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Methods to discriminate primary from secondary dengue during acute symptomatic infection.
BMC Infect Dis. 2018 08 07; 18(1):375.BI

Abstract

BACKGROUND

Dengue virus infection results in a broad spectrum of clinical outcomes, ranging from asymptomatic infection through to severe dengue. Although prior infection with another viral serotype, i.e. secondary dengue, is known to be an important factor influencing disease severity, current methods to determine primary versus secondary immune status during the acute illness do not consider the rapidly evolving immune response, and their accuracy has rarely been evaluated against an independent gold standard.

METHODS

Two hundred and ninety-three confirmed dengue patients were classified as experiencing primary, secondary or indeterminate infections using plaque reduction neutralisation tests performed 6 months after resolution of the acute illness. We developed and validated regression models to differentiate primary from secondary dengue on multiple acute illness days, using Panbio Indirect IgG and in-house capture IgG and IgM ELISA measurements performed on over 1000 serial samples obtained during acute illness.

RESULTS

Cut-offs derived for the various parameters demonstrated progressive change (positively or negatively) by day of illness. Using these time varying cut-offs it was possible to determine whether an infection was primary or secondary on single specimens, with acceptable performance. The model using Panbio Indirect IgG responses and including an interaction with illness day showed the best performance throughout, although with some decline in performance later in infection. Models based on in-house capture IgG levels, and the IgM/IgG ratio, also performed well, though conversely performance improved later in infection.

CONCLUSIONS

For all assays, the best fitting models estimated a different cut-off value for different days of illness, confirming how rapidly the immune response changes during acute dengue. The optimal choice of assay will vary depending on circumstance. Although the Panbio Indirect IgG model performs best early on, the IgM/IgG capture ratio may be preferred later in the illness course.

Authors+Show Affiliations

Hospital for Tropical Diseases, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.Hospital for Tropical Diseases, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam. hclapham@oucru.org. Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK. hclapham@oucru.org.Hospital for Tropical Diseases, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.Hospital for Tropical Diseases, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.Hospital for Tropical Diseases, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.Hospital for Tropical Diseases, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam.Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, Bethesda, MD, USA.Hospital for Tropical Diseases, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam. Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK. Nossal Institute of Global Health, School of Population and Global Health, University of Melbourne, Parkville, VIC, Australia.Hospital for Tropical Diseases, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam. Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.Hospital for Tropical Diseases, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam. Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Pub Type(s)

Evaluation Study
Journal Article

Language

eng

PubMed ID

30086716

Citation

Nguyen, Thi Hanh Tien, et al. "Methods to Discriminate Primary From Secondary Dengue During Acute Symptomatic Infection." BMC Infectious Diseases, vol. 18, no. 1, 2018, p. 375.
Nguyen THT, Clapham HE, Phung KL, et al. Methods to discriminate primary from secondary dengue during acute symptomatic infection. BMC Infect Dis. 2018;18(1):375.
Nguyen, T. H. T., Clapham, H. E., Phung, K. L., Nguyen, T. K., DInh, T. T., Nguyen, T. H. Q., Tran, V. N., Whitehead, S., Simmons, C., Wolbers, M., & Wills, B. (2018). Methods to discriminate primary from secondary dengue during acute symptomatic infection. BMC Infectious Diseases, 18(1), 375. https://doi.org/10.1186/s12879-018-3274-7
Nguyen THT, et al. Methods to Discriminate Primary From Secondary Dengue During Acute Symptomatic Infection. BMC Infect Dis. 2018 08 7;18(1):375. PubMed PMID: 30086716.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Methods to discriminate primary from secondary dengue during acute symptomatic infection. AU - Nguyen,Thi Hanh Tien, AU - Clapham,Hannah E, AU - Phung,Khanh Lam, AU - Nguyen,Thanh Kieu, AU - DInh,The Trung, AU - Nguyen,Than Ha Quyen, AU - Tran,Van Ngoc, AU - Whitehead,Stephen, AU - Simmons,Cameron, AU - Wolbers,Marcel, AU - Wills,Bridget, Y1 - 2018/08/07/ PY - 2018/01/08/received PY - 2018/07/26/accepted PY - 2018/8/9/entrez PY - 2018/8/9/pubmed PY - 2019/7/10/medline KW - Algorithms KW - Dengue KW - ELISA KW - IgG KW - IgM KW - Immune status SP - 375 EP - 375 JF - BMC infectious diseases JO - BMC Infect Dis VL - 18 IS - 1 N2 - BACKGROUND: Dengue virus infection results in a broad spectrum of clinical outcomes, ranging from asymptomatic infection through to severe dengue. Although prior infection with another viral serotype, i.e. secondary dengue, is known to be an important factor influencing disease severity, current methods to determine primary versus secondary immune status during the acute illness do not consider the rapidly evolving immune response, and their accuracy has rarely been evaluated against an independent gold standard. METHODS: Two hundred and ninety-three confirmed dengue patients were classified as experiencing primary, secondary or indeterminate infections using plaque reduction neutralisation tests performed 6 months after resolution of the acute illness. We developed and validated regression models to differentiate primary from secondary dengue on multiple acute illness days, using Panbio Indirect IgG and in-house capture IgG and IgM ELISA measurements performed on over 1000 serial samples obtained during acute illness. RESULTS: Cut-offs derived for the various parameters demonstrated progressive change (positively or negatively) by day of illness. Using these time varying cut-offs it was possible to determine whether an infection was primary or secondary on single specimens, with acceptable performance. The model using Panbio Indirect IgG responses and including an interaction with illness day showed the best performance throughout, although with some decline in performance later in infection. Models based on in-house capture IgG levels, and the IgM/IgG ratio, also performed well, though conversely performance improved later in infection. CONCLUSIONS: For all assays, the best fitting models estimated a different cut-off value for different days of illness, confirming how rapidly the immune response changes during acute dengue. The optimal choice of assay will vary depending on circumstance. Although the Panbio Indirect IgG model performs best early on, the IgM/IgG capture ratio may be preferred later in the illness course. SN - 1471-2334 UR - https://www.unboundmedicine.com/medline/citation/30086716/Methods_to_discriminate_primary_from_secondary_dengue_during_acute_symptomatic_infection_ L2 - https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-018-3274-7 DB - PRIME DP - Unbound Medicine ER -