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Rationale: Previous studies investigating the impact of comorbidities on the effectiveness of biologic agents have been relatively small and of short duration and have not compared classes of biologic agents. Objectives: To determine the association between type 2-related comorbidities and biologic agent effectiveness in adults with severe asthma (SA). Methods: This cohort study used International Severe Asthma Registry data from 21 countries (2017-2022) to quantify changes in four outcomes before and after biologic therapy-annual asthma exacerbation rate, FEV 1 % predicted, asthma control, and long-term oral corticosteroid daily dose-in patients with or without allergic rhinitis, chronic rhinosinusitis (CRS) with or without nasal polyps (NPs), NPs, or eczema/atopic dermatitis. Measurements and Main Results: Of 1,765 patients, 1,257, 421, and 87 initiated anti-IL-5/5 receptor, anti-IgE, and anti-IL-4/13 therapies, respectively. In general, pre- versus post-biologic therapy improvements were noted in all four asthma outcomes assessed, irrespective of comorbidity status. However, patients with comorbid CRS with or without NPs experienced 23% fewer exacerbations per year (95% CI, 10-35%; P  < 0.001) and had 59% higher odds of better post-biologic therapy asthma control (95% CI, 26-102%; P  < 0.001) than those without CRS with or without NPs. Similar estimates were noted for those with comorbid NPs: 22% fewer exacerbations and 56% higher odds of better post-biologic therapy control. Patients with SA and CRS with or without NPs had an additional FEV 1 % predicted improvement of 3.2% (95% CI, 1.0-5.3; P  = 0.004), a trend that was also noted in those with comorbid NPs. The presence of allergic rhinitis or atopic dermatitis was not associated with post-biologic therapy effect for any outcome assessed. Conclusions: These findings highlight the importance of systematic comorbidity evaluation. The presence of CRS with or without NPs or NPs alone may be considered a predictor of the effectiveness of biologic agents in patients with SA.

The Global Initiative for Asthma (GINA) Strategy Report provides clinicians with an annually updated evidence-based strategy for asthma management and prevention, which can be adapted for local circumstances (e.g., medication availability). This article summarizes key recommendations from GINA 2021, and the evidence underpinning recent changes. GINA recommends that asthma in adults and adolescents should not be treated solely with short-acting β 2 -agonist (SABA), because of the risks of SABA-only treatment and SABA overuse, and evidence for benefit of inhaled corticosteroids (ICS). Large trials show that as-needed combination ICS-formoterol reduces severe exacerbations by ⩾60% in mild asthma compared with SABA alone, with similar exacerbation, symptom, lung function, and inflammatory outcomes as daily ICS plus as-needed SABA. Key changes in GINA 2021 include division of the treatment figure for adults and adolescents into two tracks. Track 1 (preferred) has low-dose ICS-formoterol as the reliever at all steps: as needed only in Steps 1-2 (mild asthma), and with daily maintenance ICS-formoterol (maintenance-and-reliever therapy, "MART") in Steps 3-5. Track 2 (alternative) has as-needed SABA across all steps, plus regular ICS (Step 2) or ICS-long-acting β 2 -agonist (Steps 3-5). For adults with moderate-to-severe asthma, GINA makes additional recommendations in Step 5 for add-on long-acting muscarinic antagonists and azithromycin, with add-on biologic therapies for severe asthma. For children 6-11 years, new treatment options are added at Steps 3-4. Across all age groups and levels of severity, regular personalized assessment, treatment of modifiable risk factors, self-management education, skills training, appropriate medication adjustment, and review remain essential to optimize asthma outcomes.

