Juan Carlos Villar
	Julio Lazzari
	Anis Rassi Jr y James Maguire
	Management of clinical disease *

This document will discuss the care of those individuals who are diagnosed with the chronic phase of T. cruzi infection, whether or not there are clinical findings of Chagas disease. We attempt to articulate the management currently available to these patients within their socio-cultural context, whether they live in endemic or non-endemic countries. We also identify key gaps in present knowledge that need be addressed in order to improve our ability to care for persons already infected and thus prevent adverse sequelae, improve quality of life, and lessen the burden of Chagas disease for society as a whole.

Clinicians caring for patients chronically infected with T. cruzi need to make a diagnosis and offer a prognosis. Treatment is in order when there is a favorable balance between scientific evidence of benefit versus risks and costs, the patient's values and preferences, and the clinician's own clinical judgment. The most common situation facing primary care physicians seeing patients with T. cruzi infection, is the apparently healthy young adult with positive serological tests and an epidemiological history of exposure to the parasite. The clinician may either follow such a patient closely or initiate treatment to prevent complications (the "prevention scenario"). Although Chagas disease may affect a variety of organs, clinical attention focuses on cardiac and digestive disease. The second most common scenario is that of chronically infected persons who develop symptoms and seek specialized care. For these patients, clinicians prescribe treatment in hope of alleviating symptoms and preventing further damage (the "treatment scenario"). Chronic Chagas cardiomyopathy (CCC) is the cause of virtually all the burden of disease caused by infection with T. cruzi . It stands out among other cardiomyopathies because of the myriad of rhythm and conduction abnormalities and the unusual heart enlargement. Digestive forms of Chagas disease result from lesions in neural and electrical pathways that co-ordinate activity of hollow organs. Digestive disease, which may occur concomitantly with CCC, also evolves slowly and leads to marked visceral enlargement (the "megas"). These features are both common in, and distinctive of, full-blown Chagas disease.

Current approaches for disease staging: pros and cons
Clinical differentiation of CCC or digestive forms of Chagas disease from other causes of cardiac disease or visceral dilatation is not always possible. Moreover, most chronically infected individuals have no symptoms at all. With a confirmed diagnosis of infection, physicians employ diagnostic tools to rule out signs of disease when symptoms are absent or to confirm Chagas disease and estimate its extent when there are suspicious findings. The electrocardiogram (ECG) and radiographs of the heart and digestive tract have been available since the disease was first described and even today are primary tools for evaluating affected organs. In fact, an expert panel agreed that in the absence of abnormalities by these two diagnostic techniques, asymptomatic persons in the chronic phase of T. cruzi infection have its indeterminate form [1]. Persons who have progressed beyond that stage are said to have the determinate form , either cardiac (i.e. CCC) or digestive or both. Expanding upon this dichotomous classification, Kuschnir has proposed to discriminate different stages of CCC by integrating symptoms with findings on the ECG and chest radiograph [2]. Kuschnir's stage 0 corresponds to the indeterminate stage, and stages (1-3) refer to increasingly more advanced CCC. According to his classification, CCC is first manifested by ECG abnormalities (stage 1), then by cardiac enlargement on the chest radiograph (stage 2), and finally by symptoms of disease (stage 3). No parallel classification has been proposed for the digestive forms of the disease.

Prevention scenario: the absence of ECG findings rules out most cases of chronic infection without disease (i.e., there is good "specificity"). Moreover, ECG findings in CCC are measured reliably [3], and have been extensively validated by well-conducted community-based cohort (i.e. follow-up) studies [4-7].

