African Trypanosomiasis (Sleeping Sickness; Trypanosoma brucei Complex)

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Chapter 278 African Trypanosomiasis (Sleeping Sickness; Trypanosoma brucei Complex)

Edsel Maurice T. Salvana, Robert A. Salata

Over 60 million people in nearly 40 countries are at risk for infection with Trypanosoma brucei complex, the causative agent of sleeping sickness. Also known as human African trypanosomiasis (HAT), this disease is restricted to sub-Saharan Africa, the range of the tsetse fly vector, where at least 300,000 people are infected. It is a disease of extreme poverty, with an increasing burden observed in remote rural areas. HAT comes in 2 geographically and clinically distinct forms. Trypanosoma brucei gambiense causes a chronic infection lasting years and mostly affects people who live in Western and Central Africa (West African sleeping sickness, Gambian trypanosomiasis). Trypanosoma brucei rhodesiense, a zoonosis, presents as an acute illness lasting several weeks and usually occurs in residents of eastern and southern Africa (East African sleeping sickness, Rhodesian trypanosomiasis).

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

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