Update Journal- Respiratory Medicine

VOL 6 ● ISSUE 9 ● 2020

RESPIRATORY MEDICINE

IRISH RESEARCH

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ERS 2020 C L I N I CAL ARTIC LE S ON

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Volume 6 | Issue 9 | 2020 | Respiratory medicine

Learning and adapting amid the new normal A message from Priscilla Lynch, Editor

A

s we come towards the end of 2020, Covid-19 continues to cast an inescapable shadow over daily life and our health services.

Despite all the media headlines about ICU numbers, it is acute respiratory services that remain most impacted, as the majority of Covid-19 related hospital admissions are for respiratory issues. Moreover, the regular workload for the spectrum of respiratory conditions does not just stop because there is a pandemic.

It remains a very worrying time for vulnerable respiratory patients and it is a credit to all healthcare professionals for swiftly adapting to radical service changes in order to continue caring for their patients in such a challenging time.

As telemedicine is likely to continue to be a key part of services going forward, this issue contains a very practical piece on how to best conduct virtual COPD and asthma patient reviews.

As well as a focus on the latest updates on Covid-19, including a dedicated piece on when to consider lung transplantation, this edition also contains expert clinical articles on a wide range of topics including the latest GINA guideline updates for asthma, sinus disease related to asthma, overviews on non-tuberculous mycobacteria infections and acute viral respiratory tract infections, the latest developments within the field of cystic fibrosis, and an overview of alpha-1 antitrypsin deficiency incidence and research in Ireland.

In the area of interstitial lung diseases (ILD) there is an update on the latest international research findings and a piece outlining exciting Irish research on the development of inhaled therapies for idiopathic pulmonary fibrosis. Further concerning national and international research findings on e-cigarettes are also explored in a separate article.

This year the seasonal influenza vaccination programme has been extended to all children aged two-to-12 years to reduce the spread of flu and its complications in children and vulnerable groups and the National Immunisation Office has written a comprehensive outline of the new programme for Update.

The influenza vaccine being offered to children is the quadrivalent live attenuated influenza vaccine (LAIV), which is given intranasally and is available free of charge from GPs and community pharmacists.

One the conference front, while some major events have had to be cancelled, thankfully most meetings have been able to go ahead online. This issue features a roundup of some of the most topical research presented at the virtual 2020 European Respiratory Society International Congress, and as the Irish Thoracic Society prepares to host its annual Scientific Meeting online in early December, Covid-19 will be a key topic, but so too will the usual topics like asthma, COPD, and ILD, ITS President Dr Aidan O’Brien tells Update in a preview chat.

This month saw the marking of World

COPD Day, which served as a timely reminder that while services and treatments for Irish patients continue to improve, we still have 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 is responsible for more deaths than any nonrespiratory cancer.

This issue thus features an expert clinical article on the latest management approaches to COPD, which incorporate the 2019 GOLD guideline updates and a focus on earlier diagnosis to try to improve patient outcomes.

There is also an update from the Irish Lung Fibrosis Association on what actions they have taken to support and inform their members during the pandemic, which highlights the value of patient advocacy to ensure those with rarer conditions have their voices heard.

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

Thank you to 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. â–

1

Contents

03 08

ERS International Congress 2020 report

How Covid-19 has affected Irish respiratory care

10

Global Initiative for Asthma (GINA) – What’s new in 2020

17

Understanding asthma and sinus disease

20

Virtual asthma and COPD reviews

32 33

Patient advocacy – improving the lives of people with lung fibrosis

Qudrivalent live attenuated influenza (LAIV) nasal vaccine for children

38

Covid-19 - when to consider lung transplantation?

41

Acute respiratory viral infections

44

Positive developments within the field of cystic fibrosis

46

Non-tuberculous mycobacteria: An overview

22

COPD – 2020 a paradigm shift

28

Recent updates in interstitial lung disease

49

An overview of alpha-1 antitrypsin deficiency in Ireland

30

Irish and international research on the risks of e-cigarettes

52

Idiopathic pulmonary fibrosis and inhaled drug development

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 2020 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

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Respiratory Medicine | Volume 6 | Issue 9 | 2020

ERS International Congress report Priscilla Lynch presents a round-up of the most topical research presented at the 2020 European Respiratory Society International Congress (7-9 September)

First trial of personalised care for children with asthma suggests benefits of prescribing according to genetic differences Selecting treatments according to genetic differences could help children and teenagers with asthma, according to research presented at the 2020 European Respiratory Society (ERS) International Congress.

The trial compared patients treated according to small genetic differences with patients treated according to existing guidelines. It is the first trial of its kind in children and teenagers.

The researchers say that more work is needed, but their findings suggest that children’s asthma symptoms could be better controlled with personalised treatments.

The study was presented at the virtual conference by Dr Tom Ruffles, honorary consultant in paediatric respiratory medicine, UK. Dr Ruffles told the conference: “In the UK, for example, asthma affects one-in-11 children and every 18 minutes a child is admitted to hospital because of their asthma.

“We have a number of medicines that are generally effective in treating children with asthma, but they don’t work equally well for all children. We think that genetic differences could have an effect on whether these medicines work, and that’s what we wanted to examine in this study.”

The research involved 241 children aged between 12 and 18 years, who were all being

treated for asthma by their GPs. The children were randomly assigned either to receive treatment according to existing guidelines, or to receive treatment according to particular genetic differences (their genotype), an approach known as personalised medicine.

Treatment according to genotype meant the children were asked to give a sample of cells scraped from the inside of their cheeks. These samples were tested for different versions of a particular gene, using a test that costs less than €20.

The researchers were testing for a small difference in the gene that contains instructions for making the beta-2 receptor and they were looking for children either with one copy of the altered gene or with two copies of the altered gene. As the beta-2 receptor is the molecule targeted by asthma treatments, researchers believe that different versions of the gene for making this receptor can influence how well treatments work.

Previous research suggests that the majority of children with asthma will benefit from standard treatment with an asthma preventer called salmeterol in addition to their regular steroid inhaler. However, around one-inseven children have a small genetic difference that means using this medication could actually result in these children having more asthma symptoms.

In this trial, children in the personalised

medicine group who had this genetic difference were treated with an alternative asthma medicine - montelukast.

Researchers followed the children for a year to monitor their quality-of-life, with a score between one and seven according to how their symptoms were, whether their normal activities were limited by their asthma and how their asthma made them feel.

They compared the average score of the group of children who had their medication decided on the basis of their genetics with the average score of children who were treated according to current practice that does not involve any genetic testing, and found only a small improvement of 0.16 with those who received personalised care.

However, when the researchers looked specifically at the children who were found to have two copies of the altered beta-2 receptor gene, they found a greater benefit, with children experiencing an average 0.42 improvement in their quality-of-life score.

The researchers say this would translate to a noticeably better quality-of-life for the children with two altered gene copies.

Study co-author Prof Somnath Mukhopadhyay said: “These results are very promising because they show, for the first time, that it could be beneficial to test for certain genetic differences in children with asthma and select medication according to those differences.

“In this study, we saw only a modest effect, but this may be partly because the children’s asthma was generally very well controlled and only a few children experienced any serious symptoms during the 12-month period. Larger trials, with a focus on those with poorer asthma control, may help us determine the true benefit for children of prescribing in this way.”

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Volume 6 | Issue 9 | 2020 | Respiratory Medicine

Covid-19 patients suffer long-term lung and heart damage, but it can improve with time Covid-19 patients can suffer long-term lung and heart damage but, for many, this tends to improve over time, according to the first, prospective follow-up of patients infected with the coronavirus, presented at the ERS 2020 International Congress.

Researchers in the Covid-19 ‘hot spot’ in the Tyrolean region of Austria recruited consecutive hospitalised coronavirus patients to their study in Münster, Austria.

In their presentation to the virtual congress, they reported on the first 86 patients enrolled between 29 April and 9 June, although now they have over 150 patients participating.

the evaluations at 24 weeks.

“The bad news is that people show lung impairment from Covid-19 weeks after discharge; the good news is that the impairment tends to ameliorate over time, which suggests the lungs have a mechanism for repairing themselves,” said Dr Sabina Sahanic, part of the team that carried out the study.

The patients were scheduled to return for evaluation six, 12, and 24 weeks after their discharge from hospital.

The average age of the 86 patients included in this presentation was 61 years and 65 per cent of them were male. Nearly half of them were current or former smokers and 65 per cent of hospitalised Covid-19 patients were overweight or obese. Eighteen (21 per cent) had been in ICU, 16 (19 per cent) had had invasive mechanical ventilation, and the average length of stay in hospital was 13 days.

At the time of their first visit, more than half of the patients had at least one persistent symptom, predominantly breathlessness and coughing, and CT scans still showed lung damage in 88 per cent of patients. However, by the time of their next visit 12 weeks after discharge, the symptoms had improved and lung damage was reduced to 56 per cent. At this stage, it is too early to have results from

A total of 56 patients (65 per cent) showed persistent symptoms at the time of their sixweek visit; dyspnoea was the most common symptom (40 patients, 47 per cent), followed by coughing (13 patients, 15 per cent).

By the 12-week visit, breathlessness had improved and was present in 31 patients (39 per cent); however, 13 patients (15 per cent) were still coughing.

At the six-week visit, the echocardiograms showed that 48 patients (58.5 per cent) had dysfunction of the left ventricle of the heart (diastole). Biological indicators of heart damage, blood clots, and inflammation were all significantly elevated.

Dr Sahanic said: “We do not believe left ventricular diastolic dysfunction is specific to Covid-19, but more a sign of severity of the disease in general. Fortunately, in the Innsbruck cohort, we did not observe any severe coronavirus-associated heart dysfunction in the post-acute phase. The diastolic dysfunction that we observed also tended to improve with time.”

She concluded: “The findings from this study show the importance of implementing structured follow-up care for patients with severe Covid-19 infection.

Importantly, CT unveiled lung damage in this patient group that was not identified by lung function tests. Knowing how patients have been affected long-term by the coronavirus might enable symptoms and lung damage to be treated much earlier and might have a significant impact on further medical recommendations and advice.”

‘Social smokers’ face disproportionately high risk of death from lung disease and lung cancer ‘Social smokers’ are more than twice as likely to die of lung disease and more than eight times as likely to die of lung cancer than non-smokers, according to research presented at the 2020 ERS International Congress.

The study also shows that the risk of lung cancer death for ‘social smokers’ – those who smoke less than 10 cigarettes per day – is not substantially lower than those who smoke more than 20 cigarettes a day.

4

Researchers say their study suggests that cutting down, or combining fewer cigarettes with vaping, is no substitute for quitting smoking.

The research was by Dr Pallavi Balte and Dr Elizabeth Oelsner at Columbia University Medical Centre, New York, US. Dr Balte told the virtual conference: “Everyone knows that smoking is bad for you, but it’s easy to assume that if you only smoke a little, the risks won’t be too high.

“Previous research suggests that people are cutting down on smoking, for example in the US the proportion of smokers smoking less than 10 cigarettes per day has increased from 16 per cent to 27 per cent. So, we wanted to study the risks to social smokers compared to people who don’t smoke and compared to heavier smokers.”

The study included 18,730 people selected from a multi-ethnic sample of the general US population with an average age of 61.

Respiratory Medicine | Volume 6 | Issue 9 | 2020

Researchers followed the people for an average of 17 years, during which time 649 died of respiratory disease and 560 died of lung cancer.

per cent died from lung cancer. For heavy smokers (people who smoked more than 20 cigarettes a day), these proportions were 10.1 per cent and 12.9 per cent, respectively.

Among non-smokers, the proportion of people who died from respiratory diseases was 1.8 per cent and the proportion who died of lung cancer was 0.6 per cent. Among social smokers (people who smoked less than 10 cigarettes a day), around 3.3 per cent died from respiratory diseases and 4.7

The researchers calculated the death rates from respiratory disease and lung cancer and compared these rates between nonsmokers, social smokers, and heavy smokers.

After adjusting for multiple risk factors, they found that social smokers were 2.5

Dr Balte and her colleagues continue to study the effects of social smoking as well as investigating the effects of new habits such as vaping.

Bronchitis as a child predicts worse lung health in middle age

The participants were followed up for an average of 46 years. In 2004, 5,729 of the participants responded to a further survey.

Between 2012 and 2016, 3,609 participants completed another questionnaire and 2,629 underwent a clinical examination that included spirometry before and after using a bronchodilator to open the airways, in order to assess the difference in lung function.

who had non-recurrent, recurrent or protracted recurrent episodes of bronchitis as children had a 1.4-fold, two-fold and 3.2-fold increased risk of pneumonia, respectively, by the time they reached the average age of 53; a 1.3-fold, 2.7-fold and 6.4-fold increased risk of ever suffering from asthma, respectively; and a 1.3-fold, 2-fold and 4.5-fold increased risk of currently suffering from asthma, respectively.

The researchers categorised 3,085 participants into four groups: The reference group of those who never suffered from bronchitis before the age of seven (1,616 participants, 53 per cent), the non-recurrent group who had between one and five episodes (873, 28 per cent) lasting less than a month, the recurrent group who had at least six episodes (555, 18 per cent) lasting less than a month, and the protracted recurrent group who had six or more episodes (41, 1.3 per cent) lasting an average of a month or more.

The data showed that approximately 14 out of every 100 people in the reference group who did not have bronchitis as children were diagnosed with pneumonia by middle age, nine in every 100 suffered from current, chronic asthma, and 19 in every 100 had an asthma diagnosis by middle age.

People who had bronchitis at least once before the age of seven years are more likely to develop lung problems in later life, according to new research presented at the virtual 2020 ERS International Congress.

However, the lung diseases they suffer from by the age of 53 were usually asthma and pneumonia rather than chronic bronchitis, said Dr Jennifer Perret, a researcher in the Allergy and Lung Health Unit at the University of Melbourne, Australia.

The findings come from the Tasmanian Longitudinal Health Study, which followed 8,583 people who were born in Tasmania in 1961 and started school in 1968. When the participants joined the study as children, the researchers investigated their lung function using a spirometer to measure FVC and FEV1.

Their parents completed a questionnaire that asked whether the children had suffered asthma or bronchitis by the age of seven. Childhood bronchitis was defined as a “loose, rattly or chesty cough�.

In the reference group who had parents that did not recall a history of childhood bronchitis, the prevalence of chronic bronchitis in the previous two years or current asthma within the past year by the time the participants reached the average age of 53 was 5 per cent and 8.5 per cent, respectively; and the prevalence of ever having pneumonia or asthma diagnosed by a doctor was 14 per cent and 19 per cent respectively.

Compared to the reference group, people

times as likely to die of respiratory disease and 8.6 times as likely to die of lung cancer, compared to non-smokers. Social smokers had around half the rate of death from respiratory disease as heavy smokers, but their rate of lung cancer death was twothirds that of heavy smokers.

In comparison, among those who suffered from non-recurrent, recurrent or protracted recurrent bronchitis as children, the researchers estimated that approximately 19, 25 and 35 in every 100, respectively, would be diagnosed with pneumonia by middle age, 11, 16, and 29 in every 100, respectively, would suffer from chronic asthma, and 33, 50, and 70 in every 100, respectively, would ever have had asthma diagnosed by a doctor. However, the estimates for those who had protracted recurrent bronchitis as children need to be interpreted cautiously due to the small numbers in this group.

Dr Perret said: “The associations with asthma and pneumonia strengthened with increasing severity of childhood bronchitis.

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Volume 6 | Issue 9 | 2020 | Respiratory Medicine

However, there was no statistically significant link between childhood bronchitis and chronic bronchitis in middle-age. This was an unexpected finding and further study would be informative. We are currently exploring these associations.”

The link between childhood bronchitis

and lung function in middle age was also less clear. When the researchers looked at how well the lungs functioned without the help of an asthma reliever inhaler in middle age, they found that the association between childhood bronchitis and worse lung function became stronger the more often a person had suffered from bronchitis as a child.

“However, there were too few people who had protracted recurrent bronchitis as children to estimate confidently the associations for this subgroup.

We will investigate whether this and the other associations are still present after excluding people who also had a history of childhood asthma or wheezing,” said Dr Perret.

Exposure to air pollution within EU limits linked to impaired breathing in children and asthma in adults Babies exposed to levels of air pollution within EU standards develop poorer lung function as children and teenagers, according to research presented at the 2020 ERS International Congress.

The study also suggests that some of the risk from exposure to pollution can be reduced if babies are breastfed for at least 12 weeks.

A second study presented at the Congress showed that adults who are exposed to air pollution, even at low levels, over a period of decades are more likely to develop asthma.

Researchers say their findings indicate that more needs to be done to reduce levels of air pollution to protect children’s developing lungs and prevent asthma in adults.

The first study was presented by Dr Qi Zhao from IUF – Leibniz Research Institute for Environmental Medicine in Düsseldorf, Germany. “Evidence is growing that exposure to air pollution is a threat to children’s respiratory health. However, most studies have looked at the effects of recent exposure to pollution.

“Babies’ lungs are especially vulnerable because they are growing and developing, so we wanted to see if there are longer-term impacts for babies who are exposed to air pollution as they grow up.”

The study included 915 children living in two regions of Germany: Munich and Wesel.

6

The children had tests to measure their breathing at the ages of six, 10, or 15 years.

The tests recorded forced vital capacity (FVC) and FEV1.

Researchers compared these measures with estimates of the levels of pollution in the areas where the children lived in the first year of life, taking account of other factors that are linked to poorer lung function, such as whether the children’s mothers smoked.

They found that the higher the levels of air pollution babies were exposed to, the worse their lung function was as they grew into children and teenagers. They saw an even bigger impact on lung function in children who developed asthma. The results also suggested some of the damage linked to air pollution was reduced in babies who were breastfed.

Dr Zhao added: “Our results suggest that babies who grow up breathing polluted air, even at levels below EU regulations, have poorer breathing as they grow into children and adults. This is worrying because previous research suggests that damage to lungs in the first year of life can affect respiratory health throughout life.”

The second study included 23,000 Danish nurses who were recruited to the study in either 1993 or 1999. Researchers used data from the country’s National Patient Register to see whether the nurses were ever referred for asthma treatment. They compared this

information with levels of two air pollutants – nitrogen dioxide (NO2) and particulate matter smaller than 2.5 microns (PM2.5) – and the levels of road traffic noise where the nurses lived. The researchers took into account other factors that are linked to asthma, such as smoking and obesity.

They found that while noise pollution was not linked to rates of asthma, there was a link between long-term exposure to air pollution and the likelihood of being diagnosed with asthma. There was a 29 per cent rise in asthma risk for each increase in PM2.5 of 6.3 micrograms per cubic metre. And there was a 16 per cent rise in asthma risk for each increase of NO2 of 8.2 micrograms per cubic metre.

The levels of air pollution that the nurses were exposed to was relatively low compared to many European cities, averaging around 18.9 micrograms per cubic metre for PM2.5 and 12.8 micrograms per cubic metre for NO2.

The current European standards for PM2.5 and NO2 are 25 and 40 micrograms per cubic metre, respectively.

The research was presented by Shuo Liu from University of Copenhagen, Denmark.

He told the conference: “The fact that we found a link with asthma, even at relatively low levels of exposure, suggests that there is no safe threshold for air pollution. This is strong evidence that our regulations on air pollution need to be stricter if we want to prevent cases of asthma.”

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Side (≥1/10): effects: Side effects: Very Headache, Common Very Common (≥1/10): nasopharyngitis. (≥1/10): Headache, Headache, nasopharyngitis. nasopharyngitis. and where patients are not adequately controlled on inhaled corticosteroids and recurrence. Asthma-related adverse events and exacerbations may occur during benefits. Side effects: Very Common (≥1/10): Headache, nasopharyngitis.

Patients should continue treatment but seek medical advice if treatment. asthma treatment.

Patients Patients should should continue continue treatment treatment but seek but seek medical adviceadvice if Candidiasis asthma if asthma “as needed” “as needed” short-acting short-acting inhaledinhaled β 2-agonists, β 2-agonists, or where or where patients patients are already are already Common (≥1/100 tomedical <1/10): Common Common (≥1/100 of the (≥1/100 to <1/10): mouth to <1/10): Candidiasis and Candidiasis ofthroat, the ofmouth the mouth and pneumonia, throat, and throat, pneumonia, pneumonia, “as needed” short-acting inhaled β 2-agonists, or where patients are already treatment. Patients should continue treatment but seek medical advice if asthma Common (≥1/100 to <1/10): Candidiasis of the mouth and throat, pneumonia, remain uncontrolled or worsen after initiation Relvar.

Systemic symptoms symptoms remainremain uncontrolled uncontrolled or worsen or upper worsen after initiation after initiation of Relvar. of Relvar.

Systemic Systemic controlled controlled on both on inhaled both inhaled corticosteroid corticosteroid and long-acting and long-acting βof -agonist. β -agonist.

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FEV1<70% FEV1<70% predicted predicted normal normal (post-bronchodilator) (post-bronchodilator) an and exacerbation anexacerbation exacerbation history history back muscle spasms, fractures, back back pain, pain, muscle pyrexia. muscle spasms, spasms, Uncommon fractures, fractures, pyrexia. pyrexia. (≥1/1,000 Uncommon Uncommon (≥1/1,000 (≥1/1,000 to to to to forforlong butbut much likely than with oral corticosteroids.

FEV1<70% predicted normal (post-bronchodilator) and an history back pain, muscle spasms, fractures, pyrexia.

Uncommon (≥1/1,000 stemic effects include: Cushing’s syndrome, Cushingoid features, Possible Possible Systemic Systemic effects effects include: include: Cushing’s Cushing’s syndrome, syndrome, Cushingoid Cushingoid features, features, despite despite regular regular bronchodilator bronchodilator therapy). therapy).

Dosage Dosage and administration: andadministration: administration: Inhalation Inhalation <1/100): Hyperglycaemia, vision blurred, <1/100): <1/100): Hyperglycaemia, extrasystoles.

Hyperglycaemia, vision vision blurred, Rare blurred, extrasystoles. extrasystoles. (≥1/10,000 Rare Rare (≥1/10,000 to to to to Possible Systemic effects include: Cushing’s syndrome, Cushingoid features, despite regular bronchodilator therapy).

Dosage and Inhalation <1/100): Hyperglycaemia, vision blurred, extrasystoles.

Rare(≥1/10,000 (≥1/10,000 ppression, decrease in Patients bone density, growth retardation adrenal adrenal suppression, suppression, decrease decrease in bone bone mineral mineral density, density, growth growth retardation retardation only. Asthma: only. Asthma: Asthma: Patients Patients with asthma withmineral asthma should should be given begiven the given strength thestrength strength of Relvar Relvar Ellipta Ellipta <1/1,000): Hypersensitivity reactions <1/1,000): <1/1,000): including Hypersensitivity Hypersensitivity anaphylaxis, reactions reactions including including anaphylaxis, angioedema, anaphylaxis, angioedema, angioedema, adrenal suppression, decrease in inbone mineral density, growth retardation only. with asthma should be the ofofRelvar Ellipta <1/1,000): Hypersensitivity reactions including anaphylaxis, angioedema, and adolescents, cataract, glaucoma.

More rarely, a range in children in children of and adolescents, and adolescents, cataract, cataract, glaucoma. glaucoma.

More More rarely, rarely, a range a range of of containing containing the appropriate the appropriate fluticasone fluticasone furoate furoate (FF) dosage (FF) dosage for the for severity the severity of of rash and urticaria; palpitations, tachycardia, rash and rash urticaria; and urticaria; palpitations, tremor, palpitations, tachycardia, anxiety, tachycardia, tremor, tremor, paradoxical anxiety, anxiety, paradoxical paradoxical containing the appropriate fluticasone furoate (FF) dosage for the severity of in children and adolescents, cataract, glaucoma. More rarely, a range of rash and urticaria; palpitations, tachycardia, tremor, anxiety, paradoxical al or behavioural effects including psychomotor hyperactivity, psychological sleep psychological or behavioural orbehavioural behavioural effects effects including including psychomotor psychomotor hyperactivity, hyperactivity, sleep sleep their disease. their disease.

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Marketing (MA) Marketing authorisation Holder: authorisation (MA) GlaxoSmithKline (MA) Holder: Holder: GlaxoSmithKline GlaxoSmithKline psychological orbronchospasm. effects including psychomotor hyperactivity, sleep their disease.

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Increased Increased 100 mcg 100once mcg daily once daily isdaily approximately approximately equivalent equivalent to fluticasone fluticasone propionate propionate (FP) Increased (FP) (Ireland) 12 Riverwalk, Citywest (Ireland) (Ireland) Limited, Business Limited, 12 12 Riverwalk, 12 Riverwalk, Campus, Citywest Citywest Business Dublin Business Campus, 24, Campus, Dublin Ireland.

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Increased 100 mcg isis approximately equivalent totofluticasone propionate (FP) (Ireland) Limited, Riverwalk, Citywest Business Campus, Dublin Ireland. f pneumonia, pneumonia requiring hospitalisation, incidence incidence has of pneumonia, pneumonia, including pneumonia pneumonia requiring requiring hospitalisation, hospitalisation, hashas has 250 including mcg 250twice mcg twice twice daily, daily, while daily, FF while 200 FFmcg 200once mcg daily oncedaily isdaily approximately approximately equivalent equivalent MA including Nrs: 92/22mcg 1x30 doses [EU/1/13/886/002]; MAMA Nrs: MA 92/22mcg Nrs: 92/22mcg 1x30 doses 1x30 doses 184/22mcg [EU/1/13/886/002]; [EU/1/13/886/002]; 184/22mcg 1x30 184/22mcg doses 1x30 1x30 doses incidence ofofpneumonia, including pneumonia requiring hospitalisation, 250 mcg while FF 200 mcg once isisapproximately equivalent Nrs: 92/22mcg 1x30 doses [EU/1/13/886/002]; 184/22mcg 1x30doses doses ved in patients with COPD receiving inhaled corticosteroids. been observed been If a observed in patients in patients with COPD with COPD receiving receiving inhaled inhaled corticosteroids. corticosteroids.

If a If a to FP to to 500 FP mcg 500 twice mcg twice daily. daily.

Adults Adults and adolescents and adolescents ≥12 years: ≥12 years: one inhalation one inhalation [EU/1/13/886/005].

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POM [EU/1/13/886/005].

B. Last Legal date Legal category: category: of POM revision: B. POM Last B. date Last of date June revision: of revision: 2019.

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FP 500 mcg twice daily. Adults and adolescents ≥12 years: one inhalation been observed in patients with COPD receiving inhaled corticosteroids. If a [EU/1/13/886/005]. Legal category: POM B. Last date of revision: June 2019. sents with visual disturbance they should berequire considered for referral patient presents presents withCode: visual withvisual visual disturbance disturbance theythey should they should be considered considered for referral referral once daily once of: daily Relvar of: Relvar Relvar 92/22mcg 92/22mcg for patients forpatients patients who require who require a lowa ato low mid middose of doseofpatient of PI-2046.

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Further information available on request from GlaxoSmithKline, halmologist for evaluation of possible causes -agonist.

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10/30/2020 10/30/2020 10/30/2020 7:47:21 7:47:21 7:47:21 PM PM 10/30/2020 7:47:21 PMPM

Volume 6 | Issue 9 | 2020 | Respiratory Medicine

How Covid-19 has affected respiratory care Dr Sarah O’Beirne, Consultant Respiratory Physician, speaks to Niamh Cahill, while Irish Thoracic Society President Dr Aidan O’Brien speaks to Paul Mulholland about how the sudden shifts in Irish respiratory services caused by Covid-19 could have a lasting impact One of the most significant outcomes of the Covid-19 pandemic to date has been the immense changes it has wrought on the delivery of our healthcare services.

Given the nature of the coronavirus and its impact on the lungs, respiratory services have been particularly affected.

Dr Sarah O’Beirne, Consultant Respiratory Physician at St Michael’s and St Vincent’s University Hospitals, Dublin, spent much of her time during the first wave of the pandemic looking after hospitalised Covid-19 patients, and speaking to Update said that without doubt the pandemic has had a huge impact.

“The service has changed so much in the last six months. Like everything else in medicine we’ve all had to completely reorganise our practice. If anything, it’s shown us how we can adapt and adapt quickly. People have worked well together in these challenging times.”

She added that following the ‘first wave’ and the initial shutdown of all ‘non acute’ health services, the focus remains on keeping services up and running as much as possible and to try to stop waiting lists climbing further.

“Since July services regular have become more normalised and I think a big push at the moment is to provide as much routine care as possible, despite the pandemic, provided it’s safe, to avoid increased morbidity and mortality in the future.”

pulmonary rehab programme, which began during the pandemic.

Dr Sarah O’Beirne

Dr Aidan O’Brien

pulmonary rehabilitation outpatient classes for patients with chronic lung disease, a development that will have a long-lasting impact on the structure of healthcare, Dr O’Beirne believes.

Pulmonary rehabilitation is the standard care for patients with chronic lung disease, ongoing symptoms and limitations despite maximised medical treatment. It is a vital component of care, as rehabilitation reduces hospitalisations.

A 2018 report found that Ireland has the highest rate of hospital admission with COPD of any country in the OECD. A study, published in JAMA earlier this year, showed that pulmonary rehabilitation within 90 days of a COPD exacerbation reduces mortality.

Typically, pulmonary rehabilitation is provided in an outpatient setting with patients participating in a class run over six-to-12 weeks, depending on the programme. It includes an exercise component, as well as a focus on education and behavioural change.

Amid the upheaval and efforts to continue regular care, completely new services for patients suffering from postCovid respiratory symptoms are being developed to offer continuing care to those still affected by the virus.

But group classes for patients with chronic lung disease are not feasible during the pandemic, according to Dr O’Beirne. “So, the standard outpatient pulmonary rehabilitation programme we provided has been on hold since the pandemic began in earnest in March in this country.

Going virtual One of the biggest shifts since Covid-19 emerged has been the move to virtual

“That’s led, as with other services, to a shift towards more virtual pulmonary rehabilitation. We’ve been running a virtual

8

“We’ve had several groups complete the programme already and have seen good results with it. This is a programme people do from home where they log into live sessions and complete an exercise component. We also have the educational parts. It’s all done virtually apart from the pre- and post-rehab assessments, which are done in the hospital.

It’s a much safer way from an infection control perspective for patients and for staff.”

There have been definite improvements in symptoms, quality-of-life scores and walk distance scores in patients who took part in the virtual programme.

Dr O’Beirne said the virtual nature of the clinic has helped increase numbers among those who may not have been able to travel to clinics.

Despite this, it is evident that virtual clinics are not suitable for all patients, she acknowledged. “The downside is it’s not suitable for everyone. We know from contacting people on our waiting list for the regular rehab programme that only 50 or 60 per cent of them would be suitable to partake in the programme, due to a combination of access to technology, technological literacy and disease severity.