However, the use of other established diagnostic tools in cardiology reveals abnormal findings in approximately 20%-30% of asymptomatic patients whose ECG is normal, and significantly more than what is found among seronegative controls [8]. This rate of abnormalities, similar to that of people who ultimately develop full-blown disease, challenges the value of conventional staging to detect sub-clinical disease (i.e. their "sensitivity" and "negative predictive value"). It has become apparent that the ECG and especially, chest X-rays may miss opportunely cases with mild, but potentially relevant cardiac abnormalities. Since CCC evolves slowly, more sensitive tools may be important for young adults with chronic infection, increasing the opportunities and time window for prevention. Sometimes CCC appears as a sudden death, stroke or pulmonary embolism, without prior symptoms. Most previously studied patients with rapid progression to end points of CCC are known to have ECG findings. However, predictors of such course of disease among asymptomatic patients are yet to be identified. Although such devastating events are relatively infrequent among patients with asymptomatic chronic infection (sudden death is estimated to occur in 2 out of 1000 persons/year of such individuals [9]), these are potentially preventable of productive years lost in endemic countries.

In general practice, highly specific tests should be used to confirm the diagnosis of a disease (e.g. western-blot serology to confirm diagnosis of HIV infection). In contrast, highly sensitive tests are used for screening to rule out a disease (e.g. serological tests in blood banks to avoid transfusion of infected blood products, even at the cost of discarding donations that have false-positive results). In light of this, there are two issues of relevance to our prevention scenario: First, clinicians screening for sub-clinical CCC may not be using sufficiently sensitive tools. Second, there is a need for a single test that is simple to perform, inexpensive, and highly sensitive (i.e. can capture all positive cases during the earliest stage of disease) and can rule out those with low risk. The implications of these limitations are tremendous when one proposes screening of the population at large, in which the expected prevalence of disease is much lower than in referral centres.

Why are these seemingly sub-optimal approaches to staging still in use in the prevention scenario? There is no simple explanation, but there are several reasons to explain our failure to fully challenge the concept of the indeterminate form of the chronic phase. First, the prognostic importance of sub-clinical cardiac findings (i.e. the abnormalities shown by other tests among asymptomatic patients with normal ECG) has not yet been well established. Second, the efficacy of preventive treatment remains uncertain (see below). These two gaps in current knowledge are inter-related, because the effort and costs of doing additional diagnostic investigations can only be justified when positive results lead clinicians to introduce or change a treatment. At present, clinicians are clearly divided on whether or not to use more sensitive yet readily available diagnostic tests (e.g. echocardiography or continuous ECG monitoring for ca). Other tests with potential prognostic relevance may be markers of parasitic-load, host responses to it, or genetic predisposition for progression. The controversy becomes even more significant when deciding whether to prescribe the available therapy to prevent the progression of disease.

Available treatments: Are they useful?
Successful treatment usually requires sufficient understanding of the disease and its prognosis, the existence of effective therapeutic options, and accessibility of therapy to those who need it. These requirements unfortunately are unmet for most patients with chronic T. cruzi infection.

Prevention scenario: The most important decision facing clinicians today is whether to prescribe treatment against the parasite (i.e. trypanocidal therapy, TT). As discussed, the continuing controversy over treatment stems from the fact that clinicians' uncertainty about the risk/benefit ratio of TT outweighs the biological rationale to prescribe it. Parasites are believed to play a causal role in the development of CCC [16,17], and trypanocidal therapy (TT) can cure acute infections and reduce markers of T. cruzi infection in school children with chronic infection [18,19]. However, evidence that TT prevents progression to CCC among chronically infected persons remains weak. Reduction of clinical manifestations has not been reported among chronically infected adults receiving TT compared with similar patients receiving placebo after random assignment of treatments (i.e. in randomized, placebo-controlled trials, the standard tool to test health care interventions of uncertain efficacy) [20,21]. Data regarding patient-important outcomes of CCC (e.g. progress to symptomatic disease, death, etc) have been recorded for non experimental or "observational" studies, considered to carry less weight (i.e., are of ‘lower hierarchy' mainly because of underlying differences in the prognosis of the groups receiving or not treatment). As a body of evidence, the best quality observational studies are encouraging results (i.e. smaller incidence of adverse outcomes among individuals receiving TT compared with those untreated), but they are inconclusive (i.e. not statistically significant) and inconsistent (i.e. not reproducible across studies) [22].

