Listeria monocytogenes Associated with Pasteurized Chocolate Milk, Ontario, Canada.

In an investigation of a listeriosis outbreak in Ontario, Canada, during November 2015-June 2016, pasteurized chocolate milk was identified as the source. Because listeriosis outbreaks associated with pasteurized milk are rare in North America, these findings highlight that dairy products can be contaminated after pasteurization.

Healthcare resource use and costs of severe, uncontrolled eosinophilic asthma in the UK general population.

BACKGROUND: Little is known about the prevalence of severe, uncontrolled eosinophilic asthma (SUEA) and associated costs. AIMS: We sought to determine the prevalence of SUEA and compare asthma-related healthcare resource use (HCRU) and associated costs with overall means for a general asthma population. METHODS: This cohort study evaluated anonymised medical record data (December 1989 through June 2015) from the Clinical Practice Research Datalink and the Optimum Patient Care Research Database to study UK patients with active asthma (diagnostic code and one or more drug prescriptions in the baseline year), aged 5 years and older, without concomitant COPD, and with recorded eosinophil count. SUEA was defined as two or more asthma attacks during 1 baseline year preceding a high blood eosinophil count (≥0.3×109/L) for patients prescribed long-acting ß2-agonist (LABA) and high-dosage inhaled corticosteroids (ICS) during baseline plus 1 follow-up year. We compared asthma-related HCRU and associated direct costs (2015 pounds sterling, £) during the follow-up year for SUEA versus the general asthma population. RESULTS: Of 363 558 patients with active asthma and recorded eosinophil count, 64% were women, mean (SD) age was 49 (21) years; 43% had high eosinophil counts, 7% had two or more attacks in the baseline year and 10% were prescribed high-dosage ICS/LABA for 2 study years. Overall, 2940 (0.81%; 95% CI 0.78% to 0.84%) patients had SUEA. Total mean per-patient HCRU and associated costs were four times greater for SUEA versus all patients (HCRU and cost ratios 3.9; 95% CI 3.7 to 4.1). CONCLUSIONS: Less than 1% of patients in a general asthma population had SUEA. These patients accounted for substantially greater asthma-related HCRU and costs than average patients with asthma.

Effectiveness of initiating extrafine-particle versus fine-particle inhaled corticosteroids as asthma therapy in the Netherlands.

BACKGROUND: Most randomised clinical trials typically exclude a significant proportion of asthma patients, including those at higher risk of adverse events, with comorbidities, obesity, poor inhaler technique and adherence, or smokers. However, these patients might differentially benefit from extrafine-particle inhaled corticosteroids (ICS). This matched cohort, database study, compared the effectiveness of extrafine-particle with fine-particle ICS in a real-life population initiating ICS therapy in the Netherlands. METHODS: Data were from the Pharmo Database Network, comprising pharmacy and hospital discharge records, representative of 20 % of the Dutch population. The study population included patients aged 12 - 60, with a General Practice-recorded diagnosis for asthma (International Classification of Primary Care code R96), when available, ≥2 prescriptions for asthma therapy at any time in their recorded history, and receiving first prescription of ICS therapy as either extrafine-particle (ciclesonide or hydrofluoroalkane beclomethasone dipropionate [BDP]) or fine-particle ICS (fluticasone propionate or non-extrafine-particle-BDP). Patients were matched (1:1) on relevant demographic and clinical characteristics over 1-year baseline. Primary outcomes were severe exacerbation rates, risk domain asthma control and overall asthma control during the year following first ICS prescription. Secondary outcomes, treatment stability and being prescribed higher versus lower category of short-acting ß2 agonists (SABA) dose, were compared over a 1-year outcome period using conditional logistic regression models. RESULTS: Following matching, 1399 patients were selected in each treatment cohort (median age: 43 years; males: 34 %). Median (interquartile range) initial ICS doses (fluticasone-equivalents in µg) were 160 (160 - 320) for extrafine-particle versus 500 (250 - 500) for fine-particle ICS (p < 0.001). Following adjustment for residual confounders, matched patients prescribed extrafine-particle ICS had significantly lower rates of exacerbations (adjusted rate ratio [95 % CI], 0.59 [0.47-0.73]), and significantly higher odds of achieving asthma control and treatment stability in the year following initiation than those prescribed fine-particle ICS, and this occurred at lower prescribed doses. Patients prescribed extrafine-particle ICS had lower odds of being prescribed higher doses of SABA (0.50 [0.44-0.57]). CONCLUSION: In this historical, matched study, extrafine-particle ICS was associated with better odds of asthma control than fine-particle ICS in patients prescribed their first ICS therapy in the Netherlands. Of importance, this was reached at significantly lower prescribed dose.

