Attacking asthma

Severe asthma is categorised into two subtypes based on the underlying pathological process – type-2 inflammation and non-type-2 inflammation. These categories are based on a patient’s response to treatment. Type-2 inflammation includes allergic (IgE-mediated) asthma and eosinophilic asthma, while non-type-2 inflammation includes neutrophilic asthma.

SUB-TYPES

1. Type 2 inflammation (Also known as T2 high inflammation)

Allergic asthma
This is caused by exposure to allergens such as pollen, pet dander, and mould. Patients diagnosed with allergic asthma nearly always have a diagnosis of hay fever. Exposure to allergens triggers the immune system to produce immunoglobulin E (IgE) that attaches to cells, causing an allergic reaction. Symptoms include sneezing, itchy/watery eyes, airway sensitivity, and anaphylaxis.

Eosinophilic asthma
Approximately 40 per cent of people with severe asthma have eosinophilic asthma. This is asthma caused by high levels of eosinophils. High levels of eosinophils cause the airways to become inflamed. It can be diagnosed with a blood test.

Eosinophilic asthma is often characterised by other symptoms of inflammation such as eczema, sinusitis, and nasal polyps because eosinophilic cells cause inflammation not only in the respiratory system but anywhere in the body. Biologic drugs may be needed to control eosinophilic asthma.

2. Non-type 2 inflammation (Also known as T2 low inflammation)

Non-eosinophilic asthma
Patients with this type of asthma have few to no eosinophils in test results. Neutrophilic asthma is a type of non-eosinophilic asthma. Neutrophils are the most common white blood cells in the body. They can cause non-type-2 inflammation in the airways. This type of asthma does not respond well to inhaled corticosteroids and using them can cause an increase in neutrophils. The subtype also does not respond to biologics. It is associated with chronic bacterial or viral infections, smoking, obesity, and airway smooth muscle abnormalities.

Diagnosis

The following questions can help ascertain if asthma is the problem:

• Is there a family history of asthma?
• Are symptoms frequent and do they affect quality-of-life?
• Has there been an attack or recurrent attacks of wheezing?
• Is there a regular night-time cough?
• Does exercise trigger wheezing or coughing?
• Is there wheezing, chest tightness, or cough after exposure to airborne allergens or pollutants?
• Does the patient suffer from constant chest infections?
• Do chest infections take longer to clear up?
• Are symptoms improved by using a reliever inhaler?

Answering yes to any of these questions may indicate asthma. The following tests contribute to the diagnosis of asthma:

• Spirometry provides measurements of lung function. It is common to measure lung function with a spirometer before and after a dose of reliever to see if lung function has improved.
• Peak flow meter to measure peak expiratory flow rate (PEFR). The PEFR test is only suitable for children over five years of age.
• An exercise test to check if exercise worsens asthma symptoms.

The following are signs of a severe asthma attack:

• The reliever inhaler does not help symptoms at all.
• The symptoms of wheezing, coughing, and tight chest are severe and constant.
• Too breathless to speak.
• Pulse is racing.
• Feeling agitated or restless.
• Lips or fingernails look blue.

Management

Asthmatics should be advised strongly not to smoke and to lose weight. Allergen avoidance measures may be helpful, but the benefit of avoiding allergens such as dust mite or animal fur has not been proven in studies.

There is insufficient or no evidence of the clinical benefit of complementary therapy for asthma such as Chinese medicine, acupuncture, breathing exercises, and homeopathy.

Treatment is based on relief of symptoms and preventing future attacks. Successful prevention can be achieved through a combination of medicines, lifestyle changes, and identification and avoidance of
asthma triggers.

Short-acting beta 2-agonist

A short-acting beta 2-agonist (SABA) opens the airways and is best known to patients as a reliever inhaler. These work quickly to relieve asthma. They work by relaxing the muscles surrounding the narrowed airways. Examples of beta 2-agonists include salbutamol and terbutaline.

They are generally safe medicines with few side-effects unless they are overused. It is important for every asthmatic to have a beta-2 agonist inhaler. If an asthmatic needs to use their beta agonist inhaler too regularly (three or more times per week), they should have their therapy reviewed.

