Long-term efficacy and safety of omalizumab for nasal polyposis in an open-label extension study.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) frequently remains uncontrolled despite maximal medical therapy and sinonasal surgery, presenting several unmet needs and challenges. Omalizumab previously demonstrated efficacy in CRSwNP in duplicate phase 3, randomized, placebo-controlled trials (POLYP 1, POLYP 2). OBJECTIVE: This open-label extension evaluated the continued efficacy, safety, and durability of response of omalizumab in adults with CRSwNP who completed POLYP 1 or 2. METHODS: After 24 weeks of omalizumab or placebo in POLYP 1 and 2, patients (n = 249) received open-label omalizumab plus background nasal mometasone therapy for 28 weeks and were subsequently followed for 24 weeks after omalizumab discontinuation. Efficacy end points assessed change from baseline for the coprimary end points, Nasal Polyp Score and Nasal Congestion Score, and the secondary end points of Sino-Nasal Outcome Test 22, Total Nasal Symptom Score and its components, and University of Pennsylvania Smell Identification Test scores. Safety objectives included incidence of adverse events and adverse events leading to omalizumab discontinuation. RESULTS: Patients who continued omalizumab experienced further improvements across coprimary end points and secondary end points through 52 weeks. Patients who switched from placebo to omalizumab experienced favorable responses across end points through week 52 that were similar to POLYP 1 and 2 at week 24. After omalizumab discontinuation, scores gradually worsened over the 24-week follow-up, but remained improved from pretreatment levels for both groups. The safety profile was similar to previous reports. CONCLUSIONS: The efficacy and safety profile from this study supports extended omalizumab treatment up to 1 year for CRSwNP with inadequate response to nasal corticosteroids.

Usage of long-acting muscarinic antagonists and biologics as add-on therapy for patients in the United States with moderate-to-severe asthma.

Many asthma patients remain uncontrolled on inhaled corticosteroids (ICS) and long-acting beta agonists (LABAs), but guidance for selecting add-on therapies, including long-acting muscarinic antagonists (LAMAs) or biologics, is limited. We describe how prescribing practices for add-on LAMA and biologic therapy have changed with increased treatment options and revised treatment guidelines. We further identify differences in treatment initiation and discontinuation rates by patient characteristics, including concomitant COPD.This retrospective cohort study analyzed insurance claims in the IBM Marketscan database for adult US asthma patients treated with medium- or high-dose ICS/LABA between 2012 and 2019 (n = 277,373). We used negative binomial regression models to evaluate LAMA and biologic initiation rates and their association with patient characteristics, and survival analysis methods for assessing discontinuation rates.Between 2012 and 2019, LAMA and biologic uptake increased approximately 5-fold and 20-fold, respectively. LAMA initiation was significantly higher among patients with concomitant COPD, a group typically unstudied in clinical trials, versus those with asthma only (rate ratio of 5.90, 95% CI: 5.76-6.04). High-dose ICS/LABA treatment and the need for oral corticosteroid (OCS) bursts had stronger associations with biologic initiation. Probability of discontinuation (i.e. non-persistence) in the first year was 40.5% and 22.7% for those initiating LAMAs and biologics, respectively, with higher LAMA discontinuation rates among patients with asthma only versus those with concomitant COPD.Our results provide insights into how clinicians apply treatment guidelines for initiating add-on LAMA and biologic therapies in moderate-to-severe asthma patients and highlight patients who have an unmet treatment need after discontinuation.

Pharmacokinetics and exposure-efficacy relationships of omalizumab in patients with nasal polyps.

