Medilinks: 31 May 2002

No longer asleep – Africa Sleeping Sickness is back

By John Kiwanuka Ssemakula

The deadly disease Sleeping Sickness transmitted by the infamous tsetse fly is once again re-emerging in Sub Saharan Africa to threaten the lives of millions. Sleeping sickness is a devastating disease. The WHO estimates that 300,000 to 500,000 people contract sleeping sickness every year of which 66,000 die annually. And the situation is getting worse. The disease is caused by the parasite Trypanosma brucei  with two variant sub species. The Trypanosma brucei  rhodesiense variant is found in east and southern Africa, and the Trypanosma brucei gambiense is commonly found in central and western Africa.

The T b. gambiense variety causes a delayed chronic illness that can last years, whereas the T b. rhodesiense variety manifests with more acute symptoms that can result in death in weeks or months. Symptoms start with fever, headache, joint pain and once the parasites crosses the blood brain barrier, characteristic neurological symptoms and signs present; altered mental state, irritability, sensory disturbances, and coordination problems. At this stage, the disease causes a reversal of the daily sleep/wake cycle with the victim becoming extremely agitated at night. Eventually they fall into coma. Untreated the condition is invariably fatal

There are seven different species of tsetse fly which can transmit the disease, and all are found uniquely in Sub-Saharan Africa.

Trypanosomiasis not only affects humans but is also a serious disease affecting livestock and is responsible for the deaths of many animals. About 10 million km2 of sub-Saharan Africa is unable to exploit its full agricultural potential because of tsetse flies.

Tsetse flies are found in vegetation near water such as lakes and rivers and people are affected when performing activities such as gathering water, hunting, fishing, keeping cattle or cultivating land.  

The disease is currently epidemic in the Democratic republic of Congo, Sudan, Uganda and parts of Angola, and is endemic in 19 other countries.

60 million people are at risk from the disease in Sub Saharan Africa. In epidemic areas the prevalence can be as high as 80% in local village populations.

Sleeping Sickness is an old disease, it was known to slave traders who would reject people who had symptoms of the disease. The current epidemic began in the 1970’s. In the current climate of the HIV/AIDS epidemic in Africa, it is perhaps easy to forget what a devastating disease trypanosomiasis was. 

The first documented epidemic occurred from 1896 to 1906 in Uganda and the Congo basin, and eventually resulted in hundreds of thousands of people having to be relocated from islands in the Lake Victoria region.

The second epidemic occurred during the 1920’s and was only halted by intensive systematic screening and treatment of infected people by mobile teams. In The 1950’s the disease was controlled by insecticide spraying, brush clearing, relocation of affected villages and prompt treatment. (Silberg S, 2002). The illness was practically eliminated by 1960. With the near complete disappearance of the disease, complacency set in and active population screening was discontinued. War, economic problems and political stability contributed to the breakdown of the control system allowing the re-emergence of the disease as a major health problem.

Large numbers of people have reportedly either died or fled from villages abandoning crops and animals, where the prevalence rate is up to 70 –80%, in the most severely affected countries Angola, DRC and Sudan.  In the DRC 34 400 new cases were estimated to have occured in 1994, according to Ekwanzala et al 2 and the mortality rate from sleeping sickness is now the same order of magnitude as that caused by AIDS. (WHO, 1997)

Case management

§          Screening of potentially infected people involving the checking for clinical signs or the use of serological tests.

§          The only clinical sign is the presence of swollen cervical glands.

§          Staging the disease is showing the phase progression of the disease which entails examining cerebrospinal fluid (csf) to see if the parasite has crossed the blood brain barrier.

Treatment

Initial Phase treatment

If detected and treated early chances for a cure are good. The early drugs suramine and pentamidine affected only one subtype and had moderate to severe side effects. They are used in the initial stage of the disease. Suramine discovered in 1921 and is used in the initial phase of T b.rhodisiense, Pentamidine is used in the T. b gambiense  form of the disease.

Late stage treatment

There are only two effective drugs for the late, neurological stages of African trypansomiasis.

Melarsoprol discovered in 1949 was until recently the only drug that could cross the blood brain barrier to reach the parasite in the later stages of the disease, no matter which parasite was the cause. It is the last arsenic derivative in existence. Melarsoprol treatment frequently has severe adverse effects. The most serious complication of melarsoprol treatment is reactive encephalopathies. They occur at varying frequencies in 5–10% of treated cases. The reaction is fatal for about 10–70% of the patients afflicted. There is also significant drug resistance rising to 30% in some areas of central Africa. (WHO,2000)

Eflornithine:

Eflornithine (difluoromethylornithine or DMFO) was first registered for in sleeping sickness in 1990. decade and was the first new drug to be approved for use in African trypanosomiasis for over 40 years.  It was hailed as a ‘miracle drug’ because of it’s ability to resurrect comatose patients. However, the drug has number of drawbacks: it is only effective in cases of T b. gambiense infection; it is expensive, 14 vials are required to treat each patient at a cost that varies from US$884 to US$392. (Khonde & Mpia, 1998) Furthermore, because it is given intravenously, it can only be administered in a hospital setting to the patient.