The main side-effects include a mild shaking of the hands, headache, and muscle cramps. These usually only occur with high doses and usually only last for a few minutes.

Excessive use of short-acting relievers has been associated with asthma deaths. This is not the fault of the reliever medication, but down to the fact that the patient failed to get treatment for their worsening asthma symptoms.

Corticosteroids

Corticosteroid inhalers are slower-acting inhalers that reduce inflammation in the airways and prevent asthma attacks. The corticosteroid inhaler must be used daily for some time before full benefit is achieved. Examples of corticosteroids used in inhalers include beclomethasone, budesonide, and fluticasone.

The dose of inhaler will be increased gradually until symptoms ease. For example, a patient may start on a beclamethasone 100mcg inhaler and may be put on a beclamethasone 250mcg inhaler if there is not enough improvement in symptoms.

Preventer treatment is normally recommended if the patient:

• Has asthma symptoms more than twice a week.
• Wakes up once a week due to
  asthma symptoms.
• Must use a reliever inhaler more than twice a week.

Regular inhaled corticosteroids have been shown to reduce symptoms, exacerbations, hospital readmissions, and asthma deaths.

The UK’s National Institute of Clinical Excellence (NICE) guidance for inhaled corticosteroid use as updated in March 2021 is as follows:

• For adults aged 17 and over:
  400 micrograms (or less) of budesonide or equivalent is defined as low dose; 400-800 micrograms of budesonide or equivalent is defined as moderate dose; greater than 800 micrograms budesonide or equivalent is defined as high dose.
• For children aged 16 and under:
  200 micrograms (or less) of budesonide or equivalent is defined as a low paediatric dose; 200 micrograms to 400 micrograms budesonide or equivalent is defined as a moderate paediatric dose; greater than 400 micrograms budesonide or equivalent is defined as a high a high paediatric dose.

The dose of corticosteroid inhaler maintenance therapy should be adjusted over time, aiming for the lowest dose that gives effective asthma control. The majority of patients require a dose of less than 400 micrograms per day to achieve maximum or near maximum benefit. Smoking can reduce the effects of preventer inhalers.

Corticosteroids are very safe at usual doses, although they can cause some side effects at high doses, especially with long-term use. The main side-effect of corticosteroid inhalers is oral candidiasis of the mouth or throat. This can be prevented by rinsing the mouth with water after inhaling a dose. The patient may also develop a hoarse voice. Using a spacer can help prevent these side-effects.

Long-acting beta 2-agonists

If SABA and corticosteroid inhalers are not providing enough symptom relief, a long-acting beta 2-agonist (LABA) may be tried. Inhalers combining an inhaled steroid and a long-acting bronchodilator (combination inhaler) are more commonly prescribed than LABAs on their own.

LABAs work in the same way as short-acting relievers, but they take longer to work and can last up to 12 hours. Long-acting relievers may cause similar side-effects to short-acting relievers, including mild shaking of the hands, headache, and muscle cramps.

Long-acting reliever inhalers should only be used in combination with a preventer inhaler. Studies have shown that using a LABA on its own can increase asthma attacks and can even increase the risk of death from asthma, though this increased risk is small. In November 2005, the Food and Drug Administration in the US issued an alert indicating potential increased risk of worsening symptoms and sometimes death associated with the use of LABA monotherapy.

Combination inhalers

Combination inhalers containing beta 2-agonists and corticosteroids can be very effective in attaining asthma control. They have been shown to have better outcomes compared to leukotriene receptor antagonists such as montelukast.

In studies, both treatment options led to improved asthma control; however, compared to leukotriene receptor antagonists, the addition of a LABA to inhaled corticosteroids is associated with significantly improved lung function, symptom-free days, need for SABA, night awakenings, and quality-of-life, although the magnitude of some of these differences is small.

Long-acting muscarinic antagonists

Long-acting muscarinic antagonists (LAMAs) have been long recognised in the treatment of chronic obstructive pulmonary disease (COPD). LAMAs work by opening narrowed airways for at least 24 hours.

