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WOODSTOCK 2004 What’s New in Allergy and Asthma? Robert B. Klein, MD Director, Asthma and Allergy Center Professor of Pediatrics, Brown Medical School Discussion Topics The Future of Allergy/Asthma Atopic condition is important Disparity – one size doesn’t fit all Hygiene Hypothesis Phamacogenetics - introduction Optimal Asthma Management Severity vrs. Control Multiple controllers – low dose ICS Therapies Omalizumab (anti-IgE) - Xolair Theophylline and Allergy Shots – a new look Leukotrienes place in therapy Discussion Topics The Future of Allergy/Asthma Atopic condition is important Disparity – one size doesn’t fit all Hygiene Hypothesis Phamacogenetics - introduction The Future of Allergy/Asthma Pediatric respiratory/asthma inpatient admissions by month 200 180 160 140 120 100 80 60 40 20 0 Pediatric ED respiratory/asthma visits by month 350 300 250 200 150 100 50 0 Oct- Nov- Dec- Jan01 01 01 02 Feb- Mar02 02 Apr- May- Jun02 02 02 Jul02 Aug- Sep- Oct02 02 02 Nov- Dec- Jan- Feb- Mar- Apr- May- Jun02 02 03 03 03 03 03 03 BRONCHIOLITIS 2003-4 Modern definition: Lower airway obstruction associated with a viral respiratory infection during infancy (<12 months) With regard to subsequent wheezing, longitudinal studies have associated bronchiolitis with 3 eventual phenotypes (Martinez: Pediatrics 109: 362, 2002): •Transient early wheezing: prematurity; low expiratory flow at birth; day care; pre- or postnatal maternal smoking •Non-atopic asthma: normal expiratory flow at birth •Atopic asthma: normal expiratory flow at birth; IgE; maternal asthma; eczema; clear rhinorrhea between VRIs; Hispanic origin Question 1 Dr. Patricia Nolan Immune System Balance in Asthma Development Immune System Development and the Hygiene Hypothesis Birth:TH2 Older siblings: Many infections [TH1 stimuli] TH1 No allergies Allergen Exposure Only child: Few infections Still TH2 Allergies Source: Busse WW, Lemanske RF. N Engl J Med 2001. Role of “Western” Lifestyle • Increase in indoor furnishings • Humidity and indoor temperature • Decreased ventilation • Increased time indoors • Reduction in physical activity • Can Result in allergic sensitization and “priming” for asthma development Factors Influencing Atopy Newest Version of Hygiene Hypothesis Persistent challenges to the immune system enhance the production of regulatory cells that inhibit both TH1 and TH2 responses. Pharmacogenetics LOWER BRONCHODLATOR RESPONSIVENESS IN PR THAN MEXICANS SUBJECTS WITH ASTHMA In USA PR and Mexicans have the highest & lowest asthma prevalence, morbidity and mortality respectively 684 subjects in SF, NYC, PR and Mexico City PR had 7.3% lower bronchodilator responsiveness to B2-adrenergics in asthma during ER visits Subgroup analysis shows more severe disease in PR subjects Burchard , Rodriguez-Santana et. al. AJRCCM 2004 Genetics Asthma is a complex genetic disorder with variable phenotypes. Current state of knowledge is inadequate. Many polymorphisms. Many inconclusive results. Small select samples. Potential Chromosomes Linkage, association studies, and genome-wide screening suggest many genes located on several chromosomes are involved. Susceptibility loci have been located for the cytokine gene cluster, the IL-4 receptor, and the high affinity IgE receptor. B2AR Gene Efforts to explain individual differences in response to B-agonist and tachyphylaxis have focused on the B2AR gene. The coding variants within B2AR gene (chromosome 5q31-32, position 16) have been shown to be functionally important. CAMP program looked at 707 and 8 SNPs (single nucleotide polymorphisms) Silverman et.al. JACI Vol. 112, Nov 2003 Palmer, Weiss et.al.2002 AJRCCM ALOX5 Gene ALOX5 is the enzyme required for the production of LTC4, LTD4, LTE4, and LTB4. Patients with variable nucleotide tandem repeat other than the wild type have diminished transcription of the ALOX5 gene and produce fewer leukotrienes. Drazen et.al. Nat Genet 1999 Discussion Topics The Future of Allergy/Asthma Atopic condition is important Disparity – one size doesn’t fit all Hygiene Hypothesis Phamacogenetics - introduction Optimal Asthma Management Severity vrs. Control Multiple controllers – low dose ICS How Do We Define Asthma Severity and Disease Control? Mild Persistent Asthma (NAEPP) Clinical features before treatment or adequate control1 Symptoms >2 per week but <1 per day1 Nighttime symptoms >2 nights per month1,2 FEV1 or PEF 80%1,2 PEF variability 20%–30%1,2 Exacerbations may affect activity2 1. Guidelines for the Diagnosis and Management of Asthma—Update on Selected Topics 2002. NIH, NHLBI. 