Current Diagnosis & Treatment in Infectious Diseases

Section VII - Parasitic Infections

85. Leishmania & Trypanosoma

  1. Scott Smith MD

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.


Essentials of Diagnosis

  • Epidemiologic factors: time spent in an endemic zone and exposure to sandfly vector.
  • Physical exam: nonhealing ulcer (cutaneous infection); nonhealing mucosal membrane lesion, nasal obstruction, epistaxis, nasal septum perforation (mucocutaneous infection); fever, hepatosplenomegaly, emaciation (visceral infection).
  • Laboratory examination of affected tissue:
  • Giemsa stain shows phagosomal cells contain amatigotes at leading edge of biopsied ulcer.
  • Histological analysis of bone, liver, or spleen tissue shows amastigotes.
  • Culture of biopsied tissue, ie, skin, spleen, liver, or bone, reveals promastigotes.
  • Serologic analysis using immunofluorescence assay (available through the Centers for Disease Control and Prevention [CDC]).
  • Xenodiagnostic analyses of macerated tissue samples injected into animals for specific identification via growth in vivo.
  • Polymerase chain reaction (PCR) (helpful but not widely available).

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.

  • Epidemiology.Leishmaniasis is endemic in ≥ 82 countries, with an at-risk population of 350 million people worldwide. The World Health Organization (WHO) estimates 12 million current cases, with an annual incidence of 600,000 new cases and 75,000 deaths. Reliable estimates are scarce owing to lack of surveillance or active reporting and the large number of asymptomatic or subclinical cases, as well as the challenge of diagnostic confirmation.

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.

  • Microbiology and Pathogenesis.Species of the genus Leishmania display a dimorphic life cycle; in the insect vector they assume a flagellated form (the promastigote), and, in human and mammalian hosts, the parasite takes on the amastigote form (devoid of flagellum) (Figure 85-1B). Amastigotes survive inside phagosomal cells, such as the histiocytes of the skin and other cells of reticuloendothelial origin. Amastigotes are 2–3 µm in length and can be round or oval. The species are morphologically indistinguishable from each other and from Trypanosoma cruzi, but Leishmania spp. can easily be differentiated from T cruzi in clinical specimens based on tissue tropism. The amastigotes transform into promastigotes once inside the sandfly gut. They then migrate forward to the proboscis to infect another host. Besides the insect vector, the life cycle usually includes a nonhuman animal reservoir. Humans are incidental hosts for Leishmania spp. Promastigotes are passed from the female sandfly to the skin of a vertebrate host during a blood meal. These promastigotes invade the reticuloendothelial cells of the vertebrate host, change into amastigote forms, multiply further, and invade other reticuloendothelial cells. Mammalian blood is essential to the sandfly's life cycle and promotes egg maturation within the female; only female sandflies seek blood meals. Once Leishmania amastigotes infect a sandfly, disease transmission to a new mammalian host is delayed for at least 7–10 days while the parasite undergoes differentiation.

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.


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

  • Cutaneous Leishmaniasis.Cutaneous leishmaniasis begins as papules and, less commonly, as nodules at the site of the vector bite; it then progresses to ulcer formation (Figure 85-2). It is most commonly caused by Leishmania major and Leishmania tropica in the Old World and by Leishmania mexicana, Leishmania braziliensis, and L panamensis in the New World, and the infection exhibits an incubation period of 2–8 weeks. Satellite lesions appear in some cases. Most forms of the disease (> 80%) heal spontaneously within 3 months, although, on occasion, the cutaneous form can be disfiguring. In a more recently described form of cutaneous disease associated with L braziliensis, lymphadenopathy was found in three-fourths of patients and preceded the development of skin lesions; the latter healed spontaneously in only 20% of patients by 3 months after initial infection.
  • Mucocutaneous Leishmaniasis.Mucocutaneous leishmaniasis involves the mucosal membranes of the nose and mouth but may also involve the oropharynx and the larynx. L braziliensis is the cause of most mucocutaneous disease. An estimated 3% of patients with infection by this species develop mucosal disease. The disease begins as a primary cutaneous ulcer at the site of inoculation. During early stages it cannot be distinguished clinically from the more benign cutaneous forms of disease. The time delay from cutaneous disease to development of mucosal involvement can vary from 1 month to 24 years. Mucosal disease may present as nasal obstruction or epistaxis. A slight reddening and swelling in the septum can be seen, which may progress to perforation. Although the disease is termed mucocutaneous, tracheal and genital mucosal involvement is rare.

