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David A. Warrell

, Janet Hemingway

, Kevin Marsh

, Robert E. Sinden

, Geoffrey A. Butcher

, and Robert W. Snow



Epidemiology—decreasing global mortality, estimated at 655 000 deaths in 2010, 26% lower than in 2000; mortality in India variously estimated at between 2000 and 277 000.

Parasite biology—new data on merozoite invasion.

Plasmodium ovale—two species distinguished: Plasmodium ovale curtisi (classic) and P. o. wallikeri (variant).

Plasmodium gaboni sp. nov.—found in chimpanzees in Gabon, close to P. falciparum and P. reichenowi and might infect humans.

Plasmodium vivax—increasing evidence of severe infections.

Mosquitoes—increasing pyrethroid kdr resistance and threat to the bed net campaign.

Malaria-induced immunosuppression—malaria causes bacteraemia in sub-Saharan Africa; mechanism of secondary nontyphoid salmonella infections.

Chemotherapy—artemisinin resistance, superiority of artesunate in African children, use of prereferral rectal artesunate.

Vaccine—controversial interim analysis of RTS,S/AS01vaccine phase III trial; volunteer trials of irradiated sporozoite vaccine.

Updated on 31 May 2012. The previous version of this content can be found here.
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date: 25 March 2017

According to WHO’s World Malaria Report for 2010, there were an estimated 216 million cases of malaria worldwide in 2010 with 655 000 deaths, 5% fewer than in 2009 and 26% fewer than in 2000. Africa accounted for 81% of the cases and 91% of deaths; 86% of the deaths were in children aged less than 5 years. Malaria remains endemic in 106 countries. Nigeria, Democratic Republic of Congo, Burkina Faso, Mozambique, Ivory Coast, and Mali account for 60% of malaria deaths.

Human malaria parasites, mosquitoes, and transmission of malaria

Malaria parasites and their impact on the human genome—six species of Plasmodium commonly cause malaria in humans: P. falciparum, P. vivax, P. ovale (two species), P. malariae and P. knowlesi. The genome of P. falciparum, the most pathogenic species, has been completely sequenced. This parasite has exercised immense selection pressure on the human genome, as is evident from the global distribution of the many human genes that constrain malarial development, such as a point mutation in position 6 of the β‎-globin chain (sickle cell haemoglobin), and deletion of α‎-globin genes (α‎ thalassaemia).

Biology of the parasite and mosquito vector—sporozoites are injected into humans during the female anopheles mosquito’s blood meal. They invade hepatocytes. Hepatic schizogony releases merozoites into the blood stream where they invade red blood corpuscles (RBCs) and undergo further asexual multiplications before gametocytes form. If these are ingested by mosquitoes, male and female gametes fuse, resulting in ookinetes that penetrate the mosquito’s midgut and develop into oocysts. Daughter sporozoites are released. They invade the mosquito’s salivary glands, ready to infect a new human host. Persistent latent forms (hypnozoites) of P. vivax and P. ovale remain in the liver to give rise to later relapses of parasitaemia and symptoms. All the stages express distinct antigen, repertoires excite different immune responses, and are equipped survive in different microenvironmants.

Mosquito biology—species of the Anopheles gambiae complex, the most effective malaria vectors, prefer to feed on humans to whom they are attracted by smell: other species are less particular. They vary in their choice of breeding habitats. MacDonald’s equation for vectorial capacity and the related basic reproduction number (R0) allows prediction of the impact of vector control methods under different conditions. The genome sequence of An. gambiae is known. Important mosquito phenotypes that have a genetic basis include blood feeding preference, habitat choice, insecticide susceptibility, and vectorial capacity.

Other mechanisms of transmission—malaria can be transmitted by transfusion of blood products, marrow transplants, and contaminated needles.


In 2007, 2.4 billion people were exposed to P. falciparum infection across 87 countries, and 3.18 billion people were exposed to P. vivax across 63 countries. Intensity of malarial transmission depends on the varying efficiencies of the local anopheline vectors and their frequency of contact with humans.

