Disease Watch Focus: Human African trypanosomiasis
BACKGROUND
CAUSATIVE AGENTS. Human African trypanosomiasis (HAT), also known as sleeping sickness, is caused by single-celled parasites, Trypanosoma brucei, which are transmitted to humans by infected tsetse flies. Two sub-species of T. brucei cause different forms of the disease. T. b. gambiense causes chronic infection, whereas T. b. rhodesiense generally causes a more acute infection. The parasites first develop in the blood, lymph and peripheral organs (stage 1), then spread to the central nervous system (stage 2), where they cause serious neurological disorders. Without treatment, the disease is fatal.
DISTRIBUTION. HAT is known to occur in rural areas of 36 countries in sub-saharan Africa, where tsetse flies are endemic. T. b. gambiense is found in central, west and some parts of eastern Africa, whereas T. b. rhodesiense is found in southern and eastern Africa.
CURRENT GLOBAL STATUS. The disease has re-emerged in epidemic proportions in several foci over the past 30 years. As the disease occurs in very remote areas, often where there is civil conflict, it is difficult to estimate the number of cases. In some villages, the prevalence has been reported to be as high as 20–50% and, in these places, HAT has emerged as a greater cause of morbidity and mortality than HIV/AIDS [1]. Since the 1970s, serious epidemics of the gambiense form of the disease have occurred in Angola, the Democratic Republic of Congo, southern Sudan, and Uganda. Failure rates of 26.9% have been reported after treatment of gambiense infections with melarsoprol in some foci in Uganda, Angola and Sudan [2].
RECENT DEVELOPMENTS
NEW BASIC KNOWLEDGE. The genome sequence of T. brucei is near completion, but the pathogenetic mechanisms involved in HAT are not fully understood. The methods by which trypanosomes cross the blood–brain barrier (BBB) remain speculative, but it is hypothesized that the loss of cells that participate in the BBB (for example, microglial and endothelial cells) might be important in the brain lesions of stage 2 HAT [3]; synaptic changes in neurons of the suprachiasmatic nuclei could also be important in the neuropathogenesis [4]. Several reports describe programmed cell death (PCD) in the non-dividing trypanosomes that develop in the blood and are infective to the tsetse. The role of PCD in trypanosomes is unclear [5], but characterization of the pathway could provide information about pathogenesis. Recent research indicates that, like T. b. rhodesiense, T. b. gambiense might be zoonotic. In addition, further understanding of the symbiotic organisms Wigglesworthia and Sodalis sp. that are found in the tsetse midgut and which influence tsetse physiology and reproductive biology, also promises new control strategies [6].
NEW TOOLS AND INTERVENTION METHODS. A serological card agglutination test for trypanosomiasis (CATT) is used for mass screening for gambiense HAT, but there is no satisfactory screening tool for T. b. rhodesiense. A LATEX test (latex particles coated with three variable surface glycoproteins of T. b. gambiense) was found to have higher specificity than the CATT [7]. Saliva testing has also been found to be possible using an indirect enzyme-linked immunosorbent assay to detect trypanosome-specific antibodies, thereby providing an alternative to blood testing [8].
After diagnosis, it is necessary to determine the stage of the disease. Current methods all involve lumbar puncture, which is not ideal. In an evaluation of the PCR (which detects trypanosome DNA) and LATEX agglutination (which detects immunoglobulin M, indicating neuroinflammation) tests, the PCR test seemed the more sensitive, but the LATEX/IgM test seemed more appropriate for therapeutic decision [9]. Research to optimize the use of existing anti-trypanosomal drugs and/or minimize their toxicity is ongoing. Recently, a ten-day course of treatment for gambiense HAT with melarsoprol proved as effective as a standard 26-day treatment schedule [10, 11]. The growing number of cases that are refractory to melarsoprol treatment has driven clinicians to consider combination therapy, and initial data indicate this to be more efficacious [12, 13]. At present, the only drug in development is DB-289 (an oral diamidine pro-drug), for the treatment of stage 1 infection [14, 15]. New diamidines are being investigated as pro-drugs to pass the BBB and cure stage 2 disease [16]. Other research is focused on drug targets that are related to the biochemical peculiarities of the trypanosome — for example, its glucose metabolism pathway [17]. Antimicrobial peptides, which are being developed as antibiotics against bacterial and fungal infections, have also been examined for use in HAT [18]. Recent evidence for the presence of plant-like enzymes has opened new perspectives for the identification of new drug targets [19]. One novel control strategy under development involves reducing the ability of the tsetse to transmit trypanosomes by expressing anti-trypanosomal molecules in Sodalis, the commensal symbiont in the tsetse midgut which is in close proximity to trypanosomes [20].
NEW STRATEGIES, POLICIES AND PARTNERSHIPS. The governments of disease-endemic countries are committed to control of the disease, and several initiatives to coordinate efforts have begun. These include the Pan-African Tsetse and Trypanosomiasis Eradication Campaign, and the Programme Against African Trypanosomiasis. The field activities of non-governmental organizations, such as Mйdecins Sans Frontiиres, are also invaluable in the control of HAT, and an agreement between Aventis Pharma, Bayer and the WHO guarantees stocks of all trypanocides up to 2006. transmission.
CONCLUSIONS AND FUTURE OUTLOOK
HAT remains a challenge for health services, medical personnel and researchers. The pan-African initiatives to coordinate control efforts provide some hope for the future, but epidemics could be amplified by war and civil conflict, so stability, growth and development in Africa will be important factors in disease control.
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