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BRONCHIAL ASTHMA Dr. Romulo T. Uy Pulmonary Medicine HISTORICAL BACKGROUND OF ASTHMA Referred to by Hippocrates (400 B.C.) Described in detail in second century – “facial anxiety, rapid, noisy respirations, fear of suffocation, and scanty foamy expectoration” From the Greek meaning “panting” OVERVIEW - ASTHMA Chronic inflammatory disease of the airways (mast cells, lymphocytes, eosinophils, epith cells) leading to: HYPERRESPONSIVENESS Worsening on exposure to various stimuli OBSTRUCTION Variable and usually reversible SYMPTOMS Recurrent wheezing, shortness of breath, chest tightness, and/or cough PREVALENCE OF ASTHMA A very common disease worldwide & increasing trend 6% in USA Occurs predominantly in early life Philippines – 12% in children (13-14 yrs old); 17-22% older age group Male-female ratio <10 yrs 2:1; equal 30 yrs Highest prevalence in Australia, UK & New Zealand ASTHMA PREVALENCE IN ASIA ISAAC Study 1998 Country Children Adolescents (6-7 yrs old) (13-14 yrs old) CHINA - 4.2% HONGKONG 9.7% 12.4% MALAYSIA 6.1% 9.6% PHILIPPINES 11.3% 12.3% SINGAPORE 15.7% 9.7% KOREA 13.3% 7.7% TAIWAN 9.6% 5.2% Asthma is a variable disease Symptoms and use of reliever medication Exacerbation Exacerbation Oral course of corticosteroids Effect of inhaled corticosteroids during periods of worsening Time Cellular effects of the mono-components Virus? Adenosine Exercise Fog Bronchoconstriction Sensory nerve Mast cell Plasma leak Antigen activation Macrophage Eosinophil Airway hyper- responsivene ss Virus? T- lymphocyte Asthma - an inflammatory disease Normal Asthma Laitinen LA et al, J Allergy Clin Immunol 1992 PATHOPHYSIOLOGY Normal airway Airway during acute attack REDUCTION IN AIRWAY DIAMETER smooth mm contraction, vascular congestion, edema of bronchial wall, & thick tenacious secretions. INCREASE IN AIRWAY RESISTANCE DECREASE IN FEV1 & FLOW RATES HYPERINFLATION OF LUNGS & THORAX INCREASED WORK OF BREATHING ALTERATIONS IN RESPIRATORY MUSCLE FUNCTION Post-mortem airways V/Q MISMATCH HYPOXEMIA, HYPERCAPNIA RESPIRATORY ALKALOSIS AIRWAY REMODELING Increase in airway hyperresponsiveness Non-reversibility of airway obstruction & residual obstruction after bronchodilators Accelerated decline in FEV1 STIMULI THAT INCITE ASTHMA Allergens – Activated by interaction of Ag with mast cell-bound IgE molecules dendritic cells in airway epithelium migrate to local lymph nodes THo + IL4 TH2 – Usually airborne – Usually seasonal and seen in children and young adults – Nonseasonal – animal danders, dust mites, molds – Early response occurs immediately – Late response – 6-10 hrs Pharmacologic – Aspirin and NSAID’s, beta-blockers, coloring agents, sulfiting agents Environmental – Air pollutants – ozone, nitrogen dioxide, sulfur dioxide STIMULI THAT INCITE ASTHMA Occupational – High mol wt compds – wood and vegetable dust, drugs (antibiotics, cimetidine), animal & insect dusts – Low mol wt – metal salts, industrial chemicals & plastics Infectious – – respiratory viruses > bacteria Exercise-induced – does not evoke any long term sequelae, nor does it increase airway reactivity – Severe attacks in increase ventilatory effort & cold air Emotional – bronchoconstriction thru vagal efferents or endorphins?? CLINICAL FEATURES Triad – cough, dyspnea & wheezing Attacks – prolonged expiration, tachypnea, tachycardia, mild increase in SBP; Severe obstruction – use of accessory muscles and paradoxical pulse Cyanosis – late CLINICAL FEATURES Curschmann’s spirals eosinophils & Charcot-Leyden crystals In severe attacks – wheezing absent, ineffective cough, gasping Pneumothorax or pneumomediastinum STATUS ASTHMATICUS Severe asthmatic attacks not responsive to drugs and associated with signs and symptoms of potential acute respiratory failure DIAGNOSIS OF ASTHMA History – triad, temporal waxing and waning of sx, a positive family history, provoked by exogenous factors, & improvement of symptoms