Sustainability and impact of an intervention to improve initiation of tuberculosis preventive treatment: results from a follow-up study of the ACT4 randomized trial.

Background: In a cluster randomized trial (clinicaltrials.gov: NCT02810678) a flexible but comprehensive health system intervention significantly increased the number of household contacts (HHC) identified and started on tuberculosis preventive treatment (TPT). A follow-up study was conducted one year later to test the hypotheses that these effects were sustained, and were reproducible with a simplified intervention. Methods: We conducted a follow-up study from May 1, 2018 until April 30, 2019, as part of a multinational cluster randomized trial. Eight sites in 4 countries that had received the intervention in the original trial received no further intervention; eight other sites in the same countries that had not received the intervention (control sites in the original trial) now received a simplified version of the intervention. This consisted of repeated local evaluation of the Cascade of care for TB infection, and stakeholder decision making. The number of HHC identified and starting TPT were repeatedly measured at all 16 sites and expressed as rates per 100 newly diagnosed index TB patients. The sustained effect of the original intervention was estimated by comparing these rates after the intervention in the original trial with the last 6 months of the follow-up study. The reproducibility was estimated by comparing the pre-post intervention changes in rates at sites receiving the original intervention with the pre-post changes in rates at sites receiving the later, simplified intervention. Findings: With regard to the sustained impact of the original intervention, compared to the original post-intervention period, the number of HHC identified and treated per 100 newly diagnosed TB patients was 10 more (95% confidence interval: 84 fewer to 105 more), and 1 fewer (95% CI: 22 fewer to 20 more) respectively up to 14 months after the end of the original intervention. With regard to the reproducibility of the simplified intervention, at sites that had initially served as control sites, the number of HHC identified and treated per 100 TB patients increased by 33 (95% CI: -32, 97), and 16 (-69, 100) from 3 months before, to up to 6 months after receiving a streamlined intervention, although differences were larger, and significant if the post-intervention results were compared to all pre-intervention periods. Interpretation: Up to one year after it ended, a health system intervention resulted in sustained increases in the number of HHC identified and starting TPT. A simplified version of the intervention was associated with non-significant increases in the identification and treatment of HHC. Inferences are limited by potential bias due to other temporal effects, and the small number of study sites. Funding: Funded by the Canadian Institutes of Health Research (Grant number 143350).

High-dose, short-duration versus standard rifampicin for tuberculosis preventive treatment: a partially blinded, three-arm, non-inferiority, randomised, controlled trial.

BACKGROUND: Tuberculosis preventive treatment (TPT) is a key component of tuberculosis elimination. To improve completion and reduce the burden for people and health systems, short, safe, and effective TPT regimens are needed. We aimed to compare safety and treatment completion of various doses and durations of rifampicin in people who were recommended to receive TPT. METHODS: This partially blinded, parallel-arm, non-inferiority, randomised, controlled, phase 2b trial was done at seven university-affiliated clinics in Canada, Indonesia, and Viet Nam. Participants aged 10 years or older were included if they had an indication for TPT according to WHO guidelines for Indonesia and Viet Nam, or Canadian guidelines for Canadian sites, and a positive tuberculin skin test or interferon-γ release assay. Participants were randomly assigned (1:1:1) to receive oral rifampicin at 10 mg/kg once daily for 4 months (standard-dose group), 20 mg/kg daily for 2 months (20 mg/kg group), or 30 mg/kg daily for 2 months (30 mg/kg group). The randomisation sequence was computer generated with blocks of variable size (three, six, and nine) and stratified by country for Indonesia and Viet Nam, and by city within Canada. Participants and investigators were masked to dose in high-dose groups, but unmasked to duration in all groups. The two co-primary outcomes were safety (in the safety population, in which participants received at least one dose of the study drug) and treatment completion (in the modified intention-to-treat [mITT] population, excluding those ineligible after randomisation). Protocol-defined adverse events were defined as grade 3 or worse, or rash or allergy of any grade, judged by an independent and masked panel as possibly or probably related to the study. A margin of 4% was used to assess non-inferiority. This study is registered with ClinicalTrials.gov, NCT03988933 (active). FINDINGS: Between Sept 1, 2019, and Sept 30, 2022, 1692 people were assessed for eligibility, 1376 were randomly assigned, and eight were excluded after randomisation. 1368 participants were included in the mITT population (454 in the standard group, 461 in the 20 mg/kg group, and 453 in the 30 mg/kg group). 589 (43%) participants were male and 779 (57%) were female. 372 (82%) in the standard-dose group, 329 (71%) in the 20 mg/kg group, and 293 (65%) in the 30 mg/kg group completed treatment. No participants in the standard-dose group, one (<1%) of 441 participants in the 20 mg/kg group, and four (1%) of 423 in the 30 mg/kg group developed grade 3 hepatotoxicity. Risk of protocol-defined adverse events was higher in the 30 mg/kg group than in the standard-dose group (adjusted risk difference 4·6% [95% CI 1·8 to 7·4]) or the 20 mg/kg group (5·1% [2·3 to 7·8]). There was no difference in the risk of adverse events between the 20 mg/kg and standard-dose groups (-0·5% [95% CI -2·4 to 1·5]; non-inferiority met). Completion was lower in the 20 mg/kg group (-7·8% [95% CI -13·6 to -2·0]) and the 30 mg/kg group (-15·4% [-21·4 to -9·4]) than in the standard-dose group. INTERPRETATION: In this trial, 2 months of 30 mg/kg daily rifampicin had significantly worse safety and completion than 4 months of 10 mg/kg daily and 2 months of 20 mg/kg daily (the latter, a fully blinded comparison); we do not consider 30 mg/kg to be a good option for TPT. Rifampicin at 20 mg/kg daily for 2 months was as safe as standard treatment, but with lower completion. This difference remains unexplained. FUNDING: Canadian Institutes of Health Research.

