Tweaking algorithms. Technopolitical issues associated with artificial intelligence based tuberculosis detection in global health.

Computer-aided detection algorithms based on artificial intelligence are increasingly being tested and used as a means for detecting tuberculosis in countries where the epidemic is still present. Computer-aided detection tools are often presented as a global solution that can be deployed in all the geographical areas concerned by tuberculosis, but at the same time, they need to be adjusted and calibrated according to local populations' characteristics. The aim of this article is to analyze the tensions between the standardization of computer-aided detection algorithms and their local adaptation and the political issues associated with these tensions. We undertook a qualitative analysis of practices associated with tuberculosis detection algorithms in different contexts, contrasting the perspectives of various stakeholders. Algorithms embed the promise of standardization through automation and the bypassing of variable human expertise such as that of radiologists, they are nonetheless objects of local practices that we have characterized as "tweaking." This work of tweaking reveals how the technology is situated but also the many concerns of the users and workers (insertion in care, control over infrastructure, and political ownership). This should be better considered to truly make computer-aided detection innovative tools for tuberculosis management in global health.

Diagnostic Accuracy of Computer-Aided Detection During Active Case Finding for Pulmonary Tuberculosis in Africa: A Systematic Review and Meta-analysis.

Background: Computer-aided detection (CAD) may be a useful screening tool for tuberculosis (TB). However, there are limited data about its utility in active case finding (ACF) in a community-based setting, and particularly in an HIV-endemic setting where performance may be compromised. Methods: We performed a systematic review and evaluated articles published between January 2012 and February 2023 that included CAD as a screening tool to detect pulmonary TB against a microbiological reference standard (sputum culture and/or nucleic acid amplification test [NAAT]). We collected and summarized data on study characteristics and diagnostic accuracy measures. Two reviewers independently extracted data and assessed methodological quality against Quality Assessment of Diagnostic Accuracy Studies-2 criteria. Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Diagnostic Test Accuracy Studies (PRISMA-DTA) guidelines were followed. Results: Of 1748 articles reviewed, 5 met with the eligibility criteria and were included in this review. A meta-analysis revealed pooled sensitivity of 0.87 (95% CI, 0.78-0.96) and specificity of 0.74 (95% CI, 0.55-0.93), just below the World Health Organization (WHO)-recommended target product profile (TPP) for a screening test (sensitivity ≥0.90 and specificity ≥0.70). We found a high risk of bias and applicability concerns across all studies. Subgroup analyses, including the impact of HIV and previous TB, were not possible due to the nature of the reporting within the included studies. Conclusions: This review provides evidence, specifically in the context of ACF, for CAD as a potentially useful and cost-effective screening tool for TB in a resource-poor HIV-endemic African setting. However, given methodological concerns, caution is required with regards to applicability and generalizability.

Self-tests for COVID-19: What is the evidence? A living systematic review and meta-analysis (2020-2023).

COVID-19 self-testing strategy (COVIDST) can rapidly identify symptomatic and asymptomatic SARS-CoV-2-infected individuals and their contacts, potentially reducing transmission. In this living systematic review, we evaluated the evidence for real-world COVIDST performance. Two independent reviewers searched six databases (PubMed, Embase, Web of Science, World Health Organization database, Cochrane COVID-19 registry, Europe PMC) for the period April 1st, 2020, to January 18th, 2023. Data on studies evaluating COVIDST against laboratory-based conventional testing and reported on diagnostic accuracy, feasibility, acceptability, impact, and qualitative outcomes were abstracted. Bivariate random effects meta-analyses of COVIDST accuracy were performed (n = 14). Subgroup analyses (by sampling site, symptomatic/asymptomatic infection, supervised/unsupervised strategy, with/without digital supports) were conducted. Data from 70 included studies, conducted across 25 countries with a median sample size of 817 (range: 28-784,707) were pooled. Specificity and DOR was high overall, irrespective of subgroups (98.37-99.71%). Highest sensitivities were reported for: a) symptomatic individuals (73.91%, 95%CI: 68.41-78.75%; n = 9), b) mid-turbinate nasal samples (77.79%, 95%CI: 56.03-90.59%; n = 14), c) supervised strategy (86.67%, 95%CI: 59.64-96.62%; n = 13), and d) use of digital interventions (70.15%, 95%CI: 50.18-84.63%; n = 14). Lower sensitivity was attributed to absence of symptoms, errors in test conduct and absence of supervision or a digital support. We found no difference in COVIDST sensitivity between delta and omicron pre-dominant period. Digital supports increased confidence in COVIDST reporting and interpretation (n = 16). Overall acceptability was 91.0-98.7% (n = 2) with lower acceptability reported for daily self-testing (39.5-51.1%). Overall feasibility was 69.0-100.0% (n = 5) with lower feasibility (35.9-64.6%) for serial self-testing. COVIDST decreased closures in school, workplace, and social events (n = 4). COVIDST is an effective rapid screening strategy for home-, workplace- or school-based screening, for symptomatic persons, and for preventing transmission during outbreaks. These data will guide COVIDST policy. Our review demonstrates that COVIDST has paved the way for self-testing in pandemics worldwide.

Respiratory health and its determinants among Nunavimmiut: results from the Qanuilirpitaa? 2017 Nunavik Health Survey.

OBJECTIVES: Respiratory diseases are the leading cause of hospitalization in Nunavik (northern Québec, Canada) and contribute to disparities in life expectancy with the rest of Canada. As part of Qanuilirpitaa? 2017, a cross-sectional population-based health survey, we sought to describe the prevalence of respiratory health indicators, including the first estimate of airway obstruction based on spirometry in an Inuit population, and explore their associated characteristics. METHODS: We analyzed data from 1296 participants aged 16 years and older, using multivariate logistic regression to assess characteristics associated with spirometry-determined airway obstruction and self-reported respiratory symptoms, i.e., wheezing in the last year and chronic cough during at least 3 months. RESULTS: In this relatively young population (83% aged 16 to 54), the prevalences of wheezing, chronic cough, and airway obstruction were, respectively, 27% (95% CI 24-30), 21% (18-23), and 17% (14-20). These estimates are prone to biases due to the relatively low participation rate (about 37%). The most consistent associations were with smoking (≥ 15 pack-years; odds ratio [OR] 3.13, 3.39, and 2.86 for the three indicators, respectively) and food security (OR 0.55 with wheezing and OR 0.26 with chronic cough), as defined in the Household Food Security Survey Module. Wheezing was also associated with allergic sensitization to dogs (2.60) and obesity (2.18). Chronic cough was associated with respiratory infections during childhood (2.12), housing in need of major repairs (1.72), and housing crowding (1.50), and was negatively associated with participation to traditional activities (0.62) and going on the land (0.64). Airway obstruction was associated with being underweight (3.84) and post-secondary education (0.40). Among young adults and women, wheezing was also associated with any inhalation of solvents for recreational purposes during their lifetime (2.62 and 1.56, respectively), while airway obstruction was associated with regular marijuana use (2.22 and 1.84, respectively). CONCLUSION: Smoking and food insecurity are both highly prevalent and strongly associated with respiratory symptoms in Nunavik. Together with essential smoking prevention and cessation programs, our findings suggest that solving food security and housing crises, improving socioeconomic conditions, and promoting traditional lifestyle may improve respiratory health in Nunavik.

RéSUMé: OBJECTIFS: Les maladies respiratoires sont la première cause d'hospitalisation au Nunavik (Nord-du-Québec, Canada) et contribuent aux écarts d'espérance de vie avec le reste du Canada. Dans le cadre de l'enquête transversale et populationnelle Qanuilirpitaa? 2017, cette étude décrit la prévalence d'indicateurs de santé respiratoire et explore les caractéristiques qui leur sont associées. Elle fournit le premier estimé de la prévalence d'obstruction respiratoire par spirométrie dans la population inuite. MéTHODES: Les données de 1 296 participants âgés de 16 ans et plus ont été analysées par régression logistique multivariée pour évaluer les caractéristiques associées avec le wheezing (dans la dernière année), la toux chronique (durant au moins 3 mois) et l'obstruction bronchique (mesurée par spirométrie). RéSULTATS: Dans cette population relativement jeune (83 % entre 16 et 54 ans), les prévalences de wheezing, de toux chronique et d'obstruction bronchique étaient de 27 % (IC95% 24-30), 21 % (18-23) et 17 % (14-20). Ces estimés pourraient être biaisés puisque le taux de participation à l'enquête était relativement faible (environ 37 %). Les associations les plus fortes et consistantes sont observées avec le tabagisme (≥ 15 paquets-années; RC 3,13, 3,39 et 2,86 pour les trois indicateurs, respectivement) et avec la sécurité alimentaire (RC 0,55 avec le wheezing et 0,26 avec la toux chronique), définie à partir du Module d'enquête sur la sécurité alimentaire des ménages. Le wheezing était notamment associé avec la sensibilisation allergique aux chiens (2,60) et l'obésité (2,18). La toux chronique était associée avec les infections respiratoires sévères dans l'enfance (2,12), un logement ayant besoin de réparations majeures (1,72) et un logement surpeuplé (1,50); tandis que participer aux activités traditionnelles (0,62) et aller souvent dans la nature (0,64) semblaient protecteurs. L'obstruction bronchique était associée avec un faible indice de masse corporelle (3,84) et un niveau de scolarité postsecondaire (0,40). Le wheezing était aussi associé avec le fait d'avoir déjà inhalé des solvants chez les jeunes adultes (2,62) et chez les femmes (1,56), tandis que l'obstruction bronchique était associée avec la consommation régulière de cannabis chez les jeunes adultes (2,22) et chez les femmes (1,84). CONCLUSION: Le tabagisme et l'insécurité alimentaire sont fort prévalents et fortement associés avec des symptômes respiratoires au Nunavik. En plus de rappeler l'importance de la prévention du tabagisme, ces résultats supportent la pertinence des efforts communautaires et gouvernementaux pour résoudre les crises de l'insécurité alimentaire et du logement, améliorer les conditions socioéconomiques et promouvoir la culture inuite afin d'améliorer la santé respiratoire au Nunavik.

The association of SARS-CoV-2 infection and tuberculosis disease with unfavorable treatment outcomes: A systematic review.

BACKGROUND: Whether SARS-CoV-2 infection and its management influence tuberculosis (TB) treatment outcomes is uncertain. We synthesized evidence on the association of SARS-CoV-2 coinfection (Coinfection Review) and its management (Clinical Management Review) on treatment outcomes among people with tuberculosis (TB) disease. METHODS: We systematically searched the literature from 1 January 2020 to 6 February 2022. Primary outcomes included: unfavorable (death, treatment failure, loss-to-follow-up) TB treatment outcomes (Coinfection and Clinical Management Review) and/or severe or critical COVID-19 or death (Clinical Management Review). Study quality was assessed with an adapted Newcastle Ottawa Scale. Data were heterogeneous and a narrative review was performed. An updated search was performed on April 3, 2023. FINDINGS: From 9,529 records, we included 11 studies and 7305 unique participants. No study reported data relevant to our review in their primary publication and data had to be contributed by study authors after contact. Evidence from all studies was low quality. Eight studies of 5749 persons treated for TB (286 [5%] with SARS-CoV-2) were included in the Coinfection Review. Across five studies reporting our primary outcome, there was no significant association between SARS-CoV-2 coinfection and unfavorable TB treatment outcomes. Four studies of 1572 TB patients-of whom 291 (19%) received corticosteroids or other immunomodulating treatment-were included in the Clinical Management Review, and two addressed a primary outcome. Studies were likely confounded by indication and discordant findings existed among studies. When updating our search, we still did not identify any study reporting data relevant to this review in their primary publication. INTERPRETATION: No study was designed to answer our research questions of interest. It remains unclear whether TB/SARS-CoV-2 and its therapeutic management are associated with unfavorable outcomes. Research is needed to improve our understanding of risk and optimal management of persons with TB and SARS-CoV-2 infection. TRIAL REGISTRATION: Registration: PROSPERO (CRD42022309818).

Artificial intelligence-based computer aided detection (AI-CAD) in the fight against tuberculosis: Effects of moving health technologies in global health.

Computer Aided Detection software based on Artificial Intelligence (AI-CAD), combined with chest X-rays have recently been promoted as an easy fix for a complex problem: ending TB by 2030. WHO has recommended the use of such imaging devices in 2021 and many partnerships have helped propose benchmark analysis and technology comparisons to facilitate their "market access". Our aim is to examine the socio-political and health issues that stem from using AI-CAD technology in a global health context conceptualized as a set of practice and ideas organizing global intervention "in the life of others". We also question how this technology, which is not yet fully implemented in routine use, may limit or amplify some inequalities in the care of tuberculosis. We describe AI-CAD through Actor-Network-Theory framework to understand the global assemblage and composite activities associated with detection through AI-CAD, and interrogate how the technology itself may consolidate a specific configuration of "global health". We explore the various dimensions of AI-CAD "health effects model": technology design, development, regulation, institutional competition, social interaction and health cultures. On a broader level, AI-CAD represents a new version of global health's accelerationist model centered on "moving and autonomous-presumed technologies". We finally present key aspects in our research which help discuss the theories mobilized: AI-CAD ambivalent insertion in global health, the social lives of its data: from efficacy to markets and AI-CAD human care and maintenance it requires. We reflect on the conditions that will affect AI-CAD use and its promises. In the end, the risk of new detection technologies such as AI-CAD is indeed that the fight against TB could be reduced to one that is purely technical and technological, with neglect to its social determinants and effects.

Artificial intelligence-reported chest X-ray findings of culture-confirmed pulmonary tuberculosis in people with and without diabetes.

Objectives: We applied computer-aided detection (CAD) software for chest X-ray (CXR) analysis to determine if diabetes affects the radiographic presentation of tuberculosis. Methods: From March 2017-July 2018, we consecutively enrolled adults being evaluated for pulmonary tuberculosis in Karachi, Pakistan. Participants had same-day CXR, two sputum mycobacterial cultures, and random blood glucose measurement. We identified diabetes through self-report or glucose >11.1mMol/L. We included participants with culture-confirmed tuberculosis for this analysis. We used linear regression to estimate associations between CAD-reported tuberculosis abnormality score (range 0.00 to 1.00) and diabetes, adjusting for age, body mass index, sputum smear-status, and prior tuberculosis. We also compared radiographic abnormalities between participants with and without diabetes. Results: 63/272 (23%) of included participants had diabetes. After adjustment, diabetes was associated with higher CAD tuberculosis abnormality scores (p < 0.001). Diabetes was not associated with frequency of CAD-reported radiographic abnormalities apart from cavitary disease; participants with diabetes were more likely to have cavitary disease (74.6% vs 61.2% p = 0.07), particularly non-upper zone cavitary disease (17% vs 7.8%, p = 0.09). Conclusions: CAD analysis of CXR suggests diabetes is associated with more extensive radiographic abnormalities and with greater likelihood of cavities outside upper lung zones.

Comparative Effectiveness of Regimens for Drug-Susceptible Tuberculous Meningitis in Children and Adolescents: A Systematic Review and Aggregate-Level Data Meta-Analysis.

Background: Before August 2021, the only regimen recommended by the World Health Organization (WHO) to treat pediatric drug-susceptible tuberculous meningitis was a 12-month regimen consisting of isoniazid, rifampicin, ethambutol, and pyrazinamide (2HRZE/10HR). The comparative effectiveness of shorter regimens is unknown. Methods: To inform a WHO guideline update, we undertook a systematic review and meta-analysis to evaluate outcomes from regimens of 6- to less than 12-months' duration that included, at a minimum, isoniazid, rifampicin, and pyrazinamide. We included studies that applied rigorous diagnostic criteria and reported outcomes for ≥10 children or adolescents. Using generalized linear mixed models, we estimated the random effects pooled proportions of patients with key outcomes. Results: Of 7 included studies, none compared regimens head-to-head. Three studies (724 patients) used a 6-month intensive regimen, which includes isoniazid and rifampicin at higher doses, pyrazinamide, and ethionamide instead of ethambutol (6HRZEto). Outcomes for this versus the 12-month regimen (282 patients, 3 studies) were, respectively, as follows: death, 5.5% (95% confidence interval [CI], 2.1%-13.4%) vs 23.9% (95% CI, 17.5%-31.7%); treatment success (survival with or without sequelae), 94.6% (95% CI, 73.9%-99.1%) vs 75.4% (95% CI, 68.7%-81.1%); and neurological sequelae among survivors, 66.0% (95% CI, 55.3%-75.3%) vs 36.3% (95% CI, 30.1%-43.0%). Relapse did not occur among 148 patients followed-up for 2 years after completing the 6-month intensive regimen. Conclusions: Our findings are limited by the small number of studies and substantial potential for confounding. Nonetheless, the 6HRZEto regimen was associated with high treatment success and is now recommended by WHO as an alternative to the 12-month regimen.

Diagnostic accuracy of a commercially available, deep learning-based chest X-ray interpretation software for detecting culture-confirmed pulmonary tuberculosis.

BACKGROUND: Few evaluations of computer-aided detection (CAD) software for analyzing chest radiographs for tuberculosis have used mycobacterial culture as the reference standard. METHODS: Using data from a prospective study of symptomatic adults and household contacts of persons with tuberculosis who were seeking care in Karachi, we evaluated the accuracy of LUNIT INSIGHT version 3.1.0.0 (LUNIT, South Korea) for detecting pulmonary tuberculosis in the triage use case. The reference standard was liquid culture. We estimated the diagnostic accuracy using three developer-recommended threshold scores for tuberculosis: 15, 30, and 45. RESULTS: A total 269 of 2190 (12%) participants had culture-confirmed pulmonary tuberculosis. LUNIT-reported abnormalities of nodule, consolidation, fibrosis, and pleural effusion were more common with culture-confirmed tuberculosis. At the tuberculosis threshold score of 30, sensitivity and specificity were, respectively, 87.7% [95% CI: 83.2-91.4%] and 64.3% [62.1-66.4%]. Sensitivity was similar at scores of 15, 88.1% [95% CI: 83.6-91.7%] and 45, 86.6% [82.0 - 90.5%]; and specificity was 57.9% [55.7-60.2%] and 69.9% [67.8-71.9%], respectively. Sensitivity was lower for smear-negative disease, and specificity was lower with increasing age, previous tuberculosis, and decreasing body mass index. Diabetes and tobacco smoking did not modify accuracy. CONCLUSION: In a population where most tuberculosis was smear-positive, LUNIT-reported radiographic abnormalities were associated with culture-confirmed disease. Manufacturer-recommended threshold scores had limited sensitivity.

Chest X-ray Analysis With Deep Learning-Based Software as a Triage Test for Pulmonary Tuberculosis: An Individual Patient Data Meta-Analysis of Diagnostic Accuracy.

BACKGROUND: Automated radiologic analysis using computer-aided detection software (CAD) could facilitate chest X-ray (CXR) use in tuberculosis diagnosis. There is little to no evidence on the accuracy of commercially available deep learning-based CAD in different populations, including patients with smear-negative tuberculosis and people living with human immunodeficiency virus (HIV, PLWH). METHODS: We collected CXRs and individual patient data (IPD) from studies evaluating CAD in patients self-referring for tuberculosis symptoms with culture or nucleic acid amplification testing as the reference. We reanalyzed CXRs with three CAD programs (CAD4TB version (v) 6, Lunit v3.1.0.0, and qXR v2). We estimated sensitivity and specificity within each study and pooled using IPD meta-analysis. We used multivariable meta-regression to identify characteristics modifying accuracy. RESULTS: We included CXRs and IPD of 3727/3967 participants from 4/7 eligible studies. 17% (621/3727) were PLWH. 17% (645/3727) had microbiologically confirmed tuberculosis. Despite using the same threshold score for classifying CXR in every study, sensitivity and specificity varied from study to study. The software had similar unadjusted accuracy (at 90% pooled sensitivity, pooled specificities were: CAD4TBv6, 56.9% [95% confidence interval {CI}: 51.7-61.9]; Lunit, 54.1% [95% CI: 44.6-63.3]; qXRv2, 60.5% [95% CI: 51.7-68.6]). Adjusted absolute differences in pooled sensitivity between PLWH and HIV-uninfected participants were: CAD4TBv6, -13.4% [-21.1, -6.9]; Lunit, +2.2% [-3.6, +6.3]; qXRv2: -13.4% [-21.5, -6.6]; between smear-negative and smear-positive tuberculosis was: were CAD4TBv6, -12.3% [-19.5, -6.1]; Lunit, -17.2% [-24.6, -10.5]; qXRv2, -16.6% [-24.4, -9.9]. Accuracy was similar to human readers. CONCLUSIONS: For CAD CXR analysis to be implemented as a high-sensitivity tuberculosis rule-out test, users will need threshold scores identified from their own patient populations and stratified by HIV and smear status.

Gender-based differences in community-wide screening for pulmonary tuberculosis in Karachi, Pakistan: an observational study of 311 732 individuals undergoing screening.

