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.

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.

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.

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.

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.

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.

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.

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.

Interferon-gamma release assays and TB screening in high-income countries: a cost-effectiveness analysis.

OBJECTIVE: Interferon-gamma release assays (IGRA) are now available alternatives to tuberculin skin testing (TST) for detection of latent tuberculosis infection (LTBI). We compared the cost-effectiveness of TST and IGRA in different populations and clinical situations, and with variation of a number of parameters. METHODS: Markov modelling was used to compare expected TB cases and costs over 20 years following screening for TB with different strategies among hypothetical cohorts of foreign-born entrants to Canada, or contacts of TB cases. The less expensive commercial IGRA, Quanti-FERON-TB Gold (QFT), was examined. Model inputs were derived from published literature. RESULTS: For entering immigrants, screening with chest radiograph (CXR) would be the most and QFT the least cost-effective. Sequential screening with TST then QFT was more cost-effective than QFT alone in all scenarios, and more cost-effective than TST alone in selected subgroups. Among close and casual contacts, screening with TST or QFT would be cost saving; savings with TST would be greater than with QFT, except in contacts who were bacille Calmette-Guérin (BCG) vaccinated after infancy. CONCLUSIONS: Screening for LTBI, with TST or QFT, is cost-effective only if the risk of disease is high. The most cost-effective use of QFT is to test TST-positive persons.

Use of geographic and genotyping tools to characterise tuberculosis transmission in Montreal.

SETTING: In Canada, tuberculosis (TB) is increasingly an urban health problem. Montreal is Canada's second-largest city and the second most frequent destination for new immigrants and refugees. OBJECTIVES: To detect spatial aggregation of cases, areas of excess incidence and local 'hot spots' of transmission in Montreal. DESIGN: We used residential addresses to geocode active TB cases reported on the Island of Montreal in 1996-2000. After a hot spot analysis suggested two areas of overconcentration, we conducted a spatial scan, with census tracts (population 2500-8000) as the primary unit of analysis and stratification by birthplace. We linked these analyses with genotyping of all available Mycobacterium tuberculosis isolates, using IS6110-RFLP and spoligotyping. RESULTS: We identified four areas of excess incidence among the foreign-born (incidence rate ratios 1.3-4.1, relative to the entire Island) and one such area among the Canadian-born (incidence rate ratio 2.3). There was partial overlap with the two hot spots. Genotyping indicated ongoing transmission among the foreign-born within the largest high-incidence zone. While this zone overlapped the area of high incidence among Canadian-born, genotyping largely excluded transmission between the two groups. CONCLUSIONS: In a city with low overall incidence, spatial and molecular analyses highlighted ongoing local transmission.

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.

Tuberculosis surveillance among new immigrants in Montreal.

SETTING: Foreign-born persons account for over 60% of Canadian tuberculosis (TB) incidence; immigrants with TB-related lung scarring ('inactive TB') are at particularly high risk, and represent an important target for preventive efforts. OBJECTIVE: To document the performance of the immigrant surveillance programme for inactive TB in Montreal. DESIGN: All immigrants arriving with inactive TB are referred by the public health department to the Montreal Chest Institute. We prospectively recorded clinical and radiographic data for those evaluated in 1999 and 2000. We examined physicians' adherence to Canadian guidelines. We also evaluated concordance of chest radiographic interpretation. RESULTS: Of 1444 immigrants notified, 792 (55%) were sent referral letters. Most of the others lacked valid addresses. Of the 654 (45%) who were examined, 322 (22%) were diagnosed with untreated latent TB, 215 (15%) were recommended therapy, and 156 (11%) completed it. Of 388 potential candidates for treatment of latent TB, 274 (71%) underwent tuberculin tests. Treatment decisions followed guidelines for 87% of patients with full testing. Agreement between clinicians and chest radiologists as to TB-related radiographic abnormalities was frequent (K 0.63). Six 'high volume' clinicians performed better than others with respect to management and radiographic interpretation. CONCLUSION: Centralised post-immigration surveillance requires more accurate referrals, and more consistent provider performance.

In closely monitored patients, adherence in the first month predicts completion of therapy for latent tuberculosis infection.

