Malaria

Seminar
Malaria
Jeanne Rini Poespoprodjo, Nicholas M Douglas, Daniel Ansong, Steven Kho, Nicholas M Anstey
Malaria is resurging in many African and South American countries, exacerbated by COVID-19-related health service Published Online
disruption. In 2021, there were an estimated 247 million malaria cases and 619 000 deaths in 84 endemic countries. November 1, 2023
https://doi.org/10.1016/
Plasmodium falciparum strains partly resistant to artemisinins are entrenched in the Greater Mekong region and have S0140-6736(23)01249-7
emerged in Africa, while Anopheles mosquito vectors continue to evolve physiological and behavioural resistance to
Centre for Child Health and
insecticides. Elimination of Plasmodium vivax malaria is hindered by impractical and potentially toxic antirelapse Department of Child Health,
regimens. Parasitological diagnosis and treatment with oral or parenteral artemisinin-based therapy is the mainstay Faculty of Medicine, Public
of patient management. Timely blood transfusion, renal replacement therapy, and restrictive fluid therapy can Health and Nursing,
Universitas Gadjah Mada,
improve survival in severe malaria. Rigorous use of intermittent preventive treatment in pregnancy and infancy and Yogyakarta, Indonesia
seasonal chemoprevention, potentially combined with pre-erythrocytic vaccines endorsed by WHO in 2021 and 2023, (J R Poespoprodjo MD); Timika
can substantially reduce malaria morbidity. Improved surveillance, better access to effective treatment, more labour- Malaria Research Facility,
efficient vector control, continued drug development, targeted mass drug administration, and sustained political Papuan Health and Community
Development Foundation,
commitment are required to achieve targets for malaria reduction by the end of this decade. Timika, Indonesia
(J R Poespoprodjo, S Kho PhD);
Introduction geographical distribution of vector species, their Mimika District Hospital and
Malaria is a tropical and subtropical, mosquito-borne proximity to humans, and the capacity of human District Health Authority,
Timika, Indonesia
parasitic disease that is endemic in 84 countries and populations to control vectors and effectively manage (J R Poespoprodjo); Global and
causes an estimated 247 million clinical infections and infection.12 Therefore, malaria flourishes in low-income Tropical Health Division,
619 000 deaths annually.1 The infectious agent is a tropical regions and is exacerbated by social disruption, Menzies School of Health
single-celled intracellular protozoan from the genus such as war or natural disaster. Research, Charles Darwin
University, Darwin, NT,
Plasmodium. Six species commonly infect humans Of an estimated 247 million malaria cases annually, Australia (J R Poespoprodjo,
(figure 1), of which Plasmodium falciparum and 234 million (95%) occur in malaria-endemic countries in N M Douglas FRACP, S Kho,
Plasmodium vivax are the most important. Morbidity Africa where 99% of infections are caused by P falciparum Prof N M Anstey FRACP);
and mortality from malaria stem from parasitic (figure 2).1 Four African countries were estimated to Department of Infectious
Diseases, Christchurch
invasion of erythrocytes leading to haemolysis and, in account for over half of all malaria deaths in 2021: Hospital, Te Whatu Ora
P falciparum infections, sequestration of infected red Nigeria (31%), Democratic Republic of the Congo (13%), Waitaha, Christchurch,
cells in the microvasculature of vital organs.5 Most Niger (4%), and Tanzania (4%).1 7·4 million malaria New Zealand (N M Douglas);
Department of Medicine,
deaths from malaria are caused by P falciparum in cases occur in South America and the WHO South-East
University of Otago,
sub-Saharan Africa, whereas P vivax is more prevalent Asian and Western Pacific regions, where P falciparum Christchurch, New Zealand
in Asia and South America and predominantly causes and P vivax are often coendemic.1 In 2021, WHO (N M Douglas); School of
anaemia from relapsing infections.6 estimated there were 4·9 million P vivax cases.1 The Medicine and Dentistry,
Kwame Nkrumah University of
Early diagnosis and prompt effective treatment of other three human-only Plasmodium species account for
Science and Technology,
malaria prevents severe sequelae and death and reduces fewer than 0·5 million cases. Plasmodium malariae Kumasi, Ghana
the risk of onward transmission of the parasite. and the two non-recombining sympatric species (Prof D Ansong FWACP);
Prevention strategies for malaria include various forms Plasmodium ovale curtisi and Plasmodium ovale wallikeri Department of Infectious
Diseases, Royal Darwin
of chemoprophylaxis, mosquito vector control, and, in have broad geographical distributions but due to
Hospital, Darwin, NT, Australia
some regions of sub-Saharan Africa, vaccination. These difficulties in diagnosis, low parasitaemia, and relatively (Prof N M Anstey)
strategies are continually threatened by evolutionary lower virulence, are commonly diagnosed incidentally.13 Correspondence to:
adaptation of the parasite and mosquito vector. Plasmodium knowlesi infects macaque monkeys in Dr Jeanne Rini Poespoprodjo,
In the early 2000s, the large-scale introduction of southeast Asia14 and causes zoonotic, sometimes fatal, Timika Malaria Research Facility,
Papuan Health and Community
artemisinin-based combination therapies (ACTs) for malaria in humans.15 Seven other zoonotic species
Development Foundation,
uncomplicated malaria and intravenous artesunate for reported to cause geographically restricted human Timika 99910, Indonesia
severe malaria and improved parasitological diagnosis infections are rare (figure 1). [email protected]
contributed to a substantial decline in global malaria The intensity of malaria transmission determines the
mortality.1,7,8 Unfortunately, global malaria incidence age distribution of clinical malaria and malaria-associated
has increased in the past 5 years and new challenges, mortality.16 In many parts of sub-Saharan Africa,
such as spreading artemisinin resistance and individuals receive more than ten infectious mosquito
COVID-19-related disruption to health systems threaten bites per year.17 In these environments, intense parasite
malaria control.1,9,10 exposure leads to rapid development of premunition
(protection against high parasitaemia and illness without
Epidemiology eliminating the infection), skewing the burden of severe
Malaria is transmitted by female Anopheles mosquitoes malaria to children younger than 5 years.5 In such highly
that breed in freshwater bodies in warm and humid endemic settings, severe malaria in adults is unusual,
environments.11 Endemicity is determined by the but a substantial proportion of the population will have
www.thelancet.com Published online November 1, 2023 https://doi.org/10.1016/S0140-6736(23)01249-7 1

Descargado para PEDRO Campos ([email protected]) en Cayetano Heredia Pervuvian University de ClinicalKey.es por Elsevier en noviembre 14,
2023. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2023. Elsevier Inc. Todos los derechos reservados.
Seminar
Human-only species
Rings Trophozoites Schizonts Gametocytes Characteristics
• Usually higher parasitaemia compared with other species

• Maurer’s clefts can be visible in rings and trophozoites
Plasmodium • Trophozoites, schizonts, and immature gametocytes not
falciparum normally seen in blood smears (sequester and accumulate
in microvasculature and tissues)
• Schizonts comprise 8–24 merozoites
• Crescent-shape characteristic of mature gametocytes
• Larger cytoplasm in rings; Schüffner’s dots can be visible

