Effects of Selenium treatment on cardiac function in Chagas heart disease: Results from the STCC randomized Trial.

BACKGROUND: Chagas disease (caused by Trypanosoma cruzi infection) evolves to chronic chagasic cardiomyopathy (CCC) affecting 1.8 million people worldwide. This is the first randomized, placebo-controlled, double-blinded, clinical trial designed to estimate efficacy and safety of selenium (Se) treatment in CCC. METHODS: 66 patients with CCC stages B1 (left ventricular ejection fraction [LVEF] > 45% and no heart failure; n = 54) or B2 (LVEF < 45% and no heart failure; n = 12) were randomly assigned to receive 100 mcg/day sodium selenite (Se, n = 32) or placebo (Pla, n = 34) for one year (study period: May 2014-September 2018). LVEF changes over time and adverse effects were investigated. Trial registration number: NCT00875173 (clinicaltrials.gov). FINDINGS: No significant differences between the two groups were observed for the primary outcome: mean LVEF after 6 (ß= +1.1 p = 0.51 for Se vs Pla) and 12 months (ß= +2.1; p = 0.23). In a subgroup analysis, statistically significant longitudinal changes were observed for mean LVEF in the stage B2 subgroup (ß= +10.1; p = 0.02 for Se [n = 4] vs Pla [n = 8]). Se treatment was safe for CCC patients, and the few adverse effects observed were similarly distributed across the two groups. INTERPRETATION: Se treatment did not improve cardiac function (evaluated from LVEF) in CCC. However, in the subgroup of patients at B2 stage, a potential beneficial influence of Se was observed. Complementary studies are necessary to explore diverse Se dose and/or associations in different CCC stages (B2 and C), as well as in A and B1 stages with longer follow-up. FUNDING: Brazilian Ministry of Health, Fiocruz, CNPq, FAPERJ.

Benznidazole decreases the risk of chronic Chagas disease progression and cardiovascular events: A long-term follow up study.

BACKGROUND: Chagas disease (CD) remains an important endemic disease in Latin America. However, CD became globalized in recent decades. The majority of the chronically infected individuals did not receive etiologic treatment for several reasons, among them the most conspicuous is the lack of access to diagnosis. The impact of trypanocidal treatment on CD chronic phase, without cardiac involvement (indeterminate form ICF), is yet to be determined. We aimed to evaluate the effect of trypanocidal treatment with benznidazole (BZN) on the rate of progression to Chagas heart disease in patients with ICF. METHODS: This is a retrospective cohort observational study including patients with ICF treated with BZN and compared to a group of non-treated patients matched for age, sex, region of origin, and the year of cohort entry. We reviewed the medical charts of all patients followed from May 1987 to June 2020 at the outpatient center of the Evandro Chagas National Institute of Infectious Diseases (INI) of the Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil. Patients' follow-up included at least one annual medical visit and one annual electrocardiogram (ECG). Echocardiographic exams were performed at baseline and during the follow-up. Disease progression from ICF to cardiac form was defined by changes in baseline ECG. Cumulative incidence and the incidence rate were described in the incidence analysis. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for the association between BZN and CD progression, cardiovascular events or death. FINDINGS: One hundred and fourteen treated patients met the study inclusion criteria. A comparison group of 114 non-treated patients matched for age, sex, region of origin, and the year of cohort entry was also included, totalizing 228 patients. Most patients included in the study were male (70.2%), and their mean age was 31.3 (+7.4) years. Over a median follow-up of 15.1 years (ranging from 1.0 to 32.4), the cumulative CD progression incidence in treated patients was 7.9% vs. 21.1% in the non-treated group (p = 0.04) and the CD progression rate was 0.49 per 1.000 patients/year in treated patients vs. 1.10 per 1.000 patients/year for non-treated patients (p = 0.02). BZN treatment was associated with a decreased risk of CD progression in both unadjusted (HR 0.46; 95%CI 0.21 to 0.98) and adjusted (HR 0.43; 95%CI 0.19 to 0.96) models and with a decreased risk of occurrence of the composite of cardiovascular events only in the adjusted (HR 0.15; 95%CI 0.03 to 0.80) model. No association was observed between BZN treatment and mortality. INTERPRETATION: In a long-term follow-up, BZN treatment was associated with a decreased incidence of CD progression from ICF to the cardiac form and also with a decreased risk of cardiovascular events. Therefore, our results indicate that BZN treatment for CD patients with ICF should be implemented into clinical practice.

