Malaria

 1. Introduction

            Malaria is the most important parasitic disease in the world, causing hundreds of millions of illnesses and about a million deaths each year. It is transmitted by mosquitoes, primarily in the tropics. Transmission, morbidity, and mortality are greatest in Africa, where most deaths from malaria are in young children; pregnant women are also at particular risk. Malaria is also common in those who travel from areas where malaria is not transmitted to endemic regions.

 

Figure 1. Map of malaria endemicity (source World Health Organization: World Malaria Report, 2005)

 

2. Biology of malaria parasites

2.1. Species that cause human malaria. Malaria is caused by protozoan parasites of the genus Plasmodium. Other protozoan parasites cause a number of other serious human illnesses, most of them tropical diseases, including trypanosomiasis, leishmaniasis, toxoplasmosis, and amebiasis. Four species of Plasmodium commonly cause malaria in humans. Plasmodium falciparum is responsible for nearly all severe disease. It is endemic in most malarious areas and is by far the predominant species in Africa. Plasmodium vivax is about as common as P. falciparum, except in Africa, but seldom causes severe disease. Plasmodium ovale and Plasmodium malariae are much less common causes of disease, and generally do not cause severe illness. Plasmodium knowlesi, a parasite of primates in Asia, can rarely cause severe human disease.

2.2. Mosquito vectors. Malaria is transmitted by the bite of infected female anopheline mosquitoes. Many species of Anopheles transmit malaria in different parts of the world; different species have varied abilities to transmit the disease. Among the most competent malaria vectors are Anopheles gambiae and Anopheles funestus in Africa and Anopheles darlingi in the Amazon basin.

2.3. Life cycle of malaria parasites. The malaria parasite has a complex life cycle, including infection of both mosquitoes and humans. During feeding, mosquitoes inject into humans about 10-100 sporozoites, which circulate to the liver, and rapidly infect hepatocytes (liver cells). Liver cell infection is asymptomatic (without symptoms). After about a week, merozoites are released from the liver, and they rapidly infect erythrocytes (red blood cells) to begin the stage of infection that is responsible for human disease. The erythrocytic cycle lasts about 48 hours for P. falciparum, P. vivax, and P. ovale, and about 72 hours for P. malariae. During each cycle, parasites develop from small ring forms to larger, more metabolically active trophozoites, and then multinucleated schizonts. Mature schizonts, containing up to about 36 nuclei, rupture erythrocytes, releasing infective merozoites that rapidly invade other erythrocytes. Multiple rounds of erythrocytic development lead to large numbers of circulating parasites and clinical illness. Some erythrocytic parasites also develop into the sexual stage known as gametocytes. When mature gametocytes are taken up by a mosquito, they exit the erythrocyte to form gametes. Male and female gametes fuse to form a zygote, and the zygote transforms to an ookinete, which traverses the wall of the mosquito midgut, and forms an oocyst. In oocysts, multiple rounds of cell division lead to the production of thousands of sporozoites. By about 12 days after mosquito ingestion, oocysts migrate to salivary glands, where they become infectious to humans. Development in the mosquito is slower with lower temperatures, and indeed malaria transmission is limited in cold climates when the duration of the parasite life cycle exceeds the mosquito life span. Of clinical relevance, the time from mosquito bite to first symptoms of malaria is, at the shortest, about eight days, although it can be much longer, in particular with species other than P. falciparum.

In P. falciparum and P. malariae infections, only one cycle of liver cell invasion and multiplication occurs, and liver infection ceases in less than four weeks. Thus, treatment that eliminates eryth­rocytic parasites will cure these infections. In P. vivax and P. ovale infections, a dormant liver stage, the hypnozoite, is not eradicated by most drugs, and can lead to subsequent erythrocytic infections and clinical illness after treatment. Eradication of both erythrocytic and hepatic parasites is thus required to cure these infections.

Figure 2. Life cycle of malaria parasites. The malaria parasite life cycle involves two hosts. During a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the human host . Sporozoites infect liver cells and mature into schizonts , which rupture and release merozoites . (Of note, in P. vivax and P. ovale a dormant stage [hypnozoites] can persist in the liver and cause relapses by invading the bloodstream weeks, or even years later.) After this initial replication in the liver (exo-erythrocytic schizogony ), the parasites undergo asexual multiplication in the erythrocytes (erythrocytic schizogony ). Merozoites infect red blood cells . The ring stage trophozoites mature into schizonts, which rupture releasing merozoites . Some parasites differentiate into sexual erythrocytic stages (gametocytes) . Blood stage parasites are responsible for the clinical manifestations of the disease.

