Update Journal - Respiratory Medicine

inhaler with confirmed dose delivery

RESPIRATORY MEDICINE

simple to use patients with COPD

EXPERT ARTICLES ON

CYSTIC LUNG DISEASE

RSV

ALPHA-1 ANTITRYPSIN DEFICIENCY

SPECIAL FOCUS ON COPD AND ASTHMA:

Product a white contains 375 Maintenance pulmonary micrograms correctly as instruct the elderly adolescents. treatments. patients with arrhythmia within functional with dental hyperplasia or hereditary malabsorption. No other lactation: risk-bene t Side-e ects: Uncommon stomatitis, rash, anaphylactic Marketing AB, SECastlecourt, available updated: quick report any Dublin medsafety@ Ireland

Please

Summary of Product Characteristics (SPC) for the full prescribing information.

Inhalation powder in a white inhaler with an integral dose indicator and an orange

Each delivered dose contains 396 µg aclidinium bromide (equivalent to 340 µg

2021 GINA and GOLD updates, new Irish COPD clinical guidelines, latest treatment and prevention strategies

Use: bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive For inhalation use. Recommended dose is one inhalation µg twice daily. Patients should be instructed on how to administer the product Genuair inhaler may work di erently from inhalers used previously. It is important patients to read the Instructions for Use in the pack. No dose adjustments are required patients, or those with renal or hepatic impairment. No relevant use in children and Hypersensitivity to the active substances or to any of the excipients. Do not use in asthma. Stop use if paradoxical bronchospasm occurs other treatments. Do not use for the relief of acute episodes of bronchospasm. Use in patients with myocardial infarction in the previous 6 months, unstable angina, newly arrhythmia within the previous 3 months, or hospitalisation within the previous heart failure functional classes III and IV. Discontinue if increases in pulse rate, blood changes in ECG occur. Use with caution in patients with a history of or known prolongation QTc interval or treated with products a ecting the QTc interval. Use with caution severe cardiovascular disorders, convulsive disorders, thyrotoxicosis and phaeochromocytoma. Hypokalaemia may occur, is usually transient and supplementation not needed. severe COPD, hypokalaemia may be potentiated by hypoxia and concomitant treatment. caution in patients with symptomatic prostatic hyperplasia, urinary retention or with glaucoma. Dry mouth, observed with anticholinergic treatment, may be associated caries in the long term. Do not use in patients with rare hereditary problems of galactose Do with other anticholinergic and/or long-acting β2-adrenergic agonist containing medicinal Caution in use with methylxanthine derivatives, steroids, non-potassium-sparing β-adrenergic blockers or medicinal products known to prolong the QTc interval. Please No data on use in pregnancy. risk-bene t before using during lactation. Unlikely to a ect fertility at the recommended Common (1-10%): Nasopharyngitis, urinary tract infection, sinusitis tooth abscess, anxiety, headache, dizziness, tremor, cough, diarrhoea, nausea, dry mouth, myalgia, peripheral oedema, increased blood creatine phosphokinase. Uncommon (0.1- 1%): hyperglycaemia, agitation, dysgeusia, blurred vision, tachycardia, electrocardiogram palpitations, angina pectoris, dysphonia, throat irritation, stomatitis, rash, pruritus, urinary increased blood pressure. Rare (0.01-0.1%): Hypersensitivity, bronchospasm, including Carton containing 1 inhaler EU/1/14/963/001

LONG COVID

Marketed

Pharmaceuticals Ireland Ltd., Castlecourt, Monkstown Farm, Monkstown, Glenageary, T924. Further information is available on request to A. Menarini Pharmaceuticals Ireland

The evidence to date and emerging treatment strategies

This medicinal product is subject to additional monitoring. This will identi cation of new safety information. Healthcare professionals are asked suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie;

hpra.ie. Adverse events should also be reported to A. Menarini Pharmaceuticals

Fictional patient, for illustrative purposes only

For COPD patients on treatment with ICS/LABA and at risk of exacerbation* 1

*A worsening of symptoms or a history of exacerbation treated with antibiotics or oral corticosteroids in the past 12 months

It’s the things you

do today

that

make a big difference to their

tomorrows1-3

TRELEGY Ellipta provides your patients with statistically superior improvements in lung function and health-related quality of life, and reduction in annualised rate of moderate/ severe exacerbations** vs. budesonide/formoterol***1–3

Moderate exacerbation is a worsening of symptoms or a history of exacerbation treated with antibiotics or oral corticosteroids. A severe exacerbation is a worsening in symptoms that required hospitalisation.

TRELEGY Ellipta (FF/UMEC/VI) 92/55/22 mcg OD is indicated for maintenance treatment in adult patients with moderate to severe COPD who are not adequately treated by a combination of an ICS and a LABA or a combination of a LAMA and a LABA1

▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

***Co-primary endpoints were change from baseline in trough FEV1 and SGRQ at week 24 (n=1810). A subset of patients (n=430) remained on blinded study treatment for 52 weeks. Trelegy showed an improvement in trough FEV1 of 171mL versus budesonide/formoterol (p < 0.001, 95% CI 148,194) at week 24. Trelegy showed an improvement in health-related quality of life (SGRQ) of 2.2 units (p <0.001, 95% CI 3.5, 1.0) at week 24. At week 52 in a subset of patients Trelegy showed a 44% reduction in annualised rate of moderate/severe exacerbations versus budesonide/formoterol (95% CI 15,63, p=0.006, Absolute difference 0.16).

TRELEGY Ellipta is generally well tolerated. Common adverse reactions include: pneumonia, upper respiratory tract infection, bronchitis, pharyngitis, rhinitis, sinusitis, influenza, nasopharyngitis, candidiasis of mouth and throat, urinary tract infection, headache, cough, oropharyngeal pain, constipation, arthralgia, back pain1 FF, fluticasone furoate; ICS, inhaled corticosteroid; LABA, long-acting ß2-agonist; LAMA, long-acting muscarinic antagonist; OD, once-daily; UMEC, umeclidinium, VI, vilanterol

References: 1. TRELEGY Ellipta SmPC 2019. 2. Lipson DA et al. Am J Respir Crit Care Med 2017; 196:438–446. 3. Lipson DA et al.N Engl J Med 2018; 378:1671–1680.

Trelegy▼ Ellipta (fluticasone furoate/umeclidinium/vilanterol [as trifenatate]) Prescribing information. Please consult the full Summary of Product Characteristics (SmPC) before prescribing Trelegy Ellipta (fluticasone furoate/umeclidinium/vilanterol [as trifenatate]) inhalation powder. Each single inhalation of fluticasone furoate (FF) 100 micrograms (mcg), umeclidinium bromide (UMEC) 62.5 micrograms and vilanterol as trifenatate (VI) 25 mcg provides a delivered dose of 92 mcg FF, 55 mcg UMEC and 22 mcg VI. Indications: Maintenance treatment in adult patients with moderate to severe COPD who are not adequately treated by a combination of an inhaled corticosteroid (ICS) and a long-acting ß2-agonist (LABA) or a combination of a LABA and a long acting muscarinic antagonist. Dosage and administration: One inhalation once daily at the same time each day. Contraindications: Hypersensitivity to the active substances or to any of the excipients (lactose monohydrate & magnesium stearate). Precautions: Paradoxical bronchospasm, unstable or life-threatening cardiovascular disease or heart rhythm abnormalities, convulsive disorders or thyrotoxicosis, pulmonary tuberculosis or patients with chronic or untreated infections, narrow-angle glaucoma, urinary retention, hypokalaemia, patients predisposed to low levels of serum potassium, diabetes mellitus. In patients with moderate to severe hepatic impairment patients should be monitored for systemic corticosteroid-related adverse reactions. Eye symptoms such as blurred vision may be due to underlying serious conditions such as cataract, glaucoma or central serous chorioretinopathy (CSCR); consider referral to ophthalmologist. Increased incidence of pneumonia has been observed in patients with COPD receiving inhaled corticosteroids. Risk factors for pneumonia include: current smokers, old age, patients with a history of prior pneumonia, patients with a low body mass index and severe COPD. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Trelegy. Acute symptoms: Not for acute symptoms, use short-acting inhaled bronchodilator. Warn patients to seek medical advice if short-acting inhaled bronchodilator use increases. Therapy should not be abruptly stopped without physician supervision due to risk of symptom recurrence. Systemic effects: Systemic effects of ICSs may occur, particularly at high doses for long periods, but much less likely than with oral corticosteroids. Interactions with other medicinal products: Caution should be exercised with concurrent use of ß-blockers. Caution is advised when co-administering with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, cobicistat-containing products), hypokalaemic treatments or non-potassium-sparing diuretics. Co-administration with other long-acting muscarinic antagonists or long acting ß2-adrenergic agonists is not

Start your patients on TRELEGY Ellipta today, expect more from tomorrow 1,2

recommended. Pregnancy and breast-feeding: Experience limited. Balance risks against benefits. Side effects: Common (≥1/100 to <1/10): pneumonia, upper respiratory tract infection, bronchitis, pharyngitis, rhinitis, sinusitis, influenza, nasopharyngitis, candidiasis of mouth and throat, urinary tract infection, headache, cough, oropharyngeal pain, arthralgia, back pain. Uncommon (≥1/1,000 to <1/100): viral respiratory tract infection, supraventricular tachyarrhythmia, tachycardia, atrial fibrillation, dysphonia, dry mouth, fractures. Rare (≥1/10,000 to <1/1,000): Hypersensitivity reactions, including anaphylaxis, angioedema, urticaria, and rash. Not known (cannot be estimated from the available data): vision blurred. Marketing Authorisation (MA) Holder: GlaxoSmithKline Trading Services Limited, 12 Riverwalk, Citywest Business Campus, Dublin 24, Ireland. MA No. [EU/1/17/1236/002]. Legal category: POM B. Last date of revision: September 2020. Code: PI-6725. Further information available on request from GlaxoSmithKline, 12 Riverwalk, Citywest Business Campus, Dublin 24. Tel: 01-4955000.

Adverse events should be reported to the Health Products Regulatory Authority (HPRA) using an Adverse Reaction Report Form obtained either from the HPRA or electronically via the website at www.hpra.ie. Adverse reactions can also be reported to the HPRA by calling: (01) 6764971. Adverse events should also be reported to GlaxoSmithKline on 1800 244 255.

Protecting respiratory services amid the new normal

A message from Priscilla Lynch, Editor

As we come towards the end of 2021, Covid-19 continues to cast an inescapable shadow over daily life and our health services.

Acute respiratory services are still among the most impacted by the pandemic, with care no where near back to ‘normal’, and it remains a very worrying time for vulnerable respiratory patients.

For those already infected by Covid-19, lingering symptoms continue to be a significant issue for many patients and indeed healthcare staff infected on the frontline. Therefore this issue of Update carries a dedicated article on long Covid, by two of Ireland’s leading respiratory experts on the issue, who are proving care in a dedicated long Covid clinic. There is much to learn about this condition, and Ireland lags behind many countries who have put dedicated pathways and interim guidelines in place.

November is lung cancer awareness month, which is a timely reminder of the need for patients with symptoms or concerns to feel comfortable presenting to their clinicians, despite the all-consuming presence of Covid-19 meaning a cough is now often seen as something not to investigate further than a PCR test. Lung cancer is the fifth most common cancer in Ireland, with over 2,700 people being diagnosed each year and remains the biggest cause of cancer-related death. It is imperative that awareness of the risks and symptoms of lung cancer are communicated to the public, to enable earlier detection and treatment.

This month also saw the marking of World COPD Day, which highlighted that Ireland still has one of the highest rates of COPD-related hospitalisation among OECD countries. COPD is the second most common cause of death from respiratory disease in Ireland and this issue of Update has dedicated three articles to the disease, as well as a separate piece on reintroducing spirometry to primary care.

There is an expert clinical article on the latest management approaches to COPD, which incorporate the 2021 GOLD guidelines update; there is an outline of the new National Clinical Effectiveness Guideline on COPD, which was developed by a multidisciplinary group supported by the HSE National Clinical Programme for Respiratory Medicine; and there is an expert article detailing the role exercise prescriptions can play in managing COPD symptoms and improving quality-of-life.

On the conference front, this issue features a round-up of some of the most topical research presented at the virtual 2021 European Respiratory Society International Congress, and a preview of the upcoming Irish Thoracic Society Annual Scientific Meeting.

The National Immunisation Office has written a comprehensive outline of this year’s national seasonal influenza vaccination programme for Update. It has a focus on the intranasal quadrivalent live attenuated influenza vaccine (LAIV) for children aged two-to-17 years, which is available free of charge from GPs and community pharmacists. While there were no recorded cases of flu in Ireland last year, a remarkable occurrence likely due to the social distancing, lockdowns, grounding of international travel, and

increased hygiene measures during Covid-19, this year confirmed cases have already been recorded, with serious concern about the potential impact on our already crippled health system if flu levels are significant. The HSE hopes the record high uptake of the flu vaccine last year will be replicated this year, and has ordered 2.2 million doses of flu vaccine for the 2021/2022 flu season, which is 20 per cent more for at-risk groups compared to last season.

Speaking of the return of seasonal non-Covid-19 respiratory viruses, there has been a significant surge in respiratory syncytial virus (RSV)related presentations in primary care in the last two months, so the comprehensive article on RSV in this issue is a must read.

There is also an update from the Irish Lung Fibrosis Association, as well as expert clinical articles on a wide range of topics including adult-onset asthma, the latest GINA guidelines, asthma prevention strategies, cystic lung disease, and an overview of alpha-1 antitrypsin deficiency incidence and research in Ireland.

So all in all, this is a packed issue that should hopefully prove interesting and useful to all our readers.

Thank you to all our expert contributors for taking the time to share their knowledge and advice for the betterment of patient care.

We always welcome new contributors and suggestions for future content, as well as any feedback on our content to date. Please contact me at priscilla@mindo.ie if you wish to give any feedback or contribute an article. ■

Editor Priscilla Lynch priscilla@mindo.ie

Sub-editor Emer Keogh emer@greenx.ie

Creative Director Laura Kenny laura@greenx.ie

Advertisements Graham Cooke graham@greenx.ie

Administration Daiva Maciunaite daiva@greenx.ie

Update is published by GreenCross Publishing Ltd, Top Floor, 111 Rathmines Road Lower, Dublin 6 Tel +353 (0)1 441 0024 greencrosspublishing.ie

© Copyright GreenCross Publishing Ltd 2021

The contents of Update are protected by copyright. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form by any means – electronic, mechanical or photocopy recording or otherwise – whole or in part, in any form whatsoever for advertising or promotional purposes without the prior written permission of the editor or publisher.

Disclaimer

The views expressed in Update are not necessarily those of the publishers, editor or editorial advisory board. While the publishers, editor and editorial advisory board have taken every care with regard to accuracy of editorial and advertisement contributions, they cannot be held responsible for any errors or omissions contained.

GreenCross Publishing is owned by Graham Cooke graham@greenx.ie

For patients not adequately controlled on dual therapy with moderate to severe COPD

UNLEASH THE PROTECTION OF TRIXEO1,2

Significant protection against exacerbations*

TRIXEO Aerosphere is indicated as a maintenance treatment in adult patients with moderate to severe chronic obstructive pulmonary disease (COPD) who are not adequately treated by a combination of an inhaled corticosteroid and a long-acting beta2-agonist or combination of a long-acting beta2-agonist and a long-acting muscarinic antagonist.1

*Significant reductions in the rate of moderate or severe exacerbations vs LAMA/LABA (24%, n=2137 vs n=2120, annual rates 1.08 vs 1.42, 95% CI 0.69–0.83; p<0.001) and ICS/LABA (13%, n=2137 vs n=2131, annual rates 1.08 vs 1.24, 95% CI 0.79–0.95; p=0.003).1,2 COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroid; LABA, long-acting beta2-agonist; LAMA, long-acting muscarinic antagonist. In the clinical trial programme for TRIXEO, LAMA/LABA refers to glycopyrronium/formoterol fumarate and ICS/LABA refers to budesonide/formoterol fumarate. ©AstraZeneca 2021. All rights reserved.

ABRIDGED PRESCRIBING INFORMATION

TRIXEO AEROSPHERE® 5 micrograms/7.2 micrograms/160 micrograms pressurised inhalation, suspension (formoterol fumarate dihydrate/ glycopyrronium/ budesonide)

Consult Summary of Product Characteristics (SmPC) before prescribing.

Indication: Trixeo Aerosphere is indicated as a maintenance treatment in adult patients with moderate to severe chronic obstructive pulmonary disease (COPD) who are not adequately treated by a combination of an inhaled corticosteroid and a long acting beta2 agonist or combination of a long-acting beta2 agonist and a long acting muscarinic antagonist. Presentation: Pressurised inhalation, suspension. Each single actuation (delivered dose, ex-actuator) contains 5 micrograms of formoterol fumarate dihydrate, glycopyrronium bromide 9 micrograms, equivalent to 7.2 micrograms of glycopyrronium and budesonide 160 micrograms. This corresponds to a metered dose of 5.8 micrograms of formoterol fumarate dihydrate, glycopyrronium bromide 10.4 micrograms, equivalent to 8.2 micrograms of glycopyrronium and budesonide 182 micrograms. Dosage and Administration: The recommended and maximum dose is two inhalations twice daily (two inhalations morning and evening). If a dose is missed, take as soon as possible and take the next dose at the usual time. A double dose should not be taken to make up for a forgotten dose. Special populations: Elderly: No dose adjustments required in elderly patients. Renal impairment: Use at recommended dose in patients with mild to moderate renal impairment. Can also be used at the recommended dose in patients with severe renal impairment or end-stage renal disease requiring dialysis, only if expected benefit outweighs the potential risk. Hepatic impairment: Use at recommended dose in patients with mild to moderate hepatic impairment. Can also be used at the recommended dose in patients with severe hepatic impairment, only if expected benefit outweighs the potential risk. Paediatric

Population: No relevant use in children and adolescents (<18 years of age).

Method of administration: For inhalation use. To ensure proper administration of the medicinal product, the patient should be shown how to use the inhaler correctly by a physician or other healthcare professional, who should also regularly check the adequacy of the patient’s inhalation technique. Patients who find it difficult to coordinate actuation with inhalation may use Trixeo Aerosphere with a spacer to ensure proper administration of the medicinal product. Contraindications: Hypersensitivity to the active substances or to any of the excipients. Warnings and Precautions: Not for acute use: Not indicated for treatment of acute episodes of bronchospasm, i.e. as a rescue therapy.

Paradoxical bronchospasm: Administration of formoterol/glycopyrronium/ budesonide may produce paradoxical bronchospasm with an immediate wheezing and shortness of breath after dosing and may be life threatening. Treatment should be discontinued immediately if paradoxical bronchospasm occurs. Assess patient and institute alternative therapy if necessary.

Deterioration of disease: Recommended that treatment should not be stopped abruptly. If patients find the treatment ineffective, continue treatment but seek medical attention. Increasing use of reliever bronchodilators indicates worsening of the underlying condition and warrants reassessment of the therapy. Sudden and progressive deterioration in the symptoms of COPD is potentially life threatening, patient should undergo urgent medical assessment.

Cardiovascular effects: Cardiovascular effects, such as cardiac arrhythmias, e.g. atrial fibrillation and tachycardia, may be seen after the administration of muscarinic receptor antagonists and sympathomimetics, including glycopyrronium and formoterol. Use with caution in patients with clinically significant uncontrolled and severe cardiovascular disease such as unstable ischemic heart disease, acute myocardial infarction, cardiomyopathy, cardiac arrhythmias and severe heart failure. Caution should also be exercised when treating patients with known or suspected prolongation of the QTc interval (QTc > 450 milliseconds for males or > 470 milliseconds for females), either congenital or induced by medicinal products. Systemic corticosteroid effects: May occur with any inhaled corticosteroid, particularly at high doses prescribed

for long periods. These effects are much less likely to occur with inhalation treatment than with oral corticosteroids. Systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, cataract and glaucoma. Potential effects on bone density should be considered particularly in patients on high doses for prolonged periods that have co existing risk factors for osteoporosis. Visual disturbances: May be reported with systemic and topical corticosteroid use. If patient presents symptoms such as blurred vision or other visual disturbances, consider ophthalmologist referral for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR). Transfer from oral therapy: Care is needed in patients transferring from oral steroids, since they may remain at risk of impaired adrenal function for a considerable time. Patients who have required high dose corticosteroid therapy or prolonged treatment at the highest recommended dose of inhaled corticosteroids, may also be at risk. These patients may exhibit signs and symptoms of adrenal insufficiency when exposed to severe stress. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery. Pneumonia in patients with COPD: An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has been observed in patients with COPD receiving inhaled corticosteroids. Remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations. Risk factors for pneumonia include current smoking, older age, low body mass index (BMI) and severe COPD. Hypokalaemia: Potentially serious hypokalaemia may result from β2-agonist therapy. This has potential to produce adverse cardiovascular effects. Caution is advised in severe COPD as this effect may be potentiated by hypoxia. Hypokalaemia may also be potentiated by concomitant treatment with other medicinal products which can induce hypokalaemia, such as xanthine derivatives, steroids and diuretics.

Hyperglycaemia: Inhalation of high doses ofβ2-adrenergic agonists may produce increases in plasma glucose. Blood glucose should be monitored during treatment following established guidelines in patients with diabetes. Co-existing conditions: Use with caution in patients with thyrotoxicosis. Anticholinergic activity: Due to anticholinergic activity, use with caution in patients with symptomatic prostatic hyperplasia, urinary retention or with narrow-angle glaucoma. Patients should be informed about the signs and symptoms of acute narrow-angle glaucoma and should be informed to stop using this medicinal product and to contact their doctor immediately should any of these signs or symptoms develop. Co-administration of this medicinal product with other anticholinergic containing medicinal products is not recommended. Renal impairment: Patients with severe renal impairment (creatinine clearance of <30 mL/min), including those with end-stage renal disease requiring dialysis, should only be treated with this medicinal product if the expected benefit outweighs the potential risk. Hepatic impairment: In patients with severe hepatic impairment, use only if the expected benefit outweighs the potential risk. These patients should be monitored for potential adverse reactions. Drug Interactions: Co-treatment with strong CYP3A inhibitors, e.g. itraconazole, ketoconazole, HIV protease inhibitors and cobicistat-containing products are expected to increase the risk of systemic side effects. Should be avoided unless the benefit outweighs the increased risk, in which case patients should be monitored for systemic corticosteroid adverse reactions. This is of limited clinical importance for short-term (1-2 weeks) treatment. Since glycopyrronium is eliminated mainly by the renal route, drug interaction could potentially occur with medicinal products affecting renal excretion mechanisms. Other antimuscarinics and sympathomimetics: Co-administration with other anticholinergic and/or long-acting β2-adrenergic agonist containing medicinal products is not recommended as it may potentiate known inhaled muscarinic antagonist or β2-adrenergic agonist adverse reactions. Concomitant use of other beta-adrenergic medicinal products can have potentially additive effects. Caution required when prescribed concomitantly with formoterol. Medicinal product-induced

hypokalaemia: Possible initial hypokalaemia may be potentiated by xanthine derivatives, steroids and non potassium sparing diuretics. Hypokalaemia may increase the disposition towards arrhythmias in patients who are treated with digitalis glycosides. β-adrenergic blockers: β-adrenergic blockers (including eye drops) can weaken or inhibit the effect of formoterol. Concurrent use of β-adrenergic blockers should be avoided unless the expected benefit outweighs the potential risk. If required, cardio-selective β-adrenergic blockers are preferred. Other pharmacodynamic interactions: Concomitant treatment with quinidine, disopyramide, procainamide, antihistamines, monoamine oxidase inhibitors, tricyclic antidepressants and phenothiazines can prolong QT interval and increase the risk of ventricular arrhythmias. L-dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance towards beta2sympathomimetics. Concomitant treatment with monoamine oxidase inhibitors, including medicinal products with similar properties such as furazolidone and procarbazine, may precipitate hypertensive reactions. Elevated risk of arrhythmias in patients receiving concomitant anaesthesia with halogenated hydrocarbons.Pregnancy and Lactation: Administration to pregnant women/women who are breast-feeding should only be considered if the expected benefit to the mother justifies the potential risk to the foetus/ child. Ability to Drive and Use Machines: Dizziness is an uncommon side effect which should be taken into account. Undesirable Events: Consult SmPC for a full list of side effects. Common (≥ 1/100 to < 1/10): Oral candidiasis, pneumonia, hyperglycaemia, anxiety, insomnia, headache, palpitations, dysphonia, cough, nausea, muscle spasms, urinary tract infection. Uncommon (≥ 1/1,000 to < 1/100): Hypersensitivity, depression, agitation, restlessness, nervousness, dizziness, tremor, angina pectoris, tachycardia, cardiac arrhythmias (atrial fibrillation, supraventricular tachycardia and extrasystoles), throat irritation, bronchospasm, dry mouth, bruising, urinary retention, chest pain. Very Rare (< 1/10,000): Signs or symptoms of systemic glucocorticosteroid effects, e.g. hypofunction of the adrenal gland, abnormal behaviour. Not known: Angioedema, vision blurred, cataract, glaucoma.

Legal Category: Product subject to prescription which may be renewed (B)

Marketing Authorisation Number: EU/1/20/1498/002 120 actuations

Marketing Authorisation Holder: AstraZeneca AB, SE-151 85, Södertälje, Sweden.

Further product information available on request from: AstraZeneca Pharmaceuticals (Ireland) DAC, Block B, Liffey Valley Office Campus, Dublin 22.

Tel: +353 1 609 7100.

TRIXEO and AEROSPHERE are trademarks of the AstraZeneca group of companies.

Date of API preparation: 07/2021 Veeva ID: IE-2842

Adverse events should be reported directly to; HPRA Pharmacovigilance, Website: www.hpra.ie Adverse events should also be reported to AstraZeneca Patient Safety on Freephone 1800 800 899

1. TRIXEO AEROSPHERE 5 micrograms/7.2 micrograms/160 micrograms pressurised inhalation, suspension. Summary of Product Characteristics. Available at www.medicines.ie

2. Rabe KF et al. Triple inhaled therapy at two glucocorticoid doses in modeate-to-very-severe COPD. N Engl J Med. 2020;383:35–48. doi: 10.1056/ NEJMoa1916046 COPD. N Engl J Med. 2020;383:35–48. doi: 10.1056/NEJMoa1916046

European Respiratory Society 2021 International Congress

Priscilla Lynch provides a round-up of some of the most topical research presented at this year’s European Respiratory Society (ERS) 2021 International Congress, which took place online from 5-8 September

Artificial intelligence could help diagnose lung cancer a year earlier

An artificial intelligence (AI) programme can spot signs of lung cancer on CT scans a year before they can be diagnosed with existing methods, according to research presented at the European Respiratory Society (ERS) 2021 International Congress.

Lung cancer is the most common cause of cancer death with around 1.8 million lives lost around the world each year.

Researchers hope that using AI to support lung cancer screening could make the process quicker and more efficient, and ultimately help diagnose more patients at an early stage.

Trials using CT scans to screen people with a high risk of lung cancer have shown promise, however screening is hampered by the practical difficulty of a radiologist reviewing each image, one at a time, to decide who needs further tests.

The new study was presented by Benoît Audelan, a researcher from France’s National Institute for Research in Digital Science and Technology at Université Côte d’Azur.

The researchers trained their AI programme using a set of CT scans from 888 patients that had already been examined by radiologists to identify suspicious growths. Then they tested it on different set of 1,179 patients who were part of a lung screening trial with three year follow-up, using CT scans that were taken in the last two years of the trial. These included 177 patients who were diagnosed with lung cancer via a biopsy after their final scan in the trial.

The programme identified 172 of the 177 malignant tumours in those CT scans, meaning it was 97 per cent effective in detecting cancers. The five tumours that the programme missed were near the centre of the chest, where tumours are harder to distinguish from healthy parts of the body.

Researchers also tested the programme on scans taken a year before the tumours were diagnosed in the same 1,179 patients and it was able to identify 152 suspicious areas that were later diagnosed as cancer.

However, researchers say the programme also identifies too many suspicious areas that are not cancer (false positives) and

this would need to be vastly improved before the programme could be used in the clinic because investigating all these would result in unnecessary biopsies.

The researchers plan to work on a new system that will be better able to differentiate between malignant and nonmalignant tissue to help radiologists decide which patients should be investigated further.

Commenting on the findings, Prof Joanna Chorostowska-Wynimko, ERS Secretary General and a Consultant in Respiratory Medicine at the National Institute of Tuberculosis and Lung Diseases in Warsaw, Poland, said: “Diagnosing lung cancer earlier is vital to improving survival rates and screening would be an important step towards that aim. Research shows that screening with CT scans could reduce lung cancer deaths.

“This work is promising because it shows that AI could help us to review lots of scans quickly and even pick up signs of cancer at an earlier stage. However, before this programme can be used, researchers will need to make it better at distinguishing between lung tissue that is abnormal but benign and tissue that is probably cancer.”

Overweight and obesity may affect asthmatic children’s response to inhaled steroids

Asthmatic children are less likely to respond to inhaled steroid medication if they are overweight or obese, and this leads to more frequent asthma attacks, according to research presented at the virtual 2021 ERS International Congress.

The international study is the first to use information on genetic variants linked to body mass index (BMI) to investigate if a poor response to inhaled corticosteroids (ICS) is likely to be due to excess weight or to other factors, such as living in neighbourhoods with poor air quality or being exposed to cigarette smoke.

Study author Dr Cristina Longo, assistant professor at the University of Montreal, Quebec, Canada, said: “We know that children with asthma, whose symptoms are poorly controlled, tend to gain weight. This is possibly because they exercise less. Children with asthma who are overweight or obese are more likely to have worse symptoms despite being on the recommended treatment of inhaled corticosteroids, making it not only challenging to achieve a healthy weight, but also to improve their quality-of-life.

“Treatment guidelines recommend steroids for children with asthma who have a higher-than-normal BMI. Our research group felt that the one-size fits-all approach to treating children with asthma with inhaled steroids as their first-line treatment, particularly those with excess weight, warrants revision. At the very least, research identifying potential alternative treatments should be encouraged and prioritised, especially since 30 per cent of children with asthma are also obese. With the childhood obesity epidemic rising, we expect this percentage to increase meaning this problem of poor control will be seen more frequently in routine clinical practice.”

Dr Longo and colleagues used data on 1,511 children with asthma, aged between two and 16 years, from five studies. All the children were using ICS and a poor response was defined as one or more asthma attacks requiring urgent medical care and/or a course of oral corticosteroids.

The researchers developed a ‘risk score’ (BMI z-score) where the more BMI-related genetic variants a child had, the higher their score, which was used to predict increases and decreases in the children’s BMI z-scores and evaluate differences between the children in how they responded to ICS.

However, whether alternative treatments, like biologicals, are more effective in this subgroup of children remains to be investigated.

“For children and their parents, our results shed light on the reasons why some children may not be responding to their steroid inhaler as expected, especially if they are having more frequent asthma attacks than expected after starting this therapy. Our results might also be the catalyst that parents and their children need to modify their diet and increase exercise. This might improve the child’s BMI status and their response to inhaled steroids.”

In a related presentation to the meeting, Dr Longo investigated whether genetic variants previously shown to be associated with poor ICS response were more common in obese versus non-obese children with asthma.

“In the 1,511 children with asthma who were taking ICS, the average BMI z-score was 0.69 and 318 (21 per cent) were obese. Although poor ICS response ranged from 20-to-80 per cent between the five international studies, we consistently show that the proportion of children with poor ICS response more than doubled for each one unit increase in the BMI z-score,” she said.

“These results suggest that clinicians need to take a more personalised approach to treating overweight and obese children. Paediatricians and asthma specialists need to be aware that children with higher BMI could be taking ICS without any benefit.

“We found that a particular variant in the NEGR1 gene was significantly more common in obese versus non-obese children. This variant has been implicated in dysfunction of a hormone called leptin that regulates feelings of hunger. This could suggest that leptin dysfunction could be a potential culprit for poor ICS response in children with obesity-related asthma,” she said.

Commenting, Prof Chris Brightling, Chair of the ERS Science Council and Professor of Respiratory Medicine at the University of Leicester, UK, said: “This is very good and fascinating research with findings that are important and novel. It sheds light on the complex interplay between genes, weight, and response to inhaled corticosteroids, underscoring the need to combine drug treatments with lifestyle and diet modifications. Policymakers, healthcare providers and families need to do much more to tackle the growing obesity epidemic in young people.”

...research identifying potential alternative treatments should be encouraged and prioritised, especially since 30 per cent of children with asthma are also obese

E-cigarettes containing nicotine cause blood clotting and make small blood vessels less adaptable

Using e-cigarettes containing nicotine causes an immediate increase in the formation of blood clots and a deterioration in the ability of small blood vessels to expand and dilate, as well as raised heart rate and blood pressure, according to research presented at the 2021 ERS International Congress.

Researchers say these effects are similar to those caused by smoking traditional cigarettes and with long-term use, they could result in heart attack or stroke.

The study was presented by Gustaf Lyytinen, a clinician at Helsingborg Hospital and researcher at the Karolinska Institute in Stockholm, Sweden. He and his colleagues carried out detailed experiments with a group of 22 women and men aged between 18 and 45 years who were occasional smokers but otherwise healthy.

The participants inhaled 30 puffs of e-cigarettes with or without nicotine

with a wash-out period of one week. Blood samples were collected at baseline, 15 and 60 minutes following exposure and analysed with the Total-Thrombusformation analysis system. Two different chips, simulating fibrin-rich thrombus formation and platelet thrombus formation, were used. Microcirculation was assessed at baseline and 30 minutes after exposure to evaluate the endotheliumdependent and -independent pathways.

E-cigarettes exposure with nicotine had several impacts. There was an average 23 per cent increase in blood clots after 15 minutes that returned to normal levels after 60 minutes. There were also increases in volunteers’ heart rates (from an average of 66 beats per minute/bpm to an average of 73bpm) and blood pressure (from an average of 108 millimetres of mercury/mmHg to an average of 117mmHg). Researchers found that the volunteers’ blood vessels became temporarily narrower after they used nicotine-containing e-cigarettes.

These effects were not seen after volunteers used e-cigarettes that did not contain nicotine.

Dr Lyytinen said: “Our results suggest that using e-cigarettes that contain nicotine have similar impacts on the body as smoking traditional cigarettes. This effect on blood clots is important because we know that in the long-term this can lead to clogged up and narrower blood vessels, and that of course puts people at risk of heart attacks and strokes.”

Prof Jonathan Grigg, Chair of the ERS Tobacco Control Committee and Professor of Paediatric Respiratory and Environmental Medicine at Queen Mary University of London, UK, said: “E-cigarettes are relatively new, so we know much less about what they do to the body. This is a small study, so we’d like to see more research looking at these effects.”

Modest differences in lung function could help spot people at risk of sudden cardiac death

People who have modestly, but measurably worse lung function are more likely to suffer sudden cardiac death (SCD), according to research presented at the 2021 ERS International Congress.

Researchers hope their finding could help spot people at risk of SCD and prevent deaths in the future.

The study was presented by Dr Suneela Zaigham, a researcher at the Department of Clinical Sciences –Cardiovascular Epidemiology at Lund University, Sweden.

Dr Zaigham and her colleagues studied a group of 28,584 middle-aged people with no known heart problems who were living in Malmö, Sweden. All took part in spirometry tests. Over the following approximately 40 years, researchers recorded any SCDs (death on the day of a coronary event) or any non-fatal coronary events (coronary events where people survived the first 24 hours)

They found that measurably lower lung function in middle-aged people (one standard deviation lower in the amount of air they could blow out in one second,

which equates to around 0.8 litres) was more strongly related to suffering SCD (a 23 per cent increase in risk) than a non-fatal coronary event (an 8 per cent increase in risk) later on in life.

Smoking is known to affect both lung and heart health, however the pattern of risk remained even in people who had never smoked.

Dr Zaigham said: “We believe this is the first study to directly compare the risk of sudden cardiac death and non-fatal coronary events and their links with lung

function in the general population.

“Our findings suggest that testing people’s lungs when they are middle-aged and healthy could help spot those who have a higher risk of sudden cardiac death. This could enable people to take steps to potentially reduce the risk of

this devastating event.”

A potential weakness in the study is that the tests and questionnaires all took place at the start of the study and many risk factors could have changed in the intervening years.

The researchers hope to continue their

work by looking at whether SCD could be prevented by testing lung function as part of current cardiovascular risk assessment. They also want to investigate the link between lung function and SCD further to see if heart abnormalities, variable blood pressure or genetic susceptibility to poorer lung function are involved.

Hotter

weather

is linked to notable increase in COPD exacerbations

Warmer weather is linked to a worsening of chronic obstructive pulmonary disease (COPD) symptoms, according to research presented at the 2021 ERS International Congress.

Analysis of data from 1,177 current and former smokers with COPD in the US showed that approximately two days after an increase in ambient temperatures, there was an increase in COPD exacerbations.

Dr Supaksh Gupta, a pulmonary and critical care fellow at the University of Washington, US, told the Congress: “We found that each one-degree Celsius increase in ambient temperature was associated with a 2 per cent increase in the likelihood of COPD exacerbations in the following two days among this group of patients.

“This study is one of the few to explore the impact of ambient temperature on the risk of COPD exacerbations in a group of people with established COPD for whom we have detailed medical information. Overall, it contributes to the emerging body of knowledge regarding ambient temperature and risk of COPD-related health problems. A major strength of the study is the number of people included, who live in various major US towns and cities.

“Other studies have shown a connection between extreme heat exposure and increased risk of health problems and death in people with COPD. There are concerns that these problems will accelerate with

the ongoing and worsening climate crisis. Therefore, it is important to quantify the health risks associated with changes in ambient temperature, while also determining who is most at risk to inform policy-makers and healthcare providers.”

Dr Gupta and colleagues looked at current and former smokers who had enrolled in the SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS) between 2010 and 2015, and who had had at least one COPD exacerbation since joining the study. They assessed the risk of COPD exacerbations based on local, ambient temperatures recorded on the day of the exacerbation and in the preceding seven days.

The average age of the participants was 64 years and the average time to the first exacerbation was 603 days. The risk of exacerbations increased with increasing temperatures during the preceding six days, with the highest risk two days after temperatures rose. The researchers were able to adjust their results to take account of humidity levels, which have been implicated in the risk of exacerbations.

“Our findings raise concerns about the risk of increased exacerbations with climate change. While not conclusive, the study suggests that those living with COPD may want to avoid exposure to adverse and extreme environmental conditions by limiting outdoor activities during periods of elevated temperatures relative

to normal. Moreover, while not within the scope of this paper but based on previously existing literature, those who reside in areas with increased temperature, or increased temperature variability, may benefit from access to indoor air cooling,” said Dr Gupta.

The mechanisms involved in the link between heat and COPD exacerbations are not entirely understood, but may include hyperventilation, which increases the possibility of ‘dynamic hyperinflation’, where a person does not exhale completely before starting to inhale again. This can lead to less efficient and effective breaths. At its extreme, dynamic hyperinflation could lead to increased pressure in the chest cavity and a subsequent decrease in blood flow back to the heart. Elderly patients are also less able to adjust their body temperatures and maintain adequate hydration. Additionally, some asthma studies have suggested that breathing hot, humid air can result in constriction of the airways.

Dr Gupta concluded: “I wanted to contribute to research involving a disease process that affects the lives of many of my patients. My goal is to help inform our understanding of the ongoing climate crisis on healthcare outcomes and utilisation. I hope our research will help guide public policy recommendations and promote health precaution guidelines for people with COPD during periods of increased ambient temperature.”

Lung function appears to be unaffected after Covid-19 infection in young adults

Covid-19 infection does not appear to affect the lung function of young adults, according to new research presented at the 2021 ERS International Congress.

In the first study to investigate the impact of Covid-19 infection on lung function, researchers led by Dr Ida Mogensen, a post-doctoral fellow at the Karolinska Institute, Stockholm, Sweden, found that even patients with asthma did not show a statistically significant deterioration in lung function, although there was a trend towards slightly lower measurements for the amount of air they could exhale forcibly in one second (FEV1).

A second study presented at the Congress

showed that the lung function in children and adolescents was also unimpaired after Covid-19 infection, apart from those who experienced a severe infection.

Dr Mogensen said: “The Covid-19 pandemic has raised questions about if and how the lung is affected after clearance of the coronavirus infection, especially in young people from the general population with less severe disease. Until now, this has not been known.”

Dr Mogensen and her colleagues gathered information from 661 young people with an average age 22 years who were part of a large follow-up study that enrolled children born between 1994

and 1996 in Stockholm. The most recent pre-pandemic clinical examination was carried out between 2016 and 2019. The examinations at the Covid-19 followup took place between October 2020 and May 2021. Collected data included measurements of lung function, inflammation and white blood cells called eosinophils, which are part of the immune system.

Of the 661 participants, 178 (27 per cent) had antibodies against SARS-CoV-2 indicating they had been infected. The researchers measured FEV1, FVC (forced vital capacity), and FEV1 /FVC ratio, which is an indicator of narrowed airways.

“Our analysis showed similar lung 

function irrespective of Covid-19 history,” said Dr Mogensen. “When we included 123 participants with asthma in the analysis, the 24 per cent who had had Covid-19 tended towards having a slightly lower lung function, but this was not statistically significant.”

There was no difference in lung function among patients who had had Covid-19 with respect to eosinophils, indicators of inflammation, allergy responses or use of inhaled corticosteroids.

“These results are reassuring for young adults. However, we will continue to analyse data from more people. In particular, we want to look more closely at people with asthma as the group in this study was fairly small. We are also curious as to whether the length of time after the infection is important, as well as the severity of disease and symptoms.”

The second study, presented by Dr Anne Schlegtendal, a specialist in paediatric and adolescent medicine and paediatric pulmonology at University Children’s Hospital, Ruhr-University-Bochum, Germany, looked at the long-term effects of Covid-19 infection between August 2020 and March 21 in 73 children and adolescents aged between five and 18 years.

She and her colleagues carried out lung function tests between two weeks and six months following Covid-19 infection and compared the results with a control group of 45 children who had not been infected with the coronavirus but may have had some other infection. The participants had different severity of disease. An infection was considered severe if patients suffered breathlessness, a fever above 38.5 degrees Celsius for more than five days, had bronchitis, pneumonia or stayed in hospital for more than a day.

Nineteen children and adolescents in the Covid-19 group had persistent or new symptoms following SARS-CoV-2 infection; eight reported at least one respiratory symptom; six of whom suffered

ongoing breathing problems, and two had a persistent cough. Two of these eight patients showed abnormal lung function.

“When we compared the Covid-19 patients with the control group, we found no statistically significant differences in the frequency of abnormal lung function. They occurred in 16 per cent of the Covid-19 group and 28 per cent of the control group. However, further analysis revealed a reduction in the volume of air in the lungs that can be exhaled after a deep breath – forced vital capacity – in patients who had suffered a severe infection, whether Covid-19 or some other infection,” said Dr Schlegtendal.

“These findings should offer some reassurance to children, adolescents and their families. Severity of infection proved to be the only predictor for mild lung function changes and this is independent of a Covid-19 infection. The discrepancy between persistent breathing problems and normal lung function suggests there may be a different underlying cause, such as dysfunctional breathing, which is a problem that has also been identified in adults.”

Limitations of the study include the small number of participants, the fact that they were recruited at a single hospital, that patients self-reported their symptoms, and a lack of information on long-term outcomes in the control group. In addition, the Covid-19 group did not include those with severe breathing problems during the acute phase of the infection.

Prof Anita Simonds, who was not involved in the research, President of the ERS, Honorary Consultant in Respiratory and Sleep Medicine at Royal Brompton Hospital, and Professor of Respiratory and Sleep Medicine at NHLI, Imperial College London, UK, said: “The findings from these two studies provide important reassurance about the impact of Covid infection on lung function in children and young adults.”

Asthma can be caused by office work, but finding and tackling the cause can keep employees in work

New research presented at the 2021 ERS International Congress suggests that the seemingly innocuous environment of an office can cause asthma in some workers.

The study found a variety of triggers from printer toner and cleaning products to poor ventilation and mould circulating in air conditioning. It also found that employees with asthma brought on by office work left their jobs and, if employers did not make changes to tackle the problem, this was more common.

Researchers say that their work provides another reason for allowing home working to continue beyond Covid-19 restrictions, to benefit office workers’ health and help businesses retain staff.

The study was presented by Dr Christopher Huntley, from Birmingham Regional Occupational Lung Disease Service, UK. He said that any work environment can induce occupational asthma if it harbours a respiratory sensitiser.

“We usually think of an office as a safe environment, so it’s possible that when asthma is diagnosed in office workers, occupational causes may be overlooked. As a result, there has been very little research on this issue.

“However, we have been diagnosing increasing cases of occupational asthma in patients who work in office environments, as well as detecting clusters of cases in specific offices.”

Dr Huntley and his colleagues studied the cases of 47 office workers

with occupational asthma that had been reported to the Birmingham Regional Occupational Lung Disease Service. The majority had had their asthma confirmed by serial peak flow monitoring, and 17 of the patients had also been tested and found to have lungs that react strongly to a test for sensitive airways.

Dr Huntley said: “Although we only looked at the patients who were referred to our service and this is a relatively small study, it is still one of the largest studies reporting occupational asthma in office workers. We discovered some key causes to be aware of in an office environment, but there will certainly be others.

“If a worker develops occupational asthma, workplace adjustments can and should be made to improve asthma symptoms and help retain staff.”

The researchers identified three main categories that were causes of occupational asthma in the office workers. These were triggers found inside the office (printer toner, floor tile adhesive, mould, and cleaning products), triggers coming from the office ventilation system (mould in air conditioning and ventilation shafts that had been installed incorrectly), and triggers from the office’s immediate environment (nearby workshops, paint and vehicle fumes).

They also investigated whether employers made any adjustments to support office workers with occupational asthma and what workers did as a result. Their most striking finding was that when employers failed to act, workers were 100 times more likely to quit their job.

Dr Huntley says that there have been fewer new referrals for patients with occupational asthma during Covid-19 restrictions and that those already suffering with occupational asthma have seen improvements while working from home. He adds: “Working from home has been useful for patients in both establishing their diagnosis and as a form of non-pharmacological treatment. Allowing workers with occupational asthma to continue working from home may help keep office workers in their jobs as they require fewer sick days.”

Commenting on the findings, Prof Arzu Yorgancıo ğ lu, Chair of the ERS Advocacy Council and Professor in Pulmonology at Celal Bayar University, Turkey, said: “For office workers with asthma who experience an unexplained deterioration in their symptoms, this study highlights the importance of identifying and removing any potential occupational triggers. Where we see clusters of work-related asthma in offices it is vital to investigate the underlying cause, as the causes may be surprising.” ■

Allowing workers with occupational asthma to continue working from home may help keep office workers in their jobs as they require fewer sick days

New National Clinical Effectiveness Guideline on chronic obstructive pulmonary disease

AUTHOR: Priscilla Lynch

The National Clinical Effectiveness Committee has published a new National Clinical Guideline on the Management of chronic obstructive pulmonary disease (COPD).

This new guideline was developed by a multidisciplinary guideline development group supported by the HSE National Clinical Programme for Respiratory Medicine, and chaired since 2020 by Dr Desmond Murphy, and previously by Prof Tim McDonnell.

This guideline outlines the best practice care and services for people with COPD or at risk of developing COPD. This guideline will help healthcare workers provide care based on the best available evidence. NCEC National Clinical Guideline No 27 was quality assured by the Department of Health’s National Clinical Effectiveness Committee (NCEC).

COPD is the most prevalent respiratory disease in adults and is a major cause of morbidity and mortality for patients in Ireland. At least 1,500 patients die each year of this disease and over 15,000 patients are admitted to hospital with COPD in Ireland.

COPD has considerable impact on the quality-of-life of the patient, families, and carers, involving ongoing medical care, frequent hospital admissions for treatment of exacerbations, and often resulting in premature death.

The development of this national clinical guideline for COPD is a major step forward in that it will ensure that COPD patients across the country receive consistent and standardised care, based on the best available evidence, according to the Department.

This document has been written with the intention of providing assistance to healthcare professionals in all healthcare settings when assessing and managing COPD,

by outlining evidence-based treatment protocols. In doing so, it also aims to assist policy makers and those planning services for COPD patients. It covers the full spectrum of care provided in hospitals and in the community.

The Model of Care for COPD outlined in this document details how physicians, nurses, physiotherapists, and other healthcare professionals will work with patients to make the clinical decisions most appropriate to a patient’s circumstances. It is envisaged that this will facilitate self-management by patients at home through their empowerment and by promoting collaboration with and between specialist healthcare professionals in providing optimal care.

Specifically, the key aims are to:

 Prevent or delay the onset of COPD;

 Improve the delivery of care to people with COPD across all levels of care; and

 Save the lives of people with COPD.

Through the implementation of the end-to end COPD Model of Care, the Irish health service will be ensuring that the right care is delivered to people with COPD at the right time and in the right place.

Dr Desmond Murphy, Chair of the Guideline Development Group and Clinical Lead, HSE National Clinical Programme, Respiratory, commented that: “The NCEC document for COPD represents the culmination of a lot of work, by a lot of people to develop a framework to support the provision of optimal care for COPD patients in Ireland. The document has been reviewed by multiple different elements within the Irish healthcare provider system and also by patient advocacy groups, with feedback incorporated. Furthermore, it has been reviewed by recognised international experts in COPD. It is a pleasure to see the document

launched. I believe this represents significant progress for patients with COPD in Ireland.”

COPD impact

The guideline notes that Ireland has the highest rate of hospitalisation for COPD of all OECD countries. In 2015 (the latest year for which OECD data are currently available), the age-standardised hospitalisation rate in Ireland based on OECD age-standardisation equated to 367 per 100,000 population. The national age-sex standardised hospitalisation rate for COPD increased slightly between 2009 and 2018, with 354 hospitalisations per 100,000 population in 2018 compared with 303 hospitalisations per 100,000 population in 2009. Most countries in the OECD have reported a reduction in hospitalisation rates for COPD over recent years, perhaps as a result of improvements in access to, and the quality of, primary care. As in previous years, the OECD reported that Ireland had the highest age-sex standardised hospitalisation rate for COPD in 2015. While Ireland’s average rate has decreased from 379 hospitalisations per 100,000 population in 2005, to 367 in 2016, the OECD average also declined (214 to 187).

In Ireland during the three-year period from 2016-2018, the age-sex standardised hospitalisation rate by county of residence ranged from 242 hospitalisations per 100,000 population in Kerry to 552 hospitalisations per 100,000 population in Offaly. Episodes of care with a primary or secondary diagnosis of COPD accounted for almost 12 per cent of inpatient bed days in adult acute hospitals in Ireland in 2016, among adults aged 35 years and older, so the burden of COPD on our hospital system is significant and needs to be further addressed. ■

The full guideline is available at: www.gov.ie/en/publication/5df41-nationalclinical-guideline-no27-management-of-chronicobstructive-pulmonary-disease-copd/

Promoting ‘respiratory health values’ in the era of Covid-19

AUTHOR: Paul Mulholland

It had been hoped, until recently, that the 2021 Irish Thoracic Society (ITS) Annual Scientific Meeting on 19 November would be a face-to-face event. However, according to Dr Michael Henry, Consultant Respiratory Physician, Cork University Hospital (CUH), the ITS believed this was too great a risk given the deteriorating Covid-19 situation in the country. Instead, the meeting, which will feature an impressive range of speakers, will be held virtually for the second year running.

Covid-19, of course, is not just still affecting educational meetings, but the day-to-day working lives of medical professionals across the country. Dr Henry told Update that three specialties have been most negatively impacted by the current crisis: Infectious disease; intensive care; and respiratory medicine.

“And all three services, particularly respiratory and intensive care – you see it on the news every day – are struggling badly,” he said.

Advocating for patients

One of the key roles of the ITS, especially at the current time, is to advocate for patient safety. In terms of Covid-19, this includes the promotion of healthcare guidelines, such as handwashing and mask-wearing. It also means agitating for more resources for the specialty and the protection of staff working in respiratory medicine. Regarding the latter, the ongoing roll-out of booster Covid-19 vaccines for healthcare workers is “massively important”, according to Dr Henry.

“Most healthcare workers are young and healthy and they are not going to get very sick,” he said.

“But they will be off work. And if they are off work from a service that is already struggling, then you are really going to struggle to provide services for everybody with respiratory disease. So we need to highlight that as much as we can.”

Covid-19 has had a direct impact on the staff working in the respiratory medicine department in CUH. Dr Henry himself was diagnosed with Covid-19 in January, and two of the other three respiratory medicine consultants have also been infected.

“All of the registrars have had it,” Dr Henry said. “None of us have been particularly sick – some have been a little sicker than others – but you’re off, you’re gone. The service is dead when you’re off.”

The department has been struggling not only in terms of staff, but also due to a lack of resources. Dr Henry has not seen

much evidence in CUH of the additional funding that has been released to cope with the pandemic.

“The extra resource that has been put in to deal with Covid amounts to one Covid ward that is staffed to just look after Covid patients,” he said.

“But you have no choice but to do that. Every hospital has to have an isolation ward where Covid patients go. Other than that, access to extra staff, diagnostics, treatment, I would say if anything has gotten worse, not better, over the last 12 months.”

Covid-19 impact on respiratory services

While Dr Henry said the effect of the cyber attack on the HSE was as bad, if not worse, than the pandemic, services for other conditions have been “devastated” over the past year-and-a-half because of Covid-19. To take one example: CUH’s pulmonary function laboratory has only worked at approximately a quarter of its capacity since the Covid-19 crisis began. This is due to a range of factors, such as the emergency department appropriating part of the workspace, the greater need for sterilisation, and the safety concerns of staff.

“The knock-on effect of it all is that we get less than a quarter of the number of tests done that we need to get done,” he told Update.

“So if you have a lung cancer patient who needs an urgent part of their lung removed, we can’t get it done for weeks. It shouldn’t be holding process at all. Also, I run a lung fibrosis clinic that

Dr Michael Henry

I’m doing this afternoon. I would have 20-something patients coming; most of them should have had their pulmonary function tests done. I would say I’d be lucky if three or four have them done. This is how you monitor if patients are getting better or worse. Most of it, not all of it, is down to Covid. That has a huge impact on how we manage all of these complex respiratory patients.”

The department’s outpatient space was also appropriated at the beginning of the pandemic. As a result, respiratory outpatient consultations have moved off-site, and now take place in a local convent.

“The facility is just really poor, and not fit for an outpatient service. And that is the direct result of the other area that was previously used now being taken for Covid pathways. To put it mildly, it has devastated our service here. It will be different in different hospitals. But I’m sure everybody will tell you the same thing. It is having a huge effect on how we are running our service. We are not running our service very well because of this.”

ITS meeting

While there is disappointment about not having a face-to-face event, Dr Henry said the ITS meeting is still crucial in having members come together, albeit virtually, and hear about the latest developments in their fields.

“Because very few of us have had the opportunity to travel to international educational meetings [during Covid-19],” he explained.

“There’s been no opportunity really. Some of it has been online and we have been trying to keep up-to-date. But it is critical for our own continuing development in medical education that we have these programmes coming online or face-to-face regularly so we can keep up-to-dateas to what is going on.”

Dr Henry emphasised the annual meeting has arranged “great speakers”, both national, and international.

On the national side, Prof Cormac McCarthy, Consultant Respiratory Physician, St Vincent’s University Hospital, Dublin, will speak about diffuse cystic lung diseases.

“That’s going to be really good; he is a world leader in that area,” commented Dr Henry.

The meeting will also hear from Prof John Cryan, Professor and Chair, Department of Anatomy and Neuroscience, University College Cork. The title of Prof Cryan’s talk is ‘Gut microbiome: Our inner friends with benefits’.

who will speak about bronchoscopic interventions for COPD and chronic bronchitis. Both are world leaders in their respective fields.

According to Dr Henry, one of the highlights of the meeting will be a talk on lung cancer screening to be delivered by Prof Harry de Koning, Professor of Public Health and Screening Evaluation, Erasmus University Medical Centre, Rotterdam, Netherlands. The title of the lecture is ‘Implementation of lung cancer screening: Prime time!’.

“There is a lot of work around the world on screening for lung cancer,” according to Dr Henry.

“And clearly that is really topical. It hasn’t really reached prime time in Ireland yet. He [Prof de Koning] is one of the leads in a very big European lung cancer screening trial. And he is going to bring us up to date on that. And hopefully that will push the agenda in Ireland on screening for lung cancer in the same way we screen for breast cancer, colon cancer, etc. We don’t, as of yet, have that programme here. But I think these types of people speaking in Ireland to Irish audiences will help promote that.”

“If you know anything about the Department [of Anatomy and Neuroscience] here in Cork, it is one of the top five international research centres in the world. He is looking at the gut microbiome and its effect on the lung. That might sound very highfaluting, but I think that is going to be very exciting for us.”

The international speakers include Prof Thierry Troosters, Professor in Rehabilitation Sciences, KU Leuven, who will speak about pulmonary rehibition; and Prof Dirk-Jan Slebos, Professor of Interventional Pulmonology, University Medical Centre Groningen, Netherlands,

In conclusion, Dr Henry said the huge challenges in dealing with the pandemic makes events such as the ITS Annual Scientific Meeting particularly important.

“I think it is really critical for health workers that we all, at least, have the chance to get together, even if it is virtually. That we get a chance to meet as a community to try and keep a certain degree of solidarity going, encourage each other, and promote, not just Covid research and development, but other areas as well. Because it is important, as a respiratory community, that we don’t lose touch with each other in this era of Covid; that we stay in touch, and try to promote proper respiratory health values in the situation we find ourselves in.” ■

To put it mildly, [Covid-19] has devastated our service here. It will be different in different hospitals. But I’m sure everybody will tell you the same thing

Long Covid: Navigating uncharted waters

Dr Abhilash

With the Covid-19 pandemic evolving into an endemic strain, there is a growing urgency to look beyond Covid-19 mortality figures to morbidity related to the increasing number of patients with ongoing symptomatic sequelae from acute SARS-CoV-2 infection. Clinical experience following the MERS and SARS coronavirus outbreaks meant a high likelihood of significant chronic symptomatology following the current novel coronavirus infection. Studies have already shown a higher probability of prolonged symptoms post-Covid when compared to MERS, SARS or influenza. In one study looking at 270,000 survivors, 42 per cent had at least one symptom six months after acute Covid-19 infection compared with 30 per cent of postinfluenza patients. The constellation of prolonged symptoms is referred to as ‘long Covid’ or post-acute sequelae of SARS-CoV-2 infection (PASC).

