1. Medicine
  2. Microbiology and Infectious Disease
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Combination of inflammatory and vascular markers in the febrile phase of dengue is associated with more severe outcomes

  1. Nguyen Lam Vuong  Is a corresponding author
  2. Phung Khanh Lam
  3. Damien Keng Yen Ming
  4. Huynh Thi Le Duyen
  5. Nguyet Minh Nguyen
  6. Dong Thi Hoai Tam
  7. Kien Duong Thi Hue
  8. Nguyen VV Chau
  9. Ngoun Chanpheaktra
  10. Lucy Chai See Lum
  11. Ernesto Pleités
  12. Cameron P Simmons
  13. Kerstin D Rosenberger
  14. Thomas Jaenisch
  15. David Bell
  16. Nathalie Acestor
  17. Christine Halleux
  18. Piero L Olliaro
  19. Bridget A Wills
  20. Ronald B Geskus
  21. Sophie Yacoub  Is a corresponding author
  1. Oxford University Clinical Research Unit (OUCRU), Viet Nam
  2. University of Medicine and Pharmacy at Ho Chi Minh City, Viet Nam
  3. Department of Infectious Disease, Imperial College London, United Kingdom
  4. Hospital for Tropical Diseases, Viet Nam
  5. Angkor Hospital for Children, Cambodia
  6. University of Malaya Medical Centre, Malaysia
  7. Hospital Nacional de Niños Benjamin Bloom, El Salvador
  8. Centre for Tropical Medicine and Global health, Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom
  9. Institute for Vector-Borne Disease, Monash University, Australia
  10. Section Clinical Tropical Medicine, Department for Infectious Diseases, Heidelberg University Hospital, Germany
  11. Heidelberg Institute of Global Health (HIGH), Heidelberg University Hospital, Germany
  12. Independent consultant, United States
  13. Consultant, Intellectual Ventures, Global Good Fund, United States
  14. UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases, World Health Organization, Switzerland
Research Article
Cite this article as: eLife 2021;10:e67460 doi: 10.7554/eLife.67460
11 figures, 21 tables and 1 additional file

Figures

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.

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.

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
Biomarker levels by individual.

Y-axes are transformed using the fourth root transformation.

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
Results from single models for severe/moderate dengue with the interaction with serotype.
Appendix 5—figure 2
Results from global model for severe/moderate dengue with the interaction with serotype.
Appendix 6—figure 1
Results from models for severe dengue endpoint.
Appendix 6—figure 2
Results from models for severe dengue or dengue with warning signs endpoint.
Appendix 6—figure 3
Results from models for hospitalization endpoint.
Appendix 8—figure 1
Results from models for severe/moderate dengue including viremia as a potential biomarker.

Tables

Table 1
Summary of clinical data by primary outcome.
All patientsChildrenAdults
Uncomplicated dengue
(N = 556)
Severe/moderate dengue
(N = 281)
Uncomplicated dengue
(N = 337)
Severe/moderate dengue
(N = 127)
Uncomplicated dengue
(N = 219)
Severe/moderate dengue
(N = 154)
Country, n (%)
- Cambodia39 (7)30 (11)37 (11)29 (23)2 (1)1 (1)
- El Salvador23 (4)18 (6)23 (7)18 (14)0 (0)0 (0)
- Malaysia58 (10)29 (10)3 (1)1 (1)55 (25)28 (18)
- Vietnam436 (78)204 (73)274 (81)79 (62)162 (74)125 (81)
Age (years), median (1st, 3rd quartiles)12 (9, 22)16 (10, 24)10 (8, 12)10 (7, 12)26 (20, 34)22 (18, 30)
Gender male, n (%)299 (54)170 (60)173 (51)80 (63)126 (58)90 (58)
Illness day at enrolment, n (%)
- 191 (16)49 (17)57 (17)25 (20)34 (16)24 (16)
- 2260 (47)130 (46)156 (46)52 (41)104 (47)78 (51)
- 3205 (37)102 (36)124 (37)50 (39)81 (37)52 (34)
Serotype, n (%)
- DENV-1228 (41)121 (43)161 (48)61 (48)67 (31)60 (39)
- DENV-274 (13)47 (17)22 (7)16 (13)52 (24)31 (20)
- DENV-359 (11)29 (10)43 (13)18 (14)16 (7)11 (7)
- DENV-4161 (29)70 (25)91 (27)26 (20)70 (32)44 (29)
- Unknown34 (6)14 (5)20 (6)6 (5)14 (6)8 (5)
Immune status, n (%)
- Probable primary124 (22)41 (15)86 (26)15 (12)38 (17)26 (17)
- Probable secondary355 (64)218 (78)202 (60)100 (79)153 (70)118 (77)
- Inconclusive77 (14)22 (8)49 (15)12 (9)28 (13)10 (6)
Obesity*, n (%)78 (14)29 (10)62 (18)19 (15)16 (7)10 (6)
Diabetes, n (%)4 (1)1 (0)0 (0)0 (0)4 (2)1 (1)
WHO 2009 classification, n (%)
- Mild dengue266 (48)49 (17)168 (50)17 (13)98 (45)32 (21)
- Dengue with warning signs288 (52)186 (66)169 (50)81 (64)119 (54)105 (68)
- Severe dengue0 (0)43 (15)0 (0)27 (21)0 (0)16 (10)
- Unknown2 (0)3 (1)0 (0)2 (2)2 (1)1 (1)
Hospitalization, n (%)175 (31)161 (57)127 (38)83 (65)48 (22)78 (51)
  1. *Obesity is defined as body mass index of higher than 30 kg/m2 (for patients of older than 18 years) or two standard deviations of the median of body mass index for age (for patients of 18 years or below). WHO: World Health Organization.

