Impact of type 2 targeting biologics on acute exacerbations of chronic rhinosinusitis.

Background: Acute exacerbations of chronic rhinosinusitis (AECRS) are associated with significant morbidity and decreased quality of life. There are sparse data assessing the real-world impact of biologics on AECRS. Objectives: We sought to determine the impact of type 2-targeting biologics on the frequency of medication use for AECRS episodes. Methods: Antibiotic and/or systemic corticosteroid courses for AECRS were identified in a retrospective study from November 2015 to February 2020, at a single academic health system. The estimated yearly rates for antibiotic and corticosteroid courses were evaluated before and after initiation of type 2 biologics. Results: One-hundred and sixty-five patients with chronic rhinosinusitis (CRS) had received either omalizumab (n = 12), mepolizumab (n = 42), benralizumab (n = 44), dupilumab (n = 61), or reslizumab (n = 6). Seventy percent had CRS with nasal polyps, and 30% had CRS without nasal polyps. All the patients had asthma. When all the biologics were combined, the estimated yearly rate for antibiotics for AECRS decreased from 1.34 (95% confidence interval [CI], 1.12-1.59) to 0.68 (95% CI, 0.52-0.88) with biologic use (49% reduction, p < 0.001). Those with frequent AECRS (three or more courses of antibiotics in the 1 year before biologic use) had a larger degree of reduction, with an estimated yearly rate of 4.15 (95% CI, 3.79-4.55) to 1.58 (95% CI, 1.06-2.35) with biologic use (n = 27; 62% reduction; p < 0.001). Within the total cohort, the estimated yearly rate for systemic corticosteroids for AECRS decreased from 1.69 (95% CI, 1.42-2.02) to 0.68 (95% CI, 0.53-0.88) with biologic use (60% reduction; p < 0.001). Conclusion: Type 2-targeting biologics reduced medication use for AECRS. This suggested that biologics may be a therapeutic option for patients with frequent AECRS.

Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and progressive airflow obstruction. Tobacco smoking is the leading cause but not the only one. A postbronchodilator FEV1-FVC ratio less than 0.70 is required for a diagnosis of COPD. Inhaler therapy is the backbone of treatment and should be complemented by a multifaceted management strategy that includes counseling and pharmacotherapy for smoking cessation, pulmonary rehabilitation, treatment of comorbidities, administration of influenza and pneumococcal immunizations, and prescription of long-term oxygen therapy in hypoxemic patients.

Distinct associations of sputum and oral microbiota with atopic, immunologic, and clinical features in mild asthma.

BACKGROUND: Whether microbiome characteristics of induced sputum or oral samples demonstrate unique relationships to features of atopy or mild asthma in adults is unknown. OBJECTIVE: We sought to determine sputum and oral microbiota relationships to clinical or immunologic features in mild atopic asthma and the impact on the microbiota of inhaled corticosteroid (ICS) treatment administered to ICS-naive subjects with asthma. METHODS: Bacterial microbiota profiles were analyzed in induced sputum and oral wash samples from 32 subjects with mild atopic asthma before and after inhaled fluticasone treatment, 18 atopic subjects without asthma, and 16 nonatopic healthy subjects in a multicenter study (NCT01537133). Associations with clinical and immunologic features were examined, including markers of atopy, type 2 inflammation, immune cell populations, and cytokines. RESULTS: Sputum bacterial burden inversely associated with bronchial expression of type 2 (T2)-related genes. Differences in specific sputum microbiota also associated with T2-low asthma phenotype, a subgroup of whom displayed elevations in lung inflammatory mediators and reduced sputum bacterial diversity. Differences in specific oral microbiota were more reflective of atopic status. After ICS treatment of patients with asthma, the compositional structure of sputum microbiota showed greater deviation from baseline in ICS nonresponders than in ICS responders. CONCLUSIONS: Novel associations of sputum and oral microbiota to immunologic features were observed in this cohort of subjects with or without ICS-naive mild asthma. These findings confirm and extend our previous report of reduced bronchial bacterial burden and compositional complexity in subjects with T2-high asthma, with additional identification of a T2-low subgroup with a distinct microbiota-immunologic relationship.

Features of the bronchial bacterial microbiome associated with atopy, asthma, and responsiveness to inhaled corticosteroid treatment.