• Trophozoites amoeboid-shaped; irregular cytoplasm
Plasmodium • Schizonts enlarged and comprise 12–24 merozoites
vivax • Round-to-oval-shaped gametocytes; scattered pigment
• All stages present in blood smears (most biomass present
in several organs, predominantly the spleen)
• Strict tropism for infecting immature (CD71+) reticulocytes
• Parasitised red cells not enlarged

• Rings sometimes small with large chromatin dot
Plasmodium • Trophozoites have compact cytoplasm; occasionally
malariae present as band forms; coarse, dark pigment
• Schizonts comprise 6–12 merozoites around dark pigment
mass; merozoites occasionally form rosettes
• All stages present in blood smears
Plasmodium • Robust cytoplasm in rings; Schüffner’s dots can be visible

ovale wallikeri • Trophozoites round to oval, often tear-drop shaped;
and compact cytoplasm with large chromatin dot
Plasmodium • Schizonts comprise 6–14 merozoites around pigment mass
ovale curtisi • All stages present in blood smears
• Strict tropism for infecting immature (CD71+) reticulocytes
• Occasionally misidentified as P vivax
Zoonotic species
• Rings resemble P falciparum

• Trophozoites have compact cytoplasm; occasionally
Plasmodium present as band form; resemble P malariae
knowlesi • Schizonts comprise up to 16 merozoites around dark
pigment mass; merozoites occasionally form rosettes
• All stages present in blood smears
• Geographical distribution: southeast Asia
Characteristics Geographical distribution in humans
Plasmodium cynomolgi Morphologically similar to P vivax Southeast Asia
Plasmodium inui Morphologically similar to P malariae Malaysia and Thailand
Plasmodium coatneyi Morphologically similar to P falciparum Malaysia
Plasmodium semiovale Morphologically similar to P ovale Malaysia
Plasmodium simium Morphologically and molecularly similar to P vivax Brazil
Plasmodium brasilianum Morphologically and molecularly similar to P malariae Central and South America
Plasmodium fieldi Morphologically similar to P vivax and P ovale Thailand (co-infection)
Figure 1: Microscopy of Plasmodium species infecting humans

Geographical distribution of P cynomolgi, P inui, P semiovale, P coatneyi, P simium, and P brasilianum described in Antinori et al,2 and Yap et al.3 Cryptic P fieldi infections
recently discovered in Thailand.4
asymptomatic, submicroscopic parasitaemia.5 Asympto P vivax malaria tends to develop earlier than for
m
atic parasitaemia is a major contributor to malaria P falciparum in coendemic locations.19,20 Non-immune
transmission.18 travellers and people displaced into endemic regions are
Outside of Africa, transmission of P falciparum and at high risk of severe malaria at any age.5
P vivax is generally lower with many areas having
seasonal or sporadic incidence.19 In these lower- Biology
endemicity environments, all age groups are at risk of Sporozoites from female Anopheles mosquitoes enter the
severe falciparum malaria.19 Submicroscopic, asymptom human circulation following a blood meal and are
atic parasitaemia is also common. Premunition against transported to the liver to invade hepatocytes (figure 3).
2 www.thelancet.com Published online November 1, 2023 https://doi.org/10.1016/S0140-6736(23)01249-7

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Endemic P falciparum with no PfKelch13

mutated strains or ACT failure
Endemic P falciparum with PfKelch13 mutated
strains, but no consistent ACT failure*
Endemic P falciparum with PfKelch13 mutated
strains and ACT failure†
Endemic chloroquine-susceptible
P vivax
Endemic chloroquine-resistant P vivax‡
Figure 2: Map of Plasmodium falciparum (A) and Plasmodium vivax (B) endemicity and antimalarial drug resistance as at Jan 31, 2023
ACT=artemisinin-based combination therapies. *≥5% of isolates in one or more provinces positive for one or more WHO-validated or WHO-associated
PfKelch13 mutations associated with partial artemisinin resistance. †≥5% of isolates in one or more provinces positive for one or more WHO-validated or WHO- For the tracking of PfKelch13
associated PfKelch13 mutations associated with partial artemisinin resistance and consistent day-28 failure rate of ≥10% after artemether–lumefantrine, mutations see https://www.
dihydroartemisinin–piperaquine, or artesunate–mefloquine. ‡At least one study showing day-28 failure ≥10% after chloroquine treatment. Figure created with wwarn.org/tracking-resistance/
mapchart.net. artemisinin-molecular-surveyor
After 5–8 days of pre-erythrocytic incubation merozoites released into the bloodstream reinvade
(approximately 15 days for P malariae21), merozoites are surrounding erythrocytes, thus commencing a new
released from rupturing hepatic schizonts and enter asexual cycle. Although P falciparum invades red blood
circulation to invade red blood cells, initiating the cells of all ages, P vivax and P ovale only invade young
intraerythrocytic lifecycle responsible for malaria reticulocytes expressing CD71.22 During physiological
symptoms. Asexual parasite development in erythrocytes splenic passage, asexual stages of P falciparum and
occurs over 24–72 h depending on species, progressing P vivax are retained in the spleen initiating an
from rings, to trophozoites, and finally to multinucleated endosplenic lifecycle in both species.23 The reticulocyte-
erythrocytic schizonts (figure 1). At schizogony, rich spleen sustains the majority of asexual-stage

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P falciparum P vivax
Liver stage Endosplenic Mosquito cycle Liver stage Endosplenic

asexual asexual
cycle cycle
Hypnozoite
Bone marrow
sexual development Bone marrow niche
Circulating Circulating
asexual cycle asexual cycle
Figure 3: Plasmodium falciparum and Plasmodium vivax lifecycle

Human infection begins when a mosquito inoculates sporozoites into the skin during a blood meal. Sporozoites subsequently infect hepatocytes. Pre-erythrocytic
incubation ends when hepatic schizonts release merozoites (green dots) from the liver into the bloodstream to commence the intraerythrocytic asexual lifecycle.
Asexual stages (rings, trophozoites, and schizonts) undergo maturation within erythrocytes followed by erythrocyte rupture, with subsequent reinvasion of
merozoites (purple dots) into uninfected erythrocytes in the spleen (greater for P vivax than P falciparum) and peripheral blood. Sexual-stage development occurs in
the bone marrow. Mature gametocytes are released into the bloodstream and are subsequently ingested by a mosquito during a blood meal, facilitating onward
parasite transmission.
biomass in P vivax infections.24 Asexual parasites are also cells.5,28 Sequestered parasite biomass and endothelial
found in the bone marrow in falciparum and vivax activation are each independently associated with impaired
infections.25,26 Multiple cycles of intravascular asexual perfusion, severity of organ dysfunction, and mortality.29,30
replication allow the parasite to proliferate rapidly and Cytoadherence is mediated by binding of the PfEMP1
drive pathogenesis. Individuals infected with P vivax or family of proteins expressed on parasitised erythrocytes to
P ovale develop latent hypnozoites within hepatocytes, receptors on endothelial cells and other red cells. Different
which can activate weeks or months after the initial PfEMP1 variants encoded by var genes have different
infection, causing relapsing blood-stage infection. binding affinities to receptors differentially expressed in
The bone marrow is a major site for the development different organs, thereby contributing to risk of specific
of sexual stages, whereby sexually committed rings severe malaria manifestations.31,32 Endothelial receptors
differentiate into gametocytes following environmental include EPCR, ICAM-1, and CD36. PfEMP1 variants with
and host cues favouring transmission. After 9–12 days, increased binding to EPCR, especially dual binding to
mature P falciparum gametocytes enter circulation and EPCR and ICAM-1, are associated with cerebral malaria.
become infectious after a further 2–3 days.27 P vivax These variants mediate not only sequestration of
gametocytes mature faster (2–3 days) and infectious parasitised red cells,31,33 but also loss of EPCR-dependent
gametocytes are typically found in circulation before the cytoprotection,28,34 including localised fibrin deposition,
onset of symptoms. After gametocyte ingestion by a platelet activation, loss of endothelial barrier-function, and
competent mosquito, sexual reproduction occurs in the microhaemorrhages. Endothelial dysfunction in malaria is
mid-gut to form a zygote. Gut ookinetes transform into exacerbated by degradation of cytoprotective glycocalyx,
an oocyst containing thousands of sporozoites, which reduced bioavailability of nitric oxide, Weibel-Palade body
migrate to salivary glands for onward transmission. exocytosis, release of free haem and parasite histones from
red cells, and release of neutrophil extracellular traps, with
Pathogenesis each of these processes associated with disease
P falciparum severity.28,29,35–37
Severe falciparum malaria is caused by microvascular Autopsy studies in cerebral malaria show strong
sequestration and obstruction from parasitised red cells associations between depth of coma, the magnitude of
cytoadhering to activated and dysfunctional endothelial sequestration of parasitised red cells, and vascular

