MALARIA

Malaria in humans is caused by one of four protozoan species of the genus Plasmodium: P. falciparum, P. vivax, P. ovale, and P. malariae. All are transmitted by the bite of an infected female Anopheles mosquito. Occasionally transmission occurs by blood transfusion or congenitally from mother to fetus. The disease is characterized by fever and flu-like symptoms, including chills, headache, myalgias, and malaise; these symptoms may occur at intervals. Malaria may be associated with anemia and jaundice, and P. falciparum infections may cause kidney failure, coma, and death. Deaths due to malaria are preventable; methods to prevent malaria infection are described in this chapter.

Information on malaria risk in specific countries (pp. 13-73) is derived from various sources, including the World Health Organization. While this is the most accurate information available at the time of publication, factors that may vary from year to year, such as local weather conditions, mosquito vector density, and prevalence of infection, can have a marked effect on local malaria transmission patterns.

Risk of Acquiring Malaria

Malaria transmission occurs in large areas of Central and South America, Hispaniola, sub-Saharan Africa, the Indian subcontinent, Southeast Asia, the Middle East, and Oceania. The estimated risk of a traveler acquiring malaria varies markedly from area to area. This variability is a function of the intensity of transmission within the various regions and of the itinerary and time and type of travel. From 1980-1992, 2,548 cases of P. falciparum among U.S. civilians were reported to the CDC. Of these, 2,096 (82%) were acquired in sub-Saharan Africa; 191 (8%) were acquired in Asia; 129 (5%) were acquired in the Caribbean and South America; and 132 (5%) were acquired in other parts of the world. During this time period there were 45 fatal malaria infections among U.S. civilians; 44 (98%) were caused by P. falciparum, -- of which 36 (82%) were acquired in sub-Saharan Africa.

Thus, most imported P. falciparum malaria among American travelers was acquired in Africa south of the Sahara, even though only 130,000 arrivals from the United States were reported by countries in that region in 1991. In contrast, 20 million arrivals from the United States were reported that year in other countries with malaria (including15 million travelers to Mexico, (World Tourism Organization). This disparity in the risk of acquiring malaria reflects the fact that travelers to Africa tend to spend considerable time, including evening and nightime hours, in rural areas where malaria risk is highest. Travelers to Asia and South America, however, spend most of their time in urban or resort areas where there is limited, if any, risk of exposure and travel to rural areas mainly during daytime hours when the risk of infection is limited.

Estimating the risk of infection for different categories of travelers is difficult and may be significantly different even for persons who travel or reside temporarily in the same general areas within a country. For example, tourists staying in air conditioned hotels may be at lower risk than backpackers or adventure travelers. Similarly, longer-term residents living in screened and air-conditioned housing are less likely to be exposed than are missionaries or Peace Corps volunteers.

No hay imagen. Distribution of Malaria and Chloroquine-resistant Plasmodium falciparum, 1995

Drug Resistance

Resistance of P. falciparum to chloroquine has been confirmed or is probable in all countries with P. falciparum malaria except the Dominican Republic, Haiti, Central America west of the Panama Canal Zone, Egypt, and most countries in the Middle East. In addition, resistance to both chloroquine and Fansidar(R) is widespread in Thailand, Myanmar (formerly Burma), Cambodia, and the Amazon basin area of South America, and resistance has also been reported in sub-Saharan Africa. Resistance to mefloquine has been confirmed in those areas of Thailand with malaria transmission.

General Advice for Travelers to Malaria-Endemic Areas

All travelers to malarious areas of the world are advised to use an appropriate drug regimen and personal protection measures to prevent malaria; however, travelers should be informed that regardless of methods employed, malaria still may be contracted. Malaria symptoms can develop as early as 8 days after initial exposure in a malaria-endemic area and as late as several months after departure from a malarious area, after chemoprophylaxis has been terminated. Travelers should understand that malaria can be treated effectively early in the course of the disease, but that delay of appropriate therapy can have serious or even fatal consequences. Individuals who have symptoms of malaria should seek prompt medical evaluation, including thick and thin blood smears, as soon as possible.

