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Malaria is infection with Plasmodium sp. Symptoms are fever (which may be periodic), chills, sweating, hemolytic anemia, and splenomegaly. Diagnosis is by seeing Plasmodium in a peripheral blood smear. Treatment and prophylaxis depend on the species and drug sensitivity and include chloroquine, quinine, the fixed combination of atovaquone and proguanil, mefloquine, doxycycline, and artemisinin derivatives. Patients infected with P. vivax and P. ovale also receive primaquine to prevent relapse.
Malaria is endemic in Africa, much of South and Southeast Asia, North and South Korea, Mexico, Central America, Haiti, the Dominican Republic, northern South America (including northern parts of Argentina), the Middle East (including Turkey, Syria, Iran, and Iraq), and Central Asia. There are 300 to 500 million infected people worldwide, with 1 to 2 million deaths yearly, most in children < 5 yr in Africa. Malaria once was endemic in the US but has been virtually eliminated. About 1500 cases/yr occur in the US. Nearly all are acquired abroad, but a small number result from blood transfusions or rare autochthonous transmission by local mosquitoes that feed on infected immigrants.
Pathophysiology
The Plasmodium species that are spread among humans are
Also, simian malaria has been reported in humans; P. knowlesi is implicated most often. Whether P. knowlesi is transmitted from human to human via the mosquito, without the natural intermediate monkey host, has not been determined.
The basic elements of the life cycle are the same for all Plasmodium sp. (see Fig. 1: Extraintestinal Protozoa: Plasmodium life cycle. ) Transmission begins when a female Anopheles mosquito feeds on a person with malaria and ingests blood containing gametocytes. During the following 1 to 2 wk, 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 wk later when the hepatocyte ruptures. Each merozoite can invade an RBC and there transform into a trophozoite. Trophozoites grow and develop into erythrocyte schizonts; schizonts produce further merozoites, which 48 to 72 h 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.
With P. vivax and P. ovale (but not P. falciparum or P. malariae), tissue schizonts may persist as hypnozoites in the liver for up to 3 yr. 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 responsible for the clinical symptoms. If severe, hemolysis 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.
Falciparum malaria:
Unlike other forms of malaria, P. falciparum causes microvascular obstruction because infected RBCs adhere to vascular endothelial cells. Ischemia develops with resultant tissue hypoxia, particularly in the brain, kidneys, lungs, and GI 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 required for the 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, hemoglobin C, thalassemia, G6PD deficiency, or elliptocytosis.
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
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, and about 1 mo (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 yr after infection.
Manifestations common to all forms of malaria include
The malarial paroxysm coincides with release of merozoites from ruptured RBCs. 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 h, fever falls, and profuse sweating occurs for 2 to 3 h, followed by extreme fatigue. Fever is often hectic at the start of infection. In established infections, malarial paroxysms typically occur about every 2 to 3 days depending on the species; intervals are not rigid.
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 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. Patients with cerebral malaria may develop symptoms ranging from irritability to seizures and coma. Acute respiratory distress syndrome (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 spontaneous abortion, stillbirth, or sometimes congenital infection.
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-h intervals. 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-h intervals.
In patients who have been taking chemoprophylaxis (see Extraintestinal Protozoa: Chemoprophylaxis), malaria may be atypical. The incubation period may extend weeks after the drug is stopped. Those infected may develop headache, backache, and irregular fever. Parasites may initially be difficult to find in blood samples.
Diagnosis
Fever and chills (particularly recurrent attacks) in a traveler returning from an endemic region should prompt immediate assessment for malaria. Most cases occur within the first 6 mo, but onset may take up to 2 yr or, rarely, longer.
Malaria is typically 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 1: Extraintestinal Protozoa: Diagnostic Features of Plasmodium Species in Blood Smears ). Blood smears should be repeated at 4- to 6-h intervals if the initial smear is negative.
Thin blood smears stained with Wright-Giemsa stain allow assessment of parasite morphology within RBCs and determination of percentage parasitemia. Thick smears are more sensitive but more difficult to prepare and interpret as the RBCs are lysed before staining.
Commercial rapid assays have been developed to diagnose malaria 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 P. vivax) and detection of plasmodium-associated lactate dehydrogenase (pLDH). However, the rapid tests are no more sensitive for detecting low levels of parasitemia than evaluation of a blood smear by an experienced microscopist and do not detect dual infections.
