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402 articles reviewed from July 1, 2008 to June 30, 2009, with 23 articles identified as having impact on the GINA Report (updated 2009)..

overviewasthmachronic inflammatory disorder of airways in which many cells and cellular elements play a role300 million affected worldwideHost factors (genetic) and environmental Airway hyperresponsiveness: wheezing, breathlessness, chest tightness, coughing (night or early am)Widespread but variable airflow obstruction within the lung that is often reversibleManifestations can be controlled

Multiple genes 4 areas1) production of allergen-specific IgE antibodies (atopy)2)expression of airway hyperresponsiveness3) generation of inflamamtory mediators (cytokines, chemokines, growth factors)4) determination of Th1/Th2 immune responses ratio (as relevant to hygiene hypothesis of asthma Obesity: leptins affect airway function, increases likelihood to develop asthmaSEX: male, esp before age 14 (males 2x as female), by adulthood F>M. Unclear why, but lung size at birth MF.Infections: viruses associated with inception of asthmatic phenotype esp in infancy. Ex. Respiratory syncytial virus and parainfluenza virus produce symptoms including bronchiolitis that parallel features of asthma; long term prospective studies show 40% continuing to wheeze or develop asthma in later childhood; while other infections measles (even RSV) may protect vs asthma; parasites do not protect, but hookworm may reduce the risk

hygiene hypothesis: suggests that exposure to infections early in life influences devt of childs immune system along a nonallergic pathway hence reduced risk of developing asthma6mechanismInflammatory disorder affecting all airways, most pronounced in medium sized bronchiActivated mast cells, increased eosinophils, increased T cell receptor invariant natural killer T cells and T helper 2 lymphocytes (Th2) releasing mediators

Special mechanismsACUTE EXACERBATIONS: transient worsening due to exposure to triggers (exercise, pollutants, thunderstorm, infections, other allergens)NOCTURNAL ASTHMA: not clear but may be related to circadian rhythms of circulating hormones (epinephrine, cortisol, melatonin)special mechanismsDIFFICULT TO TREAT ASTHMA-accounts for those who are difficult to manage and relatively insensitive to effects of glucocorticosteroids-not well understood-associated with poor compliance and psychologic/psychiatric disorders; also genetic-difficult to treat from the onset vs progressing from milder asthma-airway closure leads to air trapping and hyperinflation-with an increase in neutrophils, more small airways involvement and more structural changesSMOKING AND ASTHMA:More difficult to control, with more frequent exacerbations and hospital admissions, with rapid decline in lung function, increased risk of deathNeutrophil predominant inflammationpoorly responsive to glucocorticosteroidsDiagnosis and classificationdiagnosis

PFT by spirometery or perk expiratory flow continues to be recommended as aid to diagnosis and monitoring.Measuring variability of airflow limitation is given increased prominence, as it is key to both asthma diagnosis and assessment of asthma control.Spirometry: forced expiratory volume in 1 sec and forced vital capacityReversibility: rapid improvements in FEV1 or PEF measured within minutes after inhalation of rapid acting bronchodilator (eg 200-400 ug salbutamol) or more sustained improvement over days or weeks after introduction of effective controller treatment (inhaled GCS). In spirometry, 12% and 200 ml from pre-bronchodilator value. (may not exhibit variability in each assessment esp if in tx, hence lacks sensitivity. Repeated testing at different visit is advised).Airflow limitation FEV1/FVC normally >.75-.80 (>.90 in children). In PEF: a 60 L/min (or 20% prebronchodilator PEF) imnpreovement after bronchodilator or diurnal variation of PEF of >20% (with 2x daily readings, more than 10%) suggests asthmaVariability: improvement or deterioration in symptoms and lung fucntion occuring over time may be diurnal, month to month or seasonal.

14Some definitionSpirometry: forced expiratory volume in 1 sec and forced vital capacity

REVERSIBILITY: rapid improvements in FEV1 or PEF measured within minutes after inhalation of rapid acting bronchodilator (eg 200-400 ug salbutamol) or more sustained improvement over days or weeks after introduction of effective controller treatment (inhaled GCS).

In spirometry, 12% and 200 ml from pre-bronchodilator value. may not exhibit variability in each assessment esp if in tx, hence lacks sensitivity. Repeated testing at different visit is advised.