To date, over 500,000 people in Ireland have been diagnosed with Covid-19 (HPSC data, Nov 2021). Long-term follow-up data is increasingly robust and confirms that long Covid/PASC phenomena are increasingly recognised. Several definitions have been proposed for long Covid, including the presence of any symptom one, two, five or six months after an acute, objectively confirmed or clinically likely Covid-19 infection. For this review, we have focused on studies that include symptoms at six months.

Current evidence

The growing body of long Covid research suggests the current number of patients attending post-Covid follow-up is only the tip of the iceberg. The most extensive systematic review to date of 57 studies

looking at 250,000 Covid survivors showed that one-in-two patients had evidence of PASC, especially pulmonary, mental health, and neurologic disorders. Fatigue was frequently the most common, most severe and most prolonged symptom. 2 PASC was frequently not related to the severity of the initial acute infection. A similar prevalence has been reported amongst patients managed in community and hospital settings.

The most common respiratory problems were dyspnoea, cough, and increased oxygen requirements. Chest imaging abnormalities were surprisingly common, with a median of 62.2 per cent. Despite

this, the absence of thoracic imaging abnormalities does not rule out long Covid. Cardiac symptoms mainly were chest pain and palpitations. Reassuringly, long-term structural cardiac damage occurred rarely.

Critical aspects of executive cognitive function can remain impaired more than six months post-Covid in another study. Abnormalities studied included impairments in processing speed, category fluency, memory encoding, and recall, which could explain the ‘brain fog’ typically described by survivors.

Autonomic dysfunction was highlighted in 14 of 675 patients with PASC from the UK. This is a rare feature not mentioned in the earlier JAMA review. Patients in this UK study were referred to a cardiovascular autonomic specialist clinic for definitive diagnosis and follow up. 6

Reassuringly, a longitudinally planned study from Holland showed most patients did report a gradual improvement in all organ systems affected. However, a significant number of persisting

AUTHORS:

Sahadevan, Consultant in Respiratory Medicine, and Prof Seamus Linnane, Consultant in Respiratory Medicine, Beacon Hospital, Dublin

FIGURE 1: Blood plasma from healthy controls contrasted to patients with long Covid (credit E Pretorious)

HEALTHY BLOOD PLASMA

MICRO-CLOTS IN PLASMA FROM AN INDIVIDUAL WITH LONG COVID

The growing body of long Covid research suggests the current number of patients attending postCovid follow-up is only the tip of the iceberg

symptoms remained at six months. 3 More data is awaited from ongoing prospective studies with longer follow-up periods, including the CO-FLOW Dutch trial, which is following a cohort of more than 500,000 patients for up to two years after acute infection.

PASC/long Covid symptoms

 Breathing difficulties/dyspnoea;

 Fatigue/malaise;

 Chest/throat pain;

 Headache;

 Abdominal symptoms;

 Myalgia;

 Cognitive symptoms;

 Anxiety/depression.

Pathobiology and pathophysiology

It remains unclear why long Covid occurs. In the Erasmus study, it was noted that Covid survivors had a sustained humoral response after Covid-19 infection.

Anti-SARS-CoV-2 IgM antibodies were detectable in 36 per cent of patients at six months, and 78 per cent of this same cohort had already been noted to have IgM antibodies at six weeks. Hence there was a gradual reduction between six weeks and six months. Initially, antiSARS-CoV-2 IgM was used as a marker of acute infection. The significance of these antibodies in patients’ circulation so long after the acute infection has yet to be delineated, but could fit the narrative explaining long Covid as a sustained critical inflammatory response. A prospective cohort study also showed PASC at six months was associated independently with increased convalescent anti-SARS-CoV-2 spike IgG titres and micro-neutralising antibody titres compared with levels at two months post-acute infection.

Micro clotting similar to that initially noted in acute Covid-19 has been suggested in long Covid. Plasma from patients with PASC contains both microclots and high levels of inflammatory proteins (see Figure 1). The direct effect of these inflammatory proteins and excess fibrinogen in long Covid patients is under investigation. 5

Autopsy studies of cerebral tissue from Covid-19 fatalities have highlighted microvascular brain damage characterised by increased dead capillaries, also known as string vessels (see Figure 2). Using non-Covid-19 control samples, an increase was seen in proteases cleaving NEMO, an endothelial protein found in the brain.7 In another study of 40 patients with neurological PASC, corneal confocal microscopy identified corneal small nerve fibre loss (see Figure 3) and increased dendritic cell density in the eyes.1

Diagnostic criteria including investigations

There is currently a wide variation in how long Covid is investigated. Due to extensive symptoms and variable clinical presentations, a clinic exclusively dealing with long Covid is recommended and has been established at the Beacon Hospital, Dublin, and other centres nationally. Patients should be triaged before arrival, either via electronic or paper form-based assessment, to best investigate and manage individual symptoms. This preconsultation evaluation can also direct the need for subspecialist referrals. Considering the increased frequency of neuropsychiatric PASC, routine screening for depression, anxiety and post-traumatic stress disorder (PTSD) is recommended. Current evidence has shown no role for neuroimaging in the event of mental/ cognitive impairments alone. Yet specific symptoms like headache and dizziness might benefit from once-off neuroimaging.

In the absence of parenchymal abnormalities or physiological impairments, dyspnoea should be considered in the context of fatigue, deconditioning or dysfunctional breathing patterns. Hyperventilation syndrome is suspected with a high Nijmegen questionnaire score or positive provocation test using end-tidal Co2 monitoring. Respiratory function is usually preserved. In the event of cardiac symptoms, an ECG and rhythm monitor should be done. Cardiology referral, including

FIGURE 3: Corneal confocal microscopic images of healthy participant (A) and long Covid patient (B) (credit J Wenzel)

FIGURE 2: Dead capillaries (string vessels) indicating cerebral microvascular damage in Covid-19 patients (credit G Bitirgen)

echocardiogram can be considered. The role of cardiac MRI is unclear and currently under investigation.

There potentially could be a role for acute and convalescent paired serologies in differentiating patients with acute infection, re-infection, and long Covid. Significant differentials to consider will be fibromyalgia and chronic fatigue syndrome, which have overlapping presentations.

Management

Management of PASC continues to evolve. Care plans are currently extrapolated from analogous disease states and non-randomised data. The current best practice is a hybrid model of outpatient care facilitating both virtual consultations and inperson reviews. Ideally, the screening assessment is done electronically to plan a tailored individualised consultation.

Turnbull et al describe a framework for establishing a multidisciplinary PASC service mostly built from experiences with post-intensive care syndrome (PISC). 4 It highlights the need for partnership between specialist care and primary care. This partnership has to evolve bi-directional as there is a paucity of longer-term studies on long Covid prognosis. Increasing burdens on primary and hospital outpatients due to Covid-19 restrictions and delayed non-Covid-19 healthcare will contribute to lengthy PASC waiting times as the number of those seeking help increases.

Primary care physicians are more familiar with a patient’s baseline. Hospitals have easier access to complex diagnostic pathways and subspecialist teams. The patient benefits from primary care’s experience coordinating care between multiple specialists, allied health professionals, community therapies, public health nurses and the patient’s family. Hospital-based specialists should liaise closely with GPs to help the patient recover and chart a joint management plan.

Physiotherapy

All long Covid sufferers should be referred to a physiotherapy rehabilitation programme. Physiotherapists in this setting benefit from familiarity with both acute and long Covid or specialist respiratory training. However, many of the principles of long Covid rehabilitation are familiar across the discipline, and workforce considerations may not facilitate subspecialty care. The key goal is to avoid a delay in rehabilitation and progressive deconditioning. Virtual rehabilitation platforms will likely gain popularity for patients not showing evidence of exercise-induced

feedback should be used frequently to help motivate and plot disease trajectory.

If system capacity allows, it is recommended cardiorespiratory demand is also evaluated. Maximal oxygen uptake and lactate thresholds are the gold standard indices; however, various field tests such as the six-minute walk test have been shown to map these parameters. Intermittent measurement of basic cardiac and respiratory function during rehabilitation exercises will help build an understanding of patients’ individual responses to rehabilitation.

cardiorespiratory abnormalities, eg, cardiac ischaemia or exercise-induced desaturation. Physiotherapists are also skilled at screening for respiratory PASC beyond physiological impairments. This can include observing for dysfunctional breathing patterns and hyperventilation syndromes. Hyperventilation syndromes respond well to breathing retraining exercises.

Rehabilitation is initially focused on optimising physical functioning using compensatory strategies. On reaching an exercise plateau, a combination of aerobic exercise and endurance work can help further overcome functional limits. Patients are challenged with increasing intensity of exercises until a supervised overload. The linear progression of a graduated exercise programme is controversial, however. Frequent dips or relapses are common, meaning that exercise tolerance can be variable. Failure to accommodate this variability can be counterproductive and lead to frustration and risk of disengagement. Functional outcome measurements such as walking distance and visual analogue scale

Pharmacological interventions

There are no current evidence-based recommended therapies for long Covid. Pharmacists and other allied health professionals can help by advocating against expensive nonallopathic remedies or cures. Screening for polypharmacy and interactions with prescribed and over-the-counter medications is also helpful.

Social work and employer engagement is crucial as patients are often struggling to return to full-time employment. Inflexible working conditions can hamper recovery as patients cope with the physical and mental sequelae of Covid-19. There is a lack of uniform response as employers come to terms with this emerging clinical syndrome. We find it notable that a sympathetic and engaged employer approach facilitates a speedier return to full employment. Medical support for a graduated return to work is helpful. A hybrid inhouse/work-from-home model with a graduated return to work is most likely to be successful. Returning too early or

Management of PASC continues to evolve. Care plans are currently extrapolated from analogous disease states and non-randomised data

unrealistic expectations on either side risks an unsuccessful return and a more protracted overall absence.

Other resources and websites

 NHS website www.yourcovidrecovery. nhs.uk/

 Ireland covid.recovery@beaconhospital.ie

 Long Covid Ireland Support (Facebook group).

 Long Covid Support group (Facebook group).

 UK-based Long Covid-19 Foundation (Facebook group).

Experimental therapies

A range of therapies has been proposed, including melatonin, opiate antagonists, and even hyperbaric oxygen therapy. Patients are sometimes desperate for help and need guidance on the weight of evidence behind any proposed intervention or scientific merit of an unproven approach.

Despite the benefits of vaccinations in reducing the risk of Covid-19 infection, transmission and mortality, vaccines may not reduce post-Covid-19 morbidity. There are multiple anecdotal reports of sometimes dramatic improvement following vaccination. A six-month follow-

References

1. Bitirgen G, Korkmaz C, Zamani A, et al. (2021). Corneal confocal microscopy identifies corneal nerve fibre loss and increased dendritic cells in patients with long Covid. British Journal of Ophthalmology, bjophthalmol-2021-319450. doi:10.1136/ bjophthalmol-2021-319450

2. Groff D, Sun A, Ssentongo AE, et al. (2021). Short-term and long-term rates of postacute sequelae of SARS-CoV-2 infection: A systematic review. JAMA Netw Open, 4(10), e2128568. doi:10.1001/ jamanetworkopen.2021.28568

3. Hellemons ME, Huijts S, Bek L, et al.

up of vaccinated patients who contracted Covid-19 showed no apparent benefit from being vaccinated in mitigating PASC.

Previous murine modelling has shown that melatonin can reduce lung injury by increasing apelin 13 expression and reducing reactive oxygen species released during lung injury. Melatonin has shown benefits in lowering delirium in intensive care patients. In sleep studies, melatonin is associated with significant improvement in neuropsychological testing and reduced depression and improved sleep. Melatonin is potentially helpful for both neurological and respiratory PASC. There is no substantial evidence to support its routine use at the moment, but it is the subject of several ongoing trials.

Therapies for narcolepsy and chronic fatigue syndrome could also have a role in long Covid sufferers with overlapping symptomatology. A holistic approach is probably the safest, pending evidence supporting newer or repurposed therapies.

The future

The pharmaceutical industry is busy trying to meet this evolving event. The recent European Respiratory Society

(ERS) 2021 International Congress saw promising phase 1a trial results for LYT100, a deuterated form of pirfenidone and phase 2 trials are already in progress for respiratory long Covid. Another dry powder molecule, ASA1125, which has been shown to improve mitochondrial function within the skeletal muscle, will be trialled in patients suffering from muscle fatigue and malaise post-Covid. AT-537, another molecule, is being studied prospectively to evaluate any benefits of the drug on long Covid symptoms after initially being given as an antiviral during acute Covid-19. For now, it appears prevention remains the best bet.

Conclusion

It is essential to follow Covid-19 survivors for as long as they are symptomatic until we understand the true gravity of long Covid. This is a multi-system disease requiring multidisciplinary input. While therapeutic evidence accumulates, patients need significant support and astute use of approaches proven in analogous presentations. ■

Dr Abhilash Sahadevan and Prof Seamus Linnane see long Covid patients at the Beacon Hospital Post Covid Clinic; covid.recovery@beaconhospital.ie

(2021). Persistent health problems beyond pulmonary recovery up to six months after hospitalisation for SARS-CoV-2; a longitudinal study of respiratory, physical, and psychological outcomes. Ann Am Thorac Soc. doi:10.1513/AnnalsATS.202103-340OC

4. Parker AM, Brigha E, Connolly B, et al. (2021). Addressing the post-acute sequelae of SARS-CoV-2 infection: A multidisciplinary model of care. Lancet Respir Med, 9(11), 1328-1341. doi:10.1016/ s2213-2600(21)00385-4

5. Pretorius E, Vlok M, Venter C, et al. (2021). Persistent clotting protein pathology in Long Covid/post-acute sequelae of Covid-19

(PASC) is accompanied by increased levels of antiplasmin. Cardiovasc Diabetol, 20(1), 172. doi:10.1186/s12933-021-01359-7

6. Taylor RR, Trivedi B, Patel N, et al. (2021). Post-Covid symptoms reported at asynchronous virtual review and stratified follow-up after COovid-19 pneumonia. Clin Med (Lond), 21(4), e384-391. doi:10.7861/ clinmed.2021-0037

7. Wenzel J, Lampe J, Müller-Fielitz H, et al. (2021). The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells. Nature Neuroscience, 24(11), 1522-1533. doi:10.1038/s41593-021-00926-1

Primary prevention of asthma: Current recommendations and potential for future interventions

Asthma is a common debilitating, and potentially fatal disease. In Ireland the prevalence of asthma is 7.6 per cent, the fourth highest in the world, and a person dies from asthma here every six days.1

Asthma is a heterogeneous chronic respiratory disease. It is characterised by airway inflammation, and there is usually assumed to be airway hyperresponsiveness. 2 Symptoms of cough, wheeze dyspnoea and chest tightness can vary overtime. Airflow limitation may become permanent. Patients’ experience of asthma can vary vastly depending on their ‘phenotype’, such as presence of absence of atopy, normal or impaired lung function, and persistent or intermittent course of illness.

There are recognised phenotypes such as allergic and non-allergic asthma, adult-onset asthma, airflow-limitation asthma, and asthma with obesity. The Global Initiative for Asthma (GINA), however, note these are not a strong indicator of pathological process or treatment responses. 3

‘Causes’ of asthma are complex and multifactorial with an overlap between genes and environment.3 These interactions generally occur early in life, and in utero. While many underlying molecular endotypes have been identified in asthma, their uncertain contribution to asthmarelated traits and their overlap mean that prevention and treatment cannot target a single mechanism, and a variety of approaches need to be adopted.

Primary prevention then, looks at what strategies can be developed to reduce asthma both on a population level and to reduce an individual’s risk of developing the disease.

Smoking

A large meta-analysis has demonstrated exposure to tobacco via maternal smoking in utero to be associated with an increase in asthma onset under two years of age (OR=1.85), and even with onset at five-to-12 years (OR=1.21).4 In mouse models maternal

Vitamin D

Vitamin D deficiency in pregnant women has been associated with an increased risk of asthma in offspring. Two metaanalyses suggested that high intake of vitamin D or fish oil, or both, during pregnancy could decrease the risk of wheeze in pre-school children, but not of asthma in school-aged children. 2

A 2016 randomised control trial 5 looking at supplementation of higher dose

nicotine exposure was shown to alter airway length and diameter and collagen expression, and alter offspring pulmonary function and increase their risk of asthma.4

Exposure to passive smoking increases the risk of asthma by 20-to-85 per cent across a meta-analysis, and wheeze by 28-to-70 per cent. Evidence of positive impacts of ‘smoking bans’ have been seen, for example, in Scotland in 2006, where cessation and reduction in overall exposure to secondhand smoke led to a decrease in admission rates for children.2

GINA recommend avoiding exposure to tobacco smoke both prenatally and in early life to prevent asthma.3

(4400IU/d vs 400IU/d) prenatally, showed a reduced incidence of asthma and wheeze at three years (6.1 per cent), but failed to reach statistical significance. It may have been underpowered, however. There is ongoing research on the role of vitamin D supplementation in pregnancy and pre-conceptually. 2

GINA recommend identifying and correcting vitamin D deficiency in women with asthma or atopy who are pregnant or planning to conceive.3

Obesity

Overweight or obesity is increasingly recognised as a possible risk factor for childhood asthma.

AUTHORS: Dr Michelle McCarthy, GP Registrar; and Dr Dermot Nolan, former ICGP National Clinical Lead on Asthma, and member of the Asthma Society Medical Advisory Group

...high intake of vitamin D or fish oil, or both, during pregnancy could decrease the risk of wheeze in pre-school children but not of asthma in school-aged children

A large meta-analysis found children in the obese range were more likely to develop asthma (OR=1.30) and wheeze (OR=1.90). 6 Mechanisms put forward to explain this include the reduction in lung volume associated with higher BMIs, changes in hormones, dyslipidaemia, and inflammatory mediators. This could explain why the higher incidence of asthma in pre-schoolage boys compared with their female peers is reversed at adolescence, as girls and women will have higher adipose tissue during and after puberty. 6 This is yet another reason to monitor children who are obese or at risk of obesity and to tackle the global epidemic of childhood obesity.

Maternal obesity and weight gain during pregnancy may play a role in the development of asthma in offspring. 2 This is difficult to tackle based on identifying at-risk individuals. While maternal weight gain in pregnancy and obesity may be associated with asthma, weight loss should not be encouraged during pregnancy. 3 These preventative measures are likely to be more successful as part of a public health strategy rather than at an individual preventative level.

Allergens

Sensitisation to indoor allergens appears to be more significant than outdoor allergens in the development of asthma. 2

Some studies. such as the Isle of Wight Study,7 have looked at strict allergen avoidance from infancy, in children with two or more first-degree relative with asthma or atopy. Avoidance strategies included feeding with an extensively hydrolysed formula or breastfeeding with a low-allergen maternal diet from birth, and use of mattress covers and an acaricide treatment on carpets and upholstery to avoid house dust mites. This showed a positive result for prevention of wheeze (OR=0.26), asthma (OR=0.11), and atopy (OR=0.21) at eight years of age. It is unclear which particular avoidance strategies were beneficial and to what extent.

As allergic rhinitis can precede asthma onset, there have been studies looking at whether immunotherapy could play a preventative role, however, evidence is inconclusive. The blinded GRAZAX study demonstrated reduced asthma symptoms and medication use when sublingual grass-pollen treatment was given to children with grass pollen allergy, but there was no effect at the two-year follow-up. 8 Currently GINA do not recommend using immunotherapy for children with allergic rhinoconjunctivitis associated with grass pollen as an asthma prevention strategy. 2

Protective factors; ‘the hygiene hypothesis’

Asthma affects between 1-to-18 per cent of the population of any country, however with vastly different prevalences within countries. 2 There have been long noted protective factors for wheeze in pre-school-age children and asthma in school-aged children such as growing up in a farming environment and living in a rural area. Studies that demonstrate this difference in incidence of asthma between those from the same ethnic backgrounds have been replicated across the world; including China, Europe, and Mongolia. Asthma is almost nonexisting in areas with strong protective environmental exposures.

Previously, it was thought that delayed introduction of solid food might prevent sensitisation, however, that is no longer recommended. The inverse was actually found to be true in terms of introducing peanuts to children at high-risk of peanut allergy. 2 It remains to see if similar preventative approaches may have a role in allergic asthma. There is no evidence for alteration of maternal diet in pregnancy to avoid allergens. While GINA encourage breastfeeding for all its other health benefits, there is no evidence that breastfed infants are at decreased risk of developing asthma. 3

Indoor dampness and mould are associated with increased asthma risk, however it is unclear what the underlying culprits (eg, fungi or volatile organic compounds) are. There are no recommendations to target this as a mode of primary prevention at this time. 2

One theory is the link in the development of respiratory health, immune status, commensal colonisation and pathogen exposure, as the respiratory microbiome develops in the first two years of life. A lack of diversity in the respiratory microbiome in early life, combined with reduced pro-inflammatory cytokines, leads to an increased propensity to respiratory illness with persistent wheeze and a risk of asthma in later life. In mouse models, exposure to environmental probiotic bacteria, such as farm bacteria, protected against allergic airway inflammation. While recurrent respiratory infections such as RSV and HRV in early life increase the risk of persistent wheeze and asthma, exposure to farm animals is inversely related to both viral-induced wheeze and asthma.

Another theory is that the development of asthma is related to the gut microbiome. Indeed, the increased prevalence of asthma in Westernised countries appears to correlate to changes in the gut microbiome. Studies in knock-out mouse models have supported the existence of a ‘gut-lung access’ in which microbial-derived metabolites or immunomodulatory molecules produced in the gut can exert effects in the lungs. Children living in farming and rural

Previously, it was thought that delayed introduction of solid food might prevent sensitisation, however that is no longer recommended

communities generally have a more diverse gut microbiome due to contact with animals, soil, higher fibre intake, and ingestion of fermented foods.

This interaction between the microbiome and the environment is further demonstrated by larger families, having two or more pets, and exposure to the mother’s vaginal flora via vaginal delivery being protective for asthma.

There is an increased risk of asthma associated with antibiotic use in the first year of life (OR: 2.18),9 which increases with repeated courses of antibiotics and is highest with more than four courses.9 This is possibly due to alteration in the microbiome due to repeated antibiotic use. GINA now recommend that broadspectrum antibiotics be avoided where possible in the first year of life. 3 They also recommend encouraging a vaginal delivery where possible as primary prevention measures. 3

Developing an understanding of the role of environmental protective mechanisms

References

1. The Asthma Society of Ireland. Fact sheet on asthma. Available online at: www. asthma.ie/get-help/resources/facts-figuresasthma

2. Von Mutius E, Smits HH. Primary prevention of asthma: From risk and protective factors to targeted strategies for prevention. Asthma 2020 396;10254,854-866

3. Global initiative for Asthma. Global strategy for asthma management and prevention, 2021 update. Available at: www. ginasthma.org

4. Burke H, Leonardi-Bee J, Hashim A, et al. Prenatal and passive smoke exposure and incidence of asthma and wheeze: Systematic review and meta-analysis.

and their interaction with the respiratory system and the gut has led to ongoing research by several companies into potential therapies or interventions that could target these pathways for intervention. 2

Key messages

At present the key mechanisms of preventing asthma in children involve limiting pre- and postnatal exposure to passive smoking, identifying and correcting low vitamin D levels in pregnant mothers and those trying to conceive, and limiting the Caesarean section rate where possible. The prescription of broad spectrum antibiotics in early life should also be limited.

Currently there is insufficient evidence to recommend either early exposure to or avoidance of potential allergens and any recommendations would need to take into account the acceptably of such measures as well as the practicalities in implementation.

While there is a better understanding of potential pathways to target, there are questions such as whether the oral or nasal route should be utilised, what frequency therapeutics would be required for, and indeed approval in the young age group required here is a challenge.

Understanding the complex interplay between genes, the environment, the microbiome and potential contributory pathways is leading to the development of new therapies for the primary prevention of asthma. ■

Pediatrics 2012;129:735-44

5. Litonjua AA, Carey VJ, Laranjo N et al. Effect of prenatal supplementation with vitamin D on asthma or recurrent wheezing in offspring by age three years: The VDAART randomised clinical trial. JAMA . 2016 Jan 26;315(4):362-70

6. Deng X, Ma J, Yuan Y, Zhang Z, Niu W. Association between overweight or obesity and the risk for childhood asthma and wheeze: An updated meta-analysis on 18 articles and 73,252 children. Pediatr Obes 2019;14:e12532

7. Arshad SH, Bateman B, Matthews SM. Primary prevention of asthma and atopy during childhood by allergen avoidance in infancy: A randomised controlled study.

Thorax 2003;58:489-93

8. Valovirta E, Petersen TH, Teresa Piotrowska T, et al. Results from the fiveyear SQ grass sublingual immunotherapy tablet asthma prevention (GAP) trial in children with grass pollen allergy. Journal of Allergy and Clinical Immunology, 2018:141:2529-538

9. Ahmadizar F, Vijverberg SJG, Arets HGM, et al. Early life antibiotic use and the risk of asthma and asthma exacerbations in children. Paediatric Allergy and Immunology, 2017;28(5):430-437

10. Marra F, Marra CA, Richardson K, et al. Antibiotic use in children is associated with increased risk of asthma. Pediatrics 2009;123:1003-10

There is an increased risk of asthma associated with antibiotic use in the first year of life ... which increases with repeated courses of antibiotics ...

* Relvar Ellipta is indicated for the regular treatment of asthma in adults and adolescents aged 12 years and older where use of a combination medicinal product (long-acting β 2-agonist and inhaled corticosteroid) is appropriate: patients not adequately controlled with inhaled corticosteroids and ‘as needed’ inhaled short acting β 2-agonists or patients already adequately controlled on both inhaled corticosteroid and long-acting β 2 - agonist 2

For Healthcare Professionals only. Images used are for illustrative purposes only. Relvar is well tolerated. Most common adverse events are nasopharyngitis and headache2 PM-IE-FFV-ADVT-200005 December 2020

Relvar Ellipta was developed in collaboration with

Relvar® Ellipta® (fluticasone furoate/ vilanterol [as trifenatate]) Prescribing information

(Please consult the full Summary of Product Characteristics (SmPC) before prescribing)

Relvar® Ellipta® (fluticasone furoate/vilanterol [as trifenatate]) inhalation powder. Each single inhalation of fluticasone furoate (FF) 100 micrograms (mcg) and vilanterol (VI) 25mcg provides a delivered dose of 92mcg FF and 22mcg VI. Each single inhalation of FF 200mcg and VI 25mcg provides a delivered dose of 184mcg of FF and 22mcg of VI. Indications: Asthma: Regular treatment of asthma in patients ≥12 years and older where a long-acting β2-agonist and inhaled corticosteroid combination is appropriate and where patients are not adequately controlled on inhaled corticosteroids and ‘’as needed” short-acting inhaled β2-agonists, or where patients are already controlled on both inhaled corticosteroid and long-acting β2-agonist. COPD (Relvar 92/22mcg only): Symptomatic treatment of adults with COPD with a FEV1<70% predicted normal (post-bronchodilator) and an exacerbation history despite regular bronchodilator therapy). Dosage and administration: Inhalation only. Asthma: Patients with asthma should be given the strength of Relvar Ellipta containing the appropriate fluticasone furoate (FF) dosage for the severity of their disease. Prescribers should be aware that in patients with asthma, FF 100 mcg once daily is approximately equivalent to fluticasone propionate (FP) 250 mcg twice daily, while FF 200 mcg once daily is approximately equivalent to FP 500 mcg twice daily. Adults and adolescents ≥12 years: one inhalation once daily of: Relvar 92/22mcg for patients who require a low to mid dose of inhaled corticosteroid in combination with a long-acting β2-agonist. If patients are inadequately controlled then the dose can be increased to one inhalation once daily Relvar 184/22mcg. Relvar 184/22mcg can also be considered for patients who require a higher dose of inhaled corticosteroid in combination with a long-acting β2-agonist. Regularly review patients and reduce dose to lowest that maintains effective symptom control. COPD: one inhalation once daily of Relvar 92/22mcg. Contraindications: Hypersensitivity to the active substances or to any of the excipients (lactose

KEEP ASTHMA TAMED

Proactive asthma control that lasts1,2

RELVAR ELLIPTA (fluticasone furoate/vilanterol)

monohydrate & magnesium stearate). Precautions: Pulmonary tuberculosis, severe cardiovascular disorders, heart rhythm abnormalities, thyrotoxicosis, uncorrected hypokalaemia or patients predisposed to low levels of serum potassium. chronic or untreated infections, diabetes mellitus. Paradoxical bronchospasm – substitute alternative therapy if necessary. In patients with hepatic with moderate to severe impairment 92/22mcg dose should be used. Acute symptoms: Not for acute symptoms, use short-acting inhaled bronchodilator. Warn patients to seek medical advice if short-acting inhaled bronchodilator use increases. Therapy should not be abruptly stopped without physician supervision due to risk of symptom recurrence. Asthma-related adverse events and exacerbations may occur during treatment. Patients should continue treatment but seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation of Relvar. Systemic effects: Systemic effects of inhaled corticosteroids may occur, particularly at high doses for long periods, but much less likely than with oral corticosteroids. Possible Systemic effects include: Cushing’s syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, growth retardation in children and adolescents, cataract, glaucoma. More rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). Increased incidence of pneumonia, including pneumonia requiring hospitalisation, has been observed in patients with COPD receiving inhaled corticosteroids. If a patient presents with visual disturbance they should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma, or rare diseases such as central serous chorioretinopathy. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations. Risk factors for pneumonia include: current smoking, older age, low body mass index and severe COPD. The incidence of pneumonia in patients with asthma was common at the higher dose of Relvar (184/22mcg). Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption

should not use Relvar. Interactions with other medicinal products: Interaction studies have only been performed in adults. Avoid β-blockers. Caution is advised when co-administering with strong CYP 3A4 inhibitors (e.g. ketoconazole, ritonavir, cobicistat-containing products). Concomitant administration of other sympathomimetic medicinal products may potentiate the adverse reactions of FF/VI. Relvar should not be used in conjunction with other longacting β2-adrenergic agonists or medicinal products containing long-acting β2-adrenergic agonists. Pregnancy and breast-feeding: Experience limited. Balance risks against benefits. Side effects: Very Common (≥1/10): Headache, nasopharyngitis. Common (≥1/100 to <1/10): Candidiasis of the mouth and throat, pneumonia, bronchitis, upper respiratory tract infection, influenza, oropharyngeal pain, sinusitis, pharyngitis, rhinitis, cough, dysphonia, abdominal pain, arthralgia, back pain, muscle spasms, fractures, pyrexia. Uncommon (≥1/1,000 to <1/100): Hyperglycaemia, vision blurred, extrasystoles. Rare (≥1/10,000 to <1/1,000): Hypersensitivity reactions including anaphylaxis, angioedema, rash and urticaria; palpitations, tachycardia, tremor, anxiety, paradoxical bronchospasm. Marketing authorisation (MA) Holder: GlaxoSmithKline (Ireland) Limited, 12 Riverwalk, Citywest Business Campus, Dublin 24, Ireland. MA Nrs: 92/22mcg 1x30 doses [EU/1/13/886/002]; 184/22mcg 1x30 doses [EU/1/13/886/005].

Legal category: POM B. Last date of revision: June 2019. Code: PI-2046. Further information available on request from GlaxoSmithKline, 12 Riverwalk, Citywest Business Campus, Dublin 24. Tel: 01-4955000.

Adverse events should be reported directly to the Health Products Regulatory Authority (HPRA) on their website: www.hpra.ie. Adverse events should also be reported to GlaxoSmithKline on 1800 244 255.

References: 1. Bernstein DI et al. J Asthma 2015; 52: 1073-1083. 2. Relvar Ellipta SmPC, 2019, available on www.medicines.ie

Adult-onset asthma

AUTHOR: Dr Amy Rigby, Consultant in Respiratory and General Internal Medicine, Beacon Hospital, Dublin

Asthma is defined as a chronic disease of variable airway obstruction due to mucous hypersecretion and bronchial hyperreactivity.1 The diagnosis is made on pulmonary function tests (PFTs) demonstrating a significant response to bronchodilator (defined by the American Thoracic Society as greater than 200ml and 12 per cent increase in FEV1 after bronchodilator).1

Although asthma is often diagnosed in childhood, there is also a subset who are diagnosed in adulthood. This diagnosis is often delayed due to an atypical presentation.

Therapy is individualised based on severity of symptoms and is then upor down-titrated depending on response. Therapy is becoming increasingly focused on phenotype and there are a number of adjunctive therapies available.

CASE STUDY 2

A 43-year-old woman presented with exertional dyspnoea. Her past medical history was significant for Hashimoto’s thyroiditis and allergic rhinitis, and both her father and cousins had a history of asthma. She had had pertussis as a young child and had a frequent dry cough until the age of six, but was never diagnosed with asthma and was well for the remainder of her childhood. She grew up on a farm around animals and hay. Occasionally during her 20s she would find it hard to catch her breath and would develop a wheeze with exercise.

Since having a lower respiratory tract infection eight years prior to presentation she had had episodes of nocturnal dyspnoea and wheeze; a year prior to presentation she was commenced on budesonide-

formoterol, but did not experience any symptomatic improvement. At the time of assessment she was having symptoms of dyspnoea and wheeze two-to-three days a week, with nocturnal dyspnoea and a wheeze with exercise. PFTs demonstrated a mild obstructive deficit with a significant response to bronchodilator, consistent with a diagnosis of asthma. Skin prick testing was negative for all allergens, and a serum IgE was normal, thus there was no evidence of associated atopy. She was switched to fluticasonesalmeterol, initially two puffs BD, and upon review had no symptoms of asthma, did not require her PRN salbutamol and was able to take up running again with no exacerbation of symptoms. The combination preventer therapy has now been reduced to one puff BD.

Patient education remains paramount, particularly with respect to daily monitoring of peak flow and symptoms, and with respect to correct technique with inhaler therapy. This is particularly important in older patients with asthma and suboptimal control, in whom poor inhaler technique may contribute significantly to lack of improvement with therapy. Regular review is important to ensure therapy remains appropriate for both severity and level of control.

CASE STUDY 1

A 70-year-old male patient presented for review of a chronic cough. He had a history of childhood asthma, but had not been treated for asthma as an adult. He had worked in the navy previously.

He described a chronic cough for two years productive of small amounts of sputum. He had been treated with several courses of antibiotics with no improvement.

A CT chest demonstrated some minor atelectasis but lung fields were otherwise clear. Pulmonary function tests were consistent with a diagnosis of asthma - within normal limits, but with a significant response to bronchodilator.

Presentation

Most asthma begins in childhood, with 95 per cent of asthma patients having had their first epodes before the age of six years. The main risk factors in asthma beginning in childhood are: Genetic predisposition/a family history of allergy/asthma, viral respiratory infections, bacterial colonisation, allergic sensitisation, and tobacco exposure. 2 Patients with childhood asthma tend to

have a Th2-predominant inflammatory pattern and a good response to corticosteroids. 3,4 Asthma that begins in adulthood is often non-atopic, more severe and associated with a faster decline in lung function.1,2 It often requires treatment with high doses of inhaled and/or oral steroids. 3 In recent years phenotypic types of asthma have begun to emerge. In the Severe Asthma Research Programme, five clusters were identified, and 80 per cent of those studied could be divided into a subtype using three variables: Baseline FEV1; maximum FEV1 after bronchodilator; and age of onset of asthma. The cluster with the most severe phenotype was largely made up of patients with a diagnosis in adulthood. 2

Risk factors

The factors associated with adult-onset asthma are less well-known. It appears to

mainly affect females, has a low remission rate, and is less associated with allergy/ atopy. 2,3,5 Additionally, individuals who had asthma as a child may redevelop symptoms in adulthood. 5 There appears to be a large number of possible triggers associated with adult-onset asthma including respiratory tract infections, moulds, cigarette smoke, occupational exposure, and environmental pollutants.4 Obesity is a risk factor for adult-onset asthma and increases the risk by up to 50 per cent. 3 One study has examined long-term outcomes in adultonset asthma and changes in asthma severity over time. Practically all, 95 per cent, of the patients in the study had ongoing active asthma five years after diagnosis, and half had moderate to severe disease. 2 In a study assessing severity of adult-onset asthma, those with severe disease were less likely to be sensitised to common allergens, had more nasal

symptoms, and were more likely to have a history of nasal polyposis.4

Several phenotypic patterns appear in the context of adult-onset asthma (see Figures 1 and 2). These have been described based on presentation (allergic, non-allergic, occupational), airway inflammation (eosinophilic and non-eosinophilic), and severity. 6 Of these, presence or absence of eosinophilic inflammation (Th2- or non-Th2-associated) is a key phenotypic differentiator. 5

Studies suggest low levels of eosinophilia in obesity-related asthma. 3 Obesity is associated with low-level systemic inflammation, with increases in many inflammatory markers including CRP, IL-6, TNF-alpha, and leptin, which may play a role in the link between obesity and adultonset asthma. 3 However, patients with

severe asthma appear to have higher levels of both blood and sputum eosinophilia than those with mild-to-moderate asthma.4

Women are significantly more likely to develop asthma following puberty, and have more severe disease. 2,3 Asthma is 20 per cent more common in females than in males over the age of 35 years. 2 It appears that it is the non-allergic asthma that has a higher incidence in women of reproductive age, whereas there is no similar difference seen in the incidence of allergic asthma. 2 Phases of the menstrual cycle have also been associated with asthma severity and atopy in women. 3 Thus there appears to be a hormonal role, possibly oestrogenic, although the exact link remains unclear.

Whilst there remains considerable debate about the exact definitions and phenotypic subtypes of adult-onset asthma (and asthma in general), studies have begun to identify various groups of patients that have different risk factor profiles, but also very different responses to treatment. The Seinajoki Adult Asthma Study of patients with new-onset adult asthma identified five phenotypes: non-rhinitic asthma, smoking asthma, female asthma, obesityrelated asthma, and early-onset atopic adult asthma.6 In a study by Amelink et al,4 patients were classified into three groups: Patients with severe eosinophilic inflammation-predominant asthma and persistent airflow limitation despite highintensity anti-inflammatory treatment; obese women with frequent symptoms, need for frequent medical care, and low sputum eosinophils; and patients with mild-moderate, well-controlled asthma with normal lung function and low inflammatory markers.

As phenotypic variants become increasingly identified, this assists healthcare practitioners to focus on specific assessments and subsequently to individualise therapy.

Investigations

In adult-onset asthma associated with the Th2 phenotype and related to rhinosinusitis, it is important to identify

FIGURE 1: Key phenotypes and risk factors for late-onset asthma6

the phenotype early, as pulmonary function is poor from onset and exacerbations occur frequently5 – (see Figure 3). Thus utilising a biomarker, such as fractional exhaled nitric oxide (FENO) that identifies Th2-type inflammation may be highly useful. 5

Th2-type biomarkers including blood eosinophils, FENO, and periostin are used to identify those patients with Th2-driven adult-onset asthma. 5 These biomarkers are particularly useful to assess asthma/COPD overlap syndromes, and may assist with prediction of response to corticosteroids. 5

Management

In childhood-onset allergic asthma, treatment with daily corticosteroids combined with long-acting beta-agonists is usually very effective.

In contrast, many patients with adult-onset asthma do not have a good response to corticosteroids. 2,5 Specifically, non-Th2-

type adult-onset asthma may require other treatment strategies including macrolides, diet/weight loss and smoking cessation. 5

In addition to avoidance of exposure to known precipitants such as cigarette smoke and occupational sensitisers, targeted treatments based on phenotype are now being increasingly developed.

Omalizumab

Omalizumab is a humanised antibody against IgE. It was originally developed to treat severe allergic asthma, but has been shown to have efficacy on non-allergic asthma and nasal polyps, so may be of benefit to certain patients with adult-onset asthma, 2 although its efficacy appears to be greater for early-onset asthma. 5

Mepolizumab

Mepolizumab is a humanised monoclonal antibody against IL-5 that selectively targets and inhibits eosinophilic airway inflammation. In some recent studies

it has been shown to be effective and safe as a treatment for patients with severe eosinophilic asthma; it has also been demonstrated to have efficacy in treatment of severe nasal polyposis. 2

Lebrikizumab

Lebrikizumab is a humanised monoclonal antibody that binds to IL-1.³ It has been shown to be useful for patients with moderate asthma, particularly the subset who had circulating levels of periostin above the median with a high Th2 phenotype. 2

Reslizumab

Reslizumab is a humanised monoclonal antibody against IL-5, which has been shown to reduce exacerbations and improve lung function to a greater degree in those with adult-onset asthma than childhood asthma. 5

Bronchial thermoplasty

Bronchial thermoplasty is a bronchoscopic

FIGURE 2: Phenotypes of late-onset asthma3

procedure during which controlled thermal energy is applied to the airway wall, decreasing the amount of smooth muscle. 2

It may offer one of very few therapeutic options for patients with adult-onset non-eosinophilic severe asthma. Studies have shown improvement in lung function, airway hyperresponsiveness, quality-of-life, and symptom scores, with a reduction in exacerbations and hospitalisations. 2

Bariatric surgery

For obese patients with non-eosinophilic asthma, the only treatment option at present is significant weight loss, and a study has demonstrated improved asthma control following bariatric surgery in this cohort of patients. 2

Conclusion

In summary, asthma investigation and management is becoming increasingly individualised. Adult-onset asthma has distinct phenotypic variants that require specific investigations

References

1. Tommola M, Won HK, Ilmarinen P, et al. Relationship between age and bronchodilator response at diagnosis in adult-onset asthma. Respir Res 2020; 21:179. doi: 10.1186/ s12931-020-01441-w

2. De Nijs SB, Venekamp N, Bel EH. Adult-onset asthma: is it really different? Eur Respir Rev 2013; 22:44-52. doi: 10.1183/09059180.00007112

3. Ilmarinen P, Tuomisto LE, Kankaanranta H. Phenotypes, risk factors, and mechanisms of adult-onset asthma. Mediators of

and often a different therapeutic approach than childhood asthma, with less reliance on inhaled corticosteroids and an increased focus on lifestyle modifications and targetedmonoclonal therapies. ■

Inflammation 2015. doi: 10.1155/2015/514868

4. Amelink M, de Groot JC, de Nijs SB, et al. Severe adult-onset asthma: A distinct phenotype. J All Clin Immunol 2013; 132(2): 336-341. doi: 10.1016/j.jaci.2013.04.052

5. Hirano T, Matsunaga K. Late-onset asthma: current perspectives. J Asthma Allergy 2018; 11: 19-27. doi: 10.2147/JAA.S125948

6. Quirce S, Heffler E, Nenasheva N, et al. Revisiting late-onset asthma: Clinical characteristics and association with allergy. J Asthma Allergy 2020; 13: 743-752. doi: 10.2147/JAA.S282205

FIGURE 3: Time course of adult-onset asthma5

Global Initiative for Asthma 2021 – executive summary on asthma management and prevention

The Global Initiative for Asthma (GINA) has published an executive summary of its updated evidence-based strategy for asthma treatment and prevention. The executive summary was published online in the American Journal of Respiratory and Critical Care Medicine, the European Respiratory Journal, Respirology and Journal of Allergy and Clinical Immunology: In Practice

GINA was established through a 1993 collaboration between the World Health Organisation (WHO) and US National Heart, Lung, and Blood Institute to develop an asthma prevention and management strategy. This strategy is updated each year based on the latest scientific evidence.

Following is a summary of key recommendations from the GINA 2021 executive summary.

A more complete discussion of these recommendations, including the rationale for key changes, can be found in the GINA 2021 Strategy Report (available at https:// ginasthma.org/reports/ ).

1. In adults, adolescents and children six years old or older, confirm the diagnosis of asthma before starting controller treatment, as confirmation is more difficult once treatment starts.

2. Personalise and adjust therapy in a continual cycle of assessment, treatment and review. This strategy will minimise symptoms and prevent exacerbations.

3. Do not only include medications in asthma management, but also incorporate treatment of modifiable risk factors and comorbidities, non-pharmacological strategies, and education and skills training – especially for inhaler technique and adherence.

4. Asthma in adults and adolescents, as well as in children, should not be managed solely with short-acting beta2 agonists (SABA). All adults, adolescents and children six-to-11 years with asthma should be treated with inhaled corticosteroid (ICS)-containing therapy. Frequency of treatment (daily or as needed) should depend on the severity of patients’ asthma.

5. This year, GINA treatment for adults and adolescents was divided into two tracks, depending on the inhaled reliever medication, with each track having five steps. (See the American Journal of Respiratory and Critical Care Medicine for detail.)

adolescents into two tracks

6. For children five years or under, manage wheezing episodes initially with inhaled SABA.

7. Before stepping up treatment to control symptoms and prevent exacerbations, confirm that the symptoms are due to asthma, and identify and address modifiable risk factors.

8. Once asthma is well controlled for two-three months, consider stepping down gradually to find the minimum effective dose.

9. As part of supported asthma selfmanagement, provide all patients with a personalised written asthma action plan, tailored to their health literacy, to

enable them to recognise and respond to worsening asthma.

10. Refer patients for expert advice if:

 You are unable to confidently confirm an asthma diagnosis;

 For children five years of age or under, strongly consider referral for further diagnostic investigations if the patient has very early onset of symptoms, failure to respond to treatment, or features suggesting alternative diagnoses;

 Occupational asthma is suspected;

 The patient has any risk factors for asthmarelated death;

 Symptoms or exacerbations remain uncontrolled despite medium/high-dose ICSlong-acting beta2 agonist (LABA);

 The patient needs urgent healthcare or oral corticosteroids (OCS) more than once a year;

 There is evidence or high risk of treatment side-effects; or

 Food allergy is suspected.

According to the GINA authors, as stated in recommendation No 5 above, a key change from GINA 2020 is the division of treatment recommendations for adults and adolescents into two tracks:

 Track 1 (preferred) has low-dose ICSformoterol as the reliever at all steps: as-needed only in Steps 1-2 (mild asthma), and with daily maintenance ICS-formoterol (maintenanceand-reliever therapy, MART) in Steps 3-5.

MART is also added as a new treatment option for children six-to-11 years at Steps 3-4.

 Track 2 (alternative) has as-needed SABA across all steps, plus regular ICS (Step 2) or ICS-LABA (Steps 3-5).

 For adults with moderate-to-severe asthma, GINA makes additional recommendations in Step 5 of both tracks for add-on long-acting muscarinic antagonists and azithromycin, with add-on biologic therapies for patients with severe asthma. ■

A key change from GINA 2020 is the division of treatment recommendations for adults and

Update from the Irish Lung Fibrosis Association

The Irish Lung Fibrosis Association (ILFA) was established in 2002 with the aims of providing research, education, and support for idiopathic pulmonary fibrosis (IPF). From humble beginnings, ILFA has seen remarkable growth in our vision, activities, membership, effectiveness, and standing in the respiratory community. The charity is committed to meeting our aims and serving patients diagnosed with IPF and their families, and to providing educational opportunities and information resources to healthcare professionals working in respiratory medicine.

Advocacy activities

The arrival of the Covid-19 pandemic presented many great challenges to ILFA and to pulmonary fibrosis patients. In 2020, ILFA campaigned with the Irish Thoracic Society to ensure that pulmonary fibrosis was recognised as an extremely medically vulnerable condition for Covid-19. This had implications for our patients, who were advised to cocoon and prioritised for Covid-19 vaccination in early 2021. ILFA is now included in the HSE Stakeholders Group to receive important communications, and updates in relation to Covid-19.

Patient-centred activities and information resources

ILFA successfully transitioned to the virtual world and have continued to deliver weekly online exercise classes to patients, thanks to a team of respiratory physiotherapists who volunteered to help. ILFA also hosts online support group meetings approximately every two weeks that enable people living all over the country to stay connected and share their experiences and tips with their peers. Sing Strong for Pulmonary Fibrosis classes were delivered as an online pilot study in 2021 and the classes were enthusiastically appreciated by all the participants, and a new 12-week programme has just commenced. In 2021, three online patient information days will be delivered with financial support

from pharmaceutical companies and a HSE/ National Lottery grant.

ILFA produced two new information leaflets in 2020/2021 entitled Telemedicine Phone and video consultations: A guide for patients and Acute Exacerbations of Pulmonary Fibrosis. The leaflets were awarded the Plain English Mark by the National Adult Literacy Agency that ensures the language used is appropriate and presented in plain English. We are grateful to the patients and healthcare professionals who helped review the leaflets and provided valuable feedback.

Research and publications

In 2020 and 2021, ILFA undertook quantitative and qualitative surveys to determine the impact of the Covid-19 pandemic on our stakeholders. Research articles entitled ‘Perspectives of Interstitial Lung Disease Healthcare Professionals during Covid-19’ and ‘Perspectives of Interstitial Lung Disease Patients and Carers during Covid-19’ were published in the Irish Medical Journal.

An article entitled ‘Fibrotic interstitial lung disease – palliative care needs: A World-Café qualitative study’ was published in the British Medical Journal Supportive and Palliative Care in October 2021. This paper represents an important and successful collaboration with an expert team of healthcare professionals, patients, and caregivers and describes the methodology and outcomes of the ILFA World Cafe on Palliative Care and Planning for the Future that took place in 2018.

ILFA World Café on pulmonary fibrosis services in Ireland during Covid-19 and beyond

Approximately 1,000 people in Ireland are living with pulmonary fibrosis, however, ILFA is aware of inadequacies in care delivery for those diagnosed with the condition. It has been proposed that many of the issues

around the accessibility and quality of care for pulmonary fibrosis could be resolved by the development of a national clinical care pathway for pulmonary fibrosis, as exists for other diseases. Our stakeholder surveys conducted in 2020 showed patients, caregivers and healthcare professionals all ranked advocating for a clinical care pathway for pulmonary fibrosis as the most important area of ILFA’s advocacy work. Taking this into account, the ‘ILFA World Café on Pulmonary Fibrosis Services in Ireland during Covid-19 and Beyond’ was developed to capture stakeholders’ experiences around care access for pulmonary fibrosis, before and during the Covid-19 pandemic, to better understand the challenges in obtaining and providing highquality pulmonary fibrosis care and gain insights on the priorities for future care.

The World Café took place virtually in April 2021 and was a great success with 75 people participating. It was a dynamic, inclusive event that enabled participants to share their views openly and supportively. ILFA was enormously grateful to receive funding from the Community Foundation of Ireland/ RTÉ Does Comic Relief Adapt and Respond fund, and Roche Pharmaceuticals Ireland to support this important project.

The ILFA World Café on Pulmonary Fibrosis Services in Ireland during Covid-19 and Beyond report (available at www.ilfa.ie) details the inadequacies in healthcare delivery for pulmonary fibrosis. This valuable document will help shape ILFA’s future advocacy work and strengthen our collaborative efforts with the Irish Thoracic Society and leading respiratory healthcare professionals in seeking improvements in pulmonary fibrosis care in Ireland. ILFA’s World Café project has been short-listed for a 2021 Irish Healthcare Award in the Best Patient Organisation category. ■

References on request

Can an exercise prescription improve COPD outcomes?

AUTHORS: David Regan, Chartered Physiotherapist and Clinical Exercise Specialist; Eoin Lombard, Chartered Physiotherapist and Clinical Exercise Specialist; and Andrew Dunne, Chartered Physiotherapist and Clinical Exercise Specialist, Personal Health – Medical Exercise Clinic, Rathmines, Dublin

In the past chronic obstructive pulmonary disease (COPD) was thought to be an untreatable condition. While it is still incurable, pharmacological management alongside exercise prescription is proven to enhance the lifestyles of individuals living with this condition.

Pathophysiology

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines’ definition of COPD is a disease state characterised by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal (magnified) inflammatory response of the lungs to noxious particles or gases.

As a result physiological abnormalities in the lungs include mucus hypersecretion, ciliary dysfunction, airflow limitation, hyperinflation and gas exchange abnormalities. At advanced stages of the condition pulmonary hypertension and cor pulmonale are evident.

Medical management

The most commonly prescribed medications for COPD are bronchodilators, corticosteroids and antibiotics. In more severe cases supplemental oxygen therapy may be required.

Bronchodilators are central to the symptomatic management of COPD. Short-acting bronchodilators are considered to relieve intermittent or worsening symptoms. Similarly, by using short-acting bronchodilators immediately before exercise training (in those with airflow limitation) pulmonary function can be maximised. This can reduce dyspnoea and improve exercise tolerance.

CASE REPORT 1

A 63-year-old woman presented with worsening shortness of breath along with wheezing and chronic cough. She was diagnosed with COPD in 2017 and has had multiple exacerbations and two hospitalisations in the last two years. Her GP referred her for an exercise prescription in a bid to improve her quality-of-life.

She is currently working full-time as a civil servant. She describes work as a stressful environment with limited time for exercise. She has accumulated a smoking pack year history of 40 years. She admits to only being active during ‘short strolls’ with friends at the weekend. She experiences shortness of breath and a wheeze that worsens during these walks with minimal sputum expectorated. She has to take breaks throughout these short strolls. She drives a short distance to work (approximately a five-minute drive) because she reports that she cannot walk 100 metres without taking a rest. She would love to walk to work, but currently is unsure whether this is attainable. Regardless, she is currently planning for retirement in the next 1824 months and her primary goal is to be fitter and stronger upon retirement, without underlying concerns about hospitalisation and poor quality-of-life.

In addition, her medical history includes osteoporosis (her most recent T-score reading being -2.7 on a DEXA scan at neck of femur bilaterally), hypertension and hyperlipidaemia.

These conditions are medicated with a combination of denosumab, amlodipine, and atorvastatin, respectively. Recently she has been prescribed salbutamol to be taken PRN and tiotropium for longer term management.

Previous investigations from her last hospital stay included a chest x-ray which showed evidence of hyperinflation and mild consolidation in lower zones. Her FEV1 score was 46 per cent, putting her into GOLD stage 3 for COPD. Upon discharge her arterial oxygen saturation was SaO2 = 95 per cent post oxygen therapy.

On presenting to the clinic for her proposed exercise prescription, her SaO2 had decreased to 91 per cent, explaining her recent subjective history of worsening symptoms. This was again reflected in her subjective outcome measures, the CAT (a COPD assessment scale) and mMRC (dyspnoea scale) scored 18 and Grade 3, respectively. Initial assessment included:

 Six-minute walk test (6MWT).

 30-second sit to stand (STS).

 Five-time (reps) STS (5xSTS).

With a score of <200m (in 6MWT) increasing the likelihood of a COPDrelated hospitalisation, the patient walked 190m with frequent breaks required during the test. Her STS and 5xSTS were also below age-specific normative values. Her 30-second STS score was eight reps (15 reps being the average for her age group) and 17 seconds for her 5xSTS (11 seconds being the average for her age group).

Despite ongoing debate over the effectiveness of corticosteroids, this treatment has shown favourable responses during an acute exacerbation, primarily by breaking down phospholipids involved in the inflammatory process. However chronic treatment with systemic corticosteroids should be avoided because of unfavourable side-effects; hyperglycaemia, osteoporosis, muscle myopathy, and peptic ulcer.

While the exact mechanisms by which antibiotics reduce exacerbations are not fully understood, their effectiveness may be due to altering mucus production, reducing oxidative stress and/or bacterial infection while simultaneously altering the inflammatory process.

Exercise prescription as part of the medical treatment plan

Before giving guidance on physical activity or formal exercise, a number of COPD considerations must be addressed. It is essential to determine the level of hypoxia during rest and physical activity, as well as cardiac risk stratification. As a result, if the patient is deemed to require supplemental oxygen during exercise it is best that the patient is seen in a formal, hospital-based pulmonary rehabilitation setting (as an outpatient). Otherwise the patient can appropriately and safely be referred to a chartered physiotherapist or clinical exercise specialist.

Collaborating with a physiotherapist/ clinical exercise specialist (who has the benefit of greater time available per consultation with patients) can significantly impact adherence, behaviour change and motivation for the COPD patient. Furthermore, the medic can outsource the time-consuming assessment work, such as taking objective outcome measures. Finally, specificity around frequency, intensity, type and time (FITT) principles of the proposed exercise can also be determined by the chosen allied health professional.

I only have a couple of minutes at the end of a consultation.How do I make my exercise advice more specific for COPD patients?

Aerobic exercise (AER)

Aerobic exercise is recommended for individuals in all stages of COPD (who are deemed suitable for exercise by the criteria listed above). Exertional dyspnoea is a common symptom in COPD, therefore the modified Borg Category Ratio 0-10 (CR10) is used extensively for accuracy and patient reassurance (Figure 2). Individuals should be given specific, standardised instructions on how to relate the wording on the scale with their level of breathlessness.

Given that these Borg dyspnoea scales are subjective, some caution is advised in their interpretation. For example, an inexperienced ‘exerciser’ may have an ‘up-regulated’ sympathetic nervous system response to their underlying dyspnoea. As a result, further shallow breathing can cause unnecessary panic for the participant. This can result in a loss of confidence, leading to the all too familiar fear/ avoidance cycle with exercise.

Strength/resistance training (RES)

It is well documented that pulmonary disease has a negative effect on the lungs. Crucially, however, it can also have a negative effect on the skeletal muscles, through lack of usage, resultant

FIGURE 1: COPD definition (GOLD)

FIGURE 2: Modified Borg CR10 scale

atrophy and weakness. Therefore strength training is the most potent intervention to address the level of muscle dysfunction seen in COPD. It should be an integral part of the overall exercise prescription.

Furthermore, because individuals with COPD may experience greater dyspnoea while performing ‘activities of daily living’ (ADLs) involving the thorax and upper extremities, it is advisable to include strength training exercises for the upper body in particular.

