Thursday, April 14, 2011

Trypanosomiasis Part 1: Sleeping Sickness


This week and next we are going to discuss another arthropod-borne infection that occurs differently in different hemispheres of the world, i.e Africa and the Americas. In Africa, the disease, while heterogenous from west to east Africa, is often fatal within a year of becoming infected and is known as sleeping sickness. In the Americas, the disease is more typically associated with long-term chronic infection that ultimately leads to premature death due to cardiac failure.

Like malaria, trypanosomiasis is caused by protozoan parasites. But rather than Plasmodium species, the pathogenic parasites in this case are trypanosomes. Trypanosomes are in the family Mastigophora, which means that they are flagellated protozoa. Flagellated protozoa have a flagellum, which is a long tail-like structure that provides motility to the parasite. In addition to the flagellum, trypanosomes have undulating membranes that extend laterally down the length of the organism. This structure provides further motility to the parasite. Here are some pictures that highlight the unique structures of trypanosomes:




Notice the flagellum and undulating membrane structures. This particular flagellated protozoan is further classified as a hemoflagellate, because it is transmitted by blood-sucking insects. The hemoflagellates include both the trypanosoma as well as the leishmania (which I will cover following the posts on trypanosomes).

So, trypanosomiasis, both the African and American forms, are caused by the hemoflagellate protozoan parasite of the genus Tyrpanosoma. Below is a picture depicting different morphological forms that kinetoplastids (a group of flagellated protozoa that includes both Trypanosoma and Leishmania) can express through different stages of development. This will be useful as a reference as we discuss the life cycles of the different Trypanosoma species :



The parent species that causes the African disease is Trypanosoma brucei, and the parent species that causes the American disease is T. cruzi. We will consider T. brucei and it's disease, African trypanosomiasis in this post, and T. cruzi and American trypanosomiasis in next week's post.

African trypanosomiasis, or sleeping sickness as it is more commonly known, can be a debilitating and deadly disease if left untreated. As mentioned above it is caused by T. brucei, which requires a vector for transmission to humans. The vector for T. brucei is the tsetse fly (Glossina spp.).

Relative to the other protozoan parasites (Plasmodium) we've discussed so far at Infection Landscapes, T. brucei has a more straightforward life cycle. The trypanosomes are introduced into the human host by injection when the tsetse fly takes its blood meal. Metacyclic trypomastigotes are injected into the host during the fly's feeding. These then transform into bloodstream trypomastigotes, which can then be transported to more distal sites within the host. These trypomastigotes proliferate by binary fission in blood, lymph and cerebral spinal fluid (CSF). Those that remain in blood circulation can be taken up during subsequent blood meals from different tsetse flies. When the bloodstream trypomastigotes find themselves in the new environment of the fly gut, they transform into procyclic trypomastigotes. At this point, the parasite again proliferates through binary fission. The procyclic trypomastigotes then migrate out of the fly gut and transform into epimastigotes, which will multiply in the salivary glands of the fly. Finally, as they proliferate in the salivary glands, the epimastigotes will transform one last time into the metacyclic trypomastigotes, which are the infectious stage for humans and can initiate new infections as the fly takes its next blood meal. The Centers for Disease Control and Prevention (CDC) have produced a nice graph depicting the different stages of the life cycle for T. brucei:


This is the general life cycle of T. brucei. While the life cycle is fairly constant across subspecies of T. brucei, the subspecies do vary dramatically across geography in sub-Saharan Africa, and these spatial distinctions correspond to differences in the manifestation and severity of disease. T. brucei gambiense occurs in West Africa and is associated with slower progression of disease. T. brucei rhodesiense occurs in East Africa and is associated with more rapid progression of disease. Below is a nice map produced by Dickson Despommier at medicalecology.org, which depicts this geographic boundary as well as the level of endemicity of infection:



These geographic distinctions in parasite distribution and disease occurrence are largely demarcated by the landscapes that define different ecologies for Glossina species. The picture below depicts the most important Glossina species for human trypanosome transmission. The fly series on the left shows the different developmental stages of Glossina palpalis, which is the riverine tsetse fly, with the adult fly at the top. The fly series on the right shows the different developmental stages of Glossina morsitans, which is the savannah tsetse fly, again with the adult fly at the top.

