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Background The detection of Mycobacterium tuberculosis (MTB) in the intensive care unit (ICU) presents several challenges, mainly associated to the clinical state of the patient. The presence of HIV infection further aggravates this scenario, requiring a reliable collection method, with better performance in the microbiological/molecular techniques to be used. We evaluated the performance of two methods for sample collection, mini bronchoalveolar lavage (Mini-BAL) and endotracheal aspirate (ETA), for diagnosis of pulmonary tuberculosis (PTB) in critically ill patients. Methods This prospective study involved 26 HIV positive ICU internalized patients, with presumptive PTB who required mechanical ventilation. Two samples were obtained prospectively from 26 HIV ICU patients with presumptive PTB by Mini-BAL and ETA. The samples were processed for smear microscopy, Löwenstein-Jensen medium and the BACTEC Mycobacteria Growth Indicator Tube 960 system®. We define as confirmed PTB patients with positive MTB culture. Furthermore, all samples obtained through the Mini-BAL were analyzed by Xpert® MTB/RIF. Results Our results demonstrated that the respiratory samples obtained by Mini-BAL were able to increase MTB detection in critically ill patients with presumptive PTB. The Mini-BAL allowed 30% increased recovery and guaranteed enough sample volume for processing in all methods. In addition, the larger volume of the samples obtained with this technique enabled the Xpert® MTB/RIF molecular test for diagnosis of TB. Conclusions The Mini-BAL showed be an acceptable alternative to ETA in this population, since these critically ill and often-immunocompromised patients are more likely to develop complications related to invasive procedures.

The interferon gamma release assay (IGRA) has emerged as a useful tool for identifying latent tuberculosis infection (LTBI). This assay can be performed through testing platforms such as the QuantiFERON-TB Gold Plus (QFT-Plus) assay. This in vitro test has been incorporated into several guidelines worldwide and has recently been considered by the World Health Organization (WHO) for the diagnosis of LTBI. The possibility of systematically implementing IGRAs such as the QFT-Plus assay in centers that perform LTBI screening has been accelerated by the decreased availability of the tuberculin skin test (TST) in several countries. Nevertheless, the process to implement IGRA testing in routine clinical care has many gaps. The study utilized the expertise acquired by the laboratory teams of the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil consortium during study protocol implementation of LTBI screening of tuberculosis (TB) close contacts. RePORT-Brazil includes clinical research sites from Brazilian cities and is the largest multicenter cohort of TB close contacts in the country to date. Operational and logistical challenges faced during IGRA implementation in all study laboratories are described, as well as the solutions that were developed and led to the successful establishment of IGRA testing in RePORT-Brazil. The descriptions of the problems identified and resolved in this study can assist laboratories implementing IGRAs, in addition to manufacturers of IGRAs providing effective technical support. This will facilitate the implementation of IGRA testing in countries with large TB burdens, such as Brazil. IMPORTANCE The IGRA has emerged as a useful tool for identifying persons with LTBI. Although the implementation of IGRAs is of utmost importance, to our knowledge there is scarce information on the identification of logistical and technical challenges for systematic screening for LTBI on a large scale. Thus, the descriptions of the problems identified and resolved in this study can assist laboratories implementing IGRAs, in addition to manufacturers of IGRAs providing effective technical support. This will facilitate the implementation of IGRA testing in countries with large TB burdens, such as Brazil.

BackgroundInterferon-gamma release assay (IGRA) has emerged as a useful tool in identifying latent tuberculosis infection (LTBI). This assay can be performed through testing platforms, such as QuantiFERON-TB Gold Plus (QFT®-Plus). This in vitro test has been incorporated by several guidelines worldwide and has recently been considered for the diagnosis of LTBI by the World Health Organization (WHO). The possibility of systematically implementing IGRAs such as QFT®-Plus in centers that perform LTBI screening has been accelerated by the decreased availability of tuberculin skin testing (TST) in several countries. Nevertheless, the process to implement IGRA testing in routine clinical care has many gaps.MethodsThe study utilized the expertise acquired by the laboratory teams of the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil consortium during study protocol implementation of LTBI screening of TB close contacts.ResultsRePORT-Brazil includes clinical research sites from Brazilian cities and is the largest multicenter cohort of TB close contacts to date in the country. Operational and logistical challenges faced during IGRA implementation in all four study laboratories are described, as well as the solutions that were developed and led to the successful establishment of IGRA testing in RePORT-Brazil.ConclusionsThe problems identified and resolved in this study can assist laboratories implementing IGRAs, in addition to manufacturers of IGRAs providing effective technical support. This will facilitate the implementation of IGRA testing in countries with a high TB burden, such as Brazil.ImportanceThe interferon-gamma release assay (IGRA) has emerged as a useful tool in identifying persons with latent tuberculosis infection (LTBI). Although the implementation of IGRAs is of utmost importance, to our knowledge, there is scarce information on identification of logistical and technical challenges of systematic screening of for LTBI on a large scale. Thus, the problems identified and resolved in this study can assist laboratories implementing IGRAs, in addition to manufacturers of IGRAs providing effective technical support. This will facilitate the implementation of IGRA testing in countries with a high TB burden, such as Brazil.

SETTING: The incidence of tuberculosis (TB) has been decreasing in Portugal. Lisbon concentrates the largest number of cases of multidrug-resistant (MDR) TB in the country. This study aims at identifying clinical and demographic factors associated with unfavourable treatment results of patients with MDR-TB in the city.METHOD: The data on 265 MDR-TB cases, notified from 2000 to 2014 in the District of Lisbon, were collected from the Tuberculosis Surveillance System. Unfavourable cases were classified as failure, loss to follow-up (LTFU) and death. Bivariate and multivariate logistic regressions were undertaken to estimate the factors associated with unfavourable outcomes, LTFU and death.RESULTS: The proportion of unfavourable outcomes was 30.5%. These were associated mostly with being male, foreign-born and resistant to kanamycin. Death was associated with being human immunodeficiency virus-positive and resistant to kanamycin. Being foreign-born had a 4.46-fold higher odds of a LTFU outcome than did being Portuguese-born. The foreign-born patients were mostly African immigrants.CONCLUSION: The main finding in this study is that foreign-born patients are associated with a higher probability of unfavourable outcomes than Portuguese-born patients. Therefore, foreign-born patients need more careful monitoring in the control of MDR-TB.

SETTING: Rio de Janeiro, RJ, Brazil, a high tuberculosis (TB) burden city.OBJECTIVE: To compare the sociodemographics, clinical characteristics, care process indicators (CPIs) and treatment outcomes among adolescents with pulmonary TB (PTB) and those with PTB + extrapulmonary TB (EPTB), who underwent testing with Xpert® and sputum culture.DESIGN: This was a retrospective study of data from three national databases from 2014 to 2016 of adolescents (aged 10–18 years) residing and notified in Rio de Janeiro City. Three groups were identified according to their Xpert and culture results: Group 1, Xpert- and culture-positive; Group 2, Xpert-positive and culture-negative; and Group 3, Xpert- and culture-negative. Study CPIs were as follows: the time between ‘sample collection and Xpert result release', ‘sample collection and treatment initiation' and ‘notification and treatment outcome'.RESULTS: Of 258 adolescents included in the study, 223 (86.4%) were in Group 1, 20 (7.8%) in Group 2 and 15 (5.8%) in Group 3. Groups 1 and 2 had a similar profile. Compared to Group 1, Group 3 had a higher proportion of HIV-positive cases (21.4% vs. 3.0%, P = 0.016), adolescents with a hospital diagnosis (53.3% vs. 7.6%, P < 0.001), and PTB + EPTB cases (20% vs. 0.4%; P < 0.001). There were no statistically significant differences in CPIs or treatment outcomes.CONCLUSION: The clinical diagnosis was decisive in more critical or complex patients, despite Xpert-negative results.

Tuberculosis (TB) remains a major health problem within the Community of Portuguese Language Speaking Countries (CPLP). Despite the marked variation in TB incidence across its member-states and continued human migratory flux between countries, a considerable gap in the knowledge on the Mycobacterium tuberculosis population structure and strain circulation between the countries still exists. To address this, we have assembled and analysed the largest CPLP M. tuberculosis molecular and drug susceptibility dataset, comprised by a total of 1447 clinical isolates, including 423 multidrug-resistant isolates, from five CPLP countries. The data herein presented reinforces Latin American and Mediterranean (LAM) strains as the hallmark of M. tuberculosis populational structure in the CPLP coupled with country-specific differential prevalence of minor clades. Moreover, using high-resolution typing by 24-loci MIRU-VNTR, six cross-border genetic clusters were detected, thus supporting recent clonal expansion across the Lusophone space. To make this data available to the scientific community and public health authorities we developed CPLP-TB (available at http://cplp-tb.ff.ulisboa.pt), an online database coupled with web-based tools for exploratory data analysis. As a public health tool, it is expected to contribute to improved knowledge on the M. tuberculosis population structure and strain circulation within the CPLP, thus supporting the risk assessment of strain-specific trends., Highlights • The Community of Portuguese Speaking Countries (CPLP) occupies a vast geographical area. • Three CPLP countries are shortlisted in the WHO's list of Top 30 high-burden countries. • Common Mycobacterium tuberculosis population structure denote historical strain flow. • Cross-border clusters suggest recent intercontinental tuberculosis transmission. • CPLP-TB: a novel strain database and framework for collaborative studies and strain tracing.