BACKGROUND: Compositional differences in the bronchial bacterial microbiota have been associated with asthma, but it remains unclear whether the findings are attributable to asthma, to aeroallergen sensitization, or to inhaled corticosteroid treatment. OBJECTIVES: We sought to compare the bronchial bacterial microbiota in adults with steroid-naive atopic asthma, subjects with atopy but no asthma, and nonatopic healthy control subjects and to determine relationships of the bronchial microbiota to phenotypic features of asthma. METHODS: Bacterial communities in protected bronchial brushings from 42 atopic asthmatic subjects, 21 subjects with atopy but no asthma, and 21 healthy control subjects were profiled by using 16S rRNA gene sequencing. Bacterial composition and community-level functions inferred from sequence profiles were analyzed for between-group differences. Associations with clinical and inflammatory variables were examined, including markers of type 2-related inflammation and change in airway hyperresponsiveness after 6 weeks of fluticasone treatment. RESULTS: The bronchial microbiome differed significantly among the 3 groups. Asthmatic subjects were uniquely enriched in members of the Haemophilus, Neisseria, Fusobacterium, and Porphyromonas species and the Sphingomonodaceae family and depleted in members of the Mogibacteriaceae family and Lactobacillales order. Asthma-associated differences in predicted bacterial functions included involvement of amino acid and short-chain fatty acid metabolism pathways. Subjects with type 2-high asthma harbored significantly lower bronchial bacterial burden. Distinct changes in specific microbiota members were seen after fluticasone treatment. Steroid responsiveness was linked to differences in baseline compositional and functional features of the bacterial microbiome. CONCLUSION: Even in subjects with mild steroid-naive asthma, differences in the bronchial microbiome are associated with immunologic and clinical features of the disease. The specific differences identified suggest possible microbiome targets for future approaches to asthma treatment or prevention.

Caveolin modulates integrin function and mechanical activation in the cardiomyocyte.

ß1 integrins (ß1) transduce mechanical signals in many cells, including cardiac myocytes (CM). Given their close localization, as well as their role in mechanotransduction and signaling, we hypothesized that caveolin (Cav) proteins might regulate integrins in the CM. ß1 localization, complex formation, activation state, and signaling were analyzed using wild-type, Cav3 knockout, and Cav3 CM-specific transgenic heart and myocyte samples. Studies were performed under basal and mechanically loaded conditions. We found that: (1) ß1 and Cav3 colocalize in CM and coimmunoprecipitate from CM protein lysates; (2) ß1 is detected in a subset of caveolae; (3) loss of Cav3 caused reduction of ß1D integrin isoform and active ß1 integrin from the buoyant domains in the heart; (4) increased expression of myocyte Cav3 correlates with increased active ß1 integrin in adult CM; (5) in vivo pressure overload of the wild-type heart results in increased activated integrin in buoyant membrane domains along with increased association between active integrin and Cav3; and (6) Cav3-deficient myocytes have perturbed basal and stretch mediated signaling responses. Thus, Cav3 protein can modify integrin function and mechanotransduction in the CM and intact heart.

Integrins and integrin-associated proteins in the cardiac myocyte.

Integrins are heterodimeric, transmembrane receptors that are expressed in all cells, including those in the heart. They participate in multiple critical cellular processes including adhesion, extracellular matrix organization, signaling, survival, and proliferation. Particularly relevant for a contracting muscle cell, integrins are mechanotransducers, translating mechanical to biochemical information. Although it is likely that cardiovascular clinicians and scientists have the highest recognition of integrins in the cardiovascular system from drugs used to inhibit platelet aggregation, the focus of this article will be on the role of integrins specifically in the cardiac myocyte. After a general introduction to integrin biology, the article will discuss important work on integrin signaling, mechanotransduction, and lessons learned about integrin function from a range of model organisms. Then we will detail work on integrin-related proteins in the myocyte, how integrins may interact with ion channels and mediate viral uptake into cells, and also play a role in stem cell biology. Finally, we will discuss directions for future study.

Epidemiology of Chronic Obstructive Pulmonary Disease: Prevalence, Morbidity, Mortality, and Risk Factors.

Chronic obstructive pulmonary disease (COPD) remains a common and important cause of morbidity and mortality both in the United States and globally. The increasing trends of COPD prevalence, morbidity, and mortality seen in the later part of last century have not continued in the United States. COPD prevalence, hospitalizations, and deaths have remained stable or are decreasing over the last decade. This is likely a function of the overall decreasing prevalence of tobacco use over the past 50 years, along with improved therapies for COPD. Future trends in COPD will probably be driven by factors in addition to tobacco use, such as longer survival in the population, other occupational and environmental exposures, and the increasing prevalence of asthma. Globally, factors such as air pollution and chronic respiratory infections, such as tuberculosis, will remain important predictors of future trends.

