Recommendations for Screening and Diagnosis of Chagas Disease in the United States.

BACKGROUND: Chagas disease affects an estimated 326 000-347 000 people in the United States and is severely underdiagnosed. Lack of awareness and clarity regarding screening and diagnosis is a key barrier. This article provides straightforward recommendations, with the goal of simplifying identification and testing of people at risk for US healthcare providers. METHODS: A multidisciplinary working group of clinicians and researchers with expertise in Chagas disease agreed on 6 main questions, and developed recommendations based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, after reviewing the relevant literature on Chagas disease in the United States. RESULTS: Individuals who were born or resided for prolonged time periods in endemic countries of Mexico and Central and South America should be tested for Trypanosoma cruzi infection, and family members of people who test positive should be screened. Women of childbearing age with risk factors and infants born to seropositive mothers deserve special consideration due to the risk of vertical transmission. Diagnostic testing for chronic T. cruzi infection should be conducted using 2 distinct assays. CONCLUSIONS: Increasing provider-directed screening for T. cruzi infection is key to addressing this neglected public health challenge in the United States.

Critical analysis of Chagas disease treatment in different countries.

As a result of globalization and constant migratory flows, Chagas disease is now present in almost all continents. The management and treatment of the disease is often influenced by the economic and social context of the societies that host patients. In this manuscript, we aim to provide a comparative review of approaches to patients with Chagas disease in the Americas and Europe.

Integration of clinical pharmacists into a heart failure clinic within a safety-net hospital.

BACKGROUND: Management of heart failure with reduced ejection fraction (HFrEF) requires timely initiation and up-titration of guideline-directed medical therapy (GDMT). In safety-net hospitals (SNHs), limited health care staff and resources make achievement of optimal medical therapy challenging. Recent studies have shown that medication titration performed by clinical pharmacists can improve outcomes in ambulatory management of HFrEF; however, the impact of these services within an SNH remains unknown. OBJECTIVE: Determine the impact of integrating clinical pharmacists into a heart failure (HF) clinic on initiation and titration of GDMT within an SNH. METHODS: We performed a single-center retrospective cohort study of patients with HFrEF treated in an ambulatory HF medication titration clinic within an SNH before and after clinical pharmacist integration. Primary outcomes included dose optimization rates of GDMT, time between clinic visits, and time to optimization of GDMT. Exploratory secondary outcomes were all-cause, HF, and cardiovascular acute care service utilization and all-cause, HF, and cardiovascular mortality before and after clinical pharmacist integration up to 6 months after initial clinic visit. RESULTS: A total of 153 patients with HFrEF were treated. Baseline characteristics in the pre- and postintervention groups were comparable. After clinical pharmacist integration, there was a statistically significant improvement in optimization of renin-angiotensin-aldosterone system inhibitor or hydralazine-nitrate equivalent (82% vs. 94%, P = 0.02). Dose optimization rates of beta-blockers (90% vs. 83%, P = 0.22) and mineralocorticoid receptor antagonists (57% vs. 57%, P > 0.99) were unchanged. There was a statistically significant reduction in mean time between clinic visits (26 vs. 14 days, P < 0.001) and in mean time to optimization of GDMT (88 vs. 45 days, P = 0.002). All-cause mortality was reduced (13% vs. 2%, P = 0.01). CONCLUSION: In SNHs, where limited health care staff and resources present as barriers to timely initiation and titration of GDMT, integration of clinical pharmacists into HF clinics can serve as a practical solution.

Prevalence of Chagas Disease Among Family Members of Previously Diagnosed Patients in Los Angeles, California.

Chagas disease (CD) in the United States is severely underdiagnosed, due to an absence of systematic screening as part of routine healthcare. We screened 189 relatives of 86 existing patients and found a CD prevalence of 7.4%. Screening close relatives of previously diagnosed individuals can effectively identify new CD cases.

Prevalence of Chagas Disease in the Latin American-born Population of Los Angeles.

