David A. Relman MD
The genera Leishmania and Trypanosoma are members of the family Trypanosomatidae. These protozoans cause diseases with widely varied clinical presentations as well as geographic distributions, including leishmaniasis, American trypanosomiasis (Chagas' disease), and African trypanosomiasis (sleeping sickness). For example, the endemic zones for African and American trypanosomiasis do not overlap, the diseases are transmitted by different vectors, they involve distinct mechanisms of pathogenesis, and they follow different clinical courses. Nonetheless, the causative agents share important biological features. Each is a hemoflagellate with a kinetoplast containing its own chromosomal DNA with highly conserved and repeated elements, each forms a single flagellum at some point during its life cycle, and each is highly adapted to life within an insect.
LEISHMANIA
Essentials of Diagnosis
General Considerations
Infections with Leishmania spp. occur worldwide, in environments as varied as the semiarid deserts of the Middle East and the tropical rain forests of Central and South America. There are three major clinical forms of disease: visceral (kala-azar), mucocutaneous, and cutaneous. Even though each form tends to be associated with particular Leishmania species, some species can cause multiple forms of the disease, and some forms can be caused by multiple species. Leishmaniasis is a zoonosis with sandfly vectors and mammalian reservoirs. Lutzomyia sandflies are the primary vectors in the Americas, whereas Phlebotomine sandflies transmit the disease in the rest of the world.
Leishmaniasis is endemic to all countries in the Americas except Canada, Uruguay, and Chile. Southern Texas is the only endemic area in the United States. There are often small geographic foci of transmission within endemic areas. Leishmaniasis is seen in the countries surrounding the Mediterranean Sea, as well as in central Africa and across the Middle East to India and China. Of visceral leishmaniasis cases worldwide, 90% occur in India, Bangladesh, southern Sudan, and northern Brazil; and 90% of cutaneous leishmaniasis cases occur in Afghanistan, Brazil, Iran, Saudi Arabia, and Syria. The vast majority of mucocutaneous leishmaniasis cases are found in Brazil and the geographic areas after which the subspecies and complexes are named (eg, amazonensis [Amazon region], panamensis [Panama], and guyanensis [Guyana]).
Leishmaniasis is most commonly observed in humans who live or work at the forest edge, where insect vectors are most abundant. These include rural settlers, farmers clearing forests, and road construction workers, as well as military personnel. Most cases of leishmaniasis in the United States are imported by those who have been exposed in rural areas of endemic regions, including Peace Corp workers, ornithologists, and field workers. Leishmaniasis is more common in adult males, probably in part because of occupational risks. Transmission of leishmaniasis has been associated with blood transfusions and intravenous drug abuse.
Although there are > 600 species of sandflies, only about one-tenth of these transmit leishmaniasis. Among these disease transmitters, both the Phlebotomine (found in the Mediterranean and Middle East regions) and the Lutzomyia (found in the Americas) sandflies are small and hairy and have a V-shaped wing configuration. They are inactive during daylight hours, and they stay in dark moist places that are rich in organic matter. The animal reservoirs in the Americas are primarily sylvatic and include sloths, opossums, and small forest rodents. Canines also serve as reservoirs for organisms that cause the visceral forms, especially as part of a peridomestic transmission cycle (Figure 85-1A). With the notable exception of dogs and humans, the mammalian hosts that serve as reservoirs generally do not show signs of disease.
The visceral form of leishmaniasis (kala-azar) provides an exception to this cycle from insects to animal reservoirs to humans, because there are no known animal reservoirs but only direct insect-to-human transmission. In India, for example, the organism and disease persist in the human population (anthroponoses) and are maintained by patients with persistent subclinical post-kala-azar dermal leishmaniasis, from whom parasites have been isolated from normal appearing skin.
Interferon gamma and other components of the Th1 cytokine response appear to be critical for host defense against disease. In an apparent attempt to subvert these defenses, Leishmania mexicanaexpresses several cysteine proteinases that down-regulate the Th1 cytokine response and induce the Th2 cytokines such as interleukin-4, thereby enhancing susceptibility of the host to disease progression.
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Figure 85-1. Life cycle of L donovani, the agent of visceral leishmaniasis. A. Passage of promastigotes by an infected sandfly from a reservoir, such as a dog, to humans in the peridomestic setting. Illustration by Andres Patricio Reyes. B. Morphogenesis of infection. Republished by permission from Despommier DD, Karapelou JW: Parasite Life Cycles. Springer-Verlag, 1987. |
Clinical Findings
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Figure 85-2. Cutaneous leishmaniasis on the shoulder of a patient with multiple sandfly bites. Courtesy of Fernando Martinez, Centro Internacional de Investigaciones Medicas, Cali, Colombia. |
The combination of visceral leishmaniasis and HIV infection is an increasingly important problem, especially in southern Europe. In general, the clinical presentation of visceral leishmaniasis in HIV-infected patients is similar to that in uninfected persons, but the gastrointestinal tract may be more frequently involved, and sometimes the hepatosplenomegaly is less pronounced or absent.
