The health-related quality of life in patients with Chagas disease: the state of the art

ABSTRACT Chagas disease (CD) is a neglected tropical disease associated with poverty in which patients are surrounded by stigma. These factors can contribute to reducing health-related quality of life (HRQoL). Therefore, a broad discussion of HRQoL in the CD population is required. This study aimed to discuss the main findings of HRQoL in patients with CD, focusing on the association between sociodemographic and lifestyle factors, echocardiographic and functional determinants, and the effect of non-invasive interventions on HRQoL. A literature search of the MEDLINE, Web of Science, CINAHL, Scopus, and LILACS databases was performed with no data or language restrictions. Twenty-two articles were included in this meta-analysis. In general, HRQoL is worse in patients with CD than in healthy individuals, particularly in the presence of cardiovascular and/or gastrointestinal symptoms. Sex, age, functional class, level of physical activity, healthy habits, and medications received could affect HRQoL. Among the echocardiographic and functional determinants, decreased systolic function seems to negatively affect HRQoL. No association with the peak oxygen uptake was observed in the maximal tests. By contrast, well-tolerated field tests with submaximal intensities were associated with HRQoL. Both pharmaceutical care and exercise training have a positive effect on the HRQoL of patients with Chagas cardiomyopathy, and the mental component can be a prognostic marker in this population. In conclusion, assessment of HRQoL can provide important information about the health status of patients with CD, and its use in clinical practice is warranted.


Chagas disease (CD) is an infection caused by the protozoan
Trypanosoma cruzi and remains a public health problem in Latin American countries 1 . According to the World Health Organization, the prevalence of CD is estimated at 6 million worldwide, and CD is responsible for 12,000 deaths per year 2 .
In the chronic phase of the disease, patients may present with indeterminate, cardiac, digestive, or mixed forms 3 . In the indeterminate form, the patient remains asymptomatic, with a normal electrocardiogram (ECG) or minor non-specific electrocardiographic abnormalities 4 . Additional investigations using more sophisticated and sensitive complementary methods may reveal changes, such as a higher frequency of exercise-induced ventricular arrhythmias in the exercise test 5 . Gastrointestinal involvement can be detected in the digestive form, marked by the presence of megaesophagus and megacolon 6 . In the cardiac form, patients can progress with symptoms of heart failure such as fatigue and dyspnea, as well as with cardiovascular abnormalities such as malignant arrhythmias and thromboembolism 3 . However, patients can also be asymptomatic despite changes in their cardiac examination results. The cardiac form, denoted Chagas cardiomyopathy (ChC), may present with preserved cardiac function with segmental wall motion impairment until myocardial dilation with mainly left ventricular global systolic dysfunction develops 6 . Dilated ChC is responsible for the higher morbidity and mortality of the disease 3,6,7 . Finally, the mixed form presents with both cardiac and digestive impairments.
Regardless of the clinical form, interest in assessing the health-related quality of life (HRQoL) of patients with CD has increased in recent decades. Affected individuals are surrounded by stigma, depressive symptoms, social vulnerability, economic and sociodemographic disadvantages, and difficulty in accessing health services [8][9][10] , which contributes to the neglected aspect of the disease. Therefore, the present study aimed to discuss the main findings related to HRQoL of patients with CD. Two previous reviews 11,12 addressed the HRQoL of patients with CD; however, the present study focused on the sociodemographic, lifestyle, echocardiographic, and functional determinants in addition to HRQoL after non-invasive interventions in this population.

SEARCH METHOD
A narrative review using a structured search strategy was conducted to analyze the main findings regarding HRQoL in patients with CD. Potential studies were identified through a search of the The inclusion criteria were studies that assessed HRQoL in patients with CD. There were no restrictions on the language or publication year. The exclusion criteria were 1) animal studies, 2) qualitative studies, 3) review studies, and 4) studies that evaluated HRQoL after surgical or invasive procedures.
The original search identified 1,125 articles, of which 797 were duplicates. After reading the titles, abstracts, and objectives, 306 participants were excluded. A total of 22 papers were included in the present review (Figure 1).
Among the included studies, five questionnaires were used: the Short-Form of Health Survey (SF-36) 13 , World Health Organization Quality of Life Questionnaire (WHOQOL-Bref) 14 , Minnesota Living with Heart Failure Questionnaire (MLwHFQ) 15 , Assessment of The MLwHFQ is a specific questionnaire for patients with heart failure and consists of 21 questions on patient functionality. The higher the score, the worse the HRQoL. The AQUAREL is a 20-item questionnaire specific to patients with cardiac pacemakers and consists of three domains (chest discomfort, arrhythmia, and exertional dyspnea). Finally, the Kansas City Cardiomyopathy Questionnaire is a self-administered 23-item questionnaire that quantifies physical limitations, symptoms, self-efficacy, social interference, and HRQoL, specifically in patients with cardiomyopathy. The higher the score, the better the perception of HRQoL.

