MCR-1 GENE ISOLATEDMCR-1 gene isolated from human for first time in Brazil.
Surveillance, treatment, and vector control-requiring adequate infrastructure and funding-can keep African trypanosomiasis in check
John Richard Seed
Extracellular, flagellated protozoan parasites, known as trypanosomes, cause African trypanosomiasis or African sleeping sickness, a chronic disease that is transmitted by vectors. Two subspecies of trypanosomes, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, infect humans. African trypanosomiasis is one of only a few human infectious diseases that are 100% fatal when not treated. The vector, a biting fly that is restricted to the African continent, is a member of the genus Glossina and is commonly referred to as the tsetse fly.
African trypanosomes also infect domestic animals and animals native to the African continent, making it a zoonosis with many reservoir hosts. Most domestic animals that are not native to Africa have a fatal infection similar to that of humans. The disease limits domestic animal production in much of central Africa, an area approximately the size of the United States. It causes an estimated 20% decrease in calving, 25% decrease in milk production, and 3 million livestock deaths per year. Because this infection severely restricts the economic and nutritional benefits of animal farming, farmers throughout this region often must pull their own plows and carry their own goods.
Trypanosomiasis Typically Follows Two Phases, and Treatment Is Crucial
African trypanosomiasis is a frightening disease with two distinct phases. The earlier, or primary, phase produces very general symptoms such as fever and lethargy. Because many infectious agents produce similar symptoms, trypanosomiasis is difficult to diagnose during this first phase. During the primary stage, which may last for months, infected individuals are ambulatory carriers of the infection-a condition with obvious epidemiological implications.
The secondary stage is neurological in nature and becomes more severe as the disease progresses. Secondary stage involvement begins with headaches followed by a wide variety of behavior changes, ranging from aggression to lethargic, depressive states. The infection, when untreated, progresses to a sleep-like state-hence, the name sleeping sickness. Early in the secondary stage these periods of sleep or coma-like states are brief and limited. Infected individuals sometimes are observed falling rapidly into a deep sleep, even with a mouth full of food and, later, waking and resuming their meal.
With time, the sleep-like stages become longer and more frequent, until the infected individual falls into a permanent comatose state and dies. African trypanosomiasis outbreaks have caused large numbers of deaths and forced entire villages to move. The disease has restricted land use and has prohibited some of the most favorable agricultural lands throughout sub-Saharan Africa from being developed. African trypanosomiasis has therefore had a profound influence on the health, social, and economic history of much of Africa.
Several drug treatments are available, and the duration of treatment depends upon the stage of infection. Determining that stage first requires an examination of cerebrospinal fluid (CSF) for trypanosomes
or reliance on other diagnostic indicators, including high white blood cell count or elevated protein levels in CSF. If the CSF is normal and the patient shows no sign of secondary stage trypanosomiasis, the individual begins treatment with one of two drugs, pentamidine or suramin, depending upon the species of trypanosome at hand.
Pentamidine is used to treat T. brucei gambiense-infected individuals, and suramin is used for patients infected with T. brucei rhodesiense. However, neither pentamidine nor suramin crosses the blood-brain barrier in sufficient concentrations to be effective against the trypanosomes in the cerebrospinal fluid and brain. Therefore, after treatment with pentamidine or suramin both primary and secondary stage patients are treated with the more toxic organic arsenical Melarsoprol, which crosses the blood-brain barrier and thus is effective against the secondary stages of the infection.
For patients in the secondary stage of the infection, additional periods of treatment with Melarsoprol are required. If Melarsoprol fails to cure an individual with a secondary stage infection, difluoromethylorithine (DFMO), the only new drug developed in the last 50 years, is used. Unfortunately, DFMO is not very effective against T. brucei rhodesiense. Furthermore, resistance to DFMO is easily developed. DFMO is therefore held in reserve for treatment of Melarsoprol-resistant cases of trypanosomiasis.
All the trypanocides except DFMO are toxic, but Melarsoprol is especially so. It causes deaths among an estimated 5 to 10% of treated patients. To minimize drug-induced toxicity, treatment should be carried out in a hospital setting. At the present time our chemotherapeutic arsenal is very limited. Drug resistance to Melarsoprol appears to be increasing. Currently it is estimated that up to 20% of the patients treated with Melarsoprol relapse. Although new chemotherapeutic agents are urgently needed, relatively little research to develop such agents is under way, and funds for developing new trypanocides are very limited. The countries involved are poor and cannot afford the purchase of expensive drugs, yielding little incentive for pharmaceutical firms to invest in trypanocidal drug research.