Malarial endemicity expresses the amount or intensity of transmission in an area or community. Epidemic malaria implies a periodic or sharp increase in the amount of malaria. Stable transmission implies persistently high prevalence, insensitive to aberrations in climate or local habitats as in holoendemic areas of Africa; unstable malaria is characterised by great variability in space and time, as in South-East Asia. Prevalence of infection in children aged 2 to 9 years is described as hypoendemic (<10%), mesoendemic (11–50%), hyperendemic (51–75%), or holoendemic (>75%).

The epidemiological background to clinical malaria—is changing due to population growth, environmental changes (often human-induced, whether local or global), changing resistance of parasites to drugs, the HIV epidemic and the consequences of attempts at malaria control. An estimated 550 million clinical attacks of P. falciparum occurred worldwide in 2002: 71% in Africa, 23% in the low-transmission but densely populated countries of South-East Asia, and 3% in the Western Pacific. In Africa in 2005, P. falciparum is estimated to have caused 1.1 million deaths directly, 71 000 to 190 000 infant deaths following placental infection in utero, and over 3000 newly acquired persistent epilepsies through brain insults among patients surviving an episode of cerebral malaria in childhood.

Innate resistance and immunity

More human genetic polymorphisms have been associated with innate protection from malaria than for any other infectious disease. Duffy blood group negative RBCs are resistant to P. vivax infection, explaining the prevalence of the DARC(Fy) –46C/C genotype especially in West Africa, but there may be an associated susceptibility to HIV-1 infection.

In most stably endemic areas, acquisition of immunity, although never complete, ensures that death due to malaria is rare after the age of 5 years and hardly ever occurs in normally immune competent adults. Immunity allows tolerance of levels of parasitisation that would cause illness in a naive individual by neutralizing parasite toxins or down-regulating the cytokine response to challenge. However, a key aspect of immunity to malaria is control of parasite growth by interfering with parasites’ replication or accelerating their removal from the circulation. There is progressive acquisition of both ‘strain’-specific and cross-protective responses to a range of potential malarial epitopes. Immunity is stage-specific but probably acts predominantly at the blood stages. Antibody-mediated protection against blood-stage parasites is demonstrated by the relative protection of children in endemic areas during their first few months of life by passively transferred maternal antibody and by experimental amelioration of acute malaria by immune gammaglobulin. Malnutrition increases the risk of severe falciparum malaria in children.

HIV–malaria interaction—in pregnant women, HIV and P. falciparum infections are mutually synergistic. Consequences of malaria, especially anaemia, are more severe in HIV-positive women. In areas of unstable malarial transmission, HIV-positive nonimmune adults are at increased risk of severe and fatal malaria. In malaria endemic areas, HIV-positive children are at increased risk of severe malaria.

Molecular pathology, organ pathology, and pathophysiology

Molecular pathology—intravascular, asexual forms are responsible for all the pathological effects of malaria in humans. Fever and inflammation are probably initiated by interaction between parasite products and pattern recognition receptors on host cells, leading to cytokine release by macrophages. The relative virulence of P. falciparum is attributed to cytoadherence and sequestration of parasitized RBCs to venular endothelium, especially in the lungs, brain, intestines and muscles, resulting in reduced perfusion and tissue damage. Local release of potentially toxic/pharmacologically active compounds such as reactive oxygen species or nitric oxide may also be involved.

Organ pathology—the brain may be oedematous, especially in African children. Small blood are vessels congested with tightly sequestered parasitized RBCs (PRBCs) containing pigmented mature trophozoites and schizonts, making the brain slate-grey in colour. The cerebrovascular endothelium shows pseudopodial projections, closely apposed to electron-dense, knob-like protruberances on the surface of PRBCs. Other changes include petechial haemorrhages in the white matter, ring haemorrhages and Dürck’s granulomas. Among other organs and tissues, retina, bone marrow, lung, heart, liver, intestine, spleen, kidney, and placenta show variable evidence of PRBC sequestration and some other distinctive features.

