Early Diagnosis and Treatment of COPD and Asthma - A Randomized, Controlled Trial.

BACKGROUND: Many persons with chronic obstructive pulmonary disease (COPD) or asthma have not received a diagnosis, so their respiratory symptoms remain largely untreated. METHODS: We used a case-finding method to identify adults in the community with respiratory symptoms without diagnosed lung disease. Participants who were found to have undiagnosed COPD or asthma on spirometry were enrolled in a multicenter, randomized, controlled trial to determine whether early diagnosis and treatment reduces health care utilization for respiratory illness and improves health outcomes. Participants were assigned to receive the intervention (evaluation by a pulmonologist and an asthma-COPD educator who were instructed to initiate guideline-based care) or usual care by their primary care practitioner. The primary outcome was the annualized rate of participant-initiated health care utilization for respiratory illness. Secondary outcomes included changes from baseline to 1 year in disease-specific quality of life, as assessed with the St. George Respiratory Questionnaire (SGRQ; scores range from 0 to 100, with lower scores indicating better health status); symptom burden, as assessed with the COPD Assessment Test (CAT; scores range from 0 to 40, with lower scores indicating better health status); and forced expiratory volume in 1 second (FEV1). RESULTS: Of 38,353 persons interviewed, 595 were found to have undiagnosed COPD or asthma and 508 underwent randomization: 253 were assigned to the intervention group and 255 to the usual-care group. The annualized rate of a primary-outcome event was lower in the intervention group than in the usual-care group (0.53 vs. 1.12 events per person-year; incidence rate ratio, 0.48; 95% confidence interval [CI], 0.36 to 0.63; P<0.001). At 12 months, the SGRQ score was lower than the baseline score by 10.2 points in the intervention group and by 6.8 points in the usual-care group (difference, -3.5 points; 95% CI, -6.0 to -0.9), and the CAT score was lower than the baseline score by 3.8 points and 2.6 points, respectively (difference, -1.3 points; 95% CI, -2.4 to -0.1). The FEV1 increased by 119 ml in the intervention group and by 22 ml in the usual-care group (difference, 94 ml; 95% CI, 50 to 138). The incidence of adverse events was similar in the trial groups. CONCLUSIONS: In this trial in which a strategy was used to identify adults in the community with undiagnosed asthma or COPD, those who received pulmonologist-directed treatment had less subsequent health care utilization for respiratory illness than those who received usual care. (Funded by Canadian Institutes of Health Research; UCAP ClinicalTrials.gov number, NCT03148210.).

Impact of Undiagnosed Chronic Obstructive Pulmonary Disease and Asthma on Symptoms, Quality of Life, Healthcare Use, and Work Productivity.

Rationale: A significant proportion of individuals with chronic obstructive pulmonary disease (COPD) and asthma remain undiagnosed. Objectives: The objective of this study was to evaluate symptoms, quality of life, healthcare use, and work productivity in subjects with undiagnosed COPD or asthma compared with those previously diagnosed, as well as healthy control subjects. Methods: This multicenter population-based case-finding study randomly recruited adults with respiratory symptoms who had no previous history of diagnosed lung disease from 17 Canadian centers using random digit dialing. Participants who exceeded symptom thresholds on the Asthma Screening Questionnaire or the COPD Diagnostic Questionnaire underwent pre- and post-bronchodilator spirometry to determine if they met diagnostic criteria for COPD or asthma. Two control groups, a healthy group without respiratory symptoms and a symptomatic group with previously diagnosed COPD or asthma, were similarly recruited. Measurements and Main Results: A total of 26,905 symptomatic individuals were interviewed, and 4,272 subjects were eligible. Of these, 2,857 completed pre- and post-bronchodilator spirometry, and 595 (21%) met diagnostic criteria for COPD or asthma. Individuals with undiagnosed COPD or asthma reported greater impact of symptoms on health status and daily activities, worse disease-specific and general quality of life, greater healthcare use, and poorer work productivity than healthy control subjects. Individuals with undiagnosed asthma had symptoms, quality of life, and healthcare use burden similar to those of individuals with previously diagnosed asthma, whereas subjects with undiagnosed COPD were less disabled than those with previously diagnosed COPD. Conclusions: Undiagnosed COPD or asthma imposes important, unmeasured burdens on the healthcare system and is associated with poor health status and negative effects on work productivity.

Anticipating undiagnosed asthma in symptomatic adults with normal pre- and post-bronchodilator spirometry: a decision tool for bronchial challenge testing.

