Association of Mortality and Years of Potential Life Lost With Active Tuberculosis in the United States.

Importance: Active tuberculosis (TB) disease leads to substantial mortality but is preventable through screening and treatment for latent TB infection. Early mortality after TB diagnosis (≤1 year) is well described, but delayed mortality (>1 year) among patients with active TB is poorly understood. Objective: To compare early and delayed mortality and years of potential life (YPL) lost among patients with active TB disease vs an age-, sex-, and year of diagnosis-matched comparison cohort without active TB disease. Design, Setting, and Participants: This retrospective cohort study, conducted in the integrated health system of Kaiser Permanente Northern California, included patients with microbiologically confirmed active TB disease from January 1, 1997, to December 31, 2017, and a control cohort matched by age, sex, and year of diagnosis. Multivariable models were used to adjust for demographic and clinical characteristics. Patients with active TB disease prior to 1997 were excluded. Data were analyzed from January 1, 2019, to January 31, 2020. Exposure: Microbiologically confirmed TB disease. Main Outcomes and Measures: Early (≤1 year after TB diagnosis) and delayed (>1 year after TB diagnosis) all-cause mortality. Results: A total of 2522 patients who had active TB from 1997 to 2017 were identified, with 17 166 person-years of follow-up. The comparison cohort included 100 880 persons with 735 726 person-years of follow-up. In the active TB and comparison cohorts, similar percentages of persons were male (56.3% vs 55.6%), aged 45 to 64 years (33.7% vs 33.7%), and aged 65 years or older (24.7% vs 24.7%). Both early mortality (7.0%) and delayed mortality (16.3%) were higher among patients with active TB disease compared with those without active TB disease (1.1% and 12.0%, respectively). Patients with active TB disease had a significantly higher risk for early (adjusted hazard ratio [aHR], 7.29; 95% CI, 6.08-8.73) and delayed (aHR, 1.78; 95% CI, 1.61-1.98) mortality compared with the comparison cohort (P < .001). Active TB disease was associated with an adjusted -7.0 (95% CI, -8.4 to -5.5) YPL lost compared with the comparison cohort. Conclusions and Relevance: In this study, patients with active TB disease had significantly higher early and delayed all-cause mortality when adjusting for demographic and clinical characteristics. These findings suggest that TB prevention through screening and treatment of latent TB infection could reduce mortality and YPL lost due to active TB disease.

Mortality Synopsis Among Women of Reproductive Age Group in Nigeria: A Hospital-Based Study.

PURPOSE: Identification of health problems of women of reproductive age, using a reliable mortality data, is essential in evading preventable female deaths. This study aimed at investigating mortality profile of women of reproductive age group in Nigeria. MATERIALS AND METHODS: This is a descriptive, retrospective study involving women of reproductive age group of 15-49 years that died at DELSUTH from 1st January 2016 to 31st December 2018. The age, date of death and cause of death were retrieved from the hospital records and subsequently analyzed using SPSS version 21. RESULTS: One hundred and eighty-seven eligible deaths were encountered in this study, constituting 17.5% of all deaths in the hospital. Twenty four (12.8%) cases were of maternal etiology while 163 (87.2%) were of non-maternal causes. Non-communicable disease, communicable disease and external injuries accounted for 100 (53.5%), 44 (23.5%) and 19 (10.2%) deaths among the non-maternal causes. The mean age and the peak age group are 34.4 years and the 4th decade respectively. The leading specified non-maternal causes of death (in descending order) are AIDS/TB, cerebrovascular accidents (CVA), breast cancer, road traffic accident (RTA), diabetes, perioperative death and sepsis while the leading maternal causes of death are abortion, postpartum hemorrhage, eclampsia and puerperal sepsis. CONCLUSION: Most deaths affecting WRAG are preventable, with non-maternal causes in excess of maternal causes. There is need for holistic life-long interventional policies and strategies that will address the health need of these women, using evidence-based research findings.

[Tuberculosis in indigenous children and adolescents in Brazil: factors associated with death and treatment dropout]. / Tuberculose entre crianças e adolescentes indígenas no Brasil: fatores associados ao óbito e ao abandono do tratamento.

The study aimed to describe clinical and sociodemographic characteristics, estimate incidence, and analyze factors associated with dropout and death during treatment of TB cases reported in indigenous children and adolescents in Brazil from 2006 to 2016. A historical case series was performed on incidence according to age bracket and major geographic region, and multinomial logistic regression was used to explain factors associated with treatment dropout and death. Of the 2,096 reported cases, 88.2% evolved to cure, 7.2% dropped out of treatment, and 4.6% evolved to death. There was a predominance of cases in boys 15-19 years of age and a higher proportion of deaths (55.7%) in children < 4 years. Considering indigenous children and adolescents with TB in Brazil as a whole, mean incidence was 49.1/100,000, ranging from 21.5/100,000 to 97.6/100,000 in the Northeast and Central, respectively. Cases with insufficient and irregular follow-up showed higher odds of dropout (OR = 11.1; 95%CI: 5.2-24.8/OR = 4.4; 95%CI: 1.9-10.3) and death (OR = 20.3; 95%CI: 4.9-84.9/OR = 5.1; 95%CI: 1.2-22.7). Cases in retreatment (OR = 2.4; 95%CI: 2.08-8.55) and with HIV coinfection (OR = 8.2; 95%CI: 2.2-30.9) were also associated with dropout. Extrapulmonary (OR = 1.8; 95%CI: 1.1-3.3) and mixed clinical forms (OR = 5.6; 95%CI: 2.8-11.4), age < 4 years (OR = 3.1; 95%CI: 1.5-6.4), and cases from the North (OR = 2.8; 95%CI: 1.1-7.1) and Central (OR = 2.8; 95%CI: 1.1-7.0) were associated with death. TB control in indigenous children and adolescents cannot be achieved without investments in research and development and without reducing social inequalities.

