Thursday, April 28, 2011

Trypanosomiasis Part 2: Chagas Disease


Last time, we discussed African trypanosomiasis, which requires the tsetse fly as a vector and occurs exclusively in sub-Saharan Africa. This week we discuss another form of disease caused by another trypanosome parasite.


In the Americas, a different trypanosomiasis occurs in many countries and is associated with a relatively high prevalence of chronic disability. This is the American trypanosomiasis and is more commonly known as Chagas disease.


In Trypanosomiasis Part 1, we noted that both the African and American forms of this disease are caused by the hemoflagellate protozoan parasite of the genus Tyrpanosoma. Below, I am again including a picture that depicts the different morphological forms that Trypanosoma can express through different stages of development.




This can be used again as a reference as we discuss the life cycle of the unique Trypanosoma species that cause American trypanosomiasis, i.e. Trypanosoma cruzi. 


As was T. brucei, which you will remember as the trypanosome parasite that causes African trypanosomiasis, so too is T. cruzi transmitted by a vector. In this case, the vector is the reduviid bug, of which there are many species. The parasite can also be transmitted from mother to fetus during pregnancy, through breastfeeding, and by way of organ or blood transfusion. Indeed, blood transfusion is the second most common form of transmission. Nevertheless, vector-borne transmission through reduviid bugs is far and away the most usual path to human infection. We will come back to the vector, but first let's go through the life cycle of T. cruzi because even though this parasite a trypanosome, it interacts with its host quite differently from the T. brucei trypanosome we covered previously in Trypanosomiasis Part 1. 


To begin, the metacyclic trypomastigotes are not injected into the skin of the host by the mouthparts of the blood sucking vector. As the reduviid bug takes its blood meal, it defecates on the host's skin surface. The metacyclic trypomastigotes are actually in the feces of the feeding vector (for reasons I will discuss below). In order to gain entry to the host, two things are required. First, the host must aid the trypanosome parasites by rubbing the area around the site of the reduviid bug bite wound, which is facilitated by the itchyness that follows the feeding. Second, once introduced into the wound, the metacyclic trypomastigotes must penetrate host cells to become established (the host cells the metacyclic trypomastigotes are capable of infecting are many and varied). This is quite a different, and more difficult, means of entry than we saw with T. brucei and its Glossina vectors. Incredibly, once T. cruzi metacyclic trypomastigotes have gained entry into host cells, they are able to render the defensive lysosomal activity of the host cell ineffective from within the parasitophorous vacuole by maintaining a neutral pH. The parasites then enter the intracellular fluid and begin to transform into amastigotes, which then multiply by binary fission. Of key importance is that once these parasites have gained entry into the host cells, they are intracellular parasites. This is very different from T. brucei, which remains an extracellular parasite throughout its life cycle in the human host. The intracellular amastigotes eventually transform into trypomastigotes and then break through the cell and enter the blood stream. This stage can either enter other non-infected cells in the human host and continue the cycle, or be taken up by and infect other reduviid bugs during subsequent blood meals. Once the trypomastigotes have been ingested by the vector, they transform into epimastigotes in the midgut of the bug. Here the epimastigotes multiply by binary fission, transform into metacyclic trypomastigotes, and then migrate down to the hindgut. As the reduviid bug takes its blood meal it evacutes the hindgut so that it may continue feeding. As it voids, the metacyclic trypomastigotes are removed to the surface of the skin of the human host to begin the process again. The Centers for Disease Control and Prevention (CDC) have created a nice graph demonstrating the different stages of T. cruzi's life cycle:








As mentioned above, the vector for T. cruzi is the reduviid bug, also known colloquially as the assassin bug or kissing bug. In reality, these names are quite vague and actually designate an extraordinarily large group of insects in the Reduviidae family (there are approximately 7000 known species in this family). There are three genera in this family that are capable of transmitting the trypanosomes that cause Chagas disease: Triatoma, Rhodnius, and Panstrongylus. Those species of bugs in the Americas that fall into the group that can transmit T. cruzi to vertebrate hosts we can collectively refer to as the triatomines, which are those members of the subfamily, Triatominae, of the Reduviidae family. The point is that there are a lot of these bugs, they are diverse and widespread across the Americas, and they feed on a wide range of vertebrate hosts. However, Triatoma infestans and Rhodnius prolixus are the two vectors that are most important for human transmission because these are so well adapted to human habitation


Here are some pictures of these important human vectors:


Triatoma infestans

Rhodnius prolixus

There are geographic differences between these two bugs. The former, T. infestans, is widely distributed throughout the area known as the "Southern Cone", which is traditionally comprised of Chile, Argentina, Uruguay, and Paraguay. The geographic defining feature is that area south of the Tropic of Capricorn in South America, which would also include parts of southern Brazil. The distribution of T. infestans actually extends north of this Southern Cone to include Brazil, Bolivia and Peru. Here is a nice distribution map of T. infestans prepared by the Pan American Health Organization (PAHO):






For the most part, T. infestans is domestic across this region, meaning that it has adapted to the human environment, even though it can be found in quite diverse climes. It seems to be able to live wherever humans and their domestic animals can live. Vinchuca is the common name for this bug in those parts of the world where it is commonly found.


