Asthma and allergy

Explain in detail how our understanding of asthma has advanced from 1860 when Salter first described it as “paroxysmal dyspnoea of a peculiar character with intervals of healthy respiration in between attacks”, noting many of the characteristic features of this disease, including “hyperresponsiveness to cold air and exercise and attacks provoked by exposure to chemical and mechanical irritants, to particular kinds of air as well as to certain foods and wine”.

Understanding of asthma disease pathophysiology

The current definition of asthma states that it is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, T lymphocytes, macrophages, neutrophils and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness and coughing, particularly at night or early in the morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment (1).
Asthma can be explained as a “hyper-reactivity” of the airways – stimuli that in a non-asthmatic would cause little in the way of symptoms, suddenly cause an excessive response – with resultant airway constriction. This was described by Salter(2). Pathologically, asthma is characterised by thickening of the wall of the airway, in particular the bronchioles, excess mucous production and spasm of the smooth muscle within the walls of the lower airway. All of these factors are caused by an inflammatory reaction, whether it be allergic or environmentally induced – again, as described by Salter when talking of exposure to chemicals, mechanical irritants, different types of air, and certain foods and wines.
Our understanding of this complex disease has increased significantly since the days of Salter, particularly with respect to monitoring and understanding of the underlying inflammatory pathways, although many of the underlying principles remain the same.
Inflammatory cells and factors involved in asthma pathogenesis:
Mast cells
These are bone marrow derived white blood cells, similar in nature to basophils, the main difference being that mast cells are mucosally located, whereas basophils are in the blood. They have cytoplasmic granules which contain Histamine, Tryptase, Prostaglandin D2, Leukotrienes C4 and D4, and Cytokines. Mast cells in the mucosa of the lungs in asthmatics can be caused to release their granules by a situation where two IgE antibodies, already attached to Fc receptors on the mast cell membrane, become linked by their attachment to an antigen – causing an antigen-antibody complex. This then triggers a cellular response, whereby the cytoplasmic granules release their contents into surrounding tissue – causing the reaction we know as allergy.
The antigens that cause the binding of IgE antibody and subsequent mast cell degranulation are better known as allergens. This type of antigen-antibody reaction is called a type 1 hypersensitivity response, and is responsible for many diseases such as hay fever and eczema. It is the cause of asthma in the group known as allergic asthmatics.
In severe asthmatics, the distribution of mast cells dictates what the response will be to degranulation. The majority of mast cells in these cases are in the smaller airways, such as the terminal bronchioles, and are located in the bronchiolar wall, more in the outer wall than the inner (ref).

Inflammatory mediators released from Mast Cells:
Histamine release from mast cell degranulation causes the symptoms of asthma due to effects of histamine on the wall of the airway – from the main bronchi right down to the alveoli. These effects include blood vessel vasodilation, and vascular leak, smooth muscle constriction leading to bronchoconstriction and spasm, hypersecretion of mucous and stimulation of afferent nerves causing sneezing, itching and cough.
Leukotriene release causes smooth muscle constriction in the airway wall, increase in vascular permeability leading to swelling through fluid leakage into the extracellular compartment, eosinophilic recruitment and increase in mucous secretion(3).
Cytokines are subdivided onto several groups. Important in asthma are the interleukins, which are proteins synthesised by CD4 T helper cells, In particular interleukin (IL) 4,5,6 and 13. Other cytokines involved in asthma include Tumour Necrosis Factor and Granulocyte-Macrophage Colony-Stimulating Factor. The main function of these is to regulate inflammation, attracting different types of white blood cell such as eosinophils, causing B cells to differentiate and form antibody (IgE) and activate endothelial cells.
Tryptase is an enzyme, whose function is not fully understood, but is certainly involved in the inflammatory pathway and is thought to catalyse complement activation in anaphylaxis.
Prostaglandin D2 is a major component in allergic asthma, its release from mast cells causes bronchoconstriction. In addition, it helps to recruit T Helper type 2 cells (TH2), basophils and eosinophils, which are all part of the underlying inflammatory process.