Seminar
congestion with both infected and uninfected red cells.38 In in spleen and bone marrow.23–25 Circulating asexual-stage
children with cerebral malaria, brain swelling is the central infected red cells are substantially more deformable than
radiological finding39,40 and is strongly associated with P falciparum.65,66 Although less common than in
mortality, suggesting raised intracranial pressure and falciparum malaria, organ dysfunction is associated with
brainstem herniation are on the causal pathway to death in parasite biomass-related endothelial activation and
this age group.39 In addition to vascular congestion, other systemic inflammation.67,68 Severe anaemia is associated
proposed causes of brain swelling include vasogenic with repeated relapses from liver hypnozoites before
oedema and haemorrhagic breaches in the blood–brain haematological recovery, causing progressive loss of both
barrier, autoregulatory dysfunction, and, to a lesser degree, infected and uninfected red cells, with associated
cytotoxicity.38,39,41,42 In a subset with appearances similar to mortality.69–71 Chronic submicroscopic infections are
posterior reversible encephalopathy syndrome, blood– sustained by both hypnozoite relapses and release from
brain barrier dysfunction, venous congestion, and auto the extravascular splenic reservoir.23 In the placenta,
regulatory dysfunction might be causative.43 Retinal studies there is no parasite sequestration, but placental
suggest that hypoxic injury underlies neurological sequelae insufficiency is associated with inflammatory responses,
in survivors.42–44 In adult cerebral malaria, brain swelling is dysregulation of angiopoietin 1 and 2, vascular disruption,
less severe and is not associated with mortality.40,45 and maternal anaemia.72,73
Major contributors to metabolic acidosis are lactate from
inadequate tissue oxygenation and impaired clearance,5 P knowlesi
other host organic acids,46 and gut microbial acids that Fatal knowlesi malaria is associated with microvascular
translocate into the bloodstream.47 This increased gut accumulation of parasitised red cells through
permeability arises from parasite sequestration48 and mechanisms different to those in P falciparum.74 Impaired
impaired production of gut-protective citrulline and perfusion, organ injury, and severe disease are also
glutamine,49 and contributes to the increased risk of associated with reduced deformability of uninfected and
concomitant bacteraemia in severe malaria with infected erythrocytes, endothelial activation, glycocalyx
Salmonella and other Gram-negative bacteria.50 Shock is degradation, and haemolysis.74–76
less common in severe malaria than in severe sepsis, with
increased systemic vascular resistance in malaria arising Clinical presentation
from nitric oxide scavenging by haemolysis-related cell- Malaria is a non-specific febrile illness that cannot be
free haemoglobin.51 Relative hypovolaemia and reduced differentiated from other infections on clinical grounds
cardiac index reserve are found in patients before death.52 alone. Typical symptoms include fever, chills, headache,
Acute kidney injury (AKI) is associated with parasite vomiting, diarrhoea, and cough. In highly endemic areas,
sequestration, free haem-mediated oxidative damage to parasitaemia is often coincidental to an alternative cause
renal tubular epithelium, glycocalyx degradation, and of illness.77 Parasitaemia, platelet count, and plasma
endothelial activation.53–55 HRP2 thresholds for falciparum malaria have been
Anaemia in acute malaria is multifactorial. Loss of evaluated in regions of different endemicity to distinguish
uninfected red cells exceeds the destruction of parasitised the likelihood of malaria causing symptoms and to
red cells in all species.56 Oxidative damage, G6PD differentiate uncomplicated from severe malaria.77–79 In
deficiency, complement-mediated destruction, reduced non-endemic regions, a travel history is essential to
red cell deformability, and increased splenic retention ensure malaria is considered in the differential diagnosis
and clearance all contribute to loss of uninfected red and excluded.
cells.23,56,57 Dyserythropoiesis impairs erythrocyte Clinical features of severe falciparum malaria vary with
production.56 Anaemia is exacerbated by prolonged age and pregnancy status.5,80 Signs of severe malaria in
parasitaemia and delayed presentation58,59 and parasite children in endemic areas include prostration, reduced
clearance.59 Thrombocytopenia is also multifactorial, but consciousness, respiratory distress, severe anaemia,
a major cause is platelet-binding to infected red cells.60 hypoglycaemia, shock, and jaundice (panel 1).77,82 Severe
Placental malaria is caused by sequestration of AKI, acute respiratory distress syndrome (often
parasitised red cells in the intervillous spaces, mediated by commencing after treatment), and jaundice are more
P falciparum VAR2CSA binding to placental chondroitin common in adults than children, whereas severe anaemia
sulphate A61 with associated monocyte infiltration,62 and convulsions are generally less common.5 Pregnant
angiopoietin 1 and 2 dysregulation, and vascular women are particularly susceptible to hypoglycaemia,
disruption.62,63 Malaria in early pregnancy (ie, <15 weeks severe anaemia, and jaundice.83 Respiratory distress in
gestational age) alters placental angiogenesis, reduces malaria is associated with severe anaemia and metabolic
uteroplacental perfusion, and impairs fetal growth.64 acidosis.77,82 Abnormal posturing and prolonged and
repeated convulsions commonly accompany coma and
P vivax can cause long-term neurological sequalae.5,77 Blackwater
There is minimal microvascular sequestration in vivax fever is commonly reported in African children.82 AKI is
malaria, but greater extravascular parasite accumulation now recognised as an important complication in

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malaria, the risk of in-hospital death rises with a