R. prolixus is concentrated more in the northern part of South America and throughout Central America. Here is another good PAHO distribution map for R. prolixus:






R. prolixus is also mostly domestic, though there are some areas where it exists in sylvan populations. Regardless, this species is also quite robust to climate differences and is highly adapted to the human environment. Interestingly, the sylvan R. prolixus is highly adapted to palm tree habitat and the vertebrate hosts found in this setting. This is interesting because throughout northern South America and Central America, the domestic form of this bug is very closely associated with thatched-roofed habitation, which typically employs palm leaves as the source material.


Domestication is the key to understanding both of these species as established vectors for Chagas disease. Much like the Aedes aegypti mosquito, T. infestans and R. prolixus are superbly adapted to the human domestic environment (although the mosquitoes and reduviid bugs exploit very different ecological niches). Two critical factors contributing to the efficiency of the reduviid vectors are 1) housing materials, and 2) livestock animals. Thatched roofs provide some of these best habit for these reduviid bugs:






The bugs bury themselves in the roofing materials, where they remain hidden during the day, and come out for feeding during the night. Given that palm thatch is ubiquitous as a roofing material for rural homes throughout the Americas, this has become a critical component to the domestic ecology of this vector. In addition to roofing material, these reduviid bugs can also live quite happily in the crevices that are common in the mud and wood used to build walls and floors. Notice the many opportunities for these vectors in the wall of the house in this photo:






Livestock, primarily cattle and pigs, can also serve as reservoir hosts for the trypanosomes and are equally suitable hosts for the reduviid bugs. As such, the placement of such animals in proximity to human habitation is an important determinant for the human transmission capacity of these vectors. When the livestock are kept close to the home (sometimes animals are free to range in and out of the household), the potential for human trypanosome transmission is greatly increased.


It follows, then, that two of the most important approaches to vector control are 1) modifying the materials used in small scale housing production, especially in rural areas, and 2) changing livestock practices to keep domestic subsistence animals far removed from the home. Unfortunately, the economic constraints of rural domestic life often preclude these kinds of modifications because such changes are cost prohibitive. Therefore, vector control remains an ongoing problem in much of the Americas despite the widespread use of insecticides.


Let's now turn the discussion to the disease itself.


Chagas disease is most often a chronic, but nevertheless insidious, condition. Acute symptoms do present, but this stage of infection is more often asymptomatic with the exception of the chagoma, which will often develop at the site of the bite within a few days after infection. The chagoma is a lesion that forms at the intial point of infection by the metacyclic trypomastigotes after they are rubbed into the open wound left by the biting reduviid bug. Because the reduviid bugs will often bite the face around the eyes or lips, the chagoma often develops around the eye with accompanying swelling. This distinctive characteristic is known as Romana's sign:




Aside from the chagoma, systemic symptoms, such as fever and swelling of the lymph nodes, spleen and liver, may also be present, but are less common. Acute congestive heart failure can also present, but is quite rare in the acute phase.


Central to the pathogenicity of T. cruzi is its targeting of the tissues of hollow organs. In its chronic form, Chagas disease affects these organs, with the heart and the gut particularly invovled. Those trypomastigotes recently transformed from the intracellular amastigote parasites and released from their damaged host cells, will reneter the blood stream and can take up residence in the cells of many tissue types. However, they most commonly infect the cells of the heart, gut, central nervous system, reticuloendothelial system, and urogenital tract. At this point, the trypomastigotes will again transform back into the tissue-damaging intracellular amastigotes and the cycle continues...for perhaps 20 to 30 years. Roughly one third of those who are chronically infected will develop organ damage in one or more of the above mentioned organ systems. Approximately 2/3 of these will experience heart damage and 1/3 will experience gut damage. These are not mutually exclusive. In other words, some one with cardiac damage can also have intestinal damage, and can also have CNS damage. The biggest killer from chronic Chagas disease is sudden death from cardiomyopathy-induced arrhythmia. This is an example of trypanosome damage to the heart resulting in cardiomyopathy:




The descriptive epidemiology of Chagas disease is poor because the surveillance is poor. In other words, the occurrence of the disease throughout the Americas is uncertain. Much like the difficulties that surround effective surveillance of African trypanosomiasis in poor rural communities in sub-Saharan Africa, so too we find similar barriers to surveillance of American trypanosomiasis across poor rural communities in Latin America. An additional factor that impedes surveillance in the Americas is that Chagas disease is much more often a long-term chronic disease that exhibits few or no symptoms until the disease is quite advanced. Nevertheless, efforts of PAHO have yielded estimates that range between 8 to 11 million currently infected. In other words, a rough estimate of the prevalence of Chagas disease in the Americas ranges between 8-11 million people. In addition, up to 100 million people are at risk for infection throughout the Americas.  Here is a distribution map produced by the World Health Organization (WHO) showing those countries where the disease is endemic:



However, the distribution is far from uniform across the whole of Latin America. The actual distribution is closer to this map below:


Notice the two distinct geographies corresponding to the "Southern Cone" of South America and to Central America and Mexico. These follow the same distribution patterns of the different vector species, T. infestans and R. prolixus, respectively. 