Background: Approximately 1·4 million people die annually worldwide from tuberculosis. Large epidemiologic studies can identify determinants of unfavorable clinical outcomes according to age, which can guide implementation of public health policies and clinical management to improve outcomes. Methods: We obtained data from the national tuberculosis case registry: cases reported to the Brazilian National Program (SINAN) between 2010-2019. Clinical and epidemiologic variables were compared between age groups (child

Summary Objectives The diagnosis of pediatric tuberculosis (TB) presents many challenges, and is further complicated in HIV-infected patients. While many diagnostic systems have been proposed, there is no pediatric TB diagnosis gold standard. The outcomes of four TB diagnostic systems in HIV-infected children were compared in this study. Methods A retrospective cohort study was conducted at a TB/HIV reference hospital in Rio de Janeiro. HIV-infected pediatric patients evaluated for TB from 1998 to 2010 were reassessed using four diagnostic systems: Kenneth Jones, 1969; Tidjani, 1986; Ben Marais, 2006; Brazilian Ministry of Health, 2010. Results were compared to standardized diagnoses made by an expert panel of physicians. Results Of the 121 patients in the study cohort, the expert panel diagnosed 64 as TB and 57 as not TB cases. The Tidjani system showed the highest diagnostic accuracy, with and without the inclusion of microbiological data. The Tidjani and Kenneth Jones systems produced fewer false-positives, and the Ben Marais and Ministry of Health fewer false-negatives. Across systems, there was little agreement between TB diagnoses. Conclusions In HIV-infected pediatric patients, the Ben Marais and Ministry of Health systems are useful for TB diagnostic screening, whereas the Tidjani and Kenneth Jones systems are best used in a reference center setting.

Introduction This study evaluates the performance of individual and combinations tests used for pediatric tuberculosis diagnosis at a reference center. Materials and Methods Diagnostic test outcomes from children with presumed pulmonary tuberculosis evaluated from January 2005 - July 2010 were compared to a standard diagnosis made by an expert panel of physicians. Results Presence of at least one sign/symptom, history of contact, or abnormal chest X-ray (aCXR) individually showed the highest sensitivity (85.7%). While the combination of history of contact, at least one sign/symptom, positive tuberculin skin test, and aCXR had low sensitivity of 20%, but the specificity and a positive predictive value were 100%, respectively. The combination of tests used in the International Union Against Tuberculosis and Lung Disease and the Brazilian Ministry of Health systems showed sensitivity of 28.6% and 71.4% and specificity of 95.8% and 97.0%, respectively. Conclusions In the absence of a gold standard, the combination of clinical history, tuberculin skin test, and aCXR, as well as the Brazilian scoring system serve as simple, low-cost approach that can be used for pediatric TB diagnosis by first-contact care providers.

Introduction There are scarce data on the routine latent tuberculosis infection treatment (LTBIT) and factors associated with a non-completion in high tuberculosis burden countries. Therefore, in this study we aimed to evaluate the factors associated with non-completion of LTBIT. Materials and methods This was a non-matched case control study conducted at a University Hospital in Rio de Janeiro, Brazil. A total of 114 cases and 404 controls were enrolled between January/1999 and December/2009. Cases were close contacts who did not complete the LTBIT and controls were the contacts that completed it. Multivariate analysis was used to investigate risk factors associated with non-completion of LTBIT among contacts in two different periods of recruitment. Results Factors associated with non-completion LTBIT included: drug use (OR 23.33, 95% CI 1.83–296.1), TB treatment default by the index case (OR 16.97, 95% CI 3.63–79.24) and drug intolerance. TB disease rates after two years of follow up varied from 0.4% to 1.9%. The number necessary to treat to prevent one TB case among contacts was 116. Conclusions Non-completion treatment by the index case and illicit drug use were associated with not completing latent tuberculosis infection treatment and no tuberculosis disease was identified among those who completed latent tuberculosis infection treatment.

Background Weight change may inform tuberculosis treatment response, but its predictive power may be confounded by human immunodeficiency virus (HIV). Methods We prospectively followed up adults with culture-confirmed, drug-susceptible, pulmonary tuberculosis receiving standard 4-drug therapy (isoniazid, rifampin, pyrazinamide, and ethambutol) in Brazil. We examined median weight change 2 months after treatment initiation by HIV status, using quantile regression, and unsuccessful tuberculosis treatment outcome (treatment failure, tuberculosis recurrence, or death) by HIV and weight change status, using Cox regression. Results Among 547 participants, 102 (19%) were HIV positive, and 35 (6%) had an unsuccessful outcome. After adjustment for confounders, persons living with HIV (PLWH) gained a median of 1.3 kg (95% confidence interval [CI], −2.8 to .1) less than HIV-negative individuals during the first 2 months of tuberculosis treatment. PLWH were at increased risk of an unsuccessful outcome (adjusted hazard ratio, 4.8; 95% CI, 2.1–10.9). Weight change was independently associated with outcome, with risk of unsuccessful outcome decreasing by 12% (95% CI, .81%–.95%) per 1-kg increase. Conclusions PLWH gained less weight during the first 2 months of tuberculosis treatment, and lack of weight gain and HIV independently predicted unsuccessful tuberculosis treatment outcomes. Weight, an easily collected biomarker, may identify patients who would benefit from alternative treatment strategies.

Key measures to halt the spread of tuberculosis (TB) include early diagnosis, effective treatment, and monitoring disease management. We sought to evaluate the use of serum immunoglobulin levels against antigens present in cell envelope of Mycobacterium tuberculosis to monitor TB treatment response in children and adolescents with pulmonary (PTB) or extrapulmonary TB (EPTB). Blood samples were collected prior to and one, two, and six months following treatment initiation. Serum immunoglobulin levels against cardiolipin, sulfatide, mycolic acid and Mce1A protein were measured by ELISA. Serum from 53 TB patients and 12 healthy participants were analyzed. After six months of successful treatment, there was a significant decrease (p 0.0001) in IgM levels against cardiolipin, sulfatide, mycolic acid and Mce1A protein and IgG levels against Mce1A protein when compared to baseline immunoglobulin levels. There was no significant variation in antibody levels during follow-up between participants with PTB and EPTB, confirmed and unconfirmed TB diagnosis, and HIV infection status. Antibody levels in control participants without TB did not decrease during follow-up. These results suggest that immunoglobulin responses to mycobacterial cell wall products may be a useful tool to monitor treatment response in children and adolescents with PTB or EPTB.

Pulmonary tuberculosis (PTB) is associated with chronic inflammation and anemia. How anemia impacts systemic inflammation in PTB patients undergoing antitubercular therapy (ATT) is not fully understood. In the present study, data on several blood biochemical parameters were retrospectively analyzed from 118 PTB patients during the first 60 days of ATT. Multidimensional statistical analyses were employed to perform detailed inflammatory profiling of patients stratified by anemia status prior to treatment. Anemia was defined as hemoglobin levels

Summary Objectives Molecular tests show low sensitivity for smear-negative pulmonary tuberculosis (PTB). A screening and risk assessment system for smear-negative PTB using artificial neural networks (ANNs) based on patient signs and symptoms is proposed. Methods The prognostic and risk assessment models exploit a multilayer perceptron (MLP) and inspired adaptive resonance theory (iART) network. Model development considered data from 136 patients with suspected smear-negative PTB in a general hospital. Results MLP showed higher sensitivity (100%, 95% confidence interval (CI) 78–100%) than the other techniques, such as support vector machine (SVM) linear (86%; 95% CI 60–96%), multivariate logistic regression (MLR) (79%; 95% CI 53–93%), and classification and regression tree (CART) (71%; 95% CI 45–88%). MLR showed a slightly higher specificity (85%; 95% CI 59–96%) than MLP (80%; 95% CI 54–93%), SVM linear (75%, 95% CI 49–90%), and CART (65%; 95% CI 39–84%). In terms of the area under the receiver operating characteristic curve (AUC), the MLP model exhibited a higher value (0.918, 95% CI 0.824–1.000) than the SVM linear (0.796, 95% CI 0.651–0.970) and MLR (0.782, 95% CI 0.663–0.960) models. The significant signs and symptoms identified in risk groups are coherent with clinical practice. Conclusions In settings with a high prevalence of smear-negative PTB, the system can be useful for screening and also to aid clinical practice in expediting complementary tests for higher risk patients.