PCR and species-specific DNA probes may be used but are not widely available. Serologic tests may reflect prior exposure and are not useful in the diagnosis of acute malaria.
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Table 1
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| Diagnostic Features of Plasmodium Species in Blood Smears |
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Characteristic
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Plasmodium Sp*
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Vivax
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Falciparum
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Malariae†
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Infected RBCs enlarged
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Yes
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No
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No
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Schüffner's dots‡
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Yes
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No
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No
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Maurer's dots or clefts
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No
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Yes§
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No
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Multiple infections in RBCs
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Rare
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Yes
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No
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Rings with 2 chromatin dots
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Rare
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Frequent
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No
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Crescentic gametocytes
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No
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Yes
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No
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Bayonet or band trophozoites
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No
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No
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Yes
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Schizonts present in peripheral blood
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Yes
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Rare
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Yes
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Number of merozoites per schizont (mean [range])
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16 (12–24)
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12 (8–24)¶
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8 (6–12)
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*RBCs infected with P. ovale are fimbriated, oval, and slightly enlarged; the parasites otherwise resemble P. vivax.
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† P. knowlesi is morphologically similar to P. malaria and has been confused with it.
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‡Schüffner's dots are best seen when the blood smear is stained with Giemsa, not Wright's stain.
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§This feature is not always visible.
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¶Schizonts are trapped in viscera and usually are not present in peripheral blood.
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Treatment
Malaria is particularly dangerous in children < 5 yr (mortality is highest in those < 2 yr), pregnant women, and previously unexposed visitors to endemic areas. In case of a febrile illness during travel in an endemic region, prompt professional medical evaluation is essential; when this is not possible, self-medication with atovaquone-proguanil can be used pending evaluation.
If P. falciparum is suspected, therapy should be initiated immediately, even if the initial smear is negative. P. falciparum and, more recently, P. vivax have become increasingly resistant to antimalarial drugs. Recommended dosages of antimalarial drugs are listed in Table 2: Extraintestinal Protozoa: Treatment of Malaria and Table 3: Extraintestinal Protozoa: Prevention of Malaria. Common adverse effects and contraindications are listed in Table 4: Extraintestinal Protozoa: Adverse Reactions and Contraindications of Antimalarial Drugs.
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Table 2
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| Treatment of Malaria |
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Preferences
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Druga
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Adult Dosage
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Pediatric Dosage
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P. falciparum (or unidentified species acquired in areas known to harbor chloroquine-resistant P. falciparum)—Oral drugs
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Drugs of choice
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Atovaquone/proguanilb
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2 adult tablets bid for 3 days
or
4 adult tablets once/day for 3 days
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< 5 kg: Not indicated
5–8 kg: 2 pediatric tablets once/day for 3 days
9–10 kg: 3 pediatric tablets once/day for 3 days
11–20 kg: 1 adult tablet once/day for 3 days
21–30 kg: 2 adult tablets once/day for 3 days
31–40 kg: 3 adult tablets once/day for 3 days
> 40 kg: 4 adult tablets once/day for 3 days
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or
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Quinine sulfate
plus one of the following:
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650 mg q 8 h for 3 or 7 daysc
100 mg bid for 7 days
250 mg qid for 7 days
7 mg/kg tid for 7 days
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10 mg/kg q 8 h for 3 or 7 daysc
2 mg/kg bid for 7 days
6.25 mg/kg qid for 7 days
7 mg/kg tid for 7 days
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Alternatives
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Mefloquinef
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750 mg, then 500 mg 12 h later
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15 mg/kg, then 10 mg/kg 12 h later
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or
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Artemether/lumefantrineg
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6 doses (1 dose = 4 tablets) over 3 days (at 0, 8, 24, 36, 48, and 60 h)
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6 doses at intervals as for the adults; dose =
< 15 kg: 1 tablet
15–25 kg: 2 tablets
25–35 kg: 3 tablets
> 35 kg: 4 tablets
