Animal Sleeping Sickness (Trypanosomosis): An Example of the Pitfalls of Trying to Control It

Fellata nomad milking her cows in Maban, South Sudan. The Fellata cattle breed does not tolerate strangers approaching too closely and are known as a wild breed by other peoples. But their owners handle and walk among them with no trouble.     Charles Hoots

Trypanosomes are single-celled protozoan organisms, one species of which causes sleeping sickness in people and several of which cause a similar disease in animals. In its “classic” form, the animal disease is spread from wildlife to cattle in much of sub-Saharan Africa through the bite of a tsetse fly, resulting in a slow wasting away of the affected livestock (but with typically no signs of illness in the wildlife hosts).

I arrived in northeast South Sudan in 2013 to work on a livestock project for the German branch of Veterinarians Without Borders. The animal form of sleeping sickness (which I will call AAT, short for African animal trypanosomosis) was at the time a major problem in the herds of the 120,000 refugees from neighboring Sudan living in four camps in the area. But the situation was far from “classic.”

Nearly a quarter-century of civil war had led to the almost complete elimination of large wildlife species that tend to act as reservoir hosts for trypanosomes. In addition, tsetse fly vectors, the poster child for sleeping sickness in people and animals, were nowhere to be found. Our subsequent joint effort with the community to control this disease taught me valuable lessons in how good intentions can go awry in animal (and human) health planning through failure to consider every aspect.

In the months before I had even heard of Maban County (the area of South Sudan in which our project was implemented), a team of South Sudanese and European veterinarians found that almost a quarter of 94 cattle tested in Maban were positive for Trypanosoma vivax and, to a lesser extent, for T. congolense and T. evansi, all causative agents of AAT. These protozoa are notoriously difficult to find in the blood smears of infected animals, so the real rate was likely much higher.

Northeast South Sudan. Four refugee camps are located at Doro, Kaya, Batil, and Jendrasa. The River Yabus flows just south of Doro, from its source in the Ethiopian highlands to where it drains into the vast Machar wetlands. The refugee herds’ wet and dry season grazing areas are shown in red and green shading, respectively. The Fellata are nomadic pastoralists who came to Sudan from northern Nigeria over the past century and a half. Their cattle are generally vaccinated and in good health, but they too must be taken into account when designing an animal health program. Charles Hoots

Northeast South Sudan. Four refugee camps are located at Doro, Kaya, Batil, and Jendrasa. The River Yabus flows just south of Doro, from its source in the Ethiopian highlands to where it drains into the vast Machar wetlands. The refugee herds’ wet and dry season grazing areas are shown in red and green shading, respectively. The Fellata are nomadic pastoralists who came to Sudan from northern Nigeria over the past century and a half. Their cattle are generally vaccinated and in good health, but they too must be taken into account when designing an animal health program. Charles Hoots

Trypanosomes and Flies: An Intimate Link

For efficient transmission of AAT, trypanosomes must be ingested by any one of a handful of tsetse fly species (genus Glossina). Once inside the tsetse, the trypanosome develops over the coming 1-3 weeks into various forms, the last of which makes its way to the salivary glands, ready to be injected into another mammal at the tsetse’s next blood meal. Because the trypanosomes mature inside the tsetse, these flies are called “biological” vectors.

A tsetse fly (Glossina spp.) IAEA

A tsetse fly (Glossina spp.)      IAEA

Africa’s “tsetse fly belt” does not include the clay plains of Maban, but it does encompass adjacent portions of Ethiopia less than 70 km to the east. Trapping expeditions in recent decades have found that small numbers of tsetse flies descend from their Ethiopian highland abode during the rainy season, following the bed of the River Yabus as it flows into the lowlands towards Maban to the west (see map above).

Both the savannah-dwelling tsetse (Glossina morsitans submorsitans) and the riverine tsetse fly (G. fuscipes fuscipes) have been documented in low numbers as close as 30 km east of the refugee camps. But in Maban itself they appear to be non-existent or, at best, in densities so low that they cannot explain the extent of AAT transmission we were seeing.

