Kevin Schwartzman

Self-management reduces both short- and long-term hospitalisation in COPD.

The aim of the present study was to assess the long-term impact on hospitalisation of a self-management programme for chronic obstructive pulmonary disease (COPD) patients. A multicentre, randomised clinical trial was carried out involving 191 COPD patients from seven hospitals. Patients who had one or more hospitalisations in the year preceding study enrolment were assigned to a self-management programme “Living Well with COPDTM” or to standard care. Hospitalisations from all causes were the primary outcome and were documented from the provincial hospitalisation database; emergency visits were recorded from the provincial health insurance database. Most patients were elderly, not highly educated, had advanced COPD (reflected by a mean forced expiratory volume in one second of 1 L), and almost half reported a dyspnoea score of 5/5 (modified Medical Research Council). At 2 years, there was a statistically significant and clinically relevant reduction in all-cause hospitalisations of 26.9% and in all-cause emergency visits of 21.1% in the intervention group as compared to the standard-care group. After adjustment for the self-management intervention effect, the predictive factors for reduced hospitalisations included younger age, sex (female), higher education, increased health status and exercise capacity. In conclusion, in this study, patients with chronic obstructive pulmonary disease who received educational intervention with supervision and support based on disease-specific self-management maintained a significant reduction in hospitalisations after a 2-year period.

Adverse events with 4 months of rifampin therapy or 9 months of isoniazid therapy for latent tuberculosis infection: a randomized trial.

