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Stephen Chapman

, Grace Robinson

, John Stradling

, Sophie West

, and John Wrightson

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date: 05 July 2022

Definition, epidemiology, pathophysiology, aetiology


There is no universally agreed definition. Asthma is a chronic inflammatory disorder of the airway characterized by bronchial hyperreactivity to a variety of stimuli, leading to a variable degree of airway obstruction, some of which may become irreversible over many years.

It is a clinical diagnosis based on:

  • A history of recurrent episodes of wheeze, chest tightness, breathlessness, and/or cough, particularly at night

  • Evidence of generalized and variable airflow obstruction, which may be detected as intermittent wheeze on examination or via tests such as peak expiratory flow (PEF) measurement.


It is the commonest chronic respiratory disease in the UK, with a prevalence of 10–15%. There is a wide variation in disease prevalence, with highest levels seen in English-speaking countries (where there is also a high prevalence of sensitization to common aeroallergens). The reason for the increasing worldwide prevalence over the last few decades is unclear.


Best described as chronic eosinophilic bronchitis/bronchiolitis. Airway inflammation is seen, with cellular infiltration by T helper 2 (Th2) cells, lymphocytes, eosinophils, and mast cells. There is large and small airway involvement, and cytokine production (e.g. platelet-activating factor (PAF), IL5, and leukotrienes).

Airway obstruction occurs due to a combination of:

  • Inflammatory cell infiltration

  • Mucus hypersecretion with mucus plug formation

  • Smooth muscle contraction.

This may become irreversible over time due to:

  • Basement membrane thickening, collagen deposition, and epithelial desquamation

  • Airway remodelling occurs in chronic disease, with smooth muscle hypertrophy and hyperplasia. This is now recognized as increasingly important in the pathophysiology of the most difficult to treat chronic asthma.


This is due to a combination of genetic and environmental factors, with many different genes identified.

Immunological mechanisms

A subgroup of asthmatics are atopic and therefore react to antigen challenge by producing specific IgE from B-lymphocytes. This leads to the formation of IgE-antigen complexes that bind to mast cells, basophils, and macrophages, leading to the release of preformed mediators, e.g. histamine, IL5, and other eosinophil chemotactic factors. These factors cause bronchoconstriction and airway oedema.

Prostaglandins, leukotrienes, kinins, and PAF are all important 2° messengers involved in the inflammatory response.

A subgroup of asthmatics (up to 25%) are now recognized to have non-eosinophilic disease, which may be associated with a poorer short-term response to inhaled corticosteroids and is associated with neutrophilic airway inflammation and innate immunity. This subgroup may turn out to need a different treatment strategy.

Genetic factors

A hereditary component to asthma and atopy is well established, and a number of chromosomes and linkages are implicated. The multiple mechanisms and 2° messengers involved in asthma make the contribution of the effects of specific genes difficult to determine. Established susceptibility loci include the genes ADAM33, GPRA (G protein-related receptor for asthma), and ORMDL3, a member of a gene family that encodes transmembrane endoplasmic reticulum proteins. The latter was very recently identified by a genome-wide screen, and its function and role in the pathogenesis of asthma are not yet clear.

Hygiene hypothesis

This suggests that asthma may be a by-product of modern ‘first world’ cleanliness. Early life exposure to bacterial endotoxin switches off the allergic response (by reducing Th2-mediated pathways), and, when this exposure is lost, the likelihood of developing allergic diseases, such as asthma, increases considerably. Large epidemiological studies support this hypothesis.

Environmental factors

The increasing prevalence of asthma appears to be associated with a rising standard of living worldwide, and not just in westernized societies. This has implicated a number of environmental factors. A number of explanations are speculated (but not proven), including dietary changes, a reduction in childhood infections, increased immunization, or a combination of all three.

Phenotypic differences It is increasingly recognized that ‘asthma’ is likely to represent a number of different ‘diseases’ or subphenotypes, rather than one disease with a unifying pathological mechanism. Subphenotypes may differ in underlying pathophysiology, clinical features, and disease course, and research aimed at clearly identifying such disease subgroups (e.g. through the use of biomarkers, such as blood eosinophilia, or the host genetic profile) is ongoing.

Further information

McGrath KW et al. A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med 2012;185:612–19.Find this resource:

Clinical features

  • Cough

  • SOB

  • Wheeze

  • Chest tightness.


these are variable, intermittent, worse at night, associated with specific triggers, e.g. pollens, cat and dog dander, and non-specific triggers, e.g. cold air, perfumes, and bleaches, due to airway hypersensitivity. Asthma may be labelled ‘cough variant’ or ‘cough predominant’ when cough is the major symptom (see Box 18.1).


  • May be entirely normal

  • Classically, expiratory wheeze is heard

  • Chest deformity/hyperinflation—long-standing/poorly controlled asthma

  • Severe life-threatening asthma may have no wheeze and a silent chest.