Table 2
Results from models for the primary endpoint (severe or moderate dengue).
Single modelsGlobal model
Children
OR (95% CI)
Adults
OR (95% CI)
PoverallPinteractionChildren
OR (95% CI)
Adults
OR (95% CI)
PoverallPinteraction
VCAM-1 (ng/ml)<0.0010.7150.4410.213
- 1636 vs 8181.20 (1.04–1.38)1.35 (1.15–1.58)0.90 (0.73–1.10)1.22 (0.96–1.57)
- 3272 vs 16361.25 (1.02–1.53)1.48 (1.19–1.85)0.87 (0.66–1.15)1.30 (0.93–1.80)
SDC-1 (pg/ml)<0.0010.0880.0020.588
- 2519 vs 12602.67 (1.31–5.43)3.33 (1.32–8.42)2.03 (0.77–5.34)5.11 (1.56–16.78)
- 5039 vs 25191.71 (1.18–2.47)3.71 (2.09–6.58)1.76 (0.98–3.14)2.52 (1.17–5.42)
Ang-2 (pg/ml)<0.0010.5240.0390.068
- 1204 vs 6021.64 (1.39–1.94)1.51 (1.26–1.82)1.67 (1.23–2.25)1.01 (0.74–1.38)
- 2409 vs 12042.21 (1.58–3.10)2.00 (1.40–2.85)1.95 (1.25–3.05)1.01 (0.65–1.57)
IL-8 (pg/ml)<0.001<0.001<0.001<0.001
- 14 vs 71.42 (1.05–1.91)2.18 (1.47–3.24)0.91 (0.63–1.34)1.69 (1.05–2.71)
- 28 vs 140.99 (0.78–1.25)2.33 (1.63–3.33)0.53 (0.36–0.77)2.05 (1.34–3.13)
IP-10 (pg/ml)<0.0010.9840.2060.630
- 3093 vs 15461.46 (1.26–1.68)1.45 (1.21–1.73)0.94 (0.73–1.19)0.80 (0.57–1.12)
- 6186 vs 30931.68 (1.35–2.09)1.69 (1.29–2.22)1.08 (0.77–1.51)0.82 (0.52–1.29)
IL-1RA (pg/ml)<0.0010.082<0.0010.032
- 6434 vs 32171.69 (1.42–2.03)1.48 (1.21–1.81)2.07 (1.52–2.84)1.45 (0.98–2.15)
- 12868 vs 64341.82 (1.46–2.27)1.70 (1.29–2.24)2.16 (1.53–3.05)1.47 (0.94–2.30)
sCD163 (ng/ml)<0.0010.5510.2170.341
- 295 vs 1471.57 (1.14–2.15)1.49 (1.13–1.98)1.40 (0.89–2.22)1.27 (0.84–1.91)
- 589 vs 2951.46 (1.10–1.93)1.61 (1.09–2.37)1.21 (0.87–1.69)1.39 (0.89–2.18)
sTREM-1 (pg/ml)0.0590.9970.5550.393
- 85 vs 421.87 (1.23–2.84)1.79 (1.10–2.93)1.13 (0.70–1.81)1.21 (0.65–2.26)
- 169 vs 851.12 (0.91–1.38)1.12 (0.82–1.53)0.89 (0.65–1.21)0.61 (0.38–0.99)
Ferritin (ng/ml)0.0420.0540.0080.002
- 243 vs 1221.18 (1.01–1.38)1.06 (0.89–1.27)1.30 (1.04–1.64)0.78 (0.61–0.99)
- 487 vs 2431.26 (1.00–1.58)0.90 (0.66–1.23)1.22 (0.89–1.67)0.66 (0.44–1.00)
CRP (mg/l)<0.0010.0310.1840.138
- 28 vs 141.26 (1.12–1.41)1.25 (1.03–1.52)1.08 (0.93–1.25)1.10 (0.85–1.44)
- 56 vs 281.13 (0.95–1.34)1.38 (1.11–1.71)0.93 (0.75–1.15)1.36 (1.02–1.81)
  1. Poverall is derived from Wald test for the overall association of the biomarker with the endpoint; Pinteraction is from the test for the interaction between the biomarker and age. The odds ratios are estimated at age of 10 and 25 years, represented as children and adults respectively.

Table 3
Best combinations of biomarkers associated with severe or moderate dengue for children.
Best of all combinationsBest combination of 2 variablesBest combination of 3 variablesBest combination of 4 variablesBest combination of 5 variables
Variables
- VCAM-1
- SDC-1+
- Ang-2++++
- IL-8++
- IP-10+++
- IL-1RA+++++
- sCD163
- sTREM-1
- Ferritin+++++
- CRP
AIC of the selected model465.9484.7480.0473.7467.6
Bootstrap results
- Model selection frequency, n (%)134 (13.4)437 (43.7)239 (23.9)317 (31.7)440 (44.0)
- Rank by selection frequency of the selected model11211
  1. 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; AIC: Akaike information criterion.

Table 4
Best combinations of biomarkers associated with severe or moderate dengue for adults.
Best of all combinationsBest combination of 2 variablesBest combination of 3 variablesBest combination of 4 variablesBest combination of 5 variables
Variables
- VCAM-1
- SDC-1+++++
- Ang-2
- IL-8+++++
- IP-10*+
- IL-1RA+++
- sCD163+
- sTREM-1++
- Ferritin++++
- CRP
AIC of the selected model430.5441.1434.2431.6430.7
Bootstrap results
- Model selection frequency, n (%)79 (7.9)567 (56.7)432 (43.2)202 (20.2)161 (16.1)
- Rank by selection frequency of the selected model11111
  1. 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; AIC: Akaike information criterion.

    *Variable is kept as non-linear effect using natural cubic splines with three knots.

