Article Category:
Research Article

The Angiopoietin–Tie-2 Axis in Children and Young Adults with Dengue Virus Infection in the Philippines

Hridesh Mishra SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital Research Institute, Toronto, Canada;

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Michelle Ngai SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital Research Institute, Toronto, Canada;

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Valerie M. Crowley SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital Research Institute, Toronto, Canada;

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Vanessa Tran SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital Research Institute, Toronto, Canada;
Public Health Ontario, Toronto, Canada;
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada;

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Maria Salome Siose Painaga Lebumfacil–Santa Ana Medical Center, Toledo, Philippines;

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James Yared Gaite Lebumfacil–Santa Ana Medical Center, Toledo, Philippines;

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Patrick Hamilton Department of Medicine, Faculty of Medicine, University of Alberta, Edmonton, Canada;

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Kevin C. Kain Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada;
Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, UHN–Toronto General Hospital, Toronto, Canada;

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Michael T. Hawkes Department of Pediatrics, University of British Columbia, Vancouver, Canada

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DOI:
https://doi.org/10.4269/ajtmh.24-0115
Volume/Issue:
Ahead of Print
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Dengue virus (DENV) infection is associated with plasma leakage, which may progress to shock. The angiopoietin (Ang)–tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (Tie-2) axis regulates endothelial permeability. We examined the clinical utility of Ang-1, Ang-2, and the Ang-2-to-Ang-1 ratio for prediction of progression to severe DENV in a prospective cohort study of children and young adults (age 1 to <26 years) with DENV infection. Ang-1, Ang-2, Tie-2 were measured at presentation to an outpatient clinic in the Philippines from stored plasma by multiplex Luminex® assay. Patients were followed prospectively to document the clinical course (hospitalization, length of stay, intravenous fluid resuscitation, and transfer to a higher level facility). We included 244 patients (median age 9 years, 40% female). At presentation, 63 patients (26%) had uncomplicated dengue, 179 (73%) had dengue with warning signs, and 2 (0.82%) had severe dengue. One hundred eighty-one patients (74%) were hospitalized. Ang-1 levels were lower and Ang-2 higher in patients who required hospitalization. Ang-2-to-Ang-1 ratio >1 was associated with a relative risk of hospitalization of 1.20 (95% CI: 1.03–1.36, P = 0.016). A higher Ang-2-to-Ang-1 ratio was associated with longer length of hospital stay, higher frequency of transfer to a higher level facility, larger intravenous fluid requirement, hemoconcentration, and thrombocytopenia. Angiopoietin-2 was correlated with procalcitonin (Kendall’s τ = 0.17, P = 0.00012), a marker of systemic inflammation, as well as soluble vascular cell adhesion molecule-1 (τ = 0.22, P <0.0001) and Endoglin (τ = 0.14, P = 0.0017), markers of endothelial activation. In conclusion, altered Ang-2-to-Ang-1 ratio can be detected early in the course of DENV infection and predicts clinically meaningful events (hospitalization, length of stay, and fluid resuscitation).

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Author Notes

Financial support: This study was supported by the Tesari Foundation, Canadian Institutes of Health Research (CIHR) Foundation grant FDN-148439 (K. C. Kain), Canada Research Chair (K. C. Kain), and kind donations from Kim Kertland and Rotary International (K-W group). The funders had no role in study design, data collection, data analysis, data interpretation, writing of the report, or decision to submit the article for publication.

Current contact information: Hridesh Mishra, Michelle Ngai, Valerie M. Crowley, and Vanessa Tran, SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network—Toronto General Hospital Research Institute, Toronto, Canada, E-mails: hrideshkmishra@gmail.com, michelle.c.ngai@gmail.com, valerie.crowley@gmail.com, and linh.vanessa@gmail.com. Maria Salome Siose Painaga and James Yared Gaite, Lebumfacil–Santa Ana Medical Center, Toledo, Philippines, E-mails: sakepp@yahoo.com and jamesyaredgaite@gmail.com. Patrick Hamilton, Department of Undergraduate Medical Education, Faculty of Medicine, University of Alberta, Edmonton, Canada, E-mail: phamilto@ualberta.ca. Kevin C. Kain, Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada and Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, UHN—Toronto General Hospital, Toronto, Canada, E-mail: kevin.kain@uhn.ca. Michael T. Hawkes, Department of Pediatrics, University of British Columbia, Vancouver, Canada, E-mail: michael.hawkes@bcchr.ca.

Address correspondence to Michael T. Hawkes, Department of Pediatrics, University of British Columbia, A5-179, 950 West 28th Ave., Vancouver, BC V5Z 4H4, Canada. E-mail: michael.hawkes@bcchr.ca
Copyright:
© American Society of Tropical Medicine and Hygiene 2024
Received:
17 Feb 2024
|
Accepted:
16 May 2024
|
Published Online:
13 Aug 2024
Cover The American Journal of Tropical Medicine and Hygiene
The American Journal of Tropical Medicine and Hygiene
Print ISSN:
0002-9637
Online ISSN:
1476-1645
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