Impaired systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in pediatric falciparum malaria: association with disease severity.

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.

Arginine vasopressin secretion in Kenyan children with severe malaria.

Hyponatraemia is common in African children with severe malaria, but the cause is unknown. We measured plasma sodium (p[Na]) and arginine vasopressin concentrations (p[AVP]) in 30 consecutive children with severe malaria (19 had cerebral malaria), on admission, at 48 and 96 h after admission. Hyponatraemia (p[Na] < 130 mmol/l) occurred in 53 per cent of the children and was unrelated to peripheral parasite density, dehydration or abnormal renal function. The highest p[AVP] were seen in patients with cerebral malaria. Overall, p[AVP] declined 96 h after treatment. In children with hyponatraemia (cerebral and non-cerebral), p[AVP] levels were not suppressed and in 67 per cent of cases they were deemed inappropriate. Inappropriate AVP secretion is common in children with severe malaria and may influence fluid therapy after correction of initial dehydration.

Plasmodium berghei: is nitric oxide involved in the pathogenesis of mouse cerebral malaria?

To analyze whether nitric oxide may be involved in the pathogenesis of the mouse cerebral malaria (CM), nitrate and nitrite were first measured in urines of Plasmodium species infected mice. The CM-susceptible CBA/J mice were infected with either Plasmodium berghei or Plasmodium chabaudi, and the CM-resistant BALB/c mice were infected with P. berghei. No increased levels of nitrate and nitrite were detected in urine of mice infected with Plasmodium whatever the time of monitoring. In contrast, the nitrite level was found to be increased in the urine of C3H/HeJ mice infected with Trypanosoma cruzi, used as a positive control for nitrate excretion in urine. Two analogs of L-arginine, the L-NG-monomethyl-arginine acetate hydrate (L-NMMA) and N omega-nitro-L-arginine, which inhibit the nitric oxide synthase were used. CBA/J mice infected with P. berghei and treated ip with the analogs developed full neurological symptoms. Even administered intracranially, L-NMMA did not reverse CM. The role of nitric oxide in the CM pathogenesis of the mouse model is discussed.