with bronchodilators PE – maybe normal, wheezing is non- specific for asthma & doesn’t correlate with severity Objective measurement DIAGNOSIS Objective Measurements Spirometry - > 12% (200 ml in adults) improvement in FEV1 postbronchodilator Serial measures of peak expiratory flow rates (PEFR) – >20% change post BD over time Pre and post BD PEFR - >15% change after using inhaled BD in clinic Methacholine challenge – provocative doses of methacholine resulting in a 20% fall in FEV1 from the baseline (PC20) < 8 mg/ml SPIROMETRY FEV1 FVC FEV1/FVC 0 Normal 4.150 5.200 80 % Obstructive 2.350 3.900 60 % 1 2 Liter FEV1 3 obstructive 4 FEV1 FVC Normal 5 FVC 1 2 3 4 5 6 Seconds PEAK EXPIRATORY FLOW RATE Greatest flow velocity produced during a forced expiration from fully inflated lungs Advantages: – Simple and reproducible – Portable – Quantitative – Correlates with spirometry (FEV1) Disadvantages: – Effort dependent – Lung volumes are not measured – Absence of printed record DIAGNOSIS Objective Measurements Spirometry - > 12% (200 ml in adults) improvement in FEV1 postbronchodilator Serial measures of peak expiratory flow rates (PEFR) – >20% change post BD over time Pre and post BD PEFR - >15% change after using inhaled BD in clinic Methacholine challenge – provocative doses of methacholine resulting in a 20% fall in FEV1 from the baseline (PC20) < 8 mg/ml Monitor Peak Expiratory Flow Keep an Asthma diary DIAGNOSIS Objective Measurements Spirometry - > 12% (200 ml in adults) improvement in FEV1 postbronchodilator Serial measures of peak expiratory flow rates (PEFR) – >20% change post BD over time Pre and post BD PEFR - >15% change after using inhaled BD in clinic Methacholine challenge – provocative doses of methacholine resulting in a 20% fall in FEV1 from the baseline (PC20) < 8 mg/ml TABLE 1.3. Severity-Based Classification Of Chronic Asthma Intermittent Persistent Mild-Moderate Severe** Daytime sympts Monthly Weekly Daily Nocturnal < monthly Monthly to weekly Nightly awakening Rescue b2 use < weekly Weekly to daily Several times a day PEF or FEV1* > 80% predicted 60-80% predicted < 60% predicted Treatment needed to Occasional prn b2 Regular ICS + Combination ICS + control asthma only LABA combination LABA + OCS GOALS OF TREATMENT Maintain adequate oxygenation Relieve airflow obstruction Reduce airway inflammation Prevent future relapses – Elimination of causative agents from the environment of an allergic individual THERAPY QUICK-RELIEF MEDICATIONS LONG-TERM CONTROL MEDICATIONS Asthma is a chronic inflammatory lung disease Smooth Airway muscle inflammation/ B2 Agonists dysfunction remodelling ICS • Bronchoconstriction • Inflammatory cell • Bronchial hyper- infiltration/activation reactivity • Mucosal oedema • Hyperplasia • Cellular proliferation • Inflammatory • Epithelial damage mediator release • Basement membrane thickening Symptoms\exacerbations Johnson M. Current Allergy Clin Immunol 2002 What is the first line of therapy in acute asthmatic attack? Beta 2 agonists Epinephrine Anticholinergic agents Theophylline Steroids BRONCHODILATORS QUICK – RELIEF MEDICATIONS – drugs that inhibit smooth muscle contraction – Beta-agonists – Anticholinergics – Methylxanthines B2 AGONISTS – Short-acting beta2 agonists (SABA) First line therapy in the ER Interact with beta2 receptors of cells increase cAMP bronchodilatation Onset of action is rapid (5 min) Duration of action – 6 hrs Side effects are usually well tolerated BETA2 AGONISTS Catecholamines - Short-acting beta 2 agonists (SABA) – terbutaline, salbutamol Resorcinols - fenoterol Saligenins – albuterol Major side effects – tremors Active via all routes (oral, IV or inhalation) Lasts 4-6 hours Inhalation route is preferred – maximal bronchodilatation with fewer side effects BETA2 AGONISTS Catecholamines - Short-acting beta 2 agonists (SABA) – terbutaline, salbutamol 4-6 hours Long-acting beta 2 agonists (LABA) lasting for 12 hours - Salmeterol & Formoterol