The gametocytes, male (microgametocytes) and female (macrogametocytes), are ingested by an Anopheles mosquito during a blood meal . The parasites’ multiplication in the mosquito is known as the sporogonic cycle . While in the mosquito's stomach, the microgametes penetrate the macrogametes generating zygotes . The zygotes in turn become motile and elongated (ookinetes) which invade the midgut wall of the mosquito where they develop into oocysts . The oocysts grow, rupture, and release sporozoites , which make their way to the mosquito's salivary glands. Inoculation of the sporozoites into a new human host perpetuates the malaria life cycle.

2.4. Unusual means of acquiring malaria. Malaria may uncommonly be transmitted from mother to infant (congenital malaria), by blood transfusion or sharing intravenous needles, and in nonendemic areas by mosquitoes infected after biting infected immigrants or travelers.

3. Epidemiology of malaria

      3.1. Overall toll of malaria. Malaria is one of the most common and most deadly infectious diseases of humans. Hundreds of millions of cases of malaria occur annually, and infections with P. falciparum, the most virulent human malaria parasite, probably lead to over a million deaths each year. Most severe disease and deaths from malaria are in children; it has been estimated to cause 10.7% of all deaths in children under five years of age. Unfortunately, the incidence of malaria has probably not decreased appreciably in most endemic regions in recent decades, and in some areas it has increased. However, very recently there are suggestions that improved control measures may be beginning to limit the toll of malaria in some regions.

      3.2. Geographic distribution. Malaria is transmitted in much of the tropics, including most of sub-Saharan Africa, much of the Indian subcontinent, rural areas of southeast Asia, some of the Middle East, parts of Oceania, many tropical areas of South and Central America, and on Hispaniola. Malaria is most common in rural areas. Transmission in cities is also common in sub-Saharan Africa and the Indian subcontinent, but uncommon elsewhere. The intensity of transmission is greatest in Africa. Sub-Saharan Africa is unusual in that over 90% of malaria is caused by P. falciparum. In most other areas with malaria, both P. falciparum and P. vivax are common causes of disease, with P. ovale and P. malariae less common.

      3.3. Varied intensity of malaria transmission. The intensity of malaria transmission can be defined by the entomological inoculation rate (EIR), the number of infective mosquito bites per person per year. EIRs vary greatly around the world and even within small areas, with greater transmission near mosquito breeding sites. EIRs in malaria-endemic regions of the Americas and Asia typically range from under 1 to 10. In Africa, EIRs can be much higher, reaching levels above 1000 in some areas. Malaria transmission may be year-round, or in regions with distinct rainy seasons, it often peaks dramatically after the onset of rains. In some areas the incidence of P. falciparum malaria is seasonal, while P. vivax malaria, which can have a longer incubation period, occurs year-round.

      3.4. Malaria in non-endemic areas. In areas not endemic for malaria, the disease occurs sporadically in immigrants and returning travelers from endemic regions. In the United States, about 1500 episodes of malaria have been reported annually in recent years. These numbers were until recently about equally distributed between immigrants and American-born travelers, but in the last 10 years numbers have increased in American-born travelers and decreased in immigrants. Travelers from the developed world typically have no antimalarial immunity, so are at high risk of progression to severe disease if they contract falciparum malaria. About five to10 deaths from malaria occur in the United States each year.

 

4. Pathogenesis of malaria

      4.1. Malarial fevers. Fevers generally coincide with the rupture of erythrocytes by mature schizont-stage parasites. Erythrocyte rupture is accompanied by high levels of circulating tumor necrosis factor-α, which, with other cytokines (secreted proteins that affect the immune response), is likely stimulated by release of parasite substances upon erythrocyte rupture, and responsible for fever and other generalized manifestations of acute malaria.

      4.2. Severe malaria. In many highly endemic areas the most common manifestation of severe malaria is severe anemia. Children with repeated episodes of malaria, and commonly also worm infections and nutritional deficiencies that contribute to anemia, present with profound anemia and high risk of heart failure and death. Malaria causes anemia by rupture of infected erythrocytes, destruction of uninfected erythrocytes, and impairment of production of new erythrocytes.

            Acute presentations of severe malaria are common in both endemic and non-immune populations. A key feature unique to P. falciparum is its ability to cause infected erythrocytes to adhere to blood vessels. Infected erythrocytes  sequester in small blood vessels, and thereby avoid passing through the spleen, which functions to clear abnormal erythrocytes from the circulation. P. falciparum-infected erythrocytes sequester in organs throughout the body, including the brain, heart, lungs, liver, kidneys, and placenta, leading to organ dysfunction and the manifestations of severe falciparum malaria.

Sequestration of P. falciparum-infected erythrocytes is mediated by the formation of knobs on the surfaces of infected erythrocytes. P. falciparum erythrocyte membrane protein-1 (PfEMP-1) protrudes from knobs to bind to human endothelial molecules on the surfaces of blood vessels. Different parasites express different PfEMP-1 molecules, which adhere to different human molecules. Indeed, the ability to continuously change expression of PfEMP-1 (about 60 are encoded by P. falciparum) provides an important means of evading the  immune response. Molecules that bind PfEMP-1 include CD36, intracellular adhesion molecule-1, thrombospondin, platelet-endothelial cell adhesion molecule, and chondroitin sulfate A. All of these are expressed in endothelium lining blood vessels, although expression in different tissues varies.         