HRQOL IN PATIENTS WITH CHAGAS DISEASE
Ten studies (Table 1) compared the HRQoL of CD patients with that of healthy individuals, patients with cardiomyopathy from other etiologies, or among the clinical forms of the disease.
One study 18 demonstrated that, when compared to healthy individuals, the HRQoL of patients with CD was worse in the SF-36 domains of physical functioning and role-emotional, as well as in the total score of the MLwHFQ. The presence of cardiovascular symptoms in patients with CD was associated with poorer HRQoL in the physical and mental component summaries of the SF-36 as well as in the total score of the MLwHFQ. Therefore, the presence of cardiovascular symptoms seems to significantly contribute to the reduction in HRQoL of patients with CD, a finding that has been verified by other studies.
When comparing patients with CD with and without cardiomyopathy, individuals with cardiac involvement had worse HRQoL in the psychological domain of the WHOQOL-Bref 19 , and in the overall, physical, and role-emotional domains of the MLwHFQ 20 . Thus, the presence of heart disease may worsen the HRQoL of patients with CD, both physically and emotionally. Among the physical aspects, there is a reduction in functional capacity, even in the early stages of heart disease 21 . Regarding emotional aspects, in addition to the stigma surrounding CD, concern about fatalities and fear of sudden cardiac death are aggravating factors 22 .
In a sample stratified among chronic forms of the disease (indeterminate, cardiac, and digestive forms), the presence of cardiovascular or digestive symptoms was associated with worse HRQoL in many domains (physical, psychological, and social relationships) of the WHOQOL-Bref 23 . Thus, it appears that cardiovascular and digestive symptoms are responsible for the poor HRQoL of patients with CD. Esophageal and/or colonic involvement is characterized by dysphagia, odynophagia, esophageal reflux, weight loss, aspiration, cough, regurgitation, and fecaloma 6 . All of these abnormalities contribute to general malaise and social restriction, reducing the HRQoL of patients with the digestive form of CD.
Reduced HRQoL in the cardiac and digestive forms was also found in another study 24 . The authors reported that the cardiac form was associated with worse HRQoL in the WHOQOL-Bref when compared to the indeterminate form; however, the digestive form had the worst scores among the chronic forms. According to Santos-Filho et al. 8 , ChC without heart failure was independently associated with a worse score in the social relationship domain, whereas a mixed form with heart failure was associated with a worse score in the environment domain. More studies are needed to show that the HRQoL of patients with the digestive form is worse than that of patients with ChC; however, so far, it can be stated that both clinical forms have worse scores than patients with the indeterminate form.
Another study 25 compared the HRQoL of patients with cardiac pacemakers with and without CD using the AQUAREL questionnaire. It was reported that pacemaker patients with CD had worse scores in the chest discomfort and arrhythmia domains than those without CD.
Finally, in a cohort of patients with CD 26 , all of whom had some degree of cardiac impairment, there was no difference in HRQoL assessed by the WHOQOL-Bref in all domains (physical, psychological, social relationships, and environment) between patients with non-Chagas cardiomyopathy, ChC without heart failure, and ChC with heart failure. These results suggest that HRQoL is worse in patients with heart disease, regardless of the etiology or presence of heart failure. In contrast, another study 27 , composed of a population sample with more compromised cardiac function, found that patients with ChC had lower perceived HRQoL in the SF-36 domains of physical functioning and rolephysical functioning than those with non-Chagas cardiomyopathy. Similarly, another study 28 compared HRQoL using the Kansas City Cardiomyopathy Questionnaire in three groups of heart failure: ChC, ischemic, and non-ischemic. The authors demonstrated that patients with ChC had worse HRQoL than those with non-ischemic cardiomyopathy. However, there was no difference between the patients with ChC and those with ischemic cardiomyopathy. Given these conflicting results, more studies are needed to confirm whether Chagas etiology is a determinant of HRQoL in patients with heart disease.