Characterization of Mycobacterium orygis, Mycobacterium bovis, and Mycobacterium caprae Infections in Humans in Western Canada.

Epidemiologic research on zoonotic tuberculosis historically used Mycobacterium bovis as a surrogate measure, however, increased reports of human tuberculosis caused by other animal-associated Mycobacterium tuberculosis complex members like Mycobacterium orygis necessitates their inclusion. We performed a retrospective cohort study including persons infected with any animal-lineage M. tuberculosis complex species in Alberta, Canada, from January 1995 to July 2021, identifying 42 patients (20 M. bovis, 21 M. orygis, one M. caprae). Demographic, epidemiologic and clinical characteristics were compared against persons with culture-confirmed M. tuberculosis infection. The proportion of culture-positive infections caused by M. orygis increased continuously from 2016-2020. Significantly more females at a higher median age were impacted by M. orygis, with all patients originating from South Asia. M. bovis caused significantly more extra-pulmonary disease, and disproportionately impacted young females, particularly those pregnant or post-partum. All infections were acquired abroad. These findings can aid in developing targeted public health interventions.

The association between phylogenetic lineage and the subclinical phenotype of pulmonary tuberculosis: A retrospective 2-cohort study.

BACKGROUND: Subclinical pulmonary tuberculosis (PTB) is an asymptomatic disease state between established TB infection and symptomatic (clinical) TB disease. It is present in 20-25% of PTB patients in high-income countries. Mycobacterium tuberculosis complex (MTBC) genetic heterogeneity, and differential host immunological responses, have been implicated in its pathogenesis. METHODS: To determine the association between MTBC lineage and PTB disease phenotype, we used two retrospective cohorts of PTB patients in Canada and two independent lineage attribution methods (DNA fingerprinting and genome sequencing). The first cohort, Cohort 1, consisted of consecutively diagnosed PTB patients between 2014 and 2020. The second, Cohort 2, consisted of newly-arrived foreign-born PTB patients who either were or were not referred for post-landing medical surveillance between 2004 and 2017. Univariable and multivariable logistic regression models were sequentially fitted to both cohorts, adjusting for age, sex, disease type, drug resistance and HIV. Evolution of radiographic features was correlated to lineage in Cohort 2. FINDINGS: Cohort 1 and 2 included 874 (209 subclinical) and 111 (44 subclinical) patients, respectively. In both cohorts, subclinical patients were more likely than clinical patients to have relapse/retreatment disease, be smear-negative, have longer times-to-culture positivity and to harbor an ancestral MTBC lineage (Indo-Oceanic or Mycobacterium africanum). Relapse/retreatment disease and ancestral MTBC lineage were independent predictors of subclinical disease (ORs and 95% CIs in Cohort 1, 1.85 [1.07,3.28], p < 0.029 and 2.30 [1.66,3.18], p < 0.001, respectively, and Cohort 2, 5.74 [1.37-24.06], p < 0.017 and 3.21 (1.29,7.97], p < 0.012, respectively). The geographic distribution of Indo-Oceanic strains causing subclinical disease was uneven. Non-progressive lung disease was more common in patients infected with ancestral than modern lineages in Cohort 2, 56.0% vs 25.4%, p < 0.005. INTERPRETATION: MTBC lineage is a strong predictor of PTB disease phenotype. The genetic drivers of this association, and the relative contribution of other explanatory variables, are unknown.

Limitations of Chest Radiography in Diagnosing Subclinical Pulmonary Tuberculosis in Canada.

