International Journal of Infectious Diseases 26 (2014) 57–66
Contents lists available at ScienceDirect
International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
NS1-based tests with diagnostic utility for confirming dengue infection: a meta-analysis Hao Zhang a,b, Wei Li a, Junjie Wang a, Hongjuan Peng b, Xiaoyan Che c, Xiaoguang Chen b,*, Yuanping Zhou a,* a
Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510515, China Key Laboratory of Prevention and Control for Emerging Infectious Diseases of Guangdong Province, School of Public Health and Tropical Medicine, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510515, China c Center for Clinical Laboratory, Zhujiang Hospital, Southern Medical University, Guangzhou, China b
A R T I C L E I N F O
Article history: Received 22 November 2013 Received in revised form 29 January 2014 Accepted 4 February 2014 Corresponding Editor: Eskild Petersen, Aarhus, Denmark Keywords: Dengue NS1 Diagnostic accuracy Sensitivity Specificity
S U M M A R Y
Objectives: Non-structural protein 1 (NS1)-based tests may offer a larger window of opportunity for dengue diagnosis and could constitute a very useful diagnostic tool. The aim of this study was to establish the overall accuracy of NS1-based tests for diagnosing dengue infection. Methods: A meta-analysis was conducted including 18 studies published up to October 1, 2012 identified using PubMed, ISI Web of Science, Google Scholar, and the Chinese National Knowledge Infrastructure (CNKI) database. Results: For the single NS1-based tests – ELISA (Panbio Dengue Early ELISA Kit, Dengue NS1 Ag ELISA Kit, and Platelia Dengue NS1 Ag-ELISA Kit) and immunochromatography (Dengue NS1 Ag STRIP Kit and SD BIOLINE Dengue Duo Strip Kit) – the summarized sensitivities and specificities were 67% (95% confidence interval (CI) 59–74%) and 99% (95% CI 97–99%), and 71% (95% CI 61–79%) and 99% (95% CI 98–100%), respectively. The hierarchical summary receiver operating characteristics (HSROCs) were 0.92 and 0.96, respectively. For NS1 combined with an anti-dengue-specific IgM test, the summarized sensitivity, specificity, and HSROC were 83% (95% CI 68–92%), 86% (95% CI 79–91%), and 0.91 (95% CI 0.89-0.93), respectively. The accuracy for serotypes was 50.0–90.9% for DENV-1, 38.5–85.7% for DENV-2, 46.7–91.3% for DENV-3, and 21.7–87.0% for DENV-4. Conclusions: These results support the use of single NS1-based tests; they have good diagnostic utility for confirming dengue and for distinguishing serotypes DENV-1 and 3 from DENV-2 and 4, while they can be used as a screening tool when combined with an IgM test. Moreover, the Dengue NS1 Ag STRIP Kit appears to be the best for confirming and serotyping dengue infection. ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/3.0/).
1. Introduction Dengue is a vector-borne disease caused by dengue virus (DENV), occurring throughout tropical and subtropical areas. It has become one of the most serious public health problems due to the increasing morbidity.1 The World Health Organization (WHO) 2009 guidelines identify three diagnostic tests as gold standards
E-mail address: [email protected]. * Corresponding authors. Tel.: +86 20 62787425; fax: +86 20 62786530. E-mail addresses: [email protected] (X. Chen), [email protected] (Y. Zhou).
