Host biomarkers are associated with response to therapy and long-term mortality in pediatric severe malaria

Andrea L. Conroy, Michael Hawkes, Chloe R. McDonald, Hani Kim, Sarah J. Higgins, Kevin R. Barker, Sophie Namasopo, Robert O. Opoka, Chandy John, W. Conrad Liles, Kevin C. Kain

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background. Host responses to infection are critical determinants of disease severity and clinical outcome. The development of tools to risk stratify children with malaria is needed to identify children most likely to benefit from targeted interventions. Methods. This study investigated the kinetics of candidate biomarkers of mortality associated with endothelial activation and dysfunction (angiopoietin-2 [Ang-2], soluble FMS-like tyrosine kinase-1 [sFlt-1], and soluble intercellular adhesion molecule-1 [sICAM-1]) and inflammation (10 kDa interferon γ-induced protein [CXCL10/IP-10] and soluble triggering receptor expressed on myeloid cells-1 [sTREM-1]) in the context of a randomized, double-blind, placebo-controlled, parallel-arm trial evaluating inhaled nitric oxide versus placebo as adjunctive therapy to parenteral artesunate for severe malaria. One hundred eighty children aged 1-10 years were enrolled at Jinja Regional Referral Hospital in Uganda and followed for up to 6 months. Results. There were no differences between the 2 study arms in the rate of biomarker recovery. Median levels of Ang-2, CXCL10, and sFlt-1 were higher at admission in children who died in-hospital (n = 15 of 180; P <.001, P =.027, and P =.004, respectively). Elevated levels of Ang-2, sTREM-1, CXCL10, and sICAM-1 were associated with prolonged clinical recovery times in survivors. The Ang-2 levels were also associated with postdischarge mortality (P <.0001). No biomarkers were associated with neurodisability. Conclusions. Persistent endothelial activation and dysfunction predict survival in children admitted with severe malaria.

Original languageEnglish (US)
Article numberofw134
JournalOpen Forum Infectious Diseases
Volume3
Issue number3
DOIs
StatePublished - 2016

Fingerprint

Angiopoietin-2
Malaria
Biomarkers
Pediatrics
Mortality
Myeloid Cells
Intercellular Adhesion Molecule-1
Protein-Tyrosine Kinases
Placebos
Therapeutics
Uganda
Interferons
Survivors
Nitric Oxide
Referral and Consultation
Inflammation
Survival
Infection
Proteins

Keywords

  • Angiopoietin-2
  • Mortality
  • Pediatric
  • Severe malaria
  • STREM-1

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology

Cite this

Conroy, A. L., Hawkes, M., McDonald, C. R., Kim, H., Higgins, S. J., Barker, K. R., ... Kain, K. C. (2016). Host biomarkers are associated with response to therapy and long-term mortality in pediatric severe malaria. Open Forum Infectious Diseases, 3(3), [ofw134]. https://doi.org/10.1093/ofid/ofw134

Host biomarkers are associated with response to therapy and long-term mortality in pediatric severe malaria. / Conroy, Andrea L.; Hawkes, Michael; McDonald, Chloe R.; Kim, Hani; Higgins, Sarah J.; Barker, Kevin R.; Namasopo, Sophie; Opoka, Robert O.; John, Chandy; Liles, W. Conrad; Kain, Kevin C.

In: Open Forum Infectious Diseases, Vol. 3, No. 3, ofw134, 2016.

Research output: Contribution to journalArticle

Conroy, AL, Hawkes, M, McDonald, CR, Kim, H, Higgins, SJ, Barker, KR, Namasopo, S, Opoka, RO, John, C, Liles, WC & Kain, KC 2016, 'Host biomarkers are associated with response to therapy and long-term mortality in pediatric severe malaria', Open Forum Infectious Diseases, vol. 3, no. 3, ofw134. https://doi.org/10.1093/ofid/ofw134
Conroy, Andrea L. ; Hawkes, Michael ; McDonald, Chloe R. ; Kim, Hani ; Higgins, Sarah J. ; Barker, Kevin R. ; Namasopo, Sophie ; Opoka, Robert O. ; John, Chandy ; Liles, W. Conrad ; Kain, Kevin C. / Host biomarkers are associated with response to therapy and long-term mortality in pediatric severe malaria. In: Open Forum Infectious Diseases. 2016 ; Vol. 3, No. 3.
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abstract = "Background. Host responses to infection are critical determinants of disease severity and clinical outcome. The development of tools to risk stratify children with malaria is needed to identify children most likely to benefit from targeted interventions. Methods. This study investigated the kinetics of candidate biomarkers of mortality associated with endothelial activation and dysfunction (angiopoietin-2 [Ang-2], soluble FMS-like tyrosine kinase-1 [sFlt-1], and soluble intercellular adhesion molecule-1 [sICAM-1]) and inflammation (10 kDa interferon γ-induced protein [CXCL10/IP-10] and soluble triggering receptor expressed on myeloid cells-1 [sTREM-1]) in the context of a randomized, double-blind, placebo-controlled, parallel-arm trial evaluating inhaled nitric oxide versus placebo as adjunctive therapy to parenteral artesunate for severe malaria. One hundred eighty children aged 1-10 years were enrolled at Jinja Regional Referral Hospital in Uganda and followed for up to 6 months. Results. There were no differences between the 2 study arms in the rate of biomarker recovery. Median levels of Ang-2, CXCL10, and sFlt-1 were higher at admission in children who died in-hospital (n = 15 of 180; P <.001, P =.027, and P =.004, respectively). Elevated levels of Ang-2, sTREM-1, CXCL10, and sICAM-1 were associated with prolonged clinical recovery times in survivors. The Ang-2 levels were also associated with postdischarge mortality (P <.0001). No biomarkers were associated with neurodisability. Conclusions. Persistent endothelial activation and dysfunction predict survival in children admitted with severe malaria.",
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AU - Conroy, Andrea L.

