A pharmacometric multistate model for predicting long-term treatment outcomes of patients with pulmonary TB.

BACKGROUND: Studying long-term treatment outcomes of TB is time-consuming and impractical. Early and reliable biomarkers reflecting treatment response and capable of predicting long-term outcomes are urgently needed. OBJECTIVES: To develop a pharmacometric multistate model to evaluate the link between potential predictors and long-term outcomes. METHODS: Data were obtained from two Phase II clinical trials (TMC207-C208 and TMC207-C209) with bedaquiline on top of a multidrug background regimen. Patients were typically followed throughout a 24 week investigational treatment period plus a 96 week follow-up period. A five-state multistate model (active TB, converted, recurrent TB, dropout, and death) was developed to describe observed transitions. Evaluated predictors included patient characteristics, baseline TB disease severity and on-treatment biomarkers. RESULTS: A fast bacterial clearance in the first 2 weeks and low TB bacterial burden at baseline increased probability to achieve conversion, whereas patients with XDR-TB were less likely to reach conversion. Higher estimated mycobacterial load at the end of 24 week treatment increased the probability of recurrence. At 120 weeks, the model predicted 55% (95% prediction interval, 50%-60%), 6.5% (4.2%-9.0%) and 7.5% (5.2%-10%) of patients in converted, recurrent TB and death states, respectively. Simulations predicted a substantial increase of recurrence after 24 weeks in patients with slow bacterial clearance regardless of baseline bacterial burden. CONCLUSIONS: The developed multistate model successfully described TB treatment outcomes. The multistate modelling framework enables prediction of several outcomes simultaneously, and allows mechanistically sound investigation of novel promising predictors. This may help support future biomarker evaluation, clinical trial design and analysis.

Construction and validation of a predictive model of mortality of tuberculosis-destroyed lung patients requiring mechanical ventilation: A single-center retrospective cohort study.

The mortality rate for intensive care unit tuberculosis-destroyed lung (TDL) patients requiring mechanical ventilation (MV) remains high. We conducted a retrospective analysis of adult TDL patients requiring MV who were admitted to the intensive care unit of a tertiary infectious disease hospital in Chengdu, Sichuan Province, China from January 2019 to March 2023. Univariate and multivariate COX regression analyses were conducted to determine independent patient prognostic risk factors that were used to construct a predictive model of patient mortality. A total of 331 patients were included, the median age was 63.0 (50.0-71.0) years, 262 (79.2%) were males and the mortality rate was 48.64% (161/331). Training and validation data sets were obtained from 245 and 86 patients, respectively. Analysis of the training data set revealed that body mass index <18.5 kg/m2, blood urea nitrogen ≥7.14 mmol/L and septic shock were independent risk factors for increased mortality of TDL patients requiring MV. These variables were then used to construct a risk-based model for predicting patient mortality. Area under curve, sensitivity, and specificity values obtained using the model for the training data set were 0.808, 79.17%, and 68.80%, respectively, and corresponding values obtained using the validation data set were 0.876, 95.12%, and 62.22%, respectively. Concurrent correction curve and decision curve analyses confirmed the high predictive ability of the model, indicating its potential to facilitate early identification and classification-based clinical management of high-risk TDL patients requiring MV.

Effect of Cost-Exemption Policy on Treatment Interruption in Patients With Newly Diagnosed Pulmonary Tuberculosis in South Korea.

BACKGROUND: In 2021, South Korea had the highest incidence rate (49 per 100 000 population) and the third highest mortality rate (3.8 per 100 000 population) due to pulmonary tuberculosis (TB) among Organization for Economic Co-operation and Development countries. Notably, premature interruption of TB treatment interferes with TB control efforts. Therefore, we examined the effect of the co-payment waiver on treatment interruption and mortality among patients with pulmonary TB in South Korea. METHODS: Patients who had newly treated TB in South Korea from 2013 to 2019 were selected from the nationwide data of the entire Korean National Health Insurance Service (NHIS) population. The effects of policy implementation on treatment adherence and mortality rates depending on treatment interruption history were evaluated. RESULTS: In total, 73 116 and 1673 patients with drug-susceptible (DS) and multidrug-resistant (MDR) pulmonary TB, respectively, were included in the final study population. After implementing the cost-exemption policy, the treatment interruption rate tended to decrease in the continuation phase in the DS-TB group (slope change: -0.097, P=.011). However, it increased in the intensive phase in the MDR-TB group (slope change: 0.733, P=.001). MDR-TB patients were likely to experience an interruption of TB treatment (adjusted odds ratio [aOR], 6.04; 95% CI, 5.43-6.71), and treatment interruption history was a significant risk factor for 1-year and overall mortality rates (adjusted hazard ratios [aHRs]: 2.01, 95% CI, 1.86-2.18 and 1.77, 95% CI, 1.70-1.84, respectively) in the DS-TB group. CONCLUSION: Implementing the cost-exemption policy effectively reduced the treatment interruption rate among patients with DS pulmonary TB.

Epidemiology and molecular characterization of Mycobacterium tuberculosis including a drug-resistant strain associated with mortality of Asian elephants in Nepal 2019-2022.

Tuberculosis (TB) is an emerging threat to the survival of elephants in Nepal. We investigated the lung tissue samples from nine elephants that died from 2019 to 2022 in Nepal using culture, conventional PCR, and loop-mediated isothermal amplification (LAMP) and then performed genotyping of five PCR-positive isolates to understand the possible transmission dynamics of Mycobacterium tuberculosis (Mtb). Results showed that two-thirds (6/9) of elephants were confirmed to be infected from Mtb by LAMP, 5/9 by PCR, and 4/9 by culture. Genotyping of Mtb isolates showed that elephants were infected with the Indo-Oceanic and Beijing lineages including an isoniazid-resistant Beijing lineage. MIRU-VNTR-based phylogeny, gyrA, and katG sequencing showed the possibility of ongoing transmission of Indo-Oceanic lineages and likely transmission of the drug-resistant Beijing lineage from human to elephant. Implementation of comprehensive surveillance and preventive measures are urgently needed to address this zoonotic disease and protect elephants from TB in Nepal.

Factors Associated With Unfavorable Treatment Outcomes Among Persons With Pulmonary Tuberculosis: A Multicentric Prospective Cohort Study From India.

In this prospective cohort of 2006 individuals with drug-susceptible tuberculosis in India, 18% had unfavorable treatment outcomes (4.7% treatment failure, 2.5% recurrent infection, 4.1% death, 6.8% loss to follow-up) over a median 12-month follow-up period. Age, male sex, low education, nutritional status, and alcohol use were predictors of unfavorable outcomes.

The levels of soluble CD137 are increased in tuberculosis patients and associated with disease severity and prognosis.

Tuberculosis (TB) was the leading cause of death from a single infectious agent before the coronavirus pandemic. Therefore, it is important to search for severity biomarkers and devise appropriate therapies. A total of 139 pulmonary TB (PTB) patients and 80 healthy controls (HCs) were recruited for plasma soluble CD137 (sCD137) detection through ELISA. Moreover, pleural effusion sCD137 levels were measured in 85 TB patients and 36 untreated lung cancer patients. The plasma cytokine levels in 64 patients with PTB and blood immune cell subpopulations in 68 patients with PTB were analysed via flow cytometry. Blood sCD137 levels were higher in PTB patients (p = 0.012) and correlated with disease severity (p = 0.0056). The level of sCD137 in tuberculous pleurisy effusion (TPE) was markedly higher than that in malignant pleurisy effusion (p = 0.018). Several blood cytokines, such as IL-6 (p = 0.0147), IL-8 (p = 0.0477), IP-10 (p ≤ 0.0001) and MCP-1 (p = 0.0057), and some laboratory indices were significantly elevated in severe PTB (SE) patients, but the percentages of total lymphocytes (p = 0.002) and cytotoxic T cells (p = 0.036) were significantly lower in SE patients than in non-SE patients. In addition, the sCD137 level was negatively correlated with the percentage of total lymphocytes (p = 0.0008) and cytotoxic T cells (p = 0.0021), and PTB patients with higher plasma sCD137 levels had significantly shorter survival times (p = 0.0041). An increase in sCD137 is a potential biomarker for severe TB and indicates a poor prognosis.

High all-cause mortality and increasing proportion of older adults with tuberculosis in Texas, 2008-2020.

Pulmonary tuberculosis (PTB) elimination efforts must consider the global growth of the ageing population. Here we used TB surveillance data from Texas, United States (2008-2020; total n = 10656) to identify unique characteristics and outcomes in older adults (OA, ≥65 years) with PTB, compared to young adults (YA, 18-39 years) or middle-aged adults (40-64 years). We found that the proportion of OA with PTB increased from 15% in 2008 to 24% in 2020 (trend p < 0.05). Diabetes was highly prevalent in OA (32%) but not associated with adverse outcomes. Death was 13-fold higher in OA compared to YA and was 7% at the time of diagnosis which suggests diagnostic delays. However, once TB was suspected, we found no differences in culture, smear, or nucleic acid detection of mycobacteria (although less lung cavitations) in OA. During treatment, OA had less drug-resistant TB, few adverse reactions and adhered with TB treatment. We recommend training healthcare workers to 'think TB' in OA, for prompt treatment initiation to diminish deaths. Furthermore, OA should be added as a priority group to the latent TB treatment guidelines by the World Health Organization, to prevent TB disease in this highly vulnerable group.

A retrospective study on intracranial mixed infection with tuberculous meningitis in Shenzhen, China.

Tuberculous meningitis (TBM) is a prevalent global intracranial infection and the most lethal and disabling form of tuberculosis. TBM with mixed intracranial infections is clinically rare but has a higher mortality rate. To investigate the clinical characteristics of TBM with mixed intracranial infections, demographic and clinical data of TBM and pulmonary tuberculosis (PTB) patients admitted to Shenzhen Third People's Hospital between January 2015 and October 2022 were collected anonymously. A total of 207 cases of TBM were diagnosed, of which 16 cases (7.73%) were TBM with mixed intracranial infections. The overall mortality rate of TBM cases was 16.4%, while the mortality rate of TBM cases with mixed intracranial infections was as high as 35.7%. Compared to simple TBM cases, TBM cases with mixed intracranial infections had severer clinical symptoms. The percentage of human immune deficiency virus (HIV)-positive TBM cases with mixed intracranial infections reached up to 68.8%. HIV co-infection, CD4+/CD8+ T-cell counts less than 1, cranial nerve impairment, paralysis, cerebral infarction, PRO less than 450 mg/L, WBC less than 10 × 106 /L, and CL more than 120 mmol/L were risk factors for TBM cases with mixed intracranial infections. Compared to PTB, HIV co-infection, CD4+ T cell less than 550 /uL, and age less than 45 years were risk factors for TBM, and TBM was associated with higher mortality rates. Our study provides additional data to better understand single TBM and TBM with mixed intracranial infections. More than two-thirds of TBM cases with mixed intracranial infections were HIV-positive. Clinicians should consider the possibility of multiple infections in people with TBM/HIV co-infection. IMPORTANCE: TBM can cause severe neurological damage and death, and TBM with mixed intracranial infections can exacerbate the damage and poor prognosis of the disease. TBM with mixed intracranial infections is a rare disease, which has led to an incomplete understanding of its clinical features. This study investigated the clinical features of TBM and its associated factors by comparing the characteristics of TBM with mixed intracranial infections, single TBM and pulmonary tuberculosis. This information will help to improve the understanding of TBM, diagnostic accuracy and treatment outcomes.

Subclinical tuberculosis: a meta-analysis of prevalence and scoping review of definitions, prevalence and clinical characteristics.

BACKGROUND: This scoping review aimed to characterise definitions used to describe subclinical tuberculosis (TB), estimate the prevalence in different populations and describe the clinical characteristics and treatment outcomes in the scientific literature. METHODS: A systematic literature search was conducted using PubMed. We included studies published in English between January 1990 and August 2022 that defined "subclinical" or "asymptomatic" pulmonary TB disease, regardless of age, HIV status and comorbidities. We estimated the weighted pooled proportions of subclinical TB using a random-effects model by World Health Organization reported TB incidence, populations and settings. We also pooled the proportion of subclinical TB according to definitions described in published prevalence surveys. RESULTS: We identified 29 prevalence surveys and 71 other studies. Prevalence survey data (2002-2022) using "absence of cough of any duration" criteria reported higher subclinical TB prevalence than those using the stricter "completely asymptomatic" threshold. Prevalence estimates overlap in studies using other symptoms and cough duration. Subclinical TB in studies was commonly defined as asymptomatic TB disease. Higher prevalence was reported in high TB burden areas, community settings and immunocompetent populations. People with subclinical TB showed less extensive radiographic abnormalities, higher treatment success rates and lower mortality, although studies were few. CONCLUSION: A substantial proportion of TB is subclinical. However, prevalence estimates were highly heterogeneous between settings. Most published studies incompletely characterised the phenotype of people with subclinical TB. Standardised definitions and diagnostic criteria are needed to characterise this phenotype. Further research is required to enhance case finding, screening, diagnostics and treatment options for subclinical TB.

Sociodemographic and clinical risk factors associated with in-hospital tuberculosis mortality in Türkiye, 2008-2018.

Introduction: Tuberculosis (TB) is an infectious disease that can be fatal if left untreated or poorly treated, and it is associated with many morbidities. Deaths may provide better understanding of the associated factors and help guide interventions to reduce mortality. In this study, it was aimed to reveal some of the features that predict hospital mortality in patients with TB and to present some alarming findings for clinicians. Materials and Methods: Patients who had been hospitalized with the diagnosis of TB between January 2008 and December 2018 were included and analyzed retrospectively. In-hospital mortality because of any TB disease after the initiation of treatment in patients admitted to the TB Ward and the primary cause of mortality were taken as endpoint. Result: A total of 1321 patients with a mean age of 50.1 years were examined. Total mortality was 39.4% (521 deaths) and 13.1% were in-hospital deaths (173 deaths). Of the deaths, 61.8% (n= 107) occurred during the first month after TB treatment were started. On univariate analysis, age over 48.5 years, Charlson comorbidity index, extension of radiological involvement, hypoalbuminemia and lymphopenia were most predictive variables with higher odds ratios (respectively, p<0.001 for all). Conclusions: In-hospital tuberculosis disease mortality is related with older age, cavitary or extensive pulmonary involvement, low albumin levels, unemployment, cigarette smoking and especially those with concomitant malignancy and chronic pulmonary disease.

Death after cure: Mortality among pulmonary tuberculosis survivors in rural Uganda.

OBJECTIVES: To determine the incidence of mortality and its predictors among pulmonary tuberculosis (PTB) survivors treated at a rural Ugandan tertiary hospital. METHODS: We conducted a retrospective chart review of data between 2013 and 2023. We included all people that met the World Health Organisation's definition of tuberculosis cure and traced them or their next of kin to determine vital status (alive/deceased). We estimated the cumulative incidence of mortality per 1000 population, crude all-cause mortality rate per 1000 person-years, and median years of potential life lost for deceased individuals. Using Cox proportional hazard models, we investigated predictors of mortality. RESULTS: Of 334 PTB survivors enrolled, 38 (11.4%) had died. The cumulative incidence of all-cause mortality was 113.7 per 1000 population, and the crude all-cause mortality rate was 28.5 per 1000 person-years. The median years of potential life lost for deceased individuals was 23.8 years (IQR: 9.6-32.8). Hospitalization (adjusted hazard ratio (aHR): 4.3, 95% CI: 1.1-16.6) and unemployment (aHR: 7.04, 95% CI: 1.5-31.6) at TB treatment initiation predicted mortality. CONCLUSION: PTB survivors experience post high mortality rates after TB cure. Survivors who were hospitalized and unemployed at treatment initiation were more likely to die after cure. Social protection measures and long-term follow-up of previously hospitalized patients could improve the long-term survival of TB survivors.

Effect of complicated, untreated and uncontrolled diabetes and pre-diabetes on treatment outcome among patients with pulmonary tuberculosis.

BACKGROUND AND OBJECTIVE: Patients with tuberculosis and diabetes have a higher risk of unfavourable anti-tuberculosis treatment outcomes. In the present study, we aimed to evaluate the effects of various diabetes statuses on the outcomes of patients with pulmonary tuberculosis. METHODS: Among the patients with pulmonary tuberculosis enrolled in the Korea Tuberculosis Cohort (KTBC) registry and the multicentre prospective cohort study of pulmonary tuberculosis (COSMOTB), those with diabetes and complicated diabetes were identified. The primary and secondary outcomes were unfavourable outcomes and mortality, respectively. The effect of diabetes and complicated diabetes on the outcomes was assessed using multivariable logistic regression analysis. Using COSMOTB, subgroup analyses were performed to assess the association between various diabetes statuses and outcomes. RESULTS: In the KTBC, diabetes (adjusted odds ratio [aOR] = 1.93, 95% CI = 1.64-2.26) and complicated diabetes (aOR = 1.96, 95% CI = 1.67-2.30) were significantly associated with unfavourable outcomes, consistent with the COSMOTB data analysis. Based on subgroup analysis, untreated diabetes at baseline was an independent risk factor for unfavourable outcomes (aOR = 2.72, 95% CI = 1.26-5.61). Prediabetes and uncontrolled diabetes increased unfavourable outcomes and mortality without statistical significance. CONCLUSION: Untreated and complicated diabetes at the time of tuberculosis diagnosis increases the risk of unfavourable outcomes and mortality.

Admissions by tuberculosis in a regional reference Center. A complex and worrying scenario / Ingresos por tuberculosis en un hospital regional. Un escenario complejo y preocupante

OBJECTIVES: To characterize clinical aspects, evaluate the diagnostic opportunity, and identify factors associated with mortality in patients hospitalized for tuberculosis (TB). METHODS: Retrospective study of patients admitted for TB to a Regional Hospital in Chile between 2011 and 2019. RESULTS: 142 TB events required hospitalization in this period (38.2% of total cases). All risk groups were identified, with a significant increase in patients with diabetes mellitus. The pulmonary location was the most frequent (71.1%), followed by disseminated forms (16.2%). The sensitivity of microscopy smear in cases of pulmonary TB (isolated or combined) was 78.8% and lower in cases of bronchoalveolar lavage (58.3%). PCR was only occasionally applied (< 10%) with a sensitivity of 100% in sputum samples. Its use increased progressively and reached a positivity of 33% (6 out of 18 cases) in cases with negative sputum staining. The median time between symptom onset and diagnosis was prolonged (9 weeks), and 32.5% of all regional events were diagnosed at the hospital. Dose adjustments (22.1%), corticosteroid use (25%), and treatment interruptions were frequent (11%). Lethality reached 19%, and by multivariate analysis, only shock was associated with a fatal outcome. CONCLUSIONS: In this case series, the diagnosis of TB cases was delayed, scarcely diagnosed by molecular methods, highly concentrated at the hospital level, required admission in a large percentage of cases, and had a high case-fatality rate.

OBJETIVOS: Caracterizar aspectos clínicos, evaluar la oportunidad diagnóstica e identificar factores asociados a mortalidad en pacientes ingresados por tuberculosis (TB). MÉTODOS: Estudio retrospectivo de pacientes ingresados por TB a un Hospital Regional en Chile entre el 2011 y 2019. RESULTADOS: Un total de 142 eventos de TB requirieron hospitalización en el período (38,2% del total). Todos los grupos de riesgo fueron identificados con un aumento significativo de los pacientes con diabetes mellitus. La localización pulmonar fue la más frecuente (71,1%), seguida de la forma diseminada (2 o más sitios; 16,2%). La sensibilidad de la tinción de expectoración en casos de TB pulmonar (aislada o combinada) fue de 78,8% y más baja en casos de lavado broncoalveolar (58,3%). La PCR fue sólo ocasionalmente aplicada (< 10%) con una sensibilidad del 100% en muestras de expectoración. Su uso aumentó progresivamente en el período y el incremento diagnóstico de TB en casos con tinción negativa de expectoración estudiados con PCR fue de 33% (6 de 18 casos). La mediana entre inicio de síntomas y el diagnóstico fue prolongada (9 semanas) y el 32,5% de los eventos regionales fueron diagnosticados en el hospital. Los ajustes de dosis (22,1%), uso de corticoides (25%) e interrupciones del tratamiento fueron hechos frecuentes (11%). La letalidad alcanzó 19% y en el análisis multivariado sólo la aparición de shock se asoció a un desenlace fatal. CONCLUSIONES: En esta serie de casos, el diagnóstico de casos de TB fue tardío, infrecuentemente diagnosticado por métodos moleculares, concentrado en la atención terciaria, requirió hospitalización en un gran porcentaje de casos y tuvo una elevada letalidad.

Admissions by tuberculosis in a regional reference Center. A complex and worrying scenario.

OBJECTIVES: To characterize clinical aspects, evaluate the diagnostic opportunity, and identify factors associated with mortality in patients hospitalized for tuberculosis (TB). METHODS: Retrospective study of patients admitted for TB to a Regional Hospital in Chile between 2011 and 2019. RESULTS: 142 TB events required hospitalization in this period (38.2% of total cases). All risk groups were identified, with a significant increase in patients with diabetes mellitus. The pulmonary location was the most frequent (71.1%), followed by disseminated forms (16.2%). The sensitivity of microscopy smear in cases of pulmonary TB (isolated or combined) was 78.8% and lower in cases of bronchoalveolar lavage (58.3%). PCR was only occasionally applied (< 10%) with a sensitivity of 100% in sputum samples. Its use increased progressively and reached a positivity of 33% (6 out of 18 cases) in cases with negative sputum staining. The median time between symptom onset and diagnosis was prolonged (9 weeks), and 32.5% of all regional events were diagnosed at the hospital. Dose adjustments (22.1%), corticosteroid use (25%), and treatment interruptions were frequent (11%). Lethality reached 19%, and by multivariate analysis, only shock was associated with a fatal outcome. CONCLUSIONS: In this case series, the diagnosis of TB cases was delayed, scarcely diagnosed by molecular methods, highly concentrated at the hospital level, required admission in a large percentage of cases, and had a high case-fatality rate.

Impact of pathobiological diversity of Mycobacterium tuberculosis on clinical features and lethal outcome of tuberculosis.

BACKGROUND: Mycobacterium tuberculosis population in Russia is dominated by the notorious Beijing genotype whose major variants are characterized by contrasting resistance and virulence properties. Here we studied how these strain features could impact the progression of pulmonary tuberculosis (TB) concerning clinical manifestation and lethal outcome. RESULTS: The study sample included 548 M. tuberculosis isolates from 548 patients with newly diagnosed pulmonary TB in Omsk, West Siberia, Russia. Strains were subjected to drug susceptibility testing and genotyping to detect lineages, sublineages, and subtypes (within Beijing genotype). The Beijing genotype was detected in 370 (67.5%) of the studied strains. The strongest association with multidrug resistance (MDR) was found for epidemic cluster Beijing B0/W148 (modern sublineage) and two recently discovered MDR clusters 1071-32 and 14717-15 of the ancient Beijing sublineage. The group of patients infected with hypervirulent and highly lethal (in a mouse model) Beijing 14717-15 showed the highest rate of lethal outcome (58.3%) compared to Beijing B0/W148 (31.4%; P = 0.06), Beijing Central Asian/Russian (29.7%, P = 0.037), and non-Beijing (15.2%, P = 0.001). The 14717-15 cluster mostly included isolates from patients with infiltrative but not with fibrous-cavernous and disseminated TB. In contrast, a group infected with low virulent 1071-32-cluster had the highest rate of fibrous-cavernous TB, possibly reflecting the capacity of these strains for prolonged survival and chronicity of the TB process. CONCLUSIONS: The group of patients infected with hypervirulent and highly lethal in murine model 14717-15 cluster had the highest proportion of the lethal outcome (58.3%) compared to the groups infected with Beijing B0/W148 (31.4%) and non-Beijing (15.2%) isolates. This study carried out in the TB high-burden area highlights that not only drug resistance but also strain virulence should be considered in the implementation of personalized TB treatment.

Risk factors for early TB treatment interruption among newly diagnosed patients in Malaysia.

TB treatment interruption has resulted in delayed sputum conversion, drug resistance, and a high mortality rate and a prolonged treatment course, hence leading to economic and psychosocial affliction. To date, there are limited studies investigating the physico-social risk factors for early treatment interruptions. This prospective multicenter cohort study aimed to investigate the risk factors for early treatment interruption among new pulmonary tuberculosis (TB) smear-positive patients in Selangor, Malaysia. A total of 439 participants were recruited from 39 public treatment centres, 2018-2019. Multivariate Cox proportional hazard analyses were performed to analyse the risk factors for early treatment interruption. Of 439 participants, 104 (23.7%) had early treatment interruption, with 67.3% of early treatment interruption occurring in the first month of treatment. Being a current smoker and having a history of hospitalization, internalized stigma, low TB symptoms score, and waiting time spent at Directly Observed Treatment, Short-course centre were risk factors for early treatment interruption. An appropriate treatment adherence strategy is suggested to prioritize the high-risk group with high early treatment interruption. Efforts to quit smoking cessation programs and to promote stigma reduction interventions are crucial to reduce the probability of early treatment interruption.

Active pulmonary tuberculosis and coronavirus disease 2019: A systematic review and meta-analysis.

OBJECTIVE: The proportion of COVID-19 patients having active pulmonary tuberculosis, and its impact on COVID-19 related patient outcomes, is not clear. We conducted this systematic review to evaluate the proportion of patients with active pulmonary tuberculosis among COVID-19 patients, and to assess if comorbid pulmonary tuberculosis worsens clinical outcomes in these patients. METHODS: We queried the PubMed and Embase databases for studies providing data on (a) proportion of COVID-19 patients with active pulmonary tuberculosis or (b) severe disease, hospitalization, or mortality among COVID-19 patients with and without active pulmonary tuberculosis. We calculated the proportion of tuberculosis patients, and the relative risk (RR) for each reported outcome of interest. We used random-effects models to summarize our data. RESULTS: We retrieved 3,375 citations, and included 43 studies, in our review. The pooled estimate for proportion of active pulmonary tuberculosis was 1.07% (95% CI 0.81%-1.36%). COVID-19 patients with tuberculosis had a higher risk of mortality (summary RR 1.93, 95% CI 1.56-2.39, from 17 studies) and for severe COVID-19 disease (summary RR 1.46, 95% CI 1.05-2.02, from 20 studies), but not for hospitalization (summary RR 1.86, 95% CI 0.91-3.81, from four studies), as compared to COVID-19 patients without tuberculosis. CONCLUSION: Active pulmonary tuberculosis is relatively common among COVID-19 patients and increases the risk of severe COVID-19 and COVID-19-related mortality.

Pulmonary mycobacterial infection is associated with increased mortality in patients with acute respiratory distress syndrome.

ABSTRACT: Although pulmonary mycobacterial infection is associated with acute respiratory distress syndrome (ARDS) in critically ill patients, its clinical implication on patients with ARDS has not been clearly elucidated. The aim of study was to investigate the clinical significance of pulmonary mycobacterial infection in patients with ARDS.Between January 2014 and April 2019, medical records of 229 patients with ARDS who met the Berlin criteria and received invasive mechanical ventilation in medical intensive care unit were reviewed. Clinical characteristics and the rate of mortality between patients with and without pulmonary mycobacterial infection were compared. Factors associated with a 28-day mortality were analyzed statistically.Twenty two (9.6%) patients were infected with pulmonary mycobacteria (18 with tuberculosis and 4 with non-tuberculous mycobacteria). There were no differences in baseline characteristics, the severity of illness scores. Other than a higher rate of renal replacement therapy required in those without pulmonary mycobacterial infection, the use of adjunctive therapy did not differ between the groups. The 28- day mortality rate was significantly higher in patients with pulmonary mycobacterial infection (81.8% vs 58%, P = .019). Pulmonary mycobacterial infection was significantly associated with 28-day mortality (hazard ratio 1.852, 95% confidence interval 1.108-3.095, P = .019).Pulmonary mycobacterial infection was associated with increased 28-day mortality in patients with ARDS.

Mortality during tuberculosis treatment in South Africa using an 8-year analysis of the national tuberculosis treatment register.