 

5. Antimalarial immunity and genetic resistance

      5.1. Protection in infants. In malaria endemic areas infants are somewhat protected against malaria, probably due to acquisition of protective antibodies from their mothers and to the persistence of fetal hemoglobin, which appears to be less supportive of malaria infection than adult hemoglobin.

      5.2. Risk is highest in young children. From about six months of age, children in endemic areas experience frequent episodes of malaria. Initial episodes are commonly severe, and the vast majority of deaths from malaria occur in young children in endemic areas. With advancing age, increasing protection against malaria is seen, with a continuum from frequent infection, including severe disease in young children, to frequent asymptomatic infection in older children, to uncommon infection in adults. The specific ages most affected by malaria will vary depending on endemicity. In the most endemic areas, disease peaks in children less than five years of age; in less endemic areas disease may be common later in childhood, but uncommon in adults. Travelers to endemic areas, who typically have had no prior malaria infection, are at high risk of severe malaria at any age.

      5.3. Antimalarial immunity. The basis for antimalarial immunity is poorly understood. Both humoral (antibody) and cell-mediated (T cell) responses appear to play a role, but it has been difficult to identify specific responses that lead to protection. Parasites evade immune responses by switching production of antigenic proteins, in particular PfEMP-1, and protection against malaria is highly strain-specific. Thus, children in endemic areas experience multiple infections, and only gradually develop a broad protective immunity. Immunity is rather short-lived, and so it is common for individuals who return to endemic areas after extended stays in nonendemic countries to experience more frequent and severe malaria than they had experienced previously.

      5.4. Malaria during pregnancy. Pregnancy, in particular a first pregnancy, is marked by high risk of severe malaria, with potential for severe maternal disease, fetal loss, and poor birth outcomes. It appears that severe disease in pregnancy is mediated by the selection in pregnant women of parasites that express uncommon PfEMP-1 molecules that adhere to the placental molecule chondroitin sulfate A. These parasites appear to cause little disease without pregnancy, so immunity directed toward them is limited. With a first pregnancy, women can sequester large numbers of parasites in the placenta, leading to poor pregnancy outcomes. With succeeding pregnancies, and increasing immunity against placenta-adhering parasites, risks diminish.

      5.5. Human genetics and malaria. The risk of fatal malaria has offered strong evolutionary pressure through human history. Multiple genetic variants appear to have been selected, with severe genetic diseases persisting because they offer protection against another severe disease, malaria. This situation, with the risk of a genetic disease offset by protection against another risk, is known as a “balanced polymorphism.” Best characterized is sickle cell disease, which is caused by a single amino acid change in hemoglobin. Homozygous sickle cell disease (in which both copies of the beta-globin gene carry the mutation) causes severe disability, but heterozygotes (sickle cell carriers, who have one mutant and one normal beta-globin gene) are generally healthy. Sickle cell heterozygotes remain at risk of malaria, but they are relatively protected against severe disease, probably because sickle hemoglobin is less permissive than normal hemoglobin to parasite development in the erythrocyte. Thus, despite the severe disadvantages of sickle cell disease, the protection afforded to heterozygotes allows sickle hemoglobin to be common in many malarious areas of the world, in particular Africa, where prevalence may be as high as 25%. Two other mutant hemoglobins, C and E, also afford protection against malaria. Thalassemias, which are due to deletions of some of the globin genes, also cause severe abnormalities, but heterozygotes are relatively protected against malaria. Other genetic diseases that offer protection against malaria include deficiency in the enzyme glucose-6-phosphate dehydrogenase, which increases oxidant stress, and ovalocytosis, which alters erythrocyte shape. An interesting feature of human genetics is deficiency in the Duffy antigen, a protein on erythrocytes of unknown function. Duffy-negative individuals, including most Africans, have no apparent ill effects from the deficiency, and are protected against vivax malaria, since P. vivax requires the Duffy antigen to invade erythrocytes. This explains why vivax malaria is very uncommon in Africa.

 

6. Clinical features of malaria

6.1. Uncomplicated malaria. The great majority of malaria episodes are uncomplicated, especially in relatively immune populations in endemic areas. An acute attack typically begins with headache and fatigue, followed by fever and sweats. Patients may be remarkably well between attacks of fever. Fevers are usually irregular, especially early in the illness, but without therapy may become regular, with 48 (P. vivax and P. ovale) or 72 (P. malariae) hour cycles, especially with non-falciparum disease. Headache, malaise, body aches, cough, chest pain, abdominal pain, loss of appetite, nausea, vomiting, and diarrhea are common. Physical findings may be absent or include pallor, jaundice, or enlarged liver or spleen. Rash and enlarged lymph nodes are not typical in malaria, and thus suggestive of another cause of fever. When treated appropriately (see below), uncomplicated malaria generally responds well, with a mortality of about 0.1%.