The anti-immunoglobulin E (IgE) antibody, omalizumab (Xolair), is approved in the United States for the treatment of allergic asthma and chronic spontaneous urticaria, and has recently been studied for the treatment of nasal polyposis following completion of the two replicate phase 3 studies (POLYP 1 and POLYP 2). The dosing of omalizumab used in the phase 3 studies is based on a combination of patients' pre-treatment IgE level and body weight, similar to the approach used in allergic asthma. The objectives of the current analyses were to evaluate whether the pharmacokinetics (PK) of omalizumab and its pharmacodynamic (PD) effect on free and total IgE level in chronic rhinosinusitis with nasal polyps (CRSwNP) are consistent with those in allergic asthma via population PK/PD modeling and simulation, and to graphically explore exposure-response relationships and free IgE-response relationships in CRSwNP. Omalizumab PK and PD effect of total and free IgE in CRSwNP are generally consistent with those in asthma. Observed post-treatment free IgE suppressions were generally within the target range of the baseline IgE- and body weight-based omalizumab dosing table, with 74.2% and 93.0% of patients achieving a serum free IgE level below 25 ng/mL and 50 ng/mL, respectively at Week 24. Exposure-response analyses indicated that there was no clear correlation between omalizumab or free IgE concentration and key efficacy endpoints within the POLYP studies. Overall, these results indicate that the body weight and IgE-based dosing regimen of omalizumab was appropriate for use in CRSwNP patients.

Efficacy and safety of omalizumab in nasal polyposis: 2 randomized phase 3 trials.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by IgE hyperproduction and eosinophilic inflammation. The anti-IgE antibody, omalizumab, has demonstrated efficacy in patients with CRSwNP and comorbid asthma previously. OBJECTIVE: Our aim was to determine omalizumab safety and efficacy in CRSwNP in phase 3 trials (POLYP 1 and POLYP 2). METHODS: Adults with CRSwNP with inadequate response to intranasal corticosteroids were randomized (1:1) to omalizumab or placebo and intranasal mometasone for 24 weeks. Coprimary end points included change from baseline to week 24 in Nasal Polyp Score (NPS) and Nasal Congestion Score. Secondary end points included change from baseline to week 24 in Sino-Nasal Outcome Test-22 (SNOT-22) score, University of Pennsylvania Smell Identification Test, sense of smell, postnasal drip, runny nose, and adverse events. RESULTS: Patients in POLYP 1 (n = 138) and POLYP 2 (n = 127) exhibited severe CRSwNP and substantial quality of life impairment evidenced by a mean NPS higher than 6 and SNOT-22 score of approximately 60. Both studies met both the coprimary end points. SNOT-22 score, University of Pennsylvania Smell Identification Test score, sense of smell, postnasal drip, and runny nose were also significantly improved for omalizumab versus placebo. In POLYP 1 and POLYP 2, the mean changes from baseline at week 24 for omalizumab versus placebo were as follows: NPS, -1.08 versus 0.06 (P < .0001) and -0.90 versus -0.31 (P = .0140); Nasal Congestion Score, -0.89 versus -0.35 (P = .0004) and -0.70 versus -0.20 (P = .0017); and SNOT-22 score, -24.7 versus -8.6 (P < .0001) and -21.6 versus -6.6 (P < .0001). Adverse events were similar between groups. CONCLUSION: Omalizumab significantly improved endoscopic, clinical, and patient-reported outcomes in severe CRSwNP with inadequate response to intranasal corticosteroids, and it was well tolerated.

Efficacy and safety of lebrikizumab (an anti-IL-13 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical corticosteroids: A randomized, placebo-controlled phase II trial (TREBLE).

BACKGROUND: Interleukin (IL)-13 plays a key role in type 2 inflammation and is an emerging pathogenic mediator in atopic dermatitis (AD). OBJECTIVE: We investigated the efficacy and safety of lebrikizumab, an IL-13 monoclonal antibody, as an add-on to topical corticosteroid (TCS) treatment. METHODS: A randomized, placebo-controlled, double-blind, phase 2 study. Adults with moderate-to-severe AD were required to use TCS twice daily and then randomized (1:1:1:1) to lebrikizumab 125 mg single dose, lebrikizumab 250 mg single dose, lebrikizumab 125 mg every 4 weeks for 12 weeks, or placebo every 4 weeks for 12 weeks, after a 2-week TCS run-in. The primary endpoint was percentage of patients achieving Eczema Area and Severity Index (EASI)-50 at week 12. RESULTS: In total, 209 patients received the study drug. At week 12, significantly more patients achieved EASI-50 with lebrikizumab 125 mg every 4 weeks (82.4%; P = .026) than placebo every 4 weeks (62.3%); patients receiving a single dose of lebrikizumab showed no statistically significant improvements in EASI-50 compared with placebo. Adverse events were similar between groups (66.7% all lebrikizumab vs 66.0% placebo) and mostly mild or moderate. LIMITATIONS: Protocol-mandated twice daily TCS treatment limits our understanding of the efficacy of lebrikizumab as a monotherapy. The short study duration did not enable long-term efficacy or safety evaluations. CONCLUSION: When combined with TCS, lebrikizumab 125 mg taken every 4 weeks led to a significant improvement and was well tolerated in patients with moderate-to-severe AD.