This is often a clinical diagnosis but should be supported by objective measurements. Important to:

  • Identify provoking factors, e.g. cold air, bleach, perfume, and environmental aeroallergens (grasses, pollen, hay), and any occupational exposures

  • Assess disease severity. Longitudinal studies show greater decline in lung function in asthmatics than non-asthmatics—greater still in asthmatics who smoke.

Don’t forget to look for/ask about:

  • Nasal symptoms–obstruction, rhinorrhoea, hyposmia

  • Atopic dermatitis/eczema/hay fever

  • Allergies, including food allergy (see Box 18.2)

  • Reflux/GORD disease (treating reflux may improve symptoms which have been wrongly attributed to asthma, particularly cough)

  • Laryngo/pharyngeal reflux (hoarse voice, throat clearing, acid in throat)

  • Triggers, including exercise, menstruation

  • Social situation/stresses

  • Aspirin sensitivity (associated with later-onset asthma and nasal polyps; see Box 18.3)

  • Family history.


The number of investigations required depends on the certainty of the diagnosis from the history, simple spirometry, and peak flow recordings. Most patients referred for a respiratory opinion will already have completed home peak flow recordings and have had a CXR. Repeating PEFs may still be of benefit. Objective evidence of asthma is important before starting long-term therapy with potentially harmful drugs such as inhaled steroids. For differential diagnoses, see Box 18.4.

Essential investigations (on which the diagnosis is based)

  • Peak flow recording/simple spirometry looking for variability and response to treatment. Airway obstruction leads to decreased peak expiratory flow rate (PEFR) and forced expiratory volume in 1s (FEV1); may be normal between episodes of bronchospasm. If persistently normal, the diagnosis must be in doubt. The diagnosis is highly likely if:

    • 20% diurnal PEF variation on >3 days/week, in a week of peak flow diary measures

    • FEV1 >15% decrease after 6min exercise

    • FEV1 >15% (and 200mL) increase after 2-week trial of oral steroid (30mg prednisolone od)

  • Bronchodilator reversibility testing FEV1 >15% (and 200mL) increase after a single dose of a short-acting β‎2 agonist therapy (e.g. salbutamol 400 micrograms by metered dose inhaler (MDI) with spacer or 2.5mg by nebulizer) or 200 micrograms bd of inhaled beclometasone or equivalent for 6–8 weeks. A 400mL improvement is strongly suggestive of asthma; smaller improvements are less sensitive and need careful interpretation.

Non-essential/optional investigations

  • Blood tests

    • FBC (eosinophilia is common in asthma, but, if the total eosinophil count is unusually high, consider eosinophilic granulomatosis with polyangiitis (EGPA; Churg–Strauss syndrome))

    • IgE (associated atopy, i.e. positive skin prick tests to common allergens, often with associated allergic rhinitis and eczema)

  • Specific IgE if other environmental triggers suspected

  • CXR if atypical symptoms. May show hyperinflation or evidence of localized abnormality simulating wheeze, e.g. adenoma (rare)

  • Skin tests to define atopic constitution or identify potential triggers

  • Methacholine/histamine challenge measures bronchial hyperresponsiveness (BHR) as a PC20, the dose (provocative concentration) of agent (histamine or methacholine) causing a 20% fall in FEV1.

  • Asthma is suggested by a PC20 <8mg/mL (the lower the PC20, the more likely the diagnosis is asthma). Normal subjects have a PC20 >16mg/mL. The absence of BHR virtually excludes the diagnosis of asthma; however, the presence of BHR does not prove asthma.

  • Bronchial provocation tests aim to demonstrate bronchospasm to an inhaled agent, usually occupational. The response to an aerosolized sample of a suspected agent may be useful if the diagnosis of occupational asthma is suspected, but PEF recordings at home, work, and on holiday may be more useful. Should only be carried out in a tertiary referral centre, under expert supervision

  • Sputum analysis Sputum eosinophilia may help confirm the diagnosis

  • Aspergillus Specific IgE to Aspergillus or skin tests may be useful if Aspergillus sensitivity is a concern. See Asthma p. [link]

  • Laryngoscopy/ENT examination Useful if concerns about nasal symptoms or obstruction, e.g. from polyps, or to exclude upper airway obstruction, or a vocal cord abnormality

  • Bronchoscopy Rarely needed. Its main use is to exclude an obstructing airway tumour, e.g. carcinoid

  • Lung biopsy is very occasionally needed in those in whom no adequate explanation for persistent and minimally reversible airflow obstruction is seen, to exclude another cause, e.g. bronchiolitis obliterans

  • Biomarker studies support the measurement of exhaled nitric oxide concentration (feNO) to determine optimum inhaled corticosteroid dose in moderate asthma. This may also be useful in diagnosis (but is not a very specific measure), along with measures of induced sputum and blood eosinophils.

Acute severe asthma (in adults)

Most asthma deaths occur outside hospital and are:

  • In patients with chronic severe disease

  • In those receiving inadequate medical treatment

  • In those who have been symptomatically deteriorating and may have already sought medical help

  • Associated with adverse behavioural and psychosocial factors

  • See Box 18.5 for hospital management of acute asthma.

Fatality in asthma is due to cardiac arrest 2° to hypoxia and acidosis—reversal of hypoxia is paramount.

Give high-flow O2.

Risk factors for fatal or near-fatal asthma

  • Previous near-fatal asthma, e.g. previous ventilation or respiratory acidosis

  • Three or more classes of asthma medication

  • Repeated A&E attendances

  • High β‎ 2 agonist use

  • Adverse psychosocial features

  • Background difficult asthma.

Severity of acute asthma


  • Increasing symptoms

  • PEFR ≥50–75% predicted or best

  • No features of acute severe asthma

  • 1h following treatment in A&E, patients with PEF >75% predicted or best may be discharged home with appropriate changes to their asthma medication in the absence of concerns, e.g.:

    • Significant ongoing symptoms

    • Compliance concerns

    • Living alone

    • Psychological problems or learning difficulties

    • Previous near-fatal or brittle asthma

    • Nocturnal presentation

    • Pregnant

    • Exacerbation despite adequate oral steroid pre-presentation.

Severe asthma

Defined as any of:

  • PEFR 33–50% predicted or best

  • RR ≥25

  • HR ≥110

  • Inability to complete sentence in one breath.

Life-threatening asthma

Any one of:

  • PEFR <33%

  • SaO2 <92% (NB needs ABG)

  • PaO2 <8kPa

  • Normal CO2 (4.6–6kPa)

  • Silent chest

  • Cyanosis

  • Poor respiratory effort

  • Bradycardia/arrhythmia/hypotension

  • Exhaustion

  • Confusion

  • Coma.

Near-fatal asthma

  • Raised PaCO2, and/or

  • Needing mechanical ventilation with raised inflation pressures.


Consider discharge when:

  • Reduced β‎2 agonist dose

  • Off nebulized drugs and on inhalers ≥24h

  • PEF ≥75% predicted or best

  • Minimal PEF diurnal variation

  • Appropriate education has been given.

Prior to discharge, consider:

  • Reason for the exacerbation. Could it have been avoided?

  • Check patient’s self-management plan/asthma action plan

  • Check inhaler technique (see Asthma p. [link])

  • Book an appointment with GP or practice nurse for within 2 days

  • Book chest clinic appointment.

Chronic asthma: management (adults)

Aim to minimize symptoms and prevent exacerbations, prevent the potential consequences of long-standing airway inflammation leading to airway remodelling and chronic unresponsive airway obstruction, and improve QoL (see Box 18.7).

The emphasis should be on education, self-management, and personal asthma action plans. Aim for:

  • Minimal day and night symptoms

  • No exacerbations

  • Normal lung function and prevention of lung function decline with the development of fixed airflow obstruction

  • No limit to physical activity

  • Minimum steroid dose.

Treatment is based on disease severity, using a step-up/step-down approach, starting treatment at the level appropriate to disease severity, based on the history, spirometry, and medication usage.

Pharmacological management

BTS guidelines for the management of asthma

Step 1—mild intermittent asthma

  • Short-acting β‎2 agonist

  • Check compliance, inhaler technique (including with spacer, if used), and eliminate potential triggers

  • Ten puffs/day (two or more canisters/month) is a marker of poorly controlled disease.

Step 2—regular preventer therapy

  • Start at 400 micrograms/day beclometasone (BDP) or equivalent in a twice-daily dose

  • Titrate steroid dose to symptoms, aiming for lowest effective dose

  • Local steroid side effects only (oral Candida, dysphonia) from BDP ≤800 micrograms/day

  • Possible dose-related bone density effects at this dose or above

  • Fluticasone provides equal clinical activity to budesonide at half dosage. Mometasone is an alternative inhaled steroid; the current limited evidence suggests it is equivalent to twice the dose of BDP. Ciclesonide is a pro-drug, and the available evidence suggests it may have fewer local oropharyngeal side effects and less systemic activity than conventional inhaled steroids. The clinical benefit and efficacy to safety ratio data have not been fully established

  • Qvar® (beclometasone dipropionate) has a smaller particle size and may be of benefit in some; 400 micrograms bd is comparable to fluticasone 500 micrograms bd and budesonide 800 micrograms bd.

Step 3—add-on therapy

  • If taking 200–800 micrograms/day inhaled steroid, consider adding a long-acting β‎2 agonist (LABA). A combination preparation may be appropriate

  • If there is no response to a LABA, stop it and increase the inhaled steroid

  • The combination of an inhaled corticosteroid and LABA is licensed as maintenance and reliever therapy, if a rapid-onset LABA, e.g. formoterol, is used in the context of a personal asthma action plan.

Step 4—poor control on moderate-dose inhaled steroid and add-on therapy: addition of fourth drug

  • Ensure definite benefit is obtained from any of these subsequent drugs before continuing

  • Leukotriene receptor antagonist—about a third of patients respond. May be useful if atopic or for exercise-induced asthma. Trial for 1 month, and stop if there is no response. Also indicated in allergic rhinitis—so consider if this is present as well

  • Theophylline (has side effects, e.g. nausea, and needs therapeutic drug monitoring)

  • Slow-release oral β‎2 agonist, e.g. bambuterol 10–20mg nocte

  • If control is inadequate on 800 micrograms BDP equivalent with a LABA, can increase inhaled steroid dose to 2, 000 micrograms BDP equivalent in a combination inhaler

  • Consider the use of tiotropium or equivalent.

