About half of the world’s population remains at risk of malaria. Malaria is endemic in Africa, India and other areas of South Asia, Southeast Asia, North and South Korea, Mexico, Central America, Haiti, the Dominican Republic, South America (including northern parts of Argentina), the Middle East (including Turkey, Syria, Iran, and Iraq), and Central Asia. The Centers for Disease Control and Prevention (CDC) provides information about specific countries where malaria is transmitted (see CDC: Yellow Fever and Malaria Information, by Country), types of malaria, resistance patterns, and recommended prophylaxis (see CDC: Malaria).
In 2018, there were an estimated 228 million cases of malaria worldwide, with 405,000 deaths, mostly in children < 5 years. African countries bear a disproportionately high share of the global malaria burden. In 2018, 93% of malaria cases and 94% of malaria deaths occurred there. Since 2000, deaths due to malaria have decreased by approximately 60% through the efforts of the RBM (Roll Back Malaria) Partnership to End Malaria, which has > 500 partners (including endemic countries and various organizations and institutions).
Malaria once was endemic in the US. Currently, about 1500 cases occur in the US each year. Nearly all are acquired abroad, but a small number result from blood transfusions or rarely from transmission by local mosquitoes that feed on infected immigrants or returning travelers.
Pathophysiology of Malaria
The Plasmodium species that infect humans are
Concurrent infection with more than one Plasmodium species is uncommon but can occur.
P. knowlesi is an emerging pathogen in Southeast Asia, particularly in Malaysia. Macaque monkeys are the primary hosts. P. knowlesi is usually acquired by people living or working near or in forests.
The basic elements of the life cycle are the same for all Plasmodium species. Transmission begins when a female Anopheles mosquito feeds on a person with malaria and ingests blood containing gametocytes.
During the following 1 to 2 weeks, gametocytes inside the mosquito reproduce sexually and produce infective sporozoites. When the mosquito feeds on another human, sporozoites are inoculated and quickly reach the liver and infect hepatocytes.
The parasites mature into tissue schizonts within hepatocytes. Each schizont produces 10,000 to 30,000 merozoites, which are released into the bloodstream 1 to 3 weeks later when the hepatocyte ruptures. Each merozoite can invade a red blood cell (RBC) and there transform into a trophozoite.
Trophozoites grow, and most develop into erythrocyte schizonts; schizonts produce further merozoites, which 48 to 72 hours later rupture the RBC and are released in plasma. These merozoites then rapidly invade new RBCs, repeating the cycle. Some trophozoites develop into gametocytes, which are ingested by an Anopheles mosquito. They undergo sexual union in the gut of the mosquito, develop into oocysts, and release infective sporozoites, which migrate to the salivary glands.
Plasmodium life cycle
With P. vivax and P. ovale (but not P. falciparum or P. malariae), tissue schizonts may persist as hypnozoites in the liver for years. Relapse of P. ovale has occurred as late as 6 years after an episode of symptomatic malaria, and the infection was transmitted by blood transfusion from a person who was exposed 7 years before donating blood. These dormant forms serve as time-release capsules, which cause relapses and complicate chemotherapy because they are not killed by most antimalarial drugs, which typically act on bloodstream parasites.
The pre-erythrocytic (hepatic) stage of the malarial life cycle is bypassed when infection is transmitted by blood transfusions, by sharing of contaminated needles, or congenitally. Therefore, these modes of transmission do not cause latent disease or delayed recurrences.
Rupture of RBCs during release of merozoites is associated with the clinical symptoms. If severe, hemolysis Overview of Hemolytic Anemia At the end of their normal life span (about 120 days), red blood cells (RBCs) are removed from the circulation. Hemolysis is defined as premature destruction and hence a shortened RBC life span... read more causes anemia and jaundice, which are worsened by phagocytosis of infected RBCs in the spleen. Anemia may be severe in P. falciparum or chronic P. vivax infection but tends to be mild in P. malariae infection.
Unlike other forms of malaria, P. falciparum causes microvascular obstruction because infected RBCs adhere to vascular endothelial cells. Ischemia can develop with resultant tissue hypoxia, particularly in the brain, kidneys, lungs, and gastrointestinal tract. Hypoglycemia and lactic acidosis are other potential complications.