“Then there’s also the aspect that for some patients, depending on their condition, it may not be safe for them to exercise at home in a less supervised fashion.

“It’s about recognising the limitations of virtual care, while recognising its definite role, particularly when we are in the throes of a pandemic. I think in the long-term it will be a mix of virtual and standard care that we provide people.”

Respiratory Medicine | Volume 6 | Issue 9 | 2020

For those who cannot access virtual clinics, some severally ill patients have been offered inpatient rehabilitation, but the remainder are waiting for the outpatient programme to resume.

In March, the service had 60-70 people on a waiting list. Since then, this has increased and there have seen more referrals, said Dr O’Beirne. It is not yet known when standard outpatient rehabilitation services will resume.

Post-Covid rehabilitation Another major development is the introduction of rehabilitation classes for patients suffering from post-Covid symptoms.

The classes operate just like that of a pulmonary rehabilitation programme and are focused on people with respiratory symptoms, Dr O’Beirne explained.

“We’ve had nearly 20 people through so far.

The groups are smaller because of infection control risk and it is provided in person rather than virtually.”

The programme runs for eight weeks and individuals attend twice weekly in person, similar to a standard pulmonary rehabilitation programme for exercise. There is a separate educational component and an occupational therapist works with patients on relaxation techniques, to help ease anxiety, thus providing a holistic service for patients.

“Initially we had thought that it would be predominantly beneficial for hospitalised patients that had more severe illness, but we are seeing more and more referrals from the community from people who weren’t hospitalised but who have persistent exercise limitation and ongoing symptoms,” said Dr O’Beirne.

“Outpatient services we were using for outpatient rehabilitation have been redeployed to this because we are not running the in-person outpatient pulmonary rehabilitation programme.”

Dr O’Beirne believes that post-Covid rehabilitation programmes will be required countrywide in the future. However, it

remains unknown how long such services will be needed and how great the demand will be.

“Yes, this is something that will be needed around the country. It’s such a new condition, but we know that a high percentage of people have more prolonged symptoms, so you would anticipate that more of these structured programmes will be required.

“We don’t know how long this will go on for and we also don’t have long-term follow-up.

We don’t know yet how great the need might be. It certainly looks like it will be required at least in the medium-term.”

COPD While spirometry is a crucial part of any COPD diagnosis, because of the infection risks involved non-essential pulmonary function testing (PF) ceased for a time during the first wave of the pandemic in spring. Testing has since resumed, but not at the same rate, as more guidance is awaited on how spirometry could be facilitated once again in the community.

Another impact of Covid-19 for COPD patients has been the reduction in hospital admissions related to the disease to date this year. While official figures have yet to be revealed, there is anecdotal evidence to suggest that there have been fewer hospital admissions related to COPD in 2020, according to Dr O’Beirne.

“This is probably because people were cocooning more because of the pandemic… because of that I think people contracted less viral illnesses overall. I would imagine we will see a slight reduction in COPD admissions over the last six months when the data is reported.”

ITS virtual 2020 Annual Scientific Meeting Meanwhile, in a separate interview, Dr Aidan O’Brien, Irish Thoracic Society (ITS) President and Consultant Respiratory Physician, University Hospital Limerick, said respiratory services, not ICU services, are most affected by Covid-19.

“Most Covid-19 admissions are for

respiratory problems,” Dr O’Brien told Update, speaking in advance of the ITS’s Annual Scientific Meeting, which will take place virtually on 3-4 December.

“Also, people with long-term symptoms as a result of Covid is quite a significant percentage. And a lot of those symptoms are respiratory. So a lot of the follow-up that is needed is going to be done by respiratory services.”

This has had a resulting impact on non-Covid-19 services. “All the ongoing management of existing respiratory services have been affected. Patients also have avoided coming in for follow-up, which has led to the problems of prolonged waiting lists, delayed diagnosis, and more advanced stages of disease.”

Dr O’Brien said the ITS “very much welcomes” the additional investment in respiratory services outlined in the HSE’s recently published Winter Plan, but noted that the funding is mainly for the community sector, and more support is still required for the acute sector.

As a result of its significance, the first session of the ITS meeting will be dedicated to Covid-19, and will include a presentation by Prof Stefano Nava, Professor of Respiratory Medicine, University of Bologna, Italy. As well as being a world expert on non-invasive ventilation for respiratory failure, Prof Nava also has first-hand experience of the pandemic in Italy, which was one of the most badly affected countries in the first wave of Covid-19.

Dr O’Brien added that a “significant number” of research studies submitted to the Society for the meeting are related to Covid-19.

However, the coronavirus will not dominate proceedings, and the meeting will also feature expert presentations on a wide range of respiratory and sleep disorders, from interstitial lung disease to COPD and asthma.

Extensive, exclusive coverage of the meeting will be published in an upcoming issue of the Medical Independent. For further information on the meeting programme and speakers visit irishthoracicsociety.com.

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Volume 6 | Issue 9 | 2020 | Respiratory Medicine

Global initiative for asthma (GINA) – What’s new in 2020 AUTHORS: Dr Dermot Nolan, ICGP/HSE Clinical Lead for Asthma; and Dr Emer Glanville, GP Registrar, SE Training Scheme The Global Initiative for Asthma (GINA, https://ginasthma.org) is a medical guidelines organisation which works with public health officials and healthcare professionals globally to reduce asthma prevalence and mortality.

order to reduce the risk of exacerbations and death and also to set out goals of treatment and preventing exacerbations, as well as guidelines on the use and reliance of short-acting beta-agonists (SABA) in early disease.

The 2020 report of the Global Strategy for Asthma Management and Prevention sets out new scientific information about asthma and is a review of the most recent scientific literature by an international panel of experts on the GINA Science Committee.

In 2019, GINA published landmark changes in the management of asthma: ● SABA monotherapy – no longer recommended for Step 1. The background to this change was that frequent use of SABA is associated with adverse clinical outcomes – dispensing of >three canisters per year was associated with increased risk of emergency department presentations

Since 2007, GINA has been actively seeking interventions for mild asthma in

and dispensing of >12 canisters per year was associated with higher risk of death. ● In children under five years, the evidence is still unclear – a trial of ICS should be used in those not responding to as-needed SABA. ● ICS (inhaled corticosteroids) recommended for all adults and adolescents with asthma to reduce risk of serious exacerbations (regular daily treatment or as-required low-dose ICS-formoterol).

GINA recommendations on Covid-19 and asthma 2020: ▶ Advise patients to continue taking

FIGURE 1A: GINA 2020 report steps 1-5 in management of adults and adolescents over 12 years

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Figure 1b - GINA 2020 report steps 1-5 in management of Adults and adolescents over 12

Respiratory Medicine | Volume 6 | Issue 9 | 2020

Figure 1b - GINA 2020 report steps 1-5 in management of Adults and adolescents over 12

FIGURE 1B: GINA 2020 report Steps 1-5 in management of Adults and adolescents over 12 their prescribed asthma medications, particularly ICS and OCS (oral corticosteroids) if prescribed. ▶ Patient on biological therapy for

severe asthma should continue and not stop if prescribed OCS. ▶ All patients should have a written asthma action plan that should be followed and this action plan should include instructions about increasing controller and reliever when required, taking a short course of OCS for severe exacerbations if needed and outlining when to seek medical help. ▶ Nebuliser therapy should be avoided where possible due to the risk of disseminating virus to other patients and to healthcare staff. Use of a pressurised metered dose inhaler via a spacer is the preferred treatment during severe exacerbations. ▶ Spirometry and peak flow tests should be avoided, again due to the risk of dissemination and should only be carried out if there is an urgent need.

Summary of GINA 2020 recommendations ▶ Covid-19 and asthma recommendations as outlined above. ▶ All patients with asthma should be treated with ICS regularly or as required, but trialled in children under five years to be reviewed after three months of therapy. ▶ GINA no longer recommends SABA alone for first-line. ▶ For adults and adolescents over 12 years old GINA recommends ICS in combination with formoterol for asneeded symptom relief. ▶ ICS with SABA recommended in children aged six-to-11 years. ▶ Mild asthma – where reliever is required no more than twice per month. The preferred treatment is asneeded ICS-formoterol combination. ▶ All patients should be regularly reviewed and this should include assessment (1), adjustment (2), and (3) review of any response to adjustments.

(1) Assessments to include

confirmation of diagnosis, symptom control and modifiable risk factors, inhaler technique and adherence, and patient preferences and goals.

(2) Adjustments should involve treatment of modifiable risk factors and comorbidities, nonpharmacological strategies, adjustments of asthma medications and education and skills training.

(3) Response review should look at symptoms, exacerbations, side effects, lung function and patient or parent satisfaction.

Should all patients start at Step 1 of management?

Recommended options below – based on symptom prevalence – remember Assess, Adjust, and Review.

What dose of ICS-formoterol as-needed to prescribe?

The guidelines recommend as-needed low-dose budesonide-formoterol to be prescribed in maintenance and reliever

11

Volume 6 | Issue 9 | 2020 | Respiratory Medicine

Should all pa*ents start at Step 1 of management?

Recommended – based on symptom SHOULD ALL PATIENTS STARTopFons AT STEP 1 OFbelow MANAGEMENT? Recommended options below – based on symptom prevalence – remember Assess, Adjust, and Review.

Review.

prevalence – remember Assess, Adjust and

What dose of ICS-formoterol as needed to prescribe?

therapy (Steps 3-5) above or as-needed only (Step 1).recommend as Thetherapy guidelines

and reliever therapy max daily Further data is awaited on assessing dose is 48mcg (six inhalations of whether use should be needed low-dose budesonide-formoterol to beICS prescribed in included in beclomethasone-formoterol 100/6mcg). the symptom control assessment.

maintenance and reliever therapy (Steps 3-5) above or as needed only therapy (Step 1).

Max daily dose recommended is 72mcg (12 inhalations of budesonide-formoterol Max daily dose recommended is Turbohaler 200/6mcg).

In assessing symptom control and Low-dose ICS is all that is required for frequency of SABA use, GINA recommends most patients, however, some patients may Turbohaler 200/6mcg). asking the following questions in the box require medium dosing if their asthma For as-needed low-dose beclomethasonebelow (Box 2-2) and categorising them symptoms are uncontrolled despite For as needed low dose beclomethasone-formoterol prescribed in maintenance and reliever therapy formoterol prescribed in maintenance according to level of control. following correct techniques and usage.

72mcg total daily dose (12 inhalaFons of budesonide-formoterol

max daily dose is 48mcg (six inhalaFons of beclomethasone-formoterol 100/6mcg).

In assessing symptom control and frequency of SABA use, GINA recommends asking the following quesFons and categorising them according to level of control:

12Further

data is awaited on assessing whether ICS use should be included in the symptom control assessment.

NOW NOW AVAILABLE AVAILABLE

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IND/GLY/MFIND/GLY/MF 114/46/136μg 114/46/136μg

UNLOCK UNLOCK THE THE IND/GLY/MF 1x 1x 114/46/136μg daily daily POTENTIAL POTENTIAL OF OF INHALED INHALED 1x 1,2 ASTHMA ASTHMA CARE1,2 CARE daily

UNLOCK THE UNLOCK THE POTENTIAL OF POTENTIAL OF INHALED INHALED 1,2 ASTHMA CARE 1,2 ONCE-DAILY ONCE-DAILY ENERZAIR® ENERZAIR® BREEZHALER® BREEZHALER® the the first LABA/LAMA/ICS first LABA/LAMA/ICS combination combination for asthma3,4 for asthma3,4

SE ARENT

ASTHMA CARE ONCE-DAILY PROVEN EFFICACY* PROVEN CONFIRMED EFFICACY* DOSE ONCE-DAILY ONCE-DAILY & INFLAMMATION & INFLAMMATION WITH TRANSPARENT 3 DOSING DOSING3 1,2,3 3 CONTROL1,2,3 CONTROL CAPSULE

ONCE-DAILY ENERZAIR® BREEZHALER® theENERZAIR® first LABA/LAMA/ICS BREEZHALER® 3,4 combination for asthma the first LABA/LAMA/ICS

CONFIR WITH T CAPSU

ONCE DAIL Y ONCE DAILY ® ® ® ENERZAIR ENERZAIR BREEZHALER® is indicated BREEZHALER as a is indicated as a maintenance maintenance treatment of asthma treatment in adult patients of asthma in adult patients not adequately not adequately controlled with a maintenance controlled with a maintenance -agonist combination combination of a long-acting betaof a and long-acting beta2-agonist and 2 a high adose high of an inhaled dose corticosteroid of an whoinhaled corticosteroid who experienced experienced one or more asthmaone exacerbations or in more asthma exacerbations in the previous the previous year.3 year.3

combination for asthma

3,4 Indacaterol acetate / glycopyrronium bromide Indacaterol acetate / / glycopyrronium bromi de / mometasone furoate inhalation powder mometasone furoate inhalation powder

Abbreviated Abbreviated Prescribing Information Prescribing Information eing treated with monoamine oxidase inhibitors, tricyclic with caution in patientsantidepressants, being treated with monoamine oxidase inhibitors,or tricyclic antidepressants, or Please refer Please to Summaryrefer of Product to Characteristics Summary (SmPC) beforeof prescribing.

Product Characteristics (SmPC) before prescribing. to prolong the QT -interval.

Hypokalaemic treatment: medicinal products Concomitant known to prolong the QT-interval. treatment Hypokalaemic treatment: Concomitant treatment ® ® Enerzair Breezhaler® (indacaterol Breezhaler (as acetate), glycopyrronium (indacaterol bromide, mometasone(as furoate)acetate), glycopyrronium bromide, furoate) tives, steroids, Enerzair or ®non-potassium sparing diuretics may with methylxanthine potentiate derivatives, steroids, or the non-potassium possible sparing diuretics may mometasone potentiate the possible inhalation inhalation powder, hard capsules. powder, hard blockers: capsules.

2-adrenergic agonists.

Beta-adrenergic Should hypokalaemic noteffect be of beta2-adrenergic given agonists. together Beta-adrenergic blockers: with Should not be given together with Presentation: Presentation: Hard capsules forreasons inhalationHard each containing capsules 150 mcgtheir of indacaterol for inhalation (as acetate), 63Where mcg ofeach containing mcg indacaterol (as cardioselective acetate), 63 mcg of less there are compelling for use. beta-adrenergic required, blockers unless150 there are cardioselective compellingof reasons for their use. Where required, glycopyrronium glycopyrronium bromide equivalent to 50 mcgbromide ofshould glycopyrronium equivalent and 160 mcg administered of mometasone to 50 furoate.mcg Each of glycopyrronium and 160 mcg of mometasone ould be preferred, although they be beta-adrenergic with blockers caution. should be preferred, although CYP3A4 they should be administered and with caution. CYP3A4 and furoate. Each delivered delivered dose contains P-gp 114 mcg dose of indacaterol contains acetate, 46 mcgimpact 114 of glycopyrronium mcgand of 136indacaterol mcg of mometasone acetate, 46 mcg glycopyrronium and mcg of hibition of CYP3A4 and has no on the safety P-glycoproteinof inhibitors: therapeutic Inhibition of of CYP3A4 and P-gp has doses no impact on the of safety136 of therapeutic doses of mometasone furoate.

Indications: furoate.