Item does not contain fulltext BACKGROUND: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. FINDINGS: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0.15, 95% CI 0.11 to 0.18), levofloxacin (0.15, 0.13 to 0.18), carbapenems (0.14, 0.06 to 0.21), moxifloxacin (0.11, 0.08 to 0.14), bedaquiline (0.10, 0.05 to 0.14), and clofazimine (0.06, 0.01 to 0.10). There was a significant association between reduced mortality and use of linezolid (-0.20, -0.23 to -0.16), levofloxacin (-0.06, -0.09 to -0.04), moxifloxacin (-0.07, -0.10 to -0.04), or bedaquiline (-0.14, -0.19 to -0.10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I(2) method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. INTERPRETATION: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Funding: World Health Organization and Canadian Institutes of Health Research. Background: Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success, mortality, and acquired rifampicin resistance in patients with INH-R pulmonary tuberculosis given different durations of rifampicin, ethambutol, and pyrazinamide (REZ); a fluoroquinolone plus 6 months or more of REZ; and streptomycin plus a core regimen of REZ. Methods: Studies with regimens and outcomes known for individual patients with INH-R tuberculosis were eligible, irrespective of the number of patients if randomised trials, or with at least 20 participants if a cohort study. Studies were identified from two relevant systematic reviews, an updated search of one of the systematic reviews (for papers published between April 1, 2015, and Feb 10, 2016), and personal communications. Individual patient data were obtained from authors of eligible studies. The individual patient data meta-analysis was performed with propensity score matched logistic regression to estimate adjusted odds ratios (aOR) and risk differences of treatment success (cure or treatment completion), death during treatment, and acquired rifampicin resistance. Outcomes were measured across different treatment regimens to assess the effects of: different durations of REZ (≤6 months vs >6 months); addition of a fluoroquinolone to REZ (fluoroquinolone plus 6 months or more of REZ vs 6 months or more of REZ); and addition of streptomycin to REZ (streptomycin plus 6 months of rifampicin and ethambutol and 1–3 months of pyrazinamide vs 6 months or more of REZ). The overall quality of the evidence was assessed using GRADE methodology. Findings: Individual patient data were requested for 57 cohort studies and 17 randomised trials including 8089 patients with INH-R tuberculosis. We received 33 datasets with 6424 patients, of which 3923 patients in 23 studies received regimens related to the study objectives. Compared with a daily regimen of 6 months of (H)REZ (REZ with or without isoniazid), extending the duration to 8–9 months had similar outcomes; as such, 6 months or more of (H)REZ was used for subsequent comparisons. Addition of a fluoroquinolone to 6 months or more of (H)REZ was associated with significantly greater treatment success (aOR 2·8, 95% CI 1·1–7·3), but no significant effect on mortality (aOR 0·7, 0·4–1·1) or acquired rifampicin resistance (aOR 0·1, 0·0–1·2). Compared with 6 months or more of (H)REZ, the standardised retreatment regimen (2 months of streptomycin, 3 months of pyrazinamide, and 8 months of isoniazid, rifampicin, and ethambutol) was associated with significantly worse treatment success (aOR 0·4, 0·2–0·7). The quality of the evidence was very low for all outcomes and treatment regimens assessed, owing to the observational nature of most of the data, the diverse settings, and the imprecision of estimates. Interpretation: In patients with INH-R tuberculosis, compared with treatment with at least 6 months of daily REZ, addition of a fluoroquinolone was associated with better treatment success, whereas addition of streptomycin was associated with less treatment success; however, the quality of the evidence was very low. These results support the conduct of randomised trials to identify the optimum regimen for this important and common form of drug-resistant tuberculosis. Funding World Health Organization and Canadian Institutes of Health Research. Postprint

Background Multidrug-resistant tuberculosis (MDR-TB) regimens often contain pyrazinamide (PZA) even if susceptibility to the drug has not been confirmed. This gap is due to the limited availability and reliability of PZA susceptibility testing. Objectives To estimate the prevalence of PZA resistance using the Wayne assay among TB patients in Lima, Peru, to describe characteristics associated with PZA resistance and to compare the performance of Wayne with that of BACTEC™ MGIT™ 960. Methods PZA susceptibility using the Wayne assay was tested in patients diagnosed with culture-positive pulmonary TB from September 2009 to August 2012. Factors associated with PZA resistance were evaluated. We compared the performance of the Wayne assay to that of MGIT 960 in a convenience sample. Results The prevalence of PZA resistance was 6.6% (95%CI 5.8-7.5) among 3277 patients, and 47.7% (95%CI 42.7-52.6) among a subset of 405 MDR-TB patients. In multivariable analysis, MDR-TB (OR 86.0, 95%CI 54.0-136.9) and Latin American-Mediterranean lineage (OR 3.40, 95%CI 2.33-4.96) were associated with PZA resistance. The Wayne assay was in agreement with MGIT 960 in 83.9% of samples (κ 0.66, 95%CI 0.56-0.76). Conclusion PZA resistance was detected using the Wayne assay in nearly half of MDR-TB patients in Lima. This test can inform the selection and composition of regimens, especially those dependent on additional resistance.

OBJECTIVES/SPECIFIC AIMS: Previous research suggests that weight loss during early TB treatment (first two months of anti-TB therapy) is a predictor of poor tuberculosis (TB) treatment outcomes among HIV-negative populations, but the relationship has not been well studied in the context of HIV. We examined the association between HIV and weight change during the first two months of anti-tuberculosis treatment, and also assessed the effects of HIV and early weight change on tuberculosis (TB) treatment outcomes. METHODS/STUDY POPULATION: Adults with culture-confirmed, drug-susceptible, pulmonary TB, regardless of HIV status, were enrolled into the Regional Prospective Observational Research for Tuberculosis (RePORT)-Brazil cohort and followed on standard anti-TB therapy. For the primary analysis, we compared weight change in persons living with HIV (PLWH) and HIV-negative patients between baseline and two months using multivariable bootstrapped quantile regression and modified Poisson regression. For secondary analysis, we examined the separate effects of HIV and weight change on poor TB treatment outcome (treatment failure, TB recurrence, or death) using Cox proportional hazards regression. RESULTS/ANTICIPATED RESULTS: Among 323 participants, 45 (14%) were HIV-positive. On average, PLWH lost 0.7% (interquartile range (IQR): −5.1%, 4.4%) of their baseline body weight between baseline and two months; those without HIV gained 3.5% (IQR: 0.8%, 6.7%). After adjusting for age, sex, and baseline BMI, PLWH lost 4.1% (95% confidence interval (CI): −6.5%, −1.6%) more weight during the first two months of anti-TB treatment than HIV-negative individuals. HIV infection was associated with weight loss ≥5% (adjusted odds ratio = 9.3; 95% CI: 4.2-20.6). Regarding the secondary analysis, 14 patients had a poor TB treatment outcome: 2 treatment failures, 4 cases of recurrent TB, and 8 deaths. PLWH and patients who lost ≥5% weight had significantly increased risk of poor TB treatment outcome with hazard ratios of 8.77 (95% CI: 2.96-25.94) and 4.09 (95% CI: 1.11-15.14), respectively. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results suggest that HIV is associated with weight loss during early TB treatment, and both HIV and early weight loss were associated with poor treatment outcome. Future research should examine the potential etiologies of these findings and identify the types of interventions that would best promote weight gain during TB treatment, especially among PLWH, in order to prevent poor TB treatment outcomes.

