Malaria Protection for U.S. Travelers

US Pharm. 2023;48(12):38-43.

ABSTRACT: In humans, malaria is caused by intraerythrocytic protozoa of the Plasmodium genus. These parasites are transmitted through the bite of an infected female mosquito of the Anopheles species, such as Plasmodium falciparum and Plasmodium vivax. Most malaria infections in the United States occur in persons who have traveled to regions with ongoing malaria transmission. Prevention of mosquito bites is a fundamental goal. Malaria chemoprophylaxis depends on individual criteria determined by clinical and laboratory examinations as well as travel conditions (destination, season, duration of stay, and local living conditions). Standby medication should be prescribed for self-treatment of fever in areas where medical care is not readily available. Malaria is curable, but symptoms can become more severe if untreated, and the disease can eventually be fatal.

Malaria is a preventable and curable infectious disease that occurs in certain countries, mainly in rural areas, and requires the presence of standing water. In humans, malaria is caused by intraerythrocytic protozoa of the Plasmodium genus. Malaria parasites are transmitted—usually in the evening or at night—through the bite of an infected female mosquito from species of the Anopheles genus.¹ Malaria can also be transmitted congenitally from mother to fetus or to the neonate at birth, via blood transfusion or organ transplantation, or through unsafe needle-sharing practices. Each year, 25 million to 30 million people from nontropical countries visit areas where malaria is endemic, and from 10,000 to 30,000 of them contract malaria. Most malaria infections in the United States occur in persons who have traveled to regions with ongoing malaria transmission.^1-3

Five Plasmodium species cause malaria in humans; of these, Plasmodium falciparum and Plasmodium vivax pose the greatest threat. P falciparum, the deadliest malaria parasite, is most prevalent on the African continent, and P vivax is the dominant malaria parasite in most countries outside of sub-Saharan Africa. The other three species are Plasmodium malariae, Plasmodium ovale, and Plasmodium knowlesi. Typically, about 2,000 malaria cases are diagnosed each year in the U.S., mostly in returned travelers.^4,5 The prevention of mosquito bites is a fundamental goal. Malaria chemoprophylaxis (antimalarial medication taken before, during, and after travel to a country with malaria transmission) depends on individual criteria determined by clinical and laboratory examinations and on travel conditions (destination, season, duration of stay, local living conditions). Standby medication should be prescribed for self-treatment of fever in areas where medical care is not readily available.⁶

The CDC publishes U.S. state-level malaria case data annually. Based on the most recent annual malaria-surveillance report (for 2018), the six states with the highest numbers of malaria cases are Maryland (193), Texas (143), California (100), New Jersey (94), Pennsylvania (93), and Florida (70).⁷

Types of Malaria

Indigenous Malaria: Indigenous malaria (also known as locally acquired or “homegrown” malaria) is defined by the World Health Organization (WHO) as local mosquito-borne transmission of the disease with no evidence of importation and no direct link to transmission from an imported case.⁷ Malaria was successfully eliminated in the U.S. in the early 1950s, with improved sanitation and medical care, technological advances, and widespread insecticide use resulting in successful interruption of malaria transmission. Although endemic transmission of the parasite was halted, competent Anopheles vectors still exist in the U.S.; however, cases of indigenous malaria are rare.⁸ Between January 2023 and September 2023, there were nine cases of locally acquired malaria in the U.S.: seven P vivax cases in Sarasota County, Florida; one P vivax case in Cameron County, Texas; and one P falciparum case in Maryland’s Capital Region. All patients are recovering after prompt treatment at area hospitals. No evidence suggests that the cases in these three states are related.⁹

Imported Malaria: According to the WHO, imported malaria (also known as travelers’ malaria) refers to an infection that is acquired outside the area where it is diagnosed, with the diagnosis made ≤3 months after the individual returns from an endemic area. However, many countries have adopted their own definitions for imported malaria using different temporal and spatial scales best suited to their surveillance capabilities, local malaria epidemiology, and geographical position in relation to other malaria-endemic countries.¹⁰ Almost all malaria cases in the U.S. are imported and occur in persons traveling from countries with malaria transmission, many from sub-Saharan Africa and South Asia. Those going to sub-Saharan Africa are at greatest risk for contracting malaria and for dying from the infection; however, all travelers to countries where malaria exists may be at risk for infection.¹¹

Transmission Cycle

In humans, malaria infection is initiated when a female Anopheles mosquito injects Plasmodium sporozoites into the host’s skin during a blood meal. The sporozoites reach the peripheral circulation and migrate to the liver, where they replicate within hepatocytes to form merozoites, which are released into the bloodstream. The merozoites invade RBCs, then develop through the ring, trophozoite, and schizont stages before they form new merozoites, which are released at schizont egress to reinvade new RBCs.¹²

