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Allergic Asthma: Diagnosis and Treatment Eddie W. Shields, MD Arkansas Allergy and Asthma Objectives Understand the relationship between asthma and allergic rhinitis Understand the pathophysiology of allergic asthma Learn the role of environmental control, pharmacologic therapy, and allergen immunotherapy in allergic asthma Rhinitis and Asthma High prevalence, high cost illnesses Both illnesses have a major effect of the sufferer’s quality of life Both illnesses have a strong association with allergy Both rhinitis and asthma have common inflammatory pathways Improved control of rhinitis leads to improve asthma outcomes Leading Chronic Conditions* in Children Aged <18 Years 80 70 60 Cases per 1000 Children N=3355 50 40 30 20 10 0 Hay Fever Asthma Other Skin Digestive Cardiac Other Respiratory Allergies Allergies Conditions Nonallergic Conditions Allergies *Patient assessment. Adapted from Newacheck et al. J Pediatr. 1994;124:40. Allergic Rhinitis CHRONIC Inflammatory Disease of the Upper Airways 35 million Americans have allergic rhinitis– Prevalence of 10-20% of the population Productivity Peak prevalence in children and young adults 50% of patients have symptoms >4 months per year and 20% >9 months per year 28 million days of restricted activity 2 million lost school days Cost of treatment $3.5 billion total cost associated with allergic rhinitis treatment Asthma CHRONIC Inflammatory Disease of the Lower Airways Affects about 3-4% of the populations; 7% of children Most common non-traumatic admission to children’s hospitals in the U.S. Greater 200,000 hospitalizations per year in U.S. Evidence of Causal Role of Allergies in Asthma in Children Sensitization to indoor allergens and outdoor fungi increases the risk for asthma The larger the size of the skin test reaction to house dust mite, the more sensitive the patient is to methacholine, a measure of bronchial hyperreactivity. JK Peat, et al. N.Z. Med J 1994;24:270 Evidence of Causal Role of Allergies in Asthma in Children Severity of asthma is related to the level of allergen exposure 18 episodes of sudden onset, respiratory arrest in 11 patients, ages 11-25 years All occurred in summer and early fall 10/11 skin test positive for Alternaria Peak Alternaria season is June to November O’Hollaren, et al. NEJM 1991; 324:359-63 Evidence of Causal Role of Allergies in Asthma in Children Reduction of allergen exposure improves asthma symptoms and pulmonary function and reduces bronchial hyper-responsiveness. Rhinitis in Asthmatic Children Approximately 80% of children presenting with asthma have rhinitis (1) Children with a history of allergic rhinitis are more likely to suffer from exercise-induced bronchospasm (2) (1) Mercer et al. S Afr Med J 1991 (2) Bradsford et al. Int Arch Allergy Appl Immunol 1991 Allergic Rhinitis as a Risk Factor for Developing Asthma, a 23 yr Follow-up Diagnosis Total at New % as risk asthma freshman AR 152 17 p value 10.5 <0.002 Non-AR 528 19 3.6 Total 690 36 5.2 Settipane et al. Allergy Proc 1994 Hypotheses for Links of Rhinitis and Asthma Both associated with allergy Common ciliated epithelium Similar allergens are associated with both conditions Both have a familial link with atopy Possible pathophysiological mechanism-sinobronchial reflex Pathophysiology of Allergic Rhinitis and Asthma Phase 1 – Sensitization Antigenpresenting cell Allergen Processed allergen B cell CD4 T cell Plasma cell Adapted from Naclerio. N Engl J Med. 1991;325:860-869. IgE antibodies Intracellular Pathogens Interleukin 12 Interferon Interleukin 2 Cell-mediated Immunity TH1 TH0 Allergens Interleukin 4 JAMA. 1997;278:1845. TH2 Interleukin 2 Interleukin 5 Interleukin 13 Allergic Disease Humoral Immunity Phase 2 – Clinical Disease Early Phase Late Phase Allergen IgE antibodies Mast cell Mediator release Blood vessels Nerves Cellular Infiltration Late-phase reaction Eosinophils Basophils Monocytes Lymphocytes Hyperresponsiveness