Panel 1: WHO epidemiological and research criteria for severe malaria5 haemoglobin less than 5 g/dL, markedly so if less than
• Impaired consciousness: a Glasgow coma score <11 or a Blantyre coma score <3 in 3 g/dL.85 The risk for death increases in the presence of
children younger than 5 years or who have not learned to speak multiple complications. Impaired consciousness, base
• Pulmonary oedema: radiologically confirmed or oxygen saturation <92% on room deficit (base excess less than –8 mmol/L), elevated blood
air with a respiratory rate >30 per min, often with chest indrawing and crepitations urea (blood urea nitrogen ≥20 mg/dL), and clinical signs
on auscultation of underlying chronic illness (eg, lymphadenopathy) are
• Substantial bleeding: including recurrent or prolonged bleeding from the nose, gums, independent predictors of death in children, with more
or venepuncture sites; haematemesis or melaena than one complication increasing risk of mortality from
• Shock: compensated shock is defined as capillary refill ≥3 s without hypotension. 6% to 43%.8,86 A simple bedside score can predict risk of
Decompensated shock is defined as systolic blood pressure <70 mm Hg in children or death in adults with severe malaria.87
<80 mm Hg in adults, with evidence of impaired perfusion (ie, cool peripheries or The clinical features of uncomplicated vivax malaria
prolonged capillary refill) are similar to falciparum malaria. Severe manifestations
• Acidosis: a base deficit of >8 mEq/L, a plasma bicarbonate concentration of of infection are less common than in falciparum malaria
<15 mmol/L, or venous plasma lactate ≥5 mmol/L. Severe acidosis manifests clinically except for severe anaemia in infants and young children
as respiratory distress (ie, rapid, deep, and laboured breathing) in high-transmission areas, such as the island of
• Hypoglycaemia: blood or plasma glucose <2·2 mmol/L (<40 mg/dL) New Guinea.85,88,89 In these regions, relapses occur every
• Severe malarial anaemia: haemoglobin concentration ≤5 g/dL or a haematocrit of 3–6 weeks, accounting for 60–80% of clinically apparent
≤15% in children aged <12 years (haemoglobin concentration <7 g/dL and P vivax infections.88–91 Failure to prevent relapses with
haematocrit <20% in individuals aged ≥12 years) with a parasite count >10 000 per μL hypnozoitocidal therapy can lead to progressive chronic,
• Severe acute kidney injury: plasma or serum creatinine >265 μmol/L (3 mg/dL) or severe anaemia and delayed mortality.70,88,92 Organ
blood urea >20 mmol/L in individuals aged >12 years; not defined by WHO in children dysfunction is less common in vivax malaria than
aged <12 years falciparum malaria, but can include acute lung injury,
• Jaundice: plasma or serum bilirubin >50 μmol/L (3 mg/dL) with a parasite count hypotension, AKI,67,93 and, rarely, coma.94 Severe P vivax
>100 000 per μL; Plasmodium knowlesi: jaundice and parasite density >20 000 per μL malaria in very low transmission settings is rare.
• Hyperparasitaemia: Plasmodium falciparum parasitaemia >10% of infected Uncomplicated and severe knowlesi malaria presents
erythrocytes in stable high endemicity area; P knowlesi parasite density >100 000 per similarly to falciparum malaria, except that coma is notably
μL absent and over 90% of patients are adults.15,74 Although
patients can develop hyperparasitaemia, severe and fatal
Additional epidemiological criteria for severe malaria included in WHO malaria guidelines:81
disease occurs at lower parasitaemia than in falciparum
• Prostration: the person is unable to sit, stand, or walk without assistance
malaria.15,74,95 P malariae causes chronic low-parasitaemia
• Multiple convulsions: more than two episodes within 24 h
infections and anaemia.85 Nephrotic syndrome can occur
• Severe vivax malaria: defined as for falciparum malaria but with no parasite density
as a late sequela of P malariae infection in approximately
thresholds
1 in 500 microscopy-positive patients.96
Clinical criteria for use of intravenous artesunate
• Unable to take oral medications, or Laboratory diagnosis
• any research or epidemiological criteria for severe malaria, or Microscopy of thick and thin blood films remains the
• any evidence of dysfunction of vital organs, or gold standard for diagnosing malaria. This method
• high parasitaemia (for P falciparum: ≥2% in low-transmission regions and in non- can differentiate Plasmodium species and quantify
immune travellers and ≥4% in high-transmission regions; for P knowlesi: parasitaemia, both important for diagnosing and
>15 000 parasites per μL) prognosticating severe malaria, targeting appropriate
treatment, and monitoring therapeutic response.97
Unless performed by experienced technicians, micro
paediatric as well as adult severe malaria and is associated scopy results might not be reliable.97
with risk of death.84 Malaria rapid diagnostic tests (RDTs) are used as an
WHO describes epidemiological and research criteria alternative or adjunct to microscopy, particularly in
for severe malaria (panel 1).5,81 In routine clinical practice, settings with limited access to quality microscopy. RDTs
clinicians should worry less about epidemiological and that detect HRP2, an antigen exclusively produced by
research definitions of severity: a patient who is unable P falciparum, are usually sensitive for diagnosis of this
to take oral medications or has organ dysfunction or species, but cannot be used to evaluate treatment
high parasitaemia (>2%) is at increased risk of dying and response because HRP2 can persist in once-infected,
should be treated for severe malaria with parenteral parasite-free erythrocytes after splenic pitting.98
therapy and the best supportive care available.81 False-negative results arise from P falciparum isolates
Within the broad definition of severe malaria, some without either or both of the PfHRP2 and PfHRP3 genes,
syndromes are associated with lower in-hospital mortality increasingly reported across South America, Africa, and
rates (eg, severe anaemia) and others with higher Asia.98–100 These gene deletions threaten the utility of
mortality rates (eg, acidosis).81 In acute falciparum HRP2-based diagnostics.98

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Non-falciparum malaria species can be detected with Severe malaria

pLDH RDTs,97 including P knowlesi,101 although cross- All patients, regardless of infecting Plasmodium species
reactivity of species-specific pLDH remains a barrier for (figure 1) and pregnancy status, who fulfil criteria for
accurate RDT-based diagnosis in regions coendemic for severe malaria, are unable to take oral therapy, have any
multiple non-falciparum infections, including zoonotic evidence of vital organ dysfunction, or have high
species.102 parasitaemia should receive intravenous artesunate
Nucleic acid testing (NAT), including as part of multiplex immediately (panel 2). Intravenous artesunate reduces
fever panels, is highly sensitive103 and useful in reference mortality in adults by 35% and in children by 22%
laboratories. Although used in some non-endemic settings compared with intravenous quinine.7,8 If artesunate is
for acute diagnosis in undifferentiated fever, NAT is unable not available, intramuscular artemether is a less effective,
to quantitate parasitaemia to guide use of parenteral second-line alternative.105 Intravenous quinine should
therapy, and in most endemic settings is not available or only be used as monotherapy if parenteral artemisinin
ideal for immediate treatment decisions. therapy is unavailable. The addition of intravenous
quinine to artesunate has been recommended for severe
Case management malaria in regions with artemisinin resistance,5,10,106
Comprehensive guidelines for management of severe although trial evidence of improved combination efficacy
and uncomplicated malaria are provided by WHO.5,81 is not yet available.10 Parenteral antimalarial therapy for
Panel 2: Malaria treatment81

