- Basic pathological principle
- Clinical features
- Long term treatment
- Treating the emergency admission
Asthma is a chronic lung condition in which there is chronic inflammation of the airways, and hypersensitivity of the airways. Symptoms include wheeze, cough, chest tightness and SOB (dyspnoea). It is often worse at night.
- The immune response is CD4 mediated, and the lungs will show an eosinophil infiltrate
- Many patients will fall into a grey area near the boundary of these two diseases. These patients may typically be in their 30s and early 40s, and have a history of smoking, but as their airway obstruction is reversible, then they may technically be given a diagnosis of asthma. In actual fact, they are more likely to have early stage COPD. However, the diagnosis is not that significant because the treatment is very similar. Despite the fact COPD is ‘not reversible’, patients with COPD often get symptomatic relief from inhalers (although the only way to improve prognosis is to stop smoking, and give LTOT).
- In the UK about 2000 patients per year die from asthma.
Three main characteristics
- Airflow limitation – this is usually reversible, either spontaneously, or with treatment
- Airway hyper-responsiveness – this occurs to a wide range of stimuli
- Inflammation of the bronchi – with infiltration by eosinophils, T cells and mast cells. there is associated plasma exudate, oedema, smooth muscle hypertrophy, mucus plugging and epithelial damage.
- Increasing in incidence, particularly in Western countries
- 10-20% of those in the 2nd decade of life are affected. This is where prevalence is at its highest
- In children, boys are more likely to be affected
- After puberty, girls are more likely to be affected
- 50% of those who have childhood asthma, but then ‘grow out of it’, will relapse in adulthood
- Intrinsic – this often starts in middle age, and is sometimes called late onset asthma. No trigger can be identified.
Extrinsic – this usually occurs in atopic individuals who have positive skin prick test results. This type of asthma causes 90% of childhood cases, and 50% of adults with chronic asthma. It is often accompanied by eczema.
- Non-atopic individuals can develop asthma in later life via sensitisation to e.g. occupational agents, aspirin, or as a result of taking β-blockers for hypertension or angina.
- Extrinsic asthma involves a type I hypersensitivity reaction to inhaled allergens (there is also a delayed phase reaction, type IV hypersensitivity which occurs huors-days after exposure.
The trait runs in families (i.e. genetic component)
- The ADAM33 gene is associated with airway hyper-responsiveness, and airway remodelling
- The PHF11 gene is associated with increased IgE production
The individuals often have skin reactions to common allergens
The individuals have IgE antibodies to many common allergens – these antibodies are present in 30-40% of the UK population, and there is a strong correlation between the levels of IgE and the severity of asthma and airway hyper-responsiveness
The development of atopy – the hygiene hypothesis – this is a theory that states that growing up in a ‘clean’ environment in the early years of life can cause atopy. If you grow up in a ‘dirty’ environment, and are exposed to various bacterial, fungal and viral proteins, this is thought to help ‘direct’ your immune system away from recognising inert particles as allergens. It is almost as if your immune system has to attack something, and in the absence of actual pathogens, it just goes for whatever it can find.
- Does not appear to be immunologically mediated – i.e. there is not T cell involvement
- Is associated with recurrent respiratory tract infection (viral)
- Skin tests are negative
- Bronchoconstriction due to airway hyper-responsiveness, not as much due to inflammation and leukocyte infiltration.
Aspirin induced asthma
- Mechanism is unknown, but though to be due to increased leukotrienes and decreased prostaglandins, which leads to increased airway irritability.
- Aspirin inhibits COX enzymes. This reduces the production of prostaglandins. However, prostaglandin E2 controls leukotriene production – thus in some patients this allows overproduction of leukotrienes and allows for an abnormal inflammatory reaction.
- This can also occur with other NSAIDs such as ibuprofen. it is a relative contra-indication (give drug with caution) as opposed to a absolute contra-indication (the drug should NEVER be given)
- Thus, when prescribing NSAIDs you should be careful! – you may still give them but be aware that 10% of asthmatics can have a reaction to them. So ask if they have had symptoms before, and tell them to stop immediately if they have symptoms.
- Induced by hypersensitivity to an agent at work – probably a combination of types I and IV hypersensitivity reactions
- There are several products that can cause asthma via an IgE-independent route – for example paints, varnishes and sprays. These can directly bind to T cells (activating them) and other epithelial cells, without IgE.
- If you can prove that the asthma is a result of allergy to a particular product at work, then in the UK, you are entitled to compensation; if you apply within 10 yeas of working there.
- Susceptible professions include; bakers (flour dust) , electrician, carpenter, painter, electrician, working with polyurethane.
- In places where there are asthma causing agents, about 10% of the population are likely to be affected.
- Typically the onset is 3-6 months after you start working at the place, although it can take years to develop.
- May be better at the weekend, although not always
- A high sodium, and low magnesium can precipitate attacks
- Magnesium sulphate is sometimes given in an acute attack – although the mechanism is uncertain.
