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Malaria

Author: Emilio V Perez-Jorge, MD, FACP; Chief Editor: Burke A Cunha, MD more...

Updated: Aug 12, 2013

Practice Essentials

Malaria is a potentially life-threatening disease caused by infection with Plasmodium protozoa transmitted by an

infective female Anopheles mosquito. P falciparum infection carries a poor prognosis with a high mortality rate if untreated but has an excellent prognosis if diagnosed early and treated appropriately.

Essential update: FDA expands warning on antimalarial drug mefloquine

The US Food and Drug Administration (FDA) has updated its warning about the antimalarial drug mefloquine

hydrochloride to include neurologic side effects, along with the previously mentioned 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.[1, 2]

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 usedprophylactically, it should be replaced with another medication.

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

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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 concentrationPlatelet 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


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

Plasmodium falciparum

P vivax

P ovale

P malariae

P knowlesi

In the United States, patients with P falciparum infection are often treated on an inpatient basis to allow observation

for complications. Patients with non– P falciparum malaria who are well can usually be treated on an outpatient

basis.

General recommendations for pharmacologic treatment of malaria are as follows:

P falciparum malaria: Quinine-based therapy is with quinine (or quinidine) sulfate plus doxycycline or

clindamycin or pyrimethamine-sulfadoxine; alternative therapies are artemether-lumefantrine, atovaquone-

proguanil, or mefloquine

P falciparum malaria with known chloroquine susceptibility (only a few areas in Central America and the

Middle East): Chloroquine

P vivax, P ovale malaria: Chloroquine plus primaquine

P malariae malaria: Chloroquine

P knowlesi malaria: Same recommendations as for P falciparum malaria

Pregnant women (especially primigravidas) are up to 10 times more likely to contract malaria than nongravid womenand 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 (avoid in first trimester)

Sulfadoxine-pyrimethamine (avoid in first trimester)

Artemether-lumefantrine[3]

Artesunate and other antimalarials[4]

See Treatment and Medication for more detail.

Image library

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

Background

Malaria, which predominantly occurs in tropical areas, is a potentially life-threatening 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.)


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

entered the cell.

The 5 Plasmodium species known to cause malaria in humans are P falciparum, P vivax , P ovale, P malariae, and P

knowlesi .[5, 6, 7]

Timely identification of the infecting species is extremely important, as P falciparum infection can befatal 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.[6]

Each Plasmodium species has a defined area of endemicity, although geographic overlap is common. At risk for

contraction of malaria are persons living in or traveling to areas of Central America, South America, Hispaniola,

sub-Saharan Africa, the Indian subcontinent, Southeast Asia, the Middle East, and Oceania. Among these regions,sub-Saharan Africa has the highest occurrence of P falciparum transmission to travelers from the United States.

(See Epidemiology.)

Infection and reproduction

After a mosquito takes a blood meal, the malarial sporozoites enter hepatocytes (liver phase) within minutes and

then emerge in the bloodstream after a few weeks. These merozoites rapidly enter erythrocytes, where they develop

into trophozoites and then into schizonts over a period of days (during the erythrocytic phase of the life cycle).

Rupture of infected erythrocytes containing the schizont results in fever and merozoite release. The merozoites enter

new red cells, and the process is repeated, resulting in a logarithmic increase in parasite burden. (See the images

below.)

This micrograph illustrates the trophozoite form, or immature-ring form, of the malarial parasite within peripheral erythrocytes. Red

blood cells infected with trophozoites do not produce sequestrins and, therefore, are able to pass through the spleen.

A mature schizont within an erythrocyte. These red blood cells (RBCs) are sequestered in the spleen when malaria proteins,

called sequestrins, on the RBC surface bind to endothelial cells within that organ. Sequestrins are only on the surfaces of

erythrocytes that contain the schizont form of the parasite.

Other, less common routes of Plasmodium infection are through blood transfusion and maternal-fetal transmission.

Complications


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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, see Malaria, Foreign

Travel, and Insect Bites.

Etiology

Individuals with malaria typically acquired the infection in an endemic area following a mosquito bite. Cases of

infection secondary to transfusion of infected blood are extremely rare. The risk of infection depends on the intensity

of malaria transmission and the use of precautions, such as bed nets, diethyl-meta-toluamide (DEET), and malaria

prophylaxis.

The outcome of infection depends on host immunity. Individuals with immunity can spontaneously clear the

parasites. In those without immunity, the parasites continue to expand the infection. P falciparum infection can result

in death. A small percentage of parasites become gametocytes, which undergo sexual reproduction when taken upby 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 tothe 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.


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Schema of the life cycle of malaria. Image courtesy of the Centers for Disease Control and Prevention.

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.

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 uninfectedRBCs, 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.


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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.[4]

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 thiscondition

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.[9]

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


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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.[10]

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.

Contributor Information and Disclosures Author

Emilio V Perez-Jorge, MD, FACP Staff Physician, Division of Infectious Diseases, Lexington Medical Center

Emilio V Perez-Jorge, MD, FACP is a member of the following medical societies: American College of Physicians-

American Society of Internal Medicine, European Society of Clinical Microbiology and Infectious Diseases,

Infectious Diseases Society of America, Society of Hospital Medicine, and South Carolina Infectious DiseasesSociety

Disclosure: Nothing to disclose.

Coauthor(s)

Thomas E Herchline, MD Professor of Medicine, Wright State University, Boonshoft School of Medicine; Medical

Director, Public Health, Dayton and Montgomery County, Ohio

Thomas E Herchline, MD is a member of the following medical societies: Alpha Omega Alpha, Infectious

Diseases Society of America, and Infectious Diseases Society of Ohio


Chief Editor

Burke A Cunha, MD Professor of Medicine, State University of New York School of Medicine at Stony Brook;

Chief, Infectious Disease Division, Winthrop-University Hospital

Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians,

American College of Physicians, and Infectious Diseases Society of America


Additional Contributors

Michael Stuart Bronze, MD Professor, Stewart G Wolf Chair in Internal Medicine, Department of Medicine,

University of Oklahoma Health Science Center


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Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American

College of Physicians, American Medical Association, Association of Professors of Medicine, Infectious Diseases

Society of America, Oklahoma State Medical Association, and Southern Society for Clinical Investigation


Joseph Richard Masci, MD Professor of Medicine, Professor of Preventive Medicine, Mount Sinai School of

Medicine; Director of Medicine, Elmhurst Hospital Center

Joseph Richard Masci, MD is a member of the following medical societies: Alpha Omega Alpha, American

College of Physicians, Association of Professors of Medicine, and Royal Society of Medicine


Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College

of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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