Quality of life and associated factors in patients with chronic Chagas disease.

OBJECTIVES: To evaluate the quality of life (QoL) of patients with Chagas disease (CD) and the association between QoL domains and several clinical, socioeconomic and lifestyle characteristics of this population. METHODS: Cross-sectional observational study conducted from March 2014 to March 2017 including a total of 361 outpatients followed at Evandro Chagas National Institute of Infectious Disease, Brazil. QoL was assessed using the Portuguese shorter version of the original WHO Quality of Life questionnaire (WHOQOL-BREF). Information about clinical CD presentation, presence of comorbidities, functional class, previous benznidazole treatment, socioeconomic profile and lifestyle was also obtained. RESULTS: Environment and physical domains presented the worst QoL scores, while the social relationship domain presented the highest score. Multivariate regression analysis demonstrated that variables independently associated with QoL were functional class, sex, clinical presentation of CD, sleep duration, schooling, physical activity level, smoking, income per capita and residents by domicile. CONCLUSIONS: The low socioeconomic status and the physical limitations imposed by the disease presented an important impact on the QoL reduction among CD patients, especially on environment and physical domains. Strategies to improve QoL among CD patients should be tailored and consider many different variables to maximise improvements not only of patients' physical but also of their mental health.

Accuracy of a rapid real-time polymerase chain reaction assay for diagnosis of group B Streptococcus colonization in a cohort of HIV-infected pregnant women.

OBJECTIVE: There are limited data regarding Xpert performance to detect Group B Streptococcus (GBS) in HIV-infected pregnant women. We evaluated the accuracy of a rapid real-time polymerase chain reaction (PCR) test in a cohort of HIV-infected women. METHODS: At 35-37 weeks of pregnancy, a pair of combined rectovaginal swabs were collected for two GBS assays in a cohort of sequentially included HIV-infected women in Rio de Janeiro: (1) culture; and (2) real-time PCR assay [GeneXpert GBS (Cepheid, Sunnyvale, CA)]. Using culture as the reference, sensitivity, specificity, positive and negative-likelihood ratios were estimated. RESULTS: From June 2012 to February 2015, 337 pregnant women met inclusion criteria. One woman was later excluded, due to failure to obtain a result in the index test; 336 were included in the analyses. The GBS colonization rate was 19.04%. Sensitivity and specificity of the GeneXpert GBS assay were 85.94% (95% CI: 75.38-92.42) and 94.85% (95% CI: 91.55-96.91), respectively. Positive and negative predictive values were 79.71% (95% CI: 68.78-87.51) and 96.63% (95% CI: 93.72-98.22), respectively. CONCLUSIONS: GeneXpert GBS is an acceptable test for the identification of GBS colonization in HIV-infected pregnant women and represents a reasonable option to detect GBS colonization in settings where culture is not feasible.

Effects of Organizational Characteristics on Outcomes and Resource Use in Patients With Cancer Admitted to Intensive Care Units.

PURPOSE: To investigate the impact of organizational characteristics and processes of care on hospital mortality and resource use in patients with cancer admitted to intensive care units (ICUs). PATIENTS AND METHODS: We performed a retrospective cohort study of 9,946 patients with cancer (solid, n = 8,956; hematologic, n = 990) admitted to 70 ICUs (51 located in general hospitals and 19 in cancer centers) during 2013. We retrieved patients' clinical and outcome data from an electronic ICU quality registry. We surveyed ICUs regarding structure, organization, staffing patterns, and processes of care. We used mixed multivariable logistic regression analysis to identify characteristics associated with hospital mortality and efficient resource use in the ICU. RESULTS: Median number of patients with cancer per center was 110 (interquartile range, 58 to 154), corresponding to 17.9% of all ICU admissions. ICU and hospital mortality rates were 15.9% and 25.4%, respectively. After adjusting for relevant patient characteristics, presence of clinical pharmacists in the ICU (odds ratio [OR], 0.67; 95% CI, 0.49 to 0.90), number of protocols (OR, 0.92; 95% CI, 0.87 to 0.98), and daily meetings between oncologists and intensivists for care planning (OR, 0.69; 95% CI, 0.52 to 0.91) were associated with lower mortality. Implementation of protocols (OR, 1.52; 95% CI, 1.11 to 2.07) and meetings between oncologists and intensivists (OR, 4.70; 95% CI, 1.15 to 19.22) were also independently associated with more efficient resource use. Neither admission to ICUs in cancer centers compared with general hospitals nor annual case volume had an impact on mortality or resource use. CONCLUSION: Organizational aspects, namely the implementation of protocols and presence of clinical pharmacists in the ICU, and close collaboration between oncologists and ICU teams are targets to improve mortality and resource use in critically ill patients with cancer.