We describe gender-based differences in a community-wide TB screening programme in Karachi, Pakistan, in which 311 732 individuals were screened in mobile camps using symptom questionnaires and van-mounted digital chest X-ray, between 1 January 2018 and 31 December 2019. Only 22.4% (69 869) of camp attendees were women. Female attendees were less likely to have sputum collected and tested (31.5% (95% CI 30.4% to 32.7%) vs 38.5% (95% CI 37.6% to 39.1%)) or to initiate TB treatment (75.9% (95% CI 68.1% to 82.6%) vs 82.8% (95% CI 78.9% to 86.2%)), when indicated. Among the participants, the age-standardised prevalence of active TB was higher among women (prevalence ratio 1.4, 95% CI 1.1 to 1.7). These findings underscore the importance of integrating gender into the design and monitoring of TB screening programmes to ensure that women and men benefit equally from this important intervention.

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.

Impact of COVID-19 on Tuberculosis Prevention and Treatment in Canada: A Multicenter Analysis of 10 833 Patients.

We assessed the COVID-19 pandemic's impact on treatment of latent tuberculosis, and of active tuberculosis, at 3 centers in Montreal and Toronto, using data from 10 833 patients (8685 with latent tuberculosis infection, 2148 with active tuberculosis). Observation periods prior to declarations of COVID-19 public health emergencies ranged from 219 to 744 weeks, and after declarations, from 28 to 33 weeks. In the latter period, reductions in latent tuberculosis infection treatment initiation rates ranged from 30% to 66%. At 2 centers, active tuberculosis treatment rates fell by 16% and 29%. In Canada, cornerstone measures for tuberculosis elimination weakened during the COVID-19 pandemic.

Triage of Persons With Tuberculosis Symptoms Using Artificial Intelligence-Based Chest Radiograph Interpretation: A Cost-Effectiveness Analysis.

BACKGROUND: In settings without access to rapid expert radiographic interpretation, artificial intelligence (AI)-based chest radiograph (CXR) analysis can triage persons presenting with possible tuberculosis (TB) symptoms, to identify those who require additional microbiological testing. However, there is limited evidence of the cost-effectiveness of this technology as a triage tool. METHODS: A decision analysis model was developed to evaluate the cost-effectiveness of triage strategies with AI-based CXR analysis for patients presenting with symptoms suggestive of pulmonary TB in Karachi, Pakistan. These strategies were compared to the current standard of care using microbiological testing with smear microscopy or GeneXpert, without prior triage. Positive triage CXRs were considered to improve referral success for microbiologic testing, from 91% to 100% for eligible persons. Software diagnostic accuracy was based on a prospective field study in Karachi. Other inputs were obtained from the Pakistan TB Program. The analysis was conducted from the healthcare provider perspective, and costs were expressed in 2020 US dollars. RESULTS: Compared to upfront smear microscopy for all persons with presumptive TB, triage strategies with AI-based CXR analysis were projected to lower costs by 19%, from $23233 per 1000 persons, and avert 3%-4% disability-adjusted life-years (DALYs), from 372 DALYs. Compared to upfront GeneXpert, AI-based triage strategies lowered projected costs by 37%, from $34346 and averted 4% additional DALYs, from 369 DALYs. Reinforced follow-up for persons with positive triage CXRs but negative microbiologic tests was particularly cost-effective. CONCLUSIONS: In lower-resource settings, the addition of AI-based CXR triage before microbiologic testing for persons with possible TB symptoms can reduce costs, avert additional DALYs, and improve TB detection.

Diagnostic accuracy of serological tests for covid-19: systematic review and meta-analysis.

