Clinical standards for the diagnosis, treatment and prevention of TB infection.

BACKGROUND: Tuberculosis (TB) preventive therapy (TPT) decreases the risk of developing TB disease and its associated morbidity and mortality. The aim of these clinical standards is to guide the assessment, management of TB infection (TBI) and implementation of TPT.METHODS: A panel of global experts in the field of TB care was identified; 41 participated in a Delphi process. A 5-point Likert scale was used to score the initial standards. After rounds of revision, the document was approved with 100% agreement.RESULTS: Eight clinical standards were defined: Standard 1, all individuals belonging to at-risk groups for TB should undergo testing for TBI; Standard 2, all individual candidates for TPT (including caregivers of children) should undergo a counselling/health education session; Standard 3, testing for TBI: timing and test of choice should be optimised; Standard 4, TB disease should be excluded prior to initiation of TPT; Standard 5, all candidates for TPT should undergo a set of baseline examinations; Standard 6, all individuals initiating TPT should receive one of the recommended regimens; Standard 7, all individuals who have started TPT should be monitored; Standard 8, a TBI screening and testing register should be kept to inform the cascade of care.CONCLUSION: This is the first consensus-based set of Clinical Standards for TBI. This document guides clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage TBI.

Factors associated with non-completion of latent tuberculosis infection treatment in Rio de Janeiro, Brazil: A non-matched case control study.

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.

Treatment outcomes and predictive factors for multidrug-resistant TB and HIV coinfection in Rio de Janeiro State, Brazil.

BACKGROUND: Brazil ranks 14th worldwide in the number of TB cases and 19th in terms of TB-HIV co-infected cases. This study aims at identifying clinical and demographic factors associated with unsuccessful treatment outcomes (loss to follow-up, treatment failure and death) of HIV-positive patients with multidrug-resistant TB (MDR-TB) in Rio de Janeiro State, Brazil.METHODS: This was a retrospective cohort study of MDR-TB cases notified from 2000 to 2016 in RJ. Cox proportional hazard regression models were used to assess risk factors associated with unsuccessful treatment in HIV-positive patients with MDR-TB.RESULTS: Among 2,269 patients, 156 (6.9%) were HIV-positive and had a higher proportion of unsuccessful treatment outcomes (52.6%) than HIV-negative cases (43.7%). All HIV-positive cases with extensively drug-resistant TB (XDR-TB) had unsuccessful treatment outcomes. Multivariate analysis shows that previous MDR-TB treatment (HR 1.97, 95% CI 1.22-3.18) and illicit drugs use (HR 1.68, 95% CI 1.01-2.78) were associated with a greater hazard of unsuccessful treatment outcomes, while 6-month culture conversion (HR 0.48, 95% CI 0.27-0.84) and use of antiretroviral therapy (ART) (HR 0.51, 95% CI 0.32-0.80) were predictors of reduced risk.CONCLUSIONS: Unsuccessful treatment was higher among HIV patients with MDR-TB than among HIV-negative patients. Prompt initiation of ART and effective interventions are necessary to improve treatment adherence and prevent retreatment cases.

Multidrug-resistant tuberculosis in Lisbon: unfavourable treatment and associated factors, 2000-2014.

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.

Contribution of Xpert MTB/RIF to clinical diagnosis in adolescents with tuberculosis in Rio de Janeiro, Brazil.

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.

Molecular characterisation of multidrug-resistant Mycobacterium tuberculosis isolates from a high-burden tuberculosis state in Brazil.

Tuberculosis (TB) is the leading cause of death among infectious diseases worldwide. Among the estimated cases of drug-resistant TB, approximately 60% occur in the BRICS countries (Brazil, Russia, India, China and South Africa). Among Brazilian states, primary and acquired multidrug-resistant TB (MDR-TB) rates were the highest in Rio Grande do Sul (RS). This study aimed to perform molecular characterisation of MDR-TB in the State of RS, a high-burden Brazilian state. We performed molecular characterisation of MDR-TB cases in RS, defined by drug susceptibility testing, using 131 Mycobacterium tuberculosis (M.tb) DNA samples from the Central Laboratory. We carried out MIRU-VNTR 24loci, spoligotyping, sequencing of the katG, inhA and rpoB genes and RDRio sublineage identification. The most frequent families found were LAM (65.6%) and Haarlem (22.1%). RDRio deletion was observed in 42 (32%) of the M.tb isolates. Among MDR-TB cases, eight (6.1%) did not present mutations in the studied genes. In 116 (88.5%) M.tb isolates, we found mutations associated with rifampicin (RIF) resistance in rpoB gene, and in 112 isolates (85.5%), we observed mutations related to isoniazid resistance in katG and inhA genes. An insertion of 12 nucleotides (CCAGAACAACCC) at the 516 codon in the rpoB gene, possibly responsible for a decreased interaction of RIF and RNA polymerase, was found in 19/131 of the isolates, belonging mostly to LAM and Haarlem families. These results enable a better understanding of the dynamics of transmission and evolution of MDR-TB in the region.

