Definition

Asthma is a reversible, obstructive airways disease caused by inflammation, hyper‐responsiveness, and narrowing of the bronchial tree in a susceptible individual, secondary to a variety of stimuli.

Epidemiology

The exact prevalence of asthma worldwide is unknown because of historic differences in definition, diagnostic criteria, and methods of data collection. The International Study of Asthma and Allergies in Children (ISAAC) and the European Community Respiratory Health Survey (ECRHS) have been monitoring the prevalence of asthma worldwide and have reported an increase since the 1960s, with significant variation between countries. The increased prevalence is mainly in urbanised Western countries, and there are several hypotheses as to the possible reasons for this trend.

The estimated incidence of asthma is 2.6–4/1000 individuals per year in the United Kingdom (UK) and the prevalence is 3–34% worldwide. This equates to approximately 8% of adults and 20% of children with asthma. Mortality from asthma is 4/100 000 in the UK, with 1500 deaths every year.

Children with asthma are usually atopic, have had bronchial hyper‐responsiveness (BHR) and wheezing for at least 12 months, and demonstrate variability in peak expiratory flow readings. Many children with evidence of BHR and wheeze, particularly those under 5 years of age, are incorrectly diagnosed as having asthma. Viral respiratory tract infections and passive smoking, particularly maternal cigarette smoking, are risk factors for BHR and wheezing. There is some evidence that neonates who go on to develop asthma later in life have worse lung function in infancy.

Airway hyper‐responsiveness (AHR), which includes BHR, is an abnormally exaggerated response to stimuli such as infection, cold air, or exercise, resulting in the contraction of the bronchial smooth muscle. The degree of bronchoconstriction can be measured by the dose of methacholine or histamine required to cause a 20% fall in forced expiratory volume in one second (FEV₁) as discussed in Chapter 4.

Not all individuals with AHR will develop asthma, but because many will have symptoms of dry cough and wheeze when exposed to these triggers, it can be difficult to differentiate between AHR and mild asthma. In adults, the main differential diagnosis for asthma is chronic bronchitis; therefore, adult patients with a history of cigarette smoking should have investigations, including a chest X‐ray (CXR) and spirometry with reversibility testing, to establish the correct diagnosis.

A family history of asthma is an important risk factor for developing asthma, even in non‐atopic children, with 60% of the susceptibility to asthma being inherited. Twin studies have shown a 19% concordance in monozygotic twins and 4.8% concordance in dizygotic twins. The prevalence of asthma is greater in boys compared to girls, reaching a peak at puberty. The prevalence of asthma in females gradually increases with age, so that it is equal to that in men between the ages of 20 and 40, thereafter becoming more common in females. The reason for this difference is not clear. It has been postulated that it may reflect smaller relative airway size, increased atopy, and differences in the reporting of symptoms in boys.

The aetiology of asthma is multifactorial; airway inflammation occurs when a genetically susceptible individual with atopy is exposed to certain environmental factors. Atopy is the tendency to produce high amounts of immunoglobulin E (IgE) when exposed to small amounts of an antigen. These patients will demonstrate positive reactions to antigens on skin prick testing. Atopic individuals have a high prevalence of asthma, allergic rhinitis, urticaria, and eczema.

Atopy and asthma show polygenic inheritance and genetic heterogeneity, with gene linkages on chromosome 11q13. The genes responsible for the different components of asthma, such as IgE production, BHR and cytokine production, are found on chromosomes 5q, 7, 11q, 12q, 16, 17, and 21q. The ADAM33 gene on chromosome 70p13, which is a disintegrin and a metalloprotease gene, is involved in the structural airway components of asthma, such as airway remodelling. Expression of this gene may lead to the development of chronic persistent asthma, with irreversible airway obstruction and excess decline in FEV₁ over time.

