Who Severe Malaria Tmih Supplement 2014

Tropical Medicine and International Health doi:10.1111/tmi.
12313
volume 19 suppl
Severe Malaria
Recent data suggest that there
malaria is modest because were around 627 000 deaths
severe malaria has no from malaria worldwide in
Section 1: Epidemiology of severe features by which it can be 2012 (World Health
falciparum malaria Organization 2013). These
confidently distinguished
When an individual has been inoculated with a plasmo-dium from many other fatal febrile were deaths directly attribut-
parasite, a variety of clinical effects may follow, within the conditions in the absence of able to malaria (malaria also
sequence: laboratory tests (Snow et al. kills indirectly by reducing
Infection?asymptomatic parasitaemia?uncomplicated illness? 1992; Mudenda et al. 2011). birthweight and debilitating
severe malaria?death. (iii) Even when severe children with repeated infec-
Many factors influence the disease manifestations of the malaria is documented in a tions) and so would usually
infection and the likelihood of progression to the last two health facility, the diagnosis have been preceded by severe
categories. These factors include the species of the infecting may be missed or wrongly illness. With fewer than half
parasite, the levels of innate and acquired immunity of the host, applied to patients without of those who suffer severe
and the timing and efficacy of treatment, if any. malaria (Reyburn et al. 2004; malaria being able to reach a
Taylor health facility, and assum-ing
et al. 2004). Recent estimates a case-fatality rate of 90% at
based on verbal autopsies home and 20% in hos-pital
Plasmodium falciparum is the major cause of severe
suggest that there is a (Thwing et al. 2011), the
malaria
substantial mortality from global annual incidence of
Progression to severe and fatal disease is largely but not entirely malaria in older adults severe malaria can be
confined to P. falciparum infections; in this sec-tion and in most (Dhingra et al. 2010; Murray estimated at approximately 2
of this document, we will discuss severe malaria caused by P. et al. 2012), but this is not mil-lion cases. In parts of the
falciparum. Although they contrib-ute much less than P. borne out by hospital-based world where the transmission
falciparum to the global burden of severe malaria, both P. vivax studies or clin-ical of P. falciparum is intense and
and P. knowlesi can also cause severe disease and they do kill; observation (Lynch et al. stable, severe malaria is
these infections are discussed separately in Sections 13 and 14. 2012; White et al. 2012). mainly a disease of children
In endemic areas, severe from the first few months of
malaria is very unusual in life to the age of about 5
Problems in determining the epidemiology of severe years, becoming less common
malaria the elderly. [For discussion
of problems in malaria in older children and adults as
An accurate description of the incidence and distribution of diagnosis, see Section 9]. An specific acquired immunity
severe malaria requires identification of cases, and sev-eral alternative approach to gives increasing (although
factors make this problematic. (i) Malaria is most prevalent counting malaria deaths is to always incomplete)
where there is poverty and where methods of disease assume a contribution from protection. About 90% of the
identification, documentation and reporting are weakest. (ii) A malaria to all-cause mortality worlds severe and fatal
large proportion of severe malaria illnesses and deaths occur in based on data from countries malaria is estimated to affect
peoples homes without coming to the attention of a formal with very good diagnostic young children in sub-Sahara
health service: for children under 5 years of age, this proportion and reporting systems (Black Africa (Black et al. 2010). In
has been estimated at 90% in The Gambia (Greenwood et al. et al. 2010). Mathematical areas of lower endemicity,
1987) and at 49% more recently in Zambia (Mudenda et al. modelling can then be used severe malaria occurs in both
2011). Verbal autopsies have been used to identify causes of to pre-dict how various adults and children. Non-
death in community surveys, but their accuracy for measurable indices might immune travellers and
modify malaria mortality in migrant workers are
different countries. vulnerable to severe
Publication of this supplement was sponsored jointly by the World

Health Organization, the Medicines for Malaria Venture, Roll Back Estimated size and
Malaria and The Wellcome Trust. distribution of the problem
of severe malaria
2014 WHO. Tropical Medicine and International Health is published by John Wiley & Sons., 19 (Suppl. 1), 7131
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 7131 september 2014
vations ranging from high
(altitude >1200 m, very low
P. falciparum transmission
consistently reported that the intensity) to low (altitude
malaria, irrespective of the endemicity of the area where their median age of patients is <600 m, very intense
infection was acquired. Early large-scale intervention studies inversely proportional to transmission) in north-eastern
with insecticide-treated bednets (ITN) suggested that malaria transmission intensity Tan-zania. The mean age of
contributed to as much as half of all mortality in children aged (Slutsker et al. 1994; severe malaria admissions
between 1 month and 5 years (Alonso et al. 1993; Nevill et al. Modiano et al. 1998; Idro et was lowest in the most
1996). A later systematic literature review concluded that for al. 2006a; Okiro et al. 2009). intense transmission area,
the year 2000, an estimated 545 000 (uncertainty interval: 105 In populations subjected to where severe anaemia
0001 750 000) children under the age of 5 in sub-Saharan very high inoculation rates predominated, and highest in
Africa were admitted to hospital for an episode of severe year-round, severe anaemia is the low transmission area,
malaria (Roca-Feltrer et al. 2008). the most common where cerebral malaria
complication of P. falciparum predominated and case-
infection, affect-ing mainly fatality rates were highest.
infants and very young Systematic reviews of
Differences in clinical features of severe malaria between adults
children, while in areas with published articles reporting
and children
less intense or seasonal syndromes, ages and trans-
The pattern of syndromes in severe malaria differs between transmission, cerebral malaria mission patterns have
children and adults (see Table 1). It is uncertain whether these in slightly older children may confirmed this (Roca-Feltrer
differences reflect mainly the age of affected individuals or other predominate (Snow et al. et al. 2008; Carneiro et al.
differences between populations in the characteristics of host, 1994, 2005; Slutsker et al. 2010). In a study based in a
parasite, pattern of exposure or provision of health services. 1994; Modiano et al. 1998; Ken-yan district hospital, a
There are few data on the pattern of clinical disease in children Snow & Marsh 1998). declining incidence of
outside Africa (Dondorp et al. 2008b; Nanda et al. 2011). Reyburn et al. (2005) malaria admissions was
described the distribution of accompanied by an increase
severe malaria syndromes and in the mean age of children
Differing severe malaria syndrome patterns in African
children according to transmission intensity fatalities among 1984 patients admitted with malaria and by
admitted with severe malaria an increase in the ratio of
Studies of hospital admissions in different geographical sites to 10 hospitals serving cerebral malaria to severe
within high transmission areas in Africa have populations living at ele- anaemia cases
+++ +++ +++ Acidosis

Table 1 Severe manifestations of Plasmodium +++ ++ +++ +++ Hyperlactataemia
falciparum malaria in adults and children +++ ++ ++ Renal impairment
+
Prognostic value (+ to +++) + +/ ++ Hyperparasitaemia
+++ + *Infrequent.
Children Adults +++ +++ Acute kidney injury.
8 The World Health Organization retains copyright and all other rights in the manuscript of this article as submitted for publication.
spraying with effective
insecticide (Barnes et al.
2005). In some countries
several African countries, where there have been
from 0.2 to 1.0 between 1999 and 2007 (OMeara et al. 2008). notably Sao Tome & Principe, impressive reductions in
This change in ratio resulted from a fall in the incidence of Madagascar, Eritrea, hospital admis-sions and
severe anaemia, not from an absolute increase in the incidence Ethiopia, Zambia and deaths due to malaria, there
of cerebral malaria. Zanzibar in Tanzania, has been a later resurgence
between 2000 and 2009 that may reflect lack of
(Bhattarai et al. 2007; Graves sustained resources for the
Impact of malaria control measures on the incidence and pattern
of severe malaria et al. 2008; Teklehaimanot et local malaria control
al. 2009; Steketee & programme (Hamel et al.
The estimated mortality from malaria of 781 000 in 2009 and Campbell 2010). The marked 2011). In some African
627 000 in 2010 represents a decline from 985 000 in the year decline in malaria mor-bidity countries, no decline in
2000 (World Health Organization 2010b). The role of malaria and mortality in Vietnam severe or fatal malaria is yet
control measures in causing this reduction cannot be assumed, during the 1990s was detectable (Roca-Feltrer et al.
but several lines of evi-dence point to a causal link between attributed to deployment of 2008). Reliable monitoring of
deployment of effec-tive vector control measures (ITNs, artemisinin and improved hospital admissions and
insecticides) and effective drugs (ACTs) and declining mortality. access to treatment. On the deaths will remain an
Causality is likely when there are strong geographical island of Zanzibar, deploy- important tool for measuring
associations of control measures with improvements, absence of ment of ACTs in late 2003 the impact of control
changes in some other causes of death and consistency with was associated with a 75% measures on the incidence of
predictions of the likely effects of malaria-specific interventions reduction in malaria- severe and fatal malaria
(Steketee & Campbell 2010). Akachi and Atun (2011) estimated attributable mortality in during the coming decades, as
that increased coverage with ITN and indoor residual spraying children under 5 years over there is a world-wide effort to
prevented around 240 000 child deaths in sub-Saharan Africa the next 2 years (Bhattarai et move towards malaria
between 2002 and 2008. Hospital admissions and deaths, with al. 2007). The containment of elimination and eventual
identification of parasitaemia, provide the most dependable the 19952000 malaria epi- eradication (Rajaratnam et al.
indicators of the likely incidence of severe malaria in a demic in KwaZulu Natal was 2010).
population, and dramatic falls in these events have been recorded attributed to deployment of
in ACTs and indoor residual
(Molyneux et al. 1989b;
Marsh et al. 1995; Mishra et
al. 2007c; Helbok et al. 2009;
signs, the presence of one or Hanson et al. 2010; Jallow et
more of the clinical or labo- al. 2012; von Seidlein et al.
Section 2: Definitions of severe malaria
ratory features in Table 1 2012, New-ton et al 2013).
Severe malaria by definition is associated with a high mortality. classifies that patient as Coma is assessed clinically
From a clinical perspective, there is a contin-uum from suffer-ing from severe by coma scales, and acidosis
asymptomatic malaria to uncomplicated illness through to severe malaria. Many of the features is reflected clinically by the
and lethal malaria. Before artemisinin combination treatments in Table 1 are not rate and depth of breathing
(ACT) became widely available, uncomplicated falciparum independent. It is not always (English et al. 1996b)
malaria was associated with a case-specific mortality of clear which have the strongest although, if possible,
approximately 0.1% when there was ready access to effective prognostic significance, and measurement of plasma
antimalarial drug treatment. Thus, 1 patient in 1000 who not all can be recorded with bicarbonate, base deficit or
presented with apparently uncomplicated falciparum malaria equal ease. Inclusive plasma lactate is more
would deteriorate despite treatment and die. With worsening definitions to guide clinical precise.
resistance and/ or delays in access to effective drugs mortality management are outlined in
approached 1 in 100 (1%). The mortality with ACTs is lower Tables 2 and 3, and a more
than 0.1% as artemisinins are particularly effective in the group specific definition of severe Clinical approach to the
of patients with high ring-stage parasitae-mias who may appear falciparum malaria for patient with suspected severe
only mildly ill, but then deteriorate rapidly coincident with epidemiological or research malaria. Any patient with
extensive parasite red cell seques-tration. The mortality of P. purposes is detailed in malaria, who is unable to take
knowlesi infections is higher, but the mortality associated with Table 4. In recent years, medications reliably, has any
the other malarias is substantially lower than for falciparum several different prognostic evidence of vital organ
scores have been developed dysfunction or has a high
malaria. The exception is on the island of New Guinea, where
parasite count, is at increased
there is intense transmission of both P. falciparum and P. vivax, both for adults and for chil-
dren with severe malaria. risk of dying. The exact risk
and recurrent infections result in severe anaemia.
These reflect that the two depends on the infecting
malaria parasite species, the
main determinants of
degree of abnormality, the
outcome in both adults and
Definitions of severe falciparum malaria number of systems affected,
children are the level of
age, background immunity,
In a patient with a P. falciparum asexual parasitaemia and no consciousness and the degree
other confirmed cause for their symptoms or of metabolic acidosis
i e o
Table 2 Outline bedside clinical classification of r p c
severe malaria in children in a high transmission e a
area d c l
o i
Group 1 Prostrate children (prostration is the c m s
inability to sit upright in a o a e
child normally able to do so n
or to drink in the case of s C a
children too young to sit).
Three subgroups of c o
increasing severity should i m p
be distinguished: o a a
Prostrate but fully conscious u i
s ( n
P
n t f
r
e h u
o
s e l
s
s
t
i s
r
b n t
a
u a i
t
t b m
e
i u
n l l
w
o i u
i
t t s
t
y )
h
i
n t R
i
o e
m
d s
p
e l p
a
i of i e
r gro t m
a up o
t 1 < g
o (ab l
r ove 1 o
y )*. 5 b
The % i
d se n
i incl 2 u
s ude r
t chil
o i
r dre
e r a
n
s wit
s h m (
any o b
( of r l
a the e a
c foll c
i owi c k
d ng: o w
o n a
t H v t
i a u e
c e l r
m s )
b i Jaundice
o
r o
g
e n Group 3 Children who require parenteral
l
a s treatment because of persistent
t o
vomiting but who lack any
h b specific clinical or laboratory
i w features of groups 1 or 2
i
n i (above)
n
g t
) < h *If parasite
: 5 i counts are
Mild sustained nasal flaring n immediately
and/or mild intercostal g available, a
/ a parasitaemia
indrawing (recession)
over 10%
Severe the presence of d should be
either marked indrawing l 2 included in
(recession) of the bony 4 group 2.
structure of the lower o - Children are
chest wall or deep r h defined as
(acidotic) breathing <12 years
Shock compensated or p old.
h
decompensated (see definition a e
above) e r
m i
Group 2 Children who, although able to be o
a
treated with oral antimalarials, d
t
require supervised
o
management because of the
c H
risk of clinical deterioration but
r a
who show none of the features
Table 3 Outline bedside clinical classification of severe malaria in adults
Group 1 Adults at increased risk of dying immediately who require parenteral antimalarials and appropriate supportive therapy Prostrated or
obtunded adults (prostration is the inability to sit or to drink). Four subgroups of increasing
severity should be distinguished:
Prostrate but fully conscious
Prostrate with impaired consciousness but not in deep coma (GCS > 11)
Confusion and agitation (GCS > 11)
Coma (the inability to localise a painful stimulus) (GCS < 11)
Respiratory distress (acidotic breathing)
Mild sustained nasal flaring and/or mild intercostal indrawing (recession)
Severe the presence of either marked indrawing (recession) of the bony structure of the lower chest wall or deep
(acidotic) breathing
Shock (hypotension:systolic BP < 80 mmHg)
Anuria
Significant upper gastrointestinal haemorrhage
Group 2 Adults who, although able to be treated with oral ACTs, require supervised management because of the risk of clinical
deterioration but who show none of the features of group 1 (above)*. This group includes adults with any of the
following:
Haemoglobin <7 g/dl or haematocrit <20% One or
more convulsions within a 24-h period
Haemoglobinuria (blackwater)
Jaundice
Group 3 Adults who require parenteral treatment because of persistent vomiting but who lack any specific clinical or laboratory
features of groups 1 or 2 (above)
*If parasite counts are immediately available a parasitaemia over 4% should be included in group 2.
Table 4 Epidemiological and research definition of severe falciparum malaria
For epidemiological and research purposes, severe malaria is defined as one or more of the following, occurring in the absence of an identified
alternative cause, and in the presence of P. falciparum asexual parasitaemia:
Impaired consciousness: A Glasgow Coma Score <11 in adults or a Blantyre coma score <3 in children
Acidosis: A base deficit of >8 meq/l or, if unavailable, a plasma bicarbonate of <15 mM or venous plasma lactate
>5 mM. Severe acidosis manifests clinically as respiratory distress rapid, deep and laboured breathing
Hypoglycaemia: Blood or plasma glucose <2.2 mM (<40 mg/dl)
Severe malarial anaemia: A haemoglobin concentration <5 g/dl or a haematocrit of <15% in children <12 years of age (<7 g/dl and
<20%, respectively, in adults) together with a parasite count >10 000/ll
Renal impairment Plasma or serum creatinine >265 lM (3 mg/dl) or blood urea >20 mM
(acute kidney injury):
Jaundice: Plasma or serum bilirubin >50 lM (3 mg/dl) together with a parasite count >100 000/ll
Pulmonary oedema: Radiologically confirmed, or oxygen saturation <92% on room air with a respiratory rate >30/min, often
with chest indrawing and crepitations on auscultation
Significant bleeding: Including recurrent or prolonged bleeding from nose gums or venepuncture sites; haematemesis or melaena
Shock: Compensated shock is defined as capillary refill 3 s or temperature gradient on leg (mid to proximal limb),
but no hypotension. Decompensated shock is defined as systolic blood pressure <70 mm Hg in children
or <80 mm Hg in adults with evidence of impaired perfusion (cool peripheries or prolonged capillary refill)
Hyperparasitaemia: P. falciparum parasitaemia >10%
immediately at the point of at increased risk should be
pre-morbid and concomitant diseases, and access to appropriate care, but results of other lab- given the benefit of the
treatment. The patient must be assessed and treated without delay. oratory measures, if any, highest level of care
A practical bedside approach to the immediate assessment and may be available only after available. The attending
classification of children with suspected severe malaria is shown hours or days. The start of clinician should not worry
in Table 2 and for adults in Table 3. Tests such as the parasite treatment must not wait. As unduly about definitions; the
count, haematocrit and blood glucose may all be determined severe malaria is potentially severely ill patient
fatal, any patient considered
movements with deviation,
increased salivation or
abnormal respiratory
point where a clear response patterns.
Table 5 A coma scale for children (Blantyre coma scale). This scale is is obtained. A localising
for children, including those who have not learned to speak response must be
Prostration is the inability,
distinguished from a brisk
Best motor response Score
because of extreme
flexion response. The
localises painful stimulus* 2 weakness, to sit unassisted,
interpretation of appropriate
Withdraws limb from pain 1 in an adult or a child who is
cry is diffi-cult, some
Non-specific or absent response 0 normally able to do so. In
children are stoical, and the
Verbal response children not old enough to sit
Appropriate cry 2 appropriateness of verbal
up, pros-tration is defined as
Moan or inappropriate cry 1 response needs to be
the inability to breastfeed.
None 0 considered in the light of
Prostra-tion must always be
Eye movements other responses and the age
Directed (e.g. follows mothers face) 1
recorded directly and not
of the child. It is best to test
Not directed 0 based on history. Many
directed eye movement by
Total 05 patients who have a fever
asking the mother to move
and feel unwell prefer to lie
Unrousable coma 2. her face across the childs
or, in the case of children, to
*Painful stimulus: rub knuckles on patients sternum. field of vision, as the child
be carried but are capable of
Painful stimulus: firm pressure on thumbnail bed with horizon-tal may be less interested in
sitting if gently encouraged
pencil. looking at any other face or
to do so.
object.
requires immediate supportive care, and if severe malaria is a
Shock. Compensated shock
possibility, parenteral antimalarial drug treatment should be
is defined as capillary refill
started without delay. In summary - if in doubt, treat as severe Respiratory distress (acidotic
3 s or temperature gradient
malaria. breathing). Deep, laboured,
on leg (mid to proximal
Patients with a high parasite count (>4%) in a low noisy and often rapid
limb), but no hypotension
transmission setting but none of the clinical or laboratory breathing (Kussmauls
after adequate rehydration.
indicators of severe malaria should be monitored closely, breathing) with increased
Decompensated shock is
preferably in hospital for the first day of treatment. Although inspiratory and expiratory
defined as systolic blood
oral treatment with an artemisinin derivative is highly effective, chest excursion is the most
pres-sure <70 mm Hg in a
provided there is no vomiting (Luxem-burger et al. 1995), if important respiratory sign of
child and <80 mm Hg in an
there is any clinical doubt, treat-ment should be started with severe malaria. Patients with
adult, with cool peripheries
parenteral artesunate followed by an ACT. acidosis may sometimes have
(this assessment may vary
such deep laboured breathing
between observers) and
that their respiratory rates are
prolonged capillary refill 3
slow. In children, sustained
Impaired consciousness. Before the general use of coma scales, s after ade-quate rehydration.
nasal flaring and indrawing
the term cerebral malaria was used for patients with malaria Accurate blood pressure
(reces-sion) of the bony
who were unrousable, that is, unable to localise a painful measurement in young
structures of the lower chest
stimulus. This has been superseded by a Glasgow coma score of children depends on using
wall on inspiration should
less than 11 of 15 in adults (Teasdale & Jennett 1974) or a the correct sphygmo-
also be noted.
Blantyre coma score of less than 3 of 5 in children who are too manometer cuff size.
young to speak (Molyneux et al. 1989b; Newton et al. 1997a).
Multiple convulsions.
Many patients with malaria recover full consciousness after a
Generalised seizures are Pulmonary oedema is
convulsion, and so it is important to exclude transient post-ictal
common, particularly in suspected in any patient who
coma. Assessment for clinical management pur-poses should be
children, with severe develops tachypnoea
made immediately, but for classification, cerebral malaria is
malaria. Commonly, (respiratory rate >30/min),
coma which persists for > 1 h after a seizure irrespective of
convulsions, especially dyspnoea and hypoxia
anticonvulsant medications.
recurrent seizures, are subtle (oxygen saturation <92% on
(resulting in little or no room air) with
The Blantyre coma score (Table 5) requires careful local movement of limbs), and
standardisation. Care must be exercised in apply-ing the painful care should be taken to
stimuli; it is unkind and unnecessary to test responses repeatedly. detect minor manifestations
Testing should begin with a minimal stimulus, which should be
such as twitching of a digit,
increased only to the
repetitive jerky eye
severity of illness is different
in different populations and
age groups, and there has
AKIN criteria, but an been considerable debate
chest signs of diffuse wheeze or crepitations. It is con-firmed individuals previous values whether it should be included
radiologically. Abnormal bleeding is rare in severe malaria and are sel-dom available in at all in definitions of
may manifest by bleeding from the gums, nose, gastrointestinal malaria-endemic areas. As severity. In children in areas
tract or venepuncture sites. most patients with severe of unstable endemicity, a
malaria are children or peripheral parasitaemia of 4%
Jaundice. This is detected clinically by examining the sclera younger adults with normal or more (4% of circulat-ing
and/or mucosal surfaces of the mouth. Jaundice may occur in pre-morbid renal function, a red cells contain parasites)
adults with uncomplicated malaria so for a precise plasma creatinine over 265 lM carried an increased risk of
epidemiological classification of severe malaria jaundice is (3 mg/dl) is used as a death (Luxemburger et al.
defined as a combination of elevated plasma bilirubin (>50 lM criterion of severe malaria. 1995). A 4% parasitaemia in
or 3 mg/dl) together with a parasite count >100 000/ll. This corresponds to a GFR of non-immune children or
approximately <30 ml/min in adults should be considered
a man and <25 ml/min in a an indicator of high risk
Severe anaemia is suspected clinically from pale mucosal woman (eGFR requiring supervised manage-
surfaces and palms and confirmed by measurement of calculator: ment (Tables 2 and 3) but not
haemoglobin concentration or packed cell volume. Severe http://www.renal.org/egfrca by itself a criterion of severe
anaemia is defined as a haemoglobin <5 g/dl or a haemat-ocrit of lc for patients aged 18 years
malaria. In areas of stable
<15% in children (age <12 years) and a haemo-globin <7 g/dl or or more). This plasma
endemicity, parasita-emia
a haematocrit of <20% in adults. It should be specified whether creatinine level corresponds
thresholds should be derived
results are from a finger prick or venous sample. Finger prick approximately to a blood from local experience, but in
samples may underesti-mate the haemoglobin concentration by urea of 20 mM, a blood urea
the absence of local data, a
>1 g/dl if the fin-ger or ear lobe is squeezed during blood nitrogen of 57 mg/dl or parasitaemia >10% without
collection. Anaemia is common in malaria-endemic areas, blood urea of the other signs of severity
particu-larly in young children. To distinguish malaria-related
122 mg/dl, although patients described above indi-cates
anaemia from coincidental malaria for a precise epidemi-ological
with severe malaria may be severe malaria.
classification, severe anaemia is defined as above in combination
hypercatabolic and
with a parasite count >10 000/ll. It is difficult to distinguish
dehydrated which increase
chronic from acute anaemia. Chronic severe anaemia is common
the urea/ creatinine ratio. In
in areas of high malaria transmission, and areas with heavy
the past, acute kidney injury
hookworm burdens, and carries a better prognosis than rapidly Epidemiological and
has also been defined in terms
developing anaemia associated with an acute malaria infection. research definition of
of reduced urine output (<400
severe vivax malaria
ml in adults, <12 ml/kg/24 h
in children) despite rehydra- The criteria for severe vivax
Hypoglycaemia is a whole blood or plasma glucose con- tion, but this is much less malaria are the same as for
centration of <2.2 mM (<40 mg/dl). For screening pur-poses, useful as it requires accurate adults and children with
rapid tests are valuable, but their accuracy diminishes at blood monitoring and waiting 24 h. severe falciparum malaria
glucose concentrations below 3 mM and may be affected by low Oliguric renal failure rarely but with no parasitaemia
haematocrit. For research purposes, hypoglycaemia should be complicates P. falciparum density thresholds (and
confirmed on a venous sample measured with a glucose infection in young children. without the criterion of
analyser. Prognostically, a blood urea hyperparasitaemia) (see
measurement of >20 mM in Section 13). Although the
Acidosis is defined as a plasma bicarbonate concentration <15 children or adults with severe specificity is reduced without
mM or base excess below 8 meq/l. In the absence of laboratory malaria identifies a high-risk a parasitaemia threshold,
facilities, acidosis can be inferred from the presence of deep group with a mortality over parasite densities in vivax
breathing with a clear chest on ausculta-tion. Hyperlactataemia is 30% (Dondorp et al. 2005a, malaria are usually lower
defined as a plasma or whole blood lactate level >5 mM. 2010; Hanson et al. 2011a; than P. falciparum (almost
von Seidlein et al. 2012). always <2% of total red
Renal impairment or acute kidney injury is not well defined cells). The
from a single measurement. Changes in measures of glomerular
filtration rate are more important, and these are incorporated in
the widely used RIFLE and Hyperparasitaemia. The
relation of parasitaemia to
1 P. knowlesi
hyperparasitaemia
: Parasite density
a P. falciparum infection of >100 000/ll
mechanisms of severe disease may differ from those in fal- similar density. All the 2 Jaundice and parasite
ciparum malaria and are not clearly related to parasite bio-mass. severity manifestations listed density >20 000/ll
There is a 4- to 5-fold greater loss of uninfected red cells in P. for severe falciparum malaria Any patient with a
vivax infection relative to P. falciparum infec-tion at low parasite have been reported with P. knowlesi
densities, so P. vivax may cause severe anaemia at lower knowlesi malaria, except for parasitaemia of >20
parasitaemias. coma (see Section 14). 000/ll needs to be
Criteria for severe knowlesi observed very
malaria are the same as for carefully.
Epidemiological and research definition of severe
the definitions for adults and
knowlesi malaria
children with severe
Plasmodium knowlesi infections have a threefold higher risk of falciparum malaria but with
developing severe malaria than P. falciparum (Barber et al. lower parasitaemia cut-offs
2012). The risk of severe malaria is 28-fold greater with a for hyperparasitaemia and
parasitaemia >100 000/ll than the risk in jaundice as follows:
were comatose; in the same
series, 155 (62%) of the
children admitted had severe
bral malaria and metabolic anaemia (Allen et al. 1997).
acidosis. These may occur Among 6200 children
Section 3: Clinical features of severe separately or in any admitted to a rural hospital in
falciparum malaria in children
combination. The presence of Zambia, about 10% had
Most of the estimated 0.6 million malaria deaths every year impaired consciousness or severe malarial anaemia and
are in children up to 5 years old who live in areas of intense severe respiratory distress half as many had cerebral
transmission of P. falciparum, especially in sub-Saharan pre-dicted 84.4% of 64 malaria; but as the case-
Africa (World Health Organization 2013). deaths among 1844 children fatality rate in cere-bral
Severe malaria is rare in early infancy. Babies born to mothers admitted with malaria to a malaria was 19% and that of
who have malaria during pregnancy are at risk of having a lower district hospital in coastal severe malarial anaemia was
birthweight than the community average, usually as a result of Kenya. In this study, severe 9%, these two severe malaria
intrauterine growth retardation (see Section 5). Low birthweight anaemia was common but syndromes contributed
is associated with increased mortality from all causes in infancy rarely fatal unless approximately equally to the
(Steketee et al. 1996). In endemic areas neonates may have cord accompanied by impaired malaria-related mortality
blood and peripheral parasitaemia which usually disappears consciousness or severe (Biemba et al. 2000). In a
within hours or days. Congenital malaria (illness in the neonate respiratory distress (Marsh et prospective multicentre trial
resulting from malarial infection) is uncommon, but may present al. 1995). Hypoglycaemia comparing artesunate with
as fever, anaemia, and/or neonatal jaundice 10 30 days after and jaundice are additional quinine in childhood severe
delivery. This may mimic neonatal sepsis. Over the next few complications that may malaria conducted in 11
months of life, parasitaemia appears in an increasing proportion occur, usually in association centres in nine African
of children, the rate of increase in prevalence being a measure of with one or more of the countries, 5426 children were
transmission intensity. The great majority of infections are above syn-dromes. Both enrolled of whom 9.7% (527)
oligosymptomatic or symp-tomless and are reflected in the high hypoglycaemia and jaundice died. There were five highly
prevalence of asymp-tomatic parasitaemia among children in are associated with an significant independent
endemic areas. The likelihood of symptoms increases with the increased case-fatality rate predictors of mortality: base
density of parasitaemia, allowing statistical calculations of and were present in 31% and deficit [adjusted odds ratio
malaria-attributable morbidity (Smith et al. 1994). 16% of deaths, respectively, (AOR) 1.12, 95% CI 1.10
in the Kenya study. All of the 1.13], coma score (AOR 1.40,
deaths were among children 95% CI 1.341.45),
Importance of malaria as cause of severe disease and with coma or respi-ratory
mortality in older infants and children convulsions (AOR 1.72, 95%
distress. The pattern of CI 1.302.30), BUN (AOR
From the age of a few months onwards, infected infants may clinical events associated 1.02, 95% CI 1.021.03) and
develop severe disease. One study estimated that about one with death may be different chronic illness (AOR 2.12,
infection in a hundred progressed to cause complications (i.e. in the absence of hospital 95% CI 1.253.58) (von
became severe) in a population in The Gambia (Greenwood et treatment. In Nigeria, 46.5% Seidlein et al. 2012). The
al. 1991). These figures and the case-fatality rates of severe of 147 children with fatal relationships between 3 of
disease probably differ between populations dependent upon the P. falciparum infections had these predictors and their
transmission characteristics, health service provisions and cerebral malaria (Elesha et al. associated case fatalities are
availability, parasite drug sensitivities, and a variety of parasite 1993). In the Gambia, 43% of illustrated in Figure 1.
and host factors. Malaria is one of the three commonest rea-sons children admitted to hospi-tal
for admission to hospital and is a major cause of hospital death over a period of several years,
in children aged 15 years, in many ende-mic areas (Roca- and diagnosed as having
Feltrer et al. 2008; Black et al. 2010). severe malaria, were in coma Problems affecting the
diagnosis of severe
(Waller et al. 1995); the pro-
malaria in children
portion was similar 50%
in a series in Burkina Faso The difficulty of
Relative importance of different syndromes in fatal
(Modiano et al. 1995), but distinguishing clinically
malaria
considerably smaller in a between severe malaria and
Among the clinical syndromes that define severe malaria in series in Madang, Papua New pneumonia. Several studies
children (Tables 1 and 2), the most commonly encoun-tered fall Guinea, where of 249 have demon-strated the
into three main categories: severe anaemia, cere- children admitted to hospital problem of distinguishing
with severe malaria, 56 (22%) clinically between
impairm
ent and
metaboli
c
acidosis
alone or
in
combina
tion. The
sizes of
the ovals
are
Figure proporti
1 Data onal to
compile number
d from of cases.
prospect
ive
series of
severe
falciparu illnesses will also be
m accompanied by parasitaemia,
malaria yet have another cause. These
in 6189
children
illnesses include all of the
in syn-dromes that can be
studies caused by severe malaria,
conducte each of which can have other
d in causes. Vigilance for
Africa diagnoses other than malaria
and
pneumonia and malaria. In Malawi, of 471 children attending a (comorbidities), even in the
2605
hospital outpatient department who fulfilled the WHO clinical adults in presence of parasitaemia, is
definition for pneumonia, 449 (95%) also met the clinical studies important (Koram &
definition of malaria (Redd et al. 1992). Among Gambian conducte Molyneux 2007). Indicators
children with cough or breath-ing difficulty and a raised d in that malaria is a likely cause
South- of the presenting illness
respiratory rate, 38% had only malaria (parasitaemia with normal
East include high-density
chest radiograph) in the season of intense malaria transmission, Asia.
compared to 6% during the season of low malaria transmission Left side
parasitaemia and
(ODempsey et al. 1993). In Kenya, 200 children with fever, shows thrombocytopenia, although
cough, tachypnoea and additional features of respi-ratory the neither of these provide
distress, were compared with 26 children with def-inite prevalen diagnostic certainty (Figure
pneumonia (radiological consolidation, no parasitaemia) and 38 ce of 2). In the comatose patient,
different the presence of malarial
children with definite malaria (nor-mal chest radiograph, features
parasitaemia >100 000/ll); chest indrawing, unilateral signs and retinopathy is highly
of
crackles or wheeze were significantly associated with severe suggestive of a malarial
pneumonia, and pallor and deep breathing with malaria, but no falciparu aetiology of the illness [see
group of signs was entirely specific or sensitive for either m Section 8 (reti-nopathy)].
diagnosis (English et al. 1996a). malaria There have been few studies
by age, of the alternative causes of
and complicated febrile disease in
Venn
children in malar-ious
These observations indicate the need to consider and treat for diagram
both malaria and pneumonia in children with fever and chest s on the populations: in a recent
symptoms, in malarious areas, especially where either right hospital study in Malawi, of
radiological or microscopy facilities are not available (Bloland show the 513 children suspected to
mortalit have meningitis who had no
et al. 1991). [See Management of concomitant sepsis p104 for y in evidence of bacterial
discussion on the use of antibiotics in severe malaria] children
infection, 26% had PCR
and
adults evidence of at least one virus
The problem of diagnosis affects all syndromes that can
associate in the cerebrospinal fluid
resemble malaria. In a community with a high preva-lence of
asymptomatic parasitaemia, many febrile d with (Mallewa
manifest
ations of
et al. 2013). The
cerebral
and
development of bedside
renal diagnostic tests for
bacteraemias and viral infections would make an important individuals of all ages are presents with higher parasite
contribution to both epidemiology and patient care in more susceptible to severe burden, more com-plications
communities and peripheral hospitals in areas where incidental malaria (Otieno et al. 2006; and more frequent
P falciparum parasitaemia is common. Malamba et al. 2007; Imani comorbidity and carries a
et al. 2011). Severe malaria in higher case-fatality rate
Effects of HIV on childhood severe malaria. HIV-infected HIV co-infected patients (Hendriksen et al. 2012a).
cerebral malaria in 27
parasitaemic Malawian
children (Taylor et al. 2004)
causes. In most published compared autopsy evidence
Caution is needed when attributing complications to studies, the term cerebral of intracerebral parasite
P. falciparum infection, as HIV immunosuppression also malaria has been restricted to sequestration with ante-
increases susceptibility to many of the opportunistic infections the syndrome in which altered mortem clin-ical findings. In
that cause clinical illnesses that might be mis-takenly attributed consciousness, associated seven cases, autopsy revealed
to malaria in populations with a high prevalence of incidental with a malarial infec-tion, an alternative cause of death
parasitaemia. could not be attributed to and no intracerebral
convulsions, sedative drugs or sequestration, while in 20,
Strengthening the definition of severe malaria. These var-ious hypoglycaemia alone or to a there was intracerebral
considerations have led to increasing attempts to standardise the non-malarial cause. A child sequestration and no alterna-
definition of severe malaria in children, often fuelled by the need with loss of consciousness tive cause of death. Nineteen
to assess the efficacy or effec-tiveness of interventions (severe after a febrile convul-sion of the 20 with sequestered
malaria episodes being a primary endpoint) or to identify should not be considered to parasites had retinopathy
accurately patients to be recruited to pathogenesis or treatment have cerebral malaria unless before death, while none of
studies (severe malaria as enrolment criterion). The Severe coma persists for more than 1 those without intracranial
Malaria in African Children (SMAC) network aimed to quantify h after the convul-sion. parasites had retinopathy.
and describe severe malaria across a variety of epidemiologi-cal Similarly in a child with These results indicate (i) that
settings in order to design intervention studies with more precise malaria and hypoglycaemia the clinical diagnosis of CM
sample size estimates (Taylor et al. 2006a). The network enrolled who is comatose, diagnosis of is com-monly wrong and (ii)
20 333 parasitaemic children across five sites in sub-Saharan cerebral malaria cannot be that the presence of
Africa with differing malaria transmission characteristics and sustained if consciousness is retinopathy is highly
identified the incidence of various severe syndromes in these promptly restored by admin- suggestive of the presence of
diverse contexts. The programme to assess the malaria vaccine istration of glucose. Cerebral intracerebral parasite
RTS,S gave rise to a widely deliberated case definition of severe malaria is a clinical syn- sequestration, a characteristic
malaria to be used in identifying the primary end-point in the drome; the term is convenient histopathological feature of
Phase 3 multicentre trials (Vekemans et al. 2011). The definition for descriptive purposes. fatal CM. Several
included: presence of one or more clinical and/or laboratory descriptions of malarial
markers of disease severity; exclusion of four major The problem of diagnosis in retinopathy have been
comorbidities (pneumonia, men-ingitis, bacteraemia and cerebral malaria. Finding published in both children
gastroenteritis with severe dehy-dration); and a P. falciparum retinopathy improves and adults (Figure 2) (Lew-
parasitaemia density threshold (to maximise the specificity of the specificity. The syndrome of allen et al. 1996; Hero et al.
case defini-tion). This recommendation was largely based on a coma, commonly with 1997; Hien et al. 2003; Beare
prior analysis of 4583 well children and 1361 children admit-ted convulsions, that is the et al. 2004, 2006; Harding et
to a district hospital in Kenya (Bejon et al. 2007). The latter hallmark of cere-bral malaria al. 2006; Maude et al. 2009a).
study confirmed that increasing the parasita-emia threshold is like all other syndromes Retinopathy can be seen by
improved specificity but reduced sensitiv-ity of severe malaria that can complicate P. non-specialist clini-cians
diagnosis and that the malaria-attributable fraction of diagnoses falciparum infection, one that using direct or indirect
is considerably lower (61%) in areas of intense transmission than has a number of other ophthalmoscopy through
in areas of low or moderate transmission intensity (85%). possible causes. Some of dilated pupils, but training is
these are identifiable by required to achieve depend-
bedside examination or tests able results (Beare et al.
for example measles, 2002; Mohammed et al.
bacterial men-ingitis but 2011). Retinopathy can
Syndromes defining severe malaria in children many are not identifiable include any of four features.
immediately, if at all, in most Two of these are distinctive
Cerebral malaria (CM)
hospitals for example other and specific to malaria: these
Impaired consciousness. A number of different disease viral encephaliti-des, toxic are (i) patchy retinal
processes may affect consciousness in the child with malaria, syndromes, and intracranial whitening in the macula
including convulsions, hypoglycaemia, hyperpy-rexia, acidosis, vascular or mechan-ical (especially peri-foveal) and/or
severe anaemia and sedative drugs. How-ever, coma may events. Where asymptomatic in the peripheral retina; and
develop in the absence of any of these parasitaemia is common, (ii) white or orange dis-
attributing coma to malaria is colouration of retinal vessels.
problematic. A study of fatal Other features that may
conjugate gaze. Corneal and

accompany these but which may also be caused by non-malarial pupillary light reflexes are
conditions are: (iii) white-centred haemorrhages and (iv) usually retained.
papilloedema. A system for classifying and grading these Abnormalities of muscle tone
components has been proposed (Lewallen et al. 1999). and pos-ture are frequently
seen (Molyneux et al. 1989b;
Retinopathy has been used to improve the classification of Mabeza et al. 1995; Waller et
severe malaria (Lewallen et al. 2008) and to increase the al. 1995; Rey et al. 1966).
specificity of the diagnosis of CM for studies of path-ogenesis or These may take the form of
treatment (Birbeck et al. 2010a). The severity of retinopathy has muscular hypotonia or, more
been found to be prognostic in children and adults with CM com-monly, of decerebrate or
(Beare et al. 2004; Maude et al. 2009a). decorticate posturings, which
may be intermittent or
sustained. In some children,
Preceding symptoms in CM. In children with cerebral malaria extreme opisthotonos is seen Figure 2 Retina in a child with
who are admitted to hospital, the duration of febrile symptoms which may misleadingly cerebral malaria. On the macula
is usually short. In a series of 131 patients studied in Malawi, suggest a diagnosis of tetanus there is extensive retinal
the mean length of reported history was 47 h (range 2 h to 7 or meningitis. Bruxism whitening in patches, maximal
around the fovea (centre of
days) (Molyneux et al. 1989b); in 195 Zambian children with (grinding of teeth) is picture); and several white-
cerebral malaria, the median duration of preceding fever had common. Plantar reflexes are centred haemor-rhages. The optic
been 49.3 h (range 013 days) (Mabeza et al. 1995). The some-times abnormal, and disc is at the right edge of the
earliest symptom is usually fever, which is followed by failure abdominal reflexes are picture.
to eat or drink. Vomiting and cough were reported in the almost invariably absent.
majority of cases in Malawi; diarrhoea is an unusual symptom.
Convulsions are common before or after the onset of coma (see
below). Convulsions. The majority of
children with cerebral malaria
have convulsions. Cerebral
General features. Most but not all children with cerebral malaria malaria was considered to be
are febrile. Rectal temperatures range from 36 to 41 C or even the cause of convulsions in
higher. Dehydration is present in many cases (Waller et al. 1995; one-third of children admitted
English et al. 1996d), but is rarely severe. The systolic blood to a Nigerian hospital in 1988
pressure is usually normal, but there is a wide pulse pressure. (Asindi et al. 1993).
Most patients have a tachy-cardia appropriate to their fever. Convulsions may be
Cardiac arrhythmias are rare. Breathing may be rapid or generalised or focal, single or
laboured; deep breathing suggests acidosis (see below). recurrent, and unlike febrile
Examination of the heart and lungs is usually normal. A minority convulsions may occur in
of patients have cold, clammy skin with a core-to-skin chil-dren of any age (Rey et
temperature difference >10 C. Some of these patients are in a al. 1966) and at any level of
state of shock with systolic blood pressure <50 mmHg. Jaundice body temperature (Molyneux
is less com-mon in children than in adults with cerebral malaria et al. 1989b). In some patients
(White et al. 1987a; Molyneux et al. 1989b). Hepato-
splenomegaly is commonly found at presentation or during the
course of the disease. Spontaneous bleeding into the skin or
gastrointestinal tract is rare.
Neurological features. The depth of coma may be assessed by

observing the response to standard painful or vocal stimuli (see
Table 5). The gag reflex is usually but not invariably preserved.
In patients with profound coma, corneal reflexes and
oculocephalic dolls eye reflexes may be abnormal, and there
may be abnormalities of
11.5% (13.3% in survivors)
and a case fatality of 13.5%.
As the children in these
frequent observations are studies did not have pre-
(about 25% of children with cerebral malaria in a Kenyan made. In some children, morbid assessments, they
hospital), seizure activity can be demonstrated by electro- recov-ery of consciousness may include some with pre-
encephalography in the presence of only minor, if any, con- may represent the end of a existing neurological
vulsive movements of limbs or facial muscles but with jerky eye post-ictal state or emergence abnormalities. The most
movements with deviation, excessive salivation and irregular from a drug-induced stupor; common sequelae were ataxia
breathing patterns (non-convulsive status epi-lepticus) (Crawley these conditions cannot be (43%), hemiplegia (39%),
et al. 1996); in a study in Malawi, elec-troencephalography distinguished from cerebral speech disorders (39%) and
revealed seizures in 7 (19%) of 36 children with cerebral malaria malaria, but the timing of blindness (30%). Other
in whom there were no external signs of seizure activity (Birbeck recovery may be suggestive. sequelae on discharge include
et al. 2010b). behavioural disturbances,
Neurological and cognitive hypotonia, generalised
Intracranial pressure. The mean opening pressure at lumbar sequelae after cerebral spasticity and a variety of
puncture is 160 mm CSF, which is similar to that in adults, but as malaria in children. The tremors. Sowunmi (Sowunmi
the normal range is much lower in chil-dren, this means that majority of children who 1993) described two children
approximately 80% of children have intracranial pressures above survive cerebral malaria with visual and auditory
the normal range (New-ton et al. 1991; Waller et al. 1991). The make a full neurological hallucinations a few days
mechanism and pathophysiological importance of raised recov-ery, but a significant after recovery from cerebral
intracranial pres-sure are uncertain. Magnetic resonance imaging number are left with malaria.
reveals evidence of cerebral oedema in many children with cere- neurological sequelae,
bral malaria, especially in those with retinopathy, and the while others develop later
Several studies suggest that
presence of cerebral oedema is a strongly adverse prognostic cognitive and behavioural
a significant proportion of
indicator (Potchen et al. 2012). Whether raised intracranial difficulties or epilepsy
reported neurological deficits
pressure plays a causal role in coma or death remains to be (Figure 3).
actually reflect slow neuro-
determined. This topic is discussed more fully in the logical recovery. In a
pathophysiology section (Section 7). Neurological sequelae. A prospective study of 624
combined analysis of 11 early children admitted with
African series which used cerebral malaria to two
Recovery from cerebral malaria. The reported hospital case varying methodologies to hospitals in The Gambia, van
fatality of cerebral malaria in children has ranged from 10 to assess outcomes included Hensbroek et al. (1997) found
40% (Dumas et al. 1986; White et al. 1987a; Molyneux et al. 1341 children with cerebral that 23.3% of survivors had
1989b; Waller et al. 1995). In the recent large multicentre trial malaria with a case fatality of neurological sequelae on
that compared intravenous artesu-nate and quinine in the 19% and neurological discharge from the hospital,
treatment of 5425 children with severe malaria, mortality among sequelae in 6.7% (Commey et but by 1 month, the
those with cerebral malaria was 359/1825 (19.7%) (Dondorp et al. 1980; Omanga et al. 1983; proportion had decreased to
al. 2010). Most deaths of hospitalised children occurred within Schmutzhard & Gerstenbrand 8.6%, and at 6 months, only
24 h of admission, about two-thirds being from a cardio- 1984; Molyneux et al. 1989b; 4.4% of survi-vors were
respiratory arrest probably due to metabolic derange-ments, Brewster et al. 1990; Bondi found to have residual
while in the remaining one-third, there was respiratory arrest, 1992; Sowunmi 1993; neurological sequelae. In the
with clinical features of brainstem dys-function that suggested Sowunmi et al. 1993; Bojan large artesunate versus
raised intracranial pressure. In an audit of 306 children dying of et al. 1997). Studies from quinine trial (AQUAMAT) in
cerebral malaria in Kenya, 196 (65%) had simultaneous cessation Malawi (Molyneux et al. severe malaria, the proportion
of cardiac and respiratory activity, while 110 (35%) initially had 1989b), The Gambia of children surviving cerebral
cessa-tion of respiratory activity with good continuing cardiac (Brewster et al. 1990), malaria with neurological
activity (H. Bulstrode, personal communication). In survi-vors, Nigeria (Bondi 1992) and deficits [170/1466 (11.6%)]
the duration of altered consciousness after the start of treatment Kenya (Peshu, personal had also reduced significantly
ranges from a few hours to several days, the mean being about communication) used when the children were
30 h in Malawi (Molyneux et al. 1989b) and a median of 12 h in essentially similar criteria: in assessed 38 weeks later. Of
the Gambia (White et al. 1987a). The transition from coma to full these studies, a total of 1060 the 170 patients, 129 were
consciousness is sometimes very rapid and may not be witnessed children were reported with followed up between 3 and 8
unless an overall incidence of weeks later and at
neurological seque-lae of
Immediate and long term deficits

Motor deficits
Hypotonia
Monoparesis, hemiplegia, spastic quadriparesis/plegia
Movement and gait disorders
Ataxia
Tremors
Visual impairments
Cortical blindness
Speech and language deficits
Deficits in vocabulary, semantics, pragmatics, phonetics, word finding
Aphasia
Other cognitive deficits