In asthma, muscarinic antagonists (both short- and long-acting) were traditionally considered less effective than β2-agonists. Only relatively recently have studies been conducted to evaluate the efficacy of LAMAs, as add-on to either inhaled corticosteroid monotherapy or inhaled corticosteroid/LABA combinations.

These studies led to the first approval of the LAMA, tiotropium (Spiriva Respimet) as an add-on therapy in patients with poorly controlled asthma. Spiriva Respimet was approved for uncontrolled asthma in adults in 2014 and its licence was extended to uncontrolled asthma in children over six years of age in 2018.

Subsequently, a number of single-inhaler corticosteroid /LABA/LAMA triple therapies have been approved or are in clinical development for the management of asthma.

There is now substantial evidence of the efficacy and safety of LAMAs in asthma that is uncontrolled despite treatment with an inhaled corticosteroid/LABA combination.

MART regime

The maintenance and reliever therapy (MART) regime is a form of combined corticosteroid and LABA treatment using a single inhaler, containing both corticosteroids and a fast-acting LABA. It is used for both daily maintenance therapy and the relief of symptoms as required.

It is only suitable for corticosteroids and LABA combinations where the LABA has a fast-acting component, for example, a formoterol and budesonide inhaler (eg, Symbicort). It is important that the patient understands and complies with the MART regimen.

Occasional corticosteroids

Most patients only need to take a course of oral corticosteroids for one or two weeks. Once the asthma symptoms are under control, the dose can be reduced slowly over a few days.

Oral corticosteroids can cause side-effects if they are taken for more than three months or if they are taken frequently (three or four courses of corticosteroids a year).

Side-effects can include:

• Weight gain.
• Thinning of the skin.
• Osteoporosis.
• Hypertension.
• Diabetes.
• Cataracts and glaucoma.
• Easy bruising.
• Muscle weakness.

To minimise the risk associated with oral corticosteroids, patients should be advised to:

• Eat a healthy, balanced diet with plenty of calcium.
• Maintain a healthy body weight.
• Stop smoking.
• Only drink alcohol in moderation.
• Do regular exercise.

Once control is achieved and sustained, a gradual stepping down of therapy is recommended. Good control is reflected by the absence of night-time symptoms, no symptoms on exercise, and the use of relievers less than three times a week.

Patients should be maintained on the lowest effective dose of inhaled steroids, with reductions of 25-50 per cent being considered every three months.

Add-ons

If treatment of asthma is still not successful, additional preventer medicines can be tried prior to considering biologics. Possible alternatives include:

Leukotriene receptor antagonists

Leukotriene receptor antagonists (montelukast) act by blocking part of the chemical reaction involved in inflammation of the airways. Montelukast is particularly beneficial for two types of asthma:

A. Asthma predominantly induced by exercise.

B. Asthma associated with allergic rhinitis.

Other types of asthma where montelukast has shown efficacy include asthma in obese patients, asthma in smokers, aspirin-induced asthma, and viral-induced wheezing episodes. It can also reduce the need to increase an inhaled corticosteroid dose. The fact that leukotriene receptor agonists help allergic rhinitis symptoms is a positive.

Leukotriene receptor agonists do not usually cause side-effects, although there have been reports of stomach upsets, feeling thirsty, and headache.

Theophylline

Theophylline helps to widen the airways by relaxing the muscles around them. It is known to cause potential side-effects, including headaches, nausea, insomnia, vomiting, irritability, and stomach upsets. These can usually be avoided by adjusting the dose.

It has a narrow therapeutic index and the balance between sub-optimal dosage and overdosage can be difficult to manage.

Despite theophylline being around for more than 80 years, it still offers an inexpensive option as an add-on therapy where the likes of inhaled corticosteroids/ LABAs/LAMAs/leukotriene receptor antagonists have not controlled symptoms sufficiently.

Macrolides

Oral macrolide therapy has been shown to improve the quality-of-life in people with asthma. Treatment with macrolides results in an improvement in asthma symptoms in some patients, although this is small in magnitude and is not applicable to all patients with asthma.