BACKGROUND: Some patients with asthma demonstrate normal spirometry and remain undiagnosed without further testing. OBJECTIVE: To determine clinical predictors of asthma in symptomatic adults with normal spirometry, and to generate a tool to help clinicians decide who should undergo bronchial challenge testing (BCT). METHODS: Using random-digit dialling and population-based case-finding, we recruited adults from the community with respiratory symptoms and no previous history of diagnosed lung disease. Participants with normal pre- and post-bronchodilator spirometry subsequently underwent BCT. Asthma was diagnosed in those with symptoms and a methacholine provocative concentration (PC20) of < 8 mg/ml. Sputum and blood eosinophils, and exhaled nitric oxide were measured. Univariate analyses identified potentially predictive variables, which were then used to construct a multivariable logistic regression model to predict asthma. Model sensitivity, specificity, and area under the receiver operating curve (AUC) were calculated. RESULTS: Of 132 symptomatic individuals with normal spirometry, 34 (26%) had asthma. Of those ultimately diagnosed with asthma, 33 (97%) answered 'yes' to a question asking whether they experienced cough, chest tightness or wheezing provoked by exercise or cold air. Other univariate predictors of asthma included female sex, pre-bronchodilator FEV1 percentage predicted, and percent positive change in FEV1 post bronchodilator. A multivariable model containing these predictive variables yielded an AUC of 0.82 (95% CI: 0.72-0.91), a sensitivity of 82%, and a specificity of 66%. The model was used to construct a nomogram to advise clinicians which patients should be prioritized for BCT. CONCLUSIONS: Four readily available patient characteristics demonstrated a high sensitivity and AUC for predicting undiagnosed asthma in symptomatic adults with normal pre- and post-bronchodilator spirometry. These characteristics can potentially help clinicians to decide which individuals with normal spirometry should be investigated with bronchial challenge testing. However, further prospective validation of our decision tool is required.

Surveying the Epigenetic Landscape of Tuberculosis in Alveolar Macrophages.

Tuberculosis (TB) remains the leading cause of bacterial disease-related death and is among the top 10 overall causes of death worldwide. The complex nature of this infectious lung disease has proven difficult to treat, and significant research efforts are now evaluating the feasibility of host-directed, adjunctive therapies. An attractive approach in host-directed therapy targets host epigenetics, or gene regulation, to redirect the immune response in a host-beneficial manner. Substantial evidence exists demonstrating that host epigenetics are dysregulated during TB and that epigenetic-based therapies may be highly effective to treat TB. However, the caveat is that much of the knowledge that exists on the modulation of the host epigenome during TB has been gained using in vitro, small-animal, or blood-derived cell models, which do not accurately reflect the pulmonary nature of the disease. In humans, the first and major target cells of Mycobacterium tuberculosis are alveolar macrophages (AM). As such, their response to infection and treatment is clinically relevant and ultimately drives the outcome of disease. In this review, we compare the fundamental differences between AM and circulating monocyte-derived macrophages in the context of TB and summarize the recent advances in elucidating the epigenomes of these cells, including changes to the transcriptome, DNA methylome, and chromatin architecture. We will also discuss trained immunity in AM as a new and emerging field in TB research and provide some perspectives for the translational potential of targeting host epigenetics as an alternative TB therapy.

Derivation and validation of the UCAP-Q case-finding questionnaire to detect undiagnosed asthma and COPD.

BACKGROUND: Many people with asthma and COPD remain undiagnosed. We developed and validated a new case-finding questionnaire to identify symptomatic adults with undiagnosed obstructive lung disease. METHODS: Adults in the community with no prior history of physician-diagnosed lung disease who self-reported respiratory symptoms were contacted via random-digit dialling. Pre- and post-bronchodilator spirometry was used to confirm asthma or COPD. Predictive questions were selected using multinomial logistic regression with backward elimination. Questionnaire performance was assessed using sensitivity, predictive values and area under the receiver operating characteristic curve (AUC). The questionnaire was assessed for test-retest reliability, acceptability and readability. External validation was prospectively conducted in an independent sample and predictive performance re-evaluated. RESULTS: A 13-item Undiagnosed COPD and Asthma Population Questionnaire (UCAP-Q) case-finding questionnaire to predict undiagnosed asthma or COPD was developed. The most appropriate risk cut-off was determined to be 6% for either disease. Applied to the derivation sample (n=1615), the questionnaire yielded a sensitivity of 92% for asthma and 97% for COPD; specificity of 17%; and an AUC of 0.69 (95% CI 0.64-0.74) for asthma and 0.82 (95% CI 0.78-0.86) for COPD. Prospective validation using an independent sample (n=471) showed sensitivities of 93% and 92% for asthma and COPD, respectively; specificity of 19%; with AUCs of 0.70 (95% CI 0.62-0.79) for asthma and 0.81 (95% CI 0.74-0.87) for COPD. AUCs for UCAP-Q were higher compared to AUCs for currently recommended case-finding questionnaires for asthma or COPD. CONCLUSIONS: The UCAP-Q demonstrated high sensitivities and AUCs for identifying undiagnosed asthma or COPD. A web-based calculator allows for easy calculation of risk probabilities for each disease.

Lung disease burden assessment by oscillometry in a systematically disadvantaged urban population experiencing homelessness or at-risk for homelessness in Ottawa, Canada from a prospective observational study.

RATIONALE: Oscillometry is an emerging technique that offers some advantages over spirometry as it does not require forced exhalation and may detect early changes in respiratory pathology. Obstructive lung disease disproportionately impacts people experiencing homelessness with a high symptoms burden, yet oscillometry is not studied in this population. OBJECTIVES: To assess lung disease and symptom burden using oscillometry in people experiencing homelessness or at-risk of homelessness using a community-based participatory action research approach (The Bridge Model™). METHODS: Of 80 recruited, 55 completed baseline oscillometry, 64 completed spirometry, and all completed patient-reported outcomes with demographics, health, and respiratory symptom related questionnaires in the Participatory Research in Ottawa: Management and Point-of-Care for Tobacco Dependence project. Using a two-tail t-test, we compared mean oscillometry values for airway resistance (R5-20), reactance area under the curve (Ax) and reactance at 5 Hz (X5) amongst individuals with fixed-ratio method (FEV1/FVC ratio < 0.70) and LLN (FEV1/FVC ratio ≤ LLN) spirometry diagnosed chronic obstructive pulmonary disease (COPD). We compared mean oscillometry parameters based on participants' COPD assessment test (CAT) scores using ANOVA test. RESULTS: There was no significant difference between the pre- and post- bronchodilator values of R5-20 and Ax for the fixed ratio method (p = 0.63 and 0.43) and the LLN method (p = 0.45 and 0.36). There was a significant difference in all three of the oscillometry parameters, R5-20, Ax and X5, based on CAT score (p = 0.009, 0.007 and 0.05, respectively). There was a significant difference in R5-20 and Ax based on the presence of phlegm (p = 0.03 and 0.02, respectively) and the presence of wheeze (p = 0.05 and 0.01, respectively). Oscillometry data did not correlate with spirometry data, but it was associated with CAT scores and correlated with the presence of self-reported symptoms of phlegm and wheeze in this population. CONCLUSIONS: Oscillometry is associated with respiratory symptom burden and highlights the need for future studies to generate more robust data regarding the use of oscillometry in systematically disadvantaged populations where disease burden is disproportionately higher than the general population. TRIAL REGISTRATION: ClinicalTrails.gov-NCT03626064, Retrospective registered: August 2018, https://clinicaltrials.gov/ct2/show/NCT03626064.

Molecular Epidemiology of Mycobacterium tuberculosis To Describe the Transmission Dynamics Among Inuit Residing in Iqaluit Nunavut Using Whole-Genome Sequencing.

BACKGROUND: In the last decade, tuberculosis (TB) incidence among Inuit in the Canadian Arctic has been rising. Our aim was to better understand the transmission dynamics of TB in this remote region of Canada using whole-genome sequencing. METHODS: Isolates from patients who had culture-positive pulmonary TB in Iqaluit, Nunavut, between 2009 and 2015 underwent whole-genome sequencing (WGS). The number of transmission events between cases within clusters was calculated using a threshold of a ≤3 single nucleotide polymorphism (SNP) difference between isolates and then combined with detailed epidemiological data using a reproducible novel algorithm. Social network analysis of epidemiological data was used to support the WGS data analysis. RESULTS: During the study period, 140 Mycobacterium tuberculosis isolates from 135 cases were sequenced. Four clusters were identified, all from Euro-American lineage. One cluster represented 62% of all cases that were sequenced over the entire study period. In this cluster, 2 large chains of transmission were associated with 3 superspreading events in a homeless shelter. One of the superspreading events was linked to a nonsanctioned gambling house that resulted in further transmission. Shelter to nonshelter transmission was also confirmed. An algorithm developed for the determination of transmission events demonstrated very good reproducibility (κ score .98, 95% confidence interval, .97-1.0). CONCLUSIONS: Our study suggests that socioeconomic factors, namely residing in a homeless shelter and spending time in a gambling house, combined with the superspreading event effect may have been significant factors explaining the rise in cases in this predominantly Inuit Arctic community.