Rationale: Despite effective treatments, a large proportion of patients with asthma do not achieve sustained asthma control. The "preventable" burden associated with lack of proper control is likely taking a high toll at the personal and population level. Objectives: We predicted the future excess health and economic burden associated with uncontrolled asthma among American adolescents and adults for the next 20 years. Methods: We built a probabilistic model that linked state-specific estimates of population growth, aging, asthma prevalence, and asthma control levels. We conducted several meta-analyses to estimate the adjusted differences in healthcare resource use, quality-adjusted life years (QALYs), and productivity loss across control levels. We projected, nationally and at the state level, total direct and indirect (due to productivity loss) costs (in 2018 dollars) and QALYs lost because of uncontrolled asthma from 2019 to 2038. Measurements and Main Results: Total 20-year direct costs associated with uncontrolled asthma are estimated to be $300.6 billion (95% confidence interval [CI], $190.1 billion-411.1 billion). When indirect costs are added, total economic burden will be $963.5 billion (95% CI, $664.1 billion-1,262.9 billion). American adolescents and adults will lose an estimated 15.46 million (95% CI, 12.77 million-18.14 million) QALYs over this period because of uncontrolled asthma. Across states, the average 20-year per capita costs due to uncontrolled asthma ranged from $2,209 (Arkansas) to $6,132 (Connecticut). Conclusions: The burden of uncontrolled asthma is substantial and will continue to grow. Given that a substantial fraction of this burden is preventable, better adherence to evidence-informed asthma management strategies by care providers and patients has the potential to substantially reduce costs and improve quality of life.

Rationale: Lung dysbiosis promotes airway inflammation and decreased local immunity, potentially playing a role in the pathogenesis of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Objectives: We sought to determine the relationship between sputum microbiome at the time of AECOPD hospitalization and 1-year mortality in a COPD cohort. Methods: We used sputum samples from 102 patients hospitalized because of AECOPD. All subjects were followed for 1 year after discharge. The microbiome profile was assessed through sequencing of 16S rRNA gene. Microbiome analyses were performed according to 1-year mortality status. To investigate the effect of α-diversity measures and taxon features on time to death, we applied Cox proportional hazards regression models and obtained hazard ratios (HRs) associated with these variables. Measurements and Main Results: We observed significantly lower values of α-diversity (richness, Shannon index, evenness, and Faith's Phylogenetic Diversity) among nonsurvivors ( n  = 19, 18.6%) than survivors ( n  = 83, 81.4%). β-Diversity analysis also demonstrated significant differences between both groups (adjusted permutational multivariate ANOVA, P  = 0.010). The survivors had a higher relative abundance of Veillonella ; in contrast, nonsurvivors had a higher abundance of Staphylococcus . The adjusted HRs for 1-year mortality increased significantly with decreasing α-diversity. We also observed lower survival among patients in whom sputum samples were negative for Veillonella (HR, 13.5; 95% confidence interval, 4.2-43.9; P  < 0.001) or positive for Staphylococcus (HR, 7.3; 95% confidence interval, 1.6-33.2; P  = 0.01). Conclusions: The microbiome profile of sputum in AECOPD is associated with 1-year mortality and may be used to identify subjects with a poor prognosis at the time of hospitalization.

Rationale: The allergen inhalation challenge is used in clinical trials to test the efficacy of new treatments in attenuating the late-phase asthmatic response (LAR) and associated airway inflammation in subjects with allergic asthma. However, not all subjects with allergic asthma develop the LAR after allergen inhalation. Blood-based transcriptional biomarkers that can identify such individuals may help in subject recruitment for clinical trials as well as provide novel molecular insights., Objectives: To identify blood-based transcriptional biomarker panels that can predict an individual's response to allergen inhalation challenge., Methods: We applied RNA sequencing to total RNA from whole blood (n = 36) collected before and after allergen challenge and generated both genome-guided and de novo datasets: genes, gene-isoforms (University of California, Santa Cruz, UCSC Genome Browser), Ensembl, and Trinity. Candidate biomarker panels were validated using the NanoString platform in an independent cohort of 33 subjects., Measurements and Main Results: The Trinity biomarker panel consisting of known and novel biomarker transcripts had an area under the receiver operating characteristic curve of greater than 0.70 in both the discovery and validation cohorts. The Trinity biomarker panel was useful in predicting the response of subjects that elicited different responses (accuracy between 0.65 and 0.71) and subjects that elicit a dual response (accuracy between 0.70 and 0.75) upon repeated allergen inhalation challenges., Conclusions: Interestingly, the biomarker panel containing novel transcripts successfully validated compared with panels with known, well-characterized genes. These biomarker-blood tests may be used to identify subjects with asthma who develop the LAR, and may also represent members of novel molecular mechanisms that can be targeted for therapy.

Rationale: Chronic obstructive pulmonary disease (COPD) remains undiagnosed in many individuals with persistent airflow limitation. These individuals may be susceptible to exacerbation-like respiratory events that consume health care resources., Objectives: To compare exacerbation-like respiratory events, event prevalence, and differences in the odds of using medication and/or health services between subjects with diagnosed and undiagnosed COPD., Methods: Subjects sampled from the general population participating in the CanCOLD (Canadian Cohort Obstructive Lung Disease) study, with at least 12 months of exacerbation-event follow-up who were classified as having physician-diagnosed or undiagnosed COPD were assessed. Exacerbation-like respiratory events were captured using a questionnaire administered every 3 months., Measurements and Main Results: A total of 355 subjects were undiagnosed and 150 were diagnosed with COPD. Undiagnosed subjects were less symptomatic and functionally impaired, had been prescribed fewer respiratory medications, and had better health status. The incidence of reported exacerbation-like events was higher in diagnosed subjects and increased in both groups with the severity of airflow obstruction. Although subjects with diagnosed COPD were more often prescribed medication for exacerbation events, health service use for exacerbation events was similar in both groups., Conclusions: Most subjects with COPD in Canada remain undiagnosed. These subjects are less symptomatic and impaired, which may partly explain lack of diagnosis. Although patients with undiagnosed COPD experience fewer exacerbations than those with diagnosed COPD, they use a similar amount of health services for exacerbation events; thus, the overall health system burden of exacerbations in those with undiagnosed COPD is considerable.

Rationale: Ambient air pollution has been suggested as a risk factor for chronic obstructive pulmonary disease (COPD). However, there is a lack of longitudinal studies to support this assertion., Objectives: To investigate the associations of long-term exposure to elevated traffic-related air pollution and woodsmoke pollution with the risk of COPD hospitalization and mortality., Methods: This population-based cohort study included a 5-year exposure period and a 4-year follow-up period. All residents aged 45-85 years who resided in Metropolitan Vancouver, Canada, during the exposure period and did not have known COPD at baseline were included in this study (n = 467,994). Residential exposures to traffic-related air pollutants (black carbon, particulate matter <2.5 μm in aerodynamic diameter, nitrogen dioxide, and nitric oxide) and woodsmoke were estimated using land-use regression models and integrating changes in residences during the exposure period. COPD hospitalizations and deaths during the follow-up period were identified from provincial hospitalization and death registration databases., Measurements and Main Results: An interquartile range elevation in black carbon concentrations (0.97 × 10(-5)/m, equivalent to 0.78 μg/m(3) elemental carbon) was associated with a 6% (95% confidence interval, 2-10%) increase in COPD hospitalizations and a 7% (0-13%) increase in COPD mortality after adjustment for covariates. Exposure to higher levels of woodsmoke pollution (tertile 3 vs. tertile 1) was associated with a 15% (2-29%) increase in COPD hospitalizations. There were positive exposure-response trends for these observed associations., Conclusions: Ambient air pollution, including traffic-related fine particulate pollution and woodsmoke pollution, is associated with an increased risk of COPD.