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or
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Artesunateh
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4 mg/kg once/day for 3 days
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4 mg/kg once/day for 3 days
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plus
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another drugi
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P. vivax acquired in areas known to harbor chloroquine-resistant P. vivax)—Oral drugs
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Drugs of choice
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Mefloquinef
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750 mg, then 500 mg 12 h later
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15 mg/kg, then 10 mg/kg 12 h later
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or
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Atovaquone/proguanilb
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2 adult tablets bid for 3 days
or
4 adult tablets once/day for 3 days
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< 5 kg: Not indicated
5–8 kg: 2 pediatric tablets once/day for 3 days
9–10 kg: 3 pediatric tablets once/day for 3 days
11–20 kg: 1 adult tablet once/day for 3 days
21–30 kg: 2 adult tablets once/day for 3 days
31–40 kg: 3 adult tablets once/day for 3 days
> 40 kg: 4 adult tablets once/day for 3 days
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either drug followed by
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Primaquine
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30 mg base once/day for 14 days
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0.6 mg/kg once/day for 14 days
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Alternatives
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Chloroquine phosphatej
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8.3 mg base/kg q 16 h for 3 doses
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8.3 mg base/kg q 16 h for 3 doses
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or
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Quinine sulfate
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650 mg q 8 h for 3–7 daysc
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10 mg/kg q 8 h for 3 or 7 daysc
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plus
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Doxycyclined
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100 mg bid for 7 days
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2 mg/kg bid for 7 days
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either regimen followed by
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Primaquine
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30 mg base once/day for 14 days
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0.6 mg/kg once/day for 14 days
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All Plasmodium except chloroquine-resistant P. falciparum and chloroquine-resistant P. vivax—Oral drugs
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Drug of choice
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Chloroquine phosphatej
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1 g (600 mg base), then 500 mg (300 mg base) 6 h later, then 500 mg (300 mg base) at 24 and 48 h
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10 mg base/kg (up to 600 mg base), then 5 mg base/kg 6 h later, then 5 mg base/kg at 24 and 48 h
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All Plasmodium—Parenteral drugs
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Drugs of choice
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Quinidine gluconatek
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10 mg/kg loading dose (up to 600 mg) in normal saline over 1 h, then continuous infusion of 0.02 mg/kg/min until oral drugs can be started
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Same as for adults
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or
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Quinine dihydrochloridek
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20 mg/kg loading dose in 5% dextrose over 4 h, then 10 mg/kg over 2–4 h q 8 h (up to 1800 mg/day) until oral drugs can be started
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Same as for adults
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or
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Artesunate
plus
another drugi
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2.4 mg/kg IV at 0, 12, 24, and 48 h
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Same as for adults
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Prevention of relapses: P. vivax and P. ovale only
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Drug of choice
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Primaquine phosphate
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30 mg base po once/day for 14 days
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0.6 mg base/kg po once/day for 14 days
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aSee Table 4: Extraintestinal Protozoa: Adverse Reactions and Contraindications of Antimalarial Drugs for adverse reactions and contraindications.
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b
Atovaquone/proguanil is available as a fixed-dose combination tablet: adult tablets (250 mg atovaquone/100 mg proguanil) and pediatric tablets (62.5 mg atovaquone/25 mg proguanil). To enhance absorption, patients should take it with food or a milky drink. This drug is contraindicated in patients with creatinine clearance < 30 mL/min. Safety during pregnancy is unknown. Twice/day dosing reduces nausea and vomiting as does taking it with food or milk.
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cIn Southeast Asia, relative resistance to quinine has increased, and treatment should be continued for 7 days. To reduce risk of GI adverse effects, patients should take quinine with or after meals.
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dUse of tetracyclines is contraindicated during pregnancy and in children < 8 yr.
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eThis drug is to be used during pregnancy and in children < 8 yr.
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fResistance to mefloquine has been reported in some areas (eg, the Myanmar borders with Thailand, China, and Laos; Thailand-Cambodia border; southern Vietnam), where 25 mg/kg should be used. In the US, tablets are 250 mg and contain 228 mg mefloquine base; elsewhere, tablets are 275 mg and contain 250 mg base.
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gArtemether/lumefantrine is available as a fixed-dose combination tablet of 20 mg/120 mg. It is contraindicated during the 1st trimester of pregnancy; safety during the 2nd and 3rd trimesters is unknown. Patients should take the drug with food.