Diagnosis
The first step in diagnosis should be to establish an exposure history. It is important to distinguish the more innocuous cutaneous forms of leishmaniasis from the mucocutaneous forms, which are not usually self-limited. Therapy for leishmaniasis is not benign, and, therefore, diagnostic certainty is crucial. The differential diagnosis for each form of leishmaniasis is listed in Table 85-1.
The most common diagnostic approach is demonstration of the presence of parasites by microscopy in Giemsa-stained tissues or by culturing the organisms in specialized media. Aspiration and punch biopsy of the leading edge of a cutaneous or mucocutaneous lesion are the best techniques to obtain specimens for both culture and histology. The tissues of choice for diagnosis of visceral disease are liver, spleen, and bone marrow. Sternal bone biopsy is often the most easily accessible and safest procedure to obtain tissue for culture and smear. Giemsa-stained smears from either the culture (promastigotes) or the tissue biopsy specimens (amastigotes) show the distinctive rod-shaped kinetoplasts of Leishmania spp. in the cytoplasm of the parasite. The cytoplasm stains blue with Wright-Giemsa with a large eccentric red nucleus. Small red kinetoplasts are features of Leishmania spp. that distinguish them from other intracellular pathogens with somewhat similar appearance, such as Toxoplasma and Histoplasma spp.
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Table 85-1. Differential Diagnosis of leishmaniasis. |
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Many diagnostic techniques, including DNA hybridization, PCR, and monoclonal antibody tests, have been developed. These tests are not widely available or standardized. Xenodiagnostic techniques are also used. Consultation with physicians experienced in the diagnosis of leishmaniasis is available through the CDC by calling (770) 488-7760.
Treatment
The drugs of choice for leishmaniasis include the organic antimonial compound stibogluconate sodium and meglumine antimoniate (Box 85-1). Anti-Leishmania drugs can be obtained from the CDC by calling (404) 639-3670.
Several alternative regimens and therapies are used, because of increasing resistance and treatment failures including higher dosing and, in some instances, combination therapy to decrease the duration of treatment. The newer drugs include liposomal amphotericin B, pentamidine, as well as paromomicin, and cytokines (eg, interferon gamma), which are used in combination with the antimonials.
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BOX 85-1 Treatment of Leishmaniasis |
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Prevention & Control
Because leishmaniasis is so widely endemic, control of both its reservoirs and its vectors remains a challenge (Box 85-2). Therefore, primary prevention efforts should focus on limiting vector contact, by using insect repellents and fine-mesh nets. No vaccine for humans is available. A strategy for preventing transmission of visceral leishmaniasis to humans in Latin America has been suggested, based on vaccination of dogs.
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BOX 85-2 Control of Leishmaniasis |
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TRYPANOSOMA
Three human pathogens are members of the genus Trypanosoma. These are T cruzi, the agent of American trypanosomiasis (also known as Chagas' disease), and T brucei subspecies rhodesiense and gambiense, both of which cause African sleeping sickness. Both of these diseases involve persistent circulation of parasites in the blood during some part of the disease course; these organisms are therefore referred to as hemoflagellates.
Trypanosomes have morphologically and physiologically different developmental stages in their insect and mammalian hosts. Like Leishmania spp., each stage contains a kinetoplast with highly conserved and repeating DNA sequences. Aside from morphology, the agents of African and American trypanosomiasis have little in common. The endemic zones of disease do not overlap, the organisms use different vectors, and their patterns of transmission are distinct. Furthermore, the clinical courses and response to therapy of these diseases are different.
AMERICAN TRYPANOSOMIASIS (CHAGAS' DISEASE)
Essentials of Diagnosis
General Considerations
Clinical Findings
In the acute phase of American trypanosomiasis, an indurated erythematous lesion occurs a few days after inoculation of T cruzi into the skin. This is called a chagoma. Periorbital swelling results when trypanosomes are inoculated into the conjunctival mucous membranes, and it is a classic sign of acute infection known as Roma's sign. The patient experiences fever, hepatosplenomegaly, lymphadenopathy, transient skin rash, tender subcutaneous nodules (known as hematogenous chagomas), and nonpitting edema on the face or extremities. The acute phase is more commonly observed in children and is usually self-limited, lasting several weeks to months. Dissemination of organisms is common, regardless of whether chronic disease ultimately develops.
