Malaria

Practice Essentials

Malaria is a potentially life-threatening parasitic disease caused by infection with Plasmodium protozoa transmitted by an infective female Anopheles mosquito. Plasmodium falciparum infection carries a poor prognosis with a high mortality if untreated, but it has an excellent prognosis if diagnosed early and treated appropriately. See the image below.

Malarial merozoites in the peripheral blood. Note that several of the merozoites have penetrated the erythrocyte membrane and entered the cell.

Signs and symptoms of malaria Patients with malaria typically become symptomatic a few weeks after infection, though the symptomatology and incubation period may vary, depending on host factors and the causative species. Clinical symptoms include the following:

• Headache (noted in virtually all patients with malaria)

• Cough

• Fatigue

• Malaise

• Shaking chills

• Arthralgia

• Myalgia

• Paroxysm of fever, shaking chills, and sweats (every 48 or 72 hours, depending on species)

Less common symptoms include the following:

• Anorexia and lethargy

• Nausea and vomiting

• Diarrhea

• Jaundice

Most patients with malaria have no specific physical findings, but splenomegaly may be present. Severe malaria manifests as the following:

• Cerebral malaria (sometimes with coma)

• Severe anemia

• Respiratory abnormalities: Include metabolic acidosis, associated respiratory distress, and pulmonary edema; signs of malarial hyperpneic syndrome include alar flaring, chest retraction, use of accessory muscles for respiration, and abnormally deep breathing

• Renal failure (typically reversible)

Diagnosis of malaria The patient history should include inquiries into the following:

• Recent or remote travel to an endemic area

• Immune status, age, and pregnancy status

• Allergies or other medical conditions

• Medications currently being taken

The following blood studies should be ordered:

• Blood culture

• Hemoglobin concentration

• Platelet count

• Liver function

• Renal function

• Electrolyte concentrations (especially sodium)

• Monitoring of parameters suggestive of hemolysis (haptoglobin, lactic dehydrogenase [LDH], reticulocyte count)

• In select cases, rapid HIV testing

• White blood cell count: Fewer than 5% of malaria patients have leukocytosis; thus, if leukocytosis is present, the differential diagnosis should be broadened

• If the patient is to be treated with primaquine, glucose-6-phosphate dehydrogenase (G6PD) level

• If the patient has cerebral malaria, glucose level to rule out hypoglycemia

The following imaging studies may be considered:

• Chest radiography, if respiratory symptoms are present

• Computed tomography of the head, if central nervous system symptoms are present

Specific tests for malaria infection should be carried out, as follows:

• Microhematocrit centrifugation (sensitive but incapable of speciation)

• Fluorescent dyes/ultraviolet indicator tests (may not yield speciation information)

• Thin (qualitative) or thick (quantitative) blood smears (standard): Note that 1 negative smear does not exclude malaria as a diagnosis; several more smears should be examined over a 36-hour period

• Alternatives to blood smear testing (used if blood smear expertise is insufficient): Include rapid diagnostic tests, polymerase chain reaction assay, nucleic acid sequence-based amplification, and quantitative buffy coat

Histologically, the various Plasmodium species causing malaria may be distinguished by the following:

• Presence of early forms in peripheral blood

• Multiply infected red blood cells

• Age of infected RBCs

• Schüffner dots

• Other morphologic features

Management Treatment is influenced by the species causing the infection, including the following:

• Plasmodium falciparum

• P vivax

• P ovale

• P malariae

• P knowlesi

In the United States, patients with P falciparum infection are often treated on an inpatient basis to allow observation for complications. Patients with non– P falciparum malaria who are well can usually be treated on an outpatient basis. General recommendations for pharmacologic treatment of malaria are as follows:

• P falciparum malaria: Quinine-based therapy is with quinine (or quinidine) sulfate plus doxycycline or clindamycin or pyrimethamine-sulfadoxine; alternative therapies are artemether-lumefantrine, atovaquone-proguanil, or mefloquine

• P falciparum malaria with known chloroquine susceptibility (only a few areas in Central America and the Middle East): Chloroquine

• P vivax, P ovale malaria: Chloroquine plus primaquine

• P malariae malaria: Chloroquine

• P knowlesi malaria: Same recommendations as for P falciparum malaria

Pregnant women (especially primigravidas) are up to 10 times more likely to contract malaria than nongravid women and have a greater tendency to develop severe malaria. Medications that can be used for the treatment of malaria in pregnancy include the following:

• Chloroquine

• Quinine

• Atovaquone-proguanil

• Clindamycin

• Mefloquine

• Sulfadoxine-pyrimethamine (avoid in first trimester)

• Artemether-lumefantrine [1]

• Artesunate and other antimalarials [2]

Background

Malaria, which predominantly occurs in tropical areas, is a potentially life-threatening parasitic disease caused by infection with Plasmodium protozoa transmitted by an infective female Anopheles mosquito vector. Individuals with malaria may present with fever and a wide range of symptoms (see the image below). (See Etiology, Epidemiology, Presentation, and Workup.)

Malarial merozoites in the peripheral blood. Note that several of the merozoites have penetrated the erythrocyte membrane and entered the cell. The 5 Plasmodium species known to cause malaria in humans are P falciparum, P vivax, P ovale, P malariae, and P knowlesi. [3, 4, 5] Timely identification of the infecting species is extremely important, as P falciparum infection can be fatal and is often resistant to standard chloroquine treatment. P falciparum and P vivax are responsible for most new infections. (See Etiology, Prognosis, Treatment, and Medication.) The Plasmodium species can usually be distinguished by morphology on a blood smear. P falciparum is distinguished from the rest of the plasmodia by its high level of parasitemia and the banana shape of its gametocytes. (See Workup.) Among patients with malaria, 5-7% are infected with more than a single Plasmodium species. Co-infection with different Plasmodium species has also been described in the parasites’ mosquito vectors. [4] Each Plasmodium species has a defined area of endemicity, although geographic overlap is common. At risk for contraction of malaria are persons living in or traveling to areas of Central America, South America, Hispaniola, sub-Saharan Africa, the Indian subcontinent, Southeast Asia, the Middle East, and Oceania. Among these regions, sub-Saharan Africa has the highest occurrence of P falciparum transmission to travelers from the United States. (See Epidemiology.) Infection and reproduction

After a mosquito takes a blood meal, the malarial sporozoites enter hepatocytes (liver phase) within minutes and then emerge in the bloodstream after a few weeks. These merozoites rapidly enter erythrocytes, where they develop into trophozoites and then into schizonts over a period of days (during the erythrocytic phase of the life cycle). Rupture of infected erythrocytes containing the schizont results in fever and merozoite release. The merozoites enter new red cells, and the process is repeated, resulting in a logarithmic increase in parasite burden. (See the images below.)

This micrograph illustrates the trophozoite form, or immature-ring form, of the malarial parasite within peripheral erythrocytes. Red blood cells infected with trophozoites do not produce sequestrins and, therefore, are able to pass through the spleen.

A mature schizont within an erythrocyte. These red blood cells (RBCs) are sequestered in the spleen when malaria proteins, called sequestrins, on the RBC surface bind to endothelial cells within that organ. Sequestrins are only on the surfaces of erythrocytes that contain the schizont form of the parasite

Other, less common routes of Plasmodium infection are through blood transfusion and maternal-fetal transmission. Complications P falciparum can cause cerebral malaria, pulmonary edema, rapidly developing anemia, and renal problems. An important reason that the consequences of P falciparum infection are so severe is that, due to its ability to adhere to endothelial cell walls, the species causes vascular obstruction. When a red blood cell (RBC) becomes infected with P falciparum, the organism produces proteinaceous knobs that bind to endothelial cells. The adherence of these infected RBCs causes them to clump together in the blood vessels in many areas of the body, causing microvascular damage and leading to much of the damage incurred by the parasite.

