Increased pulmonary pressures and myocardial wall stress in children with severe malaria.

BACKGROUND Chronic intravascular hemolysis leads to nitric oxide (NO) depletion and pulmonary hypertension in sickle cell disease. To test whether this pathophysiology occurs in malaria, we examined in Mali 53 children who were admitted to the hospital with severe malaria (excluding cerebral malaria) and 31 age-matched controls. METHODS Severity of hemolysis was assessed from plasma levels of free hemoglobin and arginase-1. NO metabolism was assessed by whole-blood nitrite levels and plasma NO consumption. Effects on the cardiovascular system and endothelial function were assessed by using echocardiography to measure peak tricuspid regurgitant jet velocity and by evaluating plasma levels of N-terminal prohormone brain natriuretic peptide (NT-proBNP) and soluble vascular cell adhesion molecule-1. RESULTS Children with severe malaria had higher plasma levels of hemoglobin and arginase-1, reduced whole-blood levels of nitrite, and increased NO consumption relative to controls. They also had increased pulmonary arterial pressures (P< .05) with elevated levels of NT-proBNP and soluble vascular cell adhesion molecule-1 (P< .001). CONCLUSION Children with severe malaria have increased pulmonary pressures and myocardial wall stress. These complications are consistent with NO depletion from intravascular hemolysis, and they indicate that the pathophysiologic cascade from intravascular hemolysis to NO depletion and its cardiopulmonary effects is activated in children with severe malaria.

[1]  H. Coon,et al.  A new NOS2 promoter polymorphism associated with increased nitric oxide production and protection from severe malaria in Tanzanian and Kenyan children , 2002, The Lancet.

[2]  B. M. Greenwood,et al.  TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria , 1990, The Lancet.

[3]  T. Rassaf,et al.  Plasma nitrite rather than nitrate reflects regional endothelial nitric oxide synthase activity but lacks intrinsic vasodilator action , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Andrew J Tatem,et al.  Correction: A World Malaria Map: Plasmodium falciparum Endemicity in 2007 , 2009, PLoS Medicine.

[5]  J. Clegg,et al.  Severe malaria in children in Papua New Guinea. , 1996, QJM : monthly journal of the Association of Physicians.

[6]  A. Laveran,et al.  A Newly Discovered Parasite in the Blood of Patients Suffering from Malaria. Parasitic Etiology of Attacks of Malaria. , 1982 .

[7]  M. Gladwin,et al.  Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin. , 2005, The Journal of clinical investigation.

[8]  M. Gladwin,et al.  The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. , 2005, JAMA.

[9]  S. Kim,et al.  Iron deficiency anemia increases nitric oxide production in healthy adolescents , 2001, Annals of Hematology.

[10]  P. Kremsner,et al.  Blood Mononuclear Cell Nitric Oxide Production and Plasma Cytokine Levels in Healthy Gabonese Children with Prior Mild or Severe Malaria , 1999, Infection and Immunity.

[11]  R. Price,et al.  Impaired nitric oxide bioavailability and l-arginine–reversible endothelial dysfunction in adults with falciparum malaria , 2007, The Journal of experimental medicine.

[12]  M. Gladwin,et al.  Erythrocytes are the major intravascular storage sites of nitrite in human blood. , 2005, Blood.

[13]  M. Gladwin,et al.  Levels of soluble endothelium‐derived adhesion molecules in patients with sickle cell disease are associated with pulmonary hypertension, organ dysfunction, and mortality , 2005, British journal of haematology.

[14]  Vandana Sachdev,et al.  Hemodynamic and functional assessment of patients with sickle cell disease and pulmonary hypertension. , 2007, American journal of respiratory and critical care medicine.

[15]  C. Rogier,et al.  Severe falciparum malaria in children: a comparative study of 1990 and 2000 WHO criteria for clinical presentation, prognosis and intensive care in Dakar, Senegal. , 2002, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[16]  E Amukoye,et al.  Deep breathing in children with severe malaria: indicator of metabolic acidosis and poor outcome. , 1996, The American journal of tropical medicine and hygiene.

[17]  P. Kubes,et al.  Anti-adhesive effect of nitric oxide on Plasmodium falciparum cytoadherence under flow. , 2003, The American journal of pathology.

[18]  Bruce Barton,et al.  N-terminal pro-brain natriuretic peptide levels and risk of death in sickle cell disease. , 2006, JAMA.

[19]  N. Day,et al.  Reactive nitrogen intermediates and outcome in severe adult malaria. , 1998, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[20]  M. Molyneux,et al.  Blood glucose levels in Malawian children before and during the administration of intravenous quinine for severe falciparum malaria. , 1988, The New England journal of medicine.