2002. NIH publication 02-5075. 2. Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. NIH, NHLBI. 1997. NIH publication 97-4051. Questions to Consider: Asthma Care Based on Disease Severity Classification Is it possible to assess asthma severity based on “clinical features before treatment”? Does the variable nature of asthma affect severity classification? Are patients with mild persistent asthma at risk for bad outcomes? Does airway inflammation correlate with asthma severity classification? Asthma Control Protocol for Selecting Controller Treatment “Control” is defined as the achievement of the goals of asthma therapy Prevent day and nighttime troublesome symptoms Minimal or no need for rescue medications Maintain normal activity level Maintain near “normal” pulmonary function Prevent recurrent exacerbations The ultimate goal of asthma therapy is the same for all levels of disease severity: disease control Cockcroft & Swystun. J Allergy Clin Immunol. 1996;98:1016-1018. Measures of Asthma Control Symptoms: day and night Physical/social limitations Rescue albuterol use Exacerbations: ED, hospital, OCS Physiologic measures: FEV1, PEFR, PC20 methacholine Inflammatory markers: direct and surrogate measures “RULES OF TWO”* Patients Are Candidates for Maintenance Therapy If … • Use a quick-relief inhaler >2 times /week • Awaken due to asthma >2 times/month • More than 2 times/year: - Refill a quick-relief inhaler - Receive a “burst” of oral steroid - Unscheduled acute asthma care *“RULE S OF TWO TWO” is a tr ademark of the Ba ylor Health Ca re S ystem. FEV1 vs Age 4.0 Females FEV1 (L) 3.0 2.0 Caucasians African-Americans Mexican-Americans 1.0 5 15 25 35 45 Age (y) Hankinson et al. A m J Respir Cr it Care Med 19 99;1 59:179-87. 55 65 75 85 Inhaled Corticosteroids Most potent and effective long-term anti-inflammatory medication MDI, DPI, suspension for nebulization Management of persistent asthma, all levels of severity Broad action on inflammatory processes Improve symptoms and pulmonary function Reduce need for quick-relief medications Early Use of Inhaled Corticosteroids Annual change in percent predicted FEV1 12 10 8 6 4 2 0 <2 2-3 3-5 >5 Asthma duration at start of ICS therapy (years) Agertoft and Pedersen. Respir Med 1994;88:373-381. Benefit of Combination Therapy Combination therapy (long acting beta 2 agonist and inhaled steroid) improves lung function, decreases symptoms, and lessens the use of rescue therapy. May also allow a lower dose of inhaled steroid and thereby lessen steroid side effects. Discussion Topics The Future of Allergy/Asthma Atopic condition is important Disparity – one size doesn’t fit all Hygiene Hypothesis Phamacogenetics - introduction Optimal Asthma Management Severity vrs. Control Multiple controllers – low dose ICS Therapies Omalizumab (anti-IgE) - Xolair Theophylline and Allergy Shots – a new look Leukotrienes place in therapy New Treatments IgE monoclonal antibody. Regular treatment diminishes early and late phase responses to allergen challenge. Also diminishes the need for corticosteroid and beta agonist. Tolerability is excellent; there has been no evidence of anti-IgE antibodies. Asthma Studies Protocol Randomized, double-blind, placebo-controlled, multicenter, parallel-group Omalizumab versus placebo, administered subcutaneously Study population of adults and adolescents with moderate to severe symptomatic asthma treated with inhaled corticosteroids Omalizumab dosing tailored to baseline body weight and serum free IgE level 150-300 mg at 4-week intervals (1-2 injections every month) 225-375 mg at 2-week intervals (2-3 injections every 2 weeks) Busse W, et al. J Allergy Clin Immunol. 2001;108:184-190; Soler M, et al. Eur Respir J. 2001;18(2):254-261. Key Inclusion Criteria Diagnosis of asthma Diagnosed 1 year; stable 1 month FEV1 reversible 12% at screening Positive skin test to 1 perennial allergen IgE levels 30 to 700 IU/mL (BW between 30 to 150 kg) Level of disease control Residual symptoms (symptom score > 3) FEV1 40 to 80% predicted Inhaled corticosteroids 420 to 840 µg/day Beclomethasone (Busse) 500 to 1,200 µg/day Beclomethasone (Soler) No oral steroids, LABAs, LRTAs, or theophyline Busse W, et al. J Allergy Clin Immunol. 