Severe malaria for adults and children weighing ≥25 kg; children weighing
First line <25 kg: at least 2·5 mg/kg per day dihydroartemisinin and
• Intravenous artesunate: 2·4 mg/kg per dose at 0 h, 12 h, and 20 mg/kg per day piperaquine given once a day for 3 days
24 h, then every 24 h if necessary; if bodyweight is <20∙0 kg, • Artesunate–amodiaquine (sensitive P falciparum only):
give 3·0 mg/kg per dose to ensure equivalent exposure to 4 mg/kg per day artesunate (range 2–10 mg/kg) and
the drug 10 mg/kg per day amodiaquine (7·5–15 mg/kg) once a day
Alternatives if artesunate not available for 3 days
• Intramuscular artemether: initial dose 3·2 mg/kg, then • Artesunate–sulfadoxine–pyrimethamine (sensitive
1·6 mg/kg every 24 h P falciparum only): 4 mg/kg per day artesunate (range
• Intravenous quinine diluted in 5% dextrose: loading dose of 2–10 mg/kg) given once a day for 3 days and a single
20 mg/kg infused over 4 h, then 10 mg/kg every 8 h infused administration of at least 25 mg/kg sulfadoxine
no faster than 5 mg/kg per h (25–70 mg/kg) and 1·25 mg/kg pyrimethamine
• Pre-referral rectal artesunate: recommended in primary (1·25–3·5 mg/kg) given as a single dose on day 1
health-care settings in which parenteral drug administration • Infants weighing <5 kg with uncomplicated P falciparum
is not possible104 malaria: treat with ACT at the same mg/kg dose as for
children weighing 5 kg
Once eating and drinking • In the first trimester of pregnancy, use artemether–
• Give full course of oral antimalarial treatment as per lumefantrine in preference to the other ACTs
guidelines for uncomplicated malaria
• Avoid mefloquine-containing artemisinin-based Reducing risk of transmission of P falciparum in endemic areas
combination therapies (ACT) in patients initially presenting • Primaquine* single dose of 0·25 mg/kg without G6PD
with impaired consciousness because of increased risk of testing (maximum 15 mg base) given concomitantly with
post-malaria neurological syndrome blood schizontocidal treatment
Uncomplicated chloroquine-sensitive P vivax,
Uncomplicated malaria
Plasmodium malariae, and Plasmodium ovale malaria
Uncomplicated Plasmodium falciparum, Plasmodium knowlesi,
• Chloroquine: 10 mg base per kg day 1 and day 2, 5 mg base
or chloroquine-resistant Plasmodium vivax malaria
per kg on day 3; for children aged <5 years, total dose
• Artemether–lumefantrine: 0·83–4∙00 mg/kg artemether
30 mg/kg over 3 days
and 4·83–24∙00 mg/kg of lumefantrine given twice a day
for 3 days with fatty food; the first two doses should be Antirelapse therapy for P vivax or P ovale malaria
given 8 h apart • Primaquine*: 0·25–0·50 mg/kg per day for 14 days given
• Artesunate–mefloquine: 4 mg/kg per day artesunate (range concomitantly with blood schizontocidal therapy and after
2–10 mg/kg) and 8·3 mg/kg per day mefloquine exclusion of G6PD deficiency; lower risk of relapse in areas of
(7–11 mg/kg) given once a day for 3 days high relapse periodicity if a dose of 0·5 mg/kg per day is used
• Dihydroartemisinin–piperaquine: 4 mg/kg per day *Primaquine is contraindicated in pregnant women, infants aged <6 months, and women
dihydroartemisinin (range 2–10 mg/kg) and 18 mg/kg per breastfeeding infants aged <6 months.
day piperaquine (16–27 mg/kg) given once a day for 3 days

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severe malaria should be followed by a full course of oral transmission settings and should include meningitis
treatment. In general, a minimum of 24 h of intravenous cover in those with altered consciousness. Empirical
artesunate is recommended before switching to an oral broad-spectrum antibiotics should also be strongly
ACT. considered in adults diagnosed with severe malaria,
ideally after the collection of blood cultures.
Supportive treatments for severe malaria Patients with severe malaria should have frequent
Immediate supportive treatment addressing relevant monitoring of vital signs, level of consciousness, renal
manifestations of severe disease should be implemented function, haemoglobin, and glucose.77 Glucose should be
simultaneously with intravenous antimalarial treatment. replaced to ensure normoglycaemia. Parasitaemia should
Fluid therapy in both children and adults with signs of be assessed every 12–24 h during the initial phase of
impaired perfusion without hypotension should be given treatment.121
with caution, preferably crystalloids at a conservative
rate.107–110 Restrictive fluid therapy is safe and does not Adjunctive therapy for severe malaria
worsen kidney function or tissue perfusion in adults Regular paracetamol, the only adjunctive agent to show
with severe falciparum malaria.108 Aggressive fluid benefit in severe malaria, reduces haem-mediated AKI in
therapy can exacerbate intracranial hypertension109 and is adults with moderate and severe falciparum and knowlesi
associated with pulmonary oedema and increased malaria, particularly those with substantial intravascular
mortality.107,110,111 In some patients, small fluid boluses haemolysis.53,122 Various adjunctive treatments for cerebral
should be given if there are clear signs of shock, which malaria have not shown clinical benefit and should be
might be caused by concomitant bacterial infection.107,110 avoided.77 Some, including mannitol123 and phenobarbitone
Immediate whole-blood or red-cell transfusion should prophylaxis, increase mortality. Dexamethasone increases
be given for severe anaemia. Proposed arbitrary the risk of gastrointestinal bleeding by a factor of 8.124
haemoglobin thresholds for transfusion are less than
5 g/dL for children in high-transmission areas and less Uncomplicated malaria
than 7 g/dL for patients in low-transmission settings.81 Treatment of uncomplicated malaria depends on the
Overall mortality in children with severe anaemia does infecting Plasmodium species and likelihood of drug
not differ between those receiving 20 mL/kg of whole resistance. Uncomplicated P falciparum, P knowlesi, and
blood versus 30 mL/kg.112 In comatose patients, chloroquine-resistant P vivax malaria should be treated
endotracheal intubation and mechanical ventilation for with an approved ACT (panel 2; figure 2).81 ACTs include
airway protection is indicated where available.113 Lumbar a rapidly eliminated and potent artemisinin derivative
puncture is indicated in those with altered consciousness that clears parasitaemia quickly and a more slowly
to exclude meningitis and assess intracranial pressure.5 eliminated partner drug that clears residual parasites and
Lumbar puncture does not increase mortality in clinically reduces selection of artemisinin-resistant clones. Six
stable children with coma, even when brain swelling is ACTs are recommended by WHO and artemether–
present.114 Convulsions in cerebral malaria should be lumefantrine is the most used.125 Standard dosing
managed similarly to repeated seizures of any other regimens for the lumefantrine component are sub
cause.5 Phenobarbitone should not be given without optimal in young children and pregnant women and
respiratory support available.5 Renal replacement therapy should probably be prolonged to improve efficacy in
reduces mortality in severe AKI115 and is indicated in AKI these populations.126 Administration of artemether–
with substantial acidosis, hyperkalaemia or fluid lumefantrine with fatty food or milk is recommended to
overload, or if multiorgan dysfunction is present.5,113 optimise absorption.81 The most recently approved ACT,
Invasive bacterial co-infection, frequently caused by artesunate–pyronaridine, appears at least as effective as
Salmonella species, is estimated to occur in 5–12% of other ACTs and might have advantages when there is pre-
children with severe falciparum malaria and is associated existing parasite resistance to other agents.127
with up to a third of deaths in children diagnosed with Blood schizontocidal regimens active against
severe malaria.5,116 Many children are misdiagnosed with P falciparum are also active against the blood stages of
severe falciparum malaria when they have bacterial P vivax, P malariae, and P ovale. In general, chloroquine
sepsis or meningitis with incidental parasitaemia.79,117 can be used for these species as first-line therapy except
Rates of bacteraemia in adults hospitalised with where P vivax strains have developed chloroquine
falciparum malaria have varied118 from approximately resistance (panel 2; figure 2).128
1% of patients with severe malaria in Viet Nam119 to WHO now recommends artemisinin-based combin
15% of adults hospitalised for malaria in Myanmar,120 ation therapy (except for artesunate–sulfadoxine–pyrime
with bacteraemia associated with increased risk of death. thamine) for uncomplicated malaria in all trimesters of
Concomitant bacteraemia is difficult to identify clinically pregnancy following a systematic review showing fewer
in low-resource settings.120 Empirical broad-spectrum adverse pregnancy outcomes in patients treated with
antibiotics should be given to all children diagnosed artemether-lumefantrine versus quinine in the first
with severe malaria, particularly in moderate-to-high trimester.129 Artemether–lumefantrine is preferred over

