Human African trypanosomiasis: an update

20 Mar 2009

Paul Chinnock

Source: TropIKA.net

Comments

Sleeping sickness (human African trypanosomiasis, HAT) illustrates many of the problems facing researchers and policy makers concerning the infectious diseases of poverty. To begin with, there is no clear agreement as to how many people have HAT, nor a reliable assessment of the extent of the harm it causes. This issue was considered in a recent review article (1) in PLoS Neglected Tropical Diseases.

HAT, which is fatal if left untreated, is caused by infection with Trypanosoma brucei rhodesiense or Trypanosoma brucei gambiense. It is transmitted by insect vectors of the genus Glossina (tsetse flies), which are found only in Africa. T.b. gambiense occurs in West and Central Africa, and T.b. rhodesiense in East Africa, although there are concerns that an overlap may now have occurred in their ranges.

There are some important differences between the two forms of the disease. T.b. rhodesiense is a zoonosis, with several animal species (but particularly cattle) acting as reservoirs of the disease. (The animal form of the disease ‘nagana’ is itself a serious problem, causing many losses to the cattle industry in endemic areas.). T.b. gambiense is not a zoonosis – some animals are infected but they do not act as a reservoir; i.e. it is usually transmitted from one human to another via the tsetse fly. An ‘episode’ of T.b. gambiense lasts up to five years, compared with one year for T.b. rhodesiense.

The burden

HAT is overwhelmingly a disease of rural areas, which is one reason why data is so hard to obtain. Sixty million people in 36 sub-Saharan countries are considered to be at risk. The PLoS NTDs article (1) points out that relatively few cases are reported. In 2006 there were 11,382 reported cases of T.b. gambiense and only 496 of T.b. rhodesiense. Estimates of actual cases numbers have varied hugely from 70,000 to 300,000 per year. The gap between reported and actual cases is of great concern, as unreported cases are generally untreated cases and therefore result in death.

In measuring the burden resulting from a disease, it is now accepted practice to make use of the disability-adjusted life year (DALY). DALYs involve two major components: a metric for summing mortality in a population, years of life lost due to death with a condition (YLL); and a metric for summing morbidity in a population, years of life lived with a disability from a condition (YLD). For the latter it is necessary to decide upon the disability weighting associated with the condition.

The authors express their doubts as to whether the disability weighting which has been used for HAT in the Global Burden of Disease project is correct. At present the number of DALYs lost due to HAT is estimated to be around 1.3 million. This compares, for example, with 39m for malaria, 4.6m for lymphatic filariasis and 1.4m for ascariasis. However, the authors argue that the HAT estimates have not taken into account all the consequences for health at all stages of the disease and its treatment, and have not made full allowance for differences between the two forms of the disease. Sickness caused by treating HAT has not been taken in to account in burden calculations; the drugs to treat HAT are generally toxic, with a relatively high proportion of side effects.

All these factors make it hard to assess the level of disability and the economic burden due to HAT. In the view of the authors:

“The justification for many of the parameters pertaining to HAT and used in the Global Burden assessments (e.g., disability weighting, estimates of incidence) are not transparent and have not been published”.

Estimates of the burden of a disease are important. As the authors rightly say:

“Proper quantification matters greatly to the neglected diseases, because a primary reason for their neglect is that their true impact on society is not known”.

Drug treatment and CNS disease

A review article (2) dealing with HAT has been published in the Journal of Neuroimmunology. It provides a summary of the clinical effects of the infection and current approaches to drug treatment during its various stages. The authors note the poor efficacy, difficulty of administration and severe adverse reactions of the drugs now in use.

The article then moves on to discuss recent research findings and hypotheses as regards how the parasite harms the central nervous system (CNS). Considering that HAT has been known to medical science for over a century it is disappointing how little is known about this question. However, the authors describe recently developed animal and in vitro models of HAT that are helping to unveil the mechanisms by which the parasite breaches the blood brain barrier and goes on to damage the CNS.

There has also been progress towards the development of new markers that could be used to accurately diagnose the stage of the infection. “Furthermore,” the authors say, “...many studies, both human and animal are being carried out in an effort to improve chemotherapy either through the use of a combination of trypanocidal drugs or by the inclusion of adjunct therapies”.

An ‘anti-disease strategy’

In a comprehensive article review (3) by researchers in human and veterinary medicine, published in Infection and Immunity, the concept of an ‘anti-disease vaccines’ is discussed. In the development of most vaccines the goal is the complete elimination of the disease agent from the infected person or animal. However, in the case of some diseases, including HAT, it is considered that such a goal cannot be met. In contrast, the goal of an anti-disease vaccine is to neutralize the pathological effects of the parasite. Also part of an anti-disease strategy would be the provision of immunologically based support treatments.

