Anti-tuberculosis chemotherapy alters TNFR2 expression on CD4+ lymphocytes in both drug-sensitive and -resistant tuberculosis: however, only drug-resistant tuberculosis maintains a pro-inflammatory profile after a long time.

BACKGROUND: Tuberculosis (TB) is an infectious disease. During TB, regulatory T cells (Treg) are related to poor prognosis. However, information about conventional and unconventional Treg (cTreg and uTreg, respectively) is limited. The tumour necrosis factor (TNF) and its receptors (TNFR1 and TNFR2) are necessary for mycobacterial infection, and TNFR2 signalling is required to maintain Treg. METHODS: A blood sample of drug-susceptible (DS-TB) and drug-resistant tuberculosis (DR-TB) patients was obtained before (basal) and after 2 and 6 months of anti-TB therapy. Expression of TNF, TNFR1, and TNFR2 (transmembrane form, tm) on cTreg, uTreg, activated CD4+ (actCD4+), and CD4+ CD25- (CD4+) T cell subpopulations were evaluated. The main objective was to identify immunological changes associated with sensitive/resistant Mtb strains and with the use of anti-TB therapy. RESULTS: We found that after 6 months of anti-TB therapy, both DS- and DR-TB patients have decreased the frequency of cTreg tmTNF+, CD4+ tmTNFR1+ and CD4+ tmTNFR2+. Nevertheless, after 6 months of therapy, only DR-TB patients decreased the frequency of actCD4+ tmTNF+ and actCD4+ tmTNFR2+, exhibited a systemic inflammatory status (high levels of TNF, IFN-γ and IL-12), and their purified CD4+ T cells showed that TNF and TNFR2 are up-regulated at the transcriptional level. Moreover, DS- and DR-TB down-regulated TNFR1 and other proteins associated with Treg (FOXP3 and TGFß1) in response to the anti-TB therapy. CONCLUSION: These results partially explain the differences in the immune response of DS-TB vs DR-TB. The frequency of actCD4+ tmTNFR2+ cells and inflammatory status should be considered in the follow-up of therapy in DR-TB patients.

Social determinants of multidrug-resistant tuberculosis: A scoping review and research gaps.

Tuberculosis is a prime example of a social disease that requires social, economic and environmental interventions. However, research on social determinants of Multidrug-Resistant (MDR-TB) is limited. The five-stage scoping review showed the most common association of MDR-TB with multidimensional poverty (income, nutrition, education and social support) both as a contributing factor and a consequence of it. The review also found that physical environment (inadequate housing, overcrowding, poor physical environment, and smoking), health care needs, cultural determinants (race, ethnicity and gender), comorbidities had a strong influence on the development and transmission of MDR-TB. Since, epidemiology and care for MDR-TB are greatly influenced by socioeconomic factors, social, environmental and economic actions are needed in addition to the implementation of novel diagnostic techniques and treatments.

Epidemiology of skeletal tuberculosis in Beijing, China: a 10-year retrospective analysis of data.

Skeletal tuberculosis (STB) is one of the most common forms of extrapulmonary tuberculosis; however, limited epidemiological data are available on this public health concern worldwide, especially in developing countries. The aims of this study were to analyze the epidemiological characteristics of STB cases and to identify risk factors associated with drug resistance among STB cases in China. We included STB inpatients at Beijing Chest Hospital from January 2009 through December 2018. The multiple demographic and clinical variables of patients were collected from the hospital's electronic patient record. In total, 3086 STB patients were hospitalized in Beijing Chest Hospital. Of these cases, 1988 (64.4%) were spinal TB cases, 991 (32.1%) were joint TB cases, and 107 (3.5%) were concurrent spinal-joint TB cases. The most frequent localization of the infections in joints included the knee (21.5%), hip (17.9%), and elbow (10.3%). For spinal TB, lumbar, thoracic, and cervical spinal TB were present in 51.7%, 40.6%, and 4.4% of cases, respectively. Positive cultures were reported in only 16.0% of STB cases. When patients aged ≥ 60 years old were used as the control group, youths (< 18 years old) were less likely to have spinal TB (aOR, 0.29; 95% CI, 0.21-0.41). The prevalence of MDR-TB was 12.5% among the STB cases, and more female cases were afflicted with drug-resistant STB than with drug-susceptible STB (aOR, 0.50; 95% CI, 0.27-0.94). In addition, patients aged < 18 years had significantly higher odds of having drug-resistant STB compared with those aged ≥ 60 years (aOR, 20.778; 95% CI, 4.49-96.149). In conclusion, our data demonstrate that spinal TB is the most frequent form of STB in China. The youths are less likely to have spinal TB compared with elderly patients, while the patients aged < 18 years have significantly higher odds of having drug-resistant STB than elderly patients.

Prevalence of multidrug-resistant tuberculosis in Latin America and the Caribbean: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the prevalence of multidrug-resistant tuberculosis (MDR-TB) in individuals living in Latin America and the Caribbean (LAC). METHODS: We searched the MEDLINE, Embase and Literatura Latino Americana e do Caribe em Ciências da Saúde (Lilacs) databases until 08 August 2019 for all studies on the subject, without time or language restrictions. Original studies reporting the prevalence of infection with Mycobacterium tuberculosis resistant to isoniazid and rifampicin simultaneously (MDR) in LAC, the prevalence of resistance in cases with no previous treatment (new cases) and the prevalence of resistance in previously treated cases were selected. Considering the expected heterogeneity between studies, all analyses were performed using the random effects model, and heterogeneity was assessed using the I2 statistic. RESULTS: We included 91 studies from 16 countries. The estimated overall prevalence was 13.0% (95% CI 12.0-14.0%), and the heterogeneity between studies was substantial (I2  = 96.1%). In the subgroup analyses, it was observed that the prevalence of MDR-TB among new cases was 7.0% (95% CI 6.0-7.0%) and in previously treated cases was 26.0% (95% CI 24.0-28.0%). CONCLUSIONS: This review highlights multidrug resistance to antituberculosis drugs in LAC, indicating that prevention strategies have not been effective. Government institutions should invest heavily in strategies for early diagnosis and the rapid availability of effective treatments and prioritise adequate protection for health professionals. In addition, screening programmes should be adopted to prevent secondary cases.

OBJECTIFS: Evaluer la prévalence de la tuberculose multirésistante (TB-MDR) chez les personnes vivant en Amérique latine et dans les Caraïbes (ALC). MÉTHODES: Nous avons effectué des recherches dans les bases de données Medline, EMBASE et Literatura Latino Americana e do Caribe em Ciências da Saúde (Lilas) jusqu'au 08 août 2019 pour toutes les études sur le sujet, sans restriction de temps ou de langue. Des études originales faisant état de la prévalence de l'infection à Mycobacterium tuberculosis résistante à l'isoniazide et à la rifampicine simultanément (MDR) dans la région ALC, de la prévalence de la résistance dans les cas sans traitement antérieur (nouveaux cas) et de la prévalence de la résistance dans les cas précédemment traités ont été sélectionnées. Compte tenu de l'hétérogénéité attendue entre les études, toutes les analyses ont été effectuées à l' aide du modèle à effets aléatoires et l'hétérogénéité a été évaluée à l' aide de la statistique I2 . RÉSULTATS: Nous avons inclus 91 études de 16 pays. La prévalence globale était estimée à 13,0% (IC95%: 12,0%-14,0%) et l'hétérogénéité entre les études était importante (I2 = 96,1%). Dans les analyses des sous-groupes, il a été observé que la prévalence de la TB-MDR parmi les nouveaux cas était de 7,0% (IC95%: 6,0%-7,0%) et dans les cas précédemment traités de 26,0% (IC95%: 24,0%-28,0%). CONCLUSIONS: Cette revue met en évidence la multirésistance aux médicaments antituberculeux dans la région ALC, indiquant que les stratégies de prévention n'ont pas été efficaces. Les institutions gouvernementales devraient investir massivement dans les stratégies de diagnostic précoce et la disponibilité rapide de traitements efficaces et accorder la priorité à une protection adéquate pour les professionnels de la santé. De plus, des programmes de dépistage devraient être adoptés pour prévenir les cas secondaires.

Multidrug- and Extensively Drug-Resistant Mycobacterium tuberculosis Beijing Clades, Ukraine, 2015.

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) is an emerging threat to TB control in Ukraine, a country with the third highest XDR TB burden globally. We used whole-genome sequencing of a convenience sample to identify bacterial genetic and patient-related factors associated with MDR/XDR TB in this country. MDR/XDR TB was associated with 3 distinct Mycobacterium tuberculosis complex lineage 2 (Beijing) clades, Europe/Russia W148 outbreak, Central Asia outbreak, and Ukraine outbreak, which comprised 68.9% of all MDR/XDR TB strains from southern Ukraine. MDR/XDR TB was also associated with previous treatment for TB and urban residence. The circulation of Beijing outbreak strains harboring broad drug resistance, coupled with constraints in drug supply and limited availability of phenotypic drug susceptibility testing, needs to be considered when new TB management strategies are implemented in Ukraine.