OBJECTIVE: To determine the diagnostic accuracy of serological tests for coronavirus disease-2019 (covid-19). DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, bioRxiv, and medRxiv from 1 January to 30 April 2020, using subject headings or subheadings combined with text words for the concepts of covid-19 and serological tests for covid-19. ELIGIBILITY CRITERIA AND DATA ANALYSIS: Eligible studies measured sensitivity or specificity, or both of a covid-19 serological test compared with a reference standard of viral culture or reverse transcriptase polymerase chain reaction. Studies were excluded with fewer than five participants or samples. Risk of bias was assessed using quality assessment of diagnostic accuracy studies 2 (QUADAS-2). Pooled sensitivity and specificity were estimated using random effects bivariate meta-analyses. MAIN OUTCOME MEASURES: The primary outcome was overall sensitivity and specificity, stratified by method of serological testing (enzyme linked immunosorbent assays (ELISAs), lateral flow immunoassays (LFIAs), or chemiluminescent immunoassays (CLIAs)) and immunoglobulin class (IgG, IgM, or both). Secondary outcomes were stratum specific sensitivity and specificity within subgroups defined by study or participant characteristics, including time since symptom onset. RESULTS: 5016 references were identified and 40 studies included. 49 risk of bias assessments were carried out (one for each population and method evaluated). High risk of patient selection bias was found in 98% (48/49) of assessments and high or unclear risk of bias from performance or interpretation of the serological test in 73% (36/49). Only 10% (4/40) of studies included outpatients. Only two studies evaluated tests at the point of care. For each method of testing, pooled sensitivity and specificity were not associated with the immunoglobulin class measured. The pooled sensitivity of ELISAs measuring IgG or IgM was 84.3% (95% confidence interval 75.6% to 90.9%), of LFIAs was 66.0% (49.3% to 79.3%), and of CLIAs was 97.8% (46.2% to 100%). In all analyses, pooled sensitivity was lower for LFIAs, the potential point-of-care method. Pooled specificities ranged from 96.6% to 99.7%. Of the samples used for estimating specificity, 83% (10 465/12 547) were from populations tested before the epidemic or not suspected of having covid-19. Among LFIAs, pooled sensitivity of commercial kits (65.0%, 49.0% to 78.2%) was lower than that of non-commercial tests (88.2%, 83.6% to 91.3%). Heterogeneity was seen in all analyses. Sensitivity was higher at least three weeks after symptom onset (ranging from 69.9% to 98.9%) compared with within the first week (from 13.4% to 50.3%). CONCLUSION: Higher quality clinical studies assessing the diagnostic accuracy of serological tests for covid-19 are urgently needed. Currently, available evidence does not support the continued use of existing point-of-care serological tests. STUDY REGISTRATION: PROSPERO CRD42020179452.

Standardised shorter regimens versus individualised longer regimens for rifampin- or multidrug-resistant tuberculosis.

We sought to compare the effectiveness of two World Health Organization (WHO)-recommended regimens for the treatment of rifampin- or multidrug-resistant (RR/MDR) tuberculosis (TB): a standardised regimen of 9-12 months (the "shorter regimen") and individualised regimens of ≥20 months ("longer regimens").We collected individual patient data from observational studies identified through systematic reviews and a public call for data. We included patients meeting WHO eligibility criteria for the shorter regimen: not previously treated with second-line drugs, and with fluoroquinolone- and second-line injectable agent-susceptible RR/MDR-TB. We used propensity score matched, mixed effects meta-regression to calculate adjusted odds ratios and adjusted risk differences (aRDs) for failure or relapse, death within 12 months of treatment initiation and loss to follow-up.We included 2625 out of 3378 (77.7%) individuals from nine studies of shorter regimens and 2717 out of 13 104 (20.7%) individuals from 53 studies of longer regimens. Treatment success was higher with the shorter regimen than with longer regimens (pooled proportions 80.0% versus 75.3%), due to less loss to follow-up with the former (aRD -0.15, 95% CI -0.17- -0.12). The risk difference for failure or relapse was slightly higher with the shorter regimen overall (aRD 0.02, 95% CI 0-0.05) and greater in magnitude with baseline resistance to pyrazinamide (aRD 0.12, 95% CI 0.07-0.16), prothionamide/ethionamide (aRD 0.07, 95% CI -0.01-0.16) or ethambutol (aRD 0.09, 95% CI 0.04-0.13).In patients meeting WHO criteria for its use, the standardised shorter regimen was associated with substantially less loss to follow-up during treatment compared with individualised longer regimens and with more failure or relapse in the presence of resistance to component medications. Our findings support the need to improve access to reliable drug susceptibility testing.

Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline.