Airflow limitation FEV1/FVC normally >.75-.80 (>.90 in children).

In PEF: a 60 L/min (or 20% prebronchodilator PEF) improvement after bronchodilator or diurnal variation of PEF of >20% (with 2x daily readings, more than 10%) suggests ASTHMA

VARIABILITY: improvement or deterioration in symptoms and lung function occurring over time may be diurnal, month to month or seasonal.

Common clinical measurements of airflow are obtained from maneuvers in which the subject inspires to TLC and then forcibly exhales to RV. Three measurements are commonly made from a recording of forced exhaled volume versus timei.e., a spirogram: (1) the volume of gas exhaled during the first second of expiration [forced expiratory volume (FEV) in 1 s, or FEV1], (2) the total volume exhaled [forced vital capacity (FVC)], and (3) the average expiratory flow rate during the middle 50% of the VC [forced expiratory flow (FEF) between 25 and 75% of the VC, or FEF2575%, also called the maximal midexpiratory flow rate (MMFR)] (Fig. 246-2).

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classification

(old) classification of asthma severity by clinical features before treatmentINTERMITTENT: =2x/mo; >=80% predicted, variability 1x/wk, daily use of saba; 60-80% predicted; variability >30%SEVERE PERSISTENT: daily symptoms, frequent exacerbations, frequent nocturnal sx, limitation of physical activites 30%.Based on expert opinion rather than evidence. Value only on cross-sectional means of characterizing group of pts not on inhaled GCS,a s in selecting pts for asthma study; main limitaiton is poor predictive value on what tx to require and what pts response to tx might be17

treatment

treatmentControllers: inhaled and systemic GCS,leukotriene modifiers, long acting inhaled beta-2 agonists with inhaled GCS, sustained-release theophylline, cromones, anti-IgE

Relievers: rapid-acting inhaled beta-2 agonists, inhaled anti-cholinergics, short-acting theoophylline, short-acting oral beta2-agonists

treatment

CONTROLLER : INHALED GLUCOCORTICOSTEROIDSACTION: Decrease number and activity of cells in airways inflammation-macrophages, eosinophils and T-lymphocytesAnti-inflammatory: reverses mucosal edema, decreasing capillary permeability, inhibit release of leukotrienesEfficacy in reducing asthma sx, improving QOL, improving lung function, decreasing airway hyperresponsiveness, controlling airway inflammation and reducing frequency/severity of exacerbations and mortality

Do NOT cure ASTHMADeterioration of control within weeks to months if discontinuedMost benefit from low dose, equivalent to 400ug of budesonide per day.

Increasing doses=little benefit, greater side effect. Better to add another class of controller. Higher doses for smokers

SE: oropharyngeal candidiass, dysphonia, coughing. At higher doses, rarely brusing and skin thinning, rarely adrenal suppressionPrevent by: mouthwashing, use of spacer devices, some prodrugs (ciclesonide) activated in lungs but not in pharynxNO evidence of increased risk for pulmonary infections and is NOT contraindicated in active PTB

CONTROLLERS: LEUKOTRIENE MODIFIERSACTION: inihibit 5-lipooxygenase (Zileuton), and cysteinyl-leukotriene 1 (CysLT1) receptors (Montelukast, pranlukast, zafirlukast). Small and variable bronchodilator effectreduce cough, improve lung function and reduce airway inflammation and exacerbationGood response from pts with aspirin-sensitive asthmaLess effective than low dose i-GCS when used alone as controller; and less effective than long acting inhaled beta2 agonists as add-onsSE: liver toxicity (Zileuton)CONTROLLERS: LONG ACTING INHALED BETA 2 AGONISTSNOT for monotherapy as they do not influence airway inflammation; effective when combined with inhaled GCSHence the development of fixed combination inhalers delivering both GCS and inhaled LABA simultaneously (e.g.fluticasone propionate + salmeterol, budesonide + formoterol) which is as effective as giving each drug separatelyFavors convenience, compliance, and ensures that LABA is always accompanied by GCSformoterol+budesonide: both as rescue and maintenanceFormoterol has more rapid onset of action than salmeterol, making it more suitable both for symptom relief and symptom preventionPrevent exercise induced bronchospasm, longer protection than rapid B2agonistsSE: CVS stimulation, tremor, hypokalemiaPossible increased risk of asthma-related death in a small group of individuals (use of salmeterol) hence should not be used as substitute for inhaled GCS

