Effect of iron chelation therapy on mortality in Zambian children with cerebral malaria.

To examine the effect of iron chelation on mortality in cerebral malaria, we enrolled 352 children in a trial of deferoxamine in addition to standard quinine therapy at 2 centres in Zambia, one rural and one urban. Entrance criteria included age < 6 years, Plasmodium falciparum parasitaemia, normal cerebral spinal fluid, and unrousable coma. Deferoxamine (100 mg/kg/d infused for a total of 72 h) or placebo was added to a 7 d regimen of quinine that included a loading dose. Mortality overall was 18.3% (32/175) in the deferoxamine group and 10.7% (19/177) in the placebo group (adjusted odds ratio 1.8; 95% confidence interval 0.9-3.6; P = 0.074). At the rural study site, mortality was 15.4% (18/117) with deferoxamine compared to 12.7% (15/118) with placebo (P = 0.78, adjusted for covariates). At the urban site, mortality was 24.1% (14/58) with deferoxamine and 6.8% (4/59) with placebo (P = 0.061, adjusted for covariates). Among survivors, there was a non-significant trend to faster recovery from coma in the deferoxamine group (adjusted odds ratio 1.2; 95% confidence interval 0.97-1.6; P = 0.089). Hepatomegaly was significantly associated with higher mortality, while splenomegaly was associated with lower mortality. This study did not provide evidence for a beneficial effect on mortality in children with cerebral malaria when deferoxamine was added to quinine, given in a regimen that included a loading dose.

Assessment of the effect of the oral iron chelator deferiprone on asymptomatic Plasmodium falciparum parasitemia in humans.

While the parenteral iron-chelating agent desferrioxamine B has anti-malarial activity in humans, the usefulness of an orally active chelator for this indication has not been investigated previously in vivo. We conducted a prospective, double-blind, placebo-controlled, cross-over trial of deferiprone (L1; CP20; 1,2-dimethyl-3-hydroxypyridin-4-one) in 25 adult Zambians with asymptomatic Plasmodium falciparum parasitemia. Deferiprone was administered daily for three or four days in divided doses of 75 or 100 mg/kg of body weight, dosages that are effective for treating iron overload. No reduction in asexual intra-erythrocytic parasites was observed during or after deferiprone treatment. The mean peak plasma concentration of deferiprone (108.9 +/- 24.9 micromol/L) achieved was within the range demonstrated to inhibit the growth of P. falciparum in vitro, but the systemic exposure as determined by the 24-hr plasma concentration-time curve would not be predicted inhibit growth in vivo. No evidence of deferiprone-associated hematological toxicity was noted in this short-term study of these subjects, all of whom had clinical evidence of normal body iron stores. Because of the risk of neutropenia and other adverse effects with higher doses or prolonged use of the chelator, additional trials of deferiprone as a sole anti-malarial agent would not seem to be justified. In contrast, further efforts are needed to develop other orally active iron-chelating agents specifically for their anti-malarial action.

Cerebrospinal fluid levels of biopterin, nitric oxide metabolites, and immune activation markers and the clinical course of human cerebral malaria.

Cerebrospinal fluid samples from 130 children who presented with cerebral malaria were investigated to elucidate the impact of biopterin production, NO formation, and local immune activation on the clinical course of this disease. Biopterin levels were significantly lower in patients who were in a deeper coma (P = .02). Cerebrospinal fluid concentrations of NO were significantly higher in children who died than in survivors (P = .037); however, this was not the case for macrophage activation markers, neopterin, and soluble tumor necrosis factor receptor p75 (sTNFR-75). Biopterin, neopterin, and sTNFR-75 but not NO concentrations were significantly related to each other. Low biopterin levels in deep coma are compatible with an impaired local Th1 response, but the low levels could also be due to the scavenging of radicals or to decreased neurotransmitter synthesis. Local production of NO, most likely by nonimmune mechanisms, may be detrimental in cerebral malaria; however, this appears not to be the case for local Th1-mediated immune pathways.

Prolonged macrophage activation and persistent anaemia in children with complicated malaria.

OBJECTIVE: To determine if prolonged immune activation may be associated with the persistence of anaemia after treatment for severe malaria, we measured serum concentrations of neopterin and interleukin-4 during one week of antimalarial therapy and determined haemoglobin levels one month later. Neopterin is a clinically valuable marker for monitoring activation of macrophages by gamma-interferon and thus reflects the TH-1 immune response. Interleukin-4 is a major cytokine that tends to be inhibited by TH-1 activity. METHOD: The study population consisted of 26 Zambian children < 6 years of age who presented with cerebral malaria to a rural hospital in 1994 and who were treated with quinine for seven days. Six children (23%) were anaemic (haemoglobin < 11 g/dl) one month after completing antimalarial therapy. RESULTS: On admission, concentrations of neopterin were markedly elevated in all patients. During the seven days of anti-malarial therapy, neopterin levels remained elevated in the 6 children who proved to have persistent anaemia one month after finishing treatment but declined significantly (P = 0.008) in the 20 children who corrected their haemoglobin levels by that time. Conversely, interleukin-4 levels declined in the children with persistent anaemia (P = 0.043) but not in the other children. CONCLUSION: Persistence of the TH-1 mediated immune response and associated activation of macrophages may be involved in the pathogenesis of lingering anaemia after treatment of malaria.