Symptoms

Most malaria patients experience headache, often characterized as “pounding” and worsened by standing quickly. Fever, chills, headache, nausea, vomiting, and diarrhea are usually present in some combination. Symptoms usually appear 8 to 25 days after infection, and although they may seem mild at first, they can become more severe if untreated, eventually leading to death.^13,14 Individuals who develop a fever or flulike illness either while traveling in a malaria-risk area or for up to 1 year after returning home should seek immediate medical attention and inform the physician of their travel history.¹⁵

Preventing Imported Malaria

Strategies for malaria prevention in travelers combine three types of interventions: information and education, antimosquito measures, and antimalarial drugs for chemoprophylaxis or standby emergency treatment.¹⁶ The main approach to malaria prevention is denoted by the acronym “ABCD,” wherein A stands for awareness of the risk, B refers to bite prevention, C means the need for chemoprophylaxis, and D stresses the importance of rapid diagnosis and treatment (TABLE 1).^17,18

Risk Assessment and Awareness

Geographical Location and Time of Year: Transmission of malaria is not homogeneously distributed across all countries. In some destinations, malaria transmission occurs throughout the whole country, whereas in others it occurs in defined pockets. If a traveler is going to a highly endemic pocket of a generally low-transmission country during a peak transmission time, this destination may be high-risk for this individual. In some countries with significant seasonal shifts in temperature or rainfall, the transmission intensity may decrease during colder or drier months. Based on knowledge of the climatic conditions in some subtropical or temperate destinations, travelers may choose, for example, mosquito-avoidance measures only during the winter months. Risk-averse travelers should be aware that even in a low-risk situation, just a single bite from an infected female Anopheles mosquito can transmit malaria.¹⁹

Duration of Time in Area and Activities Undertaken: In addition to geographical factors and time of year, risk depends on the time the individual spends in the endemic area and the activities engaged in. For example, camping in a jungle for 3 weeks poses a much higher risk than a 3-day visit to an urban area with air-conditioned accommodations.¹⁸

Bite Avoidance

Mosquito-bite prevention is important for reducing the risk of contracting malaria, and advice on available methods should be offered in pretravel consultations. The peak time for malaria-transmitting mosquitoes to bite is from dusk to dawn; during these times, using repellents and covering up with clothing impregnated with permethrin will help prevent bites. CDC and United Kingdom guidelines recommend the following to all travelers visiting malaria-endemic areas^20,21:

• Cover all exposed skin with loose, light-colored clothing (long sleeves and long pants) when outside between dusk and dawn. Clothing (including outerwear, hats, and shoes), mosquito nets, and camping gear may be treated with the insecticide permethrin. Clothing impregnated with a concentration of 0.5% permethrin repels and kills ticks, chiggers, mosquitoes, and other biting and nuisance arthropods. Clothing and other items must be treated 24 to 48 hours before being packed for travel to allow time to dry. As with all pesticides, travelers should follow the manufacturer’s instructions on the label.
• Apply an insect repellent containing 50% diethyltoluamide (DEET) to exposed skin, following the manufacturer’s instructions (20%-50% DEET provides 6 to 12 hours of protection; no advantage for DEET concentrations >50%). Reapplication may be necessary throughout the evening. Effective alternatives to DEET are picaridin (20% picaridin has a similar duration of protection as 20% DEET), oil of lemon eucalyptus or para-menthane-diol (effective, but frequent reapplication needed), IR3535, and 2-undecanone.^17,18 Used as directed, these repellents registered by the Environmental Protection Agency have been proven safe and effective even for pregnant and breastfeeding women.
• On retiring, use a plug-in insecticide vaporizer or knockdown spray to ensure that the room is free of mosquitoes.
• When possible, sleep in a well-screened or air-conditioned room. In some situations, use an insecticide-treated mosquito net when outdoors or sleeping in a poorly screened room.

Chemoprophylaxis

In 2018, of 1,788 imported malaria cases reported to the CDC, 1,102 occurred in U.S. residents (civilians and military personnel), and data on chemoprophylaxis use were reported for 974 (88.4%). Approximately 75% (735) of these patients reported not taking any malaria-chemoprophylaxis medication, a larger proportion than was observed in 2017 (829 [71.7%] of 1,157 U.S. residents with prophylaxis-use data). Of the 864 U.S.-resident imported cases with complete information on chemoprophylaxis, 43 (5.0%) adhered to an appropriate regimen, 745 (86.2%) did not take chemoprophylaxis or used a regimen not consistent with CDC treatment guidelines, and 76 (8.8%) took an appropriate preventive medication but skipped doses. The proportion of U.S.-resident cases who adhered to a correct chemoprophylaxis regimen in 2018 was similar to that observed in 2017 (67 patients [6.7%]).⁷

