ABSTRACT
BACKGROUND: Identifying early stages of hypersensitivity pneumonitis (HP) is hampered by variable presentation, heterogeneous or undetected causal antigens and lack of gold-standard biomarkers. Krebs von den Lungen (KL)-6 is pathophysiological biomarker of alveolar epithelial damage. Pigeon fanciers, susceptible to HP, provide a model to investigate early HP. OBJECTIVE: To test the hypothesis that plasma concentrations of KL-6 are increased in early-stage acute HP. METHODS: Clinical history, spirometry and blood samples were obtained from pigeon fanciers, 20 with intermittent acute symptoms indicative of developing HP, 27 with no symptoms and 10 healthy subjects with no avian exposure. Plasma KL-6 (units/mL) and pigeon antigen-specific IgG antibody were quantified by enzyme immunoassay. Blood lymphocytes were quantified by flow cytometry and antigen specificity by in vitro cytokine production. RESULTS: KL-6 was higher in fanciers than controls, median (IQR) 452 (244, 632) vs 274 (151, 377), P = .01. Although fanciers with symptoms had similar antigen exposure and lung function, they had higher KL-6 than those without, 632 (468, 1314) vs 320 (200, 480), P < .001. KL-6 correlated with IgG antibody titre in those with symptoms, r = .591, P = .006. High KL-6, irrespective of symptom category, was associated with higher antibody (P = .006) and lymphocyte proliferation (P = .041), and lower CD4+ T lymphocyte proportion (P = .032). CONCLUSION AND CLINICAL RELEVANCE: Raised KL-6 is associated with acute symptoms of early-stage HP, and its correlation with antibody may support therapeutic strategies when HP is suspected. KL-6 may act as a mechanistic biomarker of early pathogenesis by linking lung pathophysiological changes with an endotype of immune hypersensitivity.
Subject(s)
Bird Fancier's Lung/diagnosis , Columbidae/immunology , Mucin-1/blood , Adult , Animals , Biomarkers/blood , Bird Fancier's Lung/blood , Bird Fancier's Lung/immunology , Bird Fancier's Lung/physiopathology , CD4-Positive T-Lymphocytes/immunology , Case-Control Studies , Cell Proliferation , Cells, Cultured , Cross-Sectional Studies , Early Diagnosis , Humans , Immunoglobulin G/blood , Lung/immunology , Lung/physiopathology , Lymphocyte Activation , Middle Aged , Predictive Value of Tests , Up-RegulationABSTRACT
BACKGROUND: Statins have pleiotropic immunomodulatory effects that may be beneficial in the treatment of asthma. We previously reported that treatment with atorvastatin improved asthma symptoms in smokers with asthma in the absence of a change in the concentration of a selection of sputum inflammatory mediators. OBJECTIVE: To determine the effects of atorvastatin alone and in combination with inhaled corticosteroid on a range of sputum cytokines, chemokines and growth factors implicated in the pathogenesis of asthma, and their association with asthma control questionnaire (ACQ) and/or asthma quality of life questionnaire (AQLQ) scores. METHODS: Sputum samples were analysed from a sub-group of 39 smokers with mild to moderate asthma recruited to a randomised controlled trial comparing atorvastatin (40 mg/day) versus placebo for four weeks, followed by inhaled beclometasone (400 µg/day) for a further four weeks. Induced sputum supernatant fluid was analysed (Luminex or biochemical analyses) for concentrations of 35 mediators. RESULTS: Sputum mediator concentrations were not reduced by inhaled beclometasone alone. Atorvastatin significantly reduced sputum concentrations of CCL7, IL-12p70, sCD40L, FGF-2, CCL4, TGF-α and MMP-8 compared with placebo and, when combined with inhaled beclometasone, reduced sputum concentrations of MMP-8, IL-1ß, IL-10, MMP-9, sCD40L, FGF-2, IL-7, G-CSF and CCL7 compared to ICS alone. Improvements in ACQ and/or AQLQ scores with atorvastatin and ICS were associated with decreases in G-CSF, IL-7, CCL2 and CXCL8. CONCLUSION: Short-term treatment with atorvastatin alone or in combination with inhaled beclometasone reduces several sputum cytokines, chemokines and growth factors concentrations unresponsive to inhaled corticosteroids alone, in smokers with asthma.
Subject(s)
Anti-Asthmatic Agents/pharmacology , Asthma/drug therapy , Atorvastatin/pharmacology , Beclomethasone/pharmacology , Cytokines/immunology , Sputum/immunology , Administration, Inhalation , Adult , Anti-Asthmatic Agents/administration & dosage , Atorvastatin/administration & dosage , Beclomethasone/administration & dosage , Chemokines/immunology , Drug Therapy, Combination , Female , Forced Expiratory Volume , Humans , Inflammation Mediators/immunology , Male , Middle Aged , Quality of Life , Severity of Illness IndexABSTRACT
Microgels are colloidally stable, hydrogel microparticles that have previously been used in a range of (soft) material applications due to their tunable mechanical and chemical properties. Most commonly, thermo and pH-responsive poly(N-isopropylacrylamide) (pNIPAm) microgels can be fabricated by precipitation polymerization in the presence of the co-monomer acrylic acid (AAc). Traditionally pNIPAm microgels are synthesized in the presence of a crosslinking agent, such as N,N'-methylenebisacrylamide (BIS), however, microgels can also be synthesized under 'crosslinker free' conditions. The resulting particles have extremely low (<0.5%), core-localized crosslinking resulting from rare chain transfer reactions. AFM nanoindentation of these ultralow crosslinked (ULC) particles indicate that they are soft relative to crosslinked microgels, with a Young's modulus of â¼10 kPa. Furthermore, ULC microgels are highly deformable as indicated by a high degree of spreading on glass surfaces and the ability to translocate through nanopores significantly smaller than the hydrodynamic diameter of the particles. The size and charge of ULCs can be easily modulated by altering reaction conditions, such as temperature, monomer, surfactant and initiator concentrations, and through the addition of co-monomers. Microgels based on the widely utilized, biocompatible polymer polyethylene glycol (PEG) can also be synthesized under crosslinker free conditions. Due to their softness and deformability, ULC microgels are a unique base material for a wide variety of biomedical applications including biomaterials for drug delivery and regenerative medicine.
Subject(s)
Acrylic Resins/chemistry , Hydrogels/chemistry , Acrylamides , Acrylates/chemistry , Ammonium Sulfate/chemistry , Cross-Linking Reagents/chemistry , Isocyanates/chemistry , Polyethylene Glycols/chemistry , Rheology , Silanes/chemistry , Sodium Dodecyl Sulfate/chemistryABSTRACT
BACKGROUND: Airway endotoxin might contribute to corticosteroid insensitivity in asthmatic patients. OBJECTIVE: Because cigarette smoke contains endotoxin, we tested the hypothesis that sputum endotoxin concentrations are increased in cigarette smokers and that endotoxin concentrations are associated with corticosteroid insensitivity in asthmatic patients. METHODS: Sixty-nine asthmatic patients (never smokers, smokers, and exsmokers) and 20 healthy subjects (never smokers and smokers) were recruited. Fifty-three asthmatic patients received a 2-week course of oral dexamethasone. Serum and induced sputum endotoxin and cytokine concentrations were quantified by using an enzyme immunoassay. RESULTS: Median (interquartile range [IQR]) sputum endotoxin concentration were not significantly different between asthmatic never smokers (184 endotoxin units [EU]/mL; IQR, 91-310 EU/mL), exsmokers (123 EU/mL; IQR, 39-207 EU/mL), and smokers (177 EU/mL; IQR, 41-772 EU/mL; P = .703) and healthy subjects (164 EU/mL; IQR, 106-373 EU/mL). The lung function response to oral corticosteroids decreased with increasing sputum endotoxin concentrations in the never smokers (linear regression α = .05, Spearman r = -0.503, P = .009) but not in smokers (α = .587, r = -0.282, P = .257), as confirmed by using multiple regression analysis. Asthmatic smokers had higher concentrations of serum endotoxin than asthmatic nonsmokers (0.25 EU/mL [IQR, 0.09-0.39 EU/mL] vs 0.08 EU/mL [IQR, 0.05-0.19 EU/mL], P = .042) unrelated to steroid insensitivity or serum cytokine concentrations. In the asthmatic group sputum endotoxin concentrations correlated with sputum IL-1 receptor antagonist concentrations (r = 0.510, P < .001), and serum endotoxin concentrations significantly correlated with sputum IL-6, IL-8, and chemokine motif ligand 2 concentrations. CONCLUSION: Asthmatic smokers have similar sputum endotoxin concentrations compared with those of asthmatic never smokers. The association between higher sputum endotoxin levels and an impaired lung function response to oral corticosteroids, particularly in asthmatic never smokers, suggests that airway endotoxin might contribute to corticosteroid insensitivity in asthmatic patients.
Subject(s)
Adrenal Cortex Hormones/administration & dosage , Asthma , Cytokines/metabolism , Endotoxins/metabolism , Lung , Smoking/adverse effects , Sputum/metabolism , Administration, Oral , Adult , Asthma/drug therapy , Asthma/metabolism , Asthma/physiopathology , Female , Humans , Lung/metabolism , Lung/physiopathology , Male , Middle Aged , Respiratory Function TestsABSTRACT
Asthmatic smokers have poor symptom control and accelerated decline in lung function. A reduced ratio of matrix metalloproteinase (MMP)-9/tissue inhibitors of metalloproteinases (TIMPs) in nonsmokers with asthma has been implicated in airway remodelling. We tested the hypothesis that sputum MMP-9 activity/TIMPs ratios are reduced in smokers compared with never-smokers with asthma and are associated with reduced lung function and altered computed tomography (CT) measures of airway wall dimensions. Lung function, airway dimensions by CT, and induced sputum concentrations (and activity) of MMP-9 and TIMP-1 and -2 were measured in 81 asthmatics and 43 healthy subjects (smokers and never-smokers). Respiratory epithelial MMP9 and TIMP mRNA was quantified in 31 severe asthmatics and 32 healthy controls. Sputum MMP-9 activity/TIMP-1 and TIMP-2 ratios, and nasal epithelial MMP9/TIMP1 and MMP9/TIMP2 expression ratios were reduced in smokers with asthma compared with never-smokers with asthma. Low sputum ratios in asthmatic smokers were associated with reduced post-bronchodilator forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity ratio and segmental airway lumen area. The association of a low sputum MMP-9 activity/TIMP-1 ratio with persistent airflow obstruction and reduced CT airway lumen area in smokers with asthma may indicate that an imbalance of MMP-9 and TIMPs contributes to structural changes to the airways in this group.
Subject(s)
Asthma/physiopathology , Bronchi/pathology , Matrix Metalloproteinase 9/analysis , Smoking/adverse effects , Sputum/chemistry , Tissue Inhibitor of Metalloproteinase-1/analysis , Tissue Inhibitor of Metalloproteinase-2/analysis , Adult , Bronchography/methods , Female , Forced Expiratory Volume , Humans , Male , Middle Aged , Tomography, X-Ray ComputedABSTRACT
The tunable swelling and rolling of films assembled via layer-by-layer (LbL) methods from poly(N-isopropylacrylamide-co-acrylic acid) (pNIPAm-co-AAc) microgels and poly(ethylenimine) (PEI) have been systematically studied. Microgel/PEI films assembled at pH 7.4 display a high degree of in-plane swelling at low pH that dramatically increases the film area and drives self-delamination from the substrate to form a free-standing film. The degree of film swelling can be controlled by the size of microgels used in film fabrication. Taking advantage of this feature, self-rolled scrolls can be easily obtained from microgel/PEI films prepared from microgels of two different sizes. The rolling direction can be controlled by the assembly of different size microgels in different film strata, and the final shape of the scrolls can be controlled by scratching the desired film edges. The present work contributes to a deeper understanding of microgel/PEI film swelling properties and introduces a facile and novel method to prepare free-standing films and self-rolled scrolls.
ABSTRACT
Multilayer coatings made from hydrogel microparticles (microgels) are conceptually very simple materials: thin films composed of microgel building blocks held together by polyelectrolyte "glue". However, the apparent simplicity of their fabrication and structure belies extremely complex properties, including those of "dynamic" coatings that display rapid self-healing behavior in the presence of solvent. This contribution covers our work with these materials and highlights some of the key findings regarding damage mechanisms, healing processes, film structure/composition, and how the variation of fabrication parameters can impact self-healing behavior.
Subject(s)
Gels/chemistry , Polymers/chemistryABSTRACT
A material's mechanical properties greatly control cell behavior at the cellsubstrate interface. In this work, we demonstrate that microgel multilayers have unique elastic and viscoelastic-like properties that can be modulated to produce morphological changes in fibroblasts cultured on the film. Protein adsorption is also examined and the data are contrasted with the number of cells adhered. The dynamic interaction of cell and substrate is only partially explained by conventional understanding of surfacereceptor interactions and substrate elasticity. Viscoelasticity, a mechanical property not often considered, plays a significant role at cellular length and time scales for microgel films.