Subclinical pulmonary tuberculosis (PTB) is defined as "…a state of disease due to viable Mycobacterium tuberculosis that does not cause TB-related symptoms but does cause other abnormalities that can be detected using existing radiologic and mycobacteriologic assays." In high-income countries, subclinical PTB is usually diagnosed during active case finding, is acid-fast bacilli smear negative, and associated with minimal or no lung parenchymal abnormality on chest radiograph. In the absence of symptoms, the epidemiologic risk of TB and chest radiograph are critical to making the diagnosis. In a cohort of 327 patients with subclinical PTB, we address the question-how well field radiologists perform at identifying features important to the diagnosis of PTB, the presence or absence of which have been established by a panel of expert radiologists? Although not performing badly compared with this "gold standard," field readers were nevertheless susceptible to overread or underread films and miss key diagnostic features, such as the presence of a lung parenchymal abnormality, typical pattern, or cavitation. In the context of active case finding during which most patients with subclinical PTB are discovered, limitations of the chest radiograph need to be recognized, and sputum, ideally induced, should be submitted regardless of the radiographic findings.

Time to diagnosis and treatment of pulmonary tuberculosis in indigenous peoples: a systematic review.

BACKGROUND: Time to diagnosis and treatment is a major factor in determining the likelihood of tuberculosis (TB) transmission and is an important area of intervention to reduce the reservoir of TB infection and prevent disease and mortality. Although Indigenous peoples experience an elevated incidence of TB, prior systematic reviews have not focused on this group. We summarize and report findings related to time to diagnosis and treatment of pulmonary TB (PTB) among Indigenous peoples, globally. METHODS: A Systematic review was performed using Ovid and PubMed databases. Articles or abstracts estimating time to diagnosis, or treatment of PTB among Indigenous peoples were included with no restriction on sample size with publication dates restricted up to 2019. Studies that focused on outbreaks, solely extrapulmonary TB alone in non-Indigenous populations were excluded. Literature was assessed using the Hawker checklist. Registration Protocol (PROSPERO): CRD42018102463. RESULTS: Twenty-four studies were selected after initial assessment of 2021 records. These included Indigenous groups from five of six geographical regions outlined by the World Health Organization (all except the European Region). The range of time to treatment (24-240 days), and patient delay (20 days-2.5 years) were highly variable across studies and, in at least 60% of the studies, longer in Indigenous compared to non-Indigenous peoples. Risk factors associated with longer patient delays included poor awareness of TB, type of health provider first seen, and self-treatment. CONCLUSION: Time to diagnosis and treatment estimates for Indigenous peoples are generally within previously reported ranges from other systematic reviews focusing on the general population. However among literature examined in this systematic review that stratified by Indigenous and non-Indigenous peoples, patient delay and time to treatment were longer compared to non-Indigenous populations in over half of the studies. Studies included were sparse and highlight an overall gap in literature important to interrupting transmission and preventing new TB cases among Indigenous peoples. Although, risk factors unique to Indigenous populations were not identified, further investigation is needed as social determinants of health among studies conducted in medium and high incidence countries may be shared across both population groups. Trial registration N/a.

The prevalence, risk factors, and public health consequences of peripheral lymph node-associated clinical and subclinical pulmonary tuberculosis.

OBJECTIVES: Relatively little is known about the prevalence, risk factors, and public health consequences of peripheral lymph node (PLN)-associated pulmonary tuberculosis (PTB). METHODS: We developed a 10-year (2010-2019) population-based cohort of PLNTB patients in Canada. We used systematically collected primary source data and expert reader chest radiograph interpretations in a multivariable logistic regression to determine associations between sputum culture positivity and demographic, clinical, and radiographic features. Public health risks were estimated among contacts of PLNTB patients. RESULTS: There were 306 patients with PLNTB, among whom 283 (92.5%) were 15-64 years of age, 159 (52.0%) were female, and 293 (95.8%) were foreign-born. Respiratory symptoms were present in 21.6%, and abnormal chest radiograph in 23.2%. Sputum culture positivity ranged from 12.9% in patients with no symptoms and normal lung parenchyma to 66.7% in patients with both. Respiratory symptoms, abnormal lung parenchyma, and HIV-coinfection (borderline) were independent predictors of sputum culture positivity (odds ratio [OR] 2.24 [95% confidence interval [CI] 1.15-4.39], P = 0.01, OR 4.78 [95% CI 2.41-9.48], P < 0.001, and OR 2.54 [95% CI 0.99-6.52], P = 0.05), respectively. Among contacts of sputum culture-positive PLNTB patients, one secondary case and 16 new infections were identified. CONCLUSION: Isochronous PTB is common in PLNTB patients. Routine screening of PLNTB patients for PTB is strongly recommended.

High dose rifampin for 2 months vs standard dose rifampin for 4 months, to treat TB infection: Protocol of a 3-arm randomized trial (2R2).

INTRODUCTION: Tuberculosis preventive treatment (TPT) is an essential component for TB elimination. In order to be successfully implemented on a large scale, TPT needs to be safe, affordable and widely available in all settings. Short TPT regimens, that are less burdensome than longer regimens, to patients and health systems, are needed. Doses of rifampin higher than the standard 10mg/kg/day were tolerated in studies to reduce duration of treatment for tuberculosis disease (TBD). The objective of this trial is to test the safety of high dose rifampin monotherapy to shorten the duration of the currently recommended TPT of 4 months rifampin. METHODS AND ANALYSIS: This is a phase 2b, randomised, controlled, parallel group, superiority, partially-blind trial. Primary outcomes are completion of treatment (as a proxy measure of tolerability) and safety. The two experimental arms comprise 60 days of (i) 20mg/kg/day or (ii) 30mg/kg/day rifampin; the control arm comprises 120 days of 10mg/kg/day rifampin as TPT. Participants are adults and children 10 years or older, eligible for TPT. Completion is the primary outcome, measured by pill count and is defined as taking minimum of 80% of treatment in 120% of allowed time; it will be tested for superiority by logistic regression. Safety outcome comprises proportion of grade 3-5 adverse events and grade 1-2 rash, adjudicated related to study drug, and resulting in permanent drug discontinuation; compared for non-inferiority between each of the two high dose arms and the standard arm, using Poisson regression. A sample size of 1,359 participants will give 80% power to detect a 10% difference in completion rates and a 1% difference in the safety outcome. The study is conducted in Canada, Indonesia and Vietnam. Enrolment is ongoing at all sites. ETHICS AND DISSEMINATION: Approvals from a local research ethics board (REB) have been obtained at all participating sites and by the trial coordinating centre. Approval has been given by drug regulatory agencies in Canada and Indonesia and by Ministry of Health in Vietnam; participants give written informed consent before participation. All data collected are non-nominal. Primary results will be submitted for publication in a peer-reviewed journal when all participants have completed treatment; results of secondary outcomes will be submitted for publication at the end of study; all sites will receive the final data of participants from their sites. TRIAL REGISTRATION: Trial registered in ClinicalTrials.gov (Identifier: NCT03988933). Coordinating center is the study team working at McGill University Health Center-Research Institute (MUHC-RI); sponsor is the MUHC-RI; funding has been granted by Canadian Institute of Health Research (FDN-143350).

Human resource implications of expanding latent tuberculosis patient care activities.

Introduction: The World Health Organization (WHO) declared increasing services for latent tuberculosis infection (LTBI) a priority to eliminate tuberculosis (TB) by 2035. Yet, there is little information about thehuman resource needs required to implement LTBI treatment scale-up. Our study aimed to estimate the change in healthcare workers (HCW) time spent on different patient care activities, following an intervention to strengthen LTBI services. Methods: We conducted a time and motion (TAM) study, observing HCW throughout a typical workday before and after the intervention (Evaluation and Strengthening phases, respectively) at 24 health facilities in five countries. The precise time spent on pre-specified categories of work activities was recorded. Time spent on direct patient care was subcategorized as relating to one of three conditions: LTBI, active or suspected TB, and non-TB (i.e., patients with any other medical condition). A linear mixed model (LMM) was fit to estimate the change in HCW time following the intervention. Results: A total of 140 and 143 HCW participated in the TAMs during the Evaluation and Strengthening phases, respectively. Results from intervention facilities showed an increase of 9% (95% CI: 3%, 15%) in the proportion of HCW time spent on LTBI-related services, but with a corresponding change of -11% (95% CI: -21%, -1%) on active TB services. There was no change in the proportion of time spent on LTBI care in control facilities; this remained low in both phases of the study. Discussion: Our findings suggest that additional HCW personnel will be required for expansion of LTBI services to ensure that this expansion does not reduce the time available for care of active TB patients.

Exploration of inter-jurisdictional TB programming and mobility in a Canadian First Nation community.

BACKGROUND: Colonially imposed jurisdictional boundaries that have little meaning to Indigenous peoples in Canada may confound tuberculosis (TB) prevention and care activities. This study explores how inter-jurisdictional mobility and the current accommodation of mobility through policies and programming sustain a regional TB epidemic in northwestern Saskatchewan, and northeastern Alberta. METHODS: A qualitative instrumental case study was performed using a community based participatory approach. Semi-structured interviews were conducted with First Nations peoples from a high-incidence community in Canada including community-based healthcare workers. These interview data are presented in the context of a multi-level document analysis of TB program guidelines. RESULTS: The location of the community, and related lack of access to employment, services and care, necessitates mobility across jurisdictional boundaries. There are currently no formal federal or provincial guidelines in place to accommodate highly mobile patients and clients within and across provincial TB prevention and care programs. As a result, locally developed community-based protocols, and related ad-hoc strategies ensure continuity of care. CONCLUSION: Indigenous peoples living in remote communities face unique push/pull factors that motivate mobility. When these motivations exist in communities with increased risk of contagion by communicable infectious diseases such as TB, public health risks extend into increasingly large areas with competing jurisdictional authority. Such mobility poses several threats to TB elimination. We have identified a gap in TB services to systematically accommodate mobility, with specific implications for Indigenous peoples and reconciliation. We recommend clearly defined communication paths and inter-jurisdictional coordination to ensure maintenance of care for mobile populations.

A comparison of the chest radiographic and computed tomographic features of subclinical pulmonary tuberculosis.

Subclinical pulmonary tuberculosis (PTB) is a recently described intermediate state of great interest, but about which little is known. This study sought to describe and compare the frequency of key radiologic features of subclinical PTB on chest radiograph (CXR) versus computed tomographic scan (CT), and to interpret the clinical and public health relevance of the differences. Diagnostic CXRs and CT scans of the thorax and neck in a 16-year cohort of subclinical PTB patients in Canada were re-acquired and read by two independent readers and arbitrated by a third reader. Logistic regression models were fit to determine how likely CXR features can be detected by CT scan versus CXR after adjustment for age and sex. Among 296 subclinical patients, CXRs were available in 286 (96.6%) and CT scans in 94 (32.9%). CXR features in patients with and without CT scans were comparable. Lung cavitation was 4.77 times (95% CI 1.95-11.66), endobronchial spread 19.36 times (95% CI 8.05-46.52), and moderate/far-advanced parenchymal disease 3.23 times (95% CI 1.66-6.30), more common on CT scan than CXR. We conclude that the extent to which CXRs under-detect key radiologic features in subclinical PTB is substantial. This may have public health and treatment implications.

Developing Data Governance Agreements with Indigenous Communities in Canada: Toward Equitable Tuberculosis Programming, Research, and Reconciliation.

Indigenous rights to self-determination and data sovereignty support Indigenous-led data governance, which, when adequately resourced, can act as a catalyst for Indigenous-led strategic planning and decision-making in public health research and programming. Respecting Indigenous data sovereignty and governance requires time, resources, education, and planning. Here we share our experiences and lessons learned when developing and implementing data governance agreements with select First Nations and Métis partnering communities in Canada in the context of tuberculosis prevention and care. We define the process undertaken to create a decision space, supported by data governance agreements, where researchers, program (government) stakeholders, and Indigenous community partners are equally and equitably informed to co-develop public health interventions. The decision space has implications for tackling all manner of public health concerns and can inform policy for nation-to-nation public health relationships to advance public health goals.

The Radiographic and Mycobacteriologic Correlates of Subclinical Pulmonary TB in Canada: A Retrospective Cohort Study.

BACKGROUND: Very little is known about subclinical pulmonary TB (PTB), a recently described intermediate state, in high-income countries. RESEARCH QUESTION: What is the prevalence of subclinical PTB in Canada? What are its diagnostic chest radiography features? What is the relationship between those features and time to culture positivity, and what is the association between DNA fingerprint clustering, a measure of local transmission, and radiographic or other features in the foreign-born? STUDY DESIGN AND METHODS: We used primary source data to identify a 16-year retrospective cohort of patients with PTB. Demographic and mycobacteriologic features in patients with subclinical and clinical disease were compared, and the reason for assessment of patients with subclinical disease was described. Diagnostic chest radiographs in patients with subclinical disease were read by two independent readers and were arbitrated by a third reader. Linear regression was used to compute time to culture positivity (in days) in relationship to the change in chest radiograph findings from normal or minimally abnormal to moderately or far advanced, adjusted for age and sex and stratified by reason for assessment. Multivariate logistic regression was used in foreign-born patients with subclinical disease to determine associations between DNA fingerprint clustering of Mycobacterium TB isolates and age, sex, chest radiograph features, and time since arrival. RESULTS: We identified 1,656 patients with PTB, 347 of whom (21%) were subclinical. Compared with patients with clinical disease, patients with subclinical disease were more likely to be foreign-born (90.2% vs 79.6%) and to demonstrate negative smear results (88.2% vs 43.5%). The median time to culture-positivity was 18 days (interquartile range [IQR], 14-25 days) vs 12 days (IQR, 7-17 days). Most patients with PTB (75.2%) were identified during active case finding. Parenchymal disease was absent or minimal on chest radiography in 86.4% of patients. More advanced disease on chest radiography was associated with shorter times to culture positivity in nonstratified (by 3.3 days) and stratified (by 4.5-5.8 days) analysis (active case-finding groups). DNA fingerprint clustering was associated with male sex and a longer time between arrival and diagnosis. INTERPRETATION: Subclinical patients with PTB constitute a substantial and heterogeneous minority of patients with PTB in high-income countries. DNA fingerprint clustering is consistent with some, albeit limited, local transmission.

