Kroniskt obstruktiv lungsjukdom Alf Tunsäter Föreläsning T6 2011 t Kroniskt obstruktiv lungsjukdom www.goldcopd.com www.slmf.se/kol www.mpa.se och sök KOL-rekommendationer 1
Definition av KOL Kroniskt obstruktiv lungsjukdom (KOL) är en inflammatorisk luftrörs-/lungsjukdom, som oftast är en följd av kronisk tobaksrökning KOL manifesterar sig som sänkt FEV 1 /VC-kvot vid spirometri. Försämringstakten av FEV 1 är ofta långsam KOL är i de allra flesta fall möjlig att förebygga och kan även behandlas med gynnsam effekt Lungfunktionsnedsättningen karakteriseras av att patienten aldrig uppnår normalvärden vare sig spontant eller efter behandling. Extrapulmonella manifestationer är vanliga. Svenska läkemedelsverkets rekommendationer 2009 Chronic obstructive pulmonary disease - pathogenesis Emphysema - centrilobular Bronchiolitis 2
Bronchiolitis Location of COPD Emphysema Vasculitis 4 Some pathogenetic mechanisms in COPD Bacteria Virus Mucous secretion Macrophage Increased expression of inflammatory genes histone acetylation histone deacetylase Peroxinitrate - - O 2 + NO inos MMP TNF-α IL-8 GRO-α Lymphocyte IL-17 TNF-α LTB-4 IL-1β IL-8 Proteases Bronchiolitis Emphysema Antiproteases Neutrophil 3
Other inflammatory cells involved in COPD development Mast cells Br Fibrocytes Balancing parenchyma destruction TGFβ-depedent PA COPD - local and systemic inflammation Paricles from e g smoke Local inflammatory response IL-8 Cytokines Systemic inflammatory response IL-6, IL1-β GMCSF, IL-6 IL1-β, TNF- Leucocytes och thrombocytes Acute phase proteins Endothelial activation Vascular disease Efter Eeden 2006 4
Risk Factors for COPD Nutrition Infections Socio-economic status Aging Populations 9 Diagnosis of COPD SYMPTOMS cough sputum shortness of breath EXPOSURE TO RISK FACTORS tobacco occupation indoor/outdoor pollution SPIROMETRY 5
Förekomst 400 000-700 000 i Sverige Ovanlig före 40-årsåldern - ökar starkt med stigande ålder. Dödligheten i KOL är betydande - drygt 3000 dödsfall/år. Överlevnaden starkt beroende av ålder och FEV 1 och av komplikationer såsom patologiska blodgaser, ödem och undernäring. Samtidig kardiovaskulär sjukdom försämrar överlevnaden. Förekomsten av KOL i Sverige lika bland kvinnor och män Sjukvårdskonsumtionen till följd av KOL är numera högre bland kvinnor. När bör KOL misstänkas? Exponering för luftrörsskadliga ämnen, främst cigarettrök, Ålder över 45 år samt något av följande Luftvägssymtom som hosta, slemproduktion, andfåddhet eller pip i bröstet Återkommande bronkitepisoder eller långvariga förkylningar Nedsatt prestationsförmåga Lungröntgenbild som inger misstanke om KOL Känd hjärtsjukdom med andfåddhet och nedsatt prestationsförmåga 6
Diagnostik - spirometri Ökat luftflödesmotånd tå d som kvarstår efter inandning av bronkdilaterare FEV 1 /VC Management of Stable COPD Assess and Monitor COPD: Spirometry Spirometry should be performed after the administration of an adequate dose of a shortacting inhaled bronchodilator to minimize variability. A post-bronchodilator FEV 1 /FVC < 0.70 (<0.65 if age >65) confirms the presence of airflow limitation that is not fully reversible. Where possible, values should be compared to age-related normal values to avoid overdiagnosis of COPD in the elderly. 14 7
KOL-utveckling 100 Aldrig rökt eller icke känslig för rök 75 50 25 Rökare med känslighet för rök Invaliditet Död Slutade vid 45 Slutade vid 65 0 25 50 75 Ålder Fletcher and Peto 1977 Svårighetsgrad Beror på spirometriresultat - efter fastställt kvotkriterium FEV 1 /VC <0.7(0.65) Stadium 1 FEV 1 >80% förv. Stadium 2 FEV 1 50-80% förv Stadium 3 FEV 1 30-50% förv. Stadium 4 FEV 1 <30% förv. och övrig påverkan hör till stadium 4 Svår kronisk hypoxi låg oxygenhalt i blodet Kronisk hyperkapni hög koldioxidhalt i blodet Cirkulationspåverkan (t ex perifera ödem eller takykardi). Låg kroppsvikt. BMI <21 8
