Tropical Medicine and International Health doi:10.1111/tmi.12313 volume 19 suppl Severe Malaria Section 1: Epidemiology of severe malaria is modest because severe malaria has no features falciparum malaria by which it can be confidently distinguished from many other fatal febrile conditions in the absence of laboratory When an individual has been inoculated with a plasmo- tests (Snow et al. 1992; Mudenda et al. 2011). (iii) Even dium parasite, a variety of clinical effects may follow, when severe malaria is documented in a health facility, within the sequence: the diagnosis may be missed or wrongly applied to Infection?asymptomatic parasitaemia?uncomplicated patients without malaria (Reyburn et al. 2004; Taylor illness?severe malaria?death. et al. 2004). Recent estimates based on verbal autopsies Many factors influence the disease manifestations of suggest that there is a substantial mortality from malaria the infection and the likelihood of progression to the last in older adults (Dhingra et al. 2010; Murray et al. 2012), two categories. These factors include the species of the but this is not borne out by hospital-based studies or clin- infecting parasite, the levels of innate and acquired ical observation (Lynch et al. 2012; White et al. 2012). immunity of the host, and the timing and efficacy of In endemic areas, severe malaria is very unusual in the treatment, if any. elderly. [For discussion of problems in malaria diagnosis, see Section 9]. An alternative approach to counting malaria deaths is to assume a contribution from malaria Plasmodium falciparum is the major cause of severe to all-cause mortality based on data from countries with malaria very good diagnostic and reporting systems (Black et al. Progression to severe and fatal disease is largely but not 2010). Mathematical modelling can then be used to pre- entirely confined to P. falciparum infections; in this sec- dict how various measurable indices might modify tion and in most of this document, we will discuss severe malaria mortality in different countries. malaria caused by P. falciparum. Although they contrib- ute much less than P. falciparum to the global burden of Estimated size and distribution of the problem of severe severe malaria, both P. vivax and P. knowlesi can also malaria cause severe disease and they do kill; these infections are discussed separately in Sections 13 and 14. Recent data suggest that there were around 627 000 deaths from malaria worldwide in 2012 (World Health Organization 2013). These were deaths directly attribut- Problems in determining the epidemiology of severe able to malaria (malaria also kills indirectly by reducing malaria birthweight and debilitating children with repeated infec- An accurate description of the incidence and distribution tions) and so would usually have been preceded by severe of severe malaria requires identification of cases, and sev- illness. With fewer than half of those who suffer severe eral factors make this problematic. (i) Malaria is most malaria being able to reach a health facility, and assum- prevalent where there is poverty and where methods of ing a case-fatality rate of 90% at home and 20% in hos- disease identification, documentation and reporting are pital (Thwing et al. 2011), the global annual incidence of weakest. (ii) A large proportion of severe malaria illnesses severe malaria can be estimated at approximately 2 mil- and deaths occur in people’s homes without coming to lion cases. In parts of the world where the transmission the attention of a formal health service: for children of P. falciparum is intense and stable, severe malaria is under 5 years of age, this proportion has been estimated mainly a disease of children from the first few months of at 90% in The Gambia (Greenwood et al. 1987) and at life to the age of about 5 years, becoming less common 49% more recently in Zambia (Mudenda et al. 2011). in older children and adults as specific acquired immunity ‘Verbal autopsies’ have been used to identify causes of gives increasing (although always incomplete) protection. death in community surveys, but their accuracy for About 90% of the world’s severe and fatal malaria is estimated to affect young children in sub-Sahara Africa Publication of this supplement was sponsored jointly by the (Black et al. 2010). In areas of lower endemicity, severe World Health Organization, the Medicines for Malaria Venture, malaria occurs in both adults and children. Non-immune Roll Back Malaria and The Wellcome Trust. travellers and migrant workers are vulnerable to severe © 2014 WHO. Tropical Medicine and International Health is published by John Wiley & Sons., 19 (Suppl. 1), 7–131 The World Health Organization retains copyright and all other rights in the manuscript of this article as submitted for publication. 