Introduction
Background
Malaria is the most deadly vector-borne disease in the world. Although typically an illness of tropical regions of the world, more than 1500 cases (nearly all foreign-originating) are diagnosed in the US each year. In some parts of the world, malaria is known as paludism (paludismo). Blackwater fever refers to the dark urine sometimes seen as a result of severe red blood cell hemolysis from malaria.
At least 10 of the more than 200 parasitic protozoa species of the genus Plasmodium (Plasmodium ovale, Plasmodium vivax, Plasmodium malariae, Plasmodium falciparum), and Plasmodium knowlesi, cause human malaria. P falciparum causes the most severe morbidity and mortality.
Malaria is primarily transmitted through the bite of an infected female Anopheles species mosquito. Malaria also can be transmitted via a blood transfusion or congenitally between mother and fetus, although these forms of infection are rare.
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. Of these areas, sub-Saharan Africa has the highest occurrence of P falciparum transmission to travelers from the United States.
Pathophysiology
The vector, the Anopheles species mosquito, passes plasmodia, which are contained in its saliva, into its host while obtaining a blood meal. Plasmodia enter circulating erythrocytes (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.
This 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. P falciparum, the most malignant of the 5 species of Plasmodium, may induce kidney 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, which 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 termed hemozoin (see Media file 3).
An erythrocyte filled with merozoites, which soon will rupture the cell and attempt to infect other RBCs. 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.
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.
The morbidity and mortality caused by P falciparum are increased greatly over that caused by other Plasmodium species because of the increased parasitemia of P falciparum and its ability to cytoadhere. When an RBC becomes infected with P falciparum, it 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, leading to much of the damage incurred by the parasite. Furthermore, P falciparum is able to infect RBCs of all ages, resulting in high levels of parasitemia (>5% RBCs infected). By contrast, P vivax and P ovale only infect young RBCs and thus have a relatively limited parasitemia (usually <2%).
Frequency
United States
Although cases of malaria occur in some areas of the United States in people who have not traveled outside the country and have no other known risk factors, malaria ceased to be an endemic disease to the country as of 1947. Most cases of malaria reported by those living in the United States are associated with recent travel to an endemic area. Malaria may also be transmitted at birth or trans-placentally. Rarely, malaria is transmitted through blood transfusion, needle-sharing, or organ transplant.
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 , Macaca nemestrina). This species can cause severe illness and death in people, but, under the microscope, the parasite looks similar to the more benign P malariae and has sometimes been misdiagnosed. As P malariae infection is typically relatively mild, Plasmodium knowlesi infection should be suspected in persons residing or traveling in the above geographical areas with microscopic evidence of P malariae infection who are severely ill. Diagnosis may be confirmed via polymerase chain reaction (PCR) methods.
International
Malaria remains an enormous international medical issue, with an estimated 300-500 million cases occurring annually.1 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.
HIV and malaria co-infection is a significant problem across Asia and sub-Saharan Africa where both diseases may be 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 HIV-infected patients, and HIV replication increasing in malaria infection.
Mortality/Morbidity
- Internationally, as many as 2 million deaths occur annually. Of these deaths, the overwhelming majority is among children aged 5 years or younger, and 80-90% of the deaths each year are in rural sub-Saharan Africa.1 Malaria is the world’s fourth leading cause of death in children younger than 5 years, accounting for the majority of malaria-related deaths.
- 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.
Race
The sickle cell trait (hemoglobin S), thalassemias, hemoglobin C, or glucose-6-phosphate dehydrogenase (G-6-PD) deficiency are protective against death from P falciparum malaria, with the former being relatively more protective than the latter three. Individuals with hemoglobin E may be protected against P vivax infection. Individuals heterozygotic for RBC band 3 ovalocytosis are at reduced risk of infection with P falciparum, Plasmodium knowlesi and, especially, P vivax malaria. West African populations lacking RBC Duffy antigen are completely refractory to infection by P vivax.
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 with 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.
Sex
Males and females are affected equally. However, malaria may be devastating in pregnancy to both 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 placental sequestration of (P falciparum) parasites. Anemia from malaria can be more severe in pregnant women. Fetal complications include death, premature birth, anemia, and low birth weight.
Age
- All ages are affected by malaria.
- Mortality is very high in children younger than 5 years.
Clinical
History
Most patients live in or have recently traveled to an endemic area; however, a few cases are reported each year in which the patient had no history of such travel (eg, airport malaria, from imported mosquitoes). Malaria may present over 1 year after travel to an endemic area. Previously infected patients may develop relapsing malaria, a recurrence of the disease after it has been apparently cured; this form is caused by reactivation of hypnozoites (dormant liver-stage parasites) in P vivax and P ovale infections.
- Determine the patient's immune status, age, allergies, other medical conditions, other medications, and pregnancy status.
- The patient usually remains asymptomatic for a week or more after the infecting mosquito bite.
- Clinical symptoms 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.
- Maintain a high index of suspicion for malaria in any patient exhibiting any malarial symptoms and having a history of travel to endemic areas.
• Less common symptoms include the following:
- Anorexia and lethargy
- Nausea and vomiting
- Diarrhea
- Headache
- Jaundice
Physical
- Physical signs that may be noted with malaria include the following:
- Tachycardia
- Fever
- Hypotension
- Signs of anemia
- Splenomegaly
- Icterus
Causes
- Malaria most often is caused by the bite of a female Anopheles species mosquito that is infected with species of the protozoan genus Plasmodium. The 5 most common species affecting humans are as follows:
- 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 in 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: Those infected with this species of Plasmodium remain asymptomatic for a much longer period of time than those infected with P vivax or P ovale. Recrudescence is common in those infected with P malariae. It often is associated with a nephrotic syndrome, possibly resulting from deposition of antibody-antigen complex upon the glomeruli.
- P knowlesi: Autochthonous cases have been documented in Malaysian Borneo, Thailand, Myanmar, Singapore, and in 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 seriously as those infected with falciparum malaria, as P knowlesi may cause fatal disease.2
- P falciparum: The most malignant form of malaria is caused by this species. Infection with P falciparum is not limited to RBCs of a particular age and, hence, represents the highest level of parasitemia among the 5 Plasmodium species. This species also causes vascular obstruction due to its ability to adhere to endothelial cell walls. This property leads to most complications of P falciparum infection. P falciparum can cause cerebral malaria, pulmonary edema, rapidly developing anemia, and renal problems. Blackwater fever, is the darkening of the urine seen with severe RBC hemolysis resulting from high parasitemia, and is often a sign of impending renal failure and clinical decline.
- Other less common routes of infection are through blood transfusion and maternal-fetal transmission. When P vivax and P ovale are transmitted via blood, no latent hypnozoite phase occurs and treatment with primaquine is not necessary, as it is the sporozoites that form hypnozoites in infected hepatocytes.
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Further Reading
Keywords
malaria, paludism, paludismo, black water fever, blackwater fever, mosquito vector, plasmodia, Plasmodium, Plasmodium ovale, Plasmodium vivax, Plasmodium malariae, Plasmodium falciparum, Anopheles species, mosquito, mosquito bite
