Asthma

 What is asthma?

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

It is characterised by airflow obstruction which is varied over time, and reversible. Technically, asthma exists where the obstruction is reversible by >15%, and COPD exists where it is reversible by <15%.

-          Many patients will fall into a grey area near the boundary of these two diseases. These patients may typically be in their 30’s and early 40’s, 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’, patient 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 hyperresponsiveness – 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 exudation, oedema, smooth muscle hypertrophy, mucous plugging and epithelial damage.

The disease often ‘flares up’ with viral infections – which often cause a loud wheeze.

Epidemiology

-          Increasing in incidence, particularly in Western countries

-          10-20% of those in the 2^nd 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

Aietiology

The disease can either be intrinsic (aka cryptogenic); where not causatory factor can be found, or extrinsice, where there is a definite external cause.

-          Intrinsic – this often starts in middle age, and is sometimes called late onset asthma. You cannot find the trigger.

-          Extrinsic – this usually occurs in atopic individuals who have positive skin prick test results. This type of asthma is present in 90% of childhood cases, and 50% of adults with chronic asthma. It is often accompanied by eczema.

o   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.

o   Extrinsic asthma is basically a type I hypersensitivity reaction to something in the air

Atopy

This is a term used to describe people who often have allergies / asthma / hayfever, and where:

-          The trait runs in families (i.e. genetic component)

o   The ADAM33 geneis associated with airway hyperresponsiveness, and tissue remodelling

o   The PHF11 geneis associated with increased IgE production

-          The individuals often have skin reactions to common allergens

-          The individuals have IgE antibody 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 prevelance of asthma and airway hyperresponsiveness

-          The development of atopy – they 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’ enivronemnt, and are exposed to various bacterial, fungal and viral proteins, then 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 lack of actual pathogens, it just goes for whatever it can find.

The allergens for asthma, are very similar to those that cause rhinitis. Rhinitis is inflammation of the mucosal lining of the upper respiratory tract, particularly affecting areas near the nose; thus causing a constant runny nose.

***it is thought that allergy to the faecal matter of dust mites is the largest cause of intrinsic asthma worldwide***

Airway hyperresponsiveness

You can test for this by asking the patient to inhale gradually increasing amounts of methacholine or histamine. This is known as a bronchial provocation test. This will induce transient airflow limitation in 20% of the population – and these are the patients that exhibit airway hyperresponsiveness.

Pathology

The clinical symptoms and pathology are the similar for all types of asthma, they types below are all intrinsic; the differences between types are:

-          Non-atopic asthma

o   Does not appear to be immunologically mediated – i.e. there is not T cell involvement

o   Is associated with recurrent respiratory tract infection (viral)

o   Skin tests are negative

o   Bronchoconstriction due to airway hyperresponsiveness, not as much due to inflammation and leukocyte infiltration.

-          Aspirin induced asthma

o   Mechanism is unknown, but though to be due to increased leukotrienes and decreased prostaglandins, which leads to increased airway irritability.

o   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.

o   This can also occur with other NSAID’s such as ibuprofen. it is a relative contra-indication – as opposed to a absolute contra-indication (that would apply to everybody)

o   Thus, when prescribing NSAID’s you should be careful! – you should 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.

-          Occupational asthma

o   Induced by hypersensitivity to an agent at work – probably a combination of types I and III hypersensitivity reactions

o   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 the need to IgE.

o   If you can prove that the asthma is a result of allergy to a particular product at work, the in the UK, you are entitled to compensation; if you apply within 10 yeas of working there.

o   Susceptible professions include; bakers (flour dust) , electrician, carpenter, painter, electrician, working with polyurethane.

o   In places where there are asthma causing agents, about 10% of the population are likely to be affected.

o   Typically the onset is 3-6 months after you start working at the place, although it can take years to develop.

o   May be better at the weekend, although not always

-          Food

o   A high sodium, and low magnesium can precipitate attacks

o   Magnesium sulphate is sometimes given in an acute attack – although the mechanism is uncertain.

Basic pathological principle

The pathology is not fully understood. The varying amounts of chronicity and airway hyperresponsiveness are related to an individuaos response to various antigens and to the amount of airway remodelling that occurs.