Environmental factors appear to be important in the development of asthma. The ISAAC study found an increased association between wheeze and atopy in developed, urbanised countries. As people spend more time inside, concentrations of indoor allergens become more important than outdoor allergens. This is particularly important in young children as allergen exposure early in life may be important in determining sensitisation. Exposure to the house dust mite (HDM) Dermatophagoides pteronyssinus (found in high concentrations in carpets, soft furnishings, and bedding) in early life may be associated with an increased likelihood of sensitisation to HDM by preschool age. Sensitisation to pet‐derived allergens (cat, dog, rabbit) is also common.

There is some evidence that exposure to bacterial and viral antigens in very early life may result in allergen sensitisation and the development of asthma. There appears to be a link between exposure to respiratory syncytial virus, human rhinovirus, mycoplasma pneumonia infections, and the development of asthma.

The hygiene hypothesis, in contrast, postulates that lack of childhood infections results in altered T‐cell function and a tendency to develop asthma. Some epidemiological studies have shown that close contact with animals in early life may decrease the prevalence of asthma and allergy, perhaps by the provocation of immune tolerance. The results of studies on domestic allergen avoidance, which are very difficult to conduct, are inconsistent. Atmospheric pollution can worsen asthma, but there is no evidence that it is a cause of asthma. Occupational asthma accounts for 15% of cases of asthma and is discussed in Chapter 15.

Atopic individuals produce IgE antibodies to specific allergens which can be measured in the serum. Skin prick testing can also be used to demonstrate allergy to a specific allergen. A video demonstrating how skin prick testing is performed is found in the supplementary material (www.wiley.com/go/Paramothayan/Essential_Respiratory_Medicine). Serum levels of IgE correlate better with AHR and asthma severity than skin prick testing which correlates better with allergic rhinitis. It is common for atopic individuals to be sensitive to more than one allergen. Individuals with asthma are highly likely to have other atopic conditions, such as allergic rhinitis and atopic dermatitis (eczema). Approximately a third of children with atopic dermatitis will go on to develop asthma in adolescence.

Pathophysiology of asthma

Airway inflammation, caused by various cytokines, results in reversible obstruction throughout the tracheobronchial tree. The reversibility distinguishes asthma from COPD. In a sensitised, atopic individual, inhalation of an allergen results in a two‐phase response consisting of an early reaction, reaching its climax in about 20 minutes, and a late reaction, developing 6–12 hours later. In the early response, T‐helper lymphocytes have an important role in the regulation of the inflammatory response. Th2 cells secrete pro‐inflammatory interleukins, which leads to the release of high levels of allergen‐specific IgE antibodies by plasma cells. The IgE antibodies bind to receptors on mast cells and eosinophils and stimulate them to release preformed mediators, including histamine, prostaglandins, platelet‐activating factor, tryptase, major basic protein, eosinophil cationic protein, eosinophil protein X, heparin, and cysteinyl leukotrienes. These mediators cause bronchoconstriction within minutes.

The late phase reaction is the result of infiltration of the smooth muscle layer by eosinophils, basophils, neutrophils, monocytes, and dendritic cells, which cause patchy desquamation of the epithelial cells. There is also an increase in the number of mucus glands, goblet cell hyperplasia and hypertrophy, and hyperplasia of the airway smooth muscle. Cytokines released by Th2 Helper cells results in further contraction of the airway smooth muscle, increased permeability of the blood vessels, and increased mucus secretion. Acute inflammation results in oedema and mucus‐plugging of the bronchial tree. In contrast, the Th1 cells produce cytokines that down‐regulate the atopic response.

Narrowing of bronchi of different calibres results in polyphonic wheezing. Narrowing of the smaller airways with a diameter of less than 2 cm leads to closure of these airways at low lung volumes, resulting in air trapping, an increase in residual volume (RV), an increase in total lung capacity (TLC), and dynamic hyperinflation. High‐resolution computed tomography (HRCT) images of the thorax can demonstrate the heterogeneous narrowing of the airways. Bronchoconstriction can also occur through reflex neural mechanisms.

While eosinophils are associated with acute asthma, neutrophils are more prevalent in steroid‐dependent asthma, and are associated with chronic, persistent airway inflammation and structural changes. With increased severity and chronicity of asthma, there is remodelling of the airways, with collagen deposition and fibrosis of the airway wall, resulting in fixed narrowing and a decreased response to bronchodilator medication (Figure 6.1).