Appendix 2—table 1
Definition of severe and moderate dengue components.
EndpointDefinition
Severe plasma leakageDengue shock syndrome or respiratory distress due to plasma leakage
Moderate plasma leakageDid not fulfill criteria for severe plasma leakage and had at least one of the following criteria: (1) maximum haematocrit change was 20% or more, and (2) having evidence of fluid accumulation
Severe bleedingAny bleeding into a critical organ or required any blood transfusion of packed red cells or whole blood without pre-anaemia, or bleeding with complication
Moderate bleedingDid not fulfill criteria for severe bleeding and had at least one of the following criteria: (1) severe bleeding by clinical judgement, (2) bleeding required any blood transfusion other than packed red cells or whole blood, (3) bleeding required other intervention (e.g. nasal packing, cross-match, etc.), and (4) receiving packed red cells or whole blood with pre-existing anaemia and with a consistent haemoglobin value
Severe neurologic involvementAbnormal neurologic examination and neurologic involvement that resulted in death or ongoing sequelae that impaired daily function, or required intubation, shunting or intensive care
Moderate neurology involvementSingle convulsion without hospitalization or other complication
Severe hepatic involvementJaundice or coagulopathy or encephalopathy
Moderate hepatic involvementAny alanine aminotransferase (ALT) or aspartate aminotransferase (AST) result of 400 IU/L or more
Severe other major organ failureCreatine kinase or other enzymes (e.g. troponin) abnormalities and functional abnormalities (e.g. reduced cardiac ejection fraction less than 50% or new electrocardiogram [ECG] abnormalities) or required specific intervention (e.g. inotropic support)
Moderate other major organ failureTroponin abnormalities alone or creatine kinase abnormalities without cardiac ejection fraction less than 50%
Appendix 4—table 1
Summary of clinical phenotype of the primary endpoint.
All patients
(N = 281)
Children
(N = 127)
Adults
(N = 154)
Severe dengue, n (%)38 (14)29 (23)9 (6)
- Severe plasma leakage33 (12)24 (19)9 (6)
+Dengue shock syndrome25 (9)18 (14)7 (5)
+Respiratory distress12 (4)9 (7)3 (2)
- Severe neurologic involvement3 (1)3 (2)0 (0)
- Severe bleeding2 (1)2 (2)0 (0)
- Severe other major organ failure1 (0)0 (0)1 (1)
- Severe hepatic involvement0 (0)0 (0)0 (0)
Moderate dengue, n (%)243 (86)98 (77)145 (94)
- Moderate plasma leakage159 (57)73 (57)86 (56)
- Moderate hepatic involvement102 (36)35 (28)67 (44)
- Moderate bleeding9 (3)3 (2)6 (4)
- Moderate other major organ involvement1 (0)0 (0)1 (1)
- Moderate neurologic involvement0 (0)0 (0)0 (0)
Appendix 4—table 2
Summary of biomarkers’ data.
All patientsChildrenAdults
Uncomplicated dengueSevere/moderate dengueUncomplicated dengueSevere/moderate dengueUncomplicated dengueSevere/moderate dengue
At enrollment(N = 556)(N = 281)(N = 337)(N = 127)(N = 219)(N = 154)
VCAM-1 (ng/ml)1404 (540, 2548)2027 (1122, 3577)1442 (447, 2546)2020 (1232, 3384)1356 (568, 2560)2092 (1060, 4202)
SDC-1 (pg/ml)2334 (1864, 3131)2997 (2230, 4201)2369 (1861, 3423)2846 (2164, 4173)2260 (1879, 2898)3122 (2278, 4211)
Ang-2 (pg/ml)1064 (550, 1584)1521 (899, 2318)1102 (584, 1563)1547 (967, 2318)944 (516, 1585)1516 (885, 2321)
IL-8 (pg/ml)12 (8, 22)17 (11, 28)15 (9, 26)16 (10, 27)10 (7, 15)19 (12, 29)
IP-10 (pg/ml)2502 (732, 4509)4092 (2436, 6441)2245 (458, 4531)3942 (2046, 6287)2793 (1370, 4495)4242 (2524, 6469)
IL-1RA (pg/ml)5237 (2603, 9082)9105 (5933, 14977)4491 (2318, 8977)9688 (6109, 16786)5721 (3479, 9703)8993 (5953, 12935)
sCD163 (ng/ml)278 (185, 447)322 (228, 503)326 (212, 481)386 (256, 603)226 (157, 374)291 (207, 410)
sTREM-1 (pg/ml)81 (59, 114)96 (69, 132)80 (58, 115)93 (67, 128)84 (60, 114)98 (73, 134)
Ferritin (ng/ml)233 (116, 406)261 (133, 433)177 (99, 324)224 (110, 402)303 (161, 510)278 (160, 448)
CRP (mg/l)25 (10, 54)34 (17, 72)18 (7, 41)24 (13, 58)38 (17, 65)45 (25, 80)
Viremia (106 copies/ml)15.8 (0.7, 148.5)79.2 (5.3, 582.7)21.8 (1.8, 167.0)105.4 (8.4, 646.0)9.8 (0.3, 115.5)56.2 (3.6, 496.0)
At follow-up(N = 437)(N = 231)(N = 292)(N = 112)(N = 145)(N = 119)
VCAM-1 (ng/ml)402 (102, 730)686 (344, 961)579 (182, 858)782 (402, 1078)173 (26, 388)622 (343, 835)
SDC-1 (pg/ml)2769 (2298, 3514)3417 (2815, 5495)2957 (2319, 4115)3122 (2748, 5507)2666 (2196, 3058)3745 (2971, 5495)
Ang-2 (pg/ml)953 (478, 1479)1155 (675, 1567)1163 (738, 1646)1352 (710, 1856)565 (302, 923)1044 (626, 1345)
IL-8 (pg/ml)4.9 (2.3, 12.4)5.7 (2.7, 10.4)6.8 (3.0, 15.1)5.9 (2.4, 10.5)2.7 (1.6, 4.8)5.5 (3.1, 10.4)
IP-10 (pg/ml)57 (24, 91)76 (47, 133)67 (33, 98)86 (38, 143)39 (22, 70)75 (48, 108)
IL-1RA (pg/ml)412 (279, 635)455 (328, 626)441 (323, 687)501 (352, 664)336 (210, 480)407 (308, 615)
sCD163 (ng/ml)337 (216, 553)412 (257, 661)340 (226, 562)456 (279, 680)328 (199, 523)386 (241, 589)
sTREM-1 (pg/ml)99 (73, 132)90 (68, 116)98 (72, 132)91 (67, 115)101 (73, 134)90 (70, 116)
Ferritin (ng/ml)202 (120, 309)273 (181, 382)177 (112, 263)209 (154, 311)267 (160, 404)322 (247, 436)
CRP* (mg/l)0.7 (0.3, 1.8)0.8 (0.4, 2.0)0.6 (0.3, 1.3)0.6 (0.3, 1.1)1.1 (0.5, 2.7)1.1 (0.5, 3.4)
  1. *The number of cases with available data for CRP at follow-up in the uncomplicated and severe/moderate dengue groups are 436 and 228 (all patients); 292 and 111 (children); and 218 and 152 (adults) respectively.

