Physiology of Asthma 1 Professor of Medicine, Pulmonary Medicine Director, Vermont Lung Center University of Vermont Pathophysiology of asthma - common wisdom 2 Jeffery and Haahtela BMC Pulmonary Medicine 2006 6(Suppl 1):S5; doi:10.1186/1471-2466-6-s1-s5 Asthma is: Airway inflammation Airflow limitation Small airways Reversibility Remodeling Periodicity of airflow limitation Airways hyper-responsiveness 3 1
Airflow limitation/obstruction Spirometry FEV 1 ; FVC Flow volume loops Other measures: Sgaw Forced oscillations Peak flow Lung volumes 4 Forced expiratory maneuver 5 Subject takes in a full breath to total lung volume and then exhales maximally into the spirometer The FVC maneuver 6 #1 DEEP inhalation #2 BLAST out #3 Keep blowing for 6 seconds 2
Spirometry Normal subject Volume FEV 1 FVC 7 1 2 3 4 5 Time (sec) 6 Spirometry (2) Normal subject Volume FEV 1 Asthmatic (before bronchodilator) 8 1 2 3 4 5 Time (sec) 6 FEV 1 9 After a maximal inspiration, the volume of air that can be forcefully expelled in one second Effort dependent High degree of reproducibility Reported as percent predicted Objective clinical tool to assess the severity of airway obstructive disease Predictive of asthma exacerbations Predictive of death due to all causes 3
Uses of spirometry in asthma Confirm asthma Classify asthma severity Early recognition of exacerbations - asthma control Monitor medication effectiveness 10 The flow-volume loop Flow Volume 11 Dixon & Irvin In: Middleton s Allergy7th Ed., 2008 The flow-volume loop (2) Flow Muscle force, Large airway calibre Airflow limitation Static mechanics, Muscle force, Effort Muscle force, Effort, Small airways, AIRWAY CLOSURE Volume 12 Inspiratory resistance, Muscle force, Effort 4
The flow-volume loop (3) Extrathoracic obstruction Vocal chord dysfunction Flow 13 Irvin Up-to-Date 2010 Volume Volume Cross sectional variance for FEV 1 and FVC Factor % of variance up to Sex 30% Age 8% Height 20% Weight 2% Ethnicity 12% Technical 3-10% Unexplained 30% 14 Adapted from ATS Am Rev Respir Dis 144: 1202; 1991 Spirometry is age, race and gender dependent 15 Hankinson JL, et al., AJRCCM 159: 179-187; 1999 5
Spirometry What is abnormal? %pred FEV 1 near LLN 60%-LLN Impairment Borderline* Mild 50-59% Moderate 35-49% Severe <35% Very severe 16 ERS/ATS Eur Respir J 26: 948; 2005 These cut-off points are arbitrary The FEV 1 /FVC falls with age: 60 world-wide spirometry studies 17 Swanney and The Pulmonaria Group Thorax 2008, www.spirxpert.com Accelerated decline in lung function in asthma 18 6
Accelerated decline in lung function in asthma (2) Asthmatic smokers worst lung function by the age of 80 Asthmatics the fall in lung function is fairly similar to normal Smokers show accelerated loss of lung function 19 Classifying asthma severity and initiating treatment in youths 12 years of age and adults Consider severity and interval since last exacerbation; Frequency and severity may fluctuate over time for patients in any severity category EIB = exercise-induced bronchospasm; FEV 1 = forced expiratory volume in one second; FVC = forced vital capacity Adapted from National Asthma Education and Prevention Program; Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR-3 2007); U.S. Department of Health and Human Services; Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf; Accessed August 29, 2007 20 Characteristic Daytime symptoms Limitations of activities Nocturnal symptoms/ awakening Need for rescue/ reliever treatment Lung function (PEF or FEV 1) Levels of asthma control Controlled (all of the following) None (2 or less/week) None None None (2 or less/week) Normal Partly controlled (any present in any week) More than twice/week Any Any More than twice/week < 80% predicted or personal best (if known) on any day Uncontrolled 3 or more features of partly controlled asthma present in any week Exacerbation None One or more/year 1 in any week 21 7
The heterogeneous airways 22 Courtesy J. Hogg Parallel Axial Temporal What is a SMALL airway? Silent lung zone Z 0 1 3 2 4 5 14 15 16 17 18 19 20 21 22 23 Conductive airways Acinar airways Est. 44,000 23 Adapted from: Weibel ER. Morphometry of the Human Lung; 1963 8hl R = pr 4 24 Green M, St Thomas Hosp Gazette 62: 136 1964 8
Narrowing of parallel airways 16 fold 25 8hl R = pr 4 Obstruction of parallel airways 4 fold 26 So obstruction is better than narrowing! Retrograde Catheter and small airway resistance R p = Pbr -Ppl V P br Retrograde Catheter P ao Flow V Pleural surface (Ppl) 27 9
28 Macklem and Mead J App Physiol22: 395 1967 Peripheral airway resistance 29 Wagner, Am Rev Respir Dis 151: 548; 1990 Flow (ml/min) Rp (cmh 2O/ml/min) 0.15 p = < 0.0001 * : * 0.12 4 PM 4 AM 0.09 0.06 0.03 * * 30 0 Control Kraft et al., AJRCCM 163: 1551; 2001 Non-nocturnal asthma Nocturnal asthma 10
Lung volumes 31 Irvin CG, In: Physiologic Basis of Respiratory Disease; Eds: Hamid, 2005 Hyperinflation defends the FEV 1 9 8 Increasing asthma severity Volume (liters) 7 6 5 4 3 2 VC TLC FRC Physical limit 1 RV RV RV RV 32 Normal Asthma Asthma Asthma RV N TLC N WNL FEV 1 N WNL LLN Am chest tightness correlates with RV BL-AM chest tightness-placebo 1.5 0.5-1 -0.5-0.4-0.3-0.2-0.1 0.1.2.3.4 BL-RV on placebo r = 0.20 p = 0.41 BL-AM chest tightness-montelukast 1.5 1 0.5 0-0.5-1 -0.4-0.2 0.2.4.6 BL-RV on montelukast r = 0.55 p = 0.04 33 Kraft et al., Chest 130: 1726; 2006 11
Closing volume/capacity Percent predicted 150 100 50 Unstable asthma Stable asthma p =.02 p =.03 0 FEV 1 TLC FRC RV RV/TLC dn 2 CV/VC CC/TLC 34 in t Veen, et al., AJRCCM 161: 1902; 2000 FRC RV 35 Wagers, Jaffe and Irvin In Allergy: Principles & Practices 2004 MRI + hyperpolarized 3He 36 A: Normal B: Methacholine/Exercise challenge C: Effect of salbutamol on hypoventilation areas Samee et al., J Allergy Clinical Immunol 2003 12
BDP HFA MMAD=1.1 mm Enhanced lung deposition with smaller particle size BDP CFC MMAD=3.5 mm Oral 29% 94% Lung 55% 4% 14% Exhaled 0% MMAD= mass median aerodynamic diameter Leach CL et al., Eur Respir J. 12: 1346; 1998 37 Effect of particle size on FEV 1 0.20 <5 mm Mean increase in FEV 1 (L) 0.15 0.10 0.05 5 10 mm 10 15 mm 38 0.00 0 10 20 30 40 50 Time post inhalation (min) Rees PJ et al., Eur J Respir Dis Suppl. 119: 73; 1982 60 Asthma is: Airway Inflammation Airflow limitation Small airways Reversibility Remodeling Periodicity of airflow limitation Airways hyper-responsiveness 39 13
Spirometry Normal subject Volume FEV 1 Asthmatic (After bronchodilator) Asthmatic (Before bronchodilator) 40 1 2 3 4 5 Time (sec) 6 Significant bronchodilator response Society FVC (%) FEV 1 (%) Comments ACCP1974 15-25 15-25 % baseline and 2 of 3 efforts ITS1984 15 12 % baseline ATS 1991 12 12 % baseline and 200ml ATS/ERS 2005 12 12 % baseline and 200ml ATS Am Rev Respir Dis 144: 1202; 1991 ERS/ATS Eur Respir J 26: 948; 2005 41 Airways hyper-responsiveness correlates with bronchodilator responsiveness FEV 1 Percent of Predicated 120 100 80 60 Post Bronchodilator Pre Bronchodilator 42 40 0.03 0.6 1.25.25.50 1.0 2.0 4.0 8.0 16 32 Airways Responsiveness - PC 20 Adapted from Ryan et al., Thorax 37:423 1982 14
Flow 43 Dixon & Irvin in: Middleton s Allergy7 th Ed., 2008 Volume Patterns of responses to bronchodilator therapy Flow response Volume response 44 Isovolume shift 12 Flow lps FEV 1 Before BD 3.15 After BD 3.12 12 Flow lps sgaw Before BD 0.15 After BD 0.26 8 8 4 4 2 4 6 Volume liters Volume liters 45 15
What is the best index of a bronchodilator effect? 100 consecutive patients ROA All had airflow limitation 38% COPD; 62% asthma Volume plethysmograph BD Metaproterenol 63% Albuterol 23% Isoproterenol 11% Improvement FEV 1 15% FVC 15% FEF 25-75 20% Sgaw 40% 46 Smith et al., CHEST 101: 1577-1581; 1992 What is the best index of a bronchodilator effect? (2) 47 Smith et al., CHEST 101: 1577-1581; 1992 What is the best index of a bronchodilator effect? (3) 48 Smith et al., CHEST 101: 1577-1581; 1992 16
Bronchodilator response is airway opening 49 Brown et al., J Appl Physiol101: 30; 2006 MRI + hyperpolarized 3He 50 Samee et al., JACI2003 A: Normal B: Methacholine/Exercise challenge C: Effect of salbutamol on hypoventilation areas Assumption: fall in FEV 1 is due to remodeling Loss of lung function not correlated to thickness of basement membrane van Rensen et al., AJRCCM 172: 837; 2005 51 17
Mechanisms of airway obstruction 52 Bosse et al., Ann Rev Physiol 72: 437; 2010 Airway remodeling: friend or foe? 53 Foe Lumen diameter ASM contractility Uncoupling Series ASM load Latch state Shortening velocity Adapted from McParland et al., J Appl Physiol95: 426; 2003 Friend Wall stiffening Parallel ASM load Series ASM load Barrier Clearance Asthma is: Airway Inflammation Airflow limitation Small airways Reversibility Remodeling Periodicity of airflow limitation Airways hyper-responsiveness 54 18
Peak flow rate diary in asthma 55 Irvin up-to-date 2010 Airways hyper-responsiveness correlates with PEF variability 56 PM-AM Peak Flow % of Personal Best 20 15 10 5 0 0.03 0.6 1.25.25.50 1.0 2.0 4.0 8.0 16 32 Airways Responsiveness - PC 20 Asthma: temporal periodicity 80 asthmatic with twice daily PEF PEF 57 Frey et al., Nature 438: 667; 2005 19
Forced oscillations (FOT) 58 Health Asthma Health Asthma 59 Que et al., J. Appl. Physiol. 91: 1131; 2001 Freq. of event > 100,000 X increase! 60 Que et al., AJRCCM 161: 161; 2000 Magnitude of Z 20
Asthma is: Airway Inflammation Airflow limitation Small airways Reversibility Remodeling Periodicity of airflow limitation Airways hyper-responsiveness 61 Airway hyper-responsiveness 62 Dixon & Irvin in: Middleton s Allergy7 th Ed., 2008 63 Brown et al., J Appl Physiol101: 30; 2006 21
Why perform an airways challenge test? To confirm a diagnosis of asthma or EIB Rule out the diagnosis asthma To aid in defining or guiding treatment 64 Bronchial provocation tests 65 Pharmacological direct Methacholine Histamine Physical indirect Exercise Eucapnic voluntary hyperpnea Adenosine monophosphate Hyperosmolar saline Mannitol Antigen-induced airway hyper-responsiveness 66 Cockcroft DW et al., Clin Allergy 7(6): 503; 1977 22
Exercise induced bronchospasm 67 http://aaac.duhs.duke.edu/modules/aaac_ptrsrc/index.php?id=12 68 Cockcroft et al., Clin Allergy; 7: 235-43; 1977 Inhibition of deep inspirations causes AHR in normal but not asthmatics 69 Modified from Skloot et al., J Clin Invest96: 2393; 1995 and other data courtesy of Alkis Togias, John Hopkins University 23
70 Sont J, et al., AJRCCM 159: 1043; 1991 Time courses of improvement in asthma outcome variables with ICS therapy % improvement 100 No night symptoms FEV 1 am PEF No SABA use AHR 0 Days Weeks Months Years 71 Woolcock AJ. Clin Exp Allergy Rev 1: 62; 2001 Summary Asthma is a syndrome that is characterized by pattern of physiological dysfunction that is highly variable FEV 1 (FVC) is the robust index most frequently used Small airway dysfunction characterizes asthma that is mild or in remission 72 24
Control of airway caliber & patency Smooth muscle Nerves Structure Volume 73 Smooth muscle Luminal contents Mucus Liquid Fibrin Surfactant Sheer number Summary (2) Bronchodilator responses are highly variable but reflect the underlying disease process 74 Heterogeneity of reversibility Asthma COPD 75 Fully reversible Reversibility Fixed 25
Summary (3) Variability of airflow limitation is perhaps the best marker of asthma 76 The signal is the noise Que et al., AJRCCM 161: 161; 2000 77 Summary (4) Hyper-responsiveness is a sensitive but not specific aspect of the asthmatic lung and may provide a more objective basis for therapy 78 26
Acknowledgements and dedication Colleagues Participants National Institutes of Health and American Lung Association I would like to dedicate this lecture to: Peter T. Macklem, OC, BA, MD, CM, DHC(Hon), FRCPC, FRSC 79 80 27