6.2. Severe malaria. Severe malaria is principally a result of P. falciparum infection, because this species uniquely infects erythrocytes of all ages and causes sequestration of large numbers of infected erythrocytes in small blood vessels. Severe falciparum malaria can include dysfunction of any organ system, including neurological abnormalities progressing to alterations in consciousness, repeated seizures, and coma (cerebral malaria); severe anemia; low blood pressure and shock; respiratory abnormalities; kidney failure; low blood sugar; abnormal liver function with jaundice; bleeding abnormalities; and severe bacterial infections. The most common causes of death in children are cerebral malaria and severe anemia. However, prompt therapy of severe malaria is often followed by excellent therapeutic outcomes. Pregnant women are at particular risk of severe malaria and poor pregnancy outcomes during their first pregnancy.

6.3. Laboratory abnormalities with malaria. Laboratory findings with uncomplicated malaria may include low platelets, anemia, low or high white blood cell count, and liver function abnormalities. Severe malaria can present with laboratory abnormalities related to the organ dysfunction discussed above.

6.4. Chronic disorders related to malaria. Uncommon disorders resulting from immunologic responses to chronic infection are a massively enlarged spleen and, with P. malariae infection, chronic kidney disease.

6.5. Malaria and HIV infection. Although the presentation of malaria is not as markedly affected by HIV infection as are classic opportunistic infections, HIV-infected individuals, in particular those with advanced immunodeficiency, are at increased risk for malaria and for severe disease. 

7. Diagnosis of malaria

7.1 Clinical suspicion. Malaria is the most common cause of fever in much of the tropics and in those who develop fever after return from travel to the developing world. In endemic areas, fever is often treated presumptively as malaria, although treatment should ideally be based on a specific diagnosis. In the developed world, all persons with suggestive symptoms, in particular fever, who have traveled in an endemic area should be evaluated for malaria. The risk for falciparum malaria is principally within two months of return from travel; other species may cause disease many months, and occasionally more than a year, after return from an endemic area.

7.2. Blood smears. Giemsa-stained blood smears are the mainstay of diagnosis. Thick smears provide efficient evaluation of large volumes of blood, but thin smears are simpler for inexperienced personnel and better for discrimination of parasite species. Single smears are usually positive in infected individuals, although the parasitemia (percentage of erythrocytes infected with malaria parasites) may be very low in a nonimmune person. If illness is suspected and a first smear is negative, repeating smears at 8- to 24-hour intervals is appropriate. Blood smears allow identification of infecting species, which is important, as management of different Plasmodium species varies.

7.3. Rapid diagnostic tests. A second means of diagnosis is rapid diagnostic tests to identify circulating malaria parasite proteins with a simple “dipstick” format. These tests are not yet well standardized, but are increasingly available around the world. At best, they offer sensitivity and specificity near that of high-quality blood smear analysis and are simpler to perform. 

8. Treatment of malaria

8.1. History of antimalarial therapy. Quinine, the oldest antimicrobial drug, was used to treat malaria beginning in the 1600s, first by administration of bark of the cinchona tree and, since 1820, as a purified compound. Quinine is difficult to use due to toxicity, and since the 1940s the principal treatment for malaria was for many years the related drug chloroquine, which offers rapid parasite killing, minimal toxicity, and low cost. Unfortunately, resistance of malaria parasites, in particular P. falciparum, to chloroquine has spread to nearly all parts of the malarious world. Resistance is also common with sulfadoxine-pyrimethamine, a frequent replacement for chloroquine. Very recently, there has been a strong push to treat falciparum malaria with combination regimens to increase efficacy and decrease the pressure for selection of resistant parasites. In particular, combinations that include derivatives of artemisinin, a compound extracted from the Artemisia plant, are now strongly recommended, and gradually replacing other drugs for the routine treatment of malaria. For severe malaria, the standard therapy remains quinine administered intravenously or intramuscularly, but artemisinin derivatives also have excellent efficacy for severe malaria, and will probably replace quinine for this purpose.

8.2. Parasite stages targeted by therapy. Clinical illness is caused only by asexual erythrocytic malaria parasites, and antimalarial therapy focuses on eradicating these parasites. Most drugs are not effective against other stages, but some offer activity against liver stages, which can facilitate chemoprophylaxis (preventive therapy), or against gametocytes, which diminishes parasite transmission to others. One drug, primaquine, is used to eradicate dormant stages of P. vivax and P. ovale which are not cleared by other antimalarial drugs, and if untreated can lead to subsequent relapses of clinical malaria after clearance of erythrocytic parasites with chloroquine.