Leukotriene antagonists as first-line or add-on asthma-controller therapy.

BACKGROUND: Most randomized trials of treatment for asthma study highly selected patients under idealized conditions. METHODS: We conducted two parallel, multicenter, pragmatic trials to evaluate the real-world effectiveness of a leukotriene-receptor antagonist (LTRA) as compared with either an inhaled glucocorticoid for first-line asthma-controller therapy or a long-acting beta(2)-agonist (LABA) as add-on therapy in patients already receiving inhaled glucocorticoid therapy. Eligible primary care patients 12 to 80 years of age had impaired asthma-related quality of life (Mini Asthma Quality of Life Questionnaire [MiniAQLQ] score ≤6) or inadequate asthma control (Asthma Control Questionnaire [ACQ] score ≥1). We randomly assigned patients to 2 years of open-label therapy, under the care of their usual physician, with LTRA (148 patients) or an inhaled glucocorticoid (158 patients) in the first-line controller therapy trial and LTRA (170 patients) or LABA (182 patients) added to an inhaled glucocorticoid in the add-on therapy trial. RESULTS: Mean MiniAQLQ scores increased by 0.8 to 1.0 point over a period of 2 years in both trials. At 2 months, differences in the MiniAQLQ scores between the two treatment groups met our definition of equivalence (95% confidence interval [CI] for an adjusted mean difference, -0.3 to 0.3). At 2 years, mean MiniAQLQ scores approached equivalence, with an adjusted mean difference between treatment groups of -0.11 (95% CI, -0.35 to 0.13) in the first-line controller therapy trial and of -0.11 (95% CI, -0.32 to 0.11) in the add-on therapy trial. Exacerbation rates and ACQ scores did not differ significantly between the two groups. CONCLUSIONS: Study results at 2 months suggest that LTRA was equivalent to an inhaled glucocorticoid as first-line controller therapy and to LABA as add-on therapy for diverse primary care patients. Equivalence was not proved at 2 years. The interpretation of results of pragmatic research may be limited by the crossover between treatment groups and lack of a placebo group. (Funded by the National Coordinating Centre for Health Technology Assessment U.K. and others; Controlled Clinical Trials number, ISRCTN99132811.).

Asthma outcomes and costs of therapy with extrafine beclomethasone and fluticasone.

BACKGROUND: Characteristics of inhaled corticosteroids (ICSs) differ, but data comparing the real-life effectiveness of various ICSs for asthma are lacking. OBJECTIVE: We sought to compare real-life asthma outcomes and costs of extrafine hydrofluoroalkane (HFA)-beclomethasone and fluticasone administered through a pressurized metered-dose inhaler. METHODS: This retrospective matched cohort study examined database markers of asthma control from a large US longitudinal health care claims database over 1 baseline and 1 outcome year for 10,312 patients with asthma aged 12 to 80 years receiving their first ICS as HFA-beclomethasone or fluticasone and matched on baseline demographic characteristics and asthma severity. RESULTS: Patients started on HFA-beclomethasone had significantly higher odds (adjusted odds ratio, 1.19; 95% CI; 1.08-1.31) of achieving overall control (risk and impairment), which was defined as no hospital attendance for asthma, oral corticosteroids, or antibiotics for lower respiratory tract infection and less than 2 puffs per day of short-acting ß-agonist; they also experienced a lower rate of respiratory-related hospitalizations or referrals (adjusted rate ratio, 0.82; 95% CI, 0.73-0.93) than patients started on fluticasone. Other database outcome measures were similar in the 2 cohorts. Prescribed HFA-beclomethasone doses were lower (P < .001) than fluticasone doses (median, 320 µg/d [interquartile range, 160-320 µg/d] vs 440 µg/d [interquartile range, 176-440 µg/d]). Adjusted respiratory-related health care costs were significantly lower for HFA-beclomethasone than fluticasone (mean, $1869 [95% CI, $1727-$2032] vs $2259 [95% CI, $2111-$2404]), representing a mean annual savings of $390 (95% CI, $165-$620) per patient prescribed HFA-beclomethasone rather than fluticasone. CONCLUSIONS: Asthma treatment outcomes were similar or better with HFA-beclomethasone prescribed at significantly lower doses and with lower costs than fluticasone.