In 2011, the South African HIV treatment eligibility criteria were expanded to allow all tuberculosis (TB) patients lifelong ART. The impact of this change on TB mortality in South Africa is not known. We evaluated mortality in all adults (≥ 15 years old) treated for drug-susceptible TB in South Africa between 2009 and 2016. Using a Cox regression model, we quantified risk factors for mortality during TB treatment and present standardised mortality ratios (SMR) stratified by year, age, sex, and HIV status. During the study period, 8.6% (219,618/2,551,058) of adults on TB treatment died. Older age, male sex, previous TB treatment and HIV infection (with or without the use of ART) were associated with increased hazard of mortality. There was a 19% reduction in hazard of mortality amongst all TB patients between 2009 and 2016 (adjusted hazard ratio: 0.81 95%CI 0.80-0.83). The highest SMR was in 15-24-year-old women, more than double that of men (42.3 in 2016). Between 2009 and 2016, the SMR for HIV-positive TB patients increased, from 9.0 to 19.6 in women, and 7.0 to 10.6 in men. In South Africa, case fatality during TB treatment is decreasing and further interventions to address specific risk factors for TB mortality are required. Young women (15-24-year-olds) with TB experience a disproportionate burden of mortality and interventions targeting this age-group are needed.

Impact of the diagnostic test Xpert MTB/RIF on patient outcomes for tuberculosis.

BACKGROUND: The World Health Organization (WHO) recommends Xpert MTB/RIF in place of smear microscopy to diagnose tuberculosis (TB), and many countries have adopted it into their diagnostic algorithms. However, it is not clear whether the greater accuracy of the test translates into improved health outcomes. OBJECTIVES: To assess the impact of Xpert MTB/RIF on patient outcomes in people being investigated for tuberculosis. SEARCH METHODS: We searched the following databases, without language restriction, from 2007 to 24 July 2020: Cochrane Infectious Disease Group (CIDG) Specialized Register; CENTRAL; MEDLINE OVID; Embase OVID; CINAHL EBSCO; LILACS BIREME; Science Citation Index Expanded (Web of Science), Social Sciences citation index (Web of Science), and Conference Proceedings Citation Index - Social Science & Humanities (Web of Science). We also searched the WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and the Pan African Clinical Trials Registry for ongoing trials. SELECTION CRITERIA: We included individual- and cluster-randomized trials, and before-after studies, in participants being investigated for tuberculosis. We analysed the randomized and non-randomized studies separately.  DATA COLLECTION AND ANALYSIS: For each study, two review authors independently extracted data, using a piloted data extraction tool. We assessed the risk of bias using Cochrane and Effective Practice and Organisation of Care (EPOC) tools. We used random effects meta-analysis to allow for heterogeneity between studies in setting and design.  The certainty of the  evidence in the randomized trials was assessed by GRADE. MAIN RESULTS: We included 12 studies: eight were randomized controlled trials (RCTs), and four were before-and-after studies. Most included RCTs had a low risk of bias in most domains of the Cochrane 'Risk of bias' tool. There was inconclusive evidence of an effect of Xpert MTB/RIF on all-cause mortality, both overall (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.75 to 1.05; 5 RCTs, 9932 participants, moderate-certainty evidence), and restricted to studies with six-month follow-up (RR 0.98, 95% CI 0.78 to 1.22; 3 RCTs, 8143 participants; moderate-certainty evidence). There was probably a reduction in mortality in participants known to be infected with HIV (odds ratio (OR) 0.80, 95% CI 0.67 to 0.96; 5 RCTs, 5855 participants; moderate-certainty evidence). It is uncertain whether Xpert MTB/RIF has no or a modest effect on the proportion of participants starting tuberculosis treatment who had a successful treatment outcome (OR) 1.10, 95% CI 0.96 to 1.26; 3RCTs, 4802 participants; moderate-certainty evidence). There was also inconclusive evidence of an effect on the  proportion of participants who were treated for tuberculosis (RR 1.10, 95% CI 0.98 to 1.23; 5 RCTs, 8793 participants; moderate-certainty evidence). The proportion of participants treated for tuberculosis who had bacteriological confirmation was probably higher in the Xpert MTB/RIF group (RR 1.44, 95% CI 1.29 to 1.61; 6 RCTs, 2068 participants; moderate-certainty evidence). The proportion of participants with bacteriological confirmation who were lost to follow-up pre-treatment was probably reduced (RR 0.59, 95% CI 0.41 to 0.85; 3 RCTs, 1217 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: We were unable to confidently rule in or rule out the effect on all-cause mortality of using Xpert MTB/RIF rather than smear microscopy. Xpert MTB/RIF probably reduces mortality among participants known to be infected with HIV. We are uncertain whether Xpert MTB/RIF has a modest effect or not on the proportion treated or, among those treated, on the proportion with a successful outcome. It probably does not have a substantial effect on these outcomes. Xpert MTB/RIF probably increases both the proportion of treated participants who had bacteriological confirmation, and the proportion with a laboratory-confirmed diagnosis who were treated. These findings may inform decisions about uptake alongside evidence on cost-effectiveness and implementation.