Combination of LABA + inhaled steroids – Symbicort (formoterol & budesonide) – Seretide (sslmeterol & fluticasone) B2 AGONISTS – Areas of debate Which route? Inhaled vs intravenous Which device? pMDI’s, wet nebulizers, DPI’s Which beta 2 agonist? Short-acting vs long- acting beta2 agonists What dose and intervals of administration? B2 AGONISTS – Inhaled vs Intravenous Meta-analysis 584 patients in 15 trials Inhaled route recommended than IV – faster onset, fewer adverse effects and more effective than IV (Level I) No clinical benefit of IV beta agonist either as adjunct to or replacement of inhaled bronchodilator (Level I) Travers, et. al., Chest 2002; 122 Cochrane Database 2002 B2 AGONISTS – Which inhaler device? There is no clear evidence that any one device is superior over the other. Although lung deposition studies show superiority of some inhaler devices, it is not clear whether this translates to better efficacy. (Level II) PCCP Asthma Consensus 2004 B2 AGONISTS – Which inhaler device? pMDI’s vs nebulizers – 3 RCT’s compared NEB vs pMDI + spacer in adults with mod to severe attacks – Equally efficacious in improving FEV1, PEFR & symptoms (Level I) – NEB grp – more headaches, palpitations, tremors – Use nebulizers if patient unable to coordinate Colacone, Chest 1993 Mandelberg, Chest 1997 Rodrigo, Am J Emer Med 1998 B2 AGONISTS – Which inhaler device? pMDI’s + large-volume spacers more rapid bronchodilation (1-2 min compared to 15-20 min with nebulizers), fewer side effects (Level I) Rodrigo, Chest 2004 INHALER DEVICES MDI’s compared to other handheld inhaler devices to deliver beta2 agonists in non- acute asthma – no difference between devices (Level I) Cochrane Library 2002 B2 AGONISTS – What dose/interval? Doses of administration – Should be individualized using objective measures of obstruction – Studies support use of high & repeated doses – Induce maximal stimulation of B2 receptors without causing side effects Rodrigo et al., Chest 2004 BETA 2 AGONISTS INHALER NEBULE Ventolin 100mcg/dose 0.5 mg/2.5 ml Berodual Feno 50 mcg Feno – 1.25 mg IB – 20 mcg IB – 0.5 mg Bricanyl Turbuhaler – 500 2.5 mg/ml mcg Combivent IB – 20 mcg IB – 500 mcg Salb – 120 mcg Salb – 2.5 mg USE OF INHALERS Patient instruction on proper use of device is important All clinicians should understand the correct use of aerosol devices If patient does not respond to beta2 agonist, what is your next drug of choice? Theophylline Anticholinergic drugs Another beta 2 agonist Singulair ANTICHOLINERGIC DRUGS Cholinergic-induced bronchoconstriction involves the large airways; B2 agonists relax small airways Muscarinic receptors: – M1 – within parasympathetic ganglia – M2 – postganglionic sympathetic nerves/ act as negative feedback – M3 – airway smooth muscles Nonselective anticholinergic agents – inhibits M1, M2 & M3. Ex: atropine, ipratropium bromide Selective anticholinergic drugs – inhibit M1 & M3 Ex: tiotropium bromide ANTICHOLINERGIC DRUGS Ipratropium Bromide Use of ipratropium bromide (IB) as the initial bronchodilator in adult asthmatics – inferior to beta2 agonists Addition of IB to beta2 agonists provided additional benefits to asthmatics (Level I) IB is a quaternary ammonium compd currently the only inhaled anticholinergic bronchodilator licensed in USA Slow onset of action – 30 minutes ANTICHOLINERGIC DRUGS Ipratropium Bromide Insoluble in lipids/less than 1% absorbed systemically – Does not exert unwanted side effects/stays in airways – 10X recommended dose – no side effects Slow onset of action – 30 minutes but longer duration of action (6 hrs) METHYXANTHINES - Theophylline Mild to moderate bronchodilatation Mechanism of action – uncertain Convenient long-acting oral dosage forms & IV form Therapeutic plasma concentration 5-15 ug/ml Side effects – GIT symptoms (nausea, vomiting) most common & CNS (stimulation/seizures) & cardiac (tachycardia/arrhythmia) THEOPHYLLINE Decreased metabolism ( blood levels) – Liver diseases – Congestive heart failure – Cimetidine – Quinolone – Febrile illness – Old age Increased metabolism ( blood levels) – Cigarette smoking – Young age – Phenytoin THEOPHYLLINE IV aminophylline should not be used as a first line of treatment in AAA (Level I) IV aminophyllined showed no clinical benefit compared to beta2 agonists Addition to beta-2 agonists no significant benefits but increase side effects (tremors, nausea, anxiety and tachyarrhythmias) As an option for patients where all other modalities have failed but should be used cautiously Cochrane Review 2002 THERAPY LONG-TERM CONTROL MEDICATIONS – agents that prevent/reverse inflammation – Glucocorticoids – Long-acting beta 2 agonists (LABA) – Mast-cell stabilizing agents – Leukotriene modifiers – methylxanthines Asthma is a chronic inflammatory lung disease Smooth Airway muscle inflammation/ B2 Agonists dysfunction remodelling ICS • Bronchoconstriction • Inflammatory cell • Bronchial hyper- infiltration/activation reactivity • Mucosal oedema • Hyperplasia • Cellular proliferation • Inflammatory • Epithelial damage mediator release • Basement membrane thickening Symptoms\exacerbations Johnson M. Current Allergy Clin Immunol 2002 GLUCOCORTICOIDS Most potent & most effective anti-inflammatory agent available Mechanism of action: – Inhibit synthesis of most cytokines – Reduce vascular permeability – Inhibit mediator synthesis and release Available – IV, oral or inhaled Effects not immediate - >6 hrs Dose should be tapered – ½ the dose every 3-5 days over 10-12 days Prednisone, methyprednisolone, prednisolone CORTICOSTEROIDS Reduction of symptoms Diminish airway hyperresponsiveness Prevention of exacerbations Possibly prevention of airway remodelling (Level 1) CORTICOSTEROIDS Do corticosteroids improve pulmonary function tests within 24 hours? Does parenteral (IV or IM) route improve outcome compared to oral or inhaled administration? What is the relative efficacy of the different doses – high dose vs low dose? What is the lag time for IV steroids to take effect? 1 hr 2 hrs 4 hrs 6 hrs How Soon Do Steroids Work? 140 120 Hydrocortisone FEV1 Change (%) 20 asthmatics, 31–32 yr 100 Placebo * Hydrocortisone 2 mg/kg 80 bolus, then 0.5 mg/kg/hr 60 * × 24 hr vs placebo 40 Results 20 – Initial 6 hr lag, followed by 0 progressive improvement –20 – No in PaO2 response –5 0 5 10 15 20 Time (hr) Fanta CH et al. Am J Med. 1983;74:845 *P<0.025 vs placebo META-ANALYSIS: RESULTS Pulmonary function 1st 24 hours – Patients required at least 6-24 hours to show moderate improvement in lung function – Only high doses of inhaled corticosteroids significantly improved lung function compared to placebo (ES=0.56 CI 0.15-0.97) within 3 hours Rodrigo et al., Chest 1999: 116 EFFECTS OF CORTICOSTEROID IN ACUTE ASTHMA VARIABLE SYSTEMIC INHALED STEROIDS STEROIDS Effects Anti-inflammatory Topical Time delay > 6 hours < 3 hours Mechanism Induce Up-regulate postsynap. transcriptional adrenergic receptors airway effects synthesis mucosa vasoconstrict airway of new proteins mucosa bld flow mucosal decongestion CORTICOSTEROIDS: Oral vs Parenteral 4 studies, RCT, 157 patients Compared MTP IV and po, IV hydrocortisone and Prednisone po Conclusion: oral route provided similar beneficial effects on pulmonary function when compared to IV (Level 1) Rodrigo et al., Chest 1999: 116 How much IV hydrocortisone will you give? 50 mg IV q 6 hrs 100 mg IV q 6 hrs 250 mg IV q 6 hrs 500 mg IV q 6 hrs CORTICOSTEROIDS: Meta-analysis High vs Low Dose 5 RCT’s: Low dose – 50 mg hydrocort q 6h or 15 mg MTP q 6h Medium dose – 100 mg q 6h or 40 mg MTP q 6h High dose – 500 mg q 6h or 125 mg MTP q 6h Pooled results showed a nonsignificant favorable trend toward improve outcome with medium and high doses (Level I) Rodrigo et al., Chest 1999 INHALED CORTICOSTEROIDS Potent local/topical anti-inflammatory with minimal systemic toxicity Control inflammation Prevention of symptoms Reduce need for oral