Series

Malaria in early life 2

Treatment and prevention of malaria in children
Elizabeth A Ashley, Jeanne Rini Poespoprodjo

Malaria disproportionately affects children younger than 5 years. Falciparum malaria is responsible for more than Lancet Child Adolesc Health
200 000 child deaths per year in Africa and vivax malaria is well documented as a cause of severe anaemia and excess 2020; 4: 775–89

mortality in children in Asia and Oceania. For the treatment of malaria in children, paediatric dosing recommendations This is the second in a Series of
two papers about malaria in early
for several agents, including parenteral artesunate and dihydroartemisinin–piperaquine, have belatedly been shown to be
life
suboptimal. Worsening antimalarial resistance in Plasmodium falciparum in the Greater Mekong Subregion threatens to
Lao-Oxford-Mahosot Hospital-
undermine global efforts to control malaria. Triple antimalarial combination therapies are being evaluated to try to impede Wellcome Trust Research Unit,
this threat. The RTS,S/AS01 vaccine gives partial protection against falciparum malaria and is being evaluated in large, Vientiane, Laos
pilot studies in Ghana, Malawi, and Kenya as a complementary tool to other preventive measures. Seasonal malaria (E A Ashley MBBS); Centre for
Tropical Medicine and Global
chemoprevention in west Africa has resulted in declines in malaria incidence and deaths and there is interest in scaling
Health, Nuffield Department of
up efforts by expanding the age range of eligible recipients. Preventing relapse in Plasmodium vivax infection with Medicine, University of Oxford,
primaquine is challenging because treating children who have G6PD deficiency with primaquine can cause acute Oxford, UK (E A Ashley); Timika
haemolytic anaemia. The safety of escalating dose regimens for primaquine is being studied to mitigate this risk. Research Facility, Papuan
Health and Community
Development Foundation,
Background for the same year.4,12 Since 2000, there has been good Timika, Indonesia
More than half of the estimated 405 000 deaths from progress towards reducing the burden of malaria in (J R Poespoprodjo MD); and
malaria each year are in children younger than 5 years and some countries, with a decrease in the total number of Department of Child Health,
Faculty of Medicine, Public
are caused by Plasmodium falciparum; the vast majority of countries with endemic malaria from 106 to 86 between
Health and Nursing, Gadjah
deaths occur in Africa (figure 1).1,2 Repeated exposure to 2000 and 2016. The Lancet Commission on malaria Mada University, Yogyakarta,
malaria leads to gradual acquisition of immunity in those eradication concluded “…that malaria eradication by Indonesia (J R Poespoprodjo)
children who survive their infections.3 The three countries 2050 is a bold but attainable goal”.13 Reaching this goal Correspondence to:
shouldering the highest burden of the 228 million cases will require substantial investment of an additional US$ Dr Elizabeth A Ashley, Lao-
Oxford-Mahosot Hospital-
(95% CI 206–258) of falciparum malaria in 2018 were 2 billion per year. However, worsening antimalarial drug
Wellcome Trust Research Unit,
Nigeria (25%), Democratic Republic of the Congo (12%), and insecticide resistance threaten to undermine efforts Department of Microbiology,
and Uganda (5%).1 Two World Malaria Reports published to control and eliminate malaria.14 Mahosot Hospital, Vientiane,
in 2018 and 2019 have warned of the slowing down of This paper is the second in a Series of two papers about Laos
liz@tropmedres.ac
progress in global malaria control. Evidence suggests that the treatment and prevention of malaria in children. The
Plasmodium vivax is endemic throughout Africa and is not first paper in this Series by Rose McGready and
just prevalent in the Horn of Africa and Madagascar.4 In colleagues15 focuses on pregnancy and the preconception
the Asia-Pacific region, P vivax is the predominant period and in this paper we review the treatment and
infection in infants and children younger than 5 years and prevention of malaria after birth.
is recognised as an important cause of morbidity and
mortality in malaria endemic areas in which multiple Clinical presentation
Plasmodium species circulate.5,6 In Papua province, The main clinical presentations of malaria in children
Indonesia, 40–60% of malaria infections in infancy have are divided into uncomplicated malaria and severe
been shown to be due to P vivax.7,8 Similar findings were malaria, which is typically categorised as either cerebral
described in Papua New Guinea where P vivax infections malaria or severe malarial anaemia. Congenital malaria
were most prevalent in children aged 1–4 years.9,10 P vivax
malaria also predominates in the Americas. Plasmodium
ovale wallikeri and Plasmodium ovale curtisi infections have Key messages
a global distribution, but most occur in Africa. Plasmodium • Most malaria-related deaths are in children
malariae also occurs in all malaria endemic regions at low • Paediatric dosing regimens for several antimalarials have
incidence. Plasmodium knowlesi malaria is found close to been found to be suboptimal
habitats where long-tailed macaques and pig-tailed • Resistance to most of the antimalarials in use is
macaques reside. Most cases of P knowlesi are reported increasing, particularly in southeast Asia
from Malaysia, a country where this species is the leading • Uptake of radical curative treatments for vivax malaria in
cause of malaria.11 children is low because of safety concerns with
There is uncertainty around the true burden of malaria. administering 8-aminoquinolines without G6PD testing
The Global Burden of Disease 2017 study estimated the • Seasonal malaria chemoprevention is effective at
number of deaths from falciparum malaria in 2017 to be preventing malaria episodes in the Sahel, Africa
618 700, a value 50% higher than the estimates of WHO

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 Series

700 000 Worldwide deaths

5 years of life and is associated with an increased risk of
Deaths in Africa dying from severe malaria, particularly for those
600 000 individuals with haemoglobin concentrations less than
3 g/dL.22,23 Haemolysis of infected and uninfected red
500 000
blood cells and bone marrow dyserythropoiesis contribute
Number of deaths

400 000 to the anaemia observed in acute malaria, which might be

further compounded by inadequate parasite clearance
300 000 due to ineffective treatment or antimalarial drug
resistance and parasite recurrence.22,24,25 Most descriptions
200 000
of malarial anaemia relate to falciparum malaria.
100 000 However, the risk of severe anaemia in Papuan infants
(who are Indigenous to New Guinea) with P vivax
0 infections was 2 times higher than in infants who had
P falciparum malaria.8,26 Infants and children with P vivax
0
01

02

03

04

05

06

07

08

09

10

11

12

13

14

15

16

17
0

20

20
20

20

20
20

20
20

20

20
20

20

20
20

20

20

20
20

Time (years) malaria living in tropical endemic areas are at risk of

having frequent relapses of malaria every 3–7 weeks,
Figure 1: Estimated deaths from malaria between 2000 and 2017 in children aged 1–59 months which leaves insufficient time to replace the haemolysed
An estimated 8·7 million children aged 1–59 months died of malaria between 2000 and 2017, of whom 98% were
in the African region.2 erythrocytes.27,28