AU - Hawkes, Michael

AU - McDonald, Chloe R.

AU - Kim, Hani

AU - Higgins, Sarah J.

AU - Barker, Kevin R.

AU - Namasopo, Sophie

AU - Opoka, Robert O.

AU - John, Chandy

AU - Liles, W. Conrad

AU - Kain, Kevin C.

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N2 - Background. Host responses to infection are critical determinants of disease severity and clinical outcome. The development of tools to risk stratify children with malaria is needed to identify children most likely to benefit from targeted interventions. Methods. This study investigated the kinetics of candidate biomarkers of mortality associated with endothelial activation and dysfunction (angiopoietin-2 [Ang-2], soluble FMS-like tyrosine kinase-1 [sFlt-1], and soluble intercellular adhesion molecule-1 [sICAM-1]) and inflammation (10 kDa interferon γ-induced protein [CXCL10/IP-10] and soluble triggering receptor expressed on myeloid cells-1 [sTREM-1]) in the context of a randomized, double-blind, placebo-controlled, parallel-arm trial evaluating inhaled nitric oxide versus placebo as adjunctive therapy to parenteral artesunate for severe malaria. One hundred eighty children aged 1-10 years were enrolled at Jinja Regional Referral Hospital in Uganda and followed for up to 6 months. Results. There were no differences between the 2 study arms in the rate of biomarker recovery. Median levels of Ang-2, CXCL10, and sFlt-1 were higher at admission in children who died in-hospital (n = 15 of 180; P <.001, P =.027, and P =.004, respectively). Elevated levels of Ang-2, sTREM-1, CXCL10, and sICAM-1 were associated with prolonged clinical recovery times in survivors. The Ang-2 levels were also associated with postdischarge mortality (P <.0001). No biomarkers were associated with neurodisability. Conclusions. Persistent endothelial activation and dysfunction predict survival in children admitted with severe malaria.

AB - Background. Host responses to infection are critical determinants of disease severity and clinical outcome. The development of tools to risk stratify children with malaria is needed to identify children most likely to benefit from targeted interventions. Methods. This study investigated the kinetics of candidate biomarkers of mortality associated with endothelial activation and dysfunction (angiopoietin-2 [Ang-2], soluble FMS-like tyrosine kinase-1 [sFlt-1], and soluble intercellular adhesion molecule-1 [sICAM-1]) and inflammation (10 kDa interferon γ-induced protein [CXCL10/IP-10] and soluble triggering receptor expressed on myeloid cells-1 [sTREM-1]) in the context of a randomized, double-blind, placebo-controlled, parallel-arm trial evaluating inhaled nitric oxide versus placebo as adjunctive therapy to parenteral artesunate for severe malaria. One hundred eighty children aged 1-10 years were enrolled at Jinja Regional Referral Hospital in Uganda and followed for up to 6 months. Results. There were no differences between the 2 study arms in the rate of biomarker recovery. Median levels of Ang-2, CXCL10, and sFlt-1 were higher at admission in children who died in-hospital (n = 15 of 180; P <.001, P =.027, and P =.004, respectively). Elevated levels of Ang-2, sTREM-1, CXCL10, and sICAM-1 were associated with prolonged clinical recovery times in survivors. The Ang-2 levels were also associated with postdischarge mortality (P <.0001). No biomarkers were associated with neurodisability. Conclusions. Persistent endothelial activation and dysfunction predict survival in children admitted with severe malaria.

KW - Angiopoietin-2

KW - Mortality

KW - Pediatric

KW - Severe malaria

KW - STREM-1

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