Therapy, diagnosis and prognosis of chronic Chagas disease: insight gained in Argentina

Therapy, diagnosis and prognosis of chronic Chagas disease: insight gained in Argentina     Sergio Sosa-EstaniI, II, III, +; Rodolfo ViottiIV; Elsa Leonor SeguraII, V ICentro Nacional de Diagnóstico e Investigación de Endemo-epidemias IIConsejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina IIIInstituto de Efectividad Clínica y Sanitaria, Buenos Aires, Argentina IVHospital Eva Perón de San Martín, Buenos Aires, Argentina VInstituto Nacional de Parasitología Dr. Mario Fatala Chaben, ANLIS Dr. Carlos G. Malbrán, Ministerio de Salud, Buenos Aires, Argentina     ABSTRACT The purpose of this review is to describe research findings regarding chronic Chagas disease in Argentina that have changed the standards of care for patients with Trypanosoma cruzi infection. Indirect techniques (serological tests) are still the main tools for the primary diagnosis of infection in the chronic phase, but polymerase chain reaction has been shown to be promising. The prognosis of patients with heart failure or advanced stages of chagasic cardiomyopathy is poor, but a timely diagnosis during the initial stages of the disease would allow for prescription of appropriate therapies to offer a better quality of life. Treatment of T. cruzi infection is beneficial as secondary prevention to successfully cure the infection or to delay, reduce or prevent the progression to disease and as primary disease prevention by breaking the chain of transmission. Current recommendations have placed the bulk of the diagnostic and treatment responsibility on the Primary Health Care System. Overall, the current research priorities with respect to Chagas disease should be targeted towards (i) the production of new drugs that would provide a shorter treatment course with fewer side effects; (ii) the development of new tools to confirm cure after a full course of treatment during the chronic phase and (iii) biomarkers to identify patients with a high risk of developing diseases. Key words: Chagas disease - Trypanosoma cruzi - diagnosis - prognosis - treatment     One hundred years after Carlos Chagas identified and described infection with Trypanosoma cruzi, there are still millions of people infected with it, and thousands of new cases of Chagas disease (CD) are being diagnosed each year. The scientific community, although in an intermittent manner, has increased the knowledge and understanding of how to manage patients with chronic CD infection (PAHO 2005). Nonetheless, much research is still needed to improve care and to answer many of the unknown questions regarding this debilitating and widespread disease. In the Americas, there are approximately eight million patients suffering from the chronic phases of CD (PAHO/WHO 2006). Myocarditis secondary to CD is the most common form of non-ischemic cardiomyopathy worldwide (Feldman & McNemara 2000). CD can also result in other manifestations, such as pathologies in the gastrointestinal tract (megaesophagus and megacolon) or disorders of the central and peripheral nervous system. Clinical manifestations of the chronic phase were extensively described a century ago by Carlos Chagas (Chagas 1911). The most recent figures provided by the World Health Organization indicate that about two million infected individuals have cardiomyopathy (PAHO/WHO 2006). Currently, the main challenges related to the control of CD lie in three areas: (i) consolidating and maintaining control of endemic disease by implementing sustainable epidemiological surveillance programs; (ii) providing effective medical care and social attention to individuals who are already infected and (iii) conducting research to support and guide the first two tasks. For example, studies are needed to produce better surveillance tools, to develop new anti-parasitic drugs and to establish better management plans for disease manifestations (including heart disease and other manifestations) (Pinto Dias 2006). The goal of specific treatment for T. cruzi infection is to eliminate the parasite from the infected individual, to decrease the probability of developing illness (CD) and to break the chain of disease transmission (Sosa-Estani & Segura 2006). In this paper, we present the experiences and contributions, of primarily Argentinean researchers and others, regarding therapy, diagnosis and prognosis of patients in the chronic phase of infection with T. cruzi. We conducted a review based on MEDLINE searches using the term "Chagas disease" with the subheadings diagnosis, prognosis, treatment, drug names (nifurtimox, benznidazole) and clinical trials. Recent guidelines by expert committees were also consulted. Diagnosis of infection in the chronic phase Without treatment and independent of the route of transmission, the natural history of CD is a decrease in parasitemia 90 days after infection to the point that the parasite is undetectable by direct microscopy. From this phase on, the primary method for diagnosis is serological testing, while the secondary diagnostic techniques are parasitological tests. Serological methods underwent intensive development in Argentina during the 1960s and 1970s, resulting in the development of complement fixation (Muniz & Freitas 1944, Cerisola & Rosembaum 1958), the indirect immunofluorescence assay (IFA) (Alvarez et al. 1968), and the indirect hemagglutination assay (IHA) (Cerisola et al. 1962, Vattuone & Yanovsky 1971). Furthermore, during the 1980s, the enzyme immune assay (EIA) was added as another serological test using known recombinant antigens (Cura et al. 1993, Caballero et al. 2007). At the end of the 1960s, Cerisola et al. (1969) suggested the use of at least two different serologic tests to establish CD diagnosis. Specifically, guideline recommendations were to perform a third assay or repeat sampling to confirm or exclude the diagnosis if two serological tests were in disagreement (WHO 2002). During the 1980s, intense collaborative efforts resulted in a regional consensus for diagnosis and treatment (Camargo et al. 1986). Other methods, such as rapid tests that screen for anti-T. cruzi antibodies in whole blood and serum using the immunochromatographic screening test, have been assessed and have been found to have varying degrees of performance (Luquetti et al. 2003, Ponce et al. 2005, Sosa-Estani et al. 2008). Programs to conduct population-based screening have been successful in diagnosing more cases in the chronic phase (Rosembaum & Cerisola 1961, Segura et al. 2000, Sosa-Estani 2005). Parasitological tests such as xenodiagnosis (Cerisola et al. 1971), haemoculture (Abramo Orrego et al. 1980) and, more recently, the detection of parasite DNA using polymerase chain reaction (PCR) (Avila et al. 1991, Britto et al. 1995, Silber et al. 1997, Schijman et al. 2000) are useful during the chronic phase of T. cruzi infection, although these methods are significantly less sensitive than serological t (...truncated)