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Am Fam Physician. 2022;106(3):270-278

This clinical content conforms to AAFP criteria for CME.

Author disclosure: No relevant financial relationships.

Each year, malaria causes an estimated 500,000 deaths worldwide. Most of these deaths occur in Africa and disproportionally affect children younger than five years worldwide. Human malarial disease is caused by protozoan parasites of the genus Plasmodium. The primary means of infection is through the bite of a female Anopheles mosquito. The incidence of malaria in the United States has increased since 2011, in conjunction with the increase in worldwide travel. An estimated 2,000 cases of malaria occur annually in the United States. All travelers to malaria-endemic regions should be prescribed prophylaxis. Malaria has a broad range of clinical presentations. Travelers who have symptoms of malaria should seek medical attention as soon as possible. All febrile travelers who have recently returned from a malarious area should be evaluated for malaria. The accurate, timely, and species-specific diagnosis of malaria is essential for successful treatment. Direct microscopy of Giemsa-stained blood smears is the reference standard for laboratory diagnosis. Rapid testing for malaria has emerged as an important adjunctive diagnostic modality. Malaria treatment is determined by individual patient factors and geography. The World Health Organization recommends treating uncomplicated cases of malaria with artemisinin combination therapy, except in the first trimester of pregnancy. Severe malaria is mainly caused by Plasmodium falciparum. Children, pregnant patients, and people who are not from endemic regions are at highest risk of severe malaria. Intravenous artesunate is the treatment of choice for severe malaria.

Malaria has infected humans since the beginning of recorded history.1 Some estimates place its total mortality burden at one-half of all people who have ever lived.2 Each year, the disease continues to cause an estimated 500,000 deaths worldwide.2 Most of these deaths occur in Africa and disproportionally affect children younger than five years worldwide.3

The incidence of malaria in the United States has increased since 2011, in conjunction with the increase in worldwide travel. An estimated 2,000 cases of malaria occur annually in the United States.
Rapid testing is an adjunctive diagnostic modality for malaria with excellent sensitivity and negative predictive value. In the United States, malaria rapid diagnostic tests should be used only in conjunction with thick and thin blood smears.
The first malaria vaccine approved for widespread use was recently recommended by the World Health Organization for the prevention of Plasmodium falciparum malaria in children living in endemic areas.

Human malarial disease is caused by protozoan parasites of the genus Plasmodium, which has five known species: P. falciparum, P. vivax, P. ovale, P. malariae, and the emerging zoonotic parasite P. knowlesi. Most deaths are caused by P. falciparum.4 The primary means of human infection is through the bite of a female Anopheles mosquito.

Malaria poses a threat to one-half of the world's population.5 The incidence of malaria in the United States has continued to increase annually since 2011, in conjunction with the increase in worldwide travel.6 Malaria, formerly endemic to the United States, was successfully eradicated in the country during the mid-20th century.7 In the United States today, malaria is almost exclusively found in travelers to and immigrants from endemic regions of the world.7 However, transmission can rarely occur via other means, such as exposure to infected blood products, congenital transmission, or local mosquito-borne outbreaks.8 In the United States, an estimated 2,000 cases of malaria occur annually.7

Prevention

Before a patient travels internationally, the physician should conduct a personalized risk assessment, including travel location, the season of travel, and the proposed itinerary. The regions with the highest rates of malaria transmission are sub-Saharan Africa, the Indian subcontinent, and Southeast Asia. The risk of contracting malaria varies seasonally, with the highest risk occurring during and just after the rainy season, typically between May and December.9

The primary method of malaria prevention is avoiding mosquito bites. Anopheles mosquitoes primarily feed at night; most malaria transmission occurs between dusk and dawn. Prevention strategies include personal protective measures such as using insecticide-treated bed nets, wearing clothes that minimize exposed skin, and applying mosquito-repelling chemicals. The most effective insect repellents contain 20% to 30% N, N-diethyl- m-toluamide (DEET) or 20% picaridin.10 Higher concentrations are not associated with greater protection. Applying permethrin to clothing increases protection against penetrating insect bites.11

All travelers to malaria-endemic regions should be prescribed prophylaxis.9 The choice of agent should be based on location and duration of travel, malarial resistance patterns, and the patient's medical history (Table 112,13). All prevention regimens involve beginning the medication before departure, taking the medication while in the high-risk area, and continuing the medication for a defined period after travel has ended. The use of antimalarial agents does not negate the need for personal protective measures. The Centers for Disease Control and Prevention (CDC) provides country-specific prophylaxis recommendations at http://www.cdc.gov/malaria/travelers/country_table/a.html.