(defined as peripheral parasitaemia in the first 28 days of
life) is uncommon, but important, and the diagnosis can
be missed, particularly if the mother is asymptomatic.15
Depending on the level of maternal antibody protection,
initial non-specific symptoms could be delayed beyond
the neonatal period. If symptoms of congenital malaria
occur in the early neonatal period, these symptoms can
be confused with neonatal sepsis.
Signs and symptoms of malaria in children younger
than 5 years, such as fever, poor feeding, respiratory
insufficiency, jaundice, and diarrhoea, are similar to
those of other systemic infections.8,16 For this reason, all
sick infants and children presenting to health-care
facilities in malaria endemic areas should be screened
for malaria. The serious, and sometimes fatal, conseq­
uences of not making a prompt diagnosis of malaria are
well described.17 In some settings, however, overdiagnosis
of malaria continues to occur, particularly where health-
care workers mainly rely on clinical assessment. The
most challenging patients to diagnose are those who
have an incidental peripheral parasitaemia but another
cause for their presenting symptoms.18
As well as causing avoidable deaths in young children,
malaria has other negative effects on physical and
neurocognitive health, with anaemia, impaired school
performance, and behavioural problems all associated
with previous episodes of malaria.19 Anaemia is the most
prominent adverse health outcome of malaria in children.
In Malawi, hospitalised infants with malaria living in
areas of high malaria transmission were twice as likely to
have severe anaemia than those living in low transmission
areas.20 WHO defines severe malarial anaemia in children
younger than 12 years as having a blood haemoglobin
concentration less than 5 g/dL and a peripheral blood
parasite density of more than 10 000 parasites per µL.21 In
malaria holoendemic areas in Africa, the risk of severe
anaemia associated with malaria is highest in the first
Asymptomatic infections
Asymptomatic malaria is well described and is associated
with the acquisition of immunity during the first 5 years
of life in high transmission areas. Whether some cases
of malaria can be regarded as truly asymptomatic is
disputed because there is often evidence of accompanying
inflammation, such as platelet and endothelial cell
activation.29 Asymptomatic (afebrile) infections are more
common in P vivax than in P falciparum malaria in both
high and low malaria transmission areas.30,31 A household
survey carried out in highly malaria endemic areas in
Papua, Indonesia, showed that only 4 (6%) of 72 children
younger than 5 years with vivax malaria had a fever
compared with 3 (14%) of 21 children younger than
5 years with falciparum malaria.30 Similar findings were
also observed in the Solomon Islands, an area of low
malaria transmission.31 In Africa, asymptomatic falci­
parum malaria infections are associated with the
number of infections and the speed of acquisition of
immunity to malaria. Although asymptomatic infection
might occur early in life, it is more common in children
older than 5 years.32
Treatment of malaria in children
Early detection and prompt, effective treatment is central
to achieving a good outcome in malaria caused by all
species (table 1). The objective of treatment for vivax
malaria is to clear both blood-stage and liver-stage
infections (ie, a radical cure) by the use of effective
schizontocidal and hypnozoitocidal agents (eg, prima­ -
quine) to prevent relapse. In low transmission settings, a
single, low dose of primaquine is given, in addition to
schizontocidal therapy, for P falciparum infections because
of primaquine’s effect on mature (stage V) gametocytes.
Ivermectin is being evaluated as an alternative
transmission-blocking agent.50 Although not recom­
mended for children weighing less than 15 kg, ivermectin
has been used off-label to treat scabies and other parasitic

