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When adventurer Sandra Levy, 61, of Short Hills, N.J., visited Ecuador and the Galapagos Islands in December 1993, she tried to protect herself against tropical diseases and the insects that transmit them.
Before leaving home, Levy got vaccinated against yellow fever and took medicine to ward off malaria.
At the headwaters of the Amazon River, she took precautions. Whether trekking into the jungle or canoeing across the river to see leaf-eating ants on the opposite bank, she wore long-sleeved shirts and knee-high boots and used an insect repellent containing DEET. In her thatch hut at night, she slept under mosquito netting.
After she returned home, however, Levy noticed a sore the size of a dime above her left ankle. "It didn't hurt or itch," she says, "but it didn't go away. I decided to see my dermatologist."
By the end of March, despite antibiotics, her sore had grown to the size of a silver dollar, so she made another medical appointment. "The doctor took a biopsy. Knowing I'd been in Ecuador, he had the lab check for deep fungus and leishmaniasis."
The diagnosis was indeed leishmaniasis, a tropical disease spread by infected female sandflies. Levy's doctor put her in touch with a tropical disease specialist for treatment.
As Levy's experience shows, travelers' precautions against tropical diseases are not foolproof.
"The American public shouldn't be complacent about these diseases," says Randolph Wykoff, M.D., associate commissioner for operations at the Food and Drug Administration. "Tropical diseases are absolutely devastating in other countries, killing hundreds of thousands of people. We are not immune." While most such infections are acquired during travel, Wykoff says, some people can also become infected from other travelers who bring home the disease.
Still, tropical diseases are more prevalent in developing countries, where conditions all too commonly foster their spread. War refugees migrating to other areas carry infections with them. Economic and social crises stress health systems. And unsanitary conditions due to rapid urbanization and rapid population growth foster an environment in which insects and other animals can transmit disease-producing organisms.
"King" Malaria
Sometimes called the King of Diseases, malaria yearly strikes up to 500 million people, 90 percent of them in Africa, with up to 2.7 million deaths, mostly young children.
Malaria is caused by four species of Plasmodium parasites, transmitted to humans by infected female Anopheles mosquitoes. Symptoms include a spiking fever, shaking chills, and flu-like symptoms. Anemia or liver problems may develop. If treatment is delayed, severe infection may lead to kidney failure, coma, and death.
Malaria kills so many African children because they lack immunity, says tropical disease specialist LTC Alan Magill, M.D., of Walter Reed Army Institute of Research, Department of Defense. Americans in Africa--travelers or troops--also are at risk because their immunity to malaria is like a child's, he says. They have more severe malaria than Africans who have survived past age 5 and developed immunity. "At our study site in Kenya," he says, "if you drew blood from 100 seemingly normal Africans at the local market, you'd find malaria parasites in most of their bloodstreams. They're infected, and the transmission cycle goes on, but they don't have obvious ill effects."
The national Centers for Disease Control and Prevention gets about 1,000 reports a year of malaria in the United States. Since 1957, nearly all these cases were acquired in areas of the world where malaria is known to occur.
Domestic malaria, in fact, was declared eradicated in this country in the 1940s. But from 1957 through 1994, CDC got 76 reports of malaria cases that may have been transmitted locally, including some from suburban New Jersey in 1991 and New York City in 1993. A 1995 report from Michigan was the first that far north since 1972. "In most cases, evidence indicated that locally infected mosquitoes did transmit the disease," says CDC malaria expert Lawrence Barat, M.D. "Anopheles mosquitoes are present throughout the contiguous United States. But we've never found an infected mosquito in the United States. More recently, we've had outbreaks of Plasmodium falciparum malaria, the more severe form. We want to monitor this very closely."
For several decades after the Second World War, the drug of choice for malaria treatment and prevention was chloroquine (Aralen and generics). "The drug was well-tolerated, fast-acting, and cost only 9 cents to cure a child," says Robert Gwadz, Ph.D., assistant chief, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID). However, in the 1950s, he says, resistance to chloroquine in falciparum malaria appeared in South America and Southeast Asia and spread throughout both continents and eventually into Africa. "Chloroquine is now useless in most malarious areas."
FDA has since approved numerous anti-malaria drugs. Many are not marketed here or are used here only for indications other than malaria.
Chloroquine remains the treatment of choice for patients with malaria caused by species still susceptible to the drug. Resistance to chloroquine is becoming more common, however, and alternative drugs are necessary.
