Pulmonary actinomycosis.

Pulmonary actinomycosis is a rare but important and challenging diagnosis to make. Even when the clinical suspicion is high, the disease is commonly confused with other chronic suppurative lung diseases and with malignancy. An early, accurate diagnosis will prevent the considerable psychological and physical morbidity, including unwarranted surgery, associated with delayed diagnosis. The clinical, radiological and therapeutic characteristics of the infection are reviewed here. Respiratory physicians should be aware of this important differential when investigating patients for persistent pulmonary shadowing. This will expedite the diagnosis of an otherwise highly treatable condition with an excellent prognosis if picked up early.

A randomized controlled trial of artemotil (beta-arteether) in Zambian children with cerebral malaria.

The efficacy and safety of intramuscular artemotil (ARTECEF) was compared to intravenous quinine in African children with cerebral malaria. This prospective block randomized open-label study was conducted at two centers in Zambia. Subjects were children aged 0 to 10 years of age with cerebral malaria and a Blantyre Coma Score of 2 or less. Ninety two children were studied; 48 received artemotil and 44 quinine. No significant differences in survival, coma resolution time, neurologic sequelae, parasite clearance time, and fever resolution time were seen between the two regimens. Rates for negative malaria smears one month after therapy were similar in both groups. Artemotil was a well-tolerated drug in the 48 patients in this study. It appears to be at least therapeutically equivalent to quinine for the treatment of pediatric cerebral malaria. It has the advantage of being able to be given intramuscularly once daily for only five days.

Iron chelation therapy for malaria: a review.

Malaria is one of the major global health problems, and an urgent need for the development of new antimalarial agents faces the scientific community. A considerable number of iron(III) chelators, designed for purposes other than treating malaria, have antimalarial activity in vitro, apparently through the mechanism of withholding iron from vital metabolic pathways of the intra-erythrocytic parasite. Certain iron(II) chelators also have antimalarial activity, but the mechanism of action appears to be the formation of toxic complexes with iron rather than the withholding of iron. Several of the iron(III)-chelating compounds also have antimalarial activity in animal models of plasmodial infection. Iron chelation therapy with desferrioxamine, the only compound of this nature that is widely available for use in humans, has clinical activity in both uncomplicated and severe malaria in humans.

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.

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.

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.

The association of pallor with haemoglobin concentration and mortality in severe malaria.

To identify a marker associated with poor outcome in severe malaria that requires no technology, the relationship between the presence of pallor and mortality was reviewed retrospectively in 291 Zambian children with cerebral malaria. The mean (S.D.) haemoglobin concentration among the 222 children assessed as having pallor on admission was significantly lower than that among the 69 children not considered to have pallor [6.0 (1.9) v. 9.2 (1.6) g/dl; P < 0.0005]. Thirty-nine (17.6%) of the children presenting with pallor died, compared with only five (7.2%) of those without pallor (P = 0.036). The adjusted odds of death in children with pallor on admission was 2.8 times higher than that in children without pallor (95% confidence interval = 1.03-7.7; P = 0.044). The clinical observation of pallor may therefore identify children with low haemoglobin concentrations and a high risk of mortality. Whether mothers and village health workers can be taught to recognize pallor in a child with malaria and then to seek early medical attention will need to be determined in further studies.

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.

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.