A randomized multicenter study evaluating Xolair persistence of response after long-term therapy.

BACKGROUND: Few data are available to assist clinicians with decisions regarding long-term use of asthma therapies, including omalizumab. OBJECTIVE: We sought to evaluate the benefit and persistence of response in subjects continuing or withdrawing from long-term omalizumab treatment. METHODS: Evaluating the Xolair Persistency Of Response After Long-Term Therapy (XPORT) was a randomized, double-blind, placebo-controlled withdrawal study that included subjects with moderate-to-severe persistent asthma receiving long-term omalizumab. Subjects were randomized by using a hierarchical dynamic randomization scheme to continue their same dose of omalizumab or withdraw to placebo and were then followed every 4 weeks for 1 year. The primary outcome was any protocol-defined severe asthma exacerbation. The secondary outcome was time to first protocol-defined severe asthma exacerbation. Exploratory outcomes included changes in Asthma Control Questionnaire and Asthma Control Test scores. RESULTS: Significantly more subjects in the omalizumab group (67%) had no protocol-defined exacerbation than in the placebo group (47.7%); an absolute difference of 19.3% (95% CI, 5.0%, 33.6%) represents a 40.1% relative difference. Time to first protocol-defined exacerbation analysis revealed a significantly different between-group exacerbation pattern that was consistent with the primary analysis. Subjects continuing omalizumab had significantly better asthma control (mean [SD] change from baseline to week 52: Asthma Control Test score, -1.16 [4.14] vs placebo, -2.88 [5.38], P = .0188; Asthma Control Questionnaire score, 0.22 [0.66] vs placebo, 0.63 [1.13], P = .0039). Discontinuation of omalizumab was associated with an increase in free IgE levels and an increase in basophil expression of the high-affinity IgE receptor. No safety concerns were noted. CONCLUSION: Continuation of omalizumab after long-term treatment results in continued benefit, as evidenced by improved symptom control and reduced exacerbation risk.

Cardiovascular and cerebrovascular events among patients receiving omalizumab: Results from EXCELS, a prospective cohort study in moderate to severe asthma.

BACKGROUND: EXCELS, a postmarketing observational cohort study, was a commitment to the US Food and Drug Administration to assess the long-term safety of omalizumab in an observational setting, focusing predominantly on malignancies. OBJECTIVE: The aim of this study was to examine a potential association between omalizumab and cardiovascular (CV)/cerebrovascular (CBV) events in EXCELS. METHODS: Patients (≥12 years of age) with moderate to severe allergic asthma and who were being treated with omalizumab (n = 5007) or not (n = 2829) at baseline were followed up for ≤5 years. Analyses included overall CV/CBV events, but focused on the subset of arterial thromboembolic events (ATEs), comprising CV death, myocardial infarction, ischemic stroke, transient ischemic attack, and unstable angina. A prespecified analysis of the end point of ATE was conducted to control for available potential confounders. A blinded independent expert panel adjudicated all events. RESULTS: At baseline, the 2 cohorts had similar demographic characteristics, but severe asthma was more common in the omalizumab versus the non-omalizumab group (50% vs 23%). Omalizumab-treated patients had a higher rate of CV/CBV serious adverse events (13.4 per 1,000 person years [PYs]) than did non-omalizumab-treated patients (8.1 per 1,000 PYs). The ATE rates per 1,000 PYs were 6.66 (101 patients/15,160 PYs) in the omalizumab cohort and 4.64 (46 patients/9,904 PYs) in the non-omalizumab cohort. After control for available confounding factors, the hazard ratio was 1.32 (95% CI, 0.91-1.91). CONCLUSION: This observational study demonstrated a higher incidence rate of CV/CBV events in the omalizumab versus the non-omalizumab cohort. Differences in asthma severity between cohorts likely contributed to this imbalance, but some increase in risk cannot be excluded.

