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


RESULTS
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
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.
Lovegrove
Fiona E
FE
McLaughlin-Rotman Centre for Global Health, McLaughlin Centre for Molecular Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Tangpukdee
Noppadon
N
Opoka
Robert O
RO
Lafferty
Erin I
EI
Rajwans
Nimerta
N
Hawkes
Michael
M
Krudsood
Srivicha
S
Looareesuwan
Sornchai
S
John
Chandy C
CC
Liles
W Conrad
WC
Kain
Kevin C
KC
D000293:Adolescent; D000328:Adult; D000349:Africa; D042683:Angiopoietin-1 / Q000097:blood*; D042702:Angiopoietin-2 / Q000097:blood*; D000818:Animals; D015415:Biomarkers / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D006801:Humans; D016779:Malaria, Cerebral / Q000097:blood* / Q000175:diagnosis* / Q000188:drug therapy; D016778:Malaria, Falciparum / Q000097:blood* / Q000175:diagnosis* / Q000188:drug therapy; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000276:immunology; D011379:Prognosis; D012372:ROC Curve; D012680:Sensitivity and Specificity; D013785:Thailand; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D055815:Young Adult
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D015415:Biomarkers; D014409:Tumor Necrosis Factor-alpha