Baril L: Evaluation of two new commercial tests for the diagnosis of acute dengue virus infection using NS1 antigen detection in human serum. PLoS Negl Trop Dis. 2008, 2 (8): e280-10.1371/journal.pntd.0000280.CrossRefPubMedPubMedCentral Dussart P, Petit L, Labeau B, Bremand L, Leduc A, Moua D, Matheus S, Baril L: Evaluation of two new commercial tests for the diagnosis of acute dengue virus infection using NS1 antigen detection in human serum. PLoS Negl Trop Dis. 2008, 2 (8): e280-10.1371/journal.pntd.0000280.CrossRefPubMedPubMedCentral
12.
go back to reference McBride WJ: Evaluation of dengue NS1 test kits for the diagnosis of dengue fever. Diagn Microbiol Infect Dis. 2009, 64 (1): 31-36. 10.1016/j.diagmicrobio.2009.01.002.CrossRefPubMed McBride WJ: Evaluation of dengue NS1 test kits for the diagnosis of dengue fever. Diagn Microbiol Infect Dis. 2009, 64 (1): 31-36. 10.1016/j.diagmicrobio.2009.01.002.CrossRefPubMed
13.
go back to reference Stephen S, Charles MV, Anitharaj V, Deepa C, Umadevi S: Early dengue diagnosis by nonstructural protein 1 antigen detection: Rapid immunochromotography versus two the enzyme-linked immunosorbent assay kits. Indian J Pathol Microbiol. 2014, 57 (1): 81-84. 10.4103/0377-4929.130905.CrossRefPubMed Stephen S, Charles MV, Anitharaj V, Deepa C, Umadevi S: Early dengue diagnosis by nonstructural protein 1 antigen detection: Rapid immunochromotography versus two the enzyme-linked immunosorbent assay kits. Indian J Pathol Microbiol. 2014, 57 (1): 81-84. 10.4103/0377-4929.130905.CrossRefPubMed
14.
go back to reference Gan VC, Tan LK, Lye DC, Pok KY, Mok SQ, Chua RC, Leo YS, Ng LC: Diagnosing dengue at the point-of-care: utility of a rapid combined diagnostic kit in Singapore. PLoS One. 2014, 9 (3): e90037-10.1371/journal.pone.0090037.CrossRefPubMedPubMedCentral Gan VC, Tan LK, Lye DC, Pok KY, Mok SQ, Chua RC, Leo YS, Ng LC: Diagnosing dengue at the point-of-care: utility of a rapid combined diagnostic kit in Singapore. PLoS One. 2014, 9 (3): e90037-10.1371/journal.pone.0090037.CrossRefPubMedPubMedCentral
15.
go back to reference Libraty DH, Young PR, Pickering D, Endy TP, Kalayanarooj S, Green S, Vaughn DW, Nisalak A, Ennis FA, Rothman AL: High circulating levels of the dengue virus nonstructural protein NS1 early in dengue illness correlate with the development of dengue hemorrhagic fever. J Infect Dis. 2002, 186 (8): 1165-1168. 10.1086/343813.CrossRefPubMed Libraty DH, Young PR, Pickering D, Endy TP, Kalayanarooj S, Green S, Vaughn DW, Nisalak A, Ennis FA, Rothman AL: High circulating levels of the dengue virus nonstructural protein NS1 early in dengue illness correlate with the development of dengue hemorrhagic fever. J Infect Dis. 2002, 186 (8): 1165-1168. 10.1086/343813.CrossRefPubMed
16.
go back to reference Malavige GN, Gomes L, Alles L, Chang T, Salimi M, Fernando S, Nanayakkara KD, Jayaratne S, Ogg GS: Serum IL-10 as a marker of severe dengue infection. BMC Infect Dis. 2013, 13 (1): 341-10.1186/1471-2334-13-341.CrossRefPubMedPubMedCentral Malavige GN, Gomes L, Alles L, Chang T, Salimi M, Fernando S, Nanayakkara KD, Jayaratne S, Ogg GS: Serum IL-10 as a marker of severe dengue infection. BMC Infect Dis. 2013, 13 (1): 341-10.1186/1471-2334-13-341.CrossRefPubMedPubMedCentral
17.
go back to reference WHO: Dengue guidelines for diagnosis, prevention and control. In Southeast Asian Office of the WHO: World Health Organisation; 2009. WHO: Dengue guidelines for diagnosis, prevention and control. In Southeast Asian Office of the WHO: World Health Organisation; 2009.