Multidrug-resistant Disseminated Tuberculosis Related to Infliximab in a Patient with Ulcerative Colitis and Negative Evaluation for Latent Tuberculosis.

Anti-tumor necrosis factor (anti-TNF) is an effective biological agent for the treatment of moderate-to-severe active ulcerative colitis (UC) refractory to conventional therapy. On the other hand, anti-TNF therapy is strongly associated with a potential risk of tuberculosis (TB). Active TB is a critical complication that makes it difficult to treat patients who require anti-TNF for the treatment of UC refractory to conventional therapy. Based on the clinical guidelines, patients with inflammatory bowel disease (IBD) are strongly recommended to screen for latent TB before anti-TNF administration. Considering the possibility of active or reactivated TB related to anti-TNF therapy, all patients with IBD should be monitored closely for TB during anti-TNF therapy, irrespective of the screening results for latent TB. In particular, the risk of anti-TNF-related multidrug-resistant TB (MDR-TB) in patients with IBD has not been elucidated. This paper reports the first case of disseminated MDR-TB that developed in a UC patient receiving infliximab despite the negative evaluation for latent TB screening.

A study of clinical profile of cases of MDR-TB and evaluation of challenges faced in initiation of second line Anti tuberculosis treatment for MDR-TB cases admitted in drug resistance tuberculosis center.

OBJECTIVES: To study the clinical profile of cases, evaluation of comorbidities and problems encountered in initiation of second-line drugs for multidrug-resistant tuberculosis (MDR-TB) patients. METHODOLOGY: A prospective observational study was conducted on MDR patients admitted in drug resistance tuberculosis (DRTB) center of RDGMC Surasa Ujjain, a rural medical college, over a span of one year. RESULTS: Out of 130 admitted cases, majority (30%) were between 31 and 40 years of age. Males were predominant (70%). Females were significantly younger compared to males (p=0.00308). Most patients (83.8%) were underweight (body mass index (BMI)<18.5kg/m2). According to MDR-TB suspect criteria, majority were defaulter cases (39.23%). The anemia was the most common comorbidity (73.84%) among the study group followed by diabetes mellitus (9.23%), chronic obstructive pulmonary disease (COPD) (9.23%), 10 (7.69) asthma, 10 (7.69%) thyroid disease 9 (6.92%) followed by respiratory insufficiency 4 (3%), HIV 2 (1.5%), deep venous thrombosis (DVT) 2 (1.5%), renal failure 2 (1.5%), and hepatic failure 1 (0.76%). Majority had minimal lesion - 57 (43.8%), moderate - 38 (29.2%), and moderate advanced - 23 (17.7%) while far advanced was noted on X-rays in 12 (9.2%). A total of 91 (70%) cases had non-cavitary lesions and 39 (30%) had cavitary lesions, of which 27 were unilateral and 12 were bilateral. CONCLUSION: The males were predominant in our study however females were affected at a younger age compared to the males. Most of the patients had taken Anti tuberculosis treatment (ATT) from Revised National Tuberculosis Control Program (RNTCP) in which defaulter and relapse were the major contributors of MDR-TB cases in our study. Radiological extent of lesions of these patients was less than expectation. Management of comorbidities is essential for compliance to treatment. It necessitates prolonged hospitalization and requires frequent follow-up in the DRTB center.

Burden of multidrug-resistant tuberculosis in England: a focus on prevalent cases.

The incidence of multidrug-resistant tuberculosis (MDR-TB) is routinely reported by the Public Health England, UK, but prevalence better represents burden. To estimate MDR-TB prevalence, and identify the factors associated with acquired resistance and unsuccessful outcomes in people managed by the health services. We included notified MDR-TB cases prevalent between 2010 and 2014. Multivariable logistic regression was used to identify the factors associated with acquisition of resistance and unsuccessful outcomes. The social risk factors (SRFs) recorded were alcohol, drug misuse, homelessness and incarceration. Between 2010 and 2014, there were 2.3-3.1 times more prevalent than incident cases each year, with an increasing prevalence-to-incidence ratio over time; 86% of prevalent cases were foreign-born, and 15% had an SRF. Overall, 11% of MDR-TB cases acquired resistance, including 18% of those with SRFs and 22% of UK-born MDR-TB cases acquired resistance. Half of the cases completed treatment by 24 months; those with SRFs, extensive drug resistance or acquired resistance were less likely to complete treatment. The number of prevalent cases is higher than incident cases, and increases over time, so a focus on prevalent cases enables better planning for services to support patients. We recommend that additional support be provided for those at risk of acquiring resistance, including those with SRFs. .