Personal Protection Measures

Because of the nocturnal feeding habits of Anopheles mosquitoes, malaria transmission occurs primarily between dusk and dawn. Travelers should take protective measures to reduce contact with mosquitoes especially during these hours. Such measures include: remaining in well-screened areas, using mosquito nets, and wearing clothes that cover most of the body. Additionally, travelers should be advised to purchase insect repellent before travel for use on exposed skin. The most effective repellents contain N,N diethylmethyltoluamide (DEET), an ingredient in many commercially available insect repellents. The actual concentration of DEET varies among repellents and can be as high as 95%. Repellents with DEET concentrations between 30% and 35% are quite effective and the effect should last for about 4 hours. Rarely, children exposed to DEET have had toxic encephalopathy. The possibility of adverse reactions to DEET will be minimized if the following precautions are taken: apply repellent sparingly and only to exposed skin or clothing; avoid applying high-concentration products to the skin; do not inhale or ingest repellents or get them in the eyes; avoid applying repellents to portions of children's hands that are likely to have contact with eyes or mouth; never use repellents on wounds or irritated skin; wash repellent-treated skin after coming indoors. If a reaction to insect repellent is suspected, wash treated skin and seek medical attention.

Travelers should use a pyrethroid-containing flying-insect spray in living and sleeping areas during evening and nighttime hours. In addition, persons who will not be staying in rooms which are well-screened or air-conditioned should take additional precaution, which include sleeping under mosquito netting, i.e., bednets. Permethrin (Permanone(R)) may be sprayed on clothing and bednets for additional protection against mosquitoes. Bednets are more effective if they are treated with permethrin or deltamethrin insecticides. In the United States permethrin spray or liquid can be used, while permethrin or deltamethrin liquid may be purchased overseas for the treatment of bednets.

Chemoprophylaxis

In choosing an appropriate chemoprophylactic regimen before travel, persons should consider several factors. The travel itinerary should be reviewed in detail and compared with the information on areas of risk within a given country (pp. 13-73) to determine whether the traveler will actually be at risk of acquiring malaria. Whether the traveler will be at risk of acquiring drug-resistant P. falciparum malaria should also be determined. In addition, it should be established whether the traveler has previously experienced an allergic or other reaction to the antimalarialdrug of choice and whether medical care will be readily accessible during travel.

Malaria chemoprophylaxis should preferably begin 1-2 weeks before travel to malarious areas (except for doxycycline, which can begin 1-2 days before). This allows any potential side effects to be evaluated and treated by the traveler's physician before departure. Chemoprophylaxis should continue during travel in the malarious areas and for 4 weeks after leaving the malarious areas.

Table 13a. Drugs used in the prophylaxis of malaria

Table 13b Drugs used in the presumptive treatment of malaria

Chemoprophylactic Regimens (to be used in conjunction with pp. 13-73)

Regimen A: For travel to areas of risk where chloroquine-resistant P. falciparum has NOT been reported, once-weekly use of chloroquine alone is recommended. Chloroquine is usually well tolerated. The few people who experience uncomfortable side effects may tolerate the drug better by taking it with meals, or in divided, twice-weekly doses. As an alternative, the related compound hydroxychloroquine may be better tolerated. Chloroquine prophylaxis should begin 1-2 weeks before travel to malarious areas. It should be continued weekly during travel in malarious areas and for 4 weeks after a person leaves such areas. (See Table 13a for recommended dosages.)

Regimen B: For travel to areas of risk where chloroquine-resistant P. falciparum exists, use of mefloquine alone is recommended. Mefloquine is usually well tolerated but precautions should be observed as described in the section on adverse reactions. Mefloquine prophylaxis should begin 1-2 weeks before travel to malarious areas. It should be continued weekly during travel in malarious areas and for 4 weeks after a person leaves such areas. Mefloquine can be used for long-term prophylaxis. (See Table 13a for recommended dosages.) Note: In some foreign countries a fixed combination of mefloquine and Fansidar(R) is marketed under the name Fansimef(R). Fansimef(R) should not be confused with mefloquine, and it is not recommended for prophylaxis of malaria because of the potential for severe adverse reactions associated with prophylactic use of Fansidar(R).

