Fixed Airway Obstruction Research Articles

Dupilumab improves lung function in patients with uncontrolled, moderate-to-severe asthma.

BackgroundDupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2 inflammation. In the phase 3 LIBERTY ASTHMA QUEST trial (NCT02414854) in patients with uncontrolled, moderate-to-severe asthma, add-on dupilumab 200 mg or 300 mg every 2 weeks reduced exacerbations and improved forced expiratory volume in 1 s (FEV1) and quality of life over 52 weeks. This analysis evaluates dupilimab's effect on lung function in the overall population, and subgroups with baseline elevated type 2 inflammatory biomarkers.MethodsPatients were randomised to 52 weeks of subcutaneous dupilumab 200 mg every 2 weeks, 300 mg every 2 weeks, or matched-volume placebos. Lung function outcomes were analysed in the overall population, in patients with ≥150 eosinophils·µL−1, ≥300 eosinophils·µL−1, ≥25 ppb fractional exhaled nitric oxide (FeNO), and both ≥150 eosinophils·µL−1 and ≥25 ppb FeNO, at baseline.ResultsDupilumab treatment (200 mg and 300 mg every 2 weeks) resulted in significant improvements versus placebo after 52 weeks in pre-bronchodilator FEV1 (0.20 and 0.13 L, respectively, versus placebo) and post-bronchodilator FEV1 (0.19 and 0.13 L, respectively), forced vital capacity (FVC) (0.20 and 0.14 L, respectively), forced expiratory flow (0.19 and 0.13 L·s−1, respectively) and pre-bronchodilator FEV1/FVC ratio (1.75% and 1.61%, respectively) in the overall population (p<0.001). Difference versus placebo in post-bronchodilator FEV1 slope of change (weeks 4–52) was significant (0.04 L·year−1; p<0.05). Greater improvements were achieved in patients with elevated baseline blood eosinophil and/or FeNO levels for most outcomes.ConclusionsDupilumab improves lung function outcomes, including large and small airway measurements and fixed airway obstruction, in patients with uncontrolled, moderate-to-severe asthma; particularly in patients with elevated biomarkers of type 2 inflammation.

Integrating Selective Targeted Monoclonal Antibody Therapies for Improved Outcomes in Uncontrolled Asthma

Asthma is one of the most common chronic diseases, with ≤25% of patients experiencing uncontrolled disease.1Patients with uncontrolled, moderate-to-severe asthma are at increased risk of recurrent exacerbations, accelerated decline in lung function, fixed airway obstruction, and have increased utilisation of health care resources.2,3Furthermore, reduced lung function, as assessed by measures such as forced expiratory volume in 1 second (FEV1), is a strong independent predictor of exacerbations, progressive decline in lung function, and all-cause pulmonary and cardiovascular mortality in patients with asthma.2 Achieving asthma control in these patients is therefore critical. The recognition of distinct inflammatory phenotypes within this population has been instrumental in addressing this need. In these patients, there is robust evidence of the pathogenic role of Th2 cytokines, such as IL-4 and IL-13, in the eosinophilic and allergic inflammatory processes.4This in turn has driven the development of targeted biological therapies, particularly selective targeted monoclonal antibodies such as dupilumab which inhibit the biological effects of both IL-4 and IL-13.5 This article reviews four posters displayed at the European Respiratory Society (ERS) International Congress 2019 that presented results demonstrating the efficacy and safety of dupilumab, an anti-IL-4 receptor human monoclonal antibody, compared to placebo for the treatment of uncontrolled, moderate-to-severe asthma, as measured by a range of outcomes.

Children with Asthma Have Fixed Airway Obstruction through Childhood Unaffected by Exacerbations