Rationale: Extensive evidence in animal models supports a role for IL-13 in the pathobiology of asthma. IMA-638 and IMA-026 are fully humanized IgG(1) antibodies that bind to different epitopes and neutralize IL-13 bioactivity., Objectives: We hypothesized that anti-IL-13 treatment would inhibit allergen-induced late-phase asthmatic responses, airway hyperresponsiveness, and inflammation in subjects with asthma., Methods: Fifty-six subjects with mild, atopic asthma were recruited for two double-blind, randomized, placebo-controlled, parallel group trials to compare IMA-638 and IMA-026 IL-13 antibody treatments with placebo treatment. Drug was administered on Days 1 and 8, and allergen challenges were performed on Days 14 and 35. The primary outcome variable was the late-phase area under the curve (AUC), and secondary outcome variables were the early- and late-phase maximum percent fall in FEV(1), early AUC, allergen-induced shift in airway hyperresponsiveness, and sputum eosinophils., Measurements and Main Results: The treatment difference with IMA-638 on Day 14 was -19.1 FEV(1) × hour (95% confidence interval: -36.2, -1.9) for the allergen-induced early AUC and -23.8 FEV(1) × hour (95% confidence interval: -46.4, -1.2) for the late AUC (both P < 0.05), but this effect was lost by Day 35. Treatment with IMA-026 did not attenuate the asthmatic responses on Day 14 or Day 35. There was no effect of either antibody on allergen-induced airway hyperresponsiveness or sputum eosinophils. The frequency of adverse events after administration of the IL-13 antibodies was similar to placebo., Conclusions: IL-13 has a role in allergen-induced airway responses in humans. Further study is required to determine whether anti-IL-13 monoclonal antibodies will be beneficial clinically.

Rationale: Bronchial thermoplasty (BT) reduces the potential for smooth muscle-mediated bronchoconstriction by reducing the mass of smooth muscle in the walls of conducting airways., Objectives: This study was conducted to examine the safety and impact on lung function and airway responsiveness of BT over 2 yr., Methods: The safety of BT was studied in 16 subjects with mild to moderate asthma. Baseline and 12-wk post-treatment measurements included spirometry, methacholine challenge, daily diary recordings of peak flow, symptoms, and medication usage. Subjects completed follow-up evaluations at 12 wk, 1 yr, and 2 yr., Measurements and Main Results: The procedure was well tolerated; side effects were transient and typical of what is commonly observed after bronchoscopy. All subjects demonstrated improvement in airway responsiveness. The mean PC(20) increased by 2.37 +/- 1.72 (p < 0.001), 2.77 +/- 1.53 (p = 0.007), and 2.64 +/- 1.52 doublings (p < 0.001), at 12 wk, 1 yr, and 2 yr post-procedure, respectively. Data from daily diaries collected for 12 wk indicated significant improvements over baseline in symptom-free days (p = 0.015), morning peak flow (p = 0.01), and evening peak flow (p < or = 0.007). Spirometry measurements remained stable throughout the study period., Conclusions: BT is well tolerated in patients with asthma and results in decreased airway hyperresponsiveness that persists for at least 2 yr.

The risk of occupational tuberculosis (TB) infection and associated factors was estimated among all microbiology and pathology technicians and compared with a sample of nonclinical personnel in 17 Canadian acute care hospitals. Participants underwent tuberculin skin testing and completed questionnaires. Prior skin tests and vaccinations and all patients with TB hospitalized in the preceding 3 years were reviewed. Of the work areas where direction of air flow and air changes per hour were measured, only 51% were adequately ventilated. Among participating lab workers the average annual risk of tuberculin conversion was 1.0%. This was associated with lower hourly air exchange rates (16.7 versus 32.5 in workers with no conversion, p < 0.001) work in pathology (adjusted odds ratio [OR]: 5.4; [95% confidence interval: 1.3, 22], higher proportion of patients with missed diagnosis in the first 24 hours (per 20% increase-OR: 2.0; [1.3, 3.2], treatment delayed 1 week or more (per 20% increase-OR: 2.0; [3.2, 3.2]), and higher mortality (per 20% increase-OR: 2.5; [1.1, 5.6]). We conclude that laboratory workers, with no direct patient contact, have increased risk of tuberculin conversion in hospitals where a greater proportion of patients with TB die, or have delayed, or missed diagnosis, although this may be modified by workplace ventilation.