Context Isoniazid is hepatotoxic and must be taken for 9 months by patients with latent tuberculosis infection. Contribution In this trial comparing 4 months of rifampin therapy with 9 months of isoniazid therapy, patients who took rifampin had fewer adverse events and were more likely to complete treatment. Caution The investigators did not compare efficacy of the 2 treatments. Implication These safety and adherence data justify a larger trial to compare the efficacy of rifampin and isoniazid for latent tuberculosis infection. The Editors After detection and treatment of active tuberculosis cases, the next priority in tuberculosis control is the diagnosis and treatment of persons with latent tuberculosis infection (LTBI) who are at increased risk for active tuberculosis. Treatment of such individuals can provide individual and public health benefits (14). The current recommended standard therapy in most countries is 9 months of isoniazid therapy (4, 5). The drug has more than 90% efficacy if taken the entire 9 months (6), but completion rates under routine practice conditions are about 50% or less (79). Another important disadvantage of isoniazid therapy is the occurrence of serious adverse events, particularly drug-induced hepatitis (10). Drug-induced hepatitis was not recognized as a complication of isoniazid therapy in early trials involving more than 50000 participants (11), but it was a frequent and potentially severe problem after isoniazid was recommended for tuberculosis prevention in 1970 (12) and was subsequently used more widely (13, 14). This complication makes close monitoring necessary, increasing costs. These problems have stimulated considerable interest in finding shorter and safer regimens for the treatment of LTBI (15). One alternative, 2 months of daily rifampinpyrazinamide, was recommended in 2000 (4) on the basis of evidence from several trials (1618). However, subsequent reports of severe and fatal hepatotoxicity (19, 20) have rendered this regimen unacceptable for most patients. The remaining recommended alternative is 4 months of daily rifampin, but published outcome information is limited and systematic reviews on this regimen have not been done. In the only published trial that compared 3 months of daily rifampin therapy with 6 months of daily isoniazid therapy in 332 patients, efficacy and safety were similar (21). In 2 uncontrolled case series, 6 months of daily rifampin was well tolerated in 49 homeless persons in Boston (22) and in 157 high school students in California (23). Two nonrandomized studies have described better treatment completion and less hepatotoxicity with 4 months of rifampin than with 9 months of isoniazid under program conditions (8, 9). However, rifampin has been reported to cause other problemsnotably drug interactions (24), a flu-like syndrome (24), and rare hematologic problems (immune-mediated thrombocytopenia and anemia) (25). Also, development of drug resistance is a theoretical concern. Given the experience with isoniazid and 2 months of rifampinpyrazinamide, both of which were thought to be safe on the basis of early studies but caused deaths when used more widely, we designed a multicenter, randomized trial to compare the frequency of serious adverse events and treatment completion rates in patients given 4 months of daily rifampin or 9 months of daily isoniazid for LTBI. Methods Setting, Study Sample, and Randomization This open-label trial was conducted at 9 university-affiliated hospitals: 7 in Canada and 1 each in Saudi Arabia and Brazil. We considered patients to be eligible if they were age 18 years or older and had a documented tuberculin skin test that met the criteria for a positive result (5) and if their primary treating physician initially recommended isoniazid for LTBI following national or international guidelines (4, 26, 27). Patients were ineligible if they were contacts of isoniazid- or rifampin-resistant cases (28), were allergic to isoniazid or rifamycins, or were taking concomitant medications that had clinically significant potential drug interactions that could not be easily managed. To ensure a realistic assessment of adverse events, we considered all other adults eligible, regardless of age or additional risk factors for adverse events, as long as their treating physician felt that therapy for LTBI was indicated. A Web-based program verified eligibility and randomly assigned participants (by using a random-number generator), after they signed informed consent, to 4 months of daily rifampin (10 mg per kg of body weight, up to 600 mg/d) or 9 months of daily isoniazid (5 mg/kg, up to 300 mg/d) in blocks of varying size, stratified by center. A team at the University of Sherbrooke, Sherbrooke, Quebec, Canada, prepared the Web-based program and allocation sequence. Study personnel in the different centers enrolled and registered participants, obtained consent, verified assignment, and administered treatment. All study participants signed informed consent before randomization. Institutional review boards in each participating institution approved the study. Processes and Outcomes Patients were followed in routine fashion by their usual treating physician, who made all management decisions, including discontinuation of therapy. By study protocol, all patients had blood tests (complete blood count, liver aminotransferase levels [aspartate aminotransferase and alanine aminotransferase], and bilirubin level) before and after 1 and 2 months of therapy and were seen every month for the first 4 months of therapy and (for those receiving 9 months of isoniazid) at physician discretion every 6 weeks thereafter. Adverse events could be detected at any time throughout the course of therapy. When the treating physician suspected an adverse event and therapy was suspended, investigations, including blood tests, were performed according to study protocol. The treating physician decided whether to discontinue, rechallenge with, or restart the study therapy, although the protocol specified that participants with grade 3 or 4 adverse events (Appendix Table 1) were not to be rechallenged. When all investigations were complete, and if therapy was permanently discontinued in response to the event, the patients clinical course and results of investigations and rechallenge (if any) were made available to a 3-member independent review panel who were blinded to study drug. If therapy was resumed (for example, after resolution of a grade 1 or 2 adverse event) and the event did not recur, the patients information was not reviewed by the panel. Appendix Table 1. Grading System for Adverse Events Used by Independent Panel Each review panel member had substantial experience and expertise in clinical and epidemiologic aspects of tuberculosis, and each independently judged the type and severity of the adverse events and its likely relationship to the study drug. We graded adverse events as recommended by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 2.0 (29) (Appendix Table 1). Liver aminotransferase levels that increased to 5 to 10 or 3 to 10 times the upper limit of normal in the presence of compatible symptoms met criteria for grade 3 hepatotoxicity, whereas those that exceeded 10 times the upper limit of normal met criteria for grade 4 toxicity (30). In the event of disagreement, panel members re-reviewed the information; if disagreement remained, the majority opinion was used. The studys primary outcome was the frequency of grade 3 or 4 adverse events that resulted in study drug discontinuation and were judged by the review panel to be probably related to the drug (Appendix Table 1). The studys secondary outcome was on-time treatment completion, defined as taking more than 80% of doses within a maximum of 150 days for 4 months of rifampin or 301 days (43 weeks) for 9 months of isoniazid. Doses taken were measured with the Medical Event Monitoring System, an electronic device in the pill container cap that recorded the date and time of bottle opening (APREX Corporation, Fremont, California). Other secondary outcomes included grade 1 or 2 adverse events that were judged by the independent panel to be probably study drugrelated and resulted in permanent discontinuation of therapy and changes in liver aminotransferase levels and leukocyte and platelet counts before and 1 and 2 months after beginning treatment. Statistical Analysis We initially calculated a trial sample size by assuming that the frequency of serious adverse events would be significantly higher with rifampin. We calculated that 630 patients per group would provide 90% power (2-sided = 0.05) to detect a difference between frequency of adverse events of 9% and 4% in the rifampin and isoniazid groups, respectively. This estimate also accounted for an anticipated 15% dropout rate during therapy. Because we were unsure about the actual frequency of adverse events with rifampin, we also noted that 630 patients per group provided 80% power to detect a statistically significant difference between rates of adverse events in the 2 groups if the event rates were 2% and 5% in the rifampin and isoniazid groups, respectively, and the dropout rate was 15%. To ensure safety of study participants, we planned 3 interim analyses for when 25%, 50%, and 75% of the planned total sample size had been randomly assigned. The data safety and monitoring board, blinded to the identity of the 2 groups, reviewed the overall rate of serious adverse events in each group. If the rate was significantly higher in 1 group, then the results were unblinded and the data safety and monitoring board made a decision, based on clinical judgment and statistical input, about stopping or continuing the trial. We used an value of 0.01 to account for multiple testing (31). We reported summary baseline liver function test results for each group as the ratio of each patients test result to the upper li