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other ACTs in the first trimester due to greater asymptomatic but can still cause chronic severe anaemia.147
accumulated evidence of safety. Although P falciparum causes by far the greatest burden of
maternal malaria, adverse maternal and pregnancy
Antirelapse therapy for P vivax and P ovale malaria outcomes also occur following P vivax infections.72
In addition to blood-stage therapy, patients with P vivax Obtaining a laboratory diagnosis of malaria in pregnant
or P ovale malaria should receive a hypnozoitocidal drug women is challenging. Peripheral blood microscopy might
to prevent future relapses. The 8-aminoquinoline, be parasite-negative because of placental parasite
primaquine, is the primary therapeutic option for sequestration.147 In highly endemic areas, acquired
antirelapse treatment. Tafenoquine, a new, long-acting immunity frequently limits parasitaemia to concentrations
analogue of primaquine that can be given as a single below detection thresholds for microscopy and RDTs.148
dose, was first approved for use in 2018,130 but remains Therefore, universal coverage of effective maternal malaria-
inaccessible in most countries with vivax malaria. prevention strategies in endemic regions is crucial.
Tafenoquine might require higher dosing than currently
recommended for optimal efficacy and appears to Congenital and neonatal malaria
be less active when coadministered with an ACT than Congenital and neonatal malaria is defined as parasitaemia
chloroquine.131,132 Both drugs can cause oxidative within the first 7–28 days of life.146 The estimated global
haemolysis in patients with G6PD deficiency with the prevalence of symptomatic congenital and neonatal
severity of haemolysis proportional to the dose of drug malaria is 0·1–0·6%.149 Failure to include congenital and
and degree of enzyme deficiency.133 G6PD deficiency neonatal malaria as a differential diagnosis in sick
should be excluded before prescription of either drug, neonates presenting with sepsis syndrome in endemic
but this recommendation is often not followed or areas can lead to life-threatening treatment delay.149,150
hypnozoitocidal treatment omitted altogether in endemic Maternal-to-fetal malaria transmission can occur in utero
regions due to unavailability of suitable assays.134 Point- or at delivery.151,152 Although most patients are asymptomatic
of-care G6PD tests have been developed and trialled,135 and parasitaemia might spontaneously clear, symptomatic
and are starting to be deployed in some countries. disease can manifest later between 2 and 20 weeks of
Primaquine is typically given over 14 days to achieve a age.153 The incidence of congenital P falciparum and
total dose of 3·5–7·0 mg/kg. Adherence to this protracted P vivax malaria is significantly reduced following highly
regimen can be poor.136,137 WHO endorses a shorter effective maternal malaria treatment.146,149,154
3·5 mg/kg course over 7 days (0·5 mg/kg per day) as an
alternative regimen,81 but a 7∙0 mg/kg total dose, when Antimalarial drug resistance
G6PD activity can be assessed reliably, is more efficacious The recurrence of malaria following treatment can be
in most regions138 and is the preferred regimen when because of incomplete clearance of parasitaemia (recru
administered over 14 days.139,140 Increasing the dose of descence), reinfection, or, in the case of P vivax and P ovale
primaquine to 1∙0 mg/kg per day and shortening the malaria, relapse. Recrudescence is more probable if there
total duration of treatment to 7 days is as efficacious as is initial hyperparasitaemia, suboptimal antimalarial
0·5 mg/kg per day over 14 days and is likely to improve drug dosing or absorption, use of substandard or fake
treatment adherence.141 However, the 1 mg/kg daily dose antimalarial drugs, incomplete adherence to treatment, or
is associated with gastrointestinal intolerance and risk of parasite resistance to the antimalarial drugs used.
severe haemolysis in groups with haemolytic vulnerability Antimalarial resistance has plagued efforts for malaria
(eg, G6PD-heterozygote female patients142).141 Children control since therapeutics were introduced. Chloroquine
might require higher primaquine doses to achieve is no longer active against P falciparum, except in
optimum therapeutic drug concentrations.143 central America, and is losing efficacy against P vivax
(figure 2). P falciparum resistance to mefloquine emerged
Malaria in pregnancy on the Thailand–Myanmar border in the 1990s and
Malaria in pregnancy can be fatal to both the mother and preceded the use of mefloquine as a partner drug to
fetus. In sub-Saharan Africa, maternal falciparum malaria artesunate.155
contributes to 10–20% of maternal deaths and is The derivatives of artemisinin, obtained from sweet
indirectly responsible for 75 000–200 000 infant deaths.73,144 wormwood (Artemesia annua), were developed as
Non-immune pregnant women and semi-immune pharmaceutical agents in China during the 1970s156 and
primigravidae are at particularly high risk of severe introduced in ACTs in the 1990s. Partial resistance of
malaria.145 Maternal malaria impairs placental function, P falciparum to artemisinin, manifesting as delayed
affecting fetal development and thereby increasing the parasite clearance, was first confirmed in 2007 in
risk of miscarriage, low birthweight, small for gestational Cambodia157 and is now widespread across the Greater
age, preterm delivery, and stillbirth.146 Mekong subregion.158 In some patients, pre-existing
In highly malaria-endemic areas where women of resistance to an ACT partner drug catalysed selection of
childbearing age typically have robust immunity, malaria artemisinin resistance.159 Failure of the artemisinin
in pregnancy (particularly in multigravidae) is often component has likewise accelerated selection of