Delayed diagnosis of active pulmonary tuberculosis (TB) among hospitalized patients is common and believed to contribute significantly to nosocomial transmission. This study was conducted to define the occurrence, associated patient risk factors, and outcomes among patients and exposed workers of delayed diagnosis of active pulmonary TB. Among 429 patients newly diagnosed to have active pulmonary TB between June 1992 and June 1995 in 17 acute-care hospitals in four Canadian cities, initiation of appropriate treatment was delayed 1 week or more in 127 (30%). This was associated with atypical clinical and demographic patient characteristics, and after adjustment for these characteristics, with admission to hospitals with low TB admission rate of 0.2-3.3 per 10,000 admissions (odds ratio [OR]: 7.4; 95% confidence interval [CI]: 3.2,17.5) or intermediate TB admissions of 3.4-9.9/10,000 (OR: 2.3; CI: 1.6,3.2) as well as potentially preventable (late) intensive care unit admission (OR: 16.8; CI: 2.0,144) and death (OR: 3.3; CI: 1.7,6.5]). In hospitals with low TB admission rates, initially missed diagnosis, smear-positive patients undergoing bronchoscopy, late intensive care unit admission (OR: 2.3; CI: 0.1,56), and death (OR: 3.8; CI: 1.2,12.1) were more common than in hospitals with high TB admissions (> 10/ 10,000); a similar trend was seen in hospitals with intermediate TB admissions. Even after adjustment for workers' characteristics and ventilation in patients' rooms tuberculin conversions were disproportionately high in hospitals with low and intermediate TB admission rates and significantly higher in hospitals with overall TB mortality rate above 10% (OR: 2.5; CI: 1.6,3.7). In the hospitals studied, as the rate of TB admissions decreased, the likelihood of poor outcomes and risk of transmission of TB infection per hospitalized patient with TB increased. Institutional risk of TB transmission was poorly correlated with number of patients with TB and better correlated with indicators of patient care such as delayed diagnosis and treatment and overall TB-related patient mortality.

Allele 2 of the polymorphism at position -308 in the promoter of the tumor necrosis factor alpha (TNF-alpha) gene, and the D allele of the angiotensin converting enzyme (ACE) gene, have been associated with asthma. We hypothesized that genotypes containing these alleles would show an increased prevalence in asthmatic as compared with nonasthmatic individuals, and would be associated with asthma severity. Polymerase chain reaction-based assays were developed to determine TNF-alpha and ACE genotypes among subjects with mild/moderate asthma (n = 92), fatal/near-fatal asthma (n = 159), no asthma (n = 43), and random population controls (n = 252). The TNF-alpha -308 polymorphism was increased in both subjects with mild/moderate (p = 0.03) and those with fatal/near fatal asthma (p = 0.02) versus those without asthma, and in all subjects with asthma versus random population controls (p = 0.02). The mild/moderate group was subdivided into subjects with mild (n = 43) and those with moderate (n = 33) asthma. TNF-alpha -308 was increased in the moderately asthmatic versus the nonasthmatic subjects (p = 0.003), and in the mildly asthmatic subjects (p = 0.01). However, TNF-alpha -308 was not significantly more prevalent in the fatal/near-fatal than in the mild/moderate asthmatic group. The ACE-D allele did not show an association with either asthma or asthma severity. We conclude that the TNF-alpha -308 polymorphism may be a risk factor for asthma but does not increase the risk of a fatal or a near-fatal asthma attack, whereas the ACE polymorphism is not associated with asthma in this population.

