Serum angiopoietin-1 and -2 levels discriminate cerebral malaria from uncomplicated malaria and predict clinical outcome in African children

Fiona E. Lovegrove, Noppadon Tangpukdee, Robert O. Opoka, Erin I. Lafferty, Nimerta Rajwans, Michael Hawkes, Srivicha Krudsood, Sornchai Looareesuwan, Chandy John, W. Conrad Liles, Kevin C. Kain

Research output: Contribution to journalArticle

120 Citations (Scopus)

Abstract

Background: Limited tools exist to identify which individuals infected with Plasmodium falciparum are at risk of developing serious complications such as cerebral malaria (CM). The objective of this study was to assess serum biomarkers that differentiate between CM and non-CM, with the long-term goal of developing a clinically informative prognostic test for severe malaria. Methodology/Principal Findings: Based on the hypothesis that endothelial activation and blood-brain-barrier dysfunction contribute to CM pathogenesis, we examined the endothelial regulators, angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2), in serum samples from P. falciparum-infected patients with uncomplicated malaria (UM) or CM, from two diverse populations - Thai adults and Ugandan children. Angiopoietin levels were compared to tumour necrosis factor (TNF). In both populations, ANG-1 levels were significantly decreased and ANG-2 levels were significantly increased in CM versus UM and healthy controls (p,0.001). TNF was significantly elevated in CM in the Thai adult population (p,0.001), but did not discriminate well between CM and UM in African children. Receiver operating characteristic curve analysis showed that ANG-1 and the ratio of ANG-2:ANG-1 accurately discriminated CM patients from UM in both populations. Applied as a diagnostic test, ANG-1 had a sensitivity and specificity of 100% for distinguishing CM from UM in Thai adults and 70% and 75%, respectively, for Ugandan children. Across both populations the likelihood ratio of CM given a positive test (ANG-1,15 ng/mL) was 4.1 (2.7-6.5) and the likelihood ratio of CM given a negative test was 0.29 (0.20-0.42). Moreover, low ANG-1 levels at presentation predicted subsequent mortality in children with CM (p = 0.027). Conclusions/Significance: ANG-1 and the ANG-2/1 ratio are promising clinically informative biomarkers for CM. Additional studies should address their utility as prognostic biomarkers and potential therapeutic targets in severe malaria.

Original languageEnglish (US)
Article numbere4912
JournalPLoS One
Volume4
Issue number3
DOIs
StatePublished - Mar 20 2009
Externally publishedYes

Fingerprint

Angiopoietin-2
Angiopoietin-1
Cerebral Malaria
malaria
Malaria
Serum
Biomarkers
biomarkers
Tumor Necrosis Factor-alpha
Angiopoietins
tumor necrosis factors
Population
Plasmodium falciparum
angiopoietin-1
cerebral malaria
Child Mortality
Chemical activation
blood-brain barrier
testing
Blood-Brain Barrier

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Lovegrove, F. E., Tangpukdee, N., Opoka, R. O., Lafferty, E. I., Rajwans, N., Hawkes, M., ... Kain, K. C. (2009). Serum angiopoietin-1 and -2 levels discriminate cerebral malaria from uncomplicated malaria and predict clinical outcome in African children. PLoS One, 4(3), [e4912]. https://doi.org/10.1371/journal.pone.0004912

Serum angiopoietin-1 and -2 levels discriminate cerebral malaria from uncomplicated malaria and predict clinical outcome in African children. / Lovegrove, Fiona E.; Tangpukdee, Noppadon; Opoka, Robert O.; Lafferty, Erin I.; Rajwans, Nimerta; Hawkes, Michael; Krudsood, Srivicha; Looareesuwan, Sornchai; John, Chandy; Liles, W. Conrad; Kain, Kevin C.

In: PLoS One, Vol. 4, No. 3, e4912, 20.03.2009.

Research output: Contribution to journalArticle

Lovegrove, FE, Tangpukdee, N, Opoka, RO, Lafferty, EI, Rajwans, N, Hawkes, M, Krudsood, S, Looareesuwan, S, John, C, Liles, WC & Kain, KC 2009, 'Serum angiopoietin-1 and -2 levels discriminate cerebral malaria from uncomplicated malaria and predict clinical outcome in African children', PLoS One, vol. 4, no. 3, e4912. https://doi.org/10.1371/journal.pone.0004912
Lovegrove, Fiona E. ; Tangpukdee, Noppadon ; Opoka, Robert O. ; Lafferty, Erin I. ; Rajwans, Nimerta ; Hawkes, Michael ; Krudsood, Srivicha ; Looareesuwan, Sornchai ; John, Chandy ; Liles, W. Conrad ; Kain, Kevin C. / Serum angiopoietin-1 and -2 levels discriminate cerebral malaria from uncomplicated malaria and predict clinical outcome in African children. In: PLoS One. 2009 ; Vol. 4, No. 3.
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abstract = "Background: Limited tools exist to identify which individuals infected with Plasmodium falciparum are at risk of developing serious complications such as cerebral malaria (CM). The objective of this study was to assess serum biomarkers that differentiate between CM and non-CM, with the long-term goal of developing a clinically informative prognostic test for severe malaria. Methodology/Principal Findings: Based on the hypothesis that endothelial activation and blood-brain-barrier dysfunction contribute to CM pathogenesis, we examined the endothelial regulators, angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2), in serum samples from P. falciparum-infected patients with uncomplicated malaria (UM) or CM, from two diverse populations - Thai adults and Ugandan children. Angiopoietin levels were compared to tumour necrosis factor (TNF). In both populations, ANG-1 levels were significantly decreased and ANG-2 levels were significantly increased in CM versus UM and healthy controls (p,0.001). TNF was significantly elevated in CM in the Thai adult population (p,0.001), but did not discriminate well between CM and UM in African children. Receiver operating characteristic curve analysis showed that ANG-1 and the ratio of ANG-2:ANG-1 accurately discriminated CM patients from UM in both populations. Applied as a diagnostic test, ANG-1 had a sensitivity and specificity of 100{\%} for distinguishing CM from UM in Thai adults and 70{\%} and 75{\%}, respectively, for Ugandan children. Across both populations the likelihood ratio of CM given a positive test (ANG-1,15 ng/mL) was 4.1 (2.7-6.5) and the likelihood ratio of CM given a negative test was 0.29 (0.20-0.42). Moreover, low ANG-1 levels at presentation predicted subsequent mortality in children with CM (p = 0.027). Conclusions/Significance: ANG-1 and the ANG-2/1 ratio are promising clinically informative biomarkers for CM. Additional studies should address their utility as prognostic biomarkers and potential therapeutic targets in severe malaria.",
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AU - Tangpukdee, Noppadon

AU - Opoka, Robert O.

AU - Lafferty, Erin I.

AU - Rajwans, Nimerta

AU - Hawkes, Michael

AU - Krudsood, Srivicha

AU - Looareesuwan, Sornchai

AU - John, Chandy

AU - Liles, W. Conrad

AU - Kain, Kevin C.

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