Major Mycobacterium tuberculosis Lineages Associate with Patient Country of Origin

ABSTRACT Over recent years, there has been an increasing acknowledgment of the diversity that exists among Mycobacterium tuberculosis clinical isolates. To facilitate comparative studies aimed at deciphering the relevance of this diversity to human disease, an unambiguous and easily interpretable method of strain classification is required. Presently, the most effective means of assigning isolates into a series of unambiguous lineages is the method of Gagneux et al. (S. Gagneux et al., Proc. Natl. Acad. Sci. USA 103:2869-2873, 2006) that involves the PCR-based detection of large sequence polymorphisms (LSPs). In this manner, isolates are classified into six major lineages, the majority of which display a high degree of geographic restriction. Here we describe an independent replicate of the Gagneux study carried out on 798 isolates collected over a 6-year period from mostly foreign-born patients resident on the island of Montreal, Canada. The original trends in terms of bacterial genotype and patient ethnicity are remarkably conserved within this Montreal cohort, even though the patient distributions between the two populations are quite distinct. In parallel with the LSP analysis, we also demonstrate that “clustered” tuberculosis (TB) cases defined through restriction fragment length polymorphism (RFLP) analysis (for isolates with ≥6 IS6110 copies) or RFLP in combination with spoligotyping (for isolates with <6 IS6110 copies) do not stray across the LSP-defined lineage boundaries. However, our data also demonstrate the poor discriminatory power of either RFLP or spoligotyping alone for these low-IS6110-copy-number isolates. We believe that this independent validation of the LSP method should encourage researchers to adopt this system in investigations aimed at elucidating the role of strain variation in TB.

T-Cell Assays for Tuberculosis Infection: Deriving Cut-Offs for Conversions Using Reproducibility Data

Background Although interferon-gamma release assays (IGRA) are promising alternatives to the tuberculin skin test, interpretation of repeated testing results is hampered by lack of evidence on optimal cut-offs for conversions and reversions. A logical start is to determine the within-person variability of T-cell responses during serial testing. Methodology/Principal Findings We performed a pilot study in India, to evaluate the short-term reproducibility of QuantiFERON-TB Gold In Tube assay (QFT) among 14 healthcare workers (HCWs) who underwent 4 serial QFT tests on day 0, 3, 9 and 12. QFT ELISA was repeated twice on the same sets of specimens. We assessed two types of reproducibility: 1) test-retest reproducibility (between-test variability), and 2) within-person reproducibility over time. Test-retest reproducibility: with dichotomous test results, extremely high concordance was noticed between two tests performed on the same sets of specimens: of the 56 samples, the test and re-test results agreed for all but 2 individuals (κ = 0.94). Discordance was noted in subjects who had IFN-γ values around the cut-off point, with both increases and decreases noted. With continuous IFN-γ results, re-test results tended to produce higher estimates of IFN-γ than the original test. Within-person reproducibility: when continuous IFN-γ data were analyzed, the within-person reproducibility was moderate to high. While persons with negative QFT results generally stayed negative, positive results tended to vary over time. Our data showed that increases of more than 16% in the IFN-γ levels are statistically improbable in the short-term. Conclusions Conservatively assuming that long-term variability might be at least twice higher than short-term, we hypothesize that a QFT conversion requires two conditions to be met: 1) change from negative to positive result, and 2) at least 30% increase in the baseline IFN-γ response. Larger studies are needed to confirm our preliminary findings, and determine the conversion thresholds for IGRAs.