Studies with short courses of macrolide antibiotics in asthma and in longer, lower-dose regimens (eg, azithromycin 250mg or 500mg three times a week) suggest a possible non-antimicrobial mode of action, possibly as a steroid-sparing agent.

The British Thoracic Society guidance on the use of long-term macrolides in adults with respiratory disease, published in 2019, concluded that “there is insufficient evidence to make any recommendation on the impact of oral macrolide therapy on mortality, exercise capacity, disease progression, or sputum characteristics in people with asthma”.

While macrolides do have a slightly more proven benefit at reducing symptoms of COPD, further research, over a longer period, is needed to investigate the role of long-term macrolide therapy in reducing exacerbations of asthma.

Azithromycin can cause QTc prolongation, liver function issues, and hearing loss, so patients must be closely monitored.

Biologics

Biologics reduce inflammation in the respiratory tract. Most are given by subcutaneous injection once or twice a month. All biologics are an add-on option and do not replace existing reliever and preventer medication, but patients should eventually be able to reduce the dosage of existing therapies, such as inhaled corticosteroids. Biologics are available to target the two subtypes of type-2 asthma, ie, allergic (IgE-mediated) and eosinophilic asthma

Biologic therapy drugs for severe asthma include:

• Omalizumab (Xolair);
• Mepolizumab (Nucala);
• Reslizumab (Cinqair);
• Benralizumab (Fasenra);
• Dupilumab (Dupixent).

Of the five biologics listed above, omalizumab is an anti-IgE agent, and the other four biologics are anti-eosinophilic agents.

Biologics, are expensive (average cost is €15,000 per year), require frequent monitoring, and are limited to specific clinical phenotypes, meaning use is limited to strict protocols.

The benefits of reduced exacerbations of asthma, reduced steroid burden, and the potential for decreased hospitalisations means health authorities are increasingly funding their use.

More research is required to better identify appropriate patients for use of biologics, including better use of biomarkers and phenotypes in the management of acute asthma, and the selection of biologics for the right patients at the appropriate time.

In clinical trials, all five biologics reduced annualised exacerbation rates by at least 50 per cent and they all improved asthma symptom scores, lung function and quality-of-life, and allowed reductions in maintenance oral corticosteroids while maintaining a favourable safety profile.

Biologics used for asthma have a good safety profile. The most serious potential side effect of biologic therapies is an allergic or allergic-like reaction, with some patients very rarely experiencing severe anaphylaxis.

These reactions are rare but can be serious. Symptoms of an allergic reaction can include breathing difficulties, faintness/dizziness, rash, swelling, and itching. Allergic reactions mostly occur immediately after the injection, but in some cases, symptoms may not occur for a few days after the injection.

Less severe but more common side-effects of biologics include headache, injection site reaction, and increased risk of infections, such as colds, flu, and urinary tract infections.

There are currently no set guidelines on how long a biologic should be used for severe asthma. Guidelines recommend trialling a biologic for a minimum of four months to determine if it improves severe asthma symptoms.

Treatment guidelines were produced by the European Academy of Allergy and Clinical Immunology (EAACI) and published in the journal Allergy in 2020.

Omalizumab

Omalizumab is indicated for adults, adolescents, and children (6 to <12 years of age) and the licence states that omalizumab should only be considered for patients with severe confirmed IgE-mediated asthma, ie, allergic asthma.

The EAACI suggest that adults with both allergic and nonallergic severe uncontrolled eosinophilic asthma may benefit from the addition of omalizumab. Omalizumab is ‘strongly recommended’ to reduce exacerbations, and ‘conditionally recommended’ as safe and effective for the improvement of lung function and quality-of-life, and the reduction in dosage of current traditional asthma treatment. In addition, a ‘conditional recommendation’ is given for the use of omalizumab to lower the use of inhaled corticosteroids.