steroids Prevent hospitalization INHALED CORTICOSTEROIDS Agents – budesonide, fluticasone, beclomethasone, triamcinolone, flunisolide Oral steroid sparing effects Combination with long acting beta2 agonists (LABA) – synergistic Seretide – salmeterol & fluticasone Symbicort – formoterol & budesonide INHALED CORTICOSTEROIDS Local side effects: – Oral thrush – Cough/hoarseness – Can be reduced with use of spacer or rinsing mouth Systemic side effects – Infrequent at currently recommended doses – Mild adrenal suppression possible with higher doses – Cataract formation, decreased growth in children, purpura, interference with bone metabolism MAST CELL STABILIZING AGENTS Cromolyn sodium and nedocromil sodium Inhibit degranulation of mast cells Nonsteroidal Effectively prophylactically inhibit both early and late phase reactions 4-6 weeks trial therapy Side effects of cromolyn – cough; nedocromil – unpleasant taste, nausea/vomiting LEUKOTRIENES Cysteinyl leukotrienes (LTC4, LTD4, LTE4) induce airway obstruction, bronchovascular leak, mucous gland secretion, proliferation of smooth muscles & granulocyte infiltration One of potent molecules airway obstruction Produced by eosinophils, mast cells & neutrophils LEUKOTRIENE INHIBITORS 5 lipo-oxygenase (5-LO) inhibitor – Zileuton Inhibitors of LTD4 at receptor – Montelukast (Singulair) and Zafirlukast (Accolate) Modest brochodilation, effective in exercise- induced asthma (EIA) and nocturnal symptoms Effective in aspirin-induced asthma Limited effectiveness against allergens Inhaled CS (ICS) superior to leukotriene inhibitors; add-on to ICS improved lung function LEUKOTRIENE INHIBITORS Hepatic enzymes elevate but reversed with drug withdrawal Montelukast – lesser elevation of liver enzymes Rare complication – Churg Strauss syndrome (CSS) – systemic vasculitis, peripheral eosinophilia, pulmonary infiltrates, & myocarditis CSS not direct result of leukotriene inhibitors but due to unmasking of pre-existing CSS as a result of steroid withdrawal Severity-Based Classification Of Chronic Asthma Intermittent Persistent Mild-Moderate Severe** Daytime sympts Monthly Weekly Daily Nocturnal < monthly Monthly to weekly Nightly awakening Rescue b2 use < weekly Weekly to daily Several times a day PEF or FEV1* > 80% predicted 60-80% predicted < 60% predicted Treatment needed to Occasional prn b2 Regular ICS + Combination ICS + control asthma only LABA combination LABA + OCS Chronic Treatment based on Severity* Daily Alternative Reliever controller controller medications medications Intermittent None necessary SABA prn Mid- ICS + LABA as ICS high dose SABA prn single inhaler or ICS regular Moderate combination dose + any of Persistent the following: -SR -Theophyl line -Anti-LT -Oral SR b2- agonist Severe Oral steroids + SABA prn ICS + LABA + Persistent any of the above drugs GOALS OF TREATMENT GINA GUIDELINES Minimally (ideally no) chronic symptoms including nocturnal symptoms Minimal (infrequent) exacerbations No ED visits Minimal (ideally no) use of prn beta agonists No limitations of activities, including exercise PEFR circadian variations <20% Near normal PEFR Minimal (or no) side effects from medications CONCLUSION Asthmatic – chronic inflammatory disease of the airways airway obstruction & hyperresponsiveness The mainstay of treatment – LABA + INHALED CORTICOSTEROIDS In AAA, use SABA initially; may add anticholinergic drugs CONCLUSION Quick relief medications - SABA & LABA Controller medications – inhaled steroids mainly; for attacks, oral route is effective; low dose IV steroid. Proper use of inhalers/ avoid triggers Ensure proper follow-up care after patients are discharged from the ER to prevent relapse Neutrophils INFLAMMATORY MEDIATORS STIMULI CYTOKINES GROWTH MEDIATORS MEDIATORS (GMCSF, IL-8 FACTORS (NO, PGE2, (ENDOTHELIN I) RANTES, (EGF, IGF-1, 15-HETE) EOTAXIN PDGF) BRONCHOCONSTRICTION INFLAMMATION FIBROSIS VASODILATATION SMOOTH MUSCLE HYPERPLASIA
"ASTHMA AND COPD"