Etiology

Individuals with malaria typically acquired the infection in an endemic area following a mosquito bite. Cases of infection secondary to transfusion of infected blood are extremely rare. The risk of infection depends on the intensity of malaria transmission and the use of precautions, such as bed nets, diethyl-meta-toluamide (DEET), and malaria prophylaxis. The outcome of infection depends on host immunity. Individuals with immunity can spontaneously clear the parasites. In those without immunity, the parasites continue to expand the infection. P falciparum infection can result in death. A small percentage of parasites become gametocytes, which undergo sexual reproduction when taken up by the mosquito. These can develop into infective sporozoites, which continue the transmission cycle after a blood meal in a new host. The mechanisms that underlie immunity remain poorly defined. Additionally, individuals who develop immunity to malaria who then leave the endemic area may lose protection. Travelers who return to an endemic area should be warned that waning of immunity may increase their risk of developing several malaria if reinfected. These travelers returning to endemic areas are a special population, sometimes termed visiting friends and relatives (VFRs). Incubation Each Plasmodium species has a specific incubation period. Reviews of travelers returning from endemic areas have reported that P falciparum infection typically develops within one month of exposure, thereby establishing the basis for continuing antimalarial prophylaxis for 4 weeks upon return from an endemic area. This should be emphasized to the patient to enhance posttravel compliance. Rarely, P falciparum causes initial infection up to a year later. P vivax and P ovale may emerge weeks to months after the initial infection. In addition, P vivax and P ovale have a hypnozoite form, during which the parasite can linger in the liver for months before emerging and inducing recurrence after the initial infection. In addition to treating the organism in infected blood, treating the hypnozoite form with a second agent (primaquine) is critical to prevent relapse from this latent liver stage. When P vivax and P ovale are transmitted via blood rather than by mosquito, no latent hypnozoite phase occurs and treatment with primaquine is not necessary, as it is the sporozoites that form hypnozoites in infected hepatocytes. Life cycle The vector, the Anopheles species mosquito, transmits plasmodia, which are contained in its saliva, into its host while obtaining a blood meal. Plasmodia enter circulating erythrocytes (red blood cells, or RBCs) and feed on the hemoglobin and other proteins within the cells. One brood of parasites becomes dominant and is responsible for the synchronous nature of the clinical symptoms of malaria. Malaria-carrying female Anopheles species mosquitoes tend to bite only between dusk and dawn. Schema of the life cycle of malaria. Image courtesy of the Centers for Disease Control and Prevention.View Media Gallery The protozoan brood replicates inside the cell and induces RBC cytolysis, causing the release of toxic metabolic byproducts into the bloodstream that the host experiences as flulike symptoms. These symptoms include chills, headache, myalgias, and malaise, and they occur in a cyclic pattern. The parasite may also cause jaundice and anemia due to the lysis of the RBCs. P falciparum, the most malignant of the 5 species of Plasmodium discussed here, may induce renal failure, coma, and death. Malaria-induced death is preventable if the proper treatment is sought and implemented. P vivax and P ovale may produce a dormant form that persists in the liver of infected individuals and emerges at a later time. Therefore, infection by these species requires treatment to kill any dormant protozoan as well as the actively infecting organisms. This dormant infection is caused by the hypnozoite phase of the life cycle, which involves a quiescent liver phase. (During this phase, the infection is not typically eradicated by normal courses of antimalarials and requires treatment with primaquine to prevent further episodes of disease.) Malaria-causing Plasmodium species metabolize hemoglobin and other RBC proteins to create a toxic pigment called hemozoin. (See the image below.) An erythrocyte filled with merozoites, which soon will rupture the cell and attempt to infect other red blood cells. Notice the darkened central portion of the cell; this is hemozoin, or malaria pigment, which is a paracrystalline precipitate formed when heme polymerase reacts with the potentially toxic heme stored within the erythrocyte. When treated with chloroquine, the enzyme heme polymerase is inhibited, leading to the heme-induced demise of non–chloroquine-resistant merozoites.View Media Gallery The parasites derive their energy solely from glucose, and they metabolize it 70 times faster than the RBCs they inhabit, thereby causing hypoglycemia and lactic acidosis. The plasmodia also cause lysis of infected and uninfected RBCs, suppression of hematopoiesis, and increased clearance of RBCs by the spleen, which leads to anemia as well as splenomegaly. Over time, malaria infection may also cause thrombocytopenia. P falciparum The most malignant form of malaria is caused by this species. P falciparum is able to infect RBCs of all ages, resulting in high levels of parasitemia (>5% RBCs infected). In contrast, P vivax and P ovale infect only young RBCs and thus cause a lower level of parasitemia (usually < 2%). Hemoglobinuria (blackwater fever), a darkening of the urine seen with severe RBC hemolysis, results from high parasitemia and is often a sign of impending renal failure and clinical decline. Sequestration is a specific property of P falciparum. As it develops through its 48-hour life cycle, the organism demonstrates adherence properties, which result in the sequestration of the parasite in small postcapillary vessels. For this reason, only early forms are observed in the peripheral blood before the sequestration develops; this is an important diagnostic clue that a patient is infected with P falciparum. Sequestration of parasites may contribute to mental-status changes and coma, observed exclusively in P falciparum infection. In addition, cytokines and a high burden of parasites contribute to end-organ disease. End-organ disease may develop rapidly in patients with P falciparum infection, and it specifically involves the central nervous system (CNS), lungs, and kidneys. Other manifestations of P falciparum infection include hypoglycemia, lactic acidosis, severe anemia, and multiorgan dysfunction due to hypoxia. These severe manifestations may occur in travelers without immunity or in young children who live in endemic areas. P vivax If this kind of infection goes untreated, it usually lasts for 2-3 months with diminishing frequency and intensity of paroxysms. Of patients infected with P vivax, 50% experience a relapse within a few weeks to 5 years after the initial illness. Splenic rupture may be associated with P vivax infection secondary to splenomegaly resulting from RBC sequestration. P vivax infects only immature RBCs, leading to limited parasitemia. P ovale These infections are similar to P vivax infections, although they are usually less severe. P ovale infection often resolves without treatment. Similar to P vivax, P ovale infects only immature RBCs, and parasitemia is usually less than that seen in P falciparum. P malariae Persons infected with this species of Plasmodium remain asymptomatic for a much longer period of time than do those infected with P vivax or P ovale. Recrudescence is common in persons infected with P malariae. It often is associated with a nephrotic syndrome, possibly resulting from deposition of antibody-antigen complex on the glomeruli. P knowlesi Autochthonous cases have been documented in Malaysian Borneo, Thailand, Myanmar, Singapore, the Philippines, and other neighboring countries. It is thought that simian malaria cases probably also occur in Central America and South America. Patients infected with this, or other simian species, should be treated as aggressively as those infected with falciparum malaria, as P knowlesi may cause fatal disease. [3]