Characteristics of patients preferring once-daily controller therapy for asthma and COPD: a retrospective cohort study.

BACKGROUND: Patient preference is an important factor when choosing an inhaler device for asthma or chronic obstructive pulmonary disease (COPD). AIMS: To identify characteristics of patients with asthma or COPD who prefer a once-daily controller medication regimen. METHODS: This retrospective observational study used electronic patient records and linked outcomes from patient-completed questionnaires in a primary care database. We compared the characteristics of patients indicating a preference for once-daily therapy with those who were unsure or indicating no preference. RESULTS: Of 3,731 patients with asthma, 2,174 (58%) were women; the mean age was 46 years (range 2-94). Of 2,138 patients with COPD, 980 (46%) were women; the mean age was 70 years (range 35-98). Approximately half of the patients in each cohort indicated once-daily preference, one-quarter were unsure, and one-quarter did not prefer once-daily therapy. In patients with asthma or COPD, the preference for once-daily controller medication was significantly associated with poor adherence and higher concerns about medication. In asthma, good control and low self-perceived controller medication need were associated with once-daily preference. By contrast, in COPD, a high self-perceived need for controller medication was associated with once-daily preference. There was no significant relationship between once-daily preference and age, sex, disease severity, or exacerbation history. CONCLUSIONS: Understanding patient preferences may help prescribers to individualise therapy better for asthma and COPD.

Reassessing the evidence hierarchy in asthma: evaluating comparative effectiveness.

Classical randomized controlled trials are the gold standard in medical evidence because of their high internal validity. However, their necessarily strict design can limit their external validity and the ability to extrapolate these data to real world patients. Therefore, alternatively designed studies may play a complementary role in evaluating the comparative effectiveness of therapies in nonidealized patients in more naturalistic, real world settings. Observational studies have high external validity and can evaluate real world outcomes. Their strength lies in hypothesis generation and testing and in identifying areas in which further clinical trials may be required. Pragmatic trials are designed to maximize applicability of trial results to usual care settings by relying on clinically important outcomes and enrolling a wide range of participants. A combination of these approaches is preferable and necessary.

Prescribing practices and asthma control with hydrofluoroalkane-beclomethasone and fluticasone: a real-world observational study.

BACKGROUND: Long-term randomized trials comparing asthma outcomes between inhaled corticosteroids in real-world populations are lacking. As such, rigorously conducted observational studies to complement the findings of randomized trials are needed. OBJECTIVE: We sought to compare asthma-related outcomes over 1 year as recorded in a large primary care database for patients aged 5 to 60 years receiving a first prescription (initiation population) or dose increase (step-up population) of hydrofluoroalkane (HFA)-beclomethasone or fluticasone. METHODS: We used a retrospective matched cohort study in which patients were matched on baseline demographic and disease severity measures. Coprimary outcomes were asthma control (a composite measure comprising no unplanned visit or hospitalization for asthma, oral corticosteroids, or antibiotics for lower respiratory tract infection) and exacerbation rate. RESULTS: More than 80% of patients in each population achieved asthma control; 10% and 16% of patients in the initiation and step-up populations, respectively, received add-on or combination therapy during the year. Fluticasone was prescribed at significantly higher doses than HFA-beclomethasone for both populations (P

Observational study comparing intranasal mometasone furoate with oral antihistamines for rhinitis and asthma.

