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

TH2 TN ? TH1

IL-4 IL-5 IL-13

IFNK IL-12

- 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 Dendritic cell

A g
Eosinophil

IL-5 IL-

T Lymphocyte TH2 ILIL4 ILIL13 B Lymphocyte

IL-9 ILTNF
Mast Cell Monocyte

IgIgE

Allergen s

Antigen-presenting cell (eg, dendritic cell) Processed allergens CD4 T cell

B cell IgE antibodies

B lymphocyte (Plasma cell)

Early Inflammation
Allergens

Late Inflammation

IgE antibodies Cellular infiltration

Late-phase reaction Hyperresponsiveness Priming

Resolution

Mast cell Mediator Blood release Nerves vessels Glands Sneezing Rhinorrhea Congestion

Complications

Eosinophils Basophils Monocytes Lymphocytes

Irreversible disease?

Products of Mast Cell Activation

Early (edema, bronchoconstriction, vasopermeability

Late (inflammation, cell recruitment)

= shared with basophils

Sensitized individual, sufficient exposure, end organ responses.

Asthma Pathophysiology
Smooth Muscle Dysfunction Airway Inflammation

Symptoms

Airway Remodeling

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

Mild asthma

Airway Remodeling in Asthma

Airway wall thickening Subepithelial collagen deposition Myofibroblast hyperplasia Smooth muscle hyperplasia and hypertrophy Mucus metaplasia Epithelial hypertrophy (Vascular abnormalities)

Host Factors
  

Environmental Factors
Indoor allergens  Outdoor allergens  Occupational sensitizers  Tobacco smoke  Air Pollution  Respiratory Infections  Parasitic infections  Socioeconomic factors  Family size  Diet and drugs  Obesity


 

Genetic predisposition Atopy Airway hyperresponsiveness Gender Race/Ethnicity

      

Allergens Air Pollutants Respiratory infections Exercise and hyperventilation Weather changes Sulfur dioxide Food, additives, drugs

Spontaneous
Spirometry in the office PEFR chart at home

Reversibility
Spirometry before and after B2 agonist

Provocative Testing
Exercise Cold dry air Methacholine

Skin Tests
Scratch test Prick puncture test Intradermal skin test

Serological Tests
RAST Modified RAST tests
CAP TESTING OTHER

Major criteria
Parent or sibling with asthma Atopic dermatitis Aeroallergen sensitivity

> 4 episodes/yr of wheezing lasting more than 1 day affecting sleep in a child with one MAJOR or two MINOR criteria

Minor criteria
Food sensitivity Eosinophilia (>4%) Wheezing apart from infection

Days with symptoms Mild Intermittent Mild Persistent Moderate Persistent Severe Persistent <2x/week

Nights with symptoms

PEF or FEV1

PEF Variability <20%

<2x/month >80%

3-6x/week

>2x/month >80%

20-30% 20-

Daily Continuous

>1x/week

>60>60<80% <60%

>30%

Frequent

>30%

Indoor Allergens - e.g. mites, animals, molds Outdoor Allergens Non-specific triggers Smoking - passive or active Occupational agents Drugs - e.g. F-blockers, NSAIDs

Current Treatment Paradigms for Asthma as an Allergic Disease

Allergen Avoidance Pharmacological Intervention
 Theophylli  Cromones ne  Corticosteroids  LABA  Leukotriene Modifying Drugs

Immunotherapy
 Allergen Immunotherapy  Novel Immunologic Therapies

Pharmacologic Therapy
Reliever Medications:
    

Rapid-acting inhaled

2-agonists

Systemic glucocorticosteroids Anticholinergics Methylxanthines Short-acting oral

2-agonists

Pharmacologic Therapy
Controller Medications:
Inhaled glucocorticosteroids  Systemic glucocorticosteroids  Cromones  Methylxanthines  Long-acting inhaled 2-agonists  Long-acting oral 2-agonists  Leukotriene modifiers  Anti-IgE


Delivers medication directly to the airways Minimizes systemic side effects Faster onset of action
Rescue medications

Recommended by asthma guidelines

23

Patient variables Aerosol characteristics

Particle size and velocity

Device type
Nebulizers Pressurized metered-dose inhalers (pMDIs) Dry-powder inhalers (DPIs) Attachments
Valved holding chambers and spacers Mouthpieces Face masks

24

Any age Easy to teach and use Patient coordination not required High drug doses possible No propellant Can be used with supplemental oxygen

25

Less portable than inhalers Requires power source, maintenance, and cleaning Output is device dependent Delivery may take 5 to 10 minutes or longer

26

Compact Portable High dose-dose reproducibility Short treatment time, compared with traditional jet nebulizers No content contamination

27

May be difficult to use correctly on a daily basis

Coordination/timing of actuation and inhalation Not for use in children 5 years old without a spacer

May be difficult to teach to elderly and very young High aerosol velocity leads to oropharyngeal deposition Improper technique may affect dosing Of pMDIs on the market in the United States, none are approved for patients e4 years old

28

Reduce problems with pMDIs

Coordinating actuation and inhalation Oropharyngeal drug deposition

Allow use of pMDI by

Children (with closely fitted face mask) Handicapped or elderly Any patient who has difficulty using a pMDI

29

INTERMITTENT Daily Medications

None

Quick Relief
short-acting F2 agonist prn

Education

Asthma Management
Treatment
MILD PERSISTENT Daily Medications
 Low dose ICS  Alternative: sustained-release theophylline, cromones, or leukotriene modifier

Asthma Management
Treatment
MODERATE PERSISTENT Daily Medications
 ICS plus long-acting F2 agonist  Alternative: ICS plus sustained-release theophylline, cromones, or leukotriene modifier

Asthma Management
Treatment
SEVERE PERSISTENT Daily Medications
 Higher doses of ICS plus long-acting F2 agonist  Sustained-release theophylline, cromones, or leukotriene modifier can be used in addition to or as alternative to long-acting F2 agonist  Oral steroids

Omalizumab: Mechanism of Action

Binds free IgE Reduces cell-bound IgE

Mast cell Basophil

B lymphocyte

Plasma cell

Free IgE

Reduces high-affinity receptors Allergens Pollen Dander Dust mite

Improves allergic symptoms and reduces complications

Allergic Inflammation And Airway Obstruction

Potentially reduces allergic inflammation

Inhibits cell activation

Asthma Education
Understand what asthma is Recognize and avoid triggers Understand when and why to use each medication Understand how to monitor asthma Use inhalers and peak flow meters properly Develop an asthma Action Plan Recognize acute severe asthma

Medication Usage


Patient/Physician


Difficulties associated with inhalers Complicated regimens Fears about, or actual side effects Cost

Misunderstanding/lack of information Underestimation of severity Attitudes toward ill health Cultural factors Poor communication

 

   

Obstruction of small airways

Aspiration Chronic lung disease secondary to prematurity Bronchiolitis Cystic Fibrosis

Obstruction of large airways

Foreign body Congenital malformations Cardiac disease Endobronchial tumors Extrabronchial obstruction Psychogenic

Control chronic and nocturnal symptoms Maintain normal activity levels, including exercise Maintain near-normal pulmonary function Prevent acute episodes of asthma Minimize emergency department (ED) visits and hospitalizations Avoid adverse effects of asthma medications