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.

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.

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.

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.

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.

Prompt recognition of infectious pulmonary tuberculosis is critical to achieving elimination goals: a retrospective cohort study.

INTRODUCTION: All pulmonary tuberculosis (PTB) cases are presumed to be infectious to some degree. This spectrum of infectiousness is independently described by both the acid-fast bacilli smear and radiographic findings. Smear-positive patients with chest radiographic findings that are typical for adult-type PTB are believed to be most infectious. HYPOTHESIS: Characterisation of the presumed most infectious PTB case is possible by reference to readily available clinical features and laboratory results. METHODS: Retrospective cohort study of adult, culture-positive PTB cases (151 smear-positive; 162 smear-negative) diagnosed between 1 January 2013 and 30 April 2017 in Canada. We describe cases according to demographic, clinical and laboratory features. We use multivariable multinomial logistic regression to estimate the relative risk ratio (RRR) with 95% CI of features associated with an outcome of smear-positive PTB, characterised by 'typical' chest radiograph findings. RESULTS: Being Canadian-born, symptomatic, having a subacute duration of symptoms and broad-spectrum antibiotic prescriptions were all more commonly associated with smear-positive than smear-negative disease (36% vs 20%; 95% vs 63%; 88% vs 54%; and 59% vs 28%, respectively). After combining smear status and radiographic features, we show that smear-positive patients with typical chest radiographs were younger, had a longer duration of symptoms (RRR 2.41; 95% CI 1.01 to 5.74 and 2.93; 95% CI 1.20 to 7.11, respectively) and were less likely to be foreign-born, or have a moderate to high-risk factor for reactivation (RRR 0.40; 95% CI 0.17 to 0.92 and 0.18; 95% CI 0.04 to 0.71, respectively) compared with smear-negative patients with atypical chest radiograph findings. CONCLUSION: A clear picture of the presumed most infectious PTB case emerges from available historical and laboratory information; vigilance for this presentation by front-line providers will support elimination strategies aimed at reducing transmission.

Is there a fundamental flaw in Canada's post-arrival immigrant surveillance system for tuberculosis?

BACKGROUND: New immigrants to Canada with a history of tuberculosis or evidence of old healed tuberculosis on chest radiograph are referred to public health authorities for medical surveillance. This ostensible public health protection measure identifies a subgroup of patients (referrals) who are at very low risk (compared to non-referrals) of transmission. METHODS: To assess whether earlier diagnosis or a different phenotypic expression of disease explains this difference, we systematically reconstructed the immigration and transmission histories from a well-defined cohort of recently-arrived referral and non-referral pulmonary tuberculosis cases in Canada. Incident case chest radiographs in all cases and sequential past radiographs in referrals were re-read by three experts. Change in disease severity from pre-immigration radiograph to incident radiograph was the primary, and transmission of tuberculosis, the secondary, outcome. RESULTS: There were 174 cohort cases; 61 (35.1%) referrals and 113 (64.9%) non-referrals. Compared to non-referrals, referrals were less likely to be symptomatic (26% vs. 80%), smear-positive (15% vs. 50%), or to have cavitation (0% vs. 35%) or extensive disease (15% vs. 59%) on chest radiograph. After adjustment for referral status, time between films, country-of-birth, age and co-morbidities, referrals were less likely to have substantial changes on chest radiograph; OR 0.058 (95% CI 0.018-0.199). All secondary cases and 82% of tuberculin skin test conversions occurred in contacts of non-referrals. CONCLUSIONS: Phenotypically different disease, and not earlier diagnosis, explains the difference in transmission risk between referrals and non-referrals. Screening, and treating high-risk non-referrals for latent tuberculosis is necessary to eliminate tuberculosis in Canada.

Epidemiological and genomic determinants of tuberculosis outbreaks in First Nations communities in Canada.