Maintenance Indications: treatment of asthmatransport: in Maintenance adult patients not adequately treatment controlled with a of asthma in adult patients not No adequately controlled with a ine and inhibitors of organic cation No clinically Enerzair Breezhaler. relevant Cimetidine and inhibitors drug of organic interaction cation transport: clinically relevant drug interaction maintenance maintenance combination of awith long-acting combination beta of of aan long-acting beta -agonist and a high dose inhaled corticosteroid who -agonist and aco-administered high dose of inhaled corticosteroid who onium is co-administered cimetidine or other inhibitors is expected when glycopyrronium of the is organic with cimetidine cation oran other inhibitors of the organic cation 2 2 experienced experienced one or more asthma exacerbations one in or themore previous year. asthma Dosage and Administration: exacerbations One capsule in the previous year. Dosage and Administration: g antimuscarinics and LABAs: Co-administration with transport. other Other long-acting medicinal antimuscarinics and LABAs:products Co-administration with other medicinal products One capsule once daily,once administered at the same administered time of the day each day, using at the the Enerzair same Breezhaler time inhaler. No dose of the day each day, using Enerzair Breezhaler inhaler. No dose uscarinics or LABAs isdaily, not recommended.

Fertility, containing Pregnancy long-acting antimuscarinics and or LABAs isthe not Lactation: recommended.

Fertility, Pregnancy and Lactation: adjustment adjustment is required in elderly patients, is required in patients with mild in to moderate elderly renalpatient impairment, patients, or in patients in with patients mild to moderate renal impairment, or pregnancy if the expected benefit to the justifies Should onlywith be the used during potential pregnancy if the expectedrisk benefit to the to patient the justifies the potential risk to in the patients with mild or moderate mild hepatic or impairment. moderate Caution should hepatic be observed impairment. inglycopyrronium patients with severe renalCaution impairment or should be observed in patients with in severe renal able on the presence of indacaterol, foetus. or No information mometasone available on the presence of indacaterol, furoate glycopyrronium or mometasone furoate inimpairment or end-stageend-stage renalor disease requiring renal dialysis. effects No disease data available for patients requiring severe hepatic dialysis. impairment,No only data available patients severe impairment, only n a breast-fed infant, on the onwith milk production. human milk, Aondecision the effects on for a breast-fed must infant, or on thewith effects beonmade milk production. hepatic A decision must be made in these use patients in if the these expected benefit patients outweighs the ifpotential the risk. expected The safety and efficacy benefit in paediatric outweighs the potential risk.

The efficacy in paediatric st-feeding or to use discontinue/abstain from therapy, taking whether to into discontinue breast-feeding account or to discontinue/abstain the benefit from safety therapy, takingand into account the benefit patients below patients 18 years of age below have not been 18 established. years Contraindications: of age Hypersensitivity have not to thebeen active established.

Contraindications: ild and the benefit of therapy for the woman.

Studies of breast-feeding do not for the child indicate and the benefit of therapy a for concern the woman.Hypersensitivity Studies do not indicate a concern to the active substances, substances, lactose monohydrate or magnesium lactose stearate. monohydrate Warnings/Precautions: Deterioration or magnesium of disease: stearate.

Warnings/Precautions: of disease: males or females.

Undesirable Effects: Very common regarding (≥1/10): fertility in either males or nasopharyngitis, females. Undesirable Effects: Very common Deterioration (≥1/10): nasopharyngitis, not Should be used to treat not acute asthma be used symptoms, including to treat acute episodes acute of bronchospasm. asthma Treatment symptoms, including acute episodes of bronchospasm.

Treatment mon (≥1/100 to Should <1/10): upper respiratory tract infection, asthma (exacerbation). candidiasis, Common (≥1/100 to <1/10): urinary upper respiratory tract tract infection, candidiasis, urinary tract should not should be stopped abruptly. not Hypersensitivity: be stopped Immediate hypersensitivity abruptly. reactions Hypersensitivity: have been observed Immediate hypersensitivity reactions been observed headache, tachycardia, oropharyngeal pain, cough, infection, dysphonia, hypersensitivity, headache, gastroenteritis, tachycardia, oropharyngeal pain, cough, dysphonia, have gastroenteritis, after administration. after Ifadministration. signs suggesting allergic reactions If occur, signs in particular suggesting angioedema, urticaria orallergic skin rash, reactions inpyrexia. particular angioedema, urticaria or skin rash, le spasms, pyrexia.

Uncommon (≥1/1,000 to <1/100): musculoskeletal hyperglycaemia, pain, occur, muscle spasms, Uncommon cataract, (≥1/1,000 to <1/100): hyperglycaemia, cataract, treatment should be discontinued should immediately and be alternative discontinued therapy instituted.

Paradoxical immediately bronchospasm:Characteristics and instituted. bronchospasm: dysuria. Please treatment consult the Summary of Product dry mouth,alternative rash, pruritus, dysuria. therapy Pleasefor consult the a Summary detailed of ProductParadoxical Characteristics for a detailed If paradoxical If bronchospasm paradoxical treatment bronchospasm should be discontinued immediately occurs, and alternative treatment therapy should be discontinued immediately and alternative therapy before prescribing.

Packoccurs, Size(s): Single pack containing listing of all adverse 30 eventsx before 1prescribing. hard Pack Size(s): capsules, Single pack containing 30 x 1 hard capsules, Cardiovascular effects:Cardiovascular Likecapsules, other medicinal products containing effects: beta2-adrenergic Like other medicinal products containing beta agonists, may -adrenergic agonists, may Pack containing instituted.

30 instituted. x 1 hard together with 1 together inhaler with one inhaler.

Pack and containing1 30 x sensor 1 hard capsules, together .

The with 2 1 inhaler and 1 sensor. The produce aproduce clinically significanta cardiovascular clinically effect in significant some patients as measured cardiovascular by increases in pulse rate, effect some patients as measured by increases quired for administration to the patient.

The sensor sensor and andin AppApp are not required do for administration not to control the patient. The sensor or and App do not control or in pulse rate, blood pressure, blood and/or symptoms. pressure, Useinhaler with caution and/or in patients with cardiovascular disorders Use (coronary with artery caution patients cardiovascular disorders (coronary artery medicinal product using the . symptoms.

Legal Category: POM. interfere within delivery Product of the medicinalwith product (Marketing) using the inhaler. Legal Category: POM. Product (Marketing) disease, acute disease, infarction, acute cardiacmyocardial arrhythmias, hypertension), infarction, convulsive disorders, cardiac thyrotoxicosis, arrhythmias, hypertension), convulsive disorders, thyrotoxicosis, EU/1/20/1438/002 & myocardial 003.

Product (Marketing) Authorisation Authorisation Number(s): EU/1/20/1438/002 Holder: & 003. Product Novartis (Marketing) Authorisation Holder: Novartis and in Merrion patients andwhoin are patients unusually responsivewho to beta are unusually to betaVista -adrenergic agonists. acting responsive beta2-adrenergic -adrenergic agonists.

Long acting beta2-adrenergic uilding, Elm Park, Road, Dublin 4,Long Ireland.

Full Europharm prescribing Limited, Building, Elm Park, information Merrion Road, Dublin 4, Ireland.

Full prescribing information 2 2 agonists (LABA) agonists or LABA containing (LABA) combination or products LABA suchBuilding, as containing Enerzair Breezhaler should combination be used with products such as Enerzair Breezhaler from: Novartis Ireland Limited, Vista Elm Park is available Business upon request from: Novartis Park, Ireland Limited, Elm Vista Building, Park, Elm Park Businessshould Park, Elm Park, be used with caution incaution patients with known in orpatients suspected prolongation with of theknown QT interval or who or are suspected being treated with prolongation the QT interval or who being r at www.medicines.ie.

Detailed information on this Dublin product 4. Tel: 01-2601255 is orof at www.medicines.ie. also available Detailed information on on this productare is also available on treated with medicinalmedicinal products affecting theproducts QT interval. Hypokalaemia: affecting Beta2-adrenergic the QT Hypokalaemia: Beta agonists mayinterval. produce significant -adrenergic agonists may produce significant an Medicines Agency http://www.ema.europa.eu Prescribing the website of the European Medicines Information last Prescribing Information last 2 Agency http://www.ema.europa.eu hypokalaemia hypokalaemia in some patients, which has inthesome potential to produce patients, adverse cardiovascular which effects. has The the to produce adverse cardiovascular effects. The revised:potential July 2020. decrease decrease in serum potassium is in usually serum transient, notpotassium requiring supplementation. is Inusually patients with severe transient, not requiring supplementation. In patients with severe asthma hypokalaemia asthma may hypokalaemia be potentiated by hypoxia and concomitant may be treatment, potentiated which may increase the by hypoxia and concomitant treatment, which may increase the erse reactions susceptibility of susceptibility the medicinal product is Hyperglycaemia: important Reporting suspected to adverse Novartis reactions the medicinal and product the isbeta important-adrenergic to Novartis and the to cardiac arrhythmias.

Hyperglycaemia: to cardiac Inhalation arrhythmias. of high dose of beta2-adrenergic Inhalation of of high dose of agonists and agonists and ued monitoring corticosteroids of the benefit/risk profile of theHPRA. medicinal It allows continued monitoring product. of the benefit/risk profileAll of the 2medicinal product. All corticosteroids may produce increases in plasma may glucose. produce Upon initiation ofincreases treatment, plasma glucose in plasma should glucose.

Upon initiation of treatment, plasma glucose should ons should be reported HPRA Pharmacovigilance, suspected website adverse reactions should www.hpra.ie. beeffect reported via related HPRA Pharmacovigilance, website www.hpra.ie. be monitored bemore monitored closely invia diabetic patients. more Anticholinergic closely effect related in diabetic to glycopyrronium:patients. use with Anticholinergic to glycopyrronium: use with o be reported to Novartis preferably via www.report.novartis.com Adverse events could also be reported to or Novartis by preferably email: via www.report.novartis.com or by email: caution incaution patients with narrow-angle in patients glaucoma or urinary with retention. narrow-angle Prevention of oropharyngeal glaucoma infections: or urinary retention. Prevention of oropharyngeal infections: .com or by calling 2080 612. drugsafety.dublin@novartis.com by calling 01 2080should 612.

In order01 toIn reduce order the risk ofto oropharyngeal reduce candidathe infection, risk patients of should oropharyngeal be advised to rinse their mouth candida infection, or patients be advised to rinse their mouth or gargle or with water gargle without swallowing with itwater or brush theirwithout teeth after inhaling swallowing the prescribed dose. Systemic it or brush their teeth after inhaling the prescribed dose. Systemic effects ofeffects corticosteroids: Systemic of corticosteroids: effects of inhaled corticosteroidsSystemic may occur, particularly effects at high doses of inhaled corticosteroids may occur, particularly at high doses prescribedprescribed for prolonged periods. Should for be prolonged administered with caution periods. in patients with Should pulmonary tuberculosis be administered with in2020; patients with pulmonary tuberculosis et al. Lancet Respir Med 2020; https://doi.org/10.1016/S2213-2600(20)30190-9.

References: 1. Kerstjens H, et al. caution Lancet Respir Med https://doi.org/10.1016/S2213-2600(20)30190-9. ® ® or in patients orwith inchronic patients or untreated infections. with Excipients: chronic Contains or lactose. untreated Patients with rare infections. hereditary Excipients: Contains lactose. Patients with rare hereditary atory Medicine 2020; https://doi.org/10.1016/j.rmed.2020.106021.

2. Gessner C, et al. Respiratory Medicine 3.

2020;ENERZAIR https://doi.org/10.1016/j.rmed.2020.106021.

3.

ENERZAIR ® problems problems of galactose intolerance, oftotal galactose lactase deficiencyat orintolerance, glucose galactose malabsorption total should lactase not deficiency or Characteristics. glucose galactose malabsorption should not f Product Characteristics.

Available www.medicines.ie BREEZHALER Date . Summary of accessed: Product Available October at www.medicines.ie Date accessed: October take this take medicinal product. this Interactions: medicinal No specificproduct. interaction studies Interactions: were conductedat: with indacaterol/ No 2020. specific studies with indacaterol/ es Agency CHMP Press Release.

Available https://www.ema.europa.eu/en/ 4. European interaction Medicines Agency CHMP Press Release. were Available at: conducted https://www.ema.europa.eu/en/ glycopyrronium/mometasone glycopyrronium/mometasone furoate. Information on the potential for interactions furoate. is based on the Information potential for on the potential for interactions is based the potential for mmittee-medicinal-products-human-use-chmp-28-30-april-2020 news/meeting-highlights-committee-medicinal-products-human-use-chmp-28-30-april-2020 Date accessed: Date on accessed: each of the each monotherapy ofcomponents. the monotherapy Medicinal products that prolong components.

QTc interval: Should be administered Medicinal that prolong QTc interval: Should be administered Octoberproducts 2020.

PROVEN EFFICACY* CONFIRMED DOSE & INFLAMMATION WITH TRANSPARENT 1,2,3 3 CONTROL PROVEN CAPSULE EFFICACY*

ONCE-DAILY DOSING3

& INFLAMMATION CONTROL1,2,3

with medic with hypok beta-a beta-a P-glyc Enerz is exp transp conta Shoul foetu huma wheth of bre regard asthm infect musc dry m listing toget senso interf Auth Europ is ava Dublin the w revise

CONFIR WITH T CAPSU

ONCE DAILY ENERZAIR® BREEZHALER® is indicated as a maintenance treatment of asthma in adult patients not adequately controlled with a maintenance ® beta -agonist and ® combination of a long-acting ENERZAIR BREEZHALER is indicated as a 2 a high dose of an inhaled corticosteroid who maintenance treatment of asthma in adult patients experienced one or more asthma exacerbations in not adequately controlled with a maintenance the previous year.3

Indacaterol acetate / glycopyrronium bromide / and combination of a long-acting momet beta asone furoate inhal-agonist ation powder

2 *In symptomatic *In symptomatic asthma patients despite treatment asthma with medium-patients or high-dose LABA/ICS. despite treatment with medium- or high-dose LABA/ICS.2

Date of preparation: Date of October preparation: 2020 IE02/ENE20-025 October 2020

IE02/ENE20-025

2

a high dose of an inhaled corticosteroid who

11654_Enerzair_IMT_Ad_OCT20_04.indd 11654_Enerzair_IMT_Ad_OCT20_04.indd 1

Abbreviated Prescribing Information

1

02/11/2020 02/11/2020 11:48 11:48

with caution in patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or

Rep HPR susp Adv drug

Refer 2. Ge BREE 2020. news Octob

Volume 6 | Issue 9 | 2020 | Respiratory Medicine

High-dose ICS is required for a very small cohort of patients due to the increased risk of systemic side effects with this use.

In Step 2 of management, the daily use of a leukotriene receptor antagonist such as montelukast is recommended, however, GINA recommends that its use must be closely monitored and its benefits and risks considered by the clinician prescribing, given the US FDA warning that was issued in March 2020.

The FDA warns that there is a serious risk of neuropsychiatric events including suicidality, nightmares, and behavioural problems among adolescents and adults prescribed this.

Children five years and younger A diagnosis of asthma in young children with a history of wheezing is much more likely if: ▶ It is wheezing that is associated with exercise, laughing or crying, or in absence of any respiratory infection ▶ There is the presence of another allergic disease such as eczema or allergic rhinitis, allergen sensitisation or asthma in a first-degree relative. ▶ There is worsening of symptoms with cessation of controller treatment and clinical improvement during two-tothree months of treatment.

GINA recommends a probability approach and following symptom pattern in diagnosing asthma under the age of five.

