Thursday, December 3, 2009
Our exploration of Chagas disease began with a definition. A severe disease caused by the parasite trypanosoma cruzi, and spread by triatomine, or ‘kissing’ bugs, Chagas disease kills more people yearly in Latin America than does malaria. The bugs are endemic to Latin America, and they like to live in cracks in poor housing, particularly in adobe or mud houses. There are various means of infection, the most common of which occurs when the bugs defecate near an orifice or bite site into which the victim unknowingly rubs the feces, together with the parasite. The parasite can also be ingested with food or spread through blood contact, organ transplants or from mother to child. Although mild flu-like symptoms can present immediately after infection, often there are few or no symptoms. An exception to this trend is the sign of Romana, in which small children who are infected develop one red, puffy eye. Additionally, isolated incidents have yielded more severe symptoms, such as in a recent outbreak in Brazil, where bugs were crushed into sugar cane juice. Ten to twenty years after infection, with few other symptoms, the victims can develop serious heart disease or intestinal malformation, which are often fatal. Thus, the development and presentation of Chagas disease is particularly insidious.
While the modes of infection are known, the mechanism of the disease’s function remains nebulous. Authorities do not know, for example, why ingesting the parasite with sugar cane juice might have caused more severe symptoms, although they postulate that perhaps more parasite would enter the body if it the whole bug was crushed into food and ingested, or that some strains are more virulent than others. Nevertheless, the amount of time that the parasite can survive in feces is unknown, and methods to purify foods are not widely known or practiced. Another current hypothesis is that the reaction to the parasite is, in fact, an autoimmune reaction. There is evidence of an autoimmune response to the parasite, and some researchers also wonder if the chronic inflammation seen in advanced Chagas-caused heart disease is due to lingering antigens or to long-term anti-parasitic agents, and not from the living parasite itself. However, immunosuppressant therapies have demonstrated an increase, rather than a decrease in mortality, raising questions about the autoimmune hypothesis. It has also been suggested that perhaps the response is sometimes primarily autoimmune and sometimes primarily caused by the parasite itself, depending on the strain of the parasite and the genetics of the host. In order to accurately treat Chagas disease, more research into its mechanism is desperately needed.
Some such research on the parasitic mechanism has been conducted, and has demonstrated high levels of creativity (although at great cost). In 2000, several scientists decided to study the parasite in a low-gravity environment, space, in order to try to elucidate its mechanism. They focused on one particular, unnamed enzyme, and treated it with a variety of natural compounds to try to find one that inhibited its function. While this type of research is very innovative and seems to yield promising results, it is hard to imagine that it would be financially or practically sustainable in the long term.
This lack of understanding of the exact mechanism has contributed to there being only a handful of existing pharmaceuticals that show varying degrees of effectiveness. Funding for further research and drug development has been limited, due largely to the pharmaceutical industry’s reticence to devote the R&D resources to developing drugs that will not yield much in revenue. Thus, though companies have sometimes stumbled across compounds that show some efficacy in treating Chagas, few companies have brought these drugs to market. Happily, some non-profit organizations have filled this gap. Pharmaceutical companies have donated some of these promising compounds to non-profits, which are studying them further and hope to bring them to market. While this is not the most efficient way to find a treatment or cure, it certainly provides some progress. Development of new drugs would allow us to stop using bendizole which, while being the most common drug used to treat Chagas disease, is not always effective at killing the parasites.
One of the new drugs being researched is TAK-187, an anti-fungal agent which has been effective in treating Chagas disease in mice. It seems to work by blocking ergosterol, a steroid that is vital in the parasite’s development. The hope is that it will be more effective and have less harsh side effects than the current treatments. Another antifungal, ravuconazole, is also being researched thanks to the collaboration of Eisai Co. Ltd. and Drugs for Neglected Disease Initiative (DNDi). Eisai and DNDi have collaborated to enter final testing and to develop potentially affordable marketing of E1224, a pro-drug form of ravuconazole. The drug is currently in the late stages of the approval process and if this drug is approved the company hopes to create a two tired pricing scheme which will allow ravuconazole to be sold at a lower price in endemic countries and at a more expensive price in other areas. This would make the drug affordable where it is needed most, while still providing incentive for its production. There is less hope for TAK-187 because it is still in the early stages of development and drug testing is both a lengthy and expensive process. Because the main market for the drug would be poor areas in Latin America, even if it is proven to be effective there is no guarantee that it will be mass produced.
