Asthma Update Asthma Update Suneel Kumar MD Suneel Kumar MD

Definition of Asthma National Asthma Education and Prevention Program (NAEPP) defined as: –Airway obstruction that is reversible (but not completely so in some subjects), either spontaneously or with treatment –Airway inflammation –Increased airway responsiveness to a variety of stimuli

WHO Definition of Asthma "A chronic inflammatory disorder of the airways in which many cells play a role, in particular mast cells, eosinophils, and T lymphocytes. In susceptible individuals this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough particularly at night and/or in the early morning. These symptoms are usually associated with widespread but variable airflow limitation that is at least partly reversible either spontaneously or with treatment. The inflammation also causes an associated increase in airway responsiveness to a variety of stimuli."

Symptoms Cough Wheezing Chest tightness Shortness of breath

Update in Asthma Current guidelines for treatment of asthma Beta agonist use Inhaled corticosteroids Leukotriene modifiers Chromones Anti-IgE therapy Use of exhaled nitric oxide in monitoring asthma Asthma during pregnancy

Current Guidelines for Treatment

Mild Intermittent Asthma Symptoms < 2 days/week Symptoms < 2 nights/month PEF or FEV 1 > 80% PEF variability < 20% No daily medication needed PRN beta agonists Course of systemic steroids for exacerbations

Mild Persistent Asthma Symptoms > 2 days/wk but < 1x/day > 2 nights/month PEF or FEV 1 > 80% PEF variability 20-30% Preferred treatment low dose inhaled corticosteroids Alternatives include cromolyn, leukotriene modifiers, necromodil, or sustained release theophylline

Moderate Persistent Asthma Symptoms daily > 1 night/week PEF or FEV 1 > 60% and < 80% PEF variability > 30% Preferred treatment is low to medium dose inhaled corticosteroid and a long acting inhaled beta 2 agonist Alternative includes increasing ICS within moderate dose range, or low to medium dose ICS with either leukotriene modifier or theophylline

Severe Persistent Asthma Continual symptoms Frequent nocturnal attacks PEF or FEV 1 < 60% PEF variability > 30% Preferred treatment is high dose inhaled corticosteroid and long acting beta 2 agonists If needed, can add systemic corticosteroids

Goals of Therapy Minimal or no chronic symptoms day or night Minimal or no exacerbations No limitations on activities; no school/work missed Maintain (near) normal pulmonary function Minimal use of short-acting inhaled beta 2 agonist Minimal or no adverse effects from medications

Stepwise Approach Review treatment every 1 to 6 months, and gradually step down treatment If asthma controlled not maintained, then a step up in treatment may be warranted

Reasons for Poor Asthma Control Inhaler Technique Compliance Environment Also assess for an alternative diagnosis “All that wheezes is not asthma, and not all asthma wheezes”

Factors Affecting Compliance Support of health care professional and family Route of drug administration (inhaled vs. oral) Complexity of drug regimens Side effects of medications $$ Cost $$

Beta 2 Agonists

Beta 2 Agonists Most potent and rapidly acting bronchodilators currently available for clinical use Given in different forms: –short acting = isoproterenol –intermediate acting = albuterol, metaproterenol, pirbuterol, levalbuterol, terbutaline (IV only), fenoterol [not available in the US] –long acting = salmeterol, formoterol

Mechanism of Action Beta 2 agonists interact with beta 2 receptors on the surface of a variety of cells that may play a role in asthma pathogenesis Beta agonists have the potential to relax bronchial smooth muscle, decrease mast cell mediator release, inhibit neutrophil, eosinophil, and lymphocyte functional responses, increase mucociliary transport, and affect vascular tone and edema formation

MDI with Spacer vs. Nebulizer Equivalent bronchodilation can be achieved by giving beta 2 agonist with a spacer/holding chamber or by nebulizer therapy Continuous administration with a nebulizer may be more effective in severely obstructed adults and in those who have difficulty with an MDI plus spacer

Chronic Use of Beta Agonists Arguments against chronic use: –Mortality may be increased –Control of asthma may worsen –Equal or superior efficacy can be achieved with inhaled corticosteroids

Increased Mortality with Chronic Use? A case-control study using linked health insurance databases in Saskatchewan, Canada* Increased risk of death or near-death from asthma was associated with the regular use of inhaled beta agonists, especially fenoterol (adjusted OR 6.1; 4.1 for albuterol) Did not appear to be confounded by asthma severity, and there was no relation to non–asthma mortality *Spitzer et al, NEJM Feb 1992;326(8):501-6

Increased Mortality with Chronic Use? However, increased odds ratios were also noted for theophylline (OR 2.4) and oral corticosteroids (OR 2.5) The case-control design precludes the establishment of causality *Spitzer et al, NEJM Feb 1992;326(8):501-6

