Clinical review: Asthma

Contributed by Dr David Gibeon, specialist registrar in respiratory medicine and Dr Andrew Menzies-Gow, consultant respiratory physician, Royal Brompton & Heartfield NHS Foundation Trust

Section 1 - Aetiology and epidemiology
Asthma represents a spectrum of disorders characterised by airways obstruction. The main features include hyper-responsiveness of the airways to a wide variety of exogenous and endogenous stimuli, and a specific pattern of mucosal inflammation involving activated mast cells, eosinophils and T lymphocytes.

This is associated with altered responses of structural cells in the airway, including epithelial cells.1

Epidemiology
Asthma is one of the most common chronic diseases worldwide. There are over 5 million people in the UK receiving medication for asthma and over 4.1 million GP consultations for asthma each year.

A GP with 2,000 patients will see approximately 85 patients with asthma each year and each of these will consult three times on average.2

Despite effective therapy there are approximately 1,400 deaths each year in the UK directly attributable to asthma.

Aetiology
Asthma can be divided into intrinsic asthma (or non atopic), extrinsic asthma (atopic) and occupational asthma. Identifying which type of asthma a patient has will enable the patient to make lifestyle choices and allow targeted treatment.

The exact aetiology of intrinsic asthma is unknown. It usually occurs in patients after the age of 30 and is not related to atopy. Triggers such as respiratory infections, exercise, stress, air pollution and the inhalation of chemical irritants may cause bronchoconstriction.

Extrinsic asthma is associated with atopy and appears in childhood or early adulthood. Atopy is defined as a genetic predisposition to produce IgE against common environmental allergens such as grass pollen, animal dander and house dust mite.

IgE is a class of antibody that has only been identified in mammals and is associated with type-1 hypersensitivity reactions and the immune system response to parasitic (helminthic) infection. IgE plays an important part in the pathophysiology of asthma. There are two phases involved. The first is sensitisation to the allergen and the second is clinical expression of symptoms on re-exposure to the sensitising allergen.3

Sensitisation begins with the uptake of inhaled antigen by antigen-presenting dendritic cells, which line the airways. Allergen is subsequently presented to antigen-specific T cells, which then produce cytokines that stimulate the development of IgE-producing B cells. Once synthesised and released by B cells, IgE circulates in the blood before binding to Fc receptors located on the surface of mast cells, basophils, eosinophils, monocytes, macrophages and platelets.4

Cross linking of IgE on the surface of mast cells and basophils by allergens releases histamine, prostaglandins and cytokines.

These mediators are responsible for many of the features that are associated with allergy, including bronchoconstriction in asthma, localised inflammation in eczema and increased vascular permeability in anaphylaxis.

Expression of these mediators leads to an inflammatory response, which manifests as airway hyperresponsiveness and bronchospasm.

Section 2 - Diagnosis
There is no gold standard test; the diagnosis of asthma is often a clinical one. If patients are incorrectly diagnosed with asthma they may be subjected to years of inappropriate therapy.

The presence of wheeze, breathlessness and chest tightness are secondary to variable airflow obstruction. Alternative diagnoses should always be considered and the history should explore whether symptoms are related to occupational exposures (see box, far right).

The demonstration of airflow obstruction varying over short periods of time aids diagnosis. Serial peak flow measurements using a diary to document morning and evening levels may be helpful. A diurnal variability of greater than 20 per cent over three days in a week for two weeks is typical for asthma.

An increase in peak flow measurements 10 minutes after high-dose bronchodilator through a spacer, after a six-week course of inhaled steroids or 14 days of oral steroids are suggestive of asthma. Spirometry is now available and is preferred to peak flow measurement as it can clearly identify airflow obstruction and the results are less effort dependent.5

However, it is important to remember that normal spirometry in a well patient does not exclude the diagnosis of asthma.

Investigations
A chest X-ray may be helpful in patients with an atypical presentation or with additional signs or symptoms.

Patients with prominent sputum production may require a high resolution CT scan to look for the presence of bronchiectasis. This may additionally reveal air trapping and bronchial wall thickening.

An FBC may demonstrate an eosinophilia and the serum IgE may be raised. A significant eosinophilia should prompt investigation for other diseases that can mimic asthma, such as Churg-Strauss syndrome.

A methacholine or histamine challenge test measures airway responsiveness, but is only available in specialist centres.

The measurement of exhaled nitric oxide (FeNO) in theory correlates with eosinophilic inflammation in asthmatic patients, but this has not been reflected in clinical studies and it is the opinion of the authors that FeNO should not be used in clinical practice.

A sputum eosinophil count may be used as a marker of airway inflammation.

Clinical features that aid the diagnosis of asthma5

Features that increase the probability of asthma:

  • More than one of the following symptoms: wheeze, breathlessness, chest tightness and cough, particularly if:

- symptoms worse at night and in the early morning;

- symptoms in response to exercise, allergen exposure and cold air;

- symptoms after taking aspirin or beta-blockers;

  • History of atopic disorder;
  • Family history of asthma and/or atopic disorder;
  • Widespread wheeze heard on auscultation of the chest;
  • Otherwise unexplained low FEV1 or PEF (historical or serial readings);
  • Otherwise unexplained peripheral blood eosinophilia.