    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.

  2. Summary statistics are median (1st and 3rd quartiles).

Appendix 5—table 1
Results from single models for severe/moderate dengue with the interaction with serotype.
ChildrenAdults
DENV-1
OR (95% CI)
Other serotypes
OR (95% CI)
DENV-1
OR (95% CI)
Other serotypes
OR (95% CI)
PoverallP1P2P3
VCAM-1 (ng/ml)0.0080.8220.7290.565
- 1636 vs 8181.22 (1.02–1.46)1.14 (0.95–1.37)1.42 (1.13–1.77)1.32 (1.10–1.58)
- 3272 vs 16361.28 (0.99–1.66)1.18 (0.91–1.54)1.57 (1.15–2.14)1.45 (1.13–1.86)
SDC-1 (pg/ml)<0.0010.0870.3260.352
- 2519 vs 12602.35 (0.89–6.25)2.56 (0.97–6.74)2.85 (0.80–10.12)3.10 (1.11–8.64)
- 5039 vs 25192.41 (1.47–3.96)1.22 (0.69–2.13)6.39 (2.81–14.53)3.23 (1.73–6.01)
Ang-2 (pg/ml)<0.0010.9350.9230.702
- 1204 vs 6021.67 (1.35–2.05)1.51 (1.21–1.88)1.64 (1.28–2.10)1.48 (1.20–1.83)
- 2409 vs 12042.46 (1.60–3.79)1.97 (1.25–3.11)2.40 (1.44–4.02)1.92 (1.28–2.89)
IL-8 (pg/ml)<0.001<0.001<0.0010.104
- 14 vs 71.52 (1.00–2.31)1.12 (0.76–1.65)2.83 (1.57–5.12)2.09 (1.34–3.26)
- 28 vs 141.22 (0.90–1.65)0.84 (0.60–1.17)3.04 (1.88–4.94)2.10 (1.45–3.04)
IP-10 (pg/ml)<0.0010.9750.9500.681
- 3093 vs 15461.54 (1.28–1.84)1.39 (1.13–1.70)1.64 (1.28–2.10)1.48 (1.20–1.83)
- 6186 vs 30931.84 (1.39–2.43)1.60 (1.17–2.20)2.00 (1.37–2.92)1.75 (1.27–2.40)
IL-1RA (pg/ml)<0.0010.5770.2800.805
- 6434 vs 32171.68 (1.29–2.18)1.51 (1.20–1.90)1.96 (1.34–2.86)1.76 (1.29–2.38)
- 12868 vs 64341.87 (1.43–2.44)1.77 (1.28–2.46)1.73 (1.23–2.44)1.64 (1.18–2.29)
sCD163 (ng/ml)0.0020.9830.8310.932
- 295 vs 1471.50 (1.03–2.20)1.60 (1.03–2.48)1.59 (1.02–2.47)1.69 (1.18–2.42)
- 589 vs 2951.35 (0.94–1.94)1.48 (0.99–2.21)1.50 (0.92–2.43)1.64 (1.04–2.59)
sTREM-1 (pg/ml)0.1460.9790.9980.597
- 85 vs 421.55 (0.94–2.57)2.03 (1.22–3.39)1.68 (0.92–3.07)2.20 (1.21–4.02)
- 169 vs 851.08 (0.80–1.45)1.16 (0.87–1.54)1.08 (0.68–1.71)1.16 (0.83–1.60)
Ferritin (ng/ml)0.1120.1390.1770.711
- 243 vs 1221.18 (0.97–1.44)1.12 (0.91–1.38)1.14 (0.88–1.49)1.08 (0.88–1.32)
- 487 vs 2431.28 (0.96–1.71)1.32 (0.91–1.92)0.87 (0.55–1.38)0.90 (0.64–1.27)
CRP (mg/l)<0.0010.0800.0290.755
- 28 vs 141.23 (1.06–1.43)1.36 (1.12–1.66)1.21 (0.94–1.57)1.34 (1.07–1.69)
- 56 vs 281.06 (0.85–1.33)1.24 (0.97–1.58)1.25 (0.93–1.68)1.46 (1.13–1.87)
  1. Odds ratios are estimated at age of 10 and 25 years, represented as children and adults respectively; Poverall is derived from Wald test for the overall association of the biomarker with the endpoint; P1 is from the test for the overall interaction of the biomarker; P2 is from the test for the interaction between the biomarker and age; P3 is from the test for the interaction between the biomarker and serotype.