Deficits in planning and executive functions, attention, memory and non-verbal
functioning
Behaviour problems
Attention and disruptive behaviours and conduct disorders
Epilepsy
Focal, multifocal and generalized epilepsy
0 2 4 6 8 10 12 14 16 18 20 22 24
Time in months after exposure
Figure 3 Manifestations and resolution of sequelae of cerebral malaria in children. Some sequelae of cerebral malaria (e.g. motor weakness and
spasticity), blindness or loss of speech are apparent on recovery from the coma, while others such as behaviour difficul-ties and epilepsy may not
appear until several weeks or months after discharge from hospital. Some deficits present on discharge such as generalised hypotonia, ataxia,
aphasia and blindness may resolve over the months following discharge. Thickness of shaded area corresponds approximately to relative (i.e. not
absolute) proportions.
of 132 cerebral malaria malaria (Figure 3). In Kenyan
this follow-up assessment, 68 (53%) had recovered fully, 18 survivors developed epilepsy children who had suffered
were mildly or moderately impaired, and 43 had severe ver-sus none of 264 controls malaria with impaired con-
neurological deficits (Dondorp et al. 2010). A smaller study of [odds ratio (OR) undefined; sciousness, reviewed at least
44 Ugandan children gave similar results; although neurological P < 0.0001]. In the same 42 months after exposure,
deficits were seen in 28.2% on discharge, rates decreased to study, 28 of 121 cerebral impairments in executive
9.5% at 3 months and 0% at 6 months (Boivin et al. 2007). Many malaria survivors developed functions, in particular the
patients with persistent neurological sequelae particularly new neurodisabilities, char- abil-ity to initiate, plan and
blindness, ataxia and central hypotonia also show considerable acterised by gross motor, carry out tasks, were
improvement with time (Schmutzhard & Gerstenbrand 1984; sensory or language deficits, significantly more common
Bondi 1992; John et al. 2008), but other severe neurological compared with two of 253 than in controls (Holding et
symptoms persist (Carter et al. 2005a), while others such as controls (OR 37.8, 95% CI al. 1999). Carter et al.
epilepsy and behaviour difficulties may develop after discharge 8.8161.8; P < 0.0001). A examined 152 children after
(Carter et al. 2004; Ngoun-gou et al. 2006a,b; Opoka et al. 2009; similar delayed manifestation cerebral malaria, 156 after
Birbeck et al. 2010a; Idro et al. 2010). Cortical blindness shows of epileptic seizures was malaria with multiple seizures
the most dramatic resolution; in the different series above, described in Uganda where and 179 controls, to identify
between 80 and 90% of children with cortical blindness the cumulative incidence of developmental impairments
recovered sight fully (Figure 3). seizures increased over time (Carter et al. 2004, 2005a,b,
with a total of two of 76 2006). Of children who
children (2.6%) reporting recovered from cerebral
seizures at 3 months, three of malaria 24% had deficits in at
Epilepsy developing after severe malaria. A retrospective study 74 children (4.1%) at 6 least one domain and 42% of
in Kenya identified epilepsy in 14/152 (9.2%) chil-dren who had months and 11 of 68 children those with impairments had
suffered cerebral malaria compared to 4/ 179 (2.2%) controls (16.2%) at 24 months multiple impairments.
(Carter et al. 2004), while in Mali, 5/101 (4.9%) survivors of (Opoka et al. 2009). Eighteen children (11.8%) of
cerebral malaria had epilepsy compared to 1/222 (0.5%) controls the cerebral malaria group, 14
(Ngoungou et al. 2006b). In a study in Malawi, 132 children with (9%) of the malaria with
retinop-athy-positive cerebral malaria and 264 age-matched, non- Longer term cognitive seizures group and four
comatose controls were followed up for a median of sequelae. Cognitive deficits (2.2%) of controls had
495 days (IQR 195819) (Birbeck et al. 2010b). Twelve are major sequelae of cerebral language impair-
20 2014 WHO. Tropical Medicine and International Health is published by John Wiley & Sons., 19 (Suppl. 1), 7131
The World Health Organization retains copyright and all other rights in the manuscript of this article as submitted for publication.
associated with increased
mortality (Crawley et al.
2000), and this inter-vention
but not identical, to those did not improve cognitive
ment (Carter et al. 2006). Language deficits (in compre-hension, predicting mortality. The outcome in survivors
syntax, pragmatics and word finding) and defi-cits in memory, main risk factors include (Abubakar et al. 2007). In a
attention, behaviour and motor skills were more pronounced in prolonged and repeated study to assess the memory
those with active epilepsy. Sim-ilar evidence of impaired seizures, deep and prolonged outcomes of cerebral malaria,
language development has been reported among 83 Malawian coma, and intracranial the number of seizures or
children after recovery from cerebral malaria with retinopathy hypertension (Molyneux et al. seizure duration did not
(Boivin et al. 2011). Other studies in Uganda and Senegal have 1989b; Brewster et al. 1990; independently predict
described similar cognitive deficits especially in working Crawley et al. 1996; van everyday memory (Kihara et
memory and attention (Boivin 2002; Boivin et al. 2007). Hensbroek et al. 1997; Idro et al. 2009). It is likely that
Although it has been reported, hearing loss has not been al. 2004). Others are male prolonged and recurrent
systematically examined as a sequela of severe malaria (Zhao & gender and higher admission seizures worsen an initial
Mackenzie 2011). These developmental impair-ments have been tempera-ture (Birbeck et al. neural injury that is partly
confirmed in more recent studies in Malawian children in whom 2010b); age younger than 3 responsible for the seizures
malaria retinopathy was used as an inclusion criterion to improve years (Molyneux et al. 1989b) themselves. Intracra-nial
on the diagnos-tic accuracy of cerebral malaria. In this cohort, up and a biphasic clinical course hypertension may lead to
to one-third (42/132; 32%) of children who survived cere-bral characterised by recovery of reduced cerebral perfusion
malaria developed epilepsy or new neurobehavioural consciousness followed by pressure, and impaired
impairments (Birbeck et al. 2010b; Boivin et al. 2011). Adverse recurrent convulsions and nutrient and oxygen delivery
outcomes appeared to develop sequentially, with motor, sensory coma (Brewster et al. 1990). that result in global ischaemic
or language deficits being evident initially, followed by The prevalence of sequelae injury and death, and contrib-
disruptive behaviour at a median of increases with worsening ute to clinical features
depth of coma on admission. suggesting herniation and
150 days and lastly epilepsy at a median period of about 300 In a cohort of 143 surviving brain-stem compression
days. Post-cerebral malaria epilepsy manifested as localisation- Kenyan children, 5/6 (83%) (Walker et al. 1992; Newton
related epilepsy with focal motor, complex partial, focal with with admission Blantyre et al. 1997b). There remains
secondary generalisation, multifocal or generalised tonic clonic Coma Score 0 had uncertainty how important
seizures (Birbeck et al. 2010b). impairments compared to these processes are overall as
5/18 (28%) of those with a a cause of brain damage and
Abnormal behaviour. Preliminary studies suggest that some score of 1 and 24/119 (20%) death in cerebral malaria (see
children recovering from cerebral malaria may develop of those with score 2 (Idro et pathophysiology Section 7
behavioural abnormalities including hyperactiv-ity, al. 2006b). Children who for discussion of raised
impulsiveness and inattentiveness or conduct disor-ders such were later found to have intracranial pressure, and
as aggressive, self-injurious and destructive behaviour. These impairments had a slower pathol-ogy Section 8 for
defects are particularly seen in patients with other severe recovery from coma, with a autopsy findings).
sequelae (Idro et al. 2010; Boivin et al. 2011). In the study of median time to full
Malawian children, disruptive behaviour fulfilling the DSM IV consciousness about
criteria for attention deficit and hyperactivity disorder was
described in 14/132 (10.6%) after a median follow-up period of 8 h longer than those without
495 (IQR 195819) days (Birbeck et al. 2010b). The impairments. Although Syndromes defining
pathogenesis is still poorly understood, and more detailed repeated seizures feature severe malaria in children
descriptions are awaited. The findings from all these studies prominently as a risk factor
Metabolic acidosis
suggest that (i) brain damage after cerebral malaria in children is for sequelae, the role of
more common than was originally thought; (ii) sequelae can take seizures in the causation of In many severe disease states,
many forms including defects of movement and coordination, brain injury is not clear; it is including severe malaria, the
cognitive and behavioural impairments and epilepsy; and (iii) possible that the seizures presence of acidaemia is
many of these sequelae are not evident at the time of discharge them-selves are a associated with a high case
from hospital (Figure 3). manifestation of brain injury. fatality (Stacpoole et al.
Although high-dose 1994). Acidaemia is a
prophylactic phenobarbitone manifesta-tion of severe
malaria, whether there is
Prognostic factors for neurological sequelae. Prognostic factors significantly reduced seizures
associated with neurological sequelae are similar, in cerebral malaria, it was altered
2012).
60
50
40
30
20
10
Mortality (%)
<7.0 7.0 7.1 7.2 7.3 7.4

40 pH
30
20
10 Figure 4 Relationship between

mortality and acidosis (measured
by venous pH and base deficit) in
<20 15 10 5 0 5 5426 African children admitted
Base excess (meq/L) with severe malaria (Dondorp et
al. 2010; von Seidlein et al.
metabolic two major sign of lung

acidosis (base Respir components that disease, usually
consciousness or not (Krishna et al. 1994; excess equal to atory may both pneumonia, or of
Marsh et al. 1995; Waller et al. 1995). In a or less than distres contribute to this. metabolic acidosis
selected group of Malaw-ian children minus 12) was s. Deep breathing and is usually
admitted to hospital with a primary diagno- strongly associ- Respir involves an associated with
sis of malaria, 66/145 (46%) were found to ated with risk of atory abnormally increased use of
be either acidaemic, with a pH < 7.3, or death (relative distres increased accessory muscles.
had a compensated meta-bolic acidosis risk 8) in a s is a amplitude of chest In practice, most
(Taylor et al. 1993). 72% of children who series of 299 summ excursion. It is a cases of
subsequently died were acidotic on children with ary sign of metabolic respiratory distress
admission. 42% of children with cerebral severe malaria. descri acidosis. The in association with
malaria were acidaemic, and mor-tality in In the ption increased depth of malaria constitute
these children was 28% compared to 3% in AQUAMAT applie respira-tion may deep breath-ing
the non-acidaemic group (relative risk of trial in 5426 d to be accompanied by secondary to
death for the aci-daemic group = 8.5). children with childrea degree of metabolic acidosis.
Acidosis was the major indepen-dent risk severe malaria, n who intercostal in- In a small
factor for death and was also strongly there was a have drawing proportion of
associated with hypoglycaemia, a known progressive rise obviou(recession) cases, there is
risk factor for death in malaria; all 14 in mortality sly particularly in thin concomitant
hypoglycaemic patients were aci-dotic. with increasing abnor- children with pneumonia. The
Lactic acidosis appears to be the major (but acidosis (Figure mal raised respiratory presence of either
not the only) contributing mechanism of 4) (Dondorp et breathirates, but the deep breathing or
acidosis. Serial clini-cal and metabolic al. 2010, von ng intercostal chest indrawing
changes were measured in 115 Gam-bian Seidlein et al. involv indrawing is in should be regarded
children with severe malaria (Krishna et al. 2012). ing the proportion to the as a danger sign.
1994) of whom 21 died. Mean venous expen overall increase in Although the
blood lactate was almost twice as high in diture effort and is not respiratory rate
fatal cases as survivors. After treatment, of prom-inent. The will usually be
lactate concentration fell rapidly in more second possible raised above the
survivors but fell only slightly, or rose, in effort component is true age-related normal
fatal cases. It is in the minority of patients than indrawing of the range, the actual
whose hyperlactataemia does not resolve in usual. bony structures of degree of
the first few hours of admission that the There the lower chest tachypnoea does
progno-sis is worst. In Kenya, severe are wall. This can be a not correlate well
with the overall impression of distress, respiratory rate, hunge ng). Respiratory (Lackritz et al.
whether it results from metabolic acidosis as the pattern of r distress is a major 1992). In the
or parenchymal lung disease. In fact, respiration (Kuss risk factor for majority of cases,
progressively severe metabolic acidosis changes from mauls death in children it results from
may be associ-ated with a decrease in panting to air breathiwith malaria severe
Anaemia may develop
rapidly during the course of a
malarial illness, especially if
(Jarvis et al. 2006). A large there is initial
metabolic acidosis. Among 1844 children admitted consec- randomised multicentre trial hyperparasitaemia
utively to Kilifi Hospital on the Kenyan coast with a pri-mary enrolling 3141 African (McGregor et al. 1956).
diagnosis of malaria, 14% had respiratory distress (nasal flaring, children admitted to hospital While anaemia may be
indrawing (recession) of the bony structure of the chest wall or with fever and impaired tissue present or may develop in a
deep breathing) of whom 14% died. Of all children with malaria perfusion showed that child with any complication
who subsequently died, 55% had respiratory distress on adminis-tration of additional of P. falciparum infection,
admission. Over 80% of a sub-group of these children with fluid boluses, whether severe anaemia may be the
respiratory distress were profoundly acidotic (Marsh et al. 1995). albumin or sal-ine, increased only or predominant
Respiratory distress in severe malaria may be wrongly mortality when compared to complication of malaria in a
ascribed to congestive cardiac failure secondary to severe controls given routine fluid child presenting to a health
anaemia. In a study of 24 intensively monitored Kenyan management (Maitland et al. facility; in this cir-
children with severe respiratory distress, 16 were severely 2011). Studies in adults cumstance, and in a child
anaemic (haemoglobin 2.14.9 g/dl) (English strongly suggest that found to have severe anaemia
et al. 1996a). Lactate concentrations were significantly higher in hypovolaemia is not a major in a community survey, the
the severely anaemic group, and plasma creati-nine levels were contributor to acidosis in rapidity of onset of anaemia
higher in the children with low central venous pressures. older patients (Hanson et al. can-not be determined. In a
Resuscitation with rapid transfusion of blood in the severely 2012). It is likely that survey of children aged
anaemic children (10 ml/kg over different factors may under
1 h followed by 10 ml/kg over the next 14 h) was asso-ciated contribute to acidosis in 5 years living in villages in
with rapid resolution of acidosis and clinical improvement in the different individuals, the southern Tanzania,
majority. These findings suggest that respiratory distress in the principal mechanism being Schellen-berg et al. (2003)
severely anaemic child is com-monly caused by acidosis inadequate oxygenation of reported a high prevalence
resulting from inadequate oxy-gen delivery to poorly perfused tissues, leading to anaer-obic of anaemia, especially
tissues, rather than to congestive cardiac failure. glycolysis. While the among children in the
The relative importance of the clinical syndrome of respiratory importance of hypovolaemia second half of infancy,
distress and its overlap with impaired con-sciousness and severe and shock remain uncertain, among whom 10% had
anaemia in severe childhood malaria is shown in Figure 1 and other contributory processes severe anaemia (<5 g/dl).
Figure 5 (Marsh et al. 1995). The highest mortality occurred in include sequestration in the In the great majority of
children with both neurological impairment and respiratory microvasculature and severe cases, anaemia was not
distress. Deep breathing is an accurate clinical indicator of the anaemia, and exacerbating suspected, and the infant
presence of acidosis (English et al. 1996b), a fact that has factors include was not considered by its
prompted some investigators to argue that expensive attempts to hypoglycaemia, impaired mother to be ill.
measure plasma lactate concentration or acid/ base balance are hepatic function, renal Severe anaemia is often
superfluous (Newton et al. 2005a). However, most studies impairment and recent multifactorial and is attribut-
suggest that laboratory measures are more sensitive and specific convulsions (English et al. able to malaria because of
indicators of acidosis. Aci-dosis is largely due to the 1997) (see Section 7). parasitaemia and the lack of
accumulation of both lactic acid and 3-hydroxybutyric acid as an adequate alternative
well as other unidenti-fied organic acids (Sasi et al. 2007). The explanation. In an extensive
accumulation of lactic acid in the circulation results more from Syndromes defining study in Malawi, 381 pre-
tissue anoxia and anaerobic glycolysis, together with impaired severe malaria in children school children presenting to
gluconeogenesis, than from the release of lactate by par-asitised Severe anaemia two hospitals with severe
anaemia (<5 g/dl) were com-
erythrocytes (Krishna et al. 1994).
Anaemia is an important and pared with 757 age- and
commonly life-threatening location-matched controls
The role of intravascular volume depletion in the patho-
with-out severe anaemia: this
genesis of acidosis remains uncertain. Although some stud-ies complication of falciparum
malaria in children. The study showed that severe
have reported an association of acidosis with apparent
mean age of children anaemia had multiple
hypovolaemia and shock (reviewed in Maitland & Newton
associations, including
2005), one study including 56 children with severe malaria found presenting with severe
malarial anaemia is about 1.8 malaria, bacteraemia, HIV
no evidence of volume depletion
years, compared to 3 years in infection, hookworm and
those presenting with Vitamin A and B12
cerebral malaria (Figure 1). deficiencies (Calis et al.
2008). The importance
quinine, included coma
(57%), circulatory failure
(38%), and respiratory
from the disease (White et al. distress (21%), and less
of malaria as a cause of severe anaemia is suggested by the 1987b; Taylor et al. 1988; commonly, seizures (10%).
seasonality of severe anaemia, the incidence of which tends to Bassat et al. 2008; Camara et Dis-ruption of maintenance
follow that of malaria; although nutritional and other factors may al. 2011; Nanda et al. 2011). fluids and/or blood
also change with season (Koram et al. 2000). In an area of very Hypoglycaemia is particularly transfusion coincided with
intense P. falciparum transmis-sion in Western Kenya, 83% of common in young children 42% of the hypoglycaemia
1116 paediatric hospital admissions were parasitaemic: severe (<3 years), in those with episodes. Post-admission
anaemia was identi-fied in 21% of admissions and in 12% of in- convulsions or hyper- hypoglycaemia increased the
hospital deaths (Obonyo et al. 2007). Among 8195 febrile Gabo- parasitaemia, in patients with odds of fatal out-come (24%)
nese children, almost all were anaemic to some degree, and the profound coma and those who compared to children who
risk of severe anaemia was highest among infants (Bouyou- have received quinine remained euglycae-mic (8%),
Akotet et al. 2009). Of 2433 children admitted to a Kenyan (Dondorp et al. 2010). It is odds ratio = 3.45.
hospital in 1990, 684 (29%) had severe anaemia (Hb <5.0 g/dl), associated with convulsions,
and this was strongly associated with P. falciparum parasitaemia. lactic acidosis, and high con-
18% of the severely anaemic patients died, compared to 8% of centrations of circulating Pulmonary and renal
all admissions (Lackritz et al. 1992). In this and in other studies tumour necrosis factor. Hypo- complications. Capillary
(Marsh et al. 1995; Bojang et al. 1997), the mortality among glycaemia is easily blood pO2 and arterial blood
anaemic children was increased greatly when there was overlooked clinically because oxygen saturation are normal
associated respiratory distress. In the review of 5426 Afri-can the manifestations may be in nearly all patients with
children admitted to the multicentre AQUAMAT trial (Dondorp similar to those of cerebral severe malaria. Plasma urea
et al. 2010), in which there was ready access to blood malaria. In a child with and creatinine concentrations
transfusion, mortality did not rise until the haemo-globin impaired consciousness due may be elevated on
concentration fell below 3 g/dl (von Seidlein et al. 2012). Blood to cerebral malaria, correction admission, especially in the
transfusion reduced the case-fatality rate in children with of hypoglycaemia with presence of dehydration;
anaemia and respiratory distress (Lackritz et al. 1992). In that intravenous 50% dextrose values revert to normal during
study, blood transfusion given after a delay of 2 days was not does not, by definition, result treatment (English et al.
beneficial, suggesting that mortal-ity due to severe anaemia may in immediate restoration of 1996c). Biochem-ical
be considerably greater in the community than in hospital, where consciousness. evidence of renal impairment
prompt treatment can be given. Community deaths from severe Hypoglycaemia may recur on admission is an
anaemia are difficult to identify in retrospect because of the poor during treatment of severe independent risk factor for
sensi-tivity and specificity of verbal autopsies for the diagnosis malaria; these recurrences poor outcome even though
of anaemia (Snow et al. 1992). may be due to the disease (in acute kidney injury (acute
which case plasma insulin renal failure) is rare in
concen-trations are children (von Seidlein et al.
appropriately low) or quinine- 2012) (Figure 1).
Syndromes defining severe malaria in children induced hyper-insulinaemia. Hyponatraemia was found in
Recurrent hypoglycaemia 55% of 132 children with
Other complications severe malaria in Kenya and
may be difficult to detect
Hypoglycaemia. Children are more likely than adults to develop clinically in the comatose was usually not attributable to
hypoglycaemia and may become hypoglycaemic solely as a child and may cause deep- inappropriate secretion of
result of fasting, particularly during any illness accompanied by ening coma or convulsions. antidiuretic hormone
An increase in the loading secretion (English et al.
fever and vomiting. Hypoglycaemia was found in 32% of
dose and frequency of 1996d). Chest radiographs are
Gambian children (White et al. 1987b) and 20% of Malawian
usually normal, even in the
children presenting with severe malaria (Taylor et al. 1988), and administration of quinine in
presence of deep or laboured
43 (7%) of 603 chil-dren admitted to hospital in Mozambique, in the treat-ment of severe
breathing; this is further
association with a variety of clinical conditions including malaria in children in a
evidence that pulmonary
malnutri-tion, pneumonia, and malaria (Solomon et al. 1994). Kenyan hospital did not lead
oedema or acute respiratory
Hypoglycaemia (whole blood glucose <2.2 mM) com-monly to any increase in the
distress syndrome is rare in
complicates severe malaria in children and is associated with an incidence or severity of hyp-
children. Hypokalaemia was
increased risk of dying or sequelae oglycaemia (Ogetii et al.
present on admission in only
2010). Factors associated four of 38 children with
with recurrent severe malaria and acidosis
hypoglycaemia, apart from admitted to a Kenyan district
al. 1988; Molyneux et
al. 1989b; Walker et al.
1992; Krishna et al.
mortality increasing greatly 1994; Issifou et al.
hospital, but 15 of these children became hypokalaemic within at very high levels of para- 2007; Orimadegun et al.
the first 48 h after admission, a change attributed to increased sitaemia. In young children 2007; Bassat et al.
2008; Ranque et al.
urinary loss of potassium (Maitland et al. 2004). The same group particularly from areas of
2008; Camara et al.
reported hyperkalaemia in 61/ 493 (12%) of Kenyan children high transmission, severe 2011);
with severe malaria, among whom there was a particularly high anaemia is the most
case-fatality rate (28%) (Maitland et al. 2003a). important manifestation of
malaria and mortality rises
6 blood glucose
concentrations between
Hyperpyrexia. High fever is a common feature of falci-parum significantly if the 2.2 and 4.4 mM have
malaria in children, but there is no association between the haematocrit is below 13% also been associated
with a worse prognosis
degree of fever and the presence or likeli-hood of development (haemoglobin 4 g/dl) than higher levels
of severe malaria. Convulsions in children with malaria may (Lackritz et al. 1993). (Willcox et al. 2010;
occur at body temperature, but the risk increases at Among children with Nadjm et al. 2013);
temperatures above 38.5 C (Familusi & Sinnette 1971; Patel severe malaria, features 7 biochemical
1971; Axton & Siebert 1982). Very high temperatures can associ-ated with an evidence of
increased risk of death impaired renal
contribute to altered consciousness or coma. High maternal function (Maitland
include: et al. 2003a; von
temperature causes fetal distress in pregnant women with Seidlein et al. 2012).
malaria (Looareesuwan et al. 1985). 1 depth of coma,
witnessed convulsions, 8 Whilst prognosis
age <3 years and worsens with increasing
parasite density >1 parasite densities, the
Bacteraemia and other comorbidities. Children with clin-ically million/ll in cerebral stage of parasite
diagnosed severe malaria have a higher prevalence of malaria (Molyneux et al. development is also
bacteraemia than controls (Berkley et al. 1999, 2005). In many 1989b; Krishna et al. important with a worse
1994; Mabeza et al. prognosis at any
African studies, the commonest bacterial pathogen isolated from 1995);
blood cultures has been non-typhi Salmo-nella (NTS). parasite density if more
Bacteraemia is most common in infants and is associated not 2 papilloedema and/or than 20% of parasites in
retinal oedema the periph-eral blood
only with malaria but also with malnutri-tion and HIV infection. (Lewallen et al. 1993,
1996); malarial film contain visible
Bacteraemia cannot be identified with confidence by bedside retinopathy (Beare et al.
2004); malaria pigment (i.e.
examination or immediate tests, which is why it is now they are mature
recommended that antibiotics be given in addition to 3 acidosis, evidenced trophozoites or
antimalarials in children admitted with suspected severe malaria biochemically by schizonts) (Silamut &
in high and moderate malaria transmission areas (Evans et al. reduced plasma
White 1993; Waller et
bicarbonate, increased
2004) (see section Management of concomitant sepsis p. 72). al. 1995);
plasma lactate
The presence of bacteraemia in children with severe malaria has concentration or 9 increased plasma or
been found to be associated with a higher risk of death in some clinically by acidotic cerebrospinal fluid
studies (Berkley et al. 2005; Were et al. 2011), but not in others breathing or severe concentra-tions of
(Bronzan et al. 2007). respira-tory distress
tumour necrosis factor
(Krishna et al. 1994;
Marsh et al. 1995; (Grau et al. 1989;
Maitland et al. 2003a; Kwiatkowski et al.
Issifou et al. 2007; 1990; Esamai et al.
Prognostic indices in children
Oduro 2003); and of other
Respiratory distress or altered consciousness predicted 84.4% of et al. 2007; serum biomarkers
including IL-10
64 deaths among 1844 Kenyan children admitted to hospital Orimadegun et al.
(Armah et al. 2007)
with malaria (Marsh et al. 1995). In a retrospective survey of 2007; Tripathy et al.
and elevated
2911 children admitted with malaria to hospitals in Eastern 2007; Bassat et al. angiopoietin-2 with
Thailand, cerebral malaria was associated with the worst 2008; Ranque et al. reduced angiopoietin-
prognosis (21/96 died), but convulsions in the absence of coma 2008; Winkler et al. 1 (Lovegrove et al.
were also associated with an increased risk of dying (4/225, 2008; Camara et al. 2009);
compared to 5/2590 in children without coma or con-vulsions) 2011; von Seidlein et
(Wattanagoon et al. 1994). The density of peripheral al. 2012); 10 more than 5% of
peripheral blood
parasitaemia is an indicator of risk, with neutrophils con-tain
4 increased malaria pigment
cerebrospinal fluid (Nguyen et al. 1995);
lactate concentration presence of pigment in
(White et al. 1987a;
Taylor et al. 1988); peripheral blood
polymorphs or mono-
5 hypoglycaemia (White cytes (Lyke et al. 2003)
et al. 1987a,b; Taylor et and pigment in
circulating
al. 1999; Were et al.
2011);
4 a prognostic score based
on three of these
monocytes (Mujuzi et al. indicators coma,
2006); although a study prostration and deep
of 26 296 children breathing, each of which
has been shown to be
admitted to six hospitals
prognostic alone can
in Africa concluded, after
predict outcome in a
multivariate analysis, that child with severe malaria
associa-tions between with high sen-sitivity
pigment-containing cells and specificity (Helbok
(neutrophils, et al. 2009). Similarly
mononuclear cells and various combinations of
erythrocytes) and coma, respiratory
mortality were moderate distress and severe
to nonexistent in most anaemia carry a worse
sites (Krems-ner et al. prognosis than any of the
2009); syndromes on their own
(Marsh et al. 1995);
1 degree of
thrombocytopenia 5 raised plasma PfHRP2
(Gerardin et al. 2002); concentration this
although the level of reflects the total parasite
thrombocytopenia was biomass and predicts
not related to outcome progression to cerebral
in two other studies malaria in children
(Ladhani et al. 2002;
presenting to hospital
Chimalizeni et al. 2010);
with uncomplicated
2 HIV infection malaria (Hendriksen et
Figure 5 Prevalence, overlap and mortality for major clinical subgroups (Malamba et al. 2007) al. 2012a; Fox et al.
of 1844 Kenyan children with severe malaria (Marsh et al. 1995). Total (in children with
severe malarial 2013).
numbers are given in parentheses, and mortal-ity is given as a percentage. anaemia);
3 bacteraemia (Berkley et
The diagnosis of cerebral

malaria. In the past, patients
succession during the first with headache, neck stiffness,
few hours after admission drowsiness, agitation, delir-
Section 4: Clinical features of severe to hospital. The clinical
falciparum malaria in adults features in older children ium, febrile convulsions,
focal neurological signs or
Epidemiology (>10 years) and adolescents
are similar to those in adults even behavioural
Severe malaria is caused mainly by Plasmodium falcipa-rum, (Dondorp et al. 2008b). disturbances who were not
although P. knowlesi and P. vivax may also cause severe illness. comatose were often
Severe malaria reflects an inability of host-defence mechanisms Cerebral malaria and other described as having cerebral
to control the infection so it occurs in patients with little or no malaria. In many of the
neurological abnormali-ties.
effective immunity. In areas of moderate and high stable Cerebral malaria refers to published cases, focal signs
transmission, severe malaria is confined to childhood, whereas in unrousable coma (Glas-gow and neurological sequelae
areas of low unsta-ble transmission, and in non-immune Coma Scale <11; see may well have resulted from
travellers to ende-mic areas, severe malaria may occur at any Section 2; definitions), in other central nervous system
age. In the latter context, severe malaria is predominantly a malaria having excluded, as infections or vascular disease.
disease of young men (reflecting their increased risk of malaria far as possible, other causes In adults, high fever alone
exposure). Women comprise between one quarter and one-third of coma (see below) (Table without direct involvement of
of cases. In low transmission settings, severe malaria is 6). The proportion of patients the central nervous system
particularly likely and particularly dangerous in pregnancy with severe malaria who have can produce mild impairment
(Wickramasuriya 1937). In some situations, epidemics with a cerebral malaria varies in of consciousness; variously
very high mortality may occur (Christo-phers 1911). The risk of time and place. In some parts referred to as delirium,
severe malaria is reduced in many haemoglobinopathies, and of the tropics, cerebral obtundation, obnubilation,
other inherited red cell abnormalities. As effective treatment of malaria is the most common confu-sion and psychosis. In
uncomplicated malaria prevents progression of the disease, the clinical presentation and the a febrile patient with
risk of severe malaria is determined largely by health-seeking major cause of death in adults impaired consciousness, it is
behaviour and availability of efficacious antimalarials. with severe malaria. In important to exclude other
Thailand and Vietnam, about encephal-opathies, especially
half of the cases of severe bacterial meningitis and, if
Clinical features possible, locally prevalent
falciparum malaria over the
The symptoms and signs of acute falciparum malaria are non- past 30 years had cerebral viral encephalitides. To allow
specific. The illness usually starts with a general mal-aise malaria, although the compara-bility of clinical and
followed by aching of the head, back and limbs, diz-ziness, proportion has steadily therapeutic findings, a strict
anorexia, vague abdominal pain, nausea, vomiting or less declined (Hien et al. 1996; defini-tion of cerebral
commonly mild diarrhoea. Fever, which may pre-cede or follow, Phu et al. 2010). In contrast, malaria has been developed
is erratic, and there may be chills. An ini-tial rigor is more among Melanesian adults (see Section 2; Definitions).
commonly related to P. vivax or P.ovale infections than with severe falciparum A diagnosis of cerebral
falciparum malaria. In addition to fever, physical signs may malaria in Cen-tral Province, malaria requires definite
include anaemia, jaundice, pos-tural hypotension and after some Papua New Guinea, only evidence of malaria infection;
days tender hepato-splenomegaly. In adults, features of severe 17% presented with cerebral asexual forms of P.
disease usually appear after 37 days of these non-specific flu- malaria (Lalloo et al. 1996). falciparum in the blood film
like symptoms, although there are occasional reports of non- While P. vivax infections may (or, less specifically, a
immune patients dying within 24 h of their first reported be associated with some positive rapid P. falciparum
symptom, and some patients can deteriorate rapidly or fail to central nervous system malaria test) and a Glasgow
recover consciousness following a grand-mal convulsion. dysfunction particularly Coma Score of less than 11.
Agitation or confusion may occur during fever spikes but are during paroxysms, unro- Unrousable coma is defined
ominous signs if they persist and often herald cerebral malaria. usable coma is extremely as a best motor response to
Once there is evidence of vital organ dysfunction progression unusual (see Section 13; noxious stimuli that is non-
may be rapid. In many patients, several of the manifestations of severe vivax malaria). This localising, and a best vocal
vital organ dysfunction occur together or evolve in rapid section refers to coma in response that is considered
severe falci-parum malaria. incomprehensible. This
level of unconsciousness is
Total 315
Unrousable coma<9 Cerebral
*In some patients with cerebral

