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Angiopoietin-2 levels are associated with retinopathy and predict mortality in Malawian children with cerebral malaria

A retrospective case–control study*

Conroy, Andrea L. PhD; Glover, Simon J. MD; Hawkes, Michael MD; Erdman, Laura K. PhD; Seydel, Karl B. MD, PhD; Taylor, Terrie E. DO; Molyneux, Malcolm E. MD; Kain, Kevin C. MD

doi: 10.1097/CCM.0b013e3182373157
Pediatric Critical Care

Objective: To investigate the relationship among the angiopoietin–Tie-2 system, retinopathy, and mortality in children with cerebral malaria.

Design: A case–control study of retinopathy-positive vs. retinopathy-negative children with clinically defined cerebral malaria.

Setting: Queen Elizabeth Central Hospital in Blantyre, Malawi.

Subjects: One hundred fifty-five children presenting with severe malaria and meeting a strict definition of clinical cerebral malaria (Blantyre Coma Score ≤2, Plasmodium falciparum parasitemia, no other identifiable cause for coma) were included in the study.

Interventions: None.

Measurements and Main Results: Clinical and laboratory parameters were recorded at admission and funduscopic examinations were performed. Admission levels of angiopoietin-1, angiopoietin-2, and a soluble version of their cognate receptor were measured by enzyme-linked immunosorbent assay. We show that angiopoietin-1 levels are decreased and angiopoietin-2 and soluble Tie-2 levels are increased in children with cerebral malaria who had retinopathy compared with those who did not. Angiopoietin-2 and soluble Tie-2 were independent predictors of retinopathy (adjusted odds ratio [95% CI], angiopoietin-2, 4.3 [1.3–14.6], p = .019; soluble Tie-2, 9.7 [2.1–45.8], p = .004). Angiopoietin-2 and soluble Tie-2 were positively correlated with the number of hemorrhages, the severity or retinal whitening, and the extent of capillary whitening observed on funduscopic examination (p < .05 after adjustment for multiple comparisons). Angiopoietin-2 and soluble Tie-2 levels were elevated in children with cerebral malaria who subsequently died and angiopoetin-2 was an independent predictor of death (adjusted odds ratio: 3.9 [1.2–12.7], p = .024). When combined with clinical parameters, angiopoetin-2 improved prediction of mortality using logistic regression models and classification trees.

Conclusions: These results provide insights into mechanisms of endothelial activation in cerebral malaria and indicate that the angiopoietin–Tie-2 axis is associated with retinopathy and mortality in pediatric cerebral malaria.

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From the Sandra A. Rotman Laboratories (ALC, MH, LKE, KCK), McLaughlin-Rotman Centre for Global Health, University Health Network–Toronto General Hospital, University of Toronto, Toronto, Canada; the College of Medicine (SJG, MEM), University of Malawi, Blantyre, Malawi; Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MEM), Blantyre, Malawi; Blantyre Malaria Project (KBS, TET), College of Medicine, University of Malawi, Blantyre, Malawi; the Department of Internal Medicine (KBS, TET), College of Osteopathic Medicine, Michigan State University, East Lansing, MI; Liverpool School of Tropical Medicine (MEM), Liverpool, UK; and the Tropical Disease Unit (KCK), Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Canada.

* See also p. 1025.

This work was supported by the Canadian Institutes of Health Research MOP-115160 and 13721 (KCK), Canada Research Chair (KCK), Doctoral Research Award (ALC); Genome Canada through the Ontario Genomics Institute (KCK); and a Defense Advanced Research Projects Agency (KCK). Enrollment, clinical characterization, and sampling of patients were funded by grants from The Wellcome Trust, UK; and the National Institutes of Health (5R01AI034969).

The funding source had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Patient enrollment, data, and sample collection completed at the Queen Elizabeth Central Hospital, Blantyre, Malawi, and its affiliated centers: University of Malawi, College of Medicine, Blantyre Malaria Project, and Malawi-Liverpool-Wellcome Trust Clinical Research Programme. Laboratory testing completed at the Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi, and data analysis at the McLaughlin-Rotman Centre for Global Health, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Dr. Taylor received funding from the National Institutes of Health. Dr. Molyneux received funding from the Wellcome Trust and is employed by the University of Liverpool, UK. Dr. Kain receiving funding from Defense Advanced Research Projects Agency and Canadian Institutes of Health Research. Drs. Conroy, Erdman, and Kain are all named as inventors on a patent owned by the University Health Network. The remaining authors have not disclosed any potential conflicts of interest.

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© 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins