Pathophysiology of Asthma

Asthma is usually defined clinically as reversible airflow limitation, but current definitions also recognise the presence of airway hyper-responsiveness to bronchoconstricting stimuli such as histamine, and eosinophilic airway inflammation.

Asthma may be triggered by occupational exposure, drugs (including aspirin: around 1%). Asthma attacks or exacerbations may be triggered by viral infections, allergen exposure or non-specific irritants.

Genetic analysis of asthma has defined genes linked to atopy, airway hyper-responsiveness or asthma symptoms: including genes of the IgE receptor and genes associated with defective epithelial repair.

Diagnosis

Asthma is diagnosed on the basis of variable symptoms of cough, wheeze, chest tightness and breathlessness and confirmed by demonstration of reversible airway narrowing either spontaneously over time or in response to inhaled β2 agonists.
This can be documented as 15% or more improvement in peak expiratory flow rate or FEV1. Radiology may show hyper-inflation but is not useful in diagnosis except to rule out other conditions.

AHR : A characteristic feature of asthma is exaggerated narrowing of the airways in response to specific or non-specific stimuli, termed AHR. This can be measured in the lung function laboratory by controlled inhalation of agents such as histamine to determine the dose of histamine causing a 20% fall in FEV1 from baseline (PD20). Such measurement is not usually required for diagnosis but can be helpful if there is doubt.

Allergy and asthma

A majority of asthmatics are atopic and allergic and most have co-existent nasal airway disease. Treatment of rhinitis is important for symptom control and may in itself help with asthma control although direct evidence is scant. Assessment of allergy in asthma by skin prick testing and history is important if anti-IgE therapy is considered. Allergen avoidance measures were ineffective in trials
where they were applied broadly in house dust mite sensitised
asthmatics. Further studies will be needed to determine whether focused interventions could be effective in severe asthmatics with predominant monosensitisation to house dust mites together with exposure in the home.
Acute severe asthma associated with anaphylaxis may form type 1 ‘brittle asthma’, and should be investigated for allergic sensitisation. These rare patients may require injectable epinephrine (EpiPen®) to self-inject to treat
attacks.

Airway inflammation in asthma

Patients who die of asthma show massive inflammatory infiltration of the airway at post-mortem, often with marked eosinophilia and mucus plugging. The use of bronchial biopsies and induced sputum to sample the airways showed that epithelial shedding and airway eosinophilia together with mast cell and lymphocytic infiltration are present even in mild or asymptomatic asthma. Exactly how inflammation contributes to airway narrowing and AHR in asthma remains controversial although many of these features have been correlated to disease severity measured by symptoms, airflow obstruction or AHR. Bronchial biopsy is not helpful in diagnosis of asthma at present as generally changes are not specific. However, a
‘normal’ biopsy (no remodelling or inflammation) may be helpful in apparent refractory asthma to focus on other causes for symptoms.

IgE and mast cells and basophils

A proportion of asthmatics are atopic and make IgE to common allergens. In these patients, allergen exposure may trigger attacks through cross linking high-affinity IgE receptors on mast cells and basophils leading to release of histamine, cytokines and growth factors from pre-stored sources in granules as well as de novo synthesis of leukotrienes and cytokines. Histamine and lipid mediators may cause acute airway narrowing (within minutes) due to oedema, vascular engorgement and muscle contraction and may be important in acute severe asthma linked to anaphylaxis or some cases of ‘brittle asthma’. Cytokines and growth factors are thought to contribute to further airway inflammation and airway remodelling. These factors laid the basis for development of anti-IgE treatment for asthma (Xolair®): this antibody blocks the association of IgE with its receptor on mast cells and basophils. Of note IgE is also involved in ‘antigen trapping’ since dendritic cells have high affinity IgE receptors which can act to ‘catch’ allergens for processing into peptides within the cell for subsequent presentation to and activation of T lymphocytes: anti-IgE also blocks this process. It is of note that non-atopic asthmatics also have increased IgE receptor-bearing cells in the airway, together with evidence of local airway synthesis of IgE and marginally raised serum IgE. Whether this is mechanistically important or a target for treatment remains unclear.

(Reference – Oxford Desk Reference – Respiratory Medicine)