How much do smear-negative patients really contribute to tuberculosis transmissions? Re-examining an old question with new tools.

BACKGROUND: Sputum smear microscopy is a common surrogate for tuberculosis infectiousness. Previous estimates that smear-negative patients contribute 13-20% of transmissions and are, on average, 20 to 25% as infectious as smear-positive cases are understood to be high. Herein, we use an ideal real-world setting, a comprehensive dataset, and new high-resolution techniques to more accurately estimate the true transmission risk of smear-negative cases. METHODS: We treated all adult culture-positive pulmonary TB patients diagnosed in the province of Alberta, Canada from 2003 to 2016 as potential transmitters. The primary data sources were the Alberta TB Registry and the Provincial Laboratory for Public Health. We measured, as primary outcomes, the proportion of transmissions attributable to smear-negative sources and the relative transmission rate. First, we replicated previous studies by using molecular (DNA) fingerprint clustering. Then, using a prospectively collected registry of TB contacts, we defined transmission events as active TB amongst identified contacts who either had a 100% DNA fingerprint match to the source case or a clinical diagnosis. We supplemented our analysis with genome sequencing on temporally and geographically linked DNA fingerprint clusters of cases not identified as contacts. FINDINGS: There were 1176 cases, 563 smear-negative and 613 smear-positive, and 23,131 contacts. Replicating previous studies, the proportion of transmissions attributable to smear-negative source cases was 16% (95% CI, 12-19%) and the relative transmission rate was 0.19 (95% CI, 0.14-0.26). With our combined approach, the proportion of transmission was 8% (95% CI, 3-14%) and the relative transmission rate became 0.10 (95% CI, 0.05-0.19). INTERPRETATION: When we examined the same outcomes as in previous studies but refined transmission ascertainment with the addition of conventional epidemiology and genomics, we found that smear-negative cases were ∼50% less infectious than previously thought. FUNDING: Alberta Innovates Health Solutions.

Engaging frontline providers: an important key to eliminating tuberculosis in Canada, and other high-income countries.

The greatest human cost of the rapidly moving pandemic of SARS-CoV-2 may be due to its impact on the response to other diseases. One such other disease is tuberculosis (TB). All indications suggest that COVID-19-related diversions of healthcare resources and disruptions to public health programming will exacerbate the slower moving pandemic of TB. This is expected to set back TB elimination efforts by years. This is a prediction that is especially relevant to Canada, which has repeatedly failed to meet pre-set targets for the elimination of TB even before the COVID-19 pandemic began. A collaborative approach to achieve TB elimination, one that engages all care providers, has recently been emphasized by the STOP-TB Partnership. Among TB elimination strategies, frontline providers (e.g., family physicians, emergency room physicians, and others) are well positioned to identify candidates for the treatment of latent TB infection, and make the diagnosis of infection-spreading cases of TB in a timely manner, thereby interrupting forward-moving chains of transmission. Electronic medical records offer the promise of automating these processes. In this commentary, we promote broader engagement of the workforce across multiple sectors of medicine to reduce TB associated morbidity and mortality, interrupt transmission, and shrink the reservoir of latent TB infection.

RéSUMé: Le plus grand coût humain de la pandémie de SRAS-CoV-2, une maladie à évolution rapide, pourrait être son impact sur la riposte aux autres maladies. L'une d'elles est la tuberculose. Selon tous les indicateurs, les ressources de soins de santé détournées et les programmes de santé publique perturbés pour lutter contre la COVID-19 vont exacerber la pandémie de tuberculose, dont l'évolution est plus lente. Il faut s'attendre à une régression de plusieurs années dans les efforts pour éliminer la tuberculose. C'est une prédiction qui concerne particulièrement le Canada, qui a à maintes reprises été incapable de respecter les objectifs préétablis d'élimination de la tuberculose, même avant la pandémie de COVID-19. Le Partenariat Halte à la tuberculose promulgue depuis peu une démarche concertée, impliquant tous les prestataires de soins, pour parvenir à éliminer la tuberculose. Entre autres stratégies d'élimination, on compte sur les prestataires de première ligne (médecins de famille, médecins d'urgence et autres), bien placés pour repérer les personnes candidates au traitement de la tuberculose-infection (latente) et pour diagnostiquer les cas de tuberculose-maladie (active) dans les meilleurs délais, ce qui interromprait les chaînes de transmission en mouvement. Le dossier médical électronique recèle la promesse d'automatiser ces processus. Dans notre commentaire, nous préconisons une plus grande mobilisation de la main-d'œuvre de plusieurs secteurs de la médecine afin de réduire la morbidité et la mortalité associées à la tuberculose, d'en interrompre la transmission et de réduire la taille du réservoir d'infection tuberculeuse latente.

