Malaria
Practice Essentials
Malaria is a potentially life-threatening 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.
Signs and symptoms
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)
See Clinical Presentation for more detail.
Diagnosis
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
See Workup for more detail.
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 falciparummalaria
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 disease caused by infection with Plasmodiumprotozoa transmitted by an infective female Anopheles mosquito vector.
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 Plasmodiumspecies 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 falciparumtransmission 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.
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.
Patient education
Individuals traveling to malarial regions must be provided with adequate information regarding prevention strategies, as well as tailored and effective antiprotozoal medications. For patient education information.
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 falciparuminfection 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 vivaxand 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.
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 ovaleinfect 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
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.
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 ovalemay 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 falciparumcauses 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 malariaeand 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.
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
Approach Considerations
In returning travelers from endemic areas, malaria is suggested by the triad of thrombocytopenia, elevated lactate dehydrogenase (LDH) levels, and atypical lymphocytes. These findings should prompt obtaining malarial smears.
In general, blood cultures should be drawn in a febrile patient. Patients from tropical areas may have more than 1 infection; maintaining a high suspicion for additional infections should be considered when patients do not respond to antimalarials.
Assess hemoglobin (decreased in 25% of patients, often profoundly in young children), platelet counts (thrombocytopenia in 50-68% of patients), and liver function (results abnormal in 50% of patients). Also monitor renal function, electrolytes (especially sodium), and parameters suggestive of hemolysis (haptoglobin, LDH, reticulocyte count). Rapid HIV testing may also be indicated in select cases. Importantly, fewer than 5% of patients with malaria have an elevated white blood cell (WBC) count. If leukocytosis is present, the examiner should entertain a broader list of differential diagnoses. The British Committee for Standards in Haematology has guidelines on the laboratory diagnosis of malaria. [9]
If the patient is to be treated with primaquine, a G-6-PD level should be obtained because primaquine can result in severe hemolysis in these patients.
If the patient has cerebral malaria, obtain a blood glucose level to rule out hypoglycemia as a cause of mental-status changes. Note that intravenous (IV) quinine can induce hypoglycemia; therefore, blood glucose should be monitored when IV quinine is used.
The British Committee for Standards in Haematology revised its Guidelines for the Laboratory Diagnosis of Malaria, intended for use in the United Kingdom but also potentially applicable to other nonendemic areas. [10] Recommendations include the following:
Thick and thin films should be routinely used for malaria diagnosis; thick films should be stained with Giemsa or Field stain, thin films with Giemsa or Leishman stainTwo observers should examine thick films, with each viewing a minimum of 200 high-power fields; if the films are positive, the species should be determined through examination of a thin filmIn cases of P falciparum or Plasmodium knowlesi infection, the percentage of parasitized cells or the number of parasites per microliter should be estimatedRapid diagnostic tests for malarial antigen can be used on a supplementary basis when diagnosis is performed by inexperienced staff
Imaging studies
Chest radiography may be helpful if respiratory symptoms are present. If CNS symptoms are present, a computed tomography (CT) scan of the head may be obtained to evaluate evidence of cerebral edema or hemorrhage.
Microhematocrit centrifugation
Using this method with the CBC tube is a more sensitive method of detection of malaria infection. However, microhematocrit centrifugation does not allow the identification of the species of Plasmodium. To determine species, a peripheral blood smear must be examined.
Fluorescent dyes/ultraviolet indicator tests
Several different dyes allow laboratory results to be obtained more quickly. These methods require the use of a fluorescent microscope. Fluorescent /ultraviolet tests may not yield speciation information.
Polymerase chain reaction assay
PCR assay testing is a very specific and sensitive means of determining if species of Plasmodium are present in the blood of an infected individual. PCR assay tests are not available in most clinical situations. However, they are very effective at detecting the Plasmodium species in patients with parasitemias as low as 10 parasites/mL of blood.
Lumbar puncture
If the patient exhibits mental-status changes, and even if the peripheral smear demonstrates P falciparum, a lumbar puncture should be performed to rule out bacterial meningitis.
Approach Considerations
In returning travelers from endemic areas, malaria is suggested by the triad of thrombocytopenia, elevated lactate dehydrogenase (LDH) levels, and atypical lymphocytes. These findings should prompt obtaining malarial smears.
In general, blood cultures should be drawn in a febrile patient. Patients from tropical areas may have more than 1 infection; maintaining a high suspicion for additional infections should be considered when patients do not respond to antimalarials.
Assess hemoglobin (decreased in 25% of patients, often profoundly in young children), platelet counts (thrombocytopenia in 50-68% of patients), and liver function (results abnormal in 50% of patients). Also monitor renal function, electrolytes (especially sodium), and parameters suggestive of hemolysis (haptoglobin, LDH, reticulocyte count). Rapid HIV testing may also be indicated in select cases. Importantly, fewer than 5% of patients with malaria have an elevated white blood cell (WBC) count. If leukocytosis is present, the examiner should entertain a broader list of differential diagnoses. The British Committee for Standards in Haematology has guidelines on the laboratory diagnosis of malaria. [9]
If the patient is to be treated with primaquine, a G-6-PD level should be obtained because primaquine can result in severe hemolysis in these patients.