ANTECEDENTES: La Organización Mundial de la Salud (OMS) recomienda la Xpert MTB/RIF en lugar de la baciloscopia para diagnosticar la tuberculosis (TB) y muchos países la han adoptado en sus algoritmos de diagnóstico. Sin embargo, no está claro si la mayor exactitud de la prueba se traduce en mejores desenlaces de salud. OBJETIVOS: Evaluar el impacto de la Xpert MTB/RIF en los desenlaces de las personas sometidas a pruebas para la tuberculosis. MÉTODOS DE BÚSQUEDA: Se realizaron búsquedas en las siguientes bases de datos, sin restricción de idioma, desde 2007 hasta el 24 de julio de 2020: Registro especializado del Grupo Cochrane de Enfermedades infecciosas (Cochrane Infectious Disease Group [CIDG]); CENTRAL; MEDLINE OVID; Embase OVID; CINAHL EBSCO; LILACS BIREME; Science Citation Index Expanded (Web of Science), Social Sciences citation index (Web of Science), y Conference Proceedings Citation Index ­ Social Science & Humanities (Web of Science). También se buscaron ensayos en curso en la Plataforma de registros internacionales de ensayos clínicos de la OMS, en ClinicalTrials.gov y en el Pan African Clinical Trials Registry. CRITERIOS DE SELECCIÓN: Se incluyeron ensayos aleatorizados individuales y por conglomerados, y estudios tipo antes y después (before­after studie), con participantes sometidos a pruebas para la tuberculosis. Los estudios aleatorizados y no aleatorizados se analizaron por separado. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión, de forma independiente, extrajeron los datos de cada estudio mediante una herramienta de extracción de datos analizada. El riesgo de sesgo se evaluó mediante las herramientas de Cochrane y del Grupo Cochrane para una Práctica y organización sanitarias efectivas (Effective Practice and Organisation of Care [EPOC]). Se utilizó el metanálisis de efectos aleatorios para considerar la heterogeneidad entre los estudios en cuanto al contexto y el diseño. La certeza de la evidencia en los ensayos aleatorizados se evaluó mediante el método GRADE. RESULTADOS PRINCIPALES: Se incluyeron 12 estudios: ocho eran ensayos controlados aleatorizados (ECA) y cuatro eran estudios tipo antes y después. La mayoría de los ECA incluidos tenían un bajo riesgo de sesgo en la mayoría de los dominios de la herramienta Cochrane "Risk of bias". Hubo evidencia no concluyente de un efecto de la Xpert MTB/RIF sobre la mortalidad por todas las causas, tanto en general (razón de riesgos [RR] 0,89; intervalo de confianza [IC] del 95%: 0,75 a 1,05; cinco ECA, 9932 participantes, evidencia de certeza moderada), como limitada a los estudios con seguimiento de seis meses (RR 0,98; IC del 95%: 0,78 a 1,22; tres ECA, 8143 participantes; evidencia de certeza moderada). Probablemente hubo una reducción de la mortalidad en los participantes que se sabía que estaban infectados por el VIH (odds ratio [OR] 0,80; IC del 95%: 0,67 a 0,96; cinco ECA, 5855 participantes; evidencia de certeza moderada). No está claro si la Xpert MTB/RIF no tiene efectos o tiene un efecto modesto sobre la proporción de participantes que inician el tratamiento de la tuberculosis y que tienen un desenlace exitoso del tratamiento (OR 1,10; IC del 95%: 0,96 a 1,26; tres ECA, 4802 participantes; evidencia de certeza moderada). También hubo evidencia no concluyente de un efecto sobre el porcentaje de participantes que recibieron tratamiento para la tuberculosis (RR 1,10; IC del 95%: 0,98 a 1,23; cinco ECA, 8793 participantes; evidencia de certeza moderada). Es probable que la proporción de participantes tratados por tuberculosis que tuvieron confirmación bacteriológica fuera mayor en el grupo de Xpert MTB/RIF (RR 1,44; IC del 95%: 1,29 a 1,61; seis ECA, 2068 participantes; evidencia de certeza moderada). Es probable que se redujera la proporción de participantes con confirmación bacteriológica que se perdió durante el seguimiento previo al tratamiento (RR 0,59; IC del 95%: 0,41 a 0,85; tres ECA, 1217 participantes; evidencia de certeza moderada). CONCLUSIONES DE LOS AUTORES: No fue posible descartar con seguridad el efecto sobre la mortalidad por todas las causas del uso de Xpert MTB/RIF en lugar de la baciloscopia. La Xpert MTB/RIF probablemente reduce la mortalidad en los participantes que se sabe que están infectados por el VIH. No hay certeza con respecto a si la Xpert MTB/RIF tiene un efecto modesto o no en la proporción tratada o, entre los tratados, en la proporción con un desenlace exitoso. Probablemente no tenga un efecto importante sobre estos desenlaces. La Xpert MTB/RIF probablemente aumenta la proporción de participantes tratados que tenían confirmación bacteriológica, así como la de aquellos con un diagnóstico confirmado por el laboratorio que fueron tratados. Estos hallazgos podrían servir de base para las decisiones sobre la adopción de la prueba, junto con la evidencia sobre la coste­efectividad y la aplicación.