and Asthma: Similarities and Differences and Asthma: 1 Imperial College Peter Barnes FRS, FMedSci, National Heart & Lung Institute Imperial College, London, UK p.j.barnes@imperial.ac.uk Royal Brompton Hospital Asthma vs. : clinical differences Symptoms Onset Course Smoking Resp to b/d 2 Resp to steroids Variable wheeze Usually childhood Variable, remissions rarely progressive Sometimes Good Good Persistent SOB on exertion Usually >45yr Progressive Usually Poor Poor is not asthma! Asthma and are: Both common Both increasing globally Both involve chronic inflammation of respiratory tract Both characterised by acute exacerbations Both result in airflow limitation 3 1
and Asthma: and asthma Neutrophils Macrophages CD8 + cells ~1% Eosinophils Mast cells CD4 + cells Minimal AHR No atopy Wheezy bronchitis AHR Atopy No steroid response Steroid response 4 Ex NO & sputum EOS in reversible Reversible: >15% in FEV 1 after b/d Papi A et al., AJRCCM, 2 Reversible increased exhaled NO in patient s breath compared with nonreversible Reversible patients have increased sputum eosinophils compared with nonreversible These patients can benefit from inhaled steroid treatment 5 Dutch hypothesis British hypothesis Common cause? Different causes Common mechanisms Different mechanisms Asthma Asthma [COLD] Allergy 6 irritants 2
and Asthma: 7 Tucson epidemiological study Population study: age 475 yr (n=1467) After exclusion of known asthmatics (n=169): FEV 1 related to Cigarette smoking (packyears) Age Smoking status NOT related to Atopy Serum IgE Blood eosinophilia Burrows B et al., Am. Rev. Resp. Dis. 1988 Asthma and pathology Inflammation ASM + Asthma death BM + Fibrosis Alveolar disruption Severe 8 Courtesy of Jim Hogg Airway obstruction in asthma and Bronchoconstriction (multiple b/c mediators), mast cell activation Oedema (acute exacerbations) Mucus plugging (fatal asthma) Structural changes (irreversible) Small airway fibrosis (2 to inflammation) Emphysema (loss of alveolar attachments) Mucous exudate Oedema (acute exacerbations) 9 3
Lung function: natural history and Asthma: 1 1 Normal Normal 75 75 5 Symptoms 5 Asthma Disability Severe asthma 25 Death 25 1 25 5 75 Age (years) 25 5 75 Age (years) Allergens Cigarette smoke Ep cells Mast cell Alv macrophage Ep cells CD4+ cell (Th2) Eosinophil CD8+ cell (Tc1) Neutrophil Bronchoconstriction Airway hyperresponsiveness 11 Small airway fibrosis Alveolar destruction Asthma and Mast cells Eosinophils Th2 cells Airway Inflammation Inflammatory gene expression Macrophages Neutrophils Tc1 cells Airflow limitation 12 Steroid sensitive Steroid resistant 4
Inflammation Asthma vs. Cells Mast cells Eosinophils CD4 + T cells Macrophages + Neutrophils CD8 + T cells Macrophages and Asthma: Mediators Effects LTD 4, histamine IL4, IL5 ROS + All airways Little fibrosis Ep shedding LTB 4 IL8, TNFα ROS Lung destruction Peripheral airways Fibrosis + Sq metaplasia 13 Response to steroids Peak flow (L/min) Peak flow (L/min) 5 4 3 2 1 5 4 3 2 1 14 Trial of steroids Prednisolone 3mg o.m. x 14 days 1 2 3 4 5 6 7 8 9 1 11 12 13 14 Days Prednisolone 3mg o.m. x 14 days 1 2 3 4 5 6 7 8 9 1 11 12 13 14 Treatment choices Bronchodilators Inhaled shortacting β 2 Agonist (rescue) Inhaled shortacting anticholinergic Inhaled longacting β 2 agonist Inhaled longacting anticholinergic Controllers Inhaled corticosteroids Low dose theophylline Antileukotriene AntiIgE Nacetylcysteine 15 + (+) + + (+) ++ ± ++ 5
and Asthma: 16 Comorbidities Rhinitis Weight loss ( FFM) Atopic dermatitis Skeletal muscle wasting Rhinosinusitis Depression Anaemia (normocytic) GERD Ischaemic heart disease Obesity Cardiac failure Hypertension Osteoporosis Diabetes Metabolic syndrome Barnes PJ, Celli B, ERJ, 29 vs. Asthma Eosinophils Neutrophils Tlymphocytes TNFα IL8 Oxidative stress Steroid response (+) Tc1,Th1, Th17 Severe Asthma + ++ Tc1,Th1,Th17 ++ ++ ± Mild Asthma Th2 + 17 18 Similarities between asthma and Mild asthma and severe are markedly different BUT sometimes they are similar Severe asthma Neutrophilic ± eos, oxidative stress, steroid resistance Smoking asthma Neutrophilic ± eos, oxidative stress, steroid resistance Acute exacerbations Neutrophilic ± eos, oxidative stress, steroid resistance Triggered by rhinovirus Reversible eosinophils, steroid response 6
and Asthma: Acute exacerbations Course Cause Evolve over several days Resolve over ~5 days URTI: esp rhinovirus Symptoms SOB, sputum Inflamm. eos, neutrophils Treatment Neb bronchodilators Systemic steroids No antibiotic Evolve over several days Resolve slowly (weeks) Virus (4%) Bacteria (4%) SOB, sputum eos, neutrophils Neb bronchodilators Systemic steroids Antibiotic (purulent sp) 19 Air trapping in severe asthma Sorkness RL et al., J. Appl. Physiol. 27 Patients with severe asthma were shown to have air trapping, measured by the ratio of Residual Volume to Total Lung Capacity (RV/TLC) Air trapping is greater in severe asthma compared to mild to moderate asthma 2 21 Cigarette smoking and asthma 25% of asthmatics are current smokers 2% of asthmatics are exsmokers More likely to have symptoms despite ICS More likely to be admitted to hospital >3% of asthmatics admitted to hospital are current smokers (USA) (5% believed smoking symptoms) Associated with more severe asthma Associated with more rapid decline in FEV 1 Associated with increased mortality 7
and Asthma: Smoking and response to oral steroids Prednisolone 4mg daily x 2 weeks Nonsmokers (26) Current smokers (14) Exsmokers (1) 22 3 FEV 1 p<.1 2 N.S. 1 Chaudhuri R et al., AJRCCM, 23 N.S. Δ Asthma control score.2.4.6.8 1 N.S. N.S. p<.1 Asthma control Steroid insensitivity in smoking asthmatics Thorax, 25 23 CSM reduces steroid responsiveness BEAS2B cells: IL1β stimulation Inhibition (%) 25 25 5 75 IC 5:.67x 1 9 M 25 IC 5 : >1 6 M + CSM Inhibition (%) 25 5 75 GMCSF IC 5 : >1 5 M + CSM IC 5 : 4.6 x 1 9 M IL8 24 1 11 1 9 8 7 6 5 Dexamethasone (logm) Tehireem Ahmad 1 12 11 1 9 8 7 6 5 Dexamethasone (log M) 8
and Asthma: HDAC in smoking asthmatics Fibreoptic bronchial biopsies HAT 2 HDAC HAT activity (dpm) 6 4 2 * * HDAC activity (dpm) 1 * * ** 25 Normal (n=8) Smoker (n=8) Asthmatic (n=8) Smoking asthmatic (n=4) Steroid resistance in smoking asthmatics Nonsmoking asthma Smoking asthma Inflammatory stimuli Corticosteroids Cigarette smoke Oxidative stress Peroxynitrite NFκB GR NFκB Histone acetylation 26 GMCSF IL8 eotaxin HDAC2 Steroid response Histone acetylation HDAC2 Steroid resistance Histone acetylation GMCSF IL8 eotaxin IL6 Th17 cells IL23 TGFβ Th17 RORγt STAT3 IL21 B cell TNFα IL17A IL17F IL22 IL6 CD8 + cell Neutrophils 27 CXCL1 CXCL8 Epithelial cells IL1 acute phase proteins 9
and Asthma: Conclusions 28 Asthma and are usually different: Symptoms, onset Underlying inflammatory mechanisms Pathology, comorbidities Response to therapy Some similarities however: Reversible (coexistent asthma) Severe asthma (shared genes?) Smoking asthma Neutrophilic asthma Acute exacerbations 29 1