2001;108:184-190; Soler M, et al. Eur Respir J. 2001;18(2):254-261. Study Design BDP conversion R A N D O M I Z E Run-in phase 4 - 6 wk Pivotal Studies Busse, Soler Omalizumab or placebo + stable BDP/2 Omalizumab or placebo + stepwise BDP reduction/2 Stable steroid Steroid-reduction phase phase 16 wk 12 wk Omalizumab or placebo + free treatment Extension phase 24 wk Core 28 wk Total 52 wk, double blind, placebo-controlled BDP = Beclomethasone dipropionate; 2 = Rescue albuterol. T R E A T M E N T E N D Follow-up 12 wk Exacerbations 0.8 P < .001† 0.7 0.66 0.6 0.5 0.4 0.3 P = .006† 0.54 48% 0.28 58% 0.28 0.2 0.1 0 Study 008 Study 009 Xolair™ †van Elteren test; protocol-defined analysis with imputation. 0.8 Mean exacerbations per patient Mean exacerbations per patient Stable steroid phase 16 wk Steroid-reduction phase 12 wk P < .001† 0.66 0.7 0.6 0.5 0.4 0.75 P = .003† 41% 0.39 52% 0.36 0.3 0.2 0.1 0 Study 008 Placebo Study 009 Efficacy Conclusions Both pivotal studies show that Omalizumab reduces asthma exacerbations requiring steroid interventions These reductions are statistically significant, robust to alternate analyses, and clinically relevant to patients with moderate to severe asthma All other endpoints are positive, including daytime and nightime asthma symptom scores, and pulmonary function Omalizumab Overall Safety Conclusions Omalizumab comparable with placebo AEs and SAEs Laboratory and platelet measurements Causal relationship between Omalizumab and cancer unlikely Immune responses Type I and III hypersensitivity Infection/inflammation Omalizumab is safe and well tolerated Summary of Anaphylaxis Cases Clinical course not consistent with medical definition of anaphylaxis Occurred with first dose in 2 of 3 cases History of previous allergic reactions in 2 of 3 cases Intravenous administration in 1 case Overall very low incidence in study population Data does not support more specific recommendations for monitoring beyond statement in PI New Treatments Phosphodiesterase inhibitors (increase cyclic AMP) Phosphodiesterase IV is the predominant isoenzyme in neutrophils and eosinophils and is found in mast cells and airway epithelium. Selective PDE IV inhibitors are bronchodilators and inhibit lymphocyte proliferation and cytokine release. PDE IV inhibitors may prove to be more effective and safer than theophylline. Long-Term Study on Children Source: Johnstone DE, Dutton A. Pediatrics 1968 14-year study on preventive effects of immunotherapy published in Pediatrics Allergy shots reduced number of children who developed asthma Shift from TH2 to TH1-like Response After Immunotherapy 70 60 50 40 30 20 10 0 Before SIT After 3 Months TH2 After 12 Months TH1 Source: Ebner et al. Clin Exp Allergy 1997 Leukotriene Modifiers Block LTD4 receptors Available as tablets Position of leukotriene modifiers in overall therapy not fully established now also approved for AR Maybe considered alternative therapy to low doses of ICSs for mild persistent asthma Improved symptoms, pulmonary function Reduced need for quick-relief medications MONTELUKAST DOSAGE AND ADMINISTRATION Taken once daily Seasonal Rhinitis - time may be individualized to suit needs Asthma taken in evening (both conditions use evening dosage) Adults and adolescents: 15 years and older= 10 mg Children 6-14: 5 mg Children 1-5: 4mg New Treatments Cytokine modulation therapy. IL-4 receptor antagonist have shown clinical benefit in moderate asthmatics requiring daily inhaled corticosteroids. Monoclonal antibodies to IL-5 block eosinophil recruitment but ineffective in symptomatic asthma. The Present: We Can Make A Difference Improve provider and patient understanding of asthma. Improve recognition, earlier diagnosis, and greater utilization of current effective treatments. Raise provider and patient expectations regarding goals of therapy. The Future Better genetic knowledge and improved environmental controls will reduce the prevalence of asthma. Newer, genetically appropriate and mediator-specific therapies will lessen morbidity and may influence longterm prognosis. Question 2 One Disease & one Rx Optimal Asthma Management Expect beautiful results Conclusions ASTHMA IS A DISEASE OF COMMUNICATION NOT OF INFLAMMATION Randall Brown M.D. 1999 Yogi Berra “If you ask me a question I don’t know, I’m not going to answer.” Asthma at 14 year follow-up, % Prevention of Asthma 14 Years Later 80 70 60 50 40 30 20 10 0 No Asthma Mild Control Source: Johnston & Dutton 