Marcos Roberto de Sousa

Predictors of Visceral Leishmaniasis Relapse in HIV-Infected Patients: A Systematic Review

Background and Objectives Visceral leishmaniasis (VL) is a common complication in AIDS patients living in Leishmania-endemic areas. Although antiretroviral therapy has changed the clinical course of HIV infection and its associated illnesses, the prevention of VL relapses remains a challenge for the care of HIV and Leishmania co-infected patients. This work is a systematic review of previous studies that have described predictors of VL relapse in HIV-infected patients. Review Methods We searched the electronic databases of MEDLINE, LILACS, and the Cochrane Central Register of Controlled Trials. Studies were selected if they included HIV-infected individuals with a VL diagnosis and patient follow-up after the leishmaniasis treatment with an analysis of the clearly defined outcome of prediction of relapse. Results Eighteen out 178 studies satisfied the specified inclusion criteria. Most patients were males between 30 and 40 years of age, and HIV transmission was primarily via intravenous drug use. Previous VL episodes were identified as risk factors for relapse in 3 studies. Two studies found that baseline CD4+ T cell count above 100 cells/mL was associated with a decreased relapse rate. The observation of an increase in CD4+ T cells at patient follow-up was associated with protection from relapse in 5 of 7 studies. Meta-analysis of all studies assessing secondary prophylaxis showed significant reduction of VL relapse rate following prophylaxis. None of the five observational studies evaluating the impact of highly active antiretroviral therapy use found a reduction in the risk of VL relapse upon patient follow-up. Conclusion Some predictors of VL relapse could be identified: a) the absence of an increase in CD4+ cells at follow-up; b) lack of secondary prophylaxis; and c) previous history of VL relapse. CD4+ counts below 100 cells/mL at the time of primary VL diagnosis may also be a predictive factor for VL relapse.

Efficacy of anti-leishmania therapy in visceral leishmaniasis among HIV infected patients: a systematic review with indirect comparison.

Objective We conducted a systematic literature review with indirect comparison of studies evaluating therapeutic efficacy and toxicity associated to visceral leishmaniasis (VL) therapy among HIV infected individuals. Main outcome measurements The outcomes of interest were clinical and parasitological cure, mortality, and adverse events. Methods PRISMA guidelines for systematic reviews and Cochrane manual were followed. Sources were MEDLINE, LILACS, EMBASE, Web of Knowledge databases and manual search of references from evaluated studies. We included all studies reporting outcomes after VL treatment, regardless of their design. Study quality was evaluated systematically by using the Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. Comprehensive Meta-Analysis software v.2.2.048 was used to perform one-group meta-analysis of study arms with the same drug to estimate global rates of success and adverse events with each drug. These estimates were used, when possible, to indirectly compare treatment options, adjusted for CD4 count. Direct comparison was pooled when available. Results Seventeen studies reporting five treatment regimens and outcome of 920 VL episodes occurring in HIV infected individuals were included. The main outstanding difference in outcome among the treatment regimens was observed in mortality rate: it was around 3 times higher with high-dose antimony use (18.4%, CI 95% 13.3–25%), indirectly compared to lipid formulations of amphotericin B treatment (6.1%, CI 95% 3.9–9.4%). It was observed, also by indirect comparison, higher rates of clinical improvement in study arms using amphotericin B than in study arms using pentavalent antimonial therapy (Sbv). The parasitological cure, an outcome that presented some degree of risk of selection and verification bias, had rates that varied widely within the same treatment arm, with high heterogeneity, hampering any formal comparison among drugs. One direct comparison of amphotericin and antimoniate was possible combining results of two studies and confirming the superiority of amphotericin. Conclusions Available evidence suggests that amphotericin is superior to antimony treatment. Death rate using antimoniate high dose is unacceptably high. Randomized controlled trials are necessary to compare different formulations and doses of amphotericin, alternative therapies and drug combinations.

The Diagnostic Accuracy of Serologic and Molecular Methods for Detecting Visceral Leishmaniasis in HIV Infected Patients: Meta-Analysis