18.
go back to reference Jayaratne S, Atukorale V, Gomes L, Chang T, Wijesinghe T, Fernando S, Ogg GS, Malavige GN: Evaluation of the WHO revised criteria for classification of clinical disease severity in acute adult dengue infection. BMC Res Notes. 2012, 5: 645-10.1186/1756-0500-5-645.CrossRefPubMedPubMedCentral Jayaratne S, Atukorale V, Gomes L, Chang T, Wijesinghe T, Fernando S, Ogg GS, Malavige GN: Evaluation of the WHO revised criteria for classification of clinical disease severity in acute adult dengue infection. BMC Res Notes. 2012, 5: 645-10.1186/1756-0500-5-645.CrossRefPubMedPubMedCentral
19.
go back to reference Gupta V, Yadav TP, Pandey RM, Singh A, Gupta M, Kanaujiya P, Sharma A, Dewan V: Risk factors of dengue shock syndrome in children. J Trop Pediatr. 2011, 57 (6): 451-456. 10.1093/tropej/fmr020.CrossRefPubMed Gupta V, Yadav TP, Pandey RM, Singh A, Gupta M, Kanaujiya P, Sharma A, Dewan V: Risk factors of dengue shock syndrome in children. J Trop Pediatr. 2011, 57 (6): 451-456. 10.1093/tropej/fmr020.CrossRefPubMed
20.
go back to reference Malavige GN, Huang LC, Salimi M, Gomes L, Jayaratne SD, Ogg GS: Cellular and cytokine correlates of severe dengue infection. PLoS One. 2012, 7 (11): e50387-10.1371/journal.pone.0050387.CrossRefPubMedPubMedCentral Malavige GN, Huang LC, Salimi M, Gomes L, Jayaratne SD, Ogg GS: Cellular and cytokine correlates of severe dengue infection. PLoS One. 2012, 7 (11): e50387-10.1371/journal.pone.0050387.CrossRefPubMedPubMedCentral
21.
go back to reference Lee LK, Gan VC, Lee VJ, Tan AS, Leo YS, Lye DC: Clinical relevance and discriminatory value of elevated liver aminotransferase levels for dengue severity. PLoS Negl Trop Dis. 2012, 6 (6): e1676-10.1371/journal.pntd.0001676.CrossRefPubMedPubMedCentral Lee LK, Gan VC, Lee VJ, Tan AS, Leo YS, Lye DC: Clinical relevance and discriminatory value of elevated liver aminotransferase levels for dengue severity. PLoS Negl Trop Dis. 2012, 6 (6): e1676-10.1371/journal.pntd.0001676.CrossRefPubMedPubMedCentral
22.
go back to reference Diaz-Quijano FA, Villar-Centeno LA, Martinez-Vega RA: Predictors of spontaneous bleeding in patients with acute febrile syndrome from a dengue endemic area. J Clin Virol. 2010, 49 (1): 11-15. 10.1016/j.jcv.2010.06.011.CrossRefPubMed Diaz-Quijano FA, Villar-Centeno LA, Martinez-Vega RA: Predictors of spontaneous bleeding in patients with acute febrile syndrome from a dengue endemic area. J Clin Virol. 2010, 49 (1): 11-15. 10.1016/j.jcv.2010.06.011.CrossRefPubMed
23.
go back to reference Thomas L, Brouste Y, Najioullah F, Hochedez P, Hatchuel Y, Moravie V, Kaidomar S, Besnier F, Abel S, Rosine J, Quenel P, Cesaire R, Cabie A: Predictors of severe manifestations in a cohort of adult dengue patients. J Clin Virol. 2010, 48 (2): 96-99. 10.1016/j.jcv.2010.03.008.CrossRefPubMed Thomas L, Brouste Y, Najioullah F, Hochedez P, Hatchuel Y, Moravie V, Kaidomar S, Besnier F, Abel S, Rosine J, Quenel P, Cesaire R, Cabie A: Predictors of severe manifestations in a cohort of adult dengue patients. J Clin Virol. 2010, 48 (2): 96-99. 10.1016/j.jcv.2010.03.008.CrossRefPubMed
24.
