Patterns and characteristics of TB among key risk groups in Canada, 1993-2018.

BACKGROUND: Canada has a low incidence of TB, although certain groups are disproportionately affected.OBJECTIVE: To describe and compare the epidemiology, trends and characteristics of TB in Quebec, Canada, among all patients reported during 1993-2018.METHODS: Demographics and risk factors were compared for the three groups accounting for most TB diagnoses reported in Quebec (foreign-born, Canadian-born non-Indigenous and Inuit). Average annual incidence and incidence rate ratios (IRRs) were estimated and compared using Poisson regression.RESULTS: Of 6,941 persons with a first episode of TB, 4,077 (59%) were foreign-born, 2,314 (33%) were Canadian-born non-Indigenous and 389 (6%) were Inuit. The average annual incidence for foreign-born, Canadian-born non-Indigenous and Inuit was respectively 17.0, 1.4 and 137.1 per 100,000 population. Compared to Canadian-born non-Indigenous, the IRR for foreign-born and Inuit was respectively 12.3 (95% CI 11.6-12.9) and 98.7 (95% CI 88.6-109.9). There was evidence of community transmission among the Inuit, with more than 80% of patients having a TB contact (2012-2018 data) and 65% (251/389) of diagnoses in those aged <25 years.CONCLUSION: Although TB rates among the Canadian-born non-Indigenous are extremely low, there are persistent and distinct TB epidemics among the foreign-born and Inuit. Tailored approaches to TB prevention and care are needed to address TB among high-risk populations in low TB incidence settings.

WHO target product profiles for TB preventive treatment.

BACKGROUND: The WHO has developed target product profiles (TPPs) describing the most appropriate qualities for future TPT regimens to assist developers in aligning the characteristics of new treatments with programmatic requirements.METHODS: A technical consultation group was convened by the WHO to determine regimen attributes with greatest potential impact for patients (i.e., improved risk/benefit profile) and populations (i.e., reduction in transmission and TB prevalence). The group categorised regimen attributes as 'priority´ or 'desirable´; and defined for each attribute the minimum requirements and optimal targets.RESULTS: Nine priority attributes were defined, including efficacy, treatment duration, safety, drug-drug interactions, barrier to emergence of drug resistance, target population, formulation, dosage, frequency and route of administration, stability and shelf life. Regimens meeting optimal targets were characterised, for example, as having superior efficacy, treatment duration of ≤2 weeks, and improved tolerability and safety profile compared with current regimens. The four desirable attributes included regimen cost, safety in special populations, treatment adherence and need for drug susceptibility testing in the index patient.DISCUSSION: It may be difficult for a single regimen to satisfy all characteristics so regimen developers may have to consider trade-offs. Additional operational aspects may be relevant to the feasibility and public health impact of new TPT regimens.

Resource implications of the latent tuberculosis cascade of care: a time and motion study in five countries.

BACKGROUND: The End TB Strategy calls for global scale-up of preventive treatment for latent tuberculosis infection (LTBI), but little information is available about the associated human resource requirements. Our study aimed to quantify the healthcare worker (HCW) time needed to perform the tasks associated with each step along the LTBI cascade of care for household contacts of TB patients. METHODS: We conducted a time and motion (TAM) study between January 2018 and March 2019, in which consenting HCWs were observed throughout a typical workday. The precise time spent was recorded in pre-specified categories of work activities for each step along the cascade. A linear mixed model was fit to estimate the time at each step. RESULTS: A total of 173 HCWs in Benin, Canada, Ghana, Indonesia, and Vietnam participated. The greatest amount of time was spent for the medical evaluation (median: 11 min; IQR: 6-16), while the least time was spent on reading a tuberculin skin test (TST) (median: 4 min; IQR: 2-9). The greatest variability was seen in the time spent for each medical evaluation, while TST placement and reading showed the least variability. The total time required to complete all steps along the LTBI cascade, from identification of household contacts (HHC) through to treatment initiation ranged from 1.8 h per index TB patient in Vietnam to 5.2 h in Ghana. CONCLUSIONS: Our findings suggest that the time requirements are very modest to perform each step in the latent TB cascade of care, but to achieve full identification and management of all household contacts will require additional human resources in many settings.

Validated methods for identifying tuberculosis patients in health administrative databases: systematic review.