Epidemiology

Occurrence in the United States Malaria was endemic in the southern United States until the 19th and early 20th centuries, but it has since been eradicated. Almost all US cases of malaria are imported from patients traveling from endemic areas. In very rare cases, infections in individuals who have not traveled have occurred near airports (so-called airport malaria). This is secondary to a local mosquito becoming infected through a blood meal from an infected traveler or the arrival of an infected mosquito aboard a plane; the mosquito then takes a blood meal from a local resident and transmits the infection. The CDC has recently documented an increase in the number of reported malaria cases in the United States. In 2010 there were 1,691 cases, representing a 14% increase from 2009 and a 30% increase from 2008. [6] Each year, 25-30 million people travel to tropical areas, and approximately 10,000-30,000 US and European travelers acquire malaria. International occurrence Malaria is responsible for approximately 1-3 million deaths per year, typically in children in sub-Saharan Africa infected with P falciparum. Populations at an increased risk for mortality due to malaria include primigravida individuals, travelers without immunity, and young children aged 6 months to 3 years who live in endemic areas. Worldwide, an estimated 300-500 million cases occurring annually. [7] It is most prevalent in rural tropical areas below elevations of 1000 m (3282 ft) but is not limited to these climates. P falciparum is found mostly in the tropics and accounts for about 50% of cases and 95% of malarial deaths worldwide. P vivax is distributed more widely than P falciparum, but it causes less morbidity and mortality; however, both P vivax and P ovale can establish a hypnozoite phase in the liver, resulting in latent infection. Human immunodeficiency virus (HIV) and malaria co-infection is a significant problem across Asia and sub-Saharan Africa, where both diseases are relatively common. Evidence suggests that malaria and HIV co-infection can lead to worse clinical outcomes in both disease processes, with malarial infections being more severe in patients infected with HIV and HIV replication increasing in malaria infection. Sex-related demographics Males and females are affected equally. However, malaria may be devastating during pregnancy to the mother and the fetus. P falciparum is the primary species responsible for increased morbidity and mortality in pregnancy. The prevalence of malaria is higher in primigravidas than in nonpregnant women or multigravidas. Maternal complications are thought to be mediated by pregnancy associated decreases in immune function, as well as by placental sequestration of (P falciparum) parasites. Anemia from malaria can be more severe in pregnant women. Fetal complications include premature birth, anemia, low birth weight, and death. Malaria during the first trimester of pregnancy increases the risk for miscarriage. [2] Age-related demographics Young children aged 6 months to 3 years who live in endemic areas are at an increased risk of death due to malaria. Travelers without immunity are at an increased mortality risk, regardless of age.

Prognosis

Most patients with uncomplicated malaria exhibit marked improvement within 48 hours after the initiation of treatment and are fever free after 96 hours. P falciparum infection carries a poor prognosis with a high mortality rate if untreated. However, if the infection is diagnosed early and treated appropriately, the prognosis is excellent.

Complications

Most complications are caused by P falciparum. One of them is cerebral malaria, defined as coma, altered mental status, or multiple seizures with P falciparum in the blood. Cerebral malaria is the most common cause of death in patients with malaria. If untreated, this complication is lethal. Even with treatment, 15% of children and 20% of adults who develop cerebral malaria die. The symptoms of cerebral malaria are similar to those of toxic encephalopathy. Other complications of P falciparum infection include the following:

• Seizures - Secondary to either hypoglycemia or cerebral malaria

• Renal failure - As many as 30% of nonimmune adults infected with P falciparum suffer acute renal failure

• Hypoglycemia

• Hemoglobinuria (blackwater fever) - Blackwater fever is the passage of dark urine, described as Madeira wine colored; hemolysis, hemoglobinemia, and the subsequent hemoglobinuria and hemozoinuria cause this condition

• Noncardiogenic pulmonary edema - This affliction is most common in pregnant women and results in death in 80% of patients

• Profound hypoglycemia - Hypoglycemia often occurs in young children and pregnant women; it often is difficult to diagnose because adrenergic signs are not always present and because stupor already may have occurred in the patient

• Lactic acidosis - This occurs when the microvasculature becomes clogged with P falciparum; if the venous lactate level reaches 45 mg/dL, a poor prognosis is very likely

• Hemolysis resulting in severe anemia and jaundice

• Bleeding (coagulopathy)

Mortality Internationally, malaria is responsible for approximately 1-3 million deaths per year. Of these deaths, the overwhelming majority are in children aged 5 years or younger, and 80-90% of the deaths each year are in rural sub-Saharan Africa. [7] Malaria is the world’s fourth leading cause of death in children younger than age 5 years. Malaria is preventable and treatable. However, the lack of prevention and treatment due to poverty, war, and other economic and social instabilities in endemic areas results in millions of deaths each year. Host protective factors The sickle cell trait (hemoglobin S), thalassemias, hemoglobin C, and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency are protective against death from P falciparum malaria, with the sickle cell trait being relatively more protective than the other 3. Individuals with hemoglobin E may be protected against P vivax infection. A systematic review and meta-analysis analyzed the significance of some of these hemoglobinopathies and their protective effects against malaria. However, the degree of protection that these hemoglobinopathies confer is variable and they provide mild or no protection against uncomplicated malaria and asymptomatic parasitemia. [8] Individuals who are heterozygotic for RBC band 3 ovalocytosis are at reduced risk of infection with P falciparum, P knowlesi, and, especially, P vivax malaria. West African populations lacking RBC Duffy antigen are completely refractory to infection by P vivax. Polymorphisms in a host’s TNF (tumor necrosis factor) gene can also be protective against malaria. Persons living in areas of malaria endemicity may develop partial immunity to infection with time and repeated exposure. This limited immunity reduces the frequency of symptomatic malaria and also reduces the severity of infection. Immunity to malaria infection can be lost over long periods of time spent away from endemic areas with limited exposure. As a result, those individuals born in malaria-endemic regions who move abroad for work or study and then return home may be at increased risk for developing severe malaria and complications of infection.

Patient Education

Individuals traveling to malarial regions must be provided with adequate information regarding prevention strategies, as well as tailored and effective antiprotozoal medications. Avoid mosquitoes by limiting exposure during times of typical blood meals (ie, dawn, dusk). Wearing long-sleeved clothing and using insect repellants may also prevent infection. Avoid wearing perfumes and colognes. Adult-dose 95% DEET lasts up to 10-12 hours, and 35% DEET lasts 4-6 hours. In children, use concentrations of less than 35% DEET. Use sparingly and only on exposed skin. Remove DEET when the skin is no longer exposed to potential mosquito bite. Consider using bed nets that are treated with the insecticide permethrin. While this is an effective method for prevention of malaria transmission in endemic areas, an increasing incidence of pyrethroid resistance in Anopheles spp has been reported. [9] Seek out medical attention immediately upon contracting any tropical fever or flulike illness.

Clinical Presentation

History In patients with suspected malaria, obtaining a history of recent or remote travel to an endemic area is critical. Asking explicitly if they traveled to a tropical area at anytime in their life may enhance recall. Maintain a high index of suspicion for malaria in any patient exhibiting any malarial symptoms and having a history of travel to endemic areas. Also determine the patient's immune status, age, and pregnancy status; allergies or other medical conditions that he or she may have; and medications that he or she may be using. Patients with malaria typically become symptomatic a few weeks after infection, although the host's previous exposure or immunity to malaria affects the symptomatology and incubation period. In addition, each Plasmodium species has a typical incubation period. Importantly, virtually all patients with malaria present with headache. Clinical symptoms also include the following:

• Cough

• Fatigue

• Malaise

• Shaking chills

• Arthralgia

• Myalgia

Paroxysm of fever, shaking chills, and sweats (every 48 or 72 h, depending on species) The classic paroxysm begins with a period of shivering and chills, which lasts for approximately 1-2 hours and is followed by a high fever. Finally, the patient experiences excessive diaphoresis, and the body temperature of the patient drops to normal or below normal. Many patients, particularly early in infection, do not present the classic paroxysm but may have several small fever spikes a day. Indeed, the periodicity of fever associated with each species (ie, 48 h for P falciparum, P vivax, and P ovale [or tertian fever] ; 72 h for P malariae [or quartan fever]) is not apparent during initial infection because of multiple broods emerging in the bloodstream. In addition, the periodicity is often not observed in P falciparum infections. Patients with long-standing, synchronous infections are more likely to present with classic fever patterns. In general, however, the occurrence of periodicity of fever is not a reliable clue to the diagnosis of malaria. Less common malarial symptoms include the following:

• Anorexia and lethargy

• Nausea and vomiting

• Diarrhea

• Jaundice

Notably, infection with P vivax, particularly in temperate areas of India, may cause symptoms up to 6-12 months after the host leaves the endemic area. In addition, patients infected with P vivax or P ovale may relapse after longer periods, because of the hypnozoite stage in the liver. P malariae does not have a hypnozoite stage, but patients infected with P malariae may have a prolonged, asymptomatic erythrocytic infection that becomes symptomatic years after leaving the endemic area. Tertian and quartan fevers are due to the cyclic lysis of red blood cells that occurs as trophozoites complete their cycle in erythrocytes every 2 or 3 days, respectively. P malariae causes quartan fever; P vivax and P ovale cause the benign form of tertian fever, and P falciparum causes the malignant form. The cyclic pattern of fever is very rare. Travelers to forested areas of Southeast Asia and South America have become infected by Plasmodium knowlesi, a dangerous species normally found only in long-tailed and pigtail macaque monkeys (Macaca fascicularis and M nemestrina, respectively). This species can cause severe illness and death in humans, but, under the microscope, the parasite looks similar to the more benign P malariae and has sometimes been misdiagnosed. Because P malariae infection is typically relatively mild, Plasmodium knowlesi infection should be suspected in persons residing or traveling in the above geographical areas who are severely ill and have microscopic evidence of P malariae infection. Diagnosis may be confirmed via polymerase chain reaction (PCR) assay test methods.

Physical Examination Most patients with malaria have no specific physical findings, but splenomegaly may be present. Symptoms of malarial infection are nonspecific and may manifest as a flulike illness with fever, headache, malaise, fatigue, and muscle aches. Some patients with malaria present with diarrhea and other gastrointestinal (GI) symptoms. Immune individuals may be completely asymptomatic or may present with mild anemia. Nonimmune patients may quickly become very ill. Severe malaria primarily involves P falciparum infection, although death due to splenic rupture has been reported in patients with non– P falciparum malaria. Severe malaria manifests as cerebral malaria, severe anemia, respiratory symptoms, and renal failure. In children, malaria has a shorter course, often rapidly progressing to severe malaria. Children are more likely to present with hypoglycemia, seizures, severe anemia, and sudden death, but they are much less likely to develop renal failure, pulmonary edema, or jaundice. Cerebral malaria This feature is almost always caused by P falciparum infection. Coma may occur; coma can usually be distinguished from a postictal state secondary to generalized seizure if the patient does not regain consciousness after 30 minutes. When evaluating comatose patients with malaria, hypoglycemia and CNS infections should be excluded. Severe anemia The anemia associated with malaria is multifactorial and is usually associated with P falciparum infection. In nonimmune patients, anemia may be secondary to erythrocyte infection and a loss of infected RBCs. In addition, uninfected RBCs are inappropriately cleared, and bone marrow suppression may be involved. Renal failure This is a rare complication of malarial infection. Infected erythrocytes adhere to the microvasculature in the renal cortex, often resulting in oliguric renal failure. Renal failure is typically reversible, although supportive dialysis is often needed until kidney function recovers. In rare cases, chronic P malariae infection results in nephrotic syndrome. Respiratory symptoms Patients with malaria may develop metabolic acidosis and associated respiratory distress. In addition, pulmonary edema can occur. Signs of malarial hyperpneic syndrome include alar flaring, chest retraction (intercostals or subcostal), use of accessory muscles for respiration, or abnormally deep breathing.

Differential Diagnoses

Diagnostic Considerations

Conditions to consider in the differential diagnosis of malaria include the following:

• Viral illness

• Bacteremia

• African trypanosomiasis

• Amebiasis and amebic liver abscess

• Brucellosis

• Cholera

• Collagen vascular disease

• Enteric fever

• Epidemic or louse-borne typhus

• Food-borne illness or toxin

• Hodgkin disease

• Relapsing fever

• Poliomyelitis

• Schistosomiasis (acute Katayama fever)

• Seizure disorder

• HIV infection

• Babesiosis

• Plague

• Q fever

• Viral hemorrhagic fevers

• Dengue Fever

• Encephalitis

• Gastroenteritis

• Giardiasis

• Heat exhaustion and heatstroke

• Hepatitis

• Hypothermia

• Leishmaniasis

• Mononucleosis

• Otitis media

• Pelvic inflammatory disease

• Pharyngitis

• Bacterial pneumonia

• Immunocompromised pneumonia

• Mycoplasma pneumonia

• Viral Pneumonia

• Salmonella infection

• Sinusitis

• Tetanus

• Toxoplasmosis

• Yellow fever

Differential Diagnoses

• African Trypanosomiasis (Sleeping Sickness)

• Babesiosis

• Dengue

• Ehrlichiosis

• Infective Endocarditis

• Influenza

• Leptospirosis

• Meningitis

• Toxic Shock Syndrome

• Typhoid Fever

Treatment & Management

Approach Considerations Failure to consider malaria in the differential diagnosis of a febrile illness in a patient who has traveled to an area where malaria is endemic can result in significant morbidity or mortality, especially in children and in pregnant or immunocompromised patients. Mixed infections involving more than 1 species of Plasmodium may occur in areas of high endemicity and multiple circulating malarial species. In these cases, clinical differentiation and decision making will be important; however, the clinician should have a low threshold for including the possible presence of P falciparum in the treatment considerations. Occasionally, morphologic features do not permit distinction between P falciparum and other Plasmodium species. In such cases, patients from a P falciparum –endemic area should be presumed to have P falciparum infection and should be treated accordingly. In patients from Southeast Asia, consider the possibility of P knowlesi infection. This species frequently causes hyperparasitemia and the infection tends to be more severe than infections with other non– P falciparum plasmodia. It should be treated as P falciparum infection. P falciparum is resistant to chloroquine treatment except in Haiti, the Dominican Republic, parts of Central America, and parts of the Middle East. Resistance is rare in P vivax infection, and P ovale and P malariae remain sensitive to chloroquine. Primaquine is required in the treatment of P ovale and P vivax infection in order to eliminate the hypnozoites (liver phase). In the United States, patients with P falciparum infection are often treated on an inpatient basis in order to observe for complications attributable to either the illness or its treatment. Pregnancy Pregnant women, especially primigravid women, are up to 10 times more likely to contract malaria than nongravid women. Gravid women who contract malaria also have a greater tendency to develop severe malaria. Unlike malarial infection in nongravid individuals, pregnant women with P vivax are at high risk for severe malaria, and those with P falciparum have a greatly increased predisposition for severe malaria as well. For these reasons, it is especially important that nonimmune pregnant women in endemic areas use the proper pharmacologic and nonpharmacologic prophylaxis. If a pregnant woman becomes infected, she should know that many of the antimalarial and antiprotozoal drugs used to treat malaria are safe for use during pregnancy for the mother and the fetus. Therefore, the medications should be used, since the benefits of these drugs greatly outweigh the risks associated with leaving the infection untreated. In the United States, treatment options for uncomplicated chloroquine-resistant P falciparum and P vivax malaria in pregnant women are limited to mefloquine or quinine plus clindamycin. Although the limited availability of quinine and increasing resistance to mefloquine limit these options, strong evidence now demonstrates that artemether-lumefantrine (Coartem) is effective and safe in the treatment of malaria in pregnancy. These data are supported by the World Health Organization. The CDC now recommends the use of artemether-lumefantrine as an additional treatment option for uncomplicated malaria in pregnant women in the United States during the second and third trimester of pregnancy at the same doses recommended for nonpregnant women. During the first trimester of pregnancy, mefloquine or quinine plus clindamycin should be used as treatment; however, when neither of these options is available, artemether-lumefantrine should be considered. [19] Pediatrics In children, malaria has a shorter course, often rapidly progressing to severe malaria. Children are more likely to present with hypoglycemia, seizures, severe anemia, and sudden death, but they are much less likely to develop renal failure, pulmonary edema, or jaundice. Cerebral malaria results in neurologic sequelae in 9-26% of children, but of these sequelae, approximately one half completely resolve with time. Most antimalarial drugs are very effective and safe in children, provided that the proper dosage is administered. Children commonly recover from malaria, even severe malaria, much faster than adults. Diet and activity Patients with malaria should continue intake and activity as tolerated. Monitoring Patients with non– P falciparum malaria who are well can usually be treated on an outpatient basis. Obtain blood smears every day to demonstrate response to treatment. The sexual stage of the protozoan, the gametocyte, does not respond to most standard medications (eg, chloroquine, quinine), but gametocytes eventually die and do not pose a threat to the individual's health.