Neighborhood Socioeconomic Deprivation in Young Adulthood and Future Respiratory Health: The CARDIA Lung Study.

PURPOSE: There are limited data on the relationship between neighborhood level factors and their association with lung health independent of individual socioeconomic status. We sought to determine whether baseline neighborhood level socioeconomic deprivation in young adults is associated with greater 20-year decline in lung function and higher risk of future lung disease, independent of baseline individual income, education, and smoking status. METHODS: This multicenter population-based cohort study included 2689 participants in Coronary Artery Risk Development in Young Adults (CARDIA) for whom neighborhood deprivation was determined at year 10 (baseline for study) and who had complete lung function measurements at years 10 and 30. Baseline neighborhood deprivation was defined using 1990 Census blocks as a combination of 4 factors involving median household income, poverty level, and educational achievement. The outcomes were decline in lung function over 20 years (year 10 to 30) and odds of emphysema (year 25). RESULTS: In multivariable regression models, greater baseline neighborhood deprivation was associated with greater decline in lung function (-2.34 mL/year excess annual decline in forced expiratory volume in 1 second (FEV1) in the highest versus lowest deprivation quartile (P = .014)). Furthermore, baseline neighborhood deprivation was independently associated with greater odds of emphysema (odds ratio [OR] 2.99, 95% confidence interval [CI] 1.42-6.30). CONCLUSIONS: Residence in neighborhoods with greater socioeconomic deprivation in young adulthood, independent of individual income and smoking, is associated with greater 20-year decline in forced expiratory volume in 1 second and higher risk of future emphysema.

Peak lung function during young adulthood and future long-term blood pressure variability: The Coronary Artery Risk Development in Young Adults (CARDIA) study.

BACKGROUND AND AIMS: Long-term blood pressure variability (BPV) is associated with cardiovascular events independent of mean blood pressure (BP); however, little is known about its predictors. METHODS: Using data from the CARDIA study, we investigated the association between peak lung-function and long-term BPV in 2917 individuals (mean age 24.8 years, 45.3% males, 58.6% whites) who were not taking antihypertensive medications. Lung-function was measured using forced vital capacity (FVC) and forced expiratory volume in 1-s (FEV1) at years 0, 2, 5, 10 and 20 and the maximum score attained was considered as peak lung-function. Variability independent of the mean (VIM) and coefficient of variation (CV) of BP were calculated to quantify BPV since achieving peak lung-function across 9 visits over 30 years. RESULTS: In a multivariate linear regression models, individuals in the 2nd (-0.64 mmHg; 95% CI: -1.06, -0.19), 3rd (-0.96; -1.47, -0.45), and 4th (-0.85: -1.53, -0.17) quartiles of FVC had lower VIM of systolic BP than the those in quartile 1 (p-trend = 0.005). CV of systolic BP was also lower by -0.58 (-0.98, -0.19), -0.92 (-1.42, -0.43), and -0.74 (-1.40, -0.08) percentage points, in the three progressively higher quartiles of FVC compared to quartile 1 (p-trend = 0.008). Similar findings were observed when the outcome was diastolic BPV. There was no association of FEV1 and FEV1-to-FVC ratio with BPV. CONCLUSIONS: These findings suggest that smaller lung volume or restrictive lung disease during young adulthood, which result in lower peak FVC, may independently increase the risk of higher long-term BPV during middle adulthood.

Bacterial biogeography of adult airways in atopic asthma.