Children with asthma may have a disease course with or without exacerbations, but the relationship between exacerbations and lung function development is poorly understood. To compare lung function trajectories from birth till adolescence in asthmatic children with and without exacerbations. Children with asthma from the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) birth cohort had lung function and bronchial reactivity assessed repeatedly from 1 month to 13 years. Exacerbations were diagnosed at the COPSAC clinic defined as symptoms requiring hospitalization, oral or high-dose inhaled corticosteroid treatment. Mixed models were applied to analyze lung function trajectories. Children with asthma with exacerbations (N= 50) had a trajectory of increased, fixed airway obstruction compared with children without exacerbations (N= 47): z-score difference in airway resistance (sRawz) (95% confidence interval [CI]):+0.34 (+0.03;+0.66), P= .03, and maximal mid-expiratory flow (MMEFz):-0.41 (-0.69;-0.13), P= .004, but no differences in forced expiratory volume (FEVz):-0.14 (-0.41;+0.13), P= .29, or bronchial reactivity to methacholine (PDz):+0.08 (-0.26;+0.42), P= .65. This did not change comparing lung function trajectories before and after exacerbations: z-score difference (95% CI) sRawz:-0.04 (-0.35; 0.27), P= .80; MMEFz: 0.01 (-0.02; 0.04), P= .55; FEVz: 0.02 (-0.02; 0.05), P= .42; and PDz:-0.01 (-0.06; 0.05), P= .88. Children with asthma with exacerbations compared with children with asthma without exacerbations are characterized by increased airway obstruction since infancy through childhood. The airway obstruction is a fixed trajectory without progression due to exacerbations, suggesting that exacerbations are a consequence rather than a cause of diminished airway caliber in childhood.

IDIOPATHIC LARYNOTRACHEAL STENOSIS AND LOW ALPHA-ONE ANTITRYPSIN LEVELS

SESSION TITLE: Tuesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: Idiopathic laryngotracheal stenosis (ILS) is an inflammatory condition resulting in the narrowing of the airway. (1) To date, in the literature, there has been no clear association between ILS and low alpha-one antitrypsin (A1AT) levels. We report a case in which a patient had both abnormalities and we postulate mechanisms through which low A1AT levels could cause airway stenosis. CASE PRESENTATION: A 57-year-old lady with a past medical history of Parkinson's disease was sent for a second opinion for shortness of breath and wheezing. She had been erroneously diagnosed with A1AT deficiency and was started on augmentation therapy. Physical examination demonstrated a hoarse voice and diffuse expiratory wheeze, but no stridor, emanating from the upper airway. Her A1AT level was 79 mg/dl (normal 80-220 mg/dl) and her A1AT phenotype was PI*MZ. Pulmonary function testing showed the following: FVC: 87%, FEV1: 82%, FEV1/FVC: 93% and DLCO: 91%. The flow-volume loop suggested a fixed airway obstruction. Chest and neck tomography showed a scant amount of secretions involving the superior aspect of the trachea inferior to the vocal cord. She underwent bronchoscopy, which revealed tracheal narrowing to 5mm in diameter approximately 3 cm below the vocal cords. There was a thick fibrous band on the left side and a few smaller webs tethering the trachea. There was also a tracheal diverticulum present on the left side of the thick fibrous band. The rest of the tracheobronchial tree was normal. Initially, endobronchial scissors and a YAG laser were used to cut the webs and the trachea partially unfolded. The trachea was then dilated from 10 to 15 mm in diameter. Complete tracheal patency was achieved. DISCUSSION: ILS is rare and is most commonly seen in post-menopausal women. Proposed mechanisms are related to estrogen, disruption of blood supply, gastroesophageal reflux, and unremitting cough. (2) Secondary causes of laryngotracheal stenosis include prolonged endotracheal intubation and autoimmune diseases such as granulomatosis with polyangiitis and sarcoidosis. (1) There is no clear evidence showing an association between low A1AT levels and ILS. A1AT is a potent inhibitor of proteases and is crucial in conserving the integrity of connective tissue. In patients with low A1AT levels, these proteolytic enzymes can lead to fibrosis and scarring. Though most commonly associated with emphysema, low levels of A1AT have also been associated with arterial fibromuscular dysplasia with evidence of altered extracellular matrix and connective tissue abnormalities. (3) Although causation is impossible to establish in this case, we speculate that low A1AT levels may have led to connective tissue dysregulation and stenotic lesions of the trachea. CONCLUSIONS: This case is the first report of ILS occurring in the setting of low levels of A1AT. We speculate that there may be a pathobiologic link between the two entities. Reference #1: Gelbard A, Francis DO, Sandulache VC, Simmons JC, Donovan DT, Ongkasuwan J. Causes and consequences of adult laryngotracheal stenosis.Laryngoscope.2015 May;125(5):1137-43. https://doi.org/10.1002/lary.24956. Epub 2014 Oct 7. Reference #2: Damrose EJ. On the development of idiopathic subglottic stenosis. Med Hypotheses. 2008;71(1):122-5. https://doi.org/10.1016/j.mehy.2007.12.017. Epub 2008 Mar 4. Reference #3: Schievink WI, Björnsson J, Parisi JE, Prakash UB. Arterial fibromuscular dysplasia associated with severe alpha 1-antitrypsin deficiency. Mayo Clin Proc. 1994 Nov;69(11):1040-3. DISCLOSURES: No relevant relationships by Hamzah Alfahel, source=Web Response No relevant relationships by Anthony Cucci, source=Web Response No relevant relationships by Ahmad JABRI, source=Web Response No relevant relationships by Sanjiv Tewari, source=Web Response No relevant relationships by Elizabeth Verghese, source=Web Response

Recurrent Idiopathic Subglottic Stenosis in Multiple Pregnancies: A Case Report

Introduction: Idiopathic subglottic stenosis (ISS) is a type of central airway obstruction primarily affecting adult Caucasian females. Its rarity and similar clinical presentation to asthma contribute to its frequent misdiagnosis. Timely treatment of ISS is crucial for pregnant patients who are at risk for emergent surgeries necessitating ventilation and intubation.&#x0D; Case: A 29-year-old, previously healthy female reported new onset dyspnea on exertion and a dry, non-productive cough to her family physician. Clinical exam was unremarkable; however, pulmonary function testing revealed a moderate, fixed airway obstruction. Endoscopy visualized subglottic stenosis 1.7 cmdistal to her vocal cords and surgical intervention using CO2 laser dilatation was scheduled with Otolaryngology. However, the patient received a positive pregnancy test prior to her elective surgery dateand after consideration of risks and benefits to mother and fetus, the surgery was postponed to her second trimester. Unfortunately, the patient miscarried her fetus and was scheduled for an emergent dilatation and curettage (D&amp;C). She was successfully bag-mask ventilated during the D&amp;C and subsequently underwent surgery for ISS with full resolution of her symptoms. In subsequent follow-up, the patient reported a return of dyspnea coinciding with another positive pregnancy test. ISS recurrence was diagnosed; however, as symptoms were mild, a repeat surgery was postponed until the patient safely delivered her child.&#x0D; Discussion: This case illustrates the difficulties in the diagnosis and management of ISS in pregnant patients during their childbearing years as surgical intervention will impact both the mother and fetus.

Outpatient pulmonary rehabilitation for severe asthma with fixed airway obstruction: Comparison with COPD

Background: The benefit of exercise has been demonstrated in asthma, but the role of pulmonary rehabilitation (PR) in people with severe asthma, especially with airway obstruction, has been less investigated. The activity limitation mechanisms differ in asthma and COPD, so the effect of a PR program not specific to asthma is unclear. Methods: We retrospectively compared the effect of an ambulatory PR program in nonsmoking patients with severe asthma and airway obstruction (FEV1/FVC ratio <70% and FEV1 < 80% measured twice, not under an exacerbation) and sex-, age-, FEV1-, and BMI-matched COPD controls. Results: We included 29 patients, each with asthma and COPD. Airway obstruction was moderate (median FEV1 57% [44–64]). VO2 at peak was higher for asthma than COPD patients (19.0 [15.7–22.2] vs 16.1 [15.3–19.6] ml.min−1.kg−1, p = 0.05). After PR, asthma and COPD groups showed a significant and similar increase in constant work cycling test of 378 [114–831] s and 377 [246–702] s. Changes in Hospital Anxiety and Depression Scale (HAD) total score were similar (–2.5 [–7.0 to 0.0] vs –2.0 [–5.0 to 2.0], p > 0.05). Quality of life on the St. George’s Respiratory Questionnaire (SGRQ) was significantly improved in both groups (–14.0 [–17.7 to –2.0], p < 0.005 and –8.3 [–13.0 to –3.6], p < 0.0001). Conclusion: Outpatient PR is feasible and well tolerated in patients with severe asthma with fixed airway obstruction. A nondedicated program strongly improves HAD and SGRQ scores and constant work-rate sub-maximal cycling, with similar amplitude as with COPD.