malaria who are unrousable, the
chosen because the distinction between obtundation or severe malaria, 40% of eyes may remain open (scoring
drowsiness, and unrousable coma is clear, whereas lesser patients with cerebral malaria 4), so the definition of cerebral
degrees of altered sensorium are difficult or impossible to and 80% of fatal cases (Abu malaria also encompasses E4 V3
separate from the effects of fever alone. In some patients withSayeed et al. 2011). There are M4.
cerebral malaria, the eyes remain open, and so the eye signs infour components to malaria
the Glasgow Coma Scale are of limited value in such cases. To retinopathy: retinal whit-
distinguish cerebral malaria from tran-sient post-ictal coma, ening (macular or peripheral),
unconsciousness should persist for at least 1 h after a vessel discoloration (white or
convulsion, although in some patients following a seizure, a orange), retinal haemorrhages
post-ictal state lasts for a few hours. In fatal cases, the diagnosis
(particularly with white Figure
of cerebral malaria may be confirmed post-mortem by finding centres resembling Roth 6
the cerebral capillaries and venules packed with erythrocytes spots) and papilloedema (Fig- Fundus
photogra
contain-ing mature P. falciparum parasites (mature trophozoitesure 6). The first two of these
phs of
or schizonts) at autopsy or by needle necropsy of the brain. Ifare unique to severe falcipa- an adult
the patient died after several days of treatment, then parasites
rum malaria (see Section 3, with
may be scanty or absent although there is often residual pigment
severe malaria in children). severe
(trapped in cytoadherent residual red cell membranes). Fluoroscein angiography malaria
reveals disruption of the showing
retinal capillary network and a large
Cerebral malaria is a diffuse and symmetrical encepha- white-
lopathy. Focal neurological signs are unusual. microvascular obstruction. centred
Retinal haemorrhages occur haemorr
Coma. Cerebral malaria may start with a generalised convulsion in approximately 40% of hage
followed by persisting unconsciousness or the level of adults with cerebral malaria, (big
consciousness may decline more gradually (Mish-ra et al. papilloedema in black
approximately 10% and arrow),
2007b) (Table 6).
scattered
retinal whitening in
patches
Meningism. Neck rigidity and photophobia are rare symptoms, approximately 5%. Vessel of
but mild neck stiffness is not uncommon, and posturing with retinal
hyperextension of the neck and back may occur in severely ill whitenin
adults. Table 6 Coma scale for adults: g (white
modified Glasgow Coma Scale arrows)
and
Retinal abnormalities. Careful examination of the fundus is haemorr
important in unconscious adults, just as in children, as distinctive hages
abnormalities may confirm the diagnosis of cerebral malaria. Eyes open*: (black
Spontaneously arrows)
Furthermore, the degree of retinopathy has prognostic
To speech in the
significance. Retinal abnormalities are found in a small To pain right eye
proportion of patients with uncompli-cated falciparum malaria Never and
(<5%), 20% of patients with Best verbal response: multiple
Oriented haemorr
Confused hages
Inappropriate words and
Incomprehensible sounds patches
None of
Best motor responses: retinal
Obeys commands whitenin
Localises pain g in the
Flexion/withdrawal to pain left eye
Flexor (decorticate) posture from
Extensor (decerebrate) posture Abu
None Sayeed
(2011).
herniation in the other. Brain
swelling, cortical infarcts and
hyperintense white matter
seizures are also observed. A lesions, found in three of
discolouration is seen rarely in adults. Retinal whitening may variety of non-specific elec- twelve patients with cerebral
occur without haemorrhages and can be difficult to see, troencephalographic malaria, were interpreted as
particularly when it is in the peripheral retina, so can be easily abnormalities have been intravascular engorgement
missed on direct ophthalmoscopy. Although indirect described both in oedema and demyelination
ophthalmoscopy may reveal peripheral abnormal-ities, careful uncomplicated and cerebral (Cordoliani et al. 1998). In a
examination of the fundus by an experienced clinician is almost malaria (Collomb 1977). more recent series of three
as sensitive. The retinal abnormalities resolve slowly over days patients, focal
or weeks but do not interfere with vision in survivors. hyperintensities in the
Brain imaging. Computed bilateral periventricular white
Other neurological signs. Corneal and eyelash reflexes are tomography (CT) and mag- matter, corpus callo-sum,
usually intact except in deep coma. The pupils are normal. netic resonance (MR) occipital subcortex and
Disorders of conjugate gaze are very common, the usual finding imaging are usually available bilateral thalami were noticed
in adults being divergent eyes with nor-mal oculocephalic only in urban centres, on T2-weighted and FLAIR
(dolls eye) and oculovestibular (calo-ric) reflexes. whereas adult cerebral sequences. The lesions were
Convergence spasm, implying an upper brain stem lesion, malaria occurs usually in more marked in the splenium
transient ocular bobbing, horizontal and vertical nystagmus and rural areas. Thus, reports are of the corpus callosum
sixth nerve palsies have been observed rarely. Forcible jaw usually of travel-lers or (Yadav et al. 2008).
closure and tooth grinding (bruxism) are common in cerebral unusual cases. CT of the brain
malaria. The jaw jerk may be brisk. A pout reflex is usually in adults with cere-bral
elicited indicating frontal release, but other primitive reflexes, malaria often shows evidence
such as the grasp reflex, are almost always absent. The gag reflex of cerebral swelling Neurological sequelae.
is usually preserved. The neurological findings are usually (Looareesuwan et al. 1983a; Agitation and confusion may
symmetrical. Muscle tone and tendon reflexes are often Mohanty et al. 2011; Patan- develop briefly as the patient
increased, but may be variable or reduced. Ankle and sometimes kar et al. 2002). Cerebral recovers consciousness from
patellar clonus may be elicited and the plantar responses are oedema is evident in a cerebral malaria, and transient
usually extensor. Abdominal and cremaster-ic reflexes are minority of cases and may be paranoid psychosis or
invariably absent and are a useful sign for distinguishing an agonal phenomenon delirium (brief reactive
hysterical adult patients with fevers of other causes, in whom (Looareesu-wan et al. 1983b). psychosis) sometimes
these reflexes are usually brisk. Various forms of abnormal Focal lesions, suggesting follows the acute illness
posturing may be observed, occurring spontaneously or induced infarction or haemorrhage, (Anderson 1927; Kastl et al.
or accentuated by noxious stimuli (Plum & Posner 1972). These have been demonstrated 1968). In Viet-nam, a post-
abnormal motor responses include abnormal flexor response in (Pham-Hung et al. 1990; malarial neurological
the arm(s) with extension of the leg(s) decorticate rigidity Millan et al. 1993). In a syndrome was described in 22
abnormal extensor responses in arm(s) and leg(s) decerebrate prospective study of MRI of patients, three of them
rigidity with or without opisthotonos and abnormal flexor the brain, 22 of 24 adult Thai children, all but one of whom
responses of upper and lower limbs. Sus-tained upward deviation patients with cerebral malaria had recovered from severe
of the eyes, extension of the neck, pouting and periods of had no evidence of cerebral falciparum malaria.
stertorous breathing may occur together. Extensor posturing may oedema, but MRI revealed Symptoms of either an acute
occur with hypo-glycaemia, but is seen in both hypoglycaemic that brain volume during confusional state or psychosis
and normo-glycaemic patients with cerebral malaria. acute cerebral malaria was developed in 13, six had one
Spontaneous movement implies lighter coma and therefore a slightly greater than during or more general-ised
better prognosis than immobility. the convalescent phase convulsions, two had
(Looareesuwan et al. 1995). generalised convulsions fol-
This difference was attrib- lowed by a prolonged period
uted to an increase in of acute confusion, and one
Convulsions. The incidence of convulsions in adult Thai and intracerebral blood volume. developed a cerebellar tremor.
Vietnamese patients with cerebral malaria has fallen from 50% In two fatal cases in which In a randomised trial, 4.4%
in the 1980s to less than 15% without obvi-ous explanation assisted ventilation had been (10/228) of patients with
(White 1995a) (Table 3). Seizures are usually generalised, but required, there was gross severe malaria who received
Jacksonian or persistent focal swelling of the brain in one mefloquine after parenteral
and foramen magnum treatment developed
Dondorp et al. 2005b) have
therefore set the anaemia
component of the severe
1994; Nguyen et al. 1996; malaria definition more
post-malarial neurological syndrome compared with 0.5% Maguire et al. 2005). Other strictly as a haematocrit
(1/210) of those who received quinine; relative risk 9.2 (95% CI factors implicated in malarial <20% together with a parasite
1.271.3, P = 0.012) (Nguyen et al. 1996). Similar cases have psychosis include alcohol, count >100 000/ll, as
been reported in many different set-tings (Falchook et al. 2003; alcohol-withdrawal, compared with the
Prendki et al. 2008; Markley & Edmond 2009). A variety of narcotics, stresses associated parasitaemia threshold of 10
rarer neurological abnor-malities has been reported in the acute with life or military service in 000/ll suggested in this
phase of illness including psychosis, confusion, ataxia, transient tropical countries and document.
cranial nerve palsies and a variety of tremors. exacerba-tion of pre-existing
functional psychoses (Kastl et
Unusual neurological sequelae include cranial nerve lesions, al. 1968). Psychiatric features Haemoglobinuria and
focal seizures, extrapyramidal signs, ataxia (Abdulla et al. 1997) include apathy, amnesia, Blackwater Fever. Classical
and greatly prolonged coma, but these are unusual (Warrell et al. depression, atypical descriptions of blackwater
1982). In some cases, coma recurs after recovery of depression, acute psychosis, fever mention severe
consciousness, and some of these patients have elevated personal-ity change, paranoid intravas-cular haemolysis
cerebrospinal fluid pro-tein and lymphocyte counts suggesting an psychosis and delusions, such with haemoglobinuria in
immune-medi-ated pathology. The following neurological as belief that family members patients with severe
sequelae were described in 441 Indian adults with cerebral have been killed (Kastl et al. manifestations of P.
malaria, of whom 145 had died: psychosis in 15 (5.1%), 1968; Prakash & Stein 1990; falciparum infection, such as
cerebellar ataxia in 14 (4.7%), hemiplegia in five (1.7%), Dugbartey et al. 1998). These renal failure, hypotension and
extrapyramidal rigidity in five (1.7%) and peripheral neuropathy symptoms rarely last for more coma, but scanty or absent
in three (1.0%), and isolated sixth nerve palsy in one (0.33%) than a few days, in contrast to parasitaemia and mild or
patient (Kochar & Shu-bhakaran Kumawat 2002). All survivors those attributable to absent fever. The typical
showed com-plete recovery on further follow-up. functional psychoses. patient was an expatriate
European who had lived in
the ende-mic area for several
Delayed cerebellar ataxia. Cerebellar ataxia, without impairment Anaemia. Anaemia is an months or longer, had had
of consciousness or other signs of severe malaria, have been inevitable consequence of previous attacks of malaria
described in falciparum malaria, espe-cially in India and Sri severe malaria. On admission, and was taking quinine in an
Lanka, but also, recently from the Sudan (Abdulla et al. 1997). approximately 10% of adults irregular fashion for
Three or four weeks after developing transient fever attributable are severely anaemic (Hb <7 prophylaxis and treatment.
to falciparum malaria, patients present with unsteadiness of gait g/dl, haematocrit <20%), and Symptoms associ-ated with
and of the upper limbs, vertigo, dysarthria and headache. On 7% have Hb<5 g/dl and what was initially a typical
examination, there is ataxia of gait, intention tremor, dysmetria,haematocrit <15% (Dondorp attack of malaria included
dysdiadochokinesis, nystagmus and cerebellar dysarthria. et al. 2005a) (Table 1). loin pain, abdominal
Symptoms progress for up to 2 weeks but completely resolve 3 Anaemia develops very discomfort, restlessness,
16 (median 10) weeks after their onset (Senanayake 1987). rapidly. In Thailand, vomiting, diarrhoea, polyuria
haematocrits fell below 20% followed by oliguria and
in approximately 30% of passage of dark red or black
Malarial psychoses. It is doubtful whether there is a spe-cific adult patients in one study urine. Signs included tender
malarial psychosis. However, there are many refer-ences, (Phil-lips et al. 1986a). The hepatosplenomegaly,
especially in the older literature, to a variety of psychiatric degree of anaemia correlated profound anaemia and
manifestations attributed to malaria, both as the presenting with parasitaemia, jaundice. The exaggerated
feature of an acute attack of malaria and as a sequel, in schizontaemia, serum total haemolytic response in the
convalescence, to an episode of severe or otherwise bilirubin and creatinine absence of hyperparasitaemia
uncomplicated malaria. Limitations of many of these reports are concentrations. As in was attributed to immune
failures to confirm the diagnosis of malaria and to exclude other children, the prognosis of lysis of qui-nine-sensitised
causes of the psychiatric symptoms, such as antimalarial drugs, severe anaemia without other erythrocytes (Bruce-Chwatt
for example mepa-crine, chloroquine (Akhtar & Mukherjee evidence of vital organ dys- 1987). How-ever, direct
1993) and mefloquine (Weinke et al. 1991; Luxemburger et al. function is good with a evidence for auto-immune
mortality below 5%. Several haemolysis in this condition
large trials (Hien et al. 1996; was weak. Although the
epidemiological evi-
remedies resulting in liver
dysfunction and
hypoglycaemia.
20% of those without renal
dence strongly suggests a close link with quinine use, the failure (Trang et al. 1992). Haemostatic abnormalities,
pathophysiological mechanism has not been identified. In more Apart from jaundice, signs of thrombocytopenia. In the
recent times, intravascular haemolysis with haemo-globinuria hepatic dysfunction are 1970s, bleeding was reported
has also been observed in Africa among patients who had unusual, although functional frequently in severe malaria,
repeatedly used quinine or halofantrine to treat febrile episodes disturbances evidenced by but in recent larger series,
(Vachon et al. 1992; Mojon et al. 1994). Massive haemolysis and altered metabolic clearance of bleeding has been unusual
methaemoglobinaemia were also well-recognised adverse effects antimalarial drugs are (<5% of cases) at
of 8-aminoquin-olines long before the discovery 60 years ago of common (Pukrittayakamee et presentation (Dondorp et al.
glucose-6-phosphate dehydrogenase deficiency. As G6PD defi- al. 1997). Clinical signs of 2005a). Nevertheless,
ciency is prevalent throughout the malaria affected world, with liver failure with hepatic laboratory evidence of
gene frequencies typically of 515% (but up to 35% in some encephalopathy (such as activated coagulation is very
areas), oxidant haemolysis is an important cause of blackwater asteri-xis or liver flap) are common (Clemens et al.
fever independent of malaria. In a study of 50 patients with never seen unless there is 1994). Fewer than 10% of
fever and haemoglobinuria in Viet-nam, one-third of whom had concomi-tant viral hepatitis. adult Thai patients with
malaria, quinine had been taken by more than half (Chau et al. Tender enlargement of the cerebral malaria showed
1996). In these patients, who typically had a greyish pallor, liver and spleen is, however, a clinically evident bleeding
vomiting, loin pain and passage of black/red (Coca-cola common finding in all human tendency with associ-ated
coloured) urine were common symptoms. Self-treatment with mala-rias, especially in young features of disseminated
qui-nine, often in inadequate doses, was until recently a com- children and non-immune intravascular coagulation
mon practice in Vietnam, as in the days when blackwater fever adults. The low and falling (Phillips & Warrell 1986).
was first described in West Africa. In the context of severe serum albumin concentration Bleeding gums, epistaxis,
malaria treatment, blackwater has been slightly more common in is an important index of hae-matemesis, petechiae and
artesunate or artemether recipients than quinine recipients (Hien temporary hepatic subconjunctival
et al. 1996; Dondorp et al. 2005a; Phu et al. 2010). It seems that dysfunction. Con-centrations haemorrhages were seen. If it
some patients with severe malaria and no known enzyme of aspartate and alanine does occur, bleeding usually
deficiency in oxi-dant defence systems have severe haemolysis aminotransferases may be accompanies renal,
sufficient to cause haemoglobinuria whichever antimalarial drug increased up to tenfold, but pulmonary or hepatic
they receive. never to the levels normally complications and is associ-
seen in viral hepatitis (Table ated with severe
1). 5-nucleotidase and gamma thrombocytopenia and
Severe haemolysis has recently been reported following glutamyl transpeptidase coagulopathy (Stone et al.
recovery from severe malaria in artesunate-treated patients concentrations may also be 1972; Punyagupta et al.
(Caramello et al. 2012; Rolling et al. 2012; Cen-ters for Disease moderately elevated. The 1974). Stress-related
Control & Prevention 2013). Most of these patients were prothrombin and partial gastrointestinal haemorrhage
hyperparasitaemic, and the haemoly-sis may be explained, at thromboplastin times may be may occur in severely ill
least in part, by the shortened survival of once infected pitted moderately prolonged par- patients. Thrombocytopenia is
erythrocytes (Newton ticularly if there is associated a common feature of
et al. 2001a). coagulopathy (Clemens falciparum and vivax
et al. 1994). Liver malarias and is not itself a
Jaundice and hepatic dysfunction. Jaundice is common in adult dysfunction also contributes sign of severity although
patients with malaria. In a study of 390 patients hospitalised with to lactic acidosis (reduced profound thrombocytopenia
acute falciparum malaria in Thailand, one-third (124) were lactate clearance) (Day et al. (<20 000/ ll) is more common
clinically jaundiced (total serum bili-rubin >3 mg/dl or 57 lM) 1996b), hypoglycaemia in severe falciparum malaria
(Wilairatana et al. 1994). In severe malaria, over half the patients (impaired gluconeogenesis) (Horstmann et al. 1981).
have admission val-ues above this. Hyperbilirubinaemia is (White 1983, White 1987a) Altered platelet function has
predominantly un-conjugated (a combination of haemolysis and and changes in triglycerides, also been described
hepatic dysfunction). Jaundice is associated with cerebral phospholipids, free fatty (Srichaikul 1993).
malaria, acute renal failure, pulmonary oedema, shock and other acids, cholesterol, esterified Thrombocytopenia is not
severe complications. In Vietnamese adults, 63% of those with cholesterol and non-esterified related to other measures of
acute renal failure were jaundiced, compared to fatty acids. Sometimes coagulation (prothrombin
patients with malaria may time, partial thromboplastin
take hepatotoxic herbal time) or to
mM corrected). There was no
difference between severe and
uncomplicated cases.
not dehydrated, and in some However, in 6 of 10 cases
plasma fibrinogen concentrations. Thrombocytopenia does not, cases, patients are referred studied prospectively,
in itself, indicate disseminated intravascular coagulation and is having received excess hypocalcaemia was
usually not accompanied by bleeding. Plasma fibrinogen is intravenous saline. Clinical associated with
usually in the high normal or slightly elevated range although its assess-ment, the central inappropriately low intact
breakdown is accelerated (Devakul et al. 1966), so venous pressure and invasive parathormone concentrations
concentrations of fibrin degra-dation products are usually haemody-namic monitoring in the serum (<5.0 pM) (Davis
slightly elevated (Reid & Nkrumah 1972). are inaccurate in predicting et al. 1991). Despite malaria-
the effective circulating blood associated haemolysis, hypo-
volume and tissue oxygen phosphataemia (<0.80 mM)
Renal dysfunction. Acute kidney injury is a common delivery, probably because of was found in 43% of the 172
manifestation of severe falciparum malaria and in adults is often extensive microvascular patients and 11 patients (6%)
lethal. Although evidence of renal impairment is common at all obstruction consequent upon had values <0.30 mM. Hy-
ages, oliguric renal failure occurs almost exclusively in adults sequestration (Hanson et al. perphosphataemia (>1.45
and older children. Malarial acute renal failure may be defined as 2011a, 2012, 2013). All this mM) was found in 9% (Davis
a serum creatinine con-centration > 265 lM (3 mg/dl) in patients makes management of fluid et al. 1991). Severe
who have asex-ual forms of Plasmodium falciparum in their balance difficult in severe hypophosphataemia could
peripheral blood smear. Plasma creatinine has the best prognostic malaria. contribute to disturbances of
value in terms of the subsequent need for renal replace-ment cerebral, leucocyte and
therapy and outcome (Hanson et al. 2011a, 2013). A 24-h urine Electrolyte abnormalities. platelet func-tion and to
output of <400 ml, in spite of rehydration, is a further indication. Mild hyponatraemia (serum haemolysis and is
There are two categories of patients with acute renal failure: sodium 125135 mM) is exaggerated by administra-
those with acute severe malaria and multiple organ involvement common in falciparum tion of glucose and by
(a fulminant dis-ease which carries a poor prognosis) and those malaria (Holst et al. 1994) quinine-induced
who develop progressive renal impairment after successful and is often accompanied by hyperinsulinaemia.
treatment of malaria infection (whose prognosis is good, mildly reduced plasma
provided that renal replacement therapies are available). The osmolality. The antidiuretic
latter group tends to be more anaemic and have a higher serum hormone concentrations are
creatinine concentration on admission, reflecting a longer appropriate (Hanson et al. Pulmonary oedema. This is a
duration of illness before referral (Trang et al. 1992). Acute renal 2009). Approximately 25% of grave and often fatal
failure in malaria is usu-ally oliguric (<400 ml/day), or anuric adults admitted with severe manifestation of severe
(<50 ml/day), but urine output may also be normal or rarely malaria have a plasma sodium falciparum malaria in adults
increased. The mortality of patients with renal impairment is <130 mM, and 25% also have which may develop
approxi-mately four times higher than in patients with normal a plasma potassium <3.5 mM, suddenly after one or two
renal function. In the SEAQUAMAT trial, 51 (38%) of 136 but very low values are rare days of treatment. Some
artesunate recipients and 76 (52%) of 146 quinine recipients (Dondorp et al. 2005a). Salt cases show evidence of fluid
with renal failure died, compared with 47 (9%) of 525 and 65 depletion through prolonged overload, with raised central
(13%) of 501, respectively, who did not have renal failure sweating or dilution from venous or pulmonary artery
(Dondorp et al. 2005b). Patients with renal failure have a higher administration of intravenous wedge pressures and grossly
incidence of acidosis, hypoglycaemia and jaundice, and the dextrose solutions contribute. positive fluid balance
duration of coma is significantly prolonged. Pulmonary oedema Hypocalcaemia has been (Brooks
is a common terminal event. observed in patients with et al. 1968). Other patients
severe falciparum malaria develop pulmonary oedema
(Petithory et al. 1983), but with normal or negative fluid
may be explained in part by balance and with normal or
Fluid balance. Some untreated patients with severe falci-parum associated reduced pulmonary capillary
malaria are clinically hypovolaemic (low jugular venous hypoalbuminaemia. In wedge pressure. This
pressure, postural hypotension, oliguria with high urine specific Thailand, in a cross-sectional indicates increased
gravity), and those who have been febrile for days with study of 172 adults with acute pulmonary capillary
inadequate water intake are dehydrated (reduced skin turgor) on falciparum malaria, 36% had permeability, and so malaria
admission. Other patients are mild asymptomatic pulmonary oedema
hypocalcaemia (1.792.11 resembles the acute
Gastrointestinal symptoms.
Nausea, vomiting (2030%
Acid base disturbances. of patients), abdominal pain,
respiratory distress syndrome (ARDS) (Taylor et al. 2012b; Acidosis is a major cause of which may be colicky and
Hanson et al. 2013). Patients with severe malaria are more death from severe malaria, severe, and diarrhoea (10
vulnerable than those with sepsis to volume overload and and the degree of acidosis is 20% of patients), which may
readily develop ARDS. Hyper-parasitaemia, renal failure, and the single most powerful be watery but does not
pregnancy are predis-posing factors. Hypoglycaemia and prognostic indicator (Day et contain blood or pus cells, all
metabolic acidosis are commonly associated. The first indication al. 1996b; Hanson et al. occur in adults with severe
of impending pulmonary oedema is usually an increase in the 2012). Acidotic breathing malaria and may lead to
respiratory rate, which precedes the development of other chest (hyper-ventilation, misdiagnosis of enteric
signs. Without good facilities for emergency radiography, it may Kussmauls breathing) is a infections. Patients who
be difficult to differentiate acute pulmonary oedema from poor prognostic sign although consis-tently vomit tablets
aspiration bronchopneumonia and metabolic acidosis, although it must be distinguished from should be transferred to a
in acidosis, ausculta-tion of the chest is often normal. Metabolic pulmonary oedema and place where parenteral
acidosis and pulmonary oedema may also occur together. neurogenic hyperventilation. treatment can be given unless
Although pulmonary oedema may develop at any stage of the Metabolic aci-dosis may intrarec-tal artemisinin
acute illness, it tends to occur later than the other acute develop in severely ill derivatives are available and
manifestations of malaria (Brooks et al. 1969). Hypoxia may patients as a result of can be given.
cause convulsions and deteriora-tion in the level of microcirculatory obstruction
consciousness, and the patient may die within a few hours. combined with hepatic dys-
function, in patients who are Hypoglycaemia.
shocked or are in renal Hypoglycaemia is an
failure. Hyperlactataemia important compli-cation of
Cardiovascular abnormalities, shock (algid with a high lactate/pyruvate falciparum malaria and its
treatment (White
malaria). The blood pressure of patients with malaria is usually ratio indicates an ischaemic
at the lower end of the normal range, although most patients are basis for the lactic acidosis et al. 1983a). Often
warm and well perfused. Approxi-mately 10% of patients with (Pukrittayakamee et al. 2002). hypoglycaemia is not
severe malaria are consid-ered clinically to be in shock Other unidentified organic suspected clini-cally so blood
(Dondorp et al. 2005a). Severe hypotension [systolic blood ions also contribute (Dondorp glucose concentrations must
pressure less than et al. 2004a). Clinically, there always be checked in
80 mmHg (10.7 kPa) in adults in the supine position] with is no distinction between the severely ill patients. The
features of circulatory failure (cold, clammy, cya-notic skin, metabolic acidosis incidence of hypo-glycaemia
constricted peripheral veins, prolonged capil-lary refill time) is consequent upon at presentation has fallen as
seen in patients with pulmonary oedema, metabolic acidosis, microcirculatory obstruction, use of quinine has declined.
bacteraemia (see below) and following massive gastrointestinal hepatic dysfunction, and renal In conscious patients,
haemorrhage or splenic rupture. Dehydration may also contribute impairment. On admis-sion hypoglycaemia may pres-ent
to hypoten-sion, and some patients may be admitted severely plasma lactate may be high with classical symptoms of
anxiety, breathlessness, a
dehy-drated, hypotensive and oliguric having endured high fever for various reasons including
recent seizures and very high feeling of coldness,
and inadequate fluid intake for several days. How-ever, most
catecholamine levels, which tachycardia and
adult patients with severe malaria are not sig-nificantly
lightheadedness and signs of
dehydrated or hypovolaemic, and fluid resuscitation needs to be usually fall rapidly (Day et al.
autonomic overactivity
performed carefully to avoid fluid overload and pulmonary 2000a,b). Sustained elevation
(sweating, or goose-flesh).
oedema (Hanson et al. 2013). Myocardial dysfunction, of plasma lactate carries a
More severe signs include
ventricular failure and cardiac arrhythmias are very rarely poor prognosis, whereas
coma, deteriorating
observed in severe malaria, despite the sequestration of rapidly resolving
consciousness, abnormal
parasitised erythro-cytes in the myocardial vessels and the hyperlactataemia carries a
posturing (decerebrate or
marked cardiac effects of many antimalarial drugs (Bethell et al. good prognosis. If possible,
decorticate rigidity, muscle
1996). The clinical picture of algid malaria (shock in severe plasma concentra-tions
spasms, pouting, stertorous
malaria) resembles that of septic shock, and indeed, in many should be checked 4 h after
breathing and opisthotonos)
patients (but certainly not all), there is concomitant bacteraemia. admission and after adequate
and generalised convulsions.
rehydration.
The diagnosis of
hypoglycaemia may be
overlooked
that are involved and the
severity of their dysfunction.
Mortality is increased in the
Peripheral leucocytosis. The elderly and also in pregnant
because all these clinical features are also typical of total white count is normal in women. While the qual-ity of
severe malaria per se. the majority of patients intensive care support is an
In severe malaria, many of the usual diagnostic features of (median approximately 8000/ important determinant of
hypoglycaemia may be absent and the diagnosis may be ll). Neutrophil leucocytosis outcome, by far the most
overlooked. Sweating is an inconstant sign, the pupils are may occur in severe falcipa- important factor is the spe-
frequently not dilated, the breathing may be cyclical or stertorous rum malaria, even in the cific antimalarial drug
and deep, and there may be abnormal pos-turing of the arms and absence of detectable treatment. Treatment must be
legs. There is usually a deteriora-tion in the level of secondary bacterial infection. given as early as possible in
consciousness. Following treatment with intravenous 50% Approximately 25% of the evolution of a potentially
glucose, clinical improvement is very variable from no patients have a total white lethal infection. Artesunate
apparent change to a change in the respiratory pattern and a count on admission over 12 reduces the mortality of
lightening of coma. Hypo-glycaemia complicates malaria in 000/ll (Hien et al. 1996). severe malaria in adults by
three clinical settings which may overlap: in patients with severe Leucocytosis is associated one-third compared with qui-
disease espe-cially young children, in pregnant women and in with poor progno-sis. nine (Newton et al. 2003;
patients given quinine. Quinine-induced hyperinsulinaemia is a Leukaemoid reactions have Dondorp et al. 2005a; Phu
common contributing cause of hypoglycaemia particu-larly in been reported (Stein 1987). et al. 2010). Many studies
pregnant women (White et al. 1983a; Das et al. 1988), and have examined prognostic
hypoglycaemia in this context may be recur-rent as glucose fac-tors (Newton et al. 2013).
administration stimulates further hyperin-sulinaemia. Peripheral Differences in predictive fac-
Hypoglycaemia develops during treatment of malaria gangrene/rhabdomyolysis. tors are explained by the
significantly more commonly in patients (adults and children) There are many reports of different patient populations;
treated with quinine than those treated with artesunate (Dondorp symmetrical peripheral for example, parasite density
et al. 2005b, 2010) or arteme-ther (Hien et al. 1996). gangrene occurring in acute is clearly an important
Hypoglycaemia unrelated to qui-nine is associated with acidosis malaria, both falciparum and determinant of outcome in
in severe malaria in adults and children and carries a poor vivax. Many of these have acute falciparum malaria; yet
prognosis. It is a direct result of the disease process (anaerobic followed the treatment of within strictly defined severe
glycolysis the Pasteur effect). severe falciparum malaria, falciparum malaria, the
and in some there has been density of parasitaemia has
associated coagulop-athy much less prognostic value.
(Alkizim et al. 2011). Delay in administering
Complicating and associated infections. Other severe and life- Generalised myalgia, antimalarials is clearly a
myoglo-binuria and major determinant of
threatening infections may arise in patients with severe
histological evidence of progression to severe disease,
falciparum malaria. In some cases, there are com-plicating
inflammatory skeletal muscle but once severe disease has
infections: for example, aspiration bronchopneu-monia in
necrosis have been reported developed, outcomes are
patients who have had generalised convulsions; urinary tract
(De Silva independent of the duration of
infections in patients with indwelling ure-thral catheters; infected
decubitus ulcers in patients with prolonged coma; and infection et al. 1988), but skeletal preceding illness. Dangerous
around intravenous cann-ulae. Nosocomial infection is an muscle damage sufficient to anteced-ent factors for the
important contributor to death in patients who remain seriously cause renal failure appears development of severe
to be rare. Biochemical evi- falciparum malaria include
ill for several days. In a recent study in Vietnam in a setting with
dence of muscle damage is splenectomy, pregnancy,
good intensive care facilities, nosocomial infection was consid-
much more common corticosteroid or cytotoxic
ered to contribute to a fatal outcome in 12 of the 37 deaths in the
(Miller et al. 1989). drug use,
370 adults enrolled in a clinical trial com-paring artesunate and
artemether (Phu et al. 2010). Bacteraemia may coexist with immunosuppression, lack of
severe falciparum malaria without an evident focus. Unlike previ-ous malaria exposure
children in Africa, among whom the causative organisms are Outcome and prognostic and, to a much lesser extent,
indices in adults lapsed immunity.
usually enteric bacteria, in Vietnam only one case of Gram-
negative septicaemia was detected in 500 adult patients on
The prognosis in severe
admis-sion with strictly defined severe malaria (Parry; personal
malaria is determined by the
communication).
number of vital organ systems
with >50% mortality. This
loose relationship differs
according to age and intensity
deep laboured breathing of malaria transmission. In
Clinical indicators. Any degree of central nervous system (reflecting acidosis, areas of higher transmission,
dysfunction carries an increased mortality. Confusion, agitation, pulmonary oedema or the mortality associated with
obtundation are all risk factors. In the large SEAQUAMAT study aspiration pneumonia) often this parasitaemia would be
(N = 1461, 563 with cerebral malaria), unrousable coma or termed respira-tory distress considerably lower. In non-
cerebral malaria identifies a subgroup of immune subjects, parasitae-
(GCS < 11) carried a 37% mortality in adults treated with patients at high risk of dying mias over 4% are considered
quinine and 30% in those treated with artesunate. In earlier independent of cerebral sufficiently dangerous to
series, mortality with quinine treatment was lower malaria. Respiratory dis-tress warrant closely supervised
approximately 20%. This is because mortality in comatose of this kind is usually a late treatment (Tables 2 and 3)
patients is very much determined by other vital organ sign in adults. Signifi-cant (Luxemburger et al. 1995). In
dysfunction. In patients with pure cerebral malaria, that is, no bleeding is associated with an endemic areas, the thresh-old
other vital organ dysfunction, the case fatality is <10%. Marked, increased risk of dying but is is higher. The prognostic
often violent, agitation in young adults may precede rapid unusual. Jaundice carries a value of the parasite count
deterioration. Convul-sions often progress to coma, but even poor prognosis only if may be improved
with rapid recov-ery, convulsions define a group at increased combined with other evidence considerably by assessing the
risk in areas of low or unstable transmission (Wattanagoon et al. of severe disease. stage of parasite development
1994). However, although cerebral malaria is undoubt-edly a in the peripheral blood film;
very important severe manifestation of malaria, patients of all Laboratory indices. at any parasitaemia, prognosis
ages may die without cerebral involve-ment. Laboratory indicators of poor worsens if there is a predomi-
prog-nosis reflect the size of nance of more mature parasite
During the past three decades in Vietnam and Thai-land, the the parasite burden (parasite stages. In general, if more
clinical pattern of severe malaria has changed. Over two decades count, stage of parasite than 50% of the peripheral
ago, cerebral malaria was the predomi-nant manifestation of development, neutrophil pig- blood parasites are at the tiny
severe malaria, whereas today the combination of jaundice and ment), the degree of ring stage (where the
renal failure is more com-mon. The incidence of convulsions in microvascular obstruction diameter of the nucleus is less
cerebral malaria has also declined from 50% to <20% (Warrell et (lactate, bicarbonate) and the than half the diameter of the
al. 1982). Renal impairment is an indicator of severity, and the extent of vital organ rim of cytoplasm), then the
prognosis of acute renal failure is worsened by coexis-tent dysfunction or damage (urea, prog-nosis is relatively good,
jaundice (Trang et al. 1992).The prognosis of cere-bral malaria is creatinine, glucose, bilirubin, whereas if more than 20% of
worsened considerably if there is also renal failure. The signs of transaminas-es, haemoglobin, the parasites contain visible
acidosis or uraemia represent a late stage in the progression of platelet count). The pigment (i.e. mature
the disease. Oliguria or anuria are usually present, but may not prognostic value of the trophozoites or schizonts),
have been recorded. Measurement of blood urea or creatinine is parasite count, as a measure then the prognosis is
often the only method of diagnosis. In adults, severe anaemia is of parasite burden, depends relatively bad (Silamut &
less prominent than it is in children. The prog-nosis of severe on the age and degree of White 1993). Assessment of
anaemia in the absence of other severe manifestations of malaria background immunity of the peripheral blood polymor-
is good, probably because it often represents acute on chronic patient. The classical work of phonuclear leucocyte pigment
anaemia or a protracted course of illness. For this reason, recent Field in Malaya (an area of proved to be a rapid and fairly
large randomised trials have used a stricter threshold relatively low seasonal accurate prognostic indicator
(haematocrit <20% plus parasitaemia 100 000/ll) than in the transmission) first charac- in Vietnamese adults (Nguyen
current docu-ment (where the parasitaemia threshold is 10 000/ll) terised the relationship et al. 1995). As in children,
as a criterion of severe falciparum malaria (Hien et al. 1996; between parasitaemia and recent studies in adults have
Dondorp et al. 2010; Phu et al. 2010). Many studies have progno-sis (Field & Niven shown the prognostic value of
emphasised the prognostic importance of acidosis, reflected as 1937; Field 1949). There was measuring plasma PfHRP2
acidotic breathing or measured as arterial pH, base deficit, a correlation between parasite concentrations as a surrogate
plasma bicarbonate concentration, or as arterial, venous, or CSF counts and prognosis with a measure of the parasite
lactate concentration (Day et al. 1996b; Hanson et al. 2010; significant increase in burden (Desakorn et al. 2005;
White et al. 2013a). Rapid mortality with parasitaemias Dondorp
over 2%. In Fields original
series, a parasitaemia over et al. 2005b). This has
500 000/ll was associated substantially better predictive
the Glasgow Coma Score (GCS
02). Bicarbonate-based CAM
score (04) is calculated as the
bicarbonate score (02) plus the
Table 7 Derivation of the Coma GCS (02). Respiratory rate-
value than the parasite count (Fox et al. 2013; Hendrik-sen et al. Acidosis Malaria (CAM) Score.
based CAM score (04) is
2013c). Several prognostic scores have been developed and their Bicarbonate-Based CAM Score
calculated as the respiratory score
and Respiratory Rate-Based
performance characteristics assessed. These scores are useful for CAM Score (Assessed at (02) plus the GCS score (02)
rapid bedside assessments and triage. Acidosis (base deficit) and Hospital Admission) (Hanson et al. 2010).
cerebral malaria (mea-sured as Glasgow Coma Score) are the
main independent predictors of outcome. Score
Based on data from 868 South-East Asian adults with severe Variable 0 (Normal)
malaria, Hanson et al. (2010) developed a simple 5-point Coma
Base deficit <2
Acidosis Malaria (CAM) score derived from these two variables
GCS 15
(Table 7). Mortality increased steadily with increasing score. A Bicarbonate score 24
CAM score <2 predicted survival with a positive predictive value Respiratory rate score <20
(PPV) of 95.8% [95% confidence interval (CI), 9397.7%]. Of
the 14 of 331 patients who died with a CAM score <2, 11 (79%) CAM score
had renal failure and death occurred late after hospital admission
1
(median, 108 h; range, 40-360 h). Substitu-tion of plasma
2
bicarbonate as the measure of acidosis only slightly reduced the 3
prognostic value of the model. Use of respiratory rate was 4
inferior, but a score <2 still predicted survival with a PPV of
92.2% (95% CI 89.1 94.7%). CAM score (04) is calculated as
the base deficit score (02) plus
malaria is poor.
In areas of intense, stable
transmission severe or com-
unrecognised, and cerebral plicated disease with the
effects may be mistakenly exception of severe anaemia
Section 5: Severe malaria in pregnancy is uncommon in pregnancy,
attributed to malaria.
In areas of low transmission, falciparum malaria is an important Hypoglycaemia in late and malaria is unusual as a
cause of maternal mortality (Desai et al. 2007; Rijken et al. pregnancy commonly recurs direct cause of maternal
2012a). Severe malaria in late preg-nancy is a devastating and after correction by death. The main presentation
fulminant disease with a high mortality for both mother and fetus intravenous glucose therapy. of severe malaria is severe
that is very difficult to manage, requiring close liason between anaemia. This is often multi-
physicians, obstetricians and paediatricians. The case fatality is factorial with a further
Acute pulmonary oedema
sub-stantially higher in the second half of pregnancy than in non- reduction in haematocrit as a
pregnant adults, and with quinine treatment often reached 50% Pregnant patients with severe result of pregnancy-
(Looareesuwan et al. 1985; Mengistu falciparum malaria are par- associated anaemia, iron and
et al. 2006). Reduced host-defence mechanisms and extensive ticularly prone to develop nutri-tional deficiency and
parasite sequestration in the placenta both contribute to the acute pulmonary oedema. The sometimes folate deficiency
increased risk. Severe malaria is an important cause of abortion, first signs are an increase in (Flem-ing 1989). With
stillbirth, premature deliv-ery and fetal death (Desai et al. 2007; respiratory rate, which pre- increasing success of malaria
McGready et al. 2012b). In travellers from non-endemic areas cedes the development of control measures,
and resi-dents of low transmission areas who have little or no chest signs. Dyspnoea and transmission intensities are
background immunity, pregnancy increases the risk that a hypoxia may be present on falling and this may result in
P.falciparum infection will develop into severe malaria. Any of admission or develop sudan increase in the risk of
the syndromes observed in non-preg-nant adults may occur in denly several days after maternal severe malaria. HIV
pregnant women, but two manifestations are particularly admission to hospital. Acute infection and malaria
common: hypoglycaemia and pulmonary oedema (White et al. pul-monary oedema often synergise in their harmful
1983b; Looareesu-wan et al. 1987). The anaemia of severe develops immediately after effects on pregnancy. Severe
malaria com-pounds pre-existing pregnancy-related anaemia delivery and may occur at any malaria increases the risk of
(Phillips et al. 1986a; Fleming 1989). Fetal distress is usual, and time in the first week post- vertical transmission of HIV
fetal death is common. After delivery post-partum haem-orrhage partum. Women who are infection, as does the
is common, and there is a high risk of puer-peral sepsis. If the severely anaemic or fluid- presence placental
fetus does survive, there is intra-uterine growth retardation. overloaded when they go into parasitaemia at parturition.
labour may develop acute Menendez et al. (2008)
pulmonary oedema after conducted a prospective
separation of the placenta. autopsy study between
Severe anaemia is October 2002 and December
Hypoglycaemia associated with maternal 2004 on the causes of
morbidity, an increased risk maternal death in a tertiary-
Hypoglycaemia is a common presenting feature of severe
of post-partum haemorrhage level referral hospital in
malaria in pregnancy (Looareesuwan et al. 1985). Qui-nine is
and peri-natal mortality. Maputo, Mozambique: 65 of
particularly dangerous in pregnancy because it causes marked
hyperinsulinaemia. In the past, hypo-glycaemia developed during the 139 women (46.8%) who
the course of quinine treat-ment in 50% of pregnant women with Premature labour died were HIV-positive.
cerebral malaria (White et al. 1983b). Artesunate reduces the Severe malaria was
mortality of severe malaria in adults by 35%, does not cause Symptomatic falciparum responsible for 14 (10.1%) of
hypo-glycaemia and is therefore the treatment of choice in all malaria commonly induces the maternal deaths.
trimesters of pregnancy (World Health Organization 2010a). uter-ine contractions and this
Hypoglycaemia may be associated with lactic acidosis in may precipitate premature
fulminant multisystem disease, or it may be an isolated labour. The frequency and
complication. Hypoglycaemia may be asymp-tomatic or may intensity of contractions are
present with sweating, behaviour change, altered consciousness related to the height of fever
(Looareesuwan et al. 1985).
or convulsions. There may be associated foetal bradycardia or
Fetal distress is usual. The
other signs of fetal distress. Asymptomatic hypoglycaemia is
foetal prognosis in premature
commonly
labour associated with severe
Supportive care appropriate

to the age of the infant is
crucial. Current standard
growth retardation (the baby
treatment with parenteral
being small for dates), but
Section 6: Severe malaria in the in some, it is due to
artesunate (or if unavailable
newborn premature delivery, especially
artemether) for the treatment
Babies are believed to have partial protection from malaria in the if the mother had febrile of severe malaria should be
first few months of life, owing to passively acquired maternal used, although there are few
malaria in the third trimester
IgG antibodies, the predominance of haemoglobin F (HbF) in data on appropriate dosages
(Steketee et al. 1996; Yakoob
their erythrocytes and the low levels of iron and para-amino in this age group. Quinine is
et al. 2005; Mokuolu et al.
benzoic acid (both required for parasite growth) in breast milk. 2009; Falade et al. 2010). an alternative if an
Malaria infection in the first week of life is usually called artemisinin derivative is not
Babies with low birthweight
available. Antibiotics should
congenital malaria, while that occurring in the next 3 weeks is are at increased risk from all
be given, as bacteraemia
sometimes referred to as neonatal malaria. The former is the infections that threaten
cannot be excluded
assumed to be acquired from the mother, the latter by mosquito chil-dren during infancy
immediately. Studies are
inoculation, although it is never possible for the clinician to (Mokuolu et al. 2009).
currently in progress to
distinguish between these routes of infection with con-fidence
identify optimal antimalarial
(DAlessandro et al. 2012), and transplacental infection can
Severe malaria in neonates drug schedules and to moni-
present up to 2 months after delivery.
tor the safety and efficacy of
The definition of severe these therapies.
Parasitaemia in neonates malaria in neonates is the
same as in older children.
In areas with intense transmission of P. falciparum, new-born Reported cases of severe
babies may have a low-grade P. falciparum para-sitaemia that malaria in the first month of
usually disappears without treatment by the third day of life. In a life are very few, but both P.
multicentre study in Nigeria, 5.1% of 1875 newborn babies were falciparum and P. vivax have
parasitaemic, all becoming aparasitaemic by day 3, in the been reported (Larkin &
majority without antima-larial treatment; about a third had fever Thuma 1991; Ekanem et al.
and refusal to suck, possibly attributable to malaria and 2008; Poespoprodjo et al.
responding to antimalarial treatment, and none had severe 2010). As in older children,
malaria (Falade et al. 2007). Many other studies have reported the condition is not
prevalences of P. falciparum parasitaemia in newborns varying distinguishable clinically
between 0% and nearly 50% (Runsewe-Abiodun et al. 2006; from severe septicaemia
Falade et al. 2007; Orogade et al. 2008). Infants born to non- (Pineros~-Jimenez et al.
immune mothers who have malaria at the time of delivery may 2008). Tests for malaria
develop parasitaemia and ill-ness in the first few weeks of life parasites should be included
(Brabin 2007; Vottier et al. 2008; Mwaniki et al. 2010). Clinical in the rou-tine screening of
features, which usually appear between the second and eighth febrile babies with suspected
weeks of life, include fever, anorexia, lethargy, anaemia, septicaemia in malaria-
jaundice and hepatosplenomegaly. Occasionally, severe anaemia endemic regions (Runsewe-
may develop, but other signs of severity are unusual. Abiodun et al. 2006; Orogade
et al. 2008). Conversely,
neonates with severe illness
and parasitaemia should have
blood samples taken for
Indirect effects of maternal malaria on neonates culture, and in any case
Maternal malaria exerts important indirect effects on neonates. should be treated with
Low birthweight is common in babies born to mothers who have antibiotics as well as
had malaria during pregnancy. The effects are greatest in antimalarial drugs.
primigravidae and secundagravidae, who are the most
susceptible to malaria. In most affected babies, this low
birthweight is due to intra-uterine Management
sequestration and consequent
vital organ dys-function. The
sheer amount of pathological
In the other malarias, material obstructing
Section 7: Pathophysiology of severe significant sequestration does microcirculatory flow is
falciparum malaria not occur, and all stages of staggering; it has been
the parasites development are estimated recently that the
Pathology and pathophysiology
seen on peripheral blood lethal parasite biomass on
Uncomplicated and severe disease in malaria results solely from smears. P. vivax, P. ovale and aver-age in a 60-kg adult is
the blood stage of the infection. Disease is caused by the direct P. mala-riae show selective approximately 270 ml
effects of red cell parasitisation and destruction by the asexual red cell invasion, and (=3.4 9 1012 9 80 fL) of
parasites, and the hosts reaction to this process. In P. falciparum parasitaemias are usually less parasitised red cells
blood-stage infections, protuberances appear on the surface of than 1%, whereas P. (White et al. 2013b). In
the erythrocyte 1215 h after cellu-lar invasion. These membrane falciparum and P. knowle-si the brain in fatal cerebral
knobs extrude a high molec-ular weight, antigenically variant, are less selective (Simpson et malaria, 10 20% of the
strain-specific adhesive protein (PfEMP1) that mediates al. 1999) and may be associ- total parasite biomass
cytoadherence, or attach-ment of the parasitised erythrocyte to ated with very high parasite may be sequestered,
endothelial surface receptors in veins and capillaries, resulting in densities. Initially, the host which represents an
the sequestra-tion of parasitised erythrocytes in these vessels. responds by augmenting approximate intravascular
Under febrile conditions, which enhance PfEMP1 expression, splenic immunological and volume of 50 ml. This is
cytoadhe-sion begins at approximately 12 h of parasite filtra-tive clearance functions, certainly enough to cause
development; 50% of the maximum effect is obtained at 1416 which accelerates the removal significant cerebral swelling
h, and adherence is highly effective in the second half of the of both parasitised and independently of any
parasite life cycle (Udomsangpetch et al. 2002). Once adherent, uninfected erythrocytes. vasogenic or cytotoxic
the infected red cells do not detach until schizont rupture. There Schizont rup-ture releases oedema. Recent direct
is some ring-stage adherence via separate mechanisms. Of parasite and red cell material visualisation of the
several potential receptors identified for cytoadhesion of ery- into the blood that activates microcirculation in life in
throcytes infected with the more mature parasites, intercellu-lar monocyte-macrophages and patients with falciparum
adhesion molecule 1 (ICAM-1) is probably the most important in induces the release of pro- malaria, and measure-ments
the brain, chondroitin sulphate A in the pla-centa, and CD36 in inflammatory cytokines, of individual vessel flows,
most other organs (Cooke et al. 1994). The infected erythrocytes which cause fever and other shows reversible heteroge-
adhere to the vessel walls and eventually cause heterogeneous pathologic effects. neous microvascular
blockage of the microcircu-lation (MacPherson et al. 1985; Temperatures of >40C dam- obstruction in the retinal,
Silamut et al. 1999). Parasi-tised erythrocytes may also adhere to age mature parasites. In buccal and rectal circulations
each other (agglutination) (Pain et al. 2001) and to uninfected untreated infections, these with a pattern which mirrors
erythro-cytes (rosetting) (Carlson et al. 1990). These adherence factors synchronise the closely the heterogeneous
pro-cesses are central to the pathogenesis of falciparum malaria. asexual cycle, with eventual sequestration seen in the
They result in the sequestration of red cells containing mature production of regular fever tissues examined from fatal
parasites in vital organs (including the brain), where they spikes, chills and rigors. cases (Beare et al. 2006;
interfere with microcirculatory flow and metabolism and the These regular fever patterns, Dondorp et al. 2008a). The
function of vascular endothelium (MacPherson et al. 1985, White which were once used to degree of microvascular
et al. 2013b). Sequestered P. falciparum para-sites develop safely classify the malarias obstruction observed in blood
away from splenic processing and filtra-tion. Only the younger (quotidian; fever spike daily, flow studies in life also
ring form P. falciparum parasites circulate in falciparum malaria, tertian; every 2 days, quartan; parallels clinical severity and
every 3 days), are rarely seen estab-lished prognostic
and so the peripheral para-site count may substantially
today in patients who receive measures such as plasma
underestimate the actual total parasite biomass. As the
prompt and effective lactate and base deficit
intraerythrocytic parasites mature, they make the infected red
antimalarial treatment. (Hanson et al. 2012).
cells more spherical and rigid. Severe falciparum malaria is
associated with reduced de-formability of the uninfected Tissue hypoxia from
erythrocytes, which may con-tribute to compromised flow microvascular obstruction is
Severe malaria exac-erbated by impaired
through the partially obstructed capillaries and venules, and
There is accumulating microvascular function (Yeo
shortens their sur-vival (Dondorp et al. 2002).
evidence that most of the et al. 2008a, 2012) and, in
major manifestations of contrast to sepsis, increased
severe malaria are caused by oxygen demand (Day et al.
parasitised erythrocyte 1996b; Yeo et al. 2012).
Impaired
two age groups (Newton et al.
1991, Waller et al. 1991).
Summa-rising the evidence,
hypermetabolism of sepsis) raised intracranial pressure
endothelial function may result from impaired bioavail-ability of (Day et al. 2000b). All these occurs more commonly in
nitric oxide (NO) (Anstey et al. 1996; Yeo et al. 2007) arising findings point to extensive children and is more likely to
from hypoargininaemia (Lopansri et al. 2003; Yeo et al. 2007), microvascular obstruction and develop in the later stages of
impaired NO synthase expression (Anstey et al. 1996; Yeo et al. impaired perfusion as critical cerebral malaria (Idro et al.
2007), inhibition of NO synthesis by asymmetric pathophysiological processes 2005a; Medana et al. 2011).
dimethylarginine (Yeo et al. 2010a), local quenching of NO in cerebral malaria (White et There is no evidence that
resulting from increased cell-free haemoglobin and haem (Yeo et al. 2013a,b). In adults, there pharmaco-logical measures
al. 2009) and blockade or loss of local endothelial protein C is marked endothelial directed against oedema such
receptors (Moxon et al. 2013). Reduced NO bioavailability activation (Turner et al. 1994) as high-dose corticosteroids
exacer-bates endothelial activation and exocytosis of but usually little or mannitol are beneficial.
intracellular Weibel-Palade bodies, which contain a variety of inflammation in the brain Indeed a recent study in
bioactive molecules including von Willebrand Factor (vWF) and (MacPherson et al. 1985). adults with cerebral malaria
an-giopoietin-2. Plasma concentrations are both substantially Intravascular leucocytes are in India showed that mannitol
elevated in severe malaria (Yeo et al. 2008b; De Mast more prominent in African as adjunctive therapy
et al. 2009), associated with a fatal outcome in both adults (Yeo children than in Asian adults prolonged coma duration and
et al. 2008b; Jain et al. 2011) and children (Erdman et al. 2011; who died from cere-bral increased mortality (Mohanty
Conroy et al. 2012). Angiopoietin-2 causes autocrine endothelial malaria (MacPherson et al. et al. 2011).
activation and may thereby exacer-bate microvascular 1985; Taylor et al. 2004;
sequestration of parasitised red cells (Yeo et al. 2008b). Dorovini-Zis et al. 2011). Although some patients
Concentrations of ADAMTS13, which cleaves and inactivates There is a mild generalised may remain comatose for
UL-vWF, are low in patients with severe malaria (De Mast et al. increase in the systemic hours or days after cerebral
2009; Lowenberg et al. 2010). Ultralong vWF multimers could vascular permeability. The sequestration should have
mediate cytoadher-ence and sequestration by binding activated blood brain barrier (BBB) is cleared, full neurological
platelets expressing CD36, the receptor for PfEMP1 (Bridges et functionally intact in adult recovery is the usual
al. 2010). However, vWF is not associated with either the degree cerebral malaria (Warrell et outcome. Transient disruption
of hyperlactataemia, metabolic acidosis or fatal out-come in al. 1986). Autopsy studies in of axoplasmic transport
severe malaria (Erdman et al. 2011; Phiri et al. 2011) and may African children show some provides a plausible
have an earlier, more upstream, role in severe malaria increase in BBB permeability explanation for the fully
pathogenesis. with a disruption of reversible coma and the
endothelial intercellular tight persis-tence of
junctions (Dorovini-Zis et al. unconsciousness after
Cerebral malaria. In patients who die in the acute phase of 2011). Imaging shows that parasite clearance (Medana et
cerebral malaria, many of the cerebral capillaries and venules are although there is often al. 2002). In addition, after
packed tightly with parasitised erythrocytes, whereas other cerebral swelling, mainly rupture of the schizont,
adjacent vessels are not obstructed (New-ton et al. 1991; Silamut attributed to the intracerebral residual erythrocyte
et al. 1999; Taylor et al. 2004; Dorovini-Zis et al. 2011; White et sequestered erythrocytes, membranes and malaria
al. 2013a,b). The degree of packing and congestion of the most adults have no evidence pigment may remain attached
cerebral micro-vessels with both infected and uninfected red of pronounced cerebral to the vascular endothelium
cells is asso-ciated significantly with the level of pre-mortem oedema. In African chil-dren, for days pro-viding a
coma and the interval to death (Pongponratn et al. 2003). A cerebral oedema is more continued activation
distinct and highly specific malaria retinopathy occurs in both common, particularly in the stimulus. Whereas adults
children and adults with cerebral malaria (Beare agonal stages (Potchen et al. rarely (i.e. in <3% of cases)
et al. 2006; Maude et al. 2009a). There are many simi-larities 2012). The mechanisms suffer neurological sequelae,
between the retinal and cerebral microcircula-tions. Retinal underlying cerebral oedema 315% of children surviving
whitening, haemorrhages, and whitening of the vessels (Figure in paediatric cerebral malaria cerebral malaria especially
6) all reflect the microvascular pathol-ogy observed in post- are incompletely understood. those with hypoglycaemia,
mortem ultrastructural studies (White et al. 2001, 2009). Organ- Similarly, opening pressures severe anaemia, repeated pro-
specific and systemic lac-tate/pyruvate ratios are elevated in on lumbar puncture are tracted seizures and deep
proportion to the sever-ity of illness (a different profile is seen in usually normal in adults, but coma have some residual
the are elevated in over 80% of neu-rological deficit when
children, although mean they regain consciousness;
values (approximately 160 hemiplegia, cerebral palsy,
mm CSF) are similar in the cortical blindness, deafness
and
Alveolarcapillary membrane
function is significantly
impaired in patients with
role in acidosis (Jarvis et severe malaria and
impaired cognition and learning (all of varying duration) have al. 2006; Maitland et al. deteriorates further during
been reported (Brewster et al. 1990; Dondorp et al. 2005a, 2010; 2011; Hanson et al. 2012). treatment (Maguire et al.
Idro et al. 2007) (see Section 3). Approxi-mately 10% of 2005), and a post-treatment
children surviving cerebral malaria have a persistent language Hypoglycaemia is often inflammatory response may
deficit. The incidence of epilepsy is increased and the life associated with lactic acidosis explain the frequent
expectancy decreased among these children (Birbeck et al. and a poor prognosis. It is a development of ARDS after
2010b). The discrepancy between the microvascular pathology particular problem in chil- commencement of antimalar-
observed at autopsy and the large vessel territory strokes dren and pregnant women. ial therapy. The role of
causing neurological deficit in cerebral malaria has not been Hypoglycaemia results from a parasite sequestration in the
explained satisfactorily. failure of hepatic pul-monary microvasculature
gluconeogenesis combined is unclear. Pulmonary
Severe anaemia occurs most commonly in young children in with an increase in tissue sequestration can be marked
areas of moderate and high transmission (Calis et al. 2008). consumption of glucose by in P. falciparum. Careful fluid
Anaemia results from accelerated unparasitised red cell removal both the feb-rile host (as a management is essential.
by the spleen and the obligatory erythrocyte destruction at result of anaerobic glycolysis) Rapid infusion of large vol-
parasite schizogony, compounded by inef-fective erythropoiesis and to a much smaller extent, umes of intravenous fluid in
(Price et al. 2001; Buffet et al. 2011). Severe anaemia is often the the malaria parasites (Krishna severe malaria may prove
end result of repeated infections which do not allow sufficient et al. 1994). lethal (Maitland et al. 2011).
time for the bone marrow to recover. In severe malaria, both Hyperinsulinaemic If mechanical ventilation is
infected and uninfected erythrocytes become less deformable, hypoglycaemia is caused by not available, the mortality of
and sple-nic clearance is increased (Dondorp et al. 1997, 1999; quinine treatment and is ARDS exceeds 80% in falci-
Safeukui et al. 2008; Buffet et al. 2011). Anaemia develops particularly common in preg- parum malaria, but even with
rapidly, and transfusion is often required. Slight coagula-tion nant women. Quinine is a this treatment option, mor-
abnormalities are also common in falciparum malaria, and powerful stimulant of pancre- tality exceeds 50% in most
thrombocytopenia is usual and may be profound in severe atic insulin secretion. series (Taylor et al. 2012b).
malaria (a normal platelet count should challenge the diagnosis Hyperinsulinaemic Mortality in vivax malaria
of malaria), but significant bleeding with evi-dence of hypoglycaemia occurs after ARDS, when there is
disseminated intravascular coagulation is unusual (Clemens et al. treatment and may be commonly a single-organ
1994). Haematemesis from stress ulcera-tion or acute gastric recurrent despite glu-cose failure, is much lower (see
erosions may also occur rarely (War-rell et al. 1982). administration (White et al. Section 10).
1983b).
Acidosis is an important cause of death from severe malaria and Pulmonary oedema. Acute Acute Kidney Injury is a
results from accumulation of organic acids including lactic acid respiratory distress syndrome frequent feature of severe
(Day et al. 2000b). This may be com-pounded by ketoacidosis in (ARDS) is a feared malaria. Oliguric renal
children or acute renal failure in adults. Acidotic breathing, a complication in adults with failure is common in adults
major cause of respiratory distress, is a sign of poor prognosis in severe falci-parum malaria, with severe falciparum
malaria (Marsh et al. 1995). It is often followed by circulatory and it may also develop in malaria, but rare in children.
failure refractory to volume expansion or inotropic drugs and acute vivax malaria. It behaves clinically and
ultimately by respiratory arrest. The plasma concentrations of Significantly increased pathologically as acute
bicarbon-ate or lactate are among the best biochemical pulmonary capillary per- tubular necrosis.
prognostica-tors for death in severe malaria as they rise in meability develops after start Hypertension and significant
proportion to disease severity (Krishna et al. 1994; Hanson et al. of antimalarial treatment in proteinuria never occur. The
2010; von Seidlein et al. 2012) (see Section 10). Lactic aci-dosis up to a third of patients pathogenesis is still unclear,
is caused by the combination of anaerobic glycolysis in tissues (Taylor et al. 2012b). As with but reduced microcirculatory
where sequestered parasites interfere with micro-circulatory ARDS in other settings the flow as well as inflammation
flow, lactate production by the malaria para-sites, and a failure of pathogenesis is not fully likely contribute
hepatic and renal lactate clearance. Although hypovolaemia has under-stood, although (Nguansangiam et al. 2007).
been considered a contributor to hyperlactataemia, recent studies inflammatory mediated Acute renal failure may
question its causative increased capillary occur with multiple vital
permeability or endothelial organ dysfunction (carrying
damage is a central feature. a high
of malaria before the
introduction of control
measures, which suggests that
pathological interpretations. these genetic disorders con-
mortality) or may develop as other disease manifestations Plasma PfHRP2 concentra- fer a survival advantage in the
resolve. In survivors, urine flow resumes in a median of 4 tions, which can be used to presence of malaria. Indi-
days, and serum creatinine levels return to normal in a estimate the number of viduals who are homozygous
mean of 17 days (Trang et al. 1992). Early haemofiltration or sequestered P. falciparum for the sickle cell gene suffer
dialysis considerably improve the prognosis, particularly in parasites which release this from sickle cell disease,
acute hypercatabolic renal failure (Phu et al. 2002). protein, can distinguish which confers a reduced life
Although a variety of glomerular abnormalities have been between severe malaria and expectancy, whereas the
reported associated with malaria, the clinical features, urine severe other febrile illnesses heterozygous sickle cell car-
sediment (not active), and natural history of acute kidney with incidental parasitaemia rier does not suffer from the
injury do not suggest significant glomerulonephritis. (Hendriksen et al. 2012b, haemoglobinopathy and in
2013c; Seydel et al. 2012). addition is protected from
Severe jaundice is associated with P. falciparum infec-tions; it is HIV transmission and severe malaria. These
more common among adults than among chil-dren, and results progression may be contrast-ing clinical effects
from a combination of haemolysis, hepatocyte injury and accelerated by malaria have resulted in a balanced
cholestasis. Jaundice is often accompanied by renal impairment. (Kublin et al. 2005; Abu- polymor-phism during
Liver blood flow is reduced in severe malaria (Molyneux et al. Raddad et al. 2006), whereas evolution (Williams 2012).
1989a; Puk-rittayakamee et al. 1992), and hepatic conversely, HIV infection
gluconeogenesis is impaired (White et al. 1983a,b; White et al. increases the incidence of Several different malaria
1987a,b; Taylor et al. 1988; Day et al. 2000a,b). Hepatic clinical malaria, severe protective mechanisms have
dysfunc-tion contributes to hypoglycaemia, metabolic acidosis malaria and malaria-related been identified: these include
and impaired drug metabolism. mortality in adults with decreased parasite growth at
deteriorating immune status low oxygen tensions (Hb AS),
(Whitworth et al. 2000; reduced cytoadherence (Hb
Interactions with bacterial infections and HIV/AIDS. Kublin et al. 2005; Chalwe et AC, CC, AS), reduced
Bacteraemia, especially with Gram-negative bacteria, may al. 2009). In children with invasion (ovalocytosis),
complicate severe malaria, particularly in children. African severe falciparum malaria, reduced parasite densities
children with slide-proven severe malaria have a 4.6 7.8% HIV-AIDS increases the (G6PD deficiency) and
prevalence of concomitant bacteraemia (Berkley et al. 2005; severity, number of reduced multiplication at high
Bronzan et al. 2007). Given the limited sen-sitivity of blood complications and mortality. densities (HbAE). The
culture (Gilman et al. 1975), the real number of children with (Patnaik et al. 2005; Berkley underlying mechanism has
malaria who have bacterial septicaemia could be twice as high. et al. 2009; Hendriksen et al. been worked out in detail for
Falciparum malaria has been estimated to account for more than 2012a). HbAS and HbS. In parasitised
half of invasive bacterial disease in children living in malaria- red blood cell with these
endemic areas (Scott et al. 2011). Parasite digestive vac-uoles, haemoglo-bins, the trafficking
containing malaria pigment, are rapidly phagocy-tosed by of PfEMP1 and other proteins
Other host factors
polymorphonuclear granulocytes and cause a state of functional to the red blood cell surface is
neutrophil exhaustion. This blunts their microbicidal activity Many of the common disturbed (Cyrklaff et al.
upon bacterial challenge and may well contribute to the enhanced inherited red cell disorders 2011), causing aberrant knob
susceptibility of severe malaria patients to invasive bacterial confer a relative protection formation leading to reduced
infections (Dasari et al. 2011). Inhibition of neutrophil oxidative against the development of cyto-adherence of the
burst by induction of haem oxygenase (Cunnington severe malaria, and there is infected erythrocyte (Cholera
strong evidence that malaria et al. 2008). Most of the
et al. 2012a,b), and quenching of nitric oxide (Yeo et al. has been the direct cause of haemoglobinopathies are
2009), a key anti-Salmonella mediator, are also hypothesised their evolutionary persistence. associated with a reduced risk
to increase the risk of bacteraemia in malaria. Increased The geographical of severe malaria, but HbAS
translocation of bacteria across the distributions of sickle cell has also been associated
intestinal lining may also be an important contributor. There is disease, hae-moglobins C and consistently with reduced risk
extensive misdiagnosis of severe malaria in children who have E, ovalocytosis, the of uncom-plicated malaria
severe sepsis (septicaemia, pneumonia, thalassaemias and glucose-6- (Taylor et al. 2012a).
meningitis) and incidental parasitaemia (Reyburn et al. 2004). phosphate dehydrogenase
This has confounded clinical studies and (G6PD) deficiency match that
9a). The developmental
staging of parasites within a
vessel on brain smears
suggests that they arrive,
(a)
Section 8: Pathology of severe falciparum adhere and subse-quently
malaria develop in a synchronous
manner and do not detach
Pathology studies based on post-mortem and biopsy material are
once adherent (Silamut et al.
essential for a better understanding of the pathophysiology of
1999; Milner et al. 2012a,
severe Plasmodium falciparum malaria. Two large autopsy
White et al. 2013b). In
studies (one from Vietnam and the other from Malawi)
addition to cytoadhesion of
conducted over the past twenty years have used detailed
parasitised erythrocytes to
clinicopathological corre-lation with histological, ultrastructural
microvascular endothelium,
and immunohisto-chemical features and are now applying more
factors that contribute to
advanced molecular pathological techniques to the investigation
microvascular sequestration
of fatal malaria. However, several fundamental questions
in the brain include a
regarding the pathophysiology of fatal malaria remain
reduction in RBC
controversial, such as the mode of death in malaria patients, and
deformability (Don-dorp et al.
the factors causing coma in cerebral malaria. There are very few
2004b), clumping of PRBC or
pathology reports of fatal vivax malaria (see Section 13).
adhesion via platelet/von
(b)
Willebrand factor strings
(Bridges et al. 2010) and/or
The pathological features of cerebral malaria rosette formation (Ho et al.
1991; Chotiva-nich et al.
Sequestration. The predominant histopathological fea-ture of 2000).
human cerebral malaria (CM) is the sequestration of erythrocytes
containing Plasmodium falciparum troph-ozoites and schizonts
in the capillaries and post-capillary venules of the brain, first
recognised over a century ago (Marchiafava & Bignami 1892).
Parasitised red blood cells (PRBC) sequester and reduce the
diameter or com-pletely fill the vascular lumen (Figures 7 and 8).
Although sequestration is extensive in most cases of CM, the
degree and intensity differ between organs and within areas of
the brain.
Figure 7 Sequestration of
Sequestration in cerebral microvessels tends to be more parasitised erythrocytes in
intense in the cerebral cortex, where vascularity is greater in the cerebral microvessels in post-
grey matter than in the midbrain or brainstem. mortem brain tissue from fatal
cases of cere-bral malaria.
The degree of sequestration measured histologically varies with Packing of small calibre
duration of illness prior to death and with treat-ment. However, capillaries and post-capil-lary
the measurement of sequestration using histology on brain venules is demonstrated in this
sections (Aikawa et al. 1990; Pong-ponratn et al. 1991; Taylor et section of cerebral cortex
al. 2004; Dorovini-Zis (a). Margination in larger calibre
venules due to cytoadherence can
et al. 2011; Ponsford et al. 2012), brain smears (Silamut et al. also be demonstrated (b with
1999; Milner et al. 2012a) or by electron micros-copy inset) (haematoxylin and eosin,
(Pongponratn et al. 2003) (Figure 8) confirms that high levels 9400).
are significantly associated with ante-mortem coma.
Significantly more PRBC sequestration is seen in the brain of
cerebral malaria patients compared to cases both without The microvascular
neurological complications and without clinical evidence of distribution of sequestration
cerebral sequestration (i.e. malarial retinopathy), in both adult is not uniform and vessels
and paediatric cases, regard-less of brain area, time from may contain many parasites
treatment to death or type of treatment (Pongponratn et al. in one segment, but adjacent
2003; Dorovini-Zis areas or neighbouring vessels
et al. 2011). may only demonstrate
occasional parasites (Figure
(a)
association of ICAM-1
binding phenotype with clini-
cal risk of cerebral malaria
suggest that this is a major
receptor for sequestration in
the brain during CM (Och-ola
et al. 2011). Using molecular
pathological methods of PCR
and RT-PCR from autopsy
tissues, the genotype of
parasites sequestered in
different organs shows a nar-
rower spectrum than
circulating parasites,
(b) implying some selection of
binding parasite phenotypes
(Montgomery
Figure 8 Transmission electron micrograph of a cerebral venule
showing marginated cytoadherent parasitised erythrocytes, and et al. 2006; Milner et al.
uninfected erythrocytes within the narrowed vascular lumen. Tight 2012b). However, no specific
interactions of the endothelium with parasitised red blood cells as well
as between parasitised red blood cells and unin-fected red blood cells
have been seen at this level. Focal perivas-cular oedema is present in the
Virchow-Robbins space.
(Bar = 100 lm, courtesy of Prof Emsri Pongponratn, Mahidol
University and Prof David Ferguson, Oxford University).
The calculation of a sequestration index in adult patients,