Organizational characteristics, outcomes, and resource use in 78 Brazilian intensive care units: the ORCHESTRA study.

PURPOSE: Detailed information on organization and process of care in intensive care units (ICU) in emerging countries is scarce. Here, we investigated the impact of organizational factors on the outcomes and resource use in a large sample of Brazilian ICUs. METHODS: Retrospective cohort study of 59,693 patients (medical admissions, 67 %) admitted to 78 ICUs during 2013. We retrieved patients' data from an ICU quality registry and surveyed ICUs regarding structure, organization, staffing patterns, and process of care. We used multilevel logistic regression analysis to identify factors associated with hospital mortality. Efficient resource use was assessed by estimating standardized resource use and mortality rates adjusted for the SAPS 3 score. RESULTS: ICUs were mostly medical-surgical (79 %) and located at private hospitals (86 %). Median nurse to bed ratio was 0.20 (IQR, 0.15-0.28) and board-certified intensivists were present 24/7 in 16 (21 %) of ICUs. Multidisciplinary rounds occurred in 67 (86 %) and daily checklists were used in 36 (46 %) ICUs. Most frequent protocols focused on sepsis management and prevention of healthcare-associated infections. Hospital mortality was 14.4 %. In multivariable analysis, the number of protocols was the only organizational characteristic associated with mortality [odds ratio = 0.944 (95 % CI 0.904-0.987)]. The effects of protocols were consistent across subgroups including surgical and medical patients as well as the SAPS 3 tertiles. We also observed a significant trend toward efficient resource use as the number of protocols increased. CONCLUSIONS: In emerging countries such as Brazil, organizational factors, including the implementation of protocols, are potential targets to improve patient outcomes and resource use in ICUs.

Antiphospholipid antibodies in critically ill patients with cancer: a prospective cohort study.

PURPOSE: The purpose of this study is to evaluate the prevalence and the prognostic impact of antiphospholipid antibodies (aPL) in critically ill cancer patients. METHODS: This is a prospective cohort study in adult patients admitted to the intensive care unit for more than 48 hours at a cancer center. Clinical and laboratory data including coagulation parameters were obtained. Cox proportional hazard models were used to identify predictors of 6-month mortality. RESULTS: Ninety-five (solid tumor, 79%; hematologic malignancies, 21%) patients were included, and aPL were identified in 74% of them. Median Simplified Acute Physiology Score 3 and Sequential Organ Failure Assessment scores were 51 (37-65) and 5 (2-8) points, respectively. The most frequent aPL were lupus anticoagulant (61%) and anti-ß2 glicoprotein I (32%). Vascular complications occurred in 18% of patients and were comparable between aPL+ and aPL- patients. Sepsis and need for renal replacement therapy were more frequent in aPL+ patients. Hospital and 6-month mortality rates were 44% and 56%, respectively. Higher Sequential Organ Failure Assessment scores (each point) (hazard ratios [HR]=2.83 [95% confidence interval, 1.59-5.00]), medical admissions (HR=2.66 [1.34-5.27]), and d-dimer more than 500 ng/dL (HR=1.89 (1.04-3.44]) were independently associated with mortality. After adjusting for these covariates, aPL status was not associated with outcomes (HR=1.22 [0.60-2.47]). CONCLUSIONS: Lupus anticoagulants were frequent in critically ill cancer patients. However, they were not associated with medium-term survival in these patients.