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.

  • Visceral Leishmaniasis.Visceral leishmaniasis or kala-azar is primarily caused by Leishmania donovani in the Indian subcontinent and Africa, Leishmania infantum in the Mediterranean region, and Leishmania chagasi in Latin America. The incubation period is generally 2–6 months. The disease begins with fever, hepatosplenomegaly, and pancytopenia. The onset of fever can be sudden or gradual, and there may be intervals when the patient has low-grade or no fever. Clinically evident disease is usually characterized by progressive weakness, emaciation, and, if untreated, death. Case fatality rates, even with treatment, are ≤ 11%. The ratio of inapparent infection to overt clinical disease varies depending on the age group and the endemic area but ranges from 6.5:1 to 18:1. This feature enables ongoing inapparent transmission of infection. A young age (infants and children) and malnutrition predispose to development of the disease. Viscerotropic (L tropica) disease in US troops who returned from the Persian Gulf was reported among a small number of individuals and resulted in a temporary ban on blood donations from this group.

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.


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.

Table 85-1. Differential Diagnosis of leishmaniasis.






·  Tularemia

·  Furuncle/carbuncle

·  Cellulitis

·  Yaws

·  Syphilis

·  Atypical tuberculosis

·  Tuberculosis

·  Leprosy

·  Tertiary yaws

·  Syphilis

·  Brucellosis

·  Typhoid fever

·  Tuberculosis


·  Histoplasmosis

·  Sporotrichosis

·  Lobomycosis

·  Coccidioidomycosis

·  Blastomycosis

·  Chromomycosis

·  Histoplasmosis

·  Paracoccidiodomycosis

·  Rhinosporidiosis

·  Histoplasmosis


·  Orf


·  Infectious mononucleosis


·  Drucunculiasis

·  Acute Chagas' disease

·  Schistosomiasis

·  Amebic liver abscess

·  Malaria

Other (non-infectious)

·  Basal or squamous cell carcinoma

·  Lymphoma or metastatic cancer

·  Discoid lupus

·  Sarcoidosis

·  Insect bite

·  Ecthyma

·  Kerion

·  Pyogenic granuloma

·  Foreign-body granuloma

·  Basal cell carcinoma

·  Wegener's granulomatosis

·  Mid-line granuloma

·  Sarcoidosis

·  Lymphoma

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.


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.

  • Cutaneous Leishmaniasis.Cutaneous leishmaniasis is usually self-limited, but, if it persists > 6 months or is disfiguring or disabling, then treatment is indicated. The challenge for local therapy is that the disease characteristically involves the dermis and may disseminate to the lymph nodes or mucous membranes. Antimonials are injected with or without steroids initially, on a twice-daily schedule. Infiltration of the lesions in a standardized way is difficult to achieve. Localized controlled heat has also been shown, in a placebo-controlled clinical trial, to be effective for treatment of cutaneous disease.
  • Mucocutaneous Leishmaniasis.Mucocutaneous forms of leishmaniasis are treated with stibogluconate. The electrocardiogram (ECG) should be monitored. For resistant cases, stibogluconate plus interferon gamma can be used, or amphotericin B or pentamidine is effective.
  • Visceral Leishmaniasis.Visceral leishmaniasis (kala-azar) has successfully been treated with stibogluconate. In immunocompromised patients, such as those with HIV infection, it is necessary to devise a suppressive regimen to minimize recurrence after adequate treatment has been completed. Relapses of clinical disease typically occur after appropriate therapy with either antimony or amphotericin B (which has a higher initial cure rate in this population); therefore, a suppressive regimen has been suggested. Either pentamidine or paromomycin can be used alone as an acceptable choice for suppression, or either one can be combined with one of the following: interferon, ketoconazole, or fluconazole.