AIMS: Retrospective database study comparing upper and lower airway-related outcomes for patients with rhinitis and co-morbid asthma receiving mometasone furoate--an intranasal corticosteroid with low systemic bioavailability--or an oral antihistamine. METHODS: 395 patients prescribed intranasal mometasone were matched on 10 demographic and respiratory-related criteria in a 1:2 ratio to 790 patients prescribed oral antihistamine. Asthma and rhinitis control were assessed over one year using predefined composite proxy measures. RESULTS: Asthma control was achieved by 309/395 (78.2%) versus 580/790 (73.4%; p=0.071) patients in the mometasone and antihistamine cohorts, respectively. Rhinitis control was achieved by 293 (74.2%) versus 539 (68.2%; p=0.035), respectively. The adjusted odds ratios for antihistamines, relative to mometasone, were 0.71 (95% CI, 0.52-0.98) for achieving asthma control and 0.74 (95% CI, 0.56-0.97) for achieving rhinitis control. CONCLUSIONS: Patients with rhinitis and co-morbid asthma initiating rhinitis therapy achieved significantly better upper as well as lower airway outcomes with intranasal mometasone than with oral antihistamine.

Natural history of asthma: persistence versus progression-does the beginning predict the end?

Environmental exposures during the early years and airway obstruction that develops during this time, in conjunction with genetic susceptibility, are important factors in the development of persistent asthma in childhood. Established risk factors for childhood asthma include frequent wheezing during the first 3 years, a parental history of asthma, a history of eczema, allergic rhinitis, wheezing apart from colds, and peripheral blood eosinophilia, as well as allergic sensitization to aeroallergens and certain foods. Risk factors for the development of asthma in adulthood remain ill defined. Moreover, reasons for variability in the clinical course of asthma--persistence in some individuals and progression in others--remain an enigma. The distinction between disease persistence and disease progression suggests that these are different entities or phenotypes. There is currently no consensus on whether disease progression requires either airway inflammation or airway remodeling or the combination of the two. For patients with irreversible airway obstruction, inflammation might, in part, be necessary but perhaps not entirely sufficient to induce the irreversible component, some of which could be attributed to alterations in the structure of the bronchial wall. Intervening with intermittent or daily inhaled corticosteroids in high-risk infants and children does not prevent disease progression or impaired lung growth. These findings, however, might not apply to adults, and further study in adults is needed to determine the effect of inhaled corticosteroid therapy on disease progression.

The Asthma Control Test (ACT) as a predictor of GINA guideline-defined asthma control: analysis of a multinational cross-sectional survey.

AIMS: To evaluate whether the Asthma Control Test (ACT) score is predictive of Global Initiative for Asthma (GINA) guideline-defined classification levels of asthma control. The ACT is a validated, 5-item, patient-completed measure of asthma control with a recall period of four weeks. METHODS: Cross-sectional survey comparing ACT score and GINA classification of asthma control among 2949 patients attending primary care physicians and specialists in France, Germany, Italy, Spain, the UK, and the USA. RESULTS: The area under the receiver operating characteristics curve for ACT score predicting GINA control was 0.84 (95% CI 0.82-0.85). An ACT score of <19 (not well-controlled asthma) correctly predicted GINA-defined partly controlled/uncontrolled asthma 94% of the time, while an ACT score of >20 predicted GINA-defined controlled asthma 51% of the time, with kappa statistic of 0.42, representing moderate agreement. CONCLUSIONS: An ACT score <19 is useful for identifying patients with poorly controlled asthma as defined by GINA.

Matched cohort study of therapeutic strategies to prevent preschool wheezing/asthma attacks.

