Introduction

Asthma is a major long-term, non-communicable disease affecting both adults and children. It is the most common chronic disease found in children. In 2019, asthma affected an estimated 262 million people worldwide and was responsible for 455,000 deaths.[1] In Ireland, one-in-13 people have asthma, costing €472 million per annum.

Asthma is included in the World Health Organisation (WHO) Global Action Plan for the Prevention and Control of Non-Communicable Diseases and the United Nations 2030 Agenda for Sustainable Development. Asthma cannot be cured, but it can be managed with appropriate use of medication, allowing patients to enjoy a normal and active life.

In the following CPD module we discuss the diagnosis and management of asthma in adolescents and adults.

Definition

The Global Initiative for Asthma (GINA) defines asthma as a heterogenous disease, usually characterised by chronic airway inflammation. It is defined by a history of respiratory symptoms, such as wheeze, shortness of breath, chest tightness and cough, that vary over time and intensity, together with variable expiratory airflow limitation.[2] Variations in airflow are typically triggered by factors such as exercise, allergen, or irritant exposure, change in weather or viral respiratory infections. Symptoms may resolve spontaneously or in response to medications and be absent for months at a time.

Asthma is a heterogenous disease, however recognisable clusters do emerge based on demographic, clinical and pathophysiological characteristics and are referred to as asthma phenotypes. Some of the most common phenotypes are:

• Allergic asthma: Often commences in childhood and is associated with past and/or family history of allergic disease such as eczema, allergic rhinitis, or food or drug allergy. Patients usually respond well to inhaled corticosteroid (ICS) treatment.
• Non-allergic asthma: Asthma that is not associated with allergy. Patients often display less short-term response to ICS.
• Adult-onset asthma: Asthma which presents for the first time in adult life. Patients tend to be non-allergic and often require higher doses of ICS or are relatively refractory to corticosteroid treatment. Occupational asthma should be ruled out in patients presenting with adult-onset asthma

More recently, there is growing academic endorsement for the classification of asthma into type 2 and non-type 2 asthma. Type 2 inflammation is cell mediated with T helper type 2 cells playing a key role. In response to allergens there is a release of cytokines leading to a cascade of immune responses resulting in inflammation. Typically, type 2 inflammation is linked to eosinophilia and increased IgE. Various conditions including asthma, atopic dermatitis and rhinitis are linked to type 2 inflammation. Usually, type 2 asthma has a good response to ICS. Severe asthma with type 2 inflammation is associated with a higher risk of exacerbation, hospitalisation, and death than if type 2 inflammation is not present. It is this group that is being targeted for new biological therapies for asthma. Dupilumab, for example, was endorsed in the UK by the National Institute for Health and Care Excellent (NICE) in December 2021 and is licensed for treating severe asthma with type 2 inflammation.[3]

Diagnosis

Making a diagnosis of asthma in a patient not on controller treatment is based on recognising both a characteristic pattern of respiratory symptoms and demonstrating variable expiratory airflow limitation.[4] Typical respiratory symptoms include cough, wheeze, dyspnoea and/or chest tightness. Symptoms are often worse at night or early morning. Symptoms vary over time and in intensity. Symptoms are precipitated by viral infections, exercise, allergen exposure, changes in weather, or irritants such as cigarette smoke or exhaust fumes.

Once a classical pattern of respiratory symptoms has been recognised it is important to confirm the diagnosis of asthma with documentation of variable expiratory airflow limitation. This is to avoid unnecessary treatment or over treatment, and to avoid missing alternative diagnoses. A recent study of patients aged 18 years and over with a diagnosis of asthma in the previous five years found that when subjected to spirometry, 33 per cent had asthma excluded.[5] Similarly, approximately 50 per cent of children diagnosed with asthma have been found to have been incorrectly diagnosed.[6]

Confirmation of variable expiratory airflow limitation is a two-step process. First, expiratory airflow limitation should be documented. At a time when FEV₁ is reduced, confirm that FEV₁/FVC is reduced compared to the lower limit of normal, ie, >0.75-0.80 in adults and >0.90 in children. Second, excessive variability in lung function should be documented, ideally via a bronchodilator (BD) responsiveness test. This is deemed to be positive when there is an increase in FEV₁ of ≥12 per cent and ≥200ml measured 10-15 minutes post 200-400mcg salbutamol, compared with pre-bronchodilator readings.

If spirometry is not available excessive variability can be demonstrated by diurnal peak expiratory flow (PEF) measurement over two weeks. This is positive if the average daily diurnal PEF is >10 per cent in adults and >13 per cent in children. Diurnal PEF variability is calculated from twice daily readings as the daily amplitude percent mean, ie ([day’s highest – day’s lowest]/mean of day’s highest and lowest) x 100.

