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Malaria

By

Richard D. Pearson

, MD, University of Virginia School of Medicine

Last full review/revision May 2019| Content last modified May 2019
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Malaria is infection with Plasmodium species. Symptoms and signs include fever (which may be periodic), chills, sweating, hemolytic anemia, and splenomegaly. Diagnosis is by seeing Plasmodium in a peripheral blood smear and by rapid diagnostic tests. Treatment and prophylaxis depend on the species and drug sensitivity and include artemisinin-based combination therapy, the fixed combination of atovaquone and proguanil, and regimens that contain chloroquine, quinine, or mefloquine. Patients infected with P. vivax and P. ovale also receive primaquine or a single dose of tafenoquine to prevent relapse.

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 2017, there were an estimated 219 million cases of malaria worldwide, with 435,000 deaths, mostly in children < 5 years in Africa. 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

The Plasmodium species that infect humans are

  • P. falciparum

  • P. vivax

  • P. ovale

  • P. malariae

  • P. knowlesi (rarely)

Concurrent infection with more than one Plasmodium species is uncommon.

Also, simian malaria has been reported in humans; P. knowlesi is an emerging pathogen in Southeast Asia. The degree to which P. knowlesi is transmitted from human to human via the mosquito, without the natural intermediate monkey host, is under study.

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

  • The malaria parasite life cycle involves 2 hosts. During a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the human host.

  • Sporozoites infect liver cells.

  • There, the sporozoites mature into schizonts.

  • The schizonts rupture and release merozoites. This initial replication in the liver is called the exoerythrocytic cycle.

  • Merozoites infect RBCs. There, the parasite multiplies asexually (called the erythrocytic cycle). The merozoites develop into ring-stage trophozoites. Some then mature into schizonts.

  • The schizonts rupture, releasing merozoites.

  • Some trophozoites differentiate into gametocytes.

  • During a blood meal, an Anopheles mosquito ingests the male (microgametocytes) and female (macrogametocytes) gametocytes, beginning the sporogonic cycle.

  • In the mosquito’s stomach, the microgametes penetrate the macrogametes, producing zygotes.

  • The zygotes become motile and elongated, developing into ookinetes.

  • The ookinetes invade the midgut wall of the mosquito where they develop into oocysts.

  • The oocysts grow, rupture, and release sporozoites, which travel to the mosquito’s salivary glands. Inoculation of the sporozoites into a new human host perpetuates the malaria life cycle.

<i>Plasmodium</i>  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 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 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, 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

  • 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

  • Anemia

  • Jaundice

  • Splenomegaly

  • Hepatomegaly

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 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 (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 , and P. malariae 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.

Manifestations in patients taking chemoprophylaxis

In patients who have been taking chemoprophylaxis (see table Prevention of 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

  • 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). 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 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.

Table
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Diagnostic Features of Plasmodium Species in Blood Smears

Characteristic

Plasmodium vivax*

Plasmodium falciparum

Plasmodium malariae

Infected red blood cells (RBCs) enlarged

Yes

No

No

Schüffner dots

Yes

No

No

Maurer dots or clefts

No

Yes§

No

Multiple infections in RBCs

Rare

Yes

No

Rings with 2 chromatin dots

Rare

Frequent

No

Crescentic gametocytes

No

Yes

No

Bayonet or band trophozoites

No

No

Yes

Schizonts present in peripheral blood

Yes

Rare

Yes

Number of merozoites per schizont (mean [range])

16 (12–24)

12 (8–24)

8 (6–12)

*RBCs infected with P. ovale are fimbriated, oval, and slightly enlarged; the parasites otherwise resemble P. vivax.

P. knowlesi is morphologically similar to P. malaria and has been confused with it.

Schüffner dots are best seen when the blood smear is stained with Giemsa stain.

§This feature is not always visible.

Schizonts are trapped in viscera and usually are not present in peripheral blood.

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

  • Bleeding

  • Coma or impaired consciousness

  • Jaundice

  • Seizures (recurrent)

  • Shock

Laboratory criteria for severe malaria:

  • Anemia (severe: < 7 g/dL [70 g/L])

  • Disseminated intravascular coagulation (DIC)

  • Hemoglobinuria

  • Metabolic acidosis

  • Parasite density > 5%

  • Renal failure

Treatment

  • Antimalarial drugs

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 drug of choice. Resistance to artemisinins has been reported but is not yet common.