Ruxolitinib and Steroid Refractory/Dependent Bronchiolitis Obliterans after Hematopoietic Cell Transplantation: A Steroid Sparing Agent That Also Resulted in Improved Lung Function in Children

Background: Bronchiolitis obliterans syndrome (BOS), chronic graft versus host (cGVHD) disease of the lungs after hematopoietic cell transplantation, is characterized by fixed airway obstruction, bronchiolar inflammation, and scarring and confers a dismal prognosis. While steroids are the backbone therapy for BOS, prolonged use is not recommended. There is no consensus therapy for patients who are steroid dependent or refractory (SR). Ruxolitinib, a JAK1/2 inhibitor, has potent anti-inflammatory effects by modifying T and dendritic cell signaling. It is FDA approved to treat acute GVHD, though there are also reports of its efficacy in cGVHD. We describe the experience of children with SR BOS treated with ruxolitinib.Methods: IRB approval was obtained for retrospective review of all patients treated with ruxolitinib for SR BOS after allogenic HCT. Patients were identified using departmental records. BOS was defined as SR if patients had worsening pulmonary function tests (PFTs) on therapy or required ≥0.5 mg/kg/day of steroids for greater than 30 days. 2014 NIH consensus conference criteria were used to define PFT diagnostic criteria for BOS and response to therapy. A partial response (PR) was an improvement in FEV1 of 10% and complete response (CR) an FEV1 of ≥80% predicted.Results: Five patients were treated with ruxolitinib for SR BO; 2 patients had no response to steroids and 3 were unable to wean (Figure 1). All patients received an unrelated bone marrow transplant (BMT) and the same aGVHD prophylaxis; methotrexate on days + 1, 3, 6, and 11, cyclosporine, and steroids. 3/6 patients were matched at 10/10 HLA-loci and 2 at 9/10. One patient (#5) received a second BMT for relapsed MDS, all other patients had one BMT. 2/5 patients had acute GVHD that was steroid responsive and resolved prior to BOS diagnosis.BOS developed a median of 285 days after stem cell infusion (range 131-547 days). 4/5 patients presented with dyspnea, and 1 (#4) developed a new oxygen requirement. He was developmentally delayed and could not report symptoms. Patient 4 developed extensive cGVHD 11 months after receiving a donor lymphocyte infusion for relapse of AML 3 months after HCT. Patients 2 and 5 had a concurrent pulmonary fungal infection at the time of diagnosis. Median FEV1% of predicted at diagnosis was 38% (range 23-64%). All patients were treated with corticosteroids and fluticasone, montelukast, azithromycin (FAM) after diagnosis of BOS. Ruxolitinib ranged from the third to fifth line therapy. 2/5 patients had a PR to ruxolitinib with an increase in predicted FEV1% of 10 and 24% (#2 and 3 respectively). One patient (#4) had an increase of FEV1 of 9% and was able to stop steroids. Patient 1 had stable PFTs and was able to wean steroids by 83%. Median time to response was 4 weeks.Patient 5 was treated for 4 months with ruxolitinib and was not able to have any pulmonary function tests (PFTS) during this period because of a pneumothorax. When this resolved, he had new nodules on chest CT, worsened PFTs and was found to have culture confirmed pulmonary Nocaria and Hypodontia palmae. Ruxolitinib was discontinued in the setting of a new infection. Without interim PFTs, his response was considered non-evaluable. He continues to have progressive BOS on corticosteroids and had a third relapse of his MDS. Other than this infection, the other 4/5 patients had no side effects from ruxolitinib. Doses ranged from 2.5 mg three times a week in a patient with end stage renal disease to 10 mg BID. 3/6 patients had extensive cGVHD with multiple organs involved; all other organ systems had a PR or CR to ruxolitinib. All patients are alive and 4/5 are disease free. Median follow up period after BOS diagnosis was 2 years (range 8-32 months).Conclusion: We describe 5 pediatric patients with SR BOS after hematopoietic cell transplantation. In the 4 patients with an evaluable response, 50% (2/4) had a PR to ruxolitinib and an additional patient had an improvement in predicted FEV1 of 9%. All were able to stop steroids or wean the dose by at least 50%. Responses occurred early, and the medication was well tolerated with minimal side effects. This is a small case series, but describes both improvement in pulmonary function testing and the ability to wean steroids after treatment with ruxolitinib in children with SR BOS - two measures notoriously difficult to obtain. Further prospective studies are needed to evaluate the role of ruxolitinib in children with cGVHD, particularly BOS. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical features of postinfectious bronchiolitis obliterans in children undergoing long-term nebulization treatment.