Balance training

Peripheral muscle dysfunction contributes to exercise intolerance among medical patients in general. And in those with COPD, sarcopaenia is commonplace. The prevalence of falls is thus widespread in COPD patients. Given the widespread prescribing of corticosteroids, and the resultant loss in bone mineral density, the prevention of falls are of paramount importance. Falls are multifactorial, but certainly involve muscle weakness, gait and balance abnormalities among the risk factors. Therefore, lower extremity strength and balance training are highly effective countermeasures. As such, coherent exercise advice in the medical setting ought to include some reference to aerobic training, subjective exertion levels, strength training (for the upper and lower extremities) and balance retraining.

After an exercise intervention of two 30-minute (combined AER + RES) sessions per week over a six-week period, there were significant and positive improvements in our case report patient. Testing showed an improvement in 6MWT score from 190m to 261m. This new score takes the patient out of the ‘at risk of hospitalisation’ group. The score is still below average (all patient COPD average=380m), but her prognosis with the disease has improved as a result. 6MWT scores have been shown to be significantly correlated with FEV1 and other spirometry measures as reflected in her new FEV1 of 54 per cent, lowering her into GOLD stage 2, further reflecting an improved prognosis. Her Sa02 has returned to 95 per cent and with consistency in her exercise routine, she should be able to maintain this level independently. Notably there are significant improvements in

strength and function shown in the improved scores for STS and 5xSTS. Finally, the Berg balance assessment has also seen a statistically significant shift in the patient’s falls risk status.

Summary

Empirical evidence shows that exercise is a beneficial intervention for COPD patients. Reducing risk of hospitalisation can be considered a profoundly beneficial outcome in the COPD cohort, particularly in the current public health environment.

However, the literature suggests that exercise intervention does not improve overall prognosis for lung function, given the pathophysiological trajectory of the condition. The lasting and practical benefits are seen in (patient reported) improved quality-of-life scores. For example, upper limb strength training can restore independence and dignity around ADLs. Similarly, peripheral muscle strengthening in the lower limbs can improve

It is widely acknowledged that time constraints (in a medical consultation) cannot and will not lend themselves to this level of lifestyle intervention. However, with an overwhelmingly positive evidence base in favour of exercise as a COPD management strategy, it is vital that physicians refer patients onward for appropriate intervention. Furthermore, the new HSE primary care chronic disease management programme for COPD patients provides scope for individualised patient reviews and plans and lifestyle management as a key part of a holistic approach to treating this disease. ■

References on request

Acknowledgement: Thanks to Dr Gordan Cantwell, GP, and Dr Fergal McNamara, GP, for their input.

setting ought to include some reference to aerobic training, subjective exertion levels, strength training (for the upper and lower extremities) and balance retraining.

FIGURE 3: Case report patient results/outcomes

ONCE DAILY ENERZAIR® BREEZHALER® + SENSOR*

The 1st LABA/LAMA/ICS combination for asthma

IND/GLY/MF 114/46/136μg 1x daily

INHALATION CONFIRMATION3

MEDICATION REMINDERS3

ENERZAIR® BREEZHALER® is indicated as a maintenance treatment of asthma in adult patients not adequately controlled with a maintenance combination of a long-acting beta2-agonist and a high dose of an inhaled corticosteroid who experienced one or more asthma exacerbations in the previous year.2

Abbreviated Prescribing Information

Please refer to Summary of Product Characteristics (SmPC) before prescribing. Enerzair® Breezhaler® (indacaterol (as acetate), glycopyrronium bromide, mometasone furoate) inhalation powder, hard capsules.

Presentation: Hard capsules for inhalation each containing 150 mcg of indacaterol (as acetate), 63 mcg of glycopyrronium bromide equivalent to 50 mcg of glycopyrronium and 160 mcg of mometasone furoate. Each delivered dose contains 114 mcg of indacaterol acetate, 46 mcg of glycopyrronium and 136 mcg of mometasone furoate. Indications: Maintenance treatment of asthma in adult patients not adequately controlled with a maintenance combination of a long-acting beta2-agonist and a high dose of an inhaled corticosteroid who experienced one or more asthma exacerbations in the previous year. Dosage and Administration: One capsule once daily, administered at the same time of the day each day, using the Enerzair Breezhaler inhaler. No dose adjustment is required in elderly patients, in patients with mild to moderate renal impairment, or in patients with mild or moderate hepatic impairment. Caution should be observed in patients with severe renal impairment or end-stage renal disease requiring dialysis. No data available for patients with severe hepatic impairment, only use in these patients if the expected benefit outweighs the potential risk. The safety and efficacy in paediatric patients below 18 years of age have not been established. Contraindications: Hypersensitivity to the active substances, lactose monohydrate or magnesium stearate.

Warnings/Precautions: Deterioration of disease: Should not be used to treat acute asthma symptoms, including acute episodes of bronchospasm. Treatment should not be stopped abruptly. Hypersensitivity: Immediate hypersensitivity reactions have been observed after administration. If signs suggesting allergic reactions occur, in particular angioedema, urticaria or skin rash, treatment should be discontinued immediately and alternative therapy instituted. Paradoxical bronchospasm: If paradoxical bronchospasm occurs, treatment should be discontinued immediately and alternative therapy instituted. Cardiovascular effects: Like other medicinal products containing beta2-adrenergic agonists, may produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms. Use with caution in patients with cardiovascular disorders (coronary artery disease, acute myocardial infarction, cardiac arrhythmias, hypertension), convulsive disorders, thyrotoxicosis, and in patients who are unusually responsive to beta2-adrenergic agonists. Long acting beta2-adrenergic agonists (LABA) or LABA containing combination products such as Enerzair Breezhaler should be used with caution in patients with known or suspected prolongation of the QT interval or who are being treated with medicinal products affecting the QT interval.

Hypokalaemia: Beta2-adrenergic agonists may produce significant hypokalaemia in some patients, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. In patients with severe asthma hypokalaemia may be potentiated by hypoxia and concomitant treatment, which may increase the susceptibility to cardiac arrhythmias. Hyperglycaemia: Inhalation of high dose of beta2-adrenergic agonists and corticosteroids may produce increases in plasma glucose. Upon initiation of treatment, plasma glucose should be monitored more closely in diabetic patients. Anticholinergic effect related to glycopyrronium: use with caution in patients with narrow-angle glaucoma or urinary retention. Prevention of oropharyngeal infections: In order to reduce the risk of oropharyngeal candida infection, patients should be advised to rinse their mouth or gargle with water without swallowing it or brush their teeth after inhaling the prescribed dose. Systemic effects of corticosteroids: Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. Should be administered with caution in patients with pulmonary tuberculosis or in patients with chronic or untreated infections. Excipients: Contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose galactose malabsorption should not take this medicinal product. Interactions: No specific interaction studies

REAL DATA** TO SUPPORT THERAPEUTIC DECISIONS3

ONCE DAILY

Indacaterol acetate / glycopyrronium bromide / mometasone furoate inhala tion p owder

were conducted with indacaterol/glycopyrronium/mometasone furoate. Information on the potential for interactions is based on the potential for each of the monotherapy components. Medicinal products that prolong QTc interval: Should be administered with caution in patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or medicinal products known to prolong the QT-interval. Hypokalaemic treatment: Concomitant treatment with methylxanthine derivatives, steroids, or nonpotassium sparing diuretics may potentiate the possible hypokalaemic effect of beta2-adrenergic agonists. Beta-adrenergic blockers: Should not be given together with beta-adrenergic blockers unless there are compelling reasons for their use. Where required, cardioselective beta-adrenergic blockers should be preferred, although they should be administered with caution. CYP3A4 and P-glycoprotein inhibitors: Inhibition of CYP3A4 and P-gp has no impact on the safety of therapeutic doses of Enerzair Breezhaler. Cimetidine and inhibitors of organic cation transport: No clinically relevant drug interaction is expected when glycopyrronium is co-administered with cimetidine or other inhibitors of the organic cation transport. Other long-acting antimuscarinics and LABAs: Co-administration with other medicinal products containing long-acting antimuscarinics or LABAs is not recommended. Fertility, Pregnancy and Lactation: Should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the foetus. No information available on the presence of indacaterol, glycopyrronium or mometasone furoate in human milk, on the effects on a breast-fed infant, or on the effects on milk production. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Studies do not indicate a concern regarding fertility in either males or females. Undesirable Effects: Very common (≥1/10): nasopharyngitis, asthma (exacerbation). Common (≥1/100 to <1/10): upper respiratory tract infection, candidiasis, urinary tract infection, hypersensitivity, headache, tachycardia, oropharyngeal pain, cough, dysphonia, gastroenteritis, musculoskeletal pain, muscle spasms, pyrexia. Uncommon (≥1/1,000 to <1/100): hyperglycaemia, cataract, dry mouth, rash, pruritus, dysuria. Please consult the Summary of Product Characteristics for a detailed listing of all adverse events before prescribing. Pack Size(s): Single pack containing 30 x 1 hard capsules, together with one inhaler. Pack containing 30 x 1 hard capsules, together with 1 inhaler and 1 sensor. The sensor and App are not required for administration to the patient. The sensor and App do not control or interfere with delivery of the medicinal product using the inhaler. Legal Category: POM. Product (Marketing) Authorisation Number(s): EU/1/20/1438/002 & 003. Product (Marketing) Authorisation Holder: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland. Full prescribing information is available upon request from: Novartis Ireland Limited, Vista Building, Elm Park Business Park, Elm Park, Dublin 4. Tel: 01-2601255 or at www.medicines.ie. Detailed information on this product is also available on the website of the European Medicines Agency http://www.ema.europa.eu Prescribing Information last revised: July 2020.

Reporting suspected adverse reactions of the medicinal product is important to Novartis and the HPRA. It allows continued monitoring of the benefit/risk profile of the medicinal product. All suspected adverse reactions should be reported via HPRA Pharmacovigilance, website www.hpra.ie. Adverse events could also be reported to Novartis preferably via www.report.novartis.com or by email: drugsafety.dublin@novartis.com or by calling 01 2080 612.

References: 1. European Medicines Agency CHMP Press Release. Available at: https://www.ema. europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-28-30-april-2020

Date accessed: January 2021. 2. ENERZAIR® BREEZHALER®. Summary of Product Characteristics. Available at www.medicines.ie Date accessed: January 2021. 3. Propeller® Sensor for Enerzair® Breezhaler® Instructions for Use. Available in each pack of Enerzair® Breezhaler® plus Sensor.

* The Propeller® Sensor for the BREEZHALER® device (referred to here as “Sensor”) and the Propeller® mobile app are property of Propeller Health® ** When patients opt in to data collection & sharing, real data includes information on the patient’s rescue medication use and maintenance medication adherence collected via the sensor and app, as well as information on the patient’s asthma control status (as measured by Asthma Control Test, ACT).

Now available to prescribe as a co-pack with a Sensor* and App2, which provides:

An update on COPD

AUTHOR: Ruth Morrow, Registered Advanced Nurse Practitioner (Primary Care), and Respiratory Nurse Specialist (WhatsApp Messaging Service, Asthma Society of Ireland)

Chronic obstructive pulmonary disease (COPD) is a common, preventable and treatable disease that is characterised by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases. The chronic airflow limitation that is characteristic of COPD is caused by a mixture of small airways disease (eg obstructive bronchiolitis) and parenchymal destruction (emphysema), the relative contributions of which vary from person to person (Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2021).

The risk of developing COPD is related to tobacco use, indoor air pollution, occupational exposures, outdoor air pollution, genetic factors, age and gender, lung growth and development, socioeconomic status, asthma and airway hyper-reactivity, chronic bronchitis, and infections.

A shift in the COPD paradigm

The paradigm of COPD as a predominantly male disease is changing as smoking rates in both males and females are now similar and the number of deaths due to COPD among women has surpassed that of men. Women appear more susceptible to the effects of cigarette smoke, developing COPD earlier and with lower cigarette exposure than men. Women also commonly exhibit a COPD phenotype with airway dominant disease in comparison with emphysema and they also vary in response to treatment.

Diagnosis

The diagnosis of COPD involves a detailed history, spirometry, investigations, assessment of symptoms.

History

The history should include:

 Medical and surgical history,

 Smoking history, including pack year history,

 Occupational history.

Spirometry

Post-bronchodilator ratio of FEV1 /FVC < 70 per cent or 0.7 indicates COPD. Table 1 illustrates the severity of obstruction using FEV1

Investigations

 Blood screen to include FBC and TFTs

 Chest x-ray

 ECG

Assessment of symptoms

The characteristic symptoms of COPD are chronic and progressive dyspnoea, cough, and sputum production that can be variable from day-to-day. Dyspnoea is usually progressive, persistent and characteristically worse with exercise. Patients may have an intermittent cough which may be unproductive but many patients will commonly cough up white/ clear non-purulent sputum. Symptoms can be assessed using the COPD Assessment Tool (CAT test) and the Medical Research Council Dyspnoea (MRC) scale. The CAT test is an eight-item measure of health status impairment in COPD (http://catestonline.org). The MRC scale is illustrated in Table 2

ABCD assessment tool

The ABCD assessment tool (Figure 1) is a useful tool for assessing severity of COPD. The assessment of COPD has been refined to include assessment of symptoms and risk of future exacerbations.

Pharmacological treatment

Bronchodilator therapy remains the mainstay of the management of stable COPD. Pharmacological therapies are used to reduce symptoms, reduce the severity and frequency of exacerbations, improve exercise tolerance and health status.

The main groups of medications include:

 Beta-agonists – these relax smooth muscle by stimulating the beta2 adrenergic receptors. Beta-agonists can be classified into short-acting (SABA) and long-acting (LABA). Eg, salbutamol (SABA), salmeterol (LABA), indacaterol (LABA), vilanterol (LABA), formoterol (LABA), olodaterol (LABA).

 Antimuscarinic drugs block the bronchoconstrictor effects of acetylcholine on M3 muscarinic receptors. These can also be classified into short-acting (SAMA) and long-acting (LAMA). Eg, ipratropium (SAMA), tiotropium (LAMA), umeclidinium (LAMA), aclidinium bromide (LAMA), glycopyrronium (LAMA).

TABLE 1: GOLD (2021) classification based on FEV1

PLEASE TICK IN THE BOX THAT APPLIES TO YOU (ONE BOX ONLY)

mMRC Grade 0. I only get breathless with strenuous exercise

mMRC Grade 1. I get short of breath when hurrying on the level or walking up a slight hill

mMRC Grade 2. I walk slower than people of the same age on the level because of breathlessness, or I have to stop for breath when walking on my own pace on the level

mMRC Grade 3. I stop for breath after walking about 100 meters or after a few minutes on the level

mMRC Grade 4. I am too breathless to leave the house or I am breathless when dressing or undressing

C D A B

SYMPTOMS

To-date, there is no conclusive clinical trial evidence that any existing medications for COPD modify the long-term decline in lung function (GOLD, 2021).

Pharmacological algorithms are given for the initiation, escalation or deescalation of treatment according to the individual assessment of symptoms and exacerbation risk. In previous publications of GOLD reports, recommendations were only given for treatment initiation. Table 3 illustrates the pharmacological treatment options according to the patient’s COPD classification.

Poor inhaler technique can result the use of multiple devices, lack of education on technique and older age. To improve technique, it is recommended that patients are educated and trained with the appropriate devices. The choice of device should be tailored to the individual depending on the patient’s ability to use it and taking their preference into account. Inspiratory effort can be assessed using the In-Check Dial meter to ensure the patient has sufficient inspiratory effort to inhale the appropriate device.

Ongoing monitoring and follow-up

 Combining bronchodilators may increase the degree of bronchodilation whilst lowering the risk of side-effects compared to increasing the dose of a single bronchodilator agent.

 Methylxanthines – this group of drugs remain controversial as to their mechanism of action. There is evidence of bronchodilation in stable COPD. Theophylline is the most commonly used. However, there are significant drug

interactions with its use and clearance of the drug declines with age.

 Inhaled corticosteroids (ICS) should not be used as a single agent in the management of COPD. In patients with moderate to severe COPD, the use of ICS combined with a LABA is more effective than using either agent alone in improving lung function, health status, and reducing exacerbations (GOLD, 2021).

GOLD (2021) recommends that regular review should focus on dyspnoea and exacerbations. Whichever is the most problematic for the patient should be the focus of the review. For patients with persistent breathlessness or exercise limitation on LABA/ICS treatment, LAMA can be added to escalate to triple therapy. Alternatively, switching from LABA/ICS to LABA/LAMA should be considered if the original indication for ICS was inappropriate (eg, an ICS was used to treat symptoms in the absence of a history of exacerbations), or there has been a lack of response to ICS treatment, or if ICS sideeffects warrant discontinuation (GOLD, 2021). At all stages, dyspnoea due to other causes (not COPD) should be investigated and treated appropriately. Inhaler technique and adherence should be considered as causes of inadequate treatment response

TABLE 2: Medical Research Council Scale

FIGURE 1: The revised GOLD ABCD assessment tool

COPD CLASSIFICATION TREATMENT OPTIONS AS RECOMMENDED BY GOLD

(2016)

A SABA OR SAMA

B

LABA OR LAMA

C

ICS & LABA OR LAMA

D

LABA WITH ICS AND LAMA

DRUGS

SABA: Salbutamol, terbutaline

SAMA: Ipratropium bromide

LABA: Salmeterol, formoterol, indacaterol, olodaterol

LAMA: Tiotropium, umeclidinium, aclidinium, glycopyrronium

INHALER DEVICE OPTIONS

MDI with spacer, Easi-breathe, Diskus, Turbohaler

MDI

MDI with spacer, Turbohaler, Breezhaler, Respimat

Respimat, Handihaler, Genuair, Elipta, Breezhaler

ICS/LABA: Budesonide/formoterol, vilanterol/fluticasone

ICS/LAMA: Aclidinium/formoterol

LAMA: Tiotropium, umeclidinium, aclidinium, glycopyrronium,

ICS/LABA: Budesonide/formoterol, vilanterol/fluticasone

ICS/LAMA: Aclidinium/formoterol

LAMA: T iotropium, umeclidinium, aclidinium, glycopyrronium,

Turbohaler, Spiromax, Easyhaler, Elipta

Genuair

Respimat, Handihaler, Genuair, Elipta, Breezhale

Turbohaler, Spiromax, Easyhaler, Elipta

Genuair

Respimat, Handihaler, Genuair, Elipta, Breezhaler

TABLE 3: Pharmacological treatment options based on COPD classification (GOLD, 2021)

FIGURE 2: Pharmacological treatment with the ABCD assessment tool (GOLD, 2021)

umeclidinium/vilanterol

HAS POSITIVE HEAD-TO-HEAD DATA VS. ANOTHER ONCE-DAILY

In symptomatic patients with moderate COPD

*Anoro Ellipta compared to tiotropium/olodaterol showed statistical superiority on pre-specified secondary endpoint of trough FEV1 at 8 weeks in the Intent to Treat population. ITT population n=236 (180mL vs. 128mL in trough FEV1; Difference 52ml (p<0.001, 95% CI:28,77).

The primary endpoint of non-inferiority on trough FEV1 at Week 8 in the PP population was met. Non-inferiority was met for the primary endpoint at Week 8 in the PP population (n=227) (175mL Anoro Ellipta and 122mL tiotropium/olodaterol, 95% CI: 26, 80; p<0.001)1

Learn more by visiting:

Anoro Ellipta is contraindicated for patients who are hypersensitive to the active substances or to any of the excipients. Anoro Ellipta is not indicated for the treatment of acute episodes of bronchospasm. Cardiovascular events, such as cardiac arrhythmias, may be seen after the administration of muscarinic receptor antagonists and sympathomimetic agents, including umeclidinium/vilanterol. Therefore, Anoro Ellipta should be used with caution in patients with severe cardiovasular disease. Due to antimuscarinic activity (i.e. LAMA class activity), umeclidinium/vilanterol should be used with caution in patients with urinary retention or with narrow-angle glaucoma.2

LAMA/LABA* 1

An 8-week, randomised, open-label, two-period crossover in symptomatic patients with moderate COPD (post bronchodilator FEV1 ≤70% and ≥ 50% of predicted value, mMRC≥2) and not receiving ICS at inclusion.1

COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; LABA, long-acting beta2-agonist; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council scale; ITT, intent to treat; PP, per protocol.

▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information.

Anoro Ellipta 55/22mcg is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD)2

Anoro®▼ Ellipta® (umeclidinium bromide/vilanterol [as trifenatate]) Prescribing information (Please consult the full Summary of Product Characteristics (SmPC) before prescribing)

Anoro® Ellipta® 55/22mcg (umeclidinium bromide/vilanterol [as trifenatate]) inhalation powder. Each single inhalation of umeclidinium bromide (UMEC) 62.5 micrograms (mcg) and vilanterol (VI) 25mcg provides a delivered dose of UMEC 55mcg and VI 22mcg. Each delivered dose contains approx. 25 mg lactose. Indications: COPD: Maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. Dose and administration: Inhalation only. COPD: One inhalation once daily at the same time of the day. Contraindications: Hypersensitivity to the active substances or to any of the excipients (lactose monohydrate and magnesium stearate).

Precautions: Anoro Ellipta should not be used in patients with asthma. Treatment with Anoro Ellipta should be discontinued in the event of paradoxical bronchospasm and alternative therapy initiated if necessary. Cardiovascular effects may be seen after the administration of muscarinic receptor antagonists and sympathomimetics therefore Anoro Ellipta should be used with caution in patients with severe cardiovascular disease. Anoro Ellipta should be used with caution in patients with urinary retention, narrow angle glaucoma, convulsive disorders, thyrotoxicosis, hypokalaemia, hyperglycaemia and severe hepatic

impairment. No dose adjustment is required in renal or mild to moderate hepatic impairment. Patients with rare hereditary problems of galactose intolerance, the Lapp total lactase deficiency or glucose-galactose malabsorption should not use Anoro Ellipta. Acute symptoms: Anoro Ellipta is not indicated for acute episodes of bronchospasm. Warn patients to seek medical advice if short-acting inhaled bronchodilator use increases, a re-evaluation of the patient and of the COPD treatment regimen should be undertaken. Interactions with other medicinal products: Interaction studies have only been performed in adults. Avoid β-blockers. Caution is advised when co-administering with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, itraconazole, ritonavir, telithromycin). Anoro Ellipta should not be used in conjunction with other long-acting β2-adrenergic agonists or medicinal products containing long-acting muscarinic antagonists. Caution is advised with concomitant use with methylxanthine derivatives, steroids or non-potassium-sparing diuretics as it may potentiate possible hypokalaemic effect of β2adrenergic agonists. Fertility, pregnancy, and breast-feeding: No available data. Balance risks against benefits. Side effects: Common: Urinary tract infection, sinusitis, nasopharyngitis,

References: 1. Feldman G.J et al. Adv Ther. 2017 Nov;34(11):2518-2533. 10.1007/s12325-017-0626-4.

2. Anoro Ellipta Summary of Product Characteristics. Available from: www.medicines.ie. Accessed April 2021.

ANORO ELLIPTA was developed in collaboration with ©2021 GSK group of companies. All rights reserved.

pharyngitis, upper respiratory tract infection, headache, cough, oropharyngeal pain, constipation and dry mouth. Uncommon: Hypersenstivity reactions including rash, tremor, dysgeusia, dysphonia, atrial fibrillation, supraventricular tachycardia, rhythm idioventricular, tachycardia, supraventricular extrasystoles and palpitations. Rare: Anaphylaxis, angioedema, urticaria, vision blurred, glaucoma, intraocular pressure increased, paradoxical bronchospasm, urinary retention, dysuria and bladder outlet obstruction. Frequency not known: Dizziness. Marketing Authorisation (MA) Holder: GlaxoSmithKline (Ireland) Limited, 12 Riverwalk, Citywest Business Campus, Dublin 24, Ireland. MA

Nr: 55/22mcg 1x30 doses [EU/1/14/898/002]. Legal category:

POM B. Last date of revision: January 2021. Job Ref: PI-3826. Further information available on request from GlaxoSmithKline, 12 Riverwalk, Citywest Business Campus, Dublin 24, Tel: 01-4955000.

Adverse events should be reported directly to the Health Products Regulatory Authority (HPRA) on their website: www.hpra.ie. Adverse events should also be reported to GlaxoSmithKline on 1800 244 255.

Anoro and Ellipta are registered trademarks of the GlaxoSmithKline group of companies

PM-IE-UCV-ADVT-210001

Date of Preparation: April 2021

Where exacerbations are the predominant trait, prophylactic macrolide antibiotics should be considered following cardiovascular assessment. Assessment of eosinophils can be useful when the patient is experiencing exacerbations. If the eosinophils are above 0.1 and the patient has experienced two or more exacerbations with one hospitalisation or are above 0.3, initiating or escalating ICS can be beneficial (GOLD, 2021). Roflumilast, a treatment option, is a selective inhibitor of phosphodiesterase-4 (PDE-4) that has unique anti-inflammatory activity and is used to treat and prevent exacerbations.

Non-pharmacological measures

1. Smoking cessation

Smoking cessation is of paramount importance in the management of COPD regardless of disease severity. Support given by health professionals significantly increases quit rates over self-initiated strategies. Even a brief (three-minute) period of counselling to urge a smoker to quit results in smoking quit rates of 5-to-10 per cent. Smoking cessation should be encouraged at all severities of the condition. Nicotine replacement therapy (nicotine gum, nasal spray, transdermal patch, sublingual tablet, or lozenge) as well as treatment with varenicline reliably increases long-term smoking abstinence rates and are significantly more effective than placebo (GOLD, 2021).

2. Pulmonary rehabilitation

Pulmonary rehabilitation has been proven to have significant benefits in reducing dyspnoea, fatigue, and exacerbations, and improving quality-of-life in people with COPD. Although an effective pulmonary rehabilitation programme is six weeks, the longer the programme continues, the more effective the results. If exercise training is maintained at home, the patient’s health status remains above pre-rehabilitation levels (McCarthy et al, 2015).

3. Exercise

Patients should be encouraged to carry out breathing exercises on a daily basis. These will assist in the expectoration of

sputum. Exercises such as chest and shoulder exercises, shoulder raises, step ups and sit to stand exercises should be encouraged as this will assist in maintain upper body strength with the ultimate aim of prevention of muscle wasting. Patients can be directed to www.copd.ie for videos on pursed lip breathing and the active cycle of breathing.

blood gas (ABG) or oxygen saturation while inspiring the same level of oxygen or room air to determine if oxygen is therapeutic and still indicated, respectively (GOLD, 2021).

Management of comorbidities

4. Education

Patients require ongoing education and support to assist them to live and maintain optimal lifestyles. Education about the disease process, inhaler technique, adherence to medication, immunisations, pulmonary rehabilitation, smoking cessation and long-term oxygen therapy are required. All patients should have a COPD communication card (Figure 3), which outlines their treatment including oxygen therapy.

Oxygen therapy

Long-term oxygen therapy is indicated for stable patients who have:

 PaO2 at or below 7.3 kPa (55mmHg) or SaO2 at or below 88 per cent, with or without hypercapnia confirmed twice over a three-week period; or

 PaO2 between 7.3 kPa (55mmHg) and 8.0kPa (60mmHg), or SaO2 of 88 per cent, if there is evidence of pulmonary hypertension, peripheral oedema suggesting congestive cardiac failure, or polycythaemia (haematocrit >55 per cent).

Once placed on long-term oxygen therapy (LTOT) the patient should be re-evaluated after 60-to-90 days with repeat arterial

Many patients with COPD have co-existing illness such as diabetes, cardiovascular disease, osteoporosis and depression to mention but a few. In general, the presence of comorbidities should not affect COPD treatment and co-morbidities should be treated according to standards and guidelines. Lung cancer is common in patients with COPD. Gastroesophageal reflux is common and is associated with an increased risk of exacerbations and therefore should be managed optimally. Osteoporosis is also common due to recurrent use of oral steroids, lack of weight-bearing exercise and being overor underweight. GOLD recommend that treatments for comorbidities should kept as simple as possible to avoid polypharmacy (GOLD, 2021).

Conclusion

This article has focused on the diagnosis, management and prevention of COPD. The definition, classification, pharmacological, non-pharmacological, the importance of inhaler technique and co-morbidities have been addressed. There have been significant changes to the assessment tool which has simplified the classification of COPD, which will enable practitioners to individualise the patient’s management and treatment and ultimately improve patient outcomes and quality-of-life. ■

References

1. Global Strategy for the Diagnosis, Management and Prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2021. Available from: http://www.goldcopd.org/

2. McCarthy B, Casey D, Devane D, Murphy K, Murphy E, Lacasse Y. (2015)

Pulmonary rehabilitation for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews

To-date, there is no conclusive clinical trial evidence that any existing medications for COPD modify the long-term decline in lung function (GOLD, 2021)

Fictional patient, for illustrative purposes only

For COPD patients on treatment with ICS/LABA and at risk of exacerbation* 1

*A worsening of symptoms or a history of exacerbation treated with antibiotics or oral corticosteroids in the past 12 months

It’s the things

you do today that make a big difference to their tomorrows1-3

TRELEGY Ellipta provides your patients with statistically superior improvements in lung function and health-related quality of life, and reduction in annualised rate of moderate/ severe exacerbations** vs. budesonide/formoterol***1–3

**Moderate exacerbation is a worsening of symptoms or a history of exacerbation treated with antibiotics or oral corticosteroids. A severe exacerbation is a worsening in symptoms that required hospitalisation.