Severe malaria 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). It can be obtained from the Centers for Disease Control and Prevention (CDC) under an expanded access investigation 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. When 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

  • Time is of the essence in treating severe malaria. Begin treatment with IV artesunate as soon as possible. Start interim oral therapy if IV artesunate is not immediately available. 

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 and Prevention of Malaria. Common adverse effects and contraindications are listed in table 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.

Table
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Treatment of Malaria in the United States

Preferences

Druga

Adult Dosage

Pediatric Dosageb

Uncomplicated malaria due to P. falciparum or unidentified species acquired in all malarious regions except those specified as chloroquine-sensitive—Oral drugs

Recommended drug

Artemether/lumefantrinec

6 doses (1 dose = 4 tablets) over 3 days (at 0 and 8 hours), then 1 dose twice a day for the following 2 days

6 doses at intervals as for the adults; dose =

5–< 15 kg: 1 tablet

15–< 25 kg: 2 tablets

25–< 35 kg: 3 tablets

35 kg: 4 tablets

or

Atovaquone/proguanild

4 adult tablets once a day for 3 days

< 5 kg: Not indicated

5–8 kg: 2 pediatric tablets once a day for 3 days

9–10 kg: 3 pediatric tablets once a day for 3 days

11–20 kg: 1 adult tablet once a day for 3 days

21–30 kg: 2 adult tablets once a day for 3 days

31–40 kg: 3 adult tablets once a day for 3 days

> 40 kg: 4 adult tablets once a day for 3 days

or

Quinine sulfate plus one of the following:

650 mg 3 times a day for 3 or 7 dayse

10 mg/kg 3 times a day for 3 or 7 dayse

Dose not to exceed adult dose

  • Doxycyclinef

100 mg twice a day for 7 days

2.2 mg/kg twice a day for 7 days

  • Tetracyclinef

250 mg 4 times a day for 7 days

6.25 mg/kg 4 times a day for 7 days

  • Clindamycing

7 mg/kg 3 times a day for 7 days

7 mg/kg 3 times a day for 7 days

Alternative (if other options cannot be used)

Mefloquineh

750 mg once, then 500 mg 6–12 hours later

15 mg/kg once, then 10 mg /kg 6–12 hours later

Additional options for uncomplicated malaria due to P. falciparum or unidentified species acquired in chloroquine-sensitive areas (Central America west of Panama Canal, Haiti, Dominican Republic, most of the Middle East), and P. malariae and P. knowlesi in all regions—Oral drugs

Drugsi

Chloroquine phosphatej,k

1,000 mg, then 500 mg at 6, 24, and 48 hours

16.6 mg/kg (up to 1000 mg), then 8.3 mg/kg (up to 500 mg) at 6, 24, and 48 hours

or

Hydroxychloroquine sulfatek

800 mg, then 400 mg at 6, 24, and 48 hours

13 mg/kg (up to 800 mg), then 6.5 mg/kg (up to 400 mg) at 6, 24, and 48 hours

Uncomplicated malaria due to P. ovale in all regions or P. vivax outside of Papua New Guinea and Indonesia—Oral drugs

Recommended drugsi

Chloroquine phosphatej,kor

Hydroxychloroquine sulfatek

Dosing as above

Dosing as above

plus

Primaquinel,m

30 mg once a day for 14 days

0.5 mg/kg (maximum 30 mg) once a day for 14 days

or

Tafenoquine l,m 

300 mg single dose

Only for patients ≥ 16 years, use adult dose

Uncomplicated malaria due to P. vivax acquired in areas known to harbor chloroquine-resistant P. vivaxm (Papua New Guinea, Indonesia)—Oral drugs

Recommended drugs

Quinine sulfate plus one of the following:

650 mg 3 times a day for 3 or 7 dayse

10 mg/kg 3 times a day for 3 or 7 dayse

  • Doxycyclinef

100 mg twice a day for 7 days

2.2 mg/kg twice a day for 7 days

  • Tetracyclinef

250 mg 4 times a day for 7 days

6.25 mg/kg 4 times a day for 7 days

or

Atovaquone/proguanild

4 adult tablets once a day for 3 days

< 5 kg: Not indicated

5–8 kg: 2 pediatric tablets once a day for 3 days

9–10 kg: 3 pediatric tablets once a day for 3 days

11–20 kg: 1 adult tablet once a day for 3 days

21–30 kg: 2 adult tablets once a day for 3 days

31–40 kg: 3 adult tablets once a day for 3 days

> 40 kg: 4 adult tablets once a day for 3 days

or

Mefloquineh

750 mg once, then 500 mg 6–12 hours later

15 mg/kg once, then 10 mg/kg 6–12 hours later

plus, with any of the above regimens

Primaquinel

30 mg once a day for 14 days

0.5 mg/kg (maximum 30 mg) once a day for 14 days

or

Tafenoquine l 

300 mg single dose 

Only for patients ≥ 16 years, use adult dose

Severe malarian, all Plasmodium —Parenteral drugs

Recommended drugs

IV artesunaten, available through the CDC Malaria Hotlineo (if IV artesunate is not immediately available, give interim oral treatment)

Adults 2.4 mg/kg actual body weight IV at 0, 12, 24, and 48 hours

Children < 20 kg: 3 mg/kg actual body weight IV at 0, 12, 24, and 48 hours

Children ≥ 20 kg: adult dose

followed by one of the following

Artemether-lumefantrine

Dosing as above

Dosing as above

Atovaquone-proguanild

Dosing as above

Dosing as above

Doxycyclinef

Dosing as above; same dose may also be given IV

Dosing as above; same dose may also be given IV

Clindamycing,p (in pregnant women)

Oral dosing as above, but if parenteral therapy is required, give 10 mg/kg IV loading dose followed by 5 mg/kg IV every 8 hours

Oral dosing as above, but if parenteral therapy is required, give 10 mg/kg IV loading dose followed by 5 mg/kg IV every 8 hours

plus, if P. vivax or P. ovale is likely or confirmed

Primaquinel or tafenoquinel

Dosing as above

Dosing as above

Prevention of relapses: P. vivax and P. ovale only—Oral drugs

Recommended drug

Primaquinel

30 mg once a day for 14 days after leaving the endemic area

0.5 mg/kg once a day (maximum 30 mg) for 14 days after leaving the endemic area

or

Tafenoquine l 

300 mg single dose 

Only for patients ≥ 16 years, use adult dose

aSee table Prevention of Malaria for adverse reactions and contraindications. If malaria has developed during prophylactic drug therapy, that drug should not be used as part of the treatment regimen.

bThe pediatric dose should not exceed the adult dose.

cArtemether/lumefantrine is available as a fixed-dose combination tablet of 20 mg/120 mg. Generally, this combination is not recommended for use in pregnant women, particularly during the 1st trimester, because safety data are insufficient; it may be used if other options are unavailable or are not tolerated and benefits outweigh risks. Patients should take the drug with food or whole milk. If patients vomit within 30 minutes of taking a dose, the dose should be repeated.

dAtovaquone/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 combination is contraindicated in patients with creatinine clearance < 30 mL/min. Generally, this combination is not recommended for pregnant women, particularly during the 1st trimester, because safety data are insufficient; it may be used if other options are unavailable or are not tolerated and benefits outweigh risks. Twice a day dosing reduces nausea and vomiting as does taking it with food or milk. If patients vomit within 30 min of taking a dose, the dose should be repeated.

eIn the US, quinine sulfate capsules contain 324 mg, so 2 capsules are sufficient for adults. For children, dosing may be more difficult because noncapsule forms of quinine are not available. In Southeast Asia, relative resistance to quinine has increased, and treatment should be continued for 7 days. In other regions, treatment is continued for only 3 days. To reduce risk of gastrointestinal adverse effects, patients should take quinine with food. Quinine plus doxycycline or tetracycline is generally preferred to quinine plus clindamycin because there is more data on efficacy.

fUse of tetracyclines is not recommended during pregnancy and in children < 8 years. However, doxycycline or tetracycline may be used if other treatment options are unavailable or not tolerated and if benefit is thought to outweigh risk.

gClindamycin is recommended to be used during pregnancy and in children < 8 years.

hMefloquine is not recommended unless other options cannot be used because the rate of severe neuropsychiatric reactions is higher with mefloquine than with other options. Mefloquine is contraindicated in patients who have active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, other major psychiatric disorders, or seizures. Mefloquine is not recommended for infections acquired in Southeast Asia because resistance to mefloquine has been reported in some areas (eg, the Myanmar borders with Thailand, China, and Laos; Thailand-Cambodia border; southern Vietnam).