Increased Mortality with Chronic Use? A subsequent analysis demonstrated a relationship between CV death and use of beta agonists taken orally or by nebulizer (RR = 2.4) but not when taken by MDI (RR = 1.2) Risk of CV death was also greater in patients who used theophylline (RR = 2.7) Most of CV deaths in patients with underlying CV disease, including acute coronary insufficiency and congestive cardiomyopathy* *Suissa et al, Am J Respir Crit Care Med 1996 Dec;154(6 Pt 1):

Increased Mortality with Chronic Use? A similar case-control study design demonstrated no evidence of any adverse effects on mortality with prolonged use of long-acting beta agonists Use of short-acting beta agonists in the 12 months prior to an index event was not associated with an increased risk of death from asthma, suggesting a direct causal relationship was unlikely* *Anderson et al, BMJ 2005 Jan 15;330(7483):117

Long Acting Beta Agonist Monotherapy Prolonged treatment with long-acting beta agonists and without inhaled corticosteroids has been associated with increased mortality 28-week placebo-controlled trial assessing the safety of the long-acting beta agonist salmeterol enrolled over 25,000 patients, but was stopped early when interim analysis revealed a significantly increased risk of death in those not taking concomitant inhaled corticosteroids and, independent of steroid therapy, in African-American patients* *"The Pink Sheet" FDC Reports. Chevy Chase, MD. 2003; 65(4):10

Tolerance to Beta Agonists More frequent in chronic use Induced more with oral rather than inhaled preparations Tolerance to long acting beta agonists may or may not occur (conflicting data)

Corticosteroids

Glucocorticoids Most potent antiinflammatory agents available for the treatment of asthma More effective than beta agonists, theophylline, and cromolyn sodium in reducing airway hyperresponsiveness during maintenance therapy

Glucocorticoid Mechanisms Alleviating airway inflammation Reducing collagen and tenascin deposition, two features associated with airway remodeling Inhibit the synthesis of almost all known cytokines Alteration of the number and availability of circulating leukocytes Reduction in vascular permeability Inhibition of mediator synthesis and release

Steroids and Long Acting Beta Agonists Results in greater improvements in lung function and symptom control than monotherapy with escalating doses of inhaled glucocorticoid Act synergistically to activate transcription factors, decrease smooth muscle proliferation, and impair eosinophil adhesion

Potency of Inhaled Corticosteroids

Can ICS Cause Osteoporosis? Three year prospective study looked at dose of inhaled triamcinolone and rate of bone loss in premenopausal women with asthma There was a dose-related decline in bone density in the total hip and trochanter No dose-related decline in the femoral neck or spine* *Israel et al, NEJM Sept 2001;345:941-47

Leukotriene Modifiers

Leukotriene Modification 5-lipoxygenase pathway is a series of biochemical reactions that result in the transformation of arachidonic acid into leukotrienes Produced by eosinophils and mast cells when appropriately activated

Leukotriene Modifiers Zafirlukast (Accolate) and montelukast (Singulair) are inhibitors of the action of LTD4 at its receptor Zileuton (Zyflo) is an inhibitor of 5- lipoxygenase All are oral

Leukotriene Modifiers Superior effect when compared to placebo in the treatment of patients with mild to moderate asthma Associated with both a significant decrease in the need for rescue beta agonist therapy and improved asthma symptoms, especially at night Similar in magnitude to those achieved with inhaled steroids given at recommended doses

Montelukast vs. Beclomethasone Both agents demonstrated similar efficacy with respect to preventing asthma exacerbations in moderate persistent asthma However, beclomethasone was significantly superior to montelukast in its capacity to improve objective measures of lung function as measured by average responses

Cause of Churg-Strauss? Rarely (1 out of 25,000 to 150,000 patient-years of treatment) Churg- Strauss vasculitis has been seen in patients started on leukotriene modifiers who were on systemic steroids It is unlikely that this is a direct effect of leukotriene inhibition in these patients, and is more probably due to preexisting CSS unmasked as a result of steroid withdrawal

Chromones

Chromones Cromolyn sodium and nedocromil Act as mast cell stabilizers by inhibiting chloride channels (thereby stopping degranulation) Remarkably favorable therapeutic indices

Use of Chromones Children and young adults with mild to moderate asthma requiring an antiinflammatory agent Patients with a strong allergic component to their asthma Patients with exercise-induced bronchospasm Patients who require an antiinflammatory agent but for whom ICS are contraindicated or undesirable

Anti-IgE Therapy

Anti-IgE Therapy Most asthmatic patients have elevated circulating IgE concentrations when levels are adjusted for age IgE is produced by B lymphocytes