O objetivo deste estudo foi descrever características clínicas e sociodemográficas, estimar a incidência da tuberculose (TB), além de analisar fatores associados ao abandono e ao óbito na vigência do tratamento dos casos de TB notificados entre crianças e adolescentes indígenas, no Brasil, entre 2006-2016. Realizou-se análise da série histórica de incidência, segundo faixa etária e macrorregião e utilizou-se regressão logística multinomial para elucidar fatores associados ao abandono e ao óbito. Do total de 2.096 casos notificados, 88,2% tiveram cura, 7,2% abandonaram o tratamento e 4,6% evoluíram para óbito. Houve predomínio de casos em meninos de 15-19 anos e maior proporção de óbitos (55,7%) em < 4 anos. Considerando o conjunto de crianças e adolescentes indígenas com TB no Brasil, a incidência média foi 49,1/100 mil, variando de 21,5/100 mil a 97,6/100 mil nas regiões Nordeste e Centro-oeste, respectivamente. Os casos com acompanhamento insuficiente e regular tiveram maiores chances de abandono (OR = 11,1; IC95%: 5,2-24,8/OR = 4,4; IC95%: 1,9-10,3) e óbito (OR = 20,3; IC95%: 4,9-84,9/OR = 5,1; IC95%: 1,2-22,7). Os casos em retratamento (OR = 2,4; IC95%: 2,08-8,55) e com anti-HIV positivo (OR = 8,2; IC95%: 2,2-30,9) também mostraram-se associados ao abandono. As formas clínicas extrapulmonar (OR = 1,8; IC95%: 1,1-3,3) e mista (OR = 5,6; IC95%: 2,8-11,4), os casos em < 4 anos (OR = 3,1; IC95%: 1,5-6,4) e os casos provenientes das regiões Norte (OR = 2,8; IC95%: 1,1-7,1) e Centro-oeste (OR = 2,8; IC95%: 1,1-7,0) mostraram-se associados ao óbito. Acreditamos que o controle da TB em crianças e adolescentes indígenas não poderá ser alcançado sem investimentos em pesquisa e desenvolvimento e sem a redução das desigualdades sociais.

El objetivo de este estudio fue describir características clínicas y sociodemográficas, estimar la incidencia de la tuberculosis (TB), además de analizar factores asociados al abandono y al óbito en la vigencia del tratamiento de los casos de TB, notificados entre niños y adolescentes indígenas, en Brasil entre 2006-2016. Se realizó un análisis de la serie histórica de incidencia, según la franja de edad y macrorregión y se utilizó la regresión logística multinomial para elucidar factores asociados al abandono y al óbito. Del total de 2.096 casos notificados, un 88,2% tuvieron cura, un 7,2% abandonaron el tratamiento y un 4,6% evolucionaron hacia óbito. Hubo un predominio de casos en chicos de 15-19 años y mayor proporción de óbitos (55,7%) en < 4 años. Considerando el conjunto de niños y adolescentes indígenas con TB en Brasil, la incidencia media fue 49,1/100.000, variando de 21,5/100.000 a 97,6/100.000 en las regiones Nordeste y Centro-oeste, respectivamente. Los casos con un seguimiento insuficiente y regular tuvieron mayores oportunidades de abandono (OR = 11,1; IC95%: 5,2-24,8/OR = 4,4; IC95%: 1,9-10,3) y óbito (OR = 20,3; IC95%: 4,9-84,9/OR = 5,1; IC95%: 1,2-22,7). Los casos de retorno al tratamiento (OR = 2,4; IC95%: 2,08-8,55) y con anti-VIH positivo (OR = 8,2; IC95%: 2,2-30,9) también se mostraron asociados al abandono. Las formas clínicas extrapulmonares (OR = 1,8; IC95%: 1,1-3,3) y mixta (OR = 5,6; IC95%: 2,8-11,4), los casos en < 4 años (OR = 3,1; IC95%: 1,5-6,4) y los casos procedentes de las regiones Norte (OR = 2,8; IC95%: 1,1-7,1) y Centro-oeste (OR = 2,8; IC95%: 1,1-7,0) se mostraron asociados al óbito. Creemos que el control de la TB en niños y adolescentes indígenas no se podrá alcanzar sin inversiones en investigación y desarrollo y sin la reducción de las desigualdades sociales.

Sustained positive impact on tuberculosis treatment outcomes of TB-HIV integrated care in Uganda.

To examine tuberculosis (TB) treatment outcomes from a long-term TB-HIV (human immunodeficiency virus) integrated model of care at the Infectious Diseases Institute Clinic, Kampala, Uganda. We included HIV-positive adults who were new TB cases initiated on anti-tuberculosis treatment between 2009 and 2015 during TB-HIV integration. Trends in TB treatment outcomes and TB-associated deaths were analyzed using respectively the χ² trend test and Kaplan-Meier methods. The analysis involved 1318 cases: most patients were female (>50%); the median age ranged from 34 to 36 years, and >60% were late presenters (CD4 count <200 cells/µl), with a median CD4 cell count of 100-146 cells/µl at TB diagnosis. TB treatment success (cured or treatment completed) was 67-76%. Loss to follow-up (LTFU) declined systematically from 7% in 2010 to 3.4% in 2015 (P < 0.01). Antiretroviral therapy (ART) initiation during the intensive phase improved from 47% in 2009 to 97% in 2015 (P < 0.01). The mortality rate was >15% over time, and the probability of death at month 2 of anti-tuberculosis treatment was 52% higher among late presenters than in early presenters (13% vs. 6%, P < 0.01). Significant LTFU improvement and prompt ART initiation could be due to well-implemented TB-HIV integration care; however, static TB-associated deaths may be due to late presentation. .

Active Tuberculosis in Patients with Psoriasis Receiving Biologic Therapy: A Systematic Review.

BACKGROUND: Biologic therapies pose a risk for opportunistic infections, especially for reactivating latent tuberculosis infection (LTBI). OBJECTIVE: The aim was to describe the clinical features and mortality rate of active Mycobacterium tuberculosis (TB) in psoriasis patients receiving biologic therapies. METHODS: A systematic review of PubMed, Google Scholar, ScienceDirect, Cochrane Library, and ClinicalTrials.gov databases was performed. Studies describing active TB in patients with psoriasis receiving biologic therapy from inception to May 31, 2018 were included. Clinical data as well as mortality rates were recorded. RESULTS: Fifty-one studies were included, evaluating 78 patients with active TB: 11 prospective studies, 13 retrospective, and 27 case reports/series. Most patients (73%) with active TB were male, the mean age was 48 ± 13 years, and 85% were of European or Asian origin. Pre-treatment LTBI screening was negative for 63% of patients. Disease presented in 33% of patients within the first 3 months of treatment, and in 51% within the first 6 months. Most patients (72%) presented with extra-pulmonary TB, and 49% had disseminated disease. The mortality rate was 7%. LIMITATIONS: Limitations of this review are its small sample size and inclusion of case reports. CONCLUSIONS: Some patients develop active TB despite LTBI screening. Clinicians initiating biologic therapy in patients with psoriasis should be aware of the clinical features of active TB in this scenario.

Tuberculose entre crianças e adolescentes indígenas no Brasil: fatores associados ao óbito e ao abandono do tratamento / Tuberculosis in indigenous children and adolescents in Brazil: factors associated with death and treatment dropout / Tuberculosis entre niños y adolescentes indígenas en Brasil: factores asociados al óbito y al abandono del tratamiento

Resumo: O objetivo deste estudo foi descrever características clínicas e sociodemográficas, estimar a incidência da tuberculose (TB), além de analisar fatores associados ao abandono e ao óbito na vigência do tratamento dos casos de TB notificados entre crianças e adolescentes indígenas, no Brasil, entre 2006-2016. Realizou-se análise da série histórica de incidência, segundo faixa etária e macrorregião e utilizou-se regressão logística multinomial para elucidar fatores associados ao abandono e ao óbito. Do total de 2.096 casos notificados, 88,2% tiveram cura, 7,2% abandonaram o tratamento e 4,6% evoluíram para óbito. Houve predomínio de casos em meninos de 15-19 anos e maior proporção de óbitos (55,7%) em < 4 anos. Considerando o conjunto de crianças e adolescentes indígenas com TB no Brasil, a incidência média foi 49,1/100 mil, variando de 21,5/100 mil a 97,6/100 mil nas regiões Nordeste e Centro-oeste, respectivamente. Os casos com acompanhamento insuficiente e regular tiveram maiores chances de abandono (OR = 11,1; IC95%: 5,2-24,8/OR = 4,4; IC95%: 1,9-10,3) e óbito (OR = 20,3; IC95%: 4,9-84,9/OR = 5,1; IC95%: 1,2-22,7). Os casos em retratamento (OR = 2,4; IC95%: 2,08-8,55) e com anti-HIV positivo (OR = 8,2; IC95%: 2,2-30,9) também mostraram-se associados ao abandono. As formas clínicas extrapulmonar (OR = 1,8; IC95%: 1,1-3,3) e mista (OR = 5,6; IC95%: 2,8-11,4), os casos em < 4 anos (OR = 3,1; IC95%: 1,5-6,4) e os casos provenientes das regiões Norte (OR = 2,8; IC95%: 1,1-7,1) e Centro-oeste (OR = 2,8; IC95%: 1,1-7,0) mostraram-se associados ao óbito. Acreditamos que o controle da TB em crianças e adolescentes indígenas não poderá ser alcançado sem investimentos em pesquisa e desenvolvimento e sem a redução das desigualdades sociais.

Abstract: The study aimed to describe clinical and sociodemographic characteristics, estimate incidence, and analyze factors associated with dropout and death during treatment of TB cases reported in indigenous children and adolescents in Brazil from 2006 to 2016. A historical case series was performed on incidence according to age bracket and major geographic region, and multinomial logistic regression was used to explain factors associated with treatment dropout and death. Of the 2,096 reported cases, 88.2% evolved to cure, 7.2% dropped out of treatment, and 4.6% evolved to death. There was a predominance of cases in boys 15-19 years of age and a higher proportion of deaths (55.7%) in children < 4 years. Considering indigenous children and adolescents with TB in Brazil as a whole, mean incidence was 49.1/100,000, ranging from 21.5/100,000 to 97.6/100,000 in the Northeast and Central, respectively. Cases with insufficient and irregular follow-up showed higher odds of dropout (OR = 11.1; 95%CI: 5.2-24.8/OR = 4.4; 95%CI: 1.9-10.3) and death (OR = 20.3; 95%CI: 4.9-84.9/OR = 5.1; 95%CI: 1.2-22.7). Cases in retreatment (OR = 2.4; 95%CI: 2.08-8.55) and with HIV coinfection (OR = 8.2; 95%CI: 2.2-30.9) were also associated with dropout. Extrapulmonary (OR = 1.8; 95%CI: 1.1-3.3) and mixed clinical forms (OR = 5.6; 95%CI: 2.8-11.4), age < 4 years (OR = 3.1; 95%CI: 1.5-6.4), and cases from the North (OR = 2.8; 95%CI: 1.1-7.1) and Central (OR = 2.8; 95%CI: 1.1-7.0) were associated with death. TB control in indigenous children and adolescents cannot be achieved without investments in research and development and without reducing social inequalities.

Resumen: El objetivo de este estudio fue describir características clínicas y sociodemográficas, estimar la incidencia de la tuberculosis (TB), además de analizar factores asociados al abandono y al óbito en la vigencia del tratamiento de los casos de TB, notificados entre niños y adolescentes indígenas, en Brasil entre 2006-2016. Se realizó un análisis de la serie histórica de incidencia, según la franja de edad y macrorregión y se utilizó la regresión logística multinomial para elucidar factores asociados al abandono y al óbito. Del total de 2.096 casos notificados, un 88,2% tuvieron cura, un 7,2% abandonaron el tratamiento y un 4,6% evolucionaron hacia óbito. Hubo un predominio de casos en chicos de 15-19 años y mayor proporción de óbitos (55,7%) en < 4 años. Considerando el conjunto de niños y adolescentes indígenas con TB en Brasil, la incidencia media fue 49,1/100.000, variando de 21,5/100.000 a 97,6/100.000 en las regiones Nordeste y Centro-oeste, respectivamente. Los casos con un seguimiento insuficiente y regular tuvieron mayores oportunidades de abandono (OR = 11,1; IC95%: 5,2-24,8/OR = 4,4; IC95%: 1,9-10,3) y óbito (OR = 20,3; IC95%: 4,9-84,9/OR = 5,1; IC95%: 1,2-22,7). Los casos de retorno al tratamiento (OR = 2,4; IC95%: 2,08-8,55) y con anti-VIH positivo (OR = 8,2; IC95%: 2,2-30,9) también se mostraron asociados al abandono. Las formas clínicas extrapulmonares (OR = 1,8; IC95%: 1,1-3,3) y mixta (OR = 5,6; IC95%: 2,8-11,4), los casos en < 4 años (OR = 3,1; IC95%: 1,5-6,4) y los casos procedentes de las regiones Norte (OR = 2,8; IC95%: 1,1-7,1) y Centro-oeste (OR = 2,8; IC95%: 1,1-7,0) se mostraron asociados al óbito. Creemos que el control de la TB en niños y adolescentes indígenas no se podrá alcanzar sin inversiones en investigación y desarrollo y sin la reducción de las desigualdades sociales.

Tuberculosis elimination: where are we now?

Tuberculosis (TB) still represents a major public health issue in spite of the significant impact of the efforts made by the World Health Organization (WHO) and partners to improve its control. In 2014 WHO launched a new global strategy (End TB) with a vision of a world free of TB, and a 2035 goal of TB elimination (defined as less than one incident case per million). The aim of this article is to summarise the theoretical bases of the End TB Strategy and to analyse progresses and persistent obstacles on the way to TB elimination.The evolution of the WHO recommended strategies of TB control (Directly Observed Therapy, Short Course (DOTS), Stop TB and End TB) are described and the concept of TB elimination is discussed. Furthermore, the eight core activities recently proposed by WHO as the milestones to achieve TB elimination are discussed in detail. Finally, the recently published experiences of Cyprus and Oman on their way towards TB elimination are described, together with the regional experience of Latin America.New prevention, diagnostic and treatment tools are also necessary to increase the speed of the present TB incidence decline.

Delivering Patient-Centered Care in a Fragile State: Using Patient-Pathway Analysis to Understand Tuberculosis-Related Care Seeking in Pakistan.

Background: Pakistan has the sixth largest population in the world and boasts the fifth greatest burden of tuberculosis. The Government of Pakistan has set the ambitious goal of zero deaths due to tuberculosis and universal access to tuberculosis care by 2020. Successfully reaching these goals is dependent on the country's capacity to diagnose and successfully treat an estimated 200000 unnotified or missing patients with tuberculosis. Methods: A patient-pathway analysis (PPA) was conducted at the national level, as well as for each of the 4 provinces, to assess the alignment between patient care seeking and the availability of tuberculosis diagnostic and treatment services. Results: Almost 90% of patients initiated care in the private sector, which accounts for only 15% of facilities with the capacity for tuberculosis diagnosis and treatment. Across the country, nearly 50% of tuberculosis microscopy laboratories were located in public-sector-basic health units and regional health centers. However, very few patients initiated care in these facilities. Overall, tuberculosis case detection was high given the low likelihood of patients reaching facilities with the capacity for tuberculosis service delivery during their first visit. Discussion: Improving the engagement of the informal sector and lower-level clinicians will improve the efficiency and timeliness of tuberculosis diagnosis for patients in Pakistan. Concurrently, the apparent strength of the referral networks connecting community-level workers and private clinicians to the public sector for tuberculosis diagnosis and treatment suggests that strengthening the capacity of the public sector could be valuable.

Progression of the epidemiological transition in a rural South African setting: findings from population surveillance in Agincourt, 1993-2013.

BACKGROUND: Virtually all low- and middle-income countries are undergoing an epidemiological transition whose progression is more varied than experienced in high-income countries. Observed changes in mortality and disease patterns reveal that the transition in most low- and middle-income countries is characterized by reversals, partial changes and the simultaneous occurrence of different types of diseases of varying magnitude. Localized characterization of this shifting burden, frequently lacking, is essential to guide decentralised health and social systems on the effective targeting of limited resources. Based on a rigorous compilation of mortality data over two decades, this paper provides a comprehensive assessment of the epidemiological transition in a rural South African population. METHODS: We estimate overall and cause-specific hazards of death as functions of sex, age and time period from mortality data from the Agincourt Health and socio-Demographic Surveillance System and conduct statistical tests of changes and differentials to assess the progression of the epidemiological transition over the period 1993-2013. RESULTS: From the early 1990s until 2007 the population experienced a reversal in its epidemiological transition, driven mostly by increased HIV/AIDS and TB related mortality. In recent years, the transition is following a positive trajectory as a result of declining HIV/AIDS and TB related mortality. However, in most age groups the cause of death distribution is yet to reach the levels it occupied in the early 1990s. The transition is also characterized by persistent gender differences with more rapid positive progression in females than males. CONCLUSIONS: This typical rural South African population is experiencing a protracted epidemiological transition. The intersection and interaction of HIV/AIDS and antiretroviral treatment, non-communicable disease risk factors and complex social and behavioral changes will impact on continued progress in reducing preventable mortality and improving health across the life course. Integrated healthcare planning and program delivery is required to improve access and adherence for HIV and non-communicable disease treatment. These findings from a local, rural setting over an extended period contribute to the evidence needed to inform further refinement and advancement of epidemiological transition theory.

Liver transplantation is associated with good clinical outcome in patients with active tuberculosis and acute liver failure due to anti-tubercular treatment.

BACKGROUND: Active tuberculosis (TB) is commonly considered a contraindication for liver transplantation (LT). However, in patients with TB who develop acute liver failure (ALF) due to toxicity induced by anti-tubercular treatment (ATT), LT could be the only opportunity for treatment. The aim of this study was to evaluate the feasibility of LT in this scenario. METHODS: We described 2 cases and comprehensively reviewed the literature finding 26 cases of LT performed in patients having a concomitant active TB and liver failure secondary to ATT toxicity. RESULTS: TB was classified as pulmonary in 18/26 (69%), nodal in 3/26 (11%) TB cases, while the remaining 5/26 cases included disseminated, pleural, renal, ovarian, and vertebral TB localization (1 case each). ATT following LT consisted mainly of isoniazid or rifampin (RIF)-sparing regimens and included primarily fluoroquinolones and ethambutol. Rejection episodes and liver toxicity were reported in 19% and 8% of patients respectively. Graft rejection was more frequent among patients treated with RIF-containing regimens (P<.001). Mortality rate was 15% after a median follow up of 12 months. In only one case was death attributed to uncontrolled TB infection. CONCLUSION: Our findings suggest that LT is an effective therapeutic option for patients with active TB developing ALF following ATT and should be considered for patients failing medical treatment.

Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review.

OBJECTIVES:  To evaluate the effects on non-specific and all cause mortality, in children under 5, of Bacillus Calmette-Guérin (BCG), diphtheria-tetanus-pertussis (DTP), and standard titre measles containing vaccines (MCV); to examine internal validity of the studies; and to examine any modifying effects of sex, age, vaccine sequence, and co-administration of vitamin A. DESIGN:  Systematic review, including assessment of risk of bias, and meta-analyses of similar studies. STUDY ELIGIBILITY CRITERIA:  Clinical trials, cohort studies, and case-control studies of the effects on mortality of BCG, whole cell DTP, and standard titre MCV in children under 5. DATA SOURCES:  Searches of Medline, Embase, Global Index Medicus, and the WHO International Clinical Trials Registry Platform, supplemented by contact with experts in the field. To avoid overlap in children studied across the included articles, findings from non-overlapping birth cohorts were identified. RESULTS:  Results from 34 birth cohorts were identified. Most evidence was from observational studies, with some from short term clinical trials. Most studies reported on all cause (rather than non-specific) mortality. Receipt of BCG vaccine was associated with a reduction in all cause mortality: the average relative risks were 0.70 (95% confidence interval 0.49 to 1.01) from five clinical trials and 0.47 (0.32 to 0.69) from nine observational studies at high risk of bias. Receipt of DTP (almost always with oral polio vaccine) was associated with a possible increase in all cause mortality on average (relative risk 1.38, 0.92 to 2.08) from 10 studies at high risk of bias; this effect seemed stronger in girls than in boys. Receipt of standard titre MCV was associated with a reduction in all cause mortality (relative risks 0.74 (0.51 to 1.07) from four clinical trials and 0.51 (0.42 to 0.63) from 18 observational studies at high risk of bias); this effect seemed stronger in girls than in boys. Seven observational studies, assessed as being at high risk of bias, have compared sequences of vaccines; results of a subset of these suggest that administering DTP with or after MCV may be associated with higher mortality than administering it before MCV. CONCLUSIONS:  Evidence suggests that receipt of BCG and MCV reduce overall mortality by more than would be expected through their effects on the diseases they prevent, and receipt of DTP may be associated with an increase in all cause mortality. Although efforts should be made to ensure that all children are immunised on schedule with BCG, DTP, and MCV, randomised trials are needed to compare the effects of different sequences.

Improved survival in patients with severe tuberculosis after exposure to fluoroquinolones.

BACKGROUND: The clinical impact of prior exposure to antibiotics on patients with tuberculosis (TB) is largely unknown. This study investigated the survival of patients with severe TB after exposure to a variety of antibiotics. METHODS: A retrospective cohort study was conducted in TB patients with prior exposure to fluoroquinolones (FQs) (FQ group), to third-generation cephalosporins (CEPH group), and to third-generation penicillins (PCN group). To understand the impact of monotherapy with antibiotics on survival, patients with prior exposure to only moxifloxacin, ceftriaxone, or piperacillin were investigated. RESULTS: Patients in the FQ group (N= 401) had a significantly higher survival rate (82.5%) than patients in the CEPH (N = 210) and PCN (N = 172) groups (67.6% and 62.8%, respectively; both p < 0.0001) at 180 d after TB diagnosis. Adjusted odds ratio (AOR) logistic regression analysis demonstrated that patients in the FQ group had significantly more favourable outcomes than those in the CEPH and PCN groups in terms of intensive care unit (ICU) admission rate (versus CEPH cohort: AOR, 1.70; 95% CI: 1.16-2.50; p = 0.0067, versus PCN cohort: AOR, 3.58; 95% CI: 2.42-5.29; both p < 0.0001), mechanical ventilation rate (versus CEPH cohort: AOR, 1.70; 95% CI: 1.09-2.66; p = 0.0205, versus PCN cohort: AOR, 3.92; 95% CI: 2.54-6.05; both p < 0.0001), and acute respiratory failure rate (versus CEPH cohort: AOR, 1.62; 95% CI: 1.07-2.45; p = 0.0223, versus PCN cohort: AOR, 4.29; 95% CI: 2.86-6.43; both p < 0.0001). TB patients with prior exposure to moxifloxacin (N = 198) had a significantly higher survival rate (85.9%) than that of patients with exposure to ceftriaxone (N = 119) and piperacillin (N = 172) monotherapy (survival rates: 69.8% and 62.8%, respectively; both p < 0.001). CONCLUSIONS: TB patients with prior exposure to FQs had more favourable outcomes compared with patients who had prior exposure to third-generation cephalosporins or third-generation penicillins. This study provides new insights into the impact of previous exposure to FQs on the survival of TB patients.

Nutritional supplements for people being treated for active tuberculosis.

BACKGROUND: Tuberculosis and malnutrition are linked in a complex relationship. Tuberculosis may cause undernutrition through increased metabolic demands and decreased intake, and nutritional deficiencies may worsen the disease, or delay recovery by depressing important immune functions. At present, there is no evidence-based nutritional guidance for adults and children being treated for tuberculosis. OBJECTIVES: To assess the effects of oral nutritional supplements in people being treated with antituberculous drug therapy for active tuberculosis. SEARCH METHODS: We searched the Cochrane Infectious Disease Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL; Issue 1, 2016), MEDLINE (from 1946 to 4 February 2016), EMBASE (from 1980 to 4 February 2016), LILACS (from 1982 to 4 February 2016), the metaRegister of Controlled Trials (mRCT), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and the Indian Journal of Tuberculosis up to 4 February 2016, and checked the reference lists of all included studies. SELECTION CRITERIA: Randomized controlled trials that compared any oral nutritional supplement given for at least four weeks with no nutritional intervention, placebo, or dietary advice only for people being treated for active tuberculosis. The primary outcomes of interest were all-cause death, and cure at six and 12 months. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, and extracted data and assessed the risk of bias in the included trials. We presented the results as risk ratios (RR) for dichotomous variables, and mean differences (MD) for continuous variables, with 95% confidence intervals (CIs). Where appropriate, we pooled data from trials with similar interventions and outcomes. We assessed the quality of the evidence using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Thirty-five trials, including 8283 participants, met the inclusion criteria of this review. Macronutrient supplementationSix trials assessed the provision of free food, or high-energy supplements. Only two trials measured total dietary intake, and in both trials the intervention increased calorie consumption compared to controls.The available trials were too small to reliably prove or exclude clinically important benefits on mortality (RR 0.34, 95% CI 0.10 to 1.20; four trials, 567 participants, very low quality evidence), cure (RR 0.91, 95% CI 0.59 to 1.41; one trial, 102 participants, very low quality evidence), or treatment completion (data not pooled; two trials, 365 participants, very low quality evidence).Supplementation probably produces a modest increase in weight gain during treatment for active tuberculosis, although this was not seen consistently across all trials (data not pooled; five trials, 883 participants, moderate quality evidence). Two small studies provide some evidence that quality of life may also be improved but the trials were too small to have much confidence in the result (data not pooled; two trials, 134 participants, low quality evidence). Micronutrient supplementationSix trials assessed multi-micronutrient supplementation in doses up to 10 times the dietary reference intake, and 18 trials assessed single or dual micronutrient supplementation.Routine multi-micronutrient supplementation may have little or no effect on mortality in HIV-negative people with tuberculosis (RR 0.86, 95% CI 0.46 to 1.6; four trials, 1219 participants, low quality evidence), or HIV-positive people who are not taking antiretroviral therapy (RR 0.92, 95% CI 0.69 to 1.23; three trials, 1429 participants, moderate quality evidence). There is insufficient evidence to know if supplementation improves cure (no trials), treatment completion (RR 0.99, 95% CI 0.95 to 1.04; one trial, 302 participants, very low quality evidence), or the proportion of people who remain sputum positive during the first eight weeks (RR 0.92, 95% CI 0.63 to 1.35; two trials, 1020 participants, very low quality evidence). However, supplementation may have little or no effect on weight gain during treatment (data not pooled; five trials, 2940 participants, low quality evidence), and no studies have assessed the effect on quality of life.Plasma levels of vitamin A appear to increase following initiation of tuberculosis treatment regardless of supplementation. In contrast, supplementation probably does improve plasma levels of zinc, vitamin D, vitamin E, and selenium, but this has not been shown to have clinically important benefits. Of note, despite multiple studies of vitamin D supplementation in different doses, statistically significant benefits on sputum conversion have not been demonstrated. AUTHORS' CONCLUSIONS: There is currently insufficient research to know whether routinely providing free food, or energy supplements improves tuberculosis treatment outcomes, but it probably improves weight gain in some settings.Although blood levels of some vitamins may be low in people starting treatment for active tuberculosis, there is currently no reliable evidence that routinely supplementing above recommended daily amounts has clinical benefits.

Different Risk of Tuberculosis and Efficacy of Isoniazid Prophylaxis in Rheumatoid Arthritis Patients with Biologic Therapy: A Nationwide Retrospective Cohort Study in Taiwan.

Increasing evidence indicates an increased risk of tuberculosis (TB) for rheumatoid arthritis (RA) patients receiving biologic therapy, and the effectiveness of isoniazid prophylaxis (INHP) in TB prevention. We aimed to examine 1) the incidence rate (IR) and risk factors for TB among RA patients receiving different therapies; 2) INHP effectiveness for TB prevention; 3) mortality rates after TB diagnosis in patients receiving different therapies. This retrospective study was conducted using a nationwide database: 168,720 non-RA subjects and a total of 42,180 RA patients including 36,162 csDMARDs-exposed, 3,577 etanercept-exposed, 1,678 adalimumab-exposed and 763 rituximab-exposed patients. TB risk was 2.7-fold higher in RA cohort compared with non-RA group, with an adjusted hazard ratio (aHR) of 2.58. Advanced age, male, the use of corticosteroids ≧ 5 mg/day, and the presence of diabetes mellitus (DM), chronic obstructive pulmonary disease and chronic kidney disease were risk factors for developing TB. Using csDMARDs-exposed group as reference, aHR of TB was the highest with adalimumab treatment (1.52), followed by etanercept (1.16), and the lowest with rituximab (0.08). INHP could effectively reduce TB risk in biologics-exposed patients. Mortality rates after TB diagnosis were higher in RA patients, particularly the elderly and those with DM, with lower rates in adalimumab-exposed patients compared with csDMARDs-exposed patients. In conclusion, TB risk was increased in patients receiving TNF-α inhibitors, but the risk associated with rituximab therapy was relatively low. With the effectiveness of INHP shown in the prevention of biologics-associated TB, stricter implementation of INHP should be beneficial. The mortality from biologics-associated TB may be efficiently reduced through increased awareness.

Moxifloxacin and gatifloxacin for initial therapy of tuberculosis: a meta-analysis of randomized clinical trials.

Moxifloxacin (MOX) and gatifloxacin (GAT) have exhibited promising mycobactericidal activity, and a number of clinical trials have been conducted in recent decades to compare the treatment efficacy of MOX-containing and/or GAT-containing regimens with the standard regimen. The aim of this meta-analysis for clinical trials of MOX- or GAT-containing regimens was to evaluate their treatment efficacy and safety in initial therapy for drug-sensitive tuberculosis (TB). Databases were searched for randomized controlled trials, and nine studies with 6980 patients were included. We found that fluoroquinolone substitution for isoniazid or ethambutol in short-course regimens might result in more frequent unfavorable treatment outcomes compared with the standard regimen-in particular, an increased incidence of relapse. In a per-protocol analysis, MOX-containing regimens had slightly higher rates of sputum culture conversion at two months than the standard regimen (RR 1.08, 95% CI 1.04-1.11, P <0.001); there was no significant difference in the rate of sputum conversion between the GAT-containing regimens and the standard regimen (RR 1.13, 95% CI 0.96-1.33, P = 0.13). There were no significant differences in the incidence of death from any cause, including TB, nor were there serious adverse events between the MOX- or GAT-containing regimens and the standard regimen. In conclusion, MOX or GAT might not have the ability to shorten treatment duration in the initial therapy for tuberculosis despite the non-inferiority or even slightly better efficacy in the early phase of treatment compared with the standard regimen. Furthermore, it is safe to include MOX or GAT in initial TB treatment.

Dietary pyridoxine controls efficacy of vitamin B6-auxotrophic tuberculosis vaccine bacillus Calmette-Guérin ΔureC::hly Δpdx1 in mice.

