Respiratory Physiology: Asthma Pathogenesis, influencing factors and allergic response

Asthma Overview

Asthma is a chronic disorder involving inflammation and hyper-responsiveness of the airway and affects approximately 300 million people world-wide. Approximately 250,000 deaths occur yearly in the world as a result of asthma . Most asthma deaths occur in individuals ≥ 45 years of age secondary to inadequate long-term medical care or delays in obtaining medical help during acute attacks. The under use of corticosteroids, likely secondary to non-adherence, played a large role in these deaths. It is encouraging that over the last few years, asthma morbidity and mortality rates have been declining possibly due to an improved level of disease management. Unfortunately, despite the improvement in morbidity and mortality rates, the prevalence of asthma worldwide is still increasing, especially among children.

The increased prevalence of asthma is not just found in developed countries, there is also an increasing prevalence of asthma in developing regions such as Africa, Central and South America, Asia and the Pacific as urbanization and westernization increases there. The specific causes of asthma and reasons for its increased prevalence worldwide are largely unknown. It is speculated that factors such as rise in allergic disorders and allergic sensitization, change in environment, and a more inclusive definition of asthma may have contributed to this increase in prevalence. It also appears that children are not outgrowing asthma with the disease continuing on to adulthood. Furthermore, the prevalence of asthma in older adults was likely underestimated as the asthma diagnosis is often overlooked in the elderly in lieu of diagnoses of respiratory symptoms related to other illness commonly found in the elderly such as COPD and cardiovascular disease.

Global Impact of Asthma

• Affects approximately 300 million people world- wide.
• Approximately 250,000 deaths occur yearly in the world as a result of asthma
• Improvement in morbidity . and mortality rates
• The prevalence of asthma worldwide is increasing
• Increase in sensitisation to allergic disorders
• Improved diagnosis

Factors Influencing Asthma Development

Host Factors in Asthma

• Genetics; genes predisposing to allergy genes affecting 32- receptors
• Obesity
• Gender (more prevalent in female adults)

Environmental Factors and Early Exposure

• Allergens
• Viral infection
• Occupational irritants
• Tobacco smoke (active and passive)
• Air pollution (outdoor and indoor)
• Diet

Prevention of Asthma

Few measures can be recommended for preventing asthma as the development of the disease is complex and not well understood. Other than preventing tobacco exposure in-utero and after birth, there is no proven and widely accepted intervention that can prevent asthma.

Prevention of allergic sensitization has been recommended in sensitized people. Some methods of allergic sensitization begin pre-natally to prevent the birth of an atopic child and includes antigen avoidance diet for pregnant mothers, but there is insufficient evidence supporting the efficacy of this intervention. A method of allergic sensitization avoidance focused on infants include breast feeding in lieu of feeding soy protein and cow's milk which, in some studies, have been found to be efficacious. Another method, referred to as the "hygiene hypothesis", involves exposing infants to farm animals in order to redirect the infant's immune response so as to make the child non-responsive to allergens in the future. Unfortunately, this is still a hypothesis and still merits further research to substantiate its efficacy. Finally, some studies have determined that exposing a child to cats at an early age may also prevent allergic sensitization.

Once allergic sensitization has occurred, however, there are still other opportunities to prevent the actual development of asthma including use of allergen-specific immunotherapy (allergy shots). Whether these interventions are truly effective merits further study.

Strategies for Asthma Prevention

• Prevent tobacco exposure in utero and after birth
• Prevent allergic sensitisation
  • Allergen avoidance diet in pregnant mothers
  • Breast feeding to avoid feeding soy milk or cow's milk
  • Re-direct the immune response from Th2 to Th1 by exposing infants to farm animals (the hygiene hypothesis)
• After sensitisation prevent the actual development of asthma with 'allergy shots', increasing concentrations usually subcutaneously to switch IgE response to IgG

Symptoms and Presentation of Asthma

Asthma Symptoms

• Wheezing
• Breathlessness
• Chest tightness
• Coughing

Asthma Presentation

• Often occur at night or early morning
• Recurrent episodes
• Vary in duration and severity (mild. moderate, severe)

Asthma occurs as a result of chronic inflammation of the airway which is hyper- responsive and causes obstruction and limited airflow when triggered by various factors. Airway narrowing creates the symptoms of asthma. This is due to airway smooth muscle contraction, and also airway edema, airway wall thickening ie fibrosis, and mucus hyper- secretion (see later slides). The airflow limitation plus the symptoms produced (wheezing, coughing, shortness of breath, chest tightness) continue to aggravate the inflammation and hyper-responsiveness of the airway creating a vicious cycle. The specific association of airway inflammation and hyper- responsiveness is still not well understood.

" Factors acting on the hyper-responsive airways provoking airflow limitation that cause asthma are called trigger factors. Trigger factors have little or no effect on asthma development but can be capable of triggering an effect. These include: allergens, bacterial/viral infection, exercise, weather changes, gastro-esophageal reflux, pregnancy/menstruation, and stressful/emotional situations.