Estimated probability of asthma diagnosis in under five-year-olds ▶ Symptoms (cough, wheeze and heavy breathing) for <10days during an upper respiratory tract infection with two-to-three episodes of this per year and no symptoms in between – few have asthma. ▶ Symptoms (cough, wheeze and heavy breathing) for >10 days during an upper respiratory tract infection, occurring three or more times per year and/or worsening at night-time, with often wheezy episodes in between – some have asthma.

14

The goals of asthma management in young children are similar to adult management, with the objective being to achieve good control and maintain normal activity levels as well as minimising the risk of flare-ups, impaired lung development and side effects of medications

▶ Symptoms (cough, wheeze, and heavy breathing) for >10 days during upper respiratory tract infections with >three episodes per year, worsening of symptoms at night and a history of allergic sensitisation, atopic dermatitis, food allergy or positive family history – most have asthma.

The goals of asthma management in young children are similar to adult management, with the objective being to achieve good control and maintain normal activity levels as well as minimising the risk of flare-ups, impaired lung development, and side effects of medications.

GINA recommends that all wheezy episodes in children should be treated initially with inhaled SABA, regardless of a diagnosis of asthma being present.

Asthma management in general practice The Asthma Society of Ireland has developed resources and training programmes aimed at GPs. These are up-to-date to reflect the new GINA 2020 guidelines.

Uncertainty about disease severity, implications for quality-of-life and management can often lead to non-adherence and poor control

Goals of long-term management remains to achieve and maintain symptom control and prevent any further exacerbations or mortality.

Regular review, assessment and adjustment where required will remain to ensure good adequate control of symptoms. The key to this is guiding self-management in the patient through education and training and ensuring formulation of an action plan to follow.

Uncertainty about disease severity, implications for quality-of-life and management can often lead to nonadherence and poor control.

Some barriers in general practice include the cost of devices, particularly some of the combined agents, and the unlicensed use of some of those recommended.

Summary This article sets out the key changes in the GINA 2020 recommendations.

SABA use alone is no longer recommended for first-line.

For adults and adolescents over 12 years old, GINA recommends ICS in combination with formoterol for asneeded symptom relief .

Covid-19 presence does not change asthma management, but care must be taken with use of nebulisers and aerosol equipment due to risk of disseminating virus to others. n

NOW AVAILABLE

1x

daily

FLEXIBILITY TO ADJUST TREATMENT AS NEEDED1,2 ONCE-DAILY ATECTURA® BREEZHALER®2 NEW LABA/ICS therapy option for your patients ≥12 years*2

Available in 3 doses:2 LOW

IND/MF

MEDIUM IND/MF

HIGH

IND/MF

125/260μg

125/127.5μg

125/62.5μg

PROVEN EFFICACY* & INFLAMMATION CONTROL2,3

CONFIRMED DOSE WITH TRANSPARENT CAPSULE2

ONCE-DAILY DOSING2 ONCE DAILY

ATECTURA BREEZHALER is indicated as a maintenance treatment of asthma in adults and adolescents 12 years of age and older not adequately controlled with inhaled corticosteroids and inhaled short-acting beta2-agonists.2 ®

®

Abbreviated Prescribing Information Please refer to Summary of Product Characteristics (SmPC) before prescribing.

Atectura® Breezhaler® (indacaterol (as acetate), mometasone furoate) inhalation powder, hard capsules.

Presentation: Hard capsules for inhalation available in three strengths: (indacaterol acetate/mometasone furoate) 150/80 mcg; 150/160 mcg; 150/320 mcg. Each delivered dose contains (indacaterol acetate/ mometasone furoate): 125/62.5 mcg; 125/127.5 mcg; 125/260 mcg respectively. Indications: Maintenance treatment of asthma in adults and adolescents 12 years of age and older not adequately controlled with inhaled corticosteroids and inhaled short-acting beta2-agonists. Dosage and Administration: Adults and adolescents aged 12 years and over: one capsule once daily, administered at the same time of the day each day, using the Atectura Breezhaler inhaler. The appropriate mometasone furoate dosage for the severity of disease should be given and regularly reassessed. The maximum recommended dose is 125 mcg/260 mcg once daily. Capsules must not be swallowed. After inhalation, patients should rinse their mouth with water without swallowing. No dose adjustment is required in elderly patients, in patients with renal impairment, or in patients with mild or moderate hepatic impairment. 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 12 years of age have not been established. Contraindications: Hypersensitivity to the active substances or lactose monohydrate. Warnings/Precautions: Should not be used to treat acute asthma symptoms, including acute episodes of bronchospasm. 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 Atectura 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. Hypokalemia: Beta2-adrenergic agonists may produce significant hypokalemia 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 hypokalemia 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. 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 were conducted with indacaterol/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. Hypokalemic treatment: Concomitant treatment with methylxanthine derivatives, steroids, or non-potassium sparing diuretics may potentiate the possible hypokalemic effect of beta2adrenergic agonists. Beta-adrenergic blockers: Should not be given together with beta-adrenergic blockers unless there are compelling reasons for their use. CYP3A4 and P-glycoprotein inhibitors: Inhibition of CYP3A4 and P-gp has no impact on the safety of therapeutic doses of Atectura Breezhaler. Other long acting beta2adrenergic agonists: Co-administration with other medicinal products containing LABA 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 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, hypersensitivity, headache, oropharyngeal pain, dysphonia, musculoskeletal pain. Uncommon (≥1/1,000 to <1/100): candidiasis, angioedema, hyperglycaemia, vision blurred, cataract, tachycardia, rash, pruritus, muscle spasms. Please consult the Summary of Product Characteristics for a detailed listing of all adverse events before prescribing. Pack Size(s): Single pack containing 10 x 1 or 30 x 1 hard capsules, together with one inhaler. Legal Category: POM. Product (Marketing) Authorisation Number(s): EU/1/20/1439/002, -006 & -010. 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: May 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. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2020.

Available at: https://ginasthma.org/wp-content/uploads/2020/04/GINA-2020-full-report_-final-_wms.pdf. Date accessed: October 2020. 2. ATECTURA® BREEZHALER®. Summary of Product Characteristics. Available at www.medicines.ie Date access: October 2020. 3. van Zyl-Smit RN et al. Lancet Respir Med 2020; https://doi. org/10.1016/S2213-2600(20)30178-8.

*Asthma patients not adequately controlled with ICS and inhaled SABA.1 Date of preparation: October 2020 IE02/ATE20-004

11653_Atectura_Ad_IMT_OCT_02.indd 1

02/11/2020 11:51

azelastine hydrochloride / fluticasone propionate azelastine hydrochloride / fluticasone propionate

Treating rhinitis Treating allergic allergic rhinitis patients year round round patients all all year Fast and effective treatment Fast and effective treatment1 of allergic rhinitis symptoms of allergic rhinitis symptoms1

2019 ARIA Guidelines 2019 ARIA Guidelines recommends: a combination recommends: a combination therapy forfor moderate/severe therapy moderate/severe allergic rhinitis patients allergic rhinitis patients uncontrolled onINAH INAH uncontrolled on 88 INS monotherapy or or INS monotherapy

√√

Efficacy confirmed Efficacy confirmed 6 6 in real life in real life

Well tolerated2, 7

Well tolerated2, 7

Onset action Onset ofof action within 30 minutes within 30 minutes in in 1 clinical practice clinical practice 1

Nasal & ocular Nasal & ocular 1, 2, 3 symptom relief symptom relief1, 2, 3

Suitable for Suitable use for 4 long-term

long-term use4

Combination approach leads to Combination approach leads to clinical improvement days earlier clinical than with improvement FP or AZ alone5 days earlier INS - Intranasal steroid INAH - Intranasal antihistamine AZ - Azelastine FP - Fluticasone Propionate ARIA - Allergic Rhinitis and its Impact on Asthma

than with FP or AZ alone5

INS - ABBREVIATED Intranasal steroid INFORMATION: INAH - Intranasal antihistamine AZ /- FLUTICASONE Azelastine FP - Fluticasone Propionate PRESCRIBING DYMISTA (AZELASTINE HYDROCHLORIDE PROPIONATE) 137 MICROGRAMS / 50 MICROGRAMS PER ACTUATION, NASAL SPRAY, SUSPENSION. refer to Summary Product (SmPC) before prescribing.

ARIAPlease - Allergic Rhinitisofand itsCharacteristics Impact on Asthma Indications: Relief of symptoms of moderate to severe seasonal and perennial allergic rhinitis if monotherapy with either intranasal antihistamine or glucocorticoid is not considered sufficient. Presentation: Nasal Spray, suspension. Dosage and administration: Posology For full

therapeutic benefit regular usage is essential.

Contact with the eyes should be avoided. and adolescents (12 years andMICROGRAMS older) One actuation in each nostril twice (morning and evening).

Children below 12 years Dymista Nasal Spray is not recommended for use ABBREVIATED PRESCRIBING INFORMATION: DYMISTA (AZELASTINE HYDROCHLORIDE / Adults FLUTICASONE PROPIONATE) 137 / 50 MICROGRAMS PERdaily ACTUATION, NASAL SPRAY, SUSPENSION. children below 12 years of age Characteristics as safety and efficacy has not been prescribing. established in this age group. Elderly No dose adjustment is required in this population. Renal and hepatic impairment There are no data in patients with renal and hepatic impairment. Duration of treatment Please in refer to Summary of Product (SmPC) before Dymista Nasal Spray is suitable for long-term use. The duration of treatment should correspond to the period of allergenic exposure. Method of administration Dymista Nasal Spray is for nasal use only. Instruction for use Preparing the spray: The bottle should be shaken gently

Indications: Relief of symptoms of moderate to severe seasonal and perennial allergic rhinitis if monotherapy with either intranasal antihistamine or glucocorticoid is not considered sufficient. Presentation: Nasal Spray, suspension. Dosage and administration: Posology For full before use for about 5 seconds by tilting it upwards and downwards and the protective cap be removed afterwards. Prior to first use Dymista Nasal Spray must be primed by pressing down and releasing the pump 6 times. If Dymista Nasal Spray has not been used for more than therapeutic benefit regular usage is essential. Contact with the eyes should be avoided. Adults and adolescents (12 years and older) One actuation in each nostril twice daily (morning and evening). Children below 12 years Dymista Nasal Spray is not recommended for use 7 days it must be reprimed once by pressing down and releasing the pump. Using the spray: The bottle should be shaken gently before use for about 5 seconds by tilting it upwards and downwards and the protective cap be removed afterwards. After blowing the nose the in children below 12 of age as safety efficacy has not the been established in this age Elderly No4.2 dose adjustment is required this tip population.

Renal and hepatic impairment are no data in patients Hypersensitivity with renal and to hepatic impairment.

Duration of treatment suspension is years to be sprayed once intoand each nostril keeping head tilted downward (seegroup. figure in section of the SmPC). After use the in spray is to be wiped and the protective cap to beThere replaced.

Contraindications: the active substances or to any of Dymistathe Nasal Spray is suitable for long-term The duration of precautions: treatment should to the period of allergenic exposure.

Method of administration Dymista Nasal Spray is forfluticasone nasal use propionate only. Instruction for use resulting Preparing spray: The bottle should shaken gently excipients listed in section 6.1 of the use.

SmPC. Warnings and Duringcorrespond post-marketing use, there have been reports of clinically significant drug interactions in patients receiving and ritonavir, in the systemic corticosteroid effectsbe including before use for about 5 seconds tilting suppression. it upwards and downwards and theuse protective cap be removedand afterwards. to be firstavoided, use Dymista Nasal Spray must be primed by pressing downthe and releasing the corticosteroid pump 6 times.side-effects If Dymista (see Nasal Spray 4.5 hasofnot used for more than Cushing’s syndrome and by adrenal Therefore, concomitant of fluticasone propionate ritonavir Prior should unless the potential benefit to the patient outweighs risk of systemic section thebeen SmPC).

Systemic 7 days iteffects must of benasal reprimed once by pressing down and releasing the pump. the spray: The bottle should be shaken gently before use to foroccur aboutthan 5 seconds tilting it upwards andvary downwards andpatients the protective cap be removed afterwards.

After blowing the nose the corticosteroids may occur, particularly when prescribed at Using high doses for prolonged periods.

These effects are much less likely with oralby corticosteroids and may in individual and between different corticosteroid preparations.

Potential suspension is to be sprayed once into each nostril keeping the head tilted downward (see figure growth in section 4.2 of the use the spraycataract, tip is to be wiped and protective cap toofbe replaced. Contraindications: Hypersensitivity to the active substancessleep or to any of systemic effects may include Cushing’s syndrome, Cushingoid features, adrenal suppression, retardation in SmPC). children After and adolescents, glaucoma and the more rarely, a range psychological or behavioural effects including psychomotor hyperactivity, the excipients listed in section 6.1 of the SmPC. Warnings and precautions: During post-marketing use, there have been reports of clinically significant drug interactions receiving fluticasone propionate and ritonavir, resulting in systemic including disorders, anxiety, depression or aggression (particularly in children). Dymista Nasal Spray undergoes extensive first-pass metabolism, therefore the systemic exposure in ofpatients intranasal fluticasone propionate in patients with severe liver disease is likely tocorticosteroid be increased. effects This may Cushing’s syndrome andfrequency adrenal suppression.

Therefore, concomitant of fluticasone propionate and ritonavir should avoided, the potential to corticosteroids the patient outweighs theinrisk of systemic corticosteroid side-effectsIf (see 4.5 offor the SmPC).

Systemic result in a higher of systemic adverse events.

Caution isuse advised when treating these patients.

Treatment withbe higher than unless recommended dosesbenefit of nasal may result clinically significant adrenal suppression. theresection is evidence higher than recommended doses being then additionalwhen systemic corticosteroid cover should be considered during periods of stress or elective surgery.

In general, the dose of intranasal fluticasone shouldpatients be reduced the lowest dose at which effective control of the effects of nasal corticosteroids mayused, occur, particularly prescribed at high doses for prolonged periods.

These effects are much less likely to occur than with oral corticosteroids and mayformulations vary in individual and to between different corticosteroid preparations.

Potential of rhinitis is maintained.

Higher doses than the recommended onesuppression, (see section 4.2 of the SmPC) have not beenand tested for Dymista.cataract, As with allglaucoma intranasal and corticosteroids, theatotal systemic burden of corticosteroids should beincluding considered whenever other forms of sleep systemicsymptoms effects may include Cushing’s syndrome, Cushingoid features, adrenal growth retardation in children adolescents, more rarely, range of psychological or behavioural effects psychomotor hyperactivity, corticosteroid treatment or areaggression prescribed (particularly concurrently. in Growth retardation hasNasal been Spray reported in childrenextensive receiving first-pass nasal corticosteroids attherefore licensed doses.

Since Dymista is also to adolescents, it is recommended that thewith growth of adolescents receiving treatment disorders, anxiety, depression children).

Dymista undergoes metabolism, the systemic exposure of given intranasal fluticasone propionate in patients severe liver disease is likelyprolonged to be increased.

This may nasal corticosteroids is regularly monitored, too. IfCaution growth isisslowed, therapy bethese reviewed with the aim of reducing the dose of nasal corticosteroid if possible, to corticosteroids the lowest dose at which effective controlsignificant of symptoms is maintained.

Visual If disturbance may be reported result inwith a higher frequency of systemic adverse events. advised when should treating patients.