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resistance-conferring mutations against partner drugs. Most heritable factors alter either the efficiency of
Clinical failure by day 28 after artemether–lumefantrine, parasite red-cell invasion or intraerythrocytic survival
dihydroartemisinin–piperaquine, and artesunate– and collectively account for approximately a third of the
mefloquine is now common in Thailand, Cambodia, Viet variability in risk of severe disease.184 Heterozygotes for
Nam, and Laos.160 The molecular signature of artemisinin HbS (sickle trait) are afforded 85–90% protection against
resistance is a mutated PfKelch13 gene and polymorphisms severe and fatal P falciparum malaria, but are not
causally linked or associated with phenotypic artemisinin protected against asymptomatic parasitaemia.185–188
resistance have now been detected throughout Asia and G6PD deficiency has considerable geographical overlap
in Uganda, Rwanda, Ethiopia, and Eritrea (figure 2).161–166 with malarious areas.189 Despite inconsistent evidence,
Although resistance to artemisinins and partner drugs G6PD deficiency probably confers protection against
is an important threat to global malaria control, the ACTs severe falciparum malaria.190,191 G6PD deficiency is also
remain effective in most parts of the malaria-endemic associated with protection against uncomplicated vivax
world. Triple-drug artemisinin-based therapy,167–169 and knowlesi malaria.192–194
artemisinins paired with pyronaridine,170 and longer The Duffy red blood cell antigen, a surface chemokine
treatment courses9 have been used successfully for receptor, is one of two invasion ligands for P vivax.
treatment in areas with high-grade resistance and could Mutations that prevent expression of the Duffy antigen
prolong the useful life of artemisinin-based therapies. on erythroid cells provide near-total protection against
Prioritised elimination of malaria from resistance microscopically detectable P vivax infections and
hotspot areas has been promulgated as an important have reached fixation prevalence across most of
means of limiting further spread of artemisinin-resistant sub-Saharan Africa.195
P falciparum strains. Multiple acquired factors affect the risk of both
Plasmodium infection and severe disease once infected.
Delayed complications of malaria Iron deficiency is associated with an up to 45% reduction
Long-term cognitive impairment arises from three of the in the risk of clinical falciparum malaria in children.196 The
major clinical syndromes associated with acute mortality COVID-19 pandemic disrupted access to malaria care and
in children with falciparum malaria: cerebral malaria,171,172 preventive activities. Evidence that patients with malaria
severe anaemia,173 and AKI.174 Other neurological sequelae and COVID co-infection have an increased risk of severe
of cerebral malaria include epilepsy, motor and visual disease is mixed.197–199 HIV infection increases Plasmodium
deficits, and short-term developmental delay.42,171,175 A parasitaemia and malaria severity,200 whereas malaria
reversible, post-malaria neurological syndrome can might increase HIV viral load and disease progression.201
develop rarely after recovery from severe and
uncomplicated falciparum malaria.176 AKI can lead to Prevention
chronic kidney disease.174 Chemoprevention
Haematological complications include residual severe Prompt diagnosis and effective treatment of malaria not
anaemia at hospital discharge associated with high only benefits individuals, but is also a cornerstone of
mortality in ensuing months,177 preventable with post- malaria prevention. Clearance of parasitaemia with
discharge malaria chemoprophylaxis. Post-artesunate ACTs minimises the risk of onward mosquito
delayed haemolysis because of the removal of once-infected transmission primarily by limiting development of
red cells can manifest as mild-to-moderate anaemia and, further gametocytes. This risk is reduced further by
rarely, severe anaemia or AKI 7–21 days after artesunate administering a single dose of primaquine to sterilise
treatment, particularly in those with no immunity and mature gametocytes in P falciparum malaria.
high initial parasitaemia.178–180 Splenic rupture might follow Antimalarial drugs are also used for mass-
acute vivax or falciparum malaria181 and is more common chemoprevention or targeted-chemoprevention pro
in adults than children. Chronic infection can cause grammes. Seasonal malaria chemoprevention during the
hyperreactive malarial splenomegaly.23 Cumulative heavy high-transmission season, now widely deployed across
exposure to P falciparum is associated with risk of Burkitt’s sub-Saharan Africa in preschool children, has been
lymphoma in African children.182 credited with major reductions in malaria morbidity and
The relationship between malaria and malnutrition is mortality.202 In regions with year-round malaria
bidirectional. Recurrent malaria causes malnutrition, with transmission, perennial malaria chemo prevention
malnutrition also increasing risk of severe malaria and (formerly intermittent preventive treatment of malaria in
death in both falciparum50 and vivax infections.183 Recurrent infancy81) reduces incidence of clinical malaria,
and chronic malaria also causes iron deficiency, most likely hospitalisation, and anaemia in children aged <2 years.203,204
through hepcidin-mediated block in iron absorption. Provision of three or more courses of sulfadoxine–
pyrimethamine during preg nancy (ie, intermittent
Factors that modulate the risk of malaria preventive treatment in pregnancy) is well tolerated and
Both heritable and acquired factors modulate the risk of reduces maternal moderate-to-severe anaemia, antenatal
See Online for appendix Plasmodium infection and malaria severity (appendix). parasitaemia, placental parasitaemia, spontaneous

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abortion, and low birthweight in highly endemic areas.205 clinical malaria episodes over 3–4 years by 36% in young
In some low-transmission areas outside of Africa, children first vaccinated between 5 months and 17 months
intermittent preventive treatment in pregnancy with of age and 26% in infants first vaccinated between
dihydroartemisinin–piperaquine is more effective for 6 months and 12 weeks of age.219 Protection against severe
preventing malaria than screening and treatment at the malaria was 32% in young children and 26% in infants.
initial pregnancy visit.148 Intermittent preventive treatment, R21, another pre-erythrocytic, CSP-based vaccine, has
particularly of infants, and, to a lesser extent, insecticide- potential for improved efficacy.220
treated bednets, have been estimated to be the most cost- The combination of chemoprophylaxis and vaccination
effective interventions to control malaria.206 holds greater promise than vaccines alone. Booster doses
of RTS,S before the wet season in combination with
Vector control seasonal malaria chemoprophylaxis achieved impressive
Bespoke engineering solutions that are suitable to local reductions in clinical malaria, severe malaria, and
topography and climate have historically been successful malaria-related death in west Africa.221
in reducing mosquito breeding sites and populations. Vaccine development for P vivax lags behind that of
Current vector-control strategies focus on use of long- P falciparum, but has followed similar strategies, showing
lasting insecticide-treated nets and indoor residual promise in phase 1 studies.222 Long-acting monoclonal
spraying to reduce indoor mosquito biting. These antibodies targeting CSP are efficacious in preventing
strategies have substantially reduced malaria morbidity,207,208 falciparum malaria in human volunteers223 and endemic
particularly in moderate-to-high transmission settings, but regions,224 and raise the potential for single-dose
are threatened by ongoing evolution of mosquito resistance immunoprophylaxis in non-immune travellers and
to pyrethroid insecticides.209 Bednets impregnated with seasonal immunoprophylaxis in endemic areas.
two active insecticidal ingredients with different modes of
action provide better malaria protection than single The future of malaria control and elimination
pyrethroid-only nets in areas of pre-existing mosquito Launched in 1955, the Global Malaria Eradication Program
pyrethroid resistance.210,211 The addition of the insecticide ended without success 14 years later.225 Since 1969, there
synergist piperonyl butoxide—a substance that blocks has been no further time-limited commitment to global
enzymatic resistance to pyrethroids within the mosquito— malaria eradication and its feasibility continues to be
to pyrethroid-treated nets also improves protection.212 As debated. However, malaria elimination—defined by WHO
well as chemical resistance, important Anopheles as the interruption of local transmission of a specific
vector species are increasingly displaying behavioural malaria parasite species in a defined geographical area due
resistance to standard vector-control measures by biting to deliberate activities226—is being pursued vigorously in
outdoors and during the daytime.213,214 Outdoor residual multiple countries with unstable malaria transmission.
spraying has shown promise as a potential means of The Sustainable Development Goals adopted by WHO
combating this behavioural change in Myanmar.215 in 2016 call for a reduction in malaria incidence and
Anopheles stephensi has recently spread from Asia to the mortality of at least 90% and elimination of malaria in at
Horn of Africa.216 This highly efficient vector of both least 35 countries by 2030. The E-2025 initiative, launched
P falciparum and P vivax prefers breeding in human- by WHO in 2021, aims to eliminate malaria in 25 countries
made containers and urban environments and thus primarily across Asia and Latin America by 2025.1 Progress
poses a substantial risk of increased receptivity to local has been uneven, with estimated incidence of malaria
transmission in urban Africa. rising by over 50% in two African countries and
four South American countries targeting elimination,1 and
Vaccines and monoclonals significantly in several high-burden countries in Africa in
Malaria vaccine development includes four main concept the past 5 years. Overall progress against malaria was
categories: (1) blood-stage vaccines to control erythrocytic already deteriorating before the COVID-19 pandemic.
merozoite multiplication; (2) pre-erythrocytic vaccines to Social upheaval from natural disasters, epidemics, and
prevent blood-stage infection altogether; (3) placental civil unrest (eg, Venezuela227 and Myanmar228) have
malaria vaccines targeting placenta-sequestering contributed to the resurgence of malaria in some locations.
parasites; and (4) transmission-blocking vaccines that Stagnant funding, substantial gaps in prevention and
kill sexual or mosquito stages.217 Of these categories, pre- treatment activities, and worsening antimalarial and
erythrocytic vaccines are the most advanced. Despite insecticide resistance have also contributed to varying
modest efficacy, RTS,S/AS01E, a pre-erythrocytic vaccine, degrees.1 Imprecision of country-level estimates of malaria
was recommended by WHO in 2021 for widespread use burden because of suboptimal surveillance data collection
in young children in areas of moderate and high and changes in methodology used to estimate incidence
P falciparum transmission—the first malaria vaccine to figures might also have resulted in inaccurate trends in
receive such endorsement.218 In African phase 3 clinical some locations.229
trials, three doses of the vaccine administered 1 month Consistent application of existing malaria control tools
apart followed by a booster dose 18 months later reduced might be sufficient to achieve elimination in countries that