Tuberculosis drugs' distribution and emergence of resistance in patient's lung lesions: A mechanistic model and tool for regimen and dose optimization.

BACKGROUND: The sites of mycobacterial infection in the lungs of tuberculosis (TB) patients have complex structures and poor vascularization, which obstructs drug distribution to these hard-to-reach and hard-to-treat disease sites, further leading to suboptimal drug concentrations, resulting in compromised TB treatment response and resistance development. Quantifying lesion-specific drug uptake and pharmacokinetics (PKs) in TB patients is necessary to optimize treatment regimens at all infection sites, to identify patients at risk, to improve existing regimens, and to advance development of novel regimens. Using drug-level data in plasma and from 9 distinct pulmonary lesion types (vascular, avascular, and mixed) obtained from 15 hard-to-treat TB patients who failed TB treatments and therefore underwent lung resection surgery, we quantified the distribution and the penetration of 7 major TB drugs at these sites, and we provide novel tools for treatment optimization. METHODS AND FINDINGS: A total of 329 plasma- and 1,362 tissue-specific drug concentrations from 9 distinct lung lesion types were obtained according to optimal PK sampling schema from 15 patients (10 men, 5 women, aged 23 to 58) undergoing lung resection surgery (clinical study NCT00816426 performed in South Korea between 9 June 2010 and 24 June 2014). Seven major TB drugs (rifampin [RIF], isoniazid [INH], linezolid [LZD], moxifloxacin [MFX], clofazimine [CFZ], pyrazinamide [PZA], and kanamycin [KAN]) were quantified. We developed and evaluated a site-of-action mechanistic PK model using nonlinear mixed effects methodology. We quantified population- and patient-specific lesion/plasma ratios (RPLs), dynamics, and variability of drug uptake into each lesion for each drug. CFZ and MFX had higher drug exposures in lesions compared to plasma (median RPL 2.37, range across lesions 1.26-22.03); RIF, PZA, and LZD showed moderate yet suboptimal lesion penetration (median RPL 0.61, range 0.21-2.4), while INH and KAN showed poor tissue penetration (median RPL 0.4, range 0.03-0.73). Stochastic PK/pharmacodynamic (PD) simulations were carried out to evaluate current regimen combinations and dosing guidelines in distinct patient strata. Patients receiving standard doses of RIF and INH, who are of the lower range of exposure distribution, spent substantial periods (>12 h/d) below effective concentrations in hard-to-treat lesions, such as caseous lesions and cavities. Standard doses of INH (300 mg) and KAN (1,000 mg) did not reach therapeutic thresholds in most lesions for a majority of the population. Drugs and doses that did reach target exposure in most subjects include 400 mg MFX and 100 mg CFZ. Patients with cavitary lesions, irrespective of drug choice, have an increased likelihood of subtherapeutic concentrations, leading to a higher risk of resistance acquisition while on treatment. A limitation of this study was the small sample size of 15 patients, performed in a unique study population of TB patients who failed treatment and underwent lung resection surgery. These results still need further exploration and validation in larger and more diverse cohorts. CONCLUSIONS: Our results suggest that the ability to reach and maintain therapeutic concentrations is both lesion and drug specific, indicating that stratifying patients based on disease extent, lesion types, and individual drug-susceptibility profiles may eventually be useful for guiding the selection of patient-tailored drug regimens and may lead to improved TB treatment outcomes. We provide a web-based tool to further explore this model and results at http://saviclab.org/tb-lesion/.

Primary bacillary resistance in multidrug-resistant tuberculosis and predictive factors associated with cure at a referral center in São Paulo, Brazil.

OBJECTIVE: To identify transmitted or primary resistance among cases of multidrug-resistant tuberculosis and predictive factors for cure in multidrug-resistant tuberculosis after the first treatment. METHOD: Descriptive study of a cohort from 2006 to 2010, in a reference unit of tuberculosis in São Paulo, Brazil. The data were obtained by the revision of medical records. Clinical criteria were used to classify transmitted and acquired resistance. Extended primary resistance was also defined, in this study, as cases initially treated with a standardized scheme, but with no therapeutic success, and the pre-treatment drug susceptibility test (DST) showed presence of resistance. RESULTS: 156 patients with multidrug-resistant tuberculosis and their respective sputum samples were eligible for the study. Only 7% of the patients were positive for the human immunodeficiency virus (HIV). Previous treatment occurred in 95% of the sample. The cure rate after the first treatment was 54%. The median bacteriological conversion time of those who healed was one month. Bacillary resistance was considered acquired resistance in 100 (64%) and transmitted resistance in 56 (36%). By logistic regression, patients who presented primary multidrug-resistant tuberculosis (odds ratio-OR = 6,29), without comorbidity (OR = 3,37) and with higher initial weight (OR = 1.04) were associated with cure after the first treatment. CONCLUSION: The early detection of bacillary resistance and appropriate treatment are in favor of healing. Thus, it is crucial to know exactly the primary resistance rate avoiding the use of inadequate treatments, amplification of bacillary resistance and its transmission.