Chronic American trypanosomiasis is usually insidious. There may not be a history of documented acute disease. About 10–30% of infected patients develop chronic disease. These patients progress to have cardiac or gastrointestinal damage that results in clinical disease. Chronic infection may evolve over decades and most often involves the heart. Cardiac disease is manifested by biventricular hypertrophy and electrical disturbances, including premature ventricular contractions, partial or complete atrioventricular block, and right bundle branch block. Death can result from arrhythmia or congestive heart failure. Sudden death occurs in 40% of congestive heart failure patients with Chagas' disease. The second most commonly affected organ system is the gastrointestinal tract. The autonomic ganglia are destroyed, resulting in functional denervation, impaired motility, and thus dilation, leading to megaesophagus and megacolon.
Congenital Chagas' disease is characterized by hepatosplenomegaly, sepsis, myocarditis, and hepatitis; however, two-thirds of cases of congenital Chagas' disease are asymptomatic. Thus, routine testing for disease in the infants of infected mothers is warranted.
Acute infection and reactivation of infection in immunosuppressed transplant recipients and in HIV-infected patients can result in more severe clinical signs, sometimes involving the CNS. In HIV patients, reactivation has led to cerebral abscesses.
Diagnosis
The diagnosis of acute Chagas' disease is made by detecting parasites in the blood, by using a wet preparation of anticoagulated blood or buffy coat or by using a Giemsa-stained smear of the blood.
Both enzyme immunoassay and ELISA tests are available commercially and are approved by the US Food and Drug Administration for the diagnosis of Chagas' disease. False-positive results using these tests are an ongoing challenge, because there is cross-reactivity among patients with syphilis, malaria, leishmaniasis, and other parasitic diseases. PCR tests are also actively being studied and evaluated, although they are not yet available for routine clinical use. Serum samples can be sent to the CDC for indirect immunofluorescence and complement fixation testing (phone: [770] 488-4414).
Treatment
Acute American trypanosomiasis should be treated with nifurtimox (Box 85-3). In the United States, this drug is available through the CDC (phone: [404] 639-3670). A parasitologic cure using nifurtimox has been noted in 70–95% of parasitemic patients, but clinical cures are less well defined. Side effects with this drug occur in ~ 40–70% of adult patients and primarily include CNS problems such as disorientation, insomnia, paresthesias, seizures, and polyneuritis, as well as gastrointestinal symptoms including nausea, vomiting, and abdominal pain. Additionally, skin rash has been commonly noted.
Treatment of chronic infections and patients with end-organ damage includes supportive care. For example, pacemakers for cardiac conduction defects are sometimes indicated in this setting. Antiparasitic treatment is not indicated in chronic disease.
Prevention & Control
Disease control is directly related to the control of vectors (Box 85-4). Because of the potential chronic and insidious nature of this disease, some authorities recommend serologic screening of all persons at high risk who come from endemic areas. Such screening may have two benefits: (1) cardiac disturbances can often be treated with pacemakers, and (2) congenital disease can be prevented or treated.
The safety of the blood supply is a concern in endemic areas and in other regions with immigrants from endemic areas, such as southern California. Two approaches include screening and rejection of donors based on risk factors such as prolonged residence in an endemic area and based on serology. Some endemic countries such as Brazil now use routine serologic screening and reject blood based on positive results.
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BOX 85-3 Treatment of American Trypanosomiasis |
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BOX 85-4 Control of American Trypanosomiasis (Chagas' Disease) |
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Travelers to endemic areas are advised to avoid sleeping in structures that may harbor the insect vector and to use appropriate barriers to avoid contact with the insects.
AFRICAN TRYPANOSOMIASIS
In Africa, a wide variety of trypanosomes infect wild animals but only two cause significant disease in humans: T brucei gambiense and T brucei rhodesiense.
Essentials of Diagnosis
General Considerations
Transmission of T brucei gambiense was originally thought to be exclusively person to person, via insect vectors, but several animal hosts have been shown to harbor identical strains of the parasite, including pigs, cattle, dogs, sheep, and wild ungulates such as kob and hartebeest. The importance of these animal reservoirs remains uncertain. West African trypanosomiasis affects primarily rural populations, and the duration of the illness is months to years, which increases ongoing transmission. East African trypanosomiasis, in contrast, has a shorter clinical course, lasting < 9 months, and it primarily affects rural populations in proximity to the animal source and tourists visiting game parks. The animal reservoirs for T brucei rhodesiense include several domesticated animals, most importantly cattle, but a large number of wild animals including bushbuck, waterbuck, hartebeest, and lions. Many different domesticated animals become infected, but they succumb to the disease rapidly and are therefore unlikely to be important reservoirs for ongoing transmission. The number of infections in humans fluctuates tremendously depending on migration, land development programs, human conflict, and proximity of animal reservoirs to human populations. In addition to vector-borne transmission, congenital and blood transfusion transmission have been documented.