Africa's tsetse fly belt: range of Glossina fuscipes fuscipes, a riverine tsetse fly that has been found on the upper reaches of the River Yabus as near as 20 km from Maban. The black square encloses Maban and neighboring areas shown in map above. The density of these flies is not high enough to be represented clearly on this map. G morsitans submorsitans has been found in adjacent savannah habitats near the upper reaches of the Yabus. FAO

Africa’s tsetse fly belt: range of Glossina fuscipes fuscipes, a riverine tsetse fly that has been found on the upper reaches of the River Yabus as near as 20 km from Maban. The black square encloses Maban and neighboring areas shown in map above. The density of these flies is not high enough to be represented clearly on this map. G. morsitans submorsitans has been found in adjacent savannah habitats near the upper reaches of the Yabus. FAO

A few short days of trapping along the banks of the Yabus at the beginning of the 2014 rainy season produced no tsetse flies. The negative results essentially meant nothing as it can take many days of trapping even in known tsetse areas to catch just a few flies.

Setting up a fly trap on the banks of the River Yabus. Some tsetse species are attracted by the blue color of the trap. Charles Hoots

Setting up a fly trap on the banks of the River Yabus. Some tsetse species are attracted by the blue color of the trap.    Charles Hoots

While tsetses were nowhere to be found, large numbers of horse flies (of the Tabanidae family) and stable flies (of the genus Stomoxys) constantly worried the livestock in Maban. These and other biting flies offered a possible explanation for the high prevalence of AAT in the herds.

In the absence of tsetse biological vectors, some species of trypanosomes (especially T. vivax) are transmitted between animals through the bite of other fly species. The circumstances involve a fly whose blood meal on an infected animal is interrupted, such as by the swish of a tail. The disturbed fly then settles on a different, uninfected animal and begins a new blood meal, transferring the pathogen. The transfer must occur before the blood on the fly’s mouth dries, which kills any trypanosomes contained within it.

Horse fly (Ancala africana, I believe) inside my tent in Maban. These and other biting flies can spread trypanosomes between animals when a high portion of the animal population is infected.

Horse fly (Ancala africana, I believe) inside my tent in Maban. These and other biting flies can spread trypanosomes between animals when a high portion of the animal population is infected.    Charles Hoots

There is no development of the trypanosome within the biting fly, as occurs in the tsetse, and the flies in this case are referred to as “mechanical” vectors. They are not as efficient as tsetses in spreading trypanosomes, but when the disease burden is already high in an area, they can perpetuate and possibly expand the disease. This seemed to be the driving force behind the AAT problem in Maban.

The Power of Stress

How did the cattle in Maban acquire AAT in the first place then, if a certain threshold is necessary for mechanical transmission to be a factor? As with so much in animal and human health, stress was the driving force.

The 50,000 or so cattle brought by the refugees were used to a significantly drier habitat than that of Maban. When the outbreak of fighting in their home areas forced the inhabitants to leave, livestock were driven relentlessly for up to 200 km, with little rest or grazing, to a strange place where they were frequently relegated to marginal grazing areas so as not to interfere with local livestock herds.

Moister habitats offered more opportunities for infection by liver flukes and, combined with the other stresses, significantly increased the animals’ susceptibility to trypanosomes and a host of other diseases. On their trek south, herds may have passed through pockets of tsetse fly habitat and picked up enough AAT to be sustained by non-tsetse biting flies once in Maban.

The River Yabus near Doro, South Sudan (see map above). On the left, in November at the end of the rainy season. On the right, in February, the middle of the dry season. Charles Hoots

The River Yabus near Doro, South Sudan (see map above). On the left, in November at the end of the rainy season. On the right, in February, the middle of the dry season.      Charles Hoots

In the rainy months following their arrival, the refugees were losing an estimated 400 head of cattle per week. The depletion of these livestock will make an eventual smooth return of refugees to their homeland extremely problematic, if not impossible, once peace allows them to repatriate. With no animals to plough their fields, supplement their diets with milk, or for use in barter or for cash in emergencies, the refugees would likely be forced to abandon their villages.