776 www.thelancet.com/child-adolescent Vol 4 October 2020


Uncomplicated P falciparum and P vivax in areas with high-grade, chloroquine-resistant P vivax infections
Dihydroartemisinin–
piperaquine
Artesunate–mefloquine
Artemether–lumefantrine
Artesunate–amodiaquine
Artesunate–sulfadoxine–
pyrimethamine
Uncomplicated P vivax (area
with chloroquine-sensitive
P vivax infections)
Uncomplicated P malariae,
P ovale, and P knowlesi
Children aged ≥6 months
with P vivax and P ovale
infections
Children aged ≥6 months
with P falciparum infections
Severe malaria caused by any
Plasmodium species
Congenital malaria; severe
P falciparum and P vivax
infections
Congenital malaria;
uncomplicated P vivax and
P ovale malaria
Recommendations are in line with the third edition of WHO’s Guidelines for the treatment of malaria.47 P falciparum=Plasmodium falciparum. P vivax=Plasmodium vivax. P malariae=Plasmodium malariae. P
ovale=Plasmodium ovale. P knowlesi=Plasmodium knowlesi. ACTs=artemisinin-based combination therapies.
Table 1: The treatment of malaria in children by species and presentation
www.thelancet.com/child-adolescent Vol 4 October 2020 777
Antimalarial drug options
The paediatric formulation is a fixed-dose combination of 20 mg dihydroartemisinin and
160 mg piperaquine and the adult formulation is a fixed-dose combination of 40 mg
dihydroartemisinin and 320 mg piperaquine; the target dosage when the combination is
given once daily for 3 days for adults and children weighing ≥25 kg is 4 mg/kg of
bodyweight (range 2–10) of dihydroartemisinin and 18 mg/kg of bodyweight (16–27) of
piperaquine; children <25 kg should be given a minimum dose of 2·5 mg/kg of
bodyweight of dihydroartemisinin and 20 mg/kg of bodyweight of piperaquine;
for children weighing <5 kg, give the same mg/kg of bodyweight dose as for children
weighing <25 kg
The paediatric formulation is a fixed-dose combination of 25 mg artesunate and 55 mg
mefloquine hydrochloride and the adult formulation is a fixed-dose combination of
100 mg artesunate and 220 mg mefloquine hydrochloride; the target dosage when the
combination is given once daily for 3 days is 4 mg/kg of bodyweight (range 2–10) of
artesunate and 8·3 mg/kg of bodyweight (7–11) of mefloquine
The paediatric formulation is a fixed-dose combination of 20 mg artemether and 120 mg
lumefantrine and the adult formulation is a fixed-dose combination of 40 mg
artemether and 240 mg lumefantrine; the target dosage when the combination is given
twice daily for 3 days is 5–24 mg/kg of bodyweight of artemether and 29–144 mg/kg of
bodyweight of lumefantrine
Formulations currently available are fixed-dose combinations of 25 mg artesunate and
67·5 mg amodiaquine, 50 mg artesunate and 135 mg amodiaquine, and 100 mg
artesunate and 270 mg amodiaquine; the target dosage when the combination is given
once daily for 3 days is 4 mg/kg of bodyweight (range 2–10) of artesunate and 10 mg/kg
of bodyweight (7·5–15) of amodiaquine; when patients weigh ≥50 kg, the dose range of
amodiaquine is adjusted to 11·0–19·8 mg/kg of bodyweight
The formulation is 50 mg artesunate and a fixed-dose combination of 500 mg sulfadoxine
and 25 mg pyrimethamine; target dose when artesunate is given once daily for 3 days with a
single dose of sulfadoxine–pyrimethamine is 4 mg/kg of bodyweight (range 2–10) of
artesunate; the number of sulfadoxine–pyrimethamine tablets (containing 500 mg of
sulfadoxine and 25 mg of pyrimethamine) varies according to bodyweight (<8 kg,
give 0·5 tablet; 8–13 kg, give 1 tablet; 14–24 kg, give 1·5 tablet; 25–38 kg, give 2 tablets;
39–49 kg, give 2·5 tablets; 50–68 kg, give 3 tablets; ≥69 kg, give 4 tablets)
For adults, 10 mg base/kg of bodyweight of chloroquine is given on day 1 and day 2 and
5 mg base/kg of bodyweight of chloroquine is given on day 3; for children, a total dose of
30 mg/kg of bodyweight of chloroquine is given over 3 days
As for uncomplicated P falciparum and P vivax malaria treatment
Antirelapse treatment (hypnozoitocidal agents) with 0·25–0·50 mg/kg of bodyweight of
primaquine for 14 days (maximum dose 30 mg daily)
Antigametocyte treatment with 0·25 mg/kg of bodyweight of primaquine in a single
dose (maximum dose 15 mg)
Intravenous or intramuscular artesunate given at a dose of 2·4 mg/kg of bodyweight on
hours 0, 12, and 24 to individuals with a bodyweight >20 kg or given at a dose of
3 mg/kg of bodyweight on hours 0, 12, and 24 to individuals with a bodyweight <20 kg;
after at least 24 h when oral medication is possible, switch to 3-day oral ACTs for
follow-up treatment
Intravenous or intramuscular artesunate; dose as for severe malaria; and continue with
follow-up treatment with 3-day oral ACTs
Follow treatment options according to the sensitivity of P vivax to chloroquine
Series
Comments
Preferred option in malaria endemic areas without evidence of
piperaquine resistance; consistent high efficacy against P falciparum
and P vivax malaria;33 compared with artemether–lumefantrine,
dihydroartemisinin–piperaquine has a better prophylactic effect in
P vivax infections;34 dose adjustment has been defined in children;35
dispersible tablet was similarly efficacious compared with crushed
tablet in a phase 2 trial36
Preferred option in endemic areas without evidence of mefloquine
resistance; similar effectiveness as artemether–lumefantrine for
P falciparum malaria in children younger than 5 years in Africa37 or
dihydroartemisinin–piperaquine in Asia;33 as efficacious as
dihydroartemisinin–piperaquine against recurrent P vivax malaria;38 no
dose adjustment in children is required
Alternative option for P falciparum malaria; similar efficacy to
dihydroartemisinin–piperaquine against P falciparum infections;33
dose adjustment in children younger than 3 years might be
required;39 twice daily dosing might affect treatment adherence in
young children; a flavoured paediatric dispersible tablet is available;
lumefantrine absorption is augmented by coadministration with fat
Option for treatment of P falciparum infections in Africa; in Africa,
artesunate–amodiaquine has a similar efficacy to dihydroartemisinin–
piperaquine against P falciparum malaria in children;40 in the Asia-
Pacific region, artesunate–amodiaquine is less efficacious than
dihydroartemisinin–piperaquine against P falciparum and P vivax
malaria;38 dose adjustment in patients weighing ≥50 kg is
recommended41
Least recommended ACT; lower efficacy against P falciparum malaria
compared with artemether–lumefantrine;42 lower efficacy against
P vivax compared with dihydroartemisinin–piperaquine;33,38 dose
adjustment in children older than 1 year is recommended43
More effective with an increased dose;44 requires a skilled
microscopist to differentiate species; if in doubt, treat with ACTs
Little evidence is available on the efficacy profile of ACTs in children;38
ACTs are the preferred treatment for P knowlesi45
Coadministration with chloroquine and ACTs provides a lower risk of
relapses and recurrences;34,44 should not be given to G6PD-deficient
individuals; if a G6PD test is not available, consider the risk and
benefit of adding primaquine
Coadministration with ACTs;46 G6PD testing is not required47
Preferred option for any severe malaria; highly effective for the
treatment of severe P falciparum malaria in children;48 use in severe
non-falciparum malaria is highly recommended to prevent
mortality;47 avoid mefloquine-containing ACTs because of the
increased risk of post-malaria neurological syndrome;49 if parenteral
artesunate is not available, quinine can be used as an alternative
Congenital malaria is defined as peripheral parasitaemia found in the
first 28 days of life
Radical cure is not indicated as blood-stage infections occur directly
from the mother; thus, there are no dormant hypnozoites in the liver
 Series
1·00
0·95
Proportion still alive
0·90
0·85
0·80
0
0 1 2 3
Time after entry into the study (days)
Figure 2: Reduced mortality from severe malaria after artesunate treatment compared with quinine
treatment
Between 2005 and 2010, the AQUAMAT study48 enrolled 5425 children with severe malaria in nine African
countries.
infestations in this group. More documented evidence of
the safety of ivermectin in children weighing less than
15 kg is needed. Published by WHO, evidence-based
guidelines for the treatment of malaria are freely
available.47 We are only now realising that the dosing of
several antimalarials in children is suboptimal. This
oversight is a consequence of designing dosing regimens
in a different population (ie, adults) to the one most
affected by the disease and has led to revisions of some
dosing recommendations.
The initial treatment of choice for severe falciparum
malaria is clear. Between 2005 and 2010, the AQUAMAT
study48 enrolled 5425 children with severe malaria in nine
African countries. There was a relative reduction in
mortality of 22·5% (95% CI 8·1–36·9; p=0·0022) in
artesunate-treated children compared with quinine-treated
children (figure 2). Although there has been no clinical
trial comparing mortality following intravenous artesunate
and quinine for the treatment of severe vivax malaria,
WHO recommends parenteral, preferably intravenous,
artesunate as the first-line treatment for severe vivax
malaria.47
Artemisinin-based combination therapies (ACTs) have
been recommended to treat uncomplicated falciparum
malaria since the mid-2000s. In 2015, ACTs became the
treatment of choice for malaria caused by P knowlesi
because this parasite has a shorter 24 h lifecycle and so
increases the risk of high parasite densities and severe
disease.45 Chloroquine is still the drug of choice for the
treatment of chloroquine-sensitive P vivax malaria. The
regimen suggested by WHO is a total dose of 25 mg of
base per kg of bodyweight given in three divided doses,
once daily over 3 days. ACTs can be used for the treatment
778 www.thelancet.com/child-adolescent Vol 4 October 2020
Artesunate of P vivax infections and are recommended in areas
Quinine where P vivax is highly resistant to chloroquine, such as
Indonesia and Colombia (figure 3).47,51,52 In vitro studies
have shown that arte­sunate, lumefantrine, piperaquine,
and mefloquine are all effective against P vivax.53,54
Options for treating uncomplicated malaria caused by
P ovale and P malariae include chloroquine and ACTs;
however, treatment efficacy against these malaria species
has not been well studied when compared with
falciparum and vivax malaria and more evidence to
define optimal treatment strategies is needed.38,55,56
Partner drugs in ACTs with long half-lives, such as
piperaquine (28–35 days) and lumefantrine (about 4 days),
delay time to first recurrence of malaria (re-in­fection or
relapse).57–59 Several efficacy studies have shown that
treatment with dihydroartemisinin–piperaquine alone is
consistently associated with fewer recurrences at day 42
4 than treatment with artemether–lumefantrine.34,60,61 An
analysis of re-infection data from treatment studies of
uncomplicated malaria in African children estimated that
piperaquine and lumefantrine prevent equal to
or more than 90% of re-infections for a mean of 26·2 days
(range 13·6–45·0) for piperaquine and 12·1 days
(9·0–20·6) for lumefantrine.62 For the treatment of P vivax
malaria, coadministration with primaquine resulted
in a 92% reduc­tion in recurrence on day 42 following
treatment with dihydroartemisinin–piperaquine and an
80% reduc­ tion in recurrence following treatment with
artemether–lumefantrine.34
Despite the overwhelming evidence supporting the
efficacy and safety of ACTs and parenteral artesunate,
the reality is that these drugs are still not being used
everywhere.63 Where these drugs are available, they are
not always being implemented according to international
guidelines.64
Pharmacokinetics of antimalarials in children
The pharmacokinetics of several antimalarials are different
in children younger than 10 years or who are underweight
for their age compared with children 10 years and older
and adults. In children weighing less than 25 kg, exposure
to artesunate, and artesunate’s main metabolite, dihydro­
artemisinin, is lower than in adults because of a larger
apparent volume of distribution and faster clearance.
Hence, a higher dose of 3 mg/kg, rather than 2·4 mg/kg,
is recommended for the treat­ment of severe malaria in
children weighing less than 25 kg.65,66 In a pooled analysis
of individual patient data, treatment failure following
dihydroartemisinin–piper­aquine treatment was found to
be more likely in children aged 1–5 years than in older age
groups and so dosing recom­mendations have been revised
for children weighing less than 25 kg.35,67 A similar pooled
analysis looking at artemether–lumefantrine dosing found
that treatment efficacy was lowest in Asian children
weighing 10–15 kg who received a total dose of lumefantrine
of less than 60 mg/kg of bodyweight, and in malnourished
children aged 1–3 years in Africa.39 Prolonging the duration
 Series