Background: According to an estimate from the Centers for Disease Control and Prevention (CDC), Chagas disease (CD) may affect 1.31% of Latin American immigrants in the United States, with >300 000 cases. However, there is a lack of real-world data to support this estimate. Little is known about the actual prevalence of this neglected tropical disease in the United States, and the bulk of those infected are undiagnosed. Methods: From April 2008 to May 2014, we screened 4,755 Latin American-born residents of Los Angeles County. Blood samples were tested for serologic evidence of CD. We collected demographic data and assessed the impact of established risk factors on CD diagnosis, including sex, country of origin, housing materials, family history of CD, and awareness of CD. Results: There were 59 cases of CD, for an overall prevalence of 1.24%. Prevalence was highest among Salvadorans (3.45%). Of the 3,182 Mexican respondents, those from Oaxaca (4.65%) and Zacatecas (2.2%) had the highest CD prevalence. Salvadoran origin (aOR = 6.2; 95% CI = 2.8-13.5; P < .001), prior knowledge of CD (aOR = 2.4; 95% CI = 1.0-5.8; P = .047), and exposure to all 3 at-risk housing types (adobe, mud, and thatched roof) (aOR = 2.5; 95% CI = 1.0-6.4; P = .048) were associated with positive diagnosis. Conclusions: In the largest screening of CD in the United States to date outside of blood banks, we found a CD prevalence of 1.24%. This implies >30 000 people infected in Los Angeles County alone, making CD an important public health concern. Efficient, targeted surveillance of CD may accelerate diagnosis and identify candidates for early treatment.

Safety Profile of Nifurtimox for Treatment of Chagas Disease in the United States.

BACKGROUND: Nifurtimox is 1 of only 2 medications available for treating Chagas disease (CD) and currently the only drug available in the United States, but its safety and tolerance have not been extensively studied. This is the first study to evaluate tolerance of nifurtimox in US patients with CD. METHODS: This investigation assessed side effects in a sample of 53 patients with CD, all Latin American immigrants, who underwent treatment with nifurtimox (8-10 mg/kg in 3 daily doses for 12 weeks) from March 2008 to July 2012. The frequency and severity of adverse events (AEs) was recorded. RESULTS: A total of 435 AEs were recorded; 93.8% were mild, 3.0% moderate, and 3.2% severe. Patients experienced a mean of 8.2 AEs; the most frequent were anorexia (79.2%), nausea (75.5%), headache (60.4%), amnesia (58.5%), and >5% weight loss (52.8%). Eleven patients (20.8%) were unable to complete treatment. Experiencing a moderate or severe AE (odds ratio [OR], 3.82; P < .05) and Mexican nationality (OR, 2.29; P < .05) were significant predictors of treatment discontinuation, but sex and cardiac progression at baseline were not. Patients who did not complete treatment experienced nearly 3 times more AEs per 30-day period (P = .05). CONCLUSIONS: Nifurtimox produces frequent side effects, but the majority are mild and can be managed with dose reduction and/or temporary suspension of medication. The high frequency of gastrointestinal symptoms and weight loss mirrors results from prior investigations. Special attention should be paid during the early stages of treatment to potentially severe symptoms including depression, rash, and anxiety.

Heart Failure Secondary to Chagas Disease: an Emerging Problem in Non-endemic Areas.

Chagas disease affects millions of people worldwide. Though the majority of infected individuals remain asymptomatic, approximately 30 % of patients progress to develop cardiac manifestations and eventual heart failure. While vectorial transmission occurs predominantly in South America, Central America, and Mexico, millions of people originally from these endemic regions immigrate to non-endemic countries in North America, Europe, and Asia. Outside of rare specialized centers, health-care providers lack experience diagnosing and treating this disease. This lack of experience likely leads to far fewer Chagas disease patients being diagnosed than what actually exist in non-endemic countries, with subsequent adverse effect on patient outcomes and health-care expenses. Underdiagnosis increases the risk of developing cardiomyopathy, associated heart failure, and life-threatening ventricular arrhythmias as the disease progresses.