To avoid this eventuality, it was agreed with South Sudanese officials and the animal health workers working with us from among the refugee and local communities that control of AAT should be a priority. This proved, of course, easier said than done.

A Slow Death

Trypanosomes are nothing if not fascinating. But their unique characteristics can make them complicated to deal with, and sometimes doing the wrong thing can have more serious consequences than not doing anything at all.

Trypanosomes have numerous ways of hindering or evading the immune system of mammals. After infection, each single-cell trypanosome divides to form two organisms, each of which divides again, and so on. After 10-14 days, the host immune system hones in on specific proteins embedded in the surface membrane of the trypanosomes, then produces antibodies that lead to their destruction.

However, about one in a hundred of the trypanosomes are able to alter their surface proteins to escape detection by the attacking antibodies. These survivors then continue to multiply, from very low to very high levels a couple of weeks later, by which time the immune system reacts to eliminate this group too. But a few manage to camouflage themselves and survive again – through changing their surface proteins.

These cycles result in repeated bouts of fever in the host. In the absence of effective medication, this cat-and-mouse game can go through dozens of cycles, with the trypanosomes eventually wearing the host’s immune system down. Exhaustion and death ensue.

Cow of the Kenana breed, common with refugees in Maban. This individual shows signs of unthriftiness typical of African animal trypanosomosis infection. Lack of food in the dry season, as seen here, as well as other diseases also cause wasting and complicates diagnosis. Charles Hoots

Cow of the Kenana breed, common with refugees in Maban. This individual shows signs of unthriftiness typical of African animal trypanosomosis infection. Lack of food in the dry season, as seen here, as well as other diseases also cause wasting and complicates diagnosis. Charles Hoots

Why There Is No Vaccine

The variability in the trypanosomes’ surface proteins partly explains why an effective vaccine has never been developed for either animal or human sleeping sickness. A vaccine that stimulates antibody production against one protein would be ineffective against other protein types. Vaccine research has looked at targeting other, more stable antigens to produce an immune response, but progress has been slow.

Not only are trypanosomes unaffected by vaccination, it seems they may be capable of reversing vaccine-stimulated immunity to other diseases in the animals they infect. This has been noted in people vaccinated apparently successfully against measles. After a later trypanosome infection, many of these people were no longer protected against measles, though the concentration of anti-measles antibodies in their bloodstream remained high. Vaccinating an animal or person while ill from any disease can be ineffective at best, and sometimes detrimental. But a pathogen that can “undo” previous immunization is something else altogether.

Given that a vaccination campaign against other common livestock diseases in Maban was part of our project, it was imperative that the AAT outbreak be brought under control first. Otherwise the money might have been largely wasted, AND we risked spreading AAT further through repeat use of vaccine needles between animals.

The Arsenal

Three medications are commonly used to cure trypanosome infections in cattle. All have been in use for over 50 years and widespread resistance to them has developed in trypanosomes, encouraged by chronic underdosing, fraudulent dilution of drugs to increase profits or save money, and use of expired or poorly stored drugs.

While resistance is to be expected with any drug against any pathogen over time, the rate at which trypanosomes developed resistance was surprisingly, and inexplicably, rapid. Several mechanisms have been described, including one in which the pathogens mysteriously disappear from the bloodstream as soon as they detect the presence of an anti-trypanosome drug. Where exactly they go is unclear, but after the medication is excreted from the body, they emerge from their hiding places and resume business as usual.

Local cattle in Maban return to their owners’ home at dusk. They stand amongst the smoke from smoldering fires to keep flies and other insects at bay. Charles Hoots

Local cattle in Maban return to their owners’ home at dusk. They stand amongst the smoke from smoldering fires to keep flies and other insects at bay.   Charles Hoots

“First, Do No Harm”

Choosing the appropriate drug and dose to use against AAT in a given situation is not simple, despite the limited number of options. But these must be carefully considered if we are to live up to the most important principal of veterinary medicine: “First, do no harm.”

