title: Impaired systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in pediatric falciparum malaria: association with disease severity.
abstract: Decreased bioavailability of nitric oxide (NO) is a major contributor to the pathophysiology of severe falciparum malaria. Tetrahydrobiopterin (BH4) is an enzyme cofactor required for NO synthesis from L-arginine. We hypothesized that systemic levels of BH₄ would be decreased in children with cerebral malaria, contributing to low NO bioavailability. In an observational study in Tanzania, we measured urine levels of biopterin in its various redox states (fully reduced [BH₄] and the oxidized metabolites, dihydrobiopterin [BH₂] and biopterin [B₀]) in children with uncomplicated malaria (UM, n = 55), cerebral malaria (CM, n = 45), non-malaria central nervous system conditions (NMC, n = 48), and in 111 healthy controls (HC). Median urine BH4 concentration in CM (1.10 [IQR:0.55-2.18] μmol/mmol creatinine) was significantly lower compared to each of the other three groups - UM (2.10 [IQR:1.32-3.14];p<0.001), NMC (1.52 [IQR:1.01-2.71];p = 0.002), and HC (1.60 [IQR:1.15-2.23];p = 0.005). Oxidized biopterins were increased, and the BH4:BH2 ratio markedly decreased in CM. In a multivariate logistic regression model, each Log10-unit decrease in urine BH4 was independently associated with a 3.85-fold (95% CI:1.89-7.61) increase in odds of CM (p<0.001). Low systemic BH4 levels and increased oxidized biopterins contribute to the low NO bioavailability observed in CM. Adjunctive therapy to regenerate BH4 may have a role in improving NO bioavailability and microvascular perfusion in severe falciparum malaria.
authors.affiliation: Department of Medicine, Duke University and VA Medical Centers, Durham, North Carolina, United States of America.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Rubach
authors.affiliation: Department of Pediatrics, Hubert Kairuki Memorial University, Dar es Salaam, United Republic of Tanzania.
authors.forename: Jackson
authors.initials: J
authors.lastname: Mukemba
authors.affiliation: Department of Pediatrics, Hubert Kairuki Memorial University, Dar es Salaam, United Republic of Tanzania.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Florence
authors.affiliation: Department of Medicine, Intermountain Healthcare, Salt Lake City, Utah, United States of America; Department of Medicine, University of Utah School of Medicine and VA Medical Center, Salt Lake City, Utah, United States of America.
authors.forename: Bert K
authors.initials: BK
authors.lastname: Lopansri
authors.affiliation: Neurochemistry Division, Medical Neurogenetics, Atlanta, Georgia, United States of America.
authors.forename: Keith
authors.initials: K
authors.lastname: Hyland
authors.affiliation: Department of Medicine, Duke University and VA Medical Centers, Durham, North Carolina, United States of America.
authors.forename: Alicia D
authors.initials: AD
authors.lastname: Volkheimer
authors.affiliation: Global and Tropical Health Division, Menzies School for Health Research and Charles Darwin University, Darwin, Australia; Division of Medicine, Royal Darwin Hospital, Darwin, Northern Territory, Australia; Department of Medicine, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
authors.forename: Tsin W
authors.initials: TW
authors.lastname: Yeo
authors.affiliation: Global and Tropical Health Division, Menzies School for Health Research and Charles Darwin University, Darwin, Australia; Division of Medicine, Royal Darwin Hospital, Darwin, Northern Territory, Australia.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Anstey
authors.affiliation: Department of Medicine, Duke University and VA Medical Centers, Durham, North Carolina, United States of America.
authors.forename: J Brice
authors.initials: JB
authors.lastname: Weinberg
authors.affiliation: Department of Pediatrics, Hubert Kairuki Memorial University, Dar es Salaam, United Republic of Tanzania.
authors.forename: Esther D
authors.initials: ED
authors.lastname: Mwaikambo
authors.affiliation: Department of Medicine, University of Utah School of Medicine and VA Medical Center, Salt Lake City, Utah, United States of America.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Granger
mesh_terms: D001708:Biopterins / Q000031:analogs & derivatives* / Q000652:urine; D002675:Child, Preschool; D005260:Female; D006801:Humans; D016779:Malaria, Cerebral / Q000652:urine*; D016778:Malaria, Falciparum / Q000652:urine*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D012189:Retrospective Studies
chemical_list: D001708:Biopterins; D009569:Nitric Oxide; C003402:sapropterin