Epidemiology

The exact prevalence of asthma remains uncertain because of the differing ways in which airway restriction is reported, diagnostic uncertainty (especially for children under 2 years) and the overlap with other conditions such as chronic obstructive pulmonary disease (COPD). Over 5 million people in the UK have asthma (Asthma UK, 2001) and around 300 million worldwide. Mortality from asthma is estimated at approximately 0.4 per 100,000 with around 1400 deaths per annum in the UK. Most deaths occur outside hospital; the most common reasons for death are thought to be inadequate assessment of the severity of airway obstruction by the patient and/or clinician and inadequate therapy with inhaled or oral steroids.

The probability of children having asthma-like symptoms is estimated to be between 5% and 12%, with a higher occurrence in boys than girls and in children whose parents have an allergic disorder. Between 30% and 70% of children will become symptom free by adulthood. Individuals who develop asthma at an early age, however, do have a poorer prognosis.

The prevalence of asthma actually appears to be rising despite advances in therapy. There is some doubt about this, however, due to the differing criteria for the diagnosis of asthma used in different studies. Asthma is considered to be one of the consequences of Western civilisation and appears to be related to a number of environmental factors. Air pollution resulting from industrial sources and transport may be interacting with smoking, dietary and other factors to increase the incidence of this debilitating problem.

Aetiology

The two main causes of asthma symptoms are airway hyperresponsiveness and bronchoconstriction. Hyperresponsiveness is an increased tendency of the airway to react to stimuli or triggers to cause an asthma attack. Bronchoconstriction is a narrowing of the airways that causes airflow obstruction. Possible triggers are listed in Table 25.1. One of the most common trigger factors is the allergen found in the faeces of the house dust mite, which is almost universally present in bedding, carpets and soft furnishing. Pollen from grass (prevalent in June and July) can lead to seasonal asthma. The role of occupation in the development of asthma has become apparent with increased industrialisation. There are many causes of occupational asthma, and bronchial reactivity may persist for years after exposure to the trigger factor. Drug-induced asthma can be severe and the most common causes are β-blocker drugs and prostaglandin synthetase inhibitors. The administration of β-adrenoceptor blockers to a patient, even in the form of eye drops, can cause β₂-receptor blockade and consequent bronchoconstriction. Selective β-adrenoceptor blockers are thought to pose slightly less risk, but as these lose their selectivity at higher doses, it is generally recommended that this group of drugs is avoided altogether in asthma patients. Aspirin and related non-steroidal anti-inflammatory drugs can cause severe bronchoconstriction in susceptible individuals. Aspirin inhibits the enzyme cyclo-oxygenase, which normally converts arachidonic acid to (bronchodilatory) prostaglandins. When this pathway is blocked, an alternative reaction predominates, leading to an increase in production of bronchoconstrictor (cys-) leukotrienes. Figures from differing studies vary, but between 2% and 20% of the adult asthma population are thought to be sensitive to aspirin.

Table 25.1 Examples of asthma triggers

Pathophysiology

Asthma can be classified according to the underlying pattern of airway inflammation with the presence or absence of eosinophils in the airways (eosinophilic vs. non-eosinophilic). Traditionally patients are described as having ‘extrinsic asthma’ when an allergen is thought to be the cause of their asthma. This is more common in children with a history of atopy, where triggers, such as dust mite, cause IgE production. Other environmental factors are also important, such as exposure to rhinovirus during the first 3 years of life (Holgate et al., 2010). ‘Intrinsic asthma’ develops in adulthood, with symptoms triggered by non-allergenic factors such as a viral infection, irritants which cause epithelial damage and mucosal inflammation, emotional upset which mediates excess parasympathetic input or exercise which causes water and heat loss from the airways, triggering mediator release from mast cells. In practice, patients often have features of both types of asthma and the classification is unhelpful and oversimplifies the pathogenesis of asthma.

Mast cell components are released as a result of an IgE antibody-mediated reaction on the surface of the cell. Histamine and other mediators of inflammation are released from mast cells, for example, leukotrienes, prostaglandins, bradykinin, adenosine and prostaglandin-generating factor of anaphylaxis, as well as various chemotactic agents that attract eosinophils and neutrophils. Macrophages release prostaglandins, thromboxane and platelet-activating factor (PAF). PAF appears to sustain bronchial hyperreactivity and cause respiratory capillaries to leak plasma, which increases mucosal oedema. PAF also facilitates the accumulation of eosinophils within the airways, a characteristic pathological feature of asthma. Eosinophils release various inflammatory mediators such as leukotriene C₄ (LTC₄) and PAF. Epithelial damage results and thick viscous mucus is produced that causes further deterioration in lung function. These cell-derived mediators also play a role in causing marked hypertrophy and hyperplasia of bronchial smooth muscle (these structural changes are described as ‘airway remodelling’), mucus gland hypertrophy leading to excessive mucus production and airway plugging, airway oedema, acute bronchoconstriction and impaired mucociliary clearance.