P falciparum (susceptible to
leading ACTs)
P falciparum (artemisinin-resistant;
ACTs effective)
P falciparum (ACTs commonly
ineffective)

P vivax endemic
Chloroquine-resistant P vivax

Figure 3: Maps of the distribution of drug-resistant malaria

(A) P falciparum. (B) P vivax. Countries are depicted as having evidence of chloroquine-resistant P vivax if trials have shown that there is more than a 10% recurrence
of malaria by day 28 of malaria infection (with a lower 95% CI of >5%), irrespective of confirmation of adequate blood concentration of chloroquine.51
ACTs=artemisinin-based combination therapies. P falciparum=Plasmodium falciparum. P vivax=Plasmodium vivax.

of treatment has been proposed to increase treatment
effectiveness.68 A popu­ lation pharmacokinetic analysis
with non-linear mixed effects modelling has been used
to analyse data from four studies of sulfadoxine–
pyrimethamine treatment and found that the bioavailability
of sulfadoxine was 15·3% lower, and the bioavailability of
pyrimethamine was 26·7% lower, in underweight-for-age
children for each Z-score unit below –2 than in children
with a healthy weight for their age.43 Based on simulations
derived from a population pharmacokinetic model, there
are similar concerns that amodiaquine dosing in children
might be too low.41
For the treatment of vivax malaria, subtherapeutic blood
concentrations of chloroquine on day 7 after initial dosing
have been found in children treated with a dose of 25 mg
base/kg of bodyweight and consequently increased the
risk of malaria relapse.69,70 In a meta-analysis of individual
patient data, increasing the dose of chloroquine to 30 mg
base/kg of bodyweight reduced the overall recurrence rate
by day 42 after initial dosing (adjusted hazard ratio