OBJECTIVE: To describe serum levels of the cytokines IL-10, TNF-α, and IFN-γ, as well as polymorphisms in the genes involved in their transcription, and their association with markers of the acute inflammatory response in patients with pulmonary tuberculosis.METHODS: This was a descriptive, longitudinal study involving 81 patients with pulmonary tuberculosis treated at two referral hospitals. We collected data on sociodemographic variables and evaluated bacteriological conversion at the eighth week of antituberculosis treatment, gene polymorphisms related to the cytokines studied, and serum levels of those cytokines, as well as those of C-reactive protein (CRP). We also determined the ESR and CD4+ counts.RESULTS: The median age of the patients was 43 years; 67 patients (82.7%) were male; and 8 patients (9.9%) were infected with HIV. The ESR was highest in the patients with high IFN-γ levels and low IL-10 levels. IFN-γ and TNF-α gene polymorphisms at positions +874 and −238, respectively, showed no correlations with the corresponding cytokine serum levels. Low IL-10 levels were associated with IL-10 gene polymorphisms at positions −592 and −819 (but not −1082). There was a negative association between bacteriological conversion at the eighth week of treatment and CRP levels.CONCLUSIONS: Our results suggest that genetic markers and markers of acute inflammatory response are useful in predicting the response to antituberculosis treatment. OBJETIVO: Descrever os níveis séricos das citocinas IL-10, TNF-α e IFN-γ, assim como polimorfismos presentes em genes envolvidos na sua transcrição, e sua associação com marcadores de resposta inflamatória aguda em pacientes com tuberculose.MÉTODOS: Estudo descritivo e longitudinal realizado em 81 pacientes com tuberculose pulmonar atendidos em dois hospitais de referência. Foram coletadas informações sociodemográficas, conversão bacteriológica na oitava semana de tratamento antituberculose, polimorfismos relacionados às citocinas estudadas, níveis séricos dessas citocinas, assim como de proteína C reativa (PCR). Também foram avaliados VHS e contagem de CD4+.RESULTADOS: A mediana de idade dos pacientes era de 43 anos, sendo 67 (82,7%) do sexo masculino e 8 (9,9%) infectados por HIV. Os pacientes com níveis elevados de IFN-γ e baixos níveis de IL-10 apresentaram valores mais elevados de VHS. Não houve associação dos polimorfismos do gene IFN-γ na posição +874 e do gene TNF-α na posição −238 com os níveis das citocinas correspondentes. Houve uma associação entre polimorfismos do gene IL-10 nas posições −592 e −819 (mas não −1082) e baixos níveis de IL-10. Houve uma associação negativa entre a taxa de conversão bacteriológica na oitava semana de tratamento e níveis de PCR.CONCLUSÕES: Nossos resultados sugerem que marcadores genéticos e de resposta inflamatória aguda podem ser úteis na predição da resposta ao tratamento antituberculose.

Background: Diagnosis and treatment of latent tuberculosis infection (LTBI) is a tool for global TB control, especially in close contacts. But data is scarce in high burden countries, under field conditions, including data on the benefits of LTBI management. Objective: To analyze the LTBI diagnosis and treatment cascade among contacts in primary health care (PHC) services in Sao Jose do Rio Preto-SP, Brazil. Methods: Cross-sectional design, conducted with contacts of pulmonary TB patients followed in all PHC services. Data was collected from May to September 2014 in the Reporting System for TB cases (TBWEB) and Reporting System for Chemoprophylaxis. Medical records and treatment follow-up forms were reviewed and all the nurses responsible for TB in PHC services were interviewed. Results: Among 336 contacts included, 267 (79.4%) were screened for TB or LTBI, according to the presence or not of respiratory symptoms. Among those contacts screened, 140 (52.4%) were symptomatic, 9 (3.4%) had TB disease, 106/221 (48%) had positive TST result, meeting the criteria for LTBI treatment, and 64/106 (60.4%) actually started it. Overall, among 267 screened, only 64 (24%) started LTBI treatment. The completion rates of treatment among the contacts who started it, those with positive TST result and those screened were 56.3% (36/64), 16.3% (36/221) and 13.5% (36/267), respectively. Nurses claimed that asymptomatic TB contacts pay no attention to preventive health care and do not seek medical care as they do not have symptoms of the disease. In reviewing the medical records, high proportions of contacts without evaluation, incomplete assessment, incorrect records of contraindication for LTBI treatment, lack of notes regarding the identification and evaluation of contacts were identified. Conclusions: There is a need for better organization of the surveillance and investigation routine for contacts in PHC, considering the reorganization of the work process and the features of the local health system.

Disease caused by Mycobacterium tuberculosis continues as a global epidemic: over 2 billion people harbor latent TB infection, and more than 9 million new TB cases, of whom 500,000 are multidrug-resistant (MDR), and nearly 2 million deaths are estimated to occur each year. New drugs are required to shorten treatment duration of drug-sensitive TB and for the treatment of MDR-TB. TMC207 is a first-in-class diarylquinoline compound with a novel mechanism of action, the inhibition of bacterial ATP synthase, and potent activity against drug-sensitive and drug-resistant TB. It has bactericidal and sterilizing activity against M. tuberculosis and other mycobacterial species, but little activity against other bacteria. In a Phase II efficacy study conducted in patients with MDR-TB taking TMC207 plus a standard background regimen, the drug appeared to be safe and well tolerated, and showed significant efficacy after 2 months of treatment with conversion rates of sputum culture of 48% (vs 9% in the placebo group). Given the product development partnership between Tibotec and the TB Alliance, the strategies of using TMC207 in shorter first-line regimens or using it in second-line regimens for drug-resistant M. tuberculosis infections are both being pursued. No clinical data of TMC207 in TB patients with HIV coinfection have been published; drug–drug interaction studies with antiretrovirals are being conducted. Finally, the remarkable sterilizing capacity of TMC207 also makes it an attractive drug in the strategy of TB elimination. Current and future studies will determine the role of TMC207 in a shortened treatment regimen for drug-sensitive TB, a more effective and better-tolerated regimen for MDR-TB, the treatment of latent TB infection, and intermittent-TB treatment regimens.

Costs incurred during care-seeking for chronic respiratory disease are a major problem with severe consequences for socio-economic status and health outcomes. Most of the published evidence to date relates to tuberculosis (TB) and there is a lack of information for the major non-communicable chronic respiratory diseases: asthma and chronic obstructive pulmonary disease (COPD). International policy is recognising the need to address this problem and measure progress towards eliminating catastrophic care-seeking costs (see the post-2015 TB strategy). Current tools for measuring, defining, and understanding the full consequences of catastrophic care-seeking costs are inadequate. We propose two areas of work which are urgently needed to prepare health systems and countries for the burden of chronic lung disease that will fall on poor populations in the coming 10-20 years: a) Rapid scale up of the number and scope of studies of patient costs associated with chronic non-communicable respiratory disease. b) Work towards deeper understanding and effective measurement of catastrophic care-seeking costs. This will produce a range of indicators, such as dissaving, which can more effectively inform health policy decision-making for lung health. These will also be useful for other health problems. We argue that reduction in care-seeking costs will be a key monitoring indicator for improvements in lung health in particular, and health in general, in the coming 10 to 20 years.

BACKGROUND: \ud \ud The use of liquid medium (MGIT960) for tuberculosis (TB) diagnosis was recommended by WHO in 2007. However, there has been no evaluation of its effectiveness on clinically important outcomes.\ud \ud METHODS AND FINDINGS: \ud \ud A pragmatic trial was carried out in a tertiary hospital and a secondary health care unit in Rio de Janeiro City, Brazil. Participants were 16 years or older, suspected of having TB. They were excluded if only cerebral spinal fluid or blood specimens were available for analysis. MGIT960 technique was compared with the Lowenstein-Jensen (LJ) method for laboratory diagnosis of active TB. Primary outcome was the proportion of patients who had their initial medical management changed within 2 months after randomisation. Secondary outcomes were: mean time for changing the procedure, patient satisfaction with the overall treatment and adverse events. Data were analysed by intention-to-treat. Between April 2008 and September 2011, 693 patients were enrolled (348 to MGIT, 345 to LJ). Smear and culture results were positive for 10% and 15.7% of participants, respectively. Patients in the MGIT arm had their initial medical management changed more frequently than those in the LJ group (10.1% MGIT vs 3.8% LJ, RR 2.67 95% CI 1.44-.96, p = 0.002, NNT 16, 95% CI 10-39). Mean time for changing the initial procedure was greater in LJ group at both sites: 20.0 and 29.6 days in MGIT group and 52.2 and 64.3 in LJ group (MD 33.5, 95% CI 30.6-36.4, p = 0.0001). No other important differences were observed.\ud \ud CONCLUSIONS: \ud \ud This study suggests that opting for the MGIT960 system for TB diagnosis provides a promising case management model for improving the quality of care and control of TB.\ud \ud TRIAL REGISTRATION: \ud \ud Controlled-Trials.com ISRCTN79888843.