Pharmacologic Therapy IV preparations of antimalarials are available for the treatment of severe complicated malaria, including artesunate and quinidine gluconate, which is used as a substitute for the IV quinine available in countries outside of the United States. In a 2010 randomized study done in 11 African centers, children (age < 15 years) with severe P falciparum malaria had reduced mortality after treatment with IV artesunate, as compared with IV quinine. Development of coma, seizures, and posttreatment hypoglycemia were each less common in patients treated with artesunate. [20] Evidence from a meta-analysis including 7429 subjects from 8 trials shows a decreased risk of death using parenteral artesunate compared to quinine for the treatment of severe malaria in adults and children. [21] P falciparum drug resistance is common in endemic areas, such as Africa. Standard antimalarials, such as chloroquine and antifolates (sulfadoxine-pyrimethamine), are ineffective in many areas. Because of this increasing prevalence of drug resistance and a high likelihood of resistance development to new agents, combination therapy is now becoming the standard of care for treatment of P falciparum infection worldwide. In April 2009, the US Food and Drug Administration (FDA) approved the use of artemisinins, a new class of antimalarial agent. [22] Despite the activity of artemisinin and its derivatives, monotherapy with these agents has been associated with high rates of relapse. This may be due to the temporary arrest of the growth of ring-stage parasites (dormancy) after exposure to artemisinin drugs. For this reason, monotherapy with artemisinin drugs is not recommended. [23] Rectal artesunate has been used for pretreatment of children in resource-limited settings as a bridge therapy until the patient can access health care facilities for definitive IV or oral therapy. [24] Despite their being a fairly new antimalarial class, resistance to artemisinins has been reported in some parts of southeast Asia (Cambodia). [25] In the United States, artemether and lumefantrine tablets (Coartem) can be used to treat acute uncomplicated malaria. Artesunate IV, a form of artemisinin, is indicated for initial treatment of severe malaria in adults and children. Once the patient can tolerate oral therapy, a complete treatment course of an appropriate oral antimalarial regimen should always follow artesunate. Other combinations, such as atovaquone and proguanil HCL (Malarone) or quinine in combination with doxycycline or clindamycin, remain highly efficacious. Artesunate IV was officially approved by the FDA in May 2020 (it was previously available from the CDC through an IND protocol). Approval was based the South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) and the African Quinine Artesunate Malaria Trial (AQUAMAT). These two studies examined a total of 6,886 patients, including adults, children, and pregnant women. Artesunate IV reduced mortality by 34.7% (P = 0.0002) and 22.5% (P = 0.002) compared with quinine in the SEAQUMAT and AQUAMAT studies, respectively. [20, 26] Malaria vaccine production and distribution continues to be in the research and development stage. [27, 28, 29] In 2015, European Union (EU) regulators approved the world's first malaria vaccine for use outside the EU among children aged 6 weeks to 17 months. The new vaccine (Mosquirix, GlaxoSmithKline Biologicals), as of April 2019, is entering a large-scale pilot test in Malawi, followed by Kenya and Ghana. The vaccine is to be administered to 360,000 children aged 2 years or younger to evaluate efficacy and feasibility. In trials, the vaccine reduced malaria episodes by 40%. [30] Mosquirix targets P falciparum. It limits the parasite's ability to infect, mature, and multiply in the liver. [31] When making treatment decisions, it is essential to consider the possibility of coinfection with more than 1 species. Reports of P knowlesi infection suggest that coinfection is common. [4] It has also been demonstrated that up to 39% of patients infected with this species may develop severe malaria. In cases of severe P knowlesi malaria, IV therapy with quinine or artesunate is recommended. [5] The following is a summary of general recommendations for the treatment of malaria:

• P falciparum malaria - Quinine-based therapy is with quinine (or quinidine) sulfate plus doxycycline or clindamycin or pyrimethamine-sulfadoxine; alternative therapies are artemether-lumefantrine, atovaquone-proguanil, or mefloquine

• P falciparum malaria with known chloroquine susceptibility (only a few areas in Central America and the Middle East) - Chloroquine

• P vivax, P ovale malaria - Chloroquine plus primaquine; however, a 2012 study of Indonesian soldiers demonstrated that primaquine combined with newer nonchloroquine antimalarials killed dormant P vivax parasites and prevented malaria relapse; [32, 33] the combination of dihydroartemisinin-piperaquine with primaquine had 98% efficacy against relapse, suggesting that this regimen could become a useful alternative to primaquine plus chloroquine, the clinical utility of which is being threatened by worsening chloroquine resistance

• P malariae malaria - Chloroquine

• P knowlesi malaria – Recommendations same as those for P falciparum malaria.

