MALARIA

Malaria is caused by infection with one of four microscopic protozoan parasites: Plasmodium falciparum, P. vivax, P. malariae, or P. ovale. These are transmitted in the wild by the bite of an infected Anopheles mosquito. Of the nearly 430 species of Anopheles mosquitoes, only 30 to 40 transmit malaria. Most cases of malaria acquired by U.S. citizens are contracted in sub-Saharan Africa; most of the remainder are linked to travel in Southeast Asia, Central and South America, the Indian subcontinent, the Middle East, and Oceania (Papua New Guinea, Vanuatu, and the Solomon Islands).

Mosquitoes bite humans to obtain a blood meal in order to produce eggs. When a female mosquito bites a human infected with malaria, it ingests an immature form of the parasite. In approximately 2 weeks, the parasite matures within the mosquito. When the infected mosquito bites a noninfected human, it releases malaria sporozoites (an immature form of the parasite), which mature in the human liver to become merozoites, and which then invade red blood cells. From these locations, the organisms can penetrate the vital organs, such as the brain, lungs, liver, and kidneys. Within a few days, the infected red blood cells burst and the parasites infect more red blood cells. The incubation period between acquisition of the parasites and the onset of symptoms is 8 to 40 days, depending on the species. Up to a third of victims may not show the disease until after 60 days from the time of the initial mosquito bite. Typical symptoms include a flu-like illness, with any or all of the following: headache, chills, sweats, fatigue, backache, pale skin, loss of appetite, muscle aches, nausea, diarrhea, and vomiting. These are soon followed by episodes of headache, intense chills (rigors), high fever, and sweating. Jaundice and anemia may occur. The episodes last 1 to 8 hours and are separated by 2 to 3 days, depending on the species.

Those infected with falciparum malaria may be significantly more ill, with episodes of fever and chills at closer intervals and lasting for more than 30 hours. In addition, there may be severe alteration in mental status, seizures, difficulty breathing, blood in the urine, severe anemia, and shock. Severe malaria can be fatal or lead to anemia, heart and kidney failure, and/or coma; untreated infections can cause recurrent illness for years.

Identification of the specific plasmodium is accomplished by observing the parasites under the microscope in blood smears. People infected with P. falciparum are treated with quinine sulfate in combination with pyrimethamine-sulfadoxine (Fansidar) or tetracycline. The most important new class of antimalarial drugs is the artemisinins, which are natural products that were first developed in China in the 1960s. Artemether, artesunate, artemotil, and dihydroartemisinin (all artemisinin, or qinghaosu, derivatives) have been shown to be effective in the treatment of severe P. falciparum malaria. One key advantage of these agents is that they are active against all of the red blood cell stages of the parasite. Also, so far there is limited if any resistance to these agents. Because all artemisinins are very effective in killing the parasites, they are cleared rapidly from the bloodstream; so, are combined with longer-acting drugs, such as mefloquine, lumefantrine, amodiaquine, or piperaquine in countries other than the United States. At the time of this writing, in the United States, intravenous artemesinin is still considered an investigational drug, so it must be obtained from the Centers for Disease Control and Prevention (CDC). It is used for 3 days, and then followed with a longer-acting oral drug such as doxycycline, clindamycin, atovaquone-proguanil, or mefloquine. A person infected with P. vivax, P. malariae, or P. ovale is treated with chloroquine and primaquine phosphate.

Unfortunately, there is not yet a useful vaccine against malaria. Avoidance of mosquito bites is key to prevention. Because the Anopheles mosquito tends to feed during the evening and nighttime, it is particularly important to sleep under nets or screens; spray living quarters (with, for instance, a pyrethrin-containing product) and clothing (with, for example, permethrin 0.5%, Duranon, or Repel Permanone; or concentrated Perma-Kill 4 Week Tick Killer, diluted and applied to clothing); and wear adequate clothing and insect repellent (N,N-diethyl-3-methylbenzamide, called DEET) at these times (see page 390).