go back to reference Srikiatkhachorn A, Green S: Markers of dengue disease severity. Curr Top Microbiol Immunol. 2010, 338: 67-82.PubMed Srikiatkhachorn A, Green S: Markers of dengue disease severity. Curr Top Microbiol Immunol. 2010, 338: 67-82.PubMed
25.
go back to reference Ju H, Brasier AR: Variable selection methods for developing a biomarker panel for prediction of dengue hemorrhagic fever. BMC Res Notes. 2013, 6: 365-10.1186/1756-0500-6-365.CrossRefPubMedPubMedCentral Ju H, Brasier AR: Variable selection methods for developing a biomarker panel for prediction of dengue hemorrhagic fever. BMC Res Notes. 2013, 6: 365-10.1186/1756-0500-6-365.CrossRefPubMedPubMedCentral
26.
go back to reference Duyen HT, Ngoc TV, Ha do T, Hang VT, Kieu NT, Young PR, Farrar JJ, Simmons CP, Wolbers M, Wills BA: Kinetics of plasma viremia and soluble nonstructural protein 1 concentrations in dengue: differential effects according to serotype and immune status. J Infect Dis. 2011, 203 (9): 1292-1300. 10.1093/infdis/jir014.CrossRefPubMedPubMedCentral Duyen HT, Ngoc TV, Ha do T, Hang VT, Kieu NT, Young PR, Farrar JJ, Simmons CP, Wolbers M, Wills BA: Kinetics of plasma viremia and soluble nonstructural protein 1 concentrations in dengue: differential effects according to serotype and immune status. J Infect Dis. 2011, 203 (9): 1292-1300. 10.1093/infdis/jir014.CrossRefPubMedPubMedCentral
27.
go back to reference Perez AB, Garcia G, Sierra B, Alvarez M, Vazquez S, Cabrera MV, Rodriguez R, Rosario D, Martinez E, Denny T, Guzman MG: IL-10 levels in dengue patients: some findings from the exceptional epidemiological conditions in Cuba. J Med Virol. 2004, 73 (2): 230-234. 10.1002/jmv.20080.CrossRefPubMed Perez AB, Garcia G, Sierra B, Alvarez M, Vazquez S, Cabrera MV, Rodriguez R, Rosario D, Martinez E, Denny T, Guzman MG: IL-10 levels in dengue patients: some findings from the exceptional epidemiological conditions in Cuba. J Med Virol. 2004, 73 (2): 230-234. 10.1002/jmv.20080.CrossRefPubMed
28.
go back to reference Chen LC, Lei HY, Liu CC, Shiesh SC, Chen SH, Liu HS, Lin YS, Wang ST, Shyu HW, Yeh TM: Correlation of serum levels of macrophage migration inhibitory factor with disease severity and clinical outcome in dengue patients. Am J Trop Med Hyg. 2006, 74 (1): 142-147.PubMed Chen LC, Lei HY, Liu CC, Shiesh SC, Chen SH, Liu HS, Lin YS, Wang ST, Shyu HW, Yeh TM: Correlation of serum levels of macrophage migration inhibitory factor with disease severity and clinical outcome in dengue patients. Am J Trop Med Hyg. 2006, 74 (1): 142-147.PubMed
29.
go back to reference Binh PT, Matheus S, Huong VT, Deparis X, Marechal V: Early clinical and biological features of severe clinical manifestations of dengue in Vietnamese adults. J Clin Virol. 2009, 45 (4): 276-280. 10.1016/j.jcv.2009.04.004.CrossRefPubMed Binh PT, Matheus S, Huong VT, Deparis X, Marechal V: Early clinical and biological features of severe clinical manifestations of dengue in Vietnamese adults. J Clin Virol. 2009, 45 (4): 276-280. 10.1016/j.jcv.2009.04.004.CrossRefPubMed
30.