Appendix 5—table 2
Results from global model for severe/moderate dengue with the interaction with serotype.
ChildrenAdults
DENV-1
OR (95% CI)
Other serotypes
OR (95% CI)
DENV-1
OR (95% CI)
Other serotypes
OR (95% CI)
PoverallP1P2P3
VCAM-1 (ng/ml)0.4490.2580.2480.327
- 1636 vs 8180.84 (0.62–1.13)0.88 (0.66–1.17)1.18 (0.81–1.72)1.24 (0.93–1.65)
- 3272 vs 16360.75 (0.50–1.12)0.85 (0.58–1.25)1.14 (0.70–1.85)1.29 (0.88–1.90)
SDC-1 (pg/ml)0.0270.7880.8210.316
- 2519 vs 12603.21 (0.79–12.94)1.38 (0.38–4.94)5.98 (1.00–35.72)2.57 (0.66–10.01)
- 5039 vs 25192.82 (1.21–6.57)1.45 (0.62–3.40)3.70 (1.08–12.72)1.90 (0.80–4.52)
Ang-2 (pg/ml)0.0670.1020.0430.472
- 1204 vs 6021.65 (1.10–2.47)1.79 (1.18–2.72)0.89 (0.55–1.44)0.97 (0.67–1.40)
- 2409 vs 12042.22 (1.21–4.05)1.73 (0.94–3.17)1.25 (0.63–2.48)0.97 (0.58–1.62)
IL-8 (pg/ml)<0.001<0.001<0.0010.591
- 14 vs 70.86 (0.48–1.51)0.73 (0.44–1.24)2.14 (1.01–4.53)1.84 (1.05–3.20)
- 28 vs 140.68 (0.41–1.13)0.49 (0.29–0.82)2.60 (1.27–5.32)1.88 (1.20–2.96)
IP-10 (pg/ml)0.0680.8750.7150.888
- 3093 vs 15460.98 (0.69–1.40)0.91 (0.65–1.26)0.86 (0.53–1.40)0.80 (0.53–1.19)
- 6186 vs 30931.27 (0.77–2.10)1.10 (0.70–1.74)1.04 (0.54–2.00)0.90 (0.53–1.53)
IL-1RA (pg/ml)<0.0010.3330.2300.711
- 6434 vs 32172.63 (1.65–4.20)2.11 (1.32–3.39)2.50 (1.28–4.88)2.01 (1.15–3.51)
- 12868 vs 64342.38 (1.45–3.91)1.90 (1.19–3.04)1.65 (0.88–3.09)1.32 (0.78–2.23)
sCD163 (ng/ml)0.3400.6610.4550.769
- 295 vs 1471.20 (0.65–2.20)1.54 (0.83–2.87)1.24 (0.68–2.27)1.61 (0.92–2.80)
- 589 vs 2951.20 (0.77–1.87)1.20 (0.75–1.94)1.49 (0.84–2.67)1.50 (0.85–2.61)
sTREM-1 (pg/ml)0.4410.2890.3060.071
- 85 vs 420.90 (0.48–1.67)1.23 (0.66–2.28)0.84 (0.36–1.94)1.15 (0.54–2.42)
- 169 vs 850.56 (0.33–0.96)1.18 (0.79–1.77)0.34 (0.15–0.76)0.71 (0.43–1.19)
Ferritin (ng/ml)0.0670.0330.0130.331
- 243 vs 1221.36 (1.00–1.85)1.25 (0.92–1.69)0.92 (0.62–1.36)0.84 (0.63–1.13)
- 487 vs 2431.08 (0.72–1.63)1.59 (0.97–2.61)0.55 (0.29–1.05)0.81 (0.51–1.29)
CRP (mg/l)0.1560.1030.2410.136
- 28 vs 140.95 (0.78–1.16)1.25 (0.98–1.60)0.94 (0.67–1.32)1.24 (0.90–1.70)
- 56 vs 280.80 (0.60–1.07)1.07 (0.80–1.44)1.13 (0.75–1.70)1.51 (1.09–2.09)
  1. Odds ratios are estimated at age of 10 and 25 years, represented as children and adults respectively; Poverall is derived from Wald test for the overall association of the biomarker with the endpoint; P1 is from the test for the overall interaction of the biomarker; P2 is from the test for the interaction between the biomarker and age; P3 is from the test for the interaction between the biomarker and serotype.

Appendix 6—table 1
Results from models for severe dengue endpoint.
Single modelsGlobal model
Children
OR (95% CI)
Adults
OR (95% CI)
PoverallPinteractionChildren
OR (95% CI)
Adults
OR (95% CI)
PoverallPinteraction
VCAM-1 (ng/ml)1.28 (0.77–2.12)2.13 (0.88–5.15)0.2360.2021.20 (0.35–4.12)3.13 (0.19–50.77)0.7230.491
SDC-1 (pg/ml)1.55 (0.41–5.96)3.26 (0.69–15.52)0.3070.4381.16 (0.12–11.07)0.87 (0.03–27.93)0.9870.884
Ang-2 (pg/ml)1.42 (0.70–2.88)1.79 (0.97–3.31)0.1480.5801.20 (0.33–4.31)1.02 (0.33–3.19)0.9610.830
IL-8 (pg/ml)1.04 (0.47–2.33)2.15 (0.67–6.88)0.4200.3380.81 (0.28–2.31)2.51 (0.16–38.43)0.7410.446
IP-10 (pg/ml)1.32 (0.75–2.33)1.64 (0.58–4.62)0.4430.7080.76 (0.17–3.30)0.22 (0.01–7.12)0.6930.473
IL-1RA (pg/ml)1.84 (0.81–4.16)1.78 (0.80–3.94)0.0980.9562.22 (0.51–9.64)3.35 (0.45–24.87)0.3860.696
sCD163 (ng/ml)1.43 (0.52–3.94)2.43 (0.27–21.70)0.6170.6450.98 (0.27–3.59)2.06 (0.15–27.47)0.8550.590
sTREM-1 (pg/ml)1.20 (0.44–3.28)1.29 (0.55–3.05)0.7930.9140.93 (0.30–2.88)0.38 (0.02–8.76)0.8270.541
Ferritin (ng/ml)1.13 (0.59–2.16)1.58 (0.59–4.23)0.6590.5011.12 (0.55–2.29)1.34 (0.25–7.02)0.9260.819
CRP (mg/l)1.16 (0.71–1.88)1.77 (0.56–5.62)0.6200.4180.97 (0.58–1.63)1.55 (0.33–7.32)0.7730.500
  1. Odds ratios (95% confidence intervals) are calculated for each 2-fold increase of the biomarkers and are estimated at age of 10 and 25 years, represented as children and adults respectively; Poverall is derived from Wald test for the overall association of the biomarker with the endpoint; Pinteraction is from the test for the interaction between the biomarker and age.