iAny of the drug regimens recommended for P. falciparum malaria in chloroquine-resistant areas also can be used for any organism in chloroquine-sensitive areas; the fastest acting drug for falciparum malaria is artemeter-lumefantine even if the infecting isolate is chloroquine-sensitive. For P. ovale or P. vivax infection, also give primaquine or tafenoquine (after testing to rule out G6PD deficiency).

jTo reduce risk of gastrointestinal effects, patients should take chloroquine phosphate with food.

kChloroquine or hydroxychloroquine is recommended for uncomplicated chloroquine-sensitive infections; however, regimens used to treat chloroquine-resistant infections may be used if they are more convenient or preferred or if chloroquine is unavailable.

lPrimaquine daily for 14 days or a single dose of tafenoquine is used to eradicate P. vivax and P. ovale hypnozoites that may remain dormant in the liver and thus prevent relapses of these infections. Because primaquine and tafenoquine can cause hemolytic anemia in patients with G6PD deficiency, G6PD screening must be done before starting treatment with them. For patients with borderline G6PD deficiency or as an alternate to the above regimen, primaquine 45 mg orally once a week may be given for 8 weeks; clinicians should consult with an expert in infectious disease and/or tropical medicine if this alternative regimen is being considered for G6PD-deficient patients. Primaquine and tafenoquine should not be used during pregnancy, or during breast feeding unless the newborn is tested and has a normal G6PD level.

mIf patients acquire P. vivax infection in regions not known to harbor chloroquine-resistant P. vivax infection, treatment should start with chloroquine. If they do not respond, treatment should be changed to a chloroquine-resistant P. vivax regimen, and clinicians should call the CDC Malaria Hotline.

nThe CDC recommends that patients with severe malaria be treated with parenteral (IV) artesunate as soon as possible. IV quinidine is no longer available in the US. Malaria is considered to be severe when patients have ≥ 1 of the following: impaired consciousness, coma or seizure, severe normocyctic anemia (hemoglobin < 7 g/dL [70 g/L]), renal failure, pulmonary edema, acute respiratory distress syndrome, shock, disseminated intravascular coagulation, spontaneous bleeding, acidosis, hemoglobinuria, jaundice, or parasitemia > 5%. Severe malaria is most often caused by P. falciparum. Artesunate IV also is recommended for patients who cannot take medications orally.

In the US, IV artesunate is available only through the CDC by calling the CDC Malaria Hotline. It is estimated that it may take 12-24 hours for artesunate to reach hospitals in the US.

When IV artesunate is not immediately available, start interim oral therapy with artemether-lumefantrine, atovaquone-proguanil, quinine sulfate or if nothing else is available, mefloquine. In patients who are vomiting, an antiemetic may be helpful. Those who cannot swallow may be given crushed tablets of artemether/lumefantrine or atovaquone/proguanil through a nasogastric tube.

oThe CDC Malaria Hotline is available at 770-488-7788 or 855-856-4713 toll-free Monday-Friday 9AM to 5PM EST (after hours, weekends, or holidays, 770-488-7100).

pIf patients cannot take oral clindamycin, a loading dose of 10 mg/kg is given IV, followed by 5 mg/kg every 8 hours, then switched to oral administration as soon as patients are able. Rapid IV administration should be avoided. Treatment course is 7 days.

G6PD = glucose-6-phosphate dehydrogenase; CDC = Centers for Disease Control and Prevention; FDA = US Food and Drug Administration

Table
icon

Adverse Reactions and Contraindications of Antimalarial Drugs

Drug

Some Adverse Reactions

Contraindications

Artemether/lumefantrine

Headache, anorexia, dizziness, asthenia (usually mild)

With lumefantrine, prolonged QT interval

Allergy to artemether/lumefantrine

During pregnancy, used if potential benefit justifies potential risk to fetus, which is usually the case in the 2nd and 3rd trimester and probably the first

Use of mefloquine prophylaxis

Artesunate

As with artemether

Delayed hemolysis (1); hemoglobin levels should be monitored for 4 weeks after therapy

Allergy to artesunate

During pregnancy, used if the potential benefit justifies potential risk, which is the case in most patients with severe malaria requiring parenteral therapy

Atovaquone/proguanil

Gastrointestinal disturbances, headache, dizziness, rash, pruritus

During pregnancy, used only if there are no alternatives and potential benefit justifies potential risk to fetus