BACKGROUND: An increasing number of studies are using health administrative databases for tuberculosis (TB) research. However, there are limitations to using such databases for identifying patients with TB. OBJECTIVE: To summarise validated methods for identifying TB in health administrative databases. METHODS: We conducted a systematic literature search in two databases (Ovid Medline and Embase, January 1980-January 2016). We limited the search to diagnostic accuracy studies assessing algorithms derived from drug prescription, International Classification of Diseases (ICD) diagnostic code and/or laboratory data for identifying patients with TB in health administrative databases. RESULTS: The search identified 2413 unique citations. Of the 40 full-text articles reviewed, we included 14 in our review. Algorithms and diagnostic accuracy outcomes to identify TB varied widely across studies, with positive predictive value ranging from 1.3% to 100% and sensitivity ranging from 20% to 100%. CONCLUSIONS: Diagnostic accuracy measures of algorithms using out-patient, in-patient and/or laboratory data to identify patients with TB in health administrative databases vary widely across studies. Use solely of ICD diagnostic codes to identify TB, particularly when using out-patient records, is likely to lead to incorrect estimates of case numbers, given the current limitations of ICD systems in coding TB.

Three months of weekly rifapentine plus isoniazid is less hepatotoxic than nine months of daily isoniazid for LTBI.

SETTING: Nine months of daily isoniazid (9H) and 3 months of once-weekly rifapentine plus isoniazid (3HP) are recommended treatments for latent tuberculous infection (LTBI). The risk profile for 3HP and the contribution of hepatitis C virus (HCV) infection to hepatotoxicity are unclear. OBJECTIVES: To evaluate the hepatotoxicity risk associated with 3HP compared to 9H, and factors associated with hepatotoxicity. DESIGN: Hepatotoxicity was defined as aspartate aminotransferase (AST) >3 times the upper limit of normal (ULN) with symptoms (nausea, vomiting, jaundice, or fatigue), or AST >5 x ULN. We analyzed risk factors among adults who took at least 1 dose of their assigned treatment. A nested case-control study assessed the role of HCV. RESULTS: Of 6862 participants, 77 (1.1%) developed hepatotoxicity; 52 (0.8%) were symptomatic; 1.8% (61/3317) were on 9H and 0.4% (15/3545) were on 3HP (P < 0.0001). Risk factors for hepatotoxicity were age, female sex, white race, non-Hispanic ethnicity, decreased body mass index, elevated baseline AST, and 9H. In the case-control study, HCV infection was associated with hepatotoxicity when controlling for other factors. CONCLUSION: The risk of hepatotoxicity during LTBI treatment with 3HP was lower than the risk with 9H. HCV and elevated baseline AST were risk factors for hepatotoxicity. For persons with these risk factors, 3HP may be preferred.

Sputum induction for tuberculosis diagnosis in an Arctic setting: a cost comparison.

SETTING: Tuberculosis (TB) incidence was 234 per 100 000 in Nunavut, Canada, in 2012. Until recently, some individuals seen in local clinics for presumed TB required costly air evacuation to Southern Canada (Ottawa) for investigation if they were unable to produce sputum spontaneously. OBJECTIVE: To estimate the cost per individual evaluated for TB, associated with the establishment of a sputum induction programme in Iqaluit, Nunavut, Canada. DESIGN: A decision analysis model compared the total cost per individual for two strategies: 1) initial investigation in Iqaluit, with transport to Ottawa for those requiring sputum induction; and 2) sputum induction at the hospital in Iqaluit, with further investigation in Ottawa only if needed. The model simulated diagnostic and treatment paths from the initial clinic visit to completion of TB investigation or treatment (when applicable). RESULTS: The estimated cost per person evaluated for TB with sputum induction in 1) Ottawa vs. 2) Iqaluit was CAD4798 (95% uncertainty range 2923-6650) vs. CAD2479 (1206-4256), respectively. Total costs were influenced by underlying TB prevalence, but local sputum induction consistently yielded cost savings. CONCLUSION: Providing sputum induction in a high-incidence Arctic community such as Iqaluit is projected to generate substantial cost savings in the investigation and management of individuals with presumed TB.

Risk factors for susceptibility to varicella in newly arrived adult migrants in Canada.

Varicella occurs at an older age in tropical compared to cold climates. Migrants from tropical countries provide the opportunity to gain insights into observed global differences in varicella epidemiology. Severity of varicella increases with age thus, description of risk factors for varicella susceptibility will identify those who would benefit most from vaccination. A total of 1480 migrants, with a mean age of 32 years, were recruited in the pre-vaccination period (2002-2004) in Montreal, Canada. A questionnaire was administered and serum varicella antibodies were measured. Overall 6% were susceptible and ranged from 0·8% to 14·1% in subgroups. Risk factors for susceptibility were younger age, recent arrival, and originating from a tropical country. This could be modified by conditions that increased the probability of person-to-person spread of varicella through direct contact in source countries such as larger community size or household crowding. Many new young adult migrants would benefit from targeted varicella vaccination programmes.