Features that lower the probability of asthma:

  • Prominent dizziness, light-headedness, peripheral tingling;
  • Chronic productive cough in the absence of wheeze or breathlessness;
  • Repeatedly normal physical examination of chest when symptomatic;
  • Voice disturbance;
  • Symptoms with colds only;
  • Significant smoking history (ie >20 pack years);
  • Cardiac disease;
  • Normal PEF or spirometry when symptomatic.

 

Differential diagnosis
Without airflow obstruction:
  • Chronic cough syndromes;
  • Hyperventilation syndrome;
  • Vocal cord dysfunction;
  • Rhinitis;
  • Gastro-oesophageal reflux;
  • Heart failure;
  • Pulmonary fibrosis.

With airflow obstruction:
  • COPD;
  • Bronchiectasis*;
  • Inhaled foreign body*;
  • Obliterative bronchiolitis;
  • Large airway stenosis;
  • Lung cancer*;
  • Sarcoidosis*.
* may also be associated with non-obstructive spirometry

Section 3 - Management
In patients where there is a high probability of asthma then a trial of treatment is required.

The British Thoracic Society (BTS) step wise approach to the treatment of asthma guides which medications patients should receive.5

Patients with mild asthma may only require a short-acting bronchodilator on an as-required basis. If patients develop symptoms despite this then the addition of an inhaled corticosteroid is appropriate. If patients remain uncontrolled then they are approaching step 3 and above. At this point the addition of a long-acting beta-2 agonist (LABA) may help.

There are a number of combination inhalers containing a corticosteroid and a LABA. If patients remain symptomatic then a trial of other therapies such as a leukotriene receptor antagonist may be beneficial.

Montelukast has few side-effects and a two-week trial will be sufficient to establish whether patients should continue therapy. Theophylline requires regular blood tests to ensure that the levels are not subtherapeutic.

At this stage patients with persistent poor control are at step 4 and inhaled corticosteroid may be increased to a total of 2,000 micrograms of beclometasone or equivalent per day.

Patients who are well with few or no symptoms may be able to step down their therapy.

Patients at step 4 and 5 who are poorly controlled, and patients requiring regular oral corticosteroid therapy may benefit from a review in a specialist respiratory clinic where their disease can be assessed further.

New developments
The therapies in this section are aimed at patients with severe asthma. These medications tend to be initiated and monitored by a specialist physician with an interest in allergy and asthma.

Anti-immunoglobulin E, omalizumab, is a humanised anti-IgE monoclonal antibody licensed as add-on therapy for the treatment of severe allergic (IgE mediated) asthma. Patients must fulfil criteria to be eligible.

Various immunosuppressive drugs such as ciclosporin and methotrexate may be used in severe asthma as steroid-sparing agents.

Bronchial thermoplasty involves controlled thermal energy delivered to the airway wall during several bronchoscopic procedures. This aims to decrease smooth muscle mass, which is felt to play an important role in severe asthma. Long-term studies to evaluate this treatment are being undertaken.

Current areas of interest and research include nucleic acid therapy, phosphodiesterase inhibitors and tyrosine kinase inhibitors. There is research into the development of monoclonal antibodies to counteract individual cytokines and adhesion molecules involved in asthma.6

Criteria for specialist referral in adults5
Diagnosis unclear
  • Unexpected clinical findings (i.e. crackles, clubbing, cyanosis, cardiac disease)
  • Unexpected restrictive spirometry
  • Suspected occupational asthma
  • Persistent non-variable breathlessness
  • Monophonic wheeze or stridor
  • Prominent systemic features (myalgia, fever, weight loss)
  • Chronic sputum production
  • Chest X-ray shadowing
  • Marked blood eosinophilia (>1x109/l)
  • Poor response to asthma treatment
  • Severe asthma exacerbation

 

Section 4 - Long-term management
The follow-up of asthmatics should be tailored to each individual.

The majority of patients and approximately 90 per cent of acute management is provided by primary care.7

The BTS guidelines advise that patients should be offered self-management education focusing on individual needs and reviewed regularly by a nurse or doctor with a written action plan created.5

Annual review targeting patients who are poorly controlled, those on the higher treatment steps and those overusing their bronchodilator will help pick up patients who require a change in treatment.

A register of asthmatics at each GP practice facilitates this process.

Identification
The identification of patients at 'higher risk' may allow regular consultations or reviews.

This group includes ethnic minorities, socially disadvantaged groups, adolescents, the elderly and those with communication difficulties.

The patient's primary care practice should be informed within 24 hours of discharge from the emergency department or hospital following an asthma exacerbation.

The BTS recommends that patients should be seen by their GP or asthma nurse within two working days following discharge from hospital with a hospital, specialist asthma nurse or respiratory physician review at about one month.5

References

1. Gibson J, Geddes D, Costabel U, Sterk P, Corrin B. Respiratory medicine 3rd edition. Philadelphia: WB Saunders, 2002. p1,212.

2. Asthma UK, 2006 http://www.asthma.org.uk

3. Medzhitov R, Janeway C. Innate immunity. N Engl J Med 2000; 343: 338-44.

4. Busse W, Lemanske R. Asthma. N Engl J Med 2001; 344: 350-62.

5. BTS guidelines on the management of asthma. Thorax 2008; 63 (Supp IV): iv1-121.

6. Barnes P, Woolcock A. Difficult asthma. Eur Respir J 1998; 12: 1,209-18

7. Neville R, Clark R, Hoskins G, Smith B. National asthma audit 1991-2. General Practitioners in Asthma Group. BMJ 1993; 306: 559-62.

Resources

Patient group: Asthma UK

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