Mucus production is normally a defence mechanism, but in asthma patients, there is an increase in the size of bronchial glands and goblet cells that produce mucus. Mucus transport is dependent on its viscosity. If it is very thick, it plugs the airways, which also become blocked with epithelial and inflammatory cell debris. Mucociliary clearance is also decreased due to inflammation of epithelial cells. The environmental insults causing asthma are also thought to affect the structure and function of the airway epithelium. The exact role of these cytokines, cellular mediators and the interrelationships with each other and with the causative allergenic or non-allergenic mechanisms has, however, yet to be fully determined and may vary over time (Douwes et al., 2002; Holgate et al., 2010). Fig. 25.1 outlines the main cellular mechanisms involved.

Fig. 25.1 Postulated cellular mechanisms involved in airway inflammation

(adapted from Douwes et al., 2002).

Clinical manifestations

Asthma can present in a number of ways. It may manifest as a persistent cough, but most commonly, it is described as recurrent episodes of difficulty in breathing (dyspnoea) associated with wheezing (a high-pitched noise due to turbulent airflow through a narrowed airway). Diagnosis is usually made from the clinical history confirmed by demonstration of reversible airflow obstruction and measures of lung function. The history of an asthma patient often includes the presence of atopy and allergic rhinitis in the close family. Symptoms of asthma are often intermittent, and the frequency and severity of an episode can vary from individual to individual. Between periods of wheezing and breathlessness, patients may feel quite well. The absence of an improvement in ventilation, however, cannot rule out asthma, and in younger children, it is sometimes very difficult to perform lung function tests; in this case, diagnosis relies on subjective symptomatic improvement in response to bronchodilator therapy.

Acute severe asthma is a dangerous condition that requires hospitalisation and immediate emergency treatment. It occurs when bronchospasm has progressed to a state where the patient is breathless at rest and has a degree of cardiac stress. This is usually progressive and can build up over a number of hours or even days. The breathlessness, with a peak flow rate <100 L/min, is so severe that the patient often cannot talk or lie down. Expiration is particularly difficult and prolonged as air is trapped beneath mucosal inflammation. The pulse rate can give an indication of severity; severe acute asthma can increase the pulse rate to more than 110 beats/min in adults. It is common to see hyperexpansion of the thoracic cavity and lowering of the diaphragm, which means that accessory respiratory muscles are required to try to inflate the chest. Breathing can become rapid (>30 breaths/min) and shallow, leading to low oxygen saturation (SpO₂ < 92%) with the patient becoming fatigued, cyanosed, confused and lethargic. The arterial carbon dioxide tension (PaCO₂) is usually low in acute asthma. If it is high, it should respond quickly to emergency therapy. Hypercapnia (high PaCO₂ level) that does not diminish is a more severe problem and indicates progression towards respiratory failure.

Some patients remain difficult to control with persistent symptoms and/or despite treatment at BTS/SIGN step 4 or 5. This is known as ‘refractory’ or ‘difficult to treat’ asthma. These patients must be carefully evaluated by a respiratory specialist; this will include confirming an accurate diagnosis of asthma, adherence to therapy and individual psychological factors.

Investigations

The function of the lungs can be measured to help diagnose and monitor various respiratory diseases. A series of routine tests has been developed to assess asthma as well as other respiratory diseases such as COPD.

The most useful test for abnormalities in airway function is the forced expiratory volume (FEV). This is measured by means of lung function assessment apparatus such as a spirometer. The patient inhales as deeply as possible and then exhales forcefully and completely into a mouthpiece connected to a spirometer. The FEV₁ is a measure of the FEV in the first second of exhalation. The forced vital capacity (FVC) can also be measured, which is an assessment of the maximum volume of air exhaled with maximum effort after maximum inspiration. The FEV₁ is usually expressed as a percentage of the total volume of air exhaled, reported as the FEV₁/FVC ratio. This ratio is a useful and highly reproducible measure of the capabilities of the lungs. Normal individuals can exhale at least 70% of their total capacity in 1 s. In obstructive lung disorders, such as asthma, the FEV₁ is usually decreased, the FVC normal or slightly reduced and the FEV₁/FVC ratio decreased, usually <0.7 (Fig. 25.2).

Fig. 25.2 Typical lung spirometry in normal subjects and asthma patients.