In July 2018, the FDA approved tafenoquine, an antiplasmodial 8-aminoquinoline derivative indicated for the radical cure (prevention of relapse) of P vivax malaria in patients aged 16 years or older who are receiving appropriate antimalarial therapy for acute P vivax infection. The drug is active against all stages of the P vivax life cycle. Tafenoquine is administered as a single oral dose on the first or second day of appropriate antimalarial therapy (eg, chloroquine) for acute P vivax malaria. Approval was based on an international program of more than 4000 participants. In one of the clinical trials, 329 patients were randomly assigned to a treatment group (chloroquine plus tafenoquine 50 mg [n=55], 100 mg [n=57], 300 mg [n=57], 600 mg [n=56]; or chloroquine plus primaquine [n=50]; or chloroquine alone [n=54]). Relapse-free efficacy at 6 months was 89.2% with tafenoquine 300 mg and 91.9% with tafenoquine 600 mg compared with chloroquine alone (37.5%). The results showed a significantly improved treatment difference compared with chloroquine alone of 51.7% (P< 0.0001) with tafenoquine 300 mg and 54.5% (P< 0.0001) with tafenoquine 600 mg. [34] Because tafenoquine increases the risk of hemolytic anemia in patients with G6PD deficiency, patients must be tested before initiating the drug. Tafenoquine is contraindicated in patients with G6PD deficiency (or unknown status), in patients who are breastfeeding an infant with G6PD deficiency (or unknown status), and in those with known hypersensitivity. [35] In August 2018, tafenoquine gained a second indication for adults aged 18 years or older as prophylaxis when traveling to malarious areas. For this indication, the 100-mg tablet (Arakoda) is administered as a loading dose (before traveling to endemic area), a maintenance dose while in malarious area, and then a terminal prophylaxis dose in the week exiting the area. [36] In July 2013, the FDA updated its warning about mefloquine hydrochloride to include neurologic side effects, along with the already known risk of adverse psychiatric events such as anxiety, confusion, paranoia, and depression. The information, which is included in the patient medication guide and in a new boxed warning on the label, cautions that vestibular symptoms, which include dizziness, loss of balance, vertigo, and tinnitus, can occur. [37, 38] The FDA also warns that vestibular side effects can persist long after treatment has ended and may become permanent. In addition, clinicians are warned against prophylactic mefloquine use in patients with major psychiatric disorders and are further cautioned that if psychiatric or neurologic symptoms arise while the drug is being used prophylactically, it should be replaced with another medication. Pharmacologic treatment in pregnancy Medications that can be used for the treatment of malaria in pregnancy include chloroquine, quinine, atovaquone-proguanil, clindamycin, mefloquine, sulfadoxine-pyrimethamine (avoid in first trimester) and the artemisinins (see below). Briand et al compared the efficacy and safety of sulfadoxine-pyrimethamine to mefloquine for intermittent preventive treatment during pregnancy. In their study, 1601 women of all gravidities received either sulfadoxine-pyrimethamine (1500 mg of sulfadoxine and 75 mg of pyrimethamine) or mefloquine (15 mg/kg) in a single dose twice during pregnancy. There was a small advantage for mefloquine in terms of efficacy, although the incidence of side effects was higher with mefloquine than with sulfadoxine-pyrimethamine. [39, 40] In addition to mefloquine and sulfadoxine-pyrimethamine, other medications have been used in the treatment of the pregnant patient with malaria. In a recent study in African patients, artemether-lumefantrine was as efficacious and as well tolerated as oral quinine in treating uncomplicated falciparum malaria during the second and third trimesters of pregnancy. [1] Artesunate and other antimalarials also appear to be effective and safe in the first trimester of pregnancy, when development of malaria carries a high risk of miscarriage. [2] Use of tafenoquine to prevent relapse of P vivax malaria during pregnancy is not recommended. Use during pregnancy may cause hemolytic anemia in a G6PD-deficient fetus. In addition, tafenoquine use during lactation should be avoided if the infant is G6PD deficient or of unknown G6PD status. [35]

Inpatient Care Patients with elevated parasitemia (>5% of RBCs infected), CNS infection, or otherwise severe symptoms and those with P falciparum infection should be considered for inpatient treatment to ensure that medicines are tolerated. Obtain blood smears every day to demonstrate a response to treatment. The sexual stage of the protozoan, the gametocyte, does not respond to most standard medications (eg, chloroquine, quinine), but gametocytes eventually die and do not pose a threat to the individual's health or cause any symptoms.

Deterrence and Prevention Avoid mosquitoes by limiting exposure during times of typical blood meals (ie, dawn, dusk). Wearing long-sleeved clothing and using insect repellants may also prevent infection. Avoid wearing perfumes and colognes. Adult-dose 95% DEET lasts up to 10-12 hours, and 35% DEET lasts 4-6 hours. In children, use concentrations of less than 35% DEET. Use sparingly and only on exposed skin. Remove DEET when the skin is no longer exposed to potential mosquito bite. Consider using bed nets that are treated with the insecticide permethrin. While this is an effective method for prevention of malaria transmission in endemic areas, an increasing incidence of pyrethroid resistance in Anopheles spp has been reported. [9] Seek out medical attention immediately upon contracting any tropical fever or flulike illness. Consider chemoprophylaxis with antimalarials in patients traveling to endemic areas. Chemoprophylaxis is available in many different forms. The drug of choice is determined by the destination of the traveler and any medical conditions the traveler may have that contraindicate the use of a specific drug. Before traveling, people should consult their physician and the Malaria and Traveler's Web site of the CDC to determine the most appropriate chemoprophylaxis. [41] Travel Medicine clinics are also a useful source of information and advice. Investigational malaria vaccine Malaria vaccine production and distribution continues to be in the research and development stage. [27, 28, 29] In 2015, European Union (EU) regulators approved the world's first malaria vaccine for use outside the EU among children aged 6 weeks to 17 months. The new vaccine (Mosquirix, GlaxoSmithKline Biologicals), as of April 2019, is entering a large-scale pilot test in Malawi, followed by Kenya and Ghana. The vaccine is to be administered to 360,000 children aged 2 years or younger to evaluate efficacy and feasibility. In trials, the vaccine reduced malaria episodes by 40%. [30] Mosquirix targets P falciparum. It limits the parasite's ability to infect, mature, and multiply in the liver. [31] Interim phase 3 trial results were reported in 2011 for the malaria vaccine RTS,S/AS01. The results included 6000 African children aged 5-17 months who received the malaria vaccine or a comparator vaccine and were followed for 12 months. The incidence of malaria was 0.44 case per person-year in the RTS,S/AS01 group, compared with 0.83 case per person-year in the comparator vaccine group. The vaccine efficacy rate was calculated to be 55.8%. [42, 43]

Consultations Consider consulting an infectious disease specialist for assistance with malaria diagnosis, treatment, and disease management. The CDC is an excellent resource if no local resources are available. To obtain the latest recommendations for malaria prophylaxis and treatment from the CDC, call the CDC Malaria Hotline at (770) 488-7788 or (855) 856-4713 (M-F, 9 am-5 pm, Eastern time). For emergency consultation after hours, call (770) 488-7100 and ask to talk with a CDC Malaria Branch clinician. [44] Pregnant patients with malaria are at increased risk of morbidity and mortality. [45] In addition, nonimmune mothers and immune primigravidas may be at an increased risk of low birth weight, fetal loss, and prematurity. Consult an expert in malaria to determine the safest and most effective prophylaxis or treatment in a pregnant woman.

Medication

Medication Summary The 4 major drug classes currently used to treat malaria include quinoline-related compounds, antifolates, artemisinin derivatives, and antimicrobials. No single drug that can eradicate all forms of the parasite's life cycle has been discovered or manufactured yet. Therefore, 1 or more classes of drugs often are given at the same time to combat malarial infection synergistically. Treatment regimens are dependent on the geographic location of infection, the likely Plasmodium species, and the severity of disease presentation. Beware of counterfeit antimalarial drugs being taken by patients that may have been purchased overseas or via the Internet. They may not contain any active ingredients at all and may contain dangerous materials. Antipyretics, such as acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs), are indicated to reduce the level of discomfort caused by the infection and to reduce fever. NSAIDs should be used with caution if bleeding disorder or hemolysis is suspected. Antimalarials can cause significant prolongation of the QT interval, which can be associated with an increased risk of potentially lethal ventricular dysrhythmias. Patients receiving these drugs should be assessed for QT prolongation at baseline and carefully monitored if this is present. Patients with normal QT intervals on electrocardiogram (ECG) may not be at a significantly increased risk for drug-induced dysrhythmia, but caution is advised, particularly if the patient is taking multiple drug regimens or if he or she is on other drugs affecting the QT interval. Methemoglobinemia is a complication that may be associated with high-dose regimens of quinine or the derivatives chloroquine and primaquine. [25] A patient presenting with cyanosis and a normal PaO2 on room air should be suspected of having methemoglobinemia.