BACKGROUND: In Canada, tuberculosis disproportionately affects foreign-born and First Nations populations. Within First Nations' peoples, a high proportion of cases occur in association with outbreaks. Tuberculosis transmission in the context of outbreaks is thought to result from the convergence of several factors including characteristics of the cases, contacts, the environment, and the pathogen. METHODS: We examined the epidemiological and genomic determinants of two well-characterized tuberculosis outbreaks attributed to two super-spreaders among First Nations in the province of Alberta. These outbreaks were associated with two distinct DNA fingerprints (restriction fragment-length polymorphisms or RFLPs 0.0142 and 0.0728). We compared outbreak isolates with endemic isolates not spatio-temporarily linked to outbreak cases. We extracted epidemiological variables pertaining to tuberculosis cases and contacts from individual public health records and the provincial tuberculosis registry. We conducted group analyses using parametric and non-parametric statistical tests. We carried out whole-genome sequencing and bioinformatic analysis using validated protocols. RESULTS: We observed differences between outbreak and endemic groups in the mean number of total and child-aged contacts and the number of contacts with new positive and converted tuberculin skin tests in all group comparisons (p < 0.05). Differences were also detected in the proportion of cases with cavitation on a chest radiograph and the mean number of close contacts in selected group comparisons (p < 0.02). A phylogenetic network analysis of whole-genome sequencing data indicated that most outbreak and endemic strains were closely related to the source case for the 0.0142 fingerprint. For the 0.0728 fingerprint, the source case haplotype was circulating among endemic cases prior to the outbreak. Genetic and temporal distances were not correlated for either RFLP 0.0142 (r2 = - 0.05) or RFLP 0.0728 (r2 = 0.09) when all isolates were analyzed. CONCLUSIONS: We found no evidence that endemic strains acquired mutations resulting in their emergence in outbreak form. We conclude that the propagation of these outbreaks was likely driven by the combination of characteristics of the source cases, contacts, and the environment. The role of whole-genome sequencing in understanding mycobacterial evolution and in assisting public health authorities in conducting contact investigations and managing outbreaks is important and expected to grow in the future.

Predicting pulmonary tuberculosis in immigrants: a retrospective cohort study.

Our objective was to investigate whether pulmonary tuberculosis (PTB) can be predicted from features of a targeted medical history and basic laboratory investigations in immigrants. A retrospective cohort of 391 foreign-born adults referred to the Edmonton Tuberculosis Clinic (Edmonton, AB, Canada) was studied using multiple logistic regression analysis to predict PTB. Seven characteristics of disease were used as explanatory variables. Cross-validation assessed performance. Each predictor was tested on two outcomes: "culture-positive" and "smear-positive". Receiver operating characteristic (ROC) curves were generated and the area under the ROC curve (AUC) was quantified. Symptoms, subacute duration of symptoms, risk factors for reactivation of latent TB infection and anaemia were all associated with a positive culture (adjusted OR 1.79, 2.24, 1.72 and 2.28, respectively; p<0.05). Symptoms, inappropriate prescription of broad-spectrum antibiotics and a "typical" chest radiograph were associated with smear-positive PTB (adjusted OR 2.91, 1.55 and 12.34, respectively; p<0.05). ROC curve analysis was used to test each model, yielding AUC=0.91 for the outcome "culture-positive" disease and AUC=0.94 for the outcome "smear-positive" disease. PTB among the foreign-born can be predicted from a targeted medical history and basic laboratory investigations, raising the threshold of suspicion in settings where the disease is relatively rare.

Do "Virtual" and "Outpatient" Public Health Tuberculosis Clinics Perform Equally Well? A Program-Wide Evaluation in Alberta, Canada.

BACKGROUND: Meeting the challenge of tuberculosis (TB) elimination will require adopting new models of delivering patient-centered care customized to diverse settings and contexts. In areas of low incidence with cases spread out across jurisdictions and large geographic areas, a "virtual" model is attractive. However, whether "virtual" clinics and telemedicine deliver the same outcomes as face-to-face encounters in general and within the sphere of public health in particular, is unknown. This evidence is generated here by analyzing outcomes between the "virtual" and "outpatient" public health TB clinics in Alberta, a province of Western Canada with a large geographic area and relatively small population. METHODS: In response to the challenge of delivering equitable TB services over long distances and to hard to reach communities, Alberta established three public health clinics for the delivery of its program: two outpatient serving major metropolitan areas, and one virtual serving mainly rural areas. The virtual clinic receives paper-based or electronic referrals and generates directives which are acted upon by local providers. Clinics are staffed by dedicated public health nurses and university-based TB physicians. Performance of the two types of clinics is compared between the years 2008 and 2012 using 16 case management and treatment outcome indicators and 12 contact management indicators. FINDINGS: In the outpatient and virtual clinics, respectively, 691 and 150 cases and their contacts were managed. Individually and together both types of clinics met most performance targets. Compared to outpatient clinics, virtual clinic performance was comparable, superior and inferior in 22, 3, and 3 indicators, respectively. CONCLUSIONS: Outpatient and virtual public health TB clinics perform equally well. In low incidence settings a combination of the two clinic types has the potential to address issues around equitable service delivery and declining expertise.