Production of the drug ceased completely in 1999, because it was unprofitable for  the pharmaceutical company Aventis. A campaign by Medecins Sans Frontieres and others to bring the drug back succeeded in part only because  a second drug company Bristol Myers Squibb found a potentially new lucrative use for elflornithine as a hair removal substance for women’s mustaches.  Aventis offered the license to WHO in 2000, but efforts to find donors willing to guarantee supply of eflornithine, or find anyone to produce the drug proved unsuccessful. Aventis has now agreed collaborate with the WHO in financing a 5 year project for $25 million to provide 60,000 doses of the drug. (Lewis, 2002)

The economic effects:

In areas where the disease is endemic or severe, it hinders or prevents the keeping of livestock, denying rural communities access to their livelihood. The long term impact is the disruption of the development of sustainable mixed farming, slowing down the alleviation of poverty.

The loss to agriculture each year as a result of trypanosomiasis is put at $4.75 billion dollars a year. The value of lost milk and meat production is estimated at $2.75 billion dollars a year.  (PAAT Newsletter, 2001), 35 million doses of drugs are used annually to protect cattle.

New research

Elflornothine has provided a significant boost to the management of sleeping sickness, but it only treats one form of the disease. More basic research is needed on the parasite itself, T brucei. Development of a vaccine may not be possible, because the parasite can change it’s surface features in 1000 ways (Nature, May 2002). In 1994 the African trypanosome genome project was initiated by the WHO to achieve better understanding of trypanosome genetics.  (WHO, 1997)

Other areas of research continue such as the The Card Agglutination Test for Trypanosomiasis (CATT), an antibody detection test, or the the Card Indirect Agglutination Test for Trypanosomiasis (CIATT), a simple and rapid diagnostic test for sleeping sickness, which can be performed using whole blood obtained by finger prick and  has been shown to be specific and suitable for assessing cure following chemotherapy.

A preliminary study indicates that the duration of treatment with melarsoprol can be reduced, with no decrease in effectiveness of the drug, or increase in adverse effects. The new treatment protocol reduces the amount and cost of the drug by one third and the costs of hospitalization by half. (Blum and Burri, 2002)

Other drug research are developing several new possible candidates that include phosphodiesterase inhibitors that are able to destroy T bruce1 cells, as well as a diamidine compound, an inhibitor of polyamine/S-adenosine methionine/ trypanothione (SAM), which is effective alone against T. b.

gambiense infections in mice and, against T. b.rhodisense in combination with elflornithinine.

Disease Control Efforts for Trypanosomiasis

There are several methods available for tsetse and trypanosomiasis control or eradication. All the methods have limitations based on cost, logistical feasibility or sustainability of use. The currently available and environmentally acceptable interventions are (Feldmann and Hendrichs, 1998): 

·          parasite control through:

(i)          The use of trypanocidal drugs and, in some cases,

(ii)   The promotion of trypanotolerant livestock;

·          vector control or eradication through:

(i)              Traps and insecticide treated targets, in some cases baited with attractant odours;

(ii)            Insecticide treated animals; and

(iii)           The sterile insect technique (SIT).

Some interventions used in the past, such as bush-clearing (tsetse habitat destruction) or the elimination of wild animals (tsetse reservoir hosts), are now banned for environmental reasons. Likewise indiscrimi­nate use of insecticides through aerial spraying used in the past is no longer sanctioned.

Trypanocidal Drugs

The use of trypanocidal drugs is the most widely accepted means of con­trolling the disease.  But the drugs available are relatively expensive. Their effectiveness has been reduced because of the wide spread drug resistance and cross-resistance that has developed through the widespread, unsupervised use of the few com­pounds devel­oped against the disease.

Trypanotolerance

Trypanotolerant breeds of livestock have been promoted in several parts of Africa, but they have a reputation of inherently lower productivity and milk yield.  Furthermore in areas of dense tsetse fly infestation, trypanotolerant cattle breeds will still need protection with expensive trypanocidal drugs.