Clinical risk factors associated with multidrug-resistant tuberculosis (MDR-TB) in Mali.

BACKGROUND: MDR-TB is a major threat to global TB control. In 2015, 580,000 were treated for MDR-TB worldwide. The worldwide roll-out of GeneXpert MTB/RIF® has improved diagnosis of MDR-TB; however, in many countries laboratories are unable to assess drug resistance and clinical predictors of MDR-TB could help target suspected patients. In this study, we aimed to determine the clinical factors associated with MDR-TB in Bamako, Mali. METHODS: We performed a cross-sectional study of 214 patients with presumed MDR-TB admitted to University of Bamako Teaching Hospital, Point-G between 2007 and 2016. We calculated crude and adjusted odds ratios for MDR-TB disease diagnosis using SPSS. RESULTS: We found that age ≤40years (OR=2.56. 95% CI: 1.44-4.55), two courses of prior TB treatment (OR=3.25, 95% CI: 1.44-7.30), TB treatment failure (OR=3.82, 95% CI 1.82-7.79), sputum microscopy with 3+ bacilli load (OR=1.98, 95% CI: 1.13-3.48) and a history of contact with a TB patient (OR=2.48, 95% CI: 1.11-5.50) were significantly associated with confirmation of MDR-TB disease. HIV was not a risk factor for MDR-TB (aOR=0.88, 95% CI: 0.34-1.94). CONCLUSION: We identified several risk factors that could be used to identify MDR-TB suspects and prioritize them for laboratory confirmation. Prospective studies are needed to understand factors associated with TB incidence and clinical outcomes of TB treatment and disease.

Ambient air pollution exposures and risk of drug-resistant tuberculosis.

BACKGROUND: Few epidemiological studies have explored the effects of air pollution on the risk of drug-resistant tuberculosis (DR-TB). OBJECTIVE: To investigate the short and long term residential concentrations of ambient air pollutants (particulate matter <10 µm in diameter (PM10) and particulate matter≤2.5 µm in diameter (PM2.5), nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3), and carbon monoxide (CO)) in relation to the risk of DR-TB in a typical air pollution city, Jinan city, China. METHODS: A total of 752 new culture-confirmed TB cases reported in TB prevention and control institutions of Jinan from January 1, 2014 to December 31, 2015 were included. Average individual-level concentrations of air pollution for 5 different exposure windows, vary from 90 days to 720 days to diagnosis were estimated using measurements from monitor closest to the patient home addresses. Logistic regression model adjusted for potential confounders was employed to evaluate correlation between air pollution and DR-TB risk at different five exposure windows individually. RESULTS: There were substantially increased mono-drug resistance and poly-drug resistance risks for ambient PM2.5, PM10, O3, and CO exposures. High exposure to PM2.5, PM10, and CO was also significantly associated with increased incidence of multi-drug resistance (MDR) both in the single- and multi-pollutants regression models. The dominant positive associations for PM2.5was observed at 540 days exposure, for O3 was observed at 180 days exposure, and for PM10 and CO was observed from 90 days to 540 days exposures. CONCLUSIONS: Our finding suggest that exposure to ambient air pollution (PM2.5, PM10, O3, and CO) are associated with increased risk of DR-TB. We provided epidemiological evidence of association between pollution exposure and mono-, poly- and multi-drug resistance.