Background: An inhaled corticosteroid (ICS) or leukotriene receptor antagonist (LTRA) may prevent wheezing/asthma attacks in preschoolers with recurrent wheeze when added to short-acting ß-agonist (SABA). Objective: The aim of this historical matched cohort study was to assess the effectiveness of these treatments for preventing wheezing/asthma attacks. Methods: Electronic medical records from the Optimum Patient Care Research Database were used to characterize a UK preschool population (1-5 years old) with two or more episodes of wheezing during 1 baseline year before first prescription (index date) of ICS or LTRA, or repeat prescription of SABA. Children initiating ICS or LTRA on the index date were matched 1:4 to those prescribed only SABA for age, sex, year of index prescription, mean baseline SABA dose, baseline attacks, baseline antibiotic prescriptions, and eczema diagnosis. Wheezing/asthma attacks (defined as asthma-related emergency attendance, hospital admission, or acute oral corticosteroid prescription) during 1 outcome year were compared using conditional logistic regression. Results: Matched ICS and SABA cohorts included 990 and 3,960 children, respectively (61% male; mean [SD] age 3.2 [1.3] years), and matched LTRA and SABA cohorts included 259 and 1,036 children, respectively (65% male; mean [SD] age 2.6 [1.2] years). We observed no significant difference between matched cohorts in the odds of a wheezing/asthma attack: ICS vs SABA, OR (95% CI) 1.01 (0.85-1.19) and LTRA vs SABA, OR (95% CI) 1.28 (0.96-1.72). Conclusion: We found no evidence that initiation of ICS or LTRA therapy is associated with fewer attacks during 1 outcome year than SABA alone for a heterogeneous group of preschool children with recurrent wheeze in the real-life clinical setting.

Long-Acting ß-Agonist in Combination or Separate Inhaler as Step-Up Therapy for Children with Uncontrolled Asthma Receiving Inhaled Corticosteroids.

BACKGROUND: Adding a long-acting ß2-agonist (LABA) to inhaled corticosteroids (ICS) using a fixed-dose combination (FDC) inhaler is the UK guideline recommendation for children aged more than 4 years with uncontrolled asthma. The evidence of benefit of adding an FDC inhaler over a separate LABA inhaler is limited. OBJECTIVE: The objective of this study was to compare the effectiveness of a LABA added as an FDC inhaler, and as a separate inhaler, in children with uncontrolled asthma. METHODS: Two UK primary care databases were used to create a matched cohort study with a 2-year follow-up period. We included children prescribed their first step-up from ICS monotherapy. Two cohorts were formed for children receiving an add-on LABA as an FDC inhaler, or a separate LABA inhaler. Matching variables and confounders were identified by comparing characteristics during a baseline year of follow-up. Outcomes were examined during the subsequent year. The primary outcome was an adjusted odds ratio for overall asthma control (defined as follows: no asthma-related hospital admission or emergency room visit, prescription for oral corticosteroids or antibiotic with evidence of respiratory consultation, and ≤2 puffs of short-acting ß-agonist daily). RESULTS: The final study consisted of 1330 children in each cohort (mean age 9 years; 59% male). In the separate ICS+LABA cohort, the odds of achieving overall asthma control were lower (adjusted odds ratio, 0.77 [95% confidence interval, 0.66-0.91]; P = .001) compared with the FDC cohort. CONCLUSION: The study demonstrates a small but significant benefit in achieving asthma control from an add-on LABA as an FDC, compared with a separate inhaler and this supports current guideline recommendations.

An evaluation of exact matching and propensity score methods as applied in a comparative effectiveness study of inhaled corticosteroids in asthma.

BACKGROUND: Cohort matching and regression modeling are used in observational studies to control for confounding factors when estimating treatment effects. Our objective was to evaluate exact matching and propensity score methods by applying them in a 1-year pre-post historical database study to investigate asthma-related outcomes by treatment. METHODS: We drew on longitudinal medical record data in the PHARMO database for asthma patients prescribed the treatments to be compared (ciclesonide and fine-particle inhaled corticosteroid [ICS]). Propensity score methods that we evaluated were propensity score matching (PSM) using two different algorithms, the inverse probability of treatment weighting (IPTW), covariate adjustment using the propensity score, and propensity score stratification. We defined balance, using standardized differences, as differences of <10% between cohorts. RESULTS: Of 4064 eligible patients, 1382 (34%) were prescribed ciclesonide and 2682 (66%) fine-particle ICS. The IPTW and propensity score-based methods retained more patients (96%-100%) than exact matching (90%); exact matching selected less severe patients. Standardized differences were >10% for four variables in the exact-matched dataset and <10% for both PSM algorithms and the weighted pseudo-dataset used in the IPTW method. With all methods, ciclesonide was associated with better 1-year asthma-related outcomes, at one-third the prescribed dose, than fine-particle ICS; results varied slightly by method, but direction and statistical significance remained the same. CONCLUSION: We found that each method has its particular strengths, and we recommend at least two methods be applied for each matched cohort study to evaluate the robustness of the findings. Balance diagnostics should be applied with all methods to check the balance of confounders between treatment cohorts. If exact matching is used, the calculation of a propensity score could be useful to identify variables that require balancing, thereby informing the choice of matching criteria together with clinical considerations.