Basic pathological principle
Exposure to the antigen will make CD4 T cells differentiate into T helper cells (Th2 type, as opposed to Th1), and they will begin to secrete IL-4 and IL-5.
- IL-4 will cause B cells to become plasma cells and being secreting IgE.
- IL-5 will act on eosinophils and mast cells, making them reactive to the new antigen. Other factors are also released that are chemotaxic for eosinophils.
This IgE will bind to mast cells in the mucosa. This initial exposure will not cause an allergic reaction. The IgE sits there on the mast cell surface, waiting to come into contact with the antigen again, perhaps for years
Upon re-exposure to the antigen, the mast cells will be activated, and will degranulate. This will release inflammatory mediators.
There are increased numbers of mast cells in both the airway secretion, and the epithelial lining of lung in asthmatics – thus increased response to any antigens.
This causes the initial asthma attack. This is mainly the result of histamine and prostaglandin (as well as leukotrienes; particularly LTC4) release by mast cells. This usually occurs within minutes of initial exposure to the antigen.
- Thus mast cells are responsible for the early attack
- Histamine – causes smooth muscle contraction, increased bronchial secretions, and increased vascular permeability
- The late phase reaction occurs several hours after the initial reaction. It is caused by the accumulation of eosinophils (and some neutrophils – but these are much more numerous in COPD) at the site.
- The late phase reaction is a more sustained inflammation. The initial phase is more bronchoconstriction without as much underlying inflammation.
- Bronchodilators (the β-adrenergics) are good at treating the initial phase reaction; the late phase reaction tends not to respond well.
- Steroids (and other anti-inflammatories) are good for preventing the inflammation that causes the late phase reaction.
- The late phase reaction is more likely in poorly controlled / chronic asthma, where there is already a reasonable aggregation of eosinophils in the mucosa.
- In this phase, there may also be activation of platelets, which can lead to microthrombi in the lumen.
Effects of the bronchoconstriction and inflammation on lung function
- Distal airway hyperinflation and collapse (and obviously reduced gaseous transfer to these regions)
- Mucus plugging of the bronchi – due to increased number of goblet cells – and these also secrete more than normal goblet cells
- Bronchial inflammation
- Curschmann’s spirals – these are bits of epithelium that have been shed, and can be seen on histology of the mucous plugs
- Charcot-Layden crystals – crystals that are formed as a result of eosinophil aggregation
- Thickening of the bronchial basement membrane – this is particularly important, and occurs via the process of remodelling (more on this below in the ADAM33 gene section). The submucosa becomes thickened, and this means that when the smooth muscle does contract, there is excessive narrowing of the airway in response to the contraction.
- Effects on the epithelium – the epithelium loses many of its columnar ciliated cells, and these are replaced with over-active mucous secreting cells. The mucosa also releases lots of inflammatory proteins. It is also likely to get damaged in the inflammatory processes, and this (along with the excess mucous production) increases the risk of infection.
- Effects on smooth muscle – the smooth muscle is hypertrophied, and also undergoes changes which make it more likely to contract, and more likely to stay contracted for longer.
The effect of cold air and exercise
The ADAM33 gene
The normal process of bronchoconstriction
- Wheezing attacks
- Periodic shortness of breath
- Symptoms often worse during the night
- Cough is frequent – and often misdiagnosed as bronchitis
- Nocturnal cough alone can be a presenting feature
- Some patients can have chronic symptoms
- Attacks precipitated by a very wide range of triggers
Respiratory function tests –
- PEF – the peak expiratory flow. This is the most useful test in asthma. Patients should take two readings per day, to show the variability of the disease. In patients with suspected asthma, you should get them to take two weeks worth of measurements whilst at work, and 2 weeks whilst at home, to prove the cause of the disease. It can also show variation between exercise/rest, night/day, before/after bronchodilator
Spirometry – you can show the presence of asthma by demonstrating 15% improvement in FEV1 or PEF following the inhalation of a bronchodilator
- However – in some patients you still may not be able to show reversibility this way. For example, those in remission, or those with particularly severe chronic asthma.
- The picture will be that of obstructive disease
- Carbon monoxide transfer test – this is normal for asthma
- NO – nitrous oxide – for some unknown reason, levels of this are raised in the breath of those with asthma, compared to a ‘normal’ individual.
Exercise tests – these are often used to diagnose asthma in children. The child should run on a treadmill for a max of 6 minutes – enough to increase the heart rate to at least 160bpm. Then test the peak flow before and after. Test every 15 minutes after, again looking for 15% difference. a negative test does not rule out asthma
Histamine or metacholine bronchial provocation test – this indicates hyper-responsiveness – which is found in most asthmatics. It is useful for diagnosing patients whose main/only symptom is cough. The dose of the drug needed to produce a 20% drop in FEV1 is noted, and is called the PD20 FEV1 (or PC20 FEV1). Patients with airway hyper-responsiveness require only a very small dose to achieve this (<11μmol of metacholine)
- The test should not be performed on those with ‘brittle asthma’ or those who have an FEV1<1.5L
- This is really only ever done for research purposes – it is quite dangerous! And has to be done under very strict conditions.