UNLABELLED: The only tuberculosis (TB) vaccine in use today, bacillus Calmette-Guérin (BCG), provides insufficient protection and can cause adverse events in immunocompromised individuals, such as BCGosis in HIV(+) newborns. We previously reported improved preclinical efficacy and safety of the recombinant vaccine candidate BCG ΔureC::hly, which secretes the pore-forming listeriolysin O of Listeria monocytogenes. Here, we evaluate a second-generation construct, BCG ΔureC::hly Δpdx1, which is deficient in pyridoxine synthase, an enzyme that is required for biosynthesis of the essential cofactor vitamin B6. This candidate was auxotrophic for vitamin B6 in a concentration-dependent manner, as was its survival in vivo. BCG ΔureC::hly Δpdx1 showed markedly restricted dissemination in subcutaneously vaccinated mice, which was ameliorated by dietary supplementation with vitamin B6. The construct was safer in severe combined immunodeficiency mice than the parental BCG ΔureC::hly. A prompt innate immune response to vaccination, measured by secretion of interleukin-6, granulocyte colony-stimulating factor, keratinocyte cytokine, and macrophage inflammatory protein-1α, remained independent of vitamin B6 administration, while acquired immunity, notably stimulation of antigen-specific CD4 T cells, B cells, and memory T cells, was contingent on vitamin B6 administration. The early protection provided by BCG ΔureC::hly Δpdx1 in a murine Mycobacterium tuberculosis aerosol challenge model consistently depended on vitamin B6 supplementation. Prime-boost vaccination increased protection against the canonical M. tuberculosis H37Rv laboratory strain and a clinical isolate of the Beijing/W lineage. We demonstrate that the efficacy of a profoundly attenuated recombinant BCG vaccine construct can be modulated by external administration of a small molecule. This principle fosters the development of safer vaccines required for immunocompromised individuals, notably HIV(+) infants. IMPORTANCE: Mycobacterium tuberculosis can synthesize the essential cofactor vitamin B6, while humans depend on dietary supplementation. Unlike the lipophilic vitamins A, D, and E, water-soluble vitamin B6 is well tolerated at high doses. We generated a vitamin B6 auxotroph of the phase II clinical tuberculosis vaccine candidate bacillus Calmette-Guérin ΔureC::hly. The next-generation candidate was profoundly attenuated compared to the parental strain. Adaptive immunity and protection in mice consistently depended on increased dietary vitamin B6 above the daily required dose. Control of vaccine efficacy via food supplements such as vitamin B6 could provide a fast track toward improved safety. Safer vaccines are urgently needed for HIV-infected individuals at high risk of adverse events in response to live vaccines.

The influence of integrated tuberculosis and human immunodeficiency virus service delivery on patient outcomes.

SETTING: Public health clinics in Cape Town, South Africa. OBJECTIVE: To examine the influence of integrated tuberculosis (TB) and human immunodeficiency virus (HIV) service delivery on mortality, TB cure and successful treatment completion and loss to follow-up of TB-HIV co-infected patients on concurrent anti-tuberculosis and antiretroviral treatment (ART). DESIGN: A survey instrument was used to measure the degree to which TB and HIV services were jointly delivered, and patient data were collected retrospectively from clinic sites and the Department of Health. Six domains measuring integrated TB and HIV service delivery were modelled to assess their relationship with patient outcomes. RESULTS: Two domains, integrated TB and ART service delivery and the delivery of TB and HIV care by one clinical team, were associated with lowered odds of death. Care by the same clinical team was also associated with reduced loss to follow-up. CONCLUSION: Overall, these findings show that the organization and delivery of health services are important factors that influence health outcomes. These findings strongly support efforts by local governments to integrate TB and ART services, and may help to alleviate concerns that restructuring of TB programs could have a negative impact on long-standing gains.

Impact of integrating HIV and TB care and treatment in a regional tuberculosis hospital in rural Guatemala.

Resource-limited settings have made slow progress in integrating TB and HIV care for co-infected patients. We examined the impact of integrated TB/HIV care on clinical and survival outcomes in rural western Guatemala. Prospective data from 254 newly diagnosed TB/HIV patients (99 enrolled in the pre-integrated program from August 2005 to July 2006, and 155 enrolled in the integrated program from February 2008 to January 2009) showed no significant baseline differences between clients in the two periods. They were principally male (65.5 %), Mayan (71 %), median age 33 years, and CD4 count averaged 111 cells/mm³. TB/HIV co-infected patients were more likely to receive antiretroviral therapy in the integrated program than in the pre-integrated program (72 vs. 22 %, respectively) and had lower mortality (HR 0.22, 95 % CI 0.14­0.33). This study shows how using a TB setting as the entry point for integrated TB/HIV care can improve health outcomes for HIV-positive patients in rural Guatemala.

Methadone treatment improves tuberculosis treatment among hospitalized opioid dependent patients in Ukraine.

BACKGROUND: Ukraine's volatile syndemics of tuberculosis (TB) and HIV among people who inject drugs (PWIDs) introduces numerous treatment challenges for each condition, including high mortality and development of multi-drug resistant TB (MDR-TB). METHODS: A prospective, non-randomized 90-day observational study was conducted in six Ukrainian TB treatment sites to assess the effectiveness of integrating methadone maintenance (MMT) with TB treatment using: (1) 90-day TB treatment retention; (2) time to treatment discontinuation; (3) TB medication adherence; and (4) subject disposition, including mortality. Of the 110 participants enrolled, 57 received MMT and 53 did not (non-MMT). RESULTS: All of the primary outcomes were significantly better in MMT versus non-MMT groups, including 90-day TB treatment completion (89.5% versus 73.6%; p=0.031), time to TB treatment discontinuation (p=0.039) and TB medication adherence (97.1% versus 86.2%; p<0.001) after controlling for death. The major reasons for treatment non-completion in the non-MMT group included death (N=3), administrative discharge from the clinic (N=5), loss to follow-up (N=2), and arrest (N=4). Overall, 90-day mortality was high (8.2%). After controlling for covariates differing between the two groups at baseline, the only independent predictor of completing 90 days of TB treatment was receipt of MMT in an integrated treatment setting (AOR=3.05; 95% CI 1.08-8.66). CONCLUSIONS: MMT integrated into inpatient TB treatment significantly improves retention in TB treatment and TB medication adherence among PWIDs. These findings call for policy change to increase the number of MMT sites in TB facilities and make MMT a low-threshold treatment option for opioid dependence in Ukraine.