Dupilumab Reduces Exacerbations Independent of Changes in Biomarkers in Moderate-to-Severe Asthma.

BACKGROUND: Changes from baseline in fractional exhaled nitric oxide (FeNO) and blood eosinophil count (Eos) may be related to efficacy outcomes in dupilumab-treated patients with moderate-to-severe asthma. OBJECTIVE: This post hoc analysis investigated biomarker changes in placebo- and dupilumab-treated patients with uncontrolled moderate-to-severe asthma enrolled in QUEST (NCT02414854). METHODS: Spline analyses of annualized severe exacerbation rate (AER) and change from baseline in pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) at week 52 were performed as a function of the fold change in FeNO at week 52 and the maximum fold change in Eos over weeks 0-12 (also change from baseline in pre-BD FEV1 at week 12). RESULTS: The combined placebo and dupilumab groups comprised 638 and 1264 patients, respectively. FeNO levels declined rapidly by week 2 and then gradually to week 52 in patients treated with dupilumab versus placebo; Eos, after initially increasing with dupilumab, declined slightly from baseline in both treatment groups. AER during QUEST showed no significant association with the change in biomarkers in either treatment group. The change from baseline in pre-BD FEV1 at week 52 was inversely associated with the fold change in FeNO in both groups, with a significant difference between the dupilumab and placebo curves (P = .014), and was positively associated with the fold change in Eos in both groups (P = .022). CONCLUSIONS: Relative changes in FeNO and Eos were not associated with AER, regardless of treatment arm. However, changes in both biomarkers showed a predictive value for lung function improvement; for FeNO, this was specific to the dupilumab treatment arm.

A parametric model to jointly characterize rate, duration, and severity of exacerbations in episodic diseases.

BACKGROUND: The natural history of many chronic diseases is characterized by periods of increased disease activity, commonly referred to as flare-ups or exacerbations. Accurate characterization of the burden of these exacerbations is an important research objective. METHODS: The purpose of this work was to develop a statistical framework for nuanced characterization of the three main features of exacerbations: their rate, duration, and severity, with interrelationships among these features being a particular focus. We jointly specified a zero-inflated accelerated failure time regression model for the rate, an accelerated failure time regression model for the duration, and a logistic regression model for the severity of exacerbations. Random effects were incorporated into each component to capture heterogeneity beyond the variability attributable to observed characteristics, and to describe the interrelationships among these components. RESULTS: We used pooled data from two clinical trials in asthma as an exemplary application to illustrate the utility of the joint modeling approach. The model fit clearly indicated the presence of heterogeneity in all three components. A novel finding was that the new therapy reduced not just the rate but also the duration of exacerbations, but did not have a significant impact on their severity. After controlling for covariates, exacerbations among more frequent exacerbators tended to be shorter and less likely to be severe. CONCLUSIONS: We conclude that a joint modeling framework, programmable in available software, can provide novel insights about how the rate, duration, and severity of episodic events interrelate, and enables consistent inference on the effect of treatments on different disease outcomes. Trial registration Ethics approval was obtained from the University of British Columbia Human Ethics Board (H17-00938).

Health literacy and chronic disease management: drawing from expert knowledge to set an agenda.

Understanding the nature and impact of health literacy is a priority in health promotion and chronic disease prevention and treatment. Health literacy comprises the application of a broad set of skills to access, comprehend, evaluate, communicate and act on health information for improved health and well-being. A complex concept, it involves multiple participants and is enacted across a wide variety of contexts. Health literacy's complexity has given rise to challenges achieving a standard definition and developing means to measure all its dimensions. In May 2013, a group of health literacy experts, clinicians and policymakers convened at an Expert Roundtable to review the current state of health literacy research and practice, and make recommendations about refining its definition, expanding its measurement and integrating best practices into chronic disease management. The four-day knowledge exchange concluded that the successful integration of health literacy into policy and practice depends on the development of a more substantial evidence base. A review of the successes and gaps in health literacy research, education and interventions culminated in the identification of key priorities to further the health literacy agenda. The workshop was funded by the UBC Peter Wall Institute for Advanced Studies, Vancouver.