Safety of benznidazole use in the treatment of chronic Chagas' disease.

OBJECTIVES: To assess the safety of benznidazole use in adult patients with chronic Chagas' disease. METHODS: The Naranjo algorithm was applied to classify the causality of adverse drug reactions (ADRs). RESULTS: In total, 190 patients were treated with benznidazole over a period of 4-180 days (mean 58.90 ± 36.54 days) with a dose of 50-500 mg/day (221.33 ± 57.16 mg/day). Of the 190 patients treated, 93 had ADRs and 59 of these interrupted treatment. There was a higher incidence of ADRs among female and young adult patients. There was a higher incidence of ADRs during the first 30 days of treatment. Interruption of treatment was more frequent in women. Among the patients who interrupted treatment, 39 had mild ADRs, 19 had moderate ADRs and 1 had a severe ADR. There were no interruptions in treatment for 97 patients without ADRs. The survival curves indicated that the time until interruption of treatment in patients with moderate and severe ADRs was lower than in patients with mild or no ADRs. The most frequent disorders were in the skin (26.3%), gastrointestinal system (9.5%) and nervous system (5.3%). CONCLUSIONS: The Naranjo algorithm was a useful tool to reduce the underreporting of ADRs. Events were common, but were associated with low morbidity and were reversible upon discontinuation of drug treatment. Moreover, there were no fatal events; therefore, benznidazole treatment was considered safe.

Unique CYP3A4 genetic variant in Brazilian tuberculosis patients with/without HIV.

CYP3A4 is involved in tuberculosis (TB) and human immunodeficiency virus (HIV) drug metabolism. Transcriptional activation by rifampicin involves the CYP3A4 gene 5'-upstream region. Consequently, variation may interfere with transcription and enzymatic activity and even drug response. However, genetic polymorphisms and distribution of CYP3A4 allelic frequencies in individuals from Rio de Janeiro remain unknown. The aim of this study was to conduct research into sequencing the CYP3A4 5'-upstream region in Brazilian patients with and without HIV. This follow-up study involved 106 individuals undergoing treatment for TB and/or HIV. The CYP3A4 5'-upstream region was analyzed using PCR, sequencing and clinical data. Male patients revealed a higher HIV frequency (p=0.021). The TB forms observed were pulmonary (48.1%), extrapulmonary (22.64%) and disseminated (27.36%). Lymph node form was the most frequent (70.83%) extrapulmonary form of TB. The only single nucleotide polymorphism detected in the population was c.-392A>G. Genotypes observed were CYP3A4*1A/CYP3A4*1A (45.3%), CYP3A4*1A/CYP3A4*1B (40.6%) and CYP3A4*1B/CYP3A4*1B (14.2%), revealing a different distribution with extrapulmonary TB cases (17.6% CYP3A4*1A/CYP3A4*1B and 23.5% CYP3A4*1B/CYP3A4*1B). The CYP3A4*1A allele was found to be associated with tobacco use. The CYP3A4*1B mutant allele occurred in 34% of patients. This study revealed that the CYP3A4 5'-upstream regulatory region was highly conserved with the exception of the -392 position. Genotype association with tobacco suggests that CYP3A4 may participate in tobacco metabolism. Genotype distribution inversion in extrapulmonary TB cases suggests that CYP3A4 may be involved in TB prognosis.

[Performance by cytology and hybrid capture II in screening for high-grade squamous intraepithelial lesions in women with HIV]. / Desempenho do exame citológico e da captura híbrida II no rastreamento de lesões intraepiteliais escamosas de alto grau em mulheres HIV+

HIV-infected women are at increased risk of developing high-grade squamous intraepithelial lesions (HSIL), the precursor lesions for cervical cancer. This study estimated and compared the performance of cytology and hybrid capture II in screening for precursor lesions of cervical cancer among HIV-infected women. The study population consisted of women from the open prospective cohort at the Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation (IPEC/Fiocruz). Colposcopy and histology were considered jointly in defining the gold standard. Cytology showed 31.8% sensitivity and 95.5% specificity, while hybrid capture II showed higher sensitivity (100%) and lower specificity (52%). The positive likelihood ratio was 7.1 for cytology and 2.1 for hybrid capture II, while the negative likelihood ratio was 0.7 for cytology and 0.0 for hybrid capture II.