Alternatives to Mefloquine

Persons who travel to areas where drug-resistant P. falciparum is endemic and for whom mefloquine is not recommended may elect to use an alternative regimen, as follows:

Doxycycline alone taken daily is an alternative regimen for travelers who cannot tolerate mefloquine or for whom the drug is not recommended. Doxycycline is as effective as mefloquine for travel to most malarious areas. However, it is also the only available effective prophylactic drug for prophylaxis for travelers to malaria endemic areas of Thailand. Travelers who use doxycycline should be cautioned about the possible side effects as described in the section on adverse reactions. Doxycycline prophylaxis should begin 1-2 days before travel to malarious areas. It should be continued daily during travel in malarious areas and for 4 weeks after the traveler leaves such areas. (See Table 13a for recommended dosages.)

Chloroquine alone taken weekly is only recommended for those travelers to areas with drug-resistant P. falciparum who cannot use mefloquine or doxycycline. Limited data suggest that the combination of chloroquine with daily proguanil (Paludrine(R)*) is more effective than chloroquine alone in Africa, but not in Thailand and Papua New Guinea. Therefore, travelers to Africa who use chloroquine for prophylaxis should, if possible, also take 200 mg daily (adult) of proguanil. Proguanil is not available commercially in the United States but can be obtained in Canada, Europe and many African countries.

Self-treatment

Because chloroquine (with or without proquanil) is a less effective chemoprophylaxis regimen in chloroquine-resistant areas, travelers who elect to use chloroquine either alone or with daily proguanil (except those with histories of sulfonamide intolerance) should be given a treatment dose of Fansidar(R) to be carried during travel. These travelers should take the Fansidar(R) promptly if they have a febrile illness during their travel and if professional medical care is not available within 24 hours; however, they should be aware that this self-treatment of a possible malarial infection is only a temporary measure and that prompt medical evaluation is imperative. They should continue their weekly chloroquine prophylaxis after presumptive treatment with Fansidar(R). (See Table 13a for recommended dosages for prophylaxis and Table 13b for presumptive treatment with Fansidar.)

Mefloquine should not be used for self-treatment because of the frequency of serious side effects (e.g., hallucinations, convulsions) that have been associated with the high dosages of mefloquine used for treatment of malaria.

Halofantrine (Halfan(R)) is an antimalarial drug which is licensed in the United States but is not commercially available, although the drug is available in many other countries. Halofantrine is not recommended for self-treatment of malaria because of potentially serious electrocardiogram changes which have been documented following treatment doses of halofantrine: in many of these reports halofantrine was administered in the presence of other antimalarial drugs (for example, mefloquine). The safety of halofantrine for self-treatment of persons on mefloquine prophylaxis has not been established and, since halofantrine is widely available overseas, health care providers may choose to caution travelers to avoid the use of halofantrine if they are on mefloquine.

Primaquine: Prevention of Relapses of P. vivax and P. ovale.

P. vivax and P. ovale parasites can persist in the liver and cause relapses for as long as 4 years after routine chemoprophylaxis is discontinued. Travelers to malarious areas should be alerted to this risk, and if they develop malaria symptoms after leaving a malarious area, they should report their travel history and the possibility of malaria to a physician as soon as possible. Primaquine decreases the risk of relapses by acting against the liver stages of P. vivax and P. ovale. Primaquine is administered after the traveler has left a malaria-endemic area, usually during the last 2 weeks of prophylaxis.

Since most malarious areas of the world (except Haiti) have at least one species of relapsing malaria, travelers to these areas have some risk of acquiring either P. vivax or P. ovale, although the actual risk for an individual traveler is difficult to define. Prophylaxis with primaquine is generally indicated only for persons who have had prolonged exposure in malaria-endemic areas, e.g., missionaries and Peace Corps Volunteers. Most people can tolerate the standard regimen of primaquine, with the exception of individuals deficient in glucose-6-phosphate dehydrogenase (G6PD) (see discussion of adverse reactions). (See Table 13a for recommended dosages.)