If possible, variable expiratory airflow limitation should be documented before treatment is initiated because variability typically decreases with ICS treatment as lung function improves.

Management of asthma

Medications for the management of asthma can be divided into two broad categories: controller medications and reliever medications.

Controller medications contain ICS. They reduce airway inflammation, control symptoms, and reduce future risks of exacerbations and decline in lung function.

Reliever medications are used for as-needed relief of breakthrough symptoms, including during worsening asthma or exacerbations.

In 2019 GINA endorsed a fundamental change in asthma management when it made a recommendation against the treatment of asthma in adults and adolescents with a short-acting beta agonist (SABA) alone.[7]

Low-dose ICS-formoterol as a reliever is now the preferred approach recommended by GINA. When a patient at any step along the treatment ladder has asthma symptoms they should use ICS-formoterol as needed for symptomatic relief. In addition, patients on Steps 3-5 of the GINA treatment ladder should take ICS-formoterol as regular daily treatment. This is known as low-dose ICS-formoterol as maintenance and reliever therapy (MART).

Where ICS-formoterol as reliever is not possible, GINA recommends that for those patients with mild asthma on a SABA as-needed therapy alone, they should have a low-dose ICS added to their therapy, to be taken in combination with, or right after, the SABA for symptomatic relief.

The recommendation by GINA for extending the recommendation for as-needed ICS-formoterol stemmed from several considerations. Patients with mild asthma and infrequent symptoms can still have severe or fatal exacerbations.[8] A single day with increased as-needed ICS-formoterol reduces the short-term risk of severe exacerbation compared with SABA use alone.[9] GINA points out that recommending patients be provided with a controller medication from the outset of management allows for consistent messaging. It avoids the scenario previously, where a patient starts out on a SABA alone and then is asked to add a daily controller despite treatment being adequate from the patient’s perspective, thus avoiding overreliance on SABA as the main asthma treatment.

The usual dose of as-needed budesonide-formoterol in mild asthma is a single inhalation of 200/6mcg. The maximum recommended dose of as needed budesonide-formoterol in a single day corresponds to a total of 72mcg formoterol (12 inhalations of budesonide-formoterol 200/6mcg). ICS-formoterol formulations other than budesonide-formoterol have not been studied for as-needed only use, but beclomethasone-formoterol may also be suitable. Rinsing the mouth is generally not needed after as-needed use of low-dose ICS-formoterol.

Figure 1 below sets out the step-wise approach recommended by GINA to the management of asthma.

 Figure 1. Medication management of asthma of asthma in adults and adolescents >12 years. GINA 2022

Steps 1-2 refers to patients who experience symptoms less than four-to-five days a week. As discussed above, GINA recommends as-needed ICS-formoterol for steps 1-2.

Step 3 refers to patients who experience daily symptoms or wake from sleep due to asthma once a week or more. These patients should be commenced on regular low-dose ICS-formoterol as maintenance in addition to reliever therapy, ie, MART.

Step 4 refers to those patients who experience daily symptoms or wake from sleep once a week or more and exhibit low lung function. GINA recommends in such patients increasing to medium-dose ICS-formoterol.

Step 5 refers to those with severe, uncontrolled asthma. These patients will require referral to specialist clinics with access to biologic therapies including anti-IgE (omalizumab), anti-IL5 (mepolizumab), anti-IL5R (benralizumab), anti-IL4 (dupilumab) and oral corticosteroids.

Note that for all treatment steps GINA highlights that leukotriene receptor antagonists (LTRA) and sublingual immunotherapy (SLIT) are potential alternative controller options. Immunotherapy involves desensitisation to specific allergens and works by reducing the inflammatory response to the sensitised antigen. SLIT involves delivering desensitising doses of an antigen under the tongue. Currently in Ireland, SLIT is limited to grass pollen allergy, however, house dust mite and tree pollen therapies are in development.

Once asthma treatment has been commenced, controller treatment should be adjusted up or down in a step-wise approach to achieve good symptom control and minimise risk of exacerbations. Once good control has been achieved for two-to-three months, treatment may be stepped down to find the patient’s minimum effective treatment.

If a patient has ongoing poor symptom control despite two-to-three months of controller treatment, assess for any modifiable factors before stepping up treatment. Common causes for poor symptom control include poor inhaler technique, poor adherence to treatment, persistent exposure to allergens such as cigarette smoke and air pollution, or to medications such as beta-blockers and non-steroidal anti-inflammatory drugs (NSAIDs).