Appendix 6—table 2
Results from models for severe dengue or dengue with warning signs endpoint.
Single modelsGlobal model
Children
OR (95% CI)
Adults
OR (95% CI)
PoverallPinteractionChildren
OR (95% CI)
Adults
OR (95% CI)
PoverallPinteraction
VCAM-1 (ng/ml)0.0250.3740.4690.763
- 1636 vs 8181.06 (0.93–1.22)1.11 (0.92–1.33)0.82 (0.66–1.02)0.92 (0.66–1.30)
- 3272 vs 16361.06 (0.87–1.29)1.13 (0.88–1.46)0.74 (0.55–1.01)0.88 (0.56–1.40)
SDC-1 (pg/ml)0.0320.3630.1160.773
- 2519 vs 12601.34 (0.86–2.09)1.15 (0.56–2.33)1.57 (0.89–2.75)1.89 (0.71–5.03)
- 5039 vs 25191.40 (0.90–2.17)2.00 (0.79–5.08)1.78 (1.00–3.18)2.88 (0.71–11.69)
Ang-2 (pg/ml)0.0080.6370.0090.011
- 1204 vs 6021.23 (1.05–1.44)1.12 (0.93–1.36)1.37 (1.07–1.75)0.95 (0.69–1.30)
- 2409 vs 12041.34 (0.95–1.88)1.22 (0.82–1.80)1.42 (0.91–2.21)0.85 (0.48–1.51)
IL-8 (pg/ml)0.0400.0200.0530.030
- 14 vs 71.05 (0.87–1.27)0.97 (0.67–1.41)0.96 (0.77–1.21)0.94 (0.62–1.42)
- 28 vs 141.01 (0.85–1.19)1.45 (0.94–2.22)0.78 (0.62–0.99)1.48 (0.89–2.44)
IP-10 (pg/ml)<0.0010.1760.0590.537
- 3093 vs 15461.26 (1.09–1.44)1.44 (1.16–1.80)1.16 (0.87–1.55)1.30 (0.81–2.09)
- 6186 vs 30931.39 (1.13–1.71)1.75 (1.26–2.44)1.33 (0.89–1.99)1.49 (0.78–2.87)
IL-1RA (pg/ml)0.0050.3810.4250.955
- 6434 vs 32171.17 (1.06–1.30)1.15 (0.97–1.36)1.24 (1.01–1.52)1.14 (0.80–1.63)
- 12868 vs 64341.37 (1.06–1.77)1.70 (1.13–2.55)1.38 (0.93–2.05)1.45 (0.80–2.64)
sCD163 (ng/ml)0.8540.7190.1930.419
- 295 vs 1470.96 (0.84–1.08)1.03 (0.85–1.25)0.85 (0.71–1.03)1.12 (0.81–1.55)
- 589 vs 2950.91 (0.69–1.22)1.03 (0.61–1.73)0.71 (0.50–1.00)0.80 (0.44–1.47)
sTREM-1 (pg/ml)0.2210.4720.0020.132
- 85 vs 420.75 (0.56–1.00)0.69 (0.41–1.16)0.48 (0.32–0.73)0.64 (0.36–1.16)
- 169 vs 851.04 (0.84–1.28)0.78 (0.57–1.07)0.87 (0.69–1.10)0.62 (0.39–1.00)
Ferritin (ng/ml)0.0340.2580.0240.075
- 243 vs 1221.13 (1.02–1.26)1.01 (0.85–1.19)1.17 (1.01–1.35)0.96 (0.76–1.23)
- 487 vs 2430.96 (0.77–1.20)0.76 (0.53–1.08)0.94 (0.71–1.25)0.67 (0.42–1.07)
CRP (mg/l)0.7470.6220.6620.448
- 28 vs 141.03 (0.96–1.12)0.97 (0.79–1.20)0.99 (0.89–1.10)0.84 (0.59–1.20)
- 56 vs 281.02 (0.87–1.19)1.19 (0.92–1.54)0.96 (0.79–1.17)1.06 (0.75–1.49)
  1. Odds ratios are estimated at age of 10 and 25 years, represented as children and adults respectively; Poverall is derived from Wald test for the overall association of the biomarker with the endpoint; Pinteraction is from the test for the interaction between the biomarker and age.

Appendix 6—table 3
Results from models for hospitalization endpoint.
Single modelsGlobal model
Children
OR (95% CI)
Adults
OR (95% CI)
PoverallPinteractionChildren
OR (95% CI)
Adults
OR (95% CI)
PoverallPinteraction
VCAM-1 (ng/ml)<0.0010.0090.0920.137
- 1636 vs 8181.28 (1.11–1.49)1.28 (1.03–1.60)1.16 (0.90–1.48)1.28 (0.87–1.90)
- 3272 vs 16361.42 (1.14–1.76)1.46 (1.08–1.97)1.16 (0.81–1.64)1.41 (0.84–2.37)
SDC-1 (pg/ml)<0.0010.1870.0060.406
- 2519 vs 12601.82 (1.01–3.28)0.79 (0.31–2.05)1.70 (0.84–3.41)0.62 (0.16–2.49)
- 5039 vs 25192.22 (1.36–3.63)1.81 (0.65–5.07)3.70 (1.90–7.22)1.66 (0.39–7.07)
Ang-2 (pg/ml)0.0120.3370.4970.789
- 1204 vs 6021.27 (1.07–1.52)1.21 (0.91–1.62)1.27 (0.92–1.77)1.16 (0.76–1.77)
- 2409 vs 12041.58 (1.08–2.32)1.61 (0.86–3.04)1.63 (0.90–2.93)1.45 (0.70–3.01)
IL-8 (pg/ml)0.0070.0020.0240.021
- 14 vs 71.14 (0.90–1.44)0.73 (0.47–1.15)0.94 (0.66–1.33)0.63 (0.36–1.13)
- 28 vs 140.98 (0.81–1.18)1.32 (0.85–2.05)0.70 (0.50–0.97)1.59 (0.81–3.12)
IP-10 (pg/ml)0.0020.2420.0050.212
- 3093 vs 15461.32 (1.13–1.54)1.10 (0.86–1.40)0.80 (0.56–1.14)0.77 (0.45–1.30)
- 6186 vs 30931.50 (1.18–1.90)1.17 (0.81–1.70)0.84 (0.51–1.40)0.66 (0.32–1.35)
IL-1RA (pg/ml)<0.0010.685<0.0010.389
- 6434 vs 32171.31 (1.17–1.46)1.13 (0.94–1.36)2.05 (1.57–2.66)1.18 (0.73–1.89)
- 12868 vs 64341.41 (1.11–1.80)1.17 (0.79–1.72)2.25 (1.39–3.64)1.19 (0.62–2.28)
sCD163 (ng/ml)0.2080.7220.0070.419
- 295 vs 1470.90 (0.79–1.04)0.98 (0.76–1.27)0.69 (0.53–0.89)0.96 (0.62–1.50)
- 589 vs 2950.69 (0.47–1.00)0.91 (0.46–1.82)0.49 (0.30–0.80)0.83 (0.36–1.91)
sTREM-1 (pg/ml)0.6350.3710.0110.053
- 85 vs 420.93 (0.67–1.29)1.35 (0.71–2.58)0.53 (0.34–0.81)1.74 (0.67–4.52)
- 169 vs 850.89 (0.71–1.13)0.83 (0.54–1.28)0.55 (0.36–0.83)0.57 (0.26–1.29)
Ferritin (ng/ml)<0.0010.0110.1290.117
- 243 vs 1221.22 (1.08–1.38)0.92 (0.72–1.18)1.23 (1.02–1.49)0.91 (0.68–1.21)
- 487 vs 2431.40 (1.10–1.79)0.99 (0.68–1.46)1.25 (0.89–1.75)0.93 (0.54–1.59)
CRP (mg/l)0.3790.1900.1390.053
- 28 vs 140.97 (0.89–1.06)1.01 (0.83–1.24)0.97 (0.86–1.11)0.95 (0.71–1.27)
- 56 vs 280.95 (0.78–1.15)1.35 (1.01–1.81)0.89 (0.69–1.15)1.37 (0.88–2.13)
  1. Odds ratios are estimated at age of 10 and 25 years, represented as children and adults respectively; Poverall is derived from Wald test for the overall association of the biomarker with the endpoint; Pinteraction is from the test for the interaction between the biomarker and age.

