Mycobacterium tuberculosis Transmission in High-Incidence Settings-New Paradigms and Insights.

Tuberculosis has affected humankind for thousands of years, but a deeper understanding of its cause and transmission only arose after Robert Koch discovered Mycobacterium tuberculosis in 1882. Valuable insight has been gained since, but the accumulation of knowledge has been frustratingly slow and incomplete for a pathogen that remains the number one infectious disease killer on the planet. Contrast that to the rapid progress that has been made in our understanding SARS-CoV-2 (the cause of COVID-19) aerobiology and transmission. In this Review, we discuss important historical and contemporary insights into M. tuberculosis transmission. Historical insights describing the principles of aerosol transmission, as well as relevant pathogen, host and environment factors are described. Furthermore, novel insights into asymptomatic and subclinical tuberculosis, and the potential role this may play in population-level transmission is discussed. Progress towards understanding the full spectrum of M. tuberculosis transmission in high-burden settings has been hampered by sub-optimal diagnostic tools, limited basic science exploration and inadequate study designs. We propose that, as a tuberculosis field, we must learn from and capitalize on the novel insights and methods that have been developed to investigate SARS-CoV-2 transmission to limit ongoing tuberculosis transmission, which sustains the global pandemic.

Diagnosing Tuberculosis: What Do New Technologies Allow Us to (Not) Do?

New tuberculosis (TB) diagnostics are at a crossroads: their development, evaluation, and implementation is severely damaged by resource diversion due to COVID-19. Yet several technologies, especially those with potential for non-invasive non-sputum-based testing, hold promise for efficiently triaging and rapidly confirming TB near point-of-care. Such tests are, however, progressing through the pipeline slowly and will take years to reach patients and health workers. Compellingly, such tests will create new opportunities for difficult-to-diagnose populations, including primary care attendees (all-comers in high burden settings irrespective of reason for presentation) and community members (with early stage disease or risk factors like HIV), many of whom cannot easily produce sputum. Critically, all upcoming technologies have limitations that implementers and health workers need to be cognizant of to ensure optimal deployment without undermining confidence in a technology that still offers improvements over the status quo. In this state-of-the-art review, we critically appraise such technologies for active pulmonary TB diagnosis. We highlight strengths, limitations, outstanding research questions, and how current and future tests could be used in the presence of these limitations and uncertainties. Among triage tests, CRP (for which commercial near point-of-care devices exist) and computer-aided detection software with digital chest X-ray hold promise, together with late-stage blood-based assays that detect host and/or microbial biomarkers; however, aside from a handful of prototypes, the latter category has a shortage of promising late-stage alternatives. Furthermore, positive results from new triage tests may have utility in people without TB; however, their utility for informing diagnostic pathways for other diseases is under-researched (most sick people tested for TB do not have TB). For confirmatory tests, few true point-of-care options will be available soon; however, combining novel approaches like tongue swabs with established tests like Ultra have short-term promise but first require optimizations to specimen collection and processing procedures. Concerningly, no technologies yet have compelling evidence of meeting the World Health Organization optimal target product profile performance criteria, especially for important operational criteria crucial for field deployment. This is alarming as the target product profile criteria are themselves almost a decade old and require urgent revision, especially to cater for technologies made prominent by the COVID-19 diagnostic response (e.g., at-home testing and connectivity solutions). Throughout the review, we underscore the importance of how target populations and settings affect test performance and how the criteria by which these tests should be judged vary by use case, including in active case finding. Lastly, we advocate for health workers and researchers to themselves be vocal proponents of the uptake of both new tests and those - already available tests that remain suboptimally utilized.

Tuberculosis screening among ambulatory people living with HIV: a systematic review and individual participant data meta-analysis.