comparing the parasite load within vessels with the concurrent
peripheral blood smear, allows estimation of the degree of
sequestration compared to the distribu-tion expected in a free
mixing model (Silamut et al. 1999). This shows that the load of
Figure 9 A brain smear from the
infected erythrocytes in cerebral microvessels is up to 50 times cortex of a patient who died
greater in CM than non-CM patients and also that the load in from cerebral malaria showing
cerebral vessels is greater than in other organs from the same sequestration by multisegmented
patient such as the kidney (Pongponratn et al. 2003; schizont-stage-parasitised
Nguansangiam et al. 2007). erythrocytes, whereas other
segments of the same vessels are
relatively uninvolved (Giemsa
Sequestration is mediated by specific molecular adhe-sion stain 91000). (b): A double
between parasite-encoded molecules, notably eryth-rocyte immunohistochemical stain
membrane protein 1 (PfEMP-1) expressed on the surface of the showing cere-bral endothelial
infected erythrocyte, and endothelial cell ligands such as cells (ICAM-1, red) and
parasitised erythrocytes (MSP-1,
endothelial protein C receptor (EPCR, Moxon) and ICAM-1 black) in a cerebellar venule
(brain) (Turner et al. 1994, Moxon et al. 2013), CD36 (haematoxylin counter stain
(endothelium and platelets) and chon-droitin sulphate A (CSA, 9400).
placenta) (Craig & Scherf 2001). Field isolates of parasites from
malaria cases most frequently show binding to CD36 (Cooke et
al. 1994; Newbold et al. 1997), which is widely and lial activation in all vascular
constitutively expressed on all vascular beds except the brain beds (Turner et al. 1998).
(Turner et al. 1994). The expression of several potential endothe- Colocalisation of sequestered
lial adhesins such as VCAM-1, E-selectin and ICAM-1 is PRBC with ICAM-1 (Fig-ure
increased in cerebral malaria, reflecting diffuse endothe- 12b) in brain microvessels
(Turner et al. 1994) and the
Haemorrhages are not

restricted to cerebral
orrhage may also be seen in malaria but are also seen in
relationship between the expression of specific var genes (which other organs such as heart non-cerebral cases and
encode the main parasite adhesin, PfEMP-1) and sequestration in and lung in adult cases, but sometimes in other
different organs was found (Montgomery et al. 2007). rarely in paediatric cases. conditions such as bacterial
Recent studies have provided evidence that host recep-tor and Histologically, several types infections, severe
parasite adhesin expression patterns may influ-ence sequestration of haemorrhage are seen such hypoglycaemia of the
and subsequent pathology in the brain in CM. The parasite var as simple petechial newborn, fat embolism or
genes DC8 and DC13 allow binding to a variety of endothelial haemorrhages, organised baro-trauma (Spitz 1946).
cell types from differ-ent organs and are associated with severe zonal ring haemorrhages Although increased in
and cerebral malaria (Claessens et al. 2012; Avril et al. 2013; (with central fibrin thrombi) number in the brain of CM
Bertin et al. 2013). Sequestration of PRBC to cerebral endothe- and Durcks granulomata, patients, they are not
lial cells by binding to the endothelial protein C receptor and which are formed from quantitatively associated
thrombomodulin colocalises with downregulation of EPRC, astroglial responses to older with ante-mortem coma or
which might cause local microvascular fibrin and thrombin haemorrhages (Figure 10). the presence of brain
deposition and microhaemorrhages, linking sequestration of Haemor-rhages are often oedema in Vietnamese
PRBC to local inflammatory and pro-coagulatory damage to the most prevalent in watershed adults (Ponsford et al.
bloodbrain barrier (Moxon et al. 2013). Therefore, binding of areas of vascular supply, 2012). Radiological studies
specific PRBC subsets determined by their var gene expression which may reflect their such as MRI also detect small
profile may be linked to organ-specific pathology. genesis as a con-sequence of haemorrhages in patients who
vascular obstruction and survive and make a full
hypoxicischaemic injury. In neurological recovery; hence,
paediatric cases, ring they seem a nonspe-cific
Haemorrhages
haemorrhages can contain feature of severe malaria that
The cut surface of the fresh brain in both adults and chil-dren fibrin thrombi with a zone reflects focal com-promise of
may show multiple small petechial haemorrhages, often free of red blood cells vascular integrity.
concentrated in the subcortical white matter, corpus callosum or suggesting an earlier vessel Furthermore, malaria
cerebellum (Figure 12a). This type of haem- breakdown and subsequent retinopathy changes, which
closure (due to fibrin). parallel ring haemorrhages
(a) (b)
Figure 10 Examples of microhaemorrhages found in

the brain in cerebral malaria are shown. A simple
punctate haemorrhage (a) shows red blood cells
surrounding a vessel (suggesting continued blood
brain barrier breakdown or a reperfusion injury) in
contrast to a ring haemorrhage (b) where there is a
zone of damaged brain and no red blood cells along
with a central fibrin thrombus suggesting coagulative
occlusion after breakdown (H&E 9 400). Ring
haemorrhages (c) go through various stages of (c) (d)
maturity (H&E 9 200) and can be seen resolving if a
patient has either survived the primary insult for an
extended period or subsequently dies of another
cause. Glial reaction to this process forms a lesion
termed a Durcks granuloma. As part of the damage
induced by these lesions, demyelination can be found
in white matter (d). (Luxol fast blue Cresyl Violet
stain 9200).
(a) (b)
Figure 11 MRI imaging of the brain in paediatric cerebral malaria. Severe brain swelling occurred in this patient with effacement of the 4th
ventricle, prepontine cistern and brainstem compression and tonsillar herniation (a); and normal child of similar age for com-parison (b).
Pictures supplied by Dr Sam Kampondeni.
ischaemic damage in 4, all of been reported in African chil-
in the brain, are commonly found in survivors, suggest-ing that whom suffered from neuro- dren, although the specificity
in common with sequestration haemorrhages are not solely logical sequelae (Newton et of the clinical signs is unclear
sufficient to cause mortality. However, unlike sequestration, the al. 1994). The pattern of (Pongponratn et al. 1991; Idro
number of haemorrhages is not quantitatively linked to the injury was consistent with a et al. 2005a; Seydel et al.
presence of coma pre-mortem. critical reduction in perfu- 2011). In other words it has
sion pressure, and the been unclear if the brainstem
convalescent scans showed clinical signs resulted from
cerebral atrophy. Acute CT brainstem compression or
Brain swelling and oedema findings in Malawian intrinsic dysfunction related
At autopsy, the brain may be swollen or normal in adults, children included cerebral to the disease process. Histo-
whereas brain swelling is universal in African children (Potchen oedema and acute brain logical evidence of oedema is
et al. 2010; Dorovini-Zis et al. 2011) (Figure 12a). Adult patients infarctions. In 11 children seen in over 60% of adult
with coma may have no evidence of brain swelling either with subsequent neurological cases (Medana et al. 2011),
radiographically before death or at autopsy. Computerised sequelae who had CT scans and most if not all paediatric
tomography (CT) in Indian adults with cerebral malaria showed 718 months after the initial cases (Dorovini-Zis et al.
that brain swelling occurred but was not related to coma depth or illness, 5/11 had focal and 2011) (Figure 12b). Much of
fatal outcome (Mohanty et al. 2011). CT and magnetic resonance multifocal lobar atrophy the increase in cerebral
imaging (MRI) data in paediatric cases demon-strate oedema correlating with regions of volume in adults in the acute
commonly in cerebral malaria patients with a strong association the brain affected by focal phase of illness can be
with outcome (Figure 11) (Seydel et al. 2011; Potchen et al. seizures during the acute quantitatively explained by
2012). In a study of Nigerian children, the post-mortem findings illness (Potchen et al. 2010). the intravascular load of
suggested gross cerebral oedema and raised intracranial pressure sequestered parasites and
in four of seven cases with petechial haemorrhages and small Evidence for raised uninfected erythrocytes
areas of focal necrosis (Walker et al. 1992). Com-puted intracranial pressure and (White et al. 2013b).
tomography of the brain in 14 Kenyan children recovering from subsequent frank brainstem Congestion of microvessels
cerebral malaria with raised intracranial pressures revealed herniation is uncommon in with PRBC and uninfected
evidence of brain swelling in 6 and of adults. Clinical and RBC is associated
radiological evidence for significantly with coma
brainstem herniation as a (Ponsford et al. 2012), but the
mode of death in CM has degree and patterns
(a) Figure 12 Macroscopic picture of brain swelling and petechial
haemorrhages. An autopsy brain slice from a paediatric African

case (a) of fatal CM shows swelling with obliteration of the sulci
and ventricular system, (b) a brain slice from an adult case with
less marked swelling, but multiple focal haemorrhages in the
white matter, contrasting with a lack of haemorrhages in the
grey matter (courtesy of Dr Peter King, SIAMR, Johannesburg).
Histological evidence of perivascular or bubbly parenchymal
oedema (c) in the brain is seen predominantly in paediatric cases
but may also be found in adults (H&E 9 400).
(a)
(b)
(b)
(c)
of histological oedema are

not associated with coma in
adults (Medana et al. 2011).
Brain swelling may therefore
not be due solely to
perivascular or parenchymal
oedema.
Figure 13 Pigment granules

within an early trophozoite-stage
P. falciparum-infected red cell
(a), cultured in vitro and adherent
to an endothelial cell as seen by
transmission electron micros-
copy. Note the refractile quality
of the pigment, which is both
polarisable and paramagnetic. A
transmission electron micro-graph (b) showing the developing food stage parasite shows surface Pongponratn & Prof David
vacuole (FV) containing crystalloids of haemozoin (H) the FV is knob proteins (K), which are the Ferguson).
physically separated from the parasite nucleus (N); haemozoin is toxic to site of cytoadherence (95000,
the parasite and thus sequestered in the food vacuole. This trophozoite- courtesy of Prof Emsri
and sequestration of parasites in
capil-laries (a) demonstrate
axonal injury. Swollen axonal
sheaths within the white matter
are also found (H&E staining
(a)
In contrast, in paediatric cases, oedema and brain swelling are 9400)
common at autopsy in children with other causes of coma as (b). Immunohistochemistry for
well as in cerebral malaria (Seydel et al. 2011). beta-APP, a marker of axonal
injury, demonstrates damage
in an African paediatric case
Pigment deposition (c).
The fresh cut surface of the brain may show a slate-grey-ish

discolouration reflecting the heavy deposition of malaria
pigment (haemozoin). Pigment can be seen both within vessels,
often remaining attached to ruptured erythrocyte membrane
ghosts following schizogony or phagocytised by host leucocytes
(Figure 13, 15 and 16). Rarely, focal pigment granules can be
seen within the brain parenchyma due to haemorrhage or passage
across focal disruptions to the bloodbrain barrier. Pigment loads
in brain microvessels in African paediatric cases correlate with
the degree of pigment in other organs such as the spleen and
liver, suggesting that this is a surrogate measure both of current
parasite biomass and of the number of life cycle replications that (b)
have happened within the body (Whitten et al. 2011).
Axonal injury
Acute axonal injury, detected both morphologically
as swollen axonal sheaths and bulbs, or on immunohisto-
chemistry by accumulation of beta-amyloid precursor protein, is
found in post-mortem studies of CM patients in both adult and
paediatric cases (Medana et al. 2002, Dorovini-Zis et al. 2011)
(Figure 14). This likely repre-sents a reversible but final
common pathway to neurolog-ical impairment in CM.
Cellular immune responses
Studies in Malawian children demonstrated that 75% of cases (c)

have intravascular and perivascular pathology (haemorrhages,
accumulation of pigmented leucocytes and thrombi), whereas
leucocyte aggregation, vasculitis or thrombus formation are not
commonly seen histologi-cally in adult cases. In adults,
individual vessels can show collections of leucocytes,
predominantly monocytes and T cells on immunophenotyping,
which can be marked (Pat-naik et al. 1994). However, other
vessels lack such col-lections of cells, and monocyte responses
are seen mainly in cases who die later in the course of disease,
where they show phagocytosis of pigment and ghosted
erythrocyte membranes (Figure 15).
Within the Malawian cohort of children diagnosed by

pathology as cerebral malaria, two distinct patterns were
recognised. These included the classic pattern of cerebral Figure 14 Axonal Injury:
malaria as seen in adults which demonstrates densely Swollen axonal bulbs in white
matter with background oedema
both of these patterns were
seen in both children and
adults throughout this period,
with little indication avail-
able to account for the
different histological
(a) appearances (Milner & Taylor
2006).
Platelet deposition
There is a marked difference

between the degree of plate-
let deposition in the brain
between paediatric African
and adult Asian cases (Figure
16). Deposition of platelets in
(b)
Figure 16 A brain capillary from

a case of cerebral malaria
demonstrates malaria pigment
(black) within the vessel sur-
rounded by endothelial cells and
white blood cells (pale blue
nuclei). Immunohistochemistry
for CD36, a molecule not found
in brain endothelium but
ubiquitous on platelets, highlights
the adherent clusters of platelets
within areas of sequestration.
Image at 630 9 courtesy of Prof.
Georges Grau, University of
Figure 15 Evidence for cellular inflammatory responses in the brain Sydney, Australia.
during CM is presented. Immunohistochemistry with anti-CD68 (a)
showing both intravascular monocytes, some of which contain
phagocytosed malaria pigment and perivascular/paren-chymal
macrophages (haematoxylin counterstain, scale
bar = 10 lm). (b): A transmission electron micrograph showing a cerebral ter group. Detailed studies of
vessel with a circulating monocyte (N = nucleus) which has these two pathologies with
phagocytosed a pigment granule (arrow). The cells are making multiple respect to HIV status are
contacts via pseudopodia (arrowheads) with the lining endothelial cell
currently underway; however,
(En) (scale bar = 1 lm, courtesy of Prof. Emsri Pongponratn and Prof.
David Ferguson). the general consensus is that
they may represent different
tem-poral points in a
sequestered parasites within cerebral vessels, ring haemor-rhages continuum, with the question
throughout the white matter of the cerebral cortex and excessive remaining why death has
pigment within and outside of macrophages (Taylor et al. 2004). occurred at the particular and
A second pattern showed densely sequestered parasites but little different time point in each
other pathology. Clinically, there was little difference between patient. Review of the
these two groups except for a higher incidence of HIV antibody literature for all adult and
positivity in the lat- paediatric cases published in
the last century, suggests that
2006).
paediatric African malaria

cases suggesting that, like Heterogeneity of
(a) pathology and clinical
ring haemorrhages,
misdiagnosis: What is a
thrombocytopenia alone is
pathological case
not sufficient to explain
definition of cerebral
mortality in fatal cerebral
malaria?
malaria (Dondorp et al.
2010). Autopsy-based pathology
studies often examine small
numbers of cases, making
Disruption of the bloodbrain
barrier statistical analysis difficult. In
addition, the snapshot effect
Cellular inflammatory examining individual cases
responses are apparent in whose deaths occurred at
the intrinsic astroglial cells different times in the par-
of the brain parenchyma asites maturation cycle and
(Figure 17a). Pathology in the evolution of pathology
studies have provided greatly complicates
evidence interpretation. Nevertheless, it
for a direct link between can be seen that there are
sequestration of PRBC and some differences between the
(b) dys-function and local pathology of CM in children
breakdown of the blood from high endemicity set-
brain barrier. There is leakage tings and in adults from low
of plasma proteins such as endemicity settings. The
fibrinogen into the clinical differences include
perivascular space and the time to death (more rapid
activation of pericytes, in children, within 48 h of
perivascular astrocytes and admission) and the co-exis-
microglial cells on immuno- tence of other severe
histochemistry (Figure 17b). manifestations such as shock,
Sequestration is associated acido-sis, lung disease or
with redistribution of renal failure (more prominent
endothelial cell junctional in adults). Levels of
adhesion molecules such as immunity, host
ZO-1 and vinculin (Brown et polymorphisms and/or
al. 1999), focal disruption to parasite virulence may play
the bloodbrain barrier in roles in these different
Figure 17 An immunohistochemical stain (a) for glial fibrillary acidic adults (Brown et al. 2000)
pathologies in the individual
protein (GFAP, red) shows activation of perivascular and parenchymal and Malawian children
astrocytes in a case of cerebral malaria (haemat-oxylin counter stain, patient. Pathologically, the
(Brown et al. 2000; Dorovini- differences include deposition
9200). An immunohistochemical stain (b) for fibrinogen (red) shows
leakage around a small vessel into the brain parenchyma and associated Zis et al. 2011). Parasitised of platelets and fibrin thrombi
uptake into astrocyte foot pro-cesses investing the abluminal border of erythrocytes can stimulate in children and the degree of
the Virchow-Robbins space (haematoxylin counterstain, 9400). intracellular signalling events host leucocyte reac-tion,
in endothelial cells through neither of which is marked in
direct adhesion to receptors adults. HIV co-infec-
areas of focal haemorrhage is associated with fibrin-plate-let
such as CD36 or ICAM-1
thrombi, intravascular clotting and perivascular haemorrhages in
(Jenkins et al. 2007; Tripathi
children (Grau et al. 2003; Dorovini-Zis et al. 2011).
et al. 2007). These events in
Thrombocytopenia is strongly associated with CM in these
turn affect cerebral endothe-
patients. This may reflect a systemic abnormality of clotting or
lial cell structure and
the relative abundance of CD36 on the surface of platelets.
function, which may mediate
However, the degree of thrombocytopenia counts was not
associated with adverse outcomes in a large clinical study of over changes to bloodbrain
5000 barrier function in cerebral
malaria (Medana & Turner
Lung pathology
tion is significantly associated with poorer prognosis in children is seen in combination with Respiratory distress is a
and adults, and it has been noted that in HIV-infected children malaria retinopathy (Beare common feature of severe
with fatal malaria, there is a lack of monocyte sequestration in et al. 2004, 2011; Taylor et falci-parum malaria in both
the brain (Grimwade et al. 2004; Berg et al. 2008). Where the al. 2004; Birbeck et al. children and adults (Taylor &
opportunity to exam-ine potential differences due to treatment 2010a; Dorovini-Zis et al. White 2002; Taylor et al.
has presented, no differences in the type or degree of brainstem 2011; Milner et al. 2012a). 2006c). Metabolic acidosis is
neuro-pathology were found in adult patients treated with dif- The Malawi autopsy study the most important cause of
ferent drugs (artemether versus quinine) (Hien et al. 2003). showed that approximately respiratory distress, but many
25% of clinically diagnosed other factors may contribute
Quantitative neuropathological examination using mul- CM cases did not have to it, including severe
tivariate analysis in Vietnamese cases of CM shows that the evidence of malaria parasite anaemia, pulmonary oedema
presence of coma before death was associated with the sequestration in the cerebral and aspiration pneu-monia.
neuropathological features of PRBC sequestration, micro- microvascu-lature and had Frank pulmonary oedema is
vascular congestion and axonal injury. Observed seques-tration other causes of death (Taylor more common in adults than
in brain microvessels was associated with time to death (i.e. et al. 2004). This large children and is a poor
duration of treatment), admission Glasgow Coma Score and proportion of patients in prognostic sign, although it is
density of peripheral parasitaemia. In African children, cerebral which the clinical case less common with improved
malaria was confirmed using a pathological cut-off of more than definition failed has ventilation
21% of cerebral vessels showing sequestration at post-mortem implications for both the
(Taylor et al. 2004; Milner et al. 2012a). The sensitivity of reliability of verbal autopsy
diagnosis of malaria increases, and the prognosis worsens, when (Snow et al. 1992) and the
coma interpretation of treatment or
vaccine trials.
Parasitised erythrocytes sequestered in alveolar
capillaries alongside host lymphocytes and
monocytes (b) are demonstrated in most patients
Figure 18 Examples
(c) of the pathology (H&E 9 100). Immunohistochemistry with anti-
(a) (b) CD68 (c) shows both intralveolar macrophages
(d) found in the lung
and type 2 pneumocytes and an increase in
during Plasmodium
circulating monocytes in alveolar capillaries,
falciparum malaria.
many of which contain phagocytosed malaria
Patchy pulmonary
pigment (H&E 9 400). In paediatric cerebral
oedema (a) with
malaria, the amount of pigment within
pigment deposition
macrophages is significantly greater than in non-
can be seen
CM patients. A case of pyogenic pneumonia (d)
commonly in adults
is dem-onstrated as the cause of death in a
and in about 40% of
patient who recovered from cerebral malaria but
paediatric cases
died later (H&E 9 400).
(H&E 9 100).
include thickened alveolar
septa showing monocytes
and neutrophils (often
Figure 19 Manifestations of contain-ing phagocytised
Plasmodium falciparum malaria particles of malaria pigment),
(a)
infection in the kidneys are patchy intra-alveolar
shown. Histology demonstrating
haemorrhage and pulmonary
sequestration of parasitised
erythrocytes (a) in both oedema. In individual adult
glomerular (arrowheads) and cases, hyaline membrane
peritubular capillaries. There is formation can be seen as an
associated tubular epithelial cell indicator of diffuse alveolar
swelling and degeneration damage; this pattern has not
consistent with acute tubular
been observed in children.
necrosis (ATN) (H&E staining
9200). A transmis-sion electron Pyogenic con-solidation may
micrograph (b) shows be found in some cases,
sequestered PRBC, unin-fected indicating that pneumonia
red cells (RBC), and was the true diagnosis in a
mononuclear leucocytes (M) in a patient with inci-dental
peritubular capillary. The parasitaemia whose illness
proximal tubular cell is separated
was mistakenly attrib-uted to
by the basement membrane (BM)
and is rich in mitochondria (Mi) malaria, or it may be a
(b) (Scale bar = 2 lm, courtesy of secondary complication of
Prof Emsri Pongponratn). Fibrin coma, convulsions or
thrombi within glomerular intubation in patients
capillaries (c) indicative of suffering from cerebral
microang-iopathic changes are
malaria.
seen in approximately 40% of
classic paedi-atric cerebral
malaria cases.
Renal pathology
weight with associated Renal failure is a common
pulmonary oedema on clinical manifestation of
section-ing. Pleural or severe falciparum malaria in
intrapulmonary punctuate adults, but it is uncommon in
haemorrhages can be seen in chil-dren (Trang et al. 1992;
adults (these are common in Mehta et al. 2001; Dondorp et
many organs in adults with al. 2005a). There is a clinical
fatal malaria). In contrast, association between jaundice
haem-orrhages outside of the and acute renal failure in
brain in paediatric cases have adults (Day et al. 2000a).
(c)
not been found. Alveolar Patients may have shock,
capillaries may show seques- anaemia and other
tration of PRBC, causing complications potentially
congestion of pulmonary reducing renal oxygenation. A
capil-laries, and there is study of renal blood flow and
sometimes associated intra- haemodynamics in
alveolar haemorrhage. The Vietnamese patients with
degree of host leucocyte severe malaria showed only a
response is greater in the lung small decrease in renal
than the brain, with
monocytes, neu-trophils and
lymphocytes seen in alveolar
capillaries (Duarte et al.
1985; MacPherson et al.
1985). In some cases, the
inflammatory response
and ICU level care for adult patients (Brooks et al. 1969). Adult
resembles a pneumoni-tis
patients may develop radiological and clin-ical signs of acute
(Figure 18).
respiratory distress syndrome (ARDS). At autopsy, the lungs may
be normal or increased in
The pathological features
injury, rather than an acute

blood flow in patients with severe malaria, compared to patients tubulointerstitial nephritis or
with sepsis and to controls (Day et al. 2000a). These findings glomerulonephritis.
suggest that malaria-associated acute renal failure (MARF) is not
caused by shock alone. Nevertheless, both ultrastructural Liver pathology
(Nguansangiam et al. 2007) and histo-logical studies in the
Vietnam autopsy series showed that in patients dying with Jaundice is a common finding Figure 20 Histology of the liver
(a) in P.falciparum malaria
MARF, there was a high prevalence (64%) of tubular epithelial in adult patients presenting
infection, showing dilated
cell degeneration and acute tubular injury, features that are with severe malaria. Jaundice sinusoids, red cell congestion,
known to occur in shock, and so may result from impaired may be due to severe host leucocytes and pigment
microvascular perfusion. Acute renal failure is rare in children, intravascular haemolysis or uptake by Kuppfer cells. There
but some degree of renal dysfunction has been reported in series disseminated intravascular is mini-mal cellular hepatocyte
from Africa, although this may result from dehydration and pre- coagulation (DIC), usually change (H&E 9 400). Diffuse
pigment distribution (b) and load
renal failure, which usually resolves rapidly with appropriate with the addition of hepato-
is strongly associated with the
fluid management (Maitland et al. 2004; Anochie & Eke 2005). cyte dysfunction. Malarial presence of cerebral malaria in
Recent evidence in the Malawian autopsy series has revealed hepatitis is an erroneous paediatric cases (pigment is seen
thrombin within the renal glomerular microvascu-lature, possibly term, because neither the here as refractory granules under
as a part of a systemic coagulopathy, which may cause a clinical nor the polarisation).
thrombotic microangiopathy in the kidney (D. Milner personal histopathologi-cal features
communication) (Figure 19). resemble those of viral or
toxic hepatitis. Severe liver
Pathology studies in Asian patients have reported a number of dysfunction occurs
different findings (Boonpucknavig & Sitprija 1979; Sitprija occasionally in severe malaria
1988; Barsoum 2000) correlated with the ante-mortem diagnosis in association with multiorgan
failure and poor
of MARF, including acute tubular injury (termed acute tubular
necrosis but potentially less florid), sequestration of PRBC
within glomerular and peritubular blood vessels, accumulation of
host leucocytes in peritubular capillaries and a mild
endocapillary prolif-erative glomerulonephritis (Figure 19). A (a)
study cohort of South-East Asian adults (Nguansangiam et al.
2007) showed no evidence for established immune complex-
mediated glomerulonephritis in falciparum malaria. Ear-lier
studies of renal pathology (Boonpucknavig & Sitprija 1979;
Boonpucknavig & Soontornniyomkij 2003) described an active,
immune complex-mediated glomeru-lonephritis in acute
falciparum malaria. Several have recorded marked glomerular
hypercellularity, mesangial proliferation and both
immunofluorescence and EM evi-dence of immunoglobulins,
complement components and malarial antigen deposition in
capillary loops. Immune complexes were cleared rapidly and the
glomerular injury was reversible, in contrast to immune complex
nephritis in P. malariae (Kibukamusoke & Hutt 1967). Other
clin-ical studies (Barsoum 2000; Boonpucknavig & Soon-
tornniyomkij 2003; Eiam-Ong 2003) emphasised that the clinical
and biochemical findings in MARF were more in keeping with
an ischaemic nephropathy or acute tubular necrosis (Trang et al. (b)
1992), with little or no proteinuria. The absence of associated
hypertension, the rapid resolu-tion without residual renal
impairment, together with the inactive urinary sediment
findings, all suggested that renal failure in severe malaria results
from acute tubular
findings in the acutely
infected spleen include an
increase in the red to white
(a) pulp ratio, due to
engorgement of sinusoids
prognosis (Das et al. 2007). In adult, non-immune patients in with red cells and pigment
South-East Asia and India, jaundice and liver dysfunction occur (Figure 21). The germinal
in up to 50% of cases in severe malaria, almost always as part of cen-tres (white pulp) show a
multiorgan disease. Jaundice is associated with predominantly degree of dissolution, which
conjugated hyperbilirubinaemia, unconjugated reflects trafficking of
hyperbilirubinaemia and mixed patterns being less common. leucocytes in response to
There may be prolonged prothrombin times and low malaria infection, and there
concentrations of albumin in the serum. Elevations of liver are increases in the numbers
cytoplasm enzymes are common, including raised aspartate and of den-dritic cells within the
ala-nine aminotransferases (AST and ALT) and alkaline marginal zones (Urban et al.
phosphatase, but these are never increased to the levels seen in 2005). Recent studies of an
viral hepatitis (Anand et al. 1992; Anand & Puri 2005). ex vivo model of human
splenic per-
Histopathological examination of liver biopsies during life or

autopsy samples reveals a spectrum of changes in adults (Kochar (b)
et al. 2003; Das et al. 2007; Rupani & Amarapurkar 2009). These
include PRBC sequestration within hepatic sinusoids and
adhesion of parasitised ery-throcytes to sinusoidal endothelial
cells, Kuppfer cell hyperplasia and the retention of malaria
pigment (Figure 20). Host leucocyte responses are variable.
There is some conflicting evidence as to the extent of direct
parenchymal hepatocyte damage, but several series report
hepatocyte swelling and necrosis, host leucocyte infiltrates and
focal centrilobular hepatic necrosis. Fatty change is uncommon,
and cholestasis is rarely seen. In contrast, paediatric cases of
cerebral malaria have revealed relatively normal appearing liver
with a pre-dominance of pigment-laden macrophages and little
sequestration of PRBCs (Whitten et al. 2011). A finding of
widespread hepatic necrosis at autopsy should raise the
possibility of hepatotoxicity induced by traditional medicines
taken to treat malaria before presentation. An ultrastructural
study of post-mortem liver samples from adults (Prommano et al.
2005) showed that the degree of jaundice, hepatomegaly and
liver enzyme abnormali-ties correlates with the overall parasite Figure 21 Histological
appearances of the spleen (a) in
load in the body. Parasitised red cell sequestration in the liver acute Plasmodium falciparum
was quanti-tatively associated with liver weight, serum bilirubin malaria, showing engorgement
and AST levels. of the red pulp sinusoids by
infected erythrocytes, and
numerous pig-ment-laden
monocytes (H&E 9 400). (b): An
electron micro-graph showing
Splenic pathology pitting, whereby the
Plasmodium parasite (P) is
The spleen is commonly enlarged in severe malaria and can removed from the erythrocyte as
it passes between the narrow slits
occasionally be so engorged with PRBC and uninfected RBC
between the endothelial cells
that acute splenic rupture occurs with death due to (En) lining the sinusoids (cour-
haemorrhagic shock, although this is rare (Imbert et al. 2009). tesy of Prof Emsri Pongponratn).
Chronic, repeated or relapsing malaria infection can result in
chronic splenic enlarge-ment, pigmentation, and is a cause of
the syndrome known as hyperreactive malarial splenomegaly tropical splenomegaly
(formerly syndrome). Histological
cell infiltrate of monocytes
and lymphocytes and with
some neutroph-ils. The
The pathology of placental degree of inflammation varies
malaria but is often consid-erable and
(a) can lead to a picture of
The pathological features of massive intervillositis. Host
placental malaria depend on monocytes can secrete
the timing of infection in chemokines (Abrams et al.
relation to delivery (Figure
2003), and the inflammatory
22). In active malaria
infiltrate may continue to
infection of the placenta,
affect the function of the
seques-tration of PRBC is
materno-foetal unit after
seen in the intervillous blood clear-ance of parasitaemia,
space. Sequestration in the leading to adverse pregnancy
placenta is mediated by out-come (Rogerson et al.
binding to chondroitin 2003). Deposition of malaria
sulphate A (CSA), which is pigment and fibrin in the
expressed by the intervillous space and
syncytiotrophoblast lining the phagocy-tosis of
placental intervillous space syncytiotrophoblastic cells by
(Fried & Duffy 1996). monocytes can also be seen.
(b) Placental PRBC binding to With effective treatment, the
CSA is mediated by a unique placenta can become cleared
PfEMP-1 protein VAR2CSA of acute malaria infection, but
that is immunologically subsequent episodes of
distinct from variant surface clinical malaria can cause
antigens (VSA) on other further pathological changes,
PRBC. This unique which are not specific to
pregnancy-specific VSA is malaria. These include
recognised by antibodies excessive fibrin deposition
which may then be boosted within and between villi,
when a malaria infection with thick-ening of the
the same VSA occurs in a trophoblastic basement
subsequent pregnancy (Fried membrane, loss of villous
et al. 1998). The absence of vascularity and obliteration of
such antibodies in first arterioles in the terminal stem
Figure 22 Histological features of placental malaria (a): Acute, active
pregnancies could explain in villi, and occasional focal
placental malaria infection, showing sequestration of infected part the higher suscep-tibility fibrinoid necrosis of villi.
erythrocytes in the maternal vascular space, some adher-ing to the of primigravidae to placental Several histological grading
syncytiotrophoblast cells lining the chorionic villi, with focal intervillous malaria. The close association schemes have been suggested
fibrin formation. (b): Chronic placental malaria infection, with clearance between a specific parasite to detail the pathological
of parasitised erythrocytes, numerous monocytes within the maternal binding pheno-type and
vascular space and fibrin deposi-tion within a villus. (haematoxylin and
changes in placental malaria
eosin staining 9400, images courtesy of Dr Atis Meuhlenbachs, CDC,
placental sequestration offers and relate them to maternal
USA). the hope for im-munisation and fetal outcomes in
against this specific disease pregnancy (Bulmer et al.
phenotype using vaccines 1993, Ismail et al. 2000,
fusion with PRBC (Safeukui et al. 2008) have indicated that modelled on the VAR2CSA Meuhlenbachs et al. 2010).
red cells containing late-stage parasites are removed in the protein (Orogade et al. 2008).
splenic sinusoids and that non-adherent ring-stage PRBC can
also be removed, a process that is assisted by the slowness of
sinusoidal circulation in the spleen. Active infection may be
Removal of infected red cells may contribute to both splenic associated with marked
pathology and the immune response to falciparum malaria inflam-mation, with a
(Buffet et al. 2011). predominantly mononuclear
in the staining pro-cedure,
parasitaemias as low as 30
50/ll may be detected.
Parasitological diagnosis
Section 9: Clinical and laboratory Microscopy remains the
Reliable examination of the
diagnosis of severe malaria reference standard for the
peripheral blood slide (both
Clinical diagnosis thick and thin films) requires
diag-nosis of falciparum
a degree of technical
malaria, but this requires the
Severe malaria is clinically similar to other severe febrile precision in the preparation of
avail-ability of a good
illnesses (Gwer et al. 2007). Hence, the specificity of clinical the blood slide, its han-dling
microscope, significant
diagnosis is low. Each clinical syndrome of severe malaria (e.g. and staining, and are
technical skills, good-quality
coma, severe anaemia, acidosis) can have other causes (e.g. dependent on the optical
reagents and clean slides. The
meningitis, sickle cell disease, septicaemia) (Berkley et al. 1999; quality of the microscope and
diagnostic quality of
Gwer et al. 2007; Pfeiffer et al. 2008; Poschl et al. 2010; the illumination, as well as
microscopy is very variable
Hendriksen et al. 2012a). Obtaining a parasitological diagnosis competence, care and time on
in routine hospitals in sub-
does not resolve the diagnostic problem, especially in high trans- the part of the micros-copist.
Saharan Africa (McMorrow
mission areas, where asymptomatic parasitaemia is com-mon and Common pitfalls include
et al. 2008; Nanka-birwa et
may be incidental in any severe illnesses (Gwer et al. 2007). artefacts (e.g. dye
al. 2009).
precipitation) mistaken for
Because of the fatal consequences of missing the diag-nosis of parasites, Maurers clefts con-
Peripheral blood films.
severe malaria, a traveller with a severe febrile illness who has fused with Schuffners dots
Malaria is diagnosed by
been in a malarious area within the previ-ous 2 months must be (causing P. falciparum to be
exami-nation of thick and
considered to have malaria unless proven otherwise. Similarly, in misdiagnosed as P. vivax),
thin blood smears stained
patients living in endemic countries who present with a fever, the Babesia and Bartonella infec-
with supravital dyes. Blood
suspicion of malaria should be high. tions mistaken for malaria
smears are usually stained by
and young gametocytes of
the methods described by
In countries where malaria is common, overdiagnosis is Wright, Field or Giemsa.
another possibility, diverting attention from other infec-tious Thin films are quicker to P. falciparum mistaken for P.
causes of severe febrile illness. Overdiagnosis of malaria has obtain, provide accurate vivax. In SE Asia P.
been shown to contribute to mortality (Reyburn et al. 2004). knowlesi ring stages may be
counts of high parasite
Overdiagnosis is commonly due to neglect of a negative blood densities, and allow mistaken for P. falciparum
film or to failure to obtain a blood film or rapid diagnostic test prognostic assessments and P. knowlesi mature
(RDT) at all (English et al. 1996a; Molyneux et al. 1998; Berkley based on staging of parasite trophozoites may be
et al. 2005). A parasitological diagnosis should be obtained mistaken for P. malariae.
development and assessment
whenever possible (Hendriksen et al. 2011), but the relevance of of the proportion of In P. vivax, P. ovale and P.
parasitaemia to the current illness must always be consid-ered malariae malaria, all stages
neutrophils containing
carefully (Koram & Molyneux 2007). In the absence of of parasite development may
malaria pig-ment. On the
diagnostic facilities, antimalarial treatment should not be delayed thick film, in which many be seen in the peripheral
if the patient is severely ill but should be started based on a blood film, whereas in P.
layers of red cells are falciparum infections, only
clinical suspicion while other diagno-ses are also considered. overlaid and lysed by water
Table 8 Criteria for development of falciparum assessed by light microscopy
staging the Plasmodium
Stage development Cytoplasm Nucleus Pigment
Tiny ring Ring form, width <1/2 of diameter of the nucleus 12, round at one side of cytoplasm No
Small ring Ring form, width 1/2 of diameter of the nucleus 12, round at one side of cytoplasm No
Large ring Ring form, width diameter of the nucleus 12, round or elongated No
Early trophozoite Spherical 12, inside cytoplasm Faint, pale brown
Middle trophozoite Spherical, enlarged, stained dark 12, pale inside cytoplasm Brown, clumps
Late trophozoite Spherical, 1/2 of host RBC, stained dark 12, pale inside cytoplasm Dark brown clumps
Early schizont Spherical, >1/2 of the host RBC, stained dark 35, irregular, inside cytoplasm Dark brown clumps
Late schizont Spherical, nearly fills the host RBC, stained dark >5, round or oval, inside cytoplasm Dark brown clumps
Figure 23 Plasmodium falciparum in the thin blood smear: stages of asexual parasite development (Silamut et al. 1999). Pigment-con-taining
trophozoites and schizonts is sequestered and so rarely seen on peripheral blood smears. Finding these mature stages comprise >20% of peripheral
blood parasites carries a poor prognosis in severe falciparum malaria.
Kenyan study calculated that
among children under 2 years
can present with a low old with severe disease and
parasites in the first 24 h of the 48 h asexual life cycle are parasite count, high over 2500 parasites/ll, the
usually visible (Figure 23 and Tables 8 and 9). Sexual stages of counts without signs or malaria-attributable fraction
the parasites (gametocytes) may also be seen but do not symptoms of severity are of severe disease exceeded
indicate acute infection, as their period of matura-tion and associated with increased 85% in moderate- and low
subsequent clearance is considerably slower than that of risk. In a low transmission transmission areas, but 61%
asexual stages. setting a peripheral blood in a high transmission area
Patients with uncomplicated malaria without clinical severity slide showing 4% (Bejon et al. 2007). In
symptoms have on average lower peripheral blood parasitaemias infected RBCs (around children with cerebral
than patients with severe disease. As an example, one study from 150 000/ll) without signs malaria, parasitaemias in
Thailand found a geo-metric mean parasitaemia of 62 574/ll (50 of severity is associated excess of 1 000 000/ll were
09578 144/ ll) in hospitalised patients with uncomplicated with a mortality of around significantly associated with a
disease, versus 206 395/ll (156 458272 332/ll) in patients with 3% (Luxemburger et al. fatal outcome (Moly-neux et
severe disease (Dondorp et al. 2005b). However, within the 1997). al. 1989b). Both histidine-rich
patient group with severe disease, peripheral blood parasitaemia protein 2 (Pf HRP2) and
varies greatly and is only a weak predictor of mortality in In areas of high malaria malaria pigment
falciparum malaria. This is because the less pathogenic transmission, children may phagocytosed by monocytes
circulating stages can be counted in the peripheral blood slide, tol-erate higher levels of clear more slowly than
whereas the more pathogenic sequestered mature parasitised parasitaemia without severe malaria parasites and indicate
erythrocytes are not seen. As a consequence of sequestration, two symp-toms, and low level recent infection in a parasite
identical peripheral blood parasite counts can represent a 100- parasitaemia can be detected negative patient, which is a
fold difference in sequestered parasite biomass (White & Krishna in a high proportion of not uncommon scenario in
1989). The clinician should thus not be reasssured by the asymptomatic children. The patients that have been pre-
laboratory reporting a low peripheral blood parasite count when probabil-ity that a severe treated with antimalarial
the patient has symptoms of severe disease. Although severe febrile illness is attributable drugs before hospital
malaria to malaria increases with admission (Day et al. 1996a).
higher parasitaemias. A
Table 9 Criteria for identifying developmental stages of Plasmodium falciparum in thick blood smears as assessed by light microscopy modified
from Silamut et al. (1999)
Stage
development Cytoplasm Nucleus Pigment
Ring Blue, ring shape Red dot; can be elongated, 12 dots No

Trophozoite Blue, round shape, stained darker than 12 red, big dots or irregular shape From pale brown to clumped and dark
ring (on the same slide) inside cytoplasm. brown, inside cytoplasm
Sometimes cannot see
Schizont Blue, round shape, size up to that At least 3 nuclei, purple-blue colour Dark brown, clumps in the middle of
of red cell the parasite
Gametocyte Crescent shape like a banana Not obvious Elongated, like a chopstick, in the
middle
(synchronicity) and, to a
much smaller extent, of the
parasite multiplication rate.
The blood slide should be examined not only for parasites but There may be wide
also for malaria pigment, a characteristic coal-coloured refractile differences between the
material, inside peripheral blood leucocytes. In Vietnamese number of infected cells
patients with severe malaria finding over 5% of peripheral blood circulat-ing and the number
neutrophils con-taining visible pigment indicates a poor sequestered, and rapid
prognosis (Nguyen et al. 1995). In severe malaria, the stage of changes may be anticipated in
parasite development on the peripheral blood smear also has synchronous infections
prognostic importance (Silamut & White 1993). The presence of (White & Krishna 1989).
late-stage parasites in the peripheral blood reflects a larger Microscopy with fluorescent
proportion of seques-tered late-stage parasites. In patients with staining of the buffy coat
Figure 24 Heavy Plasmodium (quantitative buffy coat
clinically severe disease but a low peripheral blood parasitaemia,
falciparum parasitaemia on the analysis or QBC) has a higher
a high proportion of late-stage parasites may be observed in the thick film. Accurate parasite
thin blood film. sensitivity to detect low
counting of high parasite
densities is not possible on thick parasitaemias, but few
films. Occasionally, particularly microscopists are familiar
if stains and microscopes are with this method.
A theoretical scenario is that a patient with a highly poor quality, microscopists will
synchronised infection presents at the moment that all the misread such a slide as negative
parasites are in the late stage of erythrocytic develop-ment and a disastrous mistake.
thus all sequestered in the microcirculation, resulting in a Rapid diagnostic tests
negative peripheral blood slide. Although this possibility has (RDTs). Compared with
micros-copy, malaria rapid
been commonly proposed, it has not been encountered with diagnostic tests (RDTs) do
certainty in untreated patients with severe malaria by the authors If there is still uncertainty, not
of this supplement. A negative blood smear in an untreated the test should be repeated
patient thus makes malaria a very unlikely diagnosis. every 12 h for 48 h.
Parasitaemia may fluctuate
Causes of apparent blood film negativity in severe widely in the first 24 h of
malaria. treatment and may rise
alarmingly despite the
1 Recent drug treatment, especially with an artemisi-nin- administration of adequate
containing therapy
antimalarial drugs. The
2 Inadequate examination of blood film quality of slides, relationship between
duration of examination, expertise of micros-copist (Figure
24) peripheral circulating ring-
form-infected erythrocytes
3 Reliance on thin film and failure to examine thick films and sequestered infected cells
4 Identification of non-falciparum parasites, leading to failure is a function (predominantly)
to search further for P. falciparum
of the stage of devel-opment
study of clinically diagnosed
severe malaria indicated that
the probability of malaria-
et al. 2005) and is attributable disease dropped
require extensive training or well-maintained equipment. They associated with young age below 50% with plasma
are increasingly used for malaria diagnosis. and severe anaemia PfHRP2 < 174 ng/ml. A semi-
Malaria RDTs are immunochromatographic tests that identify (Bronzan et al. 2007). quantitative PfHRP2 rapid
either malaria antigens [most commonly Plasmo-dium Among 31 children with test with well-chosen cut-offs,
falciparum histidine-rich-protein 2 (PfHRP2)], or the parasite slide-positive fatal cerebral if one could be developed,
enzyme Plasmodium lactate dehydrogenase (pLDH) in a drop of malaria who came to autopsy, would be a useful clinical
blood. A disadvantage of all RDTs to date is that they cannot 24 had intracerebral tool, prompting the physician
provide a quantitative result. PfHRP2-based tests can remain sequestration and no other to look for alternative
positive for up to a month after a P. falciparum infection, while cause of death, while 7 (23%) diagnoses in case the plasma
pLDH tests are positive only while there are living parasites in had no sequestration and an PfHRP2 is low.
the blood. alternative cause of death
(Taylor et al. 2004). Peripheral blood parasite
As PfHRP2 can remain in the circulation for several weeks Ophthalmoscopy during life density can also be used to
after parasite clearance depending on the parasite burden, there had identified malarial cal-culate malaria-attributable
was a concern that PfHRP2-based RDTs would have limited retinopathy in 23 of the 24 disease in slide-positive
specificity, especially in areas of intense transmission and cases with intracerebral severe malaria in African
therefore frequent infections (Iq-bal et al. 2004; Mayxay et al. sequestration, and in none of children. A study by Bejon
2001; Swarthout et al. 2007). In a large trial evaluating RDTs for the seven without it, (Bejon et al. 2007) found that
the diagnosis of severe falciparum malaria in African children, indicating that retinopathy is the case definition for severe
with expert microscopy as reference test, the sensitivity of the strongly associ-ated with malaria is improved by
PfHRP2 test was 94%, but the specificity only 71% (Hendriksen cerebral malaria and can applying a parasite density
et al. 2011). Both sensitivity and specificity of the pLDH test serve as an additional threshold (2500/ll in the
were 88%, but the sensitivity of the pLDH test was unacceptably diagnostic criterion (Beare et Kenyan setting), and by
poor for parasite densities of <1000/ll. Both RDTs performed al. 2011). The sensitivity of excluding children with
better than did the routine slide reading in a clinical hospital this finding is 96% in meningitis, lower respiratory
laboratory. Malawian children and tract infection (clinicians
around 63% in Asian adults diagnosis), bacteraemia and
(Taylor et al. 2004; Maude et gastroenteritis with severe
In a patient with severe falciparum malaria who has received
antimalarials before presentation and now has a negative blood al. 2009b). dehydration, but not by
film, a PfHRP2 based RDT will still be positive confirming the excluding children with HIV
diagnosis. PfHRP2 is released into the or malnutrition. Of course,
There is need to continue to monitor the diagnostic value of plasma compartment at the this requires accurate parasite
the PfHRP2 antigen. The PfHRP2 gene is highly polymorphic, moment of schizont rupture, counting. These criteria are
with deletion of the entire gene reported in both laboratory and and its concentration in useful for selecting patients in
plasma can serve as a
field isolates, and this could poten-tially affect expression of the clinical trials with a higher
protein, compromising the sensitivity of PfHRP2-based RDTs. measure of the total parasite chance of true severe
Reassuringly in a recent study evaluating sequence variation in bio-mass. Plasma PfHRP2 malaria, but because of
African chil-dren with severe malaria, no deletion could be concentrations have proved to limited specificity, they are
identified in the PfHRP2 gene in patients with low PfHRP2 be a promising tool to less valuable for individual
concen-trations, and sequence variation in the gene did not con- distinguish children in high patient care.
found the measurement of plasma PfHRP2 concentrations transmis-sion settings with Whenever possible, blood
(Ramutton et al. 2012). slide-positive severe cultures should be obtained
falciparum malaria from in the African child
those with severe febrile presenting with severe
illness from other causes). febrile illness, even when
Malaria-attributable disease in high transmission settings Slide-positive patients with the peripheral blood slide
low plasma PfHRP2 concen- shows the presence of
In areas of high transmission (sub-Saharan Africa), a high
trations represent children malaria parasites. Aerobic
background prevalence of peripheral parasitaemia can hamper
with a low sequestered bio- culturing is generally suffi-
the diagnosis of cerebral malaria. A positive blood slide in a
mass in whom the clinical cient to detect the most
febrile comatose child does not ade-quately exclude other
disease is likely to have a common pathogens causing
possible diagnoses. Bacteraemia can be present in up to 20% of
these patients (Berkley cause other than malaria. bac-
Modelling data from a large
they may appear in severe
disease.
conditions such as H. simplex