In the United States, Barat says, oral quinine given together with either tetracycline or sulfadoxine-pyrimethamine (Fansidar) is the best regimen for treatment of mild to moderate falciparum malaria acquired in areas where resistance to chloroquine has been identified. For patients with complicated malaria who are too ill to take oral medicine, intravenous quinidine is used in the United States. Mefloquine (Lariam) and halofantrine (Halfan) are also used to treat chloroquine-resistant falciparum malaria. Halofantrine is not currently marketed here. Intravenous quinine is used in other countries.
The incidence of malaria continues to increase, Gwadz says, "in part due to the spread of resistance to chloroquine and several of its substitutes, but also to reduced effectiveness and acceptability of mosquito-killing insecticides."
In 1995, the World Health Organization established a system to monitor the drug resistance in Southeast Asia and the Western Pacific.
The parasite can be difficult to treat because it can change form to escape the human immune system, says Neil Goldman, Ph.D., associate director for research at FDA's Center for Biologics Evaluation and Research. Goldman says scientists at the center's Laboratory of Parasitic Biology and Biochemistry conduct research "to learn how this process takes place and figure out how to interrupt it. If we make a break in the circle, maybe we can stop infection."
Gwadz and colleagues are studying how to give mosquitoes a beneficial gene that prevents transmission of the parasite. To learn more about mosquito biology, they collaborate with scientists at West Africa's National School of Medicine and Pharmacy, in Mali.
NIAID scientists also are conducting the first human trial of a vaccine to block transmission of malaria parasites from infected people.
More from Mosquitoes: Dengue Fever, Yellow Fever
Aedes mosquitoes, mainly A. aegypti, an urban-dwelling insect, can transmit four types of dengue viruses, causing about 20 million cases of disease in more than 100 countries each year. A. aegypti mosquitoes tend to bite in the daytime, especially just after dawn and just before dark.
Dengue fever begins suddenly with high fever, severe frontal headache, joint and muscle pain, and sometimes vomiting and rash. Patients usually recover without complications. More serious, dengue hemorrhagic fever can lead to shock, bleeding and death. There is no specific treatment. Symptoms can be treated with bed rest, intravenous fluids, and drugs to reduce fever.
In 1995, the worst dengue epidemic in 15 years hit Latin America and the Caribbean. Worldwide, the more than 600,000 cases of hemorrhagic fever caused 24,000 deaths. CDC in 1995 diagnosed dengue fever in 86 U.S. travelers, up from 46 during 1993-1994 and 17 in 1992.
A. aegypti mosquitoes also spread the yellow fever virus. Peru in 1995 had the biggest yellow fever epidemic in the Americas since 1950. West Africa also experienced an epidemic that year.
Mild yellow fever causes flu-like symptoms. Severe cases may involve bleeding and liver problems, sometimes leading to delirium, convulsions, coma, and death. Treatment is symptomatic. Prevention consists of vaccination and personal protection against mosquitoes.
Yellow fever vaccine must be approved by WHO and given at approved vaccination centers. The Pan American Health Organization (PAHO) helped in the vaccination campaign that controlled the Peru epidemic. PAHO is the regional WHO office for the Americas.
Elephantiasis and River Blindness
Worms related to the heartworms that can hurt dogs, can give humans lymphatic filariasis, a disease affecting about 120 million people worldwide. Infected female Aedes, Anopheles, and various other mosquitoes deposit the worm larvae while biting.
The adult worm can damage the lymph system, resulting in elephantiasis--disfiguring swelling in the legs, arms, and other areas. FDA has approved diethylcarbamazine (Hetrazan) for treatment. Surgery may be needed if certain areas, such as the scrotum, are affected.
River blindness (onchocerciasis) is caused by pre-larval and adult stages of Onchocerca volvulus, a filarial parasite transmitted by female black flies. Living near rapidly flowing rivers and streams, black flies bite by day. Most of the 17.6 million people who have onchocerciasis are in Africa, though the disease is common in certain areas of Central America as well. Short-term travelers appear to be at low risk for infection, which is usually found in Americans only when they stay in these areas a long time in roles such as missionaries, field scientists, and Peace Corps volunteers.
Symptoms include an extremely itchy rash, lumps under the skin, and eye inflammation that can lead to blindness.