Pathophysiology—anaemia results from destruction/phagocytosis of both normal red cells and PRBCs as well as from dyserythropoiesis; autoimmune haemolysis is rare. Thrombocytopenia is attributable to splenic sequestration, dysthrombopoiesis, and immune-mediated lysis. Cerebral malaria is associated with inappropriately low cerebral blood flow, increased cerebral anaerobic glycolysis and microcirculatory obstruction. In African children, plasma concentrations of TNF-α‎, IL-1α‎ and other cytokines correlate with disease severity. Cytokines may be involved in hypoglycaemia, coagulopathy, dyserythropoiesis, and leucocytosis in falciparum malaria. Pulmonary oedema may result from fluid overload, but more often there is increased pulmonary capillary permeability associated with neutrophil sequestration in the pulmonary capillaries. In African children, a syndrome of respiratory distress is associated with metabolic acidosis and severe anaemia. Hypoglycaemia is caused by impaired gluconeogenesis, reduced hepatic glycogen or hyperinsulinaemia secondary to quinine/quinidine treatment. In malarial acute renal failure, there is evidence of PRBC sequestration, and pigment (haemoglobin and myoglobin) toxicity may contribute.

Clinical features

Classic periodic febrile paroxysms with afebrile asymptomatic intervals are uncommon unless treatment is delayed.

Severe falciparum malaria—this is defined by (1) clinical features—prostration, impaired consciousness, respiratory distress/acidotic breathing, multiple convulsions, circulatory collapse, pulmonary oedema (radiological), abnormal bleeding, jaundice, and haemoglobinuria; and (2) laboratory tests—severe anaemia, hypoglycaemia, acidosis, renal impairment, and hyperlactataemia, that are of proven prognostic significance.

Cerebral malaria is defined by impaired consciousness in patients with acute P. falciparum infection in whom other causes of coma, including hypoglycaemia and transient postictal coma, have been excluded. Convulsions, dysconjugate gaze, retinal changes, symmetrical upper motor neuron signs, and abnormal posturing are common. Neurological manifestations are different in adults and children. African children surviving cerebral malaria may suffer persistent neurological, cognitive, and learning defects.

So-called benign malarias, P. ovale, P. malariae, and particularly P. vivax, can cause even more severe feverish symptoms than falciparum malaria. Splenic rupture is more common with vivax malaria. P. knowlesi, one of the monkey malarias, has recently been recognized as an important and potentially fatal zoonosis in humans in several South-East Asian countries.

Malaria in pregnancy—malaria is an important cause of maternal anaemia and death, abortion, stillbirth, premature delivery, low birth weight, and neonatal death. RBCs infected with strains of P. falciparum expressing Var2CSA bind to chondroitin sulphate A expressed on the surface of the syncytiotrophoblast. Placental dysfunction, fever, and hypoglycaemia contribute to fetal distress.

Chronic immunological complications of malaria—these include quartan malarial nephrosis, tropical splenomegaly syndrome (hyper-reactive malarial splenomegaly) and endemic Burkitt’s lymphoma.


Repeated thick and thin blood smears and rapid antigen detection over a period of 72 h are necessary to confirm or exclude the diagnosis of malaria. Differential diagnoses include other acute febrile illness: falciparum malaria has been misdiagnosed as influenza, viral hepatitis, epilepsy, viral encephalitis, or traveller’s diarrhoea, sometimes with fatal consequences.

Laboratory investigation

In falciparum malaria, blood glucose must be checked frequently, especially in children, pregnant women, and severely ill patients, whether or not the patient is receiving quinine/quinidine treatment.


The efficacy of antimalarial chemotherapy is threatened by emerging resistance of P. falciparum to available drugs. The World Health Organization (WHO) now advocates the combination of two or more different classes of antimalarial drugs with unrelated mechanisms of action to delay emergence of resistance.