Step 5—continuous or frequent use of oral steroids

  • NB Risk of side effects if on oral steroids for >3 months or 3–4 courses/year

  • Warn patient of potential side effects (hypertension, diabetes, cataracts, and gastric erosions), and ask GP to monitor. Start osteoporosis prophylaxis with calcium and vitamin D, or a bisphosphonate. Document baseline bone densitometry in those receiving prednisolone for >3 months (see Asthma p. [link]). See Asthma

  • Aim for the lowest possible dose of steroid.

Additional points

  • Regular review—to ensure patients are on appropriate treatment for their disease severity and are maintained on the lowest possible inhaled steroid dose. This may include adherence/prescription reviews. Step down treatment if patient stable for 3 months or more. Step down inhaled steroid by reducing dose by 25% at 3-monthly intervals. The Royal College of Physicians (RCP) has suggested three routine questions for monitoring (see Box 18.8)

  • Asthma action plan—all patients with severe asthma should have an agreed written asthma action plan (self-management plan), their own peak flow meter, and regular checks on compliance and inhaler technique. A self-management plan should include specific advice about recognizing loss of asthma control and action to take if asthma deteriorates. Patients on low-dose inhaled steroids (200 micrograms) should have their dose increased 5-fold at the start of an exacerbation. This should not be extrapolated to higher inhaled steroid doses. The previous recommendation of doubling the dose of inhaled steroid at the start of an exacerbation is unproven.

Chronic asthma: additional treatment options

Steroid-sparing drugs,

e.g. methotrexate, oral gold, and ciclosporin—may be useful if other treatments are unsuccessful. They may reduce long-term steroid requirements, but all have side effects and need haematological surveillance. There are very few data to support their use, and significant variability in response. Guidelines suggest a 3-month trial, once other drugs have proven unsuccessful, with treatment in a centre with experience of their use.

Continuous subcutaneous terbutaline

infusion via a portable syringe driver may be useful. Standard dose is 5mg over 24h, but up to 15mg/24h may be given. Use terbutaline nebulizer solution (2.5mg/mL), e.g. for 10mg/24h, use 4mL of nebulizer solution, with 6mL of saline and infuse the 10mL over 24h. Beneficial effects have been reported in severe asthma, but safety and efficacy have not been assessed in RCTs. Best responders may be those with marked PEF variability (‘type 1 brittle asthmatics’) to allow steroid reduction.


Recombinant humanized monoclonal antibody against IgE has been shown to reduce early and late asthmatic responses after allergen challenge and is licensed for atopic individuals with difficult-to-control disease, in combination with other standard treatments. The drug removes circulating and tissue IgE by promoting loss of high-affinity IgE receptors on mast cells, basophils, and dendritic cells, leading to reduced airway inflammation. Compared with placebo, it has been shown to reduce exacerbation rates, with improvement in asthma symptoms and QoL scores, but with no overall change in lung function. Meta-analyses suggest a reduction of around 100 micrograms of inhaled corticosteroid is achieved per day, compared with placebo.

Omalizumab is given as a subcutaneous injection every 2–4 weeks. The dose depends on the patient’s weight and serum IgE concentration; the peak response is at 12–16 weeks, and two-thirds of patients respond. The serum IgE should be 30–700IU/mL, with higher IgE levels acceptable at higher body weights. There is a high risk of anaphylaxis at higher IgE levels.

There is some debate as to whether the high cost of the drug can be justified. The 2013 NICE guideline suggest its use for severe persistent allergic asthma, which is unstable despite optimized standard therapy (continuous oral steroid or >4 courses/year), and it should be used for a trial period of a maximum of 16 weeks, ceasing if there is no clinical response.


A not yet licensed, humanized monoclonal antibody against IL5 (a growth and differentiation factor for eosinophils) has been shown in a recent RCT to approximately halve the exacerbation rate in those prone to exacerbations with evidence of eosinophilic inflammation (i.e. one or more of: sputum eosinophils ≥3%, feNO ≥50ppb, blood eosinophils ≥0.3 × 109, prompt asthma deterioration following ≤25% reduction in inhaled or oral steroid therapy).


Early evidence suggests azithromycin may reduce the rate of severe exacerbations in non-eosinophilic asthma (blood eosinophils ≤200/mL).

Further information

Walker S. Anti-IgE for chronic asthma. Cochrane Database Syst Rev 2003;3:CD003559.Find this resource:

Holgate ST. Efficacy and safety of anti-immunoglobulin-E antibody (omalizumab) in severe allergic asthma. Clin Exp Allergy 2004;34:632.Find this resource:

Pavord ID et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicenter, double-blind, placebo-controlled trial. Lancet 2012;380:651–9.Find this resource:

Brusselle GG et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicenter randomized double-blind placebo-controlled trial. Thorax 2013;68:322–9.Find this resource:

Non-pharmacological management

Allergen avoidance

may reduce severity of disease in sensitized individual; however, despite theoretical benefits, it is generally hard to demonstrate the benefit of allergen avoidance in clinical trials. House dust mite control measures need to be comprehensive—there is no current evidence to support it, although trials are ongoing. Pet removal may be useful, if the history is suggestive and sensitivity has been demonstrated by skin prick testing or raised specific IgE levels.

Smoking cessation

may reduce asthma severity. Current and previous smoking reduces the effect of inhaled steroid; these individuals may need higher steroid doses.

Complementary therapies

No consistent evidence of benefit.

Dietary manipulation

No consistent evidence and none supported by interventional trials. Low magnesium intake is associated with increased asthma prevalence. Fish oils may be beneficial.

Weight reduction

in obese asthmatics leads to improved control.


Desensitization using allergen-specific immunotherapy may be beneficial in a small subgroup of patients.

Buteyko breathing technique

is a series of breathing exercises involving breathing control. One study showed a reduction in the use of inhaled bronchodilator and steroid use in asthmatics carrying out these exercises, with no change in lung function or BHR. A Cochrane review of breathing exercises concluded that there was no evidence of improvement in lung function but improved QoL scores.

Future developments

New steroids

Research for ‘dissociated steroids’ is ongoing. These are steroids in which the useful anti-inflammatory effects (mediated by transcription factor inhibition) are dissociated from the side effects (mediated via glucocorticoid DNA binding). Safer steroids, e.g. ciclesonide, a new once-a-day inhaled steroid, appear to have an improved side effect profile. Ciclesonide is a pro-drug, activated by airway esterases, with fewer side effects due to high degrees of protein binding.

Eosinophil inhibitors

A variety of approaches to inhibit eosinophil recruitment are under investigation, including adhesion molecule inhibition and eosinophil chemotactic receptor inhibition, and IL5 inhibition (e.g. mepolizumab).

Phosphodiesterase-4 inhibitors

New-generation phosphodiesterase (PDE)-4 inhibitors, e.g. roflumilast, are being investigated in clinical trials. These drugs have a broad anti-inflammatory action, with neutrophil inhibitory effects. Early clinical trial data looks promising.

Cytokine modulators

Tumour necrosis factor (TNF)-α‎ plays an important role in the pathogenesis of asthma. Anti-TNF antibodies have been beneficial in the treatment of inflammatory bowel disease (IBD) and RA. Anti-TNF may be useful in the treatment of severe asthma, as it may block other important leukotrienes, e.g. IL13.

Bronchial thermoplasty

This is the application of controlled radiofrequency energy to the airway wall, using a specialized catheter at bronchoscopy. It heats the tissue to about 65°C, reducing muscle mass in the small and medium-sized airways, with several airways treated under direct vision at each session. Three separate sessions are required to treat all accessible airways. This has only been assessed in a small trial and is well tolerated. Improved asthma QoL scores, reduced airway hyperresponsiveness, and reduced oral steroid doses are reported, with small reductions in hospital admissions. The mechanism of action is unlikely to be improved airway contractility alone, and neurohumoral effects are postulated. A small placebo-controlled trial in 32 patients has shown significantly worse initial symptoms and side effects, but a small longer-term improvement at 22 and 52 weeks. This procedure should only be used with special arrangements for clinical governance, consent, and audit or research.

Further information

BTS/SIGN Asthma Guidelines. Asthma

NICE guidance on bronchial thermoplasty. Asthma

Wu Q et al. Meta-analysis of the efficacy and safety of bronchial thermoplasty in patients with moderate-to-severe persistent asthma. J Int Med Res 2011;39:10–22.Find this resource:

Asthma—a good site from which to download copies of the asthma guidelines in various formats and to obtain training information.



Difficult/refractory asthma

Patients with refractory asthma are a small subgroup of asthma patients (5–10%). They have disease that is difficult to treat, evidenced by high maintenance medication requirements or persistent symptoms and airflow obstruction, with multiple exacerbations, despite high medication use. They have high numbers of admissions and cause significant anxiety to their families and medical staff. There is a wide range of disease severity, including those with highly labile disease and those with severe, more chronic airflow obstruction. No consensus definition.

The disease is usually ‘defined’ on the basis of:

  • Medication requirements (continuous or near continuous oral steroids)

  • Asthma symptoms

  • Frequency of exacerbations

  • Severity of airflow limitation.

Patients exhibit the features of asthma, and it is thought that the airflow obstruction, airway hyperresponsiveness, and PEF diurnal variability are more severe in refractory disease, though the physiological reasons for this remain unclear.

These patients typically fail to completely reverse their airflow obstruction following a 2-week course of oral prednisolone and demonstrate a poor bronchodilator response to inhaled β‎2 agonists.