Resistance to infection
Most West Africans have complete resistance to P. vivax because their RBCs lack the Duffy blood group, which is involved in attachment of P. vivax to RBCs; many African Americans also have such resistance. The development of Plasmodium in RBCs is retarded in patients with hemoglobin S disease Sickle Cell Disease Sickle cell disease (a hemoglobinopathy) causes a chronic hemolytic anemia occurring almost exclusively in blacks. It is caused by homozygous inheritance of genes for hemoglobin (Hb) S. Sickle-shaped... read more , hemoglobin C disease Hemoglobin C Disease Hemoglobin C disease is a hemoglobinopathy that causes symptoms of a hemolytic anemia. (See also Overview of Hemolytic Anemia.) The prevalence of hemoglobin (Hb) C in blacks in the US is about... read more , thalassemia Thalassemias Thalassemias are a group of inherited microcytic, hemolytic anemias characterized by defective hemoglobin synthesis. Alpha-thalassemia is particularly common among people of African, Mediterranean... read more , G6PD deficiency Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked enzymatic defect common in blacks, which can result in hemolysis after acute illnesses or intake of oxidant drugs (including... read more , or elliptocytosis Hereditary Spherocytosis and Hereditary Elliptocytosis Hereditary spherocytosis and hereditary elliptocytosis are congenital red blood cell (RBC) membrane disorders that can cause a mild hemolytic anemia. Symptoms, generally milder in hereditary... read more .
Previous infections provide partial immunity. Once residents of hyperendemic areas leave, acquired immunity wanes over time (months to years), and symptomatic malaria may develop if they return home and become reinfected.
Symptoms and Signs of Malaria
The incubation period is usually
12 to 17 days for P. vivax
9 to 14 days for P. falciparum
16 to 18 days or longer for P. ovale
About 1 month (18 to 40 days) or longer (years) for P. malariae
However, some strains of P. vivax in temperate climates may not cause clinical illness for months to > 1 year after infection.
Manifestations common to all forms of malaria include
Fever and rigors—the malarial paroxysm
Malarial paroxysm is caused by hemolysis of infected RBCs, released merozoites and other malaria antigens, and the inflammatory response they elicit. The classic paroxysm starts with malaise, abrupt chills and fever rising to 39 to 41° C, rapid and thready pulse, polyuria, headache, myalgia, and nausea. After 2 to 6 hours, fever falls, and profuse sweating occurs for 2 to 3 hours, followed by extreme fatigue. Fever is often hectic at the start of infection. In established infections, malarial paroxysms typically occur every 2 to 3 days depending on the species.
Splenomegaly usually becomes palpable by the end of the first week of clinical disease but may not occur with P. falciparum. The enlarged spleen is soft and prone to traumatic rupture. Splenomegaly may decrease with recurrent attacks of malaria as functional immunity develops. After many bouts, the spleen may become fibrotic and firm or, in some patients, becomes massively enlarged (tropical splenomegaly). Hepatomegaly usually accompanies splenomegaly.
P. falciparum manifestations
P. falciparum causes the most severe disease because of its microvascular effects. It is the only species likely to cause fatal disease if untreated; nonimmune patients may die within days of their initial symptoms. Temperature spikes and accompanying symptoms typically occur in an irregular pattern but can become synchronous, occurring in a tertian pattern (temperature spikes at 48-hour intervals), particularly in residents of endemic areas who are partially immune.
Patients with cerebral malaria may develop symptoms ranging from irritability to seizures and coma. Acute respiratory distress syndrome Acute Hypoxemic Respiratory Failure (AHRF, ARDS) Acute hypoxemic respiratory failure is severe arterial hypoxemia that is refractory to supplemental oxygen. It is caused by intrapulmonary shunting of blood resulting from airspace filling or... read more (ARDS), diarrhea, icterus, epigastric tenderness, retinal hemorrhages, algid malaria (a shocklike syndrome), and severe thrombocytopenia may also occur.
Renal insufficiency may result from volume depletion, vascular obstruction by parasitized erythrocytes, or immune complex deposition. Hemoglobinemia and hemoglobinuria resulting from intravascular hemolysis may progress to blackwater fever (so named based on the dark color of the urine), either spontaneously or after treatment with quinine.
Hypoglycemia is common and may be aggravated by quinine treatment and associated hyperinsulinemia.
Placental involvement may lead to low birth weight, spontaneous abortion, stillbirth, or congenital infection.
P. vivax, P. ovale, P. malariae, and P. knowlesi manifestations
P. vivax, P. ovale, and P. malariae typically do not compromise vital organs. Mortality is rare and is mostly due to splenic rupture or uncontrolled hyperparasitemia in asplenic patients.