A peak flow meter is a useful means of self-assessment for the patient. It gives slightly less reproducible results than the spirometer but has the advantage that the patient can do regular tests at home with a hand-held meter. The peak flow meter measures peak expiratory flow (PEF) rate, the maximum flow rate that can be forced during expiration. The PEF can be used to assess the improvement or deterioration in the disease as well as the effectiveness of treatment. For all three measurements (FEV₁, FVC and PEF), there are normal values with which the patient’s results can be compared. However, these normal values vary with age, race, gender, height and weight. The measurement of FEV₁, FVC or PEF does not detect early deterioration of lung function such as bronchospasm and mucus plugging in the smaller airways.

The diagnosis of asthma can be confirmed by measuring the response to a bronchodilator or by examining a patient’s day-to-day variation in PEF readings. A diurnal variability of 60 L/min (or more than 20%) is highly suggestive of asthma (GINA, 2009). However, individuals may not have airflow obstruction at the time of the test, so the absence of an improvement does not rule out asthma. In this situation, peak flow readings can be done at home with repeated pre- and post-bronchodilator readings taken at various times of the day.

Treatment

As asthma involves inflammation and bronchoconstriction, treatment should be directed towards reducing inflammation and increasing bronchodilation. Treatment aims should include a lack of day and nighttime symptoms, no asthma exacerbations, no need for rescue medication, normal PEFs and no unwanted side effects from medication (BTS/SIGN, 2009; GINA, 2009). Anti-inflammatory drugs should be given to all but those with the mildest of symptoms. Other measures, such as avoidance of recognised trigger factors, may also contribute to the control of this disease. The lowest effective dose of drugs should be given to minimise short-term and long-term side effects. It should, however, always be remembered that asthma is a potentially life-threatening illness, is often undertreated and not all patients will achieve optimal control. Common therapeutic and practice problems encountered in the management of asthma are outlined in Box 25.1.

Chronic asthma

The pharmacological management of asthma depends upon the frequency and severity of a patient’s symptoms. Infrequent attacks can be managed by treating each attack when it occurs, but with more frequent attacks, preventive therapy needs to be used.

The preferred route of administration of the agents used in the management of asthma is by inhalation. This allows the drugs to be delivered directly to the airways in smaller doses and with fewer side effects than if systemic routes were used. Inhaled bronchodilators also have a faster onset of action than when administered systemically and give better protection from bronchoconstriction.

Treatment of chronic asthma should be managed in a stepwise progression. This section concentrates on management in adults, as outlined in Fig. 25.3, but corresponding management steps for children are available (BTS/SIGN, 2009). Therapy is moved up the steps according to the severity of the patient’s asthma symptoms and response to current treatment. When a patient has been stable for at least 3 months (GINA, 2009), therapy should be stepped back down; for example, by halving the inhaled corticosteroid (ICS) dose. International guidelines aim for management to achieve and maintain clinical control, which is defined in Table 25.2. A model for patient review and adjustment of therapy, based on assessment of asthma control, has been suggested (Crompton et al., 2006) and is shown in Fig. 25.4. To help in patient education, the terms used to describe the effects of asthma medication are similar across all manufacturers and sources of education. ‘Reliever’ is used for agents that give immediate relief of symptoms. Agents that act to reduce inflammation or give long-term bronchodilation are referred to as ‘controllers’ or ‘preventers’.

Fig. 25.3 Summary of stepwise management in adults

(reproduced by permission of the BMJ Publishing Group, from BTS/SIGN, 2009).

Table 25.2 Levels of asthma control (GINA, 2009)

Fig. 25.4 Adjusting therapy to achieve asthma control

(from Crompton et al., 2006 reproduced by permission. Copyright Elsevier publishing).

Reliever medication

Short-acting β-adrenoceptor agonist bronchodilators

β-Adrenoceptor agonists are the mainstay of asthma management. Salbutamol and terbutaline are selective β₂-agonists and have few β₁-mediated side effects such as cardiotoxicity. β₂-Receptors are, however, also present in myocardial tissue; cardiovascular stimulation resulting in tachycardia and palpitations is still the main dose-limiting toxicity with these agents when used in high dosage.

An inhaled β₂-agonist is the first-line agent in the management of asthma. This is used as required by the patient for the symptomatic relief of breathlessness and wheezing, for example, salbutamol 200 μcg when required. This may be the only treatment necessary for those with infrequent symptoms. There is no advantage to regular administration.

Additional bronchodilators

Additional bronchodilators may be required if the above therapy does not adequately control symptoms (Tables 25.3 and 25.4).

Table 25.3 Comparison of inhaled bronchodilators

Table 25.4 Daily dose range for selected bronchodilators

Inhaled anticholinergic agents

These block muscarinic (M1, M2, M3) receptors in bronchial smooth muscle but are generally of little additional value in asthma management. Ipratropium has a slower onset of action than β₂-agonists but a longer duration of action. Anticholinergics may be helpful in patients who also have a degree of obstructive airways disease.