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Figure 85-3. Distribution of human trypanosomiasis, according to Trypanosoma species (form of the disease). Republished from Mandell et al (editors): Principles and Practice of Infectious Diseases, 5th ed. Churchill Livingstone, 2000. |
Resistance to African trypanosome infections depends on the presence of host interferon gamma and a strong Th1 cytokine response, as is the case for host resistance to Leishmania infections. Humoral and cellular immune responses are directed against the VSGs, among other trypanosomal components.
Clinical Findings
There are three stages of African trypanosomiasis: (1) an initial phase characterized by a skin chancre at the site of inoculation, (2) a blood-borne and lymphatic dissemination phase, and (3) invasion of the choroid plexus and the subarachnoid space, causing meningoencephalitis—hence the term “sleeping sickness.” Chancres are reported in about one-third of infections and generally appear on the exposed surface of the skin where the flies have bitten. A chancre lasts ~ 3 weeks. Initially chancres are warm and tender but then scar or infrequently ulcerate. Lymphadenopathy develops in the area draining the ulcer.
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Figure 85-4. T brucei rhodesiense trypomastigotes in the blood of a patient with African sleeping sickness. Giemsa stain. |
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BOX 85-5 Treatment of African Trypanosomiasis |
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Once the ulcer subsides, the hemolymphatic stage appears, with characteristic periodic fevers coinciding with high parasitemia every day or two. Fatigue, arthralgia and headache, and often a fleeting truncal rash are observed with parasitemia. Patients are relatively asymptomatic between febrile periods. Myocarditis is common, and jaundice may occur from either hemolysis or hepatic damage.
In the meningoencephalitic stage, persistent headache, disturbed sleep patterns including nocturnal insomnia and diurnal somnolence, extrapyramidal and cerebellar signs, and behavioral changes are common features of disease. Wasting and nutritional deficiencies are common and may lead to secondary infection due to immunosuppression. The leukocyte count is normal or modestly elevated with a lymphocytosis. Polyclonal hypergammaglobulinemia, especially involving immunoglobulin M, is a striking and constant feature as might be expected from prolonged antigenic stimulation. Anemia and hypoalbuminemia are also observed.
Diagnosis
A Giemsa or Wright-stained smear of peripheral blood during the acute febrile period is the best means of obtaining a diagnosis (Figure 85-4). T brucei rhodesiense tends to have higher parasite loads and may be easier to detect than T brucei gambiense, which may require more frequent repeated blood smears or use of concentration techniques, eg, microhematocrit centrifugation with examination of the buffy coat. If a chancre is present, aspiration and staining may yield a diagnosis before parasitemia is present. Organisms may be demonstrated from aspirates of lymph nodes and bone marrow. The CSF should be examined even if parasitemia is confirmed. This should be done after clearance of the parasites from the blood so that parasites are not introduced into the CSF. In CNS trypanosomal infection, the CSF reveals a lymphocytic pleocytosis, elevated protein, and sometimes motile trypanosomes. Often morular or so-called Mott cells are seen, which are plasma cells with large eosinophilic inclusions containing immunoglobulin G. Several immunodiagnostic tests are available including indirect immunofluorescence, ELISA, and a card agglutination test that uses a commonly occurring variant antigen.
Treatment
The two forms of African sleeping sickness can be treated in a similar fashion. Eflornithine (difluoromethyl-ornithine) inhibits ornithine decarboxylase, an essential parasite enzyme, and is an effective drug in both the early and later CNS stages of disease (Box 85-5). The side effects include vomiting, abdominal pain, and diarrhea. Seizures occur in < 5% of cases. Unfortunately, there is a current shortfall in drug supply, with no signs of immediate improvement. Suramin has also been shown to be effective. It is available in the United States only through the CDC. The urine should be checked prior to each dose for protein, and the dose or interval between doses should be altered if the specimen is positive. Pentamidine has been used as an alternative agent, but it is not US Food and Drug Adminstration-approved for this indication. Drug information is available through the CDC (daytime phone: [404] 639-3670; nighttime, phone [404] 639-2888).
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BOX 85-6 Control of African Trypanosomiasis |
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African sleeping sickness tends to relapse, even after appropriate therapy; in this event, treatment should be repeated. Because parasitic confirmation of relapse may not be possible, increasing CSF protein or pleocytosis may be used as a marker of relapse. Infection does not confer immunity, and reinfection presents as new infection, often with chancres. Despite treatment, this disease is fatal in ~ 7% of patients.
Prevention & Control
One of the most effective public health measures for control of T brucei gambiense-associated disease may be recognition and treatment of humans, because they serve as the reservoir for this organism (Box 85-6). Control efforts that focus on clearance of tsetse fly habitat and destruction of wild game, as well as human population relocation, have not been terribly effective.
Individuals should avoid known foci of disease, wear protective clothing, and use insect repellents and mosquito nets to reduce the risk of infection. Chemoprophylaxis is not generally recommended for travelers to endemic areas. No vaccine is currently available.
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