8.3. Indications for malaria therapy. Numerous drugs are available to treat malaria (Table 1). However, many drugs suffer from one or more of three main concerns: diminishing efficacy due to the spread of drug resistant parasites, toxicity, and high cost that limits use in developing countries. It is important to consider antimalarial drugs based on three quite different indications.

Table 1. Available drugs to treat malaria

Drug	Class	Indication
Chloroquine	4-Aminoquinoline	Treatment and chemoprophylaxis of infection with sensitive parasites
Amodiaquine	4-Aminoquinoline	Treatment of infection with some chloroquine-resistant Plasmodium falciparum strains
Piperaquine	Bisquinoline	Treatment of P falciparum in fixed combination with dihydroartemisinin
Quinine	Quinoline methanol	Oral treatment of infections with chloroquine-resistant P falciparum; Intravenous therapy of severe infections with P falciparum
Quinidine	Quinoline methanol	Intravenous therapy of severe infections with P falciparum
Mefloquine	Quinoline methanol	Chemoprophylaxis and treatment of infections with P falciparum
Primaquine	8-Aminoquinoline	Radical cure and terminal prophylaxis of infections with Plasmodium vivax and Plasmodium ovale
Sulfadoxine-pyrimethamine (Fansidar)	Folate antagonist combination	Treatment of infections with some chloroquine-resistant P falciparum; Intermittent preventive therapy
Atovaquone-proguanil (Malarone)	Quinone-folate antagonist combination	Treatment and chemoprophylaxis of P falciparum infection
Chlorproguanil-dapsone (Lapdap)	Folate antagonist combination	Treatment of multidrug-resistant P falciparum in Africa
Doxycycline	Tetracycline	Treatment (with quinine) of infections with P falciparum; chemoprophylaxis
Halofantrine	Phenanthrene methanol	Treatment of infections with some chloroquine-resistant P falciparum
Lumefantrine	Amyl alcohol	Treatment of P falciparum malaria in fixed combination with artemether (Coartem)
Artemisinins     (Artesunate, artemether, dihydroartemisinin)	Sesquiterpene lactone endoperoxides	Treatment of infection with multidrug-resistant P falciparum, generally in combination regimens

 

The greatest need is for safe, inexpensive, orally administered drugs for the treatment of uncomplicated malaria in developing countries. For this indication drugs must be very inexpensive and safe enough for use in unsupervised settings. Considering the challenges of assuring patient compliance in settings with limited health care infrastructure, they should ideally be effective when used over brief courses (generally up to three days) with once-daily dosing.

A second need is for rapidly acting drugs to treat severe malaria; these drugs are typically given intravenously, but other routes (e.g., intramuscular or rectal) are of interest in settings with limited technology. Cost is less of a concern for the treatment of severe malaria, as the worldwide number of doses needed is much lower than for uncomplicated disease.

A third need is for chemoprophylaxis (preventive therapy) against infection, most commonly used in travelers from nonendemic to endemic countries. In this case, much higher costs can be tolerated. However, drugs used for chemoprophylaxis should be extremely safe and should be effective when used with weekly or once-daily dosing.



8.4. Treatment of uncomplicated malaria. Most difficulties in the treatment of malaria are with P. falciparum. Infections with other species are generally successfully treated with chloroquine, although increasing resistance of P. vivax to chloroquine has been observed. For P. vivax and P. ovale infections, primaquine must also be given to eradicate liver hypnozoites and prevent subsequent relapse of infection.

 

Table 2. WHO recommendations for the treatment of uncomplicated falciparum malaria

Regimen	Notes
Artemether-lumefantrine (Coartem, Riamet)	Coformulated, first-line therapy in multiple African countries.
Artesunate-amodiaquine (ASAQ; Coarsucam)	Coformulated, first-line therapy in multiple African countries.
Artesunate-mefloquine	Standard therapy in parts of southeast Asia
Artesunate-sulfadoxine-pyrimethamine	Efficacy low compared with other regimens in some areas
Amodiaquine-sulfadoxine-pyrimethamine	Less expensive; efficacy varies, but remains good in some areas; recommended as an interim option when efficacy established and other regimens are not available

 

For many years chloroquine was an outstanding drug for uncomplicated malaria, offering a very cheap, very safe, rapidly acting, and highly effective therapy for falciparum malaria. However, chloroquine resistant P. falciparum has gradually spread around the world, such that the use of this drug for falciparum malaria is now appropriate in only a few areas. Nonetheless, due to its low cost and the familiarity of patients and clinicians with chloroquine, it is still widely used, especially in Africa. However, there is a growing consensus that in nearly all areas chloroquine should be replaced by other drugs for the routine treatment of falciparum malaria (Table 2). Related drugs, including amodiaquine and mefloquine, offer much better efficacy in most areas, although resistance to these drugs is also a problem in some areas. Quinine retains excellent efficacy in most areas, but it is fairly expensive and toxic, relegating its use for uncomplicated malaria primarily to second-line therapy after the failure of another regimen.