Tolerance of benznidazole in a United States Chagas Disease clinic.

The US-based Center of Excellence for Chagas Disease performed an observational study on the safety and tolerance of benznidazole 5 mg/kg/day for 60 days in 30 adults with chronic Chagas disease. The side-effect profile was suboptimal, including 5 cases of debilitating neuropathy and an unusually high angioedema rate.

Fish oil (n-3 fatty acids) in drug resistant epilepsy: a randomised placebo-controlled crossover study.

BACKGROUND: n-3 fatty acids inhibit neuronal excitability and reduce seizures in animal models. High-dose fish oil has been explored in two randomised trials in drug resistant epilepsy with negative results. We performed a phase II randomised controlled crossover trial of low-dose and high-dose fish oil in participants with drug resistant epilepsy to explore whether low-dose or high-dose fish oil reduces seizures or improves cardiovascular health. METHODS: Randomised placebo-controlled trial of low-dose and high-dose fish oil versus placebo (corn oil, linoleic acid) in 24 participants with drug resistant epilepsy. A three-period crossover design was utilised lasting 42 weeks, with three 10-week treatment periods and two 6-week washout periods. All participants were randomised in double-blind fashion to receive placebo, high dose or low dose in different sequences. The primary outcome was per cent change in total seizure frequency. FINDINGS: Low-dose fish oil (3 capsules/day, 1080 mg eicosapentaenoic acid+docosahexaenoic acid) was associated with a 33.6% reduction in seizure frequency compared with placebo. Low-dose fish oil was also associated with a mild but significant reduction in blood pressure. High-dose fish oil was no different than placebo in reducing seizures or improving cardiac risk factors. INTERPRETATION: In this phase II randomised crossover trial, low-dose fish oil was effective in reducing seizures compared with placebo. The magnitude of improvement is similar to that of recent antiepileptic drug trials in drug resistant epilepsy (DRE). The results indicate that low-dose fish oil may reduce seizures and improve the health of people with epilepsy. These findings justify a large multicentre randomised trial of low-dose fish oil (n-3 fatty acids <1080 mg/day) in drug resistant epilepsy. TRIAL REGISTRATION NUMBER: NCT00871377.

Repolarization parameters are associated with mortality in chagas disease patients in the United States.

OBJECTIVE: The goal of this study was to examine the association between ECG repolarization parameters and mortality in Chagas disease (CD) patients living in the United States. METHODS: CD patients with cardiomyopathy (CM) and bundle branch block (BBB) or BBB alone were compared to age- and sex-matched controls. QT interval, QT dispersion (QTd), T wave peak to T wave end duration (Tp-Te) and T wave peak to T wave end dispersion ((Tp-Te)d) were measured. Presence of fractionated QRS (fQRS) was also assessed. The main outcome measure was the association between ECG parameters and mortality or need for cardiac transplant. RESULTS: A total of 18 CM and 13 BBB CD patients were studied with 97% originating from Mexico or Central America. QTd (60.0±15.0 ms vs 43.5±9.8 ms, P=0.0002), Tp-Te (102.6±29.3 ms vs 77.1±11.0 ms, P=0.0002) and (Tp-Te)d (39.5±9.4 ms vs 22.7±7.6 ms, P<0.0001) were prolonged in CD CM patients compared to CM controls. Chagas CM patients had more fQRS then controls (84.2±0.10% vs 33.3±0.11%, p=0.0005). QTd (59.9±15.0 ms vs 29.5±6.9 ms, P=0.0001) and (Tp-Te)d (40.0±15.9 ms vs 18.5±5.4 ms, p<0.0001) were longer in the CD BBB group compared to BBB controls. Univariate analysis showed QTd (56.9±15.0 ms vs 46.5±17.3 ms, p=0.0412) and (Tp-Te)d (36.8±13.5 ms vs 28.5±13.3 ms, p=0.0395) were associated with death and/or need for cardiac transplant. CONCLUSION: Our results indicate that P-max and PD are useful electrocardiographic markers for identifying the ß-TM-high-risk patients for AF onset, even when the cardiac function is conserved.