G. palpalis, the river tsetse fly, is, not surprisingly, associated with riverine environments. This fly has an extremely high population density along its river corridors, and is thus responsible for high levels of exposure to trypanosomes. Interestingly, though, this fly is limited in its distribution to this specific environment. If you travel only a couple hundred yards back from the river the fly's population density drops dramatically. In fact, G. palpalis is so closely tied to its narrow river habitat that it only serves as an efficient vector for trypanosomiasis within this very narrow landscape. As such, moving human settlements back from rivers can be an important control measure in reducing T. brucei gambiense transmission. However, because of the fact that many human activities (e.g., obtaining water, bathing, washing clothes, fishing, recreation) occur in the water or at the water's edge, eliminating transmission, particularly when fly density is so high, remains very difficult.

G. morsitans, the savannah tsetse fly, is associated with savannah environments. Occupying principally savannah, savannah scrub, and savannah forest habitat, this fly is much more dispersed than G. palpalis, which has a much narrower ecologic niche. However, even though G. morsitans is more robust to the landscape grades in its habitat, it is also very sparse. Indeed, field surveys have shown that the population density of this tsetse fly is approximately 1 fly per square kilometer. So, while its distribution is spatially quite broad, its very low density in any one place determine that this fly's efficiency as a vector is low.

Here are two short videos describing the life cycle of the tsetse fly.
Part 1:



Part 2;



Let's now discuss the disease itself. During the first phase of the disease the trypanosome parasites migrate through the blood to the lymph nodes, which triggers ongoing attacks of fever. These attacks can also be accompanied by headache and sometimes arthralgia. The attacks are often intermittent and can recur over a period of weeks to months. Swelling of the lymph nodes is common, and the appearance of large swelling of the lymph nodes at the back of the neck (known as Winterbottom's sign) is a strong indicator of infection:


Sustained infection can lead to cardiopathy, nephropathy, and anemia, but these conditions do not typically lead to death before the second phase of the disease ensues. Typically in African trypanosomiasis the parasites invade the central nervous system (CNS) as the disease progresses to this second, neurologic, phase. Involvement of the CNS can cause meningoencephalitis as well as associated mental confusion and disrupted sleeping habits. Prolonged diurnal sleeping is the condition from which this trypanosomiasis derives its common name. Without treatment, this neurologic condition will eventually lead to coma and death.

There are widely varying estimates of the disease burden of African trypanosomiasis because surveillance is very poor in remote areas. Nevertheless, some surveys have been undertaken with incidence estimates ranging between 10,000 and 500,000 new cases per year across the whole of the African continent. The map below by Dickson Despommier again highlights those countries with the greatest burden of disease:


The most extensive attempt to date at mapping the distribution and burden of African trypanosomiasis was published here last year in the International Journal of Health Geographics. The continent-wide distribution mapped in this study is presented below:

This map follows the expected lines of demarcation for the occurrence of T. brucei gambiense and T. brucei rhodesiense, and also suggests a high occurrence of disease. It is important to keep in mind that the cases in this map only include those that were reported or captured, and so comprise a minority of the total cases.

This last map below depicts the number of deaths per 100,000 population due to African trypanosomiasis in 2002. As you can see, the mortality associated with this disease presents a substantial burden in several countries:


This concludes the first half of our discussion on trypanosomiasis. Next week I will cover the other form of this disease, American trypanosomiasis, or Chagas disease, which is caused by a different species of Trypanosoma, i.e. T. cruzi.

Stay tuned.

25 comments:

  1. great letter.very simply and all d facts are there.thank u very much

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  2. While moving settlements away from the river can be an effective way to control transmission from the riverine tse tse fly, what can be done in areas where the savana tse tse fly is the main vector? It was mentioned that the savana tse tse is not as efficient as a vector because of its sparse distribution. Does this mean that sleeping sickness is not as big of a problem in areas with this fly? It seems like Tanzania is in savana fly territory and still has a high occurrence of sleeping sickness.

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  3. Other than moving away from the river, are there any ways to reduce the vector population, such as introducing a predator to the tsetse fly? Also, is there any way, other than the use of insecticides, to make the host environment less favorable to the vector?