INTRODUÇÃO: A solução de tuberculina é armazenada em frascos de diferentes tamanhos. Sua adsorção ao frasco pode influenciar o resultado da prova tuberculínica. OBJETIVO: Avaliar o efeito do tamanho do frasco de armazenamento da tuberculina nos resultados obtidos na prova tuberculínica. MÉTODO: Sessenta e três pacientes internados com diagnóstico de tuberculose ativa foram submetidos a duas provas tuberculínicas simultâneas, em ambos os antebraços. A técnica usada foi a de Mantoux e consistiu na aplicação de 0,1 ml de tuberculina armazenada em frascos de 5 ml ou de 1,5 ml, no antebraço direito e no antebraço esquerdo, de forma aleatória. A leitura da induração foi efetuada de forma cega por um único leitor treinado previamente. As leituras com diferenças de até 2 mm foram consideradas resultados concordantes. RESULTADOS: Vinte e um pacientes não tiveram induração e foram excluídos da análise. Entre os 42 pacientes restantes, a média dos diâmetros das indurações obtidas nas provas com tuberculina armazenada nos frascos grandes foi maior do que as obtidas com a armazenada em frascos pequenos. A concordância entre as leituras foi obtida em 40,5% delas (17/42), e a diferença foi negativa (frasco grande menor que frasco pequeno) em 16,7% (7/42) e positiva em 42,9% delas (18/42). CONCLUSÃO: O tamanho do frasco de armazenamento da tuberculina pode influenciar o resultado da prova tuberculínica. A adsorção da tuberculina à parede do frasco pode explicar o fenômeno. Os autores alertam para o impacto dessas variações nos estudos epidemiológicos e operacionais. BACKGROUND: Tuberculin purified protein derivative is stored in vials of various sizes. Its adsorption to the vial can influence the results of tuberculin tests. OBJECTIVE: To evaluate the effect of vial size on the results obtained in tuberculin tests. METHODS: Sixty-four inpatients with active tuberculosis were submitted to two simultaneous tuberculin tests using the Mantoux technique. Patients were randomly allocated to receive two 0.1-ml injections, either one in the right forearm from a 1.5-ml vial and one in the left forearm from a 5-ml vial or vice versa. Induration was determined in a blinded fashion by a single, previously trained observer. Right arm-left arm differences of 2 mm or less were considered concordant results. RESULTS: Twenty-one patients presented no induration and were excluded from analysis. Among the 42 remaining patients, mean induration diameters obtained in tuberculin tests using the larger vials were greater than those obtained in tests using the smaller vials. Concordance was achieved in 40.5% (17/42). The difference was negative (large-vial indurations smaller than small-vial indurations) in 16.7% (7/42) and positive in 42.9% (18/42). CONCLUSIONS: The size of the vial may influence tuberculin test results. Adsorption to the sides of the vial may explain this phenomenon. The authors caution others to be aware of the impact of these variations in epidemiological and operational studies.

In view of the fact that the World Health Organization has recommended the use of the mycobacteria growth indicator tube (MGIT) 960 system for the diagnosis of tuberculosis and that there is as yet no evidence regarding the clinical impact of its use in health care systems, we conducted a pragmatic clinical trial to evaluate the clinical performance and cost-effectiveness of the use of MGIT 960 at two health care facilities in the city of Rio de Janeiro, Brazil, where the incidence of tuberculosis is high. Here, we summarize the methodology and preliminary results of the trial. (ISRCTN.org Identifier: ISRCTN79888843 [http://isrctn.org/]) In view of the fact that the World Health Organization has recommended the use of the mycobacteria growth indicator tube (MGIT) 960 system for the diagnosis of tuberculosis and that there is as yet no evidence regarding the clinical impact of its use in health care systems, we conducted a pragmatic clinical trial to evaluate the clinical performance and cost-effectiveness of the use of MGIT 960 at two health care facilities in the city of Rio de Janeiro, Brazil, where the incidence of tuberculosis is high. Here, we summarize the methodology and preliminary results of the trial. (ISRCTN.org Identifier: ISRCTN79888843 [http://isrctn.org/]).

OBJECTIVE: To describe the prevalence of anemia and of its types in hospitalized patients with pulmonary tuberculosis. METHODS: This was a descriptive, longitudinal study involving pulmonary tuberculosis inpatients at one of two tuberculosis referral hospitals in the city of Rio de Janeiro, Brazil. We evaluated body mass index (BMI), triceps skinfold thickness (TST), arm muscle area (AMA), ESR, mean corpuscular volume, and red blood cell distribution width (RDW), as well as the levels of C-reactive protein, hemoglobin, transferrin, and ferritin. RESULTS: We included 166 patients, 126 (75.9%) of whom were male. The mean age was 39.0 ± 10.7 years. Not all data were available for all patients: 18.7% were HIV positive; 64.7% were alcoholic; the prevalences of anemia of chronic disease and iron deficiency anemia were, respectively, 75.9% and 2.4%; and 68.7% had low body weight (mean BMI = 18.21 kg/m2). On the basis of TST and AMA, 126 (78.7%) of 160 patients and 138 (87.9%) of 157 patients, respectively, were considered malnourished. Anemia was found to be associated with the following: male gender (p = 0.03); low weight (p = 0.0004); low mean corpuscular volume (p = 0.03);high RDW (p = 0; 0003); high ferritin (p = 0.0005); and high ESR (p = 0.004). We also found significant differences between anemic and non-anemic patients in terms of BMI (p = 0.04), DCT (p = 0.003), and ESR (p < 0.001). CONCLUSIONS: In this sample, high proportions of pulmonary tuberculosis patients were classified as underweight and malnourished, and there was a high prevalence of anemia of chronic disease. In addition, anemia was associated with high ESR and malnutrition.

OBJECTIVE: To describe the prevalence of multidrug-resistant tuberculosis (MDR-TB) among tuberculosis patients in a major Brazilian city, evaluated via the Second National Survey on Antituberculosis Drug Resistance, as well as the social, demographic, and clinical characteristics of those patients. METHODS: Clinical samples were collected from tuberculosis patients seen between 2006 to 2007 at three hospitals and five primary health care clinics participating in the survey in the city of Porto Alegre, Brazil. The samples were subjected to drug susceptibility testing. The species of mycobacteria was confirmed using biochemical methods. RESULTS: Of the 299 patients included, 221 (73.9%) were men and 77 (27.3%) had a history of tuberculosis. The mean age was 36 years. Of the 252 patients who underwent HIV testing, 66 (26.2%) tested positive. The prevalence of MDR-TB in the sample as a whole was 4.7% (95% CI: 2.3-7.1), whereas it was 2.2% (95% CI: 0.3-4.2) among the new cases of tuberculosis and 12.0% (95% CI: 4.5-19.5) among the patients with a history of tuberculosis treatment. The multivariate analysis showed that a history of tuberculosis and a longer time to diagnosis were both associated with MDR-TB. CONCLUSIONS: If our results are corroborated by other studies conducted in Brazil, a history of tuberculosis treatment and a longer time to diagnosis could be used as predictors of MDR-TB. OBJETIVO: Descrever a prevalência de tuberculose multirresistente (TBMR) em pacientes com tuberculose em uma importante cidade brasileira através do II Inquérito Nacional de Resistência aos Fármacos Antituberculose, assim como as características sociais, demográficas e clínicas desses pacientes. MÉTODOS: De 2006 a 2007, amostras clínicas de pacientes de três hospitais e das cinco unidades básicas de saúde participantes do inquérito realizado em Porto Alegre foram coletadas e submetidas ao teste de sensibilidade aos fármacos. A confirmação das espécies de micobactérias ocorreu por métodos bioquímicos. RESULTADOS: Foram incluídos 299 pacientes. Desses, 221 (73,9%) eram homens e 77 (27,3%) tinham história de tuberculose. A idade média foi de 36 anos. Dos 252 pacientes testados para HIV, 66 (26,2%) estavam infectados. A prevalência da TBMR na amostra geral foi de 4,7% (IC95%: 2,3-7,1); enquanto essa foi de 2,2% (IC95%: 0,3-4,2) nos pacientes virgens de tratamento e de 12,0% (IC 95%: 4,5-19,5) naqueles com história de tratamento antituberculose. A análise multivariada mostrou que história de tuberculose e maior tempo para o diagnóstico associaram-se a TBMR. CONCLUSÕES: Caso esses resultados sejam confirmados em outros estudos no Brasil, a história de tratamento antituberculose e o maior tempo para o diagnóstico poderão ser utilizados como preditores de TBMR.

Background Tuberculosis (TB) remains a public health issue worldwide. The lack of specific clinical symptoms to diagnose TB makes the correct decision to admit patients to respiratory isolation a difficult task for the clinician. Isolation of patients without the disease is common and increases health costs. Decision models for the diagnosis of TB in patients attending hospitals can increase the quality of care and decrease costs, without the risk of hospital transmission. We present a predictive model for predicting pulmonary TB in hospitalized patients in a high prevalence area in order to contribute to a more rational use of isolation rooms without increasing the risk of transmission. Methods Cross sectional study of patients admitted to CFFH from March 2003 to December 2004. A classification and regression tree (CART) model was generated and validated. The area under the ROC curve (AUC), sensitivity, specificity, positive and negative predictive values were used to evaluate the performance of model. Validation of the model was performed with a different sample of patients admitted to the same hospital from January to December 2005. Results We studied 290 patients admitted with clinical suspicion of TB. Diagnosis was confirmed in 26.5% of them. Pulmonary TB was present in 83.7% of the patients with TB (62.3% with positive sputum smear) and HIV/AIDS was present in 56.9% of patients. The validated CART model showed sensitivity, specificity, positive predictive value and negative predictive value of 60.00%, 76.16%, 33.33%, and 90.55%, respectively. The AUC was 79.70%. Conclusions The CART model developed for these hospitalized patients with clinical suspicion of TB had fair to good predictive performance for pulmonary TB. The most important variable for prediction of TB diagnosis was chest radiograph results. Prospective validation is still necessary, but our model offer an alternative for decision making in whether to isolate patients with clinical suspicion of TB in tertiary health facilities in countries with limited resources.