The association of the distance walked in 6 min with pre-operative peak oxygen consumption and complications 1 month after colorectal resection.

We measured the distance 112 patients walked in 6 min, as well as their peak oxygen consumption pedalling a bicycle, week before scheduled resection of benign or malignant colorectal disease. The distance walked correlated with peak oxygen consumption, the former 'accounting' for about half the variation in the latter, r² 0.52 (95% CI 0.38-0.64), p < 0.0001. In the first postoperative month, 42/112 patients experienced a complication. In multivariate analysis, complications were less likely with longer walking distances and increasing age: the odds ratio (95% CI) reduced to 0.995 (0.990-0.999) for each metre distance, and to 0.96 (0.93-0.99) with each year of age, p = 0.025 and p = 0.018, respectively. The distance walked in 6 min before surgery can provide prognostic information when cardiopulmonary exercise testing is unavailable.

A systematic review and meta-analysis of the impact of tuberculosis on health-related quality of life.

PURPOSE: To summarize the impact of tuberculosis (TB) on quantitative measures on self-reported health-related quality of life (HRQOL). METHODS: We searched eight databases to retrieve all peer-reviewed publications reporting original HRQOL data for persons with TB. All retrieved abstracts were considered for full-text review if HRQOL was quantitatively assessed among subjects with TB. Full-text articles were reviewed by two independent reviewers using a standardized abstraction form to collect data on socio-demographic characteristics, questionnaire administration, and mean HRQOL scores. Meta-analyses were performed for standardized mean differences in HRQOL scores, comparing subjects treated for active TB with subjects treated for latent TB infection (LTBI), or with healthy controls, at similar time points with respect to diagnosis and/or treatment. RESULTS: From over 15,000 abstracts retrieved, 76 full-text articles were reviewed, which represented 28 unique cohorts (6,028 subjects) reporting HRQOL among subjects with active TB; 42 % were women and mean age was 42 years. Data on key social and behavioral determinants were limited. Within individual studies and in meta-analyses, subjects with active TB disease consistently reported worse HRQOL than concurrently evaluated subjects treated for LTBI. However, meaningful improvements in HRQOL throughout active TB treatment were reported by longitudinal studies. CONCLUSIONS: In a variety of studies, in different settings and using different instruments, subjects with active TB consistently reported poorer HRQOL than persons treated for LTBI. Future research on HRQOL and TB should better address social and behavioral health determinants which may also affect HRQOL.

Mycobacterium tuberculosis transmission over an 11-year period in a low-incidence, urban setting.

SETTING: Montreal, Canada, has a mean annual tuberculosis (TB) incidence of 9 per 100,000 population, 1996-2007. OBJECTIVE: To characterise potential Mycobacterium tuberculosis transmission by patient subgroups defined by age, sex, birthplace, smear and human immunodeficiency virus status, and to estimate the proportion of cases that resulted from transmission between these patient subgroups. DESIGN: Retrospective study using DNA fingerprinting techniques, with clinical and demographic information from the public health department. Among cases with matching fingerprints, a pulmonary index case was identified. The transmission index was defined as the average number of subsequent TB cases generated directly or indirectly from an index case, and was compared among subgroups, including Haitian immigrants. RESULTS: Compared to non-Haitian foreign-born index cases, Canadian-born index cases were associated with 2.38 times as many (95%CI 1.24-4.58) subsequent cases, while Haitian-born index cases were associated with 3.58 times as many (95%CI 1.74-7.36). Smear-positive index cases were not independently associated with increased transmission. However, middle-aged Canadian-born index patients were associated with a disproportionate number of subsequent cases. CONCLUSION: In Montreal, index patients from several high-risk groups are associated with subsequent transmission. This approach can be applied to other low-incidence settings to identify where targeted interventions could potentially further reduce transmission.