Social and behavioral risk reduction strategies for tuberculosis prevention in Canadian Inuit communities: a cost-effectiveness analysis.

BACKGROUND: Tuberculosis (TB) is an important public health problem in Inuit communities across Canada, with an annual incidence rate in 2017 that was nearly 300 times higher than in Canadian-born non-Indigenous individuals. Social and behavioral factors that are prevalent in the North, such as commercial tobacco use, excessive alcohol use, food insecurity and overcrowded housing put individuals at higher risk for TB morbidity and mortality. We examined the potential impact of mitigation strategies for these risk factors, in reducing TB burden in this setting. METHODS: We created a transmission model to simulate the epidemiology of TB in Nunavut, Canada. We then used a decision analysis model to assess the potential impact of several evidence-based strategies targeting tobacco use, excessive alcohol use, food insecurity and overcrowded housing. We predicted TB incidence, TB-related deaths, quality adjusted life years (QALYs), and associated costs and cost-effectiveness over 20 years. All costs were expressed in 2018 Canadian dollars. RESULTS: Compared to a status quo scenario with no new interventions for these risk factors, the reduction strategy for tobacco use was most effective and cost-effective, reducing TB incidence by 5.5% (95% uncertainty range: 2.7-11%) over 20 years, with an estimated cost of $95,835 per TB case prevented and $49,671 per QALY gained. The addition of the food insecurity reduction strategy reduced incidence by a further 2% (0.5-3%) compared to the tobacco cessation strategy alone, but at significant cost. CONCLUSIONS: Strategies that aim to reduce commercial tobacco use and improve food security will likely lead to modest reductions in TB morbidity and mortality. Although important for the communities, strategies that address excess alcohol use and overcrowding will likely have a more limited impact on TB-related outcomes at current scale, and are associated with much higher cost. Their benefits will be more substantial with scale up, which will also likely have important downstream impacts such as improved mental health, educational attainment and food security.

The potential impact and cost-effectiveness of tobacco reduction strategies for tuberculosis prevention in Canadian Inuit communities.

BACKGROUND: Tuberculosis (TB) remains a significant public health problem in Canadian Inuit communities. In 2016, Canadian Inuit had an incidence rate 35 times the Canadian average. Tobacco use is an important risk factor for TB, and over 60% of Inuit adults smoke. We aimed to estimate changes in TB-related outcomes and costs from reducing tobacco use in Inuit communities. METHODS: Using a transmission model to estimate the initial prevalence of latent TB infection (LTBI), followed by decision analysis modelling, we conducted a cost-effectiveness analysis that compared the current standard of care for management of TB and LTBI without additional tobacco reduction intervention (Status Quo) with (1) increased tobacco taxation, (2) pharmacotherapy and counselling for smoking cessation, (3) pharmacotherapy, counselling plus mass media campaign, and (4) the combination of all these. Projected outcomes included the following: TB cases, TB-related deaths, quality-adjusted life years (QALYs), and health system costs, all over 20 years. RESULTS: The combined strategy was projected to reduce active TB cases by 6.1% (95% uncertainty range 4.9-7.0%) and TB deaths by 10.4% (9.5-11.4%) over 20 years, relative to the status quo. Increased taxation was the only cost-saving strategy. CONCLUSIONS: Currently available strategies to reduce commercial tobacco use will likely have a modest impact on TB-related outcomes in the medium term, but some may be cost saving.

The latent tuberculosis infection cascade of care in Iqaluit, Nunavut, 2012-2016.

BACKGROUND: A remote arctic region of Canada predominantly populated by Inuit with the country's highest incidence of tuberculosis. METHODS: The study was undertaken to describe the latent tuberculosis infection (LTBI) cascade of care and identify factors associated with non-initiation and non-completion of LTBI treatment. Data were extracted retrospectively from medical records for all patients with a tuberculin skin test (TST) implanted in Iqaluit, Nunavut between January 2012 and March 2016. Associations between demographic and clinical factors and both treatment non-initiation among and treatment non-completion were identified using log binomial regression models where convergence could be obtained and Poisson models with robust error variance where convergence was not obtained. RESULTS: Of 2303 patients tested, 439 (19.1%) were diagnosed with LTBI. Treatment was offered to 328 patients, was initiated by 246 (75.0% of those offered) and was completed by 186 (75.6% of initiators). In multivariable analysis, older age (adjust risk ratio [aRR] 1.17 per 5-year increase, 95%CI:1.09-1.26) and undergoing TST due to employment screening (aRR 1.63, 95%CI:1.00-2.65, compared to following tuberculosis exposure) were associated with increased non-initiation of treatment. Older age (aRR 1.13, 95%CI: 1.03-1.17, per 5-year increase) was associated with increased non-completion of treatment. CONCLUSIONS: A similar rate of treatment initiation and higher rate of treatment completion were found compared to previous North American studies. Interventions targeting older individuals and those identified via employment screening may be considered to help to address the largest losses in the cascade of care.