Ivermectin kills the parasite at the stage when it causes symptoms. Merck, Sharp & Dohme provides this drug free to countries where river blindness is common. It is available here from CDC under an agreement with FDA. According to John Becher, one of two pharmacists who oversee the drug service, "We provide certain drugs and biologics as a public health service. Most are for rare diseases." Ivermectin and other drugs for tropical diseases available through the service are not approved in the United States but are provided under investigational drug exemptions granted by FDA.
NIAID's Laboratory of Parasitic Diseases conducts research toward vaccines for elephantiasis and river blindness. While nearly everyone exposed becomes infected, a few individuals are resistant, says Thomas Nutman, M.D., who heads one immunology section. "These resistant individuals have antibodies in their blood that are specific to certain important parasite proteins. We identify the proteins, clone them, manufacture enough so we can study them, and then test them." Testing is in test tubes instead of in animals, which don't take the infection as humans do.
Flatworms, Snails and Schistosomiasis
Flatworms cause schistosomiasis. First-stage larvae infect freshwater snails, then evolve into cercariae larvae, which exit the snails and swim along to find a human host. Penetrating the skin, male and female cercariae move in the bloodstream to the intestines or bladder and mate. Eggs excreted in human waste end up in the water supply, restarting the cycle. About 200 million people worldwide are infected. Severe disease leads to about 200,000 deaths each year.
Most symptoms are due not to the worms, but to eggs trapped in tissue. Short-term infection may be symptomless or cause such symptoms as fever, itchy rash, headache, joint and muscle pain, diarrhea, and nausea. Chronic infection can damage the liver, kidneys and bladder, or intestines. FDA has approved praziquantel (Biltricide) as treatment.
Places where schistosomiasis is most prevalent include Brazil, Puerto Rico, and St. Lucia (an island in the East West Indies); Egypt and most of sub-Saharan Africa; and Southern China, the Philippines, and Southeast Asia, according to CDC. At greatest risk are people who wade, swim or bathe in fresh water in rural areas where sanitation is poor and snail hosts are present.
Travelers to such areas should not swim in fresh water; salt water like the ocean and chlorinated pools are considered low risk. Bathing water should be heated to 50 degrees Celsius (122 degrees Fahrenheit) or treated with iodine or chlorine, as for drinking. Filtering water with paper coffee filters may remove the parasites. If these methods are impossible, CDC recommends that travelers let bathing water stand three days; cercariae rarely live longer than 48 hours.
WHO-led researchers are planning to test a vaccine in humans.
Trypanosoma Diseases: Sleeping Sickness, Chagas' Disease
The parasites Trypanosoma brucei gambiense and T. brucei rhodesiense cause African sleeping sickness. About 20,000 cases worldwide are reported yearly. Infected tsetse flies, which bite during the day, transmit this extremely serious disease.
East Africa's sleeping sickness, due to T. brucei rhodesiense infection, causes symptoms within days to weeks. West Africa's chronic gambiense variety may not cause the "sleeping" part of the illness until months to years after exposure. Symptoms include fever, headache, lethargy, and confusion, which may progress to convulsions, coma and death.
Suramin, available from CDC, is for the early stages of both gambiense and rhodesiense sleeping sickness. Melarsoprol, an arsenic derivative, is also available from CDC to treat final stages of both varieties. If the patient is known to have gambiense, however, the drug eflornithine (Ornidyl), approved by FDA, is more effective and safe because melarsoprol can cause serious, even fatal, nervous system problems in some patients. Eflornithine is useful for both early and late stages of gambiense sleeping sickness; it is not effective for rhodesiense sickness.
Trypanosoma cruzi causes Chagas' disease, which affects at least 16 million people in Central and South America. The parasite infects reduviid bugs. When the bugs defecate, they deposit the parasite, which can enter a human through a break in the skin or through a mucous membrane, such as that which lines the nose, mouth or eyes. The best prevention is to avoid potential reduviid habitats--mud, adobe and thatch buildings, especially those with cracks or crevices. If this isn't feasible, spraying infested areas and using bed nets can help prevent infection.
In its short-term stage, Chagas' disease may cause no symptoms or may cause fever, swollen lymph nodes, and inflammation of the heart or, rarely, the brain. Deaths occur, mainly in children, but most patients survive, their symptoms usually disappearing after four to six weeks. Many years later, about a fourth of patients develop serious, sometimes fatal, heart infection or damaged digestive organs such as an enlarged esophagus or colon for the long term. Nifurtimox is available from CDC for the treatment of short-term Chagas' disease. There is no accepted anti-parasitic treatment for chronic illness.