Antimalarials These agents inhibit growth by concentrating within acid vesicles of the parasite, increasing the internal pH of the organism. They also inhibit hemoglobin utilization and parasite metabolism. Chloroquine phosphate (Aralen)

Chloroquine phosphate is effective against P vivax, P ovale, P malariae, and drug-sensitive P falciparum. It can be used for prophylaxis or treatment. This is the prophylactic drug of choice for sensitive malaria. Quinine (Qualaquin)

Quinine is used for malaria treatment only; it has no role in prophylaxis. It is used with a second agent in drug-resistant P falciparum. For drug-resistant parasites, the second agent is doxycycline, tetracycline, pyrimethamine sulfadoxine, or clindamycin. Quinidine gluconate

Quinidine gluconate is indicated for severe or complicated malaria and is used in conjunction with doxycycline, tetracycline, or clindamycin. Quinidine gluconate can be administered IV and is the only parenterally available quinine derivative in the United States. Doxycycline (Vibramycin, Adoxa, Doryx)

Doxycycline is used for malaria prophylaxis or treatment. When it is administered for treatment of P falciparum malaria, this drug must be used as part of combination therapy (eg, typically with quinine or quinidine). Tetracycline

Tetracycline may specifically impair the progeny of apicoplast genes, resulting in their abnormal cell division. Loss of apicoplast function in progeny of treated parasites leads to slow, but potent, antimalarial effect. Clindamycin (Cleocin HCl, Cleocin Phosphate)

Clindamycin is part of combination therapy for drug-resistant malaria (eg, typically with quinine or quinidine). It is a good second agent in pregnant patients. Mefloquine

Mefloquine acts as a blood schizonticide. It may act by raising intravesicular pH within the parasite's acid vesicles. Mefloquine is structurally similar to quinine. It is used for the prophylaxis or treatment of drug-resistant malaria. It may cause adverse neuropsychiatric reactions and should not be prescribed for prophylaxis in patients with active or recent history of depression, generalized anxiety disorder, psychosis, or schizophrenia or other major psychiatric disorders. Atovaquone and proguanil (Malarone)

Atovaquone may inhibit metabolic enzymes, which in turn inhibits the growth of microorganisms. Used for pediatric patients, this combination should be administered for uncomplicated P falciparum; can also be used in combination with chloroquine. This agent is approved in the United States for the prophylaxis and treatment of mild chloroquine-resistant malaria. It may be a good prophylactic option for patients who are visiting areas with chloroquine-resistant malaria and who cannot tolerate mefloquine. Each tab combines 250 mg of atovaquone and 100 mg of proguanil hydrochloride. The dosage for children is based on body weight; in children 40 kg (88 lb) or less, a lower-dose pediatric tablet (62.5 mg of atovaquone and 25 mg of proguanil hydrochloride) is available. Primaquine

Primaquine is not used to treat the erythrocytic stage of malaria. Administer the drug for the hypnozoite stage of P vivax and P ovale to prevent relapse. Artemether and lumefantrine (Coartem)

This drug combination is indicated for the treatment of acute, uncomplicated P falciparum malaria. It contains a fixed ratio of 20 mg artemether and 120 mg lumefantrine (1:6 parts). Both components inhibit nucleic acid and protein synthesis. Artemether is rapidly metabolized into the active metabolite dihydroartemisinin (DHA), producing an endoperoxide moiety. Lumefantrine may form a complex with hemin, which inhibits the formation of beta hematin. Artesunate

Artesunate, a form of artemisinin, is rapidly metabolized to active metabolite, dihydroartemisinin (DHA). Artesunate and DHA, like other artemisinins, contain an endoperoxide bridge that is activated by heme iron, leading to oxidative stress, inhibition of protein and nucleic acid synthesis, ultrastructural changes, and decreased parasite growth and survival. It is indicated for initial treatment of severe malaria in adults and children. Once the patient can tolerate oral therapy, a complete treatment course of an appropriate oral antimalarial regimen should always follow artesunate. Tafenoquine (Arakoda, Krintafel)

Tafenoquine is an 8-aminoquinoline derivative. The 150-mg tablet (Krintafel) is indicated for the radical cure (prevention of relapse) of P vivax malaria in patients aged 16 years or older who are receiving appropriate antimalarial therapy for acute P vivax infection. Krintafel is administered as a single 300-mg dose coadministered on the first or second day of appropriate antimalarial therapy. The drug is active against all stages of the P vivax life cycle, including hypnozoites. Tafenoquine is also indicated for adults aged 18 years or older as prophylaxis when traveling to malarious areas. For this indication, the 100-mg tablet (Arakoda) is administered as a loading dose (before traveling to endemic area), a maintenance dose while in malarious area, and then a terminal prophylaxis dose in the week exiting the area.

References

1. Piola P, Nabasumba C, Turyakira E, et al. Efficacy and safety of artemether-lumefantrine compared with quinine in pregnant women with uncomplicated Plasmodium falciparum malaria: an open-label, randomised, non-inferiority trial. Lancet Infect Dis. 2010 Nov. 10(11):762-9. [QxMD MEDLINE Link].

2. McGready R, Lee SJ, Wiladphaingern J, et al. Adverse effects of falciparum and vivax malaria and the safety of antimalarial treatment in early pregnancy: a population-based study. Lancet Infect Dis. 2012 May. 12 (5):388-96. [QxMD MEDLINE Link].

3. Cox-Singh J, Davis TM, Lee KS, et al. Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening. Clin Infect Dis. 2008 Jan 15. 46(2):165-71. [QxMD MEDLINE Link]. [Full Text].

4. Marchand RP, Culleton R, Maeno Y, Quang NT, Nakazawa S. Co-infections of Plasmodium knowlesi, P. falciparum, and P. vivax among Humans and Anopheles dirus Mosquitoes, Southern Vietnam. Emerg Infect Dis. 2011 Jul. 17(7):1232-9. [QxMD MEDLINE Link].

5. William T, Menon J, Rajahram G, et al. Severe Plasmodium knowlesi malaria in a tertiary care hospital, Sabah, Malaysia. Emerg Infect Dis. 2011 Jul. 17(7):1248-55. [QxMD MEDLINE Link].

6. Malaria Surveillance — United States, 2010. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/ss6102a1.htm?s_cid=ss6102a1_e. Accessed: March 1, 2012.

7. Centers for Disease Control and Prevention. Malaria. Available at http://www.cdc.gov/malaria. Accessed: Sep 15, 2011.

8. Taylor SM, Parobek CM, Fairhurst RM. Haemoglobinopathies and the clinical epidemiology of malaria: a systematic review and meta-analysis. Lancet Infect Dis. 2012 Jun. 12 (6):457-68. [QxMD MEDLINE Link].

9. Trape JF, Tall A, Diagne N, et al. Malaria morbidity and pyrethroid resistance after the introduction of insecticide-treated bednets and artemisinin-based combination therapies: a longitudinal study. Lancet Infect Dis. 2011 Dec. 11(12):925-32. [QxMD MEDLINE Link].

10. [Guideline] Bailey JW, Williams J, Bain BJ, Parker-Williams J, Chiodini P. General Haematology Task Force. Guideline for laboratory diagnosis of malaria. London (UK): British Committee for Standards in Haematology. 2007;19. [Full Text].

11. Bailey JW, Williams J, Bain BJ, et al. Guideline: the laboratory diagnosis of malaria. General Haematology Task Force of the British Committee for Standards in Haematology. Br J Haematol. 2013 Dec. 163 (5):573-80. [QxMD MEDLINE Link].

12. Rapid diagnostic tests for malaria ---Haiti, 2010. MMWR Morb Mortal Wkly Rep. 2010 Oct 29. 59(42):1372-3. [QxMD MEDLINE Link].

13. Wongsrichanalai C, Barcus MJ, Muth S, Sutamihardja A, Wernsdorfer WH. A review of malaria diagnostic tools: microscopy and rapid diagnostic test (RDT). Am J Trop Med Hyg. 2007 Dec. 77(6 Suppl):119-27. [QxMD MEDLINE Link].

14. Centers for Disease Control and Prevention. Notice to Readers: Malaria Rapid Diagnostic Test. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5627a4.htm. Accessed: September 30, 2011.