Besides the use of drugs, the other way that we currently treat the heart disease caused by the Chagas parasite is through heart transplants. However, this is a very complex and dangerous procedure and because Chagas disease largely affects those of low socioeconomic status, it is not feasible for the population that needs it most. The latest move has been to try to cure the disease by replacing the damaged heart cells with bone-marrow derived cells. Experiments in mice have successfully shown that this procedure lessens the inflammation and fibrosis in the heart and another trial in Brazil proved that this would be a safe procedure in humans. Because of the positive outcomes of this first trial in humans, researchers are currently working on a phase II trial to test for efficacy which will be larger randomized, double-blind and placebo controlled trial.
Some other novel treatment strategies have also been known to be effective in combating Chagas disease. Especially promising is use of genetically engineered organisms to alter the disease transmission patterns. As previously mentioned, this parasitic disease is propagated when the 'kissing bug' infects a host with the parasite. By targeting this insect population and the parasite, which act as the vectors for this condition, its spread might be halted and eradicated. Insecticides have been considered for use in this situation and in the similar malaria epidemic, which is propagated by mosquitos. Attempts to implement such measures, however, have not been entirely effective. Their lack of total success has led to the conclusion that interfering with the insect's ability to transmit the disease, rather than outright killing it, may be a better approach to take.
Armed with this new information, many researchers have turned to genetic engineering to provide a solution. This relatively new technology allows scientists to alter the genomic material of organisms, thus affecting their ability to produce certain proteins and to facilitate specific physiological functions on a molecular level. This alteration translates to a change in the organism's environmental fitness and abilities to perform functions and to survive. One model of genetic engineering has been applied to the 'kissing bug' itself. By tweaking the organism's genome such that it is unable to sexually reproduce, scientists are able to generate a cohort of sterile insects. The theory is that introducing these bugs into the wild will provide competition for fertile insects and will interfere with the species' ability to proliferate. Thus, genetically engineering the insects may decrease their survival in the natural environment and reduce the presence of the Chagas Disease vector.
Similarly, some researchers are focusing on genetic engineering that targets a bacterium upon which the disease-causing parasite depends for obtaining essential nutrients. In the natural life cycle, the parasite picks up bacterium from feces upon which it feeds, and the bacterium reside in its gut and function to facilitate nutrient absorption. This symbiotic relationship becomes vital to the parasite, and it would not be able to survive without the bacterium. Thus by interfering with this relationship, scientists can impact the disease-causing vector directly. Researchers have been successful in modifying the bacterium in such a way as is harmless to the bacterium, yet prevents its facilitation of nutrient reabsorption for the parasite. By introducing this type of genetically engineered organism into the wild, scientists hope to effect a huge reduction in the propagation of Chagas Disease.
While genetically engineered organisms may have potential to provide a halt to the Chagas Disease epidemic, several drawbacks exist to their implementation. Public sentiment is not universally supportive of such technology, which may function to alter an organism from its naturally occurring condition. Also, introducing an altered species into already balanced ecosystems may precipitate huge unforeseen changes. It is extremely difficult, if not impossible, for scientists to unravel the intricate interconnections that comprise an ecosystem. Affecting the reproductive patterns of just one part of a system, such as is proposed by genetic engineering aimed at decreasing 'kissing bug' populations, may create a huge imbalance in the predator/prey relationships that maintain current species populations. Furthermore, introducing new genetic materials into the environment may result in both vertical and horizontal transfer, which implies that the engineered genes may infiltrate unintended species. Thus while technology enables researchers to implement genetic engineering, it may not be advanced enough to do so safely.
Although it is endemic to Latin America, Chagas disease is spreading rapidly due to globalization, travel, and blood transfusions. With this level of mobility, CD is only going to become more prevalent in the United States, not less, which is why it is necessary for developed countries to allocate funding towards CD treatment. It needs to be recognized that this problem is no longer isolated to Latin America, as it once was. Gemma Ortiz, head of the Chagas campaign for Doctors Without Borders commented, “One hundred years later, the disease continues to be transmitted to lots of people. And as people move around and the world is becoming a more global place, we see it in North America, Japan, Europe, and Australia”. According to the most recent data available, 300,000 people in the United States have Chagas, and one out of every 300 Latino blood donors in Los Angeles County tests positive for Chagas, and this number has been increasing since the 1990s. This serves only to drive up health care costs, with all of the blood screening necessary, as well as hospital stays and deaths due to the heart, liver, and other problems caused by CD.