Obstructive sleep apnea is associated with fatigue in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) patients often suffer from fatigue. OBJECTIVE: We evaluated the relationship of obstructive sleep apnea (OSA) to fatigue and sleepiness in MS patients. METHODS: Ambulatory MS patients without known sleep disorders and healthy controls underwent diagnostic polysomnography and a multiple sleep latency test (objective sleepiness measure). Fatigue was measured with the Fatigue Severity Scale (FSS) and the Multidimensional Fatigue Inventory (MFI), and subjective sleepiness by Epworth Sleepiness Scale. Covariates included age, sex, body mass index, Expanded Disability Status Scale (EDSS), depression, pain, nocturia, restless legs syndrome, and medication. RESULTS: OSA (apnea-hypopnea index ≥ 15) was found in 36 of 62 MS subjects and 15 of 32 controls. After adjusting for confounders, severe fatigue (FSS ≥ 5) and MFI-mental fatigue (>group median) were associated with OSA and respiratory-related arousals in MS, but not control subjects. Subjective and objective sleepiness were not related to OSA in either group. In a multivariate model, variables independently associated with severe fatigue in MS were severe OSA [OR 17.33, 95% CI 2.53-199.84], EDSS [OR 1.88, 95% CI 1.21-3.25], and immunomodulating treatment [OR 0.14, 95% CI 0.023-0.65]. CONCLUSIONS: OSA was frequent in MS and was associated with fatigue but not sleepiness, independent of MS-related disability and other covariates.

Tuberculosis may be underestimated in Rwandan women.

BACKGROUND AND HYPOTHESIS: The majority of adult tuberculosis (TB) cases reported to the surveillance system in Rwanda are male. If this results from detection mechanisms that are less sensitive to TB in women, notified cases should be more severe in women than in men. METHODS: We analysed the 2006 series of TB cases among persons aged ≥ 15 years in Huye District and Kigali. Severe TB was defined as disease leading to death, or extra-pulmonary or disseminated TB. RESULTS: Of 1673 cases identified, 40% involved women, who were younger than men (65% vs. 54% aged <35 years). Overall severity was similar in both sexes. Considering age <35 years, women were at higher risk of severe TB than men, although the difference was not statistically significant. Smear-negative pulmonary TB (SNPTB), and human immunodeficiency virus (HIV) infection were more frequent in women than in men (59% vs. 42%, P < 0.001). For women with smear-positive pulmonary TB (SPPTB), the risk of death was twice that among men (adjusted hazard ratio 1.8; 95%CI 1.0-3.2). CONCLUSIONS: Among female TB patients, the higher risk of death with SPPTB, the higher frequency of SNPTB and the higher prevalence of HIV infection suggest that the passive system of case detection may underestimate the burden of TB in Rwandan women.

Sleep disorders and fatigue in multiple sclerosis: evidence for association and interaction.

Fatigue is highly prevalent in multiple sclerosis (MS). It appears to be multifactorial, with "primary" or disease-related factors involved, as well as "secondary" factors, including comorbidities. Sleep disturbances are frequent in MS as well, and often result from disease-related factors. Subjective sleep disturbances in MS have been extensively studied and have been associated with fatigue. Sleep disorders in the general population have been associated with fatigue as well. However, data on objectively diagnosed sleep disorders in MS are less conclusive. Studies of sleep in MS have often suffered from low numbers of study subjects and suboptimal methodology. We review the current knowledge on sleep disturbances in MS and the relationship to fatigue. Data from neuroimaging studies and studies of molecular consequences of sleep disorders in the general population, with particular attention to sleep-disordered breathing (SDB), are briefly reviewed. Potential biologic interactions with MS are discussed in this context. We conclude that further studies of sleep disorders in MS are needed, to objectively establish their significance in this disease, and also to document any impact of treatment of sleep disorders on biologic and clinical outcomes such as fatigue.

Potential cost-effectiveness of rifampin vs. isoniazid for latent tuberculosis: implications for future clinical trials.

SETTING: Standard treatment for latent tuberculosis infection (LTBI) is 9 months daily isoniazid (9INH). An alternative is 4 months daily rifampin (4RMP), associated with better completion and less toxicity; however, its efficacy remains uncertain. OBJECTIVES: To assess the cost-effectiveness of these regimens for treating LTBI in human immunodeficiency virus negative persons, using results from a recent clinical trial, plus different scenarios for 4RMP efficacy, and to estimate the costs of an adequately powered noninferiority trial and resulting savings from substitution with 4RMP. DESIGN: A decision-analysis model tracked TB contacts and lower-risk tuberculin reactors receiving 9INH, 4RMP or no treatment. For different 4RMP efficacy scenarios, we estimated the cost-effectiveness, sample size and cost of non-inferiority trials, and potential cost savings substituting 4RMP for 9INH for 10 years in Canada. RESULTS: With an assumed 4RMP efficacy of 60%, 9INH was more effective but slightly more expensive. Above a threshold efficacy of 69%, 4RMP was cheaper and more effective than 9INH. If the true efficacy of 4RMP is ≥75%, a trial powered to detect non-inferiority with a lower limit of 60% estimated efficacy (~20 000 subjects) may lead to cost savings within 10 years, even with the extreme assumption that Canada bears the entire cost. CONCLUSION: 4RMP may be a reasonable alternative to 9INH. Costs of a large-scale non-inferiority trial may be offset by subsequent savings.