Is early tuberculosis death associated with increased tuberculosis transmission?

INTRODUCTION: Tuberculosis (TB) is now a relatively uncommon disease in high income countries. As such, its diagnosis may be missed or delayed resulting in death before or shortly after the introduction of treatment. Whether early TB death is associated with increased TB transmission is unknown. To determine the transmission risk attributable to early TB death we undertook a case-control study. METHODS: All adults who were: (1) diagnosed with culture-positive pulmonary TB in the Province of Alberta, Canada between 1996 and 2012, and (2) died a TB-related death before or within the first 60 days of treatment, were identified. For each of these "cases" two sets of "controls" were randomly selected from among culture-positive pulmonary TB cases that survived beyond 60 days of treatment. "Controls" were matched by age, sex, population group, +/- smear status. Secondary cases of "cases" and "controls" were identified using conventional and molecular epidemiologic tools and compared. In addition, new infections were identified and compared in contacts of "cases" that died before treatment and contacts of their smear-matched "controls". Conditional logistic regression was used to find associations in both univariate and multivariate analysis. RESULTS: "Cases" were as, but not more, likely than "controls" to transmit. This was so whether transmission was measured in terms of the number of "cases" and smear-unmatched or -matched "controls" that had a secondary case, the number of secondary cases that they had or the number of new infections found in contacts of "cases" that died before treatment and their smear-matched "controls". CONCLUSION: In a low TB incidence/low HIV prevalence country, pulmonary TB patients that die a TB-related death before or in the initial phase of treatment and pulmonary TB patients that survive beyond the initial phase of treatment are equally likely to transmit.

A 10-year population based study of 'opt-out' HIV testing of tuberculosis patients in Alberta, Canada: national implications.

INTRODUCTION: Compliance with the recommendation that all tuberculosis (TB) patients be tested for human immunodeficiency virus (HIV) has not yet been achieved in Canada or globally. METHODS: The experience of "opt-out" HIV testing of TB patients in the Province of Alberta, Canada is described over a 10-year period, 2003-2012. Testing rates are reported before and after the introduction of the "opt-out" approach. Risk factors for HIV seropositivity are described and demographic, clinical and laboratory characteristics of TB patients who were newly diagnosed versus previously diagnosed with HIV are compared. Genotypic clusters, defined as groups of two or more cases whose isolates of Mycobacterium tuberculosis had identical DNA fingerprints over the 10-year period or within 2 years of one another, were analyzed for their ability to predict HIV co-infection. RESULTS: HIV testing rates were 26% before and 90% after the introduction of "opt-out" testing. During the "opt-out" testing years those <15 or >64 years of age at diagnosis were less likely to have been tested. In those tested the prevalence of HIV was 5.6%. In the age group 15-64 years, risk factors for HIV were: age (35-64 years), Canadian-born Aboriginal or foreign-born sub-Saharan African origin, and combined respiratory and non-respiratory disease. Compared to TB patients previously known to be HIV positive, TB patients newly discovered to be HIV positive had more advanced HIV disease (lower CD4 counts; higher viral loads) at diagnosis. Large cluster size was associated with Aboriginal ancestry. Cluster size predicted HIV co-infection in Aboriginal peoples when clusters included all cases reported over 10 years but not when clusters included cases reported within 2 years of one another. CONCLUSION: "Opt-out" HIV testing of TB patients is effective and well received. Universal HIV testing of TB patients (>80% of patients tested) has immediate (patients) and longer-term (TB/HIV program planning) benefits.