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 Series
[aHR] 0·82, 95% CI 0·69–0·97; p=0·021) and the
recurrence rate in children younger than 5 years (0·59,
0·41–0·86; p=0·0058). Adding primaquine treatment
further reduced recur­ rence by 90%.44 The different
pharmacokinetics of drugs in children might also relate to
maturation (eg, of metabolic processes, particularly in the
first 2 years of life).71 Pharmacogenomic factors affecting
drug metabolism are increasingly being studied (eg, poly­
morphisms in CYP2C8 have been associated with adverse
events following amodiaquine treatment).72 The efficacy
of prima­quine to prevent relapse in vivax malaria depends
on the metabolism of primaquine by cytochrome P450
2D6. Polymorphisms in CYP2D6 are associated with
different primaquine metaboliser phenotypes with
resulting differing efficacies for radical cure.73
Relapse prevention for vivax malaria
P vivax forms hypnozoites that can stay dormant in
hepatocytes before causing a malaria relapse later.
These liver-stage parasites are treated with primaquine, an
8-aminoquinoline antimalarial drug that might trigger
acute haemolysis in G6PD deficient individuals.74–76
In tropical regions, P vivax strains can cause relapse every
3–7 weeks (and are less susceptible to primaquine);
whereas, in temperate regions, hypnozoites can remain
dormant for about 9 months (and are more effectively
treated with primaquine).77,78 Infants and children younger
than 5 years are at a higher risk of frequent relapses than
older age groups because of lower acquired immunity and
poor treatment adherence, leading to severe anaemia.8,27,79
In view of this issue, WHO recommends the use of low
dose (0·25 mg/kg of bodyweight) primaquine for 14 days
in infants aged 6 months and older after G6PD testing, as
a follow-up treatment for malaria caused by P vivax and P
ovale. Unfortunately, point-of-care G6PD testing is not
available in most malaria endemic areas and, in this
situation, the decision to give primaquine must be based
on a risk–benefit assessment and patients must be closely
monitored for primaquine-associated acute intravascular
haemo­lysis.76,80 An ongoing trial in Thailand is assessing
the safety and tolerability of an escalating primaquine dose
regimen in healthy volun­teers with G6PD deficiencies as a
possible way to administer primaquine safely without the
need for G6PD testing.81 This trial is based on the
observation that younger erythrocytes are more resistant to
oxidant haemolysis. Therefore, after a small dose of
primaquine, there is an initial, moderate decrease in
haemoglobin, followed by reticulocytosis, and repeated
dosing does not lead to severe haemolytic anaemia.
Shortening the duration of primaquine treatment has
been proposed to improve adherence. A multicentre
clinical trial, which included infants aged 6 months and
older in whom G6PD deficiency had been excluded,
showed that 7 days of high-dose primaquine (1 mg/kg per
day) led to similar rates of symptomatic P vivax infections
within 12 months of follow-up as did 14 days of supervised
primaquine (0·5 mg/kg per day), with slightly higher rates
780 www.thelancet.com/child-adolescent Vol 4 October 2020
of gastrointestinal symptoms reported in the 7 day group.82
One of the most common complications of falciparum
malaria in southeast Asia is a vivax malaria relapse,
found to occur in 29·4% of patients by day 63 of follow-
up.83 Multiple infections within a 2 month interval can
have a considerable, detrimental haematological and
clinical effect on infants and children less than 5 years
old. Treatment with antimalarial drugs with long half-
lives is one strategy to delay recurrence;34,83 however,
applying radical cure treatment for P falciparum malaria
might also benefit children living in such settings.
Repeated infections and treatment failure
In high transmission areas, repeated infections are
common and are associated with early mortality (ie, death
by any cause within the first 30 days after first hospital
presentation with malaria) and late mortality (ie, death by
any cause from day 31 to day 365 after first hospital
presentation with malaria).25 In addition, there will always
be a proportion of children who will not respond to therapy.
Reasons for treatment failure in these children include
poor drug absorption, high parasite densities, non-
adherence to therapy, and antimalarial drug resistance.
Drug resistance is highly probable when repeat malaria
episodes occur within 14 days of the primary episode;
however, recrudescence can occur after 6–9 weeks and, in
the cases of P vivax and P ovale malaria, relapses might
present much later. Repeating the same treatment is a
reasonable approach in the event of another episode of
malaria, unless drug resistance is strongly suspected.84
Artesunate–mefloquine retreatment is an exception, a
combination that should not be given more frequently
than 2 monthly intervals because of the risk of neurotoxicity.
There is some evidence that comorbidities affect the
treatment response. High numbers of treatment failures
were observed in adults with HIV and P falciparum
malaria who had CD4 counts of less than 300 cells per uL
following treatment with sulfadoxine–pyrimethamine
and artemether–lumefantrine.85 However, an increased
risk of malaria treatment failure was not found in children
with HIV living in malaria endemic areas in Uganda.86
Dose presentations and delivery
Paediatric dosage forms are available for most of
the fixed-dose combination antimalarials taken orally.
Most antimalarials are dosed according to bodyweight.
Age-based dosing regimens have been proposed (eg, for
artesunate–amodiaquine and single, low-dose prima­
quine).87,88 To improve access to treatment, different
models of treatment delivery have been evaluated,
including community-based, school-based, and home-
based management.89 A Cochrane systematic review90
of home-based and community-based programmes
con­cluded that these programmes improve access to
treat­ment and might reduce mortality from malaria.
However, the risk of overtreatment when clinical case
definitions of malaria were used was highlighted.90

Other drug(s)
Amodiaquine Efavirenz; zidovudine
Artemether–lumefantrine Rifampicin; efavirenz; nevirapine; lopinavir–ritonavir;
darunavir–ritonavir; etravirine; mefloquine
Atovaquone–proguanil Efavirenz; lopinavir–ritonavir; atazanavir–ritonavir
Dihydroartemisinin–piperaquine Efavirenz
Primaquine Chloroquine; dihydroartemisinin–piperaquine;
artesunate pyronaridine
Quinine Rifampicin
Sulfadoxine–pyrimethamine Other antifolates (eg, trimethoprim)
Table 2: Important drug–drug interactions with antimalarials
Other formulations of non-injectable antimalarials
(eg, rectal artesunate and sublingual artemether) have
been developed to facilitate the early treatment of
severe malaria in children in remote areas.91
Supportive treatment of children with severe malaria
Children with severe malaria are frequently acidotic and
anaemic and can become unconscious.21 The avoidance
of hypoglycaemia, the treatment of seizures, careful fluid
management, and judicious blood transfusion are key
parts of supportive management. Routine prophylaxis to
prevent seizures stopped being recommended after a
trial found excess mortality in children with cerebral
malaria given phenobarbital.92
The relationship between anaemia and severe malaria is
complex.22 Findings of a retrospective analysis suggest
that moderate anaemia might protect against in-hospital
mortality in severe falciparum malaria (odds ratio
[OR] 0·87, 95% CI 0·80–0·95 for a 10% decrease in
haematocrit).93 The TRACT trial,94,95 which included
children in Africa regardless of malaria status
(ie, 984 (62·9%) of 1565 children had malaria), showed no
clinical benefit in immediately transfusing blood to all
children with uncomplicated severe anaemia compared
with the standard approach of transfusing based on
clinical severity or haemoglobin concentrations of less
than 4 g/dL. The trial also showed that there was no
advantage to transfusing 30 mL/kg of bodyweight
compared with transfusing 20 mL/kg of bodyweight.
Regarding fluid resuscitation in severe malaria, another
large study (the FEAST study96) by the same group found
excess mortality at 48 h in severely ill children (1794 [57·4%]
of 3123 children had malaria) with impaired perfusion
given an albumin or saline fluid bolus compared with
control (no bolus; relative risk [RR] 1·45, 95% CI 1·13–
1·86; p=0·003). Concomitant bacterial infection is well
described in children with severe malaria. Bacteraemia
caused by non-typhoidal Salmonella is particularly
common and empirical antibiotics are often prescribed.97
Antimalarial drug resistance
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Series
Description of interaction
Coadministration with efavirenz can cause hepatotoxicity;100 coadministration with zidovudine can
cause neutropenia
Rifampicin decreases lumefantrine (and artemether) exposure by CYP3A4 induction; efavirenz and
nevirapine reduce artemether and dihydroartemisinin exposure;101–103 lopinavir–ritonavir and
darunavir–ritonavir increase lumefantrine exposure;104,105 etravirine reduces artemether,
dihydroartemisinin, and lumefantrine exposure;105 concomitant mefloquine results in lower
lumefantrine concentrations106
Atovaquone exposure is reduced107
Piperaquine exposure is reduced108
Coadministration increases primaquine exposure109–111
Rifampicin increases the metabolic clearance of quinine
Increased risk of toxicity (eg, anaemia)
Loss of antimalarial drug effectiveness because of the
emergence of drug resistance in the parasite has
happened repeatedly since the 1950s. Of major concern
at present is the emergence and spread of P falciparum
resistant to artemisinin, piperaquine, and mefloquine in
the Greater Mekong Subregion (figure 3).98,99 The clinical
phenotype of artemisinin resistance is delayed parasite
clearance that, in Asia and Latin America, is related to
various mutations in the kelch propeller gene on
chromosome 13 of the parasite (table 2). The most well
known mutation is Cys580Tyr, which is reaching fixation
in some parts of the eastern Greater Mekong Subregion.
The risk of global spread of artemisinin resistance
presents a serious threat to child health in sub-Saharan
Africa. In the early 2000s, the rising malaria mortality in
Africa was associated with increasing chloroquine
resistance.112 Different strategies are being evaluated in
southeast Asia to replace ineffective treatments and
include extended treatment courses, the reintroduction
of drugs previously lost to resistance, and triple
antimalarial combinations.113,114
Delayed parasite clearance in P vivax infections has not
been reported, but has not been looked for extensively.
In Papua, Indonesia, where chloroquine resistance
is widespread and ACTs are the first-line treatment
for vivax malaria, P vivax malaria remains sensitive to
dihydroartemisinin–piperaquine, even after 9 years
(2006–15) of its use; in one study, all 65 patients treated
with dihydroartemisinin–piperaquine were parasite free
on day 3 after enrolment onto the study.60,115
Newer antimalarials
Newer antimalarial combinations that are ready for use
are pyronaridine–artesunate and arterolane maleate–
piperaquine.116,117 Following signs of hepatotoxicity in
earlier trials, the safety and efficacy of retreatment with
pyronaridine–artesunate was assessed in a substudy of a
large efficacy trial in west African children.118,119 On the
basis of laboratory values and reported frequencies of
adverse events, this substudy found no evidence that
retreatment with pyronaridine–artesunate increased the
 Series