Timing and duration of omalizumab response in patients with chronic idiopathic/spontaneous urticaria.

BACKGROUND: Few data are available that describe response patterns in patients with chronic idiopathic urticaria (CIU)/chronic spontaneous urticaria (CSU) treated with omalizumab. OBJECTIVE: We sought to describe response patterns by using data from the 3 pivotal omalizumab CIU/CSU trials. METHODS: Every 4 weeks, randomized patients received dosing with placebo or 75, 150, or 300 mg of omalizumab (ASTERIA I: n = 318, 24 weeks; ASTERIA II: n = 322, 12 weeks) or placebo or 300 mg of omalizumab (GLACIAL: n = 335, 24 weeks). Response was defined as well-controlled urticaria (weekly Urticaria Activity Score [UAS7] ≤ 6) or complete response (UAS7 = 0). RESULTS: Response rates were dose dependent and highest with 300 mg of omalizumab. Some patients responded early (before week 4). At week 12, a higher proportion of patients treated with 300 mg of omalizumab reported a UAS7 ≤ 6 (26.0% [75 mg of omalizumab], 40.0% [150 mg of omalizumab], 51.9% [300 mg of omalizumab], and 11.3% [placebo] for ASTERIA I; 26.8% [75 mg of omalizumab], 42.7% [150 mg of omalizumab], 65.8% [300 mg of omalizumab], and 19.0% [placebo] for ASTERIA II; and 52.4% [300 mg of omalizumab] and 12.0% [placebo] for GLACIAL) or a UAS7 = 0 (11.7% [75 mg of omalizumab], 15.0% [150 mg of omalizumab], 35.8% [300 mg of omalizumab], and 8.8% [placebo] for ASTERIA I; 15.9% [75 mg of omalizumab], 22.0% [150 mg of omalizumab], 44.3% [300 mg of omalizumab], and 5.1% [placebo] for ASTERIA II; and 33.7% [300 mg of omalizumab] and 4.8% [placebo] for GLACIAL). In patients receiving 300 mg of omalizumab with 24 weeks of treatment, median time to achieve a UAS7 ≤ 6 was 6 weeks (ASTERIA I and GLACIAL) and median time to achieve a UAS7 = 0 was 12 or 13 weeks (ASTERIA I and GLACIAL, respectively). Some patients who achieved well-controlled urticaria or complete response sustained response throughout the treatment period. CONCLUSION: Benefits of omalizumab treatment were evident early (before week 4) in some patients and persisted to week 24. Use of 300 mg of omalizumab demonstrated best results in controlling CIU/CSU symptoms.

Corticosteroid-related toxicity in patients with chronic idiopathic urticariachronic spontaneous urticaria.

BACKGROUND: Treatments for patients with chronic idiopathic urticaria (CIU)chronic spontaneous urticaria (CSU) who were unresponsive to antihistamines include oral corticosteroids (OCS). Risks of OCS-related side effects in these patients have not been described quantitatively. OBJECTIVE: To investigate the relationship between OCS use and the risk of developing side effects possibly attributable to OCS and associated health care costs in privately insured patients with CIU/CSU. METHODS: This retrospective cohort study analyzed a commercial claims data base from January 1, 2008, to December 31, 2012. Patients with CIU/CSU were identified by International Classification of Diseases, Ninth Revision, Clinical Modification codes via a validated algorithm. Possible OCS-related side effects included the following: diabetes mellitus, hypertension, lipid disorders, cataracts, depression or mania, osteoporosis or fractures, and infectious diseases. A time-dependent Cox regression (adjusted for age, sex, Charlson Comorbidity Index, and immunomodulator use) was used to separately model cumulative oral prednisone-equivalent exposure and the risk of side effects. Incremental total adjusted health care costs were compared in patients with versus patients without possible OCS-related side effects. RESULTS: Among 12,647 patients with CIU/CSU, 55.4% used OCS. An additional 1 g of prednisone-equivalent exposure was associated with a 7% increase in the likelihood of developing a possible side effect (hazard ratio, 1.07 [95% confidence interval, 1.051.08]). From the period before to the period after OCS initiation, the total mean adjusted annual health care costs increased by 1833 in users of OCS with new possible side effects and decreased by 2183 in patients without new possible side effects (p 0.001). CONCLUSION: Patients with CIU/CSU who were treated with OCS had an increased risk of possible OCS-related side effects and higher total health care costs than their counterparts not treated with OCS.