Desempenho do exame citológico e da captura híbrida II no rastreamento de lesões intraepiteliais escamosas de alto grau em mulheres HIV+ / Performance by cytology and hybrid capture II in screening for high-grade squamous intraepithelial lesions in women with HIV

As lesões intraepiteliais escamosas de alto grau (HSIL) são precursoras do câncer do colo do útero, com maior risco de ocorrência e desenvolvimento em mulheres HIV+. Neste trabalho, estimamos e comparamos o desempenho do exame citológico e da captura híbrida II no rastreamento das lesões precursoras em mulheres HIV+. A população de estudo compreendeu mulheres acompanhadas na coorte prospectiva aberta do Instituto de Pesquisa Clínica Evandro Chagas da Fundação Oswaldo Cruz (IPEC/Fiocruz). A colposcopia e histologia foram consideradas conjuntamente na definição do teste de referência. O exame citológico apresentou sensibilidade de 31,8 por cento e especificidade de 95,5 por cento, enquanto a captura híbrida II apresentou maior sensibilidade (100 por cento) e menor especificidade (52 por cento). As razões de verossimilhança para o teste positivo e negativo foram estimadas em 7,1 e 0,7 para o exame citológico e em 2,1 e 0,0 para a captura híbrida II, respectivamente.

HIV-infected women are at increased risk of developing high-grade squamous intraepithelial lesions (HSIL), the precursor lesions for cervical cancer. This study estimated and compared the performance of cytology and hybrid capture II in screening for precursor lesions of cervical cancer among HIV-infected women. The study population consisted of women from the open prospective cohort at the Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation (IPEC/Fiocruz). Colposcopy and histology were considered jointly in defining the gold standard. Cytology showed 31.8 percent sensitivity and 95.5 percent specificity, while hybrid capture II showed higher sensitivity (100 percent) and lower specificity (52 percent). The positive likelihood ratio was 7.1 for cytology and 2.1 for hybrid capture II, while the negative likelihood ratio was 0.7 for cytology and 0.0 for hybrid capture II.

ELISA versus PCR for diagnosis of chronic Chagas disease: systematic review and meta-analysis.

BACKGROUND: Most current guidelines recommend two serological tests to diagnose chronic Chagas disease. When serological tests are persistently inconclusive, some guidelines recommend molecular tests. The aim of this investigation was to review chronic Chagas disease diagnosis literature and to summarize results of ELISA and PCR performance. METHODS: A systematic review was conducted searching remote databases (MEDLINE, LILACS, EMBASE, SCOPUS and ISIWeb) and full texts bibliography for relevant abstracts. In addition, manufacturers of commercial tests were contacted. Original investigations were eligible if they estimated sensitivity and specificity, or reliability -or if their calculation was possible - of ELISA or PCR tests, for chronic Chagas disease. RESULTS: Heterogeneity was high within each test (ELISA and PCR) and threshold effect was detected only in a particular subgroup. Reference standard blinding partially explained heterogeneity in ELISA studies, and pooled sensitivity and specificity were 97.7% [96.7%-98.5%] and 96.3% [94.6%-97.6%] respectively. Commercial ELISA with recombinant antigens studied in phase three investigations partially explained heterogeneity, and pooled sensitivity and specificity were 99.3% [97.9%-99.9%] and 97.5% [88.5%-99.5%] respectively. ELISA's reliability was seldom studied but was considered acceptable. PCR heterogeneity was not explained, but a threshold effect was detected in three groups created by using guanidine and boiling the sample before DNA extraction. PCR sensitivity is likely to be between 50% and 90%, while its specificity is close to 100%. PCR reliability was never studied. CONCLUSIONS: Both conventional and recombinant based ELISA give useful information, however there are commercial tests without technical reports and therefore were not included in this review. Physicians need to have access to technical reports to understand if these serological tests are similar to those included in this review and therefore correctly order and interpret test results. Currently, PCR should not be used in clinical practice for chronic Chagas disease diagnosis and there is no PCR test commercially available for this purpose. Tests limitations and directions for future research are discussed.