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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.

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.

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.

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.

Atopic dermatitis is the most common chronic skin disease, and it primarily affects children. Although atopic dermatitis (AD) has the highest effect on burden of skin disease, no high-level studies have defined optimal therapy for severe disease. Corticosteroids have been used to treat AD since the 1950s and remain the only systemic medication with Food and Drug Administration approval for this indication in children, despite published guidelines of care that recommend against this option. Several clinical trials with level 1 evidence have supported the use of topical treatments for mild to moderate atopic dermatitis in adults and children, but these trials have had little consistency in protocol design. Consensus recommendations will help standardize clinical development and trial design for children. The Food and Drug Administration issues guidance documents for industry as a source for "the Agency's current thinking on a particular subject." Although they are nonbinding, industry considers these documents to be the standard for clinical development and trial design. Our consensus group is the first to specifically address clinical trial design in this population. We developed a draft guidance document for industry, Developing Drugs for Treatment of Atopic Dermatitis in Children (≥3 months to

Background Recent efficacy studies of asthma biologics have included highly enriched patient populations. Using a similar approach, we examined factors that predict response to omalizumab to facilitate selection of patients most likely to derive the greatest clinical benefit from therapy. Methods Data from two phase III clinical trials of omalizumab in patients with allergic asthma were examined. Differences in rates of asthma exacerbations between omalizumab and placebo groups during the 16-week inhaled corticosteroid (ICS) dose-stable phase were evaluated with respect to baseline blood eosinophil counts (eosinophils

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.

STUDY OBJECTIVES To evaluate the association between obstructive airway disease (OAD) and sleep apnea in older men. METHODS A community-based cross-sectional study of 853 community-dwelling older men (mean age 80.7 ± 4.1 years [range 73 to 90]) across 6 centers in the United States from the Outcomes of Sleep Disorders in Older Men Study. Sleep was objectively measured using full in-home polysomnography and lung function was objectively measured using spirometry. The association of OAD (pre-bronchodilator FEV1/FVC ratio < 0.7 and FEV1 < 80% predicted) and sleep apnea (apnea-hypopnea index [AHI] ≥ 15 events/hour) was assessed using logistic regression. RESULTS OAD and sleep apnea were identified in 111 (13.0%) and 247 (29.0%) men, respectively. In univariate analysis, participants with OAD had a lower AHI (mean ± SD; 8.7 ± 11.7 vs. 12.7 ± 13.8, P = 0.0009) and a lower prevalence of sleep apnea (14.4 vs. 31.1%, P = 0.0003) compared to participants without OAD. OAD remained independently associated with a lower odds of sleep apnea (odds ratio 0.30, 95% CI 0.16 to 0.55, P = 0.0001) after adjustment for demographics, body composition, smoking, and potential mediators (arousal index, time spent in rapid eye movement sleep). Individuals with OAD and sleep apnea (n = 16) had an increased arousal index and lower oxygen saturation level as compared to individuals with OAD alone (P values < 0.05). CONCLUSIONS Obstructive airway disease was associated with a lower prevalence of sleep apnea in a cohort of community-dwelling elderly men, and unexplained by differences in adiposity or sleep architecture. Although uncommon in this cohort, coexisting sleep apnea and OAD was associated with increased sleep fragmentation and nocturnal oxygen desaturation compared to OAD alone.

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.

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.

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.

Allan T Luskin,1 Evgeniya N Antonova,2 Michael S Broder,3 Eunice Y Chang,3 Theodore A Omachi,2 Dennis K Ledford4 1HealthyAirways, Madison, WI, 2Genentech, Inc., South San Francisco, 3Partnership for Health Analytic Research, LLC, Beverly Hills, CA, 4Division of Allergy and Immunology, Department of Medicine, James A. Haley Veterans’ Hospital, Morsani College of Medicine, University of South Florida, Tampa, FL, USA Background: The objective of this study was to estimate the prevalence of possible oral corticosteroid (OCS)-related side effects and health care resource use and costs in patients with asthma.Methods: This was a cross-sectional, matched-cohort, retrospective study using a commercial claims database. Adults with asthma diagnosis codes and evidence of asthma medication use were studied. Patients with high OCS use (≥30 days of OCS annually) were divided into those who did versus those who did not experience OCS-related possible side effects. Their health care resource use and costs were compared using linear regression or negative binomial regression models, adjusting for age, sex, geographic region, Charlson Comorbidity Index score, and chronic obstructive pulmonary disease status.Results: After adjustment, high OCS users with possible side effects were more likely to have office visits (23.0 vs 19.6; P

