Implementation of targeted next-generation sequencing for the diagnosis of drug-resistant tuberculosis in low-resource settings: a programmatic model, challenges, and initial outcomes.

Targeted next-generation sequencing (tNGS) from clinical specimens has the potential to become a comprehensive tool for routine drug-resistance (DR) prediction of Mycobacterium tuberculosis complex strains (MTBC), the causative agent of tuberculosis (TB). However, TB mainly affects low- and middle-income countries, in which the implementation of new technologies have specific needs and challenges. We propose a model for programmatic implementation of tNGS in settings with no or low previous sequencing capacity/experience. We highlight the major challenges and considerations for a successful implementation. This model has been applied to build NGS capacity in Namibia, an upper middle-income country located in Southern Africa and suffering from a high-burden of TB and TB-HIV, and we describe herein the outcomes of this process.

Determining the Need for Additional Testing With Quantiferon TB Gold in Patients With Positive Tuberculin Skin Tests and a History of BCG Vaccination.

OBJECTIVE:  To determine if the QuantiFERON-TB Gold (QFT) testing can be obviated for the diagnosis of latent tuberculosis infection (LTBI) in patients with a positive tuberculin skin test (TST) and a history of Bacillus Calmette-Guerin (BCG) vaccination by identifying high-risk features in patients with positive TST and a history of BCG vaccination who are associated with positive QFT. METHODS:  Retrospective chart review was done for 76 adult patients by dividing them into two groups. Group 1 consisted of true positive TST patients who had BCG vaccination and were positive for QFT. Group 2 consisted of false positive TST patients who had BCG vaccination but were negative for QFT. The two groups were compared to determine if the high-risk features of TST induration diameter of 15mm and more, TST induration of 20mm and more, recent immigration to the US, the advanced age of more than 65 years, country of origin with high TB burden, known exposure to active TB, and smoking history were more prevalent in Group 1 compared to Group 2. RESULTS:  Group 1 had 23 patients and Group 2 had 53 patients. Group 1 had a higher prevalence of patients with PPD induration of more than 10mm than Group 2, which was statistically significant with a P value of 0.03. Other risk factors of advanced age, exposure to active TB and smoking did not show statistically significant differences between Groups 1 and 2.  Conclusion: This study also confirms that if the TST induration is more than 10mm in patients with a history of BCG vaccination, the TST induration is likely because of LTBI and is less likely because of cross-reaction with BCG vaccination.

Tuberculosis in migrants: epidemiology, resistance and outcome in Milan, Italy.

BACKGROUND: Human migration and the ever-changing geopolitical scenarios are redefining the epidemiology and the management of tuberculosis (TB), especially in low-TB burden countries welcoming high rates of people from high-TB burden countries. METHODS: We conducted an observational retrospective mono-centric study in a Northern-Italy TB reference centre from 1 January 1990 to 31 December 2019, focusing on the differences in epidemiology, resistance patterns and treatment outcomes between Italians and migrants with active TB. Data were collected from medical records. RESULTS: A total of 10555 patients were included, 4614 Italians and 5941 migrants. Among migrants, higher rates of rifampin-resistant (RR) or multidrug-resistant (MDR) TB were reported, as well as higher rates of loss to follow-up. Among Italians, higher mortality rates and a higher number of extrapulmonary TB cases were found. CONCLUSION: Our study describes one of the largest cohorts of patients with active TB in Italy, highlighting the need for tailored approaches in native and migrant populations.

Incidence of pulmonary tuberculosis in suburban Bissau, Guinea-Bissau between 2004 and 2020: a prospective cohort study.

OBJECTIVES: Previous studies have found declining incidence of tuberculosis (TB) in Bissau, Guinea-Bissau. This study aimed to report incidence rates of TB for the period 2004-2020, stratifying by sex, smear-status, and HIV-status, as well as describe developments in TB case fatality rate and diagnostic delay. DESIGN AND METHODS: Data from the Bandim Health Project HDSS and the TB registry from Jan 1st, 2004 to Dec 31st, 2020 were used. Incidence rates were calculated for each year and for smear-positive, smear-negative, HIV-positive, HIV-negative, and unknown HIV-status. Incidence rate ratio and test for trend were done using a one-step Newton approximation to the log-linear Poisson regression coefficient. RESULTS: Overall TB incidence declined only slightly over the period from 294 per 100,000 in 2004 to 273 in 2020. TB/HIV coinfection declined from 108 in 2004 to 14 in 2020, as did incidence among females and smear-negative cases. CONCLUSIONS: Incidence of PTB in Bissau, Guinea-Bissau is declining slowly, if at all. TB incidence among females, smear-negative TB, TB case fatality rate, and TB/HIV coinfection and diagnostic delay are declining.

Strategies to detect and manage latent tuberculosis infection among household contacts of pulmonary TB patients in high TB burden countries - a systematic review and meta-analysis.

OBJECTIVE: To summarise latent tuberculosis infection (LTBI) management strategies among household contacts of bacteriologically confirmed pulmonary tuberculosis (TB) patients in high-TB burden countries. METHODS: PubMed/MEDLINE (NCBI) and Scopus were searched (January 2006 to December 2021) for studies reporting primary data on LTBI management. Study selection, data management and data synthesis were protocol-driven (PROSPERO-CRD42021208715). Primary outcomes were the proportions of LTBI, initiating and completing tuberculosis preventive treatment (TPT). Reported factors influencing the LTBI care cascade were qualitatively synthesised. RESULTS: From 3694 unique records retrieved, 58 studies from 23 countries were included. Most identified contacts were screened (median 99%, interquartile range [IQR] 82%-100%; 46 studies). Random-effects meta-analysis yielded pooled proportions for: LTBI 41% (95% confidence interval [CI] 33%-49%; 21,566 tested contacts); TPT initiation 91% (95% CI 79%-97%; 129,573 eligible contacts, 34 studies); TPT completion 65% (95% CI 54%-74%; 108,679 TPT-initiated contacts, 28 studies). Heterogeneity was significant (I2 ≥ 95%-100%) and could not be explained in subgroup analyses. Median proportions (IQR) were: LTBI 44% (28%-59%); TPT initiation 86% (60%-100%); TPT completion 68% (44%-82%). Nine broad themes related to diagnostic testing, health system structure and functions, risk perception, documentation and adherence were considered likely to influence the LTBI care cascade. CONCLUSION: The proportions of household contacts screened, detected with LTBI and initiated on TPT, though variable was high, but the proportions completing TPT were lower indicating current strategies used for LTBI management in high TB burden countries are not sufficient.

Early detection of Pre-XDR TB with line probe assay in a high TB burden country.

BACKGROUND: Worldwide, tuberculosis (TB) is one of the top 10 causes of death. Drug resistant tuberculosis has lately become a major public health problem that threatens progress made in Tuberculosis (TB) care and control worldwide. The aim of this study was to determine the prevalence of Pre-extensive drug resistant TB among MDR TB in North Central of Nigeria. METHODS: This study was conducted from October, 2018 to August, 2019 with 150 samples. In Nigeria, guidelines for DR-TB as recommended by WHO is followed. All the samples from the patients who gave their consent were transported to a zonal reference TB laboratory (ZRL). RESULTS: Mean age was 38.6 ± 13.4 years with peak age at 35-44. Out of these 103 samples processed with LPA, 101(98%) were rifampicin resistant and 2 were rifampicin sensitive, 99(96%) were INH resistant and 4 (4%) were INH sensitive, 5(5%) were fluoroquinolone resistant, 98(95%) were fluoroquinolone sensitive, 12 (12%) were Aminoglycoside + Capreomycin resistant, 91(83%) were Aminoglycoside + Capreomycin sensitive. CONCLUSION: Multidrug resistant TB and its severe forms (Pre-extensive & extensively drug resistant TB) can be detected early with rapid tool- Line Probe Assay rapid and prevented timely by early initiation on treatment.

Treatment outcomes of extrapulmonary tuberculosis in Bahawalpur, Pakistan; a record review.

BACKGROUND: There is limited published data form Pakistan on treatment success rate among extrapulmonary tuberculosis (EPTB) patients. The aim of this study was to assess clinical form, treatment outcomes, and identify the factors associated with unfavorable treatment outcome among EPTB patients. METHODS: A retrospective study was conducted at the Chest Disease Unit of the Bahawal Victoria Hospital, Pakistan. Medical records of EPTB patients, registered at the study site from January 1, 2015 to September 30, 2017, were reviewed to obtain the data. Final treatment outcomes among EPTB patients were evaluated in accordance with the standard Word Health Organization (WHO) criteria. Multivariate binary logistic regression analysis was used to identify the factors associated with unfavorable treatment outcome. RESULTS: A total of 651 EPTB patients were included in the study. Highest proportion of patients had pleural TB (n = 217, 33.3%). Out of the total 651 patients, 463 (71.1%) successfully completed the treatment. Among 177 (27.2%) patients with unfavorable treatment outcome, 10 (1.5%) died, while 165 (25.4%) lost to follow-up the treatment. Lymph node TB (AOR 0.65, 95% CI 0.422, 0.989) and meningeal TB (AOR 2.1, 95% CI 1.065, 4.144) were significantly associated with unfavorable treatment outcome. CONCLUSION: The treatment success (favorable outcome) rate among EPTB patients was less than the target (i.e., ≥ 90%) set by the WHO. Highest proportion of patients lost to follow-up during the treatment.

Reflecting on the updates to the World Health Organisation 2019 Tuberculosis Infection Control Guidelines through the lens of a low-income/high TB burden country.

Hospital-acquired tuberculosis infection among healthcare workers is a global concern due to the increased attributable risk of tuberculosis infection among this group. To reduce healthcare workers' exposure to airborne Mycobacterium tuberculosis, various policies and guidelines have been developed and updated by the World Health Organisation (WHO) since 1999. In March 2019, the WHO published the updated tuberculosis infection control guidelines. It had previously been suggested that the existence of multiple guidelines and the changes in the contents across versions may confuse end-users and challenge the implementation. With this issue in mind, we examined the updated WHO 2019 TB infection control guidelines. The WHO 2019 updated guideline is a shorter and more focused document that includes more of the evidence from published systematic reviews for TB infection prevention and control. The guidelines focus on implementing TB infection control as an integrated infection control and prevention 'package'. However, a few key elements have been omitted or integrated with other WHO policies that were previously included in the guidelines, many of which are also still present in other international and in many national level TB infection control guidelines. In this commentary, we highlighted the inconsistencies in the different versions of the guidelines, the challenges that the high TB burden and low-income countries may face while implementing the guidelines and some factors that may be considered in the future guidelines. The arguments we made have important implications for tuberculosis infection control strategy development and implementation in low-income and high TB burden countries.

Active Case Finding for Tuberculosis through TOUCH Agents in Selected High TB Burden Wards of Kolkata, India: A Mixed Methods Study on Outcomes and Implementation Challenges.

Active case finding (ACF) for tuberculosis (TB) was implemented in 60 selected high TB burden wards of Kolkata, India. Community volunteers called TOUCH (Targeted Outreach for Upliftment of Community Health) agents (TAs) identified and referred presumptive TB patients (PTBPs) to health facilities for TB diagnosis and treatment. We aimed to describe the "care cascade" of PTBPs that were identified during July to December 2018 and to explore the reasons for attrition as perceived by TAs and PTBPs. An explanatory mixed-methods study with a quantitative phase of cohort study using routinely collected data followed by descriptive qualitative study with in-depth interviews was conducted. Of the 3,86242 individuals that were enumerated, 1132 (0.3%) PTBPs were identified. Only 713 (63.0%) PTBPs visited a referred facility for TB diagnosis. TB was diagnosed in 177 (24.8%). The number needed to screen for one TB patient was 2183 individuals. The potential reasons for low yield were stigma and apprehension about TB, distrust about TA, wage losses for attending health facilities, and substance abuse among PTBPs. The yield of ACF was suboptimal with low PTBP identification rate and a high attrition rate. Interviewing each individual for symptoms of TB and supporting PTBPs for diagnosis through sputum collection and transport can be adopted to improve the yield.

Analysis of tuberculosis treatment outcomes among pulmonary tuberculosis patients in Bahawalpur, Pakistan.

OBJECTIVE: Monitoring tuberculosis treatment outcomes and understanding the reasons for unsuccessful treatment are important indicators for evaluating the performance of the national tuberculosis control program. The aim of this study was to evaluate the treatment outcomes among pulmonary TB (PTB) patients and identify the predictors of unsuccessful treatment outcome. RESULTS: Treatment success rate of 67.8% among new and retreatment PTB patients and 69% in new smear positive PTB patients was observed. Close to 21% (20.9%) and 15.7% PTB and new smear positive PTB patients had loss to follow-up during treatment. Overall, older patients (AOR 1.02; 95% CI 1.01-1.0), smokers (AOR 1.65; 95% CI 1.02-2.67) and retreatment cases of TB (AOR 2.34; 95% CI 1.43-3.84) were at greater risk of having unsuccessful treatment outcomes. Moreover, sputum positivity at 2 months (AOR 13.78; 95% CI 5.09-37.26) was a significant predictor of poor treatment outcomes in new smear positive PTB patients. The treatment success rate among PTB patients was lower than the recommended 85% success rate. TB patients at higher risk of unsuccessful treatment outcomes should be provided with enhanced supervision and treatment monitoring to improve the success rate of TB management in Pakistan.

New Drugs and Vaccines for Tuberculosis.