P. vivax, P. ovale, P. malariae, P. knowlesi malarias—these are treated with chloroquine. Resistant P. vivax (New Guinea, Indonesia) is treated by increasing the dose of oral chloroquine.

Uncomplicated P. falciparum malaria in malarious areas—WHO recommends the replacement of monotherapy with the combination of an artemesinin with another drug (artemisinin-based combination therapy, ACT), even in Africa, although this is more expensive and resistance to artemisinins has recently emerged in Cambodia. In South-East Asia, lumefantrine or mefloquine is added to artesunate. In Africa, lumefantrine, amodiaquine, or sulfadoxine–pyrimethamine might be added. For presumed nonimmune travellers returning to nonendemic areas, artemether–lumefantrine, atovaquone–proguanil, or quinine with doxycycline or clindamycin (pregnant women and children) are recommended.

Severe falciparum, vivax, and knowlesi malaria—urgent appropriate, parenteral chemotherapy is necessary, initiated with a loading dose. Intravenous artesunate is the drug of choice. Intramuscular artemether, or quinine by intermittent or continuous intravenous infusion or intramuscular injection are less effective. Artemisinin by rectal suppository has proved effective. Resistance to artemisinins is emerging in Cambodia, Thailand, and Burma.

Supportive care—patients with severe malaria should be transferred to the highest possible level of care. Convulsions must be controlled; fluid, electrolyte, and acid–base homeostasis restored; and organ/tissue failure treated (e.g. haemofiltration for acute renal failure). Harmful ancillary remedies of unproven value, such as corticosteroids and heparin, have no role in the treatment of cerebral malaria.


Modern malaria control and prevention aims to limit human–vector contact by indoor residual spraying (IRS) and insecticide (pyrethroid) treated nets (ITNs). ITNs can reduce all-cause childhood mortality by 17%, averting 5.5 deaths for every 1000 African children protected, preventing over 50% of clinical cases, and reducing prevalence by 13%. Repellents such as diethyltoluamide (DEET) are used for personal protection. Vectors can also be controlled by environmental modification or manipulation, and human contact can be reduced by zooprophylaxis and by modifying human dwellings and behaviour.

Intermittent preventive treatment in pregnant women (IPTp) and infants (IPTi) with sulphadoxine–pyrimethamine—efficacy is likely to decrease because IPTp works less well in HIV-positive women and there is no proven safe alternative to sulphadoxine–pyrimethamine in areas where resistance to this combination is rapidly expanding.

Malarial vaccines—obstacles to developing a malaria vaccine are the multistage complexity of the parasite, polymorphism of potential immune targets, and the parasite’s capacity for evolving evasive strategies, such as antigenic variation and diversity. However, candidate pre-erythrocytic, blood-stage, and transmission-blocking vaccines have been developed. A subunit vaccine (RTS,S) comprising a fusion protein combining part of the circumsporozoite protein of P. falciparum with HBsAg and a complex adjuvant (AS02) has achieved 53% protective efficacy against malaria disease.

Travellers—prevention of malaria in people from nonmalarious areas who are visiting endemic regions, including those visiting their friends and relatives (VFRs), has become more difficult because of resistance to antimalarial drugs. Travellers are advised to (1) be aware of the risk; (2) prevent exposure to anopheline mosquitoes; (3) take chemoprophylaxis where appropriate—malarone, mefloquine, or doxycycline is appropriate in areas of chloroquine-resistant falciparum malaria; (4) seek immediate medical advice in case of any feverish illness developing while abroad, or within 3 or more months of returning, and to mention malaria as a possibility—regardless of the precautions taken—to any doctor who sees them. Up-to-date advice is important, as the global distribution and intensity of malarial transmission is changing. Pregnant women are best advised to avoid malarious areas. Travellers spending time in the jungles of South-East Asia should be alert to the risk of contracting knowlesi malaria.

Acknowledgement: The authors and editors acknowledge the inclusion in this chapter of material contributed by Professor D J Bradley to the 4th edition of the Oxford Textbook of Medicine.

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