CONTROLLER: THEOPHYLLINEBronchodilator with modest anti-inflammatory propertiesSustained-release formulation OD/BID although little effect as first-line controllerMay benefit as add-on therapy for those who do not achieve control on inhlaed GCS aloneLess effective then LABA as add-onMetabolized by liverSE: at higher doses (10mg/kg/body wt/day or more). GI sx (nausea,vomiting; if >20 mg/L), loose stools, arrythmia (if >40mg/L), seizures, deathNarrow therapeutic window, toxicity related to plasma concentrationsShould closely monitor if at high doseInteractions: febrile illnes, pregnancy, anti-Kochs reduce levels while liver dse, CHF, cimetidine, some quinolones/macrolides increase toxicityCONTROLLER: CROMONESACTION: alter function of delayed chloride channels in cell membrane, inhibiting cellular activationaction on airway nerves thought to cause nedocromils inhibition of cough, on mast cells for inhibition of early response to antigen challenge and on eosinophils for inhibition of inflammatory response to inhalation of allergens (Katzung)

Limited role, weak antiinflammatory, less effective vs low dose iGCSMonotherapy with cromones no longer alternative to monotherapy with low dose inhaled GCS

SE: sore throat, cough, unpleasant tasteSome changes have been made to tables of equipotent daily doses of inhaled GCS for both children and adults29CONTROLLER: LONG ACTING ORAL BETA 2 AGONISTSlow release fomulations of salbutamol, terbutaline and bambuterol (prodrug converter to terb in the body)Rarely used; PRN for bronchodilationSE: tachycardia, anxiety, skeletal muscle tremor, adverse CVS reactions (if +theophylline)Harmful if regularly used aloneCONTROLLER: ANTI-IgEOmalizumabLimited to pts with elevated serum IgE, for pts with severe allergic asthma, uncontrolled on GCsSE: safe as add-on tx (study on >12 yo who were already receiving (i/o) GCS and LABACONTROLLER: SYSTEMIC GLUCOCORTICOSTEROIDSLong-term (>2 weeks) for severity of uncontrolled asthmaOral > parenteral (IM/IV) due to lower mineralocortocoid effect, relatively short half-life and lesser effect on striated muscles, with great dosing flexibility permiting titration to lowest acceptable dose that maintains controlSE: osteoporosis, arterial HPN. DM, HPA-axis suppression, obesity, cataratc, glaucoma, skin thinning, easy brusing, muscle weaknessRarely, if withdrawn: adrenal failure or may unmask Churg-strauss syndromeCaution with those who have PTB, sever parasitic infections, ospeoprorosis, glaucoma, diabetes, peptic ulcer, fatal hepres virus.

CONTROLLER: oral antiallergic compound

E.g. Tranilast, repirinast, tazanolast, pemirolast, ozagrel, celatrodast, amlexanox, ibudilastLimited anti-asthma effects, need mpre studiesSE: sedationOther controllersLow-dose methotrexate: two metaanalyses of its steroid sparing effects showed small over-all benefit, but high adverse effectsCyclosporin and gold: effective in someMacrolide, troleanromycin: small steroid-sparing effect when used with systemic methylprednisolone (but macrolide may decrease GCS metabolism)IV immunoglobulin: NOT recommendedSE: nausea, vomting, abdominal pain, occ liver toxicity (macrolide)Allergen specific immunotherapyLimited roleNeed to identify and use single well-defined clinically relevant allergenadminister in progressively higher dosetolerance75 RCT of specific immunotherapy vs placebo confirmed efficacy in reducing symptom scores, med requirements, improving allergen-specific and non-specific airway hyperresponsiveness