The clinical course with P. ovale is similar to that of P. vivax. In established infections, temperature spikes occur at 48-hour intervals—a tertian pattern.
P. malariae infections may cause no acute symptoms, but low-level parasitemia may persist for decades and lead to immune complex–mediated nephritis or nephrosis or tropical splenomegaly; when symptomatic, fever tends to occur at 72-hour intervals—a quartan pattern.
P. knowlesi is associated with the full spectrum of malaria. In contrast to P. falciparum, infection is more likely in males over 15 years living close to or working in forested areas. There are typically daily temperature spikes. Severity increases with the patient's age. The short asexual replication cycle of 24 hours can lead to high rates of parasitemia, and if untreated, death. Thrombocytopenia is common, but it is typically not associated with hemorrhage.
Manifestations in patients taking chemoprophylaxis
In patients who have been taking chemoprophylaxis (see table Prevention of Malaria Drugs Used to Prevent Malaria ), malaria may be atypical. The incubation period may extend weeks to months after the drug is stopped. Those infected may develop headache, backache, and irregular fever, but parasites may initially be difficult to find in blood samples.
Diagnosis of Malaria
Light microscopy of blood (thin and thick smears)
Rapid diagnostic tests that detect Plasmodium antigens or enzymes in blood
Fever and chills in an immigrant or traveler returning from an endemic region should prompt immediate assessment for malaria. Symptoms usually appear in the first 6 months after infection, but onset may take up to 2 years or, rarely, longer.
Malaria can be diagnosed by finding parasites on microscopic examination of thick or thin blood smears. The infecting species (which determines therapy and prognosis) is identified by characteristic features on smears (see table Diagnostic Features of Plasmodium Species in Blood Smears Diagnostic Features of Plasmodium Species in Blood Smears ). If the initial blood smear is negative, additional smears should be repeated at 12- to 24-hour intervals until 3 smears are negative.
Thin blood smears stained with Wright-Giemsa stain allow assessment of parasite morphology within red blood cells (RBCs), often speciation, and determination of percentage parasitemia (parasite density), evaluated using oil immersion magnification of portions of the smear where RBCs are more or less touching, which should show about 400 RBCs per field. Thick smears are more sensitive but more difficult to prepare and interpret as the RBCs are lysed before staining. Sensitivity and accuracy of the results depend on the examiner's experience.
Commercial rapid diagnostic tests for malaria are based on the presence of certain plasmodium antigens or enzymatic activities. Assays may involve detection of a histidine-rich protein 2 (HRP-2) associated with malaria parasites (especially P. falciparum) and detection of plasmodium-associated lactate dehydrogenase (pLDH). The rapid diagnostic tests are generally comparable in sensitivity to microscopy in detecting low levels of parasitemia, but they do not differentiate single infection from concurrent infection with more than one Plasmodium species or allow speciation except for P. falciparum.
Light microscopy and rapid diagnostic tests are complementary tests, and both should be done when available. They have similar sensitivity. Negative results even in both does not exclude malaria in a patient with low parasitemia.
Polymerase chain reaction and species-specific DNA probes can be used but are not widely available at the point of care. They can help identify the infecting Plasmodium species after malaria is diagnosed. Because serologic tests may reflect prior exposure, they are not useful in the diagnosis of acute malaria.
Severity of malaria
Severe malaria is defined by the presence of one of more of the following clinical and laboratory features. Severe malaria tends to result from P. falciparum.
Clinical criteria for severe malaria:
Acute respiratory distress syndrome/pulmonary edema
Coma or impaired consciousness
Laboratory criteria for severe malaria:
Anemia (severe: < 7 g/dL [70 g/L])
Disseminated intravascular coagulation Disseminated Intravascular Coagulation (DIC) Disseminated intravascular coagulation (DIC) involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process, increased platelet aggregation and coagulation... read more (DIC)
Parasite density > 5%
Treatment of Malaria
Antimalarial drugs are chosen based on the following:
Disease severity (clinical and laboratory criteria)
Infecting Plasmodium species
Known resistance patterns of strains in the area of acquisition
Efficacy and adverse effects of drugs available
Artemisinin-based combination therapy, such as oral artemether/lumefantrine, is the most rapidly active treatment, and in many situations, it is the treatment of choice. Resistance to artemisinins has been reported but is not yet common.