-          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.

o   IL-4 will cause B cells to become plasma cells and being secreting IgE.

o   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.

o   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

o   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:

o   Distal airway hyperinflation and collapsed (and obviously reduced gaseous transfer to these regions)

o   Mucus plugging of the bronchi – due to increased number of goblet cells – and these also secrete more than normal goblet cells

o   Bronchial inflammation

o   Curschmann’s spirals – these are bits of epithelium that have been shed, and can be seen on histology of the mucous plugs

o   Charcot-Layden crystals – crystals that are formed as a result of eosinophil aggregation

o   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.

o   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.

o   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

These both dry out the mucosa of the lung, which leads makes the lining hyperosmolar. This causes mast cells to release histamine and prostaglandins, thus causing inflammation.

Typically, the asthma attack does not occur during exercise, but afterwards.

Atmospheric pollution

Large amounts of dust, cigarette smoke, car fumes, and other allergens can trigger asthma in some individuals. Large industrial incidents can trigger these on a large scale population.

Ozone has also been a trigger in the past

Diet

High intake of fruit and vegetables is protective, possibly due to the large amounts of ‘anti-oxidants’ they contain. Also, genetic variations affecting antioxidant production can affect the severity of the disease

The ADAM33 gene

It is thought that this gene is responsible for the release of factors by eosinophils. Some of these factors include MBP (major basic protein), ECP (eosinophil cationic protein) and other factors. These factors can cause remodelling of the epithelium, and stimulate growth of fibroblasts. This increases the amount of smooth muscle present, and also makes the smooth muscle more likely to contract in response to the release of inflammatory factors. This increases airway hyperresponsiveness.

The normal process of bronchoconstriction

Occurs in response to direct parasympathetic stimulation. Antagonism of this effect is produced by freely circulating epinephrine that acts upon β-receptors. Β- blockers (e.g. atenolol) have been known to induce attacks in asthmatic patients, because they prevent epinephrine from doing its job. β – agonists (e.g. salbutamol) are used to stimulate the same receptors that epinephrine uses (β₂) to cause bronchodilation.

Clinical features

-          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

Investigations

There is no specific diagnostic test for asthma – although variability shown through twice daily measurements of PEF is probably the most useful test.

-          Respiratory function tests –

o   PEF – the peak expiratory flow. This is the most useful test in asthma. Patients should take two reading 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

o   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.

§    There is a hand drawn picture in your old notes of the bronchus in both acute and chronic asthma – this is helpful for understanding the concept!

§    The picture will be that of obstructive disease

o   Carbon monoxide transfer test – this is normal for asthma

o   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)

o   The test should not be performed on those with ‘brittle asthma’ or those who have an FEV1<1.5L

o   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, they you know it is asthma, and you can also start them on the normal management plan (which is just a bronchodilators (e.g. salbutamol) to begin with.

o   make sure you measure lung function immediately before and after the course of steroids

o   >15% improvement in FEV1 demonstrates the presence of asthma

o   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.

o   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 is cases of occupational asthma but otherwise it is not required

o   Many patients are often concerned about food allergy as the cause – unless there are systemic symptoms this is highly unlikely.

Management

Controlling extrinsic factors

You may want t try and reduce the risk of a person coming into contact with a provocating factor. Dust mite faeces is a major cause, and so changing bedding regularly is a good way to manage this risk. Patients should also avoid taking β- blockers in any form. This is an absolute contra-indication.

-          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.

Using medications

Asthma is a chronic inflammatory condition – and should be recognised as such! Thus, don’t be scared to use anti-inflammatories – i.e. steroids

 

Long term treatment

Treatment approach

The main goal of treatment is to achieve maximum control of symptoms with the fewest medications. Optimal control should include assessment of a combination of the patient's symptoms and their PFTs. The goal for optimal control is to have the patient asymptomatic with normal PFTs if possible. Once a state of control is achieved, an attempt should be made to reduce the doses of medications while maintaining optimal control.

Stepwise management of asthma

Guidelines recommend asthma severity and control be viewed as a ladder in which medication can be stepped up or stepped down based on the severity of the disease and adequacy of the control.The stepwise approach is meant to assist, not replace, the clinical decision making required to meet individual patient needs.