Clinical presentation

Asthma is a variable, reversible condition and therefore it can be difficult to make a reliable diagnosis between exacerbations when the individual is well. Chronic asthma can result in progressive disease and irreversible airway obstruction.

Clinical history: Patients with asthma present with symptoms of cough, chest tightness, breathlessness, and wheeze. These symptoms are variable and intermittent and may be precipitated by triggers at home or at work. There may be diurnal variation in symptoms, with peak flow measurements usually worse in the mornings compared to the evenings. The differential diagnosis of a patient with breathlessness and wheeze includes bronchiectasis, COPD, allergic bronchopulmonary aspergillosis (ABPA), α‐1 antitrypsin deficiency (α‐1 ATD), and left ventricular failure.

Cough‐variant asthma is common. Patients will present with a persistent dry cough, particularly at night, but with no breathlessness or wheeze. Clinical examination, a CXR, and spirometry may be normal in these individuals. The differential diagnosis of a dry cough in a non‐smoker with a normal CXR includes acid reflux, post nasal drip, use of non‐steroidal anti‐inflammatory drugs, use of angiotensin converting enzyme (ACE) inhibitors for the treatment of hypertension, inhaled foreign body, and post‐infectious cough. Vocal cord dysfunction (VCD) and hyperventilation (HV) can be difficult to differentiate from asthma and are discussed later in this chapter.

The clinician should ask the patient about a history of atopy, which includes hay fever, allergic rhinitis, and eczema, and about a family history of atopy. They should document in detail any environmental factors that may be triggering the asthma, both at home and at work. A history of smoking and passive smoking is important.

Clinical examination may be normal in between exacerbations. In patients with severe chronic asthma, there may be signs of hyperinflation as described in Chapter 5. Individuals with childhood asthma, especially if undertreated, may develop a chest deformity. During an acute asthma attack, the patient will be breathless at rest, with increased pulse and respiratory rates, and polyphonic expiratory and inspiratory wheeze due to the narrowing of bronchi of different sizes. In life‐threatening asthma, the patient may become cyanosed, have a silent chest, and become bradycardic.

Box 6.1 lists the investigations that may be required in a patient presenting with symptoms of unexplained cough and or breathlessness. Some of these investigations are to rule out other causes of these symptoms and are described in Chapter 4.

Patients with atopy and asthma often have a mildly raised peripheral blood eosinophilia and raised IgE. Results of skin prick testing must be interpreted carefully as a positive result merely indicates that the patient is sensitised to that allergen and has the potential to develop symptoms when exposed to that allergen. RAST measures the level of circulating IgE to an antigen, for example, cat. Skin prick test positivity to aspergillus fumigatus and positive aspergillus fumigatus IgE and IgG suggests allergic bronchopulmonary aspergillosis (ABPA). Further investigations, including an HRCT and sputum samples for aspergillus, would be indicated. Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg‐Strauss syndrome, can masquerade as asthma, and should be suspected if there is a very high eosinophilic count in peripheral blood and the patient appears to be steroid‐ dependent. This condition is discussed in Chapter 11.

PEF measurements may show diurnal variation in asthma (Figure 6.2), with a lower value in the morning compared to the evening. PEF homework, which means that the patient keeps a record of their PEF measurements taken in the mornings and the evenings for several weeks, can be helpful. A 20% or greater variability between mornings and evenings suggests asthma.

Spirometry will be obstructive, with a reduced FEV₁ and an FEV₁/FVC ratio of less than 70%. See Chapter 4 for the interpretation of spirometry. Improvement in symptoms and in spirometry 20 minutes after a bronchodilator is administered (200 μg inhaled salbutamol or 2.5 mg of nebulised salbutamol) is diagnostic of asthma if the FEV₁ increases by at least 15% of the baseline value or by more than 200 ml. Spirometry values are also used to establish the severity of asthma, which determines the management. Patients with chronic asthma and COPD will have little or no reversibility when given bronchodilators, as they have a fixed obstruction.