The article aims to present “...recent advances regarding parasite factors involved in HAT, with special reference to prospects for curative or preventive interventions at the level of host-parasite interaction.” Candidate vaccines, including several new candidates, are described. At present the only HAT anti-disease vaccine to have reached the trial stage is being conducted in cattle. Early stage research with immunomodulatory and other forms of anti-disease treatment is also discussed. The authors conclude that:

“Promising progress in Trypanosoma spp. genomics, proteomics, and comparative pathology studies using the mouse model will certainly bring forth exciting new pathways and challenges for research in the near future.”

New findings

Some HAT patients relapse after apparently successful treatment. Clinical guidelines recommend that patients should be followed up and tested for the presence of parasites in lymph, blood or cerebrospinal fluid (CSF), which will identify treatment failure or relapse. However, not all HAT relapse cases show this feature early enough to allow for timely re-treatment, and many treated patients do not adhere to the demanding and invasive follow-up schedule. Various other methods, mostly based on the number of white-blood cell counted in CSF, are already used by doctors seeking to detect relapse or treatment failure at an early stage, but there has been no attempt to evaluate how effective these approaches may be. A study (4) published in Tropical Medicine and International Health looked at ten of these “operational criteria for outcome”, working with some 300 patients in the Democratic Republic of the Congo. The researchers found that a simple criterion – “Trypanosomes present and ⁄ or a cerebrospinal white blood cell count ≥50 ⁄ µl” – allowed accurate and timely detection of HAT relapse, irrespective of disease stage. However, they say that their findings should be validated in a prospective study before adoption in clinical practice.
A potential new route for the development of a more effective treatment emerges from a study (5) published in Cell Death and Differentiation. The authors have found a number of compounds (endogenous neuropeptides) with potent anti-trypanosome activity, and have established their mode of action. They conclude that: “Of physiological importance is the fact that hosts respond to trypanosome infection producing neuropeptides as part of their natural innate defense. From a therapeutic point of view, targeting of intracellular compartments by neuropeptides suppose a new promising strategy for the treatment of trypanosomiasis”.
One concern in the search for new drugs to treat HAT is that, while any new drug should be evaluated for possible toxic effects to the heart, HAT itself may involve some cardiological symptoms. As the authors of a research paper (6) in PLoS NTDs say, “...without knowledge of the baseline heart involvement in HAT, cardiologic findings and drug-induced alterations will be difficult to interpret.” Based on ECG studies of over 400 patients in the Sudan, the researchers concluded that heart involvement is frequent in HAT. In most cases the changes in heart rhythm are well tolerated by patients but there could be dangers if they were to be treated with a drug that had an impact on heart function. (The patients in this study were participants in a series of clinical trials evaluating the efficacy and safety of an experimental treatment, DB289.)
Knowledge of the population genetics of parasite is also important for control programmes. A study conducted in Guinea and Côte d’Ivoire (7) examined migration of T. b. gambiense group 1 strains. The researchers concluded that migration was very restricted and that this is “most likely a strictly clonally reproducing organism”.

References

1. Fèvre EM, Wissmann Bv, Welburn SC, Lutumba P (2008). The Burden of Human African Trypanosomiasis. PLoS Negl Trop Dis 2(12): e333. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19104653

2. Rodgers J. Human African trypanosomiasis, chemotherapy and CNS disease. (2009). J Neuroimmunol; 2009:Mar 6. [Epub ahead of print]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19269696

3. Antoine-Moussiaux N, Büscher P, Desmecht D (2009). Host-parasite interactions in trypanosomiasis: On the way to an anti-disease strategy. Infect Immun; 77(4):1276-1284. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19168735

4. Mumba Ngoyi D, Lejon V, N’siesi FX, Boelaert M, Büscher P (2009). Comparison of operational criteria for treatment outcome in gambiense human African trypanosomiasis. Trop Med Int Health; 2009:Feb 17. [Epub ahead of print]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19228348

5. Delgado M, Anderson P, Garcia-Salcedo JA, Caro M, Gonzalez-Rey E (2009). Neuropeptides kill African trypanosomes by targeting intracellular compartments and inducing autophagic-like cell death. Cell Death Differ; 16(3):406-416. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19057622

6. Blum JA, Schmid C, Burri C, Hatz C, Olson C, et al. (2009) Cardiac Alterations in Human African Trypanosomiasis (T.b. gambiense) with Respect to the Disease Stage and Antiparasitic Treatment. PLoS Negl Trop Dis 3(2): e383. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19221604

7. Koffi M, De Meeûs T, Bucheton B, Solano P, Camara M, Kaba D, Cuny G, Ayala FJ, Jamonneau V (2009). Population genetics of Trypanosoma brucei gambiense, the agent of sleeping sickness in Western Africa. Proc Natl Acad Sci USA; 106(1):209-214. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19106297