Background: The American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America jointly sponsored this new practice guideline on the treatment of drug-resistant tuberculosis (DR-TB). The document includes recommendations on the treatment of multidrug-resistant TB (MDR-TB) as well as isoniazid-resistant but rifampin-susceptible TB.Methods: Published systematic reviews, meta-analyses, and a new individual patient data meta-analysis from 12,030 patients, in 50 studies, across 25 countries with confirmed pulmonary rifampin-resistant TB were used for this guideline. Meta-analytic approaches included propensity score matching to reduce confounding. Each recommendation was discussed by an expert committee, screened for conflicts of interest, according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology.Results: Twenty-one Population, Intervention, Comparator, and Outcomes questions were addressed, generating 25 GRADE-based recommendations. Certainty in the evidence was judged to be very low, because the data came from observational studies with significant loss to follow-up and imbalance in background regimens between comparator groups. Good practices in the management of MDR-TB are described. On the basis of the evidence review, a clinical strategy tool for building a treatment regimen for MDR-TB is also provided.Conclusions: New recommendations are made for the choice and number of drugs in a regimen, the duration of intensive and continuation phases, and the role of injectable drugs for MDR-TB. On the basis of these recommendations, an effective all-oral regimen for MDR-TB can be assembled. Recommendations are also provided on the role of surgery in treatment of MDR-TB and for treatment of contacts exposed to MDR-TB and treatment of isoniazid-resistant TB.

A systematic review of the diagnostic accuracy of artificial intelligence-based computer programs to analyze chest x-rays for pulmonary tuberculosis.

We undertook a systematic review of the diagnostic accuracy of artificial intelligence-based software for identification of radiologic abnormalities (computer-aided detection, or CAD) compatible with pulmonary tuberculosis on chest x-rays (CXRs). We searched four databases for articles published between January 2005-February 2019. We summarized data on CAD type, study design, and diagnostic accuracy. We assessed risk of bias with QUADAS-2. We included 53 of the 4712 articles reviewed: 40 focused on CAD design methods ("Development" studies) and 13 focused on evaluation of CAD ("Clinical" studies). Meta-analyses were not performed due to methodological differences. Development studies were more likely to use CXR databases with greater potential for bias as compared to Clinical studies. Areas under the receiver operating characteristic curve (median AUC [IQR]) were significantly higher: in Development studies AUC: 0.88 [0.82-0.90]) versus Clinical studies (0.75 [0.66-0.87]; p-value 0.004); and with deep-learning (0.91 [0.88-0.99]) versus machine-learning (0.82 [0.75-0.89]; p = 0.001). We conclude that CAD programs are promising, but the majority of work thus far has been on development rather than clinical evaluation. We provide concrete suggestions on what study design elements should be improved.

Long-term all-cause mortality in people treated for tuberculosis: a systematic review and meta-analysis.

BACKGROUND: Accurate estimates of long-term mortality following tuberculosis treatment are scarce. This systematic review and meta-analysis aimed to estimate the post-treatment mortality among tuberculosis survivors, and examine differences in mortality risk by demographic and clinical characteristics. METHODS: We systematically searched Embase, MEDLINE, and the Cochrane Database of Systematic Reviews for cohort studies published in English between Jan 1, 1997, and May 31, 2018. We included research papers that used a cohort study design, included bacteriological or clinical confirmation of tuberculosis disease for all participants, and reported, or provided enough data to calculate, mortality estimates for people with tuberculosis and a valid control group representative of the general population. We excluded studies that reported duplicate data, had a study population of fewer than 50 people overall, had a follow-up period shorter than 12 months after treatment completion, or had a loss to follow-up of more than 30%. From eligible studies, we extracted standardised mortality ratios (SMRs), or calculated them when the data were sufficient, by dividing the sum of the observed deaths by the sum of the expected deaths. For studies that did not report SMR as their mortality estimate, either mortality hazard ratios or mortality rate ratios were extracted and pooled with SMRs. Random-effects meta-analysis was used to obtain pooled SMRs. Between-study heterogeneity was estimated with I2. This study was prospectively registered in PROSPERO (CRD42018092592). FINDINGS: Of the 7283 unique studies identified, data from ten studies, reporting on 40 781 individuals and 6922 deaths, were included. The pooled SMR for all-cause mortality among people with tuberculosis, compared with the control group, was 2·91 (95% CI 2·21-3·84; I2=99%, pheterogeneity<0·0001). When restricted to people with confirmed treatment completion or cure, the pooled SMR was 3·76 (95% CI 3·04-4·66; I2=95%). Effect estimates were similar when stratified by tuberculosis type, sex, age, and country income category. Causes of mortality were extracted for 4226 deaths that occurred post-treatment, with most deaths attributable to cardiovascular disease (20% [95% CI 15-26]; I2=92%). INTERPRETATION: People treated for tuberculosis have significantly increased mortality following treatment compared with the general population or matched controls. These findings support the need for further research to understand and address the biomedical and social factors that affect the long-term prognosis of this population. FUNDING: None.