If the patient has cerebral malaria, obtain a blood glucose level to rule out hypoglycemia as a cause of mental-status changes. Note that intravenous (IV) quinine can induce hypoglycemia; therefore, blood glucose should be monitored when IV quinine is used.
The British Committee for Standards in Haematology revised its Guidelines for the Laboratory Diagnosis of Malaria, intended for use in the United Kingdom but also potentially applicable to other nonendemic areas. [10] Recommendations include the following:
Thick and thin films should be routinely used for malaria diagnosis; thick films should be stained with Giemsa or Field stain, thin films with Giemsa or Leishman stainTwo observers should examine thick films, with each viewing a minimum of 200 high-power fields; if the films are positive, the species should be determined through examination of a thin filmIn cases of P falciparum or Plasmodium knowlesi infection, the percentage of parasitized cells or the number of parasites per microliter should be estimatedRapid diagnostic tests for malarial antigen can be used on a supplementary basis when diagnosis is performed by inexperienced staff
Imaging studies
Chest radiography may be helpful if respiratory symptoms are present. If CNS symptoms are present, a computed tomography (CT) scan of the head may be obtained to evaluate evidence of cerebral edema or hemorrhage.
Microhematocrit centrifugation
Using this method with the CBC tube is a more sensitive method of detection of malaria infection. However, microhematocrit centrifugation does not allow the identification of the species of Plasmodium. To determine species, a peripheral blood smear must be examined.
Fluorescent dyes/ultraviolet indicator tests
Several different dyes allow laboratory results to be obtained more quickly. These methods require the use of a fluorescent microscope. Fluorescent /ultraviolet tests may not yield speciation information.
Polymerase chain reaction assay
PCR assay testing is a very specific and sensitive means of determining if species of Plasmodium are present in the blood of an infected individual. PCR assay tests are not available in most clinical situations. However, they are very effective at detecting the Plasmodium species in patients with parasitemias as low as 10 parasites/mL of blood.
Lumbar puncture
If the patient exhibits mental-status changes, and even if the peripheral smear demonstrates P falciparum, a lumbar puncture should be performed to rule out bacterial meningitis.
Blood Smears
A diagnosis of malaria should be supported by the identification of the parasites on a thin or thick blood smear. In rare occasions, P falciparum infection can present without detectable parasitemia. If no alternative diagnosis is found in an at-risk patient with possible cerebral malaria (ie, unrevealing lumbar puncture findings), initiate therapy for presumptive malaria and continue to obtain additional blood smears to confirm the diagnosis.
When reading a smear, 200-300 oil-immersion fields should be examined (more if the patient recently has taken prophylactic medication, because this temporarily may decrease parasitemia). One negative smear does not exclude malaria as a diagnosis; several more smears should be examined over a 36-hour period.
Thick smears
Three thick and thin smears 12-24 hours apart should be obtained. The highest yield of peripheral parasites occurs during or soon after a fever spike; however, smears should not be delayed while awaiting fever spikes.
Thick smears are 20 times more sensitive than thin smears, but speciation may be more difficult. The parasitemia can be calculated based on the number of infected RBCs. This is a quantitative test.
Thin smears
Thin smears are less sensitive than thick smears, but they allow identification of the different species. This should be considered a qualitative test.
Alternatives to Blood Smear Testing
Alternative diagnostic methods typically are used if the laboratory does not have sufficient expertise in detecting parasites in blood smears.
Rapid diagnostic tests (RDT)
Immunochromatographic tests based on antibody to histidine-rich protein-2 (PfHRP2), parasite LDH (pLDH), or Plasmodium aldolase appear to be very sensitive and specific. [11, 12] Some RDTs may be able to detect P falciparum in parasitemias that are below the threshold of reliable microscopic species identification. Only one RDT (BinaxNOW) has been approved to date for the diagnosis of malaria in the United State. [13]
In one study, RDTs were found to perform better than microscopy under routine conditions. RDTs performed by the health facility staff were 91.7% sensitive and 96.7% specific. Microscopy was 52.5% sensitive and 77% specific. [14] A recent sudy using loop-mediated amplification technique (LAMP)also suggests that RDTs have accuracy similar to that of nested PCR, with a greatly reduced time to result, and was superior to expert microscopy. [15]
In a study from Tanzania, d'Acremont et al reported that antimalarials could be safely withheld from febrile children (< 5 y) who had negative results from an RDT based on PfHRP2. [16]
RDTs are less effective when parasite levels are below 100 parasites/mL of blood, and, in rare instances, an RDT test is negative in patients with high parasitemias. For these reasons, confirm RDT test results with a second type of screening test when possible. A false-positive result from an RDT may occur up to 2 weeks or more after treatment due to persistence of circulating antigens.