[21]  E. Werner,et al.  Cerebrospinal fluid levels of biopterin, nitric oxide metabolites, and immune activation markers and the clinical course of human cerebral malaria. , 1998, The Journal of infectious diseases.

[22]  J. Weinberg,et al.  Arginine, nitric oxide, carbon monoxide, and endothelial function in severe malaria , 2008, Current opinion in infectious diseases.

[23]  M. Alpers,et al.  Nitric oxide synthase 2(Lambaréné) (G-954C), increased nitric oxide production, and protection against malaria. , 2001, The Journal of infectious diseases.

[24]  M. Gladwin,et al.  Pulmonary complications of sickle cell disease. , 2008, The New England journal of medicine.

[25]  M. Gladwin,et al.  Diastolic dysfunction is an independent risk factor for death in patients with sickle cell disease. , 2005, Journal of the American College of Cardiology.

[26]  David L. Smith,et al.  A World Malaria Map: Plasmodium falciparum Endemicity in 2007 , 2009, PLoS medicine.

[27]  N. Anstey,et al.  Nitric oxide, malaria, and anemia: inverse relationship between nitric oxide production and hemoglobin concentration in asymptomatic, malaria-exposed children. , 1999, The American journal of tropical medicine and hygiene.

[28]  In Koo Hwang,et al.  TNF-Related Activation-Induced Cytokine Enhances Leukocyte Adhesiveness: Induction of ICAM-1 and VCAM-1 via TNF Receptor-Associated Factor and Protein Kinase C-Dependent NF-κB Activation in Endothelial Cells1 , 2005, The Journal of Immunology.

[29]  Stanley L Hazen,et al.  Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. , 2005, JAMA.

[30]  M. Gladwin,et al.  Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. , 2002 .

[31]  R. Price,et al.  Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria , 2008, Proceedings of the National Academy of Sciences.

[32]  N. Anstey,et al.  Nitric oxide in Tanzanian children with malaria: inverse relationship between malaria severity and nitric oxide production/nitric oxide synthase type 2 expression , 1996, The Journal of experimental medicine.

[33]  G. Pasvol.  The treatment of complicated and severe malaria. , 2005, British medical bulletin.

[34]  S. Fox,et al.  Systemic endothelial activation occurs in both mild and severe malaria. Correlating dermal microvascular endothelial cell phenotype and soluble cell adhesion molecules with disease severity. , 1998, The American journal of pathology.

[35]  H. Augustin,et al.  Flow‐dependent regulation of angiopoietin‐2 , 2008, Journal of cellular physiology.

[36]  M. Gladwin,et al.  Measurement of circulating nitrite and S-nitrosothiols by reductive chemiluminescence. , 2007, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[37]  L. Miller,et al.  Parasite ligand-host receptor interactions during invasion of erythrocytes by Plasmodium merozoites. , 2004, International journal for parasitology.

[38]  M. Gladwin,et al.  Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. , 2004, The New England journal of medicine.

[39]  J. Loscalzo,et al.  The critical roles of platelet activation and reduced NO bioavailability in fatal pulmonary arterial hypertension in a murine hemolysis model. , 2010, Blood.

[40]  D. Nabarro.  Roll Back Malaria. , 1999, Parassitologia.

[41]  M. Dietrich,et al.  High Levels of Inducible Nitric Oxide Synthase mRNA Are Associated with Increased Monocyte Counts in Blood and Have a Beneficial Role in Plasmodium falciparum Malaria , 2000, Infection and Immunity.

[42]  K. Maitland,et al.  Defining Childhood Severe Falciparum Malaria for Intervention Studies , 2007, PLoS medicine.

[43]  D Payne,et al.  Use and limitations of light microscopy for diagnosing malaria at the primary health care level. , 1988, Bulletin of the World Health Organization.

[44]  R. Snow,et al.  Measurement of trends in childhood malaria mortality in Africa: an assessment of progress toward targets based on verbal autopsy. , 2003, The Lancet. Infectious diseases.

[45]  X. Su,et al.  The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of plasmodium falciparum-infected erythrocytes , 1995, Cell.

[46]  J. Frangos,et al.  Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria , 2006, Nature Medicine.

[47]  N. Anstey,et al.  Low plasma arginine concentrations in children with cerebral malaria and decreased nitric oxide production , 2003, The Lancet.

[48]  P. Libby,et al.  Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. , 1995, The Journal of clinical investigation.