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Severe disease falls into three overlapping syndromes: coma, respiratory distress, and severe anaemia. Recently, it has become clear that metabolic acidosis plays a major role in the pathogenesis of severe disease and is particularly important in the overlap between the different clinical syndromes. We propose that the different manifestations of severe malarial morbidity arise from the interaction of a limited number of pathogenic processes: red cell destruction, toxin\u2013mediated activation of cytokine cascades, and infected cell sequestration in tissue microvascular beds. The pattern of severe morbidity varies with age within any one endemic area, with severe anaemia predominating in the youngest children and coma having its highest incidence in older children. Between endemic areas there is a marked variation in mean age of children with severe malaria, and therefore in the importance of different clinical syndromes. The shift in mean age is due to a combination of increased challenge and more rapid development of immunity at higher levels of transmission. Recent comparative studies indicate that at higher levels of transmission the net effect of these shifts may be a paradoxical reduction in total severe malarial morbidity.\n                  <\/jats:p>","DOI":"10.1098\/rstb.1997.0124","type":"journal-article","created":{"date-parts":[[2002,10,1]],"date-time":"2002-10-01T13:23:02Z","timestamp":1033478582000},"page":"1385-1394","source":"Crossref","is-referenced-by-count":92,"title":["Host\u2014parasite interaction and morbidity in malaria endemic areas"],"prefix":"10.1098","volume":"352","author":[{"given":"Kevin","family":"Marsh","sequence":"first","affiliation":[{"name":"KEMRI-Wellcome Trust UnitPO Box 230, KilifiKenya"},{"name":"Nuffield Department of ClinicalMedicineJohn Radcliffe Hospital, Headington, Oxford OX3 9DUUK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert W.","family":"Snow","sequence":"additional","affiliation":[{"name":"Wellcome Trust Research LaboratoriesPO Box 43640, NairobiKenya"},{"name":"Nuffield Department of ClinicalMedicineJohn Radcliffe Hospital, Headington, Oxford OX3 9DUUK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"175","published-online":{"date-parts":[[1997,9,29]]},"reference":[{"key":"p_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.1980.tb05956.x"},{"key":"p_2","article-title":"Association between serum levels of reactive nitrogen intermediates and coma in children with cerebral malaria in Papua New","volume":"90","author":"Al Yaman F.","year":"1996","journal-title":"Guinea. 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