In addition to the three commonly used trypanosome medications, another drug (called quinapyramine) is occasionally used in cattle by people unaware of its dangers. When trypanosomes develop resistance to it, they simultaneously become resistant to each of the three common drugs!

During my last week in Maban on this project, on a stroll through the market established in one of the refugee camps, I found a trader selling quinapyramine. That evening we discussed between our staff and the community animal health workers whether to purchase the bottle from the trader to prevent it from being used, at the risk of encouraging him or other traders to bring in more of the drug in hopes of selling it to us. We elected to simply inform the trader of the drug’s risks and request politely that he voluntarily remove it from sale. I imagine he sold that bottle, but hopefully he did not return with any more.

Of the commonly used drugs, one (homidium) had long been in use in Maban and the veterinary team that tested cattle there before my arrival suspected trypanosomes were resistant to it. Continued use of the drug would only fuel more resistance. Instead, it was decided to use a high dose of a different drug (isometamidium), which successfully overcomes resistance to homidium. Livestock owners were initially reluctant to switch from the drug they knew, but community animal health workers were instrumental in discussing the problem with them and they agreed to use it.

Despite its complexities, Maban in many ways presented a relatively straight-forward decision. There are few or no tsetse flies to contend with, human sleeping sickness is absent, and wildlife likely plays little or no role as a reservoir for AAT there. These facts greatly simplified our calculations.

Over the coming months, the cattle in Maban appeared to improve from their general unthriftiness. Adjustment to their new environment certainly played an important role in this. We can imagine that our trypanosome treatments also contributed, though to what extent we cannot be certain.

 

References

Ahmed SK, Rahman AH, et al. An atlas of tsetse and bovine trypanosomosis in Sudan. Parasites & Vectors. 2016; 9(194).

Cnops J, Magez S, and De Trez. Escape mechanisms of African trypanosomes: why trypanosomosis is keeping us awake. Parasitology. 2015 Mar; 142(3): 417-427.

Desquesnes M and Dia ML. Mechanical transmission of Trypanosoma congolense in cattle by the African tabanid Atylotus agrestis. Experimental Parasitology. 2003 Nov-Dec. 105(3-4): 226-231.

Hoots C. Animal Health and the Role of Livestock in Maban County, Upper Nile State, South Sudan. 2014 Mar. Nairobi: Vétérinaires sans Frontières – Germany.

Rahman AHA and Chakraborty A. Observations on the trypanosomosis problem outside the tsetse belts of Sudan. Revue Scientifique et Technique de l’OIE. 2005; 24(3): 959-964.

Uilenberg G. (1998). A field guide for the diagnosis, treatment and prevention of African animal trypanosomosis. Rome: Food & Agriculture Organization.

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3 thoughts on “Animal Sleeping Sickness (Trypanosomosis): An Example of the Pitfalls of Trying to Control It

  1. Very informative and interesting article. We spread a certain species of fly at the Rescue that eats the eggs of the flies that annoy the animals. I wonder if that’s possible in that area or any African area to keep the population at a minimum?

    • Hello, Holly.
      Those are good thoughts you bring up, and this has been looked into to some extent already, thought without much luck. Several small wasp and fly species are known to parasitize tsetse fly pupae, the life cycle stage between a larva and an adult. One of the wasp species (Syntomosphyrum spp.) has been reared and released in large numbers in an effort to control tsetse populations, but the effects were negligible, probably because only a very small proportion of tsetses are actually parasitized by the wasps (about 2 in a thousand individuals). In addition, tsetses and their predator populations probably quickly strike a balance. When parasites reduce tsetse numbers, the parasites also decrease, allowing tsetses to increase again until a relative equilibrium is established.
      The other wasp and fly species are very difficult to rear in large numbers so have not been used for tsetse control.

  2. Excellent blog thanks, the only thing I am missing is whether or some animals were more resistant/resilient to the infection and could act as now the natural reservoir.

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