The pathological mechanism is likely to be ongoing airway inflammation, with increasing airway fibrosis, but this is not proven. Other possibilities include steroid resistance (see Asthma p. [link]), β‎2 receptor downregulation, or a different disease process altogether. They may represent the non-eosinophilic end of the spectrum of asthma. Treatment non-adherence is overrepresented in patients with difficult asthma.

Diagnosis of refractory asthma

  • Confirm the diagnosis is correct—this will mean going back through the notes and retaking a thorough history

  • Confirm reversible airflow limitation now or in the past (as for non-refractory asthma; see Asthma p. [link])

  • Consider other diagnoses for cough, breathlessness, and wheeze, and investigate for potential exacerbating diseases:

    • COPD/smoking/α‎1-AT deficiency

    • Bronchiectasis/CF

    • Sinus disease—consider ENT review

    • EGPA (Churg–Strauss syndrome)/eosinophilic syndromes—consider ANCA

    • Systemic disease—thyroid disease or vasculitis

    • ABPA—consider Aspergillus precipitins/skin tests/IgE

    • VCD—consider laryngoscopy

    • Hyperventilation syndrome/dysfunctional breathing

    • Gastro-oesophageal reflux—consider OGD/24h pH

    • Upper airway obstruction—consider CT or bronchoscopy

    • OSA—consider sleep study

    • Obesity

    • Cardiac dysfunction—consider echo and/or cardiological opinion

    • Psychiatric/emotional issues/depression/2° gain—consider psychiatry or psychology review

    • Functional wheeze by breathing near residual volume.

Refractory asthma

Before labelling a patient as ‘refractory’, compliance must be confirmed. This may be by checking pharmacy prescription records, using inhaler devices monitoring medication usage, or by measurement of plasma prednisolone or early morning cortisol levels.


is that of non-refractory asthma, with inhaled LABA and high-dose inhaled corticosteroids (see Asthma pp. [link][link]). Ensure treatment trials are adequate and adhered to.

  • In patients unable to tolerate a prednisolone dose <20mg/day, corticosteroid pharmacokinetic studies may be useful. However, <25% of patients with severe asthma show clinically significantly increased prednisolone clearance (usually a specific reason can be identified such as concomitant use of enzyme-inducing medication). IM steroid, e.g. triamcinolone 120mg, may be useful if compliance is a major problem

  • Nebulized budesonide (Respules®, 1–2mg bd) may be of benefit

  • Inflammatory markers, e.g. sputum or plasma eosinophil counts or feNO, may be useful to assess medication response, although no trials have demonstrated their use clinically in this group of patients

  • Anti-inflammatory and immunomodulating drugs (specialized centre only). Include methotrexate, ciclosporin, oral gold, and IV gammaglobulin. None of these have been studied in an RCT in this group of patients, and none have demonstrated improvement in airway hyperresponsiveness

  • Macrolide antibiotics have anti-inflammatory and immune modulatory effects, reducing airway reactivity and inflammation, and have been shown to reduce oral steroid requirements and reduce exacerbation rate in non-eosinophilic asthma. Persistence of airway infection by C. pneumoniae and Mycoplasma is increasingly recognized as a contributory factor in persistent airflow obstruction and recurrent exacerbations, and macrolide antibiotics may act in this situation to clear persistent infection. Use, e.g. azithromycin 250mg, on alternate days or 3 times a week, or 500mg twice weekly. 6-weekly LFT monitoring is required. Risk of hearing loss.

‘Steroid-resistant’ asthma

This subgroup of patients represents a very small proportion of refractory asthma patients. They are likely to be the non-eosinophilic end of the spectrum. Middle-aged obese women, often with other additional diagnoses, are overrepresented in this group. They require supportive treatment, without high doses of glucocorticoids. Diagnoses other than asthma are likely, and investigation should be directed towards these. Whether they represent a further ‘asthma phenotype’ is not clear.

Further information

Robinson DS et al. Systematic assessment of difficult-to-treat asthma. Eur Respir J 2003;22:478–83.Find this resource:

Thomas PS et al. Pseudo-steroid resistant asthma. Thorax 1999;54:352–6.Find this resource:

Asthma in pregnancy

  • Pregnancy can affect asthma

  • Asthma can affect the outcome of pregnancy

  • Prognosis—1/3 worsen, 1/3 improve, 1/3 no change

  • Asthma course is likely to be similar in successive pregnancies

  • Severe asthma is more likely to deteriorate than mild asthma

  • Most exacerbations occur late, in the second and third trimester, and are due to viral infections and non-adherence to inhaled corticosteroid.

Pre-pregnancy counselling

  • Asthmatics must continue normal asthma medication

  • Give smoking cessation advice

  • Monitor the pregnant asthmatic closely

  • Severe exacerbations in pregnancy are associated with low birthweight infants, an effect similar to maternal smoking in pregnancy.

Acute asthma in pregnancy

  • Risk to foetus of uncontrolled asthma outweighs any small risk of drugs

  • Asthma medications are generally safe in pregnancy

  • Steroids should be continued.