BOX 85-1 Treatment of Leishmaniasis


First Choice

Comments and Alternatives


·  Meglumine antimonate (glucantime), 20 mg/kg/d IM or IV for 10 d

·  Stiboguconate, 20mg/kg/d IV or IM, preferably in two divided doses for 10 d

·  Pentamadine, 2–4 mg/kg IM every other day × 7–15 injections

·  Local treatment with intralesional injection of stibogluconate, every other day × 8–24 injections for nondisseminated infections with L major and L mexicana mexicana


·  Stibogluconate, 20 mg/kg/d IVor IM, preferably in two divided doses, × 30 d



·  Stibogluconate, 20 mg/kg/d IV or IM, preferably in two divided doses, × 30 d

·  If resistance: pentamidine, 4 mg/kg 3 times week for 5 weeks

·  Amphotericin B, 1 mg/kg IV every other day × 20 d

·  May reduce the course from 28 to 15 d by adding aminosidine (paromomycin), 15 mg/kg/d IM

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.

BOX 85-2 Control of Leishmaniasis

Prophylactic Measures

·  Avoid exposure to sandfly vectors

·  Chemoprophylaxis not recommended

·  Immunoprophylaxis not available

Isolation Precautions

·  None


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.


Essentials of Diagnosis

  • Epidemiologic factors: time spent in an endemic zone; poor housing conditions, eg, mud or thatched housing; exposure to reduviid insect vector
  • History and physical exam: Roma-a's sign (swollen periorbital mucosal tissues after ocular inoculation); chagoma (skin nodule at the site of acute inoculation); in the chronic phase, congestive heart failure, dysphagia or regurgitation, and constipation
  • Laboratory exam:
  • Acute Chagas': trypomastigotes revealed by Giemsa smear of blood or buffy coat; culture of affected tissues, ie, the inoculation site; serologic enzyme immunoassay and enzyme-linked immunosorbent assay (ELISA); xenodiagnosis if available
  • Chronic Chagas': radiological studies show congestive heart failure, megacolon, or megaesophagus; ECG shows right bundle branch block, arrhythmias

General Considerations

  • Epidemiology.T cruzi is found only in the Western Hemisphere, where it ranges from the southern United States to Argentina. An estimated 16 million–18 million people in Latin America have chronic T cruzi infections and ~ 50,000 die of Chagas' disease each year. In the United States, there has been concern about transmission of the organism via blood transfusion from unsuspected infected donors who are immigrants from endemic zones. Similar concerns arise for organ transplant recipients.
  • Microbiology.The life cycle of T cruzi involves an insect vector, the reduviid bug, and a mammalian reservoir. The insect vector, of which there are multiple species, is commonly known as an assassin bug because it preys on other insects; it is also called the kissing bug because it tends to bite the face. After taking a blood meal from an infected reservoir, T cruzi organisms multiply in the insect mid gut as epimastigotes and then develop into the infective form, the trypomastigote, in the insect hindgut. There are several nonhuman mammalian reservoirs that enable T cruzi to persist in nature, including peridomestic animals such as cats, dogs, and rats, as well as sylvatic animals such as opossums, raccoons, and armadillos.
  • Pathogenesis.When an infected reduviid bug takes a blood meal from a human, it defecates, leaving feces on the surface of the skin that is contaminated with the infective metacyclic stage of the trypanosomes. Trypanosomes proliferate at the site of inoculation and then pruritus at the bite wound causes T cruzi organisms to be rubbed into the wound or surrounding mucous membranes, introducing the organism to the bloodstream. In the bloodstream, they preferentially infect myocytes and neurons of the peripheral and central nervous system (CNS). After the amastigotes proliferate in the cytoplasm, they differentiate into trypanomastigotes. The cell subsequently ruptures, and the newly released trypanomastigotes invade local tissues and spread hematogenously. A mononuclear inflammatory response occurs. This intense inflammation leads to destruction of autonomic ganglia in the heart and gastrointestinal tract, and diffuse fibrosis and scarring occur in these organs.

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.


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).


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.

BOX 85-3 Treatment of American Trypanosomiasis




First Choice

·  Nifurtimox, 8–10 mg/kg/d PO in 4 divided doses for 120 d

·  Nifurtimox, 15 mg/kg/d PO in 4 divided doses for 120 d


·  Benznidazole, 5 mg/kg/d PO for 60 d

·  Benznidazole, 5 mg/kg/d PO for 60 d

BOX 85-4 Control of American Trypanosomiasis (Chagas' Disease)

Prophylactic Measures

·  Avoid exposure to reduviid insect vectors

·  Chemoprophylaxis not recommended

·  Immunoprophylaxis not available

Isolation Precautions

·  None

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.