If you travel to a region where P. falciparum is resistant to chloroquine and pyrimethamine-sulfadoxine, prophylaxis (prevention) can be accomplished with mefloquine. The adult dose is 250 mg (salt) weekly. The pediatric dose varies according to the weight of the child: weight 15 to 19 kg, 63 mg; weight 20 to 30 kg, 125 mg; weight 31 to 45 kg, 188 mg; and over 45 kg, 250 mg. (For estimating purposes, 1 kg equals 2.2 lb.) Mefloquine should be started 1 to 2 weeks before travel, and then administered once a week during travel in malarious areas and for 4 weeks after you leave such areas. Mefloquine should not be taken during pregnancy. This drug should not be used by persons with psychiatric disease or history of depression or seizures. Side effects include nausea and vomiting, dizziness, mood changes, difficulty sleeping and nightmares, headache, and diarrhea.

An alternative drug for travelers who cannot take mefloquine is doxycycline (the adult dose is 100 mg a day beginning 1 to 2 days before travel and continuing for 5 to 6 weeks after; the pediatric dose for those aged more than 8 years is 2 mg/kg of body weight a day, up to the adult dose). Doxycycline is not advised for pregnant women or children under age 8 years, and may cause increased skin sensitivity to sunlight.

A final drug prophylaxis regimen against malaria is chloroquine phosphate (the adult dose is 300 mg of the base once a week; the pediatric dose, 5 mg/kg of the base, up to the adult dose, once a week), which should be taken 1 to 2 weeks before you enter a malarious region and continued until 1 month after your journey. Chloroquine is recommended for travelers, particularly pregnant women and children who weigh less than 33 lb (15 kg), who cannot take mefloquine or doxycycline. If you use chloroquine for prophylaxis, you should also carry three tablets of Fansidar to be taken in the event of a flu-like illness or other unexplained fever, assuming the absence of an allergy to sulfonamide antibiotics. Chloroquine should not be used by persons with retinal problems and has side effects of headache and itching.

Proguanil (Paludrine) is a drug that may be used for antimalarial prophylaxis in areas where P. falciparum is resistant to chloroquine. The drug is available without prescription in parts of Europe, Scandinavia, and Africa, but is as yet unavailable in the United States. It is administered in an adult dose of 200 mg daily (pediatric dose: under 2 years, 50 mg; age 2 to 6 years, 100 mg; age 7 to 10 years, 150 mg; over 10 years, 200 mg), along with weekly chloroquine (the latter to protect against other forms of malaria). It can be used by those who will spend more than 3 weeks in rural areas of East Africa (particularly Kenya and Tanzania), but does not appear to be useful in Papua New Guinea, West Africa, or Thailand.

Atovaquone in combination with proguanil hydrochloride is available as the drug Malarone. The drug is taken at the same time each day with food or a milky drink. Treatment should be started 2 days before entering a malaria-endemic area and continued for 7 days after return. The adult dose is one tablet (250 mg atovaquone/100 mg proguanil) per day. Each pediatric tablet of Malarone contains atovaquone 62.5 mg/proguanil 25 mg. The pediatric dose is based on weight: 11 to 20 kg, one pediatric tablet per day; 21 to 30 kg, 2 tablets; 31 to 40 kg, 3 tablets; greater than 40 kg, one adult tablet. It should be noted that if Malarone is taken with tetracycline, metoclopramide, rifampin, or rifabutin, it may be less bioavailable and thus potentially less effective. It should not be used by persons with significant kidney disease.

Pyrimethamine plus dapsone (drug combination: Maloprim) is prescribed in many malaria-endemic regions outside the United States. This drug cannot be used by pregnant women; it can also cause bone marrow suppression.

If you are stricken with malaria in an area where the malaria organism(s) is believed to be sensitive to chloroquine, but you have not been taking prophylaxis, begin treatment with chloroquine (adult dose, 600 mg of the base immediately, followed with 300 mg at 6 hours and once a day on days 2 and 3; pediatric dose, 10 mg/kg of body weight [up to 600 mg] of the base immediately, followed by 5 mg/kg at 6 hours and once a day on days 2 and 3). In a region where P. falciparum is resistant to chloroquine, administer quinine sulfate (adult dose, 650 mg every 8 hours for 3 days; pediatric dose, 8 mg/kg [up to 650 mg] every 8 hours for 3 days) plus tetracycline (adult dose, 250 mg four times a day for 7 days; pediatric dose, 5 mg/kg [up to 250 mg] four times a day for 7 days) or Fansidar (adult dose, 3 tablets; pediatric dose: weight 5 to 10 kg, ½ tablet; weight 11 to 20 kg, 1 tablet; weight 21 to 30 kg, 1 ½ tablets; weight 31 to 45 kg, 2 tablets; weight over 45 kg, 3 tablets). (For purposes of estimation, 1 kg equals 2.2 lb.) Malarone is sometimes used to treat acute malaria caused by P. falciparum. In this case the dosage for treatment is based on body weight: 5 to 8 kg, 2 pediatric tablets each day for 3 consecutive days; 9 to 10 kg, 3 pediatric tablets for 3 days; 11 to 20 kg, 1 adult tablet for 3 days; 21 to 30 kg, 2 adult tablets for 3 days; 31 to 40 kg, 3 adult tablets for 3 days; greater than 40 kg, 4 adult tablets for 3 days. Halofantrine (Halfan) is used to treat chloroquine-resistant P. falciparum infections in a dose of 500 mg every 6 hours for three doses, with repeat therapy in 7 days.