Recognition and screening for Chagas disease in the USA.

Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, is a public health concern, mainly among countries in South and Central America. However, despite the large number of immigrants from endemic countries living in the USA, awareness of CD is poor in the medical community, and therefore it is significantly underdiagnosed. To avoid the catastrophic cardiac complications of CD and to prevent maternal-fetal transmission, widespread educational programs highlighting the need for diagnosis are urgently needed.

Chagas Disease in the United States: A Perspective on Diagnostic Testing Limitations and Next Steps.

Chagas disease is a neglected tropical disease that affects an estimated 300,000 people in the United States. This perspective piece reviews diagnostic challenges and proposes next steps to address these shortfalls.

"You Don't Have a Normal Life": Coping with Chagas Disease in Los Angeles, California.

Chagas disease is the neglected tropical disease of greatest public health impact in the United States, where it affects over 300,000 people. Diverse barriers limit healthcare access for affected people; fewer than 1% have obtained testing or treatment. We interviewed 50 people with Chagas disease in Los Angeles, California, and administered a cultural consensus analysis questionnaire. Participants were asked about their experiences and perceptions of Chagas disease, access to healthcare, and strategies for coping with the disease. In participants' narratives, the physical and emotional impacts of the disease were closely interwoven. Participant explanatory models highlight difficulties in accessing care, despite a desire for biomedical treatment. Obtaining testing and treatment for Chagas disease poses substantial challenges for US patients.

RMSSD, a measure of vagus-mediated heart rate variability, is associated with risk factors for SUDEP: the SUDEP-7 Inventory.

OBJECTIVE: The goal of this study was to determine if specific measures of heart rate variability (HRV) are associated with the total score on a new seven-item inventory for sudden unexplained death in epilepsy (SUDEP). METHODS: Nineteen subjects with intractable partial seizures, at least three per month, were enrolled in a randomized clinical trial of omega-3 fatty acids in epilepsy. At study entry, subjects underwent a 1-hour ECG recording for the determination of HRV. To estimate the risk of SUDEP, we assembled a seven-item inventory (the SUDEP-7 Inventory) from risk factors prospectively validated by T.S. Walczak, I.E. Leppik, M. D'Amelio M, et al. (Neurology 2001;56:519-25). The SUDEP-7 score was then correlated with measures of HRV using the Pearson correlation and other parametric and nonparametric methods. RESULTS: Subjects had highly drug-resistant seizures, with a mean seizure frequency of 22.8 seizures per month. Scores on the SUDEP-7 inventory ranged from 1 to 7 of a maximum possible score of 12. RMSSD, a measure of high-frequency HRV, was inversely correlated with the SUDEP-7 score, r=-0.64, P=0.004. Subjects with higher SUDEP-7 scores had reduced levels of HRV (RMSSD). Other time-dependent measures of HRV (SDNN, SDANN) were not significantly correlated with SUDEP risk scores. CONCLUSIONS: RMSSD, a measure of HRV, which reflects the integrity of vagus nerve-mediated autonomic control of the heart, is highly associated with the total score on a new seven-item SUDEP risk inventory. Lower RMSSD values were associated with higher risk scores on the new SUDEP risk inventory. This provides new evidence that HRV (specifically RMSSD) is a marker of SUDEP risk.

COVID-19: Implications for People with Chagas Disease.

As the global COVID-19 pandemic advances, it increasingly impacts those vulnerable populations who already bear a heavy burden of neglected tropical disease. Chagas disease (CD), a neglected parasitic infection, is of particular concern because of its potential to cause cardiac, gastrointestinal, and other complications which could increase susceptibility to COVID-19. The over one million people worldwide with chronic Chagas cardiomyopathy require special consideration because of COVID-19's potential impact on the heart, yet the pandemic also affects treatment provision to people with acute or chronic indeterminate CD. In this document, a follow-up to the WHF-IASC Roadmap on CD, we assess the implications of coinfection with SARS-CoV-2 and Trypanosoma cruzi, the etiological agent of CD. Based on the limited evidence available, we provide preliminary guidance for testing, treatment, and management of patients affected by both diseases, while highlighting emerging healthcare access challenges and future research needs.