Severe malaria Severity of malaria Malaria is infection with Plasmodium species. Symptoms and signs include fever (which may be periodic), chills, rigors, sweating, diarrhea, abdominal pain, respiratory distress, confusion... read more requires urgent treatment, preferably with intravenous artesunate, which is the only drug available in the US for parenteral treatment of severe malaria (or for patients who cannot take drugs orally). If it cannot be quickly obtained from a commercial vendor, it is available for an interim period from the Centers for Disease Control and Prevention (CDC) under an expanded access investigational new drug (IND) protocol by calling the CDC Malaria Hotline at 770-488-7788 or 855-856-4713 toll-free Monday-Friday 9 AM to 5 PM EST; or after hours, on weekends or holidays, by calling 770-488-7100 and asking to speak with a Malaria Branch expert. It is estimated to take 12 to 24 hours for artesunate to reach most hospitals. If artesunate is not immediately available, start interim oral therapy with artemether-lumefantrine, atovaquone-proguanil, quinine sulfate (plus doxycycline or clindamycin intravenously), or if nothing else is available, mefloquine. In patients who are vomiting, an antiemetic may be helpful. Those who cannot swallow (eg, because of delirium) may be given crushed tablets of artemether/lumefantrine or atovaquone/proguanil through a nasogastric tube.
Pearls & Pitfalls
In some endemic areas, a significant proportion of locally available antimalarial drugs are counterfeit. Thus, some clinicians advise travelers to remote, high-risk areas to take along a full course of an appropriate treatment regimen to be used if medically confirmed malaria is acquired despite prophylaxis; this strategy also avoids depleting limited drug resources in the destination country.
Malaria is particularly dangerous in children < 5 years (mortality is highest in those < 2 years), pregnant women, and previously unexposed visitors to endemic areas.
If P. falciparum is suspected, therapy should be initiated immediately, even if the initial smear and rapid diagnostic test are negative. P. falciparum resistance to antimalarial drugs is now widespread, and chloroquine-resistant P. vivax is common in Papua New Guinea, Indonesia, and emerging in some other areas.
For recommended drugs and doses for treatment and prevention of malaria, see tables Treatment of Malaria Treatment of Malaria in the United States and Prevention of Malaria Drugs Used to Prevent Malaria . Common adverse effects and contraindications are listed in table Adverse Reactions and Contraindications of Antimalarial Drugs Adverse Reactions and Contraindications of Antimalarial Drugs . See also the CDC web site (Malaria Diagnosis and Treatment in the United States), or for emergency consultation about management, call the CDC Malaria Hotline at the numbers listed above.
In case of a febrile illness during travel in an endemic region, prompt professional medical evaluation is essential. When prompt evaluation is not possible (eg, because the region is very remote), self-medication with artemether/lumefantrine or atovaquone/proguanil can be considered pending evaluation. If travelers present with fever after returning from an endemic region and no other diagnosis is made, clinicians should consider giving empiric treatment for uncomplicated malaria even when malaria smears and/or rapid diagnostic tests are negative.
1. Aldámiz-Echevarría LT, López-Polín A, Norman FF, et al: Delayed haemolysis secondary to treatment of severe malaria with intravenous artesunate: Report on the experience of a referral centre for tropical infections in Spain. Travel Med Infect Dis 2016. pii: S1477–8939(16)30166-1. doi: 10.1016/j.tmaid.2016.10.013 [Epub ahead of print]
Prevention of Relapses of P. vivax or P. ovale Malaria
Hypnozoites must be eliminated from the liver with primaquine or tafenoquine to prevent relapses of P. vivax or P. ovale. Primaquine or tafenoquine may be given simultaneously with chloroquine or afterward. Some P. vivax strains are less sensitive, and relapse may occur, requiring repeated treatment. Primaquine is not necessary for P. falciparum or P. malariae because these species do not have a persistent hepatic phase. If exposure to P. vivax or P. ovale is intense or prolonged or if travelers are asplenic, a 14-day prophylactic course of primaquine phosphate or a single dose of tafenoquine starting when travelers return reduces the risk of recurrence. The main adverse effect is hemolysis in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD levels should be determined before primaquine or tafenoquine is given.
Primaquine is contraindicated during pregnancy and breastfeeding, unless the infant has been shown not to be G6PD deficient. In pregnant women, chemoprophylaxis with weekly chloroquine can be given for the remainder of pregnancy, and after delivery, women can be given primaquine, provided they are not G6PD deficient.
