Etiology

HAT is a vector-borne disease caused by parasitic, flagellated kinetoplastid protozoans of 2 subspecies of Trypanosoma brucei. It is transmitted to humans through the bite of Glossina, commonly known as the tsetse fly.

The tsetse fly feeds on the blood of humans and wild game animals and penetrates intact mucous membranes and skin. Humans usually contract East African HAT when they venture from towns to rural areas to visit woodlands or livestock, highlighting the importance of zoonotic reservoirs in this disease. West African HAT is contracted closer to settlements. This form only requires a small vector population and thus has been particularly difficult to eradicate. Because of low rates of infection in tsetse flies, the life cycle of this form necessitates close and repeated contact between humans and insects to permit frequent biting. While animal reservoirs occur, these reservoirs are less important than for East African HAT, and the main source of infection remains chronically infected human hosts.

Life Cycle

Trypanosoma brucei undergoes several stages of development in the insect and mammalian host. Upon ingestion with a blood meal, nonproliferative stumpy forms of the parasite, which are optimally adapted to surviving in Glossina, transform into procyclic forms in the insect’s midgut. These procyclic forms proliferate and undergo further development into epimastigotes, which then become infective metacyclic forms that migrate to the insect’s salivary glands. The life cycle within the tsetse fly takes 15-35 days. On inoculation into the mammalian host, the metacyclic stage transforms into proliferative long and slender forms in the bloodstream and the lymphatics, eventually penetrating the central nervous system. These slender forms appear in waves in the peripheral blood, with each wave followed by a febrile crisis and heralding the formation of a new antigenic variant. The slender forms transform into intermediate forms, which become nonproliferative stumpy forms that are ingested by Glossina and start the cycle anew.

Direct transmission to humans has been reported, either mechanically through contact with the contaminated mouth parts of tsetse flies with viable slender forms during feeding or vertically to infants by way of the placenta of infected mothers.

Epidemiology

HAT is a major public health problem in sub-Saharan Africa. It occurs in the region between latitudes 15 degrees north and 15 degrees south, corresponding roughly to the area where the annual rainfall creates optimal climatic conditions for Glossina flies to thrive.

Thirty-two thousand cases of HAT are reported annually, although an incidence of up to 70,000 cases/yr is estimated to occur; 24,000 deaths per year are attributed to HAT. By far, the bulk of reported cases are made up of T. brucei gambiense, with approximately two thirds of the cases coming from the Democratic Republic of the Congo. The incidence of HAT has been dropping in recent years, reflecting more aggressive and cohesive control programs, but these programs need to be sustained before the possibility of elimination can be considered realistic. Over 1.5 million disability-adjusted life years were lost to HAT in 2002, although this number does not take into account morbidity from acute and chronic infection, toxic side effects of treatment, or economic burden from losses of trypanosome-infected livestock.

T. brucei rhodesiense infection is restricted to the eastern third of the endemic area in tropical Africa, stretching from Ethiopia to the northern boundaries of South Africa. T. brucei gambiense occurs mainly in the western half of the continent’s endemic region. Glossina captured in endemic foci show a low rate of infection, usually <5%. Rhodesian HAT, which has an acute and often fatal course, greatly reduces chances of transmission to tsetse flies. The ability of T. brucei rhodesiense to multiply rapidly in the bloodstream and infect other species of mammals helps maintain its life cycle. The insect vector is able to transmit disease for up to 6 mo.

Pathogenesis

The initial entry site of the organisms develops a hard, painful, red nodule known as a trypanosomal chancre. It contains long, thin trypanosomes multiplying beneath the dermis and is surrounded by a lymphocytic cellular infiltrate. Dissemination into the blood and lymphatic systems follows, with subsequent localization to the CNS. Histopathologic findings in the brain are consistent with meningoencephalitis, with lymphocytic infiltration and perivascular cuffing of the membranes. The appearance of morular cells (large, strawberry-like cells, supposedly derived from plasma cells) is a characteristic finding in chronic disease.