Eosinophils
These cells are part of the white blood cell group. In asthma they are markers of inflammation, and when recruited and activated by cytokines released by mast cells and T helper cells type 2 (in particular Il-5), they go on to produce prostaglandin e2 and their own cytokines, in particular those interleukins involved in asthma pathogenesis (see above). The presence of eosinophils in bronchial mucous/sputum is a good marker for airway inflammation, and can be used along with bronchial biopsy assessment of eosinophilic infiltration, to gauge the degree of inflammation existing, and this helps to predict control of asthma and the likelihood of emergency admissions (4). Eosinophils are part of the allergic asthma pathway.

T Lymphocytes
These are white blood cells originating from the thymus, rather than the bone marrow (hence “T”). In inflammation, they can be looked upon as the “controller”, as they are involved in guiding the inflammatory reaction at its pivotal point. In particular, mature T cells, called T helper cells are at the centre of the type 1 inflammatory process.
They respond to antigens, this is directed by the genetically coded presence of T cell receptors on their surface. These receptors in particular recognise major histocompatibility complex proteins in Class 2 (MHC II) – these are the ones found on the surface of antigen presenting cells (APC’s – often B lymphocytes which circulate freely around the body) – critical for the type 1 (allergic) inflammatory response.
This interaction of the APC and the T cell causes activation of the T cell, with memory T cells being formed, leading to sensitisation and memory for antigens of the MHCII complex – allergy. Also, this activation causes the T cell to proliferate, mediated by IL2, becoming the group of T cells known as T helper cells – Th.
These can be further subdivided into types 1 and 2. It is Th type 2 cells that are involved in the asthma allergy process, abbreviated into Th2.
Th2 cells themselves promote the metaplasia of B lymphocytes that have bound to their antigen via the B cell receptor into plasma cells, or B memory cells. It is the plasma cells that have a particular role in asthma, as they proliferate and produce specific IgE to the attached antigen. The released IgE then acts locally and peripherally, further binding to antigen and causing mast cell degranulation (above).
Thus it is the Th2 cell that helps in the initial recognition of antigens, and then is directly involved in memory, instituting the process whereby mast cell degranulation occurs and the inflammatory response happens as a reaction to the antigen. This is the root of allergic asthma.
This intrinsic role of Th2 cells was demonstrated in a study by Hamid et al (5), where highly significant levels of Th2 gene expression were seen in the distal airways of patients with asthma, when compared to non-asthmatic controls, at post mortem.

Macrophages
These cells originate from blood monocytes (white blood cells). They have many functions, classically in phagocytosing unwanted cells such as bacteria and viruses, whose presence has been alerted to the macrophage by the release of inflammatory mediators (cytokines) and the antibody (IgG and IgM in this case) antigen complex. In asthma however, their role is less clear. What is known is that they have both pro and anti-inflammatory functions and that this modulates the inflammatory response seen in asthmatics. They may also be involved in environmental (non-allergic) asthma, due to phagocytosis of pollutants, environmental tobacco smoke, dust etc.

Neutrophils
Neutrophil infiltration in sputum is often seen in more severe cases of asthma.
Matrix metalloproteinase 9 (MMP9) and Elastase are 2 inflammatory mediators released by neutrophils through cytokines such as tumour necrosis factor and interleukins released from T helper type 1 cells (Th1) and type 17 T helper cells amongst others. These substances have similar effects to Histamine, and are more involved in environmental rather than allergic asthma.

Figure 1
Basic summary of inflammatory process in environmental and allergic asthma

Physiolology
The cellular aspects of asthma all occur at the epithelial-mesenchymal trophic unit level. The processes involved in this are highly complicated, and are outlined above. They can be broadly separated into allergic and environmental effects, which have parallel pathways. Physiologically, what happens to the airway in asthma is equally as challenging. In asthma, diurnal variable airflow obstruction occurs, superimposed on this is the effect of ageing on the asthmatic airway, and loss of bronchiolar responsiveness to Beta 2 receptor agonists – a part of the mainstay of treatment. Thus asthma control can worsen with age. Natural decline of lung function in asthmatics is further accelerated by smoking.