About 70 percent of cases occur in Argentina, Bolivia, Brazil, Chile, Paraguay, and Uruguay. In 1991, the health ministers of those six countries began a program to eliminate Chagas' disease by the end of this century. Since then, house infestation has declined 75 to 98 percent in some areas, PAHO reports.
The Leishmaniases
Sandra Levy is one of an estimated 12 million people worldwide with leishmaniasis. This group of diseases is spread through the bite of female sandflies infected with any of about 20 different species of Leishmania parasites.
Levy had cutaneous leishmaniasis, which causes skin sores that may leave ugly scars. Mucocutaneous leishmaniasis can cause disfiguring destruction of membranes in the nose, mouth, or upper throat (pharynx).
In visceral leishmaniasis, parasites invade internal organs, causing death if the symptoms are untreated. According to the Defense Department's Magill, "You have chronic fever, depression of bone marrow and blood cells, weight loss, and a huge spleen so full of parasites it comes down into the pelvis." Years may pass before symptoms appear.
Recently, 32 Persian Gulf War veterans were identified as leishmaniasis victims, 12 with viscerotropic leishmaniasis, a chronic syndrome associated with the infection, Magill says. They had fever and vague flu-like symptoms, but few signs of overt disease, he says. "Some had lymph-node enlargement that tended to come and go. A couple had slightly enlarged spleens."
A free clinical evaluation program has been set up to identify and treat all veterans infected with leishmaniasis. (See "Want More Information?")
The only current way to confirm a leishmaniasis diagnosis is by finding parasites in a clinical specimen. FDA is evaluating a skin test developed by the Defense Department for mass screening of troops.
Preventive measures are staying indoors from dusk to dawn and using bed nets with 18 or more holes per inch--sandflies are a third the size of mosquitoes. Treatment of choice is with injectable drugs containing pentavalent antimony, a potentially toxic metal. "Drugs in this class remain unapproved by FDA, and no manufacturer has applied for approval," says Andrea Meyerhoff, M.D., an infectious disease specialist with the agency.
Levy took one such drug, sodium stibogluconate, available on a patient by patient basis from CDC. Through home care, Levy had an intravenous dose each day for 20 days.
Although she had a reaction that she describes as "the worst scenario of flu symptoms," Levy urges those who get leishmaniasis, "Don't think, 'Oh, I'll knock it off.' Go on that medication if it's what your doctor ordered. It isn't worth taking a chance."
In 1994, FDA designated aminosidine, an antibiotic that does not contain antimony, as an orphan drug for visceral leishmaniasis, and a sponsor is working to develop it.
Goldman and colleagues are studying new ways to make a leishmaniasis vaccine. "We're trying to skew the immune response," he says, "so it gives a protective reaction to the infection."
Richard Kenney, M.D., a colleague, says, "Past efforts clearly show the need for a better understanding of the immune response to the parasite." Toward this end, Kenney and Shyam Sundar, of the Institute of Medical Sciences, Banaras Hindu University, India, collaborate on studies of the immune response at various stages of infection and treatment.
The Global Fight Continues
WHO Director-General Hiroshi Nakajima, M.D., Ph.D., in his message in the WHO 1996 report, writes that many diseases, including Chagas' disease and river blindness, "sooner rather than later ... will join smallpox as diseases of the past." But he also writes that the world is "on the brink of a global crisis in infectious diseases," requiring "a global response ... that goes beyond selfish interests and national boundaries."
Responses by WHO include development of a network of laboratories to strengthen collaboration in detecting and controlling outbreaks. WHO teams can be on site within 24 hours with supplies and equipment to set up epidemic control measures.
The Clinton administration last June established a Presidential Decision Directive on Emerging Infectious Diseases, including tropical disease, to improve U.S. and international disease surveillance and prevention and response measures.
Meanwhile, international travelers can find health advice in CDC's annually updated handbook, Health Information for International Travel.
As for Levy, her globetrotting has cooled. "My jungle trips are over," she says. Her latest trip, last August, was to Iceland.
Dixie Farley is a staff writer for FDA Consumer. Lenore Gelb, a press officer in the Office of Public Affairs, also contributed to this article.