Date Published: December 27, 2007
Publisher: Public Library of Science
Author(s): Rick L Tarleton, Richard Reithinger, Julio A Urbina, Uriel Kitron, Ricardo E Gürtler
Abstract: The authors discuss the key challenges that undermine the control of Chagas disease and that must be urgently addressed to ensure long-term, sustainable control.
Partial Text: Through its impact on worker productivity, premature disability, and death, Chagas disease accounts for 670,000 disability-adjusted life years per annum . This makes it the most important parasitic disease of the Americas. It is both a disease of poverty (Figures 1 and 2) and, like other neglected tropical diseases, also “poverty promoting” . Traditionally confined to Latin America, Chagas disease is becoming an important health issue in the United States and Europe. First, due to the continuous influx of immigrants from disease-endemic countries in Latin America, a proportion of whom are infected with Trypanosoma cruzi, an increasing number of infected subjects are seen in clinical practice, whether, for example, through routine screening of US blood and organ banks  or physicians’ offices in Europe . The appearance of T. cruzi in US blood banks led to the implementation of the first Food and Drug Administration–approved diagnostic blood screening test for Chagas disease earlier this year . Second, an increasing number of autochthonous Chagas disease cases have been reported in the US [6,7], which may mirror the increased reporting of T. cruzi infection in domestic animals and wildlife. Recognizing that Chagas disease can no longer be considered an “exotic” disease in the US, the American Society of Tropical Medicine and Hygiene held a clinical course in Chagas disease prior to its 2007 annual meeting (http://www.astmh.org/meetings/premeeting.cfm#clinical).
Chagas disease (also known as American trypanosomiasis) is named for the Brazilian physician Carlos Chagas, who discovered the disease exactly a century ago and published its first description in 1909. It is caused by the protozoan parasite T. cruzi and is found in wildlife, domestic animals, and humans throughout much of rural as well as peri-urban areas of Mexico, Central America, and South America. In the US T. cruzi has been reported in dogs and a range of wild animals (e.g., raccoons and opossums), with human cases being relatively rare [6,7]. T. cruzi is mainly transmitted through blood-feeding triatomine bugs, but can also occur congenitally [7,11], through blood transfusion  or organ transplantation , and through the ingestion of contaminated food or fluids . The complex life cycle involves different parasite life stages in both vector and host, all highly adapted to their respective environments, which maximizes transmission potential and/or host immune evasion and, hence, long-term parasite survival (http://www.dpd.cdc.gov/dpdx/HTML/TrypanosomiasisAmerican.htm#Life%20Cycle).
Tools to manage Chagas disease are numerous but are severely limited with regard to crucial aspects of prevention, detection, and treatment. Current vector control methods and strategies have significant limitations, diagnostics are variable and of unknown reliability, drugs for treatment are inadequate, and vaccines are nonexistent. Yet some bright spots exist, such as the decrease in transmission that has been achieved through control of insect vectors and screening of blood and blood products.
The current chemotherapies for T. cruzi infection and Chagas disease have many shortcomings, as do those in drug discovery and development. The available compounds for treatment, benznidazole (Rochagan, Roche Pharmaceuticals) and nifurtimox (Lampit, Bayer HealthCare), both have severe side effects, require long courses of treatment, and exhibit variable efficacy . At present, the World Health Organization and other sources indicate that these drugs are active only in the acute and short-term (up to a few years) chronic phase (http://www.who.int/tdr/diseases/chagas/direction.htm). A number of studies now provide reason to question this recommendation [21–27]. Although some of these studies were non-controlled and used cure parameters that may be debatable because of the absence of a diagnostic gold standard (see below), they have been remarkably consistent in showing moderate to significant efficacy in long-term chronic infections. Thus, whilst waiting for the results of, for example, the BENEFIT trial (http://clinicaltrials.gov/ct/show/NCT00123916?order=1) evaluating the efficacy of benznidazole in chronic Chagas disease patients (expected to be completed in 2011), and unless or until better drugs are available, benznidazole and nifurtimox should be more widely used, based on the published evidence that such compounds may reduce the parasite burden and moderate disease progression in all stages of the disease [21–28]. It would therefore be ethically questionable to restrict the drugs’ use to only patients with a defined duration of (acute and short-term chronic) infection, as currently recommended. However, the decision to treat chronic patients with these drugs should be made on a case-by-case basis, only after thorough clinical assessment and with continuous monitoring of potential side effects.
One of the key issues concerning Chagas disease is that of diagnosis. Without effective diagnostics, infected individuals cannot be identified and thus treated, and the effectiveness of treatment cannot be efficiently assessed. Moreover, the effectiveness of any control campaign, whether targeted at insect vectors, blocking of transmission, or vaccination of individuals, cannot be measured without competent diagnostics. Transmission via blood transfusion or tissue transplantation has been a point of concern for many years in Latin America but has only come to the fore in the US and Europe as the number of immigrants unknowingly carrying T. cruzi has increased. Most current serological tests, whether developed in-house or purchased commercially, employ crude antigen preparations from inappropriate parasite life-cycle stages (i.e., epimastigotes—which are present in the insect vector but not in mammalian hosts). Development of tests using one or more recombinant proteins/peptides may be an improvement, but even these tests often provide inconsistent and/or unreliable results [31–33]. The absence of a true gold standard (i.e., a method to consistently detect the presence of parasites in those individuals with T. cruzi infection) makes evaluation of the sensitivity of serological tests difficult. It is standard practice to use test sera that are positive on multiple other serological tests to assess the sensitivity of new tests, proving that any new test is no worse, but not necessarily any better, than existing ones. However, it is well documented that individuals with confirmed infection are typed as inconclusive or negative on multiple existing serological tests [34–36]. The design of tests to detect these inconclusive or “conventional seronegative” subjects has not been a priority. Likewise, the development of technologies that can more rapidly assess treatment efficacy, diagnose congenital infections, or determine the impact of transmission control methods has been slow. Fortunately, the development of sensitive, accurate, and practical diagnostic methods is a highly tractable problem, given an appropriate level of investment and interest. The development of highly sensitive and specific diagnostic field and laboratory tools to determine active infection is a crucial requirement for moving the entire field forward in the research, clinical, and public health arenas.
The problems of Chagas disease are many, but they are not insurmountable. There are numerous partial solutions already at hand that, if used in a coordinated manner, and with consideration of the unique characteristics of endemic areas (e.g., rural underdevelopment, poverty, lack of adequate housing, and increasingly decentralized health services), could have a significant impact. The entities that will fund and coordinate such an integrated effort remain to be identified, but clearly the involvement of the public sector is essential. Better diagnostics, drugs, and improved approaches to vector control programs will require more and better research, sharper focus, and greater rigor on the part of the research community. In addition, contributions from governments, the private sector, and nongovernmental organizations will be needed to establish the infrastructure for testing drugs and control methods as well as the platforms to develop and implement effective and affordable diagnostic tests. Fortunately, the research community has provided the majority of potential drug, vaccine, and diagnostic candidates and, via the sequencing of the T. cruzi genome and proteomes [42,43], has presented multiple leads for drug targets and diagnostic/vaccine candidates. However, neither for-profit nor nonprofit companies have taken on the challenges of developing these leads further. Effective scientific, philanthropic, and political leadership and forward-thinking coordination of a community effort in this realm, at both local and regional levels, is badly needed if we want to make significant inroads into this devastating disease. Ultimately, the success of such efforts will be heavily dependent on the long-term stability and prospects for economical, societal, and political development in the Americas.