The potential economic value of a therapeutic Chagas disease vaccine for pregnant women to prevent congenital transmission.

BACKGROUND: Currently, there are no solutions to prevent congenital transmission of Chagas disease during pregnancy, which affects 1-40% of pregnant women in Latin America and is associated with a 5% transmission risk. With therapeutic vaccines under development, now is the right time to determine the economic value of such a vaccine to prevent congenital transmission. METHODS: We developed a computational decision model that represented the clinical outcomes and diagnostic testing strategies for an infant born to a Chagas-positive woman in Mexico and evaluated the impact of vaccination. RESULTS: Compared to no vaccination, a 25% efficacious vaccine averted 125 [95% uncertainty interval (UI): 122-128] congenital cases, 1.9 (95% UI: 1.6-2.2) infant deaths, and 78 (95% UI: 66-91) DALYs per 10,000 infected pregnant women; a 50% efficacious vaccine averted 251 (95% UI: 248-254) cases, 3.8 (95% UI: 3.6-4.2) deaths, and 160 (95% UI: 148-171) DALYs; and a 75% efficacious vaccine averted 376 (95% UI: 374-378) cases, 5.8 (95% UI: 5.5-6.1) deaths, and 238 (95% UI: 227-249) DALYs. A 25% efficacious vaccine was cost-effective (incremental cost-effectiveness ratio <3× Mexico's gross domestic product per capita, <$29,698/DALY averted) when the vaccine cost ≤$240 and ≤$310 and cost-saving when ≤$10 and ≤$80 from the third-party payer and societal perspectives, respectively. A 50% efficacious vaccine was cost-effective when costing ≤$490 and ≤$615 and cost-saving when ≤$25 and ≤$160, from the third-party payer and societal perspectives, respectively. A 75% efficacious vaccine was cost-effective when ≤$720 and ≤$930 and cost-saving when ≤$40 and ≤$250 from the third-party payer and societal perspectives, respectively. Additionally, 13-42 fewer infants progressed to chronic disease, saving $0.41-$1.21 million to society. CONCLUSION: We delineated the thresholds at which therapeutic vaccination of Chagas-positive pregnant women would be cost-effective and cost-saving, providing economic guidance for decision-makers to consider when developing and bringing such a vaccine to market.

Proposed multidimensional framework for understanding Chagas disease healthcare barriers in the United States.

BACKGROUND: Chagas disease (CD) affects over 300,000 people in the United States, but fewer than 1% have been diagnosed and less than 0.3% have received etiological treatment. This is a significant public health concern because untreated CD can produce fatal complications. What factors prevent people with CD from accessing diagnosis and treatment in a nation with one of the world's most advanced healthcare systems? METHODOLOGY/PRINCIPAL FINDINGS: This analysis of barriers to diagnosis and treatment of CD in the US reflects the opinions of the authors more than a comprehensive discussion of all the available evidence. To enrich our description of barriers, we have conducted an exploratory literature review and cited the experience of the main US clinic providing treatment for CD. We list 34 barriers, which we group into four overlapping dimensions: systemic, comprising gaps in the public health system; structural, originating from political and economic inequalities; clinical, including toxicity of medications and diagnostic challenges; and psychosocial, encompassing fears and stigma. CONCLUSIONS: We propose this multidimensional framework both to explain the persistently low numbers of people with CD who are tested and treated and as a potential basis for organizing a public health response, but we encourage others to improve on our approach or develop alternative frameworks. We further argue that expanding access to diagnosis and treatment of CD in the US means asserting the rights of vulnerable populations to obtain timely, quality healthcare.

Progression of Baseline Electrocardiogram Abnormalities in Chagas Patients Undergoing Antitrypanosomal Treatment.

