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Multicenter Study
. 2021 Jun 22:10:e67460.
doi: 10.7554/eLife.67460.

Combination of inflammatory and vascular markers in the febrile phase of dengue is associated with more severe outcomes

Nguyen Lam Vuong  1   2 , Phung Khanh Lam  1   2 , Damien Keng Yen Ming  3 , Huynh Thi Le Duyen  1 , Nguyet Minh Nguyen  1 , Dong Thi Hoai Tam  1 , Kien Duong Thi Hue  1 , Nguyen Vv Chau  4 , Ngoun Chanpheaktra  5 , Lucy Chai See Lum  6 , Ernesto Pleités  7 , Cameron P Simmons  8   9 , Kerstin D Rosenberger  10 , Thomas Jaenisch  10   11 , David Bell  12 , Nathalie Acestor  13 , Christine Halleux  14 , Piero L Olliaro  8 , Bridget A Wills  1   8 , Ronald B Geskus  1   8 , Sophie Yacoub  1   8
Affiliations
Multicenter Study

Combination of inflammatory and vascular markers in the febrile phase of dengue is associated with more severe outcomes

Nguyen Lam Vuong et al. Elife. .

Abstract

Background: Early identification of severe dengue patients is important regarding patient management and resource allocation. We investigated the association of 10 biomarkers (VCAM-1, SDC-1, Ang-2, IL-8, IP-10, IL-1RA, sCD163, sTREM-1, ferritin, CRP) with the development of severe/moderate dengue (S/MD).

Methods: We performed a nested case-control study from a multi-country study. A total of 281 S/MD and 556 uncomplicated dengue cases were included.

Results: On days 1-3 from symptom onset, higher levels of any biomarker increased the risk of developing S/MD. When assessing together, SDC-1 and IL-1RA were stable, while IP-10 changed the association from positive to negative; others showed weaker associations. The best combinations associated with S/MD comprised IL-1RA, Ang-2, IL-8, ferritin, IP-10, and SDC-1 for children, and SDC-1, IL-8, ferritin, sTREM-1, IL-1RA, IP-10, and sCD163 for adults.

Conclusions: Our findings assist the development of biomarker panels for clinical use and could improve triage and risk prediction in dengue patients.

Funding: This study was supported by the EU's Seventh Framework Programme (FP7-281803 IDAMS), the WHO, and the Bill and Melinda Gates Foundation.

Keywords: biomarkers; dengue; infectious disease; medicine; microbiology; prognostic; virus.

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Conflict of interest statement

NV, PL, HD, NN, DT, KD, NC, NC, EP, CS, KR, DB, NA, CH, PO No competing interests declared, DM reports receiving personal fees from the Wellcome Trust (grant number 215010/Z/18/Z), during the conduct of the study. LL reports receiving personal fees from ROCHE Advisory Board on Severe Dengue. TJ reports receiving personal fees as members of the ROCHE Advisory Board on Severe Dengue, outside the submitted work. BW reports personal fees as a member of the Data Monitoring and Adjudication Committees for the Takeda dengue vaccine trials and as a member of the ROCHE Advisory Board on Severe Dengue, outside the submitted work. RG reports receiving personal fees from the Wellcome Trust (grant number 106680/Z/14/Z), during the conduct of the study. SY reports receiving personal fees as a member of the ROCHE Advisory Board on Severe Dengue, for work on Janssen Pharmaceuticals Advisory Board for Dengue Antiviral Development, and from the Wellcome Trust (grant number 106680/Z/14/Z).