Antibiotic consumption in children prior to diagnosis of asthma.

BACKGROUND: Asthma is difficult to diagnose in children and at times misdiagnosis of an infection can occur. However, little is known about the magnitude and patterns of antibiotic consumption in children with asthma relative to those without asthma. METHODS: Using population-based data, 128,872 children were identified with at least 6 years of follow-up. The adjusted rate-ratio (RR) of antibiotics dispensed to asthmatic as compared to non-asthmatic children was determined. RESULTS: At age six, the RR of antibiotic consumption for asthmatics compared to non-asthmatics varied between, 1.66 to 2.32, depending on the year of asthma diagnosis. Of the 18,864 children with asthma at ages 2-8, 52% (n = 9,841) had antibiotics dispensed in the 6 months prior to their index date of asthma diagnosis. The RR of antibiotic consumption in the 1 month prior to asthma diagnosis compared to 5 months prior was 1.66 (95% CI 1.60-1.71). The RR was lower in males compared to females (1.58 vs 1.77), and lower in those who received antibiotics in the first year of life relative to those that did not (1.60 vs. 1.76). CONCLUSIONS: There is higher antibiotic consumption in children with asthma compared to those without asthma. The pattern of antibiotic use suggests that diagnosis guidelines are difficult to follow in young children leading to misdiagnosis and over treatment with antibiotics.

A statistical method was used for the meta-analysis of tests for latent TB in the absence of a gold standard, combining random-effect and latent-class methods to estimate test accuracy.

OBJECTIVE: Because of the lack of a gold standard, the diagnostic performance of tests for the detection of latent tuberculosis infection (LTBI) is not known. However, statistical methods can be used to estimate the accuracy from the studies reporting the concordance among the tests. STUDY DESIGN AND SETTING: We developed a random-effect latent-class model to estimate performance characteristics of three LTBI diagnostic tests: tuberculin skin test (TST, at 10-mm cutoff), QuantiFERON-TB gold (QFG), and TSPOT-TB from the studies evaluating agreement among the tests. RESULTS: Nineteen studies were included. QFG had a sensitivity of 0.642 (95% confidence interval [CI]: 0.593-0.691) and specificity of 0.996 (95% CI: 0.989-1.000), TSPOT-TB had a sensitivity of 0.500 (95% CI: 0.334-0.666) and specificity of 0.906 (95% CI: 0.882-0.929), and TST had a sensitivity of 0.709 (95% CI: 0.658-0.761) and specificity of 0.683 (95% CI: 0.522-0.844). Results were not sensitive to the inclusion of any single study. When only the three studies that reported on TSPOT were removed, estimates for the other two tests varied minimally. CONCLUSIONS: Statistical methods can help estimate the accuracy of LTBI tests. Although the specificities were close to their reported values in the literature, the estimates for sensitivities were low; a finding that should be carefully evaluated.

Marijuana and chronic obstructive lung disease: a population-based study.

BACKGROUND: Our aim was to determine the combined and independent effects of tobacco and marijuana smoking on respiratory symptoms and chronic obstructive pulmonary disease (COPD) in the general population. METHOD: We surveyed a random sample of 878 people aged 40 years or older living in Vancouver, Canada, about their respiratory history and their history of tobacco and marijuana smoking. We performed spirometric testing before and after administration of 200 microg of salbutamol. We examined the association between tobacco and marijuana smoking and COPD. RESULTS: The prevalence of a history of smoking in this sample was 45.5% (95% confidence interval [CI] 42.2%-48.8%) for marijuana use and 53.1% (95% CI 49.8%-56.4%) for tobacco use. The prevalence of current smoking (in the past 12 months) was 14% for marijuana use and 14% for tobacco use. Compared with nonsmokers, participants who reported smoking only tobacco, but not those who reported smoking only marijuana, experienced more frequent respiratory symptoms (odds ratio [OR] 1.50, 95% CI 1.05-2.14) and were more likely to have COPD (OR 2.74, 95% CI 1.66-4.52). Concurrent use of marijuana and tobacco was associated with increased risk (adjusted for age, asthma and comorbidities) of respiratory symptoms (OR 2.39, 95% CI 1.58-3.62) and COPD (OR 2.90, 95% CI 1.53-5.51) if the lifetime dose of marijuana exceeded 50 marijuana cigarettes. The risks of respiratory symptoms and of COPD were related to a synergistic interaction between marijuana and tobacco. INTERPRETATION: Smoking both tobacco and marijuana synergistically increased the risk of respiratory symptoms and COPD. Smoking only marijuana was not associated with an increased risk of respiratory symptoms or COPD.