Vector Control

Use of Insecticides

The use of insecticides on cattle or insec­ticide impregnated targets, with or without available odour attrac­tants) has been shown to be a successful method of suppressing tsetse target populations. Failures in the past have been attributed to the loss of enthusiasm of communities when institutional support, in the form of support form government or aid agencies was removed. There is also the potential for resistance developing (as with trypanocides) through the indiscriminate, unsupervised, uncoordinated use of insecticides on targets or ani­mals. 

Sterile Insect Technique

A new campaign to control the tsetse fly, was launched by the Organisation of African Unity (OAU) in collaboration with the International Atomic Energy Agency (IAEA, in February 2002. The OAU initiative will use the Sterile Insect Technique (SIT) which was successfully used by the government of Tanzania, the IAEA, and the UN's Food and Agriculture Organisation (FAO), to eradicate sleeping sickness on the Tanzanian island of Zanzibar in 1997. The FAO/IAEA initiative was a component of an overall initiative of livestock disease and wildlife management and agricultural development, to release at least 500,000 sterile males per week in areas as of  5000 to 10,000 km² at a time. (Feldmann and Hendrichs, 1998)

Under the new OAU initiative, young male Tsetse flies bred in special centres will be sterilised by exposing them to a short burst of gamma radiation from a cobalt-60 source, strong enough to inhibit the fertility of the fly's sperm, but not affect the fly's health.  The plan is to release millions of the sterilised male tsetse flies across 37 African countries, in the hope that they mate with healthy female flies and reduce the fly population by displacing fertile male flies. This in turn will reduce the number of people and livestock infected each year.   (Nita B, 2002)

However there are concerns about using SIT alone.  It is reported that eradication failed in Nigeria and on mainland Tanzania because the infested areas could not be isolated, and only worked on Zanzibar because it was an island with only one species of fly.   (Nita B, 2002)

The best approach is an integrated disease that will include aerial spraying of insecticides. There­ is a need to develop guide­lines and assistance of co-ordination and supervision of the appro­pri­ate use of insecticides for tsetse control by gov­ernment servic­es, NGOs and the private sector. Other countries, which fall into the tsetse belt, have also started their own projects. Botswana, Tanzania, Mali, Burkina Faso, Kenya, and Uganda are breeding flies and identifying areas which need to be targeted. The OAU's PATTEC taskforce now plans to help other African countries set up their own eradication programmes.

Conclusion

Sleeping sickness is in the midst of resurgence in sub-Saharan Africa.  The current capacity in sub-Saharan African countries for effective surveillance of sleeping sickness is insufficient. Most cases occur in remoter rural areas where the peripheral health facilities lack the expertise for testing and treating patients. As a result most cases are not detected, not treated, and therefore fatal.

Source: Table 8.1  African trypanosomiasis, cases reported to WHO, number of countries reporting, and population screened, 1902-1998

What will happen at the end of 5 years when the eflornithine runs out is anyone’s guess. The long term outlook for sleeping sickness is unsure. The tsetse fly and trypanosomiasis problem characterizes the many interdependencies that involve agricultural, social, economical, and environmental issues.  Any intervention or non-interventions will have a wide range of immediate and longer-term implications.  What is certain, without any interventions, the situation will only get worse, threatening the lives of millions and rendering vast areas of economically important agricultural land unusable.

Reference:

1. Blum J. & Burri C. (2002). Treatment of late stage sleeping sickness caused by T. b. gambiense:  new approach to the use of an old drug. SWISS MED WKLY 132:51–55

2. Feldmann U. and Hendrichs J. (1998). Integrating the Sterile Insect Technique as a key component of area wide tsetse and trypansomosis intervention. Insect and Pest Control Section, Joint FAO/IAEA Division of Nuclear Techniques in Food and Agriculture November

3. Khonde N. & Mpia B. (1998) Multicentre comparative study of two treatment durations with eflornithine for late-stage T. b. gambiense sleeping sickness. WHO Tropical Disease Research Project no. 960720, 960721, 960722. October

4. Nita B. (2002). Pan African group takes lead against the tsetse fly. The Lancet.  Volume 359, Number 9307  February

5. Lewis R. (2002). African Sleeping Sickness: A recurring Epidemic. The Scientist; 16, 10,26. May

6. Programme Against African Trypanosomiasis Newsletter (2001). Issue Number 10 p5. October

7. WHO. (2000)  Report on Global Surveillance of Epidemic-prone Infectious Diseases. Chapter 8 WHO/CDS/CSR/ISR/2000.1

8. WHO. (1997). Tropical Disease Research Final Report, Trypansomisis. Chapter 10; p125 -132

Links:

The Programme Against African Trypanosomiasis (PAAT)

Integrated Control of Pathogenic Trypanosomes and their  Vectors (ICPTV)

WHO Report on Global Surveillance of Epidemic-prone Infectious Diseases