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Monday, April 15, 2013
Malaria claims approximately 1-million lives per year, the majority of which are children under 5 years of age in sub-Saharan Africa . The deadliest manifestation of malaria is cerebral malaria (CM), the clinical definition of which includes Plasmodium parasite infection and coma, in the absence of other causes of coma . The pathophysiology is incompletely understood, but consistent post-mortem findings are sequestered parasitized red blood cells (pRBCs) in the cerebral vasculature, microthrombi, and blood brain barrier dysfunction [reviewed by 3 and 4]. It is believed that this combination of cellular pathology leads to a reduction in cerebral blood flow, decreased oxygen delivery, and subsequent cellular dysfunction. This pathology is clearly reflected in the retinopathy correlated with CM . Malaria also involves RBC lysis, releasing hemoglobin into the plasma. A reduction in nitric oxide (NO) has consistently been demonstrated in both animal models and human cohorts of severe malaria, and has been correlated with an increase in plasma hemoglobin, reflecting the NO-scavenging property of plasma hemoglobin. Animal and human data have demonstrated a correlation between this reduction in NO, increased plasma hemoglobin, markers of inflammation and endothelial dysfunction, and the severity of disease [6 -7, and reviewed by 8]. In response, providing supplemental NO by way of an NO-donor  or inhaled NO  have led to improved clinical outcomes, reduction in inflammation, and quiescence of endothelial activation in animal CM models. This evidence has catalyzed the development of clinical trials in the use of inhaled NO as an adjuvant therapy in CM in Africa.
Drs. Warren Zapol and Ryan Carroll of the Anesthesiology Center for Critical Care Research and are currently leading a phase II clinical trial in the safety and efficacy of inhaled nitric oxide as an adjunctive treatment for pediatric patients with cerebral malaria in Uganda (ClinicalTrial.gov: NCT01388842). This is an open-label placebo-controlled trial being carried out at the Pediatric Ward at the Mbarara University of Science and Technology, with the help of Medicins Sans Frontiere’s research arm, Epicentre. The study has recruited over 50% of the targeted 92 patients and future assessments include inflammatory and endothelial markers of disease (IL-1, -6, -10, TNF-alpha, angiopoietin-1 and -2, etc.), nitrogen/NO metabolite (NOx) levels, as well as mortality and morbidity. The team is also assessing the feasibility of non-invasive means of measuring NO bioavailability and perfusion.
When not in the field, Dr. Carroll is assessing the role of NO and iron metabolism in experimental models of CM and severe malaria-related anemia (SMA), respectively. The experimental model of CM involves Plasmodium berghei ANKA (PbA) and C57Bl6 mice, wherein infected mice die of CNS-related complications within 5 – 10 days of inoculation. The mice are assessed clinically by the Rapid Murine Coma and Behavior Scale (RMCBS)  and brains are assessed for microhemorrhages and glial injury. The SMA model involves PbA infected balb/c mice, wherein subjects live 2 – 3 weeks and develop extremely high parasitemia levels (60-80%) and severe anemia. The role of iron metabolism, hepcidin, and inflammatory markers are being assessed in this model.
1. World Health Organization. World malaria report. Geneva, Switzerland: WHO; 2010.2. Taylor TE, Fu WJ, Carr RA, Whitten RO, Mueller JG, et al. Differentiating the pathologies of cerebral malaria by postmortem parasite count. Nat Med 2004; 10(2): 143 – 145.3. Medana IM and Turner GDH. Cerebral malaria and the blood-brain barrier. Int J for Para 2006; 36: 555 – 568. 4. Milner DA. Rethinking cerebral malaria pathology. Curr Opin Infect Dis. 2010 Oct;23(5):456-63. 5. Beare NA, Lewallen S, Taylor TE, Molyneux ME. Redefining cerebral malaria by including malaria retinopathy. Future Microbiol. 2011; 6(3): 349 – 355. 6. Yeo TW, Lampah DA, Gitwati R, Tjitra E, Kenengalem E, et al., Impaired nitric oxide bioavailability and L-arginine-reversible endothelial dysfunction in adults with falciparum malaria. JEM 2007; 204(11); 2693 – 2704.7. Lovegrove FE, Tangpukdee N, Opoka RO, Lafferty EI, Rajwans N, et al. (2009) Serum angiopoietin-1 and -2 levels discriminate cerebral malaria from uncomplicated malaria and predict clinical outcome in African children. PLoS One 4: e4912.8. Hawkes M, Opoka RO, Namasopo S, Miller C, Conroy AL, et al. Nitric oxide for the adjunctive treatment of severe malaria: hypothesis and rationale. Med Hypotheses. 2011; 77(3): 437 – 444.9. Gramaglia I, Sobolewski P, Meays D, Contreras R, Nolan JP et al. Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria. Nat Med. 2006; 12(12): 1417 – 1422. 10. Serghides L, Kim H, Z Lu, Kain DC, Miller C. et al. Inhaled nitric oxide reduces endothelial activation and parasite accumulatin in the brain, and enhances survival in experimental cerebral malaria. PLoS One. 2011; 6(11):e27714.11. Ryan W. Carroll, Wainwright MS, Kim K-Y, Kidambi T, Gómez ND, et al. A rapid murine coma and behavior scale for quantitative assessment of murine cerebral malaria. PLoS ONE. 2010; 5(10): e13124
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