A systematic review of adverse events of rifapentine and isoniazid compared to other treatments for latent tuberculosis infection.

PURPOSE: Tuberculosis (TB) remains a common cause of death globally. A regimen of 12 doses of isoniazid (INH) and rifapentine given once weekly (INH/RPT-3) has recently been recommended by the World Health Organization for the treatment of latent TB infection (LTBI). We aimed to determine whether the INH/RPT-3 regimen had similar or lesser rates of adverse events compared to other LTBI regimens, namely INH for 9 months, INH for 6 months, rifampin for 3 to 4 months, and rifampin plus INH for 3 to 4 months. METHODS: We searched MEDLINE, Embase, CENTRAL, PubMed, ICTRP, clinicaltrials.gov, and Canadian Agency for Drugs and Technologies in Health's Gray Matters Light for randomized, postmarketing, and comparative nonrandomized studies of patients with confirmed LTBI that reported the frequency of at least 1 adverse event of relevance for a regimen of interest. The search included studies published until March 2017. The frequencies of adverse events were extracted and are presented descriptively. RESULTS: Data from 23 randomized and 55 nonrandomized studies were included. Although inconsistent event reporting and high heterogeneity limited comparisons, the adverse event profile of INH/RPT-3 appeared generally favorable. Flu-like reactions were reported with an increased frequency and hepatotoxicity with a lower frequency than standard treatment. CONCLUSIONS: While INH/RPT-3 had an overall low frequency of adverse events compared to INH monotherapy, reporting of adverse events for many regimens was limited meaning results should be interpreted cautiously. Future studies of LTBI treatment would benefit from more complete collection and reporting of adverse events and more consistent definitions of hepatotoxicity.

Efficacy and completion rates of rifapentine and isoniazid (3HP) compared to other treatment regimens for latent tuberculosis infection: a systematic review with network meta-analyses.

BACKGROUND: We conducted a systematic review and network meta-analysis (NMA) to examine the efficacy and completion rates of treatments for latent tuberculosis infection (LTBI). While a previous review found newer, short-duration regimens to be effective, several included studies did not confirm LTBI, and analyses did not account for variable follow-up or assess completion. METHODS: We searched MEDLINE, Embase, CENTRAL, PubMed, and additional sources to identify RCTs in patients with confirmed LTBI that involved a regimen of interest and reported on efficacy or completion. Regimens of interest included isoniazid (INH) with rifapentine once weekly for 12 weeks (INH/RPT-3), 6 and 9 months of daily INH (INH-6; INH-9), 3-4 months daily INH plus rifampicin (INH/RFMP 3-4), and 4 months daily rifampicin alone (RFMP-4). NMAs were performed to compare regimens for both endpoints. RESULTS: Sixteen RCTs (n = 44,149) and 14 RCTs (n = 44,128) were included in analyses of efficacy and completion. Studies were published between 1968 and 2015, and there was diversity in patient age and comorbidities. All regimens of interest except INH-9 showed significant benefits in preventing active TB compared to placebo. Comparisons between active regimens did not reveal significant differences. While definitions of regimen completion varied across studies, regimens of 3-4 months were associated with a greater likelihood of adequate completion. CONCLUSIONS: Most of the active regimens showed an ability to reduce the risk of active TB relative to no treatment, however important differences between active regimens were not found. Shorter rifamycin-based regimens may offer comparable benefits to longer INH regimens. Regimens of 3-4 months duration are more likely to be completed than longer regimens.

Reevaluation of Diagnosis in Adults With Physician-Diagnosed Asthma.