Prevention of Malaria
Travelers to endemic regions should be given chemoprophylaxis (see table Prevention of Malaria Drugs Used to Prevent Malaria ). Information about countries where malaria is endemic is available from the Centers for Disease Control and Prevention (CDC) (see CDC: Yellow Fever and Malaria Information, by Country and CDC: Malaria); the information includes types of malaria, resistance patterns, geographic distribution, and recommended prophylaxis.
Malaria during pregnancy poses a serious threat to both mother and fetus. Chloroquine can be used during pregnancy in areas where Plasmodium species are susceptible, but there is no other safe and effective prophylactic regimen, so pregnant women should avoid travel to chloroquine-resistant areas whenever possible. Treatment of malaria during pregnancy depends on infecting Plasmodium species and known resistance patterns in the area of acquisition (see CDC: Treatment of Malaria: Guidelines For Clinicians (United States): Alternatives for Pregnant Women).
The safety of mefloquine during pregnancy has not been documented, but limited experience suggests that it may be used when the benefits are judged to outweigh the risks. Doxycycline, atovaquone/proguanil, primaquine, and tafenoquine should not be used during pregnancy.
Artemisinins have a short half-life and are not useful for prophylaxis.
Prophylactic measures against mosquitoes include
Using permethrin- or pyrethrum-containing residual insecticide sprays (which have prolonged duration of action)
Placing screens on doors and windows
Using mosquito netting (preferably impregnated with permethrin or pyrethrum) around beds
Treating clothing and gear (eg, boots, pants, socks, tents) with products containing 0.5% permethrin, which remain protective through several washings (pretreated clothing is available and may protect longer)
Applying mosquito repellents such as DEET (diethyltoluamide) 25 to 35% to exposed skin
Wearing protective long-sleeved shirts and pants, especially between dusk and dawn, when Anopheles mosquitoes are active
People who plan to use repellents that contain DEET should be instructed to
Apply repellents only to exposed skin as directed on the label and use them sparingly around ears (they should not be applied to or sprayed in the eyes or mouth).
Wash hands after application.
Not allow children to handle repellents (adults should apply the repellent to their hands first, then gently spread it on the child's skin).
Apply just enough repellent to cover the exposed area.
Wash the repellant off after returning indoors.
Wash clothing before wearing again unless indicated otherwise by the product label.
Most repellents can be used on infants and children < 2 months. The Environmental Protection Agency does not recommend additional precautions for using registered repellents on children or on pregnant or breastfeeding women.
On October 6, 2021, the World Health Organization (WHO) recommended widespread use of the RTS,S/AS01 (RTS,S) malaria vaccine among children in sub-Saharan Africa and in other regions with moderate to high P. falciparum malaria transmission. (See WHO recommends groundbreaking malaria vaccine for children at risk.)
In 2018, there were an estimated 228 million people with malaria worldwide, and about 405,000 deaths occurred, mostly in children < 5 years in Africa; since 2000, deaths due to malaria have decreased by about 60%.
P. falciparum causes microvascular obstruction and tissue ischemia, particularly in the brain, kidneys, lungs, and gastrointestinal tract of nonimmune infants and adults; patients may die within days of their initial symptoms.
P. vivax, P. ovale, and P. malariae typically do not compromise vital organs; mortality is rare. The full spectrum of malaria occurs with P. knowlesi. Its short asexual replication cycle can result in high parasitemia and severe, potentially fatal disease if untreated.
Manifestations include recurrent fever and rigor, headache, myalgia, and nausea; hemolytic anemia and splenomegaly are common.
Diagnose using light microscopy of blood (thin and thick smears) and rapid diagnostic blood tests.
Treat with antimalarial drugs based on the species (if known) and drug resistance patterns in the area in which infection was acquired.
Artemisinin-based therapy (eg, artemether/lumefantrine, artesunate, other artemisinin compounds) is the most rapidly active therapy; atovaquone plus proguanil is an alternative for patients with uncomplicated malaria.
Use primaquine or tafenoquine for confirmed or suspected infections with P. vivax and P. ovale to prevent relapse unless patients are pregnant, breastfeeding, have G6PD deficiency, or their G6PD status is unknown.
Give chemoprophylaxis to travelers to endemic areas, and teach them ways to prevent mosquito bites.
Drugs Mentioned In This Article
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