ASSOCIATION BETWEEN HRQOL AND SOCIODEMOGRAPHIC OR LIFESTYLE FACTORS IN PATIENTS WITH CD
Sociodemographic and lifestyle factors can significantly affect the HRQoL of both healthy individuals and patients with CD. Four studies ( Table 2) aimed to verify the association between these factors and HRQoL in patients with CD.
In a sample with several chronic forms of the disease (indeterminate, cardiac, and digestive), one study 24 showed no difference in HRQoL assessed using the WHOQOL-Bref between men and women. However, two other studies 8,23 that included a larger sample with the same chronic forms of the disease and used the same questionnaire showed different results. Ozaki et al. 23 demonstrated that women had worse scores in the environment domain and were more likely to perceive worse HRQoL than men. Santos-Filho et al. 8 also demonstrated that women were independently associated with worse HRQoL in the overall score as well as in the physical and psychological domains of the WHOQOL-Bref. Lower HRQoL in women has also been demonstrated in healthy populations 29,30 . Compared to men, women have more

SF-36 and MLwHFQ
The HRQoL of patients with CD was worse in the physical functioning (p=0.011) and role-emotional (p=0.020) SF-36 domains when compared to non-Chagas disease patients. HRQoL was also worse in the group with CD assessed using the MLwHFQ (p=0.028). In patients with CD, the presence of cardiovascular symptoms was associated with poor HRQoL in the physical (OR=4.12) and mental (OR=2.69) component summary of the SF-36. The presence of cardiovascular symptoms was also associated with worse HRQoL in patients with CD when assessed using the MLwHFQ compared to individuals without CD (OR=9.11).

WHOQOL-Bref
The variables that were associated with worse scores in the physical domain were the digestive and cardiac forms (OR=3.77 and OR=4.42 times more likely, respectively, than the indeterminate form). In the psychological domain, the associated variables were the digestive and cardiac forms (OR=3.33 and OR=2.93 times more likely, respectively, than the indeterminate form). In the social relationships domain, the associated variables were the digestive and cardiac forms (OR=3.63 and OR=2.17 times more likely, respectively, than the indeterminate form.

WHOQOL-Bref
The factors associated with lower HRQoL were age, the use of angiotensin-converting enzyme inhibitors, history of acute myocardial infarction, and no use of angiotensin receptor blockers. non-life-threatening diseases as well as a higher prevalence of mental disorders such as depression 29 . In CD, female sex was also associated with depressive symptoms 9 . Thus, we believe that female sex is associated with worse HRQoL in patients with CD.
Santos-Filho et al. 8 also demonstrated that a worse New York Heart Association (NYHA) functional class, decreased sleep duration, lower schooling, decreased physical activity levels, smoking, decreased income per capita, and residents by domicile were independently associated with poor HRQoL. In another study 26 , increased age, use of angiotensin-converting enzyme inhibitors, history of acute myocardial infarction, and not using angiotensin receptor blockers were also associated with poor HRQoL in patients with CD.
Age is associated with physical and environmental domains, and functional impairment is common with increasing age 31 , which negatively affects HRQoL. A history of a previous acute myocardial infarction was associated with worse scores in the social relationship domain, which may be explained by a lower perception of emotional support and greater fear of social interactions after a myocardial infarction 32 . Regarding the medications received, the use of angiotensin-converting enzyme inhibitors was associated with worse HRQoL in the physical domain. A common adverse effect of angiotensin-converting enzyme inhibitor is cough 33 , which may impact the physical domain of HRQoL, especially at high doses. In contrast, the use of angiotensin receptor blockers was associated with a better HRQoL in patients with CD. Angiotensin receptor blockers have a low incidence of adverse effects and are associated with better HRQoL than other therapies for patients with arterial hypertension and/or heart failure 34 .