TRELEGY Ellipta (FF/UMEC/VI) 92/55/22 mcg OD is indicated for maintenance treatment in adult patients with moderate to severe COPD who are not adequately treated by a combination of an ICS and a LABA or a combination of a LAMA and a LABA1

▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

***Co-primary endpoints were change from baseline in trough FEV1 and SGRQ at week 24 (n=1810). A subset of patients (n=430) remained on blinded study treatment for 52 weeks. Trelegy showed an improvement in trough FEV1 of 171mL versus budesonide/formoterol (p < 0.001, 95% CI 148,194) at week 24. Trelegy showed an improvement in health-related quality of life (SGRQ) of 2.2 units (p <0.001, 95% CI 3.5, 1.0) at week 24. At week 52 in a subset of patients Trelegy showed a 44% reduction in annualised rate of moderate/severe exacerbations versus budesonide/formoterol (95% CI 15,63, p=0.006, Absolute difference 0.16).

TRELEGY Ellipta is generally well tolerated. Common adverse reactions include: pneumonia, upper respiratory tract infection, bronchitis, pharyngitis, rhinitis, sinusitis, influenza, nasopharyngitis, candidiasis of mouth and throat, urinary tract infection, headache, cough, oropharyngeal pain, constipation, arthralgia, back pain1 FF, fluticasone furoate; ICS, inhaled corticosteroid; LABA, long-acting ß2-agonist; LAMA, long-acting muscarinic antagonist; OD, once-daily; UMEC, umeclidinium, VI, vilanterol

References: 1. TRELEGY Ellipta SmPC 2019. 2. Lipson DA et al. Am J Respir Crit Care Med 2017; 196:438–446. 3. Lipson DA et al.N Engl J Med 2018; 378:1671–1680.

Trelegy▼ Ellipta (fluticasone furoate/umeclidinium/vilanterol [as trifenatate]) Prescribing information. Please consult the full Summary of Product Characteristics (SmPC) before prescribing Trelegy Ellipta (fluticasone furoate/umeclidinium/vilanterol [as trifenatate]) inhalation powder. Each single inhalation of fluticasone furoate (FF) 100 micrograms (mcg), umeclidinium bromide (UMEC) 62.5 micrograms and vilanterol as trifenatate (VI) 25 mcg provides a delivered dose of 92 mcg FF, 55 mcg UMEC and 22 mcg VI. Indications: Maintenance treatment in adult patients with moderate to severe COPD who are not adequately treated by a combination of an inhaled corticosteroid (ICS) and a long-acting ß2-agonist (LABA) or a combination of a LABA and a long acting muscarinic antagonist. Dosage and administration: One inhalation once daily at the same time each day. Contraindications: Hypersensitivity to the active substances or to any of the excipients (lactose monohydrate & magnesium stearate). Precautions: Paradoxical bronchospasm, unstable or life-threatening cardiovascular disease or heart rhythm abnormalities, convulsive disorders or thyrotoxicosis, pulmonary tuberculosis or patients with chronic or untreated infections, narrow-angle glaucoma, urinary retention, hypokalaemia, patients predisposed to low levels of serum potassium, diabetes mellitus. In patients with moderate to severe hepatic impairment patients should be monitored for systemic corticosteroid-related adverse reactions. Eye symptoms such as blurred vision may be due to underlying serious conditions such as cataract, glaucoma or central serous chorioretinopathy (CSCR); consider referral to ophthalmologist. Increased incidence of pneumonia has been observed in patients with COPD receiving inhaled corticosteroids. Risk factors for pneumonia include: current smokers, old age, patients with a history of prior pneumonia, patients with a low body mass index and severe COPD. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Trelegy. Acute symptoms: Not for acute symptoms, use short-acting inhaled bronchodilator. Warn patients to seek medical advice if short-acting inhaled bronchodilator use increases. Therapy should not be abruptly stopped without physician supervision due to risk of symptom recurrence. Systemic effects: Systemic effects of ICSs may occur, particularly at high doses for long periods, but much less likely than with oral corticosteroids. Interactions with other medicinal products: Caution should be exercised with concurrent use of ß-blockers. Caution is advised when co-administering with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, cobicistat-containing products), hypokalaemic treatments or non-potassium-sparing diuretics. Co-administration with other long-acting muscarinic antagonists or long acting ß2-adrenergic agonists is not

Start your patients on TRELEGY Ellipta today, expect more from tomorrow 1,2

recommended. Pregnancy and breast-feeding: Experience limited. Balance risks against benefits. Side effects: Common (≥1/100 to <1/10): pneumonia, upper respiratory tract infection, bronchitis, pharyngitis, rhinitis, sinusitis, influenza, nasopharyngitis, candidiasis of mouth and throat, urinary tract infection, headache, cough, oropharyngeal pain, arthralgia, back pain. Uncommon (≥1/1,000 to <1/100): viral respiratory tract infection, supraventricular tachyarrhythmia, tachycardia, atrial fibrillation, dysphonia, dry mouth, fractures. Rare (≥1/10,000 to <1/1,000): Hypersensitivity reactions, including anaphylaxis, angioedema, urticaria, and rash. Not known (cannot be estimated from the available data): vision blurred. Marketing Authorisation (MA) Holder: GlaxoSmithKline Trading Services Limited, 12 Riverwalk, Citywest Business Campus, Dublin 24, Ireland. MA No. [EU/1/17/1236/002]. Legal category: POM B. Last date of revision: September 2020. Code: PI-6725. Further information available on request from GlaxoSmithKline, 12 Riverwalk, Citywest Business Campus, Dublin 24. Tel: 01-4955000.

Adverse events should be reported to the Health Products Regulatory Authority (HPRA) using an Adverse Reaction Report Form obtained either from the HPRA or electronically via the website at www.hpra.ie. Adverse reactions can also be reported to the HPRA by calling: (01) 6764971. Adverse events should also be reported to GlaxoSmithKline on 1800 244 255.

An update on alpha-1 antitrypsin deficiency in Ireland

AUTHORS: Malcolm Herron 1 , Daniel Fraughen 1 , Tomás Carroll 1,2 , Geraldine Kelly 2 , Noel G McElvaney 1 1Irish Centre for Genetic Lung Disease, RCSI Education and Research Centre, Beaumont Hospital, Dublin; and 2 Alpha-1 Foundation Ireland

In 1962, Laurell and Eriksson described an abnormal electrophoretic pattern (EP) in the serum of five Swedish patients, three of whom were noted to have significant lung disease despite a negligible smoking history. A protein missing from the EP of these patients was identified as alpha-1 antitrypsin (AAT), a serine protease inhibitor. AAT readily inhibits neutrophil elastase (NE), a serine protease produced by neutrophils. It is thought that the unopposed activity of NE in the lungs of alpha-1 antitrypsin deficient (AATD) patients results in the development of chronic obstructive pulmonary disease (COPD) and emphysema.

inheritance resulting in quantitative and/ or qualitative deficiency in AAT. M is the wildtype normal allele of AAT. Combinations of M and the commonest abnormal variant alleles S and Z account for almost all deficient genotypes encountered in clinical practice. M null or ‘Q 0 ’ mutations also exist and these do not produce any AAT protein.

World Health Organisation (WHO), American Thoracic Society (ATS), and European Respiratory Society (ERS) guidelines advocate targeted detection programmes for AATD. These guidelines recommend targeted testing of specific groups, with a special focus on COPD.

The National Targeted Detection Programme (NTDP) for AATD began in Ireland in 2004. Since then, 21,800 tests have been performed and 7,786 cases of AATD have been diagnosed.

A total of 405 ZZ individuals have been identified, as well as 413 SZ and 4,038 MZ individuals, who are also at risk of developing lung and liver disease. In addition, a large number of other clinically significant phenotypes have been detected, including IZ and FZ phenotypes. A number of very rare AAT mutations have also been identified. Two of these mutations (Nullcork and Nulldublin) have been discovered for the first time by the NTDP.

COPD is the third leading cause of death worldwide. AATD is the most common genetic cause of COPD. In addition to emphysema and bronchitis, AATD is also associated with bronchiectasis, cirrhosis, ANCA-associated vasculitis, panniculitis and difficult to control asthma.

Since the discovery of AAT, over 120 allelic variants have been described. These have autosomal co-dominant

TABLE 1: List of common AAT genotypes and simple guide to risk (based on data extrapolated from the Trinity Biobank)

In addition to emphysema and bronchitis, AATD is also associated with bronchiectasis, cirrhosis, ANCA-associated vasculitis, panniculitis and difficult to control asthma

AATD and Covid-19

At the beginning of the pandemic the Alpha-1 Foundation Ireland set up a Covid-19 specific webpage offering advice to patients on how to protect themselves against Covid-19. In addition, a helpline offered specific support to AATD patients and their families. The webpage received in excess of 16,000 hits through March to September 2020. Cocooning was a fundamental strategy employed by the severe AATD cohort during the initial waves of Covid-19.

Covid-19 led to a 12 per cent drop in sample requests to the NTDP in 2020. The laboratory remained open and all bloods were analysed, resulting in an additional 202 AATD diagnoses from March to September 2020. To date in 2021 the trend is a return to usual test request volumes.

Severe AATD qualified as a priority group permitting early Covid-19 vaccination. We have witnessed Covid-19 vaccination rates of ~99 per cent within the severe AATD patients attending the National Centre of Expertise for AATD in Beaumont Hospital, Dublin.

AATD research in RCSI

A recent phase 2 proof-of-concept study carried out in Beaumont hospital and

WHO SHOULD BE TESTED?

Adults with symptomatic emphysema or COPD (regardless of age or smoking history)

Adults with asthma with airflow obstruction that is incompletely reversible after aggressive treatment with bronchodilators

Asymptomatic individuals with persistent obstruction on pulmonary function tests with identifiable risk factors (eg, cigarette smoking, occupational exposure)

Adults with necrotising panniculitis

Siblings of individuals with AATD

Individuals with unexplained liver disease, including neonates, children, and adults, particularly the elderly

other centres with Vertex Pharmaceuticals was completed in June 2021. VX-864, an oral small molecule corrector designed to promote the proper folding of mutant Z-AAT, was shown to increase plasma AAT levels in the treatment group compared with placebo. This will potentially lay the groundwork for other studies in this area in the future.

A recent series of articles from the AATD research group in Beaumont Hospital published in the American Journal of Respiratory and Critical Care Medicine, European Respiratory Journal, and Thorax

have clarified the role of the 0.57g/dL putative protective threshold for AAT. This level was used as an efficacy target in many therapeutic studies of AAT augmentation therapy in AATD and was also used as an indication for therapy. The Beaumont/RCSI studies showed that an increased risk of COPD is not dependent on a level of 0.57g/dL, but that genotype represents a better indicator of risk, with ZZ and rare ZZ-equivalent genotypes independently associated with COPD.

These studies also confirmed that SZ and MZ AATD individuals have an increased

TABLE 2: The indications for screening for AATD

FIGURE 1: Results from the National AATD Targeted Detection Programme showing AAT phenotypes identified among 20,800 individuals tested

risk for COPD if they ever smoke, but no increased risk if they never smoke.

The AATD group in Beaumont has also explored the use of plasma purified AAT outside the area of AATD. In this regard, a double blind randomised placebo-controlled trial was conducted in Beaumont Hospital intensive care unit to look at the effects of AAT therapy on patients with Covid-19-related acute respiratory distress syndrome (ARDS). A total of 36 people with severe ARDS were enrolled and treated with AAT therapy or placebo. The results are currently pending analysis.

The future of AATD research

A new all-island study exploring the risk of AATD-related disease in families containing people with ZZ AATD (along with their MM siblings) will begin in the coming year. This follows on from our two previous successful studies of families containing either MZ or SZ AATD members. In this study we hope to clarify to what extent lung and liver disease is present in the siblings, parents and children of those with ZZ AATD, who have yet to be diagnosed or present themselves to their doctor because of lung problems. This important question regarding the natural clinical course remains unanswered and we hope to clarify the hidden burden of ZZ AATD in Ireland among families.

We also hope to clarify the clinical characteristics of the SS, IZ and FZ AATD genotypes. The risk of lung and liver disease in these patients requires further investigation. Previously, the largest study on the clinical characteristics of SS AATD included only 26 patients. To date little has been said about IZ or FZ AATD.

Kamada pharmaceutical Inc. have developed a form of AAT which can be delivered by inhalation. They will work with the Beaumont/RCSI unit to study this in a prospective phase 3 multi-centre, placebo-controlled, double

blind study evaluating its safety and efficacy in adult patients with severe AATD with moderate airflow obstruction (40 per cent ≤FEV1 ≤80 per cent of predicted; FEV1 /FVC ≤70 per cent). This study represents another avenue in the potential treatment of AATD.

Newborn screening

AATD is very common in Ireland. It is known from prevalence data that approximately one-in-25 carry a Z mutation and one-in-10 carry an S mutation. Extrapolating from this, it is estimated that there are 3,200 patients with ZZ AATD in Ireland and a further 16,000 with SZ AATD, in addition to approximately 200,000 with MZ AATD.

To date, the NTDP in Ireland has tested over 20,800 people for AATD. A total 405 patients with ZZ AATD have been identified through this programme. This means there are approximately 2,800 people with severe AATD left to be identified with similarly undiagnosed SZs and MZs. We estimate that only 12.5 per cent of patients in Ireland with ZZ AATD have thus far been identified.

Most patients with AATD remain undiagnosed, and when a diagnosis is made it typically occurs in the fifth decade of life, often long after irreversible lung or liver damage has already occurred. Those with no diagnosis or a late diagnosis will miss out on opportunities for specialist care and early behavioural interventions, and the opportunity to engage with clinical trials that are being conducted at the National Centre of Expertise for AATD at Beaumont Hospital.

It should be noted that we accept referrals from all medical professionals in Ireland and are happy to see patients with any abnormal phenotype to help with genetic counselling around their condition and to explain the rationale behind various lifestyle modifications.

Further upcoming research will include examining the plasma and bronchoalveolar lavage of MM and AATD patients to evaluate the proteaseantiprotease and neutrophil elastase theories of COPD pathogenesis. In addition, we will investigate the effects of clock genes on interleukin-6 and alpha-1 expression during normal circadian rhythms.

A diagnosis of alpha-1 provides a unique opportunity for early medical intervention and can prevent or postpone lung disease in both the affected individual and their relatives. In this regard, we advocate for national newborn screening in Ireland as the best intervention for early diagnosis. ■ Correspondence:

TABLE 3: Survey of Covid-19 infection in the Irish AATD Registry. N=185 eligible ZZ and equivalent severe genotypes; N=126 respondents (68 per cent response rate). *Double lung transplant recipient

Most patients with AATD remain undiagnosed, and when a diagnosis is made it typically occurs in the fifth decade of life, often long after irreversible lung or liver damage has already occurred

2021-2022 flu vaccine season in Ireland – child and adult vaccines

AUTHOR: Dr Tom Barrett, MB Dch MRCOG, Senior Medical Officer, HSE National Immunisation Office

This year the seasonal influenza vaccination programme includes all children aged twoto-17 years. The aim of the programme is to prevent influenza and its complications in children and to reduce the spread of influenza to others in the community. The influenza vaccine offered to children is live attenuated influenza vaccine (LAIV), which is given intranasally, and is available free of charge from GPs and community pharmacists.

Influenza disease

Influenza is a very common acute viral respiratory illness which affects all age groups. The virus is seen all year round, but peaks every winter. The degree of influenza infection is unpredictable; however, each year in Ireland influenza is responsible for between 200 and 500 deaths and as many as a 1,000 during a particularly severe season (2008/2009).1

Since the start of the Covid-19 pandemic, influenza activity has remained at low levels. Reporting worldwide has also been low with only 0.168-0.65 per cent tested specimens positive for influenza virus reported by the World Health Organisation (WHO) and CDC surveillance.3,4 However, WHO has recommended that this data be interpreted with caution. Globally influenza virus detections have increased in recent weeks, albeit at low levels.2 The very low levels of flu in the last flu season may mean decreased immunity and potentially increased susceptibility or at least unknown susceptibility for at-risk groups. With the relaxation of Covid-19 measures a rebounding in flu and Covid-19 cases may occur, which may place significant strain on the health and care system. Therefore, it is vitally important this season more than ever that those recommended the flu vaccine get vaccinated early. The flu vaccine is the best protection we have against flu.

This season three types of flu vaccines are being supplied by the HSE. All are quadrivalent flu vaccines (QIV); two nonlive and one live vaccine.

The 2021/2022 HSE seasonal flu vaccination programme will offer the following three vaccines:

 Fluad Tetra manufactured by Seqirus.

● This adjuvanted QIV is a non-live influenza vaccine.

● This is given intramuscularly.

● It is only licensed for use in people aged 65 years and over, and is the recommended vaccine for this age group.

 QIV (split virion, inactivated) manufactured by Sanofi Pasteur.

● This is a non-live QIV.

● This is given intramuscularly.

● It is licensed for use in those aged six months and over.

● It is the recommend vaccine for:

– Children aged six-to-23 months who are medically at-risk.

– Adults 18-to-64 year: who are in at-risk groups, pregnant women, healthcare workers, household contacts/carers of people with an underlying chronic health condition or Down syndrome.

 Fluenz Tetra, manufactured by AstraZeneca.

● This is a LAIV.

● This is given intranasally.

● It is only licensed for use in children aged two-to-17 years. It is the recommended vaccine for children aged two-to-17 years including those with long-term conditions.

The focus of this article is on the LAIV vaccine for children. A summary of all three vaccines is available at the end of this article.

For the 2021/2022 influenza season, the Department of Health, on National Immunisation Advisory Committee (NIAC) advice, once again includes children and

young persons in the influenza vaccination programme, providing funding to the HSE to offer Live Attenuated Influenza vaccine (LAIV) free to all children aged two-to-17 years inclusive.6

The aim of the extension of the influenza programme to children is to reduce:

 Morbidity and mortality from influenza in children.

 The number of people with influenza.

 The number of hospital admissions.

 Transmission of influenza to the elderly and persons in at-risk groups.

 Transmission to healthcare workers in families with children.

 Absenteeism of children from school and their parents from work.

Children outside of the two-to-17 years age group (aged six months to <two years) who have an underlying chronic medical condition, should receive the QIV as in previous years.

Influenza in children

Children are among the most susceptible to influenza infection. It is estimated that 20-30 per cent of children develop influenza during each influenza season compared to 5-to-10 per cent of adults.7 Children, because they have limited pre-existing immunity, are primary vectors of influenza transmission in the community and shed the virus at higher viral titres. Children transmit the influenza virus for a longer period than adults; they can transmit the influenza virus for 10 or more days, compared to six days in adults, therefore increasing spread of the disease.

Approximately 10 per cent of children under 15 years attend their GP with influenza in an average influenza season. Influenza is an important cause of pneumonia, bronchitis, otitis media, croup and bronchiolitis in children. Incidence rates are highest in the younger age groups leading to high rates of

excess outpatient visits, hospital admissions and antibiotic prescriptions.

In Ireland during the 2018/2019 influenza season, 1,245 children were hospitalised with influenza. Children aged under five years had the second highest hospitalisation rates for influenza after those aged 65 years and older.8

Between the 2009/2010 and 2018/2019 influenza seasons:

 4,750 children aged 0-14 have required hospitalisation as a result of influenza,  183 required critical care,  41 children died.1

Influenza vaccination for children in other countries

Nine European countries, the US, Canada and Australia recommend influenza vaccine for children. The UK gives LAIV to children, while Finland, the US and Canada give LAIV or QIV to children.9,10,11

In the US, LAIV has been recommended since 2004. LAIV has been authorised for use in Canada since 2011.

In 2013, the UK introduced trivalent LAIV for two- and three-year-olds with pilot programmes for primary school children. Quadrivalent LAIV was introduced during the 2014/2015 influenza season. The programme has extended year on year to include all children from two up to 15 years this year.12

In Finland, annual inactivated influenza vaccine was recommended for children aged six-to-35 months in 2007, and LAIV was introduced in 2015 to enhance vaccine uptake. Since then, all two- and threeyear old children have been eligible for vaccination with either LAIV or inactivated influenza vaccine. The programme has recently been extended to include all children up to six years of age.

In Ireland, for the 2021/2022 influenza season, vaccination of children will help minimise the burden of influenza, by preventing influenza in children and the transmission of influenza from children to those in at-risk groups. This should

reduce morbidity from influenza as well as influenza-related hospital admissions in all the at-risk groups.

This is especially important this influenza season, to minimise the impact on our health services from dual outbreaks of influenza and Covid-19.

LAIV for 2021/2022 influenza season

This flu season in Ireland the LAIV Fluenz Tetra (manufactured by Astra Zeneca) is being offered to all children aged two to 17 years. It is administered intra-nasally. The vaccine contains the following four vaccine virus strains as recommended by WHO:

 An A/Victoria/2570/2019 (H1N1)pdm09like virus;

 An A/Cambodia/e0826360/2020 (H3N2)like virus;

 A B/Washington/02/2019 (B/Victoria lineage)-like virus; and

 A B/Phuket/3073/2013 (B/Yamagata lineage)-like virus.

LAIV may contain residues of egg proteins (ovalbumin), maximum amount of less than 0.024 micrograms and gentamicin.

LAIV does not contain thiomersal or latex.

LAIV effectiveness

Since LAIV contains live attenuated viruses, it mimics natural infection with wild-type viruses, with the development of both mucosal and systemic immunity. Local mucosal antibodies protect the upper respiratory tract and may be more important for protection than serum antibodies, inducing more durable immune memory and so providing better longterm protection to children than inactivated influenza vaccines such as QIV.

In some studies, LAIV has been shown to be more effective in children compared with inactivated influenza vaccines.

In addition, LAIV may offer some protection against strains not contained in the vaccine, as well as virus strains that have undergone antigenic drift.

A recent meta-analysis of LAIV suggested an efficacy against confirmed disease of 83

per cent (95 per cent confidence interval 69-to-91 per cent).13

The UK pilot primary school programme introducing LAIV was evaluated in 2014/2015 and showed a:

 94 per cent reduction in primary school-age children GP influenza-like consultations;

 74 per cent reduction in primary schoolage emergency department attendances with respiratory complaints;

 93 per cent reduction in primary school-age confirmed influenza hospitalisations; and

 59 per cent reduction in adult GP influenza-like illness consultations.14

LAIV dose and administration

Each LAIV vaccine comes as a prefilled nasal applicator and each applicator contains 0.2ml nasal suspension. The vaccine is administered by the nasal route. One dose of LAIV is 0.2ml administered in divided doses into each nostril, ie, 0.1ml in each nostril.

If the child’s nose drips after vaccination, the vaccine dose does not need to be repeated. The vaccine is immediately absorbed after administration. Parents and guardians should be reassured the vaccine is still effective if this occurs. For the same reason the vaccine does not need to be repeated if the child sneezes or blows their nose after vaccination.

LAIV can be given together with or at any time before or after the administration of any other live attenuated (eg, MMR) or inactivated vaccines.

NIAC has recommended healthy children require one dose of LAIV. However, children in a medically at-risk group aged two-to-eight years inclusive are recommended two doses of LAIV if they have never had any influenza vaccine before (Table 1). The two doses should be given four weeks apart.

Contraindications to LAIV

 Anaphylaxis following a previous dose of influenza vaccine or any of its constituents (other than ovalbumin – see precautions).

 Asthma

● Acute exacerbation of symptoms increased wheezing and/or additional bronchodilator

treatment in the last 72 hours.

● Seek specialist advice if on regular oral steroids or previous ICU admission.

 Significant immunosuppression due to disease or treatment.

 Children who live with severely immunosuppressed persons (ie, post haematopoietic stem cell transplant).

 Concomitant use of aspirin/salicylates.

 Influenza antiviral medication within the previous 48 hours.

 Those with severe neutropaenia (absolute neutrophil count <0.5 × 109/L) to avoid an acute vaccine related febrile episode. This does not apply to those with primary autoimmune neutropaenia who can receive influenza vaccine unless contraindicated.

 Those on combination checkpoint inhibitors (eg, ipilimumab plus nivolumab) because of a potential association with immune-related adverse reactions.

 Pregnancy.

 Those post cochlear implant until the risk of a cerebrospinal fluid (CSF) leak has resolved –consult with the relevant specialist.

 Those with a cranial CSF leak.

The following are NOT contraindications

 Asymptomatic HIV infection.

 Children receiving

● Topical or inhaled corticosteroids;

● Low-dose systemic corticosteroids;

● Replacement therapy corticosteroids (eg, adrenal insufficiency).

Precautions

 Defer until recovered from an acute severe febrile illness.

 As LAIV has an ovalbumin content

≤0.024mcg per dose, it can be given to children with confirmed egg anaphylaxis or egg allergy in a primary care setting except children who have required ICU admission to hospital for a previous severe anaphylaxis to egg who should be given LAIV in hospital.

 Aspirin/salicylates should not be used for four weeks after vaccination unless medically indicated, as Reye’s syndrome has been reported following the use of salicylates during wild-type influenza infection.

 Avoid influenza antiviral medication for two weeks post vaccination.

 Children aged two-to-17 years for whom LAIV is contraindicated should be offered QIV (provided there are no contraindications to QIV).

Gelatin in LAIV

LAIV, like some other vaccines, contains gelatin derived from pork which is highly purified and hydrolysed and acts as a stabiliser. Gelatin in vaccines may cause concern to some members of the Muslim community. The National Immunisation Office has received a statement from the Chair of the Irish Council of Imams stating that vaccines containing gelatin are permitted. See www.immunisation.ie for further details.

LAIV side-effects

Very common or common (more than one-in-10 to one-in-100)

Nasal congestion/rhinorrhoea, decreased appetite, malaise, fever, headache, and myalgia. In post-marketing surveillance, overall rates of fever were similar to the rates following other childhood vaccines and were generally mild and of short duration.

Very rare (less than one-in-10,000)

Immediate allergic reactions - very rare cases of Guillain-Barré syndrome (GBS) have been observed in the post-marketing setting following influenza vaccination. The risk of GBS following influenza infection is significantly greater than that following influenza vaccination.

Can LAIV vaccine cause virus shedding?

The attenuated vaccine viruses in LAIV are cold adapted. They can replicate at the lower temperatures found in the nose, but cannot replicate efficiently at body temperature elsewhere in the body.

Vaccinated children can shed the attenuated virus for a few days after vaccination but the virus that is shed cannot cause infection. Peak incidence of shedding occurred two-to-three days postvaccination in Fluenz clinical studies.10

Each chapter of NIAC immunisation guidelines advise that: “In some circumstances, advice in these guidelines may differ from that in the Summary of Product Characteristics (SmPC). When this occurs, the recommendations in these guidelines, which are based on current expert advice from NIAC, should be followed.”

NIAC advice, based on the current expert guidance, supersedes the advice in the licensed SmPC.

NIAC guidelines advise that: “Children who live with severely immunosuppressed persons requiring isolation (eg, post haematopoietic stem cell transplant) should not receive the LAIV nasal vaccine.” This is a precautionary measure.

Therefore NIAC advice is that LAIV vaccine can be given to any child, for whom the LAIV vaccine is not contraindicated, who is living with any other person unless the adult is in isolation, eg, following a HSCT.

Children who are vaccinated with LAIV can ‘shed’ very small amounts of the weakened virus that is in the vaccine for a few days after vaccination. But the

1: Doses of LAIV required for children aged two-to-17 years

Type of vaccine

Reassortant influenza virus (live attenuated)

Active immunisation against four influenza virus strains (two A subtypes and two B types)

Licenced for Aged two-to-17 years

Target groups

Two-to-17-year-olds

Dose 0.2mls (administered as 0.1ml per nostril)

required

Two for at-risk groups or specific age groups**

Interval For those requiring two doses: Four week interval between doses

Supplied by National Cold Chain Services (NCCS)

Box of 10 nasal applicators

Store in a refrigerator (+2°C to + 8°C)

Do not freeze

Discard if the vaccine has been frozen

Keep the nasal applicator in the outer carton in order to protect from light

Appearance Nasal spray, suspension

Colourless to pale yellow

Small white particles may be visible

Influenza vaccine – surface antigen inactivated

Active immunisation against four influenza virus strains (two A subtypes and two B types)

Aged six months and over

Those aged six-to-23 months medically atrisk. Those aged 18-to-64 years who are in at-risk group, pregnant women, healthcare workers, household contacts/carers of people with underlying chronic health condition or Down syndrome

Also children aged two-to-17 years in at-risk groups ONLY if contraindicated to receive LAIV

One

Two for at-risk groups or specific age groups*

For those requiring two doses: Four week interval between doses

Box of 10 prefilled syringes with needles

Store in a refrigerator (+2°C to + 8°C)

Do not freeze Discard if the vaccine has been frozen

Keep the pre-filled syringe in the outer carton in order to protect from light

Reach room temperature before use Gently shake before use

After shaking gently, is a colourless opalescent liquid

Visually inspect - should not be used if foreign particles in the suspension

Influenza vaccine – surface antigen inactivated and adjuvanted  Adjuvant MF59C1

Active immunisation against four influenza virus strains (two A subtypes and two B types)

Aged 65 years and over only

65 years and older

*QIV - Two doses four weeks apart for children aged six months and less than nine years receiving the flu vaccine for the first time.