Assessment of parasite stage
teraemia. Positive blood culture results have been reported in encephalitis and crypto- development in thick smears
4.612.6% of African children with slide-positive severe coccal, tuberculous and
falciparum malaria (Berkley et al. 1999, 2009; Evans et al. 2004; bacterial meningitis. Few This is more difficult than in
Bronzan et al. 2007; Were et al. 2011). The sensitivity of blood studies have evaluated the thin film. Normally, the
cultures to detect bacteraemia is low, and thus, the true specifically the diagnostic parasites appear compact and
prevalence of bac-teraemia is likely to be more than twice as benefit of LP in this situation. it is not easy to identify their
high as the prevalence of culture positivity. Bone marrow If there is any doubt about the stages. This method may be
cultures diagnosis, then a lumbar used for low parasitae-mias
(1 ml) are more sensitive than blood cultures for recovery of puncture should be (<0.1% or 1/1000 rbc) or for
Salmonella typhi in typhoid fever (Gilman et al. 1975). Common performed. Some phy-sicians slides that have only thick
pathogens include non-typhoidal Salmo-nella species, S. prefer to defer LP until the smears.
pneumoniae, E. coli, S. aureus, Group A streptococci and in patient recovers con- Thick blood smears
babies, Group B streptococci. sciousness and meanwhile to containing P. falciparum
cover at least with antibiotics parasites can be assessed for
according to local protocols developmental stage using
Other tests for meningitis (Pinhas- modified criteria from
Hamiel et al. 1993). Silamut et al. (1999) which
HIV testing
divide the para-sites into three
Severe malaria in HIV co-infected patients presents with higher asexual developmental stages
parasite burden, more complications and comor-bidities, and a and one sex-ual stage
Assessment of parasite stage
higher case-fatality rate than severe malaria in HIV-uninfected (gametocytes) based on the
development in thin smears
patients. Identifying HIV infection prompts a more extensive morphology of the cytoplasm,
search for additional pathogens and for opportunistic infections Thin smears that contain P. the appearance of malarial
upon recovery (Gwer et al. 2007). falciparum parasites can be pigment and the number of
assessed for stage nuclei.
development using criteria
from Sila-mut et al. (1999),
Lumbar puncture which divide the
Should lumbar puncture (LP) be performed routinely in the developmental cycle of the
evaluation of patients with P. falciparum parasita-emia and parasite into 8 stages based
altered consciousness? Experts differ as to whether an LP should on morphology of cytoplasm,
be carried out on admission. Most agree that LP is the appearance of malarial
contraindicated if the patients breathing is precarious or if there pigment and num-ber of
is papilloedema, but is otherwise safe. The lumbar puncture is nuclei (Figure 23). Schizonts
performed to exclude alternative or additional specifically are not normally seen in the
treatable peripheral blood in P.
falciparum infections, but
Intensive care unit staff must
be familiar with the monitor
and its technol-ogy. It is
by electronic monitoring, reasonable to focus on a basic
imaging technologies and set of parameters such as
Section 10: Management of severe labo-ratory tests. The heart rate (preferably
malaria examination should be carried measured by electrocardiog-
Introduction out sys-tematically and vital raphy), blood pressure
organ functions should be (generally measured non-
As severe malaria potentially affects multiple organ sys-tems,
checked regularly, including invasively in the resource-
general care and supportive treatments are crucially important.
assessments of the level of poor setting), respiratory rate
conscious-ness (Glasgow (usually by impedance
In severe malaria, the prompt administration of an effective
Coma Score/Blantyre Coma methods) and transmission
antimalarial drug, preferably by a parenteral route, is essential.
Artesunate is the treatment of choice. Score), pres-ence of seizures oxygen saturation (pulse
(which can be subtle), oximetry). While alarm limits
Chemotherapy is discussed in Section 11. This section gives
respiratory rate and work of set too liberally put the
recommendations for supportive treatment and nurs-ing care as
breathing, blood pressure, patient at risk by delaying
well as for the treatment of concomitant dis-eases. The
pulse rate, periph-eral recognition of changes, limits
recommendations are as much evidence based as possible.
perfusion and urine output. set too tightly lead to over-
Where specific studies in severe malaria have not been carried
Clinical examinations should reporting measurement
out, some treatment strategies are extrap-olated, when
be performed several times a deviations and critically they
appropriate, from the surviving sepsis cam-paign guidelines
day at least every 6 h, but desensitise medical staff for
(Dellinger et al. 2008; Dunser et al. 2012).
more frequently in the early truly important alarms. When
phases of admission, in case these facilities are not
of instability, or whenever available, regular patient
General considerations there is a change in the observations of respiratory
patients condition. rate, effort of breathing,
Assessment and reassessment of patients with severe malaria. Hypoglycaemia should oxygen saturations (if a pulse
Most deaths in severe malaria occur during the first 48 h always be considered when oxime-ter is available), heart
following admission. The condition of a patient with severe the patient has seizures, rate, blood pressure and
malaria can worsen unexpectedly. In particular, in patients with behaviour dis-turbance or a conscious level should be
cerebral malaria, the degree of coma may worsen and the patient deterioration in the level of prioritised. At every clinical
may have convul-sions, respiratory depression or respiratory consciousness, and blood review, the patency of
arrest. In adult patients, pulmonary oedema with respiratory glucose should be monitored intravenous cannulae, the
insuf-ficiency can develop even several days after start of anti- at least every 6 h in all access site, and the rate and
malarial therapy. The patient may become haemodynamically comatose patients. A team or volume of intravenous fluids
unstable, which can indicate concomi-tant bacterial sepsis. family members con-cern should be checked.
Development of acute kidney injury is an important threat in about the patient is always a
adults with severe malaria. The patient must be observed reason to reassess the patient
frequently by a nurse (or equivalent) well instructed on when to carefully.
call for help. Implementation of an early warning system has Data documentation. A
proved to be an important intervention. Ideally, the patient should medical record including
be admitted to an intensive care unit with 24-h presence of rele-vant information about
Patient monitoring. Whenever demographic data, allergies,
trained nurses and physicians. A system of patient-centred care,
available, a continuous medical history and current
where each nurse has the responsi-bility for one or a limited
patient electronic monitor disease processes should be
number of patients, is better than a task-orientated approach,
should be used and alarm lim- kept for every patient. Vital
which dilutes responsi-bilities. If no intensive care unit is
its should be set signs should be documented
available, care of these severely ill patients should occur in a
appropriately. Patient regularly on a dedicated
dedicated unit or area of a ward where intense monitoring can be
monitors allow for continuous patient record form to allow
assured.
surveillance of vital rapid assessment of the
parameters and reduce staff disease course and to
workload. However, monitors interpret changes in the
can never replace continuous patients condition.
attendance of experienced Depending on the phase of
Clinical examination. Thorough physical examination often healthcare staff or repeated the disease, vital signs
reveals important information beyond that obtained should be documented at
clinical examinations.
higher than international Stress ulcer prophylaxis. In

intervals from hourly in unstable patients to every 6 h in standards (Rosenthal et al. adult patients, stress ulcer
stabilised patients. Body temperature, peripheral perfu-sion and 2006), and these infections prophylaxis should be
fluid balance should be recorded at least once per shift, but more increase length of stay, costs considered. No studies have
frequently when abnormal. Whenever a deterioration occurs, it of care, morbidity and been performed specifically
is crucial not only to treat symptomatically (e.g. treat seizures, mortality (Allegranzi et al. in patients with severe
stabilise haemody-namic and/or respiratory function), but also to 2011). Two important pillars malaria, but stress ulcer
identify possible underlying causes. Important and common in preventing hospital prophylaxis has been shown
causes explaining a worsened or persistently unstable condition infections are good hand to be effective in reducing
of a patient with severe malaria are recurrent hypoglycaemia, hygiene and aseptic measures upper gastrointestinal
seizures, inadequate or excessive fluid resuscitation, during inva-sive procedures haemorrhage in general ICU
concomitant septicaemia and development of ALI/ARDS or populations in resource-rich
with the patient. The hands of
acute kidney injury with metabolic disturbances. settings. Stress ulcer
medical personnel are the
prophylaxis can be provided
main culprits in transmitting
Good collaboration between all physicians and nurses with an bacteria from one patient to using H2 blockers such as
adequate handover between shifts conveying all essential another (Pittet et al. 2009), ranitidine or proton pump
information is crucial (Reader et al. 2009). Sys-tematic and washing hands before inhibitors such as omeprazole
adherence to a standardised protocol, adapted to the local setting, and after each patient contact (Levy et al. 1997).
can improve the quality and complete-ness of information flow. is essential to reduce cross-
Clear definition of daily goals for each patient using a daily goal infections in the hospital.
form increases the proportion of team members understanding Educa-tional programmes to Deep vein thrombosis
the goal of care for the day and shortens the intensive care unit implement strict hand prophylaxis. In adult
length of stay (Pronovost et al. 2003). In case of an emer-gency, hygiene and the correct patients, deep vein
lives can be saved by having essential drugs and equipment technique of hand washing thrombosis prophylaxis
immediately available. These should be kept readily to hand on have reduced the rate of should be considered,
each ward where severely ill patients are cared for. hospital-acquired infections although thrombosis risk in
(Pittet et al. 2000; Caniza et patients with severe malaria
al. 2009; Allegranzi et al. has not been assessed to
Patient Transfer. When resources are limited, inter-hos-pital 2010). Invasive pro-cedures date. It has long been
transfer to a unit with higher-level facilities may save lives. assumed that in resource-
increase the risk of infection,
However, the risks of transfer must be criti-cally weighed limited settings, the
but this risk can be
against the potential benefits. Whenever possible, a patient prevalence of deep venous
minimised by applying
being transferred should be accompa-nied by a physician or thrombosis is low, and thus,
sterile, full barrier
other experienced medical staff. Common conditions in the routine antithrom-botic
precautions including skin
patient with severe malaria warranting transfer to a higher-level disinfection with prophylaxis is not indicated
care facility include: (Osime et al. 1976).
chlorhexidine or alcohol-
However, other studies show
1 development of respiratory insufficiency requiring based rather than iodine- important morbidity and
intubation and mechanical ventilation, based disinfectants
mortality associated with
2 acute kidney injury requiring renal replacement ther-apy, (Darouiche et al. 2010). deep venous thrombosis in
Equally important is the use
this setting (Colin et al.
3 haemodynamic instability requiring vasoactive drugs and of sterile drap-ing, hand 1975; Lee et al. 2009a). A
haemodynamic monitoring. disinfection, and wearing a
large Nigerian study
In many malaria-endemic countries, patients with cere-bral cap, surgical mask, sterile
identified sepsis and
malaria but no other organ involvement are fre-quently taken gloves and gown (Pronovost
prolonged (> 4 days)
care of in settings with only basic facilities. Despite the lack of et al. 2006). Venous access
immobility as risk factors for
electronic monitoring, reported case-fatality rates in this group sites should be checked
deep vein thrombosis
of patients can be low. frequently. Urinary (Foley)
(Sotunmbi et al. 2006).
catheters should be removed
Clearly, more information is
Hygiene precautions. The rate of hospital-acquired infec-tions in when no longer needed, needed. Subcutaneous low
middle- and low-income countries is 35 times because removal is associated
molecular weight heparin is
with reduced rates of cath-
the preferred DVT
eter-associated urinary
prophylaxis. In settings
infections (Apisarnthanarak where no
et al. 2007).
neurological symptoms
should prompt a CT-scan or
MRI of the brain to
admission, as earlier differentiate intracerebral
heparin is available, either antithrombotic stockings or elastic nasogastric feeding carries a bleeding from raised
bandages can be applied on both legs (Amaragiri & Lees 2000). 33% risk of aspiration intracranial pressure, cerebral
It is important to check for correct appli-cation of elastic pneumonia (Maude et al. oedema and
bandages as unevenly applied bandages may provoke 2011). If nasogastric feeding cerebral/medullary herniation.
thrombosis. is needed after this time, the There is no evidence to
position of the nasogastric support the use of mannitol in
Mobilisation. Prolonged bed rest and immobilisation lead to tube should be checked (by the treatment of raised
numerous unwanted effects, including muscular atrophy, X-ray, or by inflation and intracranial pressure in
prolonged weakness, respiratory compromise, autonomic auscultation of a bolus of air patients with cerebral malaria.
dysfunction, hypovolaemia, gastrointestinal paralysis, deep injected through the tube), In a placebo-controlled trial
venous thrombosis and delirium (Brower 2009). Early and the head should be tilted in Ugandan children
mobilisation may prevent or counteract these effects and 15 above the horizontal. In involving 156 children, a
facilitate recovery (Schweickert et al. 2009). As soon as the an adult patient with single dose of mannitol had
patient is stable, mobilisation in and outside of the bed should prolonged coma, a possible no significant impact on the
be encouraged actively. scheme is to start feeding clinical out-come of cerebral
with 100 ml pureed feeding malaria compared to placebo
every 4 h and measure gastric (Namutangula et al. 2007).
Specific supportive treatments
retention just before next Although mannitol controlled
Care of the unconscious patient with cerebral malaria. In severe feeding. If there is no gastric intracranial pressure in
malaria patients presenting with coma, an alterna-tive cause of retention, the feeds can be patients with intermediate
the reduced level of consciousness should always be considered, increased stepwise until 300 intra-cranial hypertension, it
including hypoglycaemia, meningi-tis, septic shock, a post-ictal ml is given every 4 h, did not prevent the
state after a febrile convul-sion (much more common in children) providing around 2000 kcal development of intractable
and use of sedative drugs. Unconscious adult patients or older per day. If gastric retention intracranial hypertension in
chil-dren should be nursed in the lateral recovery position. To exceeds 200 ml, the feeds those with severe intracranial
prevent pressure sores, the patients position needs to be changed should discontinue and hypertension (Newton et al.
at least every 2 h. In adults, an oropharyngeal airway (Guedel) prokinetic drugs added, for 1997b). In adults, mannitol is
can be inserted if the lateral position alone does not maintain example metoclopramide not recommended, because it
airway patency. A patients inability to clear the airway is suppositories 20 mg, three
pro-longs coma recovery time
associated with a high risk of aspiration of saliva or regurgitated times daily. Metoclopramide and might increase mortality
can have extrapyramidal side
gastric contents. Unconscious or semi-conscious patients with (Mohanty et al. 2011).
effects. Cisapride and dom-
severe malaria often vomit. If feasible and safe, the comatose Dexamethasone failed in both
peridone are no longer
patient should be intubated to protect the airway and enable adults (Warrell et al. 1982)
recommended because of
mechanical ventilation. This needs to be per-formed swiftly and and children (Hoffman et al.
efficiently as respiratory compromise and transient hypercapnoea potential cardiotoxicity (QTc 1988) to alleviate coma or to
during a difficult intubation further increase intracranial pressure. prolongation). The eyes improve survival, although
In hospitals without access to ventilation, insertion of a should be irrigated with saline sample sizes were relatively
nasogastric tube and regular suction may protect from aspiration or artificial tears (methyl small for definitive
in patients who are unable to protect their airway (see below). cellulose) and the lids kept conclusions.
Oral hygiene (tooth brushing and cleansing with an oral closed with eye pads. In
antiseptic at least twice daily), repetitive suctioning of adults, a ure-thral (Foley)
oropharyngeal secretions and elevation of the head of the bed catheter should be inserted
(also in the lateral position) can help prevent hospital-acquired and urine out-put recorded Treatment of seizures.
pneumonia (Tantipong et al. 2008). A nasogastric tube should be accurately. Generalised convulsions
passed, and the stomach con-tents aspirated to reduce the risk of occur in over 80% of
aspiration pneumo-nia. Enteral feeding through the nasogastric In settings where scanning children on admission and
tube will eventually be necessary, but in the non-intubated adult is available, deterioration in they recur in the majority
patient, it should not be started before 60 h from the level of consciousness and (>60%) of children during
appearance of new neuro- hospitalisation; 30% have
logical features (in the status epilepticus (Crawley et
absence of hypoglycaemia) al. 1996; Idro et al.
includ-ing lateralisation of
In the absence of
intravenous access,
diazepam may be given
available. Respiratory intrarectally (0.5 mg/kg of
2005b). In contrast, seizures occur in fewer than 20% of adults monitoring is important in body weight), and
with cerebral malaria. Aspiration pneumonia is a common coma-tose patients receiving lorazepam and midazolam
immediate complication, while recurrent con-vulsions are a risk benzodiazepines. can be given by the
factor for neurological sequelae (Molyneux et al. 1989b; van Patients with recurrent buccal, sublingual or
Hensbroek et al. 1997; Idro et al. 2004, 2006b). In children, seizures or those whose intranasal routes.
convulsions frequently herald the onset of coma or are followed seizures are not terminated by Recurrent seizures
2 doses of benzodiazepine (or despite benzodiazepines
by neurologi-cal deterioration. Hypoglycaemia should always be
one dose each of may require parenteral
excluded as a causative factor, and hyperthermia can also be a
benzodiazepine and phenytoin or
trigger. In a randomised double-blind trial in adults, convulsions
paraldehyde) given phenobarbitone pref-
were prevented by a single 3.5 mg/ kg intramuscular dose of
10 min apart should be erably with artificial
phenobarbital sodium (White et al. 1988). A higher dose was
considered to have status ventilation and support.
considered necessary for seizure prophylaxis in children
epilep-ticus and given Pheno-barbitone may
(Winstanley et al. 1992) but in a large randomised trial in
intravenous phenytoin at a cause lethal respiratory
Kenyan chil-dren without access to mechanical ventilation,
loading dose of 18 mg/kg depression, so careful
prophy-laxis with phenobarbital (phenobarbitone) 20 mg/kg
over 20 min. This should be respiratory monitoring is
increased mortality, probably through respiratory depression.
followed by maintenance essential.
This was particularly likely if the drug was combined with
doses of 5 mg/kg/day for 48
multiple doses of benzodiazepines (Crawley et al. 2000).
h. Phenobarbi-tal, loading
Fosphenytoin (20 mg phenytoin equivalents/kg body weight), a
dose 15 mg/kg body weight
less respiratory depres-sant drug, did not prevent seizures Management of shock.
and maintained at a dose of
effectively (Gwer Definitions for shock
48 mg/kg/day for 48 h, may
be used instead of phenytoin. vary between different
guidelines and between
Because phenobarbital is a
et al. 2013). In both trials, prophylaxis against seizures was not strong respira-tory adults and children.
associated with improved neurological or cog-nitive outcome depressant, and prophylactic
(Abubakar et al. 2007). Thus, routine seizure prophylaxis is use has been clearly Adults. Shock is the
currently not recommended in patients with cerebral malaria. presence of hypotension
associated with increased
Active convulsions should be controlled with a benzodiazepine mortality (Crawley et al. (systolic blood pressure
(diazepam, midozalam or lorazepam) given by slow intravenous 2000), respiratory monitoring <80 mmHg) with
injection. Diazepam emulsion is less irritant to veins. In adults, is essential in these patients. evidence of impaired
the dose of intravenous diazepam is 10 mg, and for lorazepam is Respiratory support peripheral perfusion.
4 mg. In children, intravenous diaze-pam 0.3 mg/kg body weight (intubation, ventilation,
or lorazepam 0.1 mg/kg body weight is given as a slow bolus Children compensated
general anaesthesia) may well
injection over shock. Clinical markers of
be needed, particularly if
impaired perfusion [these
phenobarbital is given or
include 2 or more of
2 min. In the absence of intravenous access, diazepam may be seizures are refractory to
delayed capillary refill time
given intrarectally (0.5 mg/kg of body weight) although treatment. (CRT) 3 s, weak pulse
absorption from the rectum may be erratic and seizure
volume, severe tachycardia
recurrences more frequent (Ogutu et al. 2002). Lorazepam and
and cool peripheries (cold
midazolam can be administered by the buccal, sublingual or
hands and feet)] with a
intranasal routes (Mpimb-aza et al. 2008). Intravenous normal blood pressure.
benzodiazepines may be repeated if seizure activity does not
stop after 10 min. The alternative is paraldehyde, 0.2 mg/kg of Treatment of seizures in
body weight, given by deep intramuscular injection (or severe malaria
Intravenous diazepam (0.3

0.4 mg/kg body weight intrarectally) using a sterile glass syringe
mg/kg maximum 10 mg
because paraldehyde is adsorbed to plastic surfaces. Disposable
preferably as
plastic syringes may be used if the injection is given
emulsion which is less
immediately after the paraldehyde is drawn up and the syringe
irritant) or lo-razepam
never reused. Multiple doses of diazepam may produce severe
(0.1 mg/kg-maximum
respiratory depression and so should be avoided unless
4 mg) slow bolus
respiratory support is
injection over 2 min.
dextrose (0.30.4g/kg)
check that the intra-venous
line is patent and fluid
poor outcome in the bolus infusion rate is correct, or
Decompensated shock. One or more of the above fea-tures groups (21%) compared to stop blood transfusions
together with a low blood pressure (systolic pres-sure <70 mm the control group (13%), as and restart 5% dextrose
Hg). While there is divergent opinion on the pathological was lactic acidosis infusion. Rarely, it may be
relevance of hypovolaemia and its con-tribution to acidosis and (>5 mM); 20.5% versus 15%. necessary to give 10%
death in severe malaria, there is now agreement that rapid fluid glucose infusions for
loading in adults or children with severe malaria is dangerous. In maintenance after
children with severe malaria (defined by impaired consciousness correction of
Fluids in severe malaria
or deep breathing), signs of compensated hypovolaemic shock hypoglycaemia. These can
occurred in 57% of cases (in-hospital mortality 18%), be prepared by dilution of
These are general guides 50% glucose (usually 50
hypotension in 13% (case fatality 26%), and severe dehydration
to fluid replacement, but ml) in 450500 ml of 5%
in 6% (case fatality 28%) (Maitland et al. 2003a). Studies in
each patient needs
Kenyan children showed that low central venous pressure (CVP) dextrose.
individual assessment of
(a measure of pre-load) is present in many children with
their fluid require-ments.
metabolic acido-sis with features of impaired perfusion and that
Hypoglycaemia, which is
CVP increased into the normal range (710 mmH2O) with 2040 particularly common in
mls/kg bolus of isotonic fluids (Maitland et al. 2003b). Evidence children and pregnant
of mild to moderate myocardial impairment and inferior vena women, should be Management of shock and
caval collapsibility also improved on fluid resuscitation (Yacoub corrected imme-diately. dehydration in children with
et al. 2010). This led to a series of phase II clinical trials severe malaria
Then, the following fluid
comparing different colloids and 0.9% saline which suggested management recommen- Bolus fluids (fluid
that outcome was improved in children receiving albumin dations should be adjusted resuscitation) should not be
boluses compared to any other fluid (Akech et al. 2010). These to individual needs. given to any child with severe
studies were then extended into a large pragmatic randomised Children: Correct fluid malaria including those with
controlled trial (FEAST trial) in 6 centres in East Africa. deficits over 34 h with mod-erate hypotension,
Children with severe infection (including malaria and other 0.9% (normal) saline at severe dehydration or
infections) and with impaired peripheral perfusion clinically and 35 ml/kg/h, then switch metabolic aci-dosis. Severe
treated with standard baseline fluid therapy were randomised to to maintenance 5% dehydration should be
receive either 2040 ml boluses of normal saline or 2040 ml dextrose (23 ml/kg/h). corrected slowly; the
boluses of 5% albumin or no boluses. The trial was stopped early If solutions containing optimum rates and volumes
because of increased mortality in the intervention groups; 48-h 0.45% saline/5% recommended in IMCI
mortality was substan-tially higher in the combined groups dextrose are available, Guidelines are 5 ml/kg/h with
receiving fluid boluses (10.6%) than controls (7.3%) a relative then these are preferred frequent clinical evalua-tion
risk (RR) for any bolus vs. control of 1.45 (95% CI 1.13 1.86) for initial resuscitation. (see box above). Acidosis and
(P =0.003) (Maitland et al. 2011). Children who received fluid Adults: Start with 0.9% shock should be managed
resuscitation were more likely to no longer be in shock after 1 h (normal) saline 35 with maintenance therapy
than controls (no bolus), but this did not translate into improved ml/kg/h during the first 6 h (see section below).
survival. Car-diovascular collapse was described as the main of admission with frequent
cause of death (Maitland et al. 2013). In the subgroup with assessment of vital signs.
Then reassess and in most Maintenance fluids
cases switch to alternate For children who are unable
500 ml bags or bottles of to take or retain oral fluids
5% dextrose and 0.9% (including children with
saline for maintenance (2 impaired consciousness,
P. falciparum malaria, mortality in the bolus groups was 51%
3 ml/kg/h). respira-
higher in the intervention groups; 9.2% com-pared to 5.8% [(RR
Do NOT use colloids.
1.51(1.171.95)]. Moderate hypo-tension (systolic BP if <12
months: 5075 mmHg; or if 12 months to 5 years: 6075 In refractory or
mmHg; or if >5 years: 7085 mmHg) was also associated with recurrent hypoglycaemia,
increased mortality in the intervention groups. Signs of severe after cor-rection of the low
dehydration were also associated with increased risk of blood glucose with
intravenous hypertonic
the skin turgor, mucosal
membranes, etc., can only
give a global indica-tion
irrespective of the fluid about filling status. Based on
tory distress, shock and/or vomiting), 5%-dextrose-con-taining resuscitation strategy expert opinion, the fol-lowing
maintenance fluids should be provided at a rate of 34 ml/kg/h followed. Once the patient fluid management is
until the child is able to drink. Children with severe malaria need develops ARDS, suggested.
continuous glucose to prevent hypoglycaemia, and saline to characterised by signifi-cant
slowly restore circulating volume and replace extracellular fluid pulmonary capillary leakage, In the absence of invasive
losses. Suspected or confirmed hypoglycaemia should be liberal fluid therapy will monitoring and with no or
corrected first with a bolus of 20% glucose (2 ml/kg over 10 worsen pulmonary oedema limited possibilities for
min) or alternatively if 20% glucose is unavailable, 50% and respiratory insuffi-ciency. intubation and mechanical
glucose, 1 ml/kg over 10 min. If an intravenous saline infusion Patients who will develop venti-lation, a general
has started or can be instituted without delay, the dex-trose can ARDS later during admission recommendation for patients
be injected into the rubber tubing of the intra-venous infusion as cannot be recognised on who are not shocked, do not
hypertonic dextrose is sclerosant. Ideally, initial resuscitation admission. In addition to the appear severely dehydrated,
should start with a 0.45% saline and 5% dextrose mixture dangers of developing and are not anuric on
dextrose-half normal saline, but this is often not readily pulmonary oedema, optimis- admission, is to start fluid
available. The only two crystalloid solutions that are widely ing the intravascular filling resuscitation with 35
available are 0.9% normal saline, and 5% dextrose, in which status only partly restores tis- ml/kg/h of normal saline (250
case fluid deficits should be corrected over 34 h with 0.9% sue perfusion, probably ml/h in the aver-age 50 kg
(normal) saline, at 35 ml/kg/h. Then, the maintenance because microvascular patient) during the first 6 h of
infusion can be switched to 5% dextrose for maintenance sequestration of parasitised admission (total 1830
(infusion rate: 23 ml/kg/h) until oral fluids are tolerated. red blood cells is quantita- ml/kg) while checking for
Intravenous fluid administration should be monitored carefully tively a more important basal crepitations or an
to ensure that the line remains patent and the rate of contributor to impaired perfu- increase in work of breathing
administration is correct. sion (Hanson et al. 2013). every 2 h. After this, the fluid
Blood pressure is not status of the patient should be
compromised in the majority assessed, and further fluids
of patients with severe administration should be
malaria, justifying restricted individualised to the needs of
Fluid therapy in adult patients with severe malaria fluid management. the patients (see Box). There
Optimal fluid resuscitation in the non-intubated adult patient is no evidence for benefit,
with severe falciparum malaria is difficult. As a general rule, the However, keeping the and some evidence for harm,
old adage to keep the patient on the dry side is still valid in the patient severely dehydrated is from using colloids in
majority. For example, 84% of SEAQUAMAT participants, in a also dangerous, reducing resuscitation (Perel et al.
large pragmatic trial of all-cause severe malaria (SEAQUAMAT tissue perfusion and 2007). When the patient is
2005) did not present with decompensated shock (defined as low increasing the risk of acute clearly severely dehydrated
blood pressure with cold extremities), and thus, fluid manage- kidney injury (AKI) from on admission with a urine
ment was conservative. Fluid therapy in adult patients with acute renal tubular necrosis. output <0.5 ml/kg/h (25 ml/h
severe malaria should be individualised, because intravascular At the current stage of in the average 50 kg patient),
requirements can vary considerably between individuals and knowledge, it is difficult to which is only possible to
development of pulmonary capillary leak-age is unpredictable. A provide more concrete assess when a urinary
study in adult severe malaria on fluid resuscitation targeting the guidance for fluid man- catheter is in situ, the initial
global end-diastolic right heart volume index (GEDI assessed agement than the general fluid administration can be
with PiCCO inva-sive monitoring) recorded infusion volumes advice to keep the patient more liberal and start with 10
varying between 2 and 7 litres to reach this target (Hanson et al. (slightly) dry. Invasive ml/kg/h (or 500 ml/h in the
2013). This fluid deficit should be corrected slowly. The danger measurement of CVP or average 50 kg patient) during
of correcting this volume deficit rapidly is that, even with assess-ments of the JVP on the first 2 h, with reas-
invasive monitoring, approximately one-third of patients will physical examination are sessment of the patient after
develop pulmonary oedema a variant of the acute respiratory inaccurate measures of this, including auscultation of
distress syndrome (ARDS). ARDS often develops after the start intravascular filling status in the chest and observation of
of antimalarial treatment, patients with severe malaria urine output. If there is still
(Hanson et al. 2011b). no diuresis of more than 0.5
Measurement of CVP or JVP, ml/kg/h and provided
together with assessment of
brain and intracellular pH
(through pCO2 generation
from the infused bicarbonate
Management of metabolic and more rapid transfer across
there is no increase in the respiratory rate or work of breathing acidosis the bloodbrain barrier and
and no chest crepitations signifying pulmonary oedema, another cell membranes than HCO3
litre of fluid can be given over 4 h Severe metabolic acidosis is a
ion); and a risk of sodium
(5 ml/kg/h for 4 h). frequent feature of both adults
overload, as bicarbonate is
and children presenting with
given as the sodium salt. In
severe falciparum malaria and
patients with bacterial sepsis,
Fluid therapy and vasopressive drugs in adult malaria has a strong prognostic
patients with shock a consensus paper (Cariou et
significance for mor-tality. It
al. 2004) recommends giv-ing
is mainly a lactic acidosis,
Haemodynamic shock occurs in a minority of adults with severe bicarbonate infusion if the
although other acids can also
malaria (approximately 16% of cases) and should prompt the blood pH is 7.10, in a dose
play an important role
clinician to explore alternative expla-nations for cardiovascular of 12 meq/kg/h
(Dondorp et al. 2004a). The
instability (e.g. concomitant bacterial sepsis or, much more (corresponding to 1 ampoule
most important cause of the
rarely, gastrointestinal haemorrhage or splenic rupture). In case of 100 meq HCO3 in a 50 kg
lactic acidosis is micro-
of haemody-namic shock, not caused by haemorrhage, the patient), given over 12 h.
vascular obstruction through
patient should be treated according to the surviving sepsis Faster infusion risks a drop in
sequestration of parasitised
guidelines. A revision tailored for resource-limited set-tings has intracellular and cerebral pH,
red blood cells in the
been prepared (Dunser et al. 2012). Rapid infu-sion of through the generation of
microcirculation (Hanson et
intravenous normal (0.9% w/v) saline of 20 ml/ kg is CO2. This recommenda-tion
al. 2012; White et al. 2013b).
recommended continuously guided by the patients response to can also apply to patients
Hypovolaemia or shock, hyp-
fluid loading. It may be necessary to repeat this. As soon as with severe malaria.
oglycaemia and seizures can
adequate perfusion is achieved the infu-sion should be stopped,
also contribute. Therapy
as excess fluid may precipitate pulmonary oedema. Some adult
should target these causes,
patients may require sev-eral litres of fluids during the first 24
optimise fluid status and cor-
48 h to maintain adequate blood pressure. If the patient is not
rect hypotension. Prompt Treatment of malaria-related
rapidly responsive to fluid therapy, vasopressive drugs should be
therapy with parenteral severe anaemia
started. Although evidence is limited, norepinephrine
artesu-nate will itself
(noradrenaline) is preferred to dopamine or epinephrine For blood transfusion issues
contribute to the control of
(adrenaline) preferably infused through a central venous catheter. of blood safety, adequate sup-
acidosis as parasites are killed
Adrenaline aggravates the lactic acidosis in patients with severe ply, equitable access and
and further sequestration is
malaria (Day et al. 1996b). If cen-tral venous catheters are rational use still remain major
reduced. Bicarbonate infusion
unavailable or the medical staff has insufficient experience challenges throughout the
is not generally recommended
handling them, a peripheral venous cannula, preferably placed in malaria-endemic world.
and is only indicated if the
a large bore vein, can be used instead. It is important to check the WHO estimates the blood
blood pH drops below 7.10
site of infusion regularly for signs of drug extravasation, because requirement for countries in
as, at this pH, myocardial and
this may cause substantial skin necrosis. Norepi-nephrine the Africa region to be 1020
other vital functions are
(noradrenaline) or dopamine should be admin-istered units per 1000 population per
endan-gered and the liver
continuously using a syringe or infusion pump. When pumps are year (Tapko et al. 2007)
becomes a net exporter of
unavailable or power cuts frequently occur, dopamine can be which compares with an
lactic acid. Clinical trials in
diluted in crystalloid solution (250 mg in 500 ml) and infused average of 3.4 units of blood
septic patients with a blood
using a drop regulator or micro-infusion set. Dosing should be donated per 1000 population
pH above 7.10 have not
tailored to the clinical response so in patients requiring for malaria-endemic sub-
shown a beneficial effect on
vasopressive drugs, blood pressure and heart rate should be Saharan Africa. For anaemia
outcome with bicarbonate
measured frequently. As shock is rare in adult patients with from other causes in both
infusion, whereas there are
severe malaria and can indicate concomitant bacterial sepsis, adults (in the absence of
potential adverse effects of
prompt start of broad-spectrum antibiotics is important, after first bicarbonate infusion. These acute myo-cardial infarction
obtaining blood cultures in settings with micro-biology or unstable angina) and
include: an increase in hepatic
laboratories. children, a restrictive strategy
lactate production (probably of transfusing at a threshold
through an increase in hepatic of 7 g/dl is
intracellular pCO2); a fall in
be used. Transfusion should
be care-fully monitored, and
in severely anaemic patients,
Blood transfusion in adults the respiratory rate should be
at least as effective as, and possibly superior to, a more lib-eral with severe malaria. In monitored frequently and the
transfusion strategy (Hebert et al. 1999; Lacroix et al. 2007). countries where pathogen- lung fields should be checked
Over the past decade, the capacity of transfusion services to meet free compatible fresh blood is for crepitations to detect
the need for blood in malaria-endemic countries has greatly available in sufficient supply, hypervolaemic pulmonary
increased owing to steady declines in the intensity of malaria that is >10 units per 1000 oedema. If circulatory
transmission that have led directly to reductions in population per year, overload is suspected, an
hospitalisation of children with malaria, and indirectly to reduced transfusion should be consid- intravenous dose of
utilisation of blood transfusion services (Pedro et al. 2010). ered if the haematocrit of a furosemide (40 mg in an adult
Despite these declines, the out-come of the disease in children normally hydrated patient patient with normal renal
presenting with severe malarial anaemia remains unchanged falls below 7 g/dl. In the function) should be given, but
(Pedro et al. 2010). Clinical studies in Kenya (Lackritz et al. presence of high furosemide should not be
1992; English parasitaemia, transfusion standard treatment when a
et al. 2002) have shown that profound anaemia (Hb < 4 could be prepared for at a blood transfusion is given. In
g/dl) is independently associated with death higher haemo-globin level patients with circu-latory
(OR = 2.5), as is severe anaemia (Hb < 5 g/dl) compli-cated by because of the expected overload, anaemia is best
reduced consciousness (OR = 7.4) or respiratory distress (OR = further fall in hae-moglobin corrected by exchange
4.1). Many deaths in children with severe malarial anaemia with the loss of the transfusion (Maitland et al.
occur within 48 h of admission, with 2550% (Bojang et al. parasitised erythrocytes and 2003a). Many patients
1997; English et al. 2002; Ernest et al. 2002) occurring within 6 accelerated destruction of improve after transfusion, but
h. unparasitised red cells. In repeated transfusions may be
patients with symptoms required if there is
related to severe anaemia abnormally rapid haemolysis
Recommendations for blood transfusion of donor erythrocytes. Iron
(dyspnoea, chest pain, shock,
Blood transfusion in children with severe malaria. To avert cardiac failure, extreme and folic acid
overuse of blood products, the WHO advocates a conservative lethargy), the threshold supplementation may be
transfusion policy (World Health Organiza-tion 2005b), should also be higher. necessary when oral
reserving whole blood (20 ml/kg) or packed cells (10 ml/kg) for Concerns about shortage of medication can be taken,
all children with a Hb of <4 g/dl. Children with <5 g/dl warrant adequate blood supply or particularly in pregnant
transfusion if they have respiratory distress or cardiovascular patients and in those who
about blood borne pathogens
instability. This is a general policy. However children with severe should restrict the use of may also have hookworm
malaria or high parasite counts and Hb <5 g/dl will usually have trans-fusion, especially in anaemia (in which case
a further drop in haemoglobin, so transfusion will usually be anthelmin-thic therapy is also
areas where HIV is prevalent
necessary. Thus, the recommended transfusion thresh-old in indicated).
and facilities for screening are
severe malaria is 5 g/dl and not 4 g/dl for children in areas of inadequate. In patients with
moderate or high transmission. There is no evidence to support chronic anaemia predating the
the need for furosemide and/or digoxin in children with severe acute severe malaria epi-sode, Exchange transfusion.
malaria anaemia studies indicate that children with these Exchange transfusion (ET)
a low haematocrit is often
complications usually have signs of hypovolaemia and not of was first reported as an
much better tolerated. An
myocardial failure (English et al. 1996c). adjunct to the treatment of
absolute threshold where a
severe malaria in 1974
blood transfusion is indicated
(Gyr et al. 1974).
is a haemoglobin
Numerous reports, based
concentration below 5 g/dl or
on small case series, have
an haematocrit <15%,
Indications for blood transfusion in severe malaria been published subse-
although there are no formal
quently advocating its use
studies in adult severe malaria
In areas of moderate to high transmission, such as most of as a supportive treatment
to support this recom-
sub-Saharan Africa, children should be trans-fused if the in severe malaria.
mendation.
haemoglobin concentration falls below Recently, the role of red
5 g/dl. cell exchange transfusion
For adults and for children in other settings, has also been advocated
(Macallan et al. 2000). For
patients should be transfused if the haemoglobin con- Fully cross-matched the majority of reports,
centration falls below 7 g/dl.
packed cells, or when not poor study design
available whole blood, should
pressure measure-ments
should be performed after
every 200 ml of fluid. If a
Management of acute kidney central venous catheter is in
including the use of historical control groups, controls from injury (AKI) in adults with place, a CVP between 0 and
different centres or lack of uniformity in the definitions of severe severe malaria. Development +5 cm is recommended,
malaria makes interpretation and generalisability difficult. of renal failure during severe although the accuracy of the
Although advocated for use in cases with hyperparasitaemia malaria is much more CVP as a measure of fluid
(>10%) in adult ICU set-tings, there is evidence that exchange common in adult patients status has been questioned
transfusion may not confer a better outcome (Riddle et al. 2002). than in children, although in recently (Hanson et al. 2013).
The advent of the artemisinins in management of severe malaria, children a raised blood urea
which specifically target hyperparasitaemia, further questions the on admission also has Diuretics in oliguric patients.
role of this invasive and potentially unsafe procedure. A recent prognostic significance (von Loop diuretics have been
meta-analysis of 8 comparative studies and a large casecontrol Seid-lein et al. 2012). Acute used frequently in different
study did not find an association between exchange transfusion renal failure in severe malaria forms of AKI, in an attempt
and survival outcome (OR 0.84; 95% CI 0.441.60) (Tan et al. is usually accompanied by to convert oliguric into non-
2013). oliguria, but is non-oliguric oliguric renal failure (Ander-
in approximately one-third of son et al. 1977; Bellomo &
cases. In the latter, urine vol- Ronco 1998; Klahr & Miller
Nevertheless, there are a number of theoretical advantages of ume is not representative of 1998). The most common
exchange transfusion: the provision of new red cells, thus the glomerular filtration rate, loop diuretic used is furose-
improving the rheological properties of circulating red cell mass; which determines renal mide (frusemide). If there is
the removal of plasma contain high concentrations of cytokines function, and monitoring no urine output after fluid
and other physiologically active agents; and the provision of urine output will not detect replacement, an intravenous
fresh plasma in the donor blood that may correct deficiencies declining renal function. dose of furosemide can be
(e.g. fibrinogen). Exchange transfusion may be consid-ered as an Serum or plasma creatinine given, 40 mg initially then
adjunctive therapy in patients with persistent acidosis and/or concentrations should always increasing the dose to
multiorgan impairment unresponsive to first-line treatment, or in be mea-sured on admission 100 mg, 200 mg and 400 mg
the subgroup of children with sickle cell disease, owing to the and then daily if serum at half-hour intervals. If
inherent propensity of HbS containing red cells to become rigid creatinine oliguria persists despite
under stress, which makes this a group in whom the prognosis is >2 mg/dl (>177 lM). Blood furosemide therapy, this
much more guarded. The value of exchange transfusion or red urea or blood urea nitrogen makes the diagnosis of acute
cell exchange transfusion should be regarded as experimental (BUN) is more prone to renal failure highly likely, and
until further data become available. confounding factors such as preparation for renal
the hydration and metabolic replacement therapy should
status of the patient. Oliguria be started. If it is clear that
Management of haemoglobinuria and blackwater is defined as urine output fluid replacement and furose-
fever. In patients with haemoglobinuria, it is important to (with a Foley catheter in mide have failed to restore
continue full-dose antimalarial treatment in patients with proven situ) diuresis, it is then critical to
malaria, despite the possible association between these drugs and <0.5 ml/kg/h, which restrict intravenous fluids
haemolysis. Transfusion of fresh blood or (preferably) packed corresponds to 25 ml/h in (500 ml per day but more if
cells should aim to maintain a haematocrit above 20%, while an aver-age 50 kg adult the patient is perspiring
fluid over-load is avoided by monitoring respiratory rate and patient. A patient who is profusely) to avoid
checking for chest crepitations. Cross-matching may be difficult. oliguric and clinically overhydration and pulmonary
The patient should be monitored closely. To prevent dehydrated should receive oedema. Excessive fluid
exacerbating renal injury, it is important to keep the patient with rehydration with 0.9% administration is one of the
haemoglobinuria adequately hydrated to maintain urine output. It saline 10 ml/kg/h (or 500 commonest errors of
has been sug-gested that alkalinisation with bicarbonate infusion ml/hr in the average 50 kg management in malaria-
could be beneficial in these patients, but this has patient) during the first 2 h associated acute kidney
(total 1000 ml). To injury.
never been trialled. Alkalinisation of the urine can be prevent fluid overload,
accomplished by administration of 5% dextrose to which 100 respiratory rate, lung Once a diagnosis of
150 meq/l of sodium bicarbonate have been added. auscultation and jugular acute renal failure is
venous pressure measurement established, loop diuretics
have no further useful role,
and also if pos-sible pulse as has been
oximetry and central venous
(BUN, serum creatinine,
potassium) and decide on
RRT as early as possible,
1 Anuria (urine output 0 rather than waiting for
shown in AKI of non-malarial causes. In a placebo-con-trolled 50 ml/12 h) complete renal shut down.
clinical trial in 338 dialysis-requiring patients (none with 2 [Urea] > 35 mM
malaria), the use of high-dose loop diuretics caused no 3 [Creatinine] > 400 lM
improvements in patient survival, renal recov-ery rates, number Patients with established
of dialysis sessions required or time on dialysis, despite an
4 [K +
] > 6.5 mM or rapidly
rising acute renal failure should be
increase in urine output (Anderson et al. 1977; Van Der Voort et 5 Pulmonary oedema
unresponsive to diuretics referred if possible to an
al. 2009). High doses of loop diuretics are associated with an intensive care unit or centre
increased risk of ototoxicity.
6 Uncompensated
acidosis (pH <7.1)
metabolic
for RRT because close
7 [Na ] < 110 mM and
+
nursing care is needed.
>160 mM Haemofil-tration or
Dopamine in patients with renal failure. Dopamine has also If one criterion is present, haemodialysis is superior to
been used to treat acute renal failure (Lumlertgul RRT should be considered. peritoneal dialysis (Phu et al.
et al. 1989). This vasoactive drug can increase glomerular If two criteria are 2002), but if peritoneal
filtration rate (GFR) and sodium and water excretion through simultaneously present, dialysis is the only option,
direct effects on renal blood flow and function. These effects are renal replace-ment therapy then large amounts of
evident in patients with normal renal function, but in severe is strongly recommended. dialysate (5060 l/day) need
malaria with renal impairment, dopamine increases renal blood As AKI in the acute phase to be prepared. A positive
flow but does not increase renal oxygen delivery (Day et al. of severe malaria develops fluid balance after the onset
1996b, 2000a). In patients with early renal dysfunction (serum rapidly and is often of AKI is strongly associated
creatinine > 2 mg/dl or urine output < 0.5 ml/kg/h), dopamine compounded by severe with mortality (Grams et al.
did not alter subsequent peak serum creatinine or the need for metabolic acidosis, RRT 2011). It is critical that
renal replacement therapy (RRT). This was confirmed in a meta- should be instituted earlier intravenous fluids should be
analysis assessing the efficacy of dopamine in stopping the rather than later in the restricted so that the CVP is
progression of AKI, decreasing the need for RRT, or the diseases process. Sensitive maintained between 0 and +5
mortality of AKI (Bellomo et al. 2000; Gambaro et al. 2002; indicators of the need for cm H2O, and the body weight
Friedrich et al. 2005). Therefore, low-dose dopamine currently dialysis include anuria, falls about 0.5 kg/day.
has no role in the treatment or prevention of AKI especially in severe metabolic acido-sis, Excessive fluid
malaria. arterial blood lactate administration is one of the
concentration > 4 mM and a commonest errors of
Malaria-related AKI is particularly difficult to manage rapidly rising plasma or management leading to lethal
compared with most other AKI, because of the hypercat-abolic serum creatinine complications such as
state and concomitant multiorgan dysfunction (coma, hepatic concentration (>2.53 pulmonary oedema. While
dysfunction, etc.). To avoid rapid deterio-ration after admission, mg/dl/day or 220265 uM) arrangements for RRT are
if renal replacement therapy (RRT) is indicated, then it should be (Trang et al. 1992; Phu et al. being made patients with very
initiated if possible within 2 h. The precise indications for 2002). In contrast, some severe hyperkalaemia (>7 mM
or with alterations on the
starting RRT for malaria AKI have not been well defined. In a patients will pass small
ECG) should be treated
prospective multicentre trial involving 54 ICUs in 23 countries, volumes of urine sufficient to
maintain fluid bal-ance. immediately with (i)
tim-ing of RRT was stratified into early or late by median
Serum creatinine may rise intravenous calcium, (ii)
blood urea at the time RRT started and also categorised
slowly, while other glucose plus insulin or (iii)
temporally from ICU admission into early (<2 days), delayed (2
manifestations of severe intravenous sodium
5 days) or late (>5 days). Timing by blood urea showed no
malaria resolve. If other bicarbonate. Calcium and
significant differences in mortality. How-ever, when timing was
indica-tions for dialysis do bicarbon-ate must not be
analysed in relation to ICU admis-sion, late RRT (this may also mixed, because of
not arise, these patients can
be late AKI) was associated with greater mortality. Overall, late precipitation of cal-cium
be managed conservatively,
RRT was associated with a longer duration of RRT and stay in carbonate!
but they will need frequent
hospital and greater dialysis dependence (Bagshaw et al. 2009).
assessment. Timing of RRT
Current indications for RRT for AKI in general (i.e. not specific
may play an important role in
for malaria) are as follows (Elhassan & Schrier 2011):
determining patient
outcomes. We recommend
that physicians should assess
Oliguria (urine output < 200 ml/12 h) changes in renal function
dialysis and 36% in patients
who received haemodi-alysis
(Mishra et al. 2007a; Mishra
usually added to each litre of & Das 2008; Mishra &
Continuous veno-venous haemofiltration (CVVHF). In a study in dialysis fluid to prevent Mahanta 2012).
2002, CVVHF was shown to be superior to peri-toneal dialysis obstruction of the catheter by
and significantly reduced mortality in the treatment of infection- fibrin clots. The duration of Unfortunately, facilities for
associated AKI in Vietnam (Phu each dialysis session depends haemofiltration or haemod-
et al. 2002). Of the 70 patients randomised, 48 had malaria- on the patients urine output ialysis are seldom available in
associated renal failure, and mortality was reduced from 47% to and plasma creatinine the rural tropics. There-fore,
15%. Haemofiltration corrected acidosis and azotaemia more concentration and on the peritoneal dialysis is still a
rapidly and more com-pletely than peritoneal dialysis and was stage of the disease and varies valuable option for
associated with a shorter duration of treatment (44 vs 88 h) (Phu from 26 to 82 h (Trang et al. developing countries where
et al. 2002). It was also less expensive. Haemofiltration has 1992). Daily reassessments of malaria occurs. It reduces the
proved particularly effective in very severe metabolic aci-dosis. clinical status, biochemistry incidence of malaria-
There have been no comparisons of haemodialysis and values (electrolytes, blood associated hypoglycaemia
haemofiltration in acute malaria. In acute renal fail-ure from urea and creatinine) and 24 h and avoids the risk of
other causes, a multicentre randomised con-trolled trial in France fluid bal-ance are needed. parenteral use of
compared intermittent haemodialysis continuous renal Peritoneal dialysis should be anticoagulant. Initial doses of
replacement with haemo-filtration using the same polymer stopped when these variables antimalarial drugs should not
membrane and bicar-bonate-based buffer. A total of 360 patients return to within the normal be reduced in patients with
were randomised, and survival was similar in the two groups (32 range, and the urine output is renal failure. Doses of
versus 33%). Current evidence does not support con-tinuous above 400 ml/day. However, artemisinin and derivatives do
renal replacement therapy over intermittent ther-apies in the 30% of dialysed patients not need to be altered in renal
treatment of AKI (Vinsonneau et al. 2006; Lins et al. 2009). required repeated dialysis failure. The doses of quinine
Concerning the dialysis membranes, biocompatible membranes (T.T Hien 1995, unpublished should be reduced after 2
may reduce immune reactions but do not consistently improve data). Complications are rare: days in patients with renal
AKI outcomes (Alonso et al. 2008). Regarding the dialysate and infection has been the most failure. The additional
haemofiltration fluid, a recent study showed that bicarbonate frequent. If the dialysis clearance of quinoline
fluids led to a more rapid fall in lactate and greater improvement effluent becomes cloudy, a antimalarial drugs by
in base excess during CRRT, but not to an overall improve-ment cell count, Gram stain and peritoneal or haemodialy-sis
in the control of acidosis (Agarwal et al. 2011). As a culture of peritoneal fluid is small and should not affect
consequence, the use of bicarbonate buffer is now preferred. should be carried out, and dosage schedules.
antibiotics should be given by
both the intraperitoneal and
systemic routes. The results Prognosis. Without dialysis,
Peritoneal dialysis. When dialysis is indicated, the perito-neal of the Gram stain of death occurs rapidly in 50
catheter insertion should be performed in an operat-ing theatre concentrated peritoneal 75% of patients with acute
1
effluent guide the initial renal failure (Hien et al.
under full sterile conditions. The exchange volume of dialysate 2
is 15002000 ml with a cycle time of 60 min: inflow 10 min, choice of antibiotic while 1990). If complications can
dwell time 30 min, outflow cultures are awaited. be overcome by dialysis,
20 min. This should be modified in each individual as nec- In Brazil, a prospective most patients renal function
essary: the duration of exchange of dialysate (standard or randomised study of daily will return to normal over a
shorter dwell period) should be governed by biochemical intermittent haemodialysis period of several weeks. The
investigations, and fluid overload should be managed by the use (IHD) versus peritoneal prognosis in anuric patients is
of high glucose dialysate (this is also an excellent way to control dialy-sis (PD) in 120 AKI significantly worse both in
hypoglycaemia). Potassium chloride (2 patients showed no mortality and rate of recovery
4 mM) must be added to the dialysis solution if the patient is difference in sur-vival or of renal function. Overall, the
hypokalaemic or normokalaemic. Heparin (200 U) is recovery of renal function mortality rate of severe
(Gabriel et al. 2009), but malaria with renal
mortality in both groups was dysfunction requiring dialysis
very high (>50%). In a recent is around 25%; a fatal
1
Any acute dialysis catheter.
study from India of patients outcome being associated
2
Dialysis solution contains (meq/l) sodium 135; chloride 101; cal-cium
3.5; magnesium 1.5; acetate 45; glucose 1.5 g/100 ml (standard) or 4.25 with malaria and AKI, the
signifi-cantly with anuria, a
g/100 ml (hypertonic). mortality was 20% in short history of illness,
patients receiving perito-neal multisystem
occur only late (e.g. when
oxygen saturation by pulse
oximeter falls to <80%) and
may be difficult to recognise
Antibiotics in severe in patients with a dark com-
involvement and high parasitaemia (Trang et al. 1992). In the
malaria
series from Vietnam, most patients died during the dialysis plexion. Clinical signs of
suggesting that they were admitted to hospital too late or dialysis respiratory distress
was started too late. Recovery of renal function was unrelated to (dyspnoea, increased work of
All children presenting breathing) reflect changes in
density of parasitaemia or hae-moglobinuria; the median (range)
with severe malaria in respira-tory mechanics and
time until urine output exceeded 20 ml/kg/day was 4 (019)
areas of intermediate and may not be reliable gauges of
days, and the time (mean SD) for serum creatinine level to high malaria transmission
return to nor-mal was 17 6 days (Trang et al. 1992). hypox-aemia. Monitoring
should be given broad severe malaria patients with a
spectrum antibiotics in
Management of concomitant sepsis (for fluid manage-ment: see pulse oximeter is thus highly
addition to anti-malarial
earlier paragraph). Severe malaria by itself constitutes a risk recommended (Walker et al.
drugs.
factor for invasive bacterial infection such as pneumonia or 2009). Patients presenting
bacteraemia, although in adults concomitant invasive bacterial with hypoxaemia should
infection is less common than in children. Patients with a blood receive oxygen to achieve an
film positive for P. falciparum who also present with a clinical Management of respiratory oxygen saturation >90%, as
syndrome compatible with serious bacterial infection distress and hypoxia soon as possible. If no pulse
(meningitis, malnutrition or severe pneumonia) should receive oximeter is available, oxygen
paren-teral antibiotics together with antimalarial treatment. In General treatment of should be administered
respiratory distress in
case of concomitant severe sepsis or septic shock, the surviving empirically in all severe
patients with severe malaria.
sepsis guidelines should be followed, which have recently been malaria patients with
Respiratory distress
adapted for use in resource-poor set-tings (Dunser et al. 2012). In respiratory distress.
develops in up to 25% of
African children with severe malaria, blood culture positivity
adults with severe
rates are between 5.4 and 12%, and there is no way to distinguish falciparum malaria (Taylor Depending on the condition
this bacte-raemic group clinically or with basic laboratory tests et al. 2012b). Its aetiology is of the patient, different
(Berkley et al. 1999; Evans et al. 2004; Bronzan et al. 2007; diverse, including respira- oxygen sources can be used.
Berkley et al. 2009; Were et al. 2011). Falciparum malaria has Oxygen concentrators usu-
tory compensation of
been estimated to account for more than half of invasive bacterial ally supply flow rates up to
metabolic acidosis, non-
disease in children living in malaria-endemic areas (Scott et al. 46 l/min and are appropri-
cardiogenic pulmonary
2011). Common pathogens include non-typhoidal Salmonella ate to treat septic children and
oedema (ARDS rare in
species, S. pneumoniae, E. coli, S. aureus, Group A streptococci adults with mild hypoxaemia.
children), concomi-tant
and in infants, Group B streptococci. As the sensitivity of blood The use of oxygen
pneumonia (including
culture is limited, the real proportion could be as high as 10 concentrators is recom-
aspiration pneumonia) or
20%. Most studies (but not all) report higher mortality in the mended in areas with reliable
severe anaemia. These causes
children with concurrent invasive bacterial dis-eases. A general electric power supply. In case
have to be distinguished,
recommendation arising from these data is that all children of frequent or lengthy power
because their respective
presenting with severe malaria in areas of intermediate and high cuts, oxygen cylinders should
treatments obviously differ. A
transmission should be given broad-spectrum antibiotics in be available as a backup
physical examination helps
addition to antimalarial drugs. If at all possible, blood cultures source of oxygen. If oxy-gen
distinguish deep breathing
should be taken prior to the start of the antibiotic therapy: a flow rates >6 l/min are
(Kussmaul-type breathing)
positive result may guide antibiotic therapy, but a negative result required, an oxygen cylinder
related to metabolic acidosis,
does not rule out bacteraemia, and continued therapy should be or, when available, a hospital-
detects pulmonary oedema
guided by clinical indications. The antibiotic regimen will based pressurised oxygen
and identifies severe pallor.
depend on local hospital guidelines, and the prevailing patterns system should be used.
However, if at all possible,
of antimicrobial susceptibility, but could include Alternatively, two oxygen
additional diagnostics are
ampicillin/gentamicin combination, co-am-oxiclav, concentrators can be
indicated, including pulse
chloramphenicol or ceftriaxone. combined with a Y
oximetry, a full blood count
connector. Considering that
and basic biochemistry, and a
severely hypoxaemic patients
chest X-ray. Clinical signs of
(with min-
hypoxaemia (e.g. cyanosis)
1 ml (0.5 g) per kg over 10
min. Thereafter, blood
glucose levels should be
factors include pregnancy, checked frequently (at least
imal tolerance to interruptions of oxygen supply) com-monly malnutrition and chronic liver every hour), because there
require high oxygen flow rates, sufficient oxygen stores must disease. Blood glucose levels can be a rebound hypo-
be assured. High oxygen flow rates may empty an oxygen should be checked promptly glycaemia. The aim should be
cylinder rapidly! in any patient with altered to keep blood glucose con-
consciousness. If it is not pos- centration >4 mM (>70 mg/dl)
Management of malaria-related ARDS in adult patients with sible to check blood glucose by providing an adequate
severe malaria. ALI/ARDS may be evident at pre-sentation but immediately in a patient with glucose calorie source. In
often occurs within a few days of treatment when parasitaemia is impaired mental state, a critically ill adult patients,
falling (Krishnan & Karnad 2003; Maguire et al. 2005). Cerebral presumptive diagnosis of tight glucose control, which
malaria and malaria in pregnancy are associated with an hypoglycaemia should be includes the treatment of
increased risk of ARDS. The treatment of ARDS in malaria does made and intravenous glucose moder-ate hyperglycaemia
not differ essen-tially from that in ARDS from other infections administered. After with insulin therapy, is not
and has been reviewed elsewhere (Putensen et al. 2009). admission, blood glucose in recom-mended (Brunkhorst et
Mechani-cal ventilation is often difficult in the severely diseased patients with cerebral malaria al. 2008).
lung. Lung compliance is markedly reduced and unevenly should be checked regularly,
distributed, ventilation/perfusion is mismatched, and gas at least every 6 h, as in
diffusion is compromised. Lung protective ventilation includes contrast with patients who are
the application of pressure support ventilation with positive end- awake, a change in the level
expiratory pressure (PEEP), avoidance of both high tidal of consciousness cannot be
volumes (6 mg/kg ideal body weight) and prolonged periods of used as an indicator of Treatment of
high inspiratory oxygen pres-sures. Permissive hypercapnia is hypoglycaemia. Frequent hypoglycaemia
not recommended because this exacerbates the increased moni-toring of the coma score
intracranial pres-sure and brain swelling resulting from increased allows detection of a sudden Give an intravenous a
intravas-cular blood volume of sequestered parasitised red blood deterioration, which should bolus of 20% glucose, 2
ml per kg over 10 min.
cells (Ponsford et al. 2012). For the same reason, rapid sequence prompt an immediate check
If 20% glucose is not
intubation should be carried out to prevent hypercapnia with a of the blood glucose level.
available give 50%
subsequent further rise in intracranial pressure. Discontinuation of an intrave-
glucose, 1 ml per kg over
nous dextrose infusion has 10 min, preferably piggy-
Good respiratory care is also important, with interme-diate been associated with recur- backed into an
ballooning and suction of secretions, as well as appropriate rence of hypoglycaemia, intravenous infusion.
recruitment procedures. In refractory hypox-aemia, reversal of especially in children unable Thereafter blood glucose
the inspiration/expiration ratio is indi-cated. Putting the patient in to take oral fluids, so blood lev-els should be checked
the prone position can dramatically improve oxygenation, and a glucose should be checked frequently (at least every
recent trial has shown that early application of prolonged prone- and carefully monitored in hour), as rebound
posi-tioning sessions in patients with severe ARDS decreases 28- these circumstances. Blood hypoglycaemia is
day and 90-day mortality (Guerin et al. 2013). Some case studies glucose should also be common. Maintenance
report the successful treatment with non-invasive positive checked in the event of with 10% dextrose may be
pressure ventilation in patients with vivax malaria-associated convulsions or metabolic necessary.
ARDS (Agarwal et al. 2007), but it failed in 16 of 32 falciparum- acidosis. Hypoglycaemia
infected patients (Bru-neel et al. 2010). It is probably only (<2.2 mM) should be treated
indicated for milder respiratory compromise. promptly, because it can Management of hepatic
cause irreversible cere-bral dysfunction. Severe
damage and is associated with jaundice is common in adult
Glucose control. Hypoglycaemia is a common complica-tion of residual neurological deficit patients with severe malaria,
severe falciparum malaria. The incidence is less in adult patients in survivors. Treatment of but overt hepatic
than in children. Quinine therapy is a risk factor, because hypoglycaemia is with a dysfunction is not and rarely
quinine stimulates pancreatic insulin pro-duction. However, bolus of 20% glucose, 2 ml needs special atten-tion.
most children presenting with hypoglycaemia have not received (0.4 g) per kg over 10 min or Jaundice is uncommon in
any quinine. Other risk alternatively, if 20% glucose children with severe
is not available, 50% glucose,
Management of coma and
seizures
The general and supportive