Another class of drugs, the antifolates, offers potent antimalarial activity, and sulfadoxine-pyrimethamine (Fansidar), which inhibits the folate pathway enzymes dihydrofolate reductase and dihydropteroate synthase, has been used as an inexpensive replacement for chloroquine. However, resistance to sulfadoxine-pyrimethamine has developed rapidly after widespread use. Other folate antagonists are also effective, in particular chlorproguanil-dapsone, which was recently approved in some African countries, is less subject to resistance problems in Africa, and is under study in combination with artesunate.

In Southeast Asia, where resistance to chloroquine and sulfadoxine-pyrimethamine was seen earlier than in Africa, other drugs are now routinely used. In Thailand, the use of mefloquine was followed by the identification of parasites resistance to this drug, but the combination of mefloquine and artesunate has shown excellent efficacy against highly resistant parasites. Artesunate is one of a growing class of antimalarials derived from artemisinin, which was developed from the Artemisia plant in China. These drugs offer very rapid antimalarial activity and are not yet seriously limited by drug resistance. However, they have very short half-lives, so must be used in combination with longer-acting drugs to avoid late treatment failures.

Artemisinin-based combination therapy (ACT) is rapidly becoming the standard of care for the therapy of uncomplicated malaria. Although mefloquine-artesunate has been successful in Thailand, it is probably too toxic and too expensive for widespread use in more disadvantaged populations, such as Africa. Other ACT regimens that are increasingly used are artemether-lumefantrine (co-formulated as Coartem or Riamet), artesunate-amodiaquine (co-formulated as ASAQ or Coarsucam), and dihydroartemisinin-piperaquine (co-formulated as Artekin or Duocotexcin). Indeed, most countries in Africa have adopted either artemether-lumefantrine or artesunate-amodiaquine as standard therapy for uncomplicated malaria, although access to these new and relatively expensive drugs remains limited in many areas. Other non-ACT combination regimens can play a role in some settings. In particular, amodiaquine-sulfadoxine-pyrimethamine has shown surprisingly good efficacy, even in areas with moderate resistance to the individual components of the combination, and it remains highly efficacious in parts of West Africa. Additional antimalarial drugs show good efficacy, but are of limited utility in developing countries due to high cost (atovaquone/proguanil, marketed as Malarone) or toxicity (halofantrine). The field of antimalarial drug discovery is now increasingly active, and it is anticipated that a number of artemisinin-based and other new antimalarial drugs will be undergoing clinical testing and then brought to the market in the coming years.

In the United States, where artemisinins and a number of other orally active antimalarials are not available, standard therapies for falciparum malaria are quinine plus doxycycline (or, in children or pregnant women, plus clindamycin), mefloquine, or Malarone. Nonimmune individuals with falciparum malaria are generally hospitalized, as the disease can progress rapidly to severe illness. In many nonendemic countries in Europe and elsewhere, some ACTs, notably artemether-lumefantrine (marketed in Europe as Riamet) are also available, and probably should be considered first-line for the treatment of uncomplicated malaria.

8.5. Treatment of severe malaria. Severe malaria is nearly always due to P. falciparum infection. The standard therapy for severe malaria has for many years been quinine, which is ideally administered intravenously. In areas with limited medical infrastructure, it can also be provided by the intramuscular or rectal route. Courses of quinine, which is quite poorly tolerated, can be shortened by adding doxycycline or clindamycin; these antibiotics are slow-acting, but effective in combination. In the United States, where intravenous formulations of quinine are not available, intravenous administration of a related drug, quinidine, has been the standard therapy for severe malaria. With both quinine and quinidine, intravenous dosing can cause significant toxicity, notably cardiac arrhythmias, and should ideally be administered with cardiac monitoring.

Recent studies have shown some artemisinins to offer at least equivalent efficacy to quinine for severe malaria. In particular, intramuscular artemether was at least as effective as intramuscular quinine, and intravenous artesunate offered improved efficacy over intravenous quinine, with superior survival rates. These recent results have led to a call to replace quinine with artemisinins, ideally intravenous artesunate, as the standard therapy for severe malaria. In 2007, intravenous artesunate was made available in the United States, but only as an investigational drug; use of the drug requires contacting the CDC. In developing world settings where intravenous therapy is not available, artesunate and artemether can be provided intramuscularly, and artesunate can also be administered rectally. Good efficacy has been demonstrated with all of these dosing modalities. 