Clinical studies of iron chelators in malaria.

In 75 Zambian and Thai subjects with mild to moderate infection with Plasmodium falciparum or Plasmodium vivax, 3-day infusions of desferrioxamine B (100 mg/kg/day) as a single agent enhanced the clearance of asexual peripheral blood parasites, but recrudescence occurred in most subjects. In 83 Zambian children with cerebral malaria who were randomized to receive desferrioxamine B or placebo in addition to standard quinine-based therapy as part of a prospective double-blind trial, both parasite clearance and recovery from coma were faster with administration of the iron chelator. Retrospective studies in the children with cerebral malaria raised the possibility that, in addition to withholding iron from the parasite, desferrioxamine B may have enhanced the T helper 1 immune response and protected against iron-mediated peroxidant cerebral tissue damage.

Iron chelation as a chemotherapeutic strategy for falciparum malaria.

To examine the effect of iron chelation against human malaria, 37 Zambians with asymptomatic Plasmodium falciparum infections were randomly assigned to 72-hr infusions of desferrioxamine B or placebo. Mean concentrations of ring forms decreased significantly with desferrioxamine B (P < 0.001) but not with a placebo. Over seven days of observation, mean parasite concentrations remained at the initial levels in six individuals originally given placebo, but decreased promptly with administration of desferrioxamine B (P = 0.001). Mean parasitemia was significantly lower for up to four weeks in 16 subjects treated with desferrioxamine B when compared with the eight who had received placebo only (P = 0.027). We conclude that iron chelation has antiplasmodial activity and may offer a new therapeutic strategy for falciparum malaria.

Effect of iron chelation therapy on recovery from deep coma in children with cerebral malaria.

BACKGROUND: Cerebral malaria is a severe complication of Plasmodium falciparum infection in children, with a mortality rate of 15 to 50 percent despite antimalarial therapy. METHODS: To determine whether combining iron chelation with quinine therapy speeds the recovery of consciousness, we conducted a randomized, double-blind, placebo-controlled trial of the iron chelator deferoxamine in 83 Zambian children with cerebral malaria. To be enrolled, patients had to be less than six years old, have P. falciparum parasitemia, have normal cerebrospinal fluid without evidence of bacterial infection, and be in a coma from which they could not be aroused. Deferoxamine (100 mg per kilogram of body weight per day, infused intravenously for 72 hours) or placebo was added to standard therapy with quinine and sulfadoxine-pyrimethamine. The time to the recovery of full consciousness, time to parasite clearance, and mortality were examined with Cox proportional-hazards regression analysis. RESULTS: The rate of recovery of full consciousness among the 42 patients given deferoxamine was 1.3 times that among the 41 given placebo (95 percent confidence interval, 0.7 to 2.3); the median time to recovery was 20.2 hours in the deferoxamine group and 43.1 hours in the placebo group (P = 0.38). Among 50 patients with deep coma, the rate of recovery of full consciousness was increased 2.2-fold with deferoxamine (95 percent confidence interval, 1.1 to 4.7), decreasing the median recovery time from 68.2 to 24.1 hours (P = 0.03). Among 69 patients for whom data on parasite clearance were available, the rate of clearance with deferoxamine was 2.0 times that with placebo (95 percent confidence interval, 1.2 to 3.6). Among all 83 patients, mortality was 17 percent in the deferoxamine group and 22 percent in the placebo group (P = 0.52). CONCLUSIONS: Iron chelation therapy may hasten the clearance of parasitemia and enhance recovery from deep coma in cerebral malaria.

PIP: Cerebral malaria is a severe complication of Plasmodium falciparum infection in children, with a mortality rate of 15-50% despite antimalarial therapy. In order to determine whether combining iron chelation with quinine therapy speeds recovery of consciousness, the authors conducted a randomized, double-blind, placebo-controlled trial of the iron chelator deferoxamine in 83 Zambian children with cerebral malaria. To be enrolled, patients had to be under age 6, have P. falciparum parasitemia, have normal cerebrospinal fluid without evidence of bacterial infection, and be in a coma from which they cannot be aroused. Deferoxamine (100 mg/kg of body weight/day, infused intravenously for 72 hours) or placebo was added to standard therapy with quinine and sulfadoxine-pryimethamine. The time to recovery of full consciousness, time to parasite clearance, and mortality were examined with Cox proportional-hazards regression analysis. The rate of recovery of full consciousness among the 42 patients given deferoxamine was 1.3 time that among the 41 who received the placebo (95% confidence interval [CI], 0.7-2.3; the median time to recovery was 20.2 hours in the deferoxamine group, and 43.1 hours in the placebo group (p=0.38). Among 50 patients in deep coma, the rate of recovery of full consciousness was increased 2.2-fold with deferoxamine (95% CI, 1.1-4-7), decreasing the median recovery time from 68.2 to 24.1 hours (p=0.03). Among 69 patients for whom data on parasite clearance were available, the rate of clearance with deferoxamine was 2.0 times that with placebo (95% CI, 1.2-3.6). Among all 83 patients, mortality was 17% in the deferoxamine group and 22% in the placebo group (p=0.52). It is concluded that iron chelation therapy may speed the clearance of parasitemia and enhance recovery from deep coma in cerebral malaria.