Omalizumab may be added to existing therapy for children aged six to 11 years with moderate to severe allergic asthma not controlled by background medications, with a ‘conditional recommendation’ for its use to reduce symptom exacerbations and inhaled corticosteroids and the improvement of lung function and quality-of-life.

Mepolizumab

Mepolizumab is an IL-5 inhibitor licensed as add-on therapy in adults and children over six with severe uncontrolled eosinophilic asthma. Mepolizumab has a ‘strong recommendation’ to limit exacerbations and taper oral corticosteroids, and ‘conditional recommendations’ regarding safety and improvement in lung function, disease control, and quality-of-life.

It has ‘conditional recommendations’ as an add-on to treat adolescents aged 12-17 years who have severe uncontrolled eosinophilic asthma.

Reslizumab

Reslizumab is ‘strongly recommended’ as add-on treatment to reduce exacerbations in adults with severe uncontrolled eosinophilic asthma who are taking controller medications.

It is also ‘conditionally recommended’ as safe and effective for the improvement of lung function, disease control, and quality-of-life.

Benralizumab

Benralizumab is an IL-5 inhibitor licensed as an add-on therapy for adults with severe eosinophilic uncontrolled asthma. It is ‘strongly recommended’ as an add-on therapy to reduce severe exacerbations and taper oral corticosteroids when the blood eosinophil count is >150/µL.

It is also ‘conditionally recommended’ for improvement of lung function, disease control, and quality-of-life.

The EAACI ‘conditionally recommend’ benralizumab as an add-on treatment for patients aged 12-17 years with severe uncontrolled eosinophilic asthma and adults with uncontrolled severe allergic asthma.

Dupilumab

Dupilumab is approved for severe asthma with type 2 inflammation characterised by raised blood eosinophils and/or raised fractional exhaled nitric oxide (FeNO). It is approved as add-on therapy for adults and adolescents aged 12-17 years.

It is licensed in Ireland to treat moderate to severe atopic dermatitis (atopic eczema). The HSE Drug’s Group approved reimbursement of dupilumab for atopic dermatitis in April 2021.

In early 2021, the indication of severe asthma was added to its licence in Ireland, allowing it to be prescribed for this indication. However, like other biologics, it is not reimbursable under the HSE community drug schemes so it is not universally available to patients due to cost.

Dupilumab blocks two interleukin proteins (IL-4 and IL-13), which differentiates it from the other biologic therapies. It has shown very favourable results in asthma trials.

The EAACI ‘strongly recommends’ it as an add-on therapy to reduce symptom exacerbation and improve lung function.

For adults over 17, dupilumab is ‘conditionally recommended’ as safe and effective for the improvement of asthma control and quality-of-life, and the reduction of the need for other medications.

It is ‘conditionally recommended’ as an add-on therapy for adults and children older than 12 years with severe uncontrolled allergic asthma to increase lung function and control disease while limiting severe exacerbations.

When dupilumab is used as an add-on to treat severe uncontrolled type-2 asthma in over 12s, it is ‘strongly recommended’ to reduce exacerbations, increase lung function, and taper oral corticosteroids, and ‘conditionally recommended’ to improve quality-of-life and asthma control and the reduction of the need for other medications.

Biologics in Ireland are not approved for use under the community drug schemes meaning they are not available via the DPS/ GMS schemes. This means they are not classified as high-tech, unlike biologics for other conditions. In Ireland, biologics for asthma are paid for directly out of hospital budgets, which limits their availability.

Access to biologic therapy for patients is regulated by the HSE via a strict protocol. This has led to a so called ‘postcode lottery’ regarding access to biologics because depending on the hospital the patient attends and the part of the country in which they live, access will vary and is largely dependent on individual hospital budgets.

While mepolizumab and benralizumab are available in auto-injector pens to facilitate patient self-administration in other countries, these devices are not yet approved for use in Ireland, so biologic therapies must be administered by a specialist nurse in supervised settings, which further reduces patient access.

The Asthma Society of Ireland is leading a campaign calling on the Government to expand the national fund for biologic medication for severe asthma to allow greater patient access. The Society is also asking the Government to add asthma to the long-term-illness scheme.

References on request

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