Smooth muscle contraction
This occurs secondary to the inflammatory process, and in chronic asthma the smooth muscle of the airway wall can become thickened and fibrotic. Smooth muscle is innervated by nerves of the sympathetic nervous system, of which there are 3 receptors, all using noradrenaline as the neurotransmitter. The 3 different types of receptors are alpha 1, alpha 2 and Beta2. The alpha receptors when stimulated cause smooth muscle contraction, the beta ones cause smooth muscle dilatation. Thus blocking alpha receptors and stimulating Beta receptors will cause smooth muscle to dilate, opening the airway. This is one of the main treatment pathways in asthma – in particular using Beta-2 agonists to dilate airway smooth muscle.

Studies have shown that the airway wall changes over time in asthmatics. In particular, thick layers of collagen are laid down in the wall, plus smooth muscle hypertrophy, vasculature and glands all undergo asthma related changes. This leads to airway remodelling and further loss of elasticity, probably mediated via epidermal growth factor, as the expression of its receptor has been found to be significantly elevated in asthmatics (ref). This is thought to increase fibrosis in the airway vessel wall.
Physiologically, the bronchial hyperresponsiveness that characterises asthma causes a decrease in bronchial airflow. These changes can be demonstrated by challenging the airway with substances such as Histamine. Other triggers include smoking, exercise, cold air, inhaled allergens and viral infections. The net effect is to produce difficulty in breathing, most pronounced in expiration. Classically, this is reversible by using agents such as inhaled bronchodilators, which cause relaxation of the smooth muscle in the wall of the airway – so opening up the airway and increasing flow.

Treatment of asthma
With increasing understanding of the pathophysiology of asthma, its distinction into allergic and environmental, and knowledge of the underlying mechanisms that cause asthma symptoms, treatment is becoming increasingly effective.
Treatment is progressive, depending mainly on the severity of disease, and can be divided into pharmacological and non-pharmacological, and varies from age group to age group (6).

Pharmacological treatment approaches for asthma
Treatment has relied on 3 main pathways to improve symptoms – relaxation of smooth muscle, reduction of secretions and dampening down the inflammatory response (see table 1). As can be seen above, some treatments will positively affect all 3 of these, others just single pathways. Here are some examples of drugs which aid in asthma control, based upon our understanding of pathophysiology.
Initial treatment tends to be with a reliever for symptoms, such as the Beta 2 receptor agonist Salbutamol (relaxes smooth muscle), as an inhaler. This is followed by sequentially adding in maintainer treatment again as an inhaler, in the form of steroid such as Fluticasone (helps reduce airway inflammation), long acting Beta agonists such as Salmeterol (relaxes smooth muscle) and long or short acting anticholinergics (also relax smooth muscle, reduce secretions) such as Ipratropium Bromide.
Stepwise increase in dose of these agents occurs until asthma is controlled, defined as when clinical manifestations have been reduced sufficiently to enable the patient to carry out activities of daily living and achieve optimum quality of life.
If asthma remains poorly controlled despite full stepwise escalation of this medication, a variety of additional drug treatments may be commenced, in particular short bursts of systemic steroids, anti-leucotrienes such as Montelukast, and anti-interleukin 5 monoclonal antibodies such as Mepolizumab. The evidence for the use of these new compounds has only come about by increased understanding of the inflammatory pathway (7).
Other anti-allergy medication such as histamine H1 receptor blockers (e.g Loratidene) may also be commenced. All of these agents are designed to interrupt and suppress the chronic inflammatory response which characterises asthma. Other drugs, including sodium chromoglycate, stabilse mast cells, so inhibiting degranulation and release of inflammatory mediators such as Histamine.
Table 1 List of drugs and mechanism of action
Mechanism of action
Drug
Reduce secretions
Relax smooth muscle
Inhibit inflammation
Antihistamine (H1)
++
+
+
Anti-leukotriene
+
+
++
Beta 2 agonist inhaler