Causes of Airway Narrowing in Asthma

• smooth muscle contraction (bronchial hyperreactivity)
• inflammation (eosinophils and Th2 cells)
• airway oedema
• airway wall thickening (fibrosis)
• mucus hypersecretion

Beta 2-Adrenergic receptors are present in normal or increased numbers on asthmatic airway smooth muscle but are uncoupled in severe asthma, leading to functional hyporesponsiveness, probably due to the effects of inflammatory mediators

Trigger Factors for Increased Asthma Symptoms

• viral infection, especially rhinovirus (winter)
• bacterial infection
• specific allergen
• irritants-air pollution, tobacco smoke
• exercise
• weather changes (thunderstorm asthma)
• gastro-oesophageal reflux
• pregnancy/menstruation (role of oestrogen)
• stressful and emotional situations

The triggers for an exacerbation of asthma (acute asthma attack or 'flare up', are often the same as those involved in the on-set and development of asthma at an earlier stage, Many factors may interact to produce an exacerbation, that is an increase in symptoms requiring an increase in medication and/or hospitalization.

Phases of Allergic Asthmatic Response

The two phases of the allergic asthmatic response to specific allergen

Inhalation 3.0 1 Diluent 2.5 FEV1 (litres) 2.0 Grass pollen 1.5 - 1.0 Early phase: bronchospasm Late phase: inflammation 0 1 2 3 4 5 6 7 8 Hours Rang et al: Rang & Dale's Pharmacology, 7e Copyright @ 2011 by Churchill Livingstone, an imprint of Elsevier Ltd. All rights reserved.· NOTES

Fig 27.1 Two phases of asthma demonstrated by the changes in forced expiratory volume in 1 second (FEV1) after inhalation of grass pollen in an allergic subject. (From Cockcroft D W 1983 Lancet ii: 253.)

• FEV1: Forced Expiratory Volume in the first second. The volume of air that can be forced out in one second after taking a deep breath, an important measure of pulmonary function.
• FEV1 (%) is the value of FEV1 as a percentage of the value predicted from the age and height of an individual. Normal healthy lungs have FEV1 (%) which is 100% predicted. A decrease in FEV1 and FEV1 (%) indicates airflow obstruction
• The two phases of asthma are demonstrated by the changes in FEV1 after inhalation of grass pollen in an allergic subject.
• Development of an early-phase (0-2h) and late-phase (10-12h) airway response in response to allergen in a sensitized individual. The FEV1 falls as the airway smooth muscle contracts (bronchoconstriction) and there is increased resistance to airflow.
• The early phase fall in lung function is due to mast cell-dependent bronchospasm, mediated largely by leukotrienes and PGD2. Histamine has only a small effect .. The largest effect is due to leukotrienes, particularly LTC4 on bronchial smooth muscle.
• The late-phase response is due to an inflammatory response mediated by activated Th2 cells that produce pro-inflammatory cytokines, and the recruitment of eosinophils. Eosinophils are a source of LTC4 and further bronchospasm. Mast cell-mediated activation of Th2 cells and the amplification of Th2 recruitment occurs as a result of IgE-facilitated antigen presentation by airway dendritic cells

Cells and Mediators of Early and Late Response

Cells and mediators of the early and late response Early response Late response Bronchoconstriction Inflammation mucus production oedema Mast cells Th2-cells and eosinophils IgE-dependent IgE-dependent LTC4 LTC4

Role of Dendritic Cells in Allergic Asthma

Detecting allergens- the role of the dendritic cell in allergic asthma Dendritic cells differentiate and migrate to airway epithelium Dendritic cells form a dynamic network in the epithelium and pick up airborne allergens Dendritic cells migrate into airway mucosa Dendritic cells leave epithelium, differentiate further and migrate to local lymph nodes Immature blood dendritic cells In lymph node, mature dendritic cells present allergen to T cells

Schematic diagram of dendritic cell migration from the blood into the lungs where the cell processes detect and take up foreign proteins and carry them to naïve T-cells in the lymph nodes.

Antigen Processing and Presentation by Dendritic Cells

" The dendritic cell takes up and processes antigens (foreign proteins) in to small peptides that are presented on MHC class II molecules (green) to the T-cell receptor (purple) which specifically recognises the peptide. Each T- cell is very specific and recognises only one peptide. " The T-cell is activated by antigen presentation on MHC class II compexes (signal 1) and by additional interactions between receptor- ligand pairs on dendritic cells and the T-cell that deliver co-stimulatory signals to the T-cell (signal 2). Finally soluble mediators such as cytokines and chemokines are released by the antigen presenting cell and the T-cell response is activated and modified. The T-cells activated in asthma are the subset of CD4+ T-helper cells called Th2 that produce a specific array of cytokines that drive the allergic inflammatory response in asthma.

2 MHC class II CD4 T TCR 5 cytokines | Ag uptake Antigen presenting T 2 Ag processing 4 Th2 cell 3 Ag presentation = signal | B7-CD28 cell 4 Costimulation = signal 2 5 Soluble mediators cell