Other tests
In addition to the RDT listed above, new molecular techniques, such as PCR assay testing and nucleic acid sequence-based amplification (NASBA), are also available for diagnosis. They are more sensitive than thick smears but are expensive and unavailable in most developing countries. [17]
The quantitative buffy coat (QBC) is a technique that is as sensitive as thick smears. Because results cannot be used to speciate Plasmodium, a thin smear must be examined.
Malaria is a reportable disease. Identification of parasites by any of the above techniques should prompt notification to the local or state health department.
Histologic Findings
The table below compares histologic findings for P falciparum, P vivax, P ovale, and P malariae.
Table 1. Histologic Variations Among Plasmodium Species (Open Table in a new window)
Findings
P falciparum
P vivax
P ovale
P malariae
Only early forms present in peripheral blood
Yes
No
No
No
Multiply-infected RBCs
Often
Occasionally
Rare
Rare
Age of infected RBCs
RBCs of all ages
Young RBCs
Young RBCs
Old RBCs
Schüffner dots
No
Yes
Yes
No
Other features
Cells have thin cytoplasm, 1 or 2 chromatin dots, and applique forms.
Late trophozoites develop pleomorphic cytoplasm.
Infected RBCs become oval, with tufted edges.
Bandlike trophozoites are distinctive.
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 knowlesiinfection. 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. [18]
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. [19]
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. [20]
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 falciparuminfection worldwide. In April 2009, the US Food and Drug Administration (FDA) approved the use of artemisinins, a new class of antimalarial agent. [21]
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. [22]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. [23]
Despite their being a fairly new antimalarial class, resistance to artemisinins has been reported in some parts of southeast Asia (Cambodia). [24]
In the United States, artemether and lumefantrine tablets (Coartem) can be used to treat acute uncomplicated malaria. Artesunate, a form of artemisinin that can be used intravenously, is available from the Centers for Disease Control and Prevention (CDC). Other combinations, such as atovaquone and proguanil HCL (Malarone) or quinine in combination with doxycycline or clindamycin, remain highly efficacious.
Malaria vaccine production and distribution continues to be in the research and development stage. [25, 26, 27] 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%. [28] Mosquirix targets P falciparum. It limits the parasite's ability to infect, mature, and multiply in the liver. [29]
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 knowlesimalaria, 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;[30, 31] 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.[32]
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. [33]
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. [34]
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. [35, 36]
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. [37, 38]
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. [33]
Inpatient Care
Patients with elevated parasitemia (>5% of RBCs infected), CNS infection, or otherwise severe symptoms and those with P falciparuminfection 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.
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. [Medline].
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. [Medline].
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. [Medline]. [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. [Medline].
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. [Medline].
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. [Medline].
9 [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].
10 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 11 J Haematol. 2013 Dec. 163 (5):573-80. [Medline].
Rapid diagnostic tests for malaria ---Haiti, 2010. MMWR Morb Mortal Wkly Rep. 2010 Oct 29. 59(42):1372-3. [Medline].
12 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. [Medline].
13 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.
14 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. [Medline].
15 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. [Medline]. [Full Text].
16 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. [Medline].
17 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. [Medline].
18 [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.
19 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. [Medline]. [Full Text].
20 Sinclair D, Donegan S, Isba R, Lalloo DG. Artesunate versus quinine for treating severe malaria. Cochrane Database Syst Rev. 2012 Jun 13. 6:CD005967. [Medline].
21 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.
22 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. [Medline]. [Full Text].
23 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. [Medline].
24 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. [Medline].
25 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. [Medline]. [Full Text].
26 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. [Medline].
27 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. [Medline].
28 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.
First Malaria Vaccine Approved by EU Regulators. Medscape Medical News. Available at http://www.medscape.com/viewarticle/848608. July 24, 2015;
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.
29 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. [Medline].
30 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. [Medline].
Krintafel (tafenoquine) [package insert]. Research Triangle Park, NC: GlaxoSmithKline. July, 2018. Available at [Full Text].
31 Arakoda (tafenoquine) [package insert]. Washington DC: 60 Degrees Pharms, LLC. August, 2018. Available at [Full Text].
32 Lowes R. FDA Strengthens Warning on Mefloquine Risks. Medscape Medical News. Jul 29 2013. [Full Text].
33 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.
34 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. [Medline].
35 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. [Medline]. [Full Text].
36 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. [Medline].
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.
37 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].
White NJ. A vaccine for malaria (editorial). N Engl J Med. 2011/Oct. 365:[Full Text].
[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.
38 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. [Medline]. [Full Text].
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