Importance: Although asthma is a chronic disease, the expected rate of spontaneous remissions of adult asthma and the stability of diagnosis are unknown. Objective: To determine whether a diagnosis of current asthma could be ruled out and asthma medications safely stopped in randomly selected adults with physician-diagnosed asthma. Design, Setting, and Participants: A prospective, multicenter cohort study was conducted in 10 Canadian cities from January 2012 to February 2016. Random digit dialing was used to recruit adult participants who reported a history of physician-diagnosed asthma established within the past 5 years. Participants using long-term oral steroids and participants unable to be tested using spirometry were excluded. Information from the diagnosing physician was obtained to determine how the diagnosis of asthma was originally made in the community. Of 1026 potential participants who fulfilled eligibility criteria during telephone screening, 701 (68.3%) agreed to enter into the study. All participants were assessed with home peak flow and symptom monitoring, spirometry, and serial bronchial challenge tests, and those participants using daily asthma medications had their medications gradually tapered off over 4 study visits. Participants in whom a diagnosis of current asthma was ultimately ruled out were followed up clinically with repeated bronchial challenge tests over 1 year. Exposure: Physician-diagnosed asthma established within the past 5 years. Main Outcomes and Measures: The primary outcome was the proportion of participants in whom a diagnosis of current asthma was ruled out, defined as participants who exhibited no evidence of acute worsening of asthma symptoms, reversible airflow obstruction, or bronchial hyperresponsiveness after having all asthma medications tapered off and after a study pulmonologist established an alternative diagnosis. Secondary outcomes included the proportion with asthma ruled out after 12 months and the proportion who underwent an appropriate initial diagnostic workup for asthma in the community. Results: Of 701 participants (mean [SD] age, 51 [16] years; 467 women [67%]), 613 completed the study and could be conclusively evaluated for a diagnosis of current asthma. Current asthma was ruled out in 203 of 613 study participants (33.1%; 95% CI, 29.4%-36.8%). Twelve participants (2.0%) were found to have serious cardiorespiratory conditions that had been previously misdiagnosed as asthma in the community. After an additional 12 months of follow-up, 181 participants (29.5%; 95% CI, 25.9%-33.1%) continued to exhibit no clinical or laboratory evidence of asthma. Participants in whom current asthma was ruled out, compared with those in whom it was confirmed, were less likely to have undergone testing for airflow limitation in the community at the time of initial diagnosis (43.8% vs 55.6%, respectively; absolute difference, 11.8%; 95% CI, 2.1%-21.5%). Conclusions and Relevance: Among adults with physician-diagnosed asthma, a current diagnosis of asthma could not be established in 33.1% who were not using daily asthma medications or had medications weaned. In patients such as these, reassessing the asthma diagnosis may be warranted.

Xpert MTB/RIF testing in a low tuberculosis incidence, high-resource setting: limitations in accuracy and clinical impact.

BACKGROUND: Xpert MTB/RIF, the first automated molecular test for tuberculosis, is transforming the diagnostic landscape in low-income countries. However, little information is available on its performance in low-incidence, high-resource countries. METHODS: We evaluated the accuracy of Xpert in a university hospital tuberculosis clinic in Montreal, Canada, for the detection of pulmonary tuberculosis on induced sputum samples, using mycobacterial cultures as the reference standard. We also assessed the potential reduction in time to diagnosis and treatment initiation. RESULTS: We enrolled 502 consecutive patients who presented for evaluation of possible active tuberculosis (most with abnormal chest radiographs, only 18% symptomatic). Twenty-five subjects were identified to have active tuberculosis by culture. Xpert had a sensitivity of 46% (95% confidence interval [CI], 26%-67%) and specificity of 100% (95% CI, 99%-100%) for detection of Mycobacterium tuberculosis. Sensitivity was 86% (95% CI, 42%-100%) in the 7 subjects with smear-positive results, and 28% (95% CI, 10%-56%) in the remaining subjects with smear-negative, culture-positive results; in this latter group, positive Xpert results were obtained a median 12 days before culture results. Subjects with positive cultures but negative Xpert results had minimal disease: 11 of 13 had no symptoms on presentation, and mean time to positive liquid culture results was 28 days (95% CI, 25-47 days) compared with 14 days (95% CI, 8-21 days) in Xpert/culture-positive cases. CONCLUSIONS: Our findings suggest limited potential impact of Xpert testing in high-resource, low-incidence ambulatory settings due to lower sensitivity in the context of less extensive disease, and limited potential to expedite diagnosis beyond what is achieved with the existing, well-performing diagnostic algorithm.

Chronic respiratory disease in Indigenous peoples: a framework to address inequity and strengthen respiratory health and health care globally.