go back to reference Jaiyen Y, Masrinoul P, Kalayanarooj S, Pulmanausahakul R, Ubol S: Characteristics of dengue virus-infected peripheral blood mononuclear cell death that correlates with the severity of illness. Microbiol Immunol. 2009, 53 (8): 442-450. 10.1111/j.1348-0421.2009.00148.x.CrossRefPubMed Jaiyen Y, Masrinoul P, Kalayanarooj S, Pulmanausahakul R, Ubol S: Characteristics of dengue virus-infected peripheral blood mononuclear cell death that correlates with the severity of illness. Microbiol Immunol. 2009, 53 (8): 442-450. 10.1111/j.1348-0421.2009.00148.x.CrossRefPubMed
31.
go back to reference Mongkolsapaya J, Dejnirattisai W, Xu XN, Vasanawathana S, Tangthawornchaikul N, Chairunsri A, Sawasdivorn S, Duangchinda T, Dong T, Rowland-Jones S, Yenchitsomanus PT, McMichael A, Malasit P, Screaton G: Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nat Med. 2003, 9 (7): 921-927. 10.1038/nm887.CrossRefPubMed Mongkolsapaya J, Dejnirattisai W, Xu XN, Vasanawathana S, Tangthawornchaikul N, Chairunsri A, Sawasdivorn S, Duangchinda T, Dong T, Rowland-Jones S, Yenchitsomanus PT, McMichael A, Malasit P, Screaton G: Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nat Med. 2003, 9 (7): 921-927. 10.1038/nm887.CrossRefPubMed
32.
go back to reference Malavige GN, Jeewandara C, Alles KM, Salimi M, Gomes L, Kamaladasa A, Jayaratne SD, Ogg GS: Suppression of virus specific immune responses by IL-10 in acute dengue infection. PLoS Negl Trop Dis. 2013, 7 (9): e2409-10.1371/journal.pntd.0002409.CrossRefPubMedPubMedCentral Malavige GN, Jeewandara C, Alles KM, Salimi M, Gomes L, Kamaladasa A, Jayaratne SD, Ogg GS: Suppression of virus specific immune responses by IL-10 in acute dengue infection. PLoS Negl Trop Dis. 2013, 7 (9): e2409-10.1371/journal.pntd.0002409.CrossRefPubMedPubMedCentral
33.
go back to reference Mongkolsapaya J, Duangchinda T, Dejnirattisai W, Vasanawathana S, Avirutnan P, Jairungsri A, Khemnu N, Tangthawornchaikul N, Chotiyarnwong P, Sae-Jang K, Koch M, Jones Y, McMichael A, Xu X, Malasit P, Screaton G: T cell responses in dengue hemorrhagic fever: are cross-reactive T cells suboptimal?. J Immunol. 2006, 176 (6): 3821-3829. 10.4049/jimmunol.176.6.3821.CrossRefPubMed Mongkolsapaya J, Duangchinda T, Dejnirattisai W, Vasanawathana S, Avirutnan P, Jairungsri A, Khemnu N, Tangthawornchaikul N, Chotiyarnwong P, Sae-Jang K, Koch M, Jones Y, McMichael A, Xu X, Malasit P, Screaton G: T cell responses in dengue hemorrhagic fever: are cross-reactive T cells suboptimal?. J Immunol. 2006, 176 (6): 3821-3829. 10.4049/jimmunol.176.6.3821.CrossRefPubMed
Metadata
Title
Dengue NS1 antigen as a marker of severe clinical disease
Authors
Shiran Ajith Paranavitane
Laksiri Gomes
Achala Kamaladasa
Thiruni N Adikari
Nilanka Wickramasinghe
Chandima Jeewandara
Narangoda Liyanage Ajantha Shyamali
Graham Stuart Ogg
Gathsaurie Neelika Malavige
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Infectious Diseases / Issue 1/2014
Electronic ISSN: 1471-2334
DOI
https://doi.org/10.1186/s12879-014-0570-8

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