Tropical Medicine and International Health
12313
volume 19 suppl
Severe Malaria
Section 1: Epidemiology of severe
falciparum malaria
When an individual has been inoculated with a
plasmo- dium parasite, a variety of clinical effects
may follow, within the sequence:
Infection?asymptomatic
parasitaemia?uncomplicated illness?severe
malaria?death.
Many factors influence the disease manifestations
of the infection and the likelihood of progression to
the last two categories. These factors include the
species of the infecting parasite, the levels of innate
and acquired immunity of the host, and the timing and
efficacy of treatment, if any.
Plasmodium falciparum is the major cause of severe
malaria
Progression to severe and fatal disease is largely but not
entirely confined to P. falciparum infections; in this
sec- tion and in most of this document, we will discuss
severe malaria caused by P. falciparum. Although they
contrib- ute much less than P. falciparum to the global
burden of severe malaria, both P. vivax and P.
knowlesi can also cause severe disease and they do kill;
these infections are discussed separately in Sections 13
and 14.
Problems in determining the epidemiology of severe
malaria
An accurate description of the incidence and distribution
of severe malaria requires identification of cases, and
sev- eral factors make this problematic. (i) Malaria is
most prevalent where there is poverty and where
methods of disease identification, documentation and
reporting are weakest. (ii) A large proportion of severe
malaria illnesses and deaths occur in people’s homes
without coming to the attention of a formal health
service: for children under 5 years of age, this
proportion has been estimated at 90% in The Gambia
(Greenwood et al. 1987) and at 49% more recently in
Zambia (Mudenda et al. 2011). ‘Verbal autopsies’
have been used to identify causes of death in community
surveys, but their accuracy for
Publication of this supplement was sponsored jointly by the
World Health Organization, the Medicines for Malaria
Venture, Roll Back Malaria and The Wellcome Trust.
© 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.
doi:10.1111/tmi.
malaria is modest because severe malaria has no
features by which it can be confidently distinguished
from many other fatal febrile conditions in the absence
of laboratory tests (Snow et al. 1992; Mudenda et al.
2011). (iii) Even when severe malaria is documented
in a health facility, the diagnosis may be missed or
wrongly applied to patients without malaria (Reyburn
et al. 2004; Taylor
et al. 2004). Recent estimates based on verbal
autopsies suggest that there is a substantial mortality
from malaria in older adults (Dhingra et al. 2010;
Murray et al. 2012), but this is not borne out by
hospital-based studies or clin- ical observation (Lynch
et al. 2012; White et al. 2012). In endemic areas,
severe malaria is very unusual in the 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 to all-cause mortality based on data from
countries with very good diagnostic and reporting
systems (Black et al. 2010). Mathematical modelling
can then be used to pre- dict how various measurable
indices might modify malaria mortality in different
countries.
Estimated size and distribution of the problem of
severe malaria
Recent data suggest that there were around 627 000
deaths from malaria worldwide in 2012 (World Health
Organization 2013). These were deaths directly
attribut- able to malaria (malaria also kills indirectly by
reducing birthweight and debilitating children with
repeated infec- tions) and so would usually have been
preceded by severe illness. With fewer than half of those
who suffer severe malaria being able to reach a health
facility, and assum- ing a case-fatality rate of 90% at
home and 20% in hos- pital (Thwing et al. 2011), the
global annual incidence of severe malaria can be
estimated at approximately 2 mil- lion cases. In parts of
the world where the transmission of P. falciparum is
intense and stable, severe malaria is mainly a disease of
children from the first few months of life to the age of
about 5 years, becoming less common in older children
and adults as specific acquired immunity gives
increasing (although always incomplete) protection.
About 90% of the world’s severe and fatal malaria is
estimated to affect young children in sub-Sahara Africa
(Black et al. 2010). In areas of lower endemicity, severe
malaria occurs in both adults and children. Non-immune
travellers and migrant workers are vulnerable to severe
7
Tropical Medicine and International Health volume 19 suppl 1 pp 7–131 september 2014

malaria, irrespective of the endemicity of the area
where their infection was acquired. Early large-scale
intervention studies with insecticide-treated bednets
(ITN) suggested that malaria contributed to as much
as half of all mortality in children aged between 1
month and 5 years (Alonso et al. 1993; Nevill et al.
1996). A later systematic literature review
concluded that for the year 2000, an estimated 545
000 (uncertainty interval:
105 000–1 750 000) children under the age of 5 in
sub- Saharan Africa were admitted to hospital for an
episode of severe malaria (Roca-Feltrer et al. 2008).
Differences in clinical features of severe malaria
between adults and children
The pattern of syndromes in severe malaria differs
between children and adults (see Table 1). It is
uncertain whether these differences reflect mainly the
age of affected individuals or other differences
between populations in the characteristics of host,
parasite, pattern of exposure or provision of health
services. There are few data on the pattern of clinical
disease in children outside Africa (Dondorp et al.
2008b; Nanda et al. 2011).
Differing severe malaria syndrome patterns in
African children according to transmission intensity
Studies of hospital admissions in different
geographical sites within high transmission areas in
Africa have
Table 1 Severe manifestations of falciparum malaria in adults and children
Plasmodium
Prognostic value (+ to +++)
consistently reported that the median age of patients is
inversely proportional to transmission intensity
(Slutsker et al. 1994; Modiano et al. 1998; Idro et al.
2006a; Okiro et al. 2009). In populations subjected to
very high inoculation rates year-round, severe anaemia is
the most common complication of P. falciparum
infection, affect- ing mainly infants and very young
children, while in areas with less intense or seasonal
transmission, cerebral malaria in slightly older children
may predominate (Snow et al. 1994, 2005; Slutsker et
al. 1994; Modiano et al.
1998; Snow & Marsh 1998). Reyburn et al. (2005)
described the distribution of severe malaria
syndromes and fatalities among 1984 patients
admitted with severe malaria to 10 hospitals serving
populations living at ele- vations ranging from high
(altitude >1200 m, very low
P. falciparum transmission intensity) to low (altitude
<600 m, very intense transmission) in north-eastern
Tan- zania. The mean age of severe malaria
admissions was lowest in the most intense
transmission area, where severe anaemia
predominated, and highest in the low transmission
area, where cerebral malaria predominated and case-
fatality rates were highest. Systematic reviews of
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- yan district hospital, a declining
incidence of malaria admissions was accompanied by
an increase in the mean age of children admitted with
malaria and by an increase in the ratio of cerebral
malaria to severe anaemia cases
Frequency (+ to +++)

Children Adults Clinical manifestations Children Adults

+++ +++ Impaired consciousness +++ ++

+++ +++ Respiratory distress (acidotic breathing) +++ ++
+ ++ Multiple convulsions +++ +
+ + Prostration +++ +++
+++ +++ Shock + +
+++ +++ Pulmonary oedema (radiological) +/—* +
+++ ++ Abnormal bleeding +/—* +
++ + Jaundice + +++

Laboratory indices

+ + Severe anaemia +++ +

+++ +++ Hypoglycaemia +++ ++
+++ +++ Acidosis +++ ++
+++ +++ Hyperlactataemia +++ ++
++ ++ Renal impairment† + +++
+/— ++ 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.
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