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hIn the US, artesunate is available only as an IV preparation (obtained through the Centers for Disease Control and Prevention [CDC]).
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iOne of the following (using oral treatment doses) should be given with artesunate:
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jIf chloroquine phosphate is not available, hydroxychloroquine sulfate is as effective; 400 mg of hydroxychloroquine sulfate is equivalent to 500 mg of chloroquine phosphate. To reduce risk of GI effects, patients should take chloroquine phosphate with food.
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kIf quinidine availability is a problem, clinicians can call the manufacturer or the CDC Malaria Hotline (770-488-7788). Quinidine may have more antimalarial activity than quinine. If patients have received quinine or mefloquine, the quinidine loading dose should be reduced or omitted. If patients require parenteral treatment for > 48 h, the quinine or quinidine dose should be reduced by 30–50%.
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Used with permission from The Medical Letter on Drugs and Therapeutics, The Medical Letter, Inc., August 2004, and updated based on Treatment Guidelines from The Medical Letter 5 (supplement): e6–e8, 2007; last modification July, 2009.
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Table 3
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| Prevention of Malaria |
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Preferences
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Druga (Oral)
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Adult Dosage
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Pediatric Dosage
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Chloroquine-sensitive areas
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Drug of choice
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Chloroquine phosphateb
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500 mg (300 mg base) po once/wk
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5 mg/kg base (up to 300 mg base) po once/wk
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Chloroquine-resistant areas
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Drug of choice
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Atovaquone/proguanilc
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1 adult tablet once/day
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5–8 kg: one-half pediatric tablet once/day
9–10 kg: three-fourths pediatric tablet once/day
11–20 kg: 1 pediatric tablet once/day
21–30 kg: 2 pediatric tablets once/day
31–40 kg: 3 pediatric tablets once/day
> 40 kg: 1 adult tablet once/day
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or
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Doxycyclined
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100 mg po once/day
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2 mg/kg (up to 100 mg) po once/day
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or
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Mefloquineb,e
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250 mg po once/wk
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5–10 kg: one-eighth tablet once/wk
11–20 kg: one-fourth tablet once/wk
21–30 kg: one-half tablet once/wk
31–45 kg: three-fourths tablet once/wk
> 45 kg: 1 tablet once/wk
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Alternative
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Primaquinef
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30 mg base po once/day
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0.6 mg/kg base po once/day
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aSee Table 4: Extraintestinal Protozoa: Adverse Reactions and Contraindications of Antimalarial Drugs for adverse reactions and contraindications.
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bThe drug is begun 1 to 2 wk before travel and continued weekly during the stay and for 4 wk after leaving.
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c
Atovaquone/proguanil is available as a fixed-dose combination tablet: adult tablets (250 mg atovaquone/100 mg proguanil) and pediatric tablets (62.5 mg atovaquone/25 mg proguanil). To enhance absorption, patients should take the drug with food or a milky drink. Atovaquone/proguanil is begun 1 to 2 days before travel and continued during the stay and for 1 wk after leaving.
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dThe drug is begun 1 to 2 days before travel and continued during the stay and for 4 wk after leaving. Use of tetracyclines is contraindicated in pregnancy and in children < 8 yr.
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eResistance to mefloquine has been reported in some areas (eg, Myanmar borders with Thailand, China, and Laos; Thailand-Cambodia borders southern Vietnam); in these areas, atovaquone-proguanil or doxycycline should be used for prophylaxis. Many experts no longer recommend mefloquine because of its potential for serious neuropsychiatric effects.
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Mefloquine has not been approved for use during pregnancy. The drug is not recommended for patients who have a conduction disorder, active depression, or a history of seizures or psychosis; if patients have a psychiatric disorder, the drug should be used cautiously.
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f
Primaquine begun 1 day before travel and continued until 3 to 7 days after leaving provides effective prophylaxis against chloroquine-resistant P. falciparum. In some studies, primaquine was less effective against P. vivax. Taking the drug with food can reduce the severity of nausea and abdominal pain. Primaquine is contraindicated during pregnancy.
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Adapted with permission from The Medical Letter on Drugs and Therapeutics. The Medical Letter, Inc., August 2004, and updated based on Treatment Guidelines from The Medical Letter 5 (supplement): e6–e8, 2007; last modification July 2009.