+++

Anti-cholinergic
+++

Steroid inhaler

+
Steroid tablets

+++
Sodium Chromoglycate
+
+
+
Mepolizumab
+
+
+

Non-pharmacological treatment of asthma
Asthma can be divided into Allergic and Environmental. Salter, in his original description of asthma, described different external conditions or substances that were related to the disease. Increasing awareness of these factors, and how to eliminate them from the patient’s environment, is a big part of the strategy for overall asthma control.
Allergy
Primary prevention – this is to stop allergy developing at all. Breast feeding babies seems to be the only area recommended for this.
Secondary prevention – this seems to make sense in allergy. If the patient is tested, and has specific IgE antibodies, then whatever these antibodies are to (e.g. house dust mite faeces), then the underlying problem (dust) should be eradicated from the environment as much as possible. The same goes with allergy to pets etc. Further tests regarding allergy status, such as immunoCAP specific IgE testing, or skin prick testing, along with total IgE levels can help in the diagnosis of allergic asthma rather than environmental, and can help identify which allergens need to be avoided. Other challenge tests can be performed, such as the aspirin-lysine test in cases where aspirin sensitivity is suspected – though this is more commonly performed in a nasal provocation manner.
Desensitisation – in patients with allergic asthma, desensitisation to the antigen associated with it can be very helpful. This is particularly true of aspirin sensitivity, which is associated with severe and poorly controlled asthma, although there is currently no effective agent to help achieve it. Other desensitisation protocols, such as Grazax for grass pollen allergy, seems to be more effective in hay fever rather than asthma.

Smoking
This produces inhaled dust particles, which was described right at the outset as one of the causes of asthma. Not only is it directly related to environmental asthma, but it can cause chronic obstructive pulmonary disease, which makes asthma worse due to a further drop in pulmonary function. Smoking in teenage years also increases the risk of persistent asthma. Smoking cessation trials showed disappointing quit rates.
Air Pollution
Although it appears that this doesn’t actually cause asthma, it is likely, from epidemiological evidence that it makes asthma worse, and this certainly goes along with Salters original description of mechanical and chemical irritants, presumably smoke and dust during the industrial revolution.
Weight
Being overweight, right from birth, increases the risk of asthma. Why is not known, and evidence is poor as to the final impact weight loss has on asthma severity. However at the very least, increased weight leads to increase oxygen demand, all other factors being equal. So losing weight will reduce the requirement and make any breathing related disease such as asthma, relatively better.

Immunisations
Influenza can precipitate asthma attacks, so it seems reasonable to encourage vaccination in asthmatics. There is some evidence supporting a protective role for BCG vaccination in terms of reducing asthma incidence.
Breathing exercises
Such as Yogic, Butekyo – these concentrate on diaphragmatic breathing and can help in asthma control.
Air filters
HEPA type air filters, particularly in the bedroom, are effective at removing particles from the surrounding air – these can significantly contribute to both allergic and environmental asthma.

Monitoring
The essence of good control is active monitoring. Modern day monitoring is focussing on patient centred monitoring, where the patient does the test, and the result is analysed via remote communication from the device. A Facebook type multi-user app, where not only associated medics/nurses, but members of the family, friends etc, are also accepted via an invite system to look at results, and alerts, enable early recognition as to when a dangerous situation may be looming(8).
Children are more difficult to monitor, under the age of 7 realistically symptom score monitoring is the only good test. Symptoms such as cough, wheeze can be recorded.

Peak Flow
This is a relatively simple monitoring test, and can be done by the patient at home. This is the mainstay of remote monitoring for asthmatics, as devices with bluetooth connection into a plug-in portal at home allow instant transmission of results. There is no evidence as yet regarding the impact of this for asthma, but encouraging results have been seen in Cystic Fibrosis sufferers (ref). Otherwise, patients can record their peak flow readings in a book and bring it in for medical appointments.
The race is on to develop a user-friendly remote social media platgorm and have this accepted by clinicians and patients (8).