Hypersensitivity, breastfeeding*, severe renal impairment (creatinine clearance < 30 mL/min)

Chloroquine phosphate

Chloroquine hydrochloride

Hydroxychloroquine sulfate

Gastrointestinal disturbances, headaches, dizziness, blurred vision, rashes or pruritus, exacerbation of psoriasis, blood dyscrasias, alopecia, ECG changes, retinopathy, psychosis (rare)

Hypersensitivity, retinal or visual field changes

Clindamycin

Hypotension, bone marrow toxicity, renal dysfunction, rashes, jaundice, tinnitus, Clostridium difficile infection (pseudomembranous colitis)

Hypersensitivity

Doxycycline

Gastrointestinal upset, photosensitivity, vaginal candidiasis, C. difficile infection (pseudomembranous colitis), erosive esophagitis

Pregnancy, children < 8 years

Halofantrine

Prolongation of PR and QT intervals, cardiac arrhythmia, hypotension, gastrointestinal disturbances, dizziness, mental changes, seizures, sudden death

During pregnancy, used only if potential benefit justifies potential risk to fetus

Cardiac conduction defects, familial QT prolongation, use of drugs that affect QT interval, hypersensitivity

Mefloquine

Bad dreams, neuropsychiatric symptoms, dizziness, vertigo, confusion, psychosis, seizures, sinus bradycardia, gastrointestinal disturbances

Hypersensitivity, history of seizures or psychiatric disorders, cardiac conduction disturbances or arrhythmia, coadministration of drugs that may prolong cardiac conduction (eg, beta-blockers, calcium 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

Quinine sulfate

Quinine dihydrochloride

Gastrointestinal disturbances, tinnitus, visual disturbances, allergic reactions, mental changes, arrhythmias, cardiotoxicity

Hypersensitivity, G6PD deficiency, optic neuritis, tinnitus, pregnancy (relative contraindication), past adverse quinine reaction (continuous ECG, blood pressure [when drug is given IV], and glucose monitoring recommended)

Quinidine gluconate

Arrhythmias, widened QRS complex, prolonged QTc interval, hypotension, hypoglycemia

Hypersensitivity, thrombocytopenia (continuous ECG, blood pressure, and glucose monitoring recommended)

No loading dose in patients receiving > 40 mg/kg of quinine in the preceding 48 hours or a dose of mefloquine in preceding 12 hours

Primaquine phosphate

Severe intravascular hemolysis in people with G6PD deficiency, gastrointestinal disturbances, leukopenia, methemoglobinuria

Concomitant use of quinacrine or potentially hemolytic or bone marrow suppressing agents, G6PD deficiency, pregnancy (because G6PD status of the fetus is unknown)

Pyrimethamine/sulfadoxine

Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal neurolysis, urticaria, exfoliative dermatitis, serum sickness, hepatitis, seizures, mental changes, gastrointestinal disturbances, stomatitis, pancreatitis, bone marrow toxicity, hemolysis, fever, nephrosis

Hypersensitivity, folate deficiency anemia, infants 2 months, pregnancy, breastfeeding

Tafenoquine

Severe intravascular hemolysis in patients with G6PD deficiency, psychiatric reactions, methemoglobinemia, gastrointestinal disturbances, hypersensitivity reactions

G6PD deficiency, pregnancy (because G6PD status of the fetus is unknown), breast feeding (unless child is known to have normal G6PD), psychotic disorder, known hypersensitivity

For patients ≥ 16 years

*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.

G6PD = glucose-6-phosphate dehydrogenase.

Treatment reference

  • 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

Travelers to endemic regions should be given chemoprophylaxis (see table Prevention of 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.

Table
icon

Prevention of Malaria

Druga

Use

Adult Dosage

Pediatric Dosage

Comments

Atovaquone/proguanilb

In all areas

1 adult tablet once a day

5–8 kg: one-half pediatric tablet once a day

> 8–10 kg: three-fourths pediatric tablet once a day

> 10–20 kg: 1 pediatric tablet once a day

> 20–30 kg: 2 pediatric tablets once a day

> 30–40 kg: 3 pediatric tablets once a day

> 40 kg: 1 adult tablet once a day

Begun 1 to 2 days before travel and continued daily during the stay and for 7 days after leaving