Risk of corticosteroid-related adverse events in asthma patients with high oral corticosteroid use.

BACKGROUND: Oral corticosteroids (OCS) are a mainstay of asthma treatment. Their use increases the risk of various corticosteroid-related adverse events, but the extent of risk is poorly characterized. OBJECTIVE: To determine the incremental risk of possible corticosteroid-related adverse events (AE) in asthma among patients with high OCS use compared with patients who do not use OCS. METHODS: Patients with asthma in a commercial health care claims data base who were high-OCS users (≥30 days of OCS use annually) were matched to no-OCS users by age, sex, and geographic region, and the presence or absence of chronic obstructive pulmonary disease (COPD) as a comorbidity. We examined bone-related conditions, pneumonia, opportunistic infections, diabetes mellitus, and other disorders as potential AEs by using χ(2) tests to compare potential AE prevalence between the cohorts, with and without stratification by a COPD diagnosis. We controlled for the number of inhaled steroids (ICS) canisters filled. RESULTS: A total of 3604 patients with asthma and high OCS use were matched to 3604 patients who did not use OCS (mean age, 54.4; 68.1% female; 44.9% with COPD). Patients with high OCS use had statistically significantly higher rates of any potential AE compared with patients who did not use OCS (83.5% versus 78.1%), (p < 0.001). Rates of individual potential AEs were also higher in patients who used higher doses of OCS. Patterns of AEs were similar in patients with and those without COPD, with statistically significantly higher overall AE risk and individual risks in high-OCS users. The number of ICS canisters filled was not a significant predictor of AE. CONCLUSION: Patients with asthma who were treated with OCS for ≥30 days per year have a greater overall risk of possible corticosteroid-related AEs compared with those patients with no OCS use, whether or not they had COPD.

Risk adjustment for health care financing in chronic disease: what are we missing by failing to account for disease severity?

BACKGROUND: Adjustment for differing risks among patients is usually incorporated into newer payment approaches, and current risk models rely on age, sex, and diagnosis codes. It is unknown the extent to which controlling additionally for disease severity improves cost prediction. Failure to adjust for within-disease variation may create incentives to avoid sicker patients. We address this issue among patients with chronic obstructive pulmonary disease (COPD). METHODS: Cost and clinical data were collected prospectively from 1202 COPD patients at Kaiser Permanente. Baseline analysis included age, sex, and diagnosis codes (using the Diagnostic Cost Group Relative Risk Score) in a general linear model predicting total medical costs in the following year. We determined whether adding COPD severity measures-forced expiratory volume in 1 second, 6-Minute Walk Test, dyspnea score, body mass index, and BODE Index (composite of the other 4 measures)-improved predictions. Separately, we examined household income as a cost predictor. RESULTS: Mean costs were $12,334/y. Controlling for Relative Risk Score, each ½ SD worsening in COPD severity factor was associated with $629 to $1135 in increased annual costs (all P<0.01). The lowest stratum of forced expiratory volume in 1 second (<30% normal) predicted $4098 (95% confidence interval, $576-$8773) additional costs. Household income predicted excess costs when added to the baseline model (P=0.038), but this became nonsignificant when also incorporating the BODE Index. CONCLUSIONS: Disease severity measures explain significant cost variations beyond current risk models, and adding them to such models appears important to fairly compensate organizations that accept responsibility for sicker COPD patients. Appropriately controlling for disease severity also accounts for costs otherwise associated with lower socioeconomic status.

Lower health literacy is associated with poorer health status and outcomes in chronic obstructive pulmonary disease.