Background Human visceral leishmaniasis (VL), a potentially fatal disease, has emerged as an important opportunistic condition in HIV infected patients. In immunocompromised patients, serological investigation is considered not an accurate diagnostic method for VL diagnosis and molecular techniques seem especially promising. Objective This work is a comprehensive systematic review and meta-analysis to evaluate the accuracy of serologic and molecular tests for VL diagnosis specifically in HIV-infected patients. Methods Two independent reviewers searched PubMed and LILACS databases. The quality of studies was assessed by QUADAS score. Sensitivity and specificity were pooled separately and compared with overall accuracy measures: diagnostic odds ratio (DOR) and symmetric summary receiver operating characteristic (sROC). Results Thirty three studies recruiting 1,489 patients were included. The following tests were evaluated: Immunofluorescence Antibody Test (IFAT), Enzyme linked immunosorbent assay (ELISA), immunoblotting (Blot), direct agglutination test (DAT) and polimerase chain reaction (PCR) in whole blood and bone marrow. Most studies were carried out in Europe. Serological tests varied widely in performance, but with overall limited sensitivity. IFAT had poor sensitivity ranging from 11% to 82%. DOR (95% confidence interval) was higher for DAT 36.01 (9.95–130.29) and Blot 27.51 (9.27–81.66) than for IFAT 7.43 (3.08–1791) and ELISA 3.06 (0.71–13.10). PCR in whole blood had the highest DOR: 400.35 (58.47–2741.42). The accuracy of PCR based on Q-point was 0.95; 95%CI 0.92–0.97, which means good overall performance. Conclusion Based mainly on evidence gained by infection with Leishmania infantum chagasi, serological tests should not be used to rule out a diagnosis of VL among the HIV-infected, but a positive test at even low titers has diagnostic value when combined with the clinical case definition. Considering the available evidence, tests based on DNA detection are highly sensitive and may contribute to a diagnostic workup.

Non‐sustained ventricular tachycardia as a predictor of sudden cardiac death in patients with left ventricular dysfunction: A meta‐analysis

Identifying patients at risk of sudden cardiac death (SCD) remains a challenge.

Heart Rate Turbulence in Chagas Disease

RIBEIRO, A.L.P., et al.: Heart Rate Turbulence in Chagas Disease. Heart rate turbulence (HRT) quantifies the biphasic response of the sinus node to ventricular premature complexes (VPCs) and is a powerful electrocardiogram related risk predictor. VPCs are frequent in Chagas disease, a potentially lethal illness, and can hamper the analysis by conventional methods of autonomic heart control. The aim of the study was to examine HRT in patients with Chagas disease. Chagas disease patients and healthy controls (group 0, n = 11 ) without other diseases were submitted to a standardized protocol, including electrocardiogram, echocardiography, and 24‐hour Holter monitoring. Chagas disease patients were divided according to their left ventricular systolic function: normal (group 1, n = 103 ) and reduced ejection fraction (group 2, n = 23 ). Two HRT indices, turbulence onset (TO) and turbulence slope (TS), were calculated and compared among groups after adjustment for covariates like the prevalence of VPCs and the mean heart rate. Chagas disease patients had significantly altered TO (group 1: −0.0186, group 2: −0.0126) and TS (group 1: 10.844, group 2: 7.870) values in comparison with controls (TO − 0.0256, TS 19.829); P < 0.001 for both comparisons. In conclusion, HRT data may be useful in the electrocardiographic analysis of autonomic heart control in Chagas disease. Its prognostic value remains to be determined. (PACE 2003; 26[Pt. II]:406–410)

Comparison of parasitological, serological, and molecular tests for visceral leishmaniasis in HIV-infected patients: a cross-sectional delayed-type study.

The aim of this study was to evaluate the accuracy of invasive and non-invasive tests for diagnosis of visceral leishmaniasis (VL) in a large series of human immunodeficiency virus (HIV)-infected patients. In this delayed-type cross-sectional study, 113 HIV-infected symptomatic patients were evaluated by an adjudication committee after clinical follow-up to establish the presence or absence of VL as the target condition (reference test). The index tests were recombinant K39 antigen-based immunochromatographic test (rK39), indirect fluorescent antibody test (IFAT), prototype kit of direct agglutination test (DAT-LPC), and real-time polymerase chain reaction (qPCR) in peripheral blood. Compared with parasitological test and adjudication committee diagnosis or latent class model analyses, IFAT and rk39 dipstick test presented the lowest sensitivity. DAT-LPC exhibited good overall performance, and there was no statistical difference between DAT-LPC and qPCR diagnosis accuracy. Real-time PCR emerges as a less invasive alternative to parasitological examination for confirmation of cases not identified by DAT.

Systematic review and meta-analysis of diagnostic and prognostic studies: a tutorial

Systematic reviews with meta-analysis of studies on diagnostic tests or prognostic factors are research tools that are still being developed. The objective of the present paper is to describe the methodology of systematic review and meta-analysis of this type of studies, step by step. A literature review on the subject was made, the recommendations were compiled and the paper was organized in: a) Introduction, b) Details on the eight steps to be followed, c) Form of publication of a systematic review with meta-analysis, and d) Conclusion. The systematic review methods were thoroughly described with a critical analysis of the methods of statistical compilation of results, with emphasis on the utilization of the Summary Receiver Operator Characteristic curve. References for the details of each statistical technique used were provided in the meta-analysis. We concluded that systematic reviews with meta-analysis of diagnostic tests or prognostic factors are useful in data compilation of various studies on the same subject, since they reduce biases and increase the statistical power of the primary research.Las revisiones sistematicas con metaanalisis de estudios de examenes diagnosticos o de factores pronosticos son herramientas de investigacion aun en fase de desarrollo. El presente trabajo tiene como objetivo describir la metodologia de revision sistematica y de metaanalisis de esta clase de estudios, paso a paso. Se hizo la revision de la literatura sobre el tema, compilandose las recomendaciones con objeto de organizarse el texto en: a) Introduccion; b) Detalle de los ocho pasos a seguirse; c) Formato de publicacion de la revision sistematica con metaanalisis; y d) Conclusion. Se describieron los metodos de revision sistematica con detalle, y se analizo de manera critica los metodos de compilacion estadistica de los resultados, con enfasis en la utilizacion de la curva Summary Receiver Operator Characteristic. Se suministro referencia para los detalles de cada tecnica estadistica utilizada en el metaanalisis. Concluimos que las revisiones sistematicas con metaanalisis de examenes diagnosticos o de factores pronosticos son valiosas en la compilacion de datos de diversos estudios sobre el mismo tema, reduciendose sesgos y aumentandose el poder estadistico de la investigacion primaria.