Treatment with higher than recommended doses of nasal may result in clinically adrenal suppression. there is evidence for higher than with systemic topical corticosteroid use. Ifsystemic a patientcorticosteroid presents with symptoms suchbe asconsidered blurred vision or other visualof disturbances, the patient should be considered for of referral to an ophthalmologist for evaluation of possible causes which may dose include glaucoma or of the recommended dosesand being used, then additional cover should during periods stress or elective surgery.

In general, the dose intranasal fluticasone formulations should be reduced to the lowest at cataract, which effective control rareofdiseases as centralHigher serous doses chorioretinopathy (CSCR) which one have(see been reported useSmPC) of systemic corticosteroids.

Close is warranted in patients with change in vision or with a history of increased pressure, glaucoma symptoms rhinitis issuch maintained. than the recommended section 4.2after of the have and not topical been tested for Dymista.

As monitoring with all intranasal corticosteroids, the a total systemic burden of corticosteroids shouldocular be considered whenever and/or other forms of cataracts.

If there are is any reason toconcurrently. believe that adrenal is impaired, care must beintaken when transferring patients from systemic steroid treatment to Dymista Nasal Spray.

In patients who have tuberculosis, any type untreated infection, or have had a recent surgical corticosteroid treatment prescribed Growthfunction retardation has been reported children receiving nasal corticosteroids at licensed doses. Since Dymista is also given to adolescents, it is recommended that of the growth of adolescents receiving prolonged treatment operation or injury is toregularly the nose monitored, or mouth, the possible benefits of the treatment withbe Dymista Nasal Spray be weighed risk. Infectionsifof the nasal should with antibacterial antimycotical therapy, but do not constitute a specific with nasal corticosteroids too.

If growth is slowed, therapy should reviewed with the should aim of reducing theagainst dose ofpossible nasal corticosteroid possible, to airways the lowest dosebe attreated which effective control oforsymptoms is maintained.

Visual disturbance may be reported contraindication to treatment with Dymista Nasal Spray. Dymista contains benzalkonium chloride. It may cause irritation of the nasal mucosa and bronchospasm. Interactions with other medicinal products and other forms of interactions: Fluticasone propionate Under normal with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or circumstances, low plasma concentrations of fluticasone propionate are achieved after intranasal dosing, due to extensive first pass metabolism and high systemic clearance mediated by cytochrome P450 3A4 in the gut and liver. Hence, clinically significant drug interactions rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Close monitoring is warranted in patients with a change in vision or with a history of increased ocular pressure, glaucoma mediated by fluticasone propionate are unlikely. A drug interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can greatly increase fluticasone propionate plasma concentrations, resulting in markedly reduced serum and/or cataracts.

If there is any reasonDuring to believe that adrenal is impaired, careofmust be taken whendrug transferring patients from systemic treatment to Dymista Nasal Spray. In and patients who resulting have tuberculosis, type of untreated infection, or have recent cortisol concentrations. postmarketing use,function there have been reports clinically significant interactions in patients receivingsteroid intranasal or inhaled fluticasone propionate ritonavir, in systemicany corticosteroid effects. Co-treatment with had otheraCYP 3A4surgical operation or injury to the nose or mouth, the possible of the treatment with Nasal Spray should becombination weighed against risk.

Infections of the nasal airways should risk be of treated with antibacterial or antimycotical but do not be constitute a specific inhibitors, including cobicistat-containing productsbenefits is also expected to increase theDymista risk of systemic side-effects.

The should possible be avoided unless the benefit outweighs the increased systemic corticosteroid side-effects, in which therapy, case patients should monitored contraindication to corticosteroid treatment withside-effects.

Dymista Nasal Spray.

Dymista chloride. It P450 may 3A4 cause irritation of the nasal mucosa and Interactions within other medicinal products and other forms of interactions: Fluticasone propionate Under normal for systemic Studies have shown contains that otherbenzalkonium inhibitors of cytochrome produce negligible (erythromycin) andbronchospasm. minor (ketoconazole) increases systemic exposure to fluticasone propionate without notable reductions in serum cortisol circumstances, low plasma concentrations fluticasone are achieved after intranasal dosing, due to(e.g. extensive first pass as metabolism and high clearance mediatedtobyfluticasone cytochrome P450 3A4Azelastine in the guthydrochloride and liver. Hence, clinically significant drug interactions concentrations.

Nevertheless, care is of advised when propionate co-administering potent cytochrome P450 3A4 inhibitors ketoconazole), there is potential forsystemic increased systemic exposure propionate.

No specific interaction studies with mediated by fluticasone propionate are unlikely.

A drug interaction study in healthy subjects has shown that performed. ritonavir (aHowever, highly potent cytochrome P450to3A4 inhibitor) canspray greatly increase fluticasonenasal propionate plasma concentrations, resulting in markedly reduced azelastine hydrochloride nasal spray have been performed.

Interaction studies at high oral doses have been they bear no relevance azelastine nasal as given recommended doses result in much lower systemic exposure.

Nevertheless, care serum cortisol should concentrations.

During postmarketing use, there have beeninreports clinically significant drug or interactions in patients receiving intranasal or inhaled fluticasone propionate and ritonavir, resulting ineffect systemic Co-treatment with other be taken when administering azelastine hydrochloride patientsoftaking concurrent sedative central nervous medications because sedative effect may be enhanced.

Alcohol may also enhance this (seecorticosteroid section 4.7 of effects. the SmPC).

Fertility, pregnancy andCYP 3A4 inhibitors, including cobicistat-containing products is also expected to increase the5.3 riskofofthe systemic The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients be monitored lactation: Fertility There are only limited data with regard to fertility (see section SmPC).side-effects.

Pregnancy There are no or limited amount of data from the use of azelastine hydrochloride and fluticasone propionate in pregnant women. Therefore, Dymista Nasalshould Spray should be used during pregnancy only if the potential benefit justifies the potential riskof to cytochrome the foetus (see section of the SmPC) Lactation It is unknownand whether nasally administered azelastine or fluticasone propionate/metabolites excreted in human for systemic corticosteroid side-effects.

Studies have shown that other inhibitors P450 3A45.3 produce negligible (erythromycin) minor (ketoconazole) increases inhydrochloride/metabolites systemic exposure to fluticasone propionate without notableare reductions serum cortisol breast milk.

Dymista Nasal Spray should be usedco-administering during lactation only if thecytochrome potential benefit the potential to the newborns/ infantis(see sectionfor 5.3increased of the SmPC).

Effectsexposure on ability to drive and use machines: Dymista Nasal Spray has minor influenceinteraction on the ability to concentrations.

Nevertheless, care is advised when potent P450justifies 3A4 inhibitors (e.g.risk ketoconazole), as there potential systemic fluticasone propionate.

Azelastine hydrochloride No specific studies with drive and use machines.

In isolated weariness, exhaustion, or weakness thatbeen may also be caused by the they disease itself, may occur to when using Dymista Nasalas Spray. these cases, thenasal abilitydoses to drive andinuse machines may be impaired. may azelastine hydrochloride nasal spray have cases been fatigue, performed.

Interaction studiesdizziness at high oral doses have performed.

However, bear no relevance azelastine nasal spray givenInrecommended result much lower systemic exposure.Alcohol Nevertheless, care enhance effect.

Undesirableazelastine effects: Very common (≥1/10): Epistaxis.

Common (>1/100, <1/10): dysgeusia (unpleasant taste),sedative unpleasant smell.

Uncommon (>1/1000, <1/100): discomfortthis (including nasal irritation, itching),Fertility, sneezing, nasal should be taken this when administering hydrochloride in patients taking concurrent sedative orHeadache, central nervous medications because effect may be enhanced.

Alcohol mayNasal also enhance effect (see section 4.7stinging, of the SmPC). pregnancy and dryness, throat data irritation. details rare and rarely5.3 reported events see SmPC. lactation: Fertilitycough, There dry arethroat, only limited withFor regard toof fertility (seevery section of the adverse SmPC). Pregnancy There are no or limited amount of data from the use of azelastine hydrochloride and fluticasone propionate in pregnant women. Therefore, Dymista Nasal Spray should of suspected adverse reactions:benefit Reporting suspected adverserisk reactions after authorisation the product is important.

It allows continued monitoring of theazelastine benefit/riskhydrochloride/metabolites balance of the medicinal product.

Healthcare professionals are asked report any be usedReporting during pregnancy only if the potential justifies the potential to the foetus (see sectionof 5.3 ofmedicinal the SmPC) Lactation It is unknown whether nasally administered or fluticasone propionate/metabolites aretoexcreted in human suspected adverse via HPRA Pharmacovigilance, Earlsfort IRL – Dublin Tel: +353 1 6764971; 6762517. Website: www.hpra.ie.

E-mail: medsafety@hpra.ie. events also be reported to Pharmacovigilance, 4 –on Trident breast milk.

Dymista Nasalreactions Spray should be used during lactation only if Terrace, the potential benefit2;justifies the potentialFax: risk +to353 the1newborns/ infant (see section 5.3 of the SmPC). Effects onAdverse ability to driveshould and use machines: Dymista Nasal Spray hasMylan, minor Building influence the ability to Place, Hatfield Business Park, Mosquito Way, Hatfield, Hertfordshire, AL10 9BW, phone no: +44 (0) 800 121 8267, Email: UKPharmacovigilance@mylan.com. Legal Category: Product subject to prescription which may be renewed (B) Marketing Authorisation Number: drive and use machines. In isolated cases fatigue, weariness, exhaustion, dizziness or weakness that may also be caused by the disease itself, may occur when using Dymista Nasal Spray. In these cases, the ability to drive and use machines may be impaired. Alcohol may PA2010/059/001 Marketing Authorisation Holder: Mylan IRE Healthcare Limited, Unit 35/36, Grange Parade, Baldoyle Industrial Estate, Dublin 13, Ireland. Full Prescribing Information available on request from: Mylan Dublin, Dublin 17. Phone 01 8322250. Date of revision of enhance this effect. Undesirable effects: Very common (≥1/10): Epistaxis. Common (>1/100, <1/10): Headache, dysgeusia (unpleasant taste), unpleasant smell. Uncommon (>1/1000, <1/100): Nasal discomfort (including nasal irritation, stinging, itching), sneezing, nasal Abbreviated Prescribing Information: 20 Dec 2018 Item Code: IE-PI-Dymista-001 dryness, cough, dry throat, throat irritation. For details of rare and very rarely reported adverse events see SmPC. Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any References: suspected adverse reactions via HPRA Pharmacovigilance, EarlsfortofTerrace, IRL –hydrochloride Dublin 2; Tel: +353 1 6764971; Fax: + 353 1 6762517.

Website: of www.hpra.ie.

E-mail: rhinitis: medsafety@hpra.ie.

Adverse events should also be reported to of Pharmacovigilance, Mylan, Building 4 – Trident 1. Meltzer E et al. MP29-02 (a novel intranasal formulation azelastine and fluticasone propionate) in the treatment seasonal allergic A randomized, double-blind, placebo-controlled trial efficacy and safety.

Allergy Asthma Place, Proc.

Hatfield Business Park, Mosquito Way, Hatfield, AL10 9BW, phone no: +44 (0) 800 121 8267, Email: UKPharmacovigilance@mylan.com.

Legal2012 Category: Product1282-9 subject to prescription which may be placebo-controlled renewed (B) Marketing Authorisation 2012; 33(4):324–32.

2. Carr W, et al.

A novelHertfordshire, intranasal therapy of azelastine with fluticasone for the treatment of allergic rhinitis. J Allergy Clin Immunol May; 129(5): 3. Hampel FC, et al.

Double-blind study of azelastineNumber: PA2010/059/001 Marketing Holder: Mylan IRE Healthcare Limited, Unit 35/36, Grange Parade, Industrial Dublin Ireland.

Full Prescribing available on request from: for Mylan Dublin Phone 01 8322250.

Date of revision of ® and fluticazone in a Authorisation single nasal spray delivery device.

Ann Allergy Asthma Immunol 2010; (105): Baldoyle 168-173 4.

DymistaEstate, Summary of13, Product Characteristics 5.Information Scadding GK, et al. BSACI guideline the Dublin, diagnosis and17. management of allergic rhinitis Abbreviated Prescribing Information: 20 Dec 2018 Item Code: IE-PI-Dymista-001

(Revised Edition 2017. First edition 2007). Clin Exp Allergy 2017. 47(7): 856-889. 6. Klimek L et al. Effectiveness of MP20-02 for the treatment of allergic rhinitis in real-life: Results from a non interventional study. Allergy Asthma Proc. 2015; 36:40-47 7. Berger

References: WE, et al. Long-term, Randomized Safety Study of MP29-02 (a Novel Intranasal Formulation of Azelastine Hydrochloride and Fluticazone Propionate in an Advanced Delivery System) in Subjects With Chronic Rhinitis. J Allergy Clin Immunol Pract. 2014; 2:179-85.

Bousquet(a J, novel et al. Next-generation Allergic Rhinitis and Itshydrochloride Impact on Asthma guidelines for allergic based on of allergic Recommendations Assessment, double-blind, Development and Evaluation (GRADE) real-world evidence.

J AllergyAsthma 1. Meltzer E et al.8.MP29-02 intranasal formulation of azelastine and(ARIA) fluticasone propionate) in rhinitis the treatment ofGrading seasonal rhinitis: A randomized, placebo-controlled trialand of efficacy and safety. Allergy Clin Immunol.

2019 2. Carr W, et al. A novel intranasal therapy of azelastine with fluticasone for the treatment of allergic rhinitis. J Allergy Clin Immunol 2012 May; 129(5): 1282-9 3. Hampel FC, et al. Double-blind placebo-controlled study of azelastine Proc. 2012; 33(4):324–32. and fluticazone in a single nasal spray delivery device. Ann Allergy Asthma Immunol 2010; (105): 168-173 4. Dymista® Summary of Product Characteristics 5. Scadding GK, et al. BSACI guideline for the diagnosis and management of allergic rhinitis (Revised Edition 2017. First edition 2007). Clin Exp Allergy 2017. 47(7): 856-889. 6. Klimek L et al. Effectiveness of MP20-02 for the treatment of allergic rhinitis in real-life: Results from a non interventional study. Allergy Asthma Proc. 2015; 36:40-47 7. Berger WE, et al. Long-term, Randomized Safety Study of MP29-02 (a Novel Intranasal Formulation of Azelastine Hydrochloride and Fluticazone Propionate in an Advanced Delivery System) in Subjects With Chronic Rhinitis. J Allergy Clin Immunol Pract. 2014; 2:179-85. 8. Bousquet J, et al. Next-generation Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines for allergic rhinitis based on Grading of Recommendations Assessment, Development and Evaluation (GRADE) and real-world evidence. J Allergy Clin Immunol. 2019

Item code: DYM-2020-0138 Date of Preparation: May 2020

Item code: DYM-2020-0138 Date of Preparation: May 2020

Respiratory Medicine | Volume 6 | Issue 9 | 2020

Understanding asthma and sinus disease AUTHOR: Dr Marie Talty,1 Helen Mulryan,1 Prof Anthony Oâ&#x20AC;&#x2122;Regan,1 and Ms Mona Thornton2 1 Department of Respiratory Medicine, University Hospital Galway; 2Department of Otorhinolaryngology, University Hospital Galway For many years there has been a clearly described association between chronic rhinosinusitis (CRS) and asthma, with a prevalence of around 25 per cent of asthma in those with CRS, compared to a prevalence of up to 10 per cent in the general population. In patients with asthma, up to 90 per cent of those with allergic asthma describe rhinitis and up to 80 per cent of those with non-allergic asthma. In the adult population, chronic rhinosinusitis has been defined as the presence of two or more symptoms, one of which should be either nasal blockage, obstruction or congestion; or nasal discharge (ie, anterior or posterior nasal drip) with or without facial pain/ pressure; or reduction or loss of smell; for at least 12 weeks. Previously, CRS has been divided into two groups based on clinical history and nasoendoscopic exam, either with or without nasal polyps.