RELIEVERS: RAPID ACTING INHALED BETA 2 AGONISTSMeds of choice for bronchospasm relief during exacerbations, and pretreatment of exercise-induced bronchoconstrictionE.g. salbutamol, terbutaline, fenoterol, levalbuterol HFA, reproterol, pributerolFormoterol: also for sx relief due to rapid onset (reserve for those on inhaled GCS)Only as PRN, lowest dose and frequency requiredIncrease use (to daily): deterioration of asthma control, need to reassess txSE: tremor, tachycardia, inhaled preparationsRELIEVERS: SYSTEMIC GLUCOCORTICOIDSNot usually as relieversImportant in severe acute exacerbations as they prevent progression of asthma exacerbation, reduce need for referral to ER and hospitaliztion, prevent early relapse, reduce morbidity of illness. Effects seen in 4-6 hrs. Oral>IV40-50 mg prednisolone OD or 5-10 days depending on severity. SE: abn glucose metabolism, increase appetite, fluid retention, weight gain, rounding of face, mood ateration, hypertension, PUD, Aseptic necrosis of femur.

38RELIEVERS; ANTICHOLINERGICSE.g. Ipatropium bromide (IB), ixitropium bromideInhaled IB less effective reliever vs rapid inhaled Beta2 agonistMetaanalysis showed stat significant albeit modest improvement in pulmo fucntion and significantly reduces risk of hospitalizationNo established long-term benefit; but is recognized as alternative to those with adverse effect: tachycardia, arrythmia, tremorsSE: dryness of mouth, bitter tasteRELIEVER: THEOPHYLLINENot for patients already on sustained release theophylline unless se concentration of theophyllline is known to be low or monitored

RELIEVER: SHORT ACTING ORAL BETA 2 AGONISTIf unable to use inhaled medsAssociated with higher adverse effects

No longer 6 but FIVE-PART ASTHMA MANAGEMENT PROGRAMComponent 1: Develop Patient/Doctor PartnershipComponent 2: Identify and Reduce Exposure to Risk FactorsComponent 3: Assess, Treat and Monitor AsthmaComponent 4: Manage Asthma ExacerbationsComponent 5: Special Considerations

COMPONENT 1:Partnership bw patient and health care professionalsStrengthened by discussing and agreeing on goals of treatment, developing personalized, written self-management action plan (self-monitoring), periodically reviewing pts tx and level of controlEducation is the keyCOMPONENT 3Overall concept for asthma management now focusing on CONTROLTreatment initiated and adjusted in continuous cycle (assess control, treating to achieve control, and monitoring to maintain control) driven by level of asthma control

Treatment options: 5 stepsReflect increasing Tx intensity (dosages and/or number of meds

At ALL steps, RELIEVER meds should be provided PRN

STEPS 2-5, with variety of controller medsSTEP-UP if not controlled with current regimenWhen control maintained, may step down to find the lowest step and dose of treatment that maintains control

STEP 1: prn relieverRapid-acting inhaled b2agonist (A)Alternative: Inhaled anticholinergic, short-acting oral B2agonist, short acting theophylline, but slow onset, high risk of side effects (A)

Exercise induced asthma: rapid acting inhaled B2 agonist (oral or inhaled) prior to exercise or to relieve sx after exercise. Alternative leukotriene modifier or cromone (A)Training and sufficient warm up also reduce exercise induced asthma in athletes (B)STEP 2: reliever + controllerLow-dose inhaled GCS for all ages as initial controller (A)Alternative: leukotriene modifiers (A), those unable or unwilling to use inhaled, or those with persistent hoarseness, or concomitant allergic rhinitis (C)Sustained release theophylline has weak anti-inflammatory/controller efficacy (B)Cromones-low efficacy, favorable safety profile (A)STEP 3: reliever plus one or two controllersLow-dose iGCS + iLABA, either in combination inhaler devise or separately (A)Additive effect, low dose iGCS sufficient and may only be increased if no control within 3 or 4 mos (A)Formoterol OR formoterol+budesonide= effective as SABA in acute asthma exacerbation. Used as both rescuer and maintenance, reduce exacerbation and improve control (A)

STEP 3 (contn)Low dose iGCS+ leukotriene modifiers (A) or sustained release theophylline at low dose (B)