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    1. Pennie brings up a very important point. It would be difficult to move entire populations away from the rivers that serve as vital sources of nutrition, economy, etc. Having said that, are there any other means to prevent infection? I'm not sure how effective insect repellents are, but are there any such products that could be distributed for example by the arms of the WHO (if any) that are operating in these areas? Besides a predator, could we introduce another species (of course not a vector) that could compete for resources and thereby drive down tsetse populations? I think the robber fly is supposed to be a predator to the tsetse fly, but I'm not sure how feasible it would be to use them in this capacity.

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  4. Tsetse fly control has largely centered around the application of various pesticides for both G. palpalis and G. morsitans. These kinds of efforts typically meet with varying levels of success depending on the local ecologic and geographic conditions. Other means, such as chemical traps and fly sterilization, can be quite effective but are often too costly to be applied practically at large as would be required. Because control is difficult in both the riverine and savannah landscapes, African trypanosomiasis also continues to be a problem in both contexts. This is true even for the more dispersed savannah tsetse fly. Even though the savannah tsetse fly is far more sparse on average, seasonal variation in its population numbers can create periods when the fly is present in much greater numbers.

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  5. In addition to having different species of tsetse flies as vectors, the eastern and western forms of the disease are also different, with the savanna tsetse carrying a more virulent and fast acting disease. While the actual vector may be sparse, the disease burden is great because of the severity. Regardless, interventions to protect oneself from the disease is imperative.

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  7. When infected what are the medications used to treat it? Also, for travelers who will be visiting these high risk areas what kind of medication/vaccination are available? Are they similar to the one taken for malaria?

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    1. @ Thu Hoang, I am just going to add on to what Nachama stated. Unfortunately, there are no preventive drugs for people who travel to areas that are at high risk for Trypanosomiasis. However, the CDC does recommend the following: (1) Wear long-sleeved shirts and pants of medium-weight material in neutral colors that blend with the background environment (Tsetse flies are attracted to bright or dark colors, and they can bite through lightweight clothing). (2) Inspect vehicles before entering (Tsetse flies are attracted to the motion and dust from moving vehicles). (3) Avoid bushes (The Tsetse fly is less active during the hottest part of the day but will bite if disturbed.
      Also, I found out that recent publication of the genome sequence for Trypanosoma brucei gives increase optimism for more drug and vaccine development, so hopefully in the next couple of years we will see drugs developed to prevent Trypanosomiasis similar to those used to prevent Malaria.

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    2. The search for a vaccine against Trypanosomiasis has proved difficult for a variety of reasons, but most notably, this parasite can present with a multitude of variable surface glycoproteins. Often times, once these surface glycoproteins, or antigens, are identified, researchers use this knowledge to develop effective vaccines. However, it is not feasible to create a vaccine based on antigenic recognition when the parasite can present with an incredible variety of these markers. Thus, many researchers are striving to cultivate vaccines that would deliver partial protection. These vaccines would incorporate immunity against particular common antigens (such as those on the flagellar pocket) or cellular machinery (such as transferrin receptors ESAG 6/7) needed by the parasite in order to maximize its potency within the human body. Thus, while humans would still be susceptible to Trypanosomiasis, these sorts of vaccines would offer increased chances of defense and survival, limiting the disease burden across the region.

      For further information regarding vaccine research specific to Trypanosomiasis, I used these two articles:
      - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3323498/
      - http://iai.asm.org/content/77/1/141.long

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  8. I read that there are medications that can be used to treat trypanosomiasis depending on what stage the disease is in. Stage 1 occurs when it has attacked the lymph nodes and requires the medication Pentamidine. Stage 2 occurs when it has invaded the central nervous system and requires medications such as suramin, melarsoprol, eflornithine, or nifurtimox. Many of these medications can be acquired thru the CDC via a physician. Since in most endemic areas lack decent medical resources, most of the people with die before diagnoses and treatment.