The Millennium Development Goal target for tuberculosis control is to halt the spread of tuberculosis by 2015, and begin to reverse the worldwide incidence. After the introduction of standard control practices in 1995, 36 million people were cured and about 6 million deaths were averted. However, substantial scientific advances and innovative solutions are urgently needed together with creative new strategies. Strong international and national political commitment is essential. Urgent action is needed by national governments to fund their own programmes, and for the G8 countries and other donor governments and organisations to support governmental and non-governmental efforts. To foster the global need for urgent action to control the tuberculosis epidemic, The Lancet, in collaboration with the Stop TB Partnership, WHO, Global Fund to Fight AIDS, Tuberculosis and Malaria, and the experts participating in this Series, is launching The Lancet TB Observatory, which will assess and monitor progress in tuberculosis control and research, assess domestic and global financing, regularly disseminate information, and advocate for intensified efforts with stakeholders at all levels.

Many patients with suspected pulmonary tuberculosis (PTB) do not produce sputum spontaneously or are smear-negative for acid-fast bacilli (AFB). We prospectively compared the yield of sputum induction (SI) and fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) for the diagnosis of PTB in a region with a high prevalence of tuberculosis and human immunodeficiency virus (HIV) infection. Fifty seven percent (143 of 251) of patients had diagnoses of PTB, of whom 17% (25 of 143) were HIV seropositive. There were no significant differences in the yields of AFB smears or cultures whether obtained via SI or BAL. Among 207 HIV-seronegative patients, the AFB smear and mycobacterial culture results from specimens obtained by SI and BAL were in agreement in 97% (202 of 207) (kappa test = 0.92) and 90% (186 of 207) (kappa test = 0.78), respectively. Among HIV-seropositive patients the agreements between AFB smear and culture results for SI and BAL specimens were 98% (43 of 44) (kappa test = 0.93) and 86% (38 of 44) (kappa test = 0.69), respectively. We conclude that SI is a safe procedure with a high diagnostic yield and high agreement with the results of fiberoptic bronchoscopy for the diagnosis of PTB in both HIV-seronegative and HIV-seropositive patients.

OBJETIVO: Analisar o perfil epidemiológico dos pacientes internados em um hospital especializado no tratamento da TB. MÉTODOS: Foi realizado estudo descritivo e retrospectivo dos prontuários dos pacientes internados com TB no Hospital Estadual Santa Maria (HESM), na cidade do Rio de Janeiro, entre janeiro de 2002 e dezembro de 2003, por meio de formulário previamente padronizado. RESULTADOS: Dos 451 pacientes incluídos, 313 (69,4%) foram referenciados para o HESM por unidades de saúde, e 302 (67,0%) eram do gênero masculino. A maioria dos pacientes tinha entre 30 e 59 anos, 443 (98,2%) residiam na região metropolitana, e 298 (66,1%) residiam no município do Rio de Janeiro. O motivo de internação mais frequente foi mau estado geral (em 237, 52,5%). A AIDS foi a comorbidade mais frequente (em 137, 30,4%). Os sinais e sintomas mais frequentes no momento da internação foram emagrecimento, febre e tosse produtiva. A baciloscopia foi positiva em 122 casos (71,0%) com tosse produtiva no momento da internação. Dos 212 pacientes que estavam em retratamento, 156 (73,6%) referiram abandono a tratamento anterior. Quanto ao desfecho, 297 (65,8%) foram encaminhados para centros municipais de saúde, 83 (18,4%) evoluíram para óbito, e 44 (9,8%) curaram. As altas indesejadas ocorreram em 27 (6,0%) dos casos. CONCLUSÕES: A provisão de hospitais especializados em TB é de relevância para o controle da TB, principalmente em regiões metropolitanas. Esses hospitais precisam estar adequados a medidas de biossegurança, assim como estar mais bem equipados e capacitados para prestar atendimento a pacientes com diversas comorbidades e problemas sociais associados à TB. A realização deste estudo resultou em melhorias para o HESM. OBJECTIVE: To determine the epidemiological profile of inpatients at a TB referral hospital. METHODS: This was a descriptive, retrospective study of the medical charts of patients with TB hospitalized at the Hospital Estadual Santa Maria (HESM), in the city of Rio de Janeiro, Brazil, between January of 2002 and December of 2003. Data were collected using a standardized form. RESULTS: Of the 451 patients included in the study, 313 (69.4%) had been referred to the HESM from health care clinics, and 302 (67.0%) were male. Most of the patients were in the 30-59 year age bracket, 443 (98.2%) lived in the greater metropolitan region of Rio de Janeiro, and 298 (66.1%) lived in the city of Rio de Janeiro itself. The most common reason for hospitalization was poor health status (in 237, 52.5%). The most common comorbidity was AIDS (in 137, 30.4%). The most common signs and symptoms at admission were weight loss, fever and productive cough. Sputum smear microscopy was positive in 122 (71.0%) of the patients presenting with productive cough at admission. Of the 212 patients being retreated, 156 (73.6%) reported noncompliance with previous treatment. Regarding the outcome, 273 (65.8%) of the patients were referred to municipal health care centers, 83 (18.4%) died, 44 (9.8%) were cured, and 27 (6%) were discharged against medical advice. CONCLUSIONS: Providing hospitals specializing in TB is relevant for TB control, especially in metropolitan regions. In addition to taking biosafety measures, these hospitals must be prepared to treat patients with TB-related comorbidities and social problems. This study has resulted in improvements at the HESM.

Summary Background New treatments are needed to shorten the time required to cure tuberculosis and to treat drug-resistant strains. The fluoroquinolone moxifloxacin is a promising new agent that might have additive activity to existing antituberculosis agents. We assessed the activity and safety of moxifloxacin in the initial stage of tuberculosis treatment. Methods We undertook a phase II, double-blind, randomised controlled trial of a regimen that included moxifloxacin in adults with sputum smear-positive tuberculosis at one hospital in Rio de Janeiro, Brazil. 170 participants received isoniazid, rifampicin, and pyrazinamide at standard doses and were assigned by permuted block randomisation to receive either moxifloxacin (400 mg) with an ethambutol placebo (n=85) or ethambutol (15–20 mg/kg) plus moxifloxacin placebo (n=85) 5 days per week for 8 weeks. The primary endpoint was the proportion of patients whose sputum culture had converted to negative by week 8. Analysis was by modified intention to treat (ITT); patients whose baseline cultures were negative, contaminated, or contained drug-resistant Mycobacterium tuberculosis were excluded from the analysis. Additionally, all missing 8-week results were deemed treatment failures. This study is registered with ClinicalTrials.gov, number NCT00082173. Findings 74 patients assigned to the moxifloxacin group and 72 in the ethambutol group were included in the modified ITT population. 125 patients had 8-week data (moxifloxacin n=64, ethambutol n=61); the main reason for absence of data was culture contamination. At 8 weeks, culture conversion to negative had occurred in 59 (80%) of 74 patients in the moxifloxacin group compared with 45 (63%) of 72 in the ethambutol group (difference 17·2%, 95% CI 2·8–31·7; p=0·03). There were 16 adverse events (eight in each group) in 12 patients. Only one event was judged related to study drug (grade 3 cutaneous reaction in the ethambutol group). Interpretation Moxifloxacin improved culture conversion in the initial phase of tuberculosis treatment. Trials to assess whether moxifloxacin can be used to shorten the duration of tuberculosis treatment are justified. Funding US Food and Drug Administration Office of Orphan Product Development, with additional support from the US National Institutes of Health.

This prospective study evaluated the performance of the m icroscopic o bservation d rug s usceptibility (MODS) assay for the direct detection of Mycobacterium tuberculosis drug resistance. MODS assay sensitivity, specificity, and positive and negative predictive values were 96.7% (95% confidence interval [95% CI], 92.1 to 98.8%), 78.4% (95% CI, 73.5 to 80.6%), 82.4% (95% CI, 78.4 to 84.2%), and 95.8% (95% CI, 89.9 to 98.5%), respectively, for isoniazid resistance and 96.0% (95% CI, 90.3 to 98.6%), 82.9% (95% CI, 78.8 to 84.7%), 80.0% (95% CI, 75.2 to 82.1%), and 96.7% (95% CI, 91.9 to 98.8%), respectively, for rifampin resistance. For both rifampin and isoniazid testing, the likelihood ratio for a negative test was ≤0.05, indicating that the MODS assay may be useful for ruling out drug resistance.

