Definition of Asthma • Clinically - Widespread airway narrowing which changes in severity over short periods of time, either spontaneously or in response to treatment • Physiologically - Bronchial Hyperresponsiveness • Pathologically - Airway inflammation
Mechanisms Underlying the Definition of Asthma Risk Factors (for development of asthma) INFLAMMATION Airway Hyperresponsiveness Airflow Obstruction Symptoms Risk Factors (for exacerbations)
IL-4 IL-5 IL-13 TH2 TN ? IFN IL-12 TH1
- Asthma is characterized by a TH2 immune phenotype - 80-90% of all childhood asthma is associated with atopy skin test reactivity total & specific IgE - Allergic inflammation mediated by TH2 cytokines Ag Dendritic cell IL-5 T Lymphocyte TH2 Eosinophil IL-4 B Lymphocyte IL-9 IL-13 TNF Mast Cell Monocyte Ig-E
Allergens Processed allergens IgE antibodies B lymphocyte (Plasma cell) Pathophysiology of Allergic Inflammation: Sensitization Antigen-presenting cell (eg, dendritic cell) CD4T cell B cell
Allergens Resolution IgE antibodies Late-phase reaction Complications Cellular infiltration Hyper-responsiveness Mast cell Eosinophils Basophils Monocytes Lymphocytes Irreversible disease? Mediator release Priming Blood vessels Nerves Glands Pathophysiology of Allergic Inflammation: Clinical Disease Early Inflammation LateInflammation SneezingRhinorrheaCongestion
Products of Mast Cell Activation Early (edema, broncho- constriction, vasopermeability Late (inflammation, cell recruitment) = shared with basophils
Principles of the Allergic Response Sensitized individual, sufficient exposure, end organ responses.
Asthma Pathophysiology Smooth Muscle Dysfunction Airway Inflammation Symptoms Airway Remodeling
Mild asthma What is Asthma? • A chronic inflammatory disease of the airways. Immunohistopathologic features: • denuded respiratory epithelium • collagen deposition beneath the basement • edema • mast cell activation • inflammatory cell infiltration No asthma
Airway Remodeling in Asthma • Airway wall thickening • Subepithelial collagen deposition • Myofibroblast hyperplasia • Smooth muscle hyperplasia and hypertrophy • Mucus metaplasia • Epithelial hypertrophy • (Vascular abnormalities)
Risk Factors that Lead to Asthma Development Host Factors • Genetic predisposition • Atopy • Airway hyper- responsiveness • Gender • Race/Ethnicity • Environmental Factors • Indoor allergens • Outdoor allergens • Occupational sensitizers • Tobacco smoke • Air Pollution • Respiratory Infections • Parasitic infections • Socioeconomic factors • Family size • Diet and drugs • Obesity
Factors that Exacerbate Asthma • Allergens • Air Pollutants • Respiratory infections • Exercise and hyperventilation • Weather changes • Sulfur dioxide • Food, additives, drugs
The Burden of Asthma in the U.S. • 12 million children under the age of 16 • Prevalence increasing at 5% per year • 500,000 new cases every year • #1 cause for hospitalizations in children • #1 cause for days lost from school • Costs of > $6 billion/year
Allergic Asthma:Genes and Environment Environment Developing countries Large family size Rural homes, livestock Intestinal microflora-variable, transient Low antibiotic use high helminth burden Poor santitation, high orofaecal burden Westernized countries Small family size Affluent, urban homes Intestinal microflora-stable High antibiotic use Low or absent helminth burden Good sanitation, low orofaecal burden Allergic disorders (asthma, eczema, rhinitis) Non-allergic Genes
Asthma is characterised by • Recurrent episodes of wheezing • Troublesome cough at night • Cough or wheeze after exercise • Cough, wheeze or chest tightness after exposure to airborne allergens or pollutants • Colds “go to the chest” or take more than 10 days to clear
Diagnosing • Spontaneous • Spirometry in the office • PEFR chart at home • Reversibility • Spirometry before and after B2 agonist • Provocative Testing • Exercise • Cold dry air • Methacholine
Value of Methacholine Challenge • Excellent negative predictive value • Negative test makes active asthma unlikely • Positive predictive value depends on the population you study • if used in a random population, positive predictive value < 50% • Better positive predictive value if AHR defined as PC20 <1 mg/ml
Tests to Identify Specific IgE • Skin Tests • Scratch test • Prick puncture test • Intradermal skin test • Serological Tests • RAST • Modified RAST tests • CAP TESTING • OTHER
Serological Tests for Specific IgE • Principle of RAST testing • Solid phase covalently linked by antigen • Incubate with serum • Detect with labeled anti-human IgE • Detects in a quantitative fashion the presence of IgE antibodies with specificity for a given antigen/allergen. • Results are reported in classes and arbitrary units from a reference curve using known standards.