9. Control and prevention of malaria

9.1. Prevention in travelers. Malaria is transmitted by night-biting anopheline mosquitoes. Since no drug is completely reliable in preventing malaria, travelers from nonendemic to endemic countries should utilize measures to prevent mosquito bites. These measures include use of insect repellents (ideally containing about 30% DEET), insecticides, long-sleeved clothing, and bed nets). Chemoprophylaxis with antimalarial drugs is recommended for all travelers from nonendemic regions to endemic areas, although risks vary greatly for different locations, and some tropical areas entail no risk; specific recommendations for travel to different locales are available from the CDC (www.cdc.gov/travel; Phone: 1-877-FYI-TRIP), World Health Organization (http://www.who.int/ith/en/) and other public health organizations. Current recommendations from the CDC include the use of chloroquine for chemoprophylaxis in the few areas with only chloroquine-sensitive malaria parasites (principally the Caribbean and Central America west of the Panama Canal), mefloquine or Malarone for most other malarious areas, and doxycycline for areas with a high prevalence of multidrug-resistant falciparum malaria (principally parts of Southeast Asia) (Table 3). Dosing schedules differ for each prophylaxis regimen. Recommendations should be checked regularly because they may change in response to changing resistance patterns and increasing experience with new drugs. In some relatively low-risk circumstances, it may be appropriate for travelers to not use chemoprophylaxis but to carry supplies of drugs with them in case a febrile illness develops and medical attention is unavailable. Regimens for self-treatment may include Malarone, quinine, or ACTs. In situations with major exposure to P. vivax, it may be appropriate also to administer primaquine after completion of malaria risk to eradicate dormant liver stages of P vivax and P ovale so as to prevent subsequent relapses from emergence of liver stages. However, since P. falciparum cannot relapse, the risks of relapsing malaria are relatively modest, and prophylaxis with primaquine is not routinely used.

 

Table 3. Drugs for the prevention of malaria in travelers from nonendemic to malaria-endemic countries.¹   

Drug	Use2	Adult dosage3
Chloroquine	Areas without resistant Plasmodium falciparum	500 mg weekly
Malarone	Areas with multidrug-resistant P falciparum	1 tablet (250 mg atovaquone/100 mg proguanil) daily
Doxycycline	Areas with multidrug-resistant P falciparum	100 mg daily
Primaquine4	Terminal prophylaxis of Plasmodium vivax and Plasmodium ovale infections	30 mg base daily for 14 days after travel

 ¹Recommendations may change, as resistance to all available drugs is increasing.

2Areas without known chloroquine-resistant P falciparum are Central America west of the Panama Canal, Haiti, Dominican Republic, Egypt, and most malarious countries of the Middle East. Malarone or mefloquine is currently recommended for other malarious areas except for border areas of Thailand, where doxycycline is recommended.

3For drugs other than primaquine, begin 1–2 weeks before departure (except 2 days before for doxycycline and Malarone) and continue for 4 weeks after leaving the endemic area (except 1 week for alarone). All dosages refer to salts unless otherwise indicated.

4Screen for glucose-6-phosphate dehydrogenase deficiency before using primaquine.

 

9.2. Mosquito control. The control of malaria is very challenging. Local transmission of the disease has been eliminated from some areas, including the United States, Canada, Western Europe, and Australia, but in other areas, such as the Indian subcontinent, initial successes some decades ago were followed by failure, and the incidence of malaria is probably now as high as ever in most of the tropics. However, with a number of new and reintroduced measures at hand, there is renewed interest in serious efforts to control, and even potentially to eradicate malaria. Standard programs include control of mosquitoes using insecticides and ecologic measures to destroy breeding sites. Despite great concern about the ecological consequences of DDT, there is now general consensus that targeted indoor spraying of DDT, which remains quite effective, is relatively safe. Other insecticides that have less ecological concerns, but are more expensive, are also increasingly used. Bed nets, in particular nets treated with pyrethroid insecticides, are increasingly promoted as inexpensive means of antimalarial protection. Recent studies have demonstrated significantly decreased mortality in young children provided with insecticide-treated nets. Distribution of insecticide-impregnated bed nets is increasing rapidly, although the cost of even this inexpensive intervention has so far prevented provision to most children at greatest risk of malaria.

9.3. Intermittent preventive therapy. A key component of an effective malaria control program is the provision of effective therapy, as ineffective drugs increase the likelihood of recurrent disease and transmission to others. Drugs can also be used to prevent malaria. Regular chemoprophylaxis is not a standard management practice in developing world populations due to the expense and potential toxicities of long-term therapy. However, there is increasing interest in intermittent preventive therapy, whereby entire high risk populations receive curative antimalarial therapy (without first evaluating for active infection) at defined intervals. This strategy may decrease the incidence of symptomatic malaria while allowing antimalarial immunity to develop.