hypovolaemia. In febrile
management of coma and sei-
malaria, but its presence is associated with a worse prog-nosis children, the use of salicylates
(Marsh et al. 1995). Hepatic biotransformation is significantly or NSAIDs can cause Reyes zures are similar and will be
impaired, so metabolic drug clearance is reduced in severe described together. Initial
syndrome, and they should
malaria. management should include
not be used. In addition to
maintenance of the airway,
antipyretic medication,
support of breathing and
Management of bleeding disorders. Thrombocytopenia is always removing of clothing, tepid
sponging and fanning can be immediate correction of
present in patients with severe malaria, but bleed-ing
complications are surprisingly uncommon. In case of bleeding used to lower the body hypoxia and hypoglycaemia
disorders, disseminated intravascular coagulation (DIC) should temperature, although in metabolic disorders which
be suspected, which can be an indication of concomitant contrast with paediatric may contribute to a depressed
bacterial sepsis. Antibiotics should already have been prescribed patients, these have not been level of consciousness or
in all children with severe malaria in areas of moderate or high formally assessed for their seizure. If the child is not
malaria transmission. Low-dose heparin, antithrombin or efficacy in adults. breathing or has difficulty in
recombinant activated Protein C therapy are no longer maintaining the airway, use a
recommended for the treatment of DIC, nor is the use of fresh Guedel airway and provide
frozen plasma to correct labo-ratory clotting abnormalities Emergency assessment and short-term support by bag-
management of severe and-mask ventilation. To
unless there is bleeding (Del-linger et al. 2008). If available,
malaria in children
platelets can be administered when the platelet counts are man-age the airway of a
<5000/mm 3 As for any sick child convulsing child, do not try to
9 presenting to hospital, initial insert anything in the mouth
(5 9 10 /l) regardless of bleeding or if there is significant
3 9 manage-ment of a child to keep it open. Once
bleeding and counts are below 30 000/mm (30 9 10 /l).
presenting with suspected stabilised, place the
severe malaria should be unconscious child in the
Treatment of hyperpyrexia. Patients with severe malaria often
recovery position to prevent
have a high body temperature (>38 C), which is uncomfortable, guided by a rapid, structured,
triage assessment, aimed at aspiration and if possible
exacerbates dehydration, and may con-tribute to impaired
identifying emergency and insert a nasogastric tube to
consciousness and seizures. Paraceta-mol is an effective and
priority signs. The WHO empty the stomach contents.
inexpensive antipyretic. The adult dose is 1000 mg (or 15
General nursing care and
mg/kg) every 6 h (maximum daily dose 4000 mg), given orally Emergency Triage,
or via a nasogastric tube (as powdered tablets or suspension Assessment and Treatment regular monitoring are
which have gen-erally good bioavailability) (Ismail et al. 1995; (ETAT) advocates prioritising essential, including turning
Wilairatana et al. 1995). In children aged 36 months, the dose care for cases with emer- the unconscious child every 2
is 60 mg, from 6 months to 24 months, it is 120 mg, from 2 to 4 gency signs identified by the h, attention to pressure spots
years, it is 180 mg, from 4 to ABCD assessment (airway/ and oral and eye care (World
breathing/circulation/dehydrat Health Organization 2005a).
ion and level of conscious- For those with prolonged
8 years, it is 250 mg, from 8 to 10 years, it is 375 mg, and from
ness) (World Health coma, nasogastric feeding
10 to 12 years, it is 500 mg all given every 6 h. The rectal
Organization 2005a). Many must be planned. Other CNS
dose, as paracetamol suppositories, is the same as the oral
dosage and can be used in patients with children with severe malaria infections or intracranial
will have emergency signs haemorrhage should be
vomiting, but the time to maximum plasma concentration and
including: a compromised considered as alterna-tive
overall plasma concentrations (AUC) are lower than with oral
airway (convulsions/deep diagnoses, especially in a
administration (Kolloffel et al. 1996). There is also a paracetamol
coma); altered breathing child with neck stiffness or a
formulation for intramuscular admin-istration, but adequate
pattern; perturbations of full fontanelle.
pharmacokinetic data are lacking and in sick patients with
circulatory or hydra-tion
peripheral shutdown, the rela-tive bioavailability of i.m.
status and/or impaired
paracetamol may be reduced (Douglas et al. 2013). More
consciousness. Immediate
recently, a formulation for intravenous administration has
man-agement of these
become available, but this is not widely available in malaria-
complications should not be
endemic countries (Duggan & Scott 2009). Aspirin and
delayed, while the diagnosis
nonsteroidal anti-inflammatory agents (NSAID) are effective, but
of malaria is confirmed.
carry a risk of causing gastrointestinal bleeding and may impair
renal function in the already compromised patients with
artesunate and quinine from
South-East Asia show clear
evidence of substantial life-
saving benefit with
hydrolysed rapidly and artesunate. In the largest
Section 11: Antimalarial drug almost completely to multicentre trial from the
treatment of severe malaria dihydroar-temisinin, which region, the SE-AQUAMAT
The artemisinin derivative artesunate is now firmly estab-lished provides the main study (Dondorp et al. 2005a),
as the treatment of choice for severe malaria. The largest antimalarial effect. The ethers which enrolled 1461 patients
randomised clinical trials ever conducted in severe falciparum are water insoluble, lipid (including 202 children <15
malaria have shown a highly significant reduc-tion in mortality soluble compounds that are years old), mortality was
with intravenous or intramuscular ar-tesunate compared with formulated in oil for reduced by 34.7% (95% CI =
parenteral quinine (Dondorp intramuscular injection. They 18.5 to 47.6%; P = 0.0002) in
et al. 2005a, 2010). This reduction in mortality was not at the are absorbed slowly and the artesunate group
expense of an increase in neurological deficit, indeed there were erratically following intra- compared to the quinine
fewer neurological sequelae in artesu-nate recipients. muscular administration in group. The results of this and
Furthermore, artesunate was simpler and safer to use than the severe malaria (Murphy smaller trials (Hien et al.
previous gold standard and proved highly cost-effective. et al. 1997; Hien et al. 2004), 1992; Win et al. 1992) are
whereas artesunate is consistent and showed clearly
instantly bioavailable after and unequivocally that
intravenous injection and is artesunate is the treatment of
Artemisinin derivatives absorbed rapidly and reliably choice for adults with severe
Various artemisinin derivatives have been used in the treatment after intramuscular injection. malaria. The AQUAMAT trial
of severe malaria. These include artemether, artemisinin (rectal), These pharmacological (Dondorp et al. 2010) was a
artemotil (arteether) and artesunate. These drugs have similar advantages presumably multicen-tre comparison of
intrinsic pharmacodynamic properties. The ether derivatives explain the clinical parenteral artesunate and
artemether and artemo-til are two- to threefold less active than superiority of parenteral parenteral quinine in severe
dihydroartemisi-nin, their main metabolite and also the main artesunate over artemether malaria, which enrolled 5425
biologically active metabolite of artesunate. The ethers are also in severe malaria (Phu et al. children
2010).
metabolised to a lesser extent, and in severe fal-ciparum malaria,
the concentrations of parent com-pounds predominate. A
artesunate, by contrast, is Artesunate versus quinine.
Randomised trials comparing
comparing artesunate and quinine in severe

malaria (Dondorp et al 2010). The solid vertical
line represents equality of the two groups; the
dashed line is the overall treatment difference.
The horizontal lines and the width of the
diamonds show the CIs for the odds ratios. The
Figure 25size of the squares is proportional to the size and
Randomised therefore the weight, of the trial.
controlled trialsOR = odds ratios. *99% CIs for totals.
They show unequivocally that
artesunate is the best drug for
the treat-ment of severe
very large multicentre malaria in all patients.
<15 years of age across Africa. Mortality was 22.5% (95% CI = placebo-controlled Artemether is second choice;
8.1 to) lower in the artesunate recipients than in those children randomised trial, a single for although it has
who received quinine (P = 0.022). The incidences of dose of rectal artesunate comparable antimalarial
convulsions, coma, and hypoglycaemia developing after hospital given at the pri-mary activ-ity, its erratic absorption
admission were also significantly reduced. Importantly, there was healthcare level as pre- following intramuscular
no significant difference in the incidence of severe neurological referral treatment reduced the injection particularly in
sequelae in any of these studies. A meta-analysis of all trials risk of death or permanent shocked patients (Murphy et
comparing mortality in artesunate and quinine recipients disability in young chil-dren al. 1997; Hien et al. 2004)
provided an odds ratio of 0.69 (95% CI = 0.57 to 0.69) in favour by 25%, but in the smaller results in some patients
of artesunate (P < 0.00001) (Figure 7) (Win et al. 1992; Cao et al. group of older children and having inadequate plasma
1997; Dondorp et al. 2005a, 2010; Eltahir adults, mortality was concentrations in the critical
et al. 2010). Parenteral artesunate is therefore also the inexplicably higher in artesu- early phase of treat-ment.
treatment of choice for children with severe malaria. nate recipients. The benefits Quinine is now third choice.
The advantage of artesunate over quinine is probably a result from rectal artesunate were For pre-referral treat-ment of
of rapid killing and clearance of ring stages from the circulation, greatest in children who took patients with severe malaria,
thus preventing sequestration and micro-vascular obstruction more than 6 h to reach a or those unable to
(Udomsangpetch et al. 1996). The higher risk of severe health facility (Gomes et al.
hypoglycaemia and hyperinsulina-emia resulting from quinine 2009). Until the uncertainties
therapy, seen in adults chil-dren and especially in pregnant over adults are resolved, pre-
Treatment of severe
women (Hien et al. 1996; Dondorp et al. 2005b, 2010), is an referral rectal artesunate is malaria
additional disadvan-tage of quinine (White et al. 1983b). recommended currently only
for children 6y.
1 Artesunate (i.v. or
Artemether versus quinine. In an individual patient data meta- i.m.) 2.4 mg/kg*
analysis of 1919 patients enrolled in randomised controlled trials If referral is impossible, immediately, then at
of artemether and quinine, the mortality in artemether recipients rectal treatment should be 12, 24 h and daily
was 14% compared with 17% in quinine recipients (P = 0.08) con-tinued until the patient until oral
(Bhattacharya et al. 2013). The combined adverse outcome of can tolerate oral medication. medication can be
taken reliably. For
either death or neu-rological sequelae was significantly less (In this situation, continued children <20 kg the
common in the artemether group [odds ratio 0.77 (95% CI 0.62 efforts must still be made to parenteral
to 0.96), P = 0.02]. Among the adults with severe malaria, the achieve referral repeated artesunate dose is 3
mortality in artemether recipients was significantly lower than in rectal artesunate is not a satis- mg/kg.
quinine recipients, whereas in African chil-dren, there was no factory home treatment for If unavailable
significant difference in mortality. possible severe malaria). The
administration of an 1 Artemether
(i.m.) 3.2
Artesunate versus artemether. There has been only one artemisinin derivate by the mg/kg stat
followed by 1.6
randomised controlled trial comparing intramuscular ar- rectal route as pre-referral mg/kg daily
tesunate and artemether in severe malaria (Phu et al. treatment has been found
If unavailable
2010). This enrolled 370 Vietnamese adults; there were 13 feasible and acceptable at the
deaths in the artesunate group and 24 in the artemether group (P community level (Machado
1 Quinine
Siqueira et al. 2012; Baird dihydrochloride (20
= 0.052), and parasitaemia declined more rapidly in the mg salt/kg) by slow
artesunate group. 2013). intravenous infusion
over 4 h or by i.m.
Apart from the unexplained injection split to
Rectal artesunate. The risk of death from severe malaria is
apparent increase in mortal- both anterior thighs,
greatest in the first 24 h. In malaria-endemic areas, severe followed by 10 mg
malaria is commonly suspected in rural or remote locations, ity in adults and older salt/kg 8 h.
where parenteral treatment cannot be given. Referral to a centre children receiving rectal
where parenteral therapy is possible may involve considerable artesunate, these very large *Young children need
delay or referral time. During this delay, the patient may trials (by far the largest ever a higher dose to achieve
deteriorate and even die. In a conducted in severe malaria) com-parable exposures
provide consistent evidence. to adults see Table 10
(a) (b)
(c) (d)
Figure 26 Simulated total first-dose exposure levels (AUC012 h) of (a) artesunate and (b) DHA after the standard 2.4 mg/kg parent-eral dosing
in children at different body weights (ref is Hendriksen et al. 2013b). Simulated total first-dose exposure levels (AUC0 12 h) of (c) artesunate
and (d) DHA after the suggested adjusted dose regimen (Table 3). Open circles represent median values, and bars indicate the 25th75th
percentiles of simulations (1000 simulations at each body weight). The broken line represents the median
exposure for the largest weight group (i.e. 700 and 1230 h ng/ml for artesunate and DHA, respectively). ARS, artesunate; AUC012 h, area under
the concentrationtime curve from time points 012 h; (DHA, dihydroartemisinin).
were found to be similar for
Table 10 Bodyweight- i.m. and i.v. artesunate
take oral medications reliably, parenteral (intramuscular) adjusted i.m. artesunate dosing (Nealon et al. 2002), whereas
artesunate is also the drug of choice. If injections cannot be regimen for children that
provides similar exposure to
rec-tal artesunate needs to be
given, then rectal artesunate is indicated in young children, but that in adults receiving 2.4 given at fourfold higher doses
not in older children (>6 y) and adults until further evi-dence of mg/kg to reach similar
safety is obtained. bioavailability (Ilett et al.
Dose i.m. 2002a). Other for-mulations
Weight (kg) (mg)
Drug treatment. Severe malaria is a medical emergency. After are in development. This dose
rapid clinical assessment and confirmation of the diagnosis, full 67 20 is unchanged in renal
doses of parenteral antimalarial treatment should be started 89 25 impairment, liver
without delay with any effective anti-malarial first available. 1011 30 dysfunction, pre-treatment,
Artesunate (i.v. or i.m.) is the treatment of choice, artemether 1213 35 and the elderly. Any
(i.m.) is second choice, and quinine (i.v. or i.m.) is third choice. 1416 40
uncertainties over the safety
1720 50
Artesunate should be given in a dose of 2.43 mg/kg BW 2125
of artemisinins to
60
preferably by intravenous route or by intramuscular injec-tion on
admission (time = 0), then at 12 h and 24 h, then once a day until *For children <14 kg dilute
the patient can reliably take oral medica-tion. As children require to 10 mg/ml, for children 14
higher doses to achieve equivalent exposures to adults kg dilute to 20 mg/ml.
(Hendriksen et al. 2013b) (Figure 26, Table 10), a simple Divide over both thighs.
recommendation is to give parenteral artesunate at a dose of 3
mg/kg to patients <20 kg, and 2.4 mg/kg for heavier patients. All and given by intravenous or
the large clinical trials have been performed with one artesunate intramuscular injection. The
formulation, in which a lyophilised powder of artesunic acid is pharmacological properties,
dissolved first in 1 ml 5% sodium bicarbonate, and this solution notably the bioavailability of
is then diluted with 5% dextrose or 0.9% sodium chloride the active metabolite DHA,
patient has had impaired
consciousness, because of an
increased incidence of
followed by a full course of neuropsychiatric
the developing fetus are outweighed in severe malaria by their oral antimalarial treatment, complications associated with
enormous life-saving benefit and better safety profile in once the patient can tolerate mefloquine following
pregnancy. oral therapy. The previously cerebral malaria (Nguyen et
Artemether 3.2 mg/kg BW should be given by intra-muscular recommended options for al. 1996).
injection to the anterior thigh on admission then 1.6 mg/kg BW follow-on oral treatment are
daily thereafter until the patient can reliably take oral medication. as follows (World Health *Doxycycline is preferred
This dose is unchanged in renal impairment, liver dysfunction, Organization 2010a): to other tetracyclines because
pre-treatment, infants, children and the elderly. Intramuscular 1 artemether
lumefantrine
plus it can be given once daily and
arteme-ther is, however, absorbed very slowly in patients with does not accumulate in renal
acute malaria (Hien et al. 2003) and also with great vari-ability in 2 artesunate plus amodiaquine failure. Where available,
children with severe malaria (Mithwani et al. 2004). The 3 dihydroartemisinin
piperaquine
plus clindamycin should be
generally recommended regimen for intramus-cular artemotil substituted in children up to
4 artesunate plus sulphadoxine
pyrimethamine age of 7 years and pregnant
(available only in India) is a larger initial dose of 4.8 mg/kg
followed by the same maintenance dose of 1.6 mg/kg BW daily 5 artesunate plus clindamycin women because doxycycline
or doxycycline*
thereafter, until the patient can reliably take oral medication (Li should not be given to these
et al. 2004). 6 quinine plus clindamycin or
doxycycline groups.
Most countries have their
Quinine 20 mg dihydrochloride salt/kg BW on admis-sion (4-h own first-line treatment pol-
IV infusion or divided IM injection 10 mg salt/kg given into icy for uncomplicated
each anterior thigh). This is followed by 10 mg/kg BW every 8 h. malaria this should be
The intravenous infusion rate should not exceed 5 mg salt/kg given in full as follow-on
BW per hour. therapy after initial parenteral
treatment for severe malaria.
Follow-on treatment. Parenteral antimalarials in the treatment of The only caveat is that
severe malaria should be given for a mini-mum of 24 h, once mefloquine should be
started (irrespective of the patients ability to tolerate oral avoided as a component of
medication earlier). This should be follow-on therapy if the
2011a,b).
Selecting the antimalarial

peripheral level by rapid
drugs for pre-referral
diagnostic tests (RDTs) that treatment for severe malaria
Section 12: Community diagnosis, detect malaria parasite
management and referral antigens. Increasingly, RDTs Malaria-specific treatment
Severe malaria must be treated promptly to prevent death and are being deployed at can be initiated with paren-
disability. Severe malaria is always best managed at the highest community and small health teral or rectal artesunate,
possible level of health care, where staff and equipment are facility levels where parenteral artemether, or
available. Unfortunately, most cases occur in remote areas, and microscopy is not possible. In paren-teral or rectal quinine.
patients present to facilities that have only minimal staff and the case of a severe febrile The choice of initial pre-
laboratory capability for managing severe malaria. Patients illness, it is important that referral treatment depends on
must then be referred to a sufficiently resourced hospital, but life-saving treatment be what is available at the point
the delay in arranging or accomplishing the referral can be initiated as soon as possible, of presentation and the
dangerous for a patient with severe malaria. Giving rectal even if an RDT is not training and skills of the
artesunate immediately to cover the time spent in the referral available. Where possible, health worker initiating a pre-
process, has been shown to improve sur-vival in children (but community health and referral treatment. For
not adults) in this situation (Go-mes et al. 2009). peripheral health workers example, many community
should be pro-vided with health workers and clinicians
malaria RDTs and should be at periph-eral health facilities
taught how to use them. may only be trained to deliver
Recognising severe febrile illness at the community and rectal medicines, while others
peripheral health facility levels
In areas where malaria may be trained in delivering
In many countries, community and peripheral health facility transmission occurs, ini-tial intramuscular doses,
workers have been trained through the Integrated Management of clinical features of severe or even establishing
Childhood Illness (IMCI) and Integrated Management of malaria often overlap with intravenous access (although
Adolescent and Adult Illness (IMAI) initiatives to recognise invasive bacterial illness. the latter is generally
syndromes of severe illness requiring referral and pre-referral For this reason, both restricted to hospi-tals and
treatment. Most often these include the presence of fever or specific antimalarial and points of definitive care).
history of fever in the past 2 days, the presence of palmar pallor antibacterial treatments Depending on the availability
in chil-dren under 5 years, and one or more of the danger signs should be started of medicines and trained staff,
listed in Table 11. immediately once a severe pre-referral treatment should
febrile illness is sus-pected be initiated with one of the
even before laboratory following, in descending
testing, admission or order of preference:
Identifying parasitaemia in cases being prepared for pre-referral referral. Figure 27, below
treatment shows a simplified
Global policies now recommend parasitological confir-mation as algorithm for recognising
part of case management for malaria. A par-asitological and responding to severe
diagnosis can be accomplished at a febrile illness (World
Health Organization
febrile illness as from peripheral adapted from IMCI and IMAI algorithms
criteria for referral health facilities,
Table 11 General danger signs suggesting severe
t e h l o
IMCI for o e i s n
children d n i s
259 d g o c
months in r V n i
areas of o
i o M s
malaria u
n m u s
transmissi
k i l L n
on
t t e e
Fever or history of fever in the past 24 o i i t s
h OR palmar pallor plus one or more
r n p h s
of the following danger signs:
g l a
U b e r S
n r e g t
a e v c y i
b f
a e o
l f
s r n U
e t y v n n
f t u c e
c u mission r e
k M l Fever or history of fever in the past g c
Chest indrawing or stridor A t 24 h plus one or more of the y k
I s following danger signs:
Ve U R
f i
o n ry n e
r w c s
a ea o p
o r k n i
l e or s r
d a un
c a
e s ab
le i t
r
to o o
o
c f st u r
h an s y
i m d n
l a C e d
d l on s i
r a vu s s
e r lsi t
n i on
S r
a s
a t e
L i s
n t e
d r f s
a t f Severe
a n h abdominal
d s a n pain
Algorithm for malaria diagnosis and treatment: first visit

Do NOTperform
YES a malaria test
Suspected malaria case

High malaria risk area Low malaria risk area Danger Ask the patient to
History of fever Palmar pallor in a child History of fever or temperature 37.5 C a
or temperature 37.5 C or Hb < 8 g/dl ? without an obvious cause of fever ? signs? come back for
malaria testing in
YES YES case of (persisting)
fever
de to monitor parasite clearance come
All health facilities back:
Health facility with no inpatient
service and community level Health facility with inpatient service and community
level
1
R immedi
e ately
p POSITIVE for Perform in
case
Give e Pf or non-Pf RDT or blood slide of
and a
antima Admi dange
t r signs
larial ssion
b
and an antibiotic
b
At least one test l
Uncomplicated malaria
Give first-line anti-malarial
Febrile illness (NOT malaria)
2
POSITIVE treatment for the species after 2
o
c
Perform blo od slide +/ RDT
Refer the patient immediately Assess for other causes of days

Severe malaria o fever and treat appropriately in
Give intravenous d case
antimalarial medicine of
Give parenteral
persist
antibiotics
d s
ing
li Ask the patient to
ncomitant
bacterial
infection malariain fever
severe
patients,
especially
children,
antibiotics
should be in
given
in children: unable to drink or breastfeed,
c RDT vomit beside
is performed
everything,while
antimalarials
until have
bacterial
infections have waiting
convulsions,
for the are
result
lethargic
of the blood
or unconscious
slide to decide
and present
earlier on
with
treatment
neck stiffness,
and to document
chest indrawing
malaria
or stridor;
in patients who have receive
been ruled
(including
bacteremia out
by Figure 27 for the diagnosis, assessment and
in adults: are very weak or unable toBstand,
b Pre-referral treatment as recommended
The following general danger signs are considered criteria
e
ca
u
se
ft byfrom
o
for referral at peripheral level [adaptedh
haveare
WHO
4 blood cultures
available).
lethargic
already
if
or unconscious
cleared or have neck stiffness, convulsions, respiratory distress or severe abdominal pain
their parasites).
A practical management of malaria at the clinic
2010 Management of Childhood Illness (IMCI) and Integrated Management of Adolescent and
Integrated
a e
p
o
sib
Illness (IMAI): rectal artesunate or intramuscular
lityo quinine, artesunate or artemether and intramuscular ampicillin plus gentamicin or intramuscular ceftriaxone
Adult Illness (IMAI)]: fco algorithm level.
severe feb-rile s nvasive IMAI febrile illness; others for pre- who
1 IM artesunate illness or e bacterial guideli the presence of specific referral have
suspected v infection. nes danger signs such as stiff care. received
2PR artesunate (only for
children 6 years)* severe malaria, e African pre-
recom neck, nasal flaring or chest Clinicians
referral
3IM artemether although if no r children mend indrawing. Nevertheless, are treatmen
4IM quinine par-enteral or e with pre- children with severe advised to t
rectal severe referral febrile illness in malaria- refer to
5PR quinine
m malaria Pre-
formulation is treatme endemic Africa seldom their
*In the large available, and a are at nt for receive initial treatment national referr
multicentre study of rectal the patient can l high risk al
both with appropriate treatment treat
artesunate vs placebo still swallow a of malaria antibacterial drugs, either guidelines ments
(Gomes et al. 2009), the then oral r concomita and for pre-refer-ral or for for can
significant benefit of treatment i nt often
bacteria definitive care. Broad- antibacteri
rectal artesunate in should be a bacteraem result
l spectrum antibacterial al
children was not seen in started. ia [see in a
infectio drugs recommended for medicine
adults, in whom the a Section dram
ns. pre-referral treatment of recommen atic
provision of rectal n 10]. IMCI
The addition of Some severe febrile illness differ dations. clinic
artesunate was d and
pre-referral countri depending on local al
detrimental. es policies, age of the patient, impro
antibacterial s
drugs recom antimicrobial resistance veme
e nt,
Initial doses for each of
v mend patterns and other patient Ensuring
these regimens are It is referral but it
e antibact characteristics (such as remai
provided in the treatment impossible and
r erial immunisation and HIV definitiv ns
Table 12. WHO no longer to treatme status). These
e e essent
recommends oral distinguish ial
nt for recommendations are not manage
treatments for the pre- clinically that
i all elaborated here, but they ment of
referral management of between patients
severe are a critical element of
patients complete referral and