Current Control Strategies Depart from Those of the Early 20th Century
According to estimates, at the beginning of the 20th century there were more than 1 million human cases of African trypanosomiasis, with more than 250,000 deaths reported in Uganda alone. However, by the middle of the last century, the infection was slowly being brought under control. Estimates of 10,000 to 20,000 human cases were suggested in the 1970s. This rapid drop in prevalence was due to the use of chemotherapeutic agents effective against both stages of the disease, as well as the development of powerful insecticides, including diphenyltrichoroethane (DDT), dieldrin, and endosulfan, for control of the vector insect, Glossina.
Moreover, early on the colonial powers established an active, highly organized surveillance system for detecting cases of African trypanosomiasis that proved to be an essential control element. Surveillance permitted the treatment and removal of infected ambulatory carriers from the uninfected population at risk. Yet another series of developments that destroyed vector habitats, including the clearing of land and the removal of reservoir game animals by fencing or hunting, were also effective components in early control programs.
Today's control of African trypanosomiasis involves the same three basic elements: mobile surveillance teams, treatment of infected individuals, and vector control strategies. First, all individuals within an endemic region should be surveyed for trypanosomiasis at least once each year. A mobile surveillance team typically may consist of a driver, a microscopist, and a trained nurse or doctor. The team needs to coordinate its activities with village leaders to insure 100% participation by the village people.
Surveillance generally includes a brief physical examination looking for key signs of the infection (Fig. 1), a microscopic examination of blood and possibly lymph from a lymph node biopsy for the presence of trypanosomes (Fig. 2), and the running of a rapid field-type serological assay. There are now several serological tests, such as the Card Agglutination Test (CATT), that have been developed that take minutes to run, are easy to transport, are environmentally stable, and are relatively inexpensive. Infected individuals need to be transported to a hospital setting to undergo supervised drug treatment-the second element in current control measures. It should be noted that no vaccine is available, and none is expected in the immediate future.
The third phase of trypanosomiasis control programs focuses on vectors. Current vector control measures depend to a great extent on the application of relatively new, environmentally friendly insecticides, including synthetic pyrethroids, deltamethrin, and cypermethrin. These insecticides are applied from the air by fixed- or rotary-wing aircraft, on the ground by backpack-mounted spray devices, or in ranch settings by allowing insecticide-treated cattle to serve as targets for live tsetse flies. Another vector-control measure involving sterile tsetse-fly technology, in combination with insecticide application, is used successfully, but only in restricted geographical locations.
Additional control measures involve the use of ingeniously designed traps and flags (Fig. 3). The traps can be employed with or without the use of vector attractants. Flags are simply pieces of cloth with alternating stripes of blue and black hung from an inverted L-shaped post that can be stuck into the ground. The flag is impregnated with an insecticide, and a vial containing a slow-release, volatile vector attractant is placed at the base of the post. Both traps and flags can by themselves reduce tsetse populations dramatically. Although effective, these devices need continuous maintenance as they are subject to theft for their cloth and susceptible to animal and weather damage, and the attractants must be regularly replenished.
Estimates Point to Wide Scope of Trypanosomiasis throughout Africa
Officials at the World Health Organization estimate that there are 300,000 to 500,000 cases of human African trypanosomiasis. Some 36 countries on the continent are endemic for human African trypanosomiasis, putting about 60 million people at risk. However, less than 7% of the population is currently under surveillance for the infection.
Of the 17 nations that provide yearly records of new cases of human African trypanosomiasis, two have had dramatic increases in the interval between 1977 and 1993. Six others had ongoing epidemics in 1993, and the remainder showed little change in the number of new cases between 1977 and 1993. Four countries recently experienced, or are still experiencing, epidemics (see table).
The prevalence figures from Uganda give an excellent example of the explosiveness of this infection. In 1970 only 52 cases of human African trypanosomiasis were reported. However, during the following 10 years, approximately 8,000 new cases were recorded, and by 1981, more than 8,000 new cases occurred per year and, in some communities, the prevalence of the disease reached 25%. In Zaire (now the Democratic Republic of the Congo) the prevalence rates are 70%, the highest ever recorded, in some villages.