Asthma and Covid-19

People with asthma do not appear to be at increased risk of contracting Covid-19 and studies do not indicate that people with well-controlled asthma are at increased risk of Covid-19-related death.[10] However, the risk of Covid-19-related death was increased in those who recently required oral corticosteroids for their asthma.[11] Therefore, it is essential to continue good asthma management through the maintenance of good symptom control and the minimisation of oral corticosteroid use. It is essential that patients continue to take asthma medications as prescribed, including ICS. Stopping ICS can lead to potentially dangerous worsening of asthma.

Written asthma actions have added importance in the context of Covid-19. These enable the patient to recognise the symptoms of worsening asthma, how to increase medications, and when to seek medical help.

Nebulisers can transmit respiratory viral particles up to one metre. Use of nebulisers should be restricted to the management of life-threatening asthma exacerbations in acute care settings. In all other instances, SABA for acute asthma should be delivered via a pressurised metered-dose inhaler and spacer with a mouthpiece and tightly-fitting face mask.

Conclusion

Asthma is one of the most common chronic respiratory conditions, with burdensome implications in terms of morbidity for the patient and cost to the State. The first step in reducing this burden is for clinicians to be able to recognise the classical respiratory symptom patterns of asthma, allied to objective documentation of variable expiratory airflow limitation to confirm the diagnosis.

Treatment of asthma has evolved over the last number of years. Chief among this being GINA’s recommendation that ICS-formoterol form the cornerstone of asthma management. New biological and immunological therapies are now entering the management protocol across all severities of asthma, which will further reduce the symptom burden on patients.

Clinicians should strive to implement and encourage adherence to personalised asthma management plans, particularly in the context of the ongoing Covid-19 pandemic.

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

Disclaimer: Brands mentioned in this article are meant as examples only and not meant as preference to other brands.

Asthma is characterised by variable respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough, and variable expiratory airflow limitation. It is usually associated with airway inflammation.¹ The exact cause of asthma remains unknown. Numerous triggers can cause symptoms, and these differ from person-to-person.

It is estimated that over 80 per cent of people with asthma have allergic rhinitis (AR). AR is also a risk factor for asthma, with 10-40 per cent of people who have AR also having asthma. AR is more likely to develop initially, with asthma developing later. Therefore, people with AR should be assessed for asthma. Similarly, patients with persistent asthma should be assessed for AR.

Typical symptoms of seasonal (hay fever) and perennial AR are:

• Sneezing;
• Itchy, blocked, or runny nose;
• Red, itchy, or watery eyes;
• Itchy throat, inner ear, or mouth;
• Postnasal drip;
• Headaches;
• Loss of concentration and generally feeling unwell;
• Reduced sensation of taste and smell.

The term ‘united airway disease’ or ‘one airway disease’ is opportune, as both rhinitis and asthma are chronic inflammatory diseases affecting both the upper and lower airways. Both conditions can be triggered by allergic or non-allergic triggers and present several phenotypes. Assessment and management of AR and asthma should be jointly carried out, leading to better control of both conditions.

In 2019, the classification of ‘seasonal’ and ‘perennial’ rhinitis was changed to ‘intermittent’ and ‘perennial’ rhinitis.² Intermittent rhinitis occurs less than four days per week or for less than four weeks. Persistent rhinitis lasts more than four days and longer than four weeks. Both intermittent and persistent AR can be mild or moderate/severe (see Figure 1).

Treatment

There are several treatment options available to the patient and a combination of these options may be required for optimal relief of symptoms. These are outlined in Table 1.

Saline douching/nasal irrigation should also be encouraged and is available either as a saline rinse or saline spray. Saline rinsing involves high volume at a low pressure, whereas saline spray is a low volume delivered at high pressure. The advantages of saline douching include:

• Direct cleansing;
• Removal of mucous and inflammatory mediators;
• Reduces bacterial burden;
• Reduces mucus thickness;
• Improves mucociliary function by increasing ciliary beat frequency.
• If the nasal spray is being used for the first time, priming is required:
• Blow the nose prior to use;
• Tilt the head forward;
• Use right hand to left nostril, left hand to right nostril;
• Aim the nozzle of the spray away from the nasal septum and towards the outer aspect of the nose;
• Avoid sniffing deeply. If the nasal spray can be tasted, the patient is probably sniffing too deeply.

Smoking cessation should be encouraged at every opportunity. Smoking increases the likelihood of chronic nasal symptoms and may be associated with the development of nasal polyposis. Passive smoking, environmental exposure, e-cigarettes, and vaping also increase the likelihood of chronic nasal symptoms and nasal polyposis.