The goals of long-term management of asthma should include the following: 1) achievement and maintenance of control of symptoms; 2) prevention of asthma exacerbations; 3) maintenance of pulmonary function as close to normal levels as possible; 4) maintenance of normal activity levels, including exercise; 5) avoidance of adverse effects from asthma medications; 6) prevention of the development of irreversible airflow limitation; and 7) prevention of asthma mortality.
Until the advent of anti-inflammatory drugs, asthma was treated on an as-needed basis and treated as an acute disease rather than a chronic disease.
With the recognition that asthma is a chronic inflammatory disease, there has been a gradual move towards treating it more aggressively and earlier in the hope that this may change the natural history of asthma and prevent some of the remodelling that sometimes occurs.
There has been fairly rapid uptake of the need for treating asthma as a chronic inflammatory disease. However, asthma is still undertreated for the most part. The ideal should be minimal or almost no use of rescue medications with control being maintained by anti-inflammatory drugs . With this approach, the recognition that asthma control and asthma severity are conceptually distinct has emerged.
For example, although mild asthmatics have disease that is, by definition, relatively easy to control with rescue medications, they will occasionally suffer from acute exacerbations during which their level of control may be very poor. Similarly, individuals with moderate-to-severe asthma require more intensive treatment to control their symptoms, but with proper therapy they can experience good symptom
From the perspective of the practicing clinician, level of control may be the more relevant measure because the objective of therapy will be to control symptoms and minimise the impact of the disease on patient functioning (i.e. to achieve a good level of control) . Also, from the perspective of population-based disease management, asthma control could serve as a good indicator of the adequacy of healthcare provided to a population,
as well as serving as an indicator of patients who may benefit from more aggressive management
The clinician is faced with the question of how aggressively to treat a patient with asthma. Inherent in this question is the balance between the pros and cons of aggressive (and early) treatment. The argument in favour of early treatment is that it may reduce (or possibly prevent) the remodelling that occurs in asthma and allow lung growth and senescence to be normal.
The significance of the subepithelial fibrosis in asthma is not clear . The correlation with asthma duration is good but the correlation with asthma severity is poor. The reason why there is so much interest and focus at present on the remodelling in asthma is the hope that early aggressive treatment, before subepithelial fibrosis is established, may change the natural history of asthma .
. • The most effective management is to prevent airway inflammation by eliminating the causal factors • Asthma can be effectively controlled in most patients, although it can not be cured • The major factors contributing to asthma morbidity and mortality are under-diagnosis and inappropriate treatment
Avoid Exposure to Risk Factors • Methods to prevent onset of asthma are not yet available but this remains an important goal • Measures to reduce exposure to causes of asthma exacerbations (e.g. allergens, pollutants, foods and medications) should be implemented whenever possible
Asthma Control - Avoidance • Indoor Allergens - e.g. mites, animals, molds • Outdoor Allergens • Non-specific triggers • Smoking - passive or active • Occupational agents • Drugs - e.g. b-blockers, NSAIDs
Current Treatment Paradigms for Asthma as an Allergic Disease • Allergen Avoidance • Pharmacological Intervention • Cromones • Corticosteroids • Leukotriene Modifying Drugs • Immunotherapy • Allergen Immunotherapy • Novel Immunologic Therapies • Theophylline • LABA
The aim is to accomplish the goals of therapy with the least possible medication
The choice of treatment should be guided by: • Severity of the patient’s asthma • Patient’s current treatment • Pharmacological properties and availability of the various forms of asthma treatment • Economic considerations Cultural preferences and differing health care systems need to be considered.
Pharmacologic Therapy Reliever Medications: • Rapid-acting inhaled β2-agonists • Systemic glucocorticosteroids • Anticholinergics • Methylxanthines • Short-acting oral β2-agonists
Pharmacologic Therapy Controller Medications: • Inhaled glucocorticosteroids • Systemic glucocorticosteroids • Cromones • Methylxanthines • Long-acting inhaled β2-agonists • Long-acting oral β2-agonists • Leukotriene modifiers • Anti-IgE
Use of Long-Acting b2 Agonists in Asthma • Sustained bronchodilatation • Sustained protection • e.g. against exercise-induced asthma • Reduce requirement for inhaled corticosteroids • No significant anti-inflammatory effects • i.e. never use as sole prophylactic medication • Some individuals are prone to rapid tachyphylaxis of bronchodilator function
Use of Long-Acting b2 Agonists in Asthma • Improved symptom scores • Reduced nocturnal asthma • Improved lung function • Reduced requirement for rescue b2 agonists • Reduce exacerbations