Table 12 Pre-referral treatment of severe malaria. Where referral is delayed or
transport to a higher level of impossible
Severe malaria is a medical emergency Treatment should never be care for definitive
delayed. If there is any doubt, the physician or healthcare worker management as promptly as A number of national policies
should treat as severe malaria pending definitive diagnosis. Ideally, possi-ble. Generally, this is a include special recommen-
antimalarials should be given parenterally in severe malaria, but if that district hospital or a high- dations for the rare situation
is not possible, preferral rectal artesunate should be given to children level health centre with
when referral must be delayed
6 years. If nothing else is available, and it will take many hours to
reach a health facility, attempted oral treatment is better than nothing. personnel, laboratory and or is impossible. Frequently,
The following are the recommendations for immediate antimalarial
facilities for managing severe these recommenda-tions
drug treatment at a village or health post before referral to hospital illness 24 h a day. involve repeated IM or PR
for definitive diagnosis and treatment Community health workers doses of pre-referral
who are likely to provide pre- medications. There can be no
Choice of drug referral care should know reasonable doubt that
where to refer severely ill continued treatment is better
Older children
Order of preference Children <6 years and adults
patients from their catchment than none, even though there
areas. Providing is no evidence to support this
1 Artesunate i.m. Artesunate i.m. transportation costs and practice. But com-pleted
2 Rectal artesunate Artemether i.m. carefully involving family referral for definitive care is
3 Artemether i.m. Quinine i.m
members in the referral plan always the preferred course of
4 Quinine i.m
may improve the completion action, and every effort
Doses of referral in a timely way. should be made to achieve it.
The referring unit should Attempting, as some do, to
Drug Dose provide a referral note complete the whole course of
Artesunate i.m. 2.4 mg/kg*
outlining the patients treatment at home is not
Rectal artesunate 10 mg/kg condition including initial acceptable practice, because
Artemether i.m. 3.2 mg/kg assessment, any diagnostic the diagnosis may have been
Quinine i.m 20 mg salt/kg tests and what pre-referral wrong and complications and
*3 mg/kg is recommended in children <20 kg. treatments have been initiated comorbidities cannot be
Intramuscular injections should be given to the anterior thigh. and when. Upon arrival at the identified (Walter et al. 2009).
Quinine dihydrochloride is acidic and painful. It should be diluted to referral cen-tre, assessment
60100 mg/ml, and the dose split such that half is given to each
and management of severely
thigh. If rectal artesunate is administered, the child should be
examined to check it has been retained. If the rectocap is expelled, ill patients should proceed as
the dose should be repeated described in the remainder of
this document.
(Price et al. 2009; Anstey et
al. 2012).
Epidemiology of complicated
and severe vivax malaria
Section 13: Severe vivax malaria In the only modern autopsy
Outside of Africa, P. vivax series, at least four of 17
Plasmodium falciparum causes the majority of severe and fatal (23.5%) vivax-associated
causes almost half of all
malaria cases and has overshadowed the public health deaths in Brazil were attribut-
importance of vivax malaria (Baird 2007; Price malaria cases, with 70390
million clinical infections able to alternative causes,
et al. 2007). Plasmodium vivax is less pathogenic than P. including meningitis and yel-
each year (Price et al. 2007).
falciparum in otherwise healthy patients, but can cause low fever (Lacerda et al.
In countries endemic for both
complicated and severe disease (Price et al. 2007, 2009; Baird 2012). This proportion is
major Plasmodium species, P.
2009; Bassat & Alonso 2011; Anstey et al. 2012). In the malaria similar to the 23% of P.
therapy era, acute mortality during vivax infection can account
for up to 38% of patients falciparum-associated deaths
P. vivax therapy of neurosyphilis averaged 510% over-all attributable to other non-
hospitalised with malaria
(Swellengrebel & De Buck 1938) and up to 1014% with the falciparum aetiologies at
(Buck et al. 1983; Gopinathan
Madagascar strain (James 1933), but these were debilitated autopsy in Malawi (Taylor et
& Subramanian 1986;
patients with a fatal underlying disease. Plas-modium vivax al. 2004). An additional 41%
Maitland et al. 1997; Carrara
infection has been associated with severe and fatal disease in of the Brazilian fatal vivax
et al. 2006; Tjitra et al. 2008).
endemic areas, including Indonesia (Barcus et al. 2007; Tjitra et cases had major underly-ing
In Indonesian Papua, P. vivax
al. 2008; Lampah et al. 2011; Nurleila et al. 2012), Papua New comorbidities contributing to
accounted for 24% of malaria
Guinea (Genton et al. 2008; Manning et al. 2011), India (Kochar death at autopsy (Lac-erda et
admissions in all age groups,
et al. 2010; Yadav et al. 2012), Brazil (Andrade et al. 2010; al. 2012), an association also
but 47% (415/887) of infants
Lacerda et al. 2012), Venezuela (Rodriguez-Morales recognised in the early
(Tjitra et al. 2008). The need
for hospitalisation indicates literature (James 1925;
et al. 2008), Thailand (Luxemburger et al. 1997), Malay-sia Kitchen 1949a). The popu-
significant morbidity and at
(Barber et al. 2012) and Sudan (Mahgoub et al. 2012). Severe lation-based risk of severe
least moderately severe
manifestations associated with P. vivax infection in these series and fatal disease is not well
disease (Anstey et al. 2012).
include severe anaemia, respira-tory distress and acute lung defined. In Indonesian Papua,
This ranges from vomiting
injury (ALI), acute kidney injury (AKI), splenic rupture, where transmission is high,
and inability to tolerate oral
metabolic acidosis, jaun-dice, multiorgan dysfunction, shock and the risk of severe disease and
rarely coma. ther-apy, through to
prostration and those with death from P. vivax was
P. vivax also causes substantial morbidity, particularly severe estimated at 1 in 270 and 1 in
disease mani-festations
anaemia (Genton et al. 2008; Tjitra et al. 2008; Poespoprodjo 3959 clinical infections,
fulfilling the severity criteria
et al. 2009; Price et al. 2009; Manning et al. 2011; Nurleila et respectively, compared to
described earlier for
al. 2012) and low birthweight (Nosten et al. 1999; estimates for P. falciparum of
falciparum malaria (Section
Poespoprodjo et al. 2008; Rijken 1 in 185 and 1 in 1742,
2). The risk of severe dis-ease
et al. 2012a). While many recent series report PCR exclu-sion of respectively (Tjitra et al.
from single P.vivax infections
mixed Plasmodium infection, investigation for concurrent 2008). Mortality rates in
is very low in other-wise
infections or comorbidities has been mostly incomplete. those hospitalised in
healthy adults and older
Evidence is strong that P. vivax can cause severe anaemia (Price Indonesian Papua with
children without
et al. 2009; Douglas et al. 2012), acute respiratory distress microscopy-diagnosed P.
comorbidities, with ready
syndrome (ARDS) (Tan et al. 2008; Valecha et al. 2009; Taylor et vivax were reported as 0.8
access to early diagnosis and
al. 2012b), splenic rupture (Imbert et al. 2009) and in some areas 1.6%, similar to that of P.
effective treatment. (Price et
acute kid-ney injury (Chung et al. 2008; Kute et al. 2012b; Sinha falciparum infection (1.6
al. 2009; Anstey et al. 2012).
et al. 2012). For other reported severe malaria syn-dromes, the 2.2%) (Barcus et al. 2007;
In endemic areas, the risk of
extent to which they are attributable to Tjitra et al. 2008; Price et al.
severe disease is asso-ciated
P. vivax is not yet clear: infectious and non-infectious with young age, higher 2009). The adjusted odds
comorbidities may be additive or synergistic contributors to ratio of death from severe
transmission intensity, early
severe disease or alternative causes (Kitchen 1949b; Anstey et anaemia in Papua was 5.9 for
and frequent relapse, less
al. 2009; Price et al. 2009; Lampah et al. 2011; Anstey et al. those with P. falciparum and
access to early diagnosis and
2012; Barber et al. 2012; Lacerda 4.4 for those with P. vivax
treatment and/or greater
et al. 2012). However, the presence of comorbidities does not prevalence of comorbidities infection. Case-fatality
exclude a key role for P. vivax in the pathophysiol-ogy of severe including bacterial co-
disease.
infections and malnutrition
severe illness (Lanca et al.
2012). Such comorbidities are
in malaria-endemic regions,
Other comorbidities. Acute and their contribution to
rates in Indian children hospitalised with PCR-confirmed P. and chronic infectious and severe and fatal disease in P.
vivax mono-infection (3.9%) were also comparable to that seen non-infectious vivax infection is probably
in PCR-confirmed P. falciparum infection (3.2%) (Kochar et al. comorbidities probably underesti-mated (Anstey et al.
2010). In marked contrast, sub-stantially lower vivax mortality contribute to severe and 2009; Price et al. 2009;
(0.22%) has been reported in children hospitalised in Thailand fatal disease in P. vivax Anstey et al. 2012).
(Wattana-goon et al. 1994), and only one of 1000 sequential infection (Anstey
adult admissions with strictly defined severe malaria in Viet-nam et al. 2009; Price et al. 2009;
had P. vivax malaria (TT Hien, personal communi-cation). Anstey et al. 2012; Lacerda et
Furthermore, in contrast to the reports from some parts India, al. 2012). Haemodynamic
acute kidney injury from vivax malaria is very unusual in South- effects of the systemic Severe malaria syndromes
East Asia. The mortality of vivax malaria in low transmission inflammatory response to P. Series of severe vivax
areas is uncertain with some recent case series reporting vivax and anaemia may con- malaria have described a
significant mortality and other series reporting very low tribute to decompensation of broad range of severe
mortalities. Thus, whereas the spectrum of falciparum malaria concurrent acute and chronic manifestations in children
severity in relationship to age and transmission intensity appears disease and subsequent death, and adults, using criteria
similar across the world, there appear to be marked differences in whereas otherwise healthy developed for severe
the reported severity of vivax malaria between different areas. children and adults may make falciparum malaria.
an uncomplicated recovery
(James 1925; Kitchen 1949a). Severe anaemia. The major
In the Manaus (Brazil) severe manifestation in most
autopsy series, 10 of the 13 P. series of vivax malaria in
Vulnerable groups
vivax-associated deaths had children is severe anaemia,
Young children. In co-endemic areas, morbidity, includ-ing concurrent comorbidities, defined as a haemoglobin
severe disease from P. vivax, usually occurs at a younger age including pneumo-nia, concentration of <5 g/dl in
than from P. falciparum (Michon et al. 2007; Tjitra et al. 2008; emphysema, diabetes, children and <7 g/dl in adults
Kochar et al. 2010; Lin et al. 2010). Most severe disease in haemorrhagic stroke, decom- (Luxemburger et al. 1997;
children, especially severe anaemia, is reported from high pensated cirrhosis and Rodriguez-Morales et al.
transmission areas in chil-dren under 5 years (Genton et al. 2008; congestive heart failure 2008; Tjitra et al. 2008; Poe-
Tjitra et al. 2008; Poespoprodjo et al. 2009; Alexandre et al. (Lacerda et al. 2012). HIV co- spoprodjo et al. 2009;
2010; Kochar et al. 2010; Lanca et al. 2012). This risk is high-est infection was found in one Alexandre et al. 2010;
in infancy (Douglas et al. 2013). In Indonesian Papua, more case (Lacerda et al. 2012). Kochar
infants are hospitalised with vivax malaria than fal-ciparum HIV infection is a risk factor et al. 2010). There are few
malaria (Tjitra et al. 2008; Poespoprodjo et al. 2009) including a for severe disease and death data on the confounding
2.4-fold higher proportion with severe anaemia if hospitalised in P. falciparum infection effects of other causes and
with vivax compared with falcipa-rum malaria (Tjitra et al. (Bejon et al. 2007; Berkley et the effect of successive
2008). Infant risk starts in ute-ro, with P. vivax infection in al. 2009), but the risk in P. episodes of malaria caused
pregnancy associated with abortion, low birthweight, congenital vivax infection is not yet by reinfection and relapses.
malaria (Poe-spoprodjo et al. 2011) and a greater risk of clinical known. In the United States, Despite these limitations,
dis-ease and severe anaemia in the neonatal period deaths from P. vivax have the association between
occurred in patients with pre- vivax infection and severe
(Poespoprodjo et al. 2009; Lanca et al. 2012).
existing cardiac disease anaemia is strong,
(Stoppacher & Adams 2003). particularly in infancy
Among 24 P. vivax-infected (Michon et al. 2007;
Malnutrition. As in falciparum malaria (Berkley et al. 2009),
Genton et al. 2008; Tjitra et
malnutrition is a likely major contributor to severe disease in P. Brazilian children requiring
intensive care admission, al. 2008; Ladeia-Andrade
vivax infection. In India, malnutrition was found in 69% of
25% had concomitant acute et al. 2009; Poespoprodjo
children with severe vivax malaria and 75% of the vivax-
et al. 2009; Lin et al. 2010;
associated deaths (Kochar et al. 2010). In Brazil, 17% of vivax- gastroenteri-tis, and in total,
58% had a concurrent acute Douglas et al. 2013). Among
infected children requiring intensive care admission had patients presenting to hospital
malnutrition (Lanca et al. 2012). or chronic comorbidity that in Indonesian Papua,
may have contributed to
more frequent in children
hospitalised with falciparum
malaria (18%) than those with
appears less common than in vivax malaria (11%);
where transmission of malaria is high, the adjusted falciparum malaria, but has however, this ratio was
population fraction of severe anaemia attributable to also been reported in adult reversed in children younger
P. falciparum was 15.1% compared to 5.8% for P. vivax and severe vivax malaria than 5 years (2% and 15%,
5.9% for mixed infections. The fraction of severe anaemia (Lampah et al. 2011). In the respectively) (Kochar et al.
attributable to P. vivax was highest in infancy, when it rose to Brazilian autopsy series, 88% 2010).
30.4% compared to 20.5% for P. falcipa-rum. (Douglas et al. had respiratory distress prior
2013). In Brazil, 9% of children up to 14 years old requiring to death, again mostly
intensive care unit admission with vivax malaria had severe appearing after the start of Both hypoxaemia and
anaemia, but there were no deaths (Lanca et al. 2012). Even in antimalarial drug treatment. metabolic acidosis have been
adults, severe anaemia can be a common manifestation of severe ARDS and/ or lung oedema described in children with P
vivax disease. In Indonesian Papua, 10% of all adults hospita- was identified as the vivax-associated respiratory
lised with P. vivax infections between 2005 and 2007 had a commonest compli-cation distress (Kochar et al. 2010;
haemoglobin <5 g/dl (Tjitra et al. 2008). In other series from contributing to death, Lanca et al. 2012). The rela-
India and Brazil, severe anaemia accounted for almost a third of occurring in 35%, and in tive contributions of
all cases of severe adult vivax malaria (Kochar et al. 2009; three of the four patients in metabolic acidosis, lung
Andrade et al. 2010). Con-versely, in a hypoendemic region of whom P vivax was injury, pneumonia, sepsis and
north-western Thai-land, none of 1978 adults and children >5 considered the direct cause of severe anaemia to the
years diagnosed with acute vivax malaria over a 3-year period death (Lacerda et al. 2012). In respiratory distress associated
required hospitalisation for severe anaemia or blood transfusion two of the latter cases, lung with P. vivax in children is
(Luxemburger et al. 1997). Infection with gastrointestinal oedema occurred in unclear. Respiratory distress
helminths can cause anaemia through chronic blood loss. While conjunction with other major was the commonest
mixed infections with hook-worm and P. falciparum cause an pathology (one each with complication (67%) among
additive reduction in haemoglobin in preschool children coma/encephalitis and splenic Brazilian children admitted
(Brooker et al. 2007), in the one study co-infection with rupture (Lacerda et al. 2012). for intensive care with severe
hookworm, Ascaris and Trichuris in Brazil attenuated the disease associated with P.
reduction in hae-moglobin associated with vivax malaria (Melo Respiratory distress is also vivax, with 12.5% overall
et al. 2010). a common manifestation in having strictly defined ARDS
most series of severe (Lanca et al. 2012); none
paediatric vivax malaria died. One child with
(Gen-ton et al. 2008; Tjitra et respiratory distress (6%) had
al. 2008; Kochar et al. 2010; pneumonia and empyema
Acute lung injury (ALI) and respiratory distress. Acute lung Yadav et al. 2012). As in identified as the underlying
injury (ALI) and acute respiratory distress syndrome (ARDS) are adults, definitions used for cause (Lanca et al. 2012).
well-recognised complications of P. vivax malaria. Initial reports respiratory distress vary One of 65 Indian children
were of cases mostly managed in non-endemic country hospitals, considerably between series with PCR-confirmed severe
with a very low case-fatality rate and with the majority occurring (Taylor et al. 2006c), vivax malaria had pulmonary
after com-mencement of antimalarial drug treatment (Taylor et complicating comparisons. oedema in association with
al. 2012b). In a single case report from India, ARDS arising pre- Respi-ratory distress occurred multiorgan dys-function
treatment in vivax malaria had a fatal outcome (Vale-cha et al. more frequently in vivax (Kochar et al. 2010).
2009). More recently reported ALI/ARDS in adults have mostly malaria (60%) than
been part of larger series of severe vivax malaria from endemic falciparum malaria (41%) in
settings, generally with less-clearly defined ARDS criteria, Papua New Guinean children, Acute kidney injury.
occurring as part of multi-ple organ dysfunction/failure (Kochar and with substantially higher Evidence of acute kidney
et al. 2005, 2009; Alexandre et al. 2010; Andrade et al. 2010; proportions than those injury (AKI) has been
Lacerda reported in hospitalised reported in several series
children in Indonesia Papua, a of adult vivax malaria and
not in others (Kochar et al.
et al. 2012). Clinical ARDS/respiratory failure occurred in 10 reflection of broader
2005; Chung
32% of patients with severe vivax malaria and had case-fatality inclusion criteria. In
rates of 5067% (Kochar et al. 2005, 2009; Alexandre et al. Indonesian Papua, rates were
2010; Andrade et al. 2010), much higher than the very low similar between P. vivax
fatality rate seen in reports of single-organ ARDS (Taylor et al. (2.3%) and P. falciparum
2012b). Lactic acidosis (2.5%) (Tjitra et al. 2008). In
India, respiratory distress was
sangioproliferative and
membranoproliferative
glomerulo-nephritis from P.
been reported in children malariae (Gilles &
et al. 2008; Kochar et al. 2009; Alexandre et al. 2010; Andrade et from north-west India with Hendrickse 1960, 1963 ; van
al. 2010; Kute et al. 2012b; Sinha et al. 2012). There appear to be PCR-confirmed P. vivax Velthuysen & Florquin 2000)
geographical differences in risk and severity, with little or no mono-infection-associated has also been reported in
vivax-associated AKI being reported in returned travellers (Tan AKI, with all deaths having association with P. vivax
et al. 2008) or from some vivax-endemic areas, such as Thailand associated multiorgan infections (Bircan et al. 1997;
(Luxemburg-er et al. 1997; Piyaphanee et al. 2007) and Vietnam dysfunction (Kochar et al. David et al. 2009). Acute
(Hien et al. 1996). AKI is reported, but is rarely severe, in 2010). In contrast, in Vietnam glomerulonephritis in malaria
Korean cases of vivax malaria (Chung et al. 2008). Across and Thai-land, where the two (of any species) is very rare,
northern India, severe dialysis-requiring AKI and/ or AKI-related infections have similar so the pathological role of
death is increasingly reported (Prakash prevalence, excluding P.vivax in these latter cases
massive haemolysis in G6PD remains uncertain.
et al. 2003; Kochar et al. 2005, 2009; Kute et al. 2012a, b; Sinha deficiency, AKI in paediatric
et al. 2012), but only the Rajasthan series was P. vivax mono- vivax malaria is not seen (TT
infection confirmed by PCR. AKI in PCR-confirmed mono- Hien, NJ White; personal Shock and multiorgan
infection has also been reported from Brazil (Alexandre et al. communication). The reasons dysfunction. Shock has been
2010; Andrade et al. 2010; Lacerda et al. 2012). No population- for these substan-tial asso-ciated with adult
based data on risk of AKI have been reported from any region. differences are unclear. (Kochar et al. 2005, 2009;
It is unclear why there are such marked differences in the Other P. vivax series have Song et al. 2007; Alexandre et
apparent incidence of renal complications between differ-ent reported AKI associated al. 2010; Barber et al. 2012)
areas. with thrombotic and pae-diatric (Kochar et al.
In those series reporting AKI in vivax malaria, this was most microangiopathy (Saharan et 2010; Kaushik et al. 2012) P.
commonly associated with multiorgan dysfunction and was a risk al. 2008; Sinha et al. 2012) vivax infections usually as
factor for fatal outcome (Kute et al. 2012b). Shock was also a in both adults and children, part of multiple organ
common association. Renal biopsies in four patients with vivax- and hae-molytic-uraemic dysfunction. Culture of blood
associated AKI reported patchy cortical necrosis in three cases syndrome (HUS) in children and other fluids was not
and acute tubular necrosis in the other (Kute et al. 2012b). The (Sharma et al. 1993). In the reported, and bacterial co-
pre-sentations reported frequently mimicked AKI seen with largest series (four adults infection and bacterial sepsis
sepsis and/or shock, but the contribution of concomitant bacterial and five children), persistent are possible synergistic or
sepsis to these syndromes is not known. In the Brazilian autopsy vivax-associated AKI was alternative causes. Shock was
series of deaths associated with associated with present in 54% of Brazilian
thrombocytopenia, bleeding, children requiring ICU
P. vivax infection, all six cases with AKI were associated with anaemia, splenomeg-aly, admission in Brazil in which
pre-existing comorbidities predisposing to AKI or multiorgan with schistocytes on negative pre-antibiotic blood
dysfunction (heart failure, sickle cell haemo-lytic crisis, chronic peripheral film in 77% cultures were reported;
liver disease) or alternative aetiologies (primaquine-induced (Sinha et al. 2012); one of however, 38% of these had an
haemolysis or yellow fever) (Lacer-da et al. 2012). AKI, with the patients with identified additional
varying definitions, has also been reported increasingly as a schistocytes had infectious comorbidity
manifestation of severe vivax malaria in children (Kochar et al. concomitant coma (Sinha et potentially contributing to
2010; Manning et al. 2011; Jat et al. 2012; Kaushik et al. 2012; al. 2012). Biopsies showed shock (Lanca et al. 2012).
Yadav et al. 2012) occurring in 315% of severe cases in these universal ischaemia and
series, usually as part of multiorgan dysfunction. This contrasts endothelial injury and
with severe falciparum malaria, in which acute kidney injury is arteriolar thrombi in two Bacterial co-infection and
markedly less common and is less severe among children than in cases, consistent with bacteraemia. The
adults (Anstey et al. 1996; Hien et al. 1996; Weber et al. 1999; thrombotic micro- bacteraemia risk in severe P.
Dondorp et al. 2008b). In paediatric series describing both severe angiopathy (Sinha et al. vivax infection has not been
falciparum and severe vivax malaria, renal impairment occurred 2012). Fatal AKI associated studied sys-tematically. A
with a lower (Kochar et al. 2010) or similar (Manning et al. with crescentic large prospective blood
2011; Yadav et al. 2012) frequency in those with glomerulonephritis (Patel et culture and malaria
P. vivax infection. Mortality rates of up to 30% have al. 2012) and nephrotic microscopy study in Kolkata,
syndrome (more commonly India, showed that 6 of 89
associated with me- uncomplicated vivax malaria
cases [6.7% (95%
(Lampah et al. 2011), similar
to that occasionally seen
following coma in
reported complete, falciparum malaria (Nguyen
CI: 3.113.9%)] had concomitant bacteraemia, with 5/6 (83%) of systematic microbiological et al. 1996).
the bacteria isolated being Gram-negative (one S. typhi, one S. and radiological
paratyphi A, three other enterobacteria-ceae) (Bhattacharya et al. investigation to exclude Other, rarer, neurological
2013). Of the two cases of Salmonella bacteraemia reported from bacterial and viral infection complications reported in
Thailand in associ-ation with PCR-confirmed P. vivax mono- and other causes of coma. association with P. vivax
infection, one patient had multiorgan dysfunction (renal failure, Such studies are needed. In infection include facial
jaun-dice and hypotension), with concurrent serogroup D Sal- autopsies in two Brazilian diplegia (Kochar et al. 2007;
monella bacteraemia, and the other uncomplicated, children with vivax- Sim et al. 2010), acute
P. vivax case had non-typhoidal Salmonella bacteraemia associated coma, inflammatory polyneuropathy
(Piyaphanee et al. 2007). Gram-positive (Streptococcus encephalitis was identified (Chakravarty et al. 2004),
pneumoniae) bacteraemia has also been reported in asso-ciation in one (Lanca et al. 2012) acute dissemi-nated
with hypotension in adult vivax malaria (Barber et al. 2012). and could not be excluded in encephalomyelitis (Koibuchi
the other (Lacerda et al. et al. 2003) and ante-rior
Coma and other vivax-associated neurological complica-tions. 2012). In a prospective ischaemic optic neuropathy
Coma is much less common in vivax than falcipa-rum malaria. series of 24 cases of coma (Flowe et al. 2011). As in
Over 100 cases of P. vivax mono-infection in adults and children associated with P. vivax many of these observations
associated with coma have been described in reports or series infection diagnosed by and associations, causality is
from 1921 to 2011; how-ever, only studies in the last 15 years microscopy, 75% had PCR uncertain. While not seen in a
have been able to exclude mixed species infection with P. evidence of P. falciparum series of uncomplicated adult
falciparum by PCR methods (Beg et al. 2002; Kochar et al. 2005; (co)infection or other vivax malaria in Bangladesh
Thap-a et al. 2007; Sarkar & Bhattacharya 2008; Harish & Gupta bacterial or non-infective (Abu Sayeed et al. 2011),
2009; Kasliwal et al. 2009; Kochar et al. 2009; Parakh et al. causes of coma; almost all cases of retinal haemorrhages
2009; Thapa et al. 2009; Kochar et al. 2010; Lampah et al. 2011; PCR-confirmed cases of in pure vivax malaria have
Tanwar et al. 2011). In Indo-nesian Papua, coma associated with coma in P. vivax mono- been described elsewhere
PCR-confirmed infection in this series were without central nervous
in young adults with low system complications (Choi
P. vivax mono-infection (and without overt comorbidi-ties) parasitaemia, no other organ et al. 2004; Lee
occurred 23 times less frequently than with falcipa-rum malaria dysfunction and good et al. 2010b).
and was estimated as occurring in one in 29 500 infections outcomes (Lampah et al.
(Lampah et al. 2011). In Thailand, the risk of hospitalisation with 2011). Plasmodium vivax Splenic rupture and
impaired consciousness with microscopy-diagnosed P. vivax -associated coma has been infarction. Splenic rupture is
(not-PCR-confirmed) was 1 in 858 infections, with the risk being associated with thrombotic a life-threatening but
15.2-fold less than that with P. falciparum (Luxemburger et al. thrombocytopenic purpura probably under-reported
1997). In over 1000 prospectively studied patients with severe in one (Sinha et al. 2012), complication in adults
malaria studied in a specialist unit in Vietnam, one patient (with but not another series (Moses 1945; Kapland et al.
coma) had vivax malaria (TT Hien, per-sonal communication). (Lampah et al. 2011). Other 1946; Kitchen 1949a; Lubitz
Most other reports of coma in association with PCR-confirmed P. adult series with 1949; Imbert et al. 2009;
vivax mono-infection have been from the Indian subcontinent; Lacerda et al. 2012). In a
however, denominators of the surveillance and population-based P. vivax mono-infection have systematic review of 55 cases
risks were not reported. Only one case with no identified described coma in associ- of malaria-associated splenic
alternative aetiology has been reported from South Amer-ica, a ation with multiorgan rupture, the mortality rate
PCR-confirmed P. vivax mono-infection (Lacerda et al. 2012). dysfunction (Kochar et al. was 22%, with
2005, 2009). A post-malarial P. vivax accounting for
No reports of coma in vivax malaria, including those with neurological syndrome with approximately half of all
PCR-confirmed P. vivax mono-infection, have tremor and myoclonus has cases (Imbert et al. 2009). In
also been reported after the 2012 Brazilian P. vivax
recovery from PCR- autopsy series, three patients
confirmed P. vivax coma (18%) had splenic rupture,
2011; Liu et al. 2012),
through transpla-cental
infection in utero or during
small series from India delivery (Poespoprodjo et al.
all adults, two of whom also had pulmonary oedema (Lacerda (Kochar et al. 2005; Nayak et 2011; Rijken et al. 2012a). In
et al. 2012). Of the four deaths considered directly caused by al. 2009) with poor pregnancy Papua, P. vivax con-genital
P. vivax, splenic rupture occurred in two (Lacerda et al. 2012). outcomes but again with no infection (alone or mixed)
maternal deaths. In all occurred in 1.6 per 1000 live
Other complications. Jaundice is common in both adult [36 endemic regions, less severe births (Poespoprodjo et al.
57%; (Kochar et al. 2005, 2009; Alexandre et al. 2010; Andrade vivax-associated maternal 2011); congenital malaria was
et al. 2010)] and paediatric (Alexandre et al. 2010; Kochar et al. anaemia is common, being independently associated with
2010; Jat et al. 2012; Lanca et al. 2012) series of severe vivax approximately twice as likely low birth-weight and was
malaria, often in association with other severe manifestations. in pregnant women infected mostly asymptomatic at birth
However, in Brazilian children, jaundice did not predict need for with P. vivax than without (Poe-spoprodjo et al. 2011).
ICU admission (Lanca et al. 2012). Severe epistaxis associated (Nosten et al. 1999; Like congenital falciparum
with thrombocytopenia requiring blood and platelet transfusions Poespoprodjo et al. 2008). malaria (Poespoprodjo et al.
was reported in 5% of adults with severe vivax malaria (Kochar 2010), congenital vivax
et al. 2009), and throm-bocytopenia was associated with other malaria can cause severe
severe manifesta-tions (Kochar et al. 2005; Kochar et al. 2009; Effects on fetus and neonate. illness mimicking neonatal
Andrade et al. 2010; Alexandre et al. 2010). Fatal pulmonary Plasmodium vivax infec-tion sepsis (Del Punta et al. 2010).
haemorrhage and haematemesis have been reported (Jat et al. in pregnancy causes a
2012). Hypoglycaemia (blood glucose <2.2 mM or <40 mg/dl) reduction in birthweight
(World Health Organization 2010a) was found in 12.5% of (med-ian 108 g) (Nosten et al.
Severe and fatal
children with vivax malaria requir-ing admission to intensive 1999; Poespoprodjo et al. complications of primaquine
care unit in Brazil (Lanca 2008; Rijken et al. 2012a)
approximately 70% of that Morbidity and mortality
et al. 2012). Less common disease associations with P. vivax observed following maternal secondary to adverse effects
include haemoglobinuria in the absence of G6PD deficiency falciparum malaria (median of primaquine are likely to be
(Kochar et al. 2010) and peripheral gangrene (Raghunandan et 150192 g). With low underestimated in populations
al. 2012). Acalculous chole-cystitis has been described in both birthweight contributing to with unmonitored use of
adults and children (Curley et al. 2011), with gall bladder wall greater infant mortality primaquine and high
oedema and periportal oedema described in 32% and 35% of 34 (Luxemburger et al. 2001), P. prevalence of G6PD
vivax malaria patients undergoing CT scanning for abdominal vivax in pregnancy is thus deficiency (Baird &
pain (Kim et al. 2010). Series from the 1940s reported patients responsible for substantial Surjadjaja 2010). Primaqu-
with acute lower abdominal pain associated with vivax malaria, indirect mor-tality in the first ine-induced haemolysis in
but not with splenomegaly, mimicking appendicitis and other year of life. A single episode patients with G6PD
acute surgical conditions (Most & Hayman 1946; Kitchen of P. vivax infection in the deficiency can cause life-
1949b). first trimester also increases threatening AKI and severe
risk of mis-carriage 2.7-fold anaemia, accounting for 8%
and fourfold with of P. vivax-associated
asymptomatic and intensive care admissions in
symptomatic malaria, Brazil (Lanca et al. 2012) and
Vivax malaria in pregnancy respectively (McGready et al. 12% of deaths in the Manaus
Effects on mother. In contrast to P. falciparum, 2012b), a rate approximating autopsy series (Lacerda et al.
P. vivax rarely causes severe malaria in pregnant women (Nosten that with P. falciparum 2012). Severe haemolysis
et al. 1999; Poespoprodjo et al. 2008; McGready et al. 2012a,b; (McGready et al. 2012b). results from multiple dosing
Rijken et al. 2012a), and in a large series from the Thailand in radical treatment regimens.
Myanmar border, no maternal deaths were associated with vivax Congenital malaria. Overall, 14 deaths from pri-
malaria over a 25-year period (McGready et al. 2012a). Despite Plasmodium vivax can cause maquine toxicity have been
its rarity in very large series from Thailand and Indonesia con-genital malaria reported over the past
(Nosten et al. 1999; Poespoprodjo et al. 2008; McG-ready et al. (McGready et al. 2004;
2012b), severe vivax-associated maternal malaria, including Valecha et al. 2007; Vottier et
severe anaemia, has been reported in al. 2008; Del Punta et al.
2010; Poe-spoprodjo et al.
parasitaemias, all others have
been less than 100 000/ll
(about 2% parasitaemia):
2011) and death (Kochar et al. 2005;
60 years (Recht et al. 2013) despite over 11 million documented (Manning et al. 2011; Alexandre et al. 2010)
exposures (mainly in the course of mass drug administrations). Yadav et al. 2012). (Kochar et al. 2009), (Kochar
et al. 2010; Barber et al.
2012). Nevertheless, an
Risk factors for severe vivax malaria Pathogenesis of disease in association between disease
vivax malaria severity and semi-quanti-
As in falciparum malaria (Miller et al. 2002), host, para-site and
socio-geographical factors likely contribute to risk of severe Comparative pathobiology of tative parasitaemia (1+ to 4+)
disease and death in vivax malaria, as well as specific severe Plasmodium vivax has been reported (Lanca et
manifestations. al. 2012; Nurleila et al. 2012).
There are significant It has been hypothes-ised that
differences in pathobiology total parasite biomass in
Host and parasite genetics. P. vivax uses the red cell Duffy
between P. vivax and P. uncomplicated and severe
antigen as its main receptor for red cell invasion, so people who
falciparum that are important
are Duffy negative (such as those in most of sub-Saharan Africa) malaria may be higher than
in under-standing vivax
are largely protected against vivax malaria. Genetic that represented by peripheral
pathophysiology (Kitchen
polymorphisms have been associated with both increased risk parasitaemia due to
1949b; Anstey et al. 2009).
[alpha- and beta-thalassaemia (Williams et al. 1996; ODonnell accumulation of parasi-tised
et al. 2009)] and decreased risk [Duffy antigen negativity (Miller red cells in organs such as the
et al. 1976), G6PD deficiency (Leslie et al. 2010) and ovalocy- spleen (Machado Siqueira et
Parasite biomass. In contrast
tosis (Rosanas-Urgell et al. 2012) ] of P. vivax parasita-emia. al. 2012; Baird 2013);
to the invasion of red cells of
The role of ovalocytosis in protecting against vivax anaemia and however, this requires further
all ages by P. falciparum, P.
other severe disease syndromes is less well defined. Alpha- investigation.
vivax has a very strong
thalassaemia has been associated with reduced risk of severe
predilection for infecting red
anaemia from P. falciparum (Fow-kes et al. 2008), attributed to a
blood cells that have emerged
lesser reduction in hae-moglobin from the loss of microcytic from the bone marrow within
cells, and has been hypothesised to protect against vivax the preceding Relapse. A fundamental
anaemia through a similar mechanism (Fowkes et al. 2008). difference from P. falciparum
2 weeks (Kitchen 1949b;
Whether natu-rally acquired P. vivax strains vary in virulence is that P. vivax can relapse
Simpson et al. 1999), particu-
and risk of severe vivax malaria is unknown. from dormant hypnozoites to
larly early in the course of
infection (Kitchen 1938). cause repeated episodes of
This property contributes to clinical and subclinical infec-
Chloroquine resistance. A high prevalence of chloro-quine- the lower parasite biomass tions. Frequent recurrent
resistant P. vivax (Sumawinata & Bernadeta Leksana 2003; seen in P. vivax infections. infections may result in
Ratcliff et al. 2007) has been associated with a high risk of Unlike P. falciparum infec- insuffi-cient time for
severe vivax anaemia (Tjitra et al. 2008). The prevalence of tions, parasitaemia densities adequate haematological
chloroquine-resistant P. vivax is increasing across vivax-endemic recovery from each episode.
in vivax malaria rarely exceed
areas (Douglas et al. 2010), and its role in contributing to severe Multiple recurrences are
2% of circulating
vivax disease warrants further investigation (Price et al. 2009). associated with greater
erythrocytes (Ross &
anaemia (Douglas et al.
Thomson 1910; Kitchen
Mixed Plasmodium infections. In areas of low malaria 2013). In contrast, in
1949b; Field & Shute 1956).
endemicity such as Thailand, mixed infections with temperate areas, relapses are
Although a high P. vivax
P. vivax appear to attenuate P. falciparum disease severity fewer and delayed, and the
parasite burden (140 000/ll)
(Luxemburger et al. 1997; Price et al. 2001; Mayxay et al. haematological impact of
has been reported in fatal
2004; Snounou & White 2004). Con-versely, in areas with each recurrence is less (Song
vivax malaria (Valecha et al.
higher endemicity of both species, mixed infections are et al. 2003; Goller et al.
2009), this is very unusual.
associated with an increased risk of severe malaria (Genton et 2007; Price et al. 2009).
Although series reporting
al. 2008; Tjitra et al. 2008), including severe anaemia (Genton
parasite counts in severe
et al. 2008; Tjitra
vivax malaria have
et al. 2008; Douglas et al. 2013), coma (Manning et al.
documented moder-ately high
(Hemmer et al. 2006), vWF
(De Mast et al. 2009) and
ADAMTS-13 deficiency (De
consistent finding in P. vivax Mast et al. 2009) occur in
Inflammatory responses. Plasmodium vivax has a lower malaria, although its role in uncomplicated vivax malaria;
pyrogenic threshold than P. falciparum (Ross & Thom-son vivax pathophysiology is however, the role of altered
1910; Kitchen 1949a). Cytokine production (Karun-aweera et unknown. haemostatic pathways,
al. 1992; Hemmer et al. 2006; Yeo et al. intravascular coagula-tion and
2010b; Goncalves et al. 2012), degree of endothelial acti-vation Deformability and fragility of endothelial inflammation
(Yeo et al. 2010b) and pulmonary inflammatory responses parasitised erythrocytes. In through increased for-mation
(Anstey et al. 2007) are higher during and after P. vivax contrast to P. falciparum of ultra-large VWF and
infections than in P. falciparum infections with similar (Dondorp et al. 1999), the de- platelet aggregates in severe
parasitaemias. Although the inflammatory corre-lates of the formability of vivax-infected vivax malaria is not known.
lower pyrogenic threshold have been described, the underlying RBCs is increased (Suwana-
mechanism(s) have not. Hypothesised reasons include rusk et al. 2004; Handayani et
differences between the two species in candidate malaria al. 2009). This may enable P.
toxin(s) (Anstey et al. 2012). A lipid unique to P. vivax vivax to pass through the Pathophysiology of
narrow interendothelial slits specific syndromes of
(Karunaweera et al. 2003, 2007) may also contribute to the severe vivax malaria
greater pyroge-nicity of P. vivax. It is possible that Plasmodium of the splenic sinusoids
spp. priming of the innate immune response to bacterial prod- (Handayani et al. 2009; Severe vivax anaemia. The
ucts (Franklin et al. 2009) may be greater in P. vivax than in P. Deplaine et al. 2011). aetiology of vivax-
falciparum infections, although this remains to be demonstrated. Increased deformability may, associated anaemia is
Although P. vivax is capable of eliciting greater concentrations of however, be accompanied by complex. Anaemia results
both pro- and anti-inflamma-tory cytokines than P. falciparum increased fragility of both P. from loss of both vivax-
(Hemmer et al. 2006; Yeo et al. 2010b; Goncalves et al. 2012), vivax-infected and non- infected and uninfected red
relationships with disease severity may be different in vivax infected RBCs (Handayani et cells from the circula-tion
malaria. al. 2009), although the extent and impaired RBC
to which this is an artefact of production (Wickramasinghe
the ex vivo microfluidic et al. 1989; Anstey et al.
system used is unknown. 2009; Douglas et al. 2012).
Cytoadherence and rosetting. As all stages of P. vivax are visible
in peripheral blood, albeit with partial deple-tion of mature Malaria therapy data
stages (Rudolf & Ramsay 1927; Field & Shute 1956), Endothelial activation and demonstrated that removal of
sequestration is not thought to occur to a significant degree in altered thrombostasis. Con- red cells from the circulation
vivax malaria; so microvascular obstruction causing end-organ centrations of circulating is particularly pronounced
dur-ing acute infection
dysfunction as in P. falci-parum is not thought to occur (Anstey endothelial activation markers
are as high (ICAM-1 and E- (Kitchen 1938; Collins et al.
et al. 2009). Despite in vitro evidence of cytoadherence to
selectin) or higher 2003), over and above the
ICAM-1 (Carvalho et al. 2010) and chondroitin sulphate A
(angiopoie-tin-2), in rate modelled from
(CSA) (Chotivanich et al. 2012), evidence for sequestration-
reticulocyte loss and impaired
mediated pathology in vivax malaria in vivo is absent (Valecha et uncomplicated vivax malaria
supply of mature red cells
al. 2009) or at best modest (Ewing 1901; Billings & Post 1915; than in falciparum malaria
(McQueen & McKenzie
Bruetsch 1932; Anstey et al. 2007; Lacerda et al. 2012; Anstey et (Jakobsen et al. 1994; Yeo et
2004; Antia et al. 2008). The
al. 2012 for review), although splenic accumulation of infected al. 2010b). Endo-thelial
dysfunction and impaired NO removal of red cells occurs
and uninfected red cells as in falciparum malaria seems likely
from both extravascular loss
(Machado Siqueira et al. 2012; Baird 2013). Published placental bioavailability may be
significant contributors to in the spleen and from
his-tology is even more limited, but has shown an absence
severe falciparum malaria intravascular red cell loss
(McGready et al. 2004) or limited presence (Mayor et al. 2012)
(Yeo et al. 2007, 2009, (Douglas et al. 2012). Despite
of placental P. vivax-infected red cells. Taken together,
2010a), but their role in the lower parasite biomass of
histological findings suggest that significant microvascular
severe vivax malaria is P. vivax rel-ative to P.
obstruction from sequestration of parasi-tised red cells does not
unknown. Endothelial falciparum, red cell removal
occur in vivax malaria, although it is possible that in some
activation and damage have is comparable
circumstances and in some organs, more limited cytoadherence
been described in fatal vivax-
to endothelial cells may occur. Rosetting, adherence of non-
associated ARDS (Valecha et
infected to infected RBCs in vitro (Udomsanpetch et al. 1995) is
al. 2009). Increased
a
procoagulant activity
malaria (De Mast et al. 2009)
although they are linked to
disease severity in falciparum
sons 2006; Tan et al. 2008; malaria (Larkin et al. 2009)
because of the greater proportional removal of uninfected red Valecha et al. 2009). Onset and so might conceivably
cells following P. vivax infection. In vivax malaria, of most but not all vivax- underlie vivax thrombotic
approximately 34 uninfected red cells are removed for every associated ARDS occurs microangi-opathy in these
infected red cell (Collins et al. 2003; Douglas et al. 2012) after starting antimalarial patients.
compared to approximately 8 uninfected red cells for every treatment (Anstey et al.
infected red cell in falciparum malaria (Jakeman et al. 1999; 2009; Taylor et al. 2012b)
Price et al. 2001). Mechanisms for this differ-ence are not clear. with gas transfer studies
Although greatest during the early stages of infection, enhanced showing progressive Coma. The true incidence
removal of uninfected red blood cells has been shown to persist deterioration in alveolar and the aetiology of the coma
for at least 5 weeks after antimalarial treatment (Woodruff et al. capillary function following associated with P. vivax are
1979; Looa-reesuwan et al. 1987). An additional contributory treatment (Lomar et al. not known, and the role of
factor in the anaemia of P. vivax is relapse. In tropical latitudes, 2005; Anstey et al. 2007). co-infections remains unclear
relapses at 3- to 4-week intervals are associated with pro-gressive (Anstey et al. 2009; Lam-pah
anaemia from recurrent episodes of haemolysis and et al. 2011). The rarity of
dyserythropoiesis before haematological recovery from Acute kidney injury. Both the coma in P. vivax relative to P.
preceding infections can occur (Price et al. 2009). In some true incidence and the falciparum and its absence in
regions, severe vivax anaemia is common in chil-dren less than 2 mechanisms underlying AKI P. knowlesi (Danesh-var et
months of age (Poespoprodjo et al. 2009); multiple relapses in vivax malaria are not clear. al. 2009; William et al. 2011;
cannot explain severe anaemia at such an early age. Sustained In prospective studies of adult Barber et al. 2012) makes it
parasitaemia, initially sub-clinical, from congenital malaria may severe malaria con-ducted in unlikely that the
the explanation. In areas of chloroquine resistance, anaemia is South-East Asia, with the cerebrovascular sequestration
exacerbated further by delayed parasite clearance, and exception of haemoglobinuric of parasitised red cells
recrudescent and chronic infections (Price et al. 2007). Impaired renal failure in G6PD characteristic of P.
pro-duction of red cells is also likely to contribute to vivax- deficiency, acute renal failure falciparum occurs in the
related anaemia, particularly with chronic and repeated has never been observed in same way with these other
infections, but mechanisms are unclear. Cytokine-related vivax malaria (Trang et al. parasites. This contention is
dyserythropoiesis has been demonstrated in P. vivax malaria in 1994; T.T. Hien & N. J. supported by the absence of
adults (Wickramasinghe et al. 1989). In adults, erythroblasts can White, unpub-lished P. vivax DNA, albeit post-
be infected by P. vivax in vivo (Ru et al. 2009). observations). Whether acute treatment, in a single
tubular necrosis underlies Brazilian autopsy case of
AKI in vivax malaria in the coma attributed to P. vivax
setting of multior-gan (Lacerda et al. 2012) and
Acute lung injury. Even in uncomplicated vivax malaria, clinical dysfunction or acute cortical brain aspirates from three
pulmonary function testing shows increased pul-monary necrosis, as reported in one PNG children with fatal
phagocytic cell activity associated with reduced gas transfer at series (Kute et al. 2012b), coma associated with mixed
the alveolarcapillary membrane (Anstey et al. 2002, 2007). requires further study. Over a P. falciparum P. vivax
Autopsy findings in P. vivax ARDS have shown heavy third of fatal cases in Manaus, infection (Manning et al.
intravascular monocytic infiltrates with diffuse endothelial and Brazil, had AKI (as part of 2012).
alveolar damage (Valecha et al. 2009) or interstitial infiltrates multiorgan dysfunction)
with predominantly neutrophils (Lacerda et al. 2012). While (Lacerda et al. 2012). The
alveolarcapil-lary parasites after peripheral blood clearance extent to which thrombotic Multiorgan dysfunction and
have been reported at autopsy in vivax-associated acute lung microangiopathy causes shock. The extent to which
injury (Lacerda et al. 2012), another severe vivax ARDS autopsy vivax-associated AKI multiorgan dysfunction and
did not show sequestration of parasitised red blood cells in the (Sharma et al. 1993; Saharan shock are attributable to
pulmonary vasculature (Valecha et al. 2009). As in acute lung et al. 2008; Sinha et al. 2012) sepsis-like inflammatory
injury in other disease settings, ARDS in vivax malaria probably is also not known. Elevated responses to P. vivax,
results from soluble mediators, diffuse alveolar-endothelial vWF and low levels of the concur-rent bacteraemia (Sur
capillary damage, exacerbated by shock, with increases in vWF-cleaving protein et al. 2006; Piyaphanee et al.
alveolar perme-ability and altered alveolar fluid clearance ADAM-TS13 occur even in 2007; Barber et al. 2012), or
(Suratt & Par- uncomplicated in vivax both, requires further
difficulties of discriminating
between P. vivax and P. fal-
ciparum, the relative safety of
species infections (Mayxay artesunate compared with
study. Negative blood cultures reported in some series are limited et al. 2001, Lampah et al. quinine, the high sensitivity
by widespread pre-hospitalisation use of anti-biotics in the 2011), with PCR used as a of P. vivax to artemisinins and
community, and the known insensitivity of pre-antibiotic blood delayed gold standard in ease of use and the
cultures in bacterial sepsis (Davis excluding misdiagnosis and operational benefits of a
et al. 2011). mixed infections. unified approach to the
Aggressive microbiological treatment of vivax and
Pregnancy-associated malaria and low birth- and radiological falciparum malaria (Douglas
weight. There are few reports of placental histopathology, investigations for alter- et al. 2010), the current
showing absent (McGready et al. 2004) or modest (Mayor et al. native causes (both unified policy of intravenous
2012) placental parasite burden. Placental histopa-thology shows infectious and non- artesunate for severe malaria
little (McGready et al. 2004) or no (Mayor et al. 2012) hemozoin infectious) of severe disease from all Plasmodium species
deposition, and largely absent inflammatory changes (McGready are essential. is pragmatic and appropriate
et al. 2004). Pathologi-cal mechanisms are unknown, but vivax- (Price et al. 2011). Other
associated microvascular dysfunction may cause deleterious Management of severe vivax supportive care for severe
utero-placental haemodynamic effects and foetal growth restric- malaria malarial manifestations,
tion (McGready et al. 2004; Rogerson et al. 2007; Umbers et al. including transfusion,
2011; Rijken et al. 2012b). Maternal anaemia, com-mon in vivax In the absence of comparative intravenous antibi-otics,
malaria (Poespoprodjo et al. 2008; Rijken drug trials in severe vivax vasopressor support, dialysis
et al. 2012a), is likely to be an additional contributor to low malaria, when it does occur, and invasive ventila-tion as
birthweight (Rogerson et al. 2007). severe disease in vivax needed, should be given as
malaria has been managed in per recommendations for
the same way as severe fal- severe falciparum malaria.
Diagnosis and definition of severe vivax malaria
ciparum malaria (World
The recent series from Brazil suggests that criteria in pre-vious Health Organization 2010a;
WHO Guidelines for severe falciparum malaria (World Health Price et al. 2011). Both
Organization 2000, 2010a) are sensitive in identifying children quinine (Tjitra et al. 2008)
requiring intensive care admission (Lanca et al. 2012) and in and artesunate (Tjitra et al. Epidemiological or
research definition of
identifying patients at risk of death (Lacerda et al. 2012). Criteria 2008; Kochar et al. 2010;
severe vivax malaria
for severe vivax malaria (Box) are the same as for severe Lampah et al. 2011; Barber et
falciparum malaria with the exclusion of parasite density al. 2012) have been used
successfully. Therapeutic As for the criteria for
thresholds. This is because of the unclear association to date
responses in uncomplicated adults and children
between parasitaemia and disease severity and outcome in
with severe falciparum
P. vivax malaria, and the greater propensity for P. vivax to vivax malaria are
malaria but with no
destroy uninfected red cells. significantly faster following
parasitaemia
Microscopy remains the gold standard for the immedi-ate artesunate. Given the
thresholds and without
diagnosis of P. vivax infection in severe disease. The sensitivity importance of starting highly a criterion of
of parasite LDH-based rapid antigen tests for P. vivax has effective schizon-tocidal
hyperparasitaemia.
improved recently (who.int/tdr/publications/ tdr-research- treatment as quickly as
publications/rdt_round3/pdf/rdt3.pdf), with high sensitivity possible in severe falcipa-rum
reported in severe vivax malaria (Barber et al. 2013a). P. malaria, the magnitude of the
falciparum -specific HRP2 rapid antigen tests have proved benefit of artesunate
useful in identifying occult mixed compared to quinine in severe
falciparum malaria, the
et al. 2009). In a retrospective
tertiary referral centre study
in Sabah, 39% of P. knowlesi
et al. 2012; Rajahram admissions had severe
et al. 2012). Most malaria, with a case-fatality
Section 14: Severe knowlesi malaria cases of P. knowlesi rate in severe disease of 27%
have been reported in (William
The simian parasite, Plasmodium knowlesi, was first shown to
adults, although
be transmissible to humans in 1932 (Knowles & Das Gupta
uncomplicated malaria and
1932) and has more recently been identi-fied as a common cause et al. 2011). Reported case-
severe anaemia have also
of human malaria in Malaysian Borneo (Singh et al. 2004; Cox- fatality rates in quinine-trea-
been described in children
Singh et al. 2008; Daneshvar et al. 2009; William et al. 2011; ted severe disease of 2027%
(Barber et al. 2011). Clinical
World Health Organization 2011a,b; Barber et al. 2012; Rajah- are comparable to those
features of uncomplicated
ram et al. 2012), with isolated reports from elsewhere in South- reported in severe falciparum
knowlesi malaria are indistin-
East Asia. The potential of P. knowlesi to cause severe disease malaria (South East Asian
guishable from other species
was originally suggested by experimental simian and human Quinine Artesunate Malaria
(Daneshvar et al. 2009; Bar-
infections (Ciuca et al. 1955, 1964; Chin et al. 1968; Coatney et Trial (SEAQUAMAT) Group
ber et al. 2012).
al. 1971; White 2008). The full asexual life cycle takes only 1 2005). While age, female
day, so expansion of the infection can be very rapid. In total, 86 gender, parasitaemia,
human cases of severe and/or fatal knowlesi malaria have been schizonta-emia and severity
reported since 2008 (Cox-Singh et al. 2008, 2010; Daneshvar et Severe malaria in adults of thrombocytopenia have
al. 2009; Lee et al. 2010a; William et al. 2011; Barber et al. been associ-ated with a higher
Of the 86 cases of naturally
2012, 2011; Fatih et al. 2012; Rajah-ram et al. 2012). risk of both severe disease
acquired severe human
and death (Daneshvar et al.
P. knowlesi infection reported 2009; Lee et al. 2010a; Cox-
between 2008 and 2012, all Singh
were from Malaysia of which
19 were fatal (Cox-Singh et et al. 2011; William et al.
Transmission and epidemiology 2011; World Health Organiza-
al. 2008, 2010; Daneshvar et
The natural monkey hosts (long-tailed and pig-tailed macaques) al. 2009; Lee et al. 2010a; tion 2011a,b; Barber et al.
William et al. 2011; Barber et 2012; Rajahram et al. 2012);
and mosquito vectors (Anopheles leucosphyrus group) for P.
on multivariate analysis, only
knowlesi extend across South-East Asia from eastern India and al. 2012; Fatih
parasitaemia and schizonta-
southern China to Indonesia (Singh & Daneshvar 2013). While et al. 2012; Rajahram et al.
emia >10% were independent
this area has a population of approximately 500 million people 2012), with progression to
predictors of severe disease
poten-tially at risk of P. knowlesi infection, and thousands of death occurring in as little as
(Barber et al. 2012). Risk of
cases have been reported from Malaysia, the true burden of 3 days after symptom onset
severe disease from
disease is not known. Human P. knowlesi infections have also (Cox-Singh et al. 2008).
been reported from ChinaMyanmar (Jiang Knowlesi malaria is P. knowlesi occurs at
lower parasitaemias than
et al. 2010), Thailand (Jongwutiwes et al. 2004; Putap-orntip et associated with a high risk of
with P. falciparum,
al. 2009; Jongwutiwes et al. 2011; Sermwittayawong et al. 2012), severe disease. In the largest
increasing 11-fold with
Vietnam (van den Eede et al. 2009), Cambodia (Khim et al. prospec-tive series, from a
parasitaemia >20 000/ll
2011), Philippines (Luchavez et al. 2008), peninsular Malaysia referral hospital in Sabah, and 28-fold with
(Fong et al. 1971; Cox-Singh et al. 2008; Lee et al. 2010a), 29% of knowlesi infections parasitaemia >100 000/ll
Indonesia (Figtree et al. 2010; Sulistyaningsih et al. 2010) and were severe and P. knowlesi (Barber et al. 2012).
Sin-gapore (Ng et al. 2008), although concerns have been raised infection was associated with
Multiorgan failure is
regarding specificity of the PCR assays used in the studies of a threefold greater risk of
common in severe knowlesi
archival samples (Imwong et al. 2009). severe malaria than P.
malaria (Cox-Singh et al.
falciparum (Barber et al.
2008, 2010; Daneshvar et al.
2012). In a prospective
2009; William et al. 2011;
district hospital-based study
Clinical spectrum Barber et al. 2012; Rajahram
in Sarawak, 9% of patients et al. 2012). In one series,
Plasmodium knowlesi causes disease ranging from with P. knowlesi developed 59% had respiratory distress;
uncomplicated to severe and fatal malaria (Cox-Singh et al. severe malaria, with a case- 55%, acute renal failure; and
2008, 2010; Daneshvar et al. 2009; Lee et al. 2010a; William fatality rate of 2% (95% CI 55% shock (William et al.
et al. 2011; Barber et al. 2012; Fatih 0.26.6%) over-all and 20%
in severe disease (Daneshvar
Non-severe knowlesi
malaria has a lower median
para-sitaemia than non-
tological examination severe P. falciparum,
2011). In non-artemisinin-treated patients, the propor-tions with (Praba-Egge et al. 2002). A indicating a lower fever
hypoxaemia-associated respiratory distress and ARDS (5970%) similar histopathological threshold (pyrogenic density)
(Daneshvar et al. 2009; William et al. 2011) and shock (William appearance of widespread with P. knowlesi than with P.
et al. 2011) are higher than that reported in larger series of adult microvascu-lar accumulation falciparum (Barber et al.
severe falciparum malaria (Lichtman et al. 1990; Aursudkij et al. of parasitised and non- 2012), which may sug-gest a
1998; Bruneel et al. 2003; Krishnan & Karnad 2003; Yeo et al. parasitised ery-throcytes greater inflammatory
2007; Dondorp et al. 2008a). However, ARDS is significantly without platelet aggregation response per parasitised red
less common in knowlesi malaria series trea-ted with has been reported in multiple cell, as seen with P. vivax
artemisinins (Barber et al. 2012). Severe anae-mia is seen in both organs, including the brain, (Ross & Thomson 1910; Yeo
adults (Barber et al. 2012) and children (Barber et al. 2011). in a single autopsy report of et al. 2010a). In keeping with
Metabolic acidosis, black-water fever, jaundice and an adult human who died this, the neutrophil count is
hypoglycaemia have also been reported (William et al. 2011; from positively associated with
Barber et al. 2012). P. knowlesi multiorgan failure both P. knowlesi parasitaemia
without coma (Cox-Singh et (Cox-Singh et al. 2008;
al. 2010). Although P. William et al. 2011; Barber et
knowlesi-infected al.
Clinical spectrum in children
erythrocytes have been 2012) and disease severity
A single small series to date describes mostly uncompli-cated shown to bind to ICAM-1 in (Cox-Singh et al. 2008;
disease in older children (Barber et al. 2011). As in adults, vitro (Fatih et al. 2012), William et al. 2011; Barber et
thrombocytopenia is nearly universal, with 94% having ICAM-1 was not detected on al. 2012). Consistent with a
thrombocytopenia at diagnosis and 100% by day one of brain endothelium in this greater inflammatory
treatment. Anaemia is common, with 71% having haemoglobin autopsy, and no electron response to P. knowlesi is a
<10 g/dl. Severe anaemia has also been reported (Barber et al. microscopy studies of greater fre-quency of acute
2011). endothelial cytoadherence respiratory distress syndrome
have yet been reported. Early in non-arte-misinin-treated
microvascular imaging severe knowlesi than in
Pregnancy severe falciparum malaria
studies of severe malaria in
Severe disease has been reported in pregnancy, associated with rhesus monkeys showed (William et al. 2011). Plasma
intrauterine death (William et al. 2011). In one small series, two progressive intravascular concentrations of the pro-
(18%) of women requiring hospital admission with knowlesi agglutination of knowlesi- inflammatory cytokine,
malaria were pregnant (William et al. 2011). Pregnancy may be a infected red cells, with TNFa, are associated with
risk factor for severity as in falciparum malaria, but larger microvascular endo-thelium knowlesi disease severity, but
studies are needed. becoming sticky to and levels of the anti-inflamma-
solidly coated with, leu- tory cytokine IL-10 are not
cocytes (Knisely & (Cox-Singh et al. 2011).
Pathophysiology Peptic ulceration has been
Stratman-Thomas 1945,
reported in severe knowlesi
Little is known about the pathophysiology of human knowlesi 1948). Microvascular
malaria (Cox-Singh et al.
malaria. Plasmodium knowlesi has important differences from P. sludging of blood flow was
associated with greatly 2008; Lee et al. 2010a;
falciparum, including the 24-h blood-stage cycle (Knowles &
slowed capillary circulation Barber et al. 2012) and could
Das Gupta 1932), and conse-quent potential for more rapid
indicate gut ischaemia (White
multiplication and pro-gression to death (Cox-Singh et al. 2008). rates before death (Knisely
& Stratman-Thomas 1945, 2008). Concurrent Gram-
In simian studies, P. knowlesi infection in the long-tailed
negative bacteraemia has also
macaque, a natural host, is associated with mild clinical disease 1948). The absence of coma
in severe knowlesi malaria been reported (William et al.
or asymptomatic carriage, while infections in the non-natu-ral
suggests dif-ferent 2011; Rajahram et al. 2012),
simian hosts such as the rhesus macaques and olive baboons
but the true incidence of co-
result rapidly in death (Coatney et al. 1971; Ibi-woye et al. 1993; mechanisms and/or
infection and its contribution
Praba-Egge et al. 2002). Experimental inoculation of P. knowlesi consequences of parasite
accumulation in brain to severe disease is not
into olive baboons results in increased pro-inflammatory
known.
cytokine concentrations with widespread vascular congestion microvasculature with P.
of the capillaries with cellular necrosis in multiple organs knowlesi compared to the
demonstrated on his- cytoadherence-mediated Thrombocytopenia is
sequestration occurring in associated with the severity
of both falciparum and
severe P. falciparum malaria. knowlesi malaria
(Daneshvar et al.
2014 WHO. Tropical Medicine and International Health is published by John Wiley & Sons., 19 (Suppl. 1), 7131 93
(SEAQUAMAT) Group
2005), parenteral artesunate
is the treatment of choice for
Treatment of severe knowlesi severe P. knowlesi infection
2009; William et al. 2011; Barber et al. 2012), but patients malaria (Barber et al. 2012). Other
infected with non-severe P. knowlesi have a more profound supportive care, including
Both quinine (Cox-Singh et
thrombocytopenia than patients with non-severe falciparum transfusion, intravenous
al. 2008; Daneshvar et al.
malaria (Daneshvar et al. 2009; William et al. 2011; Barber et antibiotics, vasopressor
2009; William et al. 2011)
al. 2012). Whether this reflects platelet activation contributing support, dialysis and
and more recently, artesunate
to pathophysiol-ogy (William et al. 2011) or consumption as invasive ventilation as
(William et al. 2011; Barber
part of a beneficial antiparasitic response (Cox-Singh et al. needed, should be given as
et al. 2012) have been used.
2011) has not been determined. In one series, the only knowle- per recommendations for
Chloroquine usage following
si-infected patients who did not develop thrombocytope-nia had severe falciparum malaria.
misdiagnosis as P. malariae
had previous splenectomy (Barber et al. 2012), suggesting a and delayed parenteral
role for the spleen in platelet clearance. therapy have both been
associated with fatal
Diagnosis and definition of severe knowlesi malaria outcomes (Cox-Singh et al.
Definition of severe
2008; Rajahram
malaria in P. knowlesi
Mature trophozoites and schizonts of P. knowlesi are et al. 2012). In a retrospective infection
indistinguishable on thick film microscopy from P. mala-riae and review of treatment responses
subtle differences on thin film microscopy can-not distinguish in severe knowlesi malaria, Research definition
the species reliably (Lee et al. 2009b; World Health Organization artesunate-treated patients
As for severe
2011a,b). Ring forms resem-ble P. falciparum leading to further had faster parasite clearance falciparum malaria (see
misdiagnosis (Cox-Singh et al. 2008; Lee et al. 2009b; World times, and the case-fatality Table 4) but with
Health Organization 2011a,b). Misdiagnosis as P. vivax also rate (17%) was lower than in modified parasitaemia
occurs (Cox-Singh et al. 2008; Barber et al. 2013b). All cases of those who received quinine cut-offs:
malaria in knowlesi-endemic areas diagnosed as P. malariae (31%) (William et al. 2011), 1 Parasite density >100
should be treated immediately as P. knowlesi pending PCR-based although the study was not 000/ll
diagnosis at a reference laboratory. Parasite LDH-based rapid 2 Jaundice and
parasitaemia >20 000/ll
powered to demonstrate a
antigen tests are not specific and insufficiently sensitive overall statistically significant Clinical definition
in P. knowlesi infections, although high sensitivity has been mortality advantage. In the requiring treatment with
reported in severe knowlesi malaria (Barber et al. 2013a). largest prospective study of intrave-nous artesunate:
severe knowlesi malaria, 1 Inability to tolerate oral
therapy
The research definition of severe malaria (Box), based on early referral protocols and
those used for severe P. falciparum malaria, is derived from stan-dardised (including pre- 2 Warning signs or
clinical severity
severe knowlesi malaria series to date (Daneshvar et al. 2009; referral) use of intravenous criteria as per
severe falciparum
William et al. 2011; Barber ar-tesunate were associated malaria
et al. 2012), with relatively high specificity. The para-sitaemia with zero mortality (Barber 3 Parasitaemia >20
threshold defining hyperparasitaemia in 000/ll
et al. 2012). Given the clear
P. knowlesi is >100 000/ll (compared to >10% with P. mortality advantage in *In settings where
falciparum) with a parasitaemia threshold of 20 000/ ll for severe falciparum malaria, clinical or laboratory
jaundice (compared to >100 000/ll with P. falci-parum). In criteria of severity
faster parasite clearance
clinical settings where laboratory assessment of severity criteria time than quinine in P. cannot be assessed.
is not readily available, a practical clinical definition for severity knowlesi (William et al.
requiring treatment with intravenous artesunate is inability to 2011), dem-onstrated
tolerate oral ther-apy, any clinical or laboratory severity criteria efficacy in severe knowlesi
used for malaria (William et al. 2011;
falciparum malaria or any parasitaemia >20 000/ll. The latterBarber et al. 2012), safety
parasitaemia cut-off is more sensitive but less spe-cific for severe and ease of use (South East
disease, but nevertheless predicted an 11-fold greater risk of Asian Quinine Artesunate
severe disease in the largest series to date (Barber et al. 2012). Malaria Trial
drolysed rapidly in vivo to the
active metabolite DHA. This
reaction can also occur ex
iron (and other reactive vivo (i.e. after collection)
cations) (Lindegardh et al. both through chemical
Section 15: Pharmacology of 2011, 2008). Thus, inherent hydrolysis and esterase
antimalarials in severe malaria
properties of these drugs mediated hydrolysis and thus
Severe malaria is a medical emergency requiring immediate necessary for their potent bias the analytical results
administration of rapidly effective antimalarial drugs. In the antimalarial activity also (Linde-gardh et al. 2008).
largest randomised trials ever conducted in severe malaria, the create serious problems for Anticoagulants containing
artemisinin derivative artesunate proved to be markedly superior quantification in biological fluoride inhibit esterase
to quinine in the parenteral treatment of severe malaria and is samples. Early methods using hydrolysis but not chemical
therefore now the treatment of choice for all patients (Dondorp et UV detection following post- hydrolysis. All artemisinin
al. 2005a, 2010) (Figure 23). Artesu-nate has also considerably column online derivatisation derivatives are thermolabile
simplified the treatment of severe malaria, as it can be given by reached limits of detection at with improved stability at
intravenous or intramuscular injection, has a simple dose 30 ng/ ml (Edlund et al. lower temperatures (e.g. 4 C
regimen and requires no dose adjustments. If parenteral 1984; Batty et al. 1996). or ice). Stability of these
artesunate is not available, then intramuscular artemether is Electrochemi-cal detection drugs in plasma varies with
second choice and quinine third. For pre-referral treatment in the (ECD) methods, which are source. Some methods have
community, a rectal formulation of artesunate has been notoriously diffi-cult, were carried out the bioanalytical
developed with satisfac-tory absorption kinetics. Given in the used more widely and work on ice to minimise
community before referral to hospital, this reduced the mortality reached detection limits of degradation, while others
of severe malaria in children by 25% (Gomes et al. 2009). As the about 10 ng/ml (Navaratnam have con-ducted analysis at
malaria parasites causing illness are confined to the blood, it is et al. 1997; Na-Bang-chang ambient temperature.
the concentrations of antimalarial drugs in blood that determine et al. 1998). An indirect Artemisinins are relatively
the therapeutic response. Severe malaria affects the absorption, approach using a sensitive stable in haemolysed plasma
disposition, metabolism and elimination of many drugs. Reduced but non-specific bioassay was but are degraded rapidly
visceral blood flow (Molyneux et al. 1987; Pukrittayakamee et also used in early pharma- when they come into contact
al. 1992, 1994) and microvascu-lar sequestration may reduce oral cokinetic studies (Teja- with organic sol-vents during
and intramuscular drug absorption, respectively. Fortunately, the Isavadharm et al. 1996; sample processing
effects on paren-teral artesunate pharmacokinetics are relatively Bethell (Lindegardh et al. 2011). The
small. et al. 1997; Newton et al. result is that analysis of these
2000). None of these methods drugs in haemolysed samples
Mechanism of action provide sufficient sensitivity or samples containing active
and specificity for accurate haemolytic products are
The exact mechanism of antimalarial action of artemisinin drugs characterisation of the biased (concentrations usually
is still unknown, but a reduction of the reactive per-oxide bridge pharmacokinetic properties of underestimated) unless the
and the production of free radicals or other reactive these drugs. The preferred method uses a suitable
intermediates are thought to be essential for anti-malarial method for quantification of internal standard (i.e. stable
activity (Jansen & Soomro 2007; Haynes et al. 2010, 2012, the artemisinins [artesunate, isotope labelled artesunate,
2011). The ferrous ion (Fe++) in haem appears to be important artemether, artemotil and di- artemether or DHA) that
for bioactivation as activity is reduced in the presence of iron hydroartemisinin (DHA)] is compensates fully for this. In
chelators (desferrioxamine). Quinine is thought to interfere with liquid chromatography tan- general, these confounders
haem detoxification (as do other quinolines and structurally dem mass spectrometry (LC- result in underestimation of
related compounds). MS/MS), which reaches the drug concentrations. In
quantification limits of about summary, multiple pitfalls in
1 ng/ml using only 50 ll sample separation, storage,
Drug measurement plasma (Naik et al. 2005; Gu preparation and analysis have
Antimalarial drug measurement has improved substan-tially in et al. 2008; Lindegardh undoubtedly contributed to
recent years. Pharmacokinetic studies in severe malaria need to et al. 2008, 2011; the large intersubject
be interpreted in the light of these advances. Artemisinins have Hanpithakpong et al. 2009; variation in plasma
posed particular measurement challenges. The peroxide bridge Hodel concentration profiles
needed for antimalarial activity renders the artemisinins unstable et al. 2009). Artesunate, the reported, and the derived
and, in particular, susceptible to degradation mediated by most widely used of the arte- pharmacokinetic parameters
misinin derivatives, acts as an quoted for these drugs.
ester pro-drug and is hy-
have lower exposures to both
artesu-nate and DHA given a
standard weight adjusted dose
reportedly well tolerated and of parenteral artesunate than
Quinine has been measured using increasingly sensitive and had estimated bioavailabili- older children and adults
precise methods over the past 70 years. The initial ties of 36% and 40%, and a (Hendriksen et al. 2013b)
spectrophotometric methods developed over sixty years ago mean (SD) time to peak (Figures 28 and 29). In a
could not distinguish the parent compound from the metabolites concentration of 4.1 (2.4) and recent large population,
and substantially overestimated the correct values. The extraction 2.7 (0.4) h, respectively, in pharmacokinetic study of
fluorescence method introduced in 1963 was a significant children with moderately artesu-nate from Tanzania
improvement but still overesti-mated concentrations, as the severe malaria from Niger children weighing between 6
hydroxylated metabolites were not distinguished (this was more (Bar-ennes et al. 1995). In a and
of a problem in uncomplicated than in severe malaria) (White et later study, rectal
al. 1982; Edstein et al. 1983). Then, in the early 1980s, specific bioavailability of quinine in 10 kg body weight had 20%
HPLC methods with fluorescence detection were intro-duced, moderate severity malaria lower DHA exposure than
and finally in recent years, LC-MS methods have been used. was shown to be dose- children between 21 to 25 kg
dependent falling from 96% body weight, suggesting that
with a dose of 8 mg/kg to a higher dose is needed for
52% at 16 mg/kg (Pussard et young children (Hendrik-sen
Antimalarial drug absorption
al. 2004). et al. 2013b). In contrast, in
In severe malaria, the oral route is unreliable and in children with severe malaria
unconscious patients may be dangerous as aspiration of gastric Antimalarial drug disposition less than 2 years old, quinine
contents may occur. Fortunately, the absorption of artesunate concentrations were higher
or quinine after intramuscular injection is good even in severe The apparent volume of than in older children and
malaria (Waller et al. 1990; van Hensbroek et al. 1996; distribution of the artemisinin adults (van Hensbroek et al.
Krishna et al. 2001a; Nealon et al. 2002; Hien et al. 2004; derivatives is not greatly 1996).
Hendriksen et al. 2013c), affected by malaria, whereas
and this is an acceptable alternative route to intravenous for quinine, there is a marked
administration for these drugs. Parenteral artemether and contraction in proportion to
Antimalarial drug clearance
artemotil are oil-based injectates which can be given only by disease severity (White et al.
intramuscular injection. Absorption is slow and erratic and may 1982). This is explained in Artesunate, artemether,
be dangerously slow in some patients with severe malaria part by increased plasma artemotil are all converted in
(Murphy et al. 1997; Hien et al. 2004; Li et al. 2004). This protein binding of the basic vivo to the active metabolite
explains why they are inferior to intra-venous artesunate in qui-nine to the acute phase dihydroartemisinin, which is
severe malaria (Phu et al. 2010). Suppository formulations of reactant a1-acid glycoprotein. then inactivated by
artesunate, artemether and artemisinin are available in some Binding increases from 85 to glucuronidation (principally
countries. In a very large community-based trial, intrarectal 90% to approximately 93% in via UGT1A9 and UGT2B7)
artesunate (recto-cap ) given at a community level before referral severe malaria (Silamut et al. (Ilett et al. 2002a). The
to hospi-tal reduced malaria mortality in children by 25%, 1985; Mansor et al. 1991). principal route of artemisinin
particularly in patients who took many hours to reach hospital Thus, the free fraction in clearance is by
(Gomes et al. 2009). Rectal bioavailability of artesunate given as severe malaria is often less biotransformation to inactive
a gel-filled capsule (artesunate recto-cap ) averages than half that in healthy metabolites. Cytochrome
approximately 50% although there is con-siderable subjects. Concentrations of P450 3A4 activity is impaired
interindividual variability (see below) (Krishna et al. 2001b; quinine and DHA in in malaria, which reduces
Simpson et al. 2006). Intrarectal administra-tion of artesunate in cerebrospinal fluid in cerebral conversion of arteme-ther and
a gel-filled capsule is simple, safe and well tolerated. Quinine malaria are both <10% of artemotil to DHA and also
and Quinimax (a buffered mixture of Cinchona alkaloids corresponding plasma reduces metabolic clearance
comprising 96.1% qui-nine, 2.5% quinidine, 0.68% cinchonine concen-trations (White et al. of quinine (Pukrittayakamee
and 0.67% cinchonidine) have been also administered 1982; Davis et al. 2003). et al. 1997). Renal
intrarectally. Unbuffered quinine is irritant when instilled Drug exposure in young impairment does not affect
rectally, whereas Quinimax is generally well tolerated; rectal children with severe malaria clearance of the artemisinins
quinine gluconate as a cream and the commercial mixture of is lower than that in older
Cinchona alkaloids, Quinimax , in solution, was children and adults. Young
children with severe malaria
a relatively small
geographical area at present,
but if artemisinin resistance is
means that this class of drug suspected, then both
but reduces elimination of quinine and its main biologi-cally is not appropriate for severe artesunate and quinine should
active metabolite 3-OH quinine. In renal failure, 3-OH quinine malaria management. be given together in full doses
concentrations reach 45% of those of the parent compound, Although quinine resistance (Newton et al. 2001a).
thereby contributing 12% of the anti-malarial activity (Newton has been discussed for over a
et al. 1999). century, and there is Pharmacology of
undoubtedly reduced antimalarial drugs
Antimalarial pharmacodynamics susceptibility to quinine in P.
falciparum in parts of South- Artemisinin, also known as
The primary objective of antimalarial treatment in severe malaria East Asia and South America, qinghaosu, is a sesquiterpene
is to inhibit the development of, or to kill, a suffi-cient number of there is no hard evi-dence that lactone extracted from the
parasites to prevent death. After antimalar-ial drug treatment, the this has translated into an leaves of Artemisia annua
reduction in parasite numbers is fractional thus provided increase in quinine-treated (sweet wormwood). It has
minimum parasiticidal concen-trations are exceeded, a fixed mortality in severe malaria. In been used in China for the
fraction of the parasite bio-mass is killed per asexual cycle; a Thailand, where multidrug- treatment of fever for more
first-order process (White 1997, 2011). However, in severe resistant P. falciparum is than 2000 years. It is a potent
malaria, it is the drug effects on the current asexual cycle that are prevalent, coma recov-ery and rapidly acting blood
paramount, and drug effects on subsequent cycles are of less times and parasite clearance schizontocide and is active
importance. The pharmacodynamic properties of the antimalarial times were noted to lengthen against all Plasmodium
drugs can be described in terms of the stage specificity of their between 1981 and 1992, but species. It has an unusually
antiparasitic action during the asexual life cycle. The con- mortality did not increase broad activity against asexual
centrationeffect relationships and their maximal effects differ (Pukrittayakamee et al. 1994). malaria parasites (ter Kuile et
between the drugs. All antimalarial drugs kill the mature Occasional early treatment al. 1993), killing all stages
trophozoite stages of susceptible plasmodia. Once schizonts are failures do occur, but usually from young rings to schizo-
formed, their effects are much less. Only the artemisinins kill the can be explained by unusual nts. In P. falciparum malaria,
young circulating ring stages and thereby prevent their pharmacokinetics resulting in artemisinin also kills the
sequestration (ter Kuile et al. 1993; Watkins et al. 1993; low drug concen-trations gametocytes including the
Udomsangpetch et al. 1996). Evidence from the recent large (Looareesuwan et al. 1990; stage 4 and early stage 5 ga-
SEAQUAMAT and AQUAMAT trials indicates that the Newton et al. 2005b). There metocytes, which are
substantial life-saving advantage of ar-tesunate over quinine is is no convincing evidence for otherwise sensitive only to
explained by its parasiticidal effects on circulating ring-stage high-grade resistance primaqu-ine. The peroxide
parasites, preventing their develop-ment and sequestration anywhere in the world, so bridge is essential for
(Dondorp et al. 2005a, 2010; Caramello et al. 2012). The action quinine can still be relied antimalarial activity, but the
of both drugs on the sequestered parasites is similar, although upon everywhere in the exact mechanism of action
artesunate may also have a greater effect on mature schizonts. treatment of severe malaria. remains unknown.
The critical advantage of artesunate is reflected in the shape of The suscep-tibility of P. Artemisinin is the parent
the para-site clearance curve. Following artesunate, the decline in falciparum in Western compound, and it is still
parasitaemia is more rapid compared with quinine and any Cambodia and along the available in some areas in a
increase or plateau phase before the log-linear decline in parasite ThailandMyanmar border to suppository formulation and
numbers is attenuated (White 1997, 2011). This advantage is lost artemisinins has declined, and is still used orally in some
in artemisinin resistant parasites (Dondorp et al. 2009). In this is manifested by reduced ACTs, but it has now lar-gely
addition, the artemisinin derivatives gener-ally have a wide parasiticidal effects against given way to the more potent
therapeutic index, whereas the quinoline antimalarial drugs have younger circulating parasites dihydroartemisinin (DHA)
a narrow therapeutic index. (Saralamba and its derivatives,
et al. 2011; Phyo et al. 2012), artemether, artemotil and
which suggests that the life- artesunate. All three are
saving benefit of artesunate formulated for parenteral
Antimalarial drug resistance could be compromised. How- admin-istration in severe
ever, the extent to which this malaria. The DHA derivatives
Chloroquine resistance fatally compromised the efficacy of this are all
previously highly effective drug in severe malaria. Aside from compromises artesunate in
widespread resistance, the very late-stage activ-ity of antifols severe malaria has not been
(affecting the formation of the early schizont) determined. Fortunately,
resis-tance is still confined to
methods have generally given
more reliable assays and
therefore more reliable
acid with a separate pharma-cokinetic estimates.
converted back in vivo to DHA. For artesunate, this back ampoule of 5% Artesunate is rapidly
conversion is very rapid and DHA accounts for the majority of sodium bicar-bonate absorbed, with peak plasma
antimalarial activity in severe malaria. solution. levels occurring 0.5 h after
1 Rectal capsules intramuscular and 2 h after
containing 100 or 400 rectal administration (Nealon
Artesunate mg of sodium
artesunate. et al. 2002; Hendriksen et al.
Artesunate is the treatment of choice for severe malaria; it is the 2013a). Intramuscular
sodium salt of the hemisuccinate ester of dihyd-roartemisinin. Pharmacokinetics and bioavailability in Gabonese
Artesunate is soluble in water but has poor stability in aqueous pharmacodynamics. Early children with severe malaria
solutions at neutral or acid pH. In the most widely used meth-ods of assay for was estimated at a median of
injectable formulation, artesunate is formed by the addition of artesunate, artemether and 86%. Following rectal
sodium bicarbonate solution to freeze-dried artesunic acid dihydroarte-misinin were administration, bio-
immediately before dilution in isotonic dextrose or saline and difficult and techniques for availability is variable but
given by intravenous or intramuscular injection. Other sample preparation did not averages approximately 50%.
formulations are in devel-opment. Artesunate can be given orally, satisfactorily limit haem- Artesunate is rapidly and
rectally or by the intramuscular or intravenous routes. mediated degradation. As a almost entirely converted by
result, concentration
Formulations. measurements were
sometimes inaccurate. More
1 Ampoules for intramuscular or intravenous injection recent studies employ-ing
containing 30, 60 or 120 mg of anhydrous artesunic LC-MS/MS-based assay
DHA >24-36 months, rectal AS, 100 mg >24-36