Two doses four weeks apart if post haematopoietic stem cell transplant or post solid organ transplant and receiving the vaccine post-transplant. Cancer patients who receive the vaccine while on chemotherapy and who complete their chemotherapy in the same season require two doses with the second dose at least four weeks after the completion of chemotherapy and

at least four weeks after the first dose (regardless of influenza vaccine in the last season).

**LAIV - Two doses four weeks apart for children aged two-to-eight years who are clinically at-risk and first time receiving any influenza vaccine. See the following for more information:

 www.hse.ie/eng/health/immunisation/hcpinfo/ guidelines/chapter11.pdf

 www.hse.ie/eng/health/immunisation/pubinfo/fluvaccination/algorithmflu.pdf

One

Not applicable (one dose only per flu season)

Box of 10 prefilled syringes with needles

Store in a refrigerator (+2 °C to +8 °C).

Do not freeze

Discard if the vaccine has been frozen

Keep the pre-filled syringe in the outer carton in order to protect from light

Gently shake before use. After shaking the normal appearance is a milky-white suspension

***Those with confirmed egg anaphylaxis or egg allergy can be given all of the above influenza vaccines in a primary care or school setting with the exception of those who have required admission to ICU for a previous severe anaphylaxis to egg. Those requiring inactivated influenza vaccine who have had a previous ICU admission for a severe anaphylaxis to egg should be referred for specialist assessment with regard to vaccine administration in hospital.

NAME OF VACCINE FLUENZ TETRA LAIV

QUADRIVALENT INFLUENZA VACCINE VIRUS (SPLIT VIRON, INACTIVATED) QIV FLUAD TETRA a QIV

weakened viruses do not cause flu infection in others, or in the person vaccinated.

NIAC makes no recommendation that children avoid other vulnerable people, including a parent who is on chemotherapy or immunotherapy.

NIAC advises: “Millions of doses of LAIV have been administered in the US for over 10 years and serious illness amongst immunocompromised contacts inadvertently exposed to vaccine virus has never been observed.”

Increasing uptake of influenza vaccine Research, both in Ireland and elsewhere, has consistently shown that doctors and other healthcare professionals are the most trusted sources of information on vaccination. A recommendation by a trusted healthcare professional has been shown to increase vaccine uptake.

Reminders to patients about vaccination have also been shown to increase vaccine uptake, be that by text, phone, email or letter.

References

1. Royal College of Physicians of Ireland. Immunisation Guidelines for Ireland, Influenza Chapter 11. www.hse.ie/eng/health/immunisation/hcpinfo/guidelines/chapter11.pdf

2. Health Protection Surveillance Centre. Influenza surveillance in Ireland – Weekly report influenza week 40 2021 (4th - 10th October 2021) www.hpsc. ie/az/respiratory/influenza/seasonalinfluenza/surveillance/influenzasurveillancereports/20212022season/ Influenza_Surveillance_Report_Week%2040%20 2021_Finalv1.0_15102021.pdf

3. Adlhoch C, Mook P, Lamb F, Ferland L, Melidou A, Amato-Gauci AJ, Pebody R, the European Influenza Surveillance Network. Very little influenza in the WHO European Region during the 2020/21 season, weeks 40 2020 to 8 2021. Euro Surveill 2021;26(11):pii=2100221. doi: 10.2807/1560-7917. ES.2021.26.11.2100221

4. Centers for Disease Control. US influenza Surveillance. www.cdc.gov/flu/weekly/index.htm

5. HSE. Seasonal Influenza Programme 2020/2021. www.hse.ie/eng/health/immunisation/hcpinfo/fluinfo/

6. HSE. Seasonal Influenza Vaccination Programme 2021/2022. www.hse.ie/eng/health/immunisation/

This influenza season, your recommendation to get the influenza vaccine to parents of children and other at-risk groups will be even more important, in order to maximise uptake.

Summary

The LAIV vaccine for children will help minimise the burden of influenza by protecting children from influenza and preventing transmission of influenza from children to those in at-risk groups.

This year there are three training modules available on flu vaccination for this year’s flu season. Two on the LAIV and the other on QIV/ aQIV. These are available on www.hseland.ie.

The www.hse.ie/flu website has also been updated with materials and information on the current influenza season.

Influenza remains a major public health issue and never more so than during the Covid-19 pandemic. Influenza vaccination is the best intervention available. Continuing the influenza vaccination programme to

hcpinfo/fluinfo/

7. Antonova EN, Rycroft CE, Ambrose CS, Heikkinen T, Principi N. Burden of paediatric influenza in Western Europe: a systematic review. BMC Public Health. 2012;12:968. 2012 Nov 12. doi:10.1186/14712458-12-968

8. The NHS national flu immunisation programme 2021/22. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/ file/1018779/Influenza_vaccination_information_ document_for_healthcare_practitioners.pdf

9. Health Protection Surveillance Centre (HPSC). Annual epidemiological report, influenza and other seasonal respiratory viruses in Ireland, 2018/2019 (December 2019). www.hpsc.ie/a-z/respiratory/influenza/seasonalinfluenza/surveillance/influenzasurveillancereports/previousinfluenzaseasonssurveillancereports/20182019season/Influenza%202018-2019%20 Season_Summary.pdf

10. The NHS national flu immunisation programme 2020/21. www.england.nhs.uk/wp-content/ uploads/2020/05/national-flu-immunisation-programme-2020-2021.pdf

11. Finnish Institute for health and welfare. Vaccination programme for children and adolescents [online]. Available from: https://thl.fi/en/web/vaccina-

children aged two-to-17 years aims to protect children and reduce transmission to others, thereby reducing the burden on our health services at this crucial time. However, it is also important to continue vaccinating the other recommended groups for flu vaccine with the age-appropriate vaccine (as detailed in the reference guide at the end of the article). ■

The following resources on LAIV are available from the National Immunisation Office:

 Frequently asked questions for healthcare professionals: www.hse.ie/eng/health/ immunisation/hcpinfo/fluinfo/flufaq/

 Algorithms on flu vaccination for children for healthcare professionals: www.hse.ie/eng/ health/immunisation/pubinfo/flu-vaccination/ laivalgorithm.pdf

 Information materials for parents in different languages and posters: www. hse.ie/eng/health/immunisation/pubinfo/fluvaccination/information/

 Commonly asked questions and answers on the safety of LAIV for parents: www.hse.ie/ eng/health/immunisation/pubinfo/flu-vaccination/ flu-vaccine-for-children/fluvaccineqas.html

tion/national-vaccination-programme/vaccinationprogramme-for-children-and-adolescents

12. Canadian immunisation guide chapter on influenza and statement on seasonal influenza vaccine for 2020–2021. www.canada.ca/en/public-health/ services/publications/vaccines-immunization/canadian-immunization-guide-statement-seasonal-influenza-vaccine-2020-2021.html#I1

13. Caspard H, Mallory RM, Yu J, Ambrose CS. Live-attenuated influenza vaccine effectiveness in children from 2009 to 2015-2016: A systematic review and meta-analysis. Open Forum Infect Dis 2017 Jul 24;4(3):ofx111. doi: 10.1093/ofid/ofx111

14. Pebody RG, Green HK, Andrews N, Boddington NL, Zhao H, Yonova I, et al. Uptake and impact of vaccinating school age children against influenza during a season with circulation of drifted influenza A and B strains, England, 2014/15. Euro Surveill 2015;20(39):pii=30029. doi: 10.2807/1560-7917. ES.2015.20.39.30029.15

15. European Medicines Agency. Quadrivalent live attenuated influenza (LAIV), nasal, Fluenz Tetra (AstraZeneca Pharmaceuticals (Ireland) DAC) SmPC. www.ema.europa.eu/en/documents/product-information/fluenz-tetra-epar-product-information_ en.pdf

Cystic lung disease

CASE 1

A 19-year-old male patient presented with a chronic dry cough of two years. He denied any other respiratory symptoms of shortness of breath, chest pain, postnasal drip, or haemoptysis. He was previously trialled on lansoprazole with no effect.

He was a premature birth at 24 weeks of gestation and required ICU admission and was ventilated for a month. He had recurrent tonsillitis, otitis media, hay fever, and asthma. He has a family history of interstitial lung disease (ILD), and his maternal uncle had a lung transplant because of ILD.

His laboratory investigations and pulmonary function testing were normal. He had a CT thorax, which demonstrated multiple cysts. He was diagnosed with cystic lung disease secondary to neonatal chronic lung disease (bronchopulmonary dysplasia).

CASE 3

An 81-year woman was referred for dry cough in addition to ongoing shortness of breath on exertion for 18 months. Past medical history included hypertension, chronic kidney disease stage 2 secondary to multiple bilateral simple renal cysts, osteoarthritis, moderate dementia, dyslipidaemia, never smoker, left ventricular hypertrophy and heart failure with preserved ejection fraction with left ventricular ejection fraction (LVEF) >50 per cent on echo cardiogram. A recent coronary angiogram showed mild atheromatous disease not requiring percutaneous intervention.

The patient denied any episodes of haemoptysis or chest pain and recent weight loss. Laboratory investigations were all normal apart from an elevated creatinine of 113umol/L, consistent with CKD stage 2, with a baseline BNP of 2200ng/L. IgE levels were within normal range. Vascular endothelial growth factor (VEGF) level

CASE 2

A 48-year female was referred with exertional dyspnoea. She has background history of hypertension, high BMI, and was an ex-smoker with a 20 pack year history, and hyperuricaemia. The patient had shortness of breath on exertion with desaturations to 85-to-90 per cent. The patient complained of frequent chest infections in the last two years and an intermittent productive cough. She denied any weight loss, night sweats or haemoptysis. Imaging on chest x-ray revealed a prominent hilum and bilateral increased reticular markings, more notable in the mid and lower zones. CT thorax revealed background cysts present throughout all lobes.

Pulmonary function testing (PFT) revealed obstructive lung disease with a

was also requested, and was noted to be significantly raised at 561pg/ml.

PFTs showed an FVC 119.7 per cent predicted, FEV1 114.2 per cent predicted, FEV1/FVC 75.8 per cent and DLCO 96.2 per cent of predicted value. An outpatient CT thorax was performed which demonstrated cystic changes throughout the upper and lower lobes bilaterally. There was no evidence of bronchiectasis and no honeycombing to suggest pulmonary fibrosis. Given the presence of multiple renal cysts, findings on CT thorax, and elevated VEGF-D level, the patient was diagnosed as having lymphangioleiomyomatosis (LAM).

Based on this diagnosis, pulmonary rehabilitation was arranged with subsequent six-monthly PFTs and followup in outpatients with optimisation of symptoms with a combined inhaler comprising of fluticasone 92mcg and vilanterol 22mcg one puff once-daily, salbutamol inhaler as required, with uniphyllin 200mg twice-daily added.

diffusing capacity of the lungs for carbon monoxide (DLCO) 25.2 per cent predicted. FEV1 was 39.8 per cent predicted and FVC 75.6 per cent predicted with FEV1/FVC 45 per cent. Overnight oximetry revealed significant desaturations to as low as 80 per cent, with 69.5 per cent of time spent below 95 per cent. Six-minute-walk-test provoked significant desaturations to as low as 78 per cent. Laboratory results were normal including autoimmune screen and alpha-1 antitrypsin, serum ACE levels, brain natriuretic peptide (BNP) and serum protein electrophoresis (SPEP). The diagnosis of pulmonary Langerhans cell histiocytosis (PLCH) was confirmed on lung biopsy. The patient has had her respiratory medications optimised and ambulatory oxygen arranged. She is engaging in pulmonary rehab.

Cystic lung disease is a diverse group of disorders characterised by multiple cysts. Cysts are round or irregularly shaped, have a thin walled (less than 2mm) parenchymal lucency or low attenuation area with a well-defined interface with normal lung (Hansell et al. 2008). 3 The mechanism of cyst formation in most cases involves remodelling associated with inflammation or infiltration involved with resulting in displacement, destruction or replacement of alveolar septa, distal airways, and small vessels within the secondary lobules of the lung (Gupta et al. 2015). 2

Cystic lung disease can be classified based on underlying pathophysiology such as neoplastic, congenital, genetic, developmental, lymphoproliferative, infectious, inflammatory, or smoking related.

High resolution CT thorax has transformed the diagnostic approach

AUTHORS: Owais Rahman; Waqas Mahmood; Junaid Rasool; Timothy Healy; Kevin Burke; and Aidan O’Brien; Respiratory Department, University Hospital Limerick

to cystic lung disease, and it narrows the differential diagnosis significantly. Because of the complexity of the condition, it takes a while to come to a final diagnosis.

Making a diagnosis History

Pneumothorax used to be the most common acute presentation in cystic lung disease, but patients are increasingly diagnosed after incidental detection on CT done for other reasons. Pneumothorax in a young women should always be investigated. Recurrent pneumothorax should be a sign to investigate underlying lung disease. Therefore, a detailed history is the first step in diagnosis. Family history of pneumothorax is important as well. If there is a suspicion of tuberous sclerosis, then inquiry should be made about epilepsy, renal disease or learning difficulty in the family.

Examination

In specific cystic lung diseases, examination can be diagnostic. The skin signs of tuberous sclerosis complex can be subtle. They include subungual fibromas and nail pitting. Chest examination rarely have any diagnostic signs. Abdominal examination can occasionally reveal

renal masses. Blood pressure needs to be measured with renal angiomyolipomas.

Investigations

Bloods including full blood count (FBC), liver function tests (LFTs), electrolytes, lactate dehydrogenase, C reactive proteins (CRP), full autoantibody screen, alpha 1 antitrypsin testing, and urinalysis for microscopic haematuria is initially performed.

If immunological disorder is suspected, immunoglobulins (including IgG subclasses), protein electrophoresis, immunoelectrophoresis and urinary Bence Jones protein are helpful. VEGF-D testing in LAM can be helpful.

LFT is helpful at baseline to assess total lung capacity, diffusing capacity of the lung for carbon monoxide, and arterial blood gases. An obstructive picture is most common.

CT thorax can significantly narrow the differential diagnosis of cystic lung disease. But clinical diagnosis is made on history, examination, and CT findings.

Genetic testing, in particular testing for TSC1 and TSC2 mutation, is invaluable and can help confirm the diagnosis.

Most of these disorders need a surgical lung biopsy to collect enough sample to make a definitive diagnosis.

Table 2 summarises the characteristics of different cystic lung diseases.

PLCH

PLCH occurs in young adult smokers; 90 per cent of the patients have exposure to cigarette smoke. The patients present with non-specific shortness of breath or cough or sometimes they are asymptomatic and identified incidentally by chest radiography.

Langerhans cells are specialised epithelial-associated dendritic cells that regulate mucosal airway immunity.

Pneumothorax used to be the most common acute presentation in cystic lung disease, but patients are increasingly diagnosed after incidental detection on CT done for other reasons

lung biopsy or biopsy of extra thoracic site can confirm the diagnosis.

High resolution CT thorax has transformed the diagnostic approach to cystic lung disease, and it narrows the differential diagnosis significantly. Because of the complexity of the condition, it takes a while to come to a final diagnosis.

Making a diagnosis History

Cigarette smoke is most probably the key in activating cytokines which in turn activates Langerhans cells. The earliest lesion in PLCH is accumulation of Langerhans and other immune cells around terminal and respiratory bronchioles. Persistence of Langerhans cells and secondary recruitment of immune components results in airway remodelling and cystic changes.

The management involves smoking cessation, consideration of chemotherapy and management of complications, ie, pneumothorax.

LAM

The following patients should be screened for LAM:

 Young to middle-aged non-smoker females with pneumothorax.

 Females with TSC after the age of 18 and every five-to-10 years thereafter.

 Incidental discovery of an angiomyolipoma, lymphangiomyoma, cysts in the lung bases on abdominal CT, and unexplained chylous ascites or chylous effusions.

The diagnosis is considered in patients with smoking history, spontaneous pneumothorax, and cystic infiltrates of upper and middle lung zones.

Bronchoscopy can give a diagnosis in 30 per cent of these patients while excluding diagnosis which mimic PLCH. Surgical

Examination

LAM is caused by infiltration of lung with smooth muscle cells spread by blood and lymphatics. LAM occurs in tuberous sclerosis complex and a sporadic form not associated with tuberous sclerosis.

TSC-LAM and S-LAM are caused by mutation in either of the two known TSC genes.

Pneumothorax use to be the most common acute presentation in cystic lung disease, but patients are increasingly diagnosed after incidental detection on CT done for other reasons. Pneumothorax in a young women should always be investigated. Recurrent pneumothorax should be a sign to investigate underlying lung disease. Therefore, a detailed history is the first step in diagnosis. Family history of pneumothorax is important as well. If there is a suspicion of tuberous sclerosis, then inquiry should be made about epilepsy, renal disease or learning difficulty in the family is useful.

 Unexplained progressive dyspnoea on exertion in women with atypical presentation of chronic obstructive pulmonary disease (COPD)or asthma.

 VEGF levels of greater than 800pg/ml with characteristic findings on CT is diagnostic for LAM. ■

In specific cystic lung diseases examination can be diagnostic. The skin signs of tuberous sclerosis complex can be subtle. They include subungual fibromas and nail

TABLE 1: Types of cystic lung disease (classification table copied from Gupta et al. 2015)2

(Classification table copied from (Gupta et al. 2015)2

Table 2 summarises the characteristics of different cystic lung diseases.

Table 2 summarises the characteristics of different cystic lung diseases.

Table 2 (Ennis

References

PLCH

Table

1. Ennis S, Silverstone EJ, Yates DH. Investigating cystic lung disease: A respiratory detective approach. Breathe (Sheff). 2020;16(2):200041. doi:10.1183/20734735.0041-2020

disease. Part I. Am J Respir Crit Care Med 2015 Jun 15;191(12):1354-66. doi: 10.1164/ rccm.201411-2094CI

radiol.2462070712

PLCH

2. Gupta N, Vassallo R, Wikenheiser-Brokamp KA, McCormack FX. Diffuse cystic lung

3. Hansell DM, Bankier AA, MacMahon H, McLoud TC, Müller NL, Remy J. Fleischner Society: Glossary of terms for thoracic imaging. Radiology. 2008 Mar;246(3):697-722. doi: 10.1148/

4. Glasgow CG, Avila NA, Lin JP, Stylianou MP, Moss J. Serum vascular endothelial growth factor-D levels in patients with lymphangioleiomyomatosis reflect lymphatic involvement. Chest. 2009;135(5):1293-1300. doi:10.1378/chest.08-1160

PLCH occurs in young adult smokers; 90% of the patients have exposure to cigarette smoke. The patients present with non-specific shortness of breath or cough or sometimes they are asymptomatic and identified on incidentally by chest radiography.

PLCH occurs in young adult smokers; 90% of the patients have exposure to cigarette smoke. The patients present with non-specific shortness of breath or cough or sometimes they are asymptomatic and identified on incidentally by chest radiography.

2 (Ennis et al. 2020)1

et al. 2020)1

TABLE 2: Characteristics of different cystic lung diseases (classification table copied from Gupta et al. 2015)2

Re-introducing spirometry in general practice

AUTHOR: Ruth Morrow, Registered Advanced Nurse Practitioner (Primary Care), and Respiratory Nurse Specialist (WhatsApp Messaging Service, Asthma Society of Ireland)

Spirometry can help to confirm the diagnosis of asthma or chronic obstructive pulmonary disease (COPD), ensuring patients receive appropriate treatment. The use of diagnostic spirometry in primary care was severely disrupted by the Covid-19 pandemic. Even prior to the pandemic, spirometry services were underutilised in primary care for a number of reasons, such as lack of equipment and trained healthcare professionals. Some GP practices and respiratory units have recommenced performing spirometry. However, at the time of going to print, the author is aware the ‘green light’ has not been given for recommencement. Spirometry is considered a non-aerosol generating procedure (AGP), but as most patients will cough during the spirometry, this is a risk. Sputum induction using nebulised hypertonic saline or inhaled mannitol is also considered an AGP as inhalation of these substances may potentiate sputum production and therefore should be considered as AGPs.

The most effective method to protect healthcare workers from the risk of Covid-19 infection is vaccination. Patients likely to be infectious are those with clinical features suggestive of Covid-19 who require further evaluation, those with a diagnosis of Covid-19 who are still in the infectious period, and those who are close contacts of confirmed cases of Covid-19 still in the period of self-isolation. These people can generally be identified by appropriate clinical assessment. Staff members who are likely to be infectious should not attend work. Even after full vaccination staff

members who are symptomatic should not attend work themselves and should be assessed to determine if PCR testing is required. Pulmonary function tests can generally be deferred for patients until the infectious period has passed.1 It is important to differentiate as early as possible between those people likely to be infectious and those who are not, or in an exceptional circumstance where testing is deemed necessary.

as it may not be possible to maintain physical distance for all steps of the process. Liquid respiratory particles of different sizes are generated when talking, sneezing or coughing or during expiration for spirometry. There is therefore potential for transmission to the other person if either the patient or the nurse has an infectious respiratory disease transmitted through the air including Covid-19.

Airborne transmission: As the patient and the nurse performing the procedure share the same air space for a period of time there is potential for airborne transmission if either the patient or the nurse has an infection transmitted by the airborne route. Although Covid-19 is predominantly transmitted over a short range (droplet), the potential for longer range (airborne) transmission has increased with the emergence of the alpha and delta variants. This risk is a particular concern in poorly ventilated areas.

Risk of infection associated with spirometry

Contact transmission: The surface of equipment used in performing spirometry may become contaminated with respiratory secretions that may contain infectious organisms such as SARS-CoV-2. The patient or the nurse may then touch the contaminated surfaces and transmit the infectious organisms to their eyes, nose or mouth.

Droplet transmission: The patient and the nurse may be in close proximity

Implement physical distancing pre-procedure

 Consider to what extent adequate natural ventilation can be achieved in the clinical area.

 Consider also how to implement social distancing in waiting areas, eg, the layout of the appointments should be carefully staggered to avoid multiple patients arriving at the same time. Patients should be encouraged to wait remotely (for example in their car/ vehicle) to be admitted directly to the patient assessment area to minimise

Although Covid-19 is predominantly transmitted over a short range (droplet), the potential for longer range (airborne) transmission has increased with the emergence of the alpha and delta variants

patient numbers in the designated waiting area. The designated waiting area should be adapted (either by removing or marking seating) to ensure physical distancing is maintained. Develop contingencies in the event of unexpected congestion – identify sub-wait areas that can be used for overflow.

 Patients identified as high risk should be brought directly to the procedure room and avoid waiting in public areas.

Preparation for spirometry re-introduction

 Ensure practice is in accordance with recommended local infection control procedures to ensure health and safety of patients and staff is consistently maintained.

 Bacterial-viral filters should be used for all patients and thrown away by the patient at the end of testing.

 Immunocompromised patients should be tested at the start of the day.

 Infectious patients should be tested at the end of the day, and equipment should be stripped down and sterilised/parts replaced prior to reuse.

 Ensure there is adequate natural ventilation in the location used for testing. A gentle circulation of air rather than strong air movement is the goal.

 Consider use of a perspex screen where available – if not available, stand to the side of or behind the patient (not face-to-face).

 As spirometry is considered a nonAGP, but cough is a risk,1 this should be managed as follows:

• Ask the patient to cough through a filter; or

• Have a mask or visor ready for the patient to cough into.

 Use disposable spacers for bronchodilator reversibility testing.

During the procedure

 As a general principle, ensuring natural ventilation and increasing the distance between the nurse and the patient during the examination reduces the exposure to liquid respiratory particles from either party. Unvaccinated people accompanying the patient should not enter the testing room unless they are essential for performing the test, such as an interpreter, parent, guardian or carer. If they are accompanying the person, they should be assessed for symptoms of Covid-19. They should wear a face covering or mask and maintain a safe distance from the procedure unless they need to be close to the person for a specific reason. If a pause is required between testing, eg, when assessing response to bronchodilator therapy, the patient should remain in the room until testing is complete.

 All patients at standard risk and any accompanying persons are required to wear their own face covering in waiting areas or other areas where they are in contact with other members of the public unless their condition is such that they cannot tolerate a mask. The face covering should be worn at all times other than when removed to perform spirometry. The requirement of personal protective equipment (PPE) is based on an individual assessment of risk for the procedure. The exact level of PPE can be guided by the risk categorisation.1

Post procedure Cleaning

All staff should be aware of their role and responsibility in relation to cleaning. An adequate supply of suitable cleaning products in line with local policy should be available in the procedure room. After the procedure, cleaning of surfaces which have been in direct contact with the patient should be performed using a cleaning product in line with local policy. Where coughing or throat clearing has been provoked with potential for droplet contamination of the environment, then the surfaces in the immediate

space surrounding the patient should be wiped clean using detergent wipe/spray. Cleaning of the floor between patients is not required.

Equipment

Disposable mouth pieces with antimicrobial filters and disposable spacers should be used. Cleaning, decontamination and maintenance of equipment used for spirometry should conform to the manufacturer’s specifications. Reusable equipment that has no contact with blood/body fluids, mucus membranes or non-intact skin may be cleaned with a detergent and allowed to dry. Reusable equipment that is in direct contact with blood/ body fluids, mucus membranes or non-intact skin of a patient must be de-contaminated; that is cleaned then disinfected using a one-step or two-step cleaning method.

In summary

1. Follow local infection control policy, ensuring health and safety of patients and staff is consistently maintained.

2. Prioritise spirometry for:

 New presentations – those patients who require spirometry to confirm a diagnosis.

 Backlog patients where it may impact their management.

3. Continue with the risk assessment and infection control measures already taken prior to the pandemic, in addition to new measures to protect both staff and patients.

4. Clearly document the patient history. ■

Reference

HSE. Guidance on the infection prevention and control measures required for pulmonary function tests (PFTs) in the context of the Covid-19 pandemic. V1.3 07.07.2021. Available at: https://rb.gy/exll2u

Respiratory syncytial virus infection: An overview

AUTHOR: Theresa Lowry-Lehnen, GPN, RNP, PhD, CNS, and Associate Lecturer at Institute of Technology Carlow

Respiratory syncytial virus (RSV) is a common, ubiquitous and contagious viral pathogen that infects the respiratory tract of most children by two years of age. RSV is an RNA pneumovirus of the Paramyxoviridae family, and humans are the only natural host.

RSV is primarily a childhood infection; however, it may occur at any age and can be most severe in infants under one year of age, the immunocompromised, and in people aged 65 years and older.3,7 It infects 90 per cent of children within the first two years of life and frequently reinfects older children and adults.10

RSV infection can present as a variety of clinical syndromes including upper respiratory tract infections, bronchiolitis, pneumonia, exacerbations of asthma and viral-induced wheeze.1

Worldwide, it is estimated that RSV is responsible for approximately 33 million lower respiratory tract illnesses, three million hospitalisations, and up to 199,000 childhood deaths annually. The majority of deaths are in resource-limited countries.10 In medium- and high-resource countries, the RSV mortality rate in infants is almost nine times that of influenza.7

RSV has been shown to account for 22 per cent of all episodes of acute lower respiratory tract infection in children globally, with the greatest burden of severe disease requiring hospitalisation in infants under one year and particularly those under six months of age.2,5 For most babies and young children the infection is mild, presenting with coldlike symptoms which usually last one-totwo weeks, but for a small percentage, RSV infection can lead to serious and sometimes life-threatening problems, such as pneumonia or bronchiolitis.4 The chance of developing severe infection is highest for premature

babies, children less than 10 weeks old, children aged under two years with congenital heart or chronic lung disease, and infants and young children with a weak immune system or who are immunocompromised.3,4

Adults with weakened immune systems and those aged 65 years and older are also at increased risk of developing severe RSV disease. Approximately one-in-20 older people develop RSV infection each year. Overcrowding, smoking, and passive smoking are recognised risk factors for infection.3

RSV infection has been a notifiable disease in Ireland since January 2012, and RSV activity in Ireland is monitored by the Health Protection Surveillance Centre (HPSC).3 According to the HPSC (2020), nearly all children have been infected with RSV at least once, by two years of age. Most cases are not specifically diagnosed as RSV; however, the infection causes 80 per cent of bronchiolitis and 20 per cent of pneumonia cases in young children and RSV is a significant cause of infection and outbreaks in hospitals, neonatal units, day units, and nursing homes.3

RSV infections occur in a seasonal pattern in temperate climates with epidemics from October to April.7 Outbreaks typically occur in the winter months with the highest numbers of infections usually reported in December and January every year. The sharp winter peak varies little in timing or size from year to year, in contrast to influenza.3 In Ireland in recent weeks, there has been a significant surge in reported RSV cases and related presentations in general practice.

There is only one serotype of RSV, but it is classified into two strains, A and B, with differences consisting of variation in the structure of several structural membrane

proteins, most especially the attachment protein.10 One of the two major antigenic subgroups of RSV A or B, usually predominates each season.7

RSV typically spreads via hands, fomites and the airborne aerosol route. It spreads from person to person by aerosol droplets through coughing or sneezing, and is also spread through direct contact by touch. RSV can survive on surfaces and objects for 24 hours and spread can occur indirectly through contact with contaminated hands.1,4 Handwashing is the most effective infection control procedure.