Priming Resolution Complications Irreversible Disease? Glands Sneezing Itching Rhinorrhea Congestion Adapted from Naclerio. N Engl J Med. 1991;325:860-869 Overview of the Allergic Inflammatory Cascade in Patients with IgE-mediated Asthma B lymphocyte -switch Allergic mediators Allergic Inflammation: eosinophils and lymphocytes Plasma cell Release of IgE Allergens Mast cells Basophils Allergic Exacerbation IgE-dependent Release of Inflammatory Mediators Allergens IgE FcRI Immediate Release Granule contents: Histamine, TNF-, Proteases, Heparin Sneezing Nasal congestion Itchy, runny nose Watery eyes Over Hours Over Minutes Lipid mediators: Prostaglandins Leukotrienes Wheezing Bronchoconstriction Cytokine production: Specifically IL-4, IL-13 Mucus production Eosinophil recruitment Management of Allergic Rhinitis and Asthma Education Environmental Control Proper Pharmacologic Treatment Allergen Vaccination (Immunotherapy) Asthma Education Define asthma and explain treatment options Need to adhere to treatment plan Discuss patient’s fear about asthma and its treatment Conduct regularly scheduled follow-up office visits Provide written asthma action plan Treatment schedule, peak flow zones, and emergency numbers Environmental Control Major triggers of Allergic Rhinitis and Asthma Pollens Molds House dust mites Animals Insect aeroallergens (eg, moths) ACAAI/AAAAI Joint Task Force. Ann Allergy Asthma Immunol. 1998;81:463. Hackberry Oak Willow Grass Environmental Control Measures: Pollen Close windows, doors Avoid window/attic fans A/C on recirculate Reduce outdoor exposure as practicality allows: When pollen counts are high Highest in early AM On sunny, windy days with low humidity Shower or bathe following exposure ACAAI/AAAAI Joint Task Force. Ann Allergy Asthma Immunol. 1998;81:463518. Mold Environmental Control Measures: Molds Remain in closed environment as practicality allows A/C units, though helpful, can harbor mold Avoid lawn mowing, raking leaves, etc Face masks can be of some value Avoid/remedy dampness Dehumidifier Minimize humidifier use If used, keep very clean ACAAI/AAAAI Joint Task Force. Ann Allergy Asthma Immunol. 1998;81:463. Environmental Control Measures: House Dust Mites Vigorous methods necessary Ordinary vacuuming/dusting have little effect Simple furnishings without carpeting Especially bedroom, family room, etc Plastic, leather, wood are best ACAAI/AAAAI Joint Task Force. Ann Allergy Asthma Immunol. 1998;81:463. Environmental Control Measures: House Dust Mites Wash bedclothes at 130oF Lower temperatures do not kill mites Allergen-proof pillows, mattresses, box springs Avoid/cover quilts and comforters Cleaning of duct work has no demonstrated value in removing dust mites ACAAI/AAAAI Joint Task Force. Ann Allergy Asthma Immunol. 1998;81:463. Environmental Control Measures: Animal Allergens All furry/feathered animals Cat/dog reactivity found in 25% to 33% of patients with AR Avoidance most effective Remove pets from home, if possible Confine animal(s) to noncarpeted room (not bedroom) HEPA filter in animal room may reduce allergens in rest of home Eliminate/move litter boxes ACAAI/AAAAI Joint Task Force. Ann Allergy Asthma Immunol. 1998;81:463. Environmental Control Measures: Insect Allergens Debris of cockroaches, crickets, flies, moths, etc Careful sanitation Eliminate open or standing food, dirty dishes Store garbage in tightly closed containers Roach traps Consider professional extermination/relocation if infestation is heavy ACAAI/AAAAI Joint Task Force. Ann Allergy Asthma Immunol. 1998;81:463. Environmental Control Measures: Irritant Factors Avoid irritants Tobacco smoke Perfume, potpourri Formaldehyde School supplies/environment Markers Chalk dust ACAAI/AAAAI Joint Task Force. Ann Allergy Asthma Immunol. 