Pharmacological Effects of Selected Medicinal Plants and Vitamins Against COVID-19.

The coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). It is a serious disease that has caused multiple deaths in various countries in the world. Globally, as of May 23, 2021, the total confirmed cases of COVID-19 have reach 166,346,635 with a total of 3,449,117 deaths. Several recent scientific studies have shown that medicinal plants and vitamins can benefit and improve the health of COVID-19 patients. However, the benefits of medicinal plants and vitamins in the treatment of COVID-19 remain unproven. Therefore, the objective of this article is to expounds the benefits of using medicinal plants (Allium sativum, curcumin, Nigella sativa, Zingiber officitale) and vitamins (vitamin C and vitamin D) that possess the antiviral properties for the prevention and/or control of COVID-19. To reach our objective, we searched scientific databases of ongoing trials in the Centers for Disease Control and Prevention websites, PubMed Central, Medline databases, and Google Scholar websites. We also searched databases on World Health Organization International Clinical Trials Registry Platform to collect relevant papers. We found that all of the selected medicinal plants and vitamins possess antiviral activities, and their individual intake shows promise for the prevention and/or control of COVID-19. We conclude that, the selected medicinal plants and vitamins possess anti-viral properties that are more likely to prevent and/or disrupt the SARS-CoV-2 replication cycle, enhance the human immune system and promote good health.

Chemo-Preventive Effect of Vegetables and Fruits Consumption on the COVID-19 Pandemic.

Coronavirus disease 2019 (COVID-19) is a new disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is a global pandemic that has claimed the death of 1,536,957 human beings worldwide including 287,842 deaths in the United States as of December 3, 2020. It has become a major threat to the medical community and the entire healthcare system in every part of the world. Recently, the Food and Drug Administration (FDA) has approved the emergency use of Pfizer and Moderna COVID-19 vaccine on December 12, 2020. However, there are concern about the new COVID-19 vaccine safety, efficacy, and immunity after the vaccination. In addition, both coronavirus and COVID-19 vaccine are new at this point and there is no scientific evidence to know whether people who are vaccinated can still carry the COVID 19 pathogens and pass them along to others. Therefore, many people all over the world have an increased interest in consuming more VF for the purpose of maintaining their health and boosting their immune system. Identifying novel antiviral agents for COVID-19 is of critical importance, and VF is an excellent source for drug discovery and therapeutic development. The objective of this study is to test the hypothesis that a high intake of vegetables and/or fruits prevents COVID-19 incidence and reduces the mortality rate. To achieve this objective, we collected the diet data of COVID-19 from Kaggle (https://www.kaggle.com/mariaren/covid19-healthy-diet-dataset), and used a machine-learning algorithm to examine the effects of different food types on COVID-19 incidences and deaths. Specifically, we used the feature selection method to identify the factors (e.g., diet-related factors) that contribute to COVID-19 morbidity and mortality. Data generated from the study demonstrated that VF intake can help to combat the SARS-CoV-2. Taken together, VF may be potential chemopreventive agents for COVID-19 due to their antiviral properties and their ability to boost the human body immune system.

Effectiveness and cost-effectiveness of a health systems intervention for latent tuberculosis infection management (ACT4): a cluster-randomised trial.