Incubation period and symptoms

The incubation period for RSV-infected individuals ranges from three-to-eight days, but immunocompromised patients with severe infection may shed virus for up to four weeks. The frequent occurrence of mild or asymptomatic infection in otherwise healthy individuals makes infection control challenging.7

After inoculation into the nasopharyngeal or conjunctival mucosa, the virus rapidly spreads into the respiratory tract, where it targets its preferred growth medium, apical ciliated epithelial cells. There it binds to cellular receptors using the RSV-G glycoprotein and uses the RSV-F fusion glycoprotein to fuse with host cell membranes and insert its nucleocapsid into the host cell to begin its intracellular replication.10

Symptoms include: Fever, rhinorrhoea, pharyngitis, nasal congestion, sneezing, and coughing, which can be croupy or barking in nature, tachypnoea, sore throat, wheeze, decreased appetite, and ear infections in children. In very young infants, irritability, decreased activity and breathing difficulties may be the only symptoms of infection.

Lower respiratory tract infections, such as pneumonia or pneumonitis, are most likely to occur during a child’s first infection with RSV and may develop in 30-to-70 per cent of those with a first infection. Typically, only between 1 and 3 per cent of infected infants require hospitalisation.7

The infectious period lasts from shortly before onset to one week post the onset of symptoms. Most children recover in eight-to-15 days. Even after recovery, however, very young infants and children with weakened immune systems can continue to spread the virus for one-to-three weeks. Immunity is incomplete and short-lived. Repeated RSV respiratory infections can occur, although these are usually mild and become less common with increasing age.3,7

Bronchiolitis is an inflammatory process in the small airways of the lungs and is the most common clinical syndrome associated with RSV infection. It typically presents in infants under one year of age, but may be diagnosed in children up to two years old, and is characterised by a short history of low-grade fever, cough, coryza, dyspnoea, and reduced feeding. The symptoms usually peak in clinical severity between day three and five of the illness. RSV bronchiolitis presents a significant clinical burden. In the UK, infection with RSV is responsible for up to 80 per cent of all cases of bronchiolitis, similar to that of 65-to-70 per cent in the US.3,8

In older children, RSV typically presents as an upper respiratory tract infection, viral pneumonia, episodic viral-induced wheeze, or an acute exacerbation of asthma. Viral pneumonia is a common illness with five million cases reported globally in children annually. A meta-analysis of nine studies involving over 4,000 children investigating viruses identified by polymerase chain reaction (PCR), found that RSV was the causative organism in 11 per cent of communityacquired pneumonia cases.6

Diagnosis

Diagnosis of RSV includes a thorough medical history and a physical exam. A chest x-ray may be requested and blood and urine tests may be carried out to rule out a bacterial infection

or other conditions. Differential diagnosis can include asthma, bronchiolitis, influenza, croup, bronchitis and pneumonia.10 Respiratory viral testing may be used in a clinical setting to increase confidence in the diagnosis of a viral, rather than bacterial, cause for respiratory illness. RSV can be detected in nasopharyngeal aspirate, broncho-alveolar lavage, sputum, or swabs from the nose and throat by using realtime PCR, immunofluorescence, ELISA, and growth in cell culture. Reverse transcriptase-PCR (RT-PCR) assays are currently the gold standard in RSV testing and are available commercially. These are more sensitive than antigen detection and virus isolation methods. The sensitivity of antigen detection tests ranges from 80-to90 per cent in children, but is less sensitive in adults. Serological tests are used less for routine diagnosis and more for seroprevalence and epidemiological studies.3,7

Vaccination

There is currently no vaccine available against RSV infection. Palivizumab, which is a humanised mouse monoclonal antibody specific for the F protein of RSV, provides passive immunity against RSV. Palivizumab inhibits RSV binding to host cells and prevents fusion of infected cells with adjacent cells. It is authorised in Ireland for the prevention of serious lower respiratory tract disease requiring hospitalisation caused by RSV in children at high risk for RSV disease.7 Palivizumab prophylaxis reduces the absolute risk of RSV hospitalisation from about 10-to-5 per cent for premature babies, infants with chronic lung disease and haemodynamically significant congenital heart disease, particularly when complicated by large left-to-right shunts, and pulmonary hypertension. It does not reduce mortality or the need for mechanical ventilation.7,3

Palivizumab is given as an intramuscular injection monthly (up to five doses) during the RSV season. As it is very expensive and has a half-life of 18-to-21 days, meaning monthly injections are required to maintain protective titres, cost-benefit analyses limit its use to only the most vulnerable infants, those born prematurely with moderate or severe BPD, haemodynamically significant, acyanotic congenital heart disease, severe combined immunodeficiency, or infants

with other severe chronic lung conditions or requiring long-term ventilation.9 Differences in epidemiology, practice setting, healthcare systems and drug cost have resulted in variability in palivizumab recommendations and use nationally and internationally.

Treatment and prevention

The mainstay of treatment for the vast majority of RSV infections is supportive including rest, fluids and paracetamol, but passive preventive immunisation is available for at-risk children, including premature infants and infants with a history of cardiac, pulmonary, or neuromuscular diseases. Those with severe respiratory illness require hospitalisation, oxygen therapy, IV fluids and ventilatory support in the form of a highflow nasal cannula, CPAP, or intubation, and mechanical ventilation.7,10

Ribavirin is the only licensed antiviral medication for the specific treatment of RSV infection, but due to drug toxicity, including bone marrow suppression and potential carcinogenicity and teratogenicity and minimal clinical benefit, it has not been recommended for routine clinical use.9 Ribavirin may be considered for a small number of patients and treatment of RSV with ribavirin must be done under the supervision of an infection specialist, such as a consultant microbiologist or an infectious disease specialist.3

Other treatment modalities for bronchiolitis have been tried in the past and have failed to show broad, reproducible efficacy on clinically significant outcomes in RSV and bronchiolitis. These include albuterol, epinephrine, steroids, hypertonic saline, antibiotics, and chest physical therapy, and routine use of these interventions is not recommended.10 Antibiotics are not effective against RSV and it is important that unnecessary antibiotics are discontinued once a diagnosis is confirmed, to avoid adverse drug reactions and antibiotic resistance.3

Although palivizumab may help prevent serious complications of RSV infection, it is not used to treat RSV infection.

Infants who are recovering from RSV bronchiolitis can continue to have respiratory symptoms including cough and post-

bronchiolitis wheeze for several weeks/ months. There is no evidence for the use of steroids, montelukast or other medications in preventing these symptoms, but the acute episodes often respond to anti-asthma medication.9 High-risk infants with other comorbidities may require longer admission and some may even require mechanical ventilation. However, the majority of children with RSV make a full recovery and have an excellent outcome. The majority of children who need hospital admission are usually discharged in several days. Some infants with RSV may develop wheezing, but recent studies do not show an increased risk of asthma.10

Prevention and patient education is key, and frequent, careful handwashing is the most important measure in preventing the spread of RSV. Respiratory etiquette should be properly maintained and people with cold/ flu-like symptoms should cover their nose and mouth preferably with a tissue or cough and sneeze into their elbow and wash their hands afterwards for at least 20 seconds or use an alcohol-based rub/gel. Used tissues should be properly disposed of. Sharing utensils with persons who have RSV illness should be avoided and cleaning contaminated surfaces such as door handles may help stop the spread of RSV.3 Parental smoking is a known risk factor for RSV infection in infancy, and parents or carers who smoke should be offered smoking cessation advice and encouraged to stop smoking. Breastfeeding also offers some protection against RSV infection.9 Persons with RSV should not attend crèches, school, work, and non-residential institutions until well. It is important to prevent young infants, frail older persons and immunocompromised people coming into contact with individuals with respiratory infection.9

In the hospital setting, RSV transmission can be prevented by managing children with RSV together in the same ward, paying strict attention to handwashing guidelines, using barrier precautions and avoiding overcrowding through restriction of visitors.3 Several studies have shown that strict infection control practices including hand hygiene, the use of personal protective equipment when necessary, timely detection

and isolating or cohorting infants with RSV infection can reduce nosocomial RSV infection rates by 39-to-67 per cent.9

RSV research and outlook

The management of RSV disease in infants and children is primarily supportive with antiviral medications reserved for the most vulnerable.10 Palivizumab continues to be the only effective prophylactic medication licensed for use, however, its high cost prevents it from being used in all infants. The development of a well-tolerated, clinically effective and cost-effective RSV vaccine and therapeutic agent remains a global health priority. It is likely that a licensed RSV vaccine is several years away, however, given the burden of RSV infection and the associated costs globally there is much ongoing research into the development of a well-tolerated and effective vaccine. The main target populations for vaccination include infants, school-age children, pregnant women and older adults. Multiple different vaccine approaches are being considered including live-attenuated chimeric, whole-inactivated, particle-base, subunit, nucleic acid, and

References

1. Shi T, McAllister DA, O’Brien KL, et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: A systematic review and modelling study. Lancet 2017; 390; 946–958

2. Barr R, Greene C, Sande CJ, Drysdale SB. Respiratory syncytial virus: diagnosis, prevention and management. Ther Adv Infect Dis. January 2019. doi:10.1177/2049936119865798

3. HPSC (2020). Respiratory syncytial virus (RSV). Health Protection Surveillance Centre. Ireland. Available at: www.hpsc.ie/az/respiratory/ respiratorysyncytialvirus/factsheet/

4. Dunkin M. (2021). Respiratory syncytial virus (RSV). WebMD Medical Reference. Available at: www.webmd.com/lung/rsv-in-babies

5. Bont L, Checchia PA, Fauroux B, et al. Defining the epidemiology and burden of severe respiratory syncytial virus infection among infants and children in western countries. Infect Dis Ther. 2016;5(3):271-298. doi:10.1007/

gene-based vectors. There are also ongoing efforts to develop long-acting monoclonal antibodies for infants.2

Three agents; ribavirin, IVIG and palivizumab, have been extensively used and investigated as antiviral treatments for RSV. To-date none have proven unequivocally beneficial, and effective treatments and research continues into future therapies. At least 14 anti-RSV treatment products are undergoing phase 1 and 2 clinical trials, of which five have included paediatric patients. Novel therapeutic molecules developed to date include fusion inhibitors, non-fusion inhibitors, polymerase inhibitors, antibodies, nucleoside analogues, small-interfacing RNAs, and a benzodiazepine. They have various targets on RSV, such as the F protein, RNA polymerase, nucleoprotein, and nucleocapsid mRNA. It is hoped that one of these products will become a licensed treatment for RSV infection in children and adults over the coming years.2 The development of a successful treatment or prophylactic agent has the potential to revolutionise the care and outcome for severe RSV infections in the world’s most vulnerable infant population. ■

s40121-016-0123-0

6. Ruuskanen O, Lahti E, Jennings LC, Murdoch DR. Viral pneumonia. Lancet 2011; 377: 1264–1275. doi: 10.1016/S0140-6736(10)61459-6

7. HSE (2019). 18a Respiratory syncytial virus. Health Service Executive. Ireland. Available at: www.hse.ie/eng/health/immunisation/hcpinfo/ guidelines/rsvch18a.pdf

8. Taylor S, Taylor RJ, Lustig RL, et al. Modelling estimates of the burden of respiratory syncytial virus infection in children in the UK. BMJ Open 2016;6:e009337. doi: 10.1136/ bmjopen-2015-009337

9. Drysdale S, Greene C, Sande C. Best practice in the prevention and management of paediatric respiratory syncytial virus infection. Ther Adv Infect Dis. 2016 Apr; 3(2): 63. doi: 10.1177/2049936116630243

10. Schweitzer JW, Justice NA. Respiratory syncytial virus infection. StatPearls Publishing. Available from: www.ncbi.nlm.nih.gov/books/NBK459215/

Update on the management of COPD

This module addresses the risk factors that predispose to developing COPD, how to diagnose COPD; how to characterise disease severity and how to manage symptoms and exacerbations.

Authors: Dr Robert Rutherford, Consultant Respiratory Physician, GUH, Clinical Lead COPD, Honorary Senior Lecturer, NUIG, and Dr Fatma Gargoum, Respiratory SpR, Galway University Hospital.

it

Genuair®-has it ‘clicked’ yet?

Genuair -has

The ONLY pre lled inhaler with visual and audible confirmed dose delivery

The ONLY pre lled inhaler feedback for confi

The ONLY pre lled inhaler with visual and audible feedback for confirmed dose delivery1-4

Genuair - a simple for patients

Genuair - a simple to use inhaler for patients with COPD4

LAMA

Abbreviated Prescribing Information

Abbreviated Prescribing Information

Abbreviated Prescribing Information

Eklira® Genuair® 322 micrograms inhalation powder. Please consult the Summary of Product Characteristics (SPC) for the full prescribing information. Presentation: Inhalation powder in a white inhaler with an integral dose indicator and a green dosage button. Each delivered dose contains 375 µg aclidinium bromide equivalent to 322 µg of aclidinium. Also, contains lactose. Use: Maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Dosage: For inhalation use. Recommended dose is one inhalation of 322 micrograms aclidinium twice daily. Patients should be instructed on how to administer the product correctly as the Genuair inhaler may work di erently from inhalers used previously. It is important to instruct the patients to read the Instructions for Use in the pack. No dose adjustments are required for elderly patients, or those with renal or hepatic impairment. No relevant use in children and adolescents.

322 micrograms inhalation powder. Please consult the Summary

Eklira® Genuair® 322 micrograms inhalation powder. Please consult the Summary of Product Characteristics (SPC) for the full prescribing information. Presentation: Inhalation powder in a white inhaler with an integral dose indicator and a green dosage button. Each delivered dose contains 375 µg aclidinium bromide equivalent to 322 µg of aclidinium. Also, contains lactose. Use: Maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Dosage: For inhalation use. Recommended dose is one inhalation of 322 micrograms aclidinium twice daily. Patients should be instructed on how to administer the product correctly as the Genuair inhaler may work di erently from inhalers used previously. It is important to instruct the patients to read the Instructions for Use in the pack. No dose adjustments are required for elderly patients, or those with renal or hepatic impairment. No relevant use in children and adolescents.

Contraindications: Hypersensitivity to aclidinium bromide or to any of the excipients. Warnings and Precautions: Stop use if paradoxical bronchospasm occurs and consider other treatments. Do not use for the relief of acute episodes of bronchospasm. Use with caution in patients with myocardial infarction in the previous 6 months, unstable angina, newly diagnosed arrhythmia within the previous 3 months, or hospitalisation within the previous 12 months for heart failure functional classes III and IV. Dry mouth, observed with anticholinergic treatment, may be associated with dental caries in the long term. Use with caution in patients with symptomatic prostatic hyperplasia or bladder-neck obstruction or with narrow-angle glaucoma. Do not use in patients with rare hereditary problems of galactose intolerance, total lactose de ciency or glucose-galactose malabsorption.

Contraindications: Hypersensitivity to aclidinium bromide or to any of the excipients. Warnings and Precautions: Stop use if paradoxical bronchospasm occurs and consider other treatments. Do not use for the relief of acute episodes of bronchospasm. Use with caution in patients with myocardial infarction in the previous 6 months, unstable angina, newly diagnosed arrhythmia within the previous 3 months, or hospitalisation within the previous 12 months for heart failure functional classes III and IV. Dry mouth, observed with anticholinergic treatment, may be associated with dental caries in the long term. Use with caution in patients with symptomatic prostatic hyperplasia or bladder-neck obstruction or with narrow-angle glaucoma. Do not use in patients with rare hereditary problems of galactose intolerance, total lactose de ciency or glucose-galactose malabsorption.

Characteristics (SPC) for the full prescribing information. Presentation: Inhalation powder inhaler with an integral dose indicator and a green dosage button. Each delivered dose contains µg aclidinium bromide equivalent to 322 µg of aclidinium. Also, contains lactose. Maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive For inhalation use. Recommended dose is one inhalation of 322 micrograms aclidinium twice daily. Patients should be instructed on how to administer the product the Genuair inhaler may work di erently from inhalers used previously. It is important to instruct patients to read the Instructions for Use in the pack. No dose adjustments are required patients, or those with renal or hepatic impairment. No relevant use in children and adolescents.

Contraindications: Hypersensitivity to aclidinium bromide or to any of the excipients.

Interactions: Do not administer with other anticholinergic-containing medicinal products. No other interactions expected. Please consult the SPC for more details. Fertility, pregnancy and lactation: No data on use in pregnancy. Risk to newborns/infants cannot be excluded. Consider risk-bene t before using during lactation. Unlikely to a ect fertility at the recommended dose. Side-e ects: Common (1-10%): Sinusitis, nasopharyngitis, headache, cough, diarrhoea, nausea. Uncommon (0.1-1%): Dizziness, blurred vision, tachycardia, palpitations, dysphonia, dry mouth, stomatitis, rash, pruritus, urinary retention. Rare (0.01-0.1%): hypersensitivity. Not known: angioedema, anaphylactic reaction. Pack sizes: Carton containing 1 inhaler with 60 unit doses. Legal category: POM Marketing

Interactions: Do not administer with other anticholinergic-containing medicinal products. No other interactions expected. Please consult the SPC for more details. Fertility, pregnancy and lactation: No data on use in pregnancy. Risk to newborns/infants cannot be excluded. Consider risk-bene t before using during lactation. Unlikely to a ect fertility at the recommended dose. Side-e ects: Common (1-10%): Sinusitis, nasopharyngitis, headache, cough, diarrhoea, nausea. Uncommon (0.1-1%): Dizziness, blurred vision, tachycardia, palpitations, dysphonia, dry mouth, stomatitis, rash, pruritus, urinary retention. Rare (0.01-0.1%): hypersensitivity. Not known: angioedema, anaphylactic reaction. Pack sizes: Carton containing 1 inhaler with 60 unit doses. Legal category: POM Marketing

Authorisation Number: EU/1/12/778/002 Marketing Authorisation holder: AstraZeneca AB, SE151 85 Södertälje, Sweden. Marketed by: A. Menarini Pharmaceuticals Ireland Ltd., Castlecourt, Monkstown Farm, Monkstown, Glenageary, Co. Dublin A96 T924. Further information is available on request to A. Menarini Pharmaceuticals Ireland Ltd. or may be found in the SPC. Last updated: February 2020

and Precautions: Stop use if paradoxical bronchospasm occurs and consider other Do not use for the relief of acute episodes of bronchospasm. Use with caution in patients myocardial infarction in the previous 6 months, unstable angina, newly diagnosed arrhythmia the previous 3 months, or hospitalisation within the previous 12 months for heart failure classes III and IV. Dry mouth, observed with anticholinergic treatment, may be associated caries in the long term. Use with caution in patients with symptomatic prostatic hyperplasia bladder-neck obstruction or with narrow-angle glaucoma. Do not use in patients with rare problems of galactose intolerance, total lactose de ciency or glucose-galactose malabsorption.

Interactions: Do not administer with other anticholinergic-containing medicinal products. interactions expected. Please consult the SPC for more details. Fertility, pregnancy and No data on use in pregnancy. Risk to newborns/infants cannot be excluded. Consider before using during lactation. Unlikely to a ect fertility at the recommended dose. Side-e Common (1-10%): Sinusitis, nasopharyngitis, headache, cough, diarrhoea, nausea. Uncommon (0.1-1%): Dizziness, blurred vision, tachycardia, palpitations, dysphonia, dry mouth, stomatitis, pruritus, urinary retention. Rare (0.01-0.1%): hypersensitivity. Not known: angioedema, anaphylactic reaction. Pack sizes: Carton containing 1 inhaler with 60 unit doses. Legal category: POM

Authorisation Number: EU/1/12/778/002 Marketing Authorisation holder: AstraZeneca AB, SE151 85 Södertälje, Sweden. Marketed by: A. Menarini Pharmaceuticals Ireland Ltd., Castlecourt, Monkstown Farm, Monkstown, Glenageary, Co. Dublin A96 T924. Further information is available on request to A. Menarini Pharmaceuticals Ireland Ltd. or may be found in the SPC. Last updated: February 2020

This medicinal product is subject to additional monitoring. This will allow quick identi cation of new safety information. Healthcare professionals are asked to report any suspected adverse reactions to: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.hpra.ie, e-mail: medsafety@ hpra.ie. Adverse events should also be reported to A. Menarini Pharmaceuticals Ireland Ltd. Phone no: 01 284 6744.

This medicinal product is subject to additional monitoring. This will allow quick identi cation of new safety information. Healthcare professionals are asked to report any suspected adverse reactions to: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.hpra.ie, e-mail: medsafety@ hpra.ie. Adverse events should also be reported to A. Menarini Pharmaceuticals Ireland Ltd. Phone no: 01 284 6744.

Authorisation Number: EU/1/12/778/002 Marketing Authorisation holder: AstraZeneca

151 85 Södertälje, Sweden. Marketed by: A. Menarini Pharmaceuticals Ireland Ltd., Castlecourt, Monkstown Farm, Monkstown, Glenageary, Co. Dublin A96 T924. Further information on request to A. Menarini Pharmaceuticals Ireland Ltd. or may be found in the SPC. Last February 2020

Date of item: November 2020. IR-BRI-10-2020

Abbreviated Prescribing Information Brimica® Genuair® 340 micrograms/12 micrograms inhalation powder. Please consult the Summary of Product Characteristics (SPC) for the full prescribing information. Presentation: Inhalation powder in a white inhaler with an integral dose indicator and an orange dosage button. Each delivered dose contains 396 µg aclidinium bromide (equivalent to 340 µg of aclidinium) and 11.8 micrograms of formoterol fumarate dihydrate. Also, contains lactose. Use: Maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Dosage: For inhalation use. Recommended dose is one inhalation of 340 µg/12 µg twice daily. Patients should be instructed on how to administer the product correctly as the Genuair inhaler may work di erently from inhalers used previously. It is important to instruct the patients to read the Instructions for Use in the pack. No dose adjustments are required for elderly patients, or those with renal or hepatic impairment. No relevant use in children and adolescents. Contraindications: Hypersensitivity to the active substances or to any of the excipients. Warnings and Precautions: Do not use in asthma. Stop use if paradoxical bronchospasm occurs and consider other treatments. Do not use for the relief of acute episodes of bronchospasm. Use with caution in patients with myocardial infarction in the previous 6 months, unstable angina, newly diagnosed arrhythmia within the previous 3 months, or hospitalisation within the previous 12 months for heart failure functional classes III and IV. Discontinue if increases in pulse rate, blood pressure or changes in ECG occur. Use with caution in patients with a history of or known prolongation of the QTc interval or treated with products a ecting the QTc interval. Use with caution in patients with severe cardiovascular disorders, convulsive disorders, thyrotoxicosis and phaeochromocytoma. Hypokalaemia may occur, is usually transient and supplementation not needed. In patients with severe COPD, hypokalaemia may be potentiated by hypoxia and concomitant treatment. Use with caution in patients with symptomatic prostatic hyperplasia, urinary retention or with narrow-angle glaucoma. Dry mouth, observed with anticholinergic treatment, may be associated with dental caries in the long term. Do not use in patients with rare hereditary problems of galactose intolerance, the Lapp lactase de ciency or glucose-galactose malabsorption. Interactions: Do not administer with other anticholinergic and/or long-acting β2-adrenergic agonist containing medicinal products. Caution in use with methylxanthine derivatives, steroids, non-potassium-sparing diuretics, β-adrenergic blockers or medicinal products known to prolong the QTc interval. Please consult the SPC for more details. Fertility, pregnancy and lactation: No data on use in pregnancy. Consider risk-bene t before using during lactation. Unlikely to a ect fertility at the recommended dose. Sidee ects: Common (1-10%): Nasopharyngitis, urinary tract infection, sinusitis tooth abscess, insomnia, anxiety, headache, dizziness, tremor, cough, diarrhoea, nausea, dry mouth, myalgia, muscle spasms, peripheral oedema, increased blood creatine phosphokinase. Uncommon (0.1- 1%): Hypokalaemia, hyperglycaemia, agitation, dysgeusia, blurred vision, tachycardia, electrocardiogram QTc prolonged, palpitations, angina pectoris, dysphonia, throat irritation, stomatitis, rash, pruritus, urinary retention, increased blood pressure. Rare (0.01-0.1%): Hypersensitivity, bronchospasm, including paradoxical. Not known: anaphylactic reaction, angioedema. Pack sizes: Carton containing 1 inhaler with 60 unit doses. Legal category: POM Marketing Authorisation Number: EU/1/14/963/001 Marketing

Date of item: November 2020. IR-BRI-10-2020

Date of item: November 2020. IR-BRI-10-2020

Abbreviated Prescribing Information Brimica® Genuair® 340 micrograms/12 micrograms inhalation powder. Please consult the Summary of Product Characteristics (SPC) for the full prescribing information. Presentation: Inhalation powder in a white inhaler with an integral dose indicator and an orange dosage button. Each delivered dose contains 396 µg aclidinium bromide (equivalent to 340 µg of aclidinium) and 11.8 micrograms of formoterol fumarate dihydrate. Also, contains lactose. Use: Maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Dosage: For inhalation use. Recommended dose is one inhalation of 340 µg/12 µg twice daily. Patients should be instructed on how to administer the product correctly as the Genuair inhaler may work di erently from inhalers used previously. It is important to instruct the patients to read the Instructions for Use in the pack. No dose adjustments are required for elderly patients, or those with renal or hepatic impairment. No relevant use in children and adolescents. Contraindications: Hypersensitivity to the active substances or to any of the excipients. Warnings and Precautions: Do not use in asthma. Stop use if paradoxical bronchospasm occurs and consider other treatments. Do not use for the relief of acute episodes of bronchospasm. Use with caution in patients with myocardial infarction in the previous 6 months, unstable angina, newly diagnosed arrhythmia within the previous 3 months, or hospitalisation within the previous 12 months for heart failure functional classes III and IV. Discontinue if increases in pulse rate, blood pressure or changes in ECG occur. Use with caution in patients with a history of or known prolongation of the QTc interval or treated with products a ecting the QTc interval. Use with caution in patients with severe cardiovascular disorders, convulsive disorders, thyrotoxicosis and phaeochromocytoma. Hypokalaemia may occur, is usually transient and supplementation not needed. In patients with severe COPD, hypokalaemia may be potentiated by hypoxia and concomitant treatment. Use with caution in patients with symptomatic prostatic hyperplasia, urinary retention or with narrow-angle glaucoma. Dry mouth, observed with anticholinergic treatment, may be associated with dental caries in the long term. Do not use in patients with rare hereditary problems of galactose intolerance, the Lapp lactase de ciency or glucose-galactose malabsorption. Interactions: Do not administer with other anticholinergic and/or long-acting β2-adrenergic agonist containing medicinal products. Caution in use with methylxanthine derivatives, steroids, non-potassium-sparing diuretics, β-adrenergic blockers or medicinal products known to prolong the QTc interval. Please consult the SPC for more details. Fertility, pregnancy and lactation: No data on use in pregnancy. Consider risk-bene t before using during lactation. Unlikely to a ect fertility at the recommended dose. Sidee ects: Common (1-10%): Nasopharyngitis, urinary tract infection, sinusitis tooth abscess, insomnia, anxiety, headache, dizziness, tremor, cough, diarrhoea, nausea, dry mouth, myalgia, muscle spasms, peripheral oedema, increased blood creatine phosphokinase. Uncommon (0.1- 1%): Hypokalaemia, hyperglycaemia, agitation, dysgeusia, blurred vision, tachycardia, electrocardiogram QTc prolonged, palpitations, angina pectoris, dysphonia, throat irritation, stomatitis, rash, pruritus, urinary retention, increased blood pressure. Rare (0.01-0.1%): Hypersensitivity, bronchospasm, including paradoxical. Not known: anaphylactic reaction, angioedema. Pack sizes: Carton containing 1 inhaler with 60 unit doses. Legal category: POM Marketing Authorisation Number: EU/1/14/963/001 Marketing Authorisation holder: AstraZeneca AB, SE-151 85 Södertälje, Sweden. Marketed by: A. Menarini Pharmaceuticals Ireland Ltd., Castlecourt, Monkstown Farm, Monkstown, Glenageary, Co. Dublin A96 T924. Further information is available on request to A. Menarini Pharmaceuticals Ireland Ltd. or may be found in the SPC. Last updated: October 2019

This medicinal product is subject to additional monitoring. This will allow identi cation of new safety information. Healthcare professionals are asked to report suspected adverse reactions to: HPRA Pharmacovigilance, Earlsfort Terrace, IRL 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.hpra.ie, e-mail: medsafety@ hpra.ie. Adverse events should also be reported to A.

Authorisation holder: AstraZeneca AB, SE-151 85 Södertälje, Sweden. Marketed by: A. Menarini Pharmaceuticals Ireland Ltd., Castlecourt, Monkstown Farm, Monkstown, Glenageary, Co. Dublin A96 T924. Further information is available on request to A. Menarini Pharmaceuticals Ireland Ltd. or may be found in the SPC. Last updated: October 2019

LAMA + LABA LAMA