Limited data are available in relation to the clinical features of PIBO undergoing prolonged nebulization treatment with budesonide, terbutaline and ipratropium bromide. This retrospective study aimed to outline the features of clinical, high-resolution computed tomography (HRCT) and pulmonary function test (PFT) of PIBO, undergoing maintenance therapyutilizing a triple nebulization treatment and to determine the factors associated with prognosis. Children diagnosed with PIBO were followed up between April 2014 and March 2017. The clinical features after maintenance nebulization treatment for 12months were thereafter summarized. Thirty patients, 21 boys and 9 girls, were enrolled in the study. The median age of patients was 17.4months, with a range between 3.0 and 33months. Persistent coughing and wheezing were detected whilst wheezing and crackles were the common manifestations presented. HRCT scans revealed patchy ground and glass opacity, while PFT showed fixed airway obstruction in all patients. Four patients were lost during follow-up. After treatment, the clinical symptoms were improved greatly in all patients (P < 0.01). The mean increase in the percentage of TPEF%TE and VPEF%VE were improved greatly (P < 0.01). Images of the HRCT scan indicated marked improvements in 18 patients (81.8%) in comparison with scans obtained pre-treatment. Our data suggest a potential role of long-term nebulization treatment of budesonide, terbutaline, ipratropium bromide on PIBO, due to its efficacy as indicated in the improved clinical symptoms, pulmonary functions and CT manifestations identified in the children. New prospective and controlled studies are required to confirm this proposition.

Prevalence, morbidity, phenotypes and other characteristics of severe bronchial asthma in Russian Federation

The article provides a review on prevalence, phenotypes, endotypes, and the control of severe bronchial asthma. Severe asthma is a widespread, heterogeneous disease that affects 5 – 20% of patients with bronchial asthma. Prevalence of severe asthma in Russia significantly exceeds the official statistics data, therefore it is necessary to maintain a national register of patients with severe asthma. The conventional therapy for severe asthma is not always effective due to the uncontrolled course of the disease and eosinophilic airway inflammation. The identification of asthma phenotype/endotype is reasonable to develop a personalized approach to treatment. This approach allows achievement better control of the disease and minimization the risk of asthma exacerbations, fixed airway obstruction, and adverse effects of the pharmacological therapy. The main changes in the Global Strategy for Asthma Management and Prevention (GINA, 2018) concerning severe asthma therapy are highlighted in this article. It is also emphasized that the use of monoclonal IL-5 and IgE-antibodies could contribute to successful treatment of patients with uncontrolled severe asthma. Currently, two immunobiological drugs have been registered in Russia, omalizumab (anti-IgE antibody) and reslizumab (anti-IL-5 antibody).

Gut microbiota components are associated with fixed airway obstruction in asthmatic patients living in the tropics

Microbiome composition has been associated to several inflammatory diseases, including asthma. There are few studies exploring the relationships of gut microbiota with airway obstruction pheonotypes in adult asthma, especially those living in the tropics. We sought to evaluate the relationships of gut microbiota with the airway obstruction and other variables of interest in asthmatic patients living in the tropics according to three phenotypes: No Airway Obstruction (NAO), Reversible Airway Obstruction (RAO) or Fixed Airway Obstruction (FAO). We found that Streptococcaceae:Streptococcus and Enterobacteriaceae:Escherichia-Shigella consistently discriminated asthmatic individuals suffering FAO from NAO or RAO, plus Veillonellaceae:Megasphaera when comparing FAO and RAO (p < 0.05; FDR < 0.05). In the FAO, the network showing the genus relations was less complex and interconnected. Several Rumminococcaceae, Lachnospiraceae and Clostridiales were enriched in patients with low specific IgE levels to mites and Ascaris. All patients shared a common exposure framework; control medication usage and smoking habit were uncommon and equally distributed between them. In conclusion, in this tropical asthmatic population, components of human gut microbiota are associated with the presence of a FAO phenotype and lower specific IgE response to mites and Ascaris.

Endoscopic Airway Findings in Infants with Obstructive Sleep Apnea

Objectives: This study describes the un-sedated endoscopic airway findings in infants with obstructive sleep apnea confirmed by polysomnography (PSG). Methods: A retrospective chart review was performed on infants who had undergone both a documented airway endoscopy and PSG from 2006 to 2015 at our center. Demographics, comorbidities, findings of airway endoscopy and findings on PSG were extracted from the electronic medical record. Regression analyses were performed to determine the relationship between AHI, endoscopic airway findings and gestational age. Results: We identified 39 patients with PSG in room air and confirmed obstructive sleep apnea (Apnea Hypopnea Index (AHI) >1/hour) who had undergone unsedated airway endoscopy. The median gestational age at time of PSG was 40 weeks and for endoscopy was 40 weeks. Median AHI on PSG was 17.2/hour. Laryngomalacia [87.2%], pharyngomalacia [33.3%] and tracheomalacia [10.3%] were the three most prevalent findings on endoscopy. Surgically correctable fixed airway obstruction was uncommon. Prevalence of pharyngomalacia decreased with increased gestational maturity (p=0.05). As the postmenstrual age at PSG completion increased, there was a trend towards a decline of the AHI (p=0.087). Twenty-two (56.4%) patients had a follow up PSG performed. Using paired t test, there was a significant decrease in AHI (Δ13.41: -40.9, 15.8, 15.8) from 23.4/hour (1.3-62) to 10.0/hour (0-32), despite no interim surgical intervention. Conclusions: Dynamic airway collapse, including laryngomalacia and pharyngomalacia, were the most common findings in obstructive sleep apnea during infancy. The decreased prevalence of pharyngomalcia and trend towards improvement of AHI with time suggests airway immaturity contributes to obstructive sleep apnea observed during infancy and improves with age.

Lung Function Trajectory Types in Never-Smoking Adults With Asthma: Clinical Features and Inflammatory Patterns.

PurposeAsthma is a heterogeneous disease that responds to medications to varying degrees. Cluster analyses have identified several phenotypes and variables related to fixed airway obstruction; however, few longitudinal studies of lung function have been performed on adult asthmatics. We investigated clinical, demographic, and inflammatory factors related to persistent airflow limitation based on lung function trajectories over 1 year.MethodsSerial post-bronchodilator forced expiratory volume (FEV) 1% values were obtained from 1,679 asthmatics who were followed up every 3 months for 1 year. First, a hierarchical cluster analysis was performed using Ward's method to generate a dendrogram for the optimum number of clusters using the complete post-FEV1 sets from 448 subjects. Then, a trajectory cluster analysis of serial post-FEV1 sets was performed using the k-means clustering for the longitudinal data trajectory method. Next, trajectory clustering for the serial post-FEV1 sets of a total of 1,679 asthmatics was performed after imputation of missing post-FEV1 values using regression methods.ResultsTrajectories 1 and 2 were associated with normal lung function during the study period, and trajectory 3 was associated with a reversal to normal of the moderately decreased baseline FEV1 within 3 months. Trajectories 4 and 5 were associated with severe asthma with a marked reduction in baseline FEV1. However, the FEV1 associated with trajectory 4 was increased at 3 months, whereas the FEV1 associated with trajectory 5 was persistently disturbed over 1 year. Compared with trajectory 4, trajectory 5 was associated with older asthmatics with less atopy, a lower immunoglobulin E (IgE) level, sputum neutrophilia and higher dosages of oral steroids. In contrast, trajectory 4 was associated with higher sputum and blood eosinophil counts and more frequent exacerbations.ConclusionsTrajectory clustering analysis of FEV1 identified 5 distinct types, representing well-preserved to severely decreased FEV1. Persistent airflow obstruction may be related to non-atopy, a low IgE level, and older age accompanied by neutrophilic inflammation and low baseline FEV1 levels.

Rare adult presentation of fixed airways obstruction: remember aortic arch abnormalities

A 47-year-old woman with a history of chronic cough presented with dyspnoea. She had no history of smoking, tuberculosis and cardiovascular disease. Physical examination revealed wheezing in both lungs. We...

Distinct Asthma Phenotypes Among Older Adults with Asthma

Older adults have high rates of asthma morbidity and mortality. Asthma is now recognized as a heterogeneous disease, yet the distinct phenotypes among older adults are unknown. The objective of this study was to identify asthma phenotypes in a diverse population of elderly patients with asthma. Using cluster analysis, 180 older adults with persistent asthma were analyzed. Subjects completed detailed questionnaires, skin prick testing, and spirometry with reversibility. Twenty-four core variables were analyzed. Four groups were identified. Subjects in cluster 1 (n= 69) typically had asthma diagnosed after the age of 40 and the shortest duration of asthma. Cluster 2 (n= 40) had the mildest asthma defined by spirometry, Asthma Control test (ACT), and Asthma Quality of Life Questionnaire (AQLQ). They also had the lowest body mass index (BMI), lowest depression score, and least number of comorbidities. Cluster 3 (n= 46) had the longest duration of asthma (56 years) and the highest atopic skin test sensitization (74%). Cluster 4 (n= 25) had the most severe asthma, with extremely low FEV1% predicted (37.8%), lowest ACT, and lowest AQLQ scores. They were more likely to be black and had the highest comorbidities. Using BMI, posttreatment FEV1% predicted, and duration of asthma, 95.6% of subjects were able to be correctly classified. In older adults with asthma, distinct phenotypes vary on key features that are more pronounced among the elderly, including comorbidities, fixed airway obstruction, and duration of asthma ≥40 years. Further work is required to determine the clinical and therapeutic implications for different asthma phenotypes in older adults.

Early detection, clinical diagnosis, and management of lung disease from exposure to diacetyl.

Inhalation of diacetyl-containing products is associated with risk for occupational bronchiolitis obliterans (BO) and fixed airways obstruction, particularly in workers exposed to heated liquids and powdered formulations. This review describes the occupational settings in which diacetyl-related lung disease has been reported and the clinical presentation of disease, along with an approach to diagnosis and management. The importance of early disease recognition, appropriate removal from exposure, and medical monitoring to optimize prognosis is reviewed. The roles of public health follow-up and medical surveillance for primary and secondary prevention are discussed.

Peripheral killer cells do not differentiate between asthma patients with or without fixed airway obstruction

ABSTRACTObjective: The three main types of killer cells – CD8+ T cells, NK cells and NKT cells – have been linked to asthma and chronic obstructive pulmonary disease (COPD). However, their role in a small subset of asthma patients displaying fixed airway obstruction (FAO), similar to that seen in COPD, has not been explored. The objective of the present study was to investigate killer cell numbers, phenotype and function in peripheral blood from asthma patients with FAO, asthma patients without FAO, and healthy individuals. Methods: Peripheral CD8+ T cells (CD8+CD3+CD56−), NK cells (CD56+CD3−) and NKT-like cells (CD56+CD3+) of 14 asthma patients with FAO (post-bronchodilator FEV/FVC <0.7, despite clinician-optimised treatment), 7 asthma patients without FAO (post-bronchodilator FEV/FVC ≥ 0.7), and 9 healthy individuals were studied. Results: No significant differences were seen between the number, receptor expression, MAPK signalling molecule expression, cytotoxic mediator expression, and functional cytotoxicity of peripheral killer cells from asthma patients with FAO, asthma patients without FAO and healthy individuals. Conclusions: Peripheral killer cell numbers or functions do not differentiate between asthma patients with or without fixed airway obstruction.

Do we really need asthma–chronic obstructive pulmonary disease overlap syndrome?

The association of asthma and chronic obstructive pulmonary disease (COPD) in the same patient, which is designated as mixed asthma-COPD phenotype or overlap syndrome (ACOS), remains a controversial issue. This is primarily because many conflicting aspects in the definition of ACOS remain, and it is extremely difficult to summarize the distinctive features of this syndrome. Furthermore, we are realizing that asthma, COPD, and ACOS are not single diseases but rather syndromes consisting of several endotypes and phenotypes and, consequently, comprising a spectrum of diseases. The umbrella term ACOS blurs the lines between asthma and COPD and allows an approach that simplifies therapy. However, this approach contradicts the modern concept according to which we must move toward more targeted and personalized therapies to treat patients with these diseases. Therefore we argue that the term ACOS must be abandoned and ultimately replaced when new phenotypes and underlying endotypes are identified and a new taxonomy of airway diseases is generated.

The Role of Regulator of G-Protein-Signaling 4 (RGS4) in Control of Airway Hyper-responsiveness in Asthma

Abstract Asthma is a common respiratory disease characterized by airway hyper-responsiveness (AHR), inflammation, and airway obstruction. In most patients, this disease can be managed with steroids and bronchodilators. However, these treatments are not effective for the 15%-25% of patients with severe asthma who may develop fixed airway obstruction due to increased airway smooth muscle (ASM) mass. ASM cells control airway patency through G-protein coupled receptors (GPCRs). Namely, GPCRs can activate the IP3 pathway to induce calcium release and airway contraction. Regulators of G-protein signaling (RGS) are a family of proteins that are known to negatively regulate the activity of GPCRs. In ASM cells, RGS4 is relatively abundant compared to other RGS4 proteins. In people with asthma, increased RGS4 expression is observed in the group with greatest impairment in lung function. We hypothesize that aberrant RGS4 expression and/or function contributes to AHR through dysregulated GPCR signaling in ASM cells. We studied bacterial artificial chromosome (BAC) transgenic (Tg) mice, which overexpress both RGS4 and eGFP under the control of endogenous RGS4 promoter. In models of acute asthma, Tg mice exhibited reduced AHR as assessed by measurements of lung resistance in live, anesthetized mice and contraction of precision cut lung slices. These findings suggest that RGS4 is an important controller of bronchial tone in asthma through its effects on contraction signaling in ASM cells.

Exercise-Induced Changes in Exhaled NO Differentiates Asthma With or Without Fixed Airway Obstruction From COPD With Dynamic Hyperinflation.

Asthmatic patients with fixed airway obstruction (FAO) and patients with chronic obstructive pulmonary disease (COPD) share similarities in terms of irreversible pulmonary function impairment. Exhaled nitric oxide (eNO) has been documented as a marker of airway inflammation in asthma, but not in COPD.To examine whether the basal eNO level and the change after exercise may differentiate asthmatics with FAO from COPD, 27 normal subjects, 60 stable asthmatics, and 62 stable COPD patients were studied. Asthmatics with FAO (n = 29) were defined as showing a postbronchodilator FEV1/forced vital capacity (FVC) ≤70% and FEV1 less than 80% predicted after inhaled salbutamol (400 μg). COPD with dynamic hyperinflation (n = 31) was defined as a decrease in inspiratory capacity (ΔIC%) after a 6 minute walk test (6MWT).Basal levels of eNO were significantly higher in asthmatics and COPD patients compared to normal subjects. The changes in eNO after 6MWT were negatively correlated with the percent change in IC (r = −0.380, n = 29, P = 0.042) in asthmatics with FAO. Their levels of basal eNO correlated with the maximum mid-expiratory flow (MMEF % predicted) before and after 6MWT. In COPD patients with air-trapping, the percent change of eNO was positively correlated to ΔIC% (rs = 0.404, n = 31, P = 0.024).We conclude that asthma with FAO may represent residual inflammation in the airways, while dynamic hyperinflation in COPD may retain NO in the distal airspace. eNO changes after 6MWT may differentiate the subgroups of asthma or COPD patients and will help toward delivery of individualized therapy for airflow obstruction.

Biosignature for airway inflammation in a house dust mite-challenged murine model of allergic asthma.

ABSTRACTHouse dust mite (HDM) challenge is commonly used in murine models of allergic asthma for preclinical pathophysiological studies. However, few studies define objective readouts or biomarkers in this model. In this study we characterized immune responses and defined molecular markers that are specifically altered after HDM challenge. In this murine model, we used repeated HDM challenge for two weeks which induced hallmarks of allergic asthma seen in humans, including airway hyper-responsiveness (AHR) and elevated levels of circulating total and HDM-specific IgE and IgG1. Kinetic studies showed that at least 24 h after last HDM challenge results in significant AHR along with eosinophil infiltration in the lungs. Histologic assessment of lung revealed increased epithelial thickness and goblet cell hyperplasia, in the absence of airway wall collagen deposition, suggesting ongoing tissue repair concomitant with acute allergic lung inflammation. Thus, this model may be suitable to delineate airway inflammation processes that precede airway remodeling and development of fixed airway obstruction. We observed that a panel of cytokines e.g. IFN-γ, IL-1β, IL-4, IL-5, IL-6, KC, TNF-α, IL-13, IL-33, MDC and TARC were elevated in lung tissue and bronchoalveolar fluid, indicating local lung inflammation. However, levels of these cytokines remained unchanged in serum, reflecting lack of systemic inflammation in this model. Based on these findings, we further monitored the expression of 84 selected genes in lung tissues by quantitative real-time PCR array, and identified 31 mRNAs that were significantly up-regulated in lung tissue from HDM-challenged mice. These included genes associated with human asthma (e.g. clca3, ear11, il-13, il-13ra2, il-10, il-21, arg1 and chia1) and leukocyte recruitment in the lungs (e.g. ccl11, ccl12 and ccl24). This study describes a biosignature to enable broad and systematic interrogation of molecular mechanisms and intervention strategies for airway inflammation pertinent to allergic asthma that precedes and possibly potentiates airway remodeling and fibrosis.