Addressing the tuberculosis-depression syndemic to end the tuberculosis epidemic.

Tuberculosis (TB) and depression act synergistically via social, behavioral, and biological mechanisms to magnify the burden of disease. Clinical depression is a common, under-recognized, yet treatable condition that, if comorbid with TB, is associated with increased morbidity, mortality, community TB transmission, and drug resistance. Depression may increase risk of TB reactivation, contribute to disease progression, and/or inhibit the physiological response to anti-tuberculosis treatment because of poverty, undernutrition, immunosuppression, and/or negative coping behaviors, including substance abuse. Tuberculous infection and/or disease reactivation may precipitate depression as a result of the inflammatory response and/or dysregulation of the hypothalamic-pituitary-adrenal axis. Clinical depression may also be triggered by TB-related stigma, exacerbating other underlying social vulnerabilities, and/or may be attributed to the side effects of anti-tuberculosis treatment. Depression may negatively impact health behaviors such as diet, health care seeking, medication adherence, and/or treatment completion, posing a significant challenge for global TB elimination. As several of the core symptoms of TB and depression overlap, depression often goes unrecognized in individuals with active TB, or is dismissed as a normative reaction to situational stress. We used evidence to reframe TB and depression comorbidity as the 'TB-depression syndemic', and identified critical research gaps to further elucidate the underlying mechanisms. The World Health Organization's Global End TB Strategy calls for integrated patient-centered care and prevention linked to social protection and innovative research. It will require multidisciplinary approaches that consider conditions such as TB and depression together, rather than as separate problems and diseases, to end the global TB epidemic.

Prevalence of pyrazinamide resistance and Wayne assay performance analysis in a tuberculosis cohort in Lima, Peru.

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.

Outcomes from patients with presumed drug resistant tuberculosis in five reference centers in Brazil.

BACKGROUND: The implementation of rapid drug susceptibility testing (DST) is a current global priority for TB control. However, data are scarce on patient-relevant outcomes for presumptive diagnosis of drug-resistant tuberculosis (pDR-TB) evaluated under field conditions in high burden countries. METHODS: Observational study of pDR-TB patients referred by primary and secondary health units. TB reference centers addressing DR-TB in five cities in Brazil. Patients age 18 years and older were eligible if pDR-TB, culture positive results for Mycobacterium tuberculosis and, if no prior DST results from another laboratory were used by a physician to start anti-TB treatment. The outcome measures were median time from triage to initiating appropriate anti-TB treatment, empirical treatment and, the treatment outcomes. RESULTS: Between February,16th, 2011 and February, 15th, 2012, among 175 pDR TB cases, 110 (63.0%) confirmed TB cases with DST results were enrolled. Among study participants, 72 (65.5%) were male and 62 (56.4%) aged 26 to 45 years. At triage, empirical treatment was given to 106 (96.0%) subjects. Among those, 85 were treated with first line drugs and 21 with second line. Median time for DST results was 69.5 [interquartile - IQR: 35.7-111.0] days and, for initiating appropriate anti-TB treatment, the median time was 1.0 (IQR: 0-41.2) days. Among 95 patients that were followed-up during the first 6 month period, 24 (25.3%; IC: 17.5%-34.9%) changed or initiated the treatment after DST results: 16/29 MDRTB, 5/21 DR-TB and 3/45 DS-TB cases. Comparing the treatment outcome to DS-TB cases, MDRTB had higher proportions changing or initiating treatment after DST results (p = 0.01) and favorable outcomes (p = 0.07). CONCLUSIONS: This study shows a high rate of empirical treatment and long delay for DST results. Strategies to speed up the detection and early treatment of drug resistant TB should be prioritized.

Artificial neural network models to support the diagnosis of pleural tuberculosis in adult patients.

BACKGROUND: Clinicians in countries with high tuberculosis (TB) prevalence often treat pleural TB based on clinical grounds, as the availability and sensitivity of diagnostic tests are poor. OBJECTIVE: To evaluate the role of artificial neural networks (ANN) as an aid for the non-invasive diagnosis of pleural TB. These tools can be used in simple computer devices (tablets) without remote internet connection. METHODS: The clinical history and human immunodeficiency virus (HIV) status of 137 patients were prospectively entered in a database. Both non-linear ANN and the linear Fisher discriminant were used to calculate performance indexes based on clinical grounds. The same procedure was performed including pleural fluid test results (smear, culture, adenosine deaminase, serology and nucleic acid amplification test). The gold standard was any positive test for TB. RESULTS: In pre-test modelling, the neural model reached >90% accuracy (Fisher discriminant 74.5%). Under pre-test conditions, ANN had better accuracy compared to each test considered separately. CONCLUSIONS: ANN are highly reliable for diagnosing pleural TB based on clinical grounds and HIV status only, and are useful even in remote conditions lacking access to sophisticated medical or computer infrastructure. In other better-equipped scenarios, these tools should be evaluated as substitutes for thoracocentesis and pleural biopsy.