Mild intermittent AR treatment options include oral and nasal decongestants, which can be used as a rescue medication. These medications will reduce nasal congestion and should be used for no longer than seven days and should be avoided in pregnancy and breastfeeding. Oral H1 antagonists block the physiological effects from mast cell-derived histamine. Second-generation antihistamines are preferred due to their less sedating effect and are available over the counter. Antihistamines are also available intranasally or intraocular.

Intranasal corticosteroid (INCS) is the first-line treatment for moderate/severe intermittent and persistent AR. These medications are used once-or-twice daily in each nostril and good technique is essential and should be checked at every opportunity. If the nasal cavity is very obstructed, a nasal spray may not be effective. Nasal drops may be more effective in this scenario. The efficacy of INCS is not improved when used with oral corticosteroids (OCS).

Sublingual immunotherapy (SLIT)/allergen immunotherapy (AIT) is now recommended by GINA (2021) as a treatment option for patients with asthma who are sensitised and have AR. Immunotherapy is also recommended by ARIA (2019) for patients with AR who do not achieve an optimal response from oral H1 or INCS therapies. These medications, which are not available on the General Medical Services (GMS), can be prescribed by GPs. There are three SLIT/AIT products available in Ireland to treat allergy – grass pollen, tree pollen, and house dust mite allergy.

Figure 2 provides a stepwise approach to the management of AR.

Endonasal phototherapy has an immunosuppressive effect by inhibiting allergen-induced histamine release from mast cells. It also induces apoptosis in the T lymphocytes and eosinophils. The procedure directs a combination of UV-B, UV-A, and visible light into the nasal cavity. Endonasal phototherapy is generally well-tolerated and effective, and is a treatment option when pharmacological treatment is insufficient or contraindicated.

It is considered that AR is a medical condition that requires medical intervention. However, if symptoms are unilateral or if there is a septal deviation, nasal polyps, or tumour present, surgery should be considered. Patients will still need to have an AR plan in place post-surgical intervention.

There are a number of lifestyle interventions that can improve symptoms:

• Keep windows closed at night-time or when the pollen count is high.
• Monitor pollen levels on www.met.ie/forecasts/pollen and minimise time spent outdoors when the pollen
  count is high.
• Apply Vaseline around the nostrils when outdoors to trap pollen.
• Wear wraparound sunglasses to minimise levels of pollen irritating the eyes. Splash the eyes with cold water to help flush out pollen and soothe and cool the eyes.
• Shower, wash your hair, and change clothes if you have been outdoors for an extended time.
• Exercise in the morning rather than the evening when there are higher rates of pollen falling.
• Avoid drying clothes outdoors and shake clothes outside before bringing them inside, particularly bedclothes.
• Minimise contact with pets that have been outdoors and are likely to carry pollen.
• Put an asthma action plan in place.

An asthma action plan contains all the information a person with asthma needs to keep their condition under control. Every person with asthma should be offered a plan. It should be reviewed frequently, and any time medication is changed. These can be downloaded from www.asthma.ie and should be filled out with the patient’s healthcare professional.

Special considerations

Children under four years
Figure 3 illustrates the typical age of onset of allergies in children. Outdoor allergens are unusual in children under two. Type 2 sub-endotype IL4/IL-13 is associated with AR in children. IL-5 is associated with asthma.

Treatment of children aged under four years should focus on allergen avoidance and saline spray. Cetirizine is the oral H1 antagonist of choice. Cetirizine is licensed from two years, but good safety is reported from six months of age. For moderate/severe persistent AR, intranasal corticosteroids such as fluticasone or mometasone should be considered first-line treatment. Long-term follow-up studies suggest no growth retardation if used as a once-daily dose. Caution should be taken in children who are also using inhaled or topical corticosteroids for asthma or dermatitis. In children with resistant symptoms and those with co-existing asthma, leukotriene receptor antagonists (LTRA) should be considered. Parents should be educated about possible side-effects of sleep disturbance and mood disorders.

Pregnancy

AR affects 20 per cent of pregnancies, and women with pre-existing AR can experience an increase in symptoms. Medications should be avoided where possible and should only be used if benefits to the mother are greater than the risk to the foetus. Medication should be avoided in the first trimester if possible. Topical administration of medication should be the first line where possible.

Conclusion

This article has explored the relationship between asthma and AR. Pharmacological and non-pharmacological interventions for the management of AR have been discussed. Special considerations in children and pregnancy have also been addressed.

The impact of AR on health and wellbeing is significant, with many people experiencing impairment
of daily activities, learning and cognitive function, as well as reduced productivity at work and school. Optimal control of symptoms through pharmacological and non-pharmacological treatment regimens in combination with education, self-management, and empowerment is paramount to managing this condition.