Appendix 7—table 1
Model selection frequencies for children.
ModelIncluded variablesCountPercent
VCAM-1SDC-1Ang-2IL-8IP-10IL-1RAsCD163sTREM-1FerritinCRP
1+++++ +13413.4
2+++++++10010.0
3++++++555.5
4+++++545.4
5+++++++484.8
6+++++++474.7
7++++++++464.6
8++++++404.0
9+++++++393.9
10++++++++363.6
11++++++++282.8
12+++++++232.3
13++++++232.3
14+++++171.7
15++++++++151.5
16+++++++141.4
17++++++131.3
18+++++++121.2
19++++++++121.2
20+++++++111.1
  1. Selected model is ranked first (bold face).

Appendix 7—table 2
Model stability for children.
Initial modelSelected model
PredictorsEstimateStandard errorEstimateStandard errorBootstrap inclusion frequency (%)RMSD ratioRelative conditional bias (%)Bootstrap medianBootstrap 2.5th percentileBootstrap 97.5th percentile
(Intercept)−20.68013.0499−19.13312.8649100.01.1330−1.4929−20.3233−26.6990−14.0696
IL-1RA0.76040.14430.78850.1386100.01.23521.63380.76510.44081.1236
Ang-20.52030.15420.53710.145798.21.17107.65280.54160.22680.8804
IL-8−0.42500.1338−0.42900.130797.21.05974.5484−0.4341−0.69950
Ferritin0.29510.10440.29230.100393.51.223311.15790.311800.5358
IP-10−0.21450.1079−0.25980.092575.91.327232.1767−0.2398−0.46760
SDC-10.50790.24870.43980.230273.51.269218.55550.492301.0035
sCD1630.17780.143345.81.193569.8797000.4926
VCAM-1−0.05000.054135.21.1525125.63480−0.17630
sTREM-1−0.06890.137520.00.9176159.06960−0.35840.2162
CRP0.04380.071219.20.8804173.2343000.1754
  1. RMSD: root mean squared difference.

Appendix 7—table 3
Model selection frequencies for adults.
ModelIncluded variablesCountPercent
VCAM-1SDC-1Ang-2IL-8IP-10*IL-1RAsCD163sTREM-1FerritinCRP
1+++++++797.9
2++++++++555.5
3+++++++363.6
4+++++333.3
5+++++303.0
6++++++++292.9
7++++++262.6
8++++252.5
9++++++242.4
10+++++++202.0
11+++++++202.0
12+++++++++202.0
13+++++++191.9
14++++++171.7
15++++161.6
16++++161.6
17+++++161.6
18+++++161.6
19++++++161.6
20++++++151.5
  1. *Variable is kept as non-linear effect using natural cubic splines with three knots.

    Selected model is ranked first (bold face).

Appendix 7—table 4
Model stability for adults.
Initial modelSelected model
PredictorsEstimateStandard errorEstimateStandard errorBootstrap inclusion frequency (%)RMSD ratioRelative conditional bias (%)Bootstrap medianBootstrap 2.5th percentileBootstrap 97.5th percentile
(Intercept)−16.60853.2632−16.67803.2475100.01.32632.0586−16.7262−26.4755−9.8095
SDC-11.15240.27081.17400.260799.21.27453.00181.17670.54501.8615
IL-80.54730.14270.55440.141198.91.29735.88800.57390.24900.9520
Ferritin−0.27850.0916−0.26820.088394.61.24797.9330−0.2845−0.50120
sTREM-1−0.29610.1499−0.28640.149266.51.419128.1687−0.2807−0.64480
IL-1RA0.25820.15830.25570.142762.31.478854.98290.249400.7255
IP-10 (ns1)*−1.44271.0592−0.82690.611859.81.606436.8995−0.2108−5.26280.7003
IP-10 (ns2)*−0.10270.57630.11390.497659.81.206043.14730−1.70211.2589
sCD1630.20560.12870.23510.125359.11.333351.39320.214800.4989
CRP0.08630.099036.31.1203129.8186000.3048
VCAM-10.06600.068535.41.380898.31110−0.09230.2714
Ang-2−0.02460.119321.81.004762.86420−0.27920.3008
  1. *As IP-10 is kept as non-linear effect using natural cubic splines with three knots, there are two terms of this variable in the model.

    RMSD: root mean squared difference.