Full lung function tests with reversibility can give additional information. In those with chronic asthma, the residual volume (RV) and total lung capacity (TLC) will be increased due to air trapping, but there will be no impairment of gas exchange, so the transfer factor for carbon monoxide (TLCO) will be normal. There may be evidence of small airway disease with a reduction in FEV 25%, FEV 50% and FEV 75%.

Spirometry and lung function tests may be normal in patients with mild asthma in between exacerbations and in those with cough‐variant asthma. Additional hyper‐reactivity testing with methacholine or histamine can be diagnostic. This is described in Chapter 4. The concentration of the drug that results in a 20% decrease in FEV₁ can be calculated. Exercise can also be used to provoke airway hyper‐responsiveness. Exhaled NO levels are increased in patients with asthma and bronchiectasis but will be normal in VCD and hyperventilation, so can be useful in differentiating between these conditions.

The CXR may be normal in mild asthma (Figure 6.3), but may be hyperinflated in chronic asthma, with increased lung volumes and flat diaphragms. The CXR may appear normal in patients with mild bronchiectasis and ABPA, so an HRCT should be considered if these conditions are suspected (Figure 6.4 shows a HRCT in asthma). Differential cell count from induced sputum may show an eosinophilia in asthma. The presence of aspergillus may suggest ABPA.

Nose and throat examinations can be helpful when a patient presents with a persistent dry cough as this will detect evidence of acid reflux, oral candida, and post nasal drip. Nasal polyps may suggest asthma, which is often associated with sensitivity to aspirin. Abnormal adduction of vocal cords during inspiration, made worse by exercise, suggests VCD. Ultrasound of the vocal cords can also show abnormal adduction during inspiration suggestive of VCD.

Bronchoscopy with lavage for microbiology may be helpful if an infection is suspected. It is also important to exclude an inhaled foreign body which can be a cause of persistent cough and monophonic wheeze, especially in children. Therapeutic suctioning can clear mucus plugging which can occasionally result in lobar collapse in asthma, resulting in persistent cough, wheeze, and breathlessness.

The algorithm for the diagnosis of asthma is given in Appendix 6.A.

Management of asthma: The aim is to obliterate the symptoms of asthma so that the individual has a good quality of life, with normal exercise tolerance, and no exacerbations. This can be achieved by avoiding allergens that trigger exacerbations and using the appropriate inhaled therapy.

The aim of inhaled therapy is to reduce the need for reliever inhaler with no limitation in physical activity. Well‐controlled asthma means that the patient requires short‐acting β₂‐agonist (SABA) less than two days in a week, and less than two nights a month. Appropriate inhaled therapy should achieve the best lung function possible with the minimum of side effects. There should be no more than one exacerbation per year requiring OCS and no hospital admissions.

Inhaled therapy should be prescribed as recommended by NICE/Scottish Intercollegiate Guidelines Network (SIGN), with a stepwise increase in therapy. If the asthma is poorly controlled, then treatment should be ‘stepped up’. When there is better control, then ‘stepping‐down’ therapy can be considered. The mechanism of action of the drugs used to treat asthma, their side effects and interactions, inhaler devices, and nebulisers are discussed in Chapter 3. The management of asthma is given in Appendix 6.B.

• Step 1: mild, intermittent symptoms. Reliever short‐acting β₂‐agonist (SABA) such as salbutamol or terbutaline used as and when required. If the patient requires them more than twice a day, then move to step 2.
  
• Step 2: Regular prevention therapy. Add ICS 200–800 μg day⁻¹.
  
• Step 3: Add‐on therapy. Commence long‐acting β₂‐agonist (LABA), or increase dose of inhaled corticosteroid (ICS) to 800 μg day⁻¹, or consider leukotriene inhibitor.
  
• Step 4: Persistent poor control. Consider increasing dose of ICS further, or add theophylline.
  
• Step 5: Severe symptoms, frequent or continuous use of OCS. Use lowest dose of OCS, maintain ICS at 2000 μg day⁻¹_.