Extraction of Mycobacterium tuberculosis DNA: a question of containment.

ABSTRACT DNA fingerprinting of Mycobacterium tuberculosis by IS6110 restriction fragment length polymorphism analysis requires substantial high-quality DNA. We demonstrated that, despite extraction treatments that might be expected to inactivate this organism, M. tuberculosis remained viable during this process. These data suggest that the extraction of M. tuberculosis DNA should be performed within containment until complete.

Maternal sleep-disordered breathing and adverse pregnancy outcomes: a systematic review and metaanalysis

OBJECTIVE Symptoms of sleep-disordered breathing (SDB) are increased in pregnancy compared to the nongravid state. Maternal SDB may be associated with adverse pregnancy outcomes, but this is still under investigation. We performed a systematic literature review, and where feasible, a metaanalysis, to evaluate whether women with SDB in pregnancy have a higher risk of specific adverse pregnancy outcomes compared with women without SDB. STUDY DESIGN Original studies published until June 2012 evaluating the association between gestational hypertension/preeclampsia, gestational diabetes, low birthweight infants, and maternal SDB, defined either by symptoms or the reference standard polysomnography, were identified from PubMed, EMBASE, and Web of Science. Data were extracted on study design and outcome estimates. When appropriate, effect estimates from each study were pooled using a random-effects model. RESULTS Of the 4386 studies identified, 31 met the defined criteria. Twenty-one studies, all observational in design, reported dichotomous outcomes; 9 of these adjusted for potential confounders. Maternal SDB was significantly associated with gestational hypertension/preeclampsia (pooled adjusted odds ratio [aOR], 2.34; 95% confidence interval [CI], 1.60-3.09; 5 studies), and gestational diabetes (pooled aOR, 1.86; 95% CI, 1.30-2.42; 5 studies). CONCLUSION Based on published observational studies to date, maternal SDB is associated with an increased risk of gestational hypertension and gestational diabetes after adjusting for potential confounders. However, large-scale, prospective cohort, and interventional studies are needed to further elucidate the relationship between maternal SDB and adverse pregnancy outcomes.

Seroprevalence of Chronic Hepatitis B Virus Infection and Prior Immunity in Immigrants and Refugees: A Systematic Review and Meta-Analysis

Background International migrants experience increased mortality from hepatocellular carcinoma compared to host populations, largely due to undetected chronic hepatitis B infection (HBV). We conducted a systematic review of the seroprevalence of chronic HBV and prior immunity in migrants arriving in low HBV prevalence countries to identify those at highest risk in order to guide disease prevention and control strategies. Methods and Findings Medline, Medline In-Process, EMBASE and the Cochrane Database of Systematic Reviews were searched. Studies that reported HBV surface antigen or surface antibodies in migrants were included. The seroprevalence of chronic HBV and prior immunity were pooled by region of origin and immigrant class, using a random-effects model. A random-effects logistic regression was performed to explore heterogeneity. The number of chronically infected migrants in each immigrant-receiving country was estimated using the pooled HBV seroprevalences and country-specific census data. A total of 110 studies, representing 209,822 immigrants and refugees were included. The overall pooled seroprevalence of infection was 7.2% (95% CI: 6.3%–8.2%) and the seroprevalence of prior immunity was 39.7% (95% CI: 35.7%–43.9%). HBV seroprevalence differed significantly by region of origin. Migrants from East Asia and Sub-Saharan Africa were at highest risk and migrants from Eastern Europe were at an intermediate risk of infection. Region of origin, refugee status and decade of study were independently associated with infection in the adjusted random-effects logistic model. Almost 3.5 million migrants (95% CI: 2.8–4.5 million) are estimated to be chronically infected with HBV. Conclusions The seroprevalence of chronic HBV infection is high in migrants from most world regions, particularly among those from East Asia, Sub-Saharan Africa and Eastern Europe, and more than 50% were found to be susceptible to HBV. Targeted screening and vaccination of international migrants can become an important component of HBV disease control efforts in immigrant-receiving countries.

Feasibility and reliability of health-related quality of life measurements among tuberculosis patients.