In any case of suspected malaria, seek the advice of a physician as soon as possible. Anticipate that a stricken individual, particularly a child, may develop extremely low blood glucose (sugar).

To determine the malaria risk within a specific country and to learn of the most recent recommendations for prophylaxis and drug therapy, you can seek information from one of many sources on the Internet, such as www.cdc.gov/malaria/.

YELLOW FEVER

Yellow fever is a viral disease transmitted in the jungle by mosquitoes of the genus Haemogogus and in urban areas by Aedes aegypti mosquitoes. “Jungle” yellow fever is seen in forest-savanna zones of tropical Africa, parts of Central America, forested areas of South America, and Trinidad. The “urban” variety is seen in South America and West Africa. The disease has not yet been noted in Asia.

The illness begins 3 to 6 days after the culprit mosquito bite(s). Symptoms include sudden onset of fever, headache, red eyes, muscle aching, nausea, and vomiting. These symptoms last for 3 to 4 days, after which there may be 12 to 24 hours of remission. Soon thereafter comes an “intoxication phase,” in which the seriously stricken victim develops fever, skin rashes, altered mental status, low blood pressure, and liver and kidney failure. In such cases, the victim becomes jaundiced (hence, “yellow” fever) and bleeds easily. The disease can be fatal. Treatment is supportive and based on symptoms. Because of the bleeding problems, do not use aspirin to control fever.

Since yellow fever is so difficult to treat, it is essential to use yellow fever vaccine and mosquito control measures (see page 390). A live-virus vaccine is available. A single injection induces immunity after 10 days that is adequate for 10 years (see page 453).

DENGUE FEVER

Dengue fever is a viral (flavivirus) disease transmitted by Aedes albopictus and female A. aegypti mosquitoes. It is estimated that 50 to 100 million people in more than 100 countries are infected each year with dengue viruses. There are four different types of dengue virus, and there is no cross-immunity, so a person may be stricken with dengue fever four times in his life. The most active feeding times for dengue vector mosquitoes is for a few hours after daybreak and in the afternoon for a few hours just after dark (dusk). As opposed to the night-feeding mosquitoes that transmit malaria, these species tend to be “urban,” may also feed during daylight hours (also indoors, in the shade, and during an overcast), and are known to bite below the waist. Dengue fever is seen chiefly in the Caribbean and South America, as well as other tropical and semitropical areas, such as Southeast Asia, Africa, and Mexico. In the United States, cases have been noted in Texas. The larvae flourish in artificial water containers (e.g., vases, tires), often in a domestic environment.

The incubation period following a mosquito bite is 2 to 8 days. The disease is self-limited (5 to 7 days) and characterized in older children and adults by a sudden onset of severe headache, sore throat, fatigue, cough, high fever (greater than 39°C or 102.2°F), chills, muscle aches, sore throat, reddened eyes, enlarged lymph nodes, nausea, bone and joint pain (“breakbone fever”), and a fine, red, itchy skin rash that typically appears simultaneously with the fever on the proximal arms, legs, and trunk (it spares the face, palms, and soles). It may then spread to the face, and farther out on the arms and legs, becoming slightly darker and more solid. Although the fever usually remits spontaneously, an occasional victim will relapse. Some victims have a cycle of a few days of fever, then 1 to 3 days without fever, then fever again. It is not uncommon to suffer central nervous system manifestations, such as irritability, depression, seizures, or severe altered mental status. Children under 1 year of age appear to be particularly vulnerable to especially severe forms of dengue virus infection, associated with severe bleeding problems (dengue hemorrhagic fever: nosebleed, bleeding gums, severe abdominal pain, bloody vomit, darkened stool, restlessness, weakness, etc.) and circulatory problems that can lead to extremely low blood pressure (shock—see page 60). When this occurs, the victim may develop a diffuse, dark purple, blotchy rash caused by bleeding into the skin.