BACKGROUND: Reaching the UN General Assembly High-Level Meeting on Tuberculosis target of providing tuberculosis preventive treatment to at least 30 million people by 2022, including 4 million children under the age of 5 years and 20 million other household contacts, will require major efforts to strengthen health systems. The aim of this study was to evaluate the effectiveness and cost-effectiveness of a health systems intervention to strengthen management for latent tuberculosis infection (LTBI) in household contacts of confirmed tuberculosis cases. METHODS: ACT4 was a cluster-randomised, open-label trial involving 24 health facilities in Benin, Canada, Ghana, Indonesia, and Vietnam randomly assigned to either a three-phase intervention (LTBI programme evaluation, local decision making, and strengthening activities) or control (standard LTBI care). Tuberculin and isoniazid were provided to control and intervention sites if not routinely available. Randomisation was stratified by country and restricted to ensure balance of index patients with tuberculosis by arm and country. The primary outcome was the number of household contacts who initiated tuberculosis preventive treatment at each health facility within 4 months of the diagnosis of the index case, recorded in the first or last 6 months of our 20-month study. To ease interpretation, this number was standardised per 100 newly diagnosed index patients with tuberculosis. Analysis was by intention to treat. Masking of staff at the coordinating centre and sites was not possible; however, those analysing data were masked to assignment of intervention or control. An economic analysis of the intervention was done in parallel with the trial. ACT4 is registered at ClinicalTrials.gov, NCT02810678. FINDINGS: The study was done between Aug 1, 2016, and March 31, 2019. During the first 6 months of the study the crude overall proportion of household contacts initiating tuberculosis preventive treatment out of those eligible at intervention sites was 0·21. After the implementation of programme strengthening activities, the proportion initiating tuberculosis preventive treatment increased to 0·35. Overall, the number of household contacts initiating tuberculosis preventive treatment per 100 index patients with tuberculosis increased between study phases in intervention sites (adjusted rate difference 60, 95% CI 4 to 116), while control sites showed no statistically significant change (-12, -33 to 10). There was a difference in rate differences of 72 (95% CI 10 to 134) contacts per 100 index patients with tuberculosis initiating preventive treatment associated with the intervention. The total cost for the intervention, plus LTBI clinical care per additional contact initiating treatment was estimated to be CA$1348 (range 724 to 9708). INTERPRETATION: A strategy of standardised evaluation, local decision making, and implementation of health systems strengthening activities can provide a mechanism for scale-up of tuberculosis prevention, particularly in low-income and middle-income countries. FUNDING: Canadian Institutes of Health Research.

Individual and public health consequences associated with a missed diagnosis of pulmonary tuberculosis in the emergency department: A retrospective cohort study.

OBJECTIVES: To determine: i) the emergency department (ED) utilization history of pulmonary tuberculosis (PTB) patients, and ii) the potential individual and public health consequences of a missed diagnosis of PTB in this setting. DESIGN: Retrospective observational cohort study. PARTICIPANTS: Patients with PTB aged >16 years diagnosed between April 1, 2010 and December 31, 2016 in the Province of Alberta, Canada. METHODS: We identified valid new cases of PTB from a provincial registry and linked them to ED attendees in administrative databases. Visits are considered 'PTB', pulmonary 'other', and non-pulmonary based on the most responsible discharge diagnosis. Individual consequences of a missed diagnosis included health system delay and PTB-related death; public health consequences included nosocomial ED exposure time and secondary cases. RESULTS: Of 711 PTB patients, 378 (53%) made 845 ED visits in the six months immediately preceding the date of diagnosis. The most responsible ED discharge diagnosis was PTB in 92 (10.9%), pulmonary 'other' in 273 (32%) and non-pulmonary in 480 (56.8%). ED attendees had a median (IQR) health system delay of 27 (7,180) days and, compared to non-ED attendees were more likely to die a TB-related death 5.9% vs 1.2%, p = 0.001. Emergency attendees generated 3812 hours of ED nosocomial exposure time, and 31 secondary cases (60.8% of all secondary cases reported). Mycobacterium tuberculosis isolates from ED-attendees were more likely than non-attendees to be clustered-i.e., have an identical DNA fingerprint with another isolate (27% vs. 21%, p = 0.037). CONCLUSIONS: ED utilization by PTB patients, and related consequences, are substantial. EDs are a potential resource for earlier PTB diagnosis.

Local Transmission Plays No Important Role in the Occurrence of Multidrug-Resistant Tuberculosis in Immigrants to Canada: An In-depth Epidemiologic Analysis.

BACKGROUND: Multidrug-resistant (MDR) tuberculosis has increased among migrants in Canada. The cause(s) of this increase is unknown. METHODS: We performed a retrospective cohort study in a Canadian province with substantially increased immigration between 1982-2001 and 2002-2019. The proportion of MDR tuberculosis among migrants arriving from high MDR (HMDR) tuberculosis burden countries during these 2 periods was used to estimate the proportion of cases due to immigration versus change in proportion in the country of birth. Epidemiologic, spatiotemporal, and drug resistance pattern data were used to confirm local transmission. RESULTS: Fifty-two of 3514 (1.48%) foreign-born culture-positive tuberculosis patients had MDR tuberculosis: 8 (0.6%) in 1982-2001 and 44 (2.0%) in 2002-2019. Between time periods, the proportion of MDR tuberculosis among migrants with tuberculosis from HMDR tuberculosis countries increased from 1.11% to 3.62%, P = .003; 31.6% attributable to recent immigration and 68.4% to a higher proportion of MDR tuberculosis in cases arrived from HMDR tuberculosis countries. No cases of MDR tuberculosis were attributable to local transmission. CONCLUSIONS: In stark contrast to HMDR tuberculosis countries, local transmission plays no important role in the occurrence of MDR tuberculosis in Canada. Improved tuberculosis programming in HMDR tuberculosis countries is urgently needed.