In 1997, prevalence rates of over 40% were detected in Southern Sudan. In some villages, more than 50% of those infected were in the secondary stage of the disease. Unfortunately, it was impossible to adequately treat these infections partly because of a low supply of drugs, but even more importantly because the ongoing war in the area made the infected individuals inaccessible. In Angola there is a similar setting, with reports of 60% prevalence rates in some communities. African trypanosomiasis is truly a reemerging infection of serious dimensions and enormous public health impact throughout most of the continent.
Basic Research on Trypanosomiasis Is Also Reemerging
Although control efforts in the field are far from optimal, basic research on African trypanosomes recently has increased and, in some circles, it is something of a laboratory favorite, according to Samuel J. Black at the University of Massachusetts in Amherst. For example, the biochemistry of the parasites is extensively studied and relatively well understood. Moreover, the phenomenon of RNA editing was first described in this group, and its genome will likely be sequenced in the next few years. Researchers are studying the immune response of the host, the phenomenon of antigenic variation, and the mechanism(s) involved in natural resistance of wild mammals to trypanosomes.
The reasons for the reemergence of human African trypanosomiasis go beyond a simple understanding of the biology of the organisms involved. For example, modern Africa with its history of colonial rule, and the past political division of African territories along geographical lines with little consideration of historical, ethnic, or cultural divisions of the indigenous people, are all factors contributing to the resurgence of this disease.
In addition, the abrupt liberation of African nations from colonial rule often left them without adequate safeguards for maintaining public health and other critical infrastructures. The failure to maintain a sound economic base and the resulting political instability subsequently led to considerable civil unrest and frequent wars. Indeed, the reemergence of human African trypanosomiasis has been most severe among those countries that have experienced civil unrest or war with further breakdowns in their already strained public health systems (Fig. 4).
Other African nations with rising prevalence rates have had economic declines with similar decreases in their public health services. Without stable infrastructures, economic growth, and long-term commitment to the control of human African trypanosomiasis, this infection will continue to increase in epidemic proportions.
Little information appears in U.S. or European newspapers about the impact of this infection in Africa. One such rare newspaper reference to African trypanosomiasis alluded to its vector, "the tsetse," but this mention came in the cartoon "Blondie and Dagwood" and had nothing to say about the serious nature of this disease. In another relatively recent instance, the tsetse was wrongly described as transmitting yellow fever.
Today in Africa more than 300,000 people are estimated to be infected with a parasite that produces a frightening set of neurological disturbances and is 100% fatal if left untreated. Indeed, the disease is as fatal as rabies. Yet the general public, the public health community, and much of the scientific community are not generally aware of the infection, its public health importance, and its devastating impact. There also appears to be limited international concern or interest. Thus, African trypanosomiasis will not be an easy beast to tame.
I thank S. Black (University of Massachusetts), J. E. Hall (University of North Carolina), and J. Sechelski (University of North Carolina) for the many stimulating hours of discussion that we have had on this and related topics concerning African trypanosomiasis. These and many other colleagues have helped to give my thoughts about this infection some direction and cohesiveness.
Arbyn, M., H. Bruneel, S. Molisho, and F. Ekwanzala. 1995. Human trypanosomiasis in Zaire: a return to the situation at the beginning of the century? Arch. Public Health 53:365-371.
Barrett, M.P. 1999. The fall and rise of sleeping sickness. Lancet 353:1113-1114.
Ekwanzala, M., J. Pepin, N. Khonda, S. Molisho, H. Bruneel, and P. DeWals. 1996. In the heat of darkness: sleeping sickness in Zaire. Lancet 348:1427-1430.
Lyons, M. 1992. The colonial disease: a social history of sleeping sickness in Northern Zaire, 1900-1940. Cambridge University Press, Cambridge.
Mhlanga, J. D. M. 1996. Sleeping sickness: perspectives in African trypanosomiasis. Sci. Progr. 79:183-214.
Program against African Trypanosomiasis (PAAT) Web site. http://www.fao.org/paat/html/home.htm .
Seed, J. R. 1998. African trypanosomiasis, p. 267-282. In F. E. G. Cox, J. R. Kreier, and D. Wakelin (ed.), Topley & Wilson's microbiology and microbial infections, vol.5, Parasitology. Arnold, London.
Smith, D. H., J. Pepin, and A. H. R. Stich. 1998. Human African trypanosomiasis: an emerging public health crisis. Br. Med. Bull. 54:311-355.
WHO Expert Committee Report. 1998. Control and Surveillance of African Trypanosomiasis. WHO Technical Report Series 881. Geneva, Switzerland.