BACKGROUND: Limited health literacy is associated with poor outcomes in many chronic diseases, but little is known about health literacy in chronic obstructive pulmonary disease (COPD). OBJECTIVE: To examine the associations between health literacy and both outcomes and health status in COPD. PARTICIPANTS, DESIGN AND MAIN MEASURES: Structured interviews were administered to 277 subjects with self-report of physician-diagnosed COPD, recruited through US random-digit telephone dialing. Health literacy was measured with a validated three-item battery. Multivariable linear regression, controlling for sociodemographics including income and education, determined the cross-sectional associations between health literacy and COPD-related health status: COPD Severity Score, COPD Helplessness Index, and Airways Questionnaire-20R [measuring respiratory-specific health-related quality of life (HRQoL)]. Multivariable logistic regression estimated associations between health literacy and COPD-related hospitalizations and emergency department (ED) visits. KEY RESULTS: Taking socioeconomic status into account, poorer health literacy (lowest tertile compared to highest tertile) was associated with: worse COPD severity (+2.3 points; 95 % CI 0.3-4.4); greater COPD helplessness (+3.7 points; 95 % CI 1.6-5.8); and worse respiratory-specific HRQoL (+3.5 points; 95 % CI 1.8-4.9). Poorer health literacy, also controlling for the same covariates, was associated with higher likelihood of COPD-related hospitalizations (OR = 6.6; 95 % CI 1.3-33) and COPD-related ED visits (OR = 4.7; 95 % CI 1.5-15). Analyses for trend across health literacy tertiles were statistically significant (p < 0.05) for all above outcomes. CONCLUSIONS: Independent of socioeconomic status, poor health literacy is associated with greater COPD severity, greater COPD helplessness, worse respiratory-specific HRQoL, and higher odds of COPD-related emergency health-care utilization. These results underscore that COPD patients with poor health literacy may be at particular risk for poor health-related outcomes.

Both pulmonary and extra-pulmonary factors predict the development of disability in chronic obstructive pulmonary disease.

BACKGROUND: Although chronic obstructive pulmonary disease (COPD) is a major cause of disability worldwide, its determinants remain poorly defined. OBJECTIVE: We hypothesized that both pulmonary and extra-pulmonary factors would predict prospective disablement across a hierarchy of activities in persons with COPD. METHODS: Six hundred and nine participants were studied at baseline (T0) and 2.5 years later (T1). The Valued Life Activities (VLA) scale quantified disability (10-point scale: 0 = no difficulty and 10 = unable to perform), defining disability as any activity newly rated 'unable to perform' at T1. Predictors included pulmonary (lung function, 6-minute walk distance and COPD severity score) and extra-pulmonary (quadriceps strength and lower extremity function) factors. Prospective disability risk was tested by separate logistic regression models for each predictor (baseline value and its change, T0-T1; odds ratios were scaled at 1 standard deviation per factor. Incident disability across a hierarchy of obligatory, committed and discretionary VLA subscales was compared. RESULTS: Subjects manifested a 40% or greater increased odds of developing disability for each predictor (baseline and change over time). Disability in discretionary activities developed at a rate 2.2-times higher than observed in committed activities, which was in turn 2.5-times higher than the rate observed in obligatory activities (p < 0.05 for each level). CONCLUSIONS: Disability is common in COPD. Both pulmonary and extra-pulmonary factors are important in predicting its development.

Meaningful changes for efficacy outcomes in patients with chronic rhinosinusitis with nasal polyps.

Objective: Nasal Polyp Score (NPS) and Nasal Congestion Score (NCS) are commonly used clinical trial endpoints to determine improvements in response to treatment in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). However, limited information is available on within-patient meaningful change thresholds (MCTs) and between-group minimal important differences (MIDs) for NPS and NCS, which would aid interpretation of results. Methods: Data from phase 3 placebo-controlled trials of omalizumab in patients with CRSwNP (POLYP 1 and POLYP 2) were used to estimate MCTs and MIDs for both NPS and NCS using anchor-based methods. Sino-Nasal Outcome Test-22 (SNOT-22) and SNOT-22 Sino-Nasal Symptoms Subscale (SNSS) scores were used as anchors (≥0.35 correlation with NPS and NCS). Within- and between-group differences in NPS and NCS change scores were used to estimate MCTs and MIDs, respectively. Identified MCTs were used in unblinded responder analyses to compare the proportions of patients per treatment group achieving a meaningful improvement. Results: MCTs and MIDs were estimated at -1.0 and -0.5 for NPS and -0.50 and -0.35 for NCS, respectively, and were consistent across studies. Overall, 57.0% of patients achieved the MCT in NPS with omalizumab vs 29.9% with placebo (p < 0.0001). Similarly, 58.9% of patients achieved the MCT in NCS with omalizumab vs 30.7% with placebo (p < 0.0001). Group differences in mean change were statistically significant and exceeded the estimated MIDs. Conclusions: Meaningful change estimates for NPS and NCS could be used to assess response to treatment for patients with chronic rhinosinusitis with nasal polyps.Trial registration: POLYP1: clinicaltrails.gov NCT03280550; registered September 12, 2017; https://clinicaltrials.gov/ct2/show/NCT03280550). POLYP2 (clinicaltrials.gov NCT03280537; registered September 12, 2017; https://clinicaltrials.gov/ct2/show/NCT03280537).