Indigenous peoples around the world bear a disproportionate burden of chronic respiratory diseases, which are associated with increased risks of morbidity and mortality. Despite the imperative to address global inequity, research focused on strengthening respiratory health in Indigenous peoples is lacking, particularly in low-income and middle-income countries. Drivers of the increased rates and severity of chronic respiratory diseases in Indigenous peoples include a high prevalence of risk factors (eg, prematurity, low birthweight, poor nutrition, air pollution, high burden of infections, and poverty) and poor access to appropriate diagnosis and care, which might be linked to colonisation and historical and current systemic racism. Efforts to tackle this disproportionate burden of chronic respiratory diseases must include both global approaches to address contributing factors, including decolonisation of health care and research, and local approaches, co-designed with Indigenous people, to ensure the provision of culturally strengthened care with more equitable prioritisation of resources. Here, we review evidence on the burden of chronic respiratory diseases in Indigenous peoples globally, summarise factors that underlie health disparities between Indigenous and non-Indigenous people, propose a framework of approaches to improve the respiratory health of Indigenous peoples, and outline future directions for clinical care and research.

Impact of Dyspnea on Adults With Respiratory Symptoms Without a Defined Diagnosis.

BACKGROUND: We investigated dyspnea, its associated risk factors, and its impact on health care utilization, quality of life, and work productivity in adults with undiagnosed respiratory symptoms. RESEARCH QUESTION: What is the impact of dyspnea in adults with undiagnosed respiratory symptoms? STUDY DESIGN AND METHODS: This population-based study included 2,857 adults who were experiencing respiratory symptoms. These individuals had not been previously diagnosed with any lung conditions and were recruited from 17 Canadian centers using random digit dialing. Each participant underwent spirometry testing both before and after using a bronchodilator to determine if they met the diagnostic criteria for COPD, asthma, or preserved ratio impaired spirometry (PRISm), or if their spirometry results were normal. An age-matched control group (n = 231) was similarly recruited using random digit dialing. A dyspnea impact assessment score from 0 to 100 was produced using questions from the COPD Assessment Test and St. George's Respiratory questionnaire. RESULTS: Individuals with PRISm (n = 172) reported more impactful dyspnea (mean score, 63.0; 95% CI, 59.5-66.4) than those with undiagnosed asthma (n = 265; mean score, 56.6; 95% CI, 53.9-59.3) or undiagnosed COPD (n = 330; mean score, 57.5; 95% CI, 55.1-59.9). All groups reported significantly more impactful dyspnea than the control group (mean score, 13.8; 95% CI, 11.8-15.7). Patient-specific risk factors including age, sex, BMI, smoking, and comorbidities explained 20.6% of the variation in dyspnea. An additional 12.4% of the variation was explained by disease classification and another 1.7% by the severity of lung function impairment assessed with spirometry. After adjusting for age, sex, and BMI, greater dyspnea impact was associated with increased health care utilization, lower quality of life, and reduced work productivity. INTERPRETATION: In community-based adults with undiagnosed respiratory symptoms, those identified with PRISm experienced the greatest impact of dyspnea. Dyspnea imposes burdens on the health care system and is associated with impaired quality of life and work productivity.

Mycobacterium tuberculosis infection triggers epigenetic changes that are enriched in a type I IFN signature.

Tuberculosis, a deadly infectious lung disease caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of bacterial disease-related deaths worldwide. Mtb reprograms and disables key antibacterial response pathways, many of which are regulated by epigenetic mechanisms that control the accessibility of chromatin to the transcriptional machinery. Recent reports suggest that host phosphatases, such as PPM1A, contribute to regulating chromatin accessibility during bacterial infections. However, changes in genome-wide chromatin accessibility during Mtb infection and whether PPM1A plays a role in this process remains unknown. Herein, we use combinatorial chromatin accessibility (ATAC-seq) and transcriptomic (RNA-seq) profiling of wild-type, PPM1A knockout and PPM1A overexpressing macrophages to demonstrate that Mtb infection induces global chromatin remodelling consistent with changes in gene expression. The strongest concordant changes to chromatin accessibility and gene expression triggered by Mtb infection were enriched for genes involved in type I interferon (IFN) signalling pathways. A panel of 15 genes with the strongest concordant changes in chromatin accessibility and gene expression were validated to be significantly upregulated in Mtb-infected human monocyte-derived macrophages. PPM1A expression affects chromatin accessibility profiles during Mtb infection that are reflected in the total number, chromosome location, and directionality of change. Transcription factor binding motif analysis revealed enrichment for transcription factors involved in the type I IFN pathway during Mtb infection, including members of the IRF, MEF2, and AP-1 families. Our study shows that altered type I IFN responses in Mtb-infected macrophages occur due to genome-wide changes in chromatin accessibility, and that PPM1A could influence a subset of these signatures.

Inaccuracy of death certificate diagnosis of tuberculosis and potential underdiagnosis of TB in a region of high HIV prevalence.