BACKGROUND: Tuberculosis (TB) is an infectious disease that resulted in estimated 9.6 million new cases in 2014 and 1.5 million deaths. The available drug regimen for TB is time consuming which more often leads to the patient non compliance which then results in occurrence of drug resistant TB (Multi-drug and extremely drug resistant TB) in several portions of the world. METHODS: The dangerous combinations of TB and HIV is taking its toll on human health. The foremost factor is non- profit associated with the development of anti TB drugs. There is almost 10 different drugs in various levels of trials whereas the vaccine development is focusing more on adult vaccine rather than a child vaccine. RESULTS: More than 15 vaccine candidate are in various stages of pipelines. Present compilation gives an account for various drug candidates and vaccine products in various stages of drug development. Also included is a recent collection of patents for assay methods, potential drug candidates/classes and vaccination products. CONCLUSION: The need is for improvement in the activity and chemical and biological description of under development compounds. Lastly the set up for clinical and appropriate uses for running a reliable clinical trial is a necessary prerequisite.

Relating annual migration from high tuberculosis burden country of origin to changes in foreign-born tuberculosis notification rates in low-medium incidence European countries.

The level of immigration from high tuberculosis (TB) burden countries (HBCs) which impacts on the foreign-born TB notification rate is largely unknown. In this work, we performed a cross-sectional analysis of epidemiological data from 2000 to 2013 from nine European countries: Austria, Denmark, Finland, Hungary, Netherlands, Norway, Spain, Sweden, and the United Kingdom. Crude notification rates were calculated for foreign- and native-born populations and a multiple-linear regression model predicting notification rates with HBC population data was generated. From 2000 to 2013, the population percentage with a foreign birthplace increased on average each year in all nine countries, ranging from +0.11%/year in the Netherlands to +0.66%/year in Spain. An annual increase in HBC migrants above +0.43% per year (95% Confidence Interval: 0.24%-0.63%) corresponded with higher TB notification rates in the foreign-born population of the countries analyzed. This indicates that migration from HBCs can exert a measurable effect on the foreign-born TB notification rate. However, an increase in the foreign-born TB notification rate coincided with an average annual rise in national TB notification rates only in countries, Norway (+3.85%/year) and Sweden (+2.64%/year), which have a high proportion (>80%) of TB cases that are foreign-born.

Is Multi-Drug Resistant Tuberculosis More Prevalent in HIV-Infected Patients in Korea?

The epidemiological synergy between human immunodeficiency virus (HIV) and tuberculosis (TB) is a major threat to public health. However, the association between HIV and multi-drug resistant tuberculosis (MDR-TB) is not clear. To explore the association between HIV and MDR-TB infection, a case-control study was performed in Korea. A total of 1606 culture-proven TB patients (45 HIV vs. 1561 non-HIV) from January 2006 to October 2014 were included in this analysis. MDR-TB rates were 11.1% and 8.2% in the HIV and non-HIV groups, respectively (p=0.42), thus indicating that MDR-TB was not significantly associated with HIV infection in Korea.

Data on the descriptive overview and the quality assessment details of 12 qualitative research papers.

This data article presents the supplementary material for the review paper "Role of acceptability barriers in delayed diagnosis of Tuberculosis: Literature review from high burden countries" (Barnabishvili et al., in press) [1]. General overview of 12 qualitative papers, including the details about authors, years of publication, data source locations, study objectives, overview of methods, study population characteristics, as well as the details of intervention and the outcome parameters of the papers are summarized in the first two tables included to the article. Quality assessment process of the methodological strength of 12 papers and the results of the critical appraisal are further described and summarized in the second part of the article.

Role of acceptability barriers in delayed diagnosis of Tuberculosis: Literature review from high burden countries.

PURPOSE: Direct transmission of mutated tuberculosis (TB) strains is among major contributors to the worldwide epidemic of Drug-Resistant Tuberculosis. Expanding access to TB-services and decreasing diagnostic delays are acknowledged as potential solutions. We aimed to summarize evidence about links between health care acceptability barriers and TB diagnostic delays. Scoping and systematic review approaches were combined to determine the depth/breadth of the literature, identify gaps, and synthesize findings. METHODS: Electronic data-bases, key journals, other relevant electronic sources, and references of relevant articles were selected as potential sources through a preliminary search and experts advice. Titles and abstracts of 4046 initial records and 1796 references were screened against preliminarily developed and post-hoc inclusion/exclusion criteria. Author, year of publication, study location, study aims, overview of methods, study population, intervention type, outcomes measures and results of each included paper were extracted. Methodological quality of studies was assessed. Narrative synthesis of the study results was conducted through the thematic analysis approach. RESULTS: Patients' negative expectations, doubts about quality of services/medications and burden of stigma, as well as providers' discriminative attitudes towards patients' characteristics (age, gender, ethnicity) were reported as major barriers. Scarcity and unequal distribution of the literature and lack of attention to all potential acceptability barriers were found as major gaps in the current research. CONCLUSION: Overall, study findings indicate the significance of acceptability barriers' role in TB diagnostic delays. Emerging character of the field is demonstrated. Recommendations about further research directions are outlined.