Resistance marker Notes Geographical distribution

Amodiaquine Pfcrt; pfmdr1 SVMNT haplotype, including Lys76Thr and Asn86Tyr East Africa and southeast Asia
Artemisinin kelch13 Single mutations (ie, Phe446Ile, Pro553Leu, Asn458Tyr, Arg561His, Met476Ile, Tyr493His, Southeast Asia (Cys580Tyr) and south Asia, Guyana,
Arg539Thr, Ile543Thr, and Cys580Tyr) dominate in areas of high-level resistance and Rwanda
Atovaquone CytB Tyr268Ser, Tyr268Cys, and Tyr268Asn Cambodia (emerged rapidly after deployment of
atovaquone–proguanil in 2014)
Chloroquine Pfcrt; pfmdr1; pvcrt-0; CVIET haplotype, including Lys76Thr and Asn86Tyr, which augments resistance Worldwide
pvmdr-1
Lumefantrine pfmdr1 Gene amplification (associated with low-grade resistance in southeast Asia); selection of High failure rates of artemether–lumefantrine
pfmdr1; 86Asn allele after treatment observed in Africa documented in Cambodia (2000–05)
Mefloquine pfmdr1 Gene amplification Thailand and Myanmar
Piperaquine plasmepsin2; pfcrt Gene amplification (plasmepsin2); pfcrt variants include Phe145Ile, Gly353Val, and Cambodia, Thailand, Laos, and Vietnam; described in
Met343Leu Africa in 2019127
Pyrimethamine dhfr; pfgch1 Asn51Ile, Cys59Arg, Ser108Asn, and Ile164Leu; gene amplification Worldwide*
Sulfadoxine dhps Ser436Ala, Ser436Phe, Ala437Gly, Lys540Glu, Ala581Gly, Ala613Ser, and Ala613Thr Worldwide*
*The pfdhfr (Asn51Ile, Cys59Arg, and Ser108Asn) and pfdhps (Ala437Gly and Lys540Glu) quintuple mutant is associated with high-grade resistance to sulfadoxine–pyrimethamine.

Table 3: Molecular markers associated with antimalarial drug resistance

risk of hepatotoxicity. In a separate pharmacokinetic study, Safety of antimalarials in children

pyronaridine exposure was similar across paediatric
weight ranges.120 Arterolane maleate is a synthetic
trioxolane drug with an elimination half-life of 2–4 h. In-
vitro experiments have suggested that there is cross-
resistance between arterolane maleate and artemisinin.121
This fact, combined with the emergence and spread of
piperaquine resistance, limits the options for deployment
of the combination. Tafenoquine is a long-acting
8-aminoquinoline that was approved in 2018 by the
European Medicines Agency, the US Food and Drug
Administration, and the Australian Therapeutics Good
Administration for the prevention of vivax malaria relapse
in adults. Given in a single dose, there is a lot of interest in
tafenoquine for the possibility of overcoming the challenge
of adhering to longer courses of primaquine; however, like
primaquine, tafenoquine causes acute haemolytic
anaemia in individuals with G6PD deficiency and is
currently not recommended for use in children. An
efficacy, safety, and pharmacokinetic study of tafenoquine
in children completed recruitment in March, 2020, and
we await the results (NCT02563496).
Artefenomel, cipargamin, and ganaplacide are three
promising newer antimalarials in clinical development;
cipargamin and ganaplacide are completely unrelated
to artemisinin. Data on the use of these drugs to treat
children are scarce. A pharmacokinetic study in which
artefemonel was given with piperaquine showed that
artefemonel exposure was lower in African children
aged between 6 months and 2 years than in African or
Asian patients older than 5 years.122 A phase 2, dose-
finding multicentre study looking at the safety and
efficacy of ganaplacide combined with lumefantrine in
a solid dispersion formulation is enrolling children
aged 2–12 years with uncomplicated falciparum
malaria and is due to complete enrolment in 2021
(NCT03167242).
The antimalarials in use are generally well tolerated and
safe and have been studied in very large numbers of
children. Treatment with sulfadoxine–pyrimethamine is
sometimes associated with skin reactions and, rarely,
Stevens–Johnson syndrome. When used as prophylaxis in
the 1980s, amodiaquine was associated with liver injury
and agranulocytosis.123 A systematic review of studies
assessing intermittent preventive treatment in children
younger than 5 years reported no cases of Stevens–Johnson
syndrome among the 32  757 children who received
sulfadoxine–pyrimethamine and no cases of serious blood
dyscrasias or hepatotoxicity among the 31 327 children who
received amodiaquine.124 Mefloquine causes dose-related
vomiting within 1 h of administration, particularly in
young children. In a pooled analysis of 19 850 patients
treated with mefloquine, 106 (14·4%) of 735 children
younger than 5 years had early vomiting, compared with
108 (3·8%) of 2834 children aged 5–14 years and 81 (2·4%)
of 3310 older children and adults (p<0·001).125 Delayed
haemolytic anaemia after treatment with artesunate has
been observed in travellers from malaria endemic areas
treated for severe malaria, but this complication appears to
be an uncommon occurrence in children in endemic
areas.126 There are some important drug–drug interactions
between anti­malarials and other drug classes, such as anti­
retrovirals and anti-tuberculous therapy (table 3).127
Prevention
The negative effects of malaria infection lead to the
unavoidable conclusion that the only acceptable goal is to
prevent all episodes of malaria. Ultimately, this goal
means eradicating the disease, the feasibility of which
has been debated.128 In the meantime, minimising the
harm caused by malaria in children can be done through
infection prevention with antimalarials, vaccines,
insecticide-treated bednets, and other vector control
interventions.