    Both treatments for stage 1 and stage 2 are highly effective but are unfortunately not accessible to many who suffer in endemic areas. Furthermore, many of these drugs need multiple injections per day and can have serious side effects such as encephalopathic reaction, chronic gastrointestinal upset, and peripheral neuropathy. There is no test that can be done to determine whether an individual has rid his/her body of this parasite and to complicate matters further patients must tested with a lumbar puncture at least every 6 months for a 2 year period.

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  9. I find it astonishing how the estimate of the incidence of trypanosomiasis ranges from 10,000 to 500,000 cases per year. This is a very large difference. It is mentioned this is due to poor surveillance of the disease in very remote areas. The remoteness of the geographic areas where the disease carrying flies reside seems to be the biggest hurdle in finding an effective control measure. If the burden of the disease cannot even be accurately estimated how will a effective control measure ever be established and its effectiveness measured?

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    1. The range of cases per year is large; however, this range is an estimate across the entire African continent. The level of endemic infection differs across geographic boundaries. For example, as stated in the entry, T. brucei species differ significantly across geography in sub-Saharan Africa. Disease occurrence is also distinguished by the different ecologies for Glossina species. Although surveillance is poor, as mentioned, effective control in reducing T. brucei gambiense transmission measures include removing human settlements and activities that take place near the water.

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    2. The range of cases per year is large; however, this range is an estimate across the entire African continent. The level of endemic infection differs across geographic boundaries. For example, as stated in the entry, T. brucei species differ significantly across geography in sub-Saharan Africa. Disease occurrence is also distinguished by the different ecologies for Glossina species. Although surveillance is poor, as mentioned, effective control in reducing T. brucei gambiense transmission measures include removing human settlements and activities that take place near the water.

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  10. I remember that when dengue and malaria were discussed in class, we talked about how the vectors of these 2 diseases have adapted to the human environment; however, in the case of tsetse flies, we do not see such tendency. I wonder if this is because the human environment does not contain the characteristics of tsetse flies’ preferred breeding sites. Also, I wonder what are the current vector control methods used in the areas with high burden of disease. I saw a comment above that vector control is difficult to achieve in both riverine and savannah landscapes. Then would a more feasible way to control the disease be changing human behavior so that exposure to tsetse flies can be reduced (such as through education and to provide constant water supply so that it would not be necessary for the local people to go to river to get water)? It would be difficult to change human behavior but a community-based approach may make things a little bit easier.

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    1. A community-based approach may be a good idea for decreasing incidence of this disease in both east and west Africa. As stated earlier, vector control by pesticides may not be the best option due the large amount of differing types of landscape terrain that would need to have pesticides with certain properties that coincide with that specific landscape, which would be costly and timely for development. With the community-based approach, harmful chemicals could be avoided. Even though this approach would also be timely in order to build relationships with each community and find a trusted leader, it would in the long run be beneficial to the population of Africa to learn ways to live around the flies environment and protect themselves from bites and from contracting this disease.

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  11. I had read about Trypanosomiasis very briefly several years ago, but didn't realize the disease was so serious, I think due to the innocuous sounding name. Before reading this piece I had also subconsciously mentally categorized it as a disease exclusively endemic to Africa and South America. When reading up on it more today I found from the CDCs website that a surprising large number of Americans are infected, many unknowingly.I found it interesting that the CDC categorized it as a neglected parasitic infection, and label also shared by four other parasitic diseases (cysticercosis, toxocariasis, toxoplasmosis, and trichomoniasis) that have been targeted by CDC for special public health eradication efforts.

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    1. I think you are referring to American trypanosomiasis (i.e. Chagas disease) when you refer to the large numbers of Americans infected. This is a different disease caused by different trypanosomes and vectors. Sleeping sickness doesn't actually occur in the Americas.

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    2. Whoops you are correct, I clicked on the wrong link to post

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  12. The disease burden of trypanosomiasis in the African continent is alarming. I read an article that stated the northwards spread of acute T.b.rhodesiense in Uganda was linked to cattle movements as they were afflicted with both T.b Rhodesiense and T.b gambiense which made diagnosis and treatment impossible. The people were at risk as well as the cattle as well, it led to decreased milk production and increased mortality. One of the challenges the article stated was FUNDING because resources were allocated to fighting the big 3 diseases HIV/AIDS, Tuberculosis and Malaria. There is certainly a huge need for more resource allocation to tropical diseases such as trypanosomiasis. I feel treatment of cattle is very crucial especially since they play an important part being a reservoir for the disease: a person is more likely to acquire sleeping sickness via the bite of a tsetse fly coming from a cow than from another infected person, therefore encouraging treatments of the disease in cattle such as bringing the cattle’s in for treatment can help contain the disease much better by simply tackling the spread with restricted application.