Smear negative pulmonary tuberculosis (SNPT) accounts for 30% of pulmonary tuberculosis (PT) cases reported yearly. Rapid and accurate diagnosis of SNPT could provide lower morbidity and mortality, and case detection at a less contagious status. The main objective of this work is to evaluate a prediction model for diagnosis of SNPT, useful for outpatients who are attended in settings with limited resources. The data used for developing the proposed models werecomprised of 136 patients from health care units. They were referred to the University Hospital in Rio de Janeiro, Brazil, from March 2001 to September 2002, with clinical-radiological suspicion of SNPT. Only symptoms and physical signs were used for constructing the neural network (NN) modelling, which was able to correctly classify 77% of patients from a test sample. The achievements of the NN model suggest that mathematical modelling, developed for classifying SNPT cases could be a useful tool for optimizing application of more expensive tests, and to avoid costs of unnecessary anti-PT treatment. In addition, the main features extracted by the neural model are shown to agree with current analysis from experts in the field.

Fingerprinting of Mycobacterium tuberculosis strains from tuberculosis (TB) patients attended in Community Health Centers (CHCs) of Rio de Janeiro was performed to verify possible risk factors for TB transmission. A prospective community-based study was performed during the period of July 1996 to December 1996 by collecting sputum samples of 489 patients in 11 different CHCs in four different planning areas (APs) of the city. Bacteriological, clinical, and epidemiological information was collected and M. tuberculosis genotypes defined after restriction fragment length polymorphism (IS6110-RFLP) and double repetitive element (DRE) fingerprinting of RFLP-clustered cases. Risk factors for TB transmission were looked for using three levels of cluster stringency. Among 349 (71%) positive cultures obtained, IS6110-RFLP typing could be performed on strains from 153 different patients. When using identity of RFLP patterns as cluster definition, 49 (32%) of the strains belonged to a cluster and none of the clinical or epidemiologic characteristics was associated with higher clustering levels. However, higher clustering level was observed in the AP including the central region of the city when compared to others. This strongly suggests that more recent transmission occurs in that area and this may be related with higher incidence of TB and HIV in this region.

Background. There is an urgent need for low-cost methods for rapid, accurate detection of Mycobacterium tuberculosis in clinical specimens. The microscopic-observation drug-susceptibility (MODS) assay is a relatively low-cost and simple liquid culture method that has been proposed for use in resource-limited environments.Methods. This prospective study evaluated the performance of the MODS assay for detection of M. tuberculosis in persons undergoing evaluation for pulmonary tuberculosis in Brazil and Honduras. Respiratory specimens were evaluated using smear microscopy, culture on Lowenstein-Jensen medium, and culture using the MODS assay. A subset of specimens was also cultured using the Mycobacterial Growth Indicator Tube (MGIT) 960 automated system (Becton Dickinson). A study subject was considered to have tuberculosis if at least 1 culture on Lowenstein-Jensen medium was positive for M. tuberculosis.Findings. A total of 1639 respiratory specimens obtained from 854 study subjects were analyzed. On a per-subject basis, MODS sensitivity was 97.5% (95% confidence interval [CI], 95.7–98.6), and specificity was 94.4% (95% CI, 93.1–95.2). Median times to detection were 21 days (interquartile range [IQR], 17–25 days) and 7 days (IQR, 5–10) for culture on Lowenstein-Jensen medium and for the MODS assay, respectively (P < .01). For 64 specimens cultured using the MGIT 960 automated system, median time to growth was similar for the MODS assay (7 days; IQR, 7–10 days) and the MGIT 960 automated system (8 days; IQR, 6–11.5 days; P = .16). The percentage of contaminated cultures was lower for the MODS assay than for culture on Lowenstein-Jensen medium (3.8% vs. 5.8%; P < .01).Conclusions. The MODS assay is a relatively simple test whose good performance characteristics for detection of pulmonary tuberculosis may make it suitable for resource-limited environments.

We prospectively evaluated the diagnostic yield of acid-fast bacilli smear and culture for Mycobacterium tuberculosis using sputum induction (SI) in the workup of patients with suspected pleural tuberculosis (TB) who were unable to produce sputum spontaneously. Of the 113 patients studied, a final diagnosis of pleural TB was made in 84 patients (71 HIV seronegative) and a final diagnosis of another disease in 29 patients. Histopathologic examination of the pleural biopsy tissue had the highest diagnostic yield (78%; 66/84). The bacteriologic yield was 62% (52/84) for the pleural tissue, 12% (10/84) for pleural fluid, and 52% (44/84) for sputum cultures obtained by SI. The yield of SI culture for M. tuberculosis was 55% (35/64) in patients with a normal radiograph (except for the pleural effusion) and 45% (9/20) in those with evidence of parenchymal disease suggestive of pulmonary TB (p = 0.6). The yield of sputum cultures obtained by SI is high in patients suspected of having pleural TB even in those cases with no pulmonary parenchymal abnormalities on the chest radiograph.

Setting Seven primary health clinics and a pulmonary disease specialty clinic in Rio de Janeiro City, Brazil. Objective To evaluate a commercial immunochromatographic test kit (ICT Tuberculosis; AMRAD-ICT; Sidney, Australia) employing five recombinant Mycobacterium tuberculosis proteins for the detection of pulmonary tuberculosis (TB). Design Serology test results were compared with duplicate sputum microscopy and culture in 277 patients with symptomatic pulmonary disease (243 with pulmonary TB and 34 with nontuberculous disease). An additional 110 healthy control subjects were also tested. Results The serology test was simple and rapid to perform and detected 64.2% of smear-positive and 46.3% of smear-negative TB patients overall. HIV co-infection was present in 15.3% of TB patients, and serology was much less sensitive (overall 27.6%) in this small group, as was microscopy (13.8%). Specificity of the serology test was 100% in healthy control subjects and 85.2% in the small number of control patients with pulmonary disease, including those with prior TB. Combined with microscopy, serology detected 72.8% of TB patients. Conclusion Depending on the population studied, multiantigen serologic tests for TB may be as sensitive as microscopy, but detect a different and overlapping subset of patients. The use of multiple antigens in this kit increased test sensitivity without significant loss of specificity. Bacille Calmette-Guerin vaccination and tuberculin sensitivity did not affect serology results. Estimating specificity in clinical use will require testing a much larger cohort of symptomatic patients with nontuberculous disease. The TB diagnostic performance of this group of antigens in HIV co-infected individuals was poor.

In this manuscript, we report the current situation of tuberculosis globally and in Brazil,the need for new strategies toward tuberculosis control, focusing on new diagnostic tech-nologies. Critical comments are given on the state of the art regarding the evaluation ofnew healthtechnologies,degreeofscientificevidenceneeded,evaluationofclinicalimpact,cost-effectiveness of incorporation into the health system and the social impact.© 2013 Elsevier Editora Ltda. All rights reserved.

We assessed the infectiousness of human immunodeficiency virus (HIV)-seropositive and HIV-seronegative individuals with pulmonary tuberculosis (TB) in a prospective cohort study. We enrolled, evaluated, and followed 104 close contacts of HIV-seropositive pulmonary TB patients and 256 close contacts of HIV-seronegative pulmonary TB patients using a standardized questionnaire, symptom review, chest radiograph, HIV serology, and tuberculin skin testing (TST). Contacts were followed foror = 12 mo. TB infection at enrollment was 27% (28/104) among contacts of HIV-seropositive TB patients and 35% (90/256) among contacts of HIV-seronegative TB patients (odds ratio [OR] = 0.68, 95% confidence interval [CI] 0.41 to 1.12; p = 0.130). TST conversion occurred in 21% (42/ 204) of subjects; 8% (5/63) of contacts of HIV-seropositive index cases and 26% (37/141) of contacts of HIV-seronegative index cases (OR = 0.24, 95% CI 0.09 to 0.65; p = 0.003). TB was diagnosed in nine contacts; eight were contacts of HIV-seronegative index cases. HIV seropositivity in the index case was independently associated with a lower risk of TB infection among contacts, even among household contacts younger than 15 yr of age. Contacts of HIV-seropositive persons with pulmonary TB were less likely to have a positive TST response at 1 yr of follow-up than contacts of HIV-seronegative persons.

In order to evaluate the predictive value of acid fast bacilii (AFB) smear for the diagnosis of Mycobacterium tuberculosis in respiratory specimens in a setting with a high prevalence of AIDS and an unknown prevalence of nontuberculous mycobacteria (NTM), we retrospectively examined specimens cultured for mycobacteria between 1 September 1993 and 30 September 1994 and medical records of patients with positive culture in a General Hospital, AIDS reference in Rio de Janeiro, Brazil. Seventy three per cent (1517/2077) of samples were respiratory specimens and mycobacteria were recovered from 20.6% (313/1517) of these. M. tuberculosis was identified in 94.2% (295/313) and NTM in 5.8% (18/313). The yield of positive AFB smear and of positive culture was 6.1% (93/1517) and 20.6% (313/1517), respectively. The positive predictive value (PPV) of AFB for M. tuberculosis was 98.4% in expectorated sputum and 96.4% in bronchoalveolar lavage. Forty four percent (130/295) of specimens with positive culture for M. tuberculosis and 66.7% (12/18) for NTM were from patients HIV positive. The conclusion was that in our study population, the PPV of AFB for M. tuberculosis in respiratory specimens was high and the prevalence of NTM was low despite the high prevalence of HIV positive.