To prevent malaria, the CDC recommends that travelers receive chemoprophylaxis. No antimalarial drug is 100% protective, and it must be combined with personal protective measures (insect repellent, long sleeves and pants, sleep setting that is mosquito-free or has an insecticide-treated bed net).²² The primary goal of malaria chemoprophylaxis is to prevent P falciparum infection, which is primarily responsible for malaria fatalities.¹⁵ The main antimalarial regimens (TABLE 2) are chloroquine, hydroxychloroquine, atovaquone-proguanil, doxycycline, mefloquine, primaquine, and tafenoquine. P falciparum resistance to chloroquine—and, to a lesser degree, other antimalarials—is a worldwide problem; chloroquine’s effectiveness is limited in most locations.¹⁵

Atovaquone-Proguanil: Atovaquone-proguanil is suitable for last-minute travelers because it is started 1 to 2 days before travel; it is also good for shorter trips because it is taken for 7 days, rather than 4 weeks, after leaving the malaria-endemic area. This agent is well tolerated, and side effects are uncommon. It is not for use in pregnant or breastfeeding women or in patients with severe renal impairment. Atovaquone-proguanil is expensive and must be taken daily. The adult tablet contains atovaquone 250 mg + proguanil 100 mg; the pediatric tablet contains atovaquone 62.5 mg + proguanil 25 mg. The adult dosage is 1 tablet orally once daily. Pediatric dosing is weight-based (all dosages, orally once daily): 5 kg to <8 kg, 1/2 pediatric tablet; 8 kg to <10 kg, 3/4 pediatric tablet; 10 kg to <20 kg, 1 pediatric tablet; 20 kg to <30 kg, 2 pediatric tablets; 30 kg to <40 kg, 3 pediatric tablets; ≥40 kg: 1 adult tablet.²³

Chloroquine: Chloroquine is suitable for long trips because it is taken weekly; it is not appropriate for last-minute travelers, as it must be initiated 1 to 2 weeks before travel. It is not for use in patients with known hydroxychloroquine sensitivity. Chloroquine may be used in all trimesters of pregnancy. This drug can exacerbate psoriasis. Chloroquine should not be used in areas with chloroquine and mefloquine resistance. An additional medication may not be needed in patients who are already taking hydroxychloroquine chronically for rheumatologic conditions. The adult dosage is 300 mg base (500 mg salt) orally once weekly; the pediatric dosage is 5 mg/kg base (8.3 mg/kg salt), to a maximum dosage of 300 mg base (500 mg salt), orally once weekly.²³

Hydroxycholoroquine: This agent is an alternative to chloroquine for prophylaxis only in areas with chloroquine-sensitive malaria. Hydroxychloroquine should be initiated 1 to 2 weeks before travel to malaria-endemic areas. It is taken once weekly on the same day each week while the traveler is in malaria-endemic areas and is continued once weekly for 4 weeks after the traveler leaves endemic areas. The adult dosage is 310 mg base (400 mg salt) orally once weekly; the pediatric dosage is 5 mg/kg base (6.5 mg/kg salt), to a maximum dosage of 310 mg base (400 mg salt), orally once weekly.²³

Doxycycline: Doxycycline is a good choice for last-minute travelers because it is started 1 to 2 days before travel. It must be continued another 4 weeks after the traveler leaves malaria-endemic areas. Doxycycline is generally the least expensive antimalarial. Patients taking doxycycline chronically to prevent acne do not need an additional medication. Doxycycline should be used with caution in patients with a known sulfite hypersensitivity. Doxycycline is not for use in pregnant or breastfeeding women, children aged <8 years, or women prone to developing vaginal yeast infections from antibiotic use. Doxycycline has an increased risk of sun sensitivity and can cause upset stomach. The adult dosage is 100 mg orally once daily; for children aged ≥8 years, the dosage is 2.2 mg/kg, to a maximum dosage of 100 mg, orally once daily.^22-24

Mefloquine: Mefloquine is suitable for long trips since it is taken weekly; it is not a good choice for last-minute travelers because it must be initiated >2 weeks before travel. It may be used in all trimesters of pregnancy and in breastfeeding women. Mefloquine should not be used in areas with mefloquine-resistant Plasmodium species. Mefloquine has known neuropsychiatric side effects. This agent is not for use in patients with certain psychiatric conditions or patients with seizure disorders, and it is not recommended for patients with cardiac conduction abnormalities. The adult dosage is 228 mg base (250 mg salt) orally once weekly. Pediatric dosing is weight-based (all dosages, orally once weekly): <9 kg, 4.6 mg/kg base (5 mg/kg salt); >9 kg to 19 kg, 1/4 tablet; >19 kg to 30 kg, 1/2 tablet; >30 kg to 45 kg, 3/4 tablet; >45 kg, 1 tablet.²³

