Objective To study the diagnosis and outcomes in people admitted to hospital with a diagnosis of severe malaria in areas with differing intensities of malaria transmission. Design Prospective observational study of children and adults over the course a year. Setting 10 hospitals in north east Tanzania. Participants 17 313 patients were admitted to hospital; of these 4474 (2851 children aged under 5 years) fulfilled criteria for severe disease. Main outcome measure Details of the treatment given and outcome. Altitudes of residence (a proxy for transmission intensity) measured with a global positioning system. Results Blood film microscopy showed that 2062 (46.1%) of people treated for malaria had Plasmodium falciparum (slide positive). The proportion of slide positive cases fell with increasing age and increasing altitude of residence. Among 1086 patients aged ≥ 5 years who lived above 600 metres, only 338 (31.1%) were slide positive, while in children < 5 years living in areas of intense transmission ( < 600 metres) most (958/1392, 68.8%) were slide positive. Among 2375 people who were slide negative, 1571 (66.1%) were not treated with antibiotics and of those, 120 (7.6%) died. The case fatality in slide negative patients was higher (292/2412, 12.1%) than for slide positive patients (142/2062, 6.9%) (P < 0.001). Respiratory distress and altered consciousness were the strongest predictors of mortality in slide positive and slide negative patients and in adults as well as children. Conclusions In Tanzania, malaria is commonly overdiagnosed in people presenting with severe febrile illness, especially in those living in areas with low to moderate transmission and in adults. This is associated with a failure to treat alternative causes of severe infection. Diagnosis needs to be improved and syndromic treatment considered. Routine hospital data may overestimate mortality from malaria by over twofold.

Malaria is the most important parasitic infection in people, accounting for more than 1 million deaths a year. Malaria has become a priority for the international health community and is now the focus of several new initiatives. Prevention and treatment of malaria could be greatly improved with existing methods if increased financial and labour resources were available. However, new approaches for prevention and treatment are needed. Several new drugs are under development, which are likely to be used in combinations to slow the spread of resistance, but the high cost of treatments would make sustainability difficult. Insecticide-treated bed-nets provide a simple but effective means of preventing malaria, especially with the development of longlasting nets in which insecticide is incorporated into the net fibres. One malaria vaccine, RTS,S/AS02, has shown promise in endemic areas and will shortly enter further trials. Other vaccines are being studied in clinical trials, but it will probably be at least 10 years before a malaria vaccine is ready for widespread use.

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Microvascular sequestration was assessed in the brains of 50 Thai and Vietnamese patients who died from severe malaria (Plasmodium falciparum, 49; P. vivax, 1). Malaria parasites were sequestered in 46 cases; in 3 intravascular malaria pigment but no parasites were evident; and in the P. vivax case there was no sequestration. Cerebrovascular endothelial expression of the putative cytoadherence receptors ICAM-1 , VCAM-1 , E-selectin , and chondroitin sulfate and also HLA class II was increased. The median (range) ratio of cerebral to peripheral blood parasitemia was 40 (1.8 to 1500). Within the same brain different vessels had discrete but different populations of parasites, indicating that the adhesion characteristics of cerebrovascular endothelium change asynchronously during malaria and also that significant recirculation of parasitized erythrocytes following sequestration is unlikely. The median (range) ratio of schizonts to trophozoites (0.15:1; 0.0 to 11.7) was significantly lower than predicted from the parasite life cycle (P < 0.001). Antimalarial treatment arrests development at the trophozoite stages which remain sequestered in the brain. There were significantly more ring form parasites (age < 26 hours) in the cerebral microvasculature (median range: 19%; 0 -90%) than expected from free mixing of these cells in the systemic circulation (median range ring parasitemia: 1.8%; 0 -36.2%). All developmental stages of P. falciparum are sequestered in the brain in severe malaria. (Am J Pathol 1999, 155:395-410)Severe falciparum malaria remains one of the most important causes of death in the tropics. Cerebral malaria is the major lethal manifestation of this infection. The sequestration of red blood cells containing mature forms of Plasmodium falciparum in the cerebral microvasculature is considered to be the essential underlying pathological process, although how this leads to coma and death remains unresolved.