months, IV AS
15,00 15,00
Rectal
artesunate
100m
g
given to
10,00 children 10,00
D H A (n M )
5,000 5,00
0 0
0 2 4 6 8
Intravenous
artesunate
2.4mg/kg given to
childre
n
0 2 4 6 8
metabolite, dihydroartemisinin
Artesunate (ARS) was
(DHA),
assumed
following
to be
derived
rectal
converted
from
or immediate
age-weig
Time (h) Time (h)
intravenous administration
completely to DHA.
of artesunate
Weight (Simpson
distributions
individuals
et al.
for2006).
each
(Taylor
age gro
et a
Figure 28
elimination half-life from 2 to
8 min across the differ-ent
study populations of healthy
volunteers, adults with vivax
malaria, adults with
falciparum malaria, children
with severe malaria and
Figure 29 Prediction-corrected venous log pregnant and post-partum
plasma concentrations based on a study of the
women. For DHA
population pharmacokinetics of artesunate and
dihydroartemisinin in 70 Tanzanian children concentrations following
with severe malaria (Hendriksen et al. 2013a). intravenous administration of
Open circles, observed data points; solid lines, artesunate, the median
5th, 50th and 95th percentiles of the observed volume of distribution ranged
data; shaded area, 95% confidence interval of from 9 to 108 l, the median
simulated
clearance from 9 to 62 l/h and
(n = 2000) 5th, 50th and 95th percentiles.
the elimination half-life from
Awad et al. 2004; Hien et al. 18 to 69 min across the
2004; Sirivichayakul different study populations.
blood esterases to DHA, the active metabolite. Thus, DHA
accounts for nearly all the antimalarial effect. DHA plasma et al. 2007; McGready et al.
protein binding is estimated at approximately 75%. Red cell 2012c; Hendriksen et al.
concentrations are lower than correspond-ing plasma 2013a,b). The median times Implications for dosing. No
concentrations (Lindegardh et al. 2011). DHA is eliminated to achieve maximum ar- dose modifications are nec-
mainly by conversion to inactive glu-curonides. Elimination of tesunate concentrations were essary in renal or hepatic
within a few minutes, 7 10
artesunate is very rapid, and antimalarial activity is determined impairment. The
min and 0.51 h (Halpaap et
by dihydroartemisinin elimination (half-life approximately 45 pharmacoki-netic properties
al. 1998; Siri-vichayakul et
min) (Simpson of intravenous artesunate are
al. 2007) and to reach
et al. 2006). This rapid rate of elimination means that also relatively unaffected by
maximum plasma, DHA
concentrations may fall below the minimum parasitical pregnancy. In a study of 70
concentrations were within
concentration for the infecting parasites during the dose interval. 12 min, 2540 min and 13 h Tanzanian children aged
This does not matter for sensitive parasites, as maximum killing for intravenous, between 6 months and 11
effects are obtained with approximately 4 h exposure, but in the intramuscular and rectal years who presented with
presence of artemisinin resistance may lead to submaximal administration, respectively. severe falciparum malaria,
effects if the majority of parasites are circulating young rings body weight significantly
The median artesunate AUC0-
with reduced susceptibility (Saralamba et al. 2011). This affected clearance and
was similar for all three apparent volume of
emphasises the importance of the second dose given at 12 h as an inf
routes of administra-tion; distribution (P < 0.001),
insurance policy in case the parasites were relatively refractory
5551269 ng 9 h/ml for resulting in lower
12 h earlier when the first dose was given. Evidence suggests
intravenous, 535
that severe malaria has relatively little effect on the disposition of
parenteral artesunate. Artesunate does not penetrate to the CSF
999 ng 9 h/ml for
whereas DHA concentrations averaged 8% of those in plasma intramuscular and 548
(Davis et al. 2003).
1076 ng 9 h/ml for rectal
Summarising the literature after intravenous artesu-nate doses administration. The median
of between 1.2 and 4 mg/kg, the observed median (or mean) AUC0-inf values for DHA
maximum plasma concentrations of artesunate ranged from 13 varied widely (partly because
685 to 29 677 ng/ml and for DHA ranged from 1280 to 3277 of different dosing). The
ng/ml. After intra-muscular doses of 1. to 2.4 mg/kg, plasma ranges of median DHA
artesunate ranged from 615 to 2195 ng/ml and plasma DHA ran- AUC0-inf values were 737 to
ged from 341 to 1166 ng/ml, and following rectal doses of 2 to 3 3298 ng 9 h/ml for
intravenous, 3962474 ng 9
mg/kg, 10 mg/kg and 20 mg/kg plasma artesunate ranged from h/ml for intramuscular and
90 to 561 ng/ml and plasma DHA ranged from 180 to 1535 726 to 9576 ng 9 h/ml for
ng/ml (Batty et al. 1998a,b; Halpaap et al. 1998; Navaratnam et rectal artesunate. The median
al. 1998; Sabchareon et al. 1998; Davis et al. 2001; Krishna vol-ume of distribution for
artesunate ranged from 5 to
et al. 2001b; Ilett et al. 2002b; Nealon et al. 2002; 53 l, the median clearance
from 35 to 213 l/h and the
CYP3A4. Autoinduction of
metabolism is less than with
artemisinin. After
Artemether intramuscular administra-
artesunate and dihydroartemisinin exposure in smaller children
(Hendriksen et al. 2013a) (Figures 26 and 29). This suggests that Artemether is the methyl Artemether (nmol/L)
weight-based dosing should be adjusted and doses increased in ether of DHA. It is more 20
young children (Table 10). lipid soluble than
artemisinin or artesunate. It
can be given as an oil-based
Toxicity. Artemisinin and its derivatives are safe and remarkably
intramuscular injection or 16
well tolerated. There have been reports of mild gastrointestinal
orally. It is also co-
disturbances, dizziness, tinnitus, re-ticulocytopenia, neutropenia, formulated with
elevated liver enzyme val-ues, allergic reactions, and lumefantrine (previously
electrocardiographic abnormalities, including bradycardia and called benf-lumetol) for 12
prolongation of the QT interval, although most studies have not combination therapy.
found any electrocardiographic abnormalities (Price et al. 1999;
Maude et al. 2009a). The only potentially serious adverse effect Formulations. 8
reported with this class of drugs is type 1 hypersen-sitivity
reactions in approximately 1 in 3000 patients (Leonardi et al. 1 Ampoules of injectable 4
2001). Neurotoxicity has been reported in animal studies oil for intramuscular
(Genovese & Newman 2008), particu-larly with very high doses injection containing 80
mg of artemether in 1 0
of intramuscular artemotil and artemether, but has not been ml for adults or 40 mg
substantiated in humans (Kissinger et al. 2000; Van Vugt et al. of artemether in 1 ml 0 4 8
for paediatric use.
2000; Hien et al. 2003). Similarly, evidence of death of embryos 12 16
and mor-phological abnormalities in early pregnancy has been
20 24
demonstrated in animal studies (Longo et al. 2006; Clark 2009). Pharmacokinetics and
Embryolethality occurs within a narrow time win-dow in early pharmacodynamics. T
pregnancy and is related to specific toxicity to primitive red Following intramuscular i
blood cell precursors. In experimental studies, limb injection in severe malaria, m
developmental abnormalities were observed in rodents, but not in absorption is very variable, e
primates (Clark 2009). There is no evidence these drugs cause especially in children with (
poor peripheral perfusion: h
abortion, stillbirth or develop-mental abnormalities in humans
peak plasma concentrations )
(McGready et al. 2012b).
generally occur after around 6
h, but absorption is slow and Figure 30 Individual
erratic and times to peak can concentrationtime profiles for
At doses higher than currently recommended the artemisinins be 18 h or longer in some artemether after the first
(6 mg/kg/day for 7 days) may cause tempo-rary neutropenia cases (Murphy et al. 1997; intramuscular dose of 10.7 lmol
(Bethell et al. 2010). Following the treatment of severe malaria Hien et al. 2004; Mithwani et (3.2 mg) of ARM/kg to 10
with artesunate, particularly in hyperparasitaemic patients, there al. 2004) (Figure 30). The patients with severe falciparum
malaria (Hien
may be a delayed but severe anaemia (Zoller et al. 2011; intrinsic activity of et al. 1996). Oval highlights
Kreeftmeijer-Vegter et al. 2012; Rolling et al. 2012). This is artemether is less than that of critical early period in which
attributed, at least partly, to the accelerated destruction of once DHA, which combined with some patients may absorb very
parasi-tised erythrocytes red cells which contained a parasite the very variable absorption little drug.
which was killed and then removed by the spleen (pit-ting) in severe malaria makes it an
(Angus et al. 1997; Newton et al. 2001b). Thus, this apparent inferior treatment to artesu-
adverse effect is a direct function of the life-saving effect of nate, but probably still better
artesunate in killing young parasites in circulating red cells than quinine in severe malaria
before they can cytoadhere (Udom-sangpetch et al. 1996). (Dondorp et al. 2010; Phu et
al. 2010). Artemether is
metabolised to DHA, the
Drug interactions. Artemisinin and, to a lesser extent, artemether active metabolite.
induce their own metabolism. There are no significant Biotransfor-mation is
interactions with other drugs. The antimalarial action of these mediated predominantly via
drugs is antagonised by desferrioxamine. the cytochrome P450 enzyme
available and extensively
used, and it needs to be kept
available in case artemisinin
1 These include: resistance worsens. The
tion, artemether predominates in the blood (Teja-Isavad-harm Suppositories mechanisms of quinines
containing 100, 200,
et al. 1996; Hien et al. 2004), whereas after oral administration 300, 400 or 500 mg antimalarial actions are
DHA predominates. Artemether is 95% bound to plasma of artemisinin. thought to involve inhibition
proteins. The elimination half-life is approximately 1 h, but of parasite haem
following intramuscular adminis-tration, the elimination phase Pharmacokinetics. Peak detoxification in the food
is prolonged considerably because of continued absorption. No plasma concentrations occur vacuole, but are not well
dose modifications are necessary in renal or hepatic around 3 h after oral and understood. Quinine can be
impairment. around 11 h after rectal given orally, rectally (if
administration. Artemisinin buffered), and by intra-
Toxicity. In all species of animals tested, intramuscular is converted to inactive muscular injection (to the
artemether and artemotil cause an unusual selective pattern of metabolites via the anterior thigh, preferably
neuronal damage to certain brain stem nuclei (Brewer et al. cytochrome P450 mixed diluted to a concentration of
1994). Neurotoxicity in experimental animals is related to the function oxi-dases notably 60100 mg/ml)) or by con-
sustained blood concentrations that follow intramuscular CYP2B6 and several other stant rate intravenous
administration, because it is much less frequent when the same enzymes. Arte-misinin is a infusion. Quinine should not
doses are given orally or with similar doses of water-soluble potent inducer of its own
be given subcutaneously
drugs such as ar-tesunate. Clinical, neurophysiological and metabolism. The elimination
because this can result in skin
pathological studies in humans have not shown similar findings half-life is approximately 1 h necrosis.
(Simonsson
with therapeutic use of these compounds (Kissinger et al. 2000;
Van Vugt et al. 2000 Hien et al. 2003). Toxicity is otherwise et al. 2003; Asimus et al.
2007).
similar to that of artemisinin.
Formulations.
Toxicity. As for artesunate.
Artemotil 1 Injectable solutions of
Drug interactions. None quinine hydrochloride,
known apart from quinine dihydrochloride
Artemotil is the beta ethyl ether of dihydro artemisinin and quinine sulphate
(arteether) and is very closely related to the more widely used autoinduc-tion. containing 82%, 82%
artemether. It is oil-based so is also water insoluble. A mixture of and 82.6% quinine base,
respectively.
a and b ethers is also available in India for intramuscular
administration. Artemotil and a b arteether are given by Quinine
intramuscular injection only. Pharmacokinetics and
Quinine is an alkaloid pharmacodynamics. The
derived from the bark of the pharma-cokinetic properties
Formulations.
Cin-chona tree. Four of quinine are altered
1 Ampoules containing 150 mg of artemotil in 2 ml of antimalarial alkaloids can be significantly by malaria
injectable solution. infection, with reductions in
derived from the bark:
apparent volume of
quinine (the main alkaloid by
Pharmacokinetics. There is substantially less published distribution and clearance in
weight), quinidine,
information on artemotil than for artemether. Absorption is proportion to disease sever-
cinchonine and cinchonidine.
slower and more erratic, with some patients having undetectable ity. In children under 2 years
Quinine is the L-stereoisomer of age with severe malaria,
plasma artemotil until more than 24 h after administration
of quinidine, which was used
(Afolabi & Okoromah 2004; Li et al. 2004; Pareek et al. 2006;
as an alter-native treatment of
Mukim et al. 2011).
severe malaria in temperate
countries where quinine was
Toxicity. As for artemisinin.
not readily available. Quinine
has been the mainstay of
Drug interactions. None known.
antimalarial treatment of
severe malaria for 350 years
Artemisinin but has now been overtaken
by the artemisinin
Formulations. A wide variety of formulations for oral,
parenteral and rectal use is available. derivatives. Nevertheless,
quinine is still widely
compartment model. The
mean (SD) volume of the
central compartment (Vc) is
mean (SD) time to peak also contracted from 0.7 (0.3)
Plasma quinine (g/L) concentration of 4.1 (2.4) and in healthy Thai adults to 0.17
1600 2.7 (0.4) h, respectively, in (0.1) l/kg in cerebral malaria
children with moderately (Davis et al. 1988). In
severe malaria from Niger Kenyan children with
(Barennes et al. 1995). These cerebral malaria, the
1200 solutions were reportedly estimated volume of the
well tolerated. Rectal absorp- central compartment was
tion is dose-dependent even smaller; 0.27 (0.1) l/kg
800 (Pussard et al. 1999, 2004). or 40% lower than the value
Rec-tal quinine proved in adults (Winstanley et al.
effective in childhood 1993). This explains why
400 cerebral malaria in a recent intravenous injections (as
trial although much larger opposed to infusions) of
trials would be needed for quinine are potentially so
definitive information, and
1 2 3 dangerous in severe
before this could be
Days infections. Quinine is
recommended widely. (Achan
distributed throughout most
et al. 2007).
Figure 31 Mean plasma quinine concentration profiles in adult patients of the body fluids. The mean
with severe falciparum malaria receiving a loading dose of quinine (20 concentration in erythro-cytes
mg salt/kg over 4 h) in the upper panel (blue), the predicted plasma is approximately one-third of
concentrations based on derived pharmacoki-netic parameters without a
Disposition. A single that in plasma, rising to one
loading dose (10 mg/kg/8 h) (green) and the predicted levels in the once
compartment model is
advocated 5 mg/kg/8 h regi-men (red). Note the decline in plasma half (presumably because of
adequate to define the concentration within malaria
concentrations after the first days of treatment as systemic clearance
disposition of quinine after
improves, and the volume of distribution expands (White et al. 1983c). parasites) in severe malaria
intravenous infu-sion. The (White et al. 1983a).
concentrations are slightly higher than in older children and total apparent volume of Concentrations in saliva and
adults (van Hensbroek et al. 1996). There is no evi-dence for distribution (Vdss) in healthy in breast milk are about 30%
dose-dependent kinetics. adult subjects ranges from 1.5 of those in plasma (Salako &
to 3.5 l/kg (White et al. Sowunmi 1992, Phil-lips et
Absorption. Quinine is preferably given by rate con-trolled 1982). This is contracted in al. 1986b). Cerebrospinal
intravenous infusion to patients with severe malaria (Figure 31) malaria proportional to the fluid concentrations are 7 3%
(White et al. 1982). Quinine is also well absorbed after severity of disease (to of those in plasma in cerebral
intramuscular injection in severe malaria. Intramuscular quinine approximately 1.7 l/kg in malaria (White
has good bioavailability even in very young children (<2 years) Thai adults with
with severe malaria (Shann et al. 1985; van Hensbroek et al. uncomplicated falciparum et al. 1982). These values are
1996; Hendriksen et al. 2013c). Overall, there is good agree- malaria and 1.2 l/ kg in adults approximately half those of
ment between recent studies in African children with moderately with cerebral malaria). free (unbound) quinine in
severe to severe falciparum malaria. The overall mean (SD) peak Similar changes are seen in plasma, which suggests that
plasma quinine concentration after the 20 mg/kg loading dose is global malnutrition (Pussard quinine does not freely
15.6 (5.2) mg/l et al. 1999). Plasma traverse the bloodbrain
concentrations for a given barrier (Silamut et al. 1985).
(N = 57) (White 1995b). This compares with an overall mean dose are therefore highest in Quinine is a base and the
(SD) peak quinine concentration after intravenous administration severe malaria. In Kenyan principal plasma protein to
of 15.2 (3.6) mg/l (N = 74). Absorption is more rapid and the children with severe malaria, which it binds is the acute
intramuscular injection is less painful if quinine dihydrochloride estimated mean Vdss values phase pro-tein, a1-acid
(usual concentration 300 mg/ml) is diluted 1:2 to 1:5 before were lower; 1.22 l/kg and glycoprotein (Mihaly et al.
injection. The plasma concentration profile after intramuscular 0.87 l/kg in severe and 0.45 1987; Silamut
admin-istration may be biphasic in some patients. Rectal qui- l/kg (Winstanley et al. 1993), et al. 1991). Plasma protein
nine gluconate as a cream and the commercial mixture of and 0.75 l/kg (Winstanley et binding is therefore increased
from approximately 85% in
Cinchona alkaloids, Quinimax , in solution, had estimated al. 1994) in cerebral malaria.
healthy subjects to 9093%
bioavailabilities of 36% and 40%, and a Quinine pharmacokinetics
can be described by a two
available evidence suggests a
therapeutic range of free
quinine con-centrations
3A4 such as between 0.5 and 2.0 mg/l
in severe malaria (i.e. the free fraction is reduced by one-third to phenobarbitone and (corresponding roughly to
one half). Thus, although total plasma concentra-tions are higher rifampicin (Pukritta- total plasma concentrations of
in severe malaria, free concentrations may be no different from yakamee et al. 2003). 520 mg/l (White 1995b).
those in patients with uncom-plicated infections or healthy Modelling suggested an in
subjects. Increased protein binding may explain why relatively Children and pregnant vivo minimum parasiticidal
high total plasma qui-nine concentrations (1020 mg/l) do not women. Absorption of concentration for Thai P.
cause major tox-icity in the treatment of severe malaria. The quinine is similar in children falciparum isolates of 3.5
relationship between quinine binding (expressed as the and adults. The total apparent mg/l (Pukrittayakamee et al.
association constant) and pH is hyperbolic such that binding falls volume of distribution and 2003). Total plasma
with pH to a nadir around pH 7 (Winstanley et al. 1993). There is the volume of the central concentrations between 8 and
no clinical evidence for increased toxicity of quinine in acidosis. compart-ment are smaller in 20 mg/l in severe malaria are
children (Waller et al. 1990; usually safe and effective
Pasvol et al. 1991; (White 1987, 1995b, White et
Elimination. Extensive metabolism via the cytochrome P450 Winstanley et al. 1993), and al. 1983c).
enzyme CYP3A4 occurs in the liver (Zhao et al. 1996), and pregnant women
elimination of more polar metabolites is mainly renal. The initial (Looareesuwan et al. 1985;
metabolite 3-hydroxyquinine may accumulate in renal failure. In Phillips et al. 1985) than in Pharmacodynamics. Quinine
healthy subjects and patients with malaria, quinine is adults with disease of acts principally on the
predominantly (80%) biotransformed (White et al. 1982) first to comparable severity, but mature trophozoite stage of
3 and 2 hy-droxyquinine and then to a series of more polar elimination is more rapid in parasite development and
water-soluble metabolites. Plasma concentrations of 3-hydrox- both groups. Systemic clear- does not prevent
yquinine are approximately one-third to one-fifth of those of the ance values are therefore sequestration or further
parent compound, with a lower ratio in malaria indicating similar. Cord blood development of circulating
impairment of hepatic biotransformation. 3-hy-droxyquinine concentra-tions and breast ring stages of P. falciparum.
contributes approximately 5% of antima-larial activity in acute milk concentrations are Like other struc-turally
malaria rising to 10% in convalescence (Nontprasert et al. 1996; approximately one-third of similar antimalarials, quinine
Pukrittayakamee et al. 1997) and 12% in renal failure (Newton et those in simultaneously also kills the sexual stages of
al. 1999). sampled maternal plasma P. vivax, P. malariae and P.
(Phillips et al. 1986b). ovale, but not mature
gametocytes of P.
Approximately 20% of the quinine dose is eliminated by the falciparum. It does not kill
kidneys and the remaining 80% by hepatic bio-transformation. Areas of uncertainty. It has the pre-erythrocytic stages of
Small amounts appear in the bile and saliva. Total systemic been suggested that there be a malaria parasites.
clearance is reduced in uncompli-cated malaria, and further ceiling dose above which
reduced in severe malaria (White et al. 1982; White 1987). quinine should not be given, Toxicity. Administration of
Renal clearance and hepatic clearance are reduced in parallel. but there is no evidence to quinine or its salts regularly
support this. In obese causes a complex of
The observa-tion that plasma quinine concentrations are high in
patients, dosing should be symptoms known as
patients with acute renal failure probably relates more to the
based on ideal rather than cinchonism, which is
overall severity of disease and the consequent pharmacokinetic
observed body weight characterised in its mild form
changes, rather than to a reduction in glomerular filtration rate
(Viriyayudhakorn et al. by tinnitus, impaired high-
per se. The mean terminal elimination half-life in healthy adult
2000). Studies in malnutrition tone hearing, headache,
subjects is 11 h, compared with 16 h in uncomplicated malaria,
have given variable findings, nausea, dizziness and dyspho-
and
but overall sug-gest that no ria, and sometimes disturbed
dose alterations should be vision. More severe manifes-
18 h in cerebral malaria. The clearance of quinine is reduced, made (Salako tations include vomiting,
and the elimination half-life prolonged from 11 to 18 h in the
et al. 1989; Treluyer et al. abdominal pain, diarrhoea
elderly (age 6574 were studied) (Wan-wimolruk et al. 1991).
1996; Pussard et al. 1999). and severe vertigo.
Quinine elimination is more rapid in smokers (Wanwimolruk et
The relationship between Hypersensitivity reactions to
al. 1993), although the relevance of this to severe malaria is
plasma concentrations and quinine range
uncertain. Qui-nine clearance is increased by drugs which induce
par-asiticidal effects in severe
CYP
malaria is unclear, but
7-day course with artesunate,
artemether or quinine. It
should never be used alone to
nine is actually generally treat malaria. It is available
from urticaria, bronchospasm, flushing of the skin and fever, well tolerated in the as the hydro-chloride salt or
through antibody-mediated thrombocytopenia and haemolytic treatment of malaria. phosphate complex, or as a
anaemia, to life-threatening haemolyticurae-mic syndrome complex pre-pared from the
(which is very rare). Massive haemolysis with renal failure Drug interactions. There is a hydrochloride and calcium
(black water fever) has been linked epi-demiologically and theoretical concern that drugs chloride.
historically to quinine, but its aetiology remains uncertain. that may prolong the QT
Severe concentration-related toxicity, including hypotension, interval should not be given Formulations.
myocardial conduction and repo-larisation disturbances, with quinine, although
blindness, deafness and coma, is very unusual in the treatment of whether or not quinine 1 Capsules and tablets
containing 100 mg of
malaria with plasma con-centrations under 20 mg/l increases the risk of doxycy-cline salt as
(Pukrittayakamee et al. 1994; White 1995b). Hypoglycaemia is a iatrogenic ventricular hydrochloride.
more commonly encountered problem. Quinine is a potent tachyarrhythmia has not been
stimulus to pan-creatic insulin secretion (White et al. 1983b), and established. Antiarrhythmics, Pharmacokinetics.
hyperins-ulinaemic hypoglycaemia is particularly likely in such as flecainide and Doxycycline is readily and
pregnant women (Looareesuwan et al. 1985) who have amplified amiodarone, should probably almost completely absorbed
responses to islet cell stimulation, or patients who remain be avoided. Quinine increases from the gastrointestinal
severely ill for several days. Half of quinine-treated women with the plasma concentrations of tract, and absorption is not
severe malaria in late pregnancy develop hypoglyca-emia during digoxin (Doering 1981; affected significantly by the
treatment. Intravenous injections may cause acute cardiovascular Wilkerson 1981). Cimetidine presence of food. Peak
plasma concentrations occur
toxicity, especially after rapid intrave-nous injection, presumably inhibits quinine metab-olism,
causing increased quinine 2 h after admin-istration.
because transiently toxic blood concentrations occur before
levels and rifampicin, phe- Some 8095% is protein-
adequate distribution (Davis et al. 1988). Quinine causes an
bound and the elimi-nation
approximately 10% pro-longation of the electrocardiograph QT nobarbitone, ritonavir and
half-life is 1024 h. It is
interval mainly as a result of slight QRS widening. The effect other enzyme inducers
increase metabolic clearance widely distributed in body
on ventricular repolarisation is much less than that with
tissues and fluids. In patients
quinidine. Intra-venous quinine should be given only by infusion, leading to low plasma
with normal renal function,
never injection. Overdosage of quinine may cause oculotoxicity, concentrations and an
increased therapeutic failure 40% of doxycycline is
including blindness from direct retinal toxicity, and cardio-
rate. Combination with other excreted in the urine,
toxicity, and can be fatal. Postural hypotension is common in
antimalarials, such as the although more if the urine is
acute malaria, and this is exacerbated by quinine.
artemisinins, lumefan-trine, alkalinised. It may accumu-
Thrombocytopenia, Coombs positive haemolytic anaemia,
late in renal failure.
haemolyticuraemic syndrome and other allergic manifes-tations mefloquine and tetracyclines,
appears to be safe. However, the majority of the
are all rare in malaria treatment.
dose is excreted in the
faeces. Pharmacokinetic
Intramuscular quinine is certainly painful if concen-trated Doxycycline studies in severe malaria
acidic solutions are administered (undiluted qui-nine renal failure indicate that
dihydrochloride 300 mg/ml has a pH of 2), and in the past, these Doxycycline is a tetracycline
twice daily dosing would be
have been associated with sterile abscess formation. derivative with uses similar
preferable to the current
Intramuscular injections of undiluted quinine dihydrochloride to those of tetracycline. It
once-a-day regimen
cause pain, focal necrosis and in some cases abscess formation may be preferred to
(Newton et al. 2005b).
and in endemic areas are a com-mon cause of sciatic nerve tetracycline because of its
palsy. Tetanus associated with intramuscular quinine injections longer half-life, more reliable
is usually fatal (Yen absorption and better safety
profile in patients with renal
et al. 1994). In animals, toxic concentrations of quinine are
insuffi-ciency, where it may
oxytocic and induce premature labour. Quinine was once widely
used as an abortifacient. This has led to con-cern over the use of be used with caution. It is
quinine in pregnancy, but prospective studies (Looareesuwan et relatively water insoluble but
al. 1985) show no evidence of an oxytocic effect. Indeed very lipid soluble. It may be
administration of quinine was associated with a reduction in given orally or intravenously
uterine irritability. Despite an apparently long list of potential and is often given as a
adverse effects, qui- follow-on treatment of
severe malaria to complete a
area of The Gambia, West
Africa: 2 Mortality and
morbidity from malaria in the
study area. Transactions of the
Akech S, Ledermann H &
Royal Society of Tropical
Toxicity. Doxycyclines gastrointestinal effects are fewer than Maitland K (2010) Choice
Medicine and Hygiene
with tetracycline, although oesophageal ulceration can still be a of fluids for resuscitation in
87(Suppl 2), 1317.
problem if insufficient water is taken with tab-lets or capsules. children with severe
infection and shock: Alonso A, Lau J & Jaber BL
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systematic review. British
Doxycycline should not be given to preg-nant or lactating Medical Journal 341, c4416. hemodialysis membranes for
women, or children younger than 8 years. Akhtar S & Mukherjee S (1993) acute renal failure. The
Chloroquine induced mania. Cochrane Database of
International Journal of Systematic Reviews,
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Psychiatry in Medicine 23, CD005283.
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Ferreira CO, Siqueira AM, et
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Tropical Medicine and International Health doi:10.1111/tmi.

Publication of this supplement was sponsored jointly by the World

+++ +++ +++ Acidosis

Table 3 Outline bedside clinical classification of severe malaria in adults

Table 4 Epidemiological and research definition of severe falciparum malaria

conjugate gaze. Corneal and

Neurological features. The depth of coma may be assessed by

Immediate and long term deficits

Other cognitive deficits

<7.0 7.0 7.1 7.2 7.3 7.4

10 Figure 4 Relationship between

metabolic two major sign of lung

The diagnosis of cerebral

*In some patients with cerebral

Supportive care appropriate

The calculation of a sequestration index in adult patients,

Haemorrhages are not

Figure 10 Examples of microhaemorrhages found in

(a) Figure 12 Macroscopic picture of brain swelling and petechial

haemorrhages. An autopsy brain slice from a paediatric African

of histological oedema are

Figure 13 Pigment granules

The fresh cut surface of the brain may show a slate-grey-ish

Cellular immune responses

Studies in Malawian children demonstrated that 75% of cases (c)

Within the Malawian cohort of children diagnosed by

There is a marked difference

Figure 16 A brain capillary from

paediatric African malaria

injury, rather than an acute

Histopathological examination of liver biopsies during life or

Ring Blue, ring shape Red dot; can be elongated, 12 dots No

conditions such as H. simplex

higher than international Stress ulcer prophylaxis. In

Intravenous diazepam (0.3

The general and supportive

comparing artesunate and quinine in severe

Selecting the antimalarial

Algorithm for malaria diagnosis and treatment: first visit

Suspected malaria case

Refer the patient immediately Assess for other causes of days

patients complete referral and

DHA >24-36 months, rectal AS, 100 mg >24-36

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