The dramatic global impact of tuberculosis on mortality has been well documented, but its impact on morbidity has not been well described. The emphasis on treatment of latent tuberculosis (TB) infection highlights the tradeoff between short-term decrements in health status from ‘preventive’ therapy, and long-term gains related to fewer cases of active TB. However, these changes in health status have not been characterized. As a first step, we examined the feasibility and reliability of administering two health status questionnaires, in a multicultural TB clinic setting. The Medical Outcomes Study SF-36 and the EuroQOL EQ-5D were self-administered during 3 weekly interviews. One hundred and eighty-six potentially eligible patients were identified, of whom 112 could be evaluated; 106 (57%) were confirmed eligible. Sixty-seven (63%) agreed to participate; 24 (36%) were women. Fifty-three participants (79%) were foreign-born, with median residence in Canada of 3.5 years. Fifty (75%) of the participants completed all study measurements: 25 were treated for latent TB, 17 for active TB, and eight had previous active TB. Cronbachs α coefficients ranged from 0.73 to 0.94 for the SF-36 domain scores. Intraclass correlation coefficients were 0.66 for the SF-36 physical component summary, 0.79 for the mental component summary, and 0.73 for the EQ-5D. These instruments appeared reliable in a highly selected group of TB patients.

Tuberculosis: evidence review for newly arriving immigrants and refugees

Background: The foreign-born population bears a disproportionate health burden from tuberculosis, with a rate of active tuberculosis 20 times that of the non-Aboriginal Canadian-born population, and could therefore benefit from tuberculosis screening programs. We reviewed evidence to determine the burden of tuberculosis in immigrant populations, to assess the effectiveness of screening and treatment programs for latent tuberculosis infection, and to identify potential interventions to improve effectiveness. Methods: We performed a systematic search for evidence of the burden of tuberculosis in immigrant populations and the benefits and harms, applicability, clinical considerations, and implementation issues of screening and treatment programs for latent tuberculosis infection in the general and immigrant populations. The quality of this evidence was assessed and ranked using the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation). Results: Chemoprophylaxis with isoniazid is highly efficacious in decreasing the development of active tuberculosis in people with latent tuberculosis infection who adhere to treatment. Monitoring for hepatotoxicity is required at all ages, but close monitoring is required in those 50 years of age and older. Adherence to screening and treatment for latent tuberculosis infection is poor, but it can be increased if care is delivered in a culturally sensitive manner. Interpretation: Immigrant populations have high rates of active tuberculosis that could be decreased by screening for and treating latent tuberculosis infection. Several patient, provider and infrastructure barriers, poor diagnostic tests, and the long treatment course, however, limit effectiveness of current programs. Novel approaches that educate and engage patients, their communities and primary care practitioners might improve the effectiveness of these programs.

Sensitivities and Specificities of Spoligotyping and Mycobacterial Interspersed Repetitive Unit-Variable-Number Tandem Repeat Typing Methods for Studying Molecular Epidemiology of Tuberculosis

ABSTRACT The development of PCR-based genotyping modalities (spoligotyping and mycobacterial interspersed repetitive unit-variable-number tandem repeat [MIRU-VNTR] typing) offers promise for real-time molecular epidemiological studies of tuberculosis (TB). However, the utility of these methods depends on their capacity to appropriately classify isolates. To determine the operating parameters of spoligotyping and MIRU-VNTR typing, we have compared results generated by these newer tests to the standard typing method, IS6110 restriction fragment length polymorphism, in analyses restricted to high-copy-number IS6110 isolates. Sensitivities of the newer tests were estimated as the percentages of isolates with identical IS6110 fingerprints that had identical spoligotypes and MIRU-VNTR types. The specificities of these tests were estimated as the percentages of isolates with unique IS6110 fingerprints that had unique spoligotypes and MIRU-VNTR types. The sensitivity of MIRU-VNTR typing was 52% (95% confidence interval [CI], 31 to 72%), and the sensitivity of spoligotyping was 83% (95% CI, 63 to 95%). The specificity of MIRU-VNTR typing was 56% (95% CI, 51 to 62%), and the specificity of spoligotyping was 40% (95% CI, 35 to 46%). The proportion of isolates estimated to be due to recent transmission was 4% by identical IS6110 patterns, 19% by near-identical IS6110 patterns, 33% by MIRU-VNTR typing, and 53% by spoligotyping. The low calculated specificities of spoligotyping and MIRU-VNTR typing led to misclassification of cases, inflated estimates of TB transmission, and low positive predictive values, suggesting that these techniques have unsuitable operating parameters for population-based molecular epidemiology studies.