Reduction of markers of infection has not been consistently demonstrated in randomized, placebo-controlled trials in adults either. Inferences from observational studies suggest that such reduction may occur, but can take as long as 10 years to become evident. The lack of response may be due to drug-resistant parasites or the type of markers employed. Whereas placebo-controlled trials of TT in children showed marked reductions in markers measured by newer specialized tests, conventional serology showed little or no difference. There are no reports from placebo-controlled trials of TT in adults employing the newer tests.

Some clinicians feel comfortable to prescribe TT on the basis of the strong biological rationale and the positive parasite-related outcomes in children and selected observational studies showing positive results [23]. However, efficacy based on parasite-related (i.e. "surrogate") outcomes in children may not translate to a reduction of patient-important outcomes (death, hospitalizations, etc) at a later stage of infection. There are several noticeable examples in the field of cardiology in which no clinical benefit or even a worse outcome was demonstrated in placebo-controlled trials despite reduction of similarly plausible surrogate outcomes and/or observational studies showing benefit in terms of patient-important outcomes [24-27] Chagas disease, a condition with yet many unanswered questions, may not be an exception. We believe the decision on TT should be guided by studies as well-designed as the cardiology studies alluded to above.

Concerns about the efficacy of TT are heightened by the high rate of side effects. About 30% of the chronically infected patients treated with benznidazole (the most studied form of TT and the only drug recommended for the indication under discussion) report side effects, and 16% discontinue the medication for that reason. Itraconazole, another agent evaluated in a clinical trial, has a better safety profile but a weaker trypanocidal effect. Other agents have not been shown to be effective, have not been tested in clinical trials, or are not yet approved for clinical use. As a result, no standard recommendations have been made for adult patients with chronic T. cruzi infection concerning TT. Some patients receive treatment when their physicians believe that this option is in their best interest. In this case, clinicians should take care to warn their patients of possible side effects, monitor the safety of treatment, and inform their patients how they plan to evaluate the efficacy of treatment.

Treatment scenario: Clinicians face different challenges in caring for patients with evidence of disease. In light of the uncertainty about the risk/benefit ratio of TT in such cases, physicians could make use of generic treatments that are routinely prescribed to patients with other forms of cardiac or digestive disease. Such supportive treatments (i.e. prescribed to avoid further deterioration of cardiac function) include therapy with other types of medication and other interventions such as changes in lifestyle or diet. Unfortunately, controlled studies on the efficacy of adjuvant or symptomatic therapy in CCC are few. Most data derive from case series, notably those that assess the efficacy of amiodarone in suppressing arrhythmia and preventing sudden deaths [28,29]. Extrapolation of the sound evidence that is available on treatment of other cardiomyopathies could support the use of similar treatments for symptomatic CCC. Examples include a number of non-pharmacological interventions, ACE inhibitors, beta-blockers, spironolactone, digitalis, diuretics, [30] and amiodarone, which has been documented to reduce sudden death in other forms of cardiac disease [31]. This body of evidence would apply to CCC to the extent to which extrapolation is biologically plausible. Such treatments are probably more acceptable as CCC progresses, but there is a need to document its cost/benefit ratio in the overall CCC population.

Adequacy of care
Despite the weak knowledge base for treatment of individuals with chronic T. cruzi infection, all should receive the standard and most up-to-date care for their condition, including diagnosis, determination of prognosis, and treatment. The emphasis on these three elements of patient management varies for each scenario and from patient to patient within the same scenario. Although health care authorities in many endemic countries have issued guidelines for the care of this population, we are not aware of any evaluation of the adherence to such guidelines. Indirect observations suggest a dearth of systematic efforts to pursue the diagnosis of T. cruzi infection among people at risk, thus denying them any possibility of therapy to prevent later complications. Most cases of T. cruzi infection are diagnosed for the first time when symptoms of CCC, or sudden death occur. Analogous situations in clinical practice would be the development of cancer of the cervix in women who never underwent cytological studies (Pap smear), or the occurrence of myocardial infarction in persons who never knew their blood pressure or cholesterol levels. Although policies for community-based screening for different chronic conditions such as cancer or atherosclerosis varies among countries, it is fair to say that with few exceptions, screening for T. cruzi infection is minimal in comparison. Because T. cruzi infection affects the most vulnerable persons in low and middle income countries, access to serological screening is of highest priority and is essential for opening the door for those in need of further care. Unfortunately, the gap between numbers of diagnostic tests performed and the number of persons who need them exists both in endemic countries and in non-endemic countries that host large Latin American-born populations, such as USA and Spain. To date, access to diagnosis of T. cruzi infection is far from being systematic and comprehensive.

