Diseases

Asthma

Asthma affects breathing and is very common. Pharmaceutical research has led to medicines that make breathing easier by enlarging the airways and reducing inflammation. Today, many patients lead normal lives with much less emergency treatment in hospital.

What is asthma? Top

Asthma is a complex group of disorders involving airway constriction in the lungs, inflammation and the production of thick bronchial mucus which impairs breathing.  Asthma attacks may be triggered by many substances to which humans are allergic (allergens), or by anxiety, cold air, exercise and chemicals.  

Individuals sensitive to allergens experience what is called ‘extrinsic’ asthma, which is brought on by immunoglobulin E (IgE).  Extrinsic asthma is estimated to account for 80 per cent of cases of asthma in children and more than half of those in adults.  People with asthma but no apparent allergy are said to have ‘intrinsic’ asthma.  Acute asthma is a dangerous condition, often needing hospitalisation and emergency treatment. 

An allergic reaction in extrinsic asthma involves two stages: sensitisation and activation. Sensitisation occurs when allergens (e.g. pollen grains, animal hairs, scales or faeces of the house dust mite, food constituents, etc.) are 'processed' in the body by specialised cells which then produce IgE antibodies specific for each allergen. 

IgE circulates in the blood and eventually attaches to mast cells and eosinophil granulocytes, a subgroup of white blood cells, in the lungs.  This stage does not cause any symptoms, but it has primed the individual concerned. 

An asthma attack follows activation, which occurs when the patient is exposed to the allergen again, when it binds to the specific IgE on the mast cells and eosinophils.  These then respond by releasing molecules like leukotrienes, platelet activating factor (PAF), complement components, cytokines and neuropeptides that cause airway constriction and result in an asthma attack. 

With successive attacks, the accumulation of potentially inflammatory cells is exacerbated and a deteriorating spiral is initiated.  Ultimately, this may lead to a chronic asthmatic state that is less responsive to treatment.  Allergic rhinitis (hay fever) shares similar mechanisms to asthma, but the allergic mechanism occurs in the upper respiratory tract instead of the lung and does not lead to such severe consequences.  

Who does asthma affect? Top

Asthma is very common in the European population and is the most common chronic disease in children.  In countries of northern and central Europe, between 2.5 and ten percent of children and between four and seven per cent of adults are currently being treated for asthma.  About 300 million people suffer from Asthma worldwide, a total that is expected to rise to about 400 million over the next 20 years. 

In about 40 per cent of these cases, the symptoms of the disease are severe and frequent enough to cause significant restrictions on many aspects of daily life.  Asthma is the most frequent cause of being off sick from school and among the most common reasons for GP visits.  

 

FIGURE 1: Some of the cells and chemical messengers involved in an asthma attack. The numbers are the sites at which asthma medicines act.

Present treatments Top

Present medications can be divided into two main categories - bronchodilators and anti-inflammatory medicines, mostly given by inhalation.  They may be grouped broadly into (i) selective beta2 stimulants (agonists), (ii) non-selective beta2 agonists, (iii) anticholinergics, (iv) corticosteroids and (v) miscellaneous other agents.  In acute allergic asthma, one cause of bronchoconstriction is the release of histamine from sensitised mast cells.  Therapy with antihistamines is well established in such cases. 

Guidelines for the use of these medicines in chronic asthma advocate a ‘cascade’ approach, starting with the minimal dose of a beta2-agonist (bronchodilator) needed to control symptoms, progressing to low-dose steroids (anti-inflammatory), higher dose/frequency steroids, and then the addition of other bronchodilators to reduce the steroid requirement and, finally, adding oral steroids.  Most asthmatic individuals respond well to the available treatments of inhaled corticosteroids and beta2-adrenergic agonists; however, some ten per cent respond poorly.  A significant problem is limited response or the development of tolerance, requiring gradually stronger medication. 

Improved knowledge of asthma mechanisms has led to the recognition of different asthma phenotypes that might reflect distinct types of inflammation, explaining the effectiveness of treating patients with anti-leukotrienes or with an anti-IgE monoclonal antibody. 

The release of molecules such as leukotrienes and numerous cytokines from white blood cells leads to accumulation of cells in the lung.  By blocking the formation of the signal substances or retarding cell responsiveness to them, accumulation can be reduced.  This is one of the ways in which phosphodiesterase (PDE) inhibitors act.  Cross-linking of IgE-receptors on the surface of mast cells by antigen-specific IgE is one of the early stages in an acute asthma attack.  Infusion of anti-IgE decreases circulating IgE and much reduces the frequency of acute asthma attacks in susceptible individuals.  

What else is of interest? Top

More knowledge of the inflammatory process within the airways is still needed.  Improvements in available therapies, e.g. the development of fast-onset, once-a-day combination medicines with better safety profiles, will occur.  Other approaches that target specific pathways or mediators could, in combination with corticosteroids, reduce the corticosteroid insensitivity often seen in severe cases of asthma. 

In this area, biological agents directed against the interleukin pathways and new molecules that modulate functions of T-lymphocytes will be of major interest.  Some of these, like many of those mentioned above, will also have clinical value in the management of chronic obstructive pulmonary disease (COPD), which shares many features with allergic asthma.