BACKGROUND: Patients with chronic idiopathic/spontaneous urticaria (CIU/CSU) report difficulty with sleep. METHODS: We examined the effect of omalizumab on sleep-related outcomes during 3-6 months omalizumab or placebo treatment and a 16-week follow-up period within three Phase III double-blind randomized placebo-controlled pivotal trials in CIU/CSU: ASTERIA I, ASTERIA II, and GLACIAL. Sleep quality was assessed in all three studies using sleep-related questions included in an electronic diary, the Chronic Urticaria Quality of Life Questionnaire, and the Medical Outcomes Study Sleep Scale. Score changes from baseline in the treatment arms were compared with that in the placebo arm and adjusted for baseline score and weight. We also examined correlations of sleep scores at baseline, week 12, and week 24 and the slopes of change between sleep and itch and hive. RESULTS: Patients treated with omalizumab reported a larger reduction in sleep problems than those in the placebo arm; omalizumab 300 mg demonstrated the greatest improvement on all sleep components among all treatment arms. The largest reduction in sleep problems was reported within the first 4 weeks of therapy. After treatment discontinuation, sleep quality worsened. Sleep scores demonstrated moderate-to-strong correlation between them, and the change in sleep scores was associated with changes in itch and hives. CONCLUSIONS: Improvement in sleep was reported after the first dose of omalizumab. Sleep continued to improve throughout the active treatment period. Patients receiving omalizumab 300 mg achieved greater improvement in sleep than those in other treatment arms. Trial registration ClinicalTrials.gov, NCT01287117 (ASTERIA I), NCT01292473 (ASTERIA II), and NCT01264939 (GLACIAL). The funding for ASTERIA I, ASTERIA II, and GLACIAL was provided by Genentech, Inc., South San Francisco, CA, USA and Novartis Pharma AG, Basel, Switzerland. The funding for this study was provided by Genentech, Inc. Medical writing support for this manuscript was provided by Charlotte Kenreigh of Excel Scientific Solutions and funded by Genentech, Inc. and Novartis Pharmaceuticals Corporation.

Obesity contributes to respiratory symptoms and exercise limitation, but the relationships between obesity, airflow obstruction (AO), respiratory symptoms and functional limitation are complex. 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). 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 ≥30kg/m2) and smoking with AO (forced expiratory volume in 1s/forced vital capacity ratio

PURPOSE: The independent contribution of physical inactivity to disability in obstructive lung disease (OLD) is difficult to study, partly because inactivity may reflect disease severity. We examined the relationship of physical inactivity to disability progression over a 1-year period among a group of older adults with OLD. METHODS: A population-based cohort with self-reported physician-diagnosed emphysema, chronic obstructive pulmonary disease, or chronic bronchitis (n = 206) completed baseline interviews and in-person spirometry, with 1-year followup interviews. The Community Health Activities Model Program for Seniors physical activity questionnaire provided estimates of energy expenditure; we defined inactivity as no expenditure in moderate- or vigorous-intensity activities. Disability was measured with the Valued Life Activity (VLA) disability scale; increased disability was defined as a 10% or greater increase in VLA disability score over 1-year followup. Logistic regression tested the relationship between baseline inactivity and disability increase, controlling for age, sex, baseline VLA disability, comorbidities, smoking, and pulmonary function (forced expiratory volume in 1 second, % predicted). RESULTS: Of 206 subjects, 48 (27%) were physically inactive at baseline; 42.9% of individuals whose disability increased were inactive at baseline compared with 23.4% of those who did not experience a disability increase. With adjustment for covariates, increased disability after 1 year was significantly (P = .04) more likely among individuals who were inactive at baseline (Odds Ratio =2.4; 95% confidence interval, 1.02-5.9). CONCLUSIONS: Physically inactive individuals with OLD had more than double the odds of an increase in disability, even after controlling for baseline disability, lung function, and other covariates. These results provide strong support for the importance of maintaining physical activity among individuals with OLD.