UNLABELLED: Despite the South African antiretroviral therapy rollout, which should reduce the incidence of HIV-associated tuberculosis (TB), the number of TB-attributable deaths in KwaZuluNatal (KZN) remains high. TB is often diagnosed clinically, without microbiologic confirmation, leading to inaccurate estimates of TB-attributed deaths. This may contribute to avoidable deaths, and impact population-based TB mortality estimates. OBJECTIVES: (1) To measure the number of cases with microbiologically confirmed TB in a retrospective cohort of deceased inpatients with TB-attributed hospital deaths. (2) To estimate the rates of multi-drug resistant (MDR) and extensively drug resistant (XDR) TB in this cohort. RESULTS: Of 2752 deaths at EDH between September 2006 and March 2007, 403 (15%) were attributed to TB on the death certificate. 176 of the TB-attributed deaths (44%) had a specimen sent for smear or culture; only 64 (36%) had a TB diagnosis confirmed by either test. Of the 39 culture-confirmed cases, 27/39 (69%) had fully susceptible TB and 27/39 (69%) had smear-negative culture-positive TB (SNTB). Two patients had drug monoresistance, three patients had MDR-TB, and one had XDR-TB. CONCLUSIONS: Most TB-attributed deaths in this cohort were not microbiologically confirmed. Of confirmed cases, most were smear-negative, culture positive and were susceptible to all first line drugs.

Impact of respiratory viral infections on mortality and critical illness among hospitalized patients with chronic obstructive pulmonary disease.

BACKGROUND: Seasonal respiratory viral infections are associated with exacerbations and morbidity among patients with COPD. The real-world clinical outcomes associated with seasonal viral infections are less well established among hospitalized patients. RESEARCH QUESTION: To estimate the association between seasonal respiratory viral infections, 30-day mortality, and intensive care unit (ICU) admission among hospitalized COPD patients. STUDY DESIGN AND METHODS: We conducted an analysis of a national prospective multicenter cohort of COPD patients hospitalized with acute respiratory illness during winter seasons (2011-2015) in Canada. Nasopharyngeal swabs were performed on all patients at the onset of hospital admission for diagnosis of viral infection. Primary outcomes were 30-day mortality and ICU admissions. Secondary outcomes included invasive/non-invasive ventilation use. RESULTS: Among 3931 hospitalized patients with COPD, 28.5% (1122/3931) were diagnosed with seasonal respiratory viral infection. Viral infection was associated with increased admission to ICU (OR 1.5, 95% CI 1.2-1.9) and need for mechanical ventilation (OR 1.9, 95% CI 1.4-2.5), but was not associated with mortality (OR 1.1, 95% CI 0.8-1.4). Patients with respiratory syncytial virus (RSV) were equally likely to require ICU admission (OR 1.09, 95% CI 0.67-1.78), and more likely to need non-invasive ventilation (OR 3.1; 95% CI 1.8-5.1) compared to patients with influenza. INTERPRETATION: Our results suggest COPD patients requiring hospitalization for respiratory symptoms should routinely receive viral testing at admission, especially for RSV and influenza, to inform prognosis, clinical management, and infection control practices during winter seasons. Patients with COPD will be an important target population for newly developed RSV therapeutics. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01517191.

Effect of implementation of a 12-dose once-weekly treatment (3HP) in addition to standard regimens to prevent TB on completion rates: Interrupted time series design.

OBJECTIVES: We aimed to determine if offering a 12-dose once-weekly treatment (3HP) as an additional treatment option would result in an increase in the overall proportion of patients completing TB preventive treatment (TPT) above the baseline rate. METHODS: We analyzed outcomes in consecutive adults referred to a TB clinic from January 2010 to May 2019. Starting December 2016, 3HP was offered as an alternative to standard clinic regimens which included 9 months of daily isoniazid or 4 months of daily rifampin. The primary outcome was the proportion of patients who completed TPT among all patients who started treatment. Using segmented autoregression analysis, we compared completion at the end of the study with projected completion had the intervention not been introduced. RESULTS: A total of 2803 adults were referred for assessment over the study period. There was an absolute increase in completions among those who started a treatment of 19.0% at the end of the study between the observed intervention completion rate and the projected completion rate from the baseline study period (the completion rate had the 3HP intervention not been introduced) (76% observed vs 57% projected; 95% CI 6.6 to 31.4%; p = 0.004) and an absolute increase among those who were offered treatment (17.3%; 95% CI, 2.3 to 32.3%; p = 0.025). CONCLUSIONS: The introduction of 3HP for TPT as an alternative to the regular regimens offered resulted in a significant increase in the proportion of patients completing treatment. Our study provides evidence to support accelerated use of 3HP in Canada.