BACKGROUND: Perturbations to the composition and function of bronchial bacterial communities appear to contribute to the pathophysiology of asthma. Unraveling the nature and mechanisms of these complex associations will require large longitudinal studies, for which bronchoscopy is poorly suited. Studies of samples obtained by sputum induction and nasopharyngeal brushing or lavage have also reported asthma-associated microbiota characteristics. It remains unknown, however, whether the microbiota detected in these less-invasive sample types reflect the composition of bronchial microbiota in asthma. RESULTS: Bacterial microbiota in paired protected bronchial brushings (BB; n = 45), induced sputum (IS; n = 45), oral wash (OW; n = 45), and nasal brushings (NB; n = 27) from adults with mild atopic asthma (AA), atopy without asthma (ANA), and healthy controls (HC) were profiled using 16S rRNA gene sequencing. Though microbiota composition varied with sample type (p < 0.001), compositional similarity was greatest for BB-IS, particularly in AAs and ANAs. The abundance of genera detected in BB correlated with those detected in IS and OW (r median [IQR] 0.869 [0.748-0.942] and 0.822 [0.687-0.909] respectively), but not with those in NB (r = 0.004 [- 0.003-0.011]). The number of taxa shared between IS-BB and NB-BB was greater in AAs than in HCs (p < 0.05) and included taxa previously associated with asthma. Of the genera abundant in NB, only Moraxella correlated positively with abundance in BB; specific members of this genus were shared between the two compartments only in AAs. Relative abundance of Moraxella in NB of AAs correlated negatively with that of Corynebacterium but positively with markers of eosinophilic inflammation in the blood and BAL fluid. The genus, Corynebacterium, trended to dominate all NB samples of HCs but only half of AAs (p = 0.07), in whom abundance of this genus was negatively associated with markers of eosinophilic inflammation. CONCLUSIONS: Induced sputum is superior to nasal brush or oral wash for assessing bronchial microbiota composition in asthmatic adults. Although compositionally similar to the bronchial microbiota, the microbiota in induced sputum are distinct, reflecting enrichment of oral bacteria. Specific bacterial genera are shared between the nasal and the bronchial mucosa which are associated with markers of systemic and bronchial inflammation.

Recent advances in the management of chronic obstructive pulmonary disease.

Novel pharmacotherapies introduce additional options to providers and patients in how to best treat chronic obstructive pulmonary disease (COPD). Emerging data question the role of inhaled corticosteroids in COPD treatment, particularly as combination dual bronchodilator pharmacotherapies demonstrate robust results. For those maximized on pharmacotherapy with continued dyspnea or exacerbations or both, emerging bronchoscopic procedures may offer additional therapy in select patients. This review focuses on data supporting the use of novel ultra bronchodilators, particularly in combination, and on the role for inhaled corticosteroid withdrawal and new bronchoscopic procedures.

Pulmonary artery to aorta ratio is associated with cardiac structure and functional changes in mild-to-moderate COPD.

BACKGROUND: The ratio of the diameter of the pulmonary artery (PA) to the diameter of the aorta (PA:A) on computed tomography (CT) imaging is associated with both COPD exacerbation and pulmonary hypertension. The mechanisms of PA enlargement in COPD are poorly understood. METHODS: In this retrospective, single center study we evaluated pulmonary function, CT scans, right heart catheterizations, and echocardiography in 88 subjects with mild-to-moderately severe COPD. A sensitivity analysis was performed in 43 subjects in whom CT scan and echocardiogram were performed within 50 days of each other. To evaluate the association between PA:A ratio and echocardiographic parameters and hemodynamics, we performed simple correlations and multivariable linear regression analysis adjusting for lung function, age, sex, race, and diastolic function. RESULTS: All subjects had preserved left ventricular (LV) systolic function (LV ejection fraction 62.7%±5.5%). Among them, 56.8% had evidence of diastolic dysfunction. There was no association between PA:A ratio and the presence of diastolic dysfunction. In a multivariable model, PA:A ratio was associated with right ventricular (RV) chamber size (ß=0.015; P<0.003), RV wall thickness (ß=0.56; P<0.002), and RV function (-0.49; P=0.05). In the subgroup of subjects with testing within 50 days, the association with RV chamber size persisted (ß=0.017; P=0.04), as did the lack of association with diastolic function. PA:A ratio was also associated with elevated PA systolic pressures (r=0.62; P=0.006) and pulmonary vascular resistance (r=0.46; P=0.05), but not pulmonary arterial wedge pressure (r=0.17; P=0.5) in a subset of patients undergoing right heart catheterization. CONCLUSION: In patients with mild-to-moderately severe COPD and preserved LV function, increased PA:A ratio occurs independent of LV diastolic dysfunction. Furthermore, the PA:A ratio is associated with right heart structure and function changes, as well as pulmonary hemodynamics. These findings indicate that PA:A ratio is a marker of intrinsic pulmonary vascular changes rather than impaired LV filling.