In recent years there has been an increase in interest and popularity of the concept of a united airways disease, also sometimes termed global airways disease. It is suggested that if the role of the upper airway to act as a humidifier, filter and heat regulator for air entry onwards into the lower airways is disrupted, it leads to more generalised inflammation progressing to the lower airways. Allergic rhinitis has long been considered a risk factor for the development of asthma but there is some speculation that this is truly the early presentation of a reactive airways disease, which may then progress to asthma. There is a commonality in the factors which can trigger upper and lower airways disease. These include allergens, aspirin, infections both viral and bacterial, or irritants such as pollutants.

Also at a cellular level, the infiltrates that characterise inflammation in both asthma and CRS include eosinophils, mast cells, macrophages and T-cells. Cytokines promoting inflammation are also similar, such as histamine, interleukin 4, 5 and 13,

SPHENOID SINUS

FRONTAL SINUS NASAL CAVITY

RIGHT LUNG

LEFT LUNG

and leukotrienes. This correlates with CRS being associated with the asthma clinical subgroup of TH2 dominant asthma, which includes allergic and eosinophilic asthma.

The relationship between allergy and allergic rhinitis and the development of CRS remains unclear and incompletely understood, as CRS has not been considered as related to atopy, unlike allergic rhinitis.

Recent studies suggest in the setting of sinusitis, grouping patients on their inflammatory patterns into either type 1 or type 2 inflammation is more useful than general atopic status.

Also, in patients with upper airway sinus disease and lower respiratory symptoms it is important to consider other causes/ associations outside of asthma, including vasculitis such as granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA).

In asthmatic patients, symptoms of CRS contribute significantly to quality-of-life, however this is largely in relation to poorer asthma control due to upper airway disease.

The outcomes of poorer asthma control apart from quality-of-life including work days missed, exposure to more frequent

courses of antibiotics and steroids as well as increased State spending on hospitalisations and maintenance therapy have a clear population impact. Data from the Asthma Society of Ireland published last year revealed overall State spending of â&#x201A;Ź473 million per annum on asthma.

Treatment Treatment aims in CRS are to reduce inflammation and associated oedema, allow for adequate sinus drainage, eliminate any colonising or infecting organisms and to reduce the number of acute exacerbations.

Asthma is usually associated with diffuse bilateral sinus disease, the mainstay of treatment of which is intranasal corticosteroids and saline. Adequate delivery and technique, as well as compliance with this quite cumbersome therapy is of vital importance for treatments to have beneficial effect. Local delivery can be enhanced by saline irrigation prior to use of other topical agents, angling of the head slightly downwards, and aiming the tip of the spray away from the nasal septum.

Antimicrobial therapy in CRS has limited evidence, outside of acute exacerbations. A single course of antibiotics may often be used, especially if increasing purulent nasal

17

Volume 6 | Issue 9 | 2020 | Respiratory Medicine

discharge. In some post-operative patients there may be sinus cultures available, but generally an empiric regimen is chosen. This would need to cover anaerobic organisms, staph aureus and streptococci. Broad-spectrum agents such as co-amoxiclav and doxycycline are routinely prescribed. Doxycycline offers a synergistic anti-inflammatory effect in theory and has been shown to reduce nasal polyp size. Longer-term suppressive antibiotics including macrolides are sometimes used in secondary care, however, there is currently a low quality of evidence to support same and side effects of such should certainly be considered.

Oral steroids are often used in the shortterm for those with refractory symptoms, and can be particularly beneficial in those with nasal polyps.

Leukotriene receptor antagonists such as montelukast are used as an adjunct therapy to nasal corticosteroids and seem to show additional benefit in CRS patients with asthma or aspirin-exacerbated airways disease.

If symptoms are not responsive to usual treatment, CT of the sinuses as well as otorhinolaryngology review is recommended by the European Position Paper on Rhinosinusitis and Nasal Polyps 2020, which can identify any more localised disease, as well as suitability for surgical intervention.

Endoscopic sinus surgery in asthma has been reported to improve multiple clinical asthma parameters with improved overall asthma control, reduced frequency of asthma attacks and number of hospitalisations, as well as decreased use of oral and inhaled corticosteroids.

However, of note, endoscopic sinus surgery’s role is to optimise local treatment and as CRS is a chronic condition, ongoing medical management is still required. Naturally, this is also the case with ongoing treatment of asthma as a chronic condition.

A developing area of interest in CRS, as it is in asthma treatment, is biologic therapy.

Dupilumab was the first monoclonal

18

antibody approved as an add on therapy for chronic rhinosinusitis with nasal polyps by the European Commission in 2019. It is an interleukin 4 receptor antagonist, and modulates signalling of interleukin 4 and 13.

For asthma, omalizumab is approved for those with severe persistent asthma, with clear IgE mediation. Phase 3 trials published last year showed significantly reduced nasal congestion and polyps in

Mepolizumab, an anti-IL-5 monoclonal antibody, is approved for those with severe refractory eosinophilic asthma. A phase 3 trial preliminary data published earlier this year for mepolizumab also suggested positive results in relation to size of nasal polyps and relief of obstruction, again in CRS without polyps. However given the costly nature of these drugs, significant study is still needed into cost benefit analysis as well as very careful patient selection and optimisation of other therapies.

Role of joint care

Oral steroids are often used in the short-term for those with refractory symptoms, and can be particularly beneficial in those with nasal polyps

those with CRS, while a previous study has shown a similar benefit in alleviation of sinus symptoms with omalizumab in a cohort with co-existing severe allergic asthma and CRS with polyps. There have been no efficacy studies examining CRS without polyps.

If we look at the overlapping problems of asthma and CRS as a united airways disease, it certainly does seem strange to have it managed very separately by respiratory and otorhinolaryngology, often across different centres. Close collaboration between respiratory and otorhinolaryngology specialists leads to improved access to care and therefore intervention for asthmatic patients with difficult to control disease. In our centre, this has led to the establishment of a joint respiratory and rhinology clinic.

Certainly patients anecdotally self-report improved satisfaction with access to both services with one appointment, rather than remaining on waiting lists with ongoing symptoms or exacerbations. The management and outcomes of these patients is being evaluated in ongoing research. ■

References 1.

2.

3.

4.

Sibbald B, Rink E. Epidemiology of seasonal and perennial rhinitis: clinical presentation and medical history. Thorax.

1991;46(12):895-901. doi:10.1136/ thx.46.12.895 Ciprandi G, Caimmi D, Miraglia Del Giudice M, La Rosa M, Salpietro C, Marseglia GL. Recent developments in United airways disease. Allergy Asthma Immunol Res. 2012;4(4):171-177. doi:10.4168/ aair.2012.4.4.171 Phillips KM, Talat R, Caradonna DS, Gray ST, Sedaghat AR. Quality-of-life impairment due to chronic rhinosinusitis in asthmatics is mediated by asthma control. Rhinology.

2019;57(6):430-435. doi:10.4193/Rhin19.207 Schlosser RJ, Smith TL, Mace J, Soler ZM. Asthma quality of life and control after sinus surgery in patients with chronic

5.

6.

7.

8.

rhinosinusitis. Allergy. 2017;72(3):483-491. doi:10.1111/all.13048 Asthma Society of Ireland. www.asthma.ie/ get-help/resources/facts-figures-asthma Fokkens WJ, Lund VJ, Hopkins C, et al.

European Position Paper on Rhinosinusitis and Nasal Polyps 2020. Rhinology.

2020;58(Suppl S29):1-464. Published 2020 Feb 20. doi:10.4193/Rhin20.600 Bidder T, Sahota J, Rennie C, Lund VJ, Robinson DS, Kariyawasam HH. Omalizumab treats chronic rhinosinusitis with nasal polyps and asthma together-a real life study. Rhinology. 2018;56(1):42-45. doi:10.4193/Rhin17.139 Fokkens WJ, Lund V, Bachert C, et al.

EUFOREA consensus on biologics for CRSwNP with or without asthma. Allergy.

2019;74(12):2312-2319. doi:10.1111/all.13875

fluticasone furoate

Allergic rhinitis relief

Relieving the symptoms of allergic rhinitis in patients over 6 years1

The incidence of epistaxis during long term treatment was higher than 10% but was generally mild to moderate in intensity1

www.avamys.ie

AVAMYS 27.5 micrograms/spray, nasal spray suspension Abbeviated Prescribing Information (Refer to the full Summary of Product Characteristics before prescribing) Composition: Each spray actuation delivers 27.5 micrograms of fluticasone furoate. One actuation delivers 8.25 micrograms of benzalkonium chloride. Uses: Treatment of symptoms of allergic rhinitis in adults and children aged 6 years and over. Dosage and Administration: For intranasal use only. Adults and adolescents (12 years and older): Two sprays per nostril once daily (total daily dose, 110 micrograms). Once symptoms controlled, use maintenance dose of one spray per nostril once daily (total daily dose, 55 micrograms). Reduce to lowest dose at which effective control of symptoms is maintained.

Children aged 6 to 11 years: One spray per nostril once daily (total daily dose, 55 micrograms). If patient is not adequately responding, increase daily dose to 110 micrograms (two sprays per nostril, once daily) and reduce back down to 55 micrograms daily dose once control is achieved. Contraindication: Hypersensitivity to active substance or excipients. Special warnings and precautions: Systemic effects of nasal corticosteroids may occur, particularly when prescribed at high doses for prolonged periods. These effects are much less likely to occur than with oral corticosteroids and may vary in individual patients and between different corticosteroid preparations. Potential systemic effects may include Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, cataract, glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). Treatment with

when prescribing concurrently with other corticosteroids. A reduction in growth velocity has been observed in children treated with fluticasone furoate 110 micrograms daily for one year. Therefore, children should be maintained on the lowest possible efficacious dose which delivers adequate symptom control. It is recommended that growth of children receiving prolonged treatment with nasal corticosteroids is regularly monitored. Consider referring to a paediatric specialist. May cause irritation of the nasal mucosa. 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, central serous chorioretinopathy. Contains benzalkonium chloride; longterm use may cause oedema of the nasal mucosa. Drug interactions: Caution is recommended when co-administering fluticasone furoate with potent CYP3A inhibitors including cobicistat-containing products as an increase in the risk of systemic side effects is expected.

Co-administration should be avoided unless the benefit outweighs the increased risk. Co-administration with ritonavir is not recommended because of the risk of increased systemic exposure of fluticasone furoate. Pregnancy and Lactation: No adequate data available.

Recommended nasal doses result in minimal systemic exposure. It is unknown if fluticasone furoate nasal spray is excreted in breast milk.

Only use if the expected benefits to the mother outweigh the possible risks to the foetus or child. Side effects: Very common (≥1/10): epistaxis. Epistaxis was generally mild to moderate, with incidences in adults and adolescents higher in longer-term use (more than 6 weeks).

Common (≥1/100 and <1/10): headache, dyspnoea, nasal ulceration.

Uncommon (≥1/1000 and <1/100): rhinalgia, nasal discomfort

(<1/10,000): Nasal septum perforation. Not known: transient ocular changes, vision blurred, bronchospasm, growth retardation.

Marketing Authorisation (MA) Holder: GlaxoSmithKline (Ireland) Limited, 12 Riverwalk, Citywest Business Campus, Dublin 24, Ireland. MA Number: EU/1/07/434/003. Legal category: POM B. Last date of revision: August 2020. Job Ref: PI-5555. Further information available on request from GlaxoSmithKline, 12 Riverwalk, Citywest Business Camp, 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.

+285 ())(&7

Reference: 1. Avamys Summary of Product Characteristics, available on www.medicines.ie, accessed January 2020

Volume 6 | Issue 9 | 2020 | Respiratory Medicine

Virtual asthma and COPD reviews AUTHOR: Ruth Morrow, Respiratory Nurse Specialist, Registered Nurse Prescriber, Nurse Educator and Consultant Asthma and COPD are two conditions which are ideal for virtual consultations.

Both conditions have been the subject of many research studies over the last 20 years to address the issues of non-attendance at both primary and secondary care level appointment. “Every asthma consultation is an opportunity to review, reinforce and extend both the patient’s knowledge and skills. It is important to recognise that education is a process and not a single event” (BTS/SIGN 2019).

Ryan et al 2013 proposed a universal structured approach to a primary care asthma review ‘SIMPLES’. SIMPLES is an acronym for Smoking, Inhaler technique, Monitoring, Pharmacotherapy, Lifestyle, Education and Support. It can be adapted to the current situation where face-to-face in person reviews may not be possible or even necessary for the majority of those with asthma. It allows an increased patient focused approach whilst gathering the required information.

Anecdotally, healthcare professionals have noticed that patients are more relaxed and more honest during a virtual consultation as they are away from the clinical environment and have not been waiting in a packed waiting room. This article will address the finer points for undertaking virtual asthma and COPD reviews. It will also provide a number of resources which can be used throughout the virtual consultation.

Undertaking an effective asthma review: ▸ Identify how you will deliver the remote review, eg, will it be through video consultation or telephone? ▸ In preparation for the consultation, briefly gather information from the medical record and prescribing data to assess morbidity and compliance, looking at short-acting bronchodilator use (SABA). You can assess the patient’s reliance on SABA using the Asthma Slide Ruler. This ruler can also be

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Anecdotally, healthcare professionals have noticed that patients are more relaxed and more honest during a virtual consultation as they are away from the clinical environment and have not been waiting in a packed waiting room downloaded from: https://www.pcrs-uk.org/ resource/asthma-slide-rule. ▸ At the time of booking the appointment for the virtual asthma review, check if the patient has an Asthma Action Plan and if they are using it. If the patient does not have an Asthma Action Plan, this can be completed by the practice nurse/GP in advance of the appointment and posted to the patient.

Inform the patient that you will be referring to it and discussing it during the consultation. ▸ Start off with an introduction and establish if the patient has access to the Internet as this will be useful to signpost them to educational resources and support, both

during (where appropriate) and/or after the consultation. Ask how the patient has been since their last review. ▸ Assessing asthma control – use the Asthma Control Test (ACT) and/or the GINA Assessment of Asthma Control to monitor the patient’s asthma. The ACT can be sent to the patient (or text a link to www.asthma. com/) beforehand so it can be discussed during the consultation. An ACT score of less than 19 (scored out of 25) indicates uncontrolled or poorly controlled asthma.

If the patient has a peak flow metre, you can ask them to carry out the test and you can work out their percentage.

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▸ Explore key triggers that make their asthma worse, including where appropriate, smoking, which is a key element. Ask if there are any occupational or seasonal triggers, which impact their asthma control, and whether avoidance or reduction of these is practicable or acceptable to the patient. ▸ Check the patient’s understanding around the role of each medication in helping their asthma including dosing information and when they should be taking their medication.

Explore the Asthma Action Plan and assess the patient’s understanding of when they should increase medication. Ask the patient about SABA use – using salbutamol more than twice a week indicates poor asthma control and an over reliance on salbutamol.

If the patient is over reliant on salbutamol inform them of the risks of acute asthma attacks and fatal asthma events in the future. ▸ Ask about inhaler use and technique.

Use videos to support your discussion where access is available and signpost people.