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

  • Epidemiologic factors: living or traveling in an endemic zone; exposure to tsetse fly.
  • History and physical exam:
  • General: periodic fevers, wasting, nutritional deficiencies.
  • Skin: chancre at the site of inoculation, fleeting truncal rash, posterior cervical lymphadenopathy.
  • Neurologic: disturbed sleep patterns (diurnal somnolence, nocturnal insomnia), mental status changes, cerebellar signs.
  • Laboratory:
  • Blood smear with Giemsa stain shows hemoflagellates.
  • Aspiration and stain of chancre (may be positive for visible organisms before parasitemia occurs).
  • Serology: indirect immunofluorescence, ELISA.
  • Card agglutination test against common variant antigens.
  • Cerebrospinal fluid (CSF): lymphocytic pleocytosis, elevated protein, motile trypanosomes.


General Considerations

  • Epidemiology.An estimated 50 million people are at risk for acquiring African trypanosomiasis worldwide, and there are 20,000 reported new cases annually. This is likely an underestimate because reporting in endemic countries is incomplete. There are no natural life cycles of T brucei outside Africa; thus, the only cases seen outside Africa are imported. Both T brucei rhodesiense and T brucei gambiense are carried by the tsetse fly vector of the genus Glossina, but by different species inhabiting distinct habitats (Figure 85-3). Therefore, because of vector habitat, T brucei rhodesiense (the agent of eastern African sleeping sickness) is seen in savanna and drier zones, whereas T brucei gambiense (the agent of western African sleeping sickness) is found near rivers and in forested areas. T brucei gambiense has primarily a human reservoir, while T brucei rhodesiense is an anthropozoonosis involving ungulates, such as cattle and antelope.

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.

  • Microbiology.Blood-sucking tsetse flies of the genus Glossina become infective 18–35 days after taking a blood meal from an infected mammalian host. Trypomastigotes are ingested and multiply in the midgut of the fly. These migrate to the salivary glands and become epimastigotes, which then turn into short, stumpy infective metacyclic trypanosomes. The fly remains infective for life and transmits by subsequent bites. Both Glossina males and females feed on mammalian blood, causing infection if enough organisms are injected. In endemic areas, usually < 1% of flies are infected, whereas during epidemic periods as many as 5% of flies carry parasites.

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.

  • Pathogenesis.During the course of the infection with trypanosomes, the number of parasites in the blood and lymph tissues fluctuates according to the host's immune response. An increase in parasite number or parasitemia is related to the proliferation of parasite subpopulations that express an antigenically new or variant glycoprotein coat. A similar phenomenon is observed with Neisseria and Borrelia species. The declines in parasite number correspond with antibody-mediated destruction of trypanosomes. Each parasite carries genes encoding multiple, variant surface glycoproteins (VSG). Only one VSG is expressed at a single time, except during the switching from one VSG to another. This antigenic switching not only allows evasion of the host's immune system but also poses a major challenge to the development of a vaccine. Acquired immunity does develop, but it is specific for a limited number of VSGs.

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.


Figure 85-4. T brucei rhodesiense trypomastigotes in the blood of a patient with African sleeping sickness. Giemsa stain.

BOX 85-5 Treatment of African Trypanosomiasis




First Choice

·  Eflornithine, 400 mg/kg/d IM or IV in 4 divided doses for 14 d, then 300 mg/kg/d PO to complete 30 d

·  Suramin, 1 g IV on days 1, 3, 7, 14, 21; start with 200–mg test dose

·  Suramin, 20 mg/kg IV on days 1, 3, 7, 14, 21; start with test dose


·  Pentamadine, 4 mg/kg/d IM × 10 d

·  Pentamadine, 4 mg/kg/d IM × 10 d

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.


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.


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).

BOX 85-6 Control of African Trypanosomiasis

Prophylactic Measures

·  Avoid exposure to tsetse fly vectors

·  Chemoprophylaxis not recommended

·  Immunoprophylaxis not available

Isolation Precautions

·  None

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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