ICS are the most effective preventative drugs in adults and children for maintaining control in asthma. They should be prescribed to all who have had exacerbations or nocturnal asthma, and those using β‐2 agonist more than twice a day. A reasonable starting dose is 400 μg day⁻¹ for adults and should be titrated for effective control.

Patients at Step 4 or Step 5 should be referred to the respiratory physician. Other conditions, such as ABPA or bronchiectasis, will need to be excluded. Individuals with poor asthma control despite treatment with adequate doses of inhaled corticosteroid (ICS), long‐acting β₂‐agonist (LABA), and leukotriene inhibitor may require a higher dose of ICS, up to 2000 μg day⁻¹. Oral theophylline, a weak bronchodilator, can be introduced at Step 4, usually at a dose of 400 mg daily. The mechanism of action of theophylline, contra‐indications for its use, side effects, and drug interactions are discussed in Chapter 3.

Some patients with severe asthma appear to be steroid‐dependent and experience worsening of their symptoms when the dose of OCS is reduced below a dose of 10 mg daily. Conditions such as EGPA, COPD, and ABPA should be excluded. Compliance and inhaler technique should always be checked.

Patients with allergic asthma have high concentrations of IgE which leads to the secretion of cytokines and mediators which cause bronchoconstriction. Omalizumab (Xolair) is a recombinant humanised immunoglobulin G1 monoclonal antibody that binds to the circulating IgE, forming immune complexes that are cleared by the reticuloendothelial system. Omalizumab prevents IgE from binding to receptors on mast cells, eosinophils, and basophils, thus reducing the effect of the late phase response, with decreased production of cytokines. Omalizumab is indicated for the treatment of patients with asthma who are not controlled at Step 5, who require frequent courses of OCS, and who have high levels of IgE. It is given subcutaneously in a hospital setting as there is a risk of anaphylaxis in 1–2/1000.

There is evidence to support the hypothesis that vitamin D deficiency can worsen the control of asthma. Therefore, patients with vitamin D deficiency should be prescribed supplements. Bronchial thermoplasty, a procedure available in a few centres, is a technique whereby radio‐frequency waves are used to apply heat through a bronchoscope to reduce the amount of smooth muscle in the bronchial wall mucosa, resulting in reduced bronchoconstriction. This has been shown to improve asthma control in some patients with severe asthma who are not well controlled with other treatments. The long term benefits and risks of this treatment are not fully understood.

Role of doctor or asthma nurse: Patients with asthma should have regular reviews (at least once every six months) by a trained healthcare professional. He/She should assesses their symptoms, their compliance with therapy, any over‐use of short‐acting β₂‐agonist (SABA), possible under‐use of ICS, conduct spirometry, and assess their inhaler technique. The patient should have a self‐management plan which describes what medication to take, how to increase the medication when symptoms deteriorate, and what to do if they experience an exacerbation. The management plan should include the role of PEF monitoring, with advice to take oral corticosteroids (OCS) and seek medical help if their PEF drops below 75% of their best or predicted PEF. Patients should be aware of environmental triggers and should avoid these as much as possible. Patients who smoke should be advised to quit, and nicotine replacement therapy (NRT) prescribed, as discussed in Chapter 3. Patients with asthma should have an annual influenza vaccination and a pneumococcal vaccination. Regular review by a doctor or specialist nurse has been shown to improve daily control of asthma symptoms with a reduction in the risk of near‐fatal or fatal asthma exacerbation. Patients with moderately severe or severe asthma should have a supply of OCS to take in an emergency.

The Global Initiative for Asthma (GINA) suggests asking the following questions to assess symptom control over the past four weeks as listed in Box 6.2. There are other validated questionnaires to assess symptom control, including the Asthma Control Questionnaire (ACQ‐5) score and the ACT score.

None of the above: asthma is well controlled.

1–2 of the above: asthma partly controlled.

1–4 of the above: asthma poorly controlled.

Box 6.3 lists some of the recognised triggers for acute asthma.