Allergic Asthma: Diagnosis and Treatment Eddie W 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 Hay Fever N=3355 Cases per 1000 Children 50 40 Asthma Other Respiratory Allergies 30 Skin Allergies Other Nonallergic Conditions 20 Digestive Allergies 10 Cardiac Conditions *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 Peak prevalence in children and young adults 50% of patients have symptoms >4 months per year and 20% >9 months per year Productivity 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 hyper-reactivity. 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 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-sino-bronchial reflex

Pathophysiology of Allergic Rhinitis and Asthma

Antigen- presenting cell Phase 1 – Sensitization Allergen Antigen- presenting cell B cell Processed allergen CD4 T cell Plasma cell IgE antibodies Adapted from Naclerio. N Engl J Med. 1991;325:860-869.

TH1 TH0 TH2 Interferon  Interleukin 2 Cell-mediated Immunity Intracellular Pathogens Interleukin 12 TH1 TH0 TH2 Allergens Interleukin 4 Interleukin 2 Interleukin 5 Interleukin 13 Allergic Disease Humoral Immunity JAMA. 1997;278:1845.

Phase 2 – Clinical Disease Early Phase Late Phase Allergen IgE antibodies Resolution Complications Cellular Infiltration Glands Nerves Blood vessels Sneezing Itching Rhinorrhea Congestion Mediator release Eosinophils Basophils Monocytes Lymphocytes Mast cell Irreversible Disease? Priming Hyper- responsiveness Late-phase reaction Adapted from Naclerio. N Engl J Med. 1991;325:860-869

Inflammation: eosinophils and lymphocytes Allergic Exacerbation Overview of the Allergic Inflammatory Cascade in Patients with IgE-mediated Asthma B lymphocyte Allergic Inflammation: eosinophils and lymphocytes Allergic mediators -switch Plasma cell Release of IgE Allergens Allergic Exacerbation This slide provides an overview of the series of events that make up the allergic inflammatory cascade in IgE-mediated asthma. In response to antigen stimulation, B lymphocytes differentiate into plasma cells (the epsilon-switch), which produce and release IgE antibodies into the circulation. IgE circulates in the blood, eventually binding to high-affinity IgE receptors (FcRI) on the surface of mast cells in tissue or peripheral-blood basophils. When the subject subsequently re-encounters the offending allergen, binding of the allergen with IgE induces the release of inflammatory mediators, leading to the bronchoconstriction characteristic of an exacerbation. Mast cells Basophils

IgE-dependent Release of Inflammatory Mediators Allergens FcRI Over Minutes Lipid mediators: Prostaglandins Leukotrienes Wheezing Bronchoconstriction Over Hours Cytokine production: Specifically IL-4, IL-13 Mucus production Eosinophil recruitment Immediate Release Granule contents: Histamine, TNF-, Proteases, Heparin Sneezing Nasal congestion Itchy, runny nose Watery eyes IgE binds to high- and low-affinity receptors (FcRI or FcRII) on effector cells. The inflammatory cascade is initiated when IgE bound to effector cells is cross-linked by allergen. This results in the degranulation of effector cells and the release of a comprehensive array of mediators that are linked to the pathophysiology of asthma.

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;81:463-518.

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 Hypertrophy of mucous gland, hypersecretion of mucus Loss of epithelium; Thickening & fibrosis of basement and sub-basement membrane

Omalizumab Characteristics Murine CDRs* (< 5% of molecule) Humanized mAb against IgE Binds circulating IgE regardless of specificity Forms small, biologically inert Omalizumab:IgE complexes Does not activate complement IgG1 kappa Human framework (> 95% of molecule) Omalizumab works by forming complexes with circulating IgE which inhibits the binding of IgE to the high-affinity IgE receptor (FcRI) on the surface of mast cells and basophils. Binding of Omalizumab to IgE forms small, biologically inert complexes. To avoid the clinical problems associated with murine antibodies, humanization of the murine anti-IgE was performed. Humanized anti-IgE was developed by grafting the variable sequence of a mouse antibody (binds to the Fc3 binding domain of IgE) onto the constant IgG1 kappa human framework. Omalizumab consists of > 95% IgG1 kappa human framework and < 5% mouse sequence, which is hidden from the immune system when Omalizumab binds to IgE. (Refer to full prescribing information for questions about the immunogenicity of Omalizumab.) *CDR = complementarity-determining region Adapted with permission from Boushey H. J Allergy Clin Immunol. 2001;108:S77-S83.

IgE Binds to Mast Cells at the High Affinity Receptor (FcRI) IgE molecule FcRI binding site IgE molecule bound to mast cell FcRI receptor This illustration demonstrates the binding of IgE to a mast cell which takes place at the constant region of the IgE molecule. Molecular bridging of FcRI receptors, which occurs when an allergen interacts with receptor-bound IgE molecules, causes activation of the cell and the release of preformed and newly generated mediators. Mast cell

Omalizumab Blocks IgE Binding to Mast Cells IgE molecule Omalizumab Omalizumab FcRI receptor This slide illustrates Omalizumab binding to an IgE molecule, which also takes place at the constant region of the IgE molecule. Note that IgE binds either to the FcRI receptor on the mast Cell OR to Omalizumab, but it cannot bind to both at the same time. Omalizumab inhibits the binding of IgE to the high-affinity IgE receptor FcRI on the surface of mast cells and basophils. Reduction in surface-bound IgE on FcRI-bearing cells limits the degree of release of mediators of the allergic response. 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 Dollars Over 10 Years 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