In order to prevent these costs and this extra burden on the health care system, it is a worthwhile endeavor to put money and resources towards R&D to develop and distribute vaccinations for this disease. Improving vaccinations/prevention, early detection (as the disease is much more curable in the acute phase than in the chronic phase), and drug development is necessary in order to prevent future costs associated with CD. As Dr. Sheba Meymandi, director of cardiovascular research and invasive cardiology at the Olive View- UCLA Medical Center (the only place is the country that treats CD) said, “The goal (for surveillance and better treatment) is to catch it, and treat it before it becomes an expensive medical condition. If you can decrease the risk, that’s a huge success.” CD is no longer an isolated problem faced only by developing countries, and unless the US supports the development of prevention, early detection, and treatment, the burden on the health care system will only increase.
The fact that there is such little awareness, understanding, and research of a disease that afflicts over sixteen million people worldwide is astounding. Few effective treatments exist for the disease, due to the fact that it primarily burdens impoverished peoples and thus provides little financial incentive for pharmaceutical companies to invest in drug development. Failures in the attempts to elucidate the exact mechanism make finding an effective treatment even more of a challenge. Yet despite these enormous roadblocks, collaboration between some pharmaceutical companies, community organizations, and organizations that focus on neglected diseases, has generated some hope and allowed for some much-needed research to be conducted on the disease mechanism and treatment. New pharmaceuticals have been developed that show promise, but many are in the early stages of development and must endure a lengthy testing process before they can go to market. Exciting advances have also been made in creating genetically engineered organisms to reduce disease transmission, yet this practice raises many controversial issues that must be addressed before it is implemented on a larger scale. As Chagas disease continues to traverse national borders and become more prevalent in wealthier countries like the United States, we can only hope that this will stir awareness and incentivize more investment in development of new technologies to combat the disease. The growing prevalence has already prompted physicians in the United States to create better surveillance methods and created an urge for better research and treatment options. CD has the potential to place an enormous burden on the American healthcare system unless we invest now in technologies to prevent more expensive consequences later.
Monday, November 23, 2009
Sunday, November 22, 2009
When I traveled to rural Honduras in the summer of 2008, I had never heard of Chagas disease. By the end of my trip, I was terrified of Chagas, even though I slept underneath a mosquito net in a concrete building. The gruesome mode of transmission was enough to scare me, as horror story might, but it was the silent progression of the disease that most frightened me. I was volunteering with a clinic, and most of the homes we visited were adobe or wood homes that the kissing bug loves to infest. Surely a huge segment of the population had been infected, and wouldn’t know it for years to come, until suddenly organ failure ripped them from their families.
The community we were in was very isolated from most medical care and much medical knowledge. The town our little ill-equipped clinic was in was located literally at the end of the road (which was unpaved). To get to the nearest hospital, a three-hour drive over bumpy, unpaved roads was required. The nearest big city was six or seven hours away. Villagers hiked sometimes for hours from their unmapped, tucked-away homes just to come to our clinic. I don’t know if our clinic checked people regularly for Chagas (I believe it did not), but even if it did, treatment would be nearly impossible, since the clinic was not equipped for it, and the villagers were too poor to pay much for it. Add on top of these difficulties a cultural distrust of medicine, and the toxic effects and limited efficacy of available drugs, and the challenge Chagas poses worsens.
We saw multiple children there with one red, puffy eye. We figured they had pink-eye or something innocuous until we found out that this is Romana’s sign, which sometimes pops up in children who have been infected via the eye by the Chagas parasite. Their parents, oblivious to the meaning of such a seemingly harmless symptom, and busy tending to a whole family brood, were not even alarmed enough to ask us about it. While they lived in ignorance, and we stood essentially unable to help, the disease worked silently to deteriorate these kids’ organs.
Chagas poses a huge public health challenge for some of the poorest countries in Latin America. Largely overlooked by the international community (although its spread into the U.S. blood supply may increase interest), the disease kills thousands every year while drug companies try only half-heartedly to help. While non-profits have played a large role in spurring research into treatment, and improving patient care and teaching, they do not have the resources necessary to effect large-scale improvements in public health. Considerable money needs to be invested in methods of prevention (for example, knocking down adobe houses and building concrete ones instead, or genetically modifying the disease vectors), awareness (public health outreach efforts to teach communities about how to identify and fight infestations), and treatment (developing better drugs or vaccines, or improving stem cell therapy). Yet, while Chagas continues to affect only the poorest citizens of the poorer countries, this money appears unobtainable, and the disease's horror will persist.
- Joanna Sharpless
Dr. Sheba Meymandi discusses her attempts to raise Chagas awareness.
Developing World's Parasites, Disease Hits US
The Wall Street Journal
Stephanie Simon and Betsy McKay
22 August 2009
To complement some other posts focusing on the issue of Chagas in a broader sense, here's a story of the disease through the eyes of one woman doctor battling the disease in poor communities in California.