Primary bacillary resistance in multidrug-resistant tuberculosis and predictive factors associated with cure at a referral center in São Paulo, Brazil / Resistência bacilar primária em tuberculose multidrogarresistente e fatores preditivos associados à cura, em um centro de referência da cidade de São Paulo

ABSTRACT Objective: To identify transmitted or primary resistance among cases of multidrug-resistant tuberculosis and predictive factors for cure in multidrug-resistant tuberculosis after the first treatment. Method: Descriptive study of a cohort from 2006 to 2010, in a reference unit of tuberculosis in São Paulo, Brazil. The data were obtained by the revision of medical records. Clinical criteria were used to classify transmitted and acquired resistance. Extended primary resistance was also defined, in this study, as cases initially treated with a standardized scheme, but with no therapeutic success, and the pre-treatment drug susceptibility test (DST) showed presence of resistance. Results: 156 patients with multidrug-resistant tuberculosis and their respective sputum samples were eligible for the study. Only 7% of the patients were positive for the human immunodeficiency virus (HIV). Previous treatment occurred in 95% of the sample. The cure rate after the first treatment was 54%. The median bacteriological conversion time of those who healed was one month. Bacillary resistance was considered acquired resistance in 100 (64%) and transmitted resistance in 56 (36%). By logistic regression, patients who presented primary multidrug-resistant tuberculosis (odds ratio-OR = 6,29), without comorbidity (OR = 3,37) and with higher initial weight (OR = 1.04) were associated with cure after the first treatment. Conclusion: The early detection of bacillary resistance and appropriate treatment are in favor of healing. Thus, it is crucial to know exactly the primary resistance rate avoiding the use of inadequate treatments, amplification of bacillary resistance and its transmission.

RESUMO Objetivo: Identificar resistência transmitida ou primária entre casos de tuberculose multidrogarresistente e fatores preditivos associados à cura da tuberculose multidrogarresistente após o primeiro tratamento. Método: Estudo descritivo de uma coorte de 2006 a 2010, em uma unidade de referência em tuberculose no estado de São Paulo, Brasil. Os dados foram obtidos por meio de revisão de prontuários médicos. Critérios clínicos e laboratoriais foram utilizados para classificar resistência transmitida e adquirida. Resistência primária estendida por definição, neste estudo, abrange também casos inicialmente tratados com esquema padrão, porém sem sucesso terapêutico, e teste de sensibilidade colhido pré-tratamento demonstrou presença de resistência. Resultados: Foram elegíveis para o estudo 156 doentes com tuberculose multidrogarresistente e suas respectivas amostras de escarro. Apenas 7% dos doentes eram positivos ao vírus da imunodeficiência humana (HIV). Tratamento prévio aconteceu em 95% da amostra. A taxa de cura após o primeiro tratamento foi de 54%. A mediana do tempo de conversão bacteriológica dos que se curaram foi de um mês. Dos 156 doentes, 100 (64%) e 56 (36%) foram classificados como resistência adquirida e resistência transmitida, respectivamente. Pela regressão logística, os doentes que se apresentaram com tuberculose multidrogarresistente primária (razão de chance - RC = 6,29), sem comorbidade (RC = 3,37) e com maior peso inicial (RC = 1,04) foram associados ao desfecho cura ao final do primeiro tratamento. Conclusão: A detecção precoce da resistência bacilar e o tratamento adequado favorecem a cura. Dessa forma, é indispensável conhecer com exatidão a taxa de resistência primária evitando o uso de tratamentos inadequados, a ampliação da resistência bacilar e a sua transmissão.

Delineating the factors associated with recurrence of tuberculosis in programmatic settings of rural health block, Himachal Pradesh, India.

BACKGROUND: Tuberculosis (TB) recurrence observed to be an important event in its treatment and has future implications under national TB control efforts. The present study was carried out to assess the recurrence rate along with its risk factors among patients undergoing treatment for TB under Revised National TB Control Program (RNTCP). MATERIAL AND METHODS: Total 204 patients in health block of district Una, Himachal Pradesh were studied using pretested structured interviewer-administered questionnaire. Along with univariate a non-hierarchal multi-way frequency analysis (MFA) was done to study the one and multi-way effects between the discrete variables included in a hypothesized model. The variables were under-nutrition, pulmonary TB, injecting drug use (IDU), multi-drug resistant (MDR) TB, and past TB (recurrent cases). RESULTS: Total 29 cases (14.2%) had recurrence (17.7/100,000 population) with significantly high fraction for alternate residence (Recurrent: 50.0%, Non-recurrent: 47.4%; p = 0.001), Multi-drug resistance (MDR) TB (Recurrent: 13.8%, Non-recurrent: 2.3%; p = 0.003), and sputum negative patients (Recurrent: 51.7%, Non-recurrent: 14.5%; p = 0.000). Non-recurrent cases had significantly high fraction for sputum positive cases (Recurrent: 48.3%, Non-recurrent: 72.1%; p = 0.011), and extra-pulmonary TB (Recurrent: 00.0%, Non-recurrent: 13.4%; p = 0.036). MFA observed all significant one-way effects. Significant two-way effects were IDU and pulmonary TB (p = 0.001), MDR and past TB (p = 0.004), IDU and past TB (p = 0.019), and IDU and MDR-TB (p = 0.039). CONCLUSION: Proportion of TB recurrence was expected with a significant difference between the history of change of residence, MDR-TB, pulmonary and extra-pulmonary nature of the disease. Hypothesized model observed with a significant association of IDU, pulmonary TB, MDR-TB and past TB.