Figures

Figure 1.
Figure 1.. Study flowchart.
*The IDAMS study was performed in eight countries across Asia and Latin America. For this study, we selected cases in four countries (Vietnam, Cambodia, Malaysia, and El Salvador) as the blood samples were stored at the laboratory of the Oxford University Clinical Research Unit in Ho Chi Minh City, Vietnam.
Figure 2.
Figure 2.. Biomarker levels by groups.
VCAM-1: vascular cell adhesion molecule-1; SDC-1: syndecan-1; Ang-2: angiopoietin-2; IL-8: interleukin-8; IP-10: interferon gamma-induced protein-10; IL-1RA: interleukin-1 receptor antagonist; sCD163: soluble cluster of differentiation 163; sTREM-1: soluble triggering receptor expressed on myeloid cells-1; CRP: C-reactive protein. Y-axes are transformed using the fourth root transformation.
Figure 3.
Figure 3.. Results from models for the primary endpoint (severe or moderate dengue).
The odds ratio of severe/moderate dengue (the red and blue lines) and 95% confidence interval (the red and blue regions) are estimated from multivariable logistic regression models allowing for a non-linear relation of log-2 of the biomarker level with severe/moderate dengue using restricted cubic splines. Each single model contains the corresponding biomarker, age and their interaction, while the global model contains all biomarkers and their interaction with age. The reference values for the odds ratios (where the odds ratio is equal to 1) are represented by the vertical gray dashed lines. They are chosen as the median of the biomarker levels of the whole study population (VCAM-1: 1636 ng/ml; SDC-1: 2519 pg/ml; Ang-2: 1204 pg/ml; IL-8: 14 pg/ml; IP-10: 3093 pg/ml; IL-1RA: 6434 pg/ml; sCD163: 295 ng/ml; sTREM-1: 85 ng/ml; ferritin: 243 ng/ml; and CRP: 28 mg/l). The x-axis represents biomarker levels; it is transformed using log-2 and its range truncated by the 5th and 95th percentiles of the biomarker levels of the whole study population. The rug plot on the x-axis represents the distribution of individual cases; the bottom rug plot represents the uncomplicated dengue cases and the top rug plot represents the severe/moderate dengue cases (children [<15 years of age] are in red and adults [≥15 years of age] are in blue). The red line and region represent children; results are shown for children at age of 10 years. The blue line and region represents adults; results are shown for adults at age of 25 years. VCAM-1: vascular cell adhesion molecule-1; SDC-1: syndecan-1; Ang-2: angiopoietin-2; IL-8: interleukin-8; IP-10: interferon gamma-induced protein-10; IL-1RA: interleukin-1 receptor antagonist; sCD163: soluble cluster of differentiation 163; sTREM-1: soluble triggering receptor expressed on myeloid cells-1; CRP: C-reactive protein.
Appendix 4—figure 1.
Appendix 4—figure 1.. Biomarker levels by individual.
Y-axes are transformed using the fourth root transformation.
Appendix 4—figure 2.
Appendix 4—figure 2.. Pairwise correlation of biomarker levels at enrollment and age.
Viremia levels are transformed using log-10. All other biomarker levels are transformed using log-2. The number inside each scatter plot represents the Spearman’s rank correlation coefficient of the two variables at the corresponding column and row. When the column and row refer to the same variable, the corresponding scatter plot is replaced by a density plot to reflect the distribution of that biomarker. VCAM-1: vascular cell adhesion molecule-1; SDC-1: syndecan-1; Ang-2: angiopoietin-2; IL-8: interleukin-8; IP-10: interferon gamma-induced protein-10; IL-1RA: interleukin-1 receptor antagonist; sCD163: soluble cluster of differentiation 163; sTREM-1: soluble triggering receptor expressed on myeloid cells-1; CRP: C-reactive protein.
Appendix 5—figure 1.
Appendix 5—figure 1.. Results from single models for severe/moderate dengue with the interaction with serotype.
Appendix 5—figure 2.
Appendix 5—figure 2.. Results from global model for severe/moderate dengue with the interaction with serotype.
Appendix 6—figure 1.
Appendix 6—figure 1.. Results from models for severe dengue endpoint.
Appendix 6—figure 2.
Appendix 6—figure 2.. Results from models for severe dengue or dengue with warning signs endpoint.
Appendix 6—figure 3.
Appendix 6—figure 3.. Results from models for hospitalization endpoint.
Appendix 8—figure 1.
Appendix 8—figure 1.. Results from models for severe/moderate dengue including viremia as a potential biomarker.
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