Outpatient palliative care for chronic obstructive pulmonary disease: a case series.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have well-documented symptoms that affect quality of life. Professional societies recommend palliative care for such patients, but the optimal way of delivering this care is unknown. OBJECTIVE: To describe an outpatient palliative medicine program for patients with COPD. DESIGN: Retrospective case series. SETTING/SUBJECTS: Thirty-six patients with COPD followed in a United States academic outpatient palliative medicine clinic. MEASUREMENTS: Descriptive analysis of sociodemographic data, disease severity and comorbidities, treatments, hospitalizations, mortality, topic discussion, and symptom assessment. RESULTS: Thirty-six patients (representing 5% of the total number of patients with COPD seen in a specialty pulmonary clinic) were seen over 11 months and followed for 2 years. Seventy-seven percent of patients were Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 3-4 and 72% were on oxygen at home. No patients had documented advanced directives at the initial visit but documentation increased to 61% for those who had follow-up appointments. The most commonly documented topics included symptoms (100%), social issues (94%), psychological issues (78%), and advance care planning (75%). Of symptoms assessed, pain was the least prevalent (51.6%), and breathlessness and fatigue were the most prevalent (100%). Symptoms were often undertreated prior to the palliative care appointment. During the 3-year study period, there were 120 hospital admissions (median, 2) and 12 deaths (33%). CONCLUSIONS: The patients with COPD seen in the outpatient palliative medicine clinic had many comorbid conditions, severe illness, and significant symptom burden. Many physical and psychological symptoms were untreated prior to the palliative medicine appointment. Whether addressing these symptoms through a palliative medicine intervention affects outcomes in COPD is unknown but represents an important topic for future research.

A qualitative study of unmet healthcare needs in chronic obstructive pulmonary disease. A potential role for specialist palliative care?

RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) have high symptom burdens and poor health-related quality of life. The American Thoracic Society issued a consensus statement outlining the need for palliative care for patients with chronic respiratory diseases. A better understanding of the unmet healthcare needs among patients with COPD may help determine which aspects of palliative care are most beneficial. OBJECTIVES: To identify the unmet healthcare needs of patients with COPD hospitalized for exacerbation using qualitative methods. METHODS: We conducted 20 semistructured interviews of patients admitted for acute exacerbations of COPD focused on patient understanding of diagnosis and prognosis, effect of COPD on daily life and social relationships, symptoms, healthcare needs, and preparation for the end of life. Transcribed interviews were evaluated using thematic analysis. MEASUREMENTS AND MAIN RESULTS: Six themes were identified. (1) Understanding of disease: Most participants correctly identified their diagnosis and recognized their symptoms worsening over time. Only half understood their disease severity and prognosis. (2) SYMPTOMS: Breathlessness was universal and severe. (3) Physical limitations: COPD prevented participation in activities. (4) Emotional distress: Depressive symptoms and/or anxiety were present in most participants. (5) Social isolation: Most participants identified social limitations and felt confined to their homes. (6) Concerns about the future: Half of participants expressed fear about their future. CONCLUSIONS: There are many unmet healthcare needs among patients hospitalized for COPD exacerbation. Relief of symptoms, physical limitations, emotional distress, social isolation, and concerns about the future may be better managed by integrating specialist palliative care into our current care model.

Integrins protect cardiomyocytes from ischemia/reperfusion injury.

Ischemic damage is recognized to cause cardiomyocyte (CM) death and myocardial dysfunction, but the role of cell-matrix interactions and integrins in this process has not been extensively studied. Expression of α7ß1D integrin, the dominant integrin in normal adult CMs, increases during ischemia/reperfusion (I/R), while deficiency of ß1 integrins increases ischemic damage. We hypothesized that the forced overexpression of integrins on the CM would offer protection from I/R injury. Tg mice with CM-specific overexpression of integrin α7ß1D exposed to I/R had a substantial reduction in infarct size compared with that of α5ß1D-overexpressing mice and WT littermate controls. Using isolated CMs, we found that α7ß1D preserved mitochondrial membrane potential during hypoxia/reoxygenation (H/R) injury via inhibition of mitochondrial Ca2+ overload but did not alter H/R effects on oxidative stress. Therefore, we assessed Ca2+ handling proteins in the CM and found that ß1D integrin colocalized with ryanodine receptor 2 (RyR2) in CM T-tubules, complexed with RyR2 in human and rat heart, and specifically bound to RyR2 amino acids 165-175. Integrins stabilized the RyR2 interdomain interaction, and this stabilization required integrin receptor binding to its ECM ligand. These data suggest that α7ß1D integrin modifies Ca2+ regulatory pathways and offers a means to protect the myocardium from ischemic injury.