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Plasma levels of angiopoietin-1 and -2 predict cerebral malaria outcome in Central India

Vidhan Jain1, Naomi W Lucchi23, Nana O Wilson4, Anna J Blackstock23, Avinash C Nagpal5, Pradeep K Joel5, Mrigendra P Singh6, Venkatachalam Udhayakumar23, Jonathan K Stiles4 and Neeru Singh16*

Author Affiliations

1 Regional Medical Research Center for Tribals (ICMR), Nagpur Road, Garha, 482003 Jabalpur, Madhya Pradesh, India

2 Atlanta Research and Education foundation Decatur, GA, USA

3 Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA

4 Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, USA

5 Nethaji Subhash Chandra Bose Medical College Hospital, Jabalpur, Madhya Pradesh, India

6 National Institute of Malaria Research Field Unit (ICMR), Jabalpur, Madhya Pradesh, India

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Malaria Journal 2011, 10:383  doi:10.1186/1475-2875-10-383

Published: 23 December 2011

Abstract

Background

The mechanisms underlying the pathogenesis of cerebral malaria (CM) syndrome are not well understood. Previous studies have shown a strong association of inflammatory chemokines, apoptotic markers and angiogenic molecules with CM associated mortality. Recognizing the importance of angiopoietins (ANG) in the pathogenesis of CM, a retrospective investigation was carried out in a hospital cohort of malaria patients with Plasmodium infection in central India to determine if these factors could be suitable markers of CM associated severity.

Methods

Patients enrolled in the study were clinically characterized as healthy controls (HC), mild malaria (MM), CM survivors (CMS) and CM non-survivors (CMNS) based on their malaria status and hospital treatment outcome. Plasma ANG-1 and ANG-2 levels were assessed using sandwich ELISA. Receiver operating characteristic (ROC) curve analysis was used to calculate area under the curve (AUC) for each biomarker in order to assess predictive accuracy of individual biomarkers.

Results

The plasma levels of ANG-1 were lower in CMS and CMNS compared to control groups (mild malaria and healthy controls) at the time of hospital admission. On the contrary, ANG-2 levels positively correlated with malaria severity and were significantly higher in CMNS. The ratio of ANG-2/ANG-1 was highest in CMNS compared to other groups. Receiver operating characteristic curves revealed that compared to ANG-1 (AUC = 0.35), ANG-2 (AUC = 0.95) and ratio of ANG-2/ANG-1 (AUC = 0.90) were better markers to discriminate CMNS from MM cases. However, they were less specific in predicting fatal outcome amongst CM cases at the time of hospital admission.

Conclusion

These results suggest that at the time of admission plasma levels of ANG-2 and ratio of ANG-2/ANG-1 are clinically informative biomarkers to predict fatal CM from MM cases while they have limited usefulness in discriminating fatal CM outcomes in a pool of CM cases in endemic settings of Central India.

Keywords:
Angiopoietins; Cerebral malaria; Pathogenesis; Biomarkers; Receiver operating characteristic analysis