Relationship of obesity with respiratory symptoms and decreased functional capacity in adults without established COPD.

BACKGROUND: Obesity contributes to respiratory symptoms and exercise limitation, but the relationships between obesity, airflow obstruction (AO), respiratory symptoms and functional limitation are complex. AIMS: To determine the relationship of obesity with airflow obstruction (AO) and respiratory symptoms in adults without a previous diagnosis of chronic obstructive pulmonary disease (COPD). METHODS: We analysed data for potential referents recruited to be healthy controls for an ongoing study of COPD. The potential referents had no prior diagnosis of COPD or healthcare utilisation attributed to COPD in the 12 months prior to recruitment. Subjects completed a structured interview and a clinical assessment including body mass index, spirometry, six-minute walk test (SMWT), and the Short Performance Physical Battery (SPPB). Multiple regression analyses were used to test the associations of obesity (body mass index >30 kg/m2) and smoking with AO (forced expiratory volume in 1s/forced vital capacity ratio <0.7). We also tested the association of obesity with respiratory symptoms and impaired functional capacity (SPPB, SMWT), adjusting for AO. RESULTS: Of 371 subjects (aged 40-65 years), 69 (19%) had AO. In multivariate analysis, smoking was positively associated with AO (per 10 pack-years, OR 1.24; 95% CI 1.04 to 1.49) while obesity was negatively associated with AO (OR 0.54; 95% CI 0.30 to 0.98). Obesity was associated with increased odds of reporting dyspnoea on exertion (OR 3.6; 95% CI 2.0 to 6.4), productive cough (OR 2.5; 95% CI 1.1 to 6.0), and with decrements in SMWT distance (67 ± 9 m; 95% CI 50 to 84 m) and SPPB score (OR 1.9; 95% CI 1.1 to 3.5). None of these outcomes was associated with AO. CONCLUSIONS: Although AO and obesity are both common among adults without an established COPD diagnosis, obesity (but not AO) is linked to a higher risk of reporting dyspnoea on exertion, productive cough, and poorer functional capacity.

Development of disability in chronic obstructive pulmonary disease: beyond lung function.

BACKGROUND: COPD is a major cause of disability, but little is known about how disability develops in this condition. METHODS: The authors analysed data from the Function, Living, Outcomes and Work (FLOW) Study which enrolled 1202 Kaiser Permanente Northern California members with COPD at baseline and re-evaluated 1051 subjects at 2-year follow-up. The authors tested the specific hypothesis that the development of specific non-respiratory impairments (abnormal body composition and muscle strength) and functional limitations (decreased lower extremity function, poor balance, mobility-related dyspnoea, reduced exercise performance and decreased cognitive function) will determine the risk of disability in COPD, after controlling for respiratory impairment (FEV(1) and oxygen saturation). The Valued Life Activities Scale was used to assess disability in terms of a broad range of daily activities. The primary disability outcome measure was defined as an increase in the proportion of activities that cannot be performed of 3.3% or greater from baseline to 2-year follow-up (the estimated minimal important difference). Multivariable logistic regression was used for analysis. RESULTS: Respiratory impairment measures were related to an increased prospective risk of disability (multivariate OR 1.75; 95% CI 1.26 to 2.44 for 1 litre decrement of FEV(1) and OR 1.57 per 5% decrement in oxygen saturation; 95% CI 1.13 to 2.18). Non-respiratory impairment (body composition and lower extremity muscle strength) and functional limitations (lower extremity function, exercise performance, and mobility-related dyspnoea) were all associated with an increased longitudinal risk of disability after controlling for respiratory impairment (p<0.05 in all cases). Non-respiratory impairment and functional limitations were predictive of prospective disability, above-and-beyond sociodemographic characteristics, smoking status and respiratory impairment (area under the receiver operating characteristic curve increased from 0.65 to 0.75; p<0.001). CONCLUSIONS: Development of non-respiratory impairment and functional limitations, which reflect the systemic nature of COPD, appear to be critical determinants of disablement. Prevention and treatment of disability require a comprehensive approach to the COPD patient.