15. de Oliveira AM, Skarbinski J, Ouma PO, et al. Performance of malaria rapid diagnostic tests as part of routine malaria case management in Kenya. Am J Trop Med Hyg. 2009 Mar. 80(3):470-4. [QxMD MEDLINE Link].

16. Polley SD, Gonzalez IJ, Mohamed D, et al. Clinical evaluation of a loop-mediated amplification kit for diagnosis of imported malaria. J Infect Dis. 2013 Aug. 208(4):637-44. [QxMD MEDLINE Link]. [Full Text].

17. d'Acremont V, Malila A, Swai N, et al. Withholding antimalarials in febrile children who have a negative result for a rapid diagnostic test. Clin Infect Dis. 2010 Sep 1. 51(5):506-11. [QxMD MEDLINE Link].

18. Mens P, Spieker N, Omar S, Heijnen M, Schallig H, Kager PA. Is molecular biology the best alternative for diagnosis of malaria to microscopy? A comparison between microscopy, antigen detection and molecular tests in rural Kenya and urban Tanzania. Trop Med Int Health. 2007 Feb. 12(2):238-44. [QxMD MEDLINE Link].

19. [Guideline] Centers for Disease Control and Prevention. Updated CDC Recommendations for Using Artemether-Lumefantrine for the Treatment of Uncomplicated Malaria in Pregnant Women in the United States. Available at https://www.cdc.gov/mmwr/volumes/67/wr/mm6714a4.htm?s_cid=mm6714a4_e#contribAff. April 2018; Accessed: April 13, 2018.

20. Dondorp AM, Fanello CI, Hendriksen IC, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. 2010 Nov 13. 376(9753):1647-57. [QxMD MEDLINE Link]. [Full Text].

21. Sinclair D, Donegan S, Isba R, Lalloo DG. Artesunate versus quinine for treating severe malaria. Cochrane Database Syst Rev. 2012 Jun 13. 6:CD005967. [QxMD MEDLINE Link].

22. US Food and Drug Administration FDA Approves Coartem Tablets to Treat Malaria. FDA. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149559.htm. Accessed: April 8, 2009.

23. Teuscher F, Gatton ML, Chen N, Peters J, Kyle DE, Cheng Q. Artemisinin-induced dormancy in plasmodium falciparum: duration, recovery rates, and implications in treatment failure. J Infect Dis. 2010 Nov 1. 202(9):1362-8. [QxMD MEDLINE Link]. [Full Text].

24. Tozan Y, Klein EY, Darley S, Panicker R, Laxminarayan R, Breman JG. Prereferral rectal artesunate for treatment of severe childhood malaria: a cost-effectiveness analysis. Lancet. 2010 Dec 4. 376(9756):1910-5. [QxMD MEDLINE Link].

25. Amaratunga C, Sreng S, Suon S, et al. Artemisinin-resistant Plasmodium falciparum in Pursat province, western Cambodia: a parasite clearance rate study. Lancet Infect Dis. 2012 Nov. 12(11):851-8. [QxMD MEDLINE Link].

26. Dondorp A, Nosten F, Stepniewska K, Day N, White N, South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet. 2005 Aug 27-Sep 2. 366 (9487):717-25. [QxMD MEDLINE Link]. [Full Text].

27. Othoro C, Johnston D, Lee R, Soverow J, Bystryn JC, Nardin E. Enhanced immunogenicity of Plasmodium falciparum peptide vaccines using a topical adjuvant containing a potent synthetic Toll-like receptor 7 agonist, imiquimod. Infect Immun. 2009 Feb. 77(2):739-48. [QxMD MEDLINE Link]. [Full Text].

28. Richards JS, Stanisic DI, Fowkes FJ, et al. Association between naturally acquired antibodies to erythrocyte-binding antigens of Plasmodium falciparum and protection from malaria and high-density parasitemia. Clin Infect Dis. 2010 Oct 15. 51(8):e50-60. [QxMD MEDLINE Link].

29. Olotu A, Lusingu J, Leach A, et al. Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5-17 months in Kenya and Tanzania: a randomised controlled trial. Lancet Infect Dis. 2011 Feb. 11(2):102-9. [QxMD MEDLINE Link].

30. Hunt K. World's first malaria vaccine to go to 360,000 African children. CNN. Available at https://www.cnn.com/2019/04/23/health/malaria-africa-worlds-first-vaccine-intl/index.html?fbclid=IwAR38y1BxCtPED9-zd0h6HeFun1VQXFd1_Mrxx78aHTmBRD4DR71TQ3xFPHs. April 25, 2019; Accessed: April 26, 2019.

31. First Malaria Vaccine Approved by EU Regulators. Medscape Medical News. Available at http://www.medscape.com/viewarticle/848608. July 24, 2015;

32. Janeczko LL. Primaquine protects against P. vivax malaria relapse. Medscape Medical News. Jan 3, 2013. Available at http://www.medscape.com/viewarticle/777109. Accessed: Jan 16, 2013.

33. Sutanto I, Tjahjono B, Basri H, et al. Randomized, open-label trial of primaquine against vivax malaria relapse in Indonesia. Antimicrob Agents Chemother. 2013 Mar. 57 (3):1128-35. [QxMD MEDLINE Link].

34. Llanos-Cuentas A, Lacerda MV, Rueangweerayut R, Krudsood S, Gupta SK, Kochar SK, et al. Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study. Lancet. 2014 Mar 22. 383 (9922):1049-58. [QxMD MEDLINE Link].

35. Krintafel (tafenoquine) [package insert]. Research Triangle Park, NC: GlaxoSmithKline. July, 2018. Available at [Full Text].

36. Arakoda (tafenoquine) [package insert]. Washington DC: 60 Degrees Pharms, LLC. August, 2018. Available at [Full Text].

37. Lowes R. FDA Strengthens Warning on Mefloquine Risks. Medscape Medical News. Jul 29 2013. [Full Text].

38. US Food and Drug Administration. FDA Drug Safety Communication: FDA approves label changes for antimalarial drug mefloquine hydrochloride due to risk of serious psychiatric and nerve side effects. FDA. Available at http://www.fda.gov/downloads/Drugs/DrugSafety/UCM362232.pdf. Accessed: Aug 6 2013.

39. Briand V, Bottero J, Noel H, et al. Intermittent treatment for the prevention of malaria during pregnancy in Benin: a randomized, open-label equivalence trial comparing sulfadoxine-pyrimethamine with mefloquine. J Infect Dis. 2009 Sep 15. 200(6):991-1001. [QxMD MEDLINE Link].

40. Briand V, Cottrell G, Massougbodji A, Cot M. Intermittent preventive treatment for the prevention of malaria during pregnancy in high transmission areas. Malar J. 2007 Dec 4. 6:160. [QxMD MEDLINE Link]. [Full Text].

41. Centers for Disease Control and Prevention. Atlanta, GA: DHHS; 2009. Malaria and Travelers. Available at http://www.cdc.gov/malaria/travelers/index.html. Accessed: Sep 15, 2011.

42. The RTS,S Clinical Trials Partnership. First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children. N Engl J Med. 2011/Oct. 365:[Full Text].

43. White NJ. A vaccine for malaria (editorial). N Engl J Med. 2011/Oct. 365:[Full Text].

44. [Guideline] Centers for Disease Control and Prevention. Malaria Diagnosis and Treatment in the United States. Available at http://www.cdc.gov/malaria/diagnosis_treatment/index.html. Accessed: Sep 15, 2011.

45. Poespoprodjo JR, Fobia W, Kenangalem E, et al. Adverse pregnancy outcomes in an area where multidrug-resistant plasmodium vivax and Plasmodium falciparum infections are endemic. Clin Infect Dis. 2008 May 1. 46(9):1374-81. [QxMD MEDLINE Link]. [Full Text].