Subject(s)
Cell Adhesion , Mechanical Phenomena , Proteins/chemistry , Adsorption , Elasticity , Fibroblasts/chemistry , Fibroblasts/cytology , Humans , Microscopy, Atomic Force , Substrate SpecificityABSTRACT
BACKGROUND: Matrix metalloproteinase (MMP)-12 has been implicated in the pathogenesis of both chronic obstructive pulmonary disease (COPD) and asthma. The influence of disease severity on sputum MMP-12 concentrations and activity is not known. OBJECTIVES: We sought to examine the relationship between disease severity assessed by means of lung function and computed tomography (CT) and induced sputum MMP-12 concentrations and activity in patients with asthma and COPD. METHODS: In 208 subjects (109 asthmatic patients, smokers and never smokers, mild, moderate, and severe; 53 patients with COPD, smokers and exsmokers, mild, moderate, and severe; and 46 healthy control subjects, smokers and never smokers), we measured induced sputum MMP-12 concentrations (ELISA) and enzyme activity (fluorescence resonance energy transfer), sputum cell MMP12 mRNA expression (quantitative PCR [qPCR]), diffusing capacity for carbon monoxide (Dlco), and CT assessment of emphysema (percentage of low-attenuation areas at less -950 Hounsfield units). RESULTS: Sputum MMP-12 concentrations are greater in patients with COPD and smokers with asthma than in healthy nonsmokers (P = .003 and P = .035, respectively) but similar to those seen in healthy smokers. In patients with COPD, disease severity, when measured by means of CT-assessed emphysema, but not by means of spirometry or Dlco values, is directly associated with sputum MMP-12 concentrations and activity. In the asthma groups there is no significant association between disease severity and sputum MMP-12 concentrations or activity. CONCLUSIONS: Sputum MMP-12 concentrations and activity in patients with COPD are directly associated with the extent of emphysema measured by means of CT. This finding supports a role for MMP-12 in the pathogenesis of COPD and might suggest that blocking MMP-12 activity in patients with COPD could prevent the further development of emphysema.
Subject(s)
Asthma/immunology , Asthma/physiopathology , Matrix Metalloproteinase 12/metabolism , Pulmonary Disease, Chronic Obstructive/immunology , Pulmonary Disease, Chronic Obstructive/physiopathology , Sputum/enzymology , Adult , Aged , Asthma/complications , Asthma/diagnosis , Cross-Sectional Studies , Disease Progression , Emphysema/diagnosis , Emphysema/enzymology , Female , Fluorescence Resonance Energy Transfer , Follow-Up Studies , Humans , Male , Matrix Metalloproteinase 12/genetics , Matrix Metalloproteinase 12/immunology , Middle Aged , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/diagnosis , Respiratory Function Tests , Severity of Illness Index , Tomography, X-Ray ComputedABSTRACT
BACKGROUND: Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19. METHODS: In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012. FINDINGS: Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57-0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug. INTERPRETATION: Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19. FUNDING: Sponsored by the University of Dundee and supported through an Investigator Initiated Research award from Insmed, Bridgewater, NJ; STOP-COVID19 trial.
Subject(s)
COVID-19 Drug Treatment , Cathepsin C , Humans , Double-Blind Method , Serine Proteases , Treatment Outcome , Cathepsin C/antagonists & inhibitorsABSTRACT
Many patients with asthma have poorly controlled symptoms, and particularly for those with severe disease, there is a clear need for improved treatments. Two recent therapies licensed for use in asthma are omalizumab, a humanized monoclonal antibody that binds circulating IgE antibody, and bronchial thermoplasty, which involves the delivery of radio frequency energy to the airways to reduce airway smooth muscle mass. In addition, there are new therapies under development for asthma that have good potential to reach the clinic in the next five years. These include biological agents targeting pro-inflammatory cytokines such as interleukin-5 and interleukin-13, inhaled ultra long-acting ß2-agonists and once daily inhaled corticosteroids. In addition, drugs that block components of the arachidonic acid pathway that targets neutrophilic asthma and CRTH2 receptor antagonists that inhibit the proinflammatory actions of prostaglandin D2 may become available. We review the recent progress made in developing viable therapies for severe asthma and briefly discuss the idea that development of novel therapies for asthma is likely to increasingly involve the assessment of genotypic and/or phenotypic factors.
Subject(s)
Antibodies, Anti-Idiotypic/administration & dosage , Antibodies, Monoclonal/administration & dosage , Asthma/drug therapy , Asthma/therapy , Diathermy/methods , Immunologic Factors/administration & dosage , Adrenal Cortex Hormones/administration & dosage , Adrenergic beta-2 Receptor Agonists/administration & dosage , Anti-Inflammatory Agents/administration & dosage , Antibodies, Monoclonal, Humanized , Biomedical Research/trends , Cytokines/antagonists & inhibitors , Humans , Immunoglobulin E/immunology , OmalizumabABSTRACT
BACKGROUND: The immune modulating properties of statins may benefit smokers with asthma. We tested the hypothesis that short-term treatment with atorvastatin improves lung function or indices of asthma control in smokers with asthma. METHODS: Seventy one smokers with mild to moderate asthma were recruited to a randomized double-blind parallel group trial comparing treatment with atorvastatin (40 mg per day) versus placebo for 4 weeks. After 4 weeks treatment inhaled beclometasone (400 µg per day) was added to both treatment arms for a further 4 weeks. The primary outcome was morning peak expiratory flow after 4 weeks treatment. Secondary outcome measures included indices of asthma control and airway inflammation. RESULTS: At 4 weeks, there was no improvement in the atorvastatin group compared to the placebo group in morning peak expiratory flow [-10.67 L/min, 95% CI -38.70 to 17.37, p = 0.449], but there was an improvement with atorvastatin in asthma quality of life score [0.52, 95% CI 0.17 to 0.87 p = 0.005]. There was no significant improvement with atorvastatin and inhaled beclometasone compared to inhaled beclometasone alone in outcome measures at 8 weeks. CONCLUSIONS: Short-term treatment with atorvastatin does not alter lung function but may improve asthma quality of life in smokers with mild to moderate asthma. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00463827.
Subject(s)
Anti-Asthmatic Agents/administration & dosage , Asthma/drug therapy , Heptanoic Acids/administration & dosage , Pyrroles/administration & dosage , Smoking , Adult , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Asthma/physiopathology , Atorvastatin , Beclomethasone/therapeutic use , Double-Blind Method , Drug Administration Schedule , Drug Therapy, Combination , Female , Forced Expiratory Volume , Humans , Male , Peak Expiratory Flow Rate , Quality of Life , Surveys and Questionnaires , Treatment OutcomeABSTRACT
INTRODUCTION: The COVID-19 pandemic has led to over 100 million cases worldwide. The UK has had over 4 million cases, 400 000 hospital admissions and 100 000 deaths. Many patients with COVID-19 suffer long-term symptoms, predominantly breathlessness and fatigue whether hospitalised or not. Early data suggest potentially severe long-term consequence of COVID-19 is development of long COVID-19-related interstitial lung disease (LC-ILD). METHODS AND ANALYSIS: The UK Interstitial Lung Disease Consortium (UKILD) will undertake longitudinal observational studies of patients with suspected ILD following COVID-19. The primary objective is to determine ILD prevalence at 12 months following infection and whether clinically severe infection correlates with severity of ILD. Secondary objectives will determine the clinical, genetic, epigenetic and biochemical factors that determine the trajectory of recovery or progression of ILD. Data will be obtained through linkage to the Post-Hospitalisation COVID platform study and community studies. Additional substudies will conduct deep phenotyping. The Xenon MRI investigation of Alveolar dysfunction Substudy will conduct longitudinal xenon alveolar gas transfer and proton perfusion MRI. The POST COVID-19 interstitial lung DiseasE substudy will conduct clinically indicated bronchoalveolar lavage with matched whole blood sampling. Assessments include exploratory single cell RNA and lung microbiomics analysis, gene expression and epigenetic assessment. ETHICS AND DISSEMINATION: All contributing studies have been granted appropriate ethical approvals. Results from this study will be disseminated through peer-reviewed journals. CONCLUSION: This study will ensure the extent and consequences of LC-ILD are established and enable strategies to mitigate progression of LC-ILD.
Subject(s)
COVID-19/complications , Lung Diseases, Interstitial , Humans , Longitudinal Studies , Lung Diseases, Interstitial/epidemiology , Observational Studies as Topic , Pandemics , Prospective Studies , United Kingdom/epidemiology , Post-Acute COVID-19 SyndromeABSTRACT
Fractional exhaled nitric oxide (FeNO) is the only available point of care test to assess type-2 inflammation in asthma. In making a diagnosis of asthma, FeNO should be used together with blood eosinophils and spirometry, alongside a history. Raised FeNO in conjunction with blood eosinophilia are treatable traits of type 2 inflammation in asthma, which in turn may guide personalised management. A FeNO suppression test can be used to assess adherence and device use with ICS therapy. Furthermore FeNO may be used to provide feedback to patients in response to ICS, especially when spirometry is normal. FeNO may facilitate appropriate referral to secondary care for more definitive specialist investigations. In summary, FeNO is cost effective in the diagnosis and management of asthma and should be incorporated into primary and secondary care as part of routine clinical practice.
Subject(s)
Asthma/blood , Asthma/drug therapy , Inflammation/metabolism , Nitric Oxide/analysis , Adrenal Cortex Hormones/administration & dosage , Adrenal Cortex Hormones/therapeutic use , Adrenergic beta-Agonists/therapeutic use , Asthma/diagnosis , Asthma/physiopathology , Eosinophils , Exhalation/physiology , Humans , Inflammation/classification , Medication Adherence/psychology , Nebulizers and Vaporizers/standards , Nitric Oxide/economics , Primary Health Care/standards , Scotland/epidemiology , Spirometry/methodsSubject(s)
Asthma/complications , Asthma/drug therapy , Azithromycin/therapeutic use , Smoking , Tobacco Use Disorder/complications , Tobacco Use Disorder/drug therapy , Adolescent , Adult , Aged , Anti-Asthmatic Agents/therapeutic use , Double-Blind Method , Humans , Middle Aged , Surveys and Questionnaires , Treatment Outcome , Young AdultABSTRACT
Corticosteroids are the most effective treatment for asthma, but the therapeutic response varies considerably between individuals. Several clinical studies have found that smokers with asthma are insensitive to the beneficial effects of short- to medium-term inhaled corticosteroid treatment compared with non-smokers with asthma. It is estimated that 25% of adults in most industrialized countries smoke cigarettes, and similar surveys amongst asthmatic individuals suggest that the prevalence of smoking in this grouping mirrors that found in the general population. Therefore, cigarette smoking is probably the most common cause of corticosteroid insensitivity in asthma. Cigarette smoking and asthma are also associated with poor symptom control and an accelerated rate of decline in lung function. The mechanism of corticosteroid insensitivity in smokers with asthma is currently unexplained but could be due to alterations in airway inflammatory cell phenotypes, changes in glucocorticoid receptor alpha/beta ratio, and/or reduced histone deacetylase activity. Smoking cessation should be encouraged in all smokers with asthma. Short-term benefits include improvements in lung function and asthma control. However, the numbers of sustained quitters is disappointingly small. Additional or alternative drugs need to be identified to treat those individuals who are unable to stop smoking or who have persistent symptoms following smoking cessation.
Subject(s)
Adrenal Cortex Hormones , Asthma , Adrenal Cortex Hormones/therapeutic use , Asthma/drug therapy , Disease Management , Histone Deacetylase 2 , Humans , Smoking/epidemiology , Smoking CessationABSTRACT
BACKGROUND: Asthma in the elderly as well as asthma of adult-onset has been associated with increased morbidity, but little is known specifically about the effects of age on clinical and inflammatory outcomes in severe refractory asthma. The aims of the study were to examine the effects of age [<65 versus ≥65 years] and age of onset of asthma [childhood-onset, <18 versus adult-onset, ≥18 years] on clinical and inflammatory variables in patients with severe asthma. METHODS: In 1042 subjects with refractory asthma recruited to the British Thoracic Society Severe Asthma Registry, we compared patient demographics, disease characteristics and biomarkers of inflammation in patients aged <65 years (n = 896) versus ≥65 years (n = 146) and onset at age <18 years (n = 430) versus ≥18 years (n = 526). RESULTS: Severe asthma patients aged ≥65 years had improved symptom control, better asthma quality of life and in the last year, less emergency visits and rescue oral steroid courses [3 (1-6) versus 5 (2-7), p < 0.001] than severe asthmatics aged <65 years. Blood eosinophils were lower in the elderly group. Patients with severe adult-onset asthma had similar symptom control, lung function and health-care utilization compared to severe childhood-onset asthma. Adult-onset asthmatics had higher blood eosinophils and were less atopic. CONCLUSIONS: Patients with severe refractory asthma aged ≥65 years exhibit better clinical and health care outcomes and have lower blood eosinophils compared to those aged <65 years. Severe refractory adult-onset asthma is associated with similar levels of asthma control, higher blood eosinophils and less atopy than severe refractory childhood-onset asthma.
Subject(s)
Age of Onset , Aged/statistics & numerical data , Asthma/immunology , Hypersensitivity, Immediate/immunology , Inflammation/immunology , Adult , Asthma/drug therapy , Asthma/pathology , Asthma/physiopathology , Biomarkers , Eosinophils/immunology , Eosinophils/pathology , Female , Humans , Immunoglobulin E/blood , Inflammation/pathology , Male , Middle Aged , Nitric Oxide/metabolism , Outcome Assessment, Health Care , Quality of Life , Respiratory Function Tests/methods , Severity of Illness Index , United Kingdom/epidemiologyABSTRACT
PURPOSE OF REVIEW: Cigarette smoking and asthma are associated with poor symptom control and impaired therapeutic responses to corticosteroids. We summarize the clinical evidence for corticosteroid resistance, the mechanisms which could be responsible and potential management of this resistance. We also consider the effect smoking has on other drugs commonly used to treat patients with asthma. RECENT FINDINGS: In most developed countries the prevalence of active smoking in adults with asthma is about 25%. Compared with nonsmokers with asthma, active smokers have more severe asthma symptoms, accelerated decline in lung function and impaired short-term therapeutic responses to corticosteroids. The mechanism of corticosteroid resistance in smokers with asthma is currently unexplained but could be due to alterations in airway inflammatory cell phenotypes, changes in glucocorticoid receptor alpha to beta ratio, and reduced histone deacetylase activity. Cigarette smoking also increases the clearance of drugs such as theophylline by induction of metabolizing enzymes. Alternative or additional treatment to inhaled corticosteroids may be required for individuals with asthma who are unable to stop smoking or who have persistent symptoms following smoking cessation. SUMMARY: Smokers with chronic asthma have a reduced response to short-term corticosteroid therapy. Every effort should be made to encourage individuals with asthma who smoke to stop. Alternative or additional therapies to inhaled corticosteroids are needed for individuals with asthma who are unable to quit smoking.
Subject(s)
Adrenal Cortex Hormones/therapeutic use , Asthma/drug therapy , Smoking/adverse effects , Adolescent , Adult , Drug Resistance , Female , Humans , Male , Respiratory Function TestsABSTRACT
BACKGROUND: Elevated serum periostin is associated with airway eosinophilia and may predict response to therapies targeting Th2 inflammation. Smoking in asthma is generally associated with non-eosinophilic airway inflammation and corticosteroid insensitivity. We determined the effect of smoking status on serum periostin in asthma. METHODS: Serum periostin (ELISA; Aviscera Bioscience) was measured in 107 patients with stable asthma of different disease severity and 45 healthy controls. The effects on serum periostin of clinical indices including smoking status and of inflammatory biomarkers including sputum eosinophil count were analysed. Serum periostin was measured before and after two weeks of oral corticosteroids in a separate group of 33 non-smokers and smokers with stable asthma. RESULTS: Serum periostin (median [IQR], ng/mL) was reduced in smokers with asthma compared to never smokers with asthma; 9 (9, 307) versus 233 (34, 1108) respectively, p = 0.017. Periostin was not influenced by disease severity (p = 0.786) or atopic status (p = 0.144). There was a weak correlation between serum periostin and sputum eosinophil count in smokers with asthma (r = 0.315, p = 0.020). The proportion of patients with an elevated serum periostin concentration was greater in never smokers with asthma compared to smokers with asthma [65% versus 39% respectively, p = 0.003]. Oral steroid treatment reduced serum periostin (p = 0.030) in non-smokers with asthma. CONCLUSION: Despite lower median serum periostin concentrations in smokers with asthma compared to never smokers with asthma, approximately forty percent of this group had a high level. The potential value of a raised serum periostin concentration in predicting a beneficial response to therapies targeting Th2 inflammation in smokers with asthma requires to be investigated.