Patients may start at any step of the ladder, and medications can be added (stepped up) if needed. Increasing use of short-acting beta agonist (SABA) or use >2 days a week for symptom relief (not prevention of exercise induced bronchospasm) generally indicates inadequate control and the need to step up treatment.

Regular assessment of patient's asthma control should be carried out with the aim of stepping down the ladder if disease has been well controlled for at least 3 months.

Education and environmental control

All patients at all steps of therapy should receive adequate patient education and should take environmental control measures.

Allergen vaccine immunotherapy

For well-controlled proven allergic asthma, treatment with allergen vaccine immunotherapy is an option. This treatment is only used with documented allergies either by skin testing or specific IgE serology and should only be given with adequate supervision to prevent adverse systemic allergic reactions.

	Step	PEFR	Treatment
1	Occasional symptoms – less frequent that daily	100% predicted	PRN bronchodilators – ‘2 puffs as required’ – which will deliver a dose of around 200μg
2	Symptoms more than 3x a week (used to be symptoms more than daily)	≤80% predicted	Low dose inhaled corticosteroid (start at 200-400μg up to 800μg), or sodium cromoglicate
3	Severe symptoms	50-80% predicted	Add long-acting β2 agonist, e.g. sertide and symbicort are combinations of long acting agonists and corticosteroids
4	Severe symptoms not controlled by high dose corticosteroids	50-80% predicted	Higher dose inhaled corticosteroid – up to 2000μg. Consider leukotriene receptor antagonist (e.g. monteleukast), or theophyline
5	Severe symptoms deteriorating	<50% predicted	Add prednisolone 40mg daily
6	Severe symptoms, deteriorating despite prednisolone	<30% predicted	Hospital admission

Step 1: Mild intermittent and exercise induced asthma

Defined as:

·         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%.

For those patients with mild intermittent asthma or exercise-induced asthma, the use of a SABA as required is sufficient alone. All patients should have access to quick relief SABAs.

Increasing use of SABA or use >2 days a week for symptom relief (not prevention of exercise-induced bronchospasm) generally indicates inadequate control and the need to step up treatment.

Step 2: Mild persistent

Defined as:

·         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%.

Low-dose inhaled corticosteroids (ICS) are added if control is not achieved with SABA as needed only. Second-line options that can be used instead of low-dose ICS are either sodium cromoglicate, leukotriene receptor antagonists (LRTA), nedocromil or theophylline.

Step 3: Moderate persistent

Defined as:

·         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%.

Step 3 therapy adds long-acting beta agonist bronchodilators (LABA) to step 2 therapy (low-dose ICS and SABA as needed), or increases low-dose ICS to medium-dose ICS. Second-line alternatives to either increasing ICS dose or adding a LABA are to combine SABA as needed and ICS with either LRTAs, theophylline or zileuton.

Step 4-6: Severe persistent

Defined as:

·         Continual symptoms

·         Limited physical activity

·         Frequent exacerbations

·         Frequent night-time symptoms

·         FEV1 ≤60% of predicted

·         PEF variability >60%.

Preferred combination treatment for step 4 is medium-dose ICS plus LABA plus SABA as needed. LABA can be substituted for either LRTA, theophylline or zileuton.

Step 5 changes medium-dose ICS to high-dose ICS. Immunomodulators (omalizumab) can be considered in stage 5 for patients with allergies.

Step 6 adds oral corticosteroids to existing treatments.

This should be re-assessed at regular intervals.

Self-management plan

Tell the patient what to do with their drugs under certain circumstances:

e.g. tell them when they could increase their dose of steroid – then this avoids them having to come and see the doctor as much!

Patients should not be given nebulizers to use at home – as this encourages them to use a nebulizer when in fact they need to seek further medical attention. This practice was carried out in the past, and is thought to have resulted in many unnecessary asthma related deaths in the 1960’s and 1980’s.

The role of Xanthines

Theophyline and aminophyline (which is metabolised to theophyline) have a role in asthma treatment. They may be added to the use of β2 agonists in an acute attack. Aminophyline can be given IV, and is metabolised to theophyline.