Real-Life Outcomes for Patients with Asthma Prescribed Spacers for Use with Either Extrafine- or Fine-Particle Inhaled Corticosteroids.

BACKGROUND: Spacers are often used with pressurized metered-dose inhalers (pMDIs) to eliminate the need for coordinating inhalation with actuation. OBJECTIVE: To investigate the real-life effectiveness of spacers prescribed for use with either extrafine- or fine-particle inhaled corticosteroids (ICSs). METHODS: This historical matched cohort study examined anonymous medical record data over 2 years (1-year baseline, 1-year outcome) for patients with asthma aged 12 to 80 years initiating ICSs by pMDI with or without prescribed spacer. We compared outcomes for spacer versus no-spacer arms, matched for key baseline and asthma-related characteristics, within 2 ICS cohorts: (1) extrafine-particle ICS (beclomethasone) and (2) fine-particle ICS (fluticasone). Effectiveness end points were compared using conditional regression methods. RESULTS: Matched spacer and no-spacer arms of the extrafine-particle ICS cohort each included 2090 patients (69% females; median age, 46-47 years) and the 2 arms of the fine-particle ICS cohort each included 444 patients (67% females; median age, 45 years). With extrafine-particle ICS, we observed no significant difference between spacer and no-spacer arms in severe exacerbation rate (primary end point): adjusted rate ratio, 1.01 (95% CI, 0.83-1.23). With fine-particle ICS, the severe exacerbation rate ratio with spacers was 0.77 (0.47-1.25). Oropharyngeal candidiasis incidence was low and similar in spacer and no-spacer arms for both ICS cohorts. CONCLUSIONS: We found no evidence that prescribed spacer devices are associated with improved asthma outcomes for extrafine- or fine-particle ICS administered by pMDI. These findings challenge long-standing assumptions that spacers should improve pMDI effectiveness and indicate the need for pragmatic trials of spacers in clinical practice.

Identifying Risk of Future Asthma Attacks Using UK Medical Record Data: A Respiratory Effectiveness Group Initiative.

BACKGROUND: Asthma attacks are common, serious, and costly. Individual factors associated with attacks, such as poor symptom control, are not robust predictors. OBJECTIVE: We investigated whether the rich data available in UK electronic medical records could identify patients at risk of recurrent attacks. METHODS: We analyzed anonymized, longitudinal medical records of 118,981 patients with actively treated asthma (ages 12-80 years) and 3 or more years of data. Potential risk factors during 1 baseline year were evaluated using univariable (simple) logistic regression for outcomes of 2 or more and 4 or more attacks during the following 2-year period. Predictors with significant univariable association (P < .05) were entered into multiple logistic regression analysis with backward stepwise selection of the model including all significant independent predictors. The predictive accuracy of the multivariable models was assessed. RESULTS: Independent predictors associated with future attacks included baseline-year markers of attacks (acute oral corticosteroid courses, emergency visits), more frequent reliever use and health care utilization, worse lung function, current smoking, blood eosinophilia, rhinitis, nasal polyps, eczema, gastroesophageal reflux disease, obesity, older age, and being female. The number of oral corticosteroid courses had the strongest association. The final cross-validated models incorporated 19 and 16 risk factors for 2 or more and 4 or more attacks over 2 years, respectively, with areas under the curve of 0.785 (95% CI, 0.780-0.789) and 0.867 (95% CI, 0.860-0.873), respectively. CONCLUSIONS: Routinely collected data could be used proactively via automated searches to identify individuals at risk of recurrent asthma attacks. Further research is needed to assess the impact of such knowledge on clinical prognosis.