Causal association of antibiotic use and resistant tuberculosis infection: Casecontrol meta-analysis / Factores de riesgo para la infección por tuberculosis resistente: Metanálisis de estudios de casos y controles

BACKGROUND: In the world scientific literature, analytical research on tuberculosis has not been meta-analyzed. The objective of this study was to identify risk factors for tuberculosis infection with drug resistance and meta-analyze the causal relationship of prior antibiotic use. METHODS: Systematic review with meta-analysis of case-control studies, in five databases. An ex ante, exhaustive and reproducible protocol of search and selection was applied; with criteria of inclusion, exclusion and evaluation of methodological quality. Were performed a qualitative and quantitative synthesis of the articles that evaluated the previous consumption of antibiotics. The PRISMA guide applied and a meta-analysis of random effects was performed for the odds ratios, with analysis of Galbraith, Funelt Plot, Forest plot and sensitivity analysis. RESULTS: We included 36 articles for the qualitative synthesis and 16 in the meta-analysis. We found a wide heterogeneity in the risk factors that include sociodemographic characteristics such as age, sex, schooling, occupation and prison; Clinics as contact with infected, absence of BCG vaccine, hospitalization, chronic comorbidities, malnutrition, HIV coinfection; And microbiological variables such as infection by Beijing genotype and therapeutic adherence. In the studies that evaluated previous consumption of antibiotic, 1880 cases and 5291 controls were studied, most with moderate or low methodological quality, with a combined measure that shows that the odds of developing resistance in patients with previous antibiotic use are 12 (95% = 6.0-23.7) times found for the non-exposed, in the meta-regression the odds were 16.6 (95% CI = 4.1-67.8) for the moderate quality studies and 5.0 (95% CI = 2.9, 8.7) for those with high methodological quality. CONCLUSIONS: This meta-analysis revealed a strong causal association between the prior use of anti-tuberculosis antibiotics and drug-resistant Micobacterium tuberculosis infection.

OBJETIVO: En la literatura científica mundial no se han metanalizado investigaciones analíticas en tuberculosis. El objetivo del estudio fue identificar factores de riesgo para la infección por tuberculosis con resistencia a medicamentos y meta-analizar la relación causal del uso previo de antibióticos. METODOS: Revisión sistemática con metanálisis de estudios de casos y controles, en cinco bases de datos. Se aplicó un protocolo de búsqueda y selección ex ante, exhaustivo y reproducible; con criterios de inclusión, exclusión y evaluación de calidad metodológica. Se realizó síntesis cualitativa de los artículos y cuantitativa para los estudios que evaluaron el consumo previo de antibióticos. Se cumplió la guía PRISMA y se realizó metanálisis de efectos aleatorios para las razones de odds, con análisis de Galbraith, Funelt Plot, Forest plot y análisis de sensibilidad. RESULTADOS: Se incluyeron 36 artículos para la síntesis cualitativa y 16 en el metanálisis. Se encontró una amplia heterogeneidad en los factores de riesgo que incluyen características sociodemográficas como edad, sexo, escolaridad, ocupación y estar en prisión; clínicas como contacto con infectados, ausencia vacuna con BCG, hospitalización, comorbilidades crónicas, malnutrición, coinfección por VIH; y variables microbiológicas como infección por genotipo Beijing y adherencia terapéutica. En los estudios que evaluaron el consumo de antibióticos se estudiaron 1880 casos y 5291 controles, la mayoría con moderada o baja calidad metodológica, con una medida combinada que evidencia que la odds de desarrollar resistencia en quienes presentan consumo previo de antibióticos es 12 (IC95%= 6,0-23,7) veces la hallada para los no expuestos, en la meta-regresión la odds fue 16,6 (IC95%=4,1-67,8) para los estudios de calidad moderada y 5,0 (IC95%=2,9-8,7) para los de alta calidad metodológica. CONCLUSIONES: En este metanálisis se evidenció la asociación causal fuerte entre el uso previo de antibióticos antituberculosos y la infección por Micobacterium tuberculosis resistente a los fármacos.