ASSOCIATION BETWEEN HRQOL AND FUNCTIONAL VARIABLES, ECHOCARDIOGRAPHIC PARAMETERS, OR DISABILITIES
Seven studies verified the association between HRQoL and functional capacity, disability, and/or echocardiography findings ( Table 3).
Systolic dysfunction, assessed by left ventricular ejection fraction (LVEF), is a well-established prognostic marker in the CD population [35][36][37] , and two studies 38,39 have verified the association between HRQoL and cardiac function. One study in patients with ChC and heart failure (n=55, LVEF <45%) demonstrated a weak but significant correlation between HRQoL, as assessed by the MLwHFQ and LVEF. According to the authors, the lower the LVEF, the worse the HRQoL of the patient. Ávila et al. 39 showed an association between HRQoL and systolic dysfunction in patients with ChC. The authors stratified the sample into groups according to systolic dysfunction and preserved cardiac function. The groups with systolic dysfunction had worse QoL in the domains of physical functioning, physical role functioning, and general health perception. In addition, the accuracy of the SF-36 in identifying patients with systolic dysfunction was demonstrated. The physical component of the SF-36 showed good efficacy in identifying these patients. A score of <46 points was the optimal cutoff point for diagnostic accuracy, with a positive predictive value of 91%. Therefore, the physical component of SF-36 can be used as a risk stratification and screening tool for patients with ChC, especially when echocardiography is scarcely available.
Functional capacity, assessed by both peak oxygen uptake (VO2peak) and field tests, has clinical and prognostic importance

SF-36 and MLHFQ
There was a significant correlation between the 6MWT distance and MLwHFQ total score (r=-0. 54

SF-36
Patients with systolic dysfunction have a worse HRQoL in the physical functioning (p<0.001), role-physical functioning (p=0.041), and general health perception (p=0.013) domains when compared to those who have preserved systolic function. The best cutoff points in identifying patients with systolic dysfunction were scores ≤46 and ≤54 in the physical and mental components of the SF-36, respectively. in patients with ChC 40 . Two studies included in this review verified the association between VO2peak and HRQoL, assessed using the MLwHFQ and SF-36. One study 41 with a sample of patients with both systolic dysfunction and preserved cardiac function found no correlation between VO2peak and MLwHFQ scores. The authors also used the SF-36 questionnaire and only the physical functioning domain showed a significant correlation. Another study 38 in patients with ChC and heart failure found a weak but significant correlation between VO2peak and MLwHFQ score. These findings suggest that VO2peak and maximal functional capacity may not reflect HRQoL in patients with ChC. We hypothesized that HRQoL is more strongly associated with daily activities, usually performed at a submaximal level. Therefore, field tests can be useful tools for investigating patients' perceptions of their health.

Abbreviations
Two field tests have already been applied in patients with ChC for functional assessment: the six-minute walk test (6MWT) 20,[42][43][44][45] and incremental shuttle walk test (ISWT) [46][47][48] . The 6MWT is a field test that evaluates functional capacity by the distance covered in six minutes 49 . In patients with preserved cardiac function, the 6MWT distance was not correlated with the presence of depressive symptoms 9 . In patients with ChC and systolic dysfunction, the 6MWT distance was correlated with the MLwHFQ total score 38,50,51 and with the SF-36 domains of physical functioning, role-physical functioning, and bodily pain 50 . It has also been shown that, among functional variables, the 6MWT distance was the only determinant of HRQoL 38 . A 10-m increase in the 6MWT distance is associated with a reduction of 0.7 points in the MLwHFQ score.
The ISWT is a symptom-limited field test with progressive loads and 12 levels of intensity, where the functional capacity is evaluated by the walked distance 52 . In patients with ChC, only one study 41 verified the association between ISWT distance and HRQoL using both the SF-36 and MLwHFQ. The authors demonstrated that ISWT distance was correlated with MLHFQ total score and the physical functioning, role-physical functioning, and mental health domains of the SF-36. The results regarding the association between HRQoL and the field tests corroborate our hypothesis that submaximal tests are more representative of HRQoL than maximal tests.
Regarding disability, one study 53 verified the association between HRQoL using the WHOQOL-BREF and the degree of disability using the Modified Rankin Stroke Scale in patients with CD after stroke. It has been shown that cerebrovascular events are frequent in patients with CD, and these may be the first clinical manifestation of the disease 54 . However, the authors found no association between disability and the WHOQOL-Bref domains. Disability was associated with functional performance, whereas HRQoL was associated with depressive symptoms.