Antigenic variation of variant surface glycoproteins (VSG) on the trypanosome’s surface enables evasion of acquired immunity during infection. Both T. brucei gambiense and T. brucei rhodesiense have acquired resistance to trypanolytic factors in human serum, the most well-studied of which is apolipoprotein L-1 (APOL1), through the expression of a protein known as serum resistance-associated protein (SRA). A frameshift mutation in the APOL1 gene in 1 patient enabled infection with a nonhuman trypanosome, Trypanosoma evansi, and treatment with recombinant APOL1 restored trypanolytic activity. Mechanisms underlying virulence in HAT are still incompletely understood, although severity of disease seems to be dependent on the host inflammatory response, particularly IFN-γ production in the central nervous system (CNS) and blood.

Clinical Manifestations

Clinical presentations vary not only because of the 2 subspecies of organisms but also because of differences in host response in the indigenous population of endemic areas and in newcomers or visitors. Visitors usually suffer more from the acute symptoms, but in untreated cases death is inevitable for natives and visitors alike. Symptoms usually occur within 1-4 wk of infection. The clinical syndromes of HAT are trypanosomal chancre, hemolymphatic stage, and meningoencephalitic stage.

Diagnosis

Definitive diagnosis can be established during the early stages by examination of a fresh, thick blood smear, which permits visualization of the motile active forms (Fig. 278-1). HAT can also be detected from blood using a variety of sensitive techniques: quantitative buffy coat smears and mini anion exchange resins are common examples. The card agglutination trypanosomiasis test (CATT) is of value for epidemiologic purposes and in screening for T. brucei gambiense. Dried, Giemsa-stained smears should be examined for the detailed morphologic features of the organisms. If a thick blood or buffy coat smear is negative, concentration techniques may help.

Figure 278-1 Trypanosoma brucei sp. trypomastigotes in thick blood smear stained with Giemsa (left) and thin blood smear stained with Wright-Giemsa (right).

(From the Centers for Disease Control and Prevention: Laboratory identification of parasites of public health concern. Trypanosomiasis, African [website]. www.dpd.cdc.gov/dpdx/HTML/ImageLibrary/TrypanosomiasisAfrican_il.htm. Accessed August 30, 2010.)

Aspiration of an enlarged lymph node can also be used to obtain material for parasitologic examination. If positive, cerebrospinal fluid should also be examined for the organisms. Technology based on polymerase chain reaction (PCR) for detection of trypanosomes to the species level has been validated in animal infection but is currently unsuitable for field work and is not yet cost effective for extensive use in human populations. Several PCR methods have been developed, including those that use internal transcribed spacer (ITS) regions of ribosomal RNA and can detect mixed infections.

Treatment

The choice of chemotherapeutic agents for treatment is dependent upon the stage of the infection and the causative organisms.

Prevention

A vaccine or consistently effective prophylactic therapy is not available. A single injection of pentamidine (3-4 mg/kg IM) provides protection against Gambian trypanosomiasis for at least 6 months, but the effect against the Rhodesian form is uncertain.

Vaccine development is particularly challenging because of the antigenic variation due to VSGs. Recent work in African lions has shown some trypanosomal cross-species acquired immunity in spite of the VSGs and may suggest novel pathways for vaccine development.

Control of trypanosomiasis in endemic areas of Africa is an ongoing challenge, and even though early successes in reducing disease burden are encouraging, the increasing cost of treatment per case as the overall number of patients decline may lead to premature termination of intensive control efforts. Moreover, underreporting of cases remains a challenge. Vector control programs to control Glossina have been essential in controlling disease, coupled with the use of screens, traps, and sanitary measures. Encouraging neutral-colored clothing that is not attractive to the tsetse fly may reduce bites. Using serology and parasitologic methods, mobile medical surveillance of the population at risk by specialized staff is critical. The creation of referral centers for evaluation and treatment is still needed, especially because of the toxic nature of treatment. Ground spraying of insecticides, aerial spraying, and the use of cloth and live animal baits have proven successful. Transgenic techniques to restrict the ability of the tsetse fly to survive and transmit pathogens are also being developed.

The full genome sequencing of the T. brucei and Trypanosoma cruzi parasites has revealed a conserved core proteome of about 6,200 genes in large gene clusters. This advance has helped identify genes relevant to the disease and its possible prevention, as well as the design of new antitrypanosomal drugs including those that target specific metabolic pathways.

Wigglesworthia glossinidia is an obligate endosymbiont found in the Glossina vector and has been shown to be intimately involved in female fly fecundity and overall survival of the fly. This endosymbiont represents a new target for vector control and a possible vehicle to introduce foreign gene products that may affect the development of the parasite.