Background Psychologic factors affect how patients with COPD respond to attempts to improve their self-management skills. Learned helplessness may be one such factor, but there is no validated measure of helplessness in COPD. Methods We administered a new COPD Helplessness Index (CHI) to 1,202 patients with COPD. Concurrent validity was assessed through association of the CHI with established psychosocial measures and COPD severity. The association of helplessness with incident COPD exacerbations was then examined by following subjects over a median 2.1 years, defining COPD exacerbations as COPD-related hospitalizations or ED visits. Results The CHI demonstrated internal consistency (Cronbach α = 0.75); factor analysis was consistent with the CHI representing a single construct. Greater CHI-measured helplessness correlated with greater COPD severity assessed by the BODE (Body-mass, Obstruction, Dyspnea, Exercise) Index (r = 0.34; P Conclusions The CHI is an internally consistent and valid measure, concurrently associated with health status and predictively associated with COPD exacerbations. The CHI may prove a useful tool in analyzing differential clinical responses mediated by patient-centered attributes.

Background A comprehensive survey-based COPD severity score has usefulness for epidemiologic and health outcomes research. We previously developed and validated the survey-based COPD Severity Score without using lung function or other physiologic measurements. In this study, we aimed to further validate the severity score in a different COPD cohort and using a combination of patient-reported and objective physiologic measurements. Methods Using data from the Function, Living, Outcomes, and Work cohort study of COPD, we evaluated the concurrent and predictive validity of the COPD Severity Score among 1,202 subjects. The survey instrument is a 35-point score based on symptoms, medication and oxygen use, and prior hospitalization or intubation for COPD. Subjects were systemically assessed using structured telephone survey, spirometry, and 6-min walk testing. Results We found evidence to support concurrent validity of the score. Higher COPD Severity Score values were associated with poorer FEV 1 ( r = −0.38), FEV 1 % predicted ( r = −0.40), Body mass, Obstruction, Dyspnea, Exercise Index ( r = 0.57), and distance walked in 6 min ( r = −0.43) ( P r = −0.49) and disease-specific health-related quality of life ( r = 0.57) ( P P Conclusion The COPD Severity Score is a valid survey-based measure of disease-specific severity, both in terms of concurrent and predictive validity. The score is a psychometrically sound instrument for use in epidemiologic and outcomes research in COPD.

Background Psychological functioning is an important determinant of health outcomes in chronic lung disease. To better define the role of anxiety in chronic obstructive pulmonary disease (COPD), a study was conducted of the inter-relations between anxiety and COPD in a large cohort of subjects with COPD and a matched control group. Methods Data were used from the FLOW (Function, Living, Outcomes, and Work) cohort of patients with COPD (n=1202) and matched controls without COPD (n=302). Anxiety was measured using the Anxiety subscale of the Hospital Anxiety and Depression Scale. Results COPD was associated with a greater risk of anxiety in multivariable analysis (OR 1.85; 95% CI 1.072 to 3.18). Among patients with COPD, anxiety was related to poorer health outcomes including worse submaximal exercise performance (less distance walked during the 6-min walk test: −66.3 feet for anxious vs non-anxious groups; 95% CI −127.3 to −5.36) and a greater risk of self-reported functional limitations (OR 2.41; 95% CI 1.71 to 3.41). Subjects with COPD with anxiety had a higher longitudinal risk of COPD exacerbation in Cox proportional hazards analysis after controlling for covariates (HR 1.39; 95% CI 1.007 to 1.90). Conclusion COPD is associated with a higher risk of anxiety. Once anxiety develops among patients with COPD, it is related to poorer health outcomes. Further research is needed to determine whether systematic screening and treatment of anxiety in COPD will improve health outcomes and prevent functional decline and disability.

To examine obstructive sleep apnea (OSA) as a risk factor for work disability.Consecutive patients referred to the University of California San Francisco Sleep Disorders Center with suspected OSA (n = 183).All patients underwent overnight polysomnography after completing a written survey which assessed work disability due to sleep problems, occupational characteristics and excessive daytime sleepiness (EDS) defined as an Epworth Sleepiness Scale score10.Among 150 currently employed patients, 83 had OSA on polysomnography (apnea-hypopnea indexor = 5). Compared with patients in whom both OSA and EDS were absent, patients with the combination of OSA and EDS were at higher risk of both recent work disability (adjusted odds ratio [OR], 13.7; 95% confidence interval [CI], 3.9-48) and longer-term work duty modification (OR, 3.6; CI, 1.1-12). When either OSA or EDS were absent, the strength of the association with work disability was less than when both OSA and EDS were present. When OSA was examined without respect to EDS, patients with OSA were at increased risk of recent work disability relative to patients without OSA (OR 2.6; 95% CI 1.2-5.8), but the association of OSA with longer-term work duty modification did not meet standard criteria for statistical significance (OR = 2.0, 95% CI 0.8-5.0).The combination of OSA and EDS contributes to work disability, and OSA by itself contributes to recent work disability. These findings should highlight to employers and clinicians the importance of OSA in the workplace to encourage patients to be screened for OSA, particularly in situations of decreased productivity associated with EDS.

The authors’ objective was to analyze the impact of respiratory impairment on the risk of physical functional limitations among adults with chronic obstructive pulmonary disease (COPD). They hypothesized that greater pulmonary function decrement would result in a broad array of physical functional limitations involving organ systems remote from the lung, a key step in the pathway leading to overall disability. The authors used baseline data from the Function, Living, Outcomes, and Work (FLOW) study, a prospective cohort study of adults with COPD recruited from northern California in 2005–2007. They studied the impact of pulmonary function impairment on the risk of functional limitations using validated measures: lower extremity function (Short Physical Performance Battery), submaximal exercise performance (6-Minute Walk Test), standing balance (Functional Reach Test), skeletal muscle strength (manual muscle testing with dynamometry), and self-reported functional limitation (standardized item battery). Multiple variable analysis was used to control for confounding by age, sex, race, height, educational attainment, and cigarette smoking. Greater pulmonary function impairment, as evidenced by lower forced expiratory volume in 1 second (FEV1), was associated with poorer Short Physical Performance Battery scores and less distance walked during the 6-Minute Walk Test. Lower forced expiratory volume in 1 second was also associated with weaker muscle strength and with a greater risk of self-reported functional limitation (p < 0.05). In conclusion, pulmonary function impairment is associated with multiple manifestations of physical functional limitation among COPD patients. Longitudinal follow-up can delineate the impact of these functional limitations on the prospective risk of disability, guiding preventive strategies that could attenuate the disablement process.

BACKGROUND Safe delivery of care depends on effective communication among all health care providers, especially during transfers of care. The traditional medical chart does not adequately support such communication. We designed a patient-tracking tool that enhances provider communication and supports clinical decision making. AIM To develop a problem-based patient-tracking tool, called Sign-out, Information Retrieval, and Summary (SynopSIS), in order to support patient tracking, transfers of care (ie, sign-outs), and daily rounds. SETTING Tertiary-care, university-based teaching hospital. PROGRAM DESCRIPTION SynopSIS compiles and organizes information from the electronic medical record to support hospital discharge and disposition decisions, daily provider decisions, and overnight or cross-coverage decisions. It reflects the provider's patient-care and daily work-flow needs. PROGRAM EVALUATION We plan to use Web-based surveys, audits of daily use, and interdisciplinary focus groups to evaluate SynopSIS's impact on communication between providers, quality of sign-out, patient continuity of care, and rounding efficiency. CONCLUSIONS We expect SynopSIS to improve care by facilitating communication between care teams, standardizing sign-out, and automating daily review of clinical and laboratory trends. SynopSIS redesigns the clinical chart to better serve provider and patient needs. Journal of Hospital Medicine 2007;2:336–342. © 2007 Society of Hospital Medicine.

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.

Background: Response to biologic therapies for the treatment of asthma may be predicted by clinical and biologic markers of asthma severity. Objectives: This post-hoc analysis was conducted to determine if clinical markers of asthma severity and blood eosinophils predict response to omalizumab (OMA) treatment for severe allergic asthma. Methods: Data were pooled from 2 phase 3, double-blind, randomized, placebo (PBO)-controlled trials of OMA in allergic asthma (N=1071). The number of asthma exacerbations requiring systemic corticosteroids was analyzed over the 16-week-inhaled corticosteroid-stable dose phase of the studies. Effects of OMA on exacerbations in relation to peripheral blood eosinophil counts ( Results: Exacerbations were reduced 53% with OMA vs PBO (95% CI,33–68; P P =0.008) compared to 47% not receiving LABAs (95% CI, 23–65; P =0.001); and 63% (95% CI,34–79; P P =0.051). In patients hospitalized for asthma in the year prior to screening, there were no exacerbations in 17 OMA-treated patients and 17 exacerbations in 31 PBO patients, for a 100% reduction ( P P =0.006). Conclusions: Patients with greater asthma severity, as assessed by baseline LABA use, prior hospitalizations for asthma, or higher blood eosinophil counts, have a better response to OMA.