Primaquine: Primaquine, one of the most effective medications for preventing P vivax, is a good choice for travelers to areas that have >90% P vivax. It is a good option for shorter trips because it is taken for 7 days—rather than 4 weeks—after the traveler leaves a malaria-endemic area; it is also suitable for last-minute travelers because it is initiated 1 to 2 days before travel. Primaquine should not be used in patients with severe glucose-6-phosphate dehydrogenase (G6PD) deficiency, as it may cause hemolysis and consequently hemolytic anemia. This drug is not for use in pregnant women or breastfeeding women (unless the infant has also been tested for G6PD). It is also contraindicated in patients with severe rheumatoid arthritis or systemic lupus erythematosus because these conditions can lead to granulocytopenia. Primaquine has the potential for upset stomach, rash, and pruritus. The adult dosage is 30 mg base (52.6 mg salt) orally once daily; the pediatric dosage is 0.5 mg/kg base (0.8 mg/kg salt), to a maximum dosage of 30 mg base (52.6 mg salt), orally once daily. In both adults and children, the same dose is used for both primary and terminal prophylaxis, and the therapy duration differs.^22-24

Tafenoquine: Tafenoquine, one of the most effective agents for preventing P vivax malaria, also prevents P falciparum. This medication is suitable for shorter trips because it is taken once, 1 week after leaving the malaria-endemic area, instead of 4 weeks. It is also a good option for last-minute travelers since it is started 3 days before travel. Tafenoquine is contraindicated in patients with G6PD deficiency or those not tested for this condition. Tafenoquine is not indicated for pregnant women, breastfeeding women (unless the infant has also been tested for G6PD deficiency), or children, and it is not recommended for patients who have psychotic disorders. The adult dosage is 200 mg orally weekly.^22,23

Diagnosis

Diagnosing malaria is an important part of malaria management; misdiagnosis has potential ripple effects on the treatment, prevention, and ultimate elimination of malaria. Accurate diagnosis enables effective policymaking, planning, and budgeting.²⁵ The cellular targets of malaria diagnosis in humans include infected RBCs or leukocytes that have ingested parasites. Detectable analytes (chemical constituents) include nucleic acids, antigens, and hemozoin. Additional analytes include human antiparasite antibodies.

Microscopy: This historically has been the standard method for diagnosing malaria, and it remains the primary method in many healthcare settings around the world.²⁵ Typically, conventional blood-smear microscopy assesses a fraction of 1 mcL of whole blood. Microscopy enables individual species and developmental stages to be identified; however, as the presence of parasites declines or when an infection comprises multiple species, diagnostic accuracy can be difficult to achieve, even for experts.²⁶

Rapid Diagnostic Tests (RDTs): In locations where microscopy of thin and thick blood films or other methods for detecting Plasmodium parasites in the blood are unavailable, antigen-based RDTs may be an important technique for quick, simple diagnosis.²⁷ This approach involves applying first a blood specimen to a test card or cassette (depending on the manufacturer), then a buffer reagent. The appearance of specific bands in the test card after 15 to 30 minutes denotes the presence of plasmodium.²⁵

Molecular Method: These techniques for malaria diagnosis, which include polymerase chain reaction (PCR) and loop-mediated isothermal amplification, have great potential in locations with a low density of infections that can be easily missed by RDTs. PCR amplifies the parasite DNA, resulting in high sensitivity (0.004 parasites/mcL). PCR-based assays exhibit 100-fold greater sensitivity than microscopy, especially for low-parasitemia infections.²⁵

Conclusion

Education about risk avoidance, prophylactic drugs, repellents, and insecticide-treated bed nets can benefit persons who are traveling to or from endemic areas.²⁸ Factors that pharmacists should consider when choosing appropriate malaria chemoprophylaxis include tolerability, ease of administration, cost, possible drug-drug interactions, the travel itinerary, and drugs that provide additional protection against other infections.²⁹ Personal protective measures should be emphasized, as they offer protection against other vector-borne diseases; long, loose, and light-colored clothing should be worn, and repellents should be used appropriately (products containing 50% DEET are recommended). Mosquito nets, ideally impregnated with permethrin, are essential, and individuals traveling to high-risk areas can also treat their clothing with permethrin.³⁰ Developing an effective malaria vaccine and altering local receptivity (the relative abundance of anopheline vectors and the existence of other climatic and ecological factors favoring transmission) may provide more enduring solutions to the problem of malaria importation.²⁸

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