Intermittent preventive therapy has been best studied with sulfadoxine-pyrimethamine, a long-acting drug that is administered in a single dose. The two high-risk populations that have been best studied are pregnant women and infants. During pregnancy, sulfadoxine-pyrimethamine provided once during both the second and third trimesters has improved pregnancy outcomes. In infants, intermittent therapy with sulfadoxine-pyrimethamine has offered benefits, but dosing schedules are not standardized. With increasing resistance to sulfadoxine-pyrimethamine, it is not clear if the drug will continue to provide effective prevention or if other drugs with shorter half-lives will be effective for intermittent preventive therapy. Nonetheless, intermittent preventive therapy will likely be increasingly used as a key malaria control strategy.

9.4. Malaria vaccine. A vaccine that effectively prevents malaria would provide an ideal means of malaria control. Unfortunately, our understanding of immune responses to malaria and of optimal means of eliciting antimalarial immune responses remains limited, and progress toward a malaria vaccine has been slow. The likelihood of a fully protective vaccine in the near future is low. However, there has been progress in vaccine strategies that offer some protection to high risk populations. This approach will not replace chemoprophylaxis for the protection of travelers or other high risk populations. However, it may significantly affect the burden of malaria by decreasing the number of children with malarial morbidity and mortality. Malaria vaccines under study include protein-adjuvant, vectored, and whole parasite vaccines.

Protein-adjuvant vaccines include one or more proteins, or parts of proteins (peptides) from malaria parasites linked to an adjuvant, which is a substance that enhances the immune response. Extensive studies of many potential protein or peptide vaccine components are underway. Many experts believe that an optimal vaccine will require components that are produced in a number of different life cycle stages of the parasite. The peptide vaccine component that has been most studied is the circumsporozoite protein (CSP), which coats the sporozoite stage that is injected by mosquitoes and then invades liver cells. Recent studies with the RTS,S vaccine, which contains a specially formulated portion of CSP that elicits strong immune responses, have been promising, with about 30-60% efficacy in preventing malaria and even greater efficacy in preventing severe malaria. Vaccines containing other components, including proteins from the parasite stages that infect red blood cells and the stages that are infectious to mosquitoes, are under intensive study. Inclusion of erythrocyte stage components may be necessary to fully prevent symptomatic malaria. Inclusion of mosquito stage components may help to prevent transmission of malaria.

A second vaccine approach is to incorporate the parasite component into a DNA or viral vector. This is a promising approach toward vaccines for a number of diseases, including HIV infection and tuberculosis. Multiple malaria vaccines linked to viral vectors are currently under study.

A third and novel approach to malaria vaccines is to immunize with intact parasites that have been attenuated (disabled, but not killed) to prevent illness, but that nonetheless can cause the development of a protective immune response. This principal has been used successfully for many viral vaccines, such as those for polio and measles. The strategy is daunting for malaria, as it will require the irradiation of infected mosquitoes for attenuation followed by dissection of large numbers of sporozoites from mosquitoes and then injection into humans. Despite the obvious challenges of this approach, it is currently being pursued aggressively. The multiple vaccine approaches under study and the increasing funding available for malaria vaccines offer hope that partially effective vaccines may be available within a fairly short (perhaps five to 10 year) time frame. However, most likely the wait for a fully protective vaccine will be much longer.

10. References and links.  

American Journal of Tropical Medicine and Hygiene. Supplement December, 2007: Defining and Defeating the Intolerable Burden of Malaria. III. Progress and Perspectives (Volume 77 Supplement, pages 1-327).

  Baird, JK: Effectiveness of antimalarial drugs. New Engl J Med 2005;352:1565-77.

Franco-Paredes C, Santos-Preciado JI.: Problem pathogens: prevention of malari in travellers. Lancet Infect Dis 2006; 6:139-49

Greenwood BM, Bojang K, Whitty CJM,  Targett GAT: Malaria. Lancet 2005; 365:1487-98.

Guerin PJ, et al.: Malaria: current status of control, diagnosis, treatment, and a proposed agenda for research and development. Lancet Infect Dis 2002; 2:564-73.

Rosenthal, PJ: Artesunate for the treatment of severe falciparum malaria. New Engl J Med, in press.

Snow RW, et al.: The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature 2005; 434:214-217.

Whitty CJ, Lalloo D, Ustianowski A.: Malaria: an update on treatment of adults in non-endemic countries. BMJ 2006; 333:241-5.

World Health Organization: Guidelines for the treatment of malaria 2006. (WHO/HTM/MAL/2006.1108) www.who.int/malaria/docs/TreatmentGuidelines2006.pdf

 

Web links:

World Health Organization: http://www.who.int/topics/malaria/en/

Centers for Disease Control and Prevention: http://www.cdc.gov/malaria/

Malaria Foundation International: http://www.malaria.org/

Roll Back Malaria Partnership: http://www.rbm.who.int/