Drug*TimingAdult dosing and costChild dosingComments
Chloroquine-sensitive malaria
ChloroquineBegin one to two weeks before travel and continue for four weeks after leaving malaria-endemic area500 mg salt (300 mg base) once per week
$50 (—) for six weeks
8.3 mg salt (5 mg base) per kg once per week, up to adult dosageUsed for prophylaxis in Mexico and Central America (west of the Panama Canal) and the island of Hispaniola (Haiti and the Dominican Republic)
In the United States, hydroxychloroquine may be better tolerated
Hydroxychloroquine (Plaquenil)Begin one to two weeks before travel and continue for four weeks after leaving malaria-endemic area400 mg salt (310 mg base) once per week
$25 ($180) for eight weeks
6.5 mg salt (5 mg base) per kg once per week, up to adult dosageChloroquine may exacerbate psoriasis
May be used in all trimesters of pregnancy
Chloroquine-resistant malaria
Atovaquone/proguanil (Malarone)Begin one to two days before travel and continue for one week after leaving malaria-endemic area250 mg/100 mg once per day
$55 ($220) for four weeks
Daily dose (one children's tablet is 62.5 mg/25 mg):
 < 5 kg: not recommended
 5 kg to 8 kg: one-half of children's tablet
 9 kg to 10 kg: three-fourths of children's tablet
 11 kg to 20 kg: one children's tablet
 21 kg to 30 kg: two children's tablets
 31 kg to 40 kg: three children's tablets
 ≥ 40 kg: one adult tablet
Useful in regions of mefloquine resistance
Do not use in patients with severe renal impairment (creatinine clearance < 30 mL per minute per 1.73 m2 [0.50 mL per second per m2])
Do not use in patients who are pregnant or in breastfeeding infants weighing < 5 kg
Should be taken with food or a milky drink
High cost makes this drug less practical for longer trips
DoxycyclineBegin one to two days before travel and continue for four weeks after leaving malaria-endemic area100 mg once per day
$20 (varies by brand) for four weeks
2.2 mg per kg per day, up to the adult dosageUseful in regions of mefloquine resistance
Do not use in children younger than eight years or in patients who are pregnant or breastfeeding
May cause nausea, photosensitivity, vaginal yeast infections, and esophageal ulceration
MefloquineBegin two weeks or more before travel and continue for four weeks after leaving malaria-endemic area250 mg salt (228 mg base) once per week
$25 (—) for six weeks
Weekly dose:
 ≤ 9 kg: 5 mg salt (4.6 mg base) per kg
 > 9 kg to 19 kg: one-fourth of 250-mg tablet
 20 kg to 30 kg: one-half of 250-mg tablet
 31 kg to 45 kg: three-fourths of 250-mg tablet
 ≥ 45 kg: one 250-mg tablet
Contraindications include epilepsy, psychiatric conditions (e.g., anxiety, depression), and cardiac conduction disorders
May be used in all trimesters of pregnancy
Short-term travel to areas with more than 90% Plasmodium vivax malaria (e.g., Central and South America)
PrimaquineBegin one to two days before travel and continue for one week after leaving malaria-endemic area52.6 mg salt (30 mg base) once per day
$60 (—) for four weeks
0.8 mg salt (0.5 mg base) per kg once per day, up to adult dosageScreen for G6PD deficiency before use; can be fatal if taken by patients who are G6PD deficient
Do not use in pregnant patients or in patients who are breastfeeding unless the infant has a documented normal G6PD level
Less commonly used than other prophylactic drugs
TafenoquineSee adult dosageLoading dose: 200 mg once per day for three days before travel
Maintenance dose: 200 mg once per week starting seven days after last loading dose
Terminal dose: one 200-mg dose seven days after last maintenance dose
(—) $280 per dose package (16 tablets)
Not recommendedScreen for G6PD deficiency before use
Do not use in those with G6PD deficiency, children, and patients who are pregnant or breastfeeding
Not recommended in those with an underlying psychotic disorder

In 2021, the first malaria vaccine approved for widespread use was recommended by the World Health Organization for the prevention of P. falciparum malaria in children living in endemic areas. The vaccine has been administered to more than 1 million children in Ghana, Malawi, and Kenya.14,15

Clinical Presentation

The clinical presentation of malaria ranges from asymptomatic parasitemia or uncomplicated disease to severe disease or death. The differential diagnosis of malaria is summarized in Table 2.16 Symptoms of malaria can develop within six to seven days of exposure, but the presentation may be delayed for several months after leaving an endemic region.17 Symptomatic malaria is characterized by fevers, chills, headaches, myalgias, and malaise. It may also present as fever without a specific or obvious cause or as gastrointestinal symptoms in children. There are no typical features of malaria.10,17

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