Spirometry
This is a hospital-based test which measures FEV1 (forced expiratory volume in 1 second), FVC (forced vital capacity) and gives a ventilation profile in terms of the shape of the curve created.

Impulse oscillometry
This complements standard lung function testing such as peak flow and spirometry. It gives a value for airway impedance and resistance, which can be useful in assessing the severity of an asthma attack. Its main advantage is that it is an easy test to perform, relying only on the patient’s normal breathing into the apparatus, and as such can be used in children sometimes below the age of 7. It can be useful in monitoring of drug use and application.

FeNO
This stands for forcibly expired Nitrous Oxide. Measurement of this molecule can give a non-invasive value of airway inflammation, and demonstrate response to inhaled corticosteroids. It can also detect eosinophilic airway inflammation, which can be a more difficult version of asthma to control (see above).
It is therefore a very useful test for asthma monitoring as it assesses compliance, response to one of the two main agents (inhaled corticosteroids) and also predicts more serious and difficult to manage forms of the disease.

Sputum analysis
The presence of, and severity of Eosinophils in sputum in patients with allergic asthma gives a good indication of overall control. A sputum analysis based strategy has been shown to be effective in asthma monitoring and control.

Conclusion
An incredible amount of new understanding has happened in asthma pathophysiology since Salter first broadly described the disease. This has led to major advances in pharmacological and non-pharmacological treatment, with additional improved monitoring ensuring better control. Remote monitoring via a social media platform is an exciting latest innovation.

References
1) Expert panels report 2. Guidelines for the diagnosis and management of asthma. National asthma education and prevention programme. Second expert panel on the management of asthma. Bethesda (MD). National Hear Lung and Blood Institute USA 1997 July.
2) Salter 1860. On Asthma: Its pathology and treatment. First edition, Churchill
3) Drazen J.M., Austen K.F., Lewis R.A., Clark D.A., Goto G., Marfat A and Corey E.J. (1980) Comparative airway and vascular activities of leukotrienes C-1 and D in vivo and in vitro. Proc natl Acad Sci USA 77(7) 4354-4358
4) Green R.H., Brightling C.E., McKenna S., Hargadon B and Parker D (2002) Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 30;360(9347):1715-21.
5) Tulik M.K. and Hamid Q (2003) Contribution of the distal lung to the pathologic abd physiologic changes in asthma: potential therapeutic target. Roger S. Mitchell lecture. Chest:123(3 Suppl):348S-55S.
6) www.brit-thoracic.org.uk/document-library/clinical-information/asthma/btssign-asthma-guideline-quick-reference-guide-2014
7) Haldar P., Brightling C.E., Hargadon B., Gupta S., Monteiro W., Sousa A., Marshall R.P., Bradding P., Green R., Wardlaw A.J. and Pavord I.D. (2009) Mepolizumab and Exacerbations of Refractory eosinophilic Asthma. N Engl J Med;360:973-984
8) Jadavji A. Pers Comm.

Book Online
Mike Dilkes MS FRCS(ORL-HNS), FRCSEd, FRCS

Mike Dilkes ENT is based in Central, North, East and South London. Most of our consultations and treatments are carried out either at The Hospital of St John and St Elizabeth or The London Independent Hospital. The Hospital of St John and St Elizabeth is one of London's biggest and most prestigious private hospitals.

It is in St Johns's Wood, a leafy area of the west end, just north of Harley Street and Regent's Park. The London Independent Hospital is in Stepney Green, hidden away just behind Mile End Road, just to the East of the City of London. Formally The London Jewish Hospital, it is a purpose built modern building with full facilities, beautifully appointed rooms, state of the art laser systems and, in case anything goes wrong (it really shouldn't), a fully covered Consultant 24 hour ward and Intensive Care presence - the only private hospital in London to have this.