Chloroquine phosphate

Only in areas with chloroquine-sensitive Plasmodium

500 mg once a week

8.3 mg/kg, up to maximum 500 mg once a week

Begun 1–2 weeks before travel and continued weekly during the stay and for 4 weeks after leaving

Doxycyclinec

In all areas

100 mg once a day

≥ 8 years: 2.2 mg/kg (up to 100 mg) once a day

Begun 1–2 days before travel and continued during the stay and for 4 weeks after leaving

Hydroxychloroquine sulfated

An alternative to chloroquine only in areas with chloroquine-sensitive Plasmodium

400 mg once a week

6.5 mg/kg, up to 400 mg once a week

Begun 1–2 weeks before travel and continued during the stay and for 4 weeks after leaving

Mefloquinee

In areas with mefloquine-sensitive Plasmodium

250 mg once a week

≤ 9 kg: 5 mg once a week

> 9–19 kg: one-fourth tablet once a week

> 19–30 kg: one-half tablet once a week

> 30–45 kg: three-fourths tablet once a week

> 45 kg: 1 tablet once a week

Begun ≥ 2 weeks before travel and continued during the stay and for 4 weeks after leaving

Contraindicated in patients with a history of depression, other psychologic problems, or seizures; not recommended for patients with cardiac conduction abnormalities

Primaquinef

For prophylaxis for brief travel in areas known to harbor mainly P. vivax

52.6 mg once a day

0.8 mg/kg) up to adult dose once a day

Begun 1 to 2 days before travel and continued daily during the stay and for 7 days after departure

Document that the G6PD level is normal before use

Contraindicated in people with G6PD deficiency and in pregnant and breastfeeding women unless the breastfed infant has a normal G6PD level

For terminal prophylaxis to prevent relapse of infection in people with prolonged exposure to or prior infection with P. vivax or P. ovale

Dosed as above

Dosed as above

Given daily for 14 days after departure from endemic area. Document that the G6PD level is normal before use

Contraindications as above

Tafenoquine

For prophylaxis in travelers to all areas

200 mg once a day for 3 days before travel as a loading regimen, then 200 mg once weekly for maintenance while in the malaria region starting 7 days after the last loading dose, then a 200 mg final dose after exit 7 days following the last maintenance dose

For patients ≥ 16 years

G6PD deficiency or unknown G6PD status; all patients should be tested for G6PD deficiency prior to use

Pregnant and breastfeeding women unless the breastfed infant has a normal G6PD level; known hypersensitivity

Psychiatric adverse reactions have been observed

Use with caution in patients with a history of psychiatric illness

For terminal prophylaxisf to prevent relapse of malaria in patients with prolonged exposure to or infection with P. vivax or P. ovale

300 mg single dose 

Not for patients < 18 years

aPreventive drugs are given orally. See table Adverse Reactions and Contraindications of Antimalarial Drugs for adverse reactions and contraindications.

bAtovaquone/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 contraindicated in patients with a creatinine clearance < 30 mL/min. This combination is not recommended for children weighing < 5 kg or for pregnant or breastfeeding women.

cUse of tetracyclines is contraindicated during pregnancy and in children < 8 years.

dPhysicians should review the prescribing information for hydroxychloroquine before using it.

eMefloquine has not been approved for use during pregnancy. The drug is contraindicated in patients who have active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, other major psychiatric disorders, or seizures; if patients have psychiatric disturbances or a previous history of depression, the drug should be used cautiously. The drug is not recommended for patients with cardiac conduction abnormalities.

fPrimaquine or a single dose of tafenoquine is used as terminal prophylaxis to reduce risk of relapse in people who have taken chloroquine, hydroxychloroquine, or a drug active against chloroquine-resistant malaria as treatment or and have had prolonged exposure to P. vivax and/or P. ovale. Primaquine or tafenoquine alone can also be used for primary prophylaxis in people at risk of malaria, particularly that due to P. vivax. Primaquine and tafenoquine are contraindicated in people with G6PD deficiency and in pregnant or breastfeeding women (unless the breastfed infant has a normal G6PD level).

G6PD = glucose-6-phosphate dehydrogenase.

Adapted from the Centers for Disease Control and Prevention Yellow Book: Infectious diseases related to travel: Malaria.

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. 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.

Malaria vaccines are under development, but it is unclear when a vaccine is likely to become available.

Key Points

  • In 2017, there were an estimated 219 million people with malaria worldwide, and about 435,000 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.

  • 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.

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