Long acting β-adrenoreceptor agonist bronchodilators

When low-dose inhaled steroids fail to control asthma symptoms adequately at step 3, long-acting β₂-agonists should be added instead of increasing the steroid dose. Symptom relief after a trial period, for example, 4–6 weeks, must then be assessed to see if the LABA has been effective and whether further treatment needs to be added to or existing treatment changed.

Meta-analysis of LABA trials has shown a potential increase in asthma deaths of 1 death in 1000 patient-years of use, but this increased risk is lessened when used alongside ICSs (Saltpeter et al., 2006). Taking this evidence into account, it is advised that LABAs should

• only be added if regular use of standard-dose ICS has failed to control asthma adequately

• not be initiated in patients with rapidly deteriorating asthma

• be introduced at a low dose and the effect properly monitored before considering dose increase

• be discontinued in the absence of benefit

• be reviewed as appropriate; stepping down therapy should be considered when good long-term asthma control has been achieved (MHRA, 2008).

Combination ICS/LABA inhalers are available which may improve adherence compared to separate inhalers; as adherence to ICS is generally poor, using combination inhalers may ensure that the LABA is not used alone for variable periods of time.

A formoterol and budesonide combination inhaler can be given both as maintenance therapy and for symptomatic relief. Current trial evidence shows that this dosing method is an alternative at step 3 for adults who are poorly controlled on SABA and ICS, have experienced one or more severe exacerbations in the previous 12 months, or as an alternative to increasing the ICS dose to above 2 mg/day at step 4 (NPC, 2008).

Oral bronchodilators

Oral bronchodilators can also be added, for example, theophylline at steps 3–4 or β₂-agonists at step 4 for additional symptom control. Slow-release forms should be used, usually twice daily, although these can be used in a single night-time dose if nocturnal symptoms are troublesome.

Theophylline should be started at a dose of 400–500 mg/day in adults and, if required, increased after 7 days to 800–1000 mg/day. In children, higher doses may be required but this will be determined by the age of the child (see Chapter 10).

Theophylline has a narrow therapeutic index and its hepatic metabolism varies greatly between individuals. Theophylline clearance is affected by a variety of factors, including disease states and concurrent drug therapy. The dose used should, therefore, take into account these factors, which are listed in Table 25.5. Plasma levels may be taken after 3–4 days at the higher dose, and it has been normal practice to adjust the dose to keep the plasma level within a therapeutic window of 10–20 mg/L, although improvements in respiratory function are seen at levels as low as 5 mg/L in some patients. As the bronchodilating effects of theophylline are proportional to the log of the plasma concentrations, there is proportionally less bronchodilation as the plasma level increases. The mild side effects such as nausea and vomiting are seen at concentrations as low as 13 mg/L but are more common over 20 mg/L. Significant cardiac symptoms, tachycardia and persistent vomiting are usually seen at concentrations of 40 mg/L while severe CNS effects, such as seizures, have been seen at 30 mg/L but are more common above 50 mg/L.

Table 25.5 Factors affecting theophylline clearance

Decreased clearance	Increased clearance
Congestive cardiac failure	Cigarette smoking
Cor pulmonale	Children 1–12 years
Chronic obstructive pulmonary disease	High-protein, low-carbohydrate diet
Viral pneumonia	Barbecued meat
Acute pulmonary oedema	Carbamazepine
Cirrhosis	Phenobarbital
Premature and term babies	Phenytoin
Elderly	Sulfinpyrazone
Obesity
High-carbohydrate, low-protein diet
Cimetidine
Erythromycin
Oral contraceptives
Ciprofloxacin
Propranolol

Differing brands of theophylline have differing bioavailabilities, so brands should not be interchanged.

High-dose β₂-agonists

High-dose β₂-agonists are only considered if conventional doses do not achieve adequate symptom control. Nebulised drugs such as salbutamol 2.5–5 mg per dose are given.

Terbutaline has been given by continuous subcutaneous infusion in the maintenance treatment of difficult to treat asthma.

Preventer medication

Anti-inflammatory agents

Regular anti-inflammatory treatment should be used for patients who are not controlled on a SABA alone (BTS/SIGN, 2009). Corticosteroids are the most commonly used anti-inflammatory agents (Table 25.6), but others such as the cromones are available.

Table 25.6 Inhaled corticosteroids used for the prophylaxis of asthma

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	Total daily dosage range (MDI)
Drug and age range	Standard dose	High dose
Beclometasone diproprionate or budesonidea
Adult	100–400 μcg twice a day	400–1000 μcg twice a day
12–18 years