Risk for development of active tuberculosis in patients with chronic airway disease-a systematic review of evidence.

Reports suggest an increased risk of tuberculosis (TB) in people with chronic airway diseases (CADs) such as chronic obstructive pulmonary disease (COPD), but evidence has not been systematically reviewed. We performed a systematic review by searching MEDLINE and Embase for studies published from 1 January 1993 to 15 January 2021 reporting the association between the incident risk of TB in people with CADs (asthma, COPD and bronchiectasis). Two reviewers independently assessed the quality of individual studies. We included nine studies, with two from low-income high TB burden countries. Three cohort studies reported a statistically significant independent association between COPD and the risk of TB in high-income countries (n=711 389). Hazard ratios for incident TB ranged from 1.44 to 3.14 adjusted for multiple confounders including age, sex and comorbidity. There was large between-study heterogeneity (I2=97.0%) across studies. The direction of effect on the TB risk from asthma was inconsistent. Chronic bronchitis or bronchiectasis studies were limited. The small number of available studies demonstrated an increased risk of TB in people with COPD; however, the magnitude of the increase varies by setting and population. Data in high TB burden countries and for other CADs are limited

Evaluating patient education resources for supporting treatment decisions in latent tuberculosis infection

Objective: People with latent tuberculosis infection (LTBI) are required to make complex treatment decisions, which require an understanding of personal risk and associated benefits. However, many people with LTBI in the United Kingdom are at risk of low health literacy and can also experience language barriers, which can affect decision making. Patient education resources can support understanding but must meet the needs of the target population. The aim of this study was to evaluate the accessibility, readability and content of LTBI patient education resources. Design: Review and descriptive analysis of online LTBI patient education resources. Setting: UK-based online patient education resources. Method: We searched UK public health and charitable organisations for online LTBI patient education resources. Resources were evaluated in terms of accessibility (availability of translated versions); readability (Flesch–Kincaid Reading Ease [FKE], Flesch–Kincaid Grade Level [FKG] and Simplified Measure of Gobbledygook [SMOG]), theoretical content (Extended Common-Sense Model) and principles of shared decision making. Results: Seventeen out of 60 articles identified in the search met the prespecified criteria for inclusion. Translated materials were available for 7 of them. The overall mean ± SD readability scores and corresponding reading ages were FKE 63.51 ± 8.81 (13–15 years), FKG 9.14 ± 8.95 (13–15 years) and SMOG 8.27 ± 1.51 (13–14 years). No resources met Health Education England recommended readability levels for health-related information. Dimensions of cognitive representations of illness and treatment most commonly addressed included treatment control, cause and identity (symptom and label); no resources addressed emotional identity. Conclusion: Current and future LTBI patient education resources would benefit from greater consideration of the needs of non-English language speakers, readability and theoretical content to improve patient illness experience and support informed treatment decision making

Tuberculosis Antigen-Specific T-Cell Responses During the First 6 Months of Antiretroviral Treatment

The reconstitution of Mycobacterium tuberculosis (Mtb)-antigen-specific CD4 T cells in a cohort of HIV-infected persons starting antiretroviral treatment (ART) in high TB endemic area is described. Restoration of the antigen-specific CD4 T cell subsets mirrored the overall CD4 T cell compartment. Activation (assessed by HLA-DR expression) decreased during ART but remained elevated compared to HIV-uninfected persons. Despite known Mtb sensitisation determined by IGRA, 12/23 participants had no Mtb-specific CD4 T cells detectable by flow cytometry, combined with overall elevated T cell activation and memory differentiation, suggesting heightened turnover. Our data suggest early ART initiation to maintain polyfunctional immune memory responses

Measurement of Skin Induration Size Using Smartphone Images and Photogrammetric Reconstruction: Pilot Study

Background: The tuberculin skin test (TST) is the most common method for detecting latent tuberculosis infection (LTBI). The test requires that a patient return to the health facility or be visited by a health care worker 48 to 72 hours after the intradermal placement of tuberculin so that the size of the resulting skin induration, if any, can be measured. Objective: This study aimed to propose and evaluate an image-based method for measuring induration size from images captured using a smartphone camera. Methods: We imaged simulated skin indurations, ranging from 4.0 to 19 mm, in 10 subjects using a handheld smartphone, and performed three-dimensional reconstruction of the induration sites using photogrammetry software. An experienced TST reader measured the size of each induration using the standard clinical method. The experienced reader and an inexperienced observer both measured the size of each induration using the software. The agreement between measurements generated by the standard clinical and image-based methods was assessed using the intraclass correlation coefficient (ICC). Inter- and intraobserver agreement for the image-based method was similarly evaluated. Results: Results showed excellent agreement between the standard and image-based measurements performed by the experienced reader with an ICC value of .965. Inter- and intraobserver agreements were also excellent, indicating that experience in reading TSTs is not required with our proposed method. Conclusions: We conclude that the proposed smartphone image-based method is a potential alternative to standard induration size measurement and would enable remote data collection for LTBI screening

Update in Tuberculosis and Non-tuberculous Mycobacteria 2017.

In 2016, there were an estimated 10.4 million incident cases of tuberculosis (TB) worldwide, causing 1.7 million deaths (1). Although global TB incidence and mortality rates are falling by 2% and 3% per year, respectively, these declines are far behind what is required to achieve the World Health Organization (WHO) End TB Strategy targets, which aim for 90% and 95% reductions in TB incidence and mortality, respectively, between 2015 and 2035 (2). Consequently, major advances in the understanding of TB pathogenesis (including vaccine development) and transmission, together with new tools for the diagnosis and treatment of both active TB disease and latent infection, are needed. Furthermore, the global importance of nontuberculous mycobacterial (NTM) disease is increasingly being recognized as its incidence rises (3, 4). This review summarizes the advances in both TB and NTM published in the Journal and other journals in 2017

The South African Tuberculosis Care Cascade: Estimated Losses and Methodological Challenges

Background: While tuberculosis incidence and mortality are declining in South Africa, meeting the goals of the End TB Strategy requires an invigorated programmatic response informed by accurate data. Enumerating the losses at each step in the care cascade enables appropriate targeting of interventions and resources. / Methods: We estimated the tuberculosis burden; the number and proportion of individuals with tuberculosis who accessed tests, had tuberculosis diagnosed, initiated treatment, and successfully completed treatment for all tuberculosis cases, for those with drug-susceptible tuberculosis (including human immunodeficiency virus (HIV)–coinfected cases) and rifampicin-resistant tuberculosis. Estimates were derived from national electronic tuberculosis register data, laboratory data, and published studies. / Results: The overall tuberculosis burden was estimated to be 532005 cases (range, 333760–764480 cases), with successful completion of treatment in 53% of cases. Losses occurred at multiple steps: 5% at test access, 13% at diagnosis, 12% at treatment initiation, and 17% at successful treatment completion. Overall losses were similar among all drug-susceptible cases and those with HIV coinfection (54% and 52%, respectively, successfully completed treatment). Losses were substantially higher among rifampicin- resistant cases, with only 22% successfully completing treatment. / Conclusion: Although the vast majority of individuals with tuberculosis engaged the public health system, just over half were successfully treated. Urgent efforts are required to improve implementation of existing policies and protocols to close gaps in tuberculosis diagnosis, treatment initiation, and successful treatment completion

Concise whole blood transcriptional signatures for incipient tuberculosis: a systematic review and patient-level pooled meta-analysis

BACKGROUND: Multiple blood transcriptional signatures have been proposed for identification of active and incipient tuberculosis. We aimed to compare the performance of systematically identified candidate signatures for incipient tuberculosis and to benchmark these against WHO targets. METHODS: We did a systematic review and individual participant data meta-analysis. We searched Medline and Embase for candidate whole blood mRNA signatures discovered with the primary objective of diagnosis of active or incipient tuberculosis, compared with controls who were healthy or had latent tuberculosis infection. We tested the performance of eligible signatures in whole blood transcriptomic datasets, in which sampling before tuberculosis diagnosis was done and time to disease was available. Culture-confirmed and clinically or radiologically diagnosed pulmonary or extrapulmonary tuberculosis cases were included. Non-progressor (individuals who remained tuberculosis-free during follow-up) samples with less than 6 months of follow-up from the date of sample collection were excluded, as were participants with prevalent tuberculosis and those who received preventive therapy. Scores were calculated for candidate signatures for each participant in the pooled dataset. Receiver operating characteristic curves, sensitivities, and specificities were examined using prespecified intervals to tuberculosis (<3 months, <6 months, <1 year, and <2 years) from sample collection. This study is registered with PROSPERO, number CRD42019135618. RESULTS: We tested 17 candidate mRNA signatures in a pooled dataset from four eligible studies comprising 1126 samples. This dataset included 183 samples from 127 incipient tuberculosis cases in South Africa, Ethiopia, The Gambia, and the UK. Eight signatures (comprising 1-25 transcripts) that predominantly reflect interferon and tumour necrosis factor-inducible gene expression, had equivalent diagnostic accuracy for incipient tuberculosis over a 2-year period with areas under the receiver operating characteristic curves ranging from 0·70 (95% CI 0·64-0·76) to 0·77 (0·71-0·82). The sensitivity of all eight signatures declined with increasing disease-free time interval. Using a threshold derived from two SDs above the mean of uninfected controls to prioritise specificity and positive-predictive value, the eight signatures achieved sensitivities of 24·7-39·9% over 24 months and of 47·1-81·0% over 3 months, with corresponding specificities of more than 90%. Based on pre-test probability of 2%, the eight signatures achieved positive-predictive values ranging from 6·8-9·4% over 24 months and 11·2-14·4% over 3 months. When using biomarker thresholds maximising sensitivity and specificity with equal weighting to both, no signature met the minimum WHO target product profile parameters for incipient tuberculosis biomarkers over a 2-year period. INTERPRETATION: Blood transcriptional biomarkers reflect short-term risk of tuberculosis and only exceed WHO benchmarks if applied to 3-6-month intervals. Serial testing among carefully selected target groups might be required for optimal implementation of these biomarkers. FUNDING: Wellcome Trust and National Institute for Health Research

The diagnostic performance of novel skin-based in-vivo tests for tuberculosis infection compared with purified protein derivative tuberculin skin tests and blood-based in vitro interferon-γ release assays: a systematic review and meta-analysis

BACKGROUND: Novel skin-based tests for tuberculosis infection might present suitable alternatives to current tests; however, diagnostic performance of new tests compared with the purified protein derivative-tuberculin skin test (TST) or interferon-γ release assays (IGRA) needs systematic assessment. METHODS: In this systematic review and meta-analysis, we searched English (Medline OVID), Chinese (Chinese Biomedical Literature Database and the China National Knowledge Infrastructure), and Russian (e-library) databases from the inception of each database to May 15, 2019, (with updated search of the Russian and English databases on Oct, 20 2020) using terms "ESAT6" OR "CFP10" AND "skin test" AND "Tuberculosis" OR "C-Tb" OR "Diaskintest". We included studies reporting on the performance of index tests alone or compared with a comparator. Inclusion criteria varied according to review objectives and performance outcome, but reporting of test cut-offs for positivity applied to study population was required from all studies. We used a hierarchy of reference standards for tuberculosis infection consistent with the 2020 WHO framework to evaluate diagnostic performance. Two authors independently reviewed the titles and abstracts for English and Chinese (LF and MK) and Russian studies (MK and VN). Study quality was assessed with QUADAS-2. Pooled random-effects estimates are presented when appropriate for total agreement proportion, sensitivity in microbiologically confirmed tuberculosis and specificity in cohorts with low risk of tuberculosis infection. This study is registered with PROSPERO, CRD42019135572. FINDINGS: We identified 1466 original articles, of which 37 (2·5%) studies, including 10 915 individuals (7111 Diaskintest, 2744 C-Tb, 887 EC, 173 DPPD), were included in the qualitative analysis (29 [78%] studies of Diaskintest, five [15%] studies of C-Tb, two [5%] studies of EC-skintest, and one [3%] study of DPPD). 22 (1·5%) studies including 5810 individuals (3143 Diaskintest, 2129 C-Tb, 538 EC-skintest) were included in the quantitative analysis: 15 (68%) of Diaskintest, five (23%) of C-Tb, and two (9%) of EC-skintest. Tested sub-populations included individuals with HIV, children (0-18 years), and individuals exposed to tuberculosis. Studies were heterogeneous with moderate to high risk of bias. Nine head-to-head studies of index test versus TST and IGRA permitted direct comparisons and pooling. In a mixed cohort of people with and without tuberculosis, Diaskintest pooled agreement with IGRA was 87·16% (95% CI 79·47-92·24) and 55·45% (46·08-64·45) with TST-5 mm cut-off (TST5 mm). Diaskintest sensitivity was 91·18% (95% CI 81·72-95·98) compared with 88·24% (78·20-94·01) for TST5 mm, 89·66 (78·83-95·28) for IGRA QuantiFERON, and 90·91% (79·95-96·16) for TSPOT.TB. C-Tb agreement with IGRA in individuals with active tuberculosis was 79·80% (95% CI 76·10-83·07) compared with 78·92% (74·65-82·63) for TST5 mm/15 mm cut-off (TST5 mm/15 mm). TST5/15mm reflects threshold in cohorts that applied stratified cutoffs: 5 mm for HIV-infected, immunocompromised, or BCG-naive individuals, and 15mm for BCG-vaccinated immunocompetent individuals. C-Tb sensitivity was 74·52% (95% CI 70·39-78·25) compared with a sensitivity of 78·18% (67·75-85·94) for TST5 mm/15 mm, and 71·67% (63·44-78·68) for IGRA. Specificity was 97·85% (95% CI 93·96-99·25) for C-Tb versus 93·31% (90·22-95·48) for TST 15 mm cut-off and 99·15% (79·66-99·97) for IGRA. EC-skintest sensitivity was 86·06% (95% CI 82·39-89·07). INTERPRETATION: Novel skin-based tests for tuberculosis infection appear to perform similarly to IGRA or TST; however, study quality varied. Evaluation of test performance, patient-important outcomes, and diagnostic use in current clinical algorithms will inform implementation in key populations. FUNDING: StopTB (New Diagnostics Working Group) and FIND. TRANSLATIONS: For the Chinese and Russian translations of the abstract see Supplementary Materials section