BACKGROUND: The WHO-recommended tuberculosis screening and diagnostic algorithm in ambulatory people living with HIV is a four-symptom screen (known as the WHO-recommended four symptom screen [W4SS]) followed by a WHO-recommended molecular rapid diagnostic test (eg Xpert MTB/RIF [hereafter referred to as Xpert]) if W4SS is positive. To inform updated WHO guidelines, we aimed to assess the diagnostic accuracy of alternative screening tests and strategies for tuberculosis in this population. METHODS: In this systematic review and individual participant data meta-analysis, we updated a search of PubMed (MEDLINE), Embase, the Cochrane Library, and conference abstracts for publications from Jan 1, 2011, to March 12, 2018, done in a previous systematic review to include the period up to Aug 2, 2019. We screened the reference lists of identified pieces and contacted experts in the field. We included prospective cross-sectional, observational studies and randomised trials among adult and adolescent (age ≥10 years) ambulatory people living with HIV, irrespective of signs and symptoms of tuberculosis. We extracted study-level data using a standardised data extraction form, and we requested individual participant data from study authors. We aimed to compare the W4SS with alternative screening tests and strategies and the WHO-recommended algorithm (ie, W4SS followed by Xpert) with Xpert for all in terms of diagnostic accuracy (sensitivity and specificity), overall and in key subgroups (eg, by antiretroviral therapy [ART] status). The reference standard was culture. This study is registered with PROSPERO, CRD42020155895. FINDINGS: We identified 25 studies, and obtained data from 22 studies (including 15 666 participants; 4347 [27·7%] of 15 663 participants with data were on ART). W4SS sensitivity was 82% (95% CI 72-89) and specificity was 42% (29-57). C-reactive protein (≥10 mg/L) had similar sensitivity to (77% [61-88]), but higher specificity (74% [61-83]; n=3571) than, W4SS. Cough (lasting ≥2 weeks), haemoglobin (<10 g/dL), body-mass index (<18·5 kg/m2), and lymphadenopathy had high specificities (80-90%) but low sensitivities (29-43%). The WHO-recommended algorithm had a sensitivity of 58% (50-66) and a specificity of 99% (98-100); Xpert for all had a sensitivity of 68% (57-76) and a specificity of 99% (98-99). In the one study that assessed both, the sensitivity of sputum Xpert Ultra was higher than sputum Xpert (73% [62-81] vs 57% [47-67]) and specificities were similar (98% [96-98] vs 99% [98-100]). Among outpatients on ART (4309 [99·1%] of 4347 people on ART), W4SS sensitivity was 53% (35-71) and specificity was 71% (51-85). In this population, a parallel strategy (two tests done at the same time) of W4SS with any chest x-ray abnormality had higher sensitivity (89% [70-97]) and lower specificity (33% [17-54]; n=2670) than W4SS alone; at a tuberculosis prevalence of 5%, this strategy would require 379 more rapid diagnostic tests per 1000 people living with HIV than W4SS but detect 18 more tuberculosis cases. Among outpatients not on ART (11 160 [71·8%] of 15 541 outpatients), W4SS sensitivity was 85% (76-91) and specificity was 37% (25-51). C-reactive protein (≥10 mg/L) alone had a similar sensitivity to (83% [79-86]), but higher specificity (67% [60-73]; n=3187) than, W4SS and a sequential strategy (both test positive) of W4SS then C-reactive protein (≥5 mg/L) had a similar sensitivity to (84% [75-90]), but higher specificity than (64% [57-71]; n=3187), W4SS alone; at 10% tuberculosis prevalence, these strategies would require 272 and 244 fewer rapid diagnostic tests per 1000 people living with HIV than W4SS but miss two and one more tuberculosis cases, respectively. INTERPRETATION: C-reactive protein reduces the need for further rapid diagnostic tests without compromising sensitivity and has been included in the updated WHO tuberculosis screening guidelines. However, C-reactive protein data were scarce for outpatients on ART, necessitating future research regarding the utility of C-reactive protein in this group. Chest x-ray can be useful in outpatients on ART when combined with W4SS. The WHO-recommended algorithm has suboptimal sensitivity; Xpert for all offers slight sensitivity gains and would have major resource implications. FUNDING: World Health Organization.

Predicting Airborne Infection Risk: Association Between Personal Ambient Carbon Dioxide Level Monitoring and Incidence of Tuberculosis Infection in South African Health Workers.

BACKGROUND: High rates of tuberculosis (TB) transmission occur in hospitals in high-incidence countries, yet there is no validated way to evaluate the impact of hospital design and function on airborne infection risk. We hypothesized that personal ambient carbon dioxide (CO2) monitoring could serve as a surrogate measure of rebreathed air exposure associated with TB infection risk in health workers (HWs). METHODS: We analyzed baseline and repeat (12-month) interferon-γ release assay (IGRA) results in 138 HWs in Cape Town, South Africa. A random subset of HWs with a baseline negative QuantiFERON Plus (QFT-Plus) underwent personal ambient CO2 monitoring. RESULTS: Annual incidence of TB infection (IGRA conversion) was high (34%). Junior doctors were less likely to have a positive baseline IGRA than other HWs (OR, 0.26; P = .005) but had similar IGRA conversion risk. IGRA converters experienced higher median CO2 levels compared to IGRA nonconverters using quantitative QFT-Plus thresholds of ≥0.35 IU/mL (P < .02) or ≥1 IU/mL (P < .01). Median CO2 levels were predictive of IGRA conversion (odds ratio [OR], 2.04; P = .04, ≥1 IU/mL threshold). Ordinal logistic regression demonstrated that the odds of a higher repeat quantitative IGRA result increased by almost 2-fold (OR, 1.81; P = .01) per 100 ppm unit increase in median CO2 levels, suggesting a dose-dependent response. CONCLUSIONS: HWs face high occupational TB risk. Increasing median CO2 levels (indicative of poor ventilation and/or high occupancy) were associated with higher likelihood of HW TB infection. Personal ambient CO2 monitoring may help target interventions to decrease TB transmission in healthcare facilities and help HWs self-monitor occupational risk, with implications for other airborne infections including coronavirus disease 2019.

Reimagining the status quo: How close are we to rapid sputum-free tuberculosis diagnostics for all?

Rapid, accurate, sputum-free tests for tuberculosis (TB) triage and confirmation are urgently needed to close the widening diagnostic gap. We summarise key technologies and review programmatic, systems, and resource issues that could affect the impact of diagnostics. Mid-to-early-stage technologies like artificial intelligence-based automated digital chest X-radiography and capillary blood point-of-care assays are particularly promising. Pitfalls in the diagnostic pipeline, included a lack of community-based tools. We outline how these technologies may complement one another within the context of the TB care cascade, help overturn current paradigms (eg, reducing syndromic triage reliance, permitting subclinical TB to be diagnosed), and expand options for extra-pulmonary TB. We review challenges such as the difficulty of detecting paucibacillary TB and the limitations of current reference standards, and discuss how researchers and developers can better design and evaluate assays to optimise programmatic uptake. Finally, we outline how leveraging the urgency and innovation applied to COVID-19 is critical to improving TB patients' diagnostic quality-of-care.