Appendix 8—table 1
Results from models for severe/moderate dengue including viremia as a potential biomarker.
Single modelsGlobal model
Children
OR (95% CI)
Adults
OR (95% CI)
PoverallPinteractionChildren
OR (95% CI)
Adults
OR (95% CI)
PoverallPinteraction
VCAM-1 (ng/ml)<0.0010.7150.2860.136
- 1636 vs 8181.20 (1.04–1.38)1.35 (1.15–1.58)0.94 (0.76–1.17)1.34 (1.03–1.74)
- 3272 vs 16361.25 (1.02–1.53)1.48 (1.19–1.85)0.93 (0.69–1.24)1.45 (1.02–2.04)
SDC-1 (pg/ml)<0.0010.0880.0050.645
- 2519 vs 12602.67 (1.31–5.43)3.33 (1.32–8.42)2.07 (0.78–5.47)4.28 (1.27–14.43)
- 5039 vs 25191.71 (1.18–2.47)3.71 (2.09–6.58)1.71 (0.95–3.09)2.55 (1.17–5.57)
Ang-2 (pg/ml)<0.0010.5240.0600.070
- 1204 vs 6021.64 (1.39–1.94)1.51 (1.26–1.82)1.62 (1.19–2.20)0.97 (0.71–1.34)
- 2409 vs 12042.21 (1.58–3.10)2.00 (1.40–2.85)1.92 (1.22–3.01)0.96 (0.61–1.49)
IL-8 (pg/ml)<0.001<0.001<0.001<0.001
- 14 vs 71.42 (1.05–1.91)2.18 (1.47–3.24)0.89 (0.61–1.31)1.60 (0.99–2.59)
- 28 vs 140.99 (0.78–1.25)2.33 (1.63–3.33)0.52 (0.36–0.77)1.96 (1.28–3.02)
IP-10 (pg/ml)<0.0010.9840.1500.500
- 3093 vs 15461.46 (1.26–1.68)1.45 (1.21–1.73)0.93 (0.73–1.19)0.75 (0.53–1.06)
- 6186 vs 30931.68 (1.35–2.09)1.69 (1.29–2.22)1.07 (0.76–1.50)0.75 (0.47–1.20)
IL-1RA (pg/ml)<0.0010.082<0.0010.062
- 6434 vs 32171.69 (1.42–2.03)1.48 (1.21–1.81)1.97 (1.42–2.73)1.40 (0.93–2.09)
- 12868 vs 64341.82 (1.46–2.27)1.70 (1.29–2.24)2.03 (1.41–2.92)1.38 (0.87–2.19)
sCD163 (ng/ml)<0.0010.5510.1240.289
- 295 vs 1471.57 (1.14–2.15)1.49 (1.13–1.98)1.51 (0.94–2.42)1.30 (0.86–1.98)
- 589 vs 2951.46 (1.10–1.93)1.61 (1.09–2.37)1.24 (0.88–1.73)1.44 (0.91–2.28)
sTREM-1 (pg/ml)0.0590.9970.7450.594
- 85 vs 421.87 (1.23–2.84)1.79 (1.10–2.93)1.16 (0.71–1.91)1.24 (0.65–2.36)
- 169 vs 851.12 (0.91–1.38)1.12 (0.82–1.53)0.92 (0.67–1.27)0.67 (0.41–1.10)
Ferritin (ng/ml)0.0420.0540.0070.002
- 243 vs 1221.18 (1.01–1.38)1.06 (0.89–1.27)1.32 (1.04–1.67)0.77 (0.60–0.98)
- 487 vs 2431.26 (1.00–1.58)0.90 (0.66–1.23)1.22 (0.89–1.68)0.64 (0.42–0.98)
CRP (mg/l)<0.0010.0310.1850.113
- 28 vs 141.26 (1.12–1.41)1.25 (1.03–1.52)1.06 (0.91–1.23)1.09 (0.84–1.43)
- 56 vs 281.13 (0.95–1.34)1.38 (1.11–1.71)0.89 (0.72–1.11)1.35 (1.01–1.81)
Log-10 viremia (copies/ml)<0.0010.7470.0400.886
- 7.5 vs 6.51.34 (1.18–1.53)1.33 (1.16–1.53)1.21 (1.03–1.42)1.25 (1.04–1.51)
- 8.5 vs 7.51.53 (1.25–1.87)1.48 (1.16–1.88)1.35 (1.05–1.74)1.43 (1.05–1.95)
  1. Odds ratios are estimated at age of 10 and 25 years, represented as children and adults respectively; Poverall is derived from Wald test for the overall association of the biomarker with the endpoint; Pinteraction is from the test for the interaction between the biomarker and age.

Appendix 8—table 2
Best combinations of biomarkers associated with severe or moderate dengue for children.
Best of all combinationsBest combination of 2 variablesBest combination of 3 variablesBest combination of 4 variablesBest combination of 5 variables
Variables
- VCAM-1
- SDC-1+
- Ang-2++++
- IL-8++
- IP-10+++
- IL-1RA+++++
- sCD163
- sTREM-1
- Ferritin+++++
- CRP
- Viremia
AIC of the selected model465.9484.7480.0473.7467.6
  1. 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; AIC: Akaike information criterion.

Appendix 8—table 3
Best combinations of biomarkers associated with severe or moderate dengue for adults.
Best of all combinationsBest combination of 2 variablesBest combination of 3 variablesBest combination of 4 variablesBest combination of 5 variables
Variables
- VCAM-1
- SDC-1+++++
- Ang-2
- IL-8+++++
- IP-10*
- IL-1RA
- sCD163++
- sTREM-1
- Ferritin++++
- CRP
- Viremia+++
AIC of the selected model426.4441.1434.2428.5426.4
  1. 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; AIC: Akaike information criterion.

    *Variable is kept as non-linear effect using natural cubic splines with three knots.

Appendix 9—table 1
Results of variable selection for children.
VCAM-1SDC-1Ang-2IL-8IP-10IL-1RAsCD163sTREM-1FerritinCRP
Best subset++++++
Backward elimination++++++
Forward selection++++++
Stepwise forward++++++
Stepwise backward++++++
Augmented backward elimination+++++++
Bayesian projection+++++
Appendix 9—table 2
Results of variable selection for adults.
VCAM-1SDC-1Ang-2IL-8IP-10*IL-1RAsCD163sTREM-1FerritinCRP
Best subset+++++++
Backward elimination+++++++
Forward selection+++++
Stepwise forward+++++
Stepwise backward+++++++
Augmented backward elimination++++++++
Bayesian projection++
  1. *Variable is kept as non-linear effect using natural cubic splines with three knots.

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