1998;81:463. Medical Management of Asthma Goals of Asthma Management Primary goal The asthmatic patient should be to do ALL normal activities Other goals Maintain normal or near normal pulmonary function Prevent chronic symptoms and recurrent exacerbations No emergency department visits or hospitalizations Prevent irreversible lung disease Minimize need for rescue medications Avoid adverse reactions from medications Changes In Airway Morphology in Asthma Smooth muscle contraction Edema Vasodilation Infiltration of inflammatory cells Loss of epithelium; Thickening & fibrosis of basement and sub-basement membrane Hypertrophy of mucous gland, hypersecretion of mucus Omalizumab Characteristics Humanized Binds mAb against IgE Murine CDRs* (< 5% of molecule) circulating IgE regardless of specificity Forms small, biologically inert Omalizumab:IgE complexes Does not activate complement *CDR = complementarity-determining region Adapted with permission from Boushey H. J Allergy Clin Immunol. 2001;108:S77-S83. IgG1 kappa Human framework (> 95% of molecule) IgE Binds to Mast Cells at the High Affinity Receptor (FcRI) IgE molecule FcRI binding site FcRI receptor IgE molecule bound to mast cell Mast cell Omalizumab Blocks IgE Binding to Mast Cells IgE molecule Omalizumab Omalizumab FcRI receptor Mast cell Allergen Immunotherapy The administration of low then sequentially increasing doses of allergens in patients with IgE mediated diseases: Allergic Rhinoconjunctivitis Allergic Asthma Insect Sting Anaphylaxis Immunotherapy Allergen skin testing should be considered in patients with allergic rhinitis and asthma with persistent symptoms to determine possible allergen triggers Highly effective; disease modifying Candidates Moderate to severe symptoms Lack of improvement with other modalities Presence of comorbid conditions Evidence of specific IgE sensitization based on testing Risk of anaphylaxis Oral drops and low dose (provocation-neutralization technique) immunotherapy have not been proven effective in clinical studies Impact of Immunotherapy on Allergic Rhinitis Costs 4000 Dollars Over 10 Years 3500 3000 2500 Rx Rx + Imm 3 yrs Rx + Imm 10 yrs 2000 1500 1000 500 0 Allergic Rhinitis Sullivan in Current Views in… 1998 How early should we consider Immunotherapy? Prevention of Asthma Onset Preventive Allergy Treatment study in Northern Europe: Development of new allergies is decreased and the progression to asthma is decreased 50% reduction in asthma in children with moderate to severe allergic rhinitis who received IT compared to those without IT Moller C. et al, JACI 2002;109:251-256 How early should we consider Immunotherapy? Prevention of New Sensitizations in children 22 children with HDM allergy only IT for 3 years with HDM extract PTs New Sensitivities None cat dog Alt Grass IT 22 10 6 4 2 1 Con 22 0 12 8 6 6 p<.001 A Des Roches, et al. JACI 1997; 99:450 How early should we consider Immunotherapy? Prevention of New Sensitizations GB Pajno, et al. Clin Exp Allergy 2001;31:1392-7 F Purello-D’Ambrosio, et al. Clin Exp Allergy 2001;31:1295-1302 Key Advances in Immunotherapy IT in children with only AR decreases asthma Decreases bronchial hyper-responsiveness to methacholine Reduces risk of developing new allergies Routine series is for 3-5 years Gives long lasting relief of symptoms High-dose sublingual IT appears to be safe but less effective than injections and cost savings aren’t clear because of amount of extract required Allergy Prevention Strategies Promote breast feeding Discourage early introduction of solid and “at risk” food (milk, eggs, peanuts, seafood, ? meats) Reduce dust mite levels in homes Avoid exposure to animal dander Screen for allergy at all routine exams Encourage awareness of allergen control measures at work, school, and daycare Consultation with Specialist Identification of allergic / non-allergic triggers Education in allergen avoidance and control If allergen immunotherapy is a consideration If patient’s quality of life is significantly affected Co-morbidities: asthma, recurrent sinusitis / OM, nasal polyps Duration of rhinitis > 3 months and / or requires systemic corticosteroids to manage Poor control – persistent symptoms
