Malaria

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.

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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.

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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.

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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.

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.

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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.

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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]

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.

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.

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.