The role of methotrexate

Some studies have shown that giving 15mg of this per week can greatly reduce the amount of oral steroid needed to control severe chronic asthma. Methotrexate is a folic acid inhibitor (thus reduces the rate at which quickly dividing cells can divide)

The role of leaukotriene receptor antagonists

These block the crucial LTC₄ receptor, which contributes to much of the inflammatory response. These drugs should be considered in anyone who is not well controlled on a middle dose of corticosteroids. They are reasonably effective, but only in some individuals. A 4 week trial is recommended before commencing more long-term treatment.

They are always using in conjunction with β2 agonists, and are most often used in patients where a high dose of corticosteroid is proving ineffective.

Omalizumab

This is a drug that forms complexes with free IgE, and prevents it binding to inflammatory cells. Initial trials have been promising in both children and adults with chronic asthma.

It is a ‘recombinant humanized monoclonal antibody.

Antibiotics are very rarely required. Sometimes in an acute exacerbation, asthma patients may cough up yellow and green sputum. However, it is this colour because it contains eosinophils and bronchial cells, and not because there is bacterial infection. However, in such cases it is probable there is a viral infection – but still obviously, you should not give AB’s.

-          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

Status asthmatics – this is asmtha that has failed to resolve within 12 hours of therapy use. The term is a bit old-fshioned, and we now use acute severe asthma to mean asthma that is not controlled by the patient’s current medication.

Features of acute severe asthma:

-          Inability to complete a sentence in one breath

-          RR>25

-          Tachycardia >110 bpm

-          PEF <50% predicted (or <50% patient’s own best)

Features of life-threatening attack:

-          Silent chest

-          Feeble respiratory effort

-          Cyanosis

-          Exhaustion

-          Bradycardia

-          Hypotenson

-          Exhaustion/confusion/coma

-          PEF <30% predicted normal or best – this is approximately 150L/min in adults

Pulsus paradoxis – on inspiration, the diastolic pressure decreases by 10mmHg. This is present in about 45% of cases – but you have other things to worry about.

Tension pneumothorax is a possible complication

1)      Hospital management – ideally you should start treatment before doing investigations!

a.       (Do an ABG – it may be life-threatening if:

                                                              i.      CO2 > 5kPa (high)

                                                            ii.      O2 <8kPa (low)

                                                          iii.      Low pH)

b.      Start on 100% O2 (non-rebreathing mask) with the patient sat upright in bed

c.       Give 5mg salbutamol with 0.5mg ipratropium bromide via nebulizer on 100% O2

d.      Give hydrocortisone 100mg IV or 50mg prednisolone orally. Give both if very unwell

e.      Do CXR to exclude pneumothorax

2)      If life-threatening signs are present:

a.       Inform ITU and seniors

b.      Give magnesium sulphate 1.2-2g IV over 20 minutes

c.       Change the nebulized salbutamol every 15 minutes, or give 10mg continuously per hour. Only give more ipratropium every 4-6 hours

3)      Repeat PEF every 15-30 minutes to assess the situation. If improving then gradually reduces O2 and nebs. If not, try and find senior, keep giving nebs, and consider aminophyline.

a.       Check pulse oximetry – aiming for sats >92%

b.      Check blood gasses every 2 hours, and definitely within 2 hours of admission

c.       Record PEF’s and β-agonists when given / carried out

d.      A maximum of 60mg/day of prednisolone can be given (orally)

e.      You can give 200mg hydrocortisone every 4 hours for a max of 24 hours

f.        Give oral prednisolone for 5 days after they are starting to recover

g.       Ventilation is an option – you would have to call an anaesthetist

h.      Patients have to have >75% predicted PEF for discharge

After recovery from a severe asthma attack, oral corticosteroids should be continued until there are no residual symptoms, especially at night, and the peak expiratory flow rate is at least 80% of the person's previous best. High doses of these drugs can be stopped abruptly if used for 3 weeks or less, or tapered off if they have been used for a longer period.

Brittle asthma – ‘catastrophic sudden severe asthma’

These patients are at risk from sudden death, even if their asthma is well controlled between attacks. An attack can come on very quickly within minutes.

Self-management plan

Tell the patient what to do with their drugs under certain circumstances:

e.g. tell them when they could increase their dose of steroid – then this avoids them having to come and see the doctor as much!

  

Steroids – don’t forget – these cause an increased risk of peptic ulcer!