Matrix metalloproteinase-9 predicts pulmonary status declines in α1-antitrypsin deficiency.

BACKGROUND: Matrix metalloproteinase-9 (MMP-9) may be important in the progression of emphysema, but there have been few longitudinal clinical studies of MMP-9 including pulmonary status and COPD exacerbation outcomes. METHODS: We utilized data from the placebo arm (n=126) of a clinical trial of patients with alpha1-antitrypsin deficiency (AATD) and emphysema to examine the links between plasma MMP-9 levels, pulmonary status, and COPD exacerbations over a one year observation period. Pulmonary function, computed tomography lung density, incremental shuttle walk test (ISWT), and COPD exacerbations were assessed at regular intervals over 12 months. Prospective analyses used generalized estimating equations to incorporate repeated longitudinal measurements of MMP-9 and all endpoints, controlling for age, gender, race-ethnicity, leukocyte count, and tobacco history. A secondary analysis also incorporated highly-sensitive C-reactive protein levels in predictive models. RESULTS: At baseline, higher plasma MMP-9 levels were cross-sectionally associated with lower FEV1 (p=0.03), FVC (p<0.001), carbon monoxide transfer factor (p=0.03), resting oxygen saturation (p=0.02), and ISWT distance walked (p=0.02) but were not associated with radiographic lung density or total lung capacity (TLC). In longitudinal analyses, MMP-9 predicted a further decline in transfer factor (p=0.04) and oxygen saturation (p<0.001). MMP-9 also predicted worsening lung density (p=0.003), increasing TLC (p=0.02), and more frequent COPD exacerbations over follow-up (p=0.003). Controlling additionally for hs-CRP levels did not substantively change the longitudinal associations between MMP-9 and these outcomes. CONCLUSIONS: Increased plasma MMP-9 levels generally predicted pulmonary status declines, including worsening transfer factor and lung density as well as greater COPD exacerbations in AATD-associated emphysema.

Evaluating quality of life in patients with asthma and rhinitis: English adaptation of the rhinasthma questionnaire.

BACKGROUND: Separate health-related quality of life (HRQL) instruments exist for asthma and rhinitis. The Rhinasthma questionnaire, originally developed in Italian, is a unique measure designed for use where both conditions coexist. OBJECTIVE: We sought to assess the performance and validity of a new adaptation of the Rhinasthma questionnaire for use in English-speaking populations. METHODS: We analyzed cross-sectional data from an ongoing study of adults with asthma and rhinitis (n = 450), asthma alone (n = 75), or rhinitis alone (n = 20). Subjects were administered an English translation of the original 30-item Rhinasthma questionnaire. Health status measures simultaneously assessed include the Short Form (SF)-12, EuroQol (EQ)-5D, and Marks Asthma Quality-of-Life. RESULTS: Variable cluster analysis of the original 30-item instrument identified 5 discrete item clusters corresponding to the following domains: nasal (5 items), eye (4 items), respiratory (5 items), activity restriction (9 items), and treatment burden (5 items). Two other items were removed because of poor item-cluster correlations. Subjects with concomitant asthma and rhinitis had greater HRQL impairment, as measured by the Rhinasthma, than subjects with either asthma or rhinitis alone. The Rhinasthma correlated significantly (P < .05) with the SF-12, EQ-5D, and Marks Asthma Quality-of-Life in the anticipated direction consistent with the underlying constructs. In multiple logistic regression, poorer Rhinasthma HRQL was associated with significantly (P < .05) increased odds of both asthma- and rhinitis-related disability even after taking into account physical health status as measured by the SF-12. CONCLUSION: The 28-item English adaptation of Rhinasthma performs well in assessing HRQL in patients with asthma, rhinitis, or both conditions combined.