Anti-IgE Therapy Recombinant humanized antibody omalizumab (Xolair) binds IgE with high affinity Developed for the treatment of allergic diseases Binds to the C-epsilon-3 domain of circulating IgE but does not bind to Fc- epsilon-RI, and therefore does not activate mast cells or basophils Specific to IgE; does not bind to IgG or IgA

Omalizumab SQ injection every 2 to 4 weeks Dose determined by levels of serum IgE Considered as an add-on therapy to reduce or discontinue treatment with oral corticosteroids May also be indicated in patients who have severe allergic symptoms of asthma and rhinitis and who have very high circulating levels of IgE

Omalizumab Circulating IgE-omalizumab complexes are small No evidence of immune complex formation Elimination half-life is 1 to 4 weeks Aerosolized omalizumab (10 mg) is ineffective in protecting against allergen challenge and has no effect on circulating IgE

Asthma Control During ICS Withdrawl

Omalizumab and ICS Therapy US sites alone US and international sites

Omalizumab Necessary to obtain almost complete disappearance of circulating IgE in order to achieve clinical efficacy Dose of 150 to 375 mcg every 2 to 4 weeks Peak serum concentration is reached in 7 to 8 days Should be treated for a minimum of 12 weeks Cost is $10,000 to $12,000 per year Well tolerated

Exhaled Nitric Oxide

Nitric Oxide Effects in the Lung Regulates vascular and bronchial tone, promoting dilation of both vessels and airway Helps to facilitate the coordinated beating of ciliated epithelial cells Important neurotransmitter for non-adrenergic, non-cholinergic neurons which run in the bronchial wall

Isoforms of NOS

NO Formation nNOS and eNOS are usually constitutively active and produce low amounts of NO iNOS has the capacity to generate large quantities of NO when transcriptionally upregulated by the inflammatory cytokines TNF alpha, IL-1 beta, and IFN-gamma

FE NO in Asthma Red = normals Blue = asthmatics

FE NO Asthmatics have higher FE NO than do similar non-asthmatic subjects The magnitude of FE NO in increased in proportion to bronchial wall inflammation, induced-sputum eosinophils, and airway hyperresponsiveness

FE NO Increased FE NO levels are associated with deterioration in asthma control FE NO is reduced in a dose-dependent manner with antiinflammatory treatment Prospective randomized single-blind placebo controlled trial showed tha following FE NO levels can significantly decrease the dose of ICS without a significant change in rate of asthma exacerbations, use of oral steroids, or in level of airway inflammation* *Smith et al, NEJM May 2005; 352(21):

Pregnancy and Asthma

Beta 2 Agonists Beta agonists are safe More experience with older medications Also used as tocolytic agents

Theophylline Methylxanthines, especially theophylline and aminophylline, are considered safe Clinical use is limited Decreased protein binding during pregancy; should use levels 8 to 12 µg/mL Fetal serum levels same as maternal Decreased drug clearance during the third trimester Can inhibit uterine contraction

Inhaled Anticholinergics Safe, especially ipatropium No adverse development in fetus

Corticosteroids Small risk during pregnacy, and should be withheld unless indicated Three potential areas of concern have been raised: congenital malformations, primarily cleft palate; low birth weight; and neonatal adrenal insufficiency No data in humans to show increased risk of cleft palate in humans Palatial closure in 12 th week

Corticosteroids Some studies show a slight decrease in birth weight with systemic steroids Slight increased risk of prematurity in studies, but may be related to severity of asthma rather than use of steroids

Inhaled Corticosteroids ICS, especially beclomethasone, triamcinolone, and budesonide, have been studied The only randomized, controlled trial assessed 105 asthma exacerbations in 84 pregnant women who were managed with or without inhaled beclomethasone Associated with a decreased rate of readmission for asthma (12 vs 33%), and no adverse events or outcomes were noted* *Wendel et al,Am J Obstet Gynecol 1996 Jul;175(1):150-4

Inhaled Corticosteroids Registry-based cohort study of 2,014 Swedish women who used inhaled budesonide during early pregnancy Rate of congenital malformations was no different from that of the general population (3.8 vs 3.5%)* Based largely upon these findings, budesonide is currently the only inhaled corticosteroid with a pregnancy category B rating *Kallen et al, Obstet Gynecol 1999 Mar;93(3):392-5

Chromones Animal data and experience in 296 human pregnancies have not demonstrated an increase in fetal malformations or other adverse effects with cromolyn sodium Human data are not available for nedocromil, although preclinical animal studies suggest that this drug is also safe

Leukotriene Modifiers Animal data on zafirlukast have shown no teratogenicity at oral doses up to 160 times the maximum human daily oral dose on a mg/m 2 basis No teratogenicity has been observed with montelukast given to rats or rabbits at doses greater than 300 times the maximum human daily oral dose on a mg/m 2 basis Adequate studies in pregnant human women have not been performed

Conclusion

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