for dengue diagnosis: viral isolation and identification, nucleotide detection, and serological tests for IgM or IgG seroconversion.2 However, these have limitations, such as requests for acute infection (0–5 days post-onset) samples, the time required for viral isolation and identification (more than 1 week), the possibility of false-positive or false-negative final results, and the need for further serum samples to confirm serological tests.3 An affordable, time-saving, and convenient diagnostic test for confirming dengue infection is thus urgently needed. It was recently reported that serum or plasma DENV non-structural protein 1 (NS1) can be detected in the peripheral blood from 9 to 18 days after illness onset.4–7 Thus, the detection of NS1 may offer a larger window of opportunity for dengue diagnosis. NS1-capture
http://dx.doi.org/10.1016/j.ijid.2014.02.002 1201-9712/ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
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H. Zhang et al. / International Journal of Infectious Diseases 26 (2014) 57–66
based detection methods have been evaluated comprehensively. The two main methods for detecting dengue virus infection are currently ELISA (Panbio Dengue Early ELISA Kit, Dengue NS1 Ag ELISA Kit, and Platelia Dengue NS1 Ag-ELISA Kit) and immunochromatography (Dengue NS1 Ag STRIP Kit and SD BIOLINE Dengue Duo Strip Kit). Many of these have shown results comparable to those of the gold standard detection methods (antibody detection, nucleotide detection, or viral identification). We conducted a meta-analysis to comprehensively assess the performance of NS1-based detection in the evaluation of dengue. Through this analysis, we provide evidence of the adequate sensitivities and specificities of NS1-based tests for the diagnosis of dengue in a large population.
2. Materials and methods 2.1. Data sources and searches A search was performed to identify published articles reporting studies of dengue diagnosis methods, including virus isolation and identification, RNA detection, serological tests for IgM or IgG seroconversion, and the NS1-based capture method. NCBI PubMed, ISI Web of Science, Google Scholar, and the Chinese National Knowledge Infrastructure (CNKI) databases were searched for studies published prior to October 1, 2012, using the following search terms: dengue, NS1 or non-structure 1, diagnosis. No language limitation was applied. 2.2. Selection criteria For inclusion, studies had to meet the following criteria: (1) patients or samples with dengue infection confirmed by one of the three standard methods (viral isolation and identification, RNA detection, or serological tests for IgM and/or IgG seroconversion); (2) patients or samples also investigated by NS1-based capture method combined or not with an IgM test; (3) report of the data necessary to calculate the true positive, false positive, true negative, and false negative diagnostic results of NS1 for dengue diagnosis; (4) the inclusion of at least 50 samples from participants and a control group respectively, for good reliability; (5) a Quality Assessment for Diagnostic Accuracy Studies (QUADAS)8 score of
Contents lists available at ScienceDirect
International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
NS1-based tests with diagnostic utility for confirming dengue infection: a meta-analysis Hao Zhang a,b, Wei Li a, Junjie Wang a, Hongjuan Peng b, Xiaoyan Che c, Xiaoguang Chen b,*, Yuanping Zhou a,* a
Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510515, China Key Laboratory of Prevention and Control for Emerging Infectious Diseases of Guangdong Province, School of Public Health and Tropical Medicine, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510515, China c Center for Clinical Laboratory, Zhujiang Hospital, Southern Medical University, Guangzhou, China b
A R T I C L E I N F O
Article history: Received 22 November 2013 Received in revised form 29 January 2014 Accepted 4 February 2014 Corresponding Editor: Eskild Petersen, Aarhus, Denmark Keywords: Dengue NS1 Diagnostic accuracy Sensitivity Specificity
S U M M A R Y
Objectives: Non-structural protein 1 (NS1)-based tests may offer a larger window of opportunity for dengue diagnosis and could constitute a very useful diagnostic tool. The aim of this study was to establish the overall accuracy of NS1-based tests for diagnosing dengue infection. Methods: A meta-analysis was conducted including 18 studies published up to October 1, 2012 identified using PubMed, ISI Web of Science, Google Scholar, and the Chinese National Knowledge Infrastructure (CNKI) database. Results: For the single NS1-based tests – ELISA (Panbio Dengue Early ELISA Kit, Dengue NS1 Ag ELISA Kit, and Platelia Dengue NS1 Ag-ELISA Kit) and immunochromatography (Dengue NS1 Ag STRIP Kit and SD BIOLINE Dengue Duo Strip Kit) – the summarized sensitivities and specificities were 67% (95% confidence interval (CI) 59–74%) and 99% (95% CI 97–99%), and 71% (95% CI 61–79%) and 99% (95% CI 98–100%), respectively. The hierarchical summary receiver operating characteristics (HSROCs) were 0.92 and 0.96, respectively. For NS1 combined with an anti-dengue-specific IgM test, the summarized sensitivity, specificity, and HSROC were 83% (95% CI 68–92%), 86% (95% CI 79–91%), and 0.91 (95% CI 0.89-0.93), respectively. The accuracy for serotypes was 50.0–90.9% for DENV-1, 38.5–85.7% for DENV-2, 46.7–91.3% for DENV-3, and 21.7–87.0% for DENV-4. Conclusions: These results support the use of single NS1-based tests; they have good diagnostic utility for confirming dengue and for distinguishing serotypes DENV-1 and 3 from DENV-2 and 4, while they can be used as a screening tool when combined with an IgM test. Moreover, the Dengue NS1 Ag STRIP Kit appears to be the best for confirming and serotyping dengue infection. ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/3.0/).