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.

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 1/2 SD worsening in COPD severity factor was associated with $629 to $1135 in increased annual costs (all P

Objectives. We estimated the extent to which socioeconomic status (SES) gradients in adult asthma and rhinitis outcomes can be explained by home and neighborhood environmental factors. Methods. Using survey data for 515 adults with either asthma or rhinitis, or both, we examined environmental mediators of SES associations with disease severity, using the Severity of Asthma Scale, and health-related quality of life (HRQL), using the Rhinasthma Scale. We defined SES on the basis of education and household income. Potential environmental mediators included home type and ownership, exposures to allergens and irritants, and a summary measure of perceived neighborhood problems. We modeled each outcome as a function of SES, and controlled for age, gender, and potential mediators. Results. Gradients in SES were apparent in disease severity and HRQL. Living in a rented house partially mediated the SES gradient for both severity and HRQL (P Conclusions. Differences in home and neighborhood environments partially explained associations of SES with adult asthma and rhinitis outcomes.

Obstructive lung diseases have a variety of specific types and etiologies which are common across all age ranges, and can affect sleep in numerous ways. Chronic obstructive pulmonary disease (COPD) from smoking and other causes can cause morbidity both from sleep disruption and also sleep-related hypoxemia. Asthma is the most common obstructive lung disease, and it can disrupt sleep when not effectively controlled. Cystic fibrosis (CF) is now much more common in adult patients, and can worsen sleep both from chronic symptoms as well as during acute exacerbations. Obstructive sleep apnea commonly coexists with both COPD and asthma, but less frequently with CF. Diagnosis of these conditions is based on history, examination, pulmonary function, radiology, and specific diagnostic testing including genetic testing for CF. Treatment can involve a wide range of medications as well as oxygen, positive pressure therapy, and noninvasive ventilation.

a Evidence of IgE > 75 IU/ml at least once; b No-evidence of IgE >75 IU/ml; c t-test; d Chi-square test; e filled at any time during follow-up • Adjusted for demographics and clinical characteristics (Table 2): o Study-group patients had more asthma-related office visits (2,280 vs. 1,540; p=0.013), exacerbations (1,331 vs. 989; p=0.004), and asthma-related ED visits (30 vs. 3; p=0.0002) than their counterparts in the comparison group. o Hospitalizations (overall and asthma-related) and any-cause office visits were not statistically significantly different between groups.

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).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.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.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.

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.

Objective: To investigate the cross-sectional association between COPD severity and disturbed sleep and the longitudinal association between disturbed sleep and poor health outcomes. Methods: Ninety eight adults with spirometrically-confirmed COPD were recruited through populationbased, random-digit telephone dialing. Sleep disturbance was evaluated using a 4-item scale assessing insomnia symptoms as: difficulty falling asleep, nocturnal awakening, morning tiredness, and sleep duration adequacy. COPD severity was quantified by: FEV1 and COPD Severity Score, which incorporates COPD symptoms, requirement for COPD medications and oxygen, and hospital-based utilization. Subjects were assessed one year after baseline to determine longitudinal COPD exacerbations and emergency utilization and were followed for a median 2.4 years to assess all-cause mortality. Results: Sleep disturbance was cross-sectionally associated with cough, dyspnea, and COPD Severity Score, but not FEV1. In multivariable logistic regression, controlling for sociodemographics and bodymass index, sleep disturbance longitudinally predicted both incident COPD exacerbations (OR = 4.7; p = 0.018) and respiratory-related emergency utilization (OR = 11.5; p = 0.004). In Cox proportional hazards analysis, controlling for the same covariates, sleep disturbance predicted poorer survival (HR = 5.0; p = 0.013). For all outcomes, these relationships persisted after also controlling for baseline FEV1 and COPD Severity Score. Conclusions: Disturbed sleep is cross-sectionally associated with worse COPD and is longitudinally predictive of COPD exacerbations, emergency health care utilization, and mortality.

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.

COPD is a major cause of disability, but little is known about how disability develops in this condition.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.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 (p0.05 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; p0.001).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.