7 Tropical Medicine and International Health volume 19 suppl 1 pp 7–131 september 2014 malaria, irrespective of the endemicity of the area consistently reported that the median age of patients is where their infection was acquired. Early large-scale inversely proportional to transmission intensity (Slutsker intervention studies with insecticide-treated bednets et al. 1994; Modiano et al. 1998; Idro et al. 2006a; (ITN) suggested that malaria contributed to as much as Okiro et al. 2009). In populations subjected to very high half of all mortality in children aged between 1 month inoculation rates year-round, severe anaemia is the most and 5 years (Alonso et al. 1993; Nevill et al. 1996). A common complication of P. falciparum infection, affect- later systematic literature review concluded that for the ing mainly infants and very young children, while in year 2000, an estimated 545 000 (uncertainty interval: areas with less intense or seasonal transmission, cerebral 105 000–1 750 000) children under the age of 5 in sub- malaria in slightly older children may predominate (Snow Saharan Africa were admitted to hospital for an episode et al. 1994, 2005; Slutsker et al. 1994; Modiano et al. of severe malaria (Roca-Feltrer et al. 2008). 1998; Snow & Marsh 1998). Reyburn et al. (2005) described the distribution of severe malaria syndromes and fatalities among 1984 patients admitted with severe Differences in clinical features of severe malaria between malaria to 10 hospitals serving populations living at ele- adults and children vations ranging from high (altitude >1200 m, very low The pattern of syndromes in severe malaria differs P. falciparum transmission intensity) to low (altitude between children and adults (see Table 1). It is uncertain <600 m, very intense transmission) in north-eastern Tan- whether these differences reflect mainly the age of zania. The mean age of severe malaria admissions was affected individuals or other differences between lowest in the most intense transmission area, where populations in the characteristics of host, parasite, pattern severe anaemia predominated, and highest in the low of exposure or provision of health services. There are few transmission area, where cerebral malaria predominated data on the pattern of clinical disease in children outside and case-fatality rates were highest. Systematic reviews of Africa (Dondorp et al. 2008b; Nanda et al. 2011). published articles reporting syndromes, ages and trans- mission patterns have confirmed this (Roca-Feltrer et al. 2008; Carneiro et al. 2010). In a study based in a Ken- Differing severe malaria syndrome patterns in African yan district hospital, a declining incidence of malaria children according to transmission intensity admissions was accompanied by an increase in the mean Studies of hospital admissions in different geographical age of children admitted with malaria and by an increase sites within high transmission areas in Africa have in the ratio of cerebral malaria to severe anaemia cases Table 1 Severe manifestations of Plasmodium falciparum malaria in adults and children Prognostic value (+ to +++) Frequency (+ to +++) Children AdultsClinical manifestations Children Adults +++ +++ Impaired consciousness +++ ++ +++ +++ Respiratory distress (acidotic breathing) +++ ++ +++Multiple convulsions +++ + ++Prostration +++ +++ +++ +++ Shock ++ +++ +++ Pulmonary oedema (radiological) +/À* + +++ ++ Abnormal bleeding +/À* + ++ + Jaundice + +++ Laboratory indices ++Severe anaemia +++ + +++ +++ Hypoglycaemia +++ ++ +++ +++ Acidosis +++ ++ +++ +++ Hyperlactataemia +++ ++ ++ ++ Renal impairment† + +++ +/À ++ Hyperparasitaemia ++ + *Infrequent. †Acute kidney injury. © 2014 WHO. Tropical Medicine and International Health is published by John Wiley & Sons., 19 (Suppl. 1), 7–131 8 The World Health Organization retains copyright and all other rights in the manuscript of this article as submitted for publication. Tropical Medicine and International Health volume 19 suppl 1 pp 7–131 september 2014 from 0.2 to 1.0 between 1999 and 2007 (O’Meara et al. several African countries, notably Sao Tome & Principe, 2008). This change in ratio resulted from a fall in the Madagascar, Eritrea, Ethiopia, Zambia and Zanzibar in incidence of severe anaemia, not from an absolute Tanzania, between 2000 and 2009 (Bhattarai et al. 2007; increase in the incidence of cerebral malaria. Graves et al. 2008; Teklehaimanot et al. 2009; Steketee & Campbell 2010). The marked decline in malaria mor- bidity and mortality in Vietnam during the 1990s was Impact of malaria control measures on the incidence and attributed to deployment of artemisinin and improved pattern of severe malaria access to treatment. On the island of Zanzibar, deploy- The estimated mortality