1. Introduction Dengue is a vector-borne disease caused by dengue virus (DENV), occurring throughout tropical and subtropical areas. It has become one of the most serious public health problems due to the increasing morbidity.1 The World Health Organization (WHO) 2009 guidelines identify three diagnostic tests as gold standards
E-mail address: [email protected]. * Corresponding authors. Tel.: +86 20 62787425; fax: +86 20 62786530. E-mail addresses: [email protected] (X. Chen), [email protected] (Y. Zhou).
for dengue diagnosis: viral isolation and identification, nucleotide detection, and serological tests for IgM or IgG seroconversion.2 However, these have limitations, such as requests for acute infection (0–5 days post-onset) samples, the time required for viral isolation and identification (more than 1 week), the possibility of false-positive or false-negative final results, and the need for further serum samples to confirm serological tests.3 An affordable, time-saving, and convenient diagnostic test for confirming dengue infection is thus urgently needed. It was recently reported that serum or plasma DENV non-structural protein 1 (NS1) can be detected in the peripheral blood from 9 to 18 days after illness onset.4–7 Thus, the detection of NS1 may offer a larger window of opportunity for dengue diagnosis. NS1-capture
http://dx.doi.org/10.1016/j.ijid.2014.02.002 1201-9712/ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
58
H. Zhang et al. / International Journal of Infectious Diseases 26 (2014) 57–66
based detection methods have been evaluated comprehensively. The two main methods for detecting dengue virus infection are currently ELISA (Panbio Dengue Early ELISA Kit, Dengue NS1 Ag ELISA Kit, and Platelia Dengue NS1 Ag-ELISA Kit) and immunochromatography (Dengue NS1 Ag STRIP Kit and SD BIOLINE Dengue Duo Strip Kit). Many of these have shown results comparable to those of the gold standard detection methods (antibody detection, nucleotide detection, or viral identification). We conducted a meta-analysis to comprehensively assess the performance of NS1-based detection in the evaluation of dengue. Through this analysis, we provide evidence of the adequate sensitivities and specificities of NS1-based tests for the diagnosis of dengue in a large population.
2. Materials and methods 2.1. Data sources and searches A search was performed to identify published articles reporting studies of dengue diagnosis methods, including virus isolation and identification, RNA detection, serological tests for IgM or IgG seroconversion, and the NS1-based capture method. NCBI PubMed, ISI Web of Science, Google Scholar, and the Chinese National Knowledge Infrastructure (CNKI) databases were searched for studies published prior to October 1, 2012, using the following search terms: dengue, NS1 or non-structure 1, diagnosis. No language limitation was applied. 2.2. Selection criteria For inclusion, studies had to meet the following criteria: (1) patients or samples with dengue infection confirmed by one of the three standard methods (viral isolation and identification, RNA detection, or serological tests for IgM and/or IgG seroconversion); (2) patients or samples also investigated by NS1-based capture method combined or not with an IgM test; (3) report of the data necessary to calculate the true positive, false positive, true negative, and false negative diagnostic results of NS1 for dengue diagnosis; (4) the inclusion of at least 50 samples from participants and a control group respectively, for good reliability; (5) a Quality Assessment for Diagnostic Accuracy Studies (QUADAS)8 score of