Treatment is supportive and based on symptoms. Fever should be treated with acetaminophen, and not with aspirin. There is no vaccine available against dengue fever. Insect repellents (particularly those containing DEET; see page 390) are critical for prevention.

CHIKUNGUNYA DISEASE

Chikungunya disease is similar to dengue fever. It is indigenous to tropical Africa and Asia. Caused by transmission of an alphavirus from a bite from the mosquito Aedes aegypti or A. albopictus, Chikungunya disease carries an incubation period of 2 to 12 (usually 3 to 7) days, followed by fever, headache, pain on looking at the light, pain behind the eyes, sore throat, nausea, vomiting, and weakness. On days 1 to 3, there may appear a red rash, followed by muscle aches and painful joints with arthritis. The arthritis may last for months to years. Therapy is symptomatic. As with dengue, proper use of insect repellents is critical.

WEST NILE VIRAL DISEASE

West Nile (named from the West Nile province of Uganda) viral disease (West Nile virus: WNV) is caused by a flavivirus (such as those that cause St. Louis encephalitis, Japanese encephalitis, and Murray Valley encephalitis) carried predominantly by mosquitoes (Culex pipiens in the eastern United States, C. pipiens quinquefasciatus in the southern United States, and C. tarsalis in the western United States, Aedes, Anopheles, and many other species) and at least 160 species of birds, although it has been found in small mammals and to an alarming degree in horses. The mosquitoes become infected by feeding on birds and many animals (e.g., bats, horses, chipmunks, dogs, rabbits, reindeer, squirrels, and even alligators). It appears to be transmitted to humans by mosquito bite and has been presumed to have arrived in the United States from the Middle East. In rapid fashion, it appears to have spread across the United States. The four top species of wild birds affected by WNV are American crows, Western scrub-jays, yellow-billed magpies, and Steller’s jays. Mosquitoes bite the birds and thus acquire the virus. West Nile viral disease is endemic in Africa, the Middle East, and West Asia. The virus has been spread to the recipient of an organ transplant from an infected donor, from a pregnant mother to a fetus, by blood transfusion, and possibly through breast milk. Otherwise, it does not appear to spread from human to human. While much of the clinical WNV activity is noted in summer and autumn, it is certainly possible to acquire the disease in winter from the bite of an infected mosquito.

The incubation period after a bite from an infected mosquito until the onset of illness is 3 to 14 days. The victim usually suffers a flu-like illness lasting for 3 to 6 days, characterized by fever, headache, neck stiffness and pain, swollen lymph glands, muscle aches and weakness, loss of appetite, fatigue, diarrhea, vomiting, red bumpy rash (commonly on the chest, abdomen, and back), and aversion to light (sometimes interpreted by victims as eye “pain”). Fatigue may be a residual symptom for up to a month. In 1 in every 100 to 300 cases, the victim suffers severe encephalitis (inflammation of the brain) with stiff neck and severe altered mental status (including coma or double vision), as well as paralysis. Convulsions are rare. Elders are more prone to suffer severe or fatal illness. Death is uncommon.

Most (80%) people infected with WNV never realize that they have had the disease, because they remain without symptoms. Twenty percent of infected people develop West Nile fever, and less than 1% of people infected develop severe medical illness, including meningitis and/or encephalitis (characterized by seizures, loss of vision, and disorientation) or paralysis. There are blood tests for WNV that measure antibodies to the virus, and show positive in most infected people within 8 days of the onset of symptoms. However, they may initially be “negative” and need to be repeated at a later date. There is no specific treatment, other than supportive therapy. Recovery is generally complete for survivors, although persistent neuropsychological problems (fatigue, memory problems, weakness, tremor, word-finding difficulties, headaches, and depression) may occur, even if the acute disease was mild.

Prevention is essential. First and foremost, that means preventing mosquito bites. Here are some recommendations:

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