Philip E. Thuma

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.

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.

Severe anaemia in Zambian children with Plasmodium falciparum malaria

Summary Background   Severe anaemia and cerebral malaria are highly prevalent complications of Plasmodium falciparum malaria among African children. The mechanisms of severe malarial anaemia, and the relative importance of this condition in comparison to cerebral malaria, are not known for many regions of Africa.

Markers of inflammation in children with severe malarial anaemia

Summary OBJECTIVE   To investigate if severe malarial anaemia is associated with a specific immune response pattern, we determined serum levels of neopterin (a marker of activation of macrophages by interferon‐γ) and of the anti‐inflammatory cytokines, interleukins 4 and 10.

Predictors of severity of illness on presentation in children with cerebral malaria.

The presenting features of 195 children with cerebral malaria were analysed to determine which correlated with severity of coma and anaemia. The children, who came from a single community in southern Zambia, were enrolled in an ongoing blinded drug trial in 1992 and 1993. Children with deep coma (scoring 0-2) had significantly longer duration of coma before presentation (P = 0.019) and were more likely to have been treated with chloroquine (P = 0.022) than children with light coma (scoring 3 or 4 on the Blantyre coma scale). Children with severe anaemia (haematocrit < 18%) were younger (P = 0.005), had been febrile longer (P = 0.005), had splenomegaly (P < 0.005) and hypoglycaemia (P < 0.008) more often and were more likely to have been treated with chloroquine (P < 0.005) than those without severe anaemia. The counts of asexual parasites in the peripheral blood were not significantly correlated with depth of coma or severity of anaemia. The observed widespread and uncontrolled use of chloroquine has probably led to the development of resistant malaria and of many severe complications despite early consultation. While early treatment of febrile illnesses in young children and immediate medical attention for altered consciousness must be emphasized in the community approach to severe malaria, our data indicate that effective public health measures will be difficult to develop in the face of a high prevalence of chloroquine resistance.

Loading dose of quinine in African children with cerebral malaria

The majority of deaths from cerebral malaria occur within 48 h after admission to hospital. Because of the possibility of inadequate treatment within this period, the use of a loading dose of quinine has been proposed. We reviewed clinical and laboratory data for 113 children with cerebral malaria, who were treated with intravenous quinine, 10 mg/kg every 8 h, at Macha Mission Hospital in rural Zambia. In 1990-1991, 39 children were not given a loading dose of quinine while, in 1992-1993, 74 children received a loading dose of 20 mg/kg. Elevated serum iron levels, as reflected in transferrin saturation, were strongly associated with higher mortality. A loading dose of quinine was associated with faster recovery from coma and enhanced clearance of parasitaemia and fever. The loading dose was also associated with trends to lower mortality and higher haemoglobin levels, but these differences were not statistically significant.

Iron chelation therapy for malaria

Malaria is one of the most devastating and geographically widespread infections in man. Of the four protozoan species that cause malaria in humans, Plasmodium falciparum is responsible for the most severe clinical consequences including coma, profound anemia, renal failure and death. It is estimated that in 1986 there were 234 million clinical cases of falciparum malaria worldwide and that 2.2 million individuals died (Sturchler, 1989). Earlier in the century, the widespread application of effective insecticides and antimalarial drugs led to a decline in the incidence of malaria and the disease was eradicated from some countries. Over the past two decades, global resistance to both insecticides and antimalarials has emerged, the incidence of malaria has increased rapidly, and the geographic occurrence has become more widespread (Clyde, 1987). Efforts to develop a malaria vaccine are underway but face formidable obstacles, such as the observations that immunity resulting from natural infection is partial and of limited duration (Hoffman et al, 1987) and that the antigens of P. falciparum are highly polymorphic (Anders and Smythe, 1989). Although early tests of malaria vaccines in human volunteers have been conducted (Cox, 1993), clinically applicable vaccines will not be available for a number of years and their importance in controlling malaria is uncertain. In this setting, antimalarial chemotherapy remains the principal means available for reducing the morbidity and mortality of malaria, and the task of developing new antimalarial drugs with new mechanisms of action is of critical importance (WHO Scientific Group, {1984).