  • Drug therapy as for non-asthmatics, including inhaled and oral corticosteroids

  • Maintain O2 saturation >94–98%

  • Continuous foetal monitoring for acute severe asthma

  • Liaise with obstetrician if acute severe asthma

Leukotriene receptor antagonists

Limited safety data available for use in pregnancy, and it is recommended not to start using whilst pregnant. Continue in women who have previously demonstrated significant improvement in disease control prior to pregnancy.

Management during labour

  • Acute asthma is rare in labour (probably due to high sympathetic drive)

  • Close liaison between the respiratory and obstetric teams is paramount, with close foetal monitoring

  • Management should be as for non-pregnant individuals (see Asthma pp. [link][link]), maintaining the O2 saturation >94–98%. There is no RCT data for magnesium sulfate, although it is used in eclampsia

  • Regional anaesthetic blockade is preferable to general anaesthesia

  • Prostaglandin E2 may be safely used for induction of labour

  • Prostaglandin F2α‎ (for post-partum bleeding) may cause bronchospasm

  • Give parenteral hydrocortisone, 100mg 6–8-hourly, during labour if on oral prednisolone at >7.5mg daily for >2 weeks prior to delivery.


  • An asthmatic mother may reduce the chance of atopy in her child by breastfeeding; current opinion is divided

  • Prednisolone is secreted in breast milk, but the infant is exposed to only tiny, and clinically irrelevant, doses.

Occupational asthma

  • This is asthma due to specific workplace sensitizers and may account for 10% of adult-onset asthma

  • The diagnosis is often difficult to make

  • Early diagnosis is important, as earlier removal from the workplace in affected individuals leads to a better outcome

  • It is different to asthma exacerbated by irritants in the workplace and can occur in individuals with or without prior asthma.

  • Agents induce asthma through immunological and non-immunological mechanisms. Immunological disease appears after a latency period of exposure; thus, it is necessary for the worker to be sensitized to the causal agent. Non-immunological disease is characterized by the absence of a latent period and occurs after accidental exposure to high concentrations of a workplace irritant. This is irritant-induced asthma (previously named reactive airways dysfunction syndrome), usually caused by exposure to, e.g. smoke, vapours, or fumes, with a strong temporal relationship between irritant exposure and the development of asthma-type symptoms

  • The latency between first exposure and symptom onset can be long and depends on the sensitizing agent—an accurate history therefore includes current and past exposures

  • Once sensitized, re-exposure to very low concentrations can provoke symptoms

  • May be associated with rhinitis and urticaria

  • Improves away from work but can take several days to settle.

Risk factors

  • Atopy

  • HLA type (e.g. HLA-DQB1*0503 associated with isocyanate allergy)

  • Smoking (especially for high molecular weight agents).


  • Confirm the diagnosis of asthma

  • Confirm the relationship between asthma and work exposures

  • Find the specific cause

  • There are two useful screening questions:

    • Is your asthma worse when at work?

    • Does your asthma improve when away from work or on holiday?

Document lung function deterioration in the workplace, usually by serial peak flow recording at work, at home, and on holiday.

Bronchial provocation/challenge testing using suspected agent—only in specialized centres, but difficulties with testing and producing a valid test substance mean that a negative specific bronchial challenge in a worker with otherwise good evidence of occupational asthma is not sufficient to exclude the diagnosis.

Skin prick testing/specific IgE for certain sensitizers (although a positive test only indicates sensitization which can occur with or without disease).


  • The range of chemicals used, and look up the literature on their propensity to cause asthma (see Table 18.1)

  • Working practices

  • Use of personal protective equipment.

Table 18.1 Causes of occupational asthma

Sensitizing agent

Occupational exposure

Low molecular weight agents (act as haptens)


Paint spraying, adhesives, polyurethane foams

Acid anhydrides

Epoxy paint, varnish, resins, baking


Welding, plating, metal refining

Glutaraldehyde and other disinfectants

Health care workers


Pharmaceutical industry

High molecular weight agents

Amine dyes

Cosmetics, hair dyes, rubber workers

Wood dusts, bark

Textile workers, joiners, carpenters

Animal-derived antigens

Vets, laboratory workers (20% affected)

Biological enzymes

Detergent industry, pharmaceuticals

Plant products

Bakers, hairdressers

Fluxes, colophony

Solderers, electronics industry

Serial PEF recording in occupational asthma

  • Record every 2h from waking to sleep

  • For 4 weeks, whilst no changes to treatment

  • Document home/work periods and any holidays

  • Analysis is best made by experts, usually using a criterion-based analysis system, e.g. OASYS (a computer program that plots and interprets serial peak flow recordings; see Asthma

  • Patients may be sensitized to >1 agent, and >300 agents have been identified.

Management of occupational asthma

  • Identify the cause

  • Remove the worker from exposure

  • Support continued employment away from the cause, if at all possible

  • Early diagnosis and removal from exposure are important factors for a good outcome

  • Improvement in FEV1 may be maintained for 1y following last exposure, and for up to 2y for non-specific responsiveness

  • The decision to remove the patient from the workplace should not be taken lightly and should be made by a consultant with experience of occupational lung disease

  • The employee may be eligible for Disablement Benefit (no proof of negligence is required).