Safety and effectiveness of HAART in tuberculosis-HIV co-infected patients in Brazil.

BACKGROUND: Antiretroviral therapy (ART) significantly reduces tuberculosis (TB) incidence among persons with human immunodeficiency virus (HIV), but the safety and effectiveness of concomitant treatment for both diseases remain unclear. OBJECTIVE: To evaluate the impact of ART and anti-tuberculosis treatment on survival and risk of adverse events (AE) among co-infected individuals. METHODS: In a retrospective cohort study, clinical data were collected from 618 TB-HIV patients treated with rifampin, isoniazid and pyrazinamide ± ethambutol between 1 January 1995 and 31 December 2003. Patients were categorized into two groups: highly active ART (HAART) or no ART. Different HAART regimens were evaluated. Bivariate analysis, multivariate logistic regression and survival analysis using Cox proportional hazards regression were used. RESULTS: One-year mortality was lower for patients receiving HAART (adjusted hazard ratio [aHR] 0.17, 95%CI 0.09-0.31) compared to no ART. HAART increased the risk of AE (aHR 2.08, 95%CI 1.29-3.36). The odds of AE when receiving a ritonavir + saquinavir HAART regimen was eight-fold higher compared to no ART (OR 8.31, 95%CI 3.04-22.69), while efavirenz-based HAART was not associated with a significantly increased risk of AE (OR 1.42, 95%CI 0.76-2.65). CONCLUSION: HIV patients with TB have significantly better survival if they receive HAART during anti-tuberculosis treatment. Efavirenz-based HAART is associated with fewer AEs than protease inhibitor-based HAART.

Tuberculosis caused by RDRio Mycobacterium tuberculosis is not associated with differential clinical features.

BACKGROUND: We recently described the Mycobacterium tuberculosis RD(Rio) genotype, a clonally derived sublineage within the Latin American-Mediterranean (LAM) family. Genetic diversity of M. tuberculosis likely affects the clinical aspects of tuberculosis (TB). Prospective studies that address this issue are scarce and remain controversial. OBJECTIVE: To determine the association of differential clinical features of pulmonary TB with the RD(Rio) M. tuberculosis etiology. METHODS: Culture-proven pulmonary TB patients (n = 272) were clinically evaluated, including history, physical examination, chest X-ray and anti-human immunodeficiency virus serology. Isolates were classified as RD(Rio) or non-RD(Rio) M. tuberculosis by multiplex polymerase chain reaction and further spoligotyped. Clinical and M. tuberculosis genotype data were analyzed. RESULTS: RD(Rio) M. tuberculosis caused disease in 26.5% (72/270) of all TB cases. The LAM genotype, of which RD(Rio) strains are members, was responsible for 46.0% of the TB cases. Demographic data, major signs and symptoms, radiographic presentation, microbiological features and clinical outcomes were not significantly different among patients with TB caused by RD(Rio) and non-RD(Rio) strains. CONCLUSIONS: Disease caused by M. tuberculosis RD(Rio) strains was not clinically distinctive or more severe than disease caused by non-RD(Rio) strains in this series of TB patients. Larger prospective studies specifically designed to disclose differential clinical characteristics of TB caused by specific M. tuberculosis lineages are needed.

Interleukin-10 and interferon-gamma patterns during tuberculosis treatment: possible association with recurrence.

Interleukin (IL) 10 and interferon-gamma (IFN-) levels in induced sputum supernatants of 21 tuberculosis (TB) patients at diagnosis and during chemotherapy were correlated to recurrence rates. IL-10 decreased until day 60 of treatment (T60), and between T60 and T180 it increased again in 7 cases (Pattern 1) and further decreased in 14 cases (Pattern 2). Follow-up of 69 months was performed in 20/21 cases; 6 had recurrence of TB, of which 5/7 (71%) had Pattern 1 and 1/13 (7.7%) Pattern 2 (OR 30.0, 95%CI 2.19411.3, P 0.0072). This was not observed for IFN-. High IL-10 levels at the end of treatment may function as a risk factor for TB recurrence.

Making innovations accessible to the poor through implementation research.

Within countries, poorer populations have greater health needs and less access to good medical care than better-off populations. This is particularly true for tuberculosis (TB), the archetypal disease of poverty. Innovations also tend to become available to better-off populations well before they become available to those who need them the most. In a new era of innovations for TB diagnosis and treatment, it is increasingly important not only to be sure that these innovations can work in terms of accuracy and efficacy, but also that they will work, especially for the poor. We argue that after an innovation or a group of innovations has been endorsed, based on demonstrated accuracy and/or efficacy, introduction into routine practice should proceed through implementation by research. Cluster-randomised pragmatic trials are suited to this approach, and permit the prospective collection of evidence needed for full impact assessment according to a previously published framework. The novel approach of linking transmission modelling with operational modelling provides a methodology for expanding and enhancing the range of evidence, and can be used alongside evidence from pragmatic implementation trials. This evidence from routine practice should then be used to ensure that innovations in TB control are used for positive action for all, and particularly the poor.