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Panel 3: Priority areas for malaria research and development Search strategy and selection criteria
Vector control We searched PubMed, MEDLINE, Web of Science, Embase,
• Genetic manipulation of mosquitoes to confer refractoriness to Plasmodium and the Cochrane Database of Systematic Reviews using the
development and transmission search term “malaria”. We were unable to include all
• New insecticide classes for use in long-lasting, insecticide-impregnated bednets and references on this topic, and so we prioritised clinical trials,
indoor residual spraying systematic reviews, and studies of malaria pathogenesis or
• Novel strategies for mosquito population control, such as targeted sugar baiting epidemiology that were published in English between
Jan 1, 2018, and Jan 31, 2023. We also screened the reference
Diagnostics
lists of recently published articles for older seminal studies
• High throughput and very sensitive serological or molecular assays for detecting
and reviewed guidance documents in WHO’s online
residual Plasmodium transmission (human-only and zoonotic species) in regions
repository.
approaching elimination
• High throughput assays for detecting Plasmodium carriage in mosquitoes
• Ultrasensitive rapid tests for detecting hidden reservoirs of infection: low density populations (ie, the so-called gene-drive process) and
circulating infections, placental malaria, and splenic reservoirs attractive mosquito baits are two promising strategies.
• Rapid diagnostic tests for specifically identifying non-falciparum species New blood schizontocidal drugs that are active against
• Tests for hypnozoite carriage artemisinin-resistant strains are required. Wide
• Practicable and cheap point-of-care tests for G6PD deficiency deployment of rapid and practicable tests for G6PD
• Point-of-care diagnostic for identifying drug-resistant parasites deficiency would enable a much broader use of primaquine
Therapeutics or tafenoquine for relapse prevention in vivax malaria.
• New blood schizontocidal drugs that are active against parasites with artemisinin and Competing interests for malaria-control resources will
partner-drug resistance continue to arise, dictating greater efficiency of regulatory
• Effect and cost-effectiveness of wide deployment of triple artemisinin combination processes for research, development, and malaria
therapy in preventing or delaying the spread of artemisinin resistance interventions. Improved coordination of malaria control
• Rectal formulations of broad-spectrum antibiotics for combined use with pre-referral with other communicable disease programmes (eg, in
rectal artesunate mass drug-administration campaigns) is imperative.
• Single-dose, combination drug regimens for use in malaria treatment and Although a malaria-free world is possible, navigating the
chemoprophylaxis path to this lofty goal will require original thinking and
• Simplified primaquine regimens for Plasmodium vivax radical cure resolute perseverance.
• Optimised dosing of tafenoquine for improved P vivax radical cure Contributors
• New hypnozoitocidal drugs that do not cause oxidant haemolysis JRP, NMD, NMA, and SK performed the literature search and wrote the
first draft of the manuscript. SK prepared the figures. NMD prepared
Vaccines and monoclonals the antimalarial drug-resistance maps. JRP, NMD, and NMA prepared
the panels. DA reviewed sections relevant to the African context.
• Effect of deployment of pre-erythrocytic vaccines with improved efficacy
All authors reviewed and approved the final version of the manuscript.
• Effect and cost-effectiveness of monoclonal antibody immunoprophylaxis in different
Declaration of interests
transmission settings and pregnancy
We declare no competing interests.
• Transmission-blocking vaccines
Acknowledgments
• Vaccines for P vivax malaria We thank our many colleagues and collaborators. The Timika Research
Facility and Papuan Health and Community Development Foundation
Data
are supported by the Australian Department of Foreign Affairs and
• Improved timeliness, cohesiveness, granularity, and accessibility of malaria incidence Trade. This Seminar was supported in part by the Australian National
and resistance surveillance data Health and Medical Research Council (Senior Principal Research
• Expanded use of mobile phone technology for patient education, treatment Fellowship [1135820] granted to NMA and the Australian Centre for
Research Excellence on Malaria Elimination [1134989]).
supervision, and malaria surveillance
Editorial note: The Lancet Group takes a neutral position with respect to
territorial claims in published maps and institutional affiliations.
already have low malaria incidence and socioeconomic References
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www.thelancet.com Published online November 1, 2023 https://doi.org/10.1016/S0140-6736(23)01249-7 1

• Usually higher parasitaemia compared with other species

• Larger cytoplasm in rings; Schüffner’s dots can be visible

• Parasitised red cells not enlarged

Plasmodium • Robust cytoplasm in rings; Schüffner’s dots can be visible

• Rings resemble P falciparum

Characteristics Geographical distribution in humans

Plasmodium cynomolgi Morphologically similar to P vivax Southeast Asia

Plasmodium inui Morphologically similar to P malariae Malaysia and Thailand

Plasmodium coatneyi Morphologically similar to P falciparum Malaysia

Plasmodium semiovale Morphologically similar to P ovale Malaysia

Plasmodium simium Morphologically and molecularly similar to P vivax Brazil

Plasmodium fieldi Morphologically similar to P vivax and P ovale Thailand (co-infection)

Figure 1: Microscopy of Plasmodium species infecting humans

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Endemic P falciparum with no PfKelch13

www.thelancet.com Published online November 1, 2023 https://doi.org/10.1016/S0140-6736(23)01249-7 3

Liver stage Endosplenic Mosquito cycle Liver stage Endosplenic

Figure 3: Plasmodium falciparum and Plasmodium vivax lifecycle

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malaria, the risk of in-hospital death rises with a

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Non-falciparum malaria species can be detected with Severe malaria

Panel 2: Malaria treatment81

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