HRQOL ASSESSMENT IN LONGITUDINAL STUDIES
Recent studies 55,56 have highlighted the importance of assessing HRQoL in clinical trials as an effective tool to detect patientreported changes. Thus, HRQoL has the potential to identify improvements in health from proposed interventions and can be used as a valuable prognostic marker 56 .
The reassessment of HRQoL after drug therapy was verified in two studies. Chambela et al. 57 found that the group of patients with ChC and heart failure who received optimized drug therapy (n=40) showed a significant improvement in many domains of the SF-36 and in the total score of the MLwHFQ compared to the group receiving standard care (n=41). Therefore, the results suggest that both the SF-36 and MLwHFQ may be sensitive in identifying improvements in the health perception of patients with ChC and heart failure after drug therapy. Another study 62 that verified HRQoL after pharmacological treatments was carried out in two stages. First, all patients with ChC (n=39) were administered enalapril and spironolactone. Subsequently, there was a significant improvement in their SF-36 total scores, including in the physical functioning, role-physical functioning, bodily pain, general health perceptions, and mental health domains. Second, patients in the experimental group (n=19) received carvedilol, while those in the control group (n=20) received a placebo. There was no difference in any of the SF-36 domains between the groups after treatment with carvedilol. In addition, no improvement in hemodynamic, echocardiographic, or circulating chemokine parameters was observed.
The effects of exercise training on HRQoL were demonstrated in three studies [58][59][60] , all of which included patients with systolic dysfunction. One study 60 , which applied a three-month moderateintensity intervention, showed improvement in the vitality, roleemotional, and mental health domains of the SF-36 in the exercise group when compared to the inactive group. The improvements in the mental and emotional factors were greater than in the physical factors, despite the improvement in the functional capacity. The authors highlighted that interpersonal contact during the exercise program was important for increasing well-being and improving the psychosocial aspects. Another study 59 showed improvements in the domains of physical functioning, role-physical functioning, and bodily pain, as well as in the physical component summary, after 8 months of an exercise intervention. The study consisted of a singlearm intervention that included 12 patients with ChC and heart failure. In a reassessment analysis 58 including the same patients, the authors demonstrated an improvement in the total MLwHFQ score occurred only in patients with right ventricular dysfunction. The beneficial changes in HRQoL also accompanied the clinical changes in these patients, and individuals with the greatest severity of cardiac impairment obtained the most substantial benefits in cardiac hemodynamics, respiratory strength, and HRQoL.
Finally, in a study of 75 patients with ChC, Costa et al. 61 verified the prognostic value of HRQoL in predicting adverse cerebrovascular events. After six years of follow-up, the mental component of the SF-36 together with LVEF remained an independent predictor of adverse events. The physical component did not show significant prognostic value; however, the sample was predominantly composed of patients with preserved functional class, and studies with patients with functional impairment should be conducted. Therefore, the findings suggest that HRQoL, especially the mental aspects, should be used in clinical follow-ups, since the patient can be aware of the progression of the disease.

FINAL CONSIDERATIONS
The results of the included studies suggest that 1) HRQoL is worse in patients with CD than in healthy individuals; 2) the presence of cardiovascular and gastrointestinal symptoms are responsible for worse HRQoL scores in terms of both physical and mental aspects; 3) the HRQoL in patients with ChC compared to those with other heart diseases is still poorly understood; 4) female sex is associated with worse HRQoL; 5) other factors, including age, functional class, level of physical activity, healthy habits, and medications, can affect the HRQoL of patients; 6) HRQoL is related to systolic function; 7) functional capacity assessed by VO2peak may not reflect the HRQoL in ChC; 8) field tests may be associated with HRQoL; 9) drug therapy, in general, has a positive effect on the HRQoL of patients with ChC; 10) exercise training can also positively impact HRQoL in both physical and emotional aspects; and 11) HRQoL, especially the mental component, can be a prognostic marker in patients with ChC.