Bronchial Provocation Results: What Does It Mean? Greg King 1 Department of Respiratory Medicine, Royal North Shore Hospital, St Leonards 2065 2 Woolcock Institute of Medical Research and Sydney Medical School, The University of Sydney, Glebe 2037 TSANZSRS April, 2016
Declaration COI Between 2011-15 Travel sponsorships:boehringer Ingelheim, Novartis Pfizer, AstraZeneca and GlaxoSmithKline Research and unrestricted grants, and consultancy fees AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Menarini, MundiPharma and Novartis. Consultancy services: related to asthma and COPD, advisory boards and delivering lectures at local, national and international meetings. Competitive grants: local philanthropic foundations, Sydney University, The National Health & Medical Research Council of Australia and The Australian Lung Foundation.
AHR: What Does It Mean (asthma)? Mechanisms Clinical associations A couple of cases
SHAPE OF HISTAMINE DOSE RESPONSE CURVE FEV1 (% FALL) 60 40 20 0 MODERATE ASTHMA M = 100 α = -0.52 β = 0.97 r = 0.997 0.001 0.01 0.1 1.0 10 100 HISTAMINE DOSE (μmoles) MILD ASTHMA M = 43 α = -0.60 β = 1.06 r = 0.989 NORMAL M = 26 α = -2.05 β = 1.69 r = 0.944 Woolcock, Salome, Yan ARRD 1984
Mechanisms of AHR
Mechanisms of AHR Inflammation? Epithelial damage? Extra cellular matrix? Airway smooth muscle? Nerves? Surfactant? Parenchymal interdependence? Ventilation heterogeneity and airway closure?
Small Airways and AHR Downie et al. Thorax, 207; 62(8):684 9.
Predictors of Methacholine AHR >50yrs Is it geometry: narrower airways = greater AHR? Is it common pathways: pathophysiology = narrower airways & greater AHR? Harkaker et al. Chest, 2011; 136:1395 1401
Mechanisms of AHR Non-specific abnormality Variety of causes Different associations in different clinical settings e.g. smoking, COPD e.g. age e.g. atopy
Dose Response Plateau Peter Macklem FEV1 (% FALL) 60 40 20 0 Potential for unlimited narrowing to closure MODERATE ASTHMA 0.001 0.01 0.1 1.0 10 100 HISTAMINE DOSE (μmoles) MILD ASTHMA NORMAL
Clinical Associations Persistence of childhood wheeze Airway remodelling Exacerbations/hospitalisation Lung growth & FEV1/FVC Failure of down-titration FEV1 decline
Use Of AHR For Diagnosis? Spirometry is uncommonly used, let alone challenge testing! What is AHR negative asthma like?
% of group 100 80 60 40 Respiratory symptoms Wheeze Diagnosed asthma 20 0 Severe Moderate Mild Slight Normal Salome et al, Clin Allergy 1987;17:271
40 35 30 25 20 15 10 5 0 Normal Wheeze only AHR only Current asthma Diurnal Variability by Airflow Meter (%)
Treatment effects on methacholine DRC Placebo treatment Baseline Post 12/52 Rx fluticasone Overbeek et al EurRespirJ, 1996; 9:2256 2262
Treatment effects on methacholine DRC H Reddel et al. Eur Resp J 2000; 16:26 35 B. Lundbäck. Respiratory Medicine 2009; 103:348 55
AHR Guiding Treatment? Presenting with first mild exacerbation Severe AHR, usual Rx Mild AHR, usual Rx Severe AHR, AHR Rx Sont et al, AJRCCM 1999; 159:1043 51
AHR Guiding Treatment? Sont et al, AJRCCM 1999; 159:1043 51
Forced ICS Withdrawal Exacerbation free Exacerbations risk: AHR to both mannitol and histamine at baseline Mannitol AHR during stepdown Leuppi et al. AJRCCM 2001 163:406
Case 1: Mr DC 49 yrs old asthma for 20 years wheeze, breathlessness on moderate exercise chronic productive cough Co-morbidities nasal polyps hayfever hypertension Ex-smoker: 2 pack/years 20 years ago
Case 1: Mr DC budesonide/eformoterol 200/6 ii bd low pitched wheezes Chest X-ray: minor atelectatic band right base
Pred. LLN Pre Meas. % Pred Z-Score FEV1(L) FVC(L) FEV1/FVC(%) PEF(L/S) FEF25-75(L/S) FIVC(L) 4.02 5.10 79.16 9.98 3.66 0.00 3.15 4.00 68.29 7.60 2.12 ---- 4.11 6.13 67.09 8.73 2.57 4.38 102 120 85 87 70 ---- 0.17 1.51-1.82-0.88-1.12 ---- 110 FEV1 FEV1 (% baseline) 100 90 80 70 60 50 5 15 35 75 155 315 475 635 40 0 1 2 3 4 5 6 7 8 mannitol dose (mg)
Exercise Macrolide
Mr GW 63 yr male Wheeze, chest tightness, difficulty breathing for 2 years Triggers - viral infection but nil else Worse for several days - responsive to BDs and prednisone Near respiratory arrest under anaesthesia for hernia repair
Mr GW No FHx of asthma Normally fit and active Ex-smoker 30 yrs ago 10 pack/years 60g alcohol/day Marketing and advertising consultant
Mr GW Prednisone and SA bronchodilators intermittently Tiotropium - ceased when well Indacaterol symptomatic response takes when symptomatic
Mr GW Spirometry 2.71/3.38 FEV1 74% predicted FER 0.80. No BD response Normal lung volumes & diffusion SPT: +ve ryegrass, HDM, cat CXR & CT - normal PD20 histamine 5.87 μmol
Mr GW Budesonide 400μg bd increase to 800μg bd if still symptomatic Action Plan House dust mite allergen avoidance Discussion: lifelong asthma Asthma education information
Mr GW progress @ 2 years Few symptoms Negative methacholine challenge test Exacerbation treated with prednisone not sure what s going on here Remain on BUD 200μg bd Encouraged action plan use (ICS)
Mr GW Started high dose combination ICS/LABA 3.14/4.00 (improved) Cough & mucous (bronchitis)
Mr GW Admits to intermitted ICS/LABA use! Had stopped ICS and had URTI prior to anaesthetic!
Conclusions AHR likely has a variety of mechanistic causes Non-specific functional abnormality Well characterised clinical associations Negative and positive tests are useful Heterogeneous changes in AHR to inhaled corticosteroids have to be kept in mind