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The two main chemopreventive strategies in endemic
countries are seasonal malaria chemoprevention and
intermittent preventive therapy in infants. Seasonal
malaria chemoprevention is recommended for children
younger than 5 years in countries in the Sahel with
intense seasonal malaria transmission. A full treatment
course of sulfadoxine–pyrimethamine–amodiaquine is
given monthly, up to four times.
Seasonal malaria chemoprevention has been shown to
be highly effective in reducing the incidence of malaria
and there have been calls to expand the target group
to older children.129,130 In a cluster randomised trial in
Senegal in 2011, which enrolled 2301 children younger
than 10 years in 24 villages, seasonal malaria chemo­
prevention, in addition to community case management,
was well tolerated and associated with a decrease in
malaria cases confirmed by rapid tests (270) compared
with control villages (1472; p<0·001).129
There are different models for delivering seasonal
malaria chemoprevention, such as delivery from a fixed
point in the village, door-to-door, and school-based
methods.131 Because of concerns that the lifespan of
sulfadoxine–pyrimethamine–amodiaquine will be limited
by resistance, dihydroartemisinin–piperaquine has been
evaluated as an alternative agent for seasonal malaria
chemoprevention.132–134 Protection from malaria has been
found to be associated with piperaquine exposure and
results of pharmacokinetic and pharmacodynamic
modelling suggest that children weighing 4–20 kg should
receive the revised higher dose of dihydroartemisinin–
piperaquine given for routine treat­ment.132–134 The use of a
weekly, rather than a monthly, dosing interval for
dihydroartemisinin–piperaquine has also been put
forward as a way to maximise protective effectiveness.134
Mass drug admini­ stration with dihydroartemisinin–
piperaquine has also been deployed in some countries as
part of a targeted malaria elimination strategy.135
In 2014, a large, placebo-controlled trial, which included
19 578 children in Burkina Faso and Mali, evaluated the
addition of azithromycin, which had been shown to
reduce all-cause mortality in children following mass drug
administration for trachoma, to standard seasonal malaria
chemoprevention. Children who received azithromycin
were less likely to go on to have gastrointestinal infections
(incidence rate ratio [IRR] 0·85, 95% CI 0·79–0·91), upper
respiratory tract infections (IRR 0·85, 0·81–0·90), and
non-malarial febrile illnesses (1122 vs 1424 episodes;
IRR 0·79, 0·73–0·87) compared with placebo; however,
there was no difference in the incidence of death or
admission to hospital.136
Intermittent preventive therapy in infants
In falciparum malaria endemic areas with moderate
to high transmission where seasonal malaria chemo­
prevention is not implemented, intermittent preventive
therapy in infants with sulfadoxine–pyrimeth­ amine
is recommended by WHO,47 provided resistance
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Series
to sulfadoxine–pyrimethamine is not established
(<50% preva­ lence of the Pfdhps 540 mutation).
Intermittent preventive therapy in infants is linked to
Expanded Programmes of Immunisation and given at
10 weeks, 14 weeks, and 9 months of age. Despite
encouraging results from studies, uptake by countries
has been low; Sierra Leone was the only country that
implemented intermittent preventive therapy in infants
in 2017.137
Other chemopreventive strategies
Delivering intermittent preventive therapy to children
aged 5–20 years in schools has been evaluated in Uganda
in a cluster randomised trial.138 Schoolchildren in the
42 clusters allocated to the intervention received monthly
dihydroartemisinin–piperaquine for up to six rounds.
Parasite prevalence at the community level estimated
during the final survey (~10 months after the baseline
survey) was lower than in the control clusters (19% vs
23%; aRR 0·85, 95% CI 0·73–1·00; p=0·05).
Malaria in adolescence is an important health issue
with particular implications for young women of
reproductive age. Interventions to treat asymptomatic
malaria of any species, or latent forms of P vivax, before
conception might reduce the risks of malaria to the
mother and fetus during pregnancy.
Sulfadoxine–pyrimethamine should not be given to
children with HIV on trimethoprim–sulfamethoxazole
prophylaxis. In a randomised controlled trial comparing
different chemoprophylactic regimens in young, HIV-
exposed children in Uganda (who were subsequently
confirmed to be uninfected), dihydroartemisinin–pipera­
quine showed superior protective efficacy for malaria
prevention compared with daily trimethoprim–sulfa­
methoxazole or monthly sulfadoxine–pyrimetha­mine.139
Malaria chemoprevention in children with sickle cell
anaemia is recommended; however, there is conflicting
evidence regarding the benefit associated with preventing
sickle cell crises and associated complications triggered
by episodes of malaria.140,141 The risk of malaria rebounds
in the seasons following mass chemoprophylaxis has
been studied in several countries with inconsistent
results.142–144 There is some evidence to suggest that there
is an increase in malaria episodes after the cessation of
prophylaxis in high transmission areas, but no evidence
to suggest that this increase is followed by more severe
outcomes.
Prevention of vivax malaria
Little information is available on the prevention of vivax
malaria in children. One study from Papua New Guinea
showed that infants are relatively protected from P vivax
malaria when given routine intermittent preventive
treatment with single dose sulfadoxine–pyrimethamine
and once daily amodiaquine for 3 days at ages 3, 6, 9, and
12 months, although the effect was more pronounced in
preventing P falciparum infections.145
 Series
Panel: Recommendations for the treatment and prevention of malaria in children
National malaria control programmes
All sick children should have immediate access to early diagnosis and
prompt effective treatment:
• Microscopy or rapid diagnostic tests
• Artemisinin-based combination therapies for
uncomplicated malaria
• Parenteral artesunate for severe malaria
• Radical cure for Plasmodium vivax malaria with primaquine
in children without G6PD deficiency (if G6PD status is
unknown, consider the risks and benefits of treatment and
closely monitor urine colour in the first 3 days after
administration for signs of acute haemolysis [ie, dark urine])
Uptake of chemoprevention for Plasmodium falciparum malaria in
areas sensitive to sulfadoxine–pyrimethamine–amodiaquine in
Africa should be increased:
• Infants aged 1–12 months should be given intermittent
preventive therapy with sulfadoxine–pyrimethamine
• Children younger than 5 years should be given seasonal
malaria chemoprevention with sulfadoxine–
pyrimethamine–amodiaquine
• Drug resistance monitoring and surveillance should be
carried out regularly
• Unified treatment policy with artemisinin-based
combination therapies could be considered in areas
sensitive to artemisinin-based combination therapies
• Dihydroartemisinin–piperaquine could be used as an
alternative for intermittent preventative therapy in infants
and seasonal malaria chemoprevention in areas of high-
grade resistance to sulfadoxine–pyrimethamine
• Intermittent preventative therapy with dihydroartemisinin–
piperaquine for children aged 5–12 years could be
considered
• All children living in high malaria transmission areas should
sleep under insecticide-treated nets
Prevention in travellers
If travel to malaria endemic countries is unavoidable,
measures to avoid getting bitten by mosquitoes and
chemoprevention with a medicine appropriate to the
destination are recommended. Atovaquone–proguanil
has been prescribed off-licence to children weighing
more than 5 kg. Alternatives include weekly mefloquine,
although this drug is associated with higher vomiting
rates in young children,146 or doxycycline, which is only
recommended for children older than 8 years, despite
the fact that evidence that doxycycline causes the same
teeth staining as tetracycline is lacking.147 Primaquine is
not recommended for malaria prophylaxis in children.
Parents and guardians should be warned of the signs and
symptoms of malaria to look out for and advised to seek
testing early. Substandard and falsified antimalarial
drugs have been described in many countries.148 Buying
well known brands might reduce the risk of purchasing
substandard antimalarials. The best known topical
784 www.thelancet.com/child-adolescent Vol 4 October 2020
Research
Recommendations for research into treatment:
• Develop new safe and effective agents for radical cure of
children infected with P vivax
• Develop a primaquine treatment adherence and safety
package for health-care workers and the community in
resource-limited settings, including point-of-care G6PD
testing
• Evaluate the safety and efficacy of triple antimalarial
combinations for deployment in areas of drug-resistant
malaria
• Develop new antimalarials for treatment and evaluate these
antimalarials in children earlier in the drug development
process
Recommendations for research into prevention:
• More research to define the optimum agents for prevention
and dosing strategies and the long-term effects of these
strategies (eg, evaluate the efficacy and effectiveness of
intermittent preventive therapy and seasonal malaria
chemoprevention with dihydroartemisinin–piperaquine for
the prevention of P falciparum and P vivax malaria in infants
younger than 5 years and school-aged children (ie, aged 6–12
years) and evaluate the efficacy and effectiveness of seasonal
malaria chemoprevention expanded to other age groups)
• Develop new antimalarials for prevention
Recommendations for research related to health-care systems:
• Link studies with national Expanded Programmes of
Immunisation or other national campaigns to increase the
uptake of intermittent preventive therapy in infants
• Strengthen integrated community case management with
other causes of childhood illness
mosquito repellent is N,N-diethyl-m-toluamide. N,N-
diethyl-m-toluamide is generally considered safe for use
in children aged 2 months or older.
Vaccines
RTS,S/AS01 is a pre-erythrocytic vaccine that has been
shown to give partial protection against falciparum
malaria in a large, multicentre trial and has received a
favourable opinion from the European Medicines
Agency.149 Three large pilot implementation evaluations
are underway in Ghana, Kenya, and Malawi that will
inform decisions to introduce this vaccine into national
immunisation programmes in the future. There are
several other single stage and multistage vaccines in
clinical development.150 Vaccines against P vivax malaria
are at a much earlier stage of development than
vaccines for P falciparum, with very few human studies
to date.151