The WHO has estimated the disability-adjusted life years (DALYs) attributable to Chagas disease across the Americas:
   no data
   less than 10
   10-20
   20-30
   30-40
   40-50
   50-75
   75-100
   100-150
   150-200
   200-250
   250-450
   more than 450



Clearly, Central America and South America, and especially Bolivia, suffer much disability due to chronic infection with the trypanosome parasites.

As alluded to above, control efforts for Chagas disease are largely focused on controlling the vector. But this is a difficult prospect given the wide distribution of several species of reduviid bugs, as well as the primary vectors' close adaptation to the human environment. Indeed, these vectors' ecology is based in this human environment. The rebuilding of homes with alternative, often more expensive materials, and the lack of suitable land for livestock animals that is far removed from the environs of the home, conspire to make the elimination of this vector unlikely.

Without a vaccine and with the continued reliance on insecticides, which can ultimately lead to resistance, Chagas disease is likely to remain endemic in the Americas and be a major contributor to cardiac disease and premature death and disability for a long time to come.


Next time at Infection Landscapes, I will discuss those other kinetoplastids, kin to the Trypanosoma, the Leishmania, and their associated disease, leishmaniasis.


     

7 comments:

  1. I'm curious as to how far along progress for a Chagas disease vaccine has come. More specifically, are impediments scientific or political (read: financial) in nature?

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  2. Very informative post. When I spent a semester in southern Mexico in college, Chagas disease was one of the things we learned about. I remember learning the importance of early detection and treatment of Chagas disease. I think it would be interesting to include a section on the clinical treatment of Chagas disease and the timeframe for medical intervention in order to prevent chronic disease and future organ damage.

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    1. This comment has been removed by the author.

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    2. Hi Max,

      The most effective treatment for Chagas is to attack the parasite early in the infection with a long course of anti-parasitic drugs (benznidazole or nifurtimox). They both have fairly serious side effects (and neither is FDA approved) and likely are both expensive and logistically difficult to administer to the rural populations most at risk.
      The Mexican article below, however, makes a compelling argument for early treatment on an economic basis, showing that for a younger patient in the working population, the cost of treatment (they estimated it at about $10,000 USD) is still less than the lost potential productivity of the person. That might sound callous, but hopefully could help convince governments or other bodies to fund treatment. That of course does not even account for the human suffering that could be alleviated.
      In older patients the picture is murkier, as depending on the age of infection, the patient may die of natural causes before the more serious effects of the disease are felt.

      References:

      http://www.cdc.gov/parasites/chagas/health_professionals/tx.html

      http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0002776

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  3. Matt-

    Here is an interesting article exploring some of the issues behind a potential vaccine for Chagas disease and other so-called "neglected diseases".

    http://www.ncbi.nlm.nih.gov.newproxy.downstate.edu/pubmed/21653960

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  4. During the first year of medical school, we discussed Chaga's disease to a great extent. Because I go to school in Miami, where there are large populations of people from South America, it is actually quite common to see patients with Chaga's disease. As the article stated, due to the nature of the Trypansoma cruzi life cycle, a person may not present with cardiomyopathy until 20 to 30 years from initial infection.

    To expand a bit, the heart has three major layers: the epicardium, myocardium, and endocardium, listed from outermost to innermost. In Chaga's disease, the affected layer is typically the myocardium. Histological examination shows that the cardiac myocytes are in disarray, unlike the ordered arrangement of healthy cardiac muscle fibers. This leads to the conduction irregularities and arrhythmias.

    Chaga's disease has a similar timeline to the progression of rheumatic fever. People who had rheumatic fever as children may present with heart failure 30 years later. Like Chaga's disease, it is also typically seen in people who grew up in South America, the Caribbean, or Africa. For major cities like NYC and Miami, due to the large immigrant populations, both of these "neglected diseases" are quite relevant.

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  5. The reduviid bug is quite crafty in getting its victim to aid in his or her own victimization. They then proceed to infect their host much like how some mosquitoes do, by overtaking the mechanism and DNA of certain host target cells in order to increase transmissibility. It is frightening to know that there are about 7000 of these assassin bugs out there, with various subfamilies including Triatoma infestans and Rhodnisu prolixus being the vectors that most affect humans. These vectors are considered domesticated since they livestock and housing material put the m in close proximity to humans. I wonder what on the human face makes it attractive for attack to these bugs. Is it the amount of sinuses that exist? Vaccines are probably not going to be realized for some time because of the massive variety of bugs that exist.

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