Adverse Reactions and Contraindications to Antimalarials

The frequent or serious side effects of recommended antimalarials are discussed below. In addition, physicians should review the prescribing information in standard pharmaceutical reference texts and in the manufacturers' package inserts.

Chloroquine and hydroxychloroquine rarely cause serious adverse reactions when taken at prophylactic doses for malaria. Minor side effects that may occur include gastrointestinal disturbance, headache, dizziness, blurred vision, and pruritus, but generally these effects do not require that the drug be discontinued. High doses of chloroquine, such as those used to treat rheumatoid arthritis, have been associated with retinopathy, but this serious side effect has not been associated with routine weekly malaria prophylaxis. Chloroquine and related compounds have been reported to exacerbate psoriasis. Chloroquine may interfere with the antibody response to human diploid cell rabies vaccine when the vaccine is administered intradermally.

Mefloquine has rarely been associated with serious adverse reactions (e.g., psychoses, convulsions) at prophylactic dosage, but these reactions are more frequent with the higher dosages used in treatment. Minor side effects observed with prophylactic doses, such as gastrointestinal disturbance, insomnia, and dizziness, tend to be transient and self-limited.

Mefloquine is contraindicated for use by travelers with a known hypersensitivity to mefloquine and is not recommended for use by children <15 kg. (30 lbs.), and travelers with a history of epilepsy or severe psychiatric disorders. A review of available data suggest that mefloquine may be used in persons concurrently on beta blockers, if they have no underlying arrhythmia. However, mefloquine is not recommended for persons with cardiac conduction abnormalities until additional data are available. Caution may be advised for travelers involved in tasks requiring fine coordination and spatial discrimination, such as airline pilots.

All studies to date confirm that mefloquine is well tolerated when used for prophylaxis; however, monitoring the occurrence of severe adverse reactions is important because such reactions are possible. Users of mefloquine prophylaxis who experience serious adverse reactions should consult their physician, and the reactions should be reported to the Malaria Section, CDC, telephone (770) 488-7760.

Doxycycline may cause photosensitivity, usually manifested as an exaggerated sunburn reaction. The risk of such a reaction can be minimized by avoiding prolonged, direct exposure to the sun and by using sunscreens that absorb long-wave ultraviolet (UVA) radiation. In addition, doxycycline use is associated with an increased frequency of monilial vaginitis. Gastrointestinal side effects (nausea or vomiting) may be minimized by taking the drug with a meal. To reduce the risk of esophagitis, doxycycline should be taken before going to bed. Doxycycline is contraindicated in pregnancy and in children less than 8 years of age.

Fansidar(R) is contraindicated in persons with a history of sulfonamide intolerance and in infants less than 2 months of age.

Proguanil rarely causes serious adverse reactions at prophylactic dosage. Reported side effects include nausea, vomiting, mouth ulcers, and hair loss.

Primaquine may cause severe hemolysis in G6PD-deficient individuals. Before primaquine is used, G6PD deficiency should be ruled out by appropriate laboratory testing.

Chemoprophylaxis for Children

Children of any age can contract malaria. Consequently, the indications for prophylaxis are identical to those described for adults. Mefloquine is not recommended for children <15 kg. (30 lbs.). Doxycycline is contraindicated in children <8 years of age. (See recommended dosages in Table 13a.) Young children who cannot take mefloquine or doxycycline can be given chloroquine (with proguanil for travel to sub-Saharan Africa) for prophylaxis. Children should avoid travel to areas with chloroquine-resistant P. falciparum, unless they can take a highly effective drug, such as mefloquine or doxycycline. It should be noted that although mefloquine is not recommended for use in children <15 kg. (30 lbs.) according to the FDA labelling agreement, recently available data suggest that its use in children is safe. Consequently, mefloquine may be considered for use when travel to areas with chloroquine-resistant P. falciparum is unavoidable.

Chloroquine phosphate is manufactured in the United States in tablet form only and has a very bi