Excess beta2-agonist use in asthmatics has been associated with increased mortality and morbidity. The mechanisms responsible for these observations are unknown. We hypothesized that polymorphisms of the beta2-adrenergic receptor (beta2AR) at amino acid positions 16, 27, and 164, which are known to alter receptor functions in vitro, may predispose asthmatics to fatal/near-fatal asthma and/or modify asthma severity. In preliminary studies we found significant differences in allele frequencies due to ethnic background: Caucasian, Black, Asian Gly16 = 0.61, 0.50, 0.40 and Gln27 = 0.57, 0. 73, 0.80, respectively. beta2AR genotyping was performed on DNA from Caucasians classified as nonasthmatic/nonatopic (n = 84), fatal/near-fatal asthmatics (n = 81) and mild/moderate asthmatics (n = 86). No polymorphism or haplotype was found to be associated with fatal/near-fatal asthma. However, the Gly16/Gln27 haplotype, which undergoes enhanced downregulation in vitro, was substantially more prevalent in moderate asthmatics than in mild asthmatics (p = 0.003, odds ratio = 3.1). We conclude that the beta2AR genotype is not a major determinant of fatal or near-fatal asthma. Furthermore, allele frequency variation among ethnic groups must be considered in clinical studies of beta2AR polymorphisms in asthma.

We prospectively recruited patients admitted to the hospital with severe asthma to comprehensively evaluate the association of historical and physiologic features with the risk of near-fatal asthma (NFA). A case-control study design was used. All patients admitted with NFA (cases) were identified prospectively and compared with asthma patients admitted during the same period without respiratory failure (controls). Nineteen cases (age: 40.2 +/- 12.0 yr) (mean +/- SD) and 80 controls (age: 36 +/- 13.5 yr) were enrolled. Duration of asthma, gender, smoking status, ethnicity, and prevalence of atopy were similar in the case and control groups. More than 80% of patients in both groups reported worsening symptoms for more than 48 h before admission, and more than 50% were worse for longer than 7 d. There was no difference in degree of airways obstruction or bronchial hyperresponsiveness (PC20). Perception of dyspnea was similar in the cases and controls, but among cases the males had greater impairment than the females (Borg score: 1.9 +/- 1. 4 versus 3.9 +/- 1.2: p = 0.05). Univariate analysis identified a history of previous mechanical ventilation (OR: 27.5; 95% CI: 6.60 to 113.7), admission to the intensive care unit (ICU) (OR: 9.9; 95% CI: 3.0 to 32.9), history of worse asthma during January and February (OR: 3.5; 95% CI: 1.0 to 11.8), and use of air-conditioning (OR: 15.0; 95% CI: 1.3 to 166) as risk factors for NFA. Of concern was the dependence of most patients (59.8%) on the emergency department (ED) for initial care, and the small number of cases (16%) in which patients visited a physician before admission to the hospital. We have confirmed risk factors identified previously in retrospective studies of fatal and NFA, and have also shown that hospitalized patients with asthma, irrespective of severity of their asthma, share several characteristics, especially in terms of their failure to respond to worsening asthma.

Great emphasis is placed on educating asthmatics to use action plans to achieve better control of symptoms. The use of peak flow meters (PFM) has been recommended as an important part of self-management plans. We studied 92 (47 F) adult patients with asthma in a primary care setting to compare the effectiveness of action plans using either peak flow monitoring or symptoms to guide self-management. Each patient was instructed in the use of the action plan in the context of a 6-mo asthma education program taught by a nurse. Patients were already using inhaled corticosteroids or were newly prescribed corticosteroids by their family physician. Forty-four patients were randomized to the PFM group and 48 to the symptoms group. Spirometry, symptom scores, quality of life, medication use, and measures of health care utilization and morbidity (emergency department visits, hospitalizations, unscheduled doctor visits, and days lost from work or school) were recorded at baseline and throughout the study period. PC20 methacholine was measured at the first and at the final visits. There were significant improvements within groups for FEV1, symptoms score, PC20 methacholine, and quality of life, but no between-group differences. A significant shift from higher to lower daily use of beta-agonists (p < 0.008 for both groups) and significant shifts to higher daily doses of inhaled steroids (p < 0.001) occurred in each group. Adherence to the self-management plans was only 65% in the PFM group and 52% in the symptoms group. Outcomes for health care utilization were similar except for fewer patients making unscheduled doctor visits within the PFM group. Our findings show that education, regular follow-up, and an action plan are effective in improving asthma control and quality of life, but the routine use of PFM to guide interventions is not the only way to accomplish these objectives.