Trial of corticosteroids – this can be very useful in children at first presentation. You can trial them on e.g. 20mg (30mg for up to 2 weeks in adults) prednisolone just for several days. This initial dose is a one-off. Not only will this reduce the symptoms, but it will also mean they respond much better to bronchodilators. If they respond, then you know it is asthma, and you can also start them on the normal management plan (which is just a bronchodilator (e.g. salbutamol) to begin with.
- make sure you measure lung function immediately before and after the course of steroids
- >15% improvement in FEV1 demonstrates the presence of asthma
- If the steroids are given for 2 weeks or less, you can stop the drug without tailing off the dose
Blood and sputum tests – you can test these for high number of esosinophils; and this may help form your diagnosis, but is not diagnostic on its own
CXR – this will be normal, unless they are having a particularly bad exacerbation, in which case, overinflation may be present. The use of CXR is good at excluding the possibility of a pneumothorax.
- A pneumothorax can be a complication of asthma
skin prick tests – you should perform these on all newly diagnosed asthmatics to help find a cause
Allergen provocation tests – you may need to do this in cases of occupational asthma but otherwise it is not required
- Many patients are often concerned about food allergy as the cause – unless there are systemic symptoms this is highly unlikely.
- 50% of those with occupational asthma will have no problems if they are kept away from the cause. The other 50% may still continue to have symptoms, and will have bad exacerbations if they back into contact with the causing agent.
Long term treatment
Stepwise management of asthma
Occasional symptoms – less frequent than daily
PRN bronchodilators – ‘2 puffs as required’ – which will deliver a dose of around 200μg
Symptoms more than 3x a week (used to be symptoms more than daily)
Low dose inhaled corticosteroid (start at 200-400μg up to 800μg), or sodium cromoglicate
Add long-acting β2 agonist, e.g. sertide and symbicort are combinations of long acting agonists and corticosteroids
Severe symptoms not controlled by high dose corticosteroids
Higher dose inhaled corticosteroid – up to 2000μg. Consider leukotriene receptor antagonist (e.g. monteleukast), or theophyline
Severe symptoms deteriorating
Add prednisolone 40mg daily
Severe symptoms, deteriorating despite prednisolone
Step 1: Mild intermittent and exercise induced asthma
- Symptoms ≤2 times a week
- Asymptomatic and normal peak expiratory flow (PEF) between attacks
- Attacks are brief with varying intensity
- Night-time symptoms ≤2 times a month
- Forced expiratory flow at 1 second (FEV1) or PEF ≥80% of predicted
- PEF variability <20%.
- Symptoms >2 times a week but <1 time a day
- Exacerbations may affect activity
- Night-time symptoms >2 times a month
- FEV1 ≥80% of predicted
- PEF variability between 20% and 30%.
- Daily symptoms
- Use of short-acting beta agonists daily
- Attacks affect activity
- Exacerbations ≥2 times a week and may last for days
- Night-time symptoms >1 time a week
- FEV1 greater than 60% to less than 80% of predicted
- PEF variability >30%.
- Continual symptoms
- Limited physical activity
- Frequent exacerbations
- Frequent night-time symptoms
- FEV1 ≤60% of predicted
- PEF variability >60%.
- Occasionally, Mycoplasma or Chlamydia can cause recurrent asthma. In such cases, you need to take a sputum sample to identify the organism responsible (if one is present)
Treating the emergency admission
- Inability to complete a sentence in one breath
- Tachycardia >110 bpm
- PEF <50% predicted (or <50% patient’s own best)
- Silent chest
- Feeble respiratory effort
- PEF <30% predicted normal or best – this is approximately 150L/min in adults
(Do an ABG – it may be life-threatening if:
- CO2 > 5kPa (high)
- O2 <8kPa (low)
- Low pH
- Start on 100% O2 (non-rebreathing mask) with the patient sat upright in bed
- Give 5mg salbutamol with 0.5mg ipratropium bromide via nebulizer on 100% O2
- Give hydrocortisone 100mg IV or 50mg prednisolone orally. Give both if very unwell
- Do CXR to exclude pneumothorax
If life-threatening signs are present:
- Inform ITU and seniors
- Give magnesium sulphate 1.2-2g IV over 20 minutes
- Change the nebulized salbutamol every 15 minutes, or give 10mg continuously per hour. Only give more ipratropium every 4-6 hours
- Repeat PEF every 15-30 minutes to assess the situation. If improving then gradually reduce O2 and nebs. If not, try and find senior, keep giving nebs, and consider aminophyline.
- Check pulse oximetry – aiming for sats >92%
- Check blood gases every 2 hours, and definitely within 2 hours of admission
- Record PEF’s and β-agonists when given / carried out
- A maximum of 60mg/day of prednisolone can be given (orally)
- You can give 200mg hydrocortisone every 4 hours for a max of 24 hours
- Give oral prednisolone for 5 days after they are starting to recover
- Ventilation is an option – you would have to call an anaesthetist
- Patients have to have >75% predicted PEF for discharge