Diagnosis and staging of CCC should always be performed once the diagnosis of T. cruzi infection is established, but there are no data to indicate how often this practice is followed. Our experience suggests that physicians seeing diagnosed cases of infection order ECGs regularly and additional tests only occasionally. Availability of resources and the clinical severity of individual cases determine the patterns of care. Failure to diagnose disease among infected patients is less common than failure to diagnoses T. cruzi infection among those at risk, but has serious consequences for the continuity and comprehensiveness of clinical care in both the prevention and treatment scenarios. Asymptomatic infected patients should be treated as index cases and the starting point for an in-depth exploration of the socio-cultural milieu in which they live and work. This includes screening of their relatives and possibly neighborhoods and counseling at the work place to prevent discrimination and premature or forced retirement. Asymptomatic infected individuals need periodic follow-up, ideally according to their individual risk. The extent to which this practice takes place is largely unknown, but is probably inadequate, as inferred from the high number of new patients with CCC who never received regular care previously. For symptomatic patients, the major challenge is ensuring that their treatment is comprehensive. How often non-trypanocidal, supportive (adjuvant) therapy is given also remains unknown. The social disadvantages of CCC patients may have an even greater negative impact on the coverage, comprehensiveness and continuity of their care, unnecessarily increasing the burden of disease. Structured referral centers that offer comprehensive care of such patients are clearly advantageous. Nonetheless, such centers are scarce given the extent of T. cruzi infection, and are located almost exclusively at tertiary care centers in capitals of provinces or countries, thus widening the gap between the availability of clinical care and those who need it. There are major challenges in creating sustainable mechanisms and measurable outcomes for diagnosis and treatment of chronically infected populations.

Future directions
The above discussion highlights a number of gaps in current knowledge, which if filled will lead to enhanced capacity for health care systems to reduce the burden of CCC among people with chronic T. cruzi infection. Good clinical care begins with a systematic, efficient, valid, comprehensive, and available approach to diagnosis of infection for those at risk. For the prevention scenario, we need a formal head-to-head evaluation of the performance of traditional and newer diagnostic tools to screen for early cardiac and visceral involvement. We also need to validate the newly proposed markers for prediction of adverse outcomes. Simultaneously, we need to ascertain the value of available trypanocidal therapy, and to predict who can benefit from it and tolerate it well. Evaluation of newly developed or alternative therapies needs to be facilitated, and bridges between "bench" and "bedside" and between research and practice need to be built in a timely fashion. We also need markers to screen for subclinical disease that can also demonstrate response to therapy in order to inform patients on the change on their condition after treatment.

There is an urgent need to estimate the coverage, comprehensiveness and quality of the clinical staging of asymptomatic patients as well as the continuity of the follow-up they receive. We also need to monitor the proportion of patients who develop symptomatic CCC with or without prior care. The treatment scenario will benefit greatly from identifying efficacious interventions that are specific for CCC, but at the same time, there should be an evaluation of the coverage, comprehensiveness and sustainability of adjuvant medications and other forms of treatment and counseling. Only by gathering such data, can we organize, prioritize and evaluate actions to provide the best care to those who can benefit the most from it.

- Working document prepared for the rapporteurs of the session for discussion at the meeting at session 8 on 2.
Tuesday April 19, 2005, 12:00 – 13:00.

Bibliogaphy

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Publication: Septiembre 2005

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