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Table 4
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| Adverse Reactions and Contraindications of Antimalarial Drugs |
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Drug
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Some Adverse Reactions
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Contraindications
|
|
Artemether/lumefantrine
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Headache, anorexia, dizziness, asthenia (usually mild)
With lumefantrine, prolonged QT interval
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Pregnancy category C (the drug should be used only if potential benefit justifies potential risk to fetus)
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Artesunate
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As with artemether
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As with artemether
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Atovaquone/proguanil
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GI disturbances, headache, dizziness, rash, pruritus
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Pregnancy category C
Hypersensitivity, breastfeeding*, severe renal impairment (creatinine clearance < 30 mL/min)
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Chloroquine phosphate
Chloroquine HCl
Hydroxychloroquine sulfate
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GI disturbances, headaches, dizziness, blurred vision, rashes or pruritus, exacerbation of psoriasis, blood dyscrasias, alopecia, ECG changes, retinopathy, psychosis (rare)
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Hypersensitivity, retinal or visual field changes
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Clindamycin
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Hypotension, bone marrow toxicity, renal dysfunction, rashes, jaundice, tinnitus, Clostridium difficile infection (pseudomembranous colitis)
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Hypersensitivity
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Doxycycline
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GI upset, photosensitivity, vaginal candidiasis, C. difficile infection (pseudomembranous colitis), erosive esophagitis
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Pregnancy, children ≤ 8 yr
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Halofantrine
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Prolongation of PR and QT intervals, cardiac arrhythmia, hypotension, GI disturbances, dizziness, mental changes, seizures, sudden death
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Cardiac conduction defects, familial QT prolongation, use of drugs that affect QT interval, hypersensitivity
Pregnancy category C
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Mefloquine
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Bad dreams, neuropsychiatric symptoms, dizziness, vertigo, confusion, psychosis, seizures, sinus bradycardia, GI disturbances
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Hypersensitivity, history of seizures or psychiatric disorders, cardiac conduction disturbances or arrhythmia, coadministration of drugs that may prolong cardiac conduction (eg, β-blockers, Ca channel blockers, quinine, quinidine, halofantrine), occupations that require fine coordination and spatial discrimination and in which vertigo may be life threatening, 1st trimester of pregnancy
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Quinine sulfate
Quinine dihydrochloride
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GI disturbances, tinnitus, visual disturbances, allergic reactions, mental changes, arrhythmias, cardiotoxicity
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Hypersensitivity, G6PD deficiency, optic neuritis, tinnitus, pregnancy (relative contraindication), past adverse quinine reaction (continuous ECG, BP [when drug is given IV], and glucose monitoring recommended)
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Quinidine gluconate
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Arrhythmias, prolonged Q-Tc interval, hypotension
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Hypersensitivity, thrombocytopenia (continuous ECG, BP, and glucose monitoring recommended)
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Primaquine phosphate
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Severe intravascular hemolysis in people with G6PD deficiency, GI disturbances, leukopenia, methemoglobinuria
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Concomitant use of quinacrine or potentially hemolytic or bone marrow suppressing agents, G6PD deficiency, pregnancy (because G6PD status of the fetus is unknown)
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Pyrimethamine/sulfadoxine
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Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal neurolysis, urticaria, exfoliative dermatitis, serum sickness, hepatitis, seizures, mental changes, GI disturbances, stomatitis, pancreatitis, bone marrow toxicity, hemolysis, fever, nephrosis
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Hypersensitivity, folate deficiency anemia, infants ≤ 2 mo, pregnancy, breastfeeding
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*Proguanil is excreted in human milk; whether atovaquone is excreted in human milk is unknown. Safety and effectiveness of these drugs have not been established in children who weigh < 5 kg.
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 Clinical Calculator
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Treatment of the acute attack:
Chloroquine is the drug of choice against P. malariae, P. ovale, and chloroquine-sensitive P. falciparum and P. vivax. Chloroquine resistance is common among P. falciparum strains throughout endemic areas, with the exception of Central America north and west of the Panama Canal, Mexico, Haiti, the Dominican Republic, Paraguay, northern Argentina, North and South Korea, Georgia, Armenia, most of rural China, and some Middle Eastern countries; current location of resistant strains is available from the CDC at http://cdc-malaria.ncsa.uiuc.edu. Chloroquine resistance is not always complete, but chloroquine should be used only for malaria acquired in areas where Plasmodium sp are known to be sensitive.