Inhaler technique videos are available on www.asthma.ie/about-asthma/resources/ inhaler-technique-videos. If using video for the virtual consultation, you can check the inhaler technique and also demonstrate inhaler technique. ▸ Ask the patient about flare ups, days off work or school and establish what this means for your patient in terms of impact on their lifestyle. Ensure that the patient understands the five step rule. ▸ Discuss vaccinations in line with current recommendations. ▸ Assessment of control will naturally lead to a discussion with the patient about pharmacotherapy. You will need to consider stepping up or down of treatment as per GINA guidelines (2020). ▸ Signpost the patient to any additional psychosocial support where appropriate.

Advise the patient to use the Asthma Society of Ireland website for further resources (www.asthma.ie). Patients can also message the Beating Breathlessness WhatsApp service on 086 0590132 or phone the Asthma Adviceline on 1800 44 54 64 for further support. ▸ Discuss any follow-up and arrange review date. ▸ Summarise the discussion at the end of the review.

Undertaking an effective COPD review: ▸ Identify how you will deliver the remote review, eg, will it be through video consultation or telephone? ▸ In preparation for the consultation, briefly gather information from the medical record and prescribing data to assess morbidity and compliance. ▸ At the time of booking the appointment for the virtual COPD review, check if the patient has a COPD Communication Card and if they are using it. If the patient does not have a COPD Communication Card, this can be completed by the practice nurse/ GP in advance of the appointment and posted to the patient. Inform the patient that you will be referring to it and discussing it during the consultation.

Early recognition and treatment of exacerbations of COPD is key to avoiding hospital admission and the complications associated with hospital admission

▸ Start off with an introduction and establish if the patient has access to the Internet as this will be useful to signpost them to educational resources and support, both during (where appropriate) and/or after the consultation. Ask how the patient has been since their last review. ▸ Assessing COPD – the COPD assessment test (CAT) can be used to assess the impact COPD is having on the patient’s life. It can be downloaded from: www.catestonline. org/. The higher the CAT score (scored out of 40), the higher the impact COPD is having on the patient’s quality-of-life. The Medical Research Council Dyspnoea score (MRC) score can be used to assess the level of dyspnoea the patient is experiencing. ▸ Ask about exacerbations in the previous 12 months and if they required admission to hospital. Early recognition and treatment of exacerbations of COPD is key

to avoiding hospital admission and the complications associated with hospital admission. Assess if the patient is on the right treatment according to the ABCD classification (GOLD, 2020).

Refer to GP for further advice if necessary. ▸ Check the person’s understanding around the role of each medication in helping their COPD including dosing information and when they should be taking their medication. Explore the COPD Communication Card and COPD Self-Management Plan (available for download on www.hse.ie) and assess the patient’s understanding of when they should increase medication. ▸ Ask about inhaler use and technique.

Use videos to support your discussion where access is available and signpost people. Inhaler technique videos are available on www.asthma.ie/about-asthma/ resources/inhaler-technique-videos. If using video for the virtual consultation, you can check the inhaler technique and also demonstrate inhaler technique. ▸ Ask about smoking cessation and provide brief intervention strategies if appropriate. ▸ Discuss vaccinations in line with current recommendations. ▸ Signpost the patient to any additional psychosocial support where appropriate.

Advise the patient to use the COPD Support Ireland website for further resources (www.COPD.ie). Patients can also message the Beating Breathlessness WhatsApp service on 086 0590132 or phone the COPD adviceline on 1800 83 21 46 for further support. ▸ Discuss any follow-up and arrange review date. ▸ Summarise the discussion at the end of the review.

Conclusion Virtual reviews for chronic disease management have become a regular feature in the day-to-day running of general practice. This article has addressed the components of virtual asthma and COPD reviews. It has signposted the healthcare practitioner to various resources, which will assist in carrying out virtual reviews. ■

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COPD – 2020 a paradigm shift AUTHORS: Dr Ciara Ottewill, SpR in Respiratory Medicine; and Prof Stephen J Lane, Consultant Respiratory Physician, Department of Respiratory Medicine, Tallaght University Hospital Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Though classically it is associated with smoking, it is estimated that up to 20-45 per cent of those with COPD worldwide are non-smokers. The majority of studies to date focus on latestage disease, however, it is becoming increasingly clear that a focus on primary prevention of the disease is needed. Early detection of those with pre-COPD and early COPD should become priorities going forward.

smokers, in contrast, appears to be relatively static, with an estimated 40-50 per cent of smokers developing the disease. Genetic factors, including α-1-antitrypsin deficiency, are also known to contribute to the disease.

COPD trends in Ireland in 2020 Ireland has one of the highest rates of hospitalisation for COPD in the OECD, at approximately 400 admissions per 100,000 population, which is among the highest rates of hospital admissions for COPD globally. Though over the past 15 years there has been a notable international

Background COPD is the third common cause of death worldwide,1 and is estimated to affect up to 12 per cent of the world population. It is the cause of over three million deaths annually, far surpassing the current annual death rate from Covid-19 (which at time of publication was estimated by the World Health Organisation (WHO) to have surpassed one million in its first 10 months). It is among the most common causes of death in Ireland, surpassed only by cardiovascular disease and cancers. The OECD estimates that COPD attributes to approximately 40 per cent of respiratory mortality in Ireland.

The prevalence of COPD appears to be increasing globally, in particular in countries including China and India.

This increase appears to be primarily in non-smokers. It is estimated that approximately 25 per cent of the Irish population diagnosed with COPD are non-smokers. Prevalence of non-smokers with the diseases varies globally, with 45 per cent of patients in South Africa having never smoked. The reasons for non-smoking related COPD are becoming clearer and can be related to intrauterine factors, early life factors, exposure to inefficient combustion of biomass fuels in poorly ventilated houses, and second hand smoke for example. Prevalence of COPD in

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Ireland has one of the highest rates of hospitalisation for COPD in the OECD, at approximately 400 admissions per 100,000 population, which is among the highest rates of hospital admissions for COPD globally

decrease in mortality secondary to cancer and cardiovascular disease, including myocardial infarction, mortality from COPD remains high. COPD accounts for the primary diagnosis in over 1,500 deaths annually in Ireland, which is second only to lung cancer in causes of death from respiratory disease, as is outlined in the 2018 Respiratory Health of the Nation document from the Irish Thoracic Society.

COPD is more prevalent in lower socioeconomic groups within Ireland.

Pathophysiology Exhalatory airflow obstruction (afterload) and hyperinflation (preload)

There are two key pathological changes in COPD, ie, chronic bronchitis and emphysema. Chronic bronchitis and emphysema results in either anatomical or functional airflow obstruction. This obstruction occurs throughout the entire length of the non cartilaginous, smooth muscle containing tracheobronchial tree.

The obstruction occurs predominantly during exhalation as the airways are naturally more narrowed then than during inhalation. Thus there is increased ‘afterload’ to the process of exhalation making it more difficult and lengthy for patients to exhale at rest and during exercise. Emphysema, in addition to exhalatory obstruction, results in increased lung compliance because of parenchymal destruction. Therefore in the ‘tug of war’ between the chest wall and lung parenchyma maintained by the pleura, the outward forces of the chest wall will overcome the inward forces of the damaged elastic lung resulting in an increase of volume trapped in the lung at the end of quiet exhalation or the FRC (functional residual capacity). This trapped volume results in significant ‘preload’ to the patients with predominant emphysema subtype.

Ultimately the lung becomes hyperinflated and ‘barrel-like’ as the chest wall creeps up over the trachea. COPD patients find themselves ‘breath stacking’ because of this air trapping, which contributes substantially to breathlessness at rest and on exertion. Powerful treatments for COPD, including LAMAs (long-acting muscarinic antagonists) and LABAs (long-acting beta agonists), work by bronchodilating (as measured by an improvement in FEV1) the increased afterload of exhalatory airflow obstruction. In addition, along with lung volume reduction surgery (LVRS) and endobronchial valve therapy (EBV), they act by deflating the preload caused by the hyperinflated FRC (as measured by increasing the VC (vital capacity), which can often be significant).

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in primary care. A GP simply has to ask the patient how breathless they are and interrogate their exacerbation history, ie, a breathless patient on hills, with two exacerbations within the last 12 months, in the presence of airflow obstruction indicates grade D and interventions can be planned accordingly.2

FIGURE 1: Fletcher-Peto Curve, illustrating the decline in FEV1% in those with COPD compared to the general population

Naming, staging, and classification COPD, as we understand it today, was defined in terms of the clinical phenotypes around the time of World War II. The poor prognosis ‘blue bloater’, having a characteristic hypoxaemic respiratory failure, had airflow obstruction secondary to chronic bronchitis on post-mortem.

The better prognosis breathless ‘pink puffer’ had airflow obstruction secondary emphysematous parenchymal destruction on post mortem. In the 1950s it became possible to measure this obstruction in vivo using spirometry, and spirometry currently remains a crucial tool in both the diagnosis of COPD and in the staging of disease. In 1997 the Global Obstructive Lung Disease (GOLD) initiative formally

Category

Severity

FEV1% predicted

GOLD 1

Mild

>80%

GOLD 2

Moderate

50%<FEV1< 80%

GOLD 3

Severe

30%<FEV1 <50%

GOLD 4

Very severe

<30%

FIGURE 2.A: GOLD Classification 1997 to 2011

named this disease COPD. Expiratory airflow obstruction was defined as a ratio of FEV1/FVC <0.7, ie, COPD patients, in contrast to patients without COPD, could not exhale greater than 70 per cent of their VC in the first second of a standardised forced exhaled manoeuvre post a shortacting bronchodilator. In the presence of airflow obstruction, the biomarker of annualised percentage FEV1 was then used to stage the disease from 1 through to 4 in terms of severity as in Figure 2A, based on the Fletcher-Peto curves (Figure 1, above) validated by the larger Framingham Study.2 Since 2011, with the realisation of the limitation of outcome determination based on annualised percentage FEV1 alone, GOLD modified their classification with more emphasis being placed on symptom or breathlessness scores, eg, the CAT score or MRC dyspnoea scale, in addition to exacerbation history with grading now becoming ABCD rather than stage 1-4 (Figure 2B). In 2017, spirometry was removed from staging and used for diagnosis only. Grading of prognosis now was now to be based on symptom scores and exacerbation history alone once airflow obstruction had been confirmed.

This of course makes it much easier to use

C

D

A

B

>two exacerbations or >one leading to hospitalisation 0 or one exacerbation (not leading to hospitalisation) MmMRC 0-1 CAT <10

mMRC >2 CAT >10

FIGURE 2.B: GOLD Classification 2011 -2017. Symptom and Exacerbation Rate A-D

Natural history, pre-COPD, and early COPD Approximately 100,000 COPD patients have been studied in randomised, placebo controlled interventional trials in recent years. The average age at enrolment is 62 years and the average per cent predicted FEV1 is 50 per cent. These studies are thus focussing on very late phase disease. The endpoints studied are changes in lung function, breathlessness, exacerbation rate and all-cause mortality. Invariably these studies show some improvements in the above endpoints, but what is striking is that there remains a huge unmet need in these endpoints despite interventions.

This has now focused intense interest on the detection of pre-COPD and early COPD. There is thus now a realisation that focussing on the sole trajectory of FEV1 decline from a supposed always normal 100 per cent baseline in one’s late 20s gives a very incomplete picture as to the natural

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do about it. In the 1970s, ischaemic heart disease was managed in the ED when patients had heart attacks. Look how that has changed through earlier detection of risk factors, statins, and blood pressure management. We are now at the cusp of doing the same in COPD, but it has been a long time coming because of the nihilism surrounding COPD as a self-induced cigarette-induced disease and because of a fundamental failure of our understanding of this now â&#x20AC;&#x2DC;respectableâ&#x20AC;&#x2122; disease.

1. Trajectory 1 indicates normal gain in lung function and normal decline, which does not result in COPD 2. Trajectory 2 indicates failure of gain of lung function, but a normal decline and may or may not result in COPD

3. Trajectory 3 is what we currently base all our insight on in COPD and will be very familiar to most of us, ie, normal gain and an accelerated decline 4. Trajectory 4 illustrates failure of gain and accelerated decline, which will result in COPD2

FIGURE 3: COPD FEV1 trajectories

In our view, with a huge effort into general population FEV1 screening and a shift of our interventional studies to earlier disease, we will at last make an impact on this devastating disease as depicted in the following figure. COPD is an international public health issue.

Management course of this disease.3 It is now accepted that there are at least four different trajectories of FEV1 over time and that the starting point should be at birth or as near to it as possible. Figure 3 (above) illustrates this.

Therefore, the focus of COPD has now shifted to failure of gain of FEV1 as much as accelerated decline. How else can we explain the huge prevalence of COPD in younger people in developing countries who are exposed to inefficient biomass combustion, high prevalence rates of TB, premature birth and excess chest infections inter alia?

Furthermore, this has now shifted our thinking to individuals with pre-COPD and early COPD. Pre-COPD are individuals with no symptoms as yet and normal lung function albeit at the lower limit of normal. What defines them is the trajectory of their lung function gain and decline. These subjects would have reduced gain in FEV1 at an early stage and an accelerated decline after adult peak as per trajectories 2 and 4 above. Early COPD are individuals with no or minimal symptoms whose percentage predicted FEV1 is lower than the expected range for any given age, ie, they are picked up on screening.1

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As a result of this fundamental shift in our understanding of COPD towards earlier disease, annual measurement of FEV1 in the general population is now strongly advised in order that we may assess trajectories in individual patients.

As a result of this fundamental shift in our understanding of COPD towards earlier disease, annual measurement of FEV1 in the general population is now strongly advised in order that we may assess trajectories in individual patients

Measurement of FEV1 should be carried out, like BP or blood sugar, at each GP visit in our view. If we do not do this we will continue to manage COPD in emergency departments (EDs) at the end stage of its natural history when there is little we can

Treatment recommendations for COPD are laid out in both the GOLD guidelines, and the ICGP COPD Quick Reference Guide.

Current treatments in COPD aim to reduce symptoms, increase quality-of-life, and decrease exacerbation rates and mortality.

Exacerbations of COPD, including viral exacerbations, have been shown to contribute significantly to COPD-related mortality.1 Slowing the rate of decline in FEV1 and decreasing exacerbation may certainly aid in improving overall survival.

Through placing an emphasis on early disease detection, and slowing rate of decline in early stages of the disease may significantly reduce morbidity.

Lifestyle modifications Present management options include non-pharmacological initiatives, including smoking cessation, placing an importance on vaccination to reduce exacerbation rates, and exercise, including pulmonary rehabilitation. Despite significant public health interventions, including plain packaging, increased taxes and indoor smoking bans, smoking remains the most common avoidable health risk in the EU. Vaccination is a crucial intervention in COPD and viral infections including

in just

in just

in just

in just If you would like to order samples, please use: Web: www.fresubinsamples.ie Email: FK-Enquiries.Ireland@fresenius-kabi.com Phone: +353 (0)1 841 3030

Fresenius Kabi Limited Fresenius Kabi Ireland, Unit 3B Fingal Bay, Balbriggan, Co. Dublin, Ireland T: +353 (0)1 8413030 F: +353 (0)1 8496949 E: FK-enquiries.Ireland@fresenius-kabi.com www.fresenius-kabi.ie

Date of preparation: October 2020 Job code: EN/3.2kcal.005.20

Volume 6 | Issue 9 | 2020 | Respiratory Medicine

influenza are key areas to target with regard to prevention of exacerbations.

Minimising exposure to inhaled environmental pollutants, and early aggressive treatments of childhood infections