Prison populations are at increased risk of both human immunodeficiency virus (HIV) and Mycobacterium tuberculosis infections, but among female inmates information on such risks remains scarce, especially in developing countries. Between October 1992 and November 1993, 350 women incarcerated at a prison in Sao Paulo, Brazil, were prospectively evaluated for HIV and M. tuberculosis infection and disease. Among them, 87 (25%) were HIV seropositive, and 20 (5.7%) had tuberculosis (TB). During the incarceration period, the purified protein derivative test conversion rate was 29% for HIV-positive and 32% for HIV-negative women. However, the incidence of TB was 9.9 per 100 person-years for HIV-positive and 0.7 per 100 person-years of incarceration for HIV-negative women (p < 0.0001). A multivariate analysis indicated that HIV infection (p < 0.0001) and incarceration time < 12 months (p < 0.05) were each associated with TB. These findings indicate that new transmissions of M. tuberculosis infection are common among female inmates and that HIV-infected women are more likely to acquire active disease during the first 12 months of incarceration. Because of their role in childbearing and care female inmates are an important potential source of transmission of M. tuberculosis, and new strategies to control the spread of TB in prisons need to be developed.

OBJETIVO: Avaliar acurácia de escore clínico (sensibilidade) no diagnóstico presuntivo de tuberculose pulmonar em triagem. MÉTODOS: Estudo descritivo-analítico transversal com 1.365 pacientes atendidos no setor de pneumologia em Unidade Básica de Saúde de nível secundário da cidade do Rio de Janeiro, RJ, de 2006 a 2007. Os participantes responderam um questionário padronizado, aplicado por equipe de enfermagem, contendo informações referentes à idade, peso e sintomas clínicos. O resultado presuntivo do diagnóstico de tuberculose pulmonar foi obtido pela soma da pontuação dos dados coletados. Diagnóstico de tuberculose ativa baseou-se nos resultados bacteriológicos e na decisão médica. Foram calculados sensibilidade, especificidade, valores preditivos positivos e negativos para uma prevalência especificada, e intervalos de 95% de confiança para diversos pontos de corte do escore. O desempenho do escore foi avaliado pela curva receiver operating characteristic (ROC). RESULTADOS: Para o diagnóstico de tuberculose, tosse > 1 semana e > 3 semanas mostrou sensibilidade respectivamente de 88,2% (86,2;90,2) e de 61,1% (57,93;64,3), especificidade de 19,2% (16,6;21,8) e 51,3% (48,1;54,5). O escore clínico com 8 pontos mostrou uma sensibilidade de 83,13% (77,8;87,6), especificidade de 51,8% (48,5;55,1), valor preditivo positivo de 91,6% (90,0;83,2) e negativo 32,9% (30,1;35,7). CONCLUSÕES: Tosse (> 3 sem) apresentou baixa sensibilidade e especificidade. Escore clínico com elevada sensibilidade pode ser uma ferramenta alternativa na detecção de tuberculose pulmonar, pois, além de agilizar o atendimento do caso suspeito na unidade, permite padronizar a primeira abordagem pela enfermagem. OBJECTIVE: To assess the accuracy (sensitivity) of a clinical score for presumptive pulmonary tuberculosis cases during screening. METHODS: Descriptive cross-sectional study comprising 1,365 patients attending the department of lung diseases at a secondary care outpatient clinic in the city of Rio de Janeiro, Southeastern Brazil, during 2006 and 2007. All respondents answered a standardized questionnaire administered by the clinic's nursing staff. Information on age, weight and clinical symptoms were collected. The presumptive diagnosis of pulmonary tuberculosis was made by summing up the scores of the data collected. The diagnosis of active tuberculosis was based on bacteriological findings and medical criteria. There were estimated sensitivity, specificity, positive predictive value and negative predictive value for a set prevalence, and 95% confidence intervals for different score cutoffs. The score performance was assessed using the receiver operating characteristic (ROC) curve. RESULTS: For the diagnosis of tuberculosis, cough for more than one week and cough for more than three weeks showed a sensitivity of 88.2% (86.2, 90.2) and 61.1% (57.93, 64.3), specificity 19.2% (16.6, 21.8) and 51.3% (48.1, 54.5), respectively. The clinical score of 8 had a sensitivity of 83.13% (77.8, 87.6), specificity of 51.8% (48.5, 55.1), positive predictive value of 91.6% (90.0, 83.2) and negative predictive value of 32.9% (30.1, 35.7). CONCLUSIONS: Cough for more than three weeks showed low sensitivity and specificity. A highly sensitive clinical score can be an alternative tool for screening pulmonary tuberculosis as it allows early care of suspected cases and standard nursing care approach. OBJETIVO: Evaluar la exactitud de escore clínico (sensibilidad) en el diagnostico presuntivo de tuberculosis pulmonar en pesquisa. MÉTODOS: Estudio descriptivo-analítico transversal con 1.365 pacientes atendidos en el sector de pneumonologia en Unidad Básica de Salud de nivel secundario de la ciudad de Rio de Janeiro, Sureste de Brasil, de 2006 a 2007. Los participantes respondieron un cuestionario estandarizado, aplicado por equipo de enfermería, conteniendo informaciones referentes a la edad, peso y síntomas clínicos. El resultado presuntivo del diagnostico de tuberculosis pulmonar fue obtenido por la suma de puntuación de los datos colectados. Diagnostico de tuberculosis activa se basó en los resultados bacteriológicos y en la decisión medica. Se calcularon sensibilidad, especificidad, valores predictivos positivos negativos para una prevalencia especificada, e intervalos de 95% de confianza para diversos puntos de corte del escore. El desempeño del escore fue evaluado por la curva receiver operating characteristic (ROC). RESULTADOS: Para diagnostico de tuberculosis, tos > 1 semana y > 3 semanas mostró sensibilidad respectivamente de 88,2% (86,2;90,2) y de 61,1% (57,93;64,3), especificidad de 19,2% (16,6;21,8) y 51,3% (48,1;54,5). El escore clínico con 8 puntos mostró una sensibilidad de 83,13%(77,8;87,6), especificidad de 51,8% (48,5;55,1), valor predictivo positivo de 91,6% (90,0;83,2) negativo 32,9% (30,1;35,7). CONCLUSIONES: Tos (>3 sem) presentó baja sensibilidad y especificidad. Escore clínico con elevada sensibilidad puede ser una herramienta alternativa en la detección de tuberculosis pulmonar, pues además de agilizar la atención del caso sospechoso en la unidad, permite estandarizar el primer abordaje por la enfermera.

Background Tuberculosis is one of the most prominent health problems in the world, causing 1.75 million deaths each year. Rapid clinical diagnosis is important in patients who have co-morbidities such as Human Immunodeficiency Virus (HIV) infection. Direct microscopy has low sensitivity and culture takes 3 to 6 weeks 123. Therefore, new tools for TB diagnosis are necessary, especially in health settings with a high prevalence of HIV/TB co-infection. Methods In a public reference TB/HIV hospital in Brazil, we compared the cost-effectiveness of diagnostic strategies for diagnosis of pulmonary TB: Acid fast bacilli smear microscopy by Ziehl-Neelsen staining (AFB smear) plus culture and AFB smear plus colorimetric test (PCR dot-blot). From May 2003 to May 2004, sputum was collected consecutively from PTB suspects attending the Parthenon Reference Hospital. Sputum samples were examined by AFB smear, culture, and PCR dot-blot. The gold standard was a positive culture combined with the definition of clinical PTB. Cost analysis included health services and patient costs. Results The AFB smear plus PCR dot-blot require the lowest laboratory investment for equipment (US$ 20,000). The total screening costs are 3.8 times for AFB smear plus culture versus for AFB smear plus PCR dot blot costs (US$ 5,635,760 versus US$ 1,498, 660). Costs per correctly diagnosed case were US$ 50,773 and US$ 13,749 for AFB smear plus culture and AFB smear plus PCR dot-blot, respectively. AFB smear plus PCR dot-blot was more cost-effective than AFB smear plus culture, when the cost of treating all correctly diagnosed cases was considered. The cost of returning patients, which are not treated due to a negative result, to the health service, was higher in AFB smear plus culture than for AFB smear plus PCR dot-blot, US$ 374,778,045 and US$ 110,849,055, respectively. Conclusion AFB smear associated with PCR dot-blot associated has the potential to be a cost-effective tool in the fight against PTB for patients attended in the TB/HIV reference hospital.