Delay in admission for elective coronary-artery bypass grafting is associated with increased in-hospital mortality.

BACKGROUND: Many health care systems now use priority wait lists for scheduling elective coronary artery bypass grafting (CABG) surgery, but there have not yet been any direct estimates of reductions in in-hospital mortality rate afforded by ensuring that the operation is performed within recommended time periods. METHODS: We used a population-based registry to identify patients with established coronary artery disease who underwent isolated CABG in British Columbia, Canada. We studied whether postoperative survival during hospital admission for CABG differed significantly among patients who waited for surgery longer than the recommended time, 6 weeks for patients needing semi-urgent surgery and 12 weeks for those needing non-urgent surgery. RESULTS: Among 7316 patients who underwent CABG, 97 died during the same hospital admission, for a province-wide death rate at discharge of 1.3%. The observed proportion of patients who died during the same admission was 1.0% (27 deaths among 2675 patients) for patients treated within the recommended time and 1.5% (70 among 4641) for whom CABG was delayed. After adjustment for age, sex, anatomy, comorbidity, calendar period, hospital, and mode of admission, patients with early CABG were only 2/3 as likely as those for whom CABG was delayed to experience in-hospital death (odds ratio 0.61; 95% confidence interval [CI] 0.39 to 0.96). There was a linear trend of 5% increase in the odds of in-hospital death for every additional month of delay before surgery, adjusted OR = 1.05 (95% CI 1.00 to 1.11). CONCLUSION: We found a significant survival benefit from performing surgical revascularization within the time deemed acceptable to consultant surgeons for patients requiring the treatment on a semi-urgent or non-urgent basis.

Survival benefit of coronary-artery bypass grafting accounted for deaths in those who remained untreated.

BACKGROUND: Currently there are no direct estimates of mortality reduction afforded by coronary-artery bypass grafting (CABG) that take into account the deaths among patients for whom coronary revascularization was indicated but who did not undergo the treatment. The objective of this analysis was to compare survival after the treatment decision between patients who underwent CABG and those who remained untreated. METHODS: We used a population-based registry to identify patients with established coronary artery disease who were to undergo first-time isolated CABG. We measured the effect of surgical revascularization on survival after the treatment decision in two cohorts of patients categorized by symptoms, coronary anatomy, and left ventricular function. RESULTS: One in 10 patients died during the five years after treatment decision. The hazard of death among patients who underwent CABG was 51 percent of that for the untreated group, the adjusted hazard ratio was 0.51 (95 percent confidence interval, 0.43 to 0.61). The effect was stronger when CABG was performed within the recommended time: adjusted hazard ratios were 0.43 (95 percent confidence interval, 0.35 to 0.53) and 0.58 (95 percent confidence interval, 0.48 to 0.70) for early and late intervention, respectively; chi-square for the difference between hazard ratios was 12.2 (P < 0.001). CONCLUSION: Estimates that account for patients who died before they could undergo a required CABG indicate a significant survival benefit of performing early surgical revascularization even for patients registered to undergo the operation on the non-urgent basis.

Fluoroquinolones for the treatment of pulmonary tuberculosis.