Artemisinin derivatives, particularly artemether, artesunate, and the new synthetic arteether, are used globally for treatment of acute malaria in regions where chloroquine-resistance is present. They are usually used in combination with a 2nd drug (eg, lumefantrine); in areas where artemisinins were used as monotherapy for many years (China, Viet Nam, along the Thai-Cambodian border), resistance to artemisinins has been confirmed in P. falciparum. Artemisinin derivatives act more rapidly than other drugs and are well tolerated. Although artemisinins are embryotoxic and associated with a low incidence of teratogenicity in animals, they have not been reported to cause birth defects in humans. They are a pregnancy category C drug.
Uncomplicated chloroquine-resistant malaria can also be treated with atovaquone-proguanil. Quinine plus doxycycline has long been used for uncomplicated and complicated chloroquine-resistant infections, but quinine is associated with frequent side effects. If the patient is pregnant, quinine plus clindamycin can be used. Mefloquine is another option, but adverse effects are common.
IV quinidine, quinine dihydrochloride, or artesunate (available from the CDC) is used in patients unable to take oral drugs. If quinidine or quinine is used, hemodynamic and ECG monitoring is required; the infusion is slowed or temporarily suspended if the QT interval is > 0.6 sec or the QRS widens > 25% beyond baseline. Parenteral therapy should be continued until oral drug is tolerated. It is customary to supplement quinine and quinidine with doxycycline or clindamycin to prevent late recrudescences. These antibiotics act too slowly to be used alone for the treatment of acute malaria. Halofantrine (not available in the US) may prolong the QT interval and has been associated with sudden death.
Patients with falciparum malaria must be monitored closely for hypoglycemia and proper hydration. Exchange transfusions have been used in some patients with high parasitemia to remove infected RBCs, but there is no uniform agreement on this approach. After successful treatment, patients usually improve in 24 to 48 h, but symptoms can persist for 5 days with P. falciparum.
Chloroquine-resistant P. vivax is common in Papua New Guinea and Indonesia. It is treated with quinine plus doxycycline or with mefloquine.
Curative therapy for hypnozoites:
The hypnozoite stage must be eliminated from the liver with primaquine to prevent relapses of P. vivax or P. ovale malaria. Primaquine may be given simultaneously with chloroquine or afterward. Some P. vivax strains are less sensitive and require repeated treatment with higher doses. Primaquine therapy is not necessary for P. falciparum or P. malariae because these Plasmodium sp do not have a persistent hepatic phase.
Prevention
Prophylactic antimalarial drugs and insect repellants reduce but do not eliminate risk of malaria. Vaccines are under development, but none is currently available.
Prophylaxis against mosquitoes includes using permethrin- or pyrethrum-containing residual insecticide sprays (which have prolonged duration of action) on clothing or in homes and outbuildings, placing screens on doors and windows, using mosquito netting (preferably impregnated with permethrin or pyrethrum) around beds, using mosquito repellents such as DEET (diethyltoluamide), and wearing protective clothing, especially between dusk and dawn, when Anopheles mosquitoes are active.
Chemoprophylaxis:
Regimens and dosing vary by geographic location and patient characteristics (see Table 3: Extraintestinal Protozoa: Prevention of Malaria). Information for travelers is available from the CDC at www.cdc.gov/malaria/travelers/index.html.
If exposure to P. vivax or P. ovale is intense or prolonged or if the traveler was splenectomized, a 14-day prophylactic course of primaquine phosphate on return helps reduce the risk of recurrence. The main adverse effect is hemolysis in people with G6PD deficiency. G6PD levels should be determined before the drug is used.
Malaria during pregnancy poses a serious threat to both mother and fetus. Chloroquine can be used in areas where Plasmodium sp are susceptible. In general, pregnant women should avoid travel to chloroquine-resistant areas. 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, and primaquine should not be used during pregnancy. Artemisinins have a short half-life and are not useful for prophylaxis.
Last full review/revision December 2009 by Richard D. Pearson, MD
Content last modified July 2012
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