BACKGROUND: The objective of the study was to better understand the impact of antitrypanosomal treatment on the evolution of Chagas-related, prognostically important electrocardiogram (ECG) abnormalities. METHODS: Initial and posttreatment ECGs were obtained in a prospective cohort of Chagas patients treated with nifurtimox or benznidazole and compared to an untreated cohort. Electrocardiogram disease progression was compared in those with and without baseline abnormalities pre- and posttherapy. RESULTS: Fifty-nine patients were recruited in the treatment arm and followed for an average of 3.9 years. There were no differences between ECG groups with regards to follow-up, age, baseline ejection fraction, or therapy. In the treated cohort, 0 of 30 patients with normal ECGs developed an abnormal ECG compared with 7 of 29 patients with baseline ECG abnormalities who developed new ECG abnormalities (P = .005). In an untreated cohort of 30 patients, 3 of 7 with normal ECGs developed an abnormality compared with 14 of 23 patients with baseline abnormalities (P = .67). Untreated patients had a higher likelihood of developing new EKG abnormalities (56.7% vs 11.9%, P < .001) despite shorter follow-up, and in a multivariate analysis adjusting for baseline EKG status across both treated and untreated cohorts, treated patients were still less likely to have progression of their EKG disease (odds ratio = 0.13, P < .001). The corrected QT (QTc) interval was not significantly affected by either study medication (415 vs 421 ms, initial vs posttreatment QTc; P = .06). CONCLUSIONS: Over an average follow-up of 3.9 years, treated patients with normal baseline ECGs did not have significant changes during a course of treatment; however, those with baseline abnormal ECGs had significant progression of their conduction system disease despite treatment, and those without treatment also experienced a progression of ECG disease. These preliminary results suggest that Chagas patients with normal ejection fraction and normal ECG may benefit the most from antitrypanosomal treatment.

Economic value of a therapeutic Chagas vaccine for indeterminate and Chagasic cardiomyopathy patients.

BACKGROUND: Therapeutic vaccines to prevent Chagas disease progression to cardiomyopathy are under development because the only available medications (benznidazole and nifurtimox) are limited by their efficacy, long treatment course, and side effects. Better understanding the potential clinical and economic value of such vaccines can help guide development and implementation. METHODS: We developed a computational Chagas Markov model to evaluate the clinical and economic value of a therapeutic vaccine given in conjunction with benznidazole in indeterminate and chronic Chagas patients. Scenarios explored the vaccine's impact on reducing drug treatment dosage, duration, and adverse events, and risk of disease progression. RESULTS: When administering standard-of-care benznidazole to 1000 indeterminate patients, 148 discontinued treatment and 219 progressed to chronic disease, resulting in 119 Chagas-related deaths and 2293 DALYs, costing $18.9 million in lifetime societal costs. Compared to benznidazole-only, therapeutic vaccination administered with benznidazole (25-75% reduction in standard dose and duration), resulted in 37-111 more patients (of 1000) completing treatment, preventing 11-219 patients from progressing, 6-120 deaths, and 108-2229 DALYs (5-100% progression risk reduction), saving ≤$16,171 per patient. When vaccinating determinate Kuschnir class 1 Chagas patients, 10-197 fewer patients further progressed compared to benznidazole-only, averting 11-228 deaths and 144-3037 DALYs (5-100% progression risk reduction), saving ≤$34,059 per person. When vaccinating Kuschnir class 2 patients, 13-279 fewer progressed (279 with benznidazole-only), averting 13-692 deaths and 283-10,785 DALYs (5-100% progression risk reduction), saving ≤$89,759. Therapeutic vaccination was dominant (saved costs and provided health benefits) with ≥ 5% progression risk reduction, except when only reducing drug treatment regimen and adverse events, but remained cost-effective when costing <$200. CONCLUSIONS: Our study helps outline the thresholds at which a therapeutic Chagas vaccine may be cost-effective (e.g., <5% reduction in preventing cardiac progression, 25% reduction in benznidazole treatment doses and duration) and cost-saving (e.g., ≥5% and 25%, respectively).