Tuberculosis (TB) continues to be a significant problem globally. Treatment includes a multiple drug regimen with isoniazid, rifampicin (rifampin), pyrazinamide and ethambutol. Often, one of these medications needs to be replaced as a result of adverse events or because Mycobacterium tuberculosis develops resistance against one these first-line agents. Fluoroquinolones, particularly the newer ones, possess good in vitro (levofloxacin, gatifloxacin, moxifloxacin) and in vivo (gatifloxacin and moxifloxacin) bactericidal activity against M. tuberculosis, making them attractive agents for the treatment of pulmonary TB. All relevant clinical trials, cohort studies and case reports investigating the clinical efficacy and tolerability of fluoroquinolones when used for the treatment of pulmonary TB were evaluated for this review. Specifically, efficacy and safety in the following indications were investigated: (i) first-line treatment of drug-sensitive pulmonary TB; (ii) first-line treatment for multi-drug resistant (MDR) TB; and (iii) treatment of patients with drug intolerance. Twenty-seven articles met our inclusion criteria; nine articles presented data from randomised, controlled or cohort studies. Seven studies used fluoroquinolones as first-line agents in drug-sensitive TB (1469 patients), 15 studies used fluoroquinolones to treat MDR-TB (1025 patients) and six studies (951 patients) investigated the use of fluoroquinolones in patients intolerant to other TB medications. In patients with susceptible M. tuberculosis strains, substitution with a fluoroquinolone did not have an effect on cure or radiological improvement at 8 weeks or failure at 12 months. Substitution of older fluoroquinolones into a regimen, especially ciprofloxacin, resulted in a higher rate of relapse and a longer time to sputum-culture conversions. The use of fluoroquinolones in patients with MDR-TB is supported by some trials where others show a lack of improvement in efficacy of a regimen. Our review of the literature does not support the use of older fluoroquinolones, especially ciprofloxacin, as substitute agents for drug-sensitive or drug-resistant TB. However, newer fluoroquinolones, such as moxifloxacin, may be a reasonable alternative based on results from one large clinical trial. Fluoroquinolones have an important role as substitute agents for those who are intolerant of first-line TB agents.

Evaluating health-related quality-of-life studies in paediatric populations: some conceptual, methodological and developmental considerations and recent applications.

Although numerous paediatric-based health-related quality-of-life (HR-QOL) instruments are currently in use, there still remain conceptual, methodological and developmental issues to address. This paper provides an up-to-date critical review of the HR-QOL literature in paediatric medicine. Our analysis indicates that there is no consensus on how HR-QOL and overall QOL should be defined and measured in children. It is recommended that future studies focus on operationalising and distinguishing these constructs from each other and from traditional health-status measures. A clear empirical basis for generating instrument items and for prioritising specific domains must be described. Researchers should consider using the data gathered during their first interviews as a springboard from which to test their ideas of HR-QOL and QOL, reformulate concepts and subsequently retest their notions before developing instruments. Related to methodological challenges, consistency and agreement are still used interchangeably when comparing child and parent reports of children's HR-QOL. The Pearson correlation is a measure of co-variation in scores, and not a measure of agreement. We recommend that researchers focus on determining agreement as opposed to consistency. Few, if any, attempts have been made to account for the possibility that a response shift may have occurred in the evaluation of HR-QOL. Most studies have compared HR-QOL scores of children with illness with their healthy peers. As such, there is a dearth of knowledge regarding the normative process of adaptation within the context of illness. It is recommended that researchers focus on gathering data using a relative standard of comparison. We further recommend that researchers interpret HR-QOL data in line with their intended purpose. Regarding developmental consideration, particular attention ought to be paid to developing instruments that consider children's emerging sense of self, cognitive capacity and emotional awareness. Instruments that include items that are age appropriate are more likely to maximise reliability and validity of reports. The results of many HR-QOL instruments are applied in pharmacotherapeutic and pharmacoeconomic assessments. However, there has been relative infrequent application of economically valid HR-QOL tools (utility scales) and the use of HR-QOL scales as outcome measures in paediatric drug trials. As such, few cost-utility analyses have been performed to inform paediatric decision making. In addition, many of the concerns in the development of HR-QOL instruments should also be applied to the utility scales such that they reflect adequately children's preferences for health states.