Dr. Sheba Meymandi, a physician who runs the first Chagas clinic opened in the U.S., has committed her life to improving health in underserved communities where Chagas disease runs rampant. One weekend per month, Dr. Meymandi travels by car to impoverished Latino communities near the LA clinic and uses churches as makeshift clinics in order to test and treat patients for Chagas.
One of her biggest challenges is convincing people to get tested, as many don’t care to be tested for an “exotic” disease. Another problem is the bad reputation of the treatment regimen; the treatment therapy is associated with a slew of unfortunate side effects including memory loss and lack of sensation in the limbs. Many illegal immigrants are also unwilling to obtain treatment because they don’t want to draw attention to themselves.
Dr. Meymandi asserts that Chagas should no longer be considered an exotic disease, as it is highly prevalent particularly in shanty towns lining the U.S.-Mexico border where overcrowding, malnutrition, poor sanitation, and much animal-to-human contact are present. Poor drainage systems are cesspools for breeding of Chagas bugs, and a lack of window screens allows for easy transmission to humans.
Raising awareness of the disease burden has become a major goal, and already health care legislation is pending for a full report to congress on Chagas along with several other diseases dubbed (very appropriately) “neglected infections of poverty”. This article and video gives us another look at issues raised in many other posts in this blog regarding the social causes of Chagas, the extremely poverty associated with Chagas, and public's lack of knowledge on the issue of Chagas. Yet examining the issue through the eyes of one doctor who has made battling Chagas her life's work gives us insight that we can't see in other news reports. We can use the issue of Chagas as a lens through which we can view broader controversies in society, such as debates about healthcare and the health and human rights (or lack therof) in illegal immigrant populations in the United States. Decisions made on these broader issues will greatly influence the future impact of Chagas disease in the U.S.
Find the article at http://online.wsj.com/article/SB12
Isabela Ribeiro et al, 2009
Public Library of Science Journal- Neglected Tropical Diseases
This article discusses the need for new and improved treatments for Chagas disease, and sets up short term, medium term, and long term goals for this process. Shorter term goals include better use of existing treatments through new formulations and expanding access. Longer term goals include development of new drugs. The article discusses the 2 current treatments available (that have been mentioned in previous articles)- nifurtimox and benznidazole. However, these are limited to treating the acute phase of the disease, not the chronic phase. The article mentions that no promising new drugs are expected anytime soon, although according to other articles there is one- Ravuconazole, discovered and developed by Eisai Co.
There are many barriers to developing treatments, including the fact that there is little standardization among the protocols and parasites used by researchers in assays. Thus reproducibility has been difficult to achieve. Few rigorous trials have been conducted in CD, particularly to test drug efficacy in patients with chronic CD, since such patients often do not present any clinical disease manifestation until a very advanced stage. CD research is often deemed “too difficult” by many.
One development to help deal with these issues is the creation of non-profit product development partnerships (PDPs) which work to fill in the gaps for neglected diseases. These PDPs offer a different model, since R&D is no longer financed by a product’s sale price. A PDP is currently working on developing a better CD portfolio to address the needs of patients. They aim to deliver more effective treatment for acute, indeterminate, and chronic CD and are working on a pediatric formulation of benznidazole.
Researchers at UGA provide first look at protein expression in Chagas disease-causing parasites
Major advances have been made in elucidating the genetic processes of Trypanosoma cruzi, the parasite that causes Chagas. This article highlights findings from a study at the University of Georgia, where a research team successfully conducted a survey of protein expression in the four lifecycle stages of the parasite. Their results show distinct protein expression abundance and specificity during different stages of the life cycle.
The research is useful because it could hold the key to a new drug or vaccine target. As touched on in previous posts, current treatments for Chagas aren’t always effective and no vaccine has yet been developed. The problem with developing a vaccine lies in the complexity of this four-stage parasite lifecycle, as it complicates attempts to create an effective therapy that can target and eliminate the parasite in all its different stages. But by examining protein expression along with the recently developed gene map, scientists may be able to make decisions on the viability of specific large gene families as candidates for a vaccine.
This article shows thad advances in bioinformatics such as these are integral to drug and vaccine development for Chagas. Yet we already know that the biggest barrier to Chagas’ vaccine development is not scientific. As Chagas disease afflicts mainly impoverished peoples, there is little financial incentive for drug manufacturers to work invest in R&D for a treatment. Public-private partnerships and market commitments need to be formed in order to ensure that the different private and public goals are aligned towards finding a vaccine.
Nevertheless, these genetic breakthroughs are a hopeful sign in the pursuit of a vaccine for a life-threatening disease that afflicts more than 20 million people around the globe.
Article found at http://www.innovations-report.com/html/reports/life_sciences/report-46584.html