Association between antiretroviral therapy and antitubercular drug resistance in TB treatment outcome among Kazakh TB/HIV co-infected patients.

OBJECTIVES: Drug-resistant tuberculosis (TB) poses a serious threat to public health in Kazakhstan. This paper presents findings related to TB treatment outcome and drug resistance status among people co-infected with human immunodeficiency virus (HIV) and TB in Kazakhstan. METHODS: A cohort study using data provided by the Kazakhstan Ministry of Health's National Tuberculosis Program for 2014 and 2015 was performed. The χ2 test and logistical regression were performed to understand factors associated with drug-resistant TB status and TB treatment outcome. RESULTS: In the bivariate analysis, drug-resistant TB status was significantly associated with year of TB diagnosis (P=0.001) and viral load (P=0.03). TB treatment outcome was significantly associated with age at diagnosis (p=0.01), antiretroviral (ARV) treatment (P<0.0001) and drug-resistant TB status (P=0.02). In the adjusted analysis, drug-resistant TB status was associated with an increased likelihood of successful completion of treatment with a successful outcome compared with treatment failure (odds ratio=6.94, 95% confidence interval 1.39-34.44). CONCLUSIONS: These results suggest that having drug-resistant TB is associated with a higher likelihood of completing treatment with successful outcome, even when controlling for receipt of ARV therapy.

Review on emergence of drug-resistant tuberculosis (MDR & XDR-TB) and its molecular diagnosis in Ethiopia.

Tuberculosis (TB) remains a major global health problem and ranks as the second leading cause of death among deaths caused by infectious diseases worldwide. Although the availability of short-course regimens as first-line anti-tuberculosis drugs, the emergence of drug-resistant Mycobacterium tuberculosis strains pose a major challenge to the prevention and control efforts of national tuberculosis programs (NTPs). M. tuberculosis changes its cellular environment with the mechanisms that have been evolved since prehistoric times. The interactions between the bacteria and the host environment have been studied well. However, the studies at molecular level began to emerge recently including expression profiling of micro RNA (miRNA) and literature survey revealed that researchers find more information about their regulatory role in biological processes including immune response to infectious agents like mycobacteria. In developing countries, including Ethiopia, the burden of tuberculosis and or drug resistance profile of M. tuberculosis remains largely unexplored, mainly due to lack of quality controlled second-line laboratory tests and also lack of knowledge on molecular diagnostics. This review describes the disease etiology, pathogenesis, epidemiology, molecular mechanism and advanced molecular diagnostics for precision MDR-TB diagnosis.

Factors Associated With All-Cause Mortality Among Patients With Multidrug-Resistant Tuberculosis-United States, 1993-2013.

We assessed characteristics associated with all-cause mortality among US patients with multidrug-resistant tuberculosis. Mortality decreased from 31% during 1993-2002 to 11% during 2003-2013. Directly observed therapy coverage increased from 74% to 95% and was protective against all-cause mortality after accounting for demographics, clinical characteristics, human immunodeficiency virus status, and period of treatment.

Brotes de tuberculosis: más allá de la prueba de la tuberculina / Tuberculosis outbreaks: Beyond the tuberculin skin test

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The value of initial cavitation to predict re-treatment with pulmonary tuberculosis.

OBJECTIVE: Pulmonary cavitation is the classic hallmark of pulmonary tuberculosis (PTB) and is the site of very high mycobacterial burden associated with antimycobacterial drug resistance and treatment failure. The objective of this study was to investigate the relationship between re-treatment PTB and initial pulmonary cavitation coordinated with other clinical factors. METHODS: We conducted a case-control study of 291 newly diagnosed cases of pulmonary TB in The Infectious Hospital of Wuxi from Dec 2009 to Dec 2011 with complete follow-up information until December 31st of 2014. 68 patients were followed-up with PTB re-treatment; the rest of the PTB patients (n = 223) had completed anti-TB treatment, and cured without re-treatment were selected as controls. RESULTS: The univariate analysis [hazard ratio (HR) 1.885, 95 % CI 1.170-3.035, P = 0.009] and the multivariable analysis (HR 2.242, 95 % CI 1.294-3.882, P = 0.004) demonstrated that the initial pulmonary cavitation was a prognostic predictor for TB re-treatment. Additionally, the re-treatment rates in PTB patients with cavitation and no-cavitation were 27.1 and 15.5 %, respectively, with significant difference (log-rank test; P = 0.010). Other factors, age of ≥60 and history of smoking, were also prognostic variables. CONCLUSION: Initial pulmonary cavitation of chest X-ray was a significant predictor for PTB re-treatment.