Latex allergy is seen in up to 18% of health care workers and is the leading cause of occupational asthma in this group due to the widespread use of latex gloves. It is potentially serious, with avocado, bananas, kiwi, and chestnuts cross-reacting to give a similar clinical picture. Treatment is absolute avoidance; those affected should wear a MedicAlert bracelet and always use non-latex gloves.

Vocal cord dysfunction

A proportion of patients labelled as having severe asthma will have symptoms originating from the upper airway. This can be due to VCD and/or so-called ‘upper airway hyperresponsiveness’; these are different but overlap. VCD is likely to arise from interrelationships between laryngeal hyperresponsiveness and autonomic imbalance, with inputs from potential aetiological/aggravating factors such as reflux, psychological stress, hypocapnia (hyperventilation). Increased laryngeal hyperresponsiveness can occur following respiratory tract infections and possibly asthma itself. Upper airway hyperresponsiveness may include more than just the larynx, but this is not clear.

Patients will typically present with asthma symptoms, with associated triggers, e.g. odours, cold air. They typically have no reduction in peak flow or response to asthma medications (though this is possible).

A careful history will reveal shortness of breath that is of short duration, worse on inspiration, and extremely sudden in onset, with symptom-free periods.


  • Recent URTI, may take months to settle

  • Post-nasal drip/chronic sinusitis

  • GORD with micro-aspiration

  • Chronic laryngitis

  • Hyperventilation in association with anxiety/panic

  • It is postulated that the origin of the vocal cord closure may stem from a reflex airway protective mechanism.


is based on excluding other causes of cough and breathlessness. It may be suggested by hearing a more stridulous noise and lack of basal wheeze. The gold standard is visualization of abnormal vocal cord movement at laryngoscopy, where there is excessive adduction of the anterior two-thirds of cords with the creation of a posterior ‘glottic chink’, although this finding may not always be present at the time of study. The flow–volume loop should show inspiratory flow limitation, with ‘stuttering’ of the flow.


(for which there are no RCTs)

  • Speech therapy

  • Panting (autopeep)

  • Coughing and cough suppression techniques

  • Inspiratory resistance devices

  • HELIOX/nebulized saline/lidocaine spray

  • Sedatives

  • Exercise.

Further information

Newman KB et al. Clinical features of vocal cord dysfunction. Am J Respir Crit Care Med 1995;152:1382–6.Find this resource:

Stanton AE, Bucknall CE. Vocal cord dysfunction. A review. Breathe 2005;2:31–7 (Asthma this resource:

Allergic rhinitis (hay fever)

This is the syndrome of nasal discharge or blockage, with nasal and/or eye itching and sneezing. It is often associated with post-nasal drip, cough, fatigue, and with significant morbidity. Allergic rhinitis is defined as perennial if the symptoms occur year round, and seasonal if occurring at a particular time of year. The prevalence is increasing and affects up to 15% of the UK population. Up to 30% of patients with persistent allergic rhinitis have asthma.


The lining of the nose is in continuum with the lower respiratory tract, and inflammation of the upper and lower airways often coexists. Common aeroallergens provoking seasonal allergic rhinitis are tree pollen in the spring and grass pollen in the summer months. Perennial rhinitis usually reflects allergy to indoor allergens such as house dust mite (the provoking allergen is a digestive enzyme that is shed in the faeces), cat salivary protein, cockroaches, or animal dander.


Symptoms occur following the inhalation of allergen to which the subject is sensitized and against which they have IgE antibodies. These antibodies bind to mast cell IgE receptors, with the release of mediators, including tryptase and histamine, causing symptoms immediately after exposure.


is usually made from the history, which should identify the triggers to the disease. The main differential diagnosis is with sinusitis due to bacterial infection and upper airway involvement due to vasculitis. Asthma is common in association with rhinitis, and treatment of rhino-sinusitis in association with asthma leads to improved asthma control. Up to 50% of asthma patients will have allergic rhinitis.


  • Allergen avoidance This may be easier said than done. It can take up to 20 weeks to remove cat allergen from a house. Keeping car and house windows shut may help avoid pollen. Pollen counts are highest in the afternoon and early evening. Wearing sunglasses may reduce the ill-understood ‘photic-sneeze’ reflex, commoner in allergic rhinitis sufferers.

  • Desensitization with increasing doses of the subcutaneous allergen (see Asthma p. [link]), debatable value, small risk of anaphylaxis during such therapy

  • Non-sedating antihistamines improve sneezing and itching but have less effect on nasal blockage

  • Topical intranasal steroid, e.g. budesonide, triamcinolone

  • Topical anticholinergics, e.g. ipratropium, may be useful for rhinorrhoea, if uncontrolled with topical nasal steroids

  • Topical sodium cromoglicate may be beneficial, particularly for allergic conjunctivitis

  • Decongestants, e.g. oxymetazoline, may help, but rebound nasal blockage and tachyphylaxis are a potential problem if used regularly

  • Leukotriene receptor antagonists (e.g. montelukast) may be beneficial.