Predicting outcomes and drug resistance with standardised treatment of active tuberculosis.

New World Health Organization guidelines recommend initial treatment of active tuberculosis (TB) with a 6-month regimen utilising rifampin throughout. We have modelled expected treatment outcomes, including drug resistance, with this regimen, compared to an 8-month regimen with rifampin for the first 2 months only, followed by standardised retreatment. A deterministic model was used to predict treatment outcomes in hypothetical cohorts of 1,000 new smear-positive cases from seven countries with varying prevalence of initial drug resistance. Model inputs were taken from published systematic reviews. Predicted outcomes included number of deaths, failures and relapses, plus the proportion with drug resistance. Sensitivity analyses examined different risks of acquired drug resistance. Compared to use of the standardised 8-month regimen, for every 1,000 new TB cases treated with the 6-month regimen we predict that 48-86 fewer persons will require retreatment, and 3-12 deaths would be avoided. However, the proportion failing or relapsing after retreatment is predicted to be higher, because with the 6-month regimen 50-94% of failures and 3-56% of relapses will have multidrug-resistant TB. We predict substantial public health benefits from changing from the 8-month to the 6-month regimen. However in almost all settings the current standardised retreatment regimen will no longer be adequate.

Global tuberculosis trends: a reflection of changes in tuberculosis control or in population health?

BACKGROUND: Many international organizations are advocating for new funds for tuberculosis (TB) specific interventions. Although this approach should help reduce TB incidence, improvements in population health may also be important. We have analyzed the association between changes in population health and health service indicators, and concomitant changes in TB incidence between 1990 and 2005. METHODS: Country level data on population health and health services, economic and epidemiologic indicators were obtained for 165 countries. Regression methods were used to estimate the association of changes in potential predictors with changes in TB incidence. RESULTS: Improvements in population health and health services are associated with improvements in TB outcomes. In adjusted analyses, each 1 year increase in life expectancy was associated with a 7.8/100,000 decline in TB incidence. A 1/1000 decrease in mortality rate in children aged <5 years and a 1% increase in measles vaccination coverage (serving as a general health services indicator) was associated with approximately a 1/100,000 decrease in TB incidence. In countries with a lower prevalence of human immunodeficiency virus (HIV) infection, a 1% increase in TB treatment success rate was also associated with a 1/100,000 decrease in incidence. CONCLUSION: Investment in improving population health and health services may be as important as targeted strategies for controlling TB.

Obstructive sleep apnoea and its association with gestational hypertension.

Hypertension develops in 10% of pregnancies. Snoring, a marker of obstructive sleep apnoea, is a newly identified risk factor for gestational hypertension. Moreover, obstructive sleep apnoea is an independent risk factor for incident hypertension in the non-pregnant population. The aim of the present study was to test the hypothesis that obstructive sleep apnoea is associated with new onset of hypertension among pregnant females. A case-control study was performed involving 17 pregnant females with gestational hypertension and 33 pregnant females without hypertension. Subjects were frequency-matched for gestational age and recruited in a tertiary obstetrical centre. Obstructive sleep apnoea was ascertained by polysomnography and defined by an apnoea/hypopnoea index (AHI) of >or=15 events x h(-1), without requirement for desaturation. The mean+/-sd AHI for normotensive pregnant females was 18.2+/-12.2 events x h(-1) compared with 38.6+/-36.7 events x h(-1) for females with hypertensive pregnancies. The crude odds ratio for the presence of obstructive sleep apnoea given the presence of gestational hypertension was 5.6. The odds ratio was 7.5 (95% confidence interval 3.5-16.2), based on a logistic regression model with adjustment for maternal age, gestational age, pre-pregnancy body mass index, prior pregnancies, and previous live births. In conclusion, gestational hypertension appears to be strongly associated with the presence of obstructive sleep apnoea.