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  13. Upon researching this disease, I found out that the maturation process of trypanosomes is so complex and so difficult to complete that only about 0.1% of tsetse flies carry mature, infective trypanosomes (See Brun et al., 2010). This is compounded with the fact that the viable habitat for the tsetse fly is so narrow as stated in the post. It is incredible that a disease and vector that have such specific necessities for survival are such a burden. Due to poor healthcare infrastructure in the areas that African trypanosomiasis is endemic, many people who have the disease do not, and in many cases, cannot seek out treatment. The clinical progression of the disease leads the infected individual to be unable to work or provide, and ultimately death. When the infected individual does seek out and receive care, most of the treatments for African trypanosomiasis are ineffective and dangerous that they can also death. However, there is hope that with the appropriate concentrated efforts programs can provide comprehensive diagnosis and control of this disease. I am a proponent of active case detection, mostly because this technique is based on the knowledge of existing cases. In areas where the disease is endemic, mobile teams can go out and actively screen and diagnosis those that have the disease. There is also a rapid test for the disease called the card agglutination test (CATT) that has 98% sensitivity and 95% specificity (See Brun et al., 2010). Active case detection has lead to decreased prevalence of the disease and elimination in certain areas (See Legros et al., 2002). This can in turn lead to more streamlined measures for vector control and treatment.

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  14. According to Doctors Without Borders, it is difficult to diagnose Sleeping Sickness before the second stage in which neurologic symptoms occur. In order to properly diagnose, determine the stage of the diseases, and assign the proper treatment, a lumbar puncture needs to be performed. Because the symptoms in the first stage are not particular to Sleeping Sickness, detection and diagnosis of Sleeping Sickness often does not happen until the disease has further progressed and attacked the nervous system. It would be great if Sleeping Sickness can be screened for in the population since it is endemic to Central Africa. However, performing lumbar punctures across communities is both exhaustive, expensive, and painful. I would like to know if there are other means of detecting Sleeping Sickness without lumbar puncture procedures.

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  15. Given G. Palpalis' limited habitat (close to rivers), one intervention that could be attempted would be to provide mosquito netting (along with education on how to use it) to communities which require river access. This netting could be donned when going down to the river, and as a way of keeping costs of the intervention down, could be shared within communities for use when needed. Given, again, the fly's habitat, this could also help to isolate cases, as the flies would have one less source of T. brucei infected blood to feed from.

    As a side note, there is a seeming discrepancy between the maps from the International Journal of Health Geographics, which shows Ethiopia as having no reporting of cases after data processing was completed, and the last map (source unknown) which seems to indicate a high rate of deaths in Ethiopia. Professor Walsh: am I misinterpreting the phrase "no reporting"?

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    1. Good question. The maps differ because of their source data. The map from IJHG is based on a single study (albeit covering the period 200-2009), under which cases were not identified. The other maps are derived from long-term (above) reporting of cases from multiple governmental sources as well as mortality (below), which is itself a different outcome and reported/captured differently.

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  16. Interesting disease, especially the unique demonstrations of disease according to the varied African terrain. I have read of many various Tsetse fly control methods including completely destroying forest habitat, crop dusting, routine insecticide spraying of bushes, special sticky clothing and special traps with insecticide and black cloth (they are attracted to black), all of which do not seem ideal and quite costly to implement. I wonder what types of educational approaches have been utilized in order to decrease the risk of exposure for the local people. Although moving people away from the water decreases risk exposure it does not seem likely to keep people away from the river as it is essential to living. Furthermore, if the Tsetse fly infects animal host like cattle, I would think it would have a negative impact of production in terms of growth, reproduction and providing meat and dairy, further burdening the population. I would be interested in knowing what prevention methods there are for livestock.

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