Leishmania-HIV co-infection: clinical presentation and outcomes in an urban area in Brazil.

Background Visceral leishmaniasis (VL) is an emerging condition affecting HIV-infected patients living in Latin America, particularly in Brazil. Leishmania-HIV coinfection represents a challenging diagnosis because the clinical picture of VL is similar to that of other disseminated opportunistic diseases. Additionally, coinfection is related to treatment failure, relapse and high mortality. Objective To assess the clinical-laboratory profile and outcomes of VL-HIV-coinfected patients using a group of non HIV-infected patients diagnosed with VL during the same period as a comparator. Methods The study was conducted at a reference center for infectious diseases in Brazil. All patients with suspected VL were evaluated in an ongoing cohort study. Confirmed cases were divided into two groups: with and without HIV coinfection. Patients were treated according to the current guidelines of the Ministry of Health of Brazil, which considers antimony as the first-choice therapy for non HIV-infected patients and recommends amphotericin B for HIV-infected patients. After treatment, all patients with CD4 counts below 350 cells/mm3 received secondary prophylaxis with amphotericin B. Results Between 2011 and 2013, 168 patients with suspected VL were evaluated, of whom 90 were confirmed to have VL. In total, 51% were HIV coinfected patients (46 patients). HIV-infected patients had a lower rate of fever and splenomegaly compared with immunocompetent patients. The VL relapse rate in 6 months was 37% among HIV-infected patients, despite receiving secondary prophylaxis. The overall case-fatality rate was 6.6% (4 deaths in the HIV-infected group versus 2 deaths in the non HIV-infected group). The main risk factors for a poor outcome at 6 months after the end of treatment were HIV infection, bleeding and a previous VL episode. Conclusion Although VL mortality rates among HIV-infected individuals are close to those observed among immunocompetent patients treated with amphotericin B, HIV coinfection is related to a low clinical response and high relapse rates within 6 months.

Prevention of hypertension in patients with pre-hypertension: protocol for the PREVER-prevention trial

BackgroundBlood pressure (BP) within pre-hypertensive levels confers higher cardiovascular risk and is an intermediate stage for full hypertension, which develops in an annual rate of 7 out of 100 individuals with 40 to 50 years of age. Non-drug interventions to prevent hypertension have had low effectiveness. In individuals with previous cardiovascular disease or diabetes, the use of BP-lowering agents reduces the incidence of major cardiovascular events. In the absence of higher baseline risk, the use of BP agents reduces the incidence of hypertension. The PREVER-prevention trial aims to investigate the efficacy, safety and feasibility of a population-based intervention to prevent the incidence of hypertension and the development of target-organ damage.MethodsThis is a randomized, double-blind, placebo-controlled clinical trial, with participants aged 30 to 70 years, with pre-hypertension. The trial arms will be chlorthalidone 12.5 mg plus amiloride 2.5 mg or identical placebo. The primary outcomes will be the incidence of hypertension, adverse events and development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG. The secondary outcomes will be fatal or non-fatal cardiovascular events: myocardial infarction, stroke, heart failure, evidence of new sub-clinical atherosclerosis, and sudden death. The study will last 18 months. The sample size was calculated on the basis of an incidence of hypertension of 14% in the control group, a size effect of 40%, power of 85% and P alpha of 5%, resulting in 625 participants per group. The project was approved by the Ethics committee of each participating institution.DiscussionThe early use of blood pressure-lowering drugs, particularly diuretics, which act on the main mechanism of blood pressure rising with age, may prevent cardiovascular events and the incidence of hypertension in individuals with hypertension. If this intervention shows to be effective and safe in a population-based perspective, it could be the basis for an innovative public health program to prevent hypertension in Brazil.Trial RegistrationClinical Trials NCT00970931.

Diagnostic accuracy of intravascular ultrasound-derived minimal lumen area compared with fractional flow reserve--meta-analysis: pooled accuracy of IVUS luminal area versus FFR.

Although intravascular ultrasound minimal luminal area (IVUS‐MLA) is one of many anatomic determinants of lesion severity, it has been proposed as an alternative to fractional flow reserve (FFR) to assess severity of coronary artery disease.