BACKGROUND: Current therapy for latent TB infection (LTBI) is long, and requires close follow-up. This results in sub-optimal adherence-the major reason for failure of therapy. METHODS: In an open label randomised trial comparing 4 months of rifampicin with 9 months of isoniazid, the proportion and regularity of doses taken, measured with an electronic monitoring system (MEMS), and provider estimates of adherence in the first month of therapy, were assessed as predictors of treatment completion. RESULTS: Of 104 patients analysed, 86 took more than 80% of doses within the expected interval, 11 took more than 80% of doses but over a longer time interval than usually allowed, and seven did not complete treatment. Treatment completion was associated with the number of doses taken, and the variability of intervals between doses during the first month of treatment. CONCLUSIONS: Adherence in the first month, based on the number of doses and variability of times when taken, could be useful to predict completion of LTBI therapy. Interventions could be targeted to patients with suboptimal adherence in the first month.

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.

Strategies incorporating spiral CT for the diagnosis of acute pulmonary embolism: a cost-effectiveness analysis.

OBJECTIVE: To assess the cost-effectiveness of spiral CT for the diagnosis of acute pulmonary embolism. DESIGN: Computer-based cost-effectiveness analysis. PATIENTS: Simulated cohort of 1,000 patients with suspected acute pulmonary embolism (PE), with a prevalence of 28.4%, as in the Prospective Investigation of Pulmonary Embolism Diagnosis study. INTERVENTIONS: Using a decision-analysis model, seven diagnostic strategies were compared, which incorporated combinations of ventilation-perfusion (V/Q) scans, duplex ultrasound of the legs, spiral CT, and conventional pulmonary angiography. MEASUREMENTS AND RESULTS: Expected survival and cost (in Canadian dollars) at 3 months were estimated. Four of the strategies yielded poorer survival at higher cost. The three remaining strategies were as follows: (1) V/Q +/- leg ultrasound +/- spiral CT, with an expected survival of 953.4 per 1,000 patients and a cost of $1,391 per patient; (2) V/Q +/- leg ultrasound +/- pulmonary angiography (the "traditional" algorithm), with an expected survival of 953.7 per 1,000 patients and a cost of $1,416 per patient; and (3) spiral CT +/- leg ultrasound, with an expected survival of 958.2 per 1,000 patients and a cost of $1,751 per patient. The traditional algorithm was then excluded by extended dominance. The cost per additional life saved was $70,833 for spiral CT +/- leg ultrasound relative to V/Q +/- leg ultrasound +/- spiral CT. CONCLUSIONS: Spiral CT can replace pulmonary angiography in patients with nondiagnostic V/Q scan and negative leg ultrasound findings. This approach is likely as effective as-and possibly less expensive than-the current algorithm for diagnosis of acute PE. When spiral CT is the initial diagnostic test, followed by leg ultrasound, expected survival improves but costs are also considerably higher. These findings were robust to variations in the assumed sensitivity and specificity of spiral CT.

Local determinants of response to endobronchial high-dose rate brachytherapy in bronchogenic carcinoma.

STUDY OBJECTIVE: We evaluated bronchoscopic tumor appearance and tumor location as determinants of response to high-dose rate brachytherapy (HDR-BT) in patients with symptomatic unresectable bronchogenic carcinoma previously treated with external-beam irradiation. PATIENTS AND METHODS: Thirty patients with symptomatic endobronchial bronchogenic carcinoma who had previously completed external irradiation were divided into two groups based on whether the initial bronchoscopic appearance showed an endoluminal mass or submucosal infiltration/extrinsic compression. Furthermore, patients were also classified based on tumor location: central (trachea or mainstem bronchi) and peripheral (lobar or segmental bronchi). Patients underwent three treatments of 800 cGy intraluminal irradiation at 2-week intervals, with follow-up evaluation 4 weeks later. We evaluated response in tumor extent based on bronchoscopic and chest radiograph appearance, as well as symptoms with standardized scales. RESULTS: Fifteen of 24 patients who underwent follow-up bronchoscopy had reductions in the degree of endobronchial obstruction. Seven of 24 patients had radiographic improvement in the extent of atelectasis. Patients with both tumor appearances (endoluminal and submucosal/extrinsic compression) had significant improvements following HDR-BT with regard to hemoptysis. Patients with submucosal disease also had improvement in cough. Patients with peripheral tumors had better rates of response for hemoptysis and cough than did those with central tumors. CONCLUSION: HDR-BT may result in symptomatic improvement in patients with bronchogenic carcinoma, whether characterized endoscopically as endoluminal projection or submucosal infiltration/extrinsic compression. Peripheral tumors have better rates of response than central tumors, possibly on the basis of less extensive disease.