Differential Diagnosis: COPD and Asthma COPD Onset in mid-life Symptoms slowly progressive Long smoking history Dyspnea during exercise Largely irreversible airflow limitation ASTHMA Onset early in life (often childhood) Symptoms vary from day to day Symptoms at night/early morning Allergy, rhinitis, and/or eczema also present Family history of asthma Largely reversible airflow limitation Systemic effects of COPD Systemic inflammation Nutritional abnormalities and weight loss Skeletal muscle dysfunction Osteoporosis Cardiovascular effects Neurological effects Infectious disease s tuberculosis ul? Evaluate systemic disease manifestations! 9
What does an exacerbation mean to a patient? Decline in lung function 1,2 Greater anxiety 3 Increased symptoms (I.e. breathlessness) 6 Worsening quality of life 4,5 Social withdrawal More exacerbations 6,7 Increased risk of mortality 8 Increased risk of 1. Garcia-Aymerich J et al. 2001 hospitalisation 1,2 2. Donaldson D et al. 2002 3. Gore JM et al. 2000 4. Seemungal T et al. 1998 5. Pauwels Pet al. 2001 6. Seemungal T et al. 2000 7. Garcia-Aymerich J et al. 2003 8. Anto JM et al. 2001 * Acute esacerbations of COPD prior to entry to study requiring hospital management Soler-Cataluna et al Thorax 2005 10
ERS/ATS definition(2004) An event in the natural course of the disease characterised by a change in the patient s baseline dyspnoea, cough and/or sputum beyond day to day variability sufficient to warrant a change in management www.ersnet.org Celli B et al Eur Respir J 2004:23:932-46 ERS/ATS (2004) Severity grading(arbitrary) Level 1: Treated at home Level 2: Requires hospitalisation Level 3: Develops respiratory failure www.ersnet.org Celli B et al Eur Respir J 2004:23:932-46 11
Symptoms during an exacerbation Shortness of breath Cough Chest tightness Night-time awakenings Calverley PM et al Eur Respir J 2005:26:406-13 Prevention improving immune function 12
Viral and bacterial causes Bacteria Haemophilus hl influezae, Moraxella catharalis Streptococci, Pneumococci Virus Rhinovirus, respiratory syncytial virus, influensa A and B Flu vaccianation in COPD 125 patients randomised to vaccine or placebo relative risk [RR], 0.24, [p 0.005]; vaccine effectiveness 76% Wongsurakiat P et al Chest 2004:125:2011-20 13
Prevention non-pharmacological treatment Management of Stable COPD Reduce Risk Factors: Key Points Reduction of total personal exposure to tobacco smoke, occupational dusts and chemicals, and indoor and outdoor air pollutants are important goals to prevent the onset and progression of COPD. Smoking cessation is the single most effective and cost effective intervention in most people to reduce the risk of developing COPD and stop its progression (Evidence A). 28 14
Brief Strategies to Help the Patient Willing to Quit Smoking ASK Systematically y identify all tobacco users at every visit. ADVISE Strongly urge all tobacco users to quit. ASSESS Determine willingness to make a quit attempt. ASSIST Aid the patient t in quitting. ARRANGE Schedule follow-up contact. Management of Stable COPD Reduce Risk Factors: Smoking Cessation Counseling delivered by physicians significantly increases quit rates over self-initiated strategies. A brief (3-minute) period of counseling to urge a smoker to quit results in smoking cessation rates of 5-10%. Pharmacotherapies for smoking cessation are available and is recommended when counseling is not sufficient to help patients quit smoking. 30 15
Management of Stable COPD Reduce Risk Factors: Indoor/Outdoor Air Pollution Reducing the risk from indoor and outdoor air pollution requires a combination of public policy and protective steps taken by individual patients. Reduction of exposure to smoke from biomass fuel, particularly among women and children, is a crucial goal to reduce the prevalence of COPD worldwide. 31 Therapy at Each Stage of COPD I: Mild FEV 1 /FVC < 70% FEV 1 > 80% predicted II: Moderate FEV 1 /FVC < 70% 50% < FEV 1 < 80% predicted III: Severe FEV 1 /FVC < 70% 30% < FEV 1 < 50% predicted IV: Very Severe FEV 1 /FVC < 70% FEV 1 < 30% predicted or FEV 1 < 50% predicted plus chronic respiratory failure Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed) Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation Add inhaled glucocorticosteroids if repeated exacerbations Pharmacotherapy: Symptomatic Add long term oxygen if chronic respiratory failure. Consider surgical treatments Profylactic against exacerbations 16
Effect on mortality of oxygen treatment NOTT-trial MRC-trial >15 h/24h >18 h/24h >15 h/24h No oxygen Ann Int Med 1980:93:391-198 Lancet 1981:93:681-685 Long-term oxygen treatment Reduces hospitalisations Given on strict indications pao2 <7.3 24-h/day 17
Rehabilitation Effect of rehabilitation is well established Physiotherapy Muscular training Dietic measures Coping strategies Rehabilitation randomised controlled trial Griffiths TL et al Lancet 2000:355:362-8 18
Prevention pharmacological treatment Bronchodilators - LABA Decreaseing symptoms and effect on exacerbations Formoterol one study 30 % reduction in exacerbation frequency (Rossi A Chest 2002:121:1058-69) Others have not shown an effect Salmeterol TRISTAN shows 20 % recuction in exacerbation rate, 29 % reduction in oral steroid courses (Calverley PM et al Lancet 2003:361:449-56) TORCH 19
Bronchodilators symptomatic and profylactic effects Tiotropium n=497 Placebo n=506 Dusser D et al. Eur Respir J 2006; 27: 547 555 1 year study Decreased the number of exacerbations by 35% and exacerbation days by 37% versus placebo. Reductions in the use of concomitant respiratory medications, antibiotics and oral steroids, and the number of unscheduled physician contacts. Inhaled corticosteroids EUROSCOP - The yearly rate of severe exacerbations (estimated t from courses of oral corticosteroids) was reduced in the budesonide group versus placebo group by 37% (0.05 versus 0.07, p=0.002), corresponding to a yearly y exacerbation rate ratio of 0.63 (95% CI 0.47 0.85). Löfdahl CG et al Eur Respir J 2007 2007; 29: 1115 1119 20
Inhaled corticosteroids ISOLDE exacerbations reduced 25 % (Fluticasone vs. Placebo) (Burge PS BMJ 2000:320:1297-303) TRISTAN 20% reduction with fluticasone (Calverley PM et al Lancet 2003:361:449-56) TORCH Combination ICS and LABA TRISTAN fluticasone and salmeterol reduced d exacerbation 25 % Budesonide and formoterol reduced 24 % in two studies (Szafranski et al Eur Respir J 2003:21:74-81, Calverley PM et al Eur Respir J 2003:22:912-19) 21
TORCH 6112 patients followed for 3 years randomised d to Placebo Fluticasone 500 μg x 2 Salmeterol 50 μg x 2 combination Calverley PM et al New Engl J Med 2007;356:775-89. Moderate and severe exacerbations 1,2 1 0,8 0,6 TORCH 0,4 0,2 0 Placebo Salmeterol Fluticasone Combination 22
0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0 Oral corticosteroids Placebo Salmeterol Fluticasone Combination TORCH Hospitalisations TORCH n.s n.s n.s 23
Cardio-ischemic events in COPD patients effect of inhaled corticosteroids EUROSCOP - 1175 patients followed for 3 years Without cardiac disease at randomisation 60 new events in 49 patients: 31/582 in placebo and 18/592 in budesonide group (p<0.05) Post-hoc study showing a preventive effect on cardioiscemic events with inhaled corticosteroids in COPD Löfdahl CG et al ERJ 2007:29(6):1115-9 24
Conclusions Knowledge on pathogenetic mechanims is increasing Diagnosis dependent on spirometry Smoking cessation!! Symptomatic and preventive treatment Several interventions can prevent exacerbations in COPD Influensa-vaccination Pneumococcal vaccination (?) LTOT (?) Rehbilitation Pharmacologic treatment Bronchodilators Inhaled corticosteroids Combination treatment 25