STEP 4: reliever + two or more controllersIf not controlled in step 3, may refer to ASTHMA expert/specialist Medium or high-dose iGCS+ iLABA and/or 3rd controller (leukotriene mod or SR theophylline), although in most patients, this provides very little benefit (A)High dose recommended only on trial basis for 3-6 mos (B); need twice daily dosing (A)Efficacy may be improved with Budesonide but with more frequent dosing (4x daily) (B)STEP 4 (cont)+ Leukotriene modifiers to med/high dose iGCS provide benefit (A) but less that that if + LABA (A)+ low sustained theophylline to med/high dose iGCS and LABA may also provide benefit (B)STEP 5: reliever + controller option+ oral GCS to other controller (D), with severe side effects (A) Consider only if severely uncontrolled on Step 4+ Anti IgE to other controllers: improve control when it has not been achieved on combi of other controllers (including highdose inhaled or oral GCS) (B).monitoringPts are seen 1-3 mos after the initial visit,Every 3 mos thereafter

After exacerbation, ff-up within 2 weeks-1 mo (D)

Duration and tx adjustmentImprovement within days of initiating txFull benefit after 3-4 mos

STEPPING DOWNLittle data on optimal timingMed-high iGCS alone: attempt 50% reduction in dose (3 mos interval) (B)Control at low dose iGCS alone: may swithc to once daily dosing (A)Stepping downiGCS+LABA: reduce iGCS by 50% while continuing LABA (B)If control maintained, further reduce GCS until low-dose, LABA may be stopped (D)Alternative: switch daily tx to ODOr d/c LABA earlier and substitute combination tx with iGCS monotherapy at same dose contained in combination inhalerlikely lead to loss of control (B)Stepping downiGCS + other controllers aside fr LABA: reduce iGCS by 50% until low dose then stop combinaiton treatment (D)Controller tx may be stopped if asthma remains controlled on lowest dose of controller + no recurrence for 1 year (D)Stepping upRapidonset SABA or LABA: repeated dosing provides temporary relief, if rpt dosing over 1 or two days, consider increase of controller txInhaled GCS: doubling not effective (A). A 4-fold or greater increase equivalent to short course of oral GCS in adults with acute deterioration (A)Maintain higher dose x 7-14 days (more research needed)Combination iGCS + rapid and LABA (formoterol)Effective in conrtoling and reducing exacerbation (A)Benefit of exacerbation consequence of early intervention

Difficult to treat asthmaNo acceptable level of control at step 4Mainstay: glucocorticosteroids. InvestigateConfirm asthma. Exclude COPD. t/c vocal cord dysfunctionConfirm treatment complianceConsider smoking, current & past, encourage complete cessationComorbidities that may aggravate asthma (chornic sinusitis, GER, obesity/obstructive sleep apnea, psych d/o)Accepted frequent rescuersComponent 4: manage exacerbations

Bronchodilators:Mild-moderate: rapid inhaled B2 agonists (2-4 puffs q 20 mins for 1st hour)Mild will respond to 2-4 puffs q3-4 hrsModerate: 6-10 puffs q1-2 hrs

May monitor PEF after bronchodilator tx. If given via MDI, ideally with a spacer, produces equivalent improvement in lung funcion as via nebulizer no addl. meds if PEF returns to greater than 80% of predicted or personal best, and response lasts x 3-4 hrs)GlucocorticosteroidsOral (0.5-1 mg prednisone/kg or equivalent during 24 hr period) should be used to traet exacerbations especially of they develop after giving the other short-term tx options If no response to bronchodilator tx as indicated by persistent airflow obsturction, prompt transfer to an acute care setting is recommended

FOR EXACERBATIONSOXYGEN: goal is arterial oxygen satn of >90% via NC, FM or head box (infants).

RAPID ACTING INHALED B2AGONIST: should be at regular intervals (A). Usually have short duration but FORMOTEROL, wc has rapid onset and long duration is shown to be EFFECTIVE w/o increasing SE, but more expensive.

Conflicting studies on intermittent vs continuous nebulized short-acting B2 agonists One study on pts requiring hospitalizations showed intermittent on-demand nebulization led to significantly shorter stay, fewer nebs, and fewer palpitations vs intermittent tx q4 hrsHence reasonable approach would be initial use of continuous therapy intermittent in-demand therapy for hospitalized pts.No evidence on routine IV B2 agonists with severe exacerbationsEPINEPHRINE: SC/IM injection for acute tx of anaphylaxis and angioedema but not routine on asthma exacerbationsCriteria for discharge from ER vs hospitalizationPre-treatment FEV1 or PEF