Search strategy and selection criteria
We searched PubMed on Sept 22, 2019, using the terms
(((“malaria”) AND “treatment”) AND “child”) AND
(“2014/10/01”[Date - Publication]: “3000”[Date -
Publication], and (((“malaria”) AND “prevention”) AND
“child”) AND (“2014/10/01”[Date - Publication]: “3000”[Date
- Publication]) for articles published between Oct 1, 2014,
and Sept 22, 2019. This identified 3080 references, of which
881 were duplicates. We screened the titles and abstracts of
all articles published in English. We prioritised high quality
systematic reviews for selection in line with the scope of this
Review. We added additional original references published
before 2014 from bibliographical searches of these articles
and key documents on malaria from WHO.
Vector control measures
Insecticide-treated nets have been shown to reduce the
incidence of malaria and child mortality and are a key
intervention in the control of malaria.152 However,
increasing pyrethroid resistance in Anopheles mosquitoes
is a concern. In response to this issue, the pyrethroids in
insecticide-treated nets have been combined with
piperonyl butoxide, a synergist selected for its inhibitory
effect on certain mosquito metabolic enzymes.153 In a
cluster randomised trial in Tanzania, the prevalence of
malaria, as assessed by rapid diagnostic tests, was lower
in children who received piperonyl butoxide-containing
nets (531 [28·7%] of 1852 children) than in those who
received insecticide-treated nets without piperonyl
butoxide 9 months after net distribution (767 [42·4%] of
1809; OR 0·37, 95% CI 0·21–0·65; p=0·0011).154
Indoor residual spraying with insecticides is another
strategy to prevent malaria, but household coverage
needs to be high (≥80%) to maximise the potential of
this method. The duration of protection provided by
indoor residual spraying is approximately 3–6 months.
Results from trials evaluating the effect of adding indoor
residual spraying to insecticide-treated nets with
pyrethroid and non-pyrethroid insecticides on the
incidence of malaria have been mixed, making
recommending policies to national programmes with
finite resources difficult.155
Research continues to be done on transgenic
mosquitoes. The leading approach focuses on genetic
engineering and the release of sterile male mosquitoes.156
Piloted in a contained study in Burkina Faso with
encouraging results, another novel approach to mosquito
control is the introduction of transgenic Metarhizium
pingshaense carrying toxins that are lethal to mosquitoes.157
Conclusion
The childhood burden of malaria has been high for so
long that the annual malaria statistics no longer provoke
the outrage and action these data deserve. Since 2010,
more than 3 million children have died from malaria
www.thelancet.com/child-adolescent Vol 4 October 2020 785
Series
and a failure to control malaria will inevitably increase
this number. Stagnation of progress to reduce malaria in
several countries suggests that action is needed now,
action such as increasing investment in malaria control
efforts that use existing tools and continuing to develop
new insecticides, vaccines, and drugs for the treatment
and prevention of uncomplicated and severe malaria,
including safer agents for the prevention of vivax malaria
relapse (panel). Resistance-proofing strategies need to be
prioritised at the development stage and when deciding
how many and which drugs to incorporate into new
combinations. Antimalarial dosing in children needs to
be evaluated earlier in the clinical development process
to avoid launching new treatments at suboptimal doses
in this vulnerable group.
Contributors
EAA wrote the first draft of the sections on falciparum malaria.
JRP wrote the first draft of the sections on vivax malaria. Both authors
reviewed and edited the manuscript before submission.
Declaration of interests
We declare no competing interests.
Acknowledgments
We thank Nicholas J White for providing figure 2. The Lao-Oxford-
Mahosot Hospital-Wellcome Trust Research Unit is part of the MORU
Tropical Health Network funded by the Wellcome Trust. The Timika
Research Facility and Papuan Health and Community Development
Foundation were supported by the Australian Agency for Internationa
Development, Department of Foreign Affairs and Trade (known as
AusAID).
Editorial note: the Lancet Group takes a neutral position with respect to
territorial claims in published maps and institutional affiliations.
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