1968 Moderate SIT Severe Asthma at 14 year follow-up, % Prevention of Asthma 14 Years Later 80 70 60 50 40 30 20 10 0 No Asthma Mild Control Source: Johnston & Dutton 1968 Moderate SIT Severe Mechanisms Underlying the Definition of Asthma Risk Factors (for development of asthma) Airway Hyperresponsiveness Risk Factors (for exacerbation) Airflow Limitation Symptoms Growth and Decline of FEV1 There are three ways to reach a low level: 1) Decreased maximal growth 2) Premature decline 3) Accelerated decline Rijken B. Bronchial responsiveness and COPD risk: an epidemiologic study (postdoctoral dissertation, 1991). The Burden of Asthma In 2000, the national prevalence rate for asthma was 5.6%. In Rhode Island, the adult asthma prevalence was 8.5%, the fifth highest among the 50 states. The Burden of Asthma The highest rates were seen in young males, women over 65 years, and people of especially low income. Asthma mortality rates decreased from 1989-1997. NHLBI Guidelines June 2002 Gaps in the Application of Asthma Treatment Guidelines The guidelines are not followed because of: Lack of awareness or familiarity with details. Lack of agreement with guidelines. Lack of self-efficacy to carry it out properly. Lack of confidence in outcomes. Inertia of previous practice. Source: Cabana and Lewis. Improving Physician Adherence to Asthma Guidelines. JCOM. 8(3), March 2001. Consequences of Improper Assessment of Asthma Severity • Inadequate utilization of controller therapy – – High usage of short-acting beta2-agonists alone Underutilization of ICS in persistent asthma • Inadequate patient monitoring • Unnecessary morbidity and mortality Education for a Partnership in Asthma Care Key educational messages to teach and reinforce at every opportunity Basic facts about asthma Environmental control measures Role of medications Medication skills and self monitoring Asthma action plan Work With The Patient To Develop Treatment Goals Determine patient’s own treatment goals Agree upon the goals of treatment Share the general goals of asthma treatment with patient and family Action Plans Versus Medical Management: Monitoring Answer #1 Data are insufficient to support or refute the use of written action plans In a Cochrane review, self-management education with a written action plan had the greatest benefits for improving lung function and reducing emergency department visits and hospitalizations NIH/NHLBI Guideline Update. June 2002. NIH Publication No. 02-5075. Modern View of Asthma Allergen Macrophage/ dendritic cell Mast cell Th2 cell Mucus plug Neutrophil Eosinophil Epithelial shedding Nerve activation Plasma leak Oedema Vasodilatation Mucus New vessels hypersecretion s Hyperplasia Barnes PJ Subepithelial fibrosis Sensory nerve activation Cholinergic reflex Bronchoconstriction Hypertrophy/hyperplasia Chronic Care Model (http://www.improvingchroniccare.org) Community and Health System Resources Informed Activated Patients Prepared Practice Teams Improved Outcome Chronic Care Model Community and Health Care System Self Management Support Delivery System Design Decision Support Clinical Information Systems Self Management Support Emphasis on patient role Standardized assessment Effective intervention Care planning and problem solving Clinical Information Systems Care planning Care reminders Feedback Individual treatment plan Airway Inflammation Other Important Players Airway smooth muscle can also secrete cytokines, chemokines and express cell adhesion molecules that modify submucosal inflammation. Vascular permeability may result from the excess production of nitric oxide. Development of the Immune System Conclusions Hygiene Hypothesis Less asthma in rural America. Endotoxins and microbial heat shock proteins (HSP) are found in high concentrations in rural areas especially farm environments. These allergens have been found to trigger the release of IL-12, favoring the TH1 response. Hygiene Hypothesis The hygiene hypothesis states that infants in modern industrial societies (improved sanitation, widespread use of vaccines and broad spectrum antibiotics) are exposed to fewer viruses and bacteria and thus exhibit greater TH2 cell activity. Determinants of TH1 vs. TH2 Viruses and bacteria (endotoxins) can stimulate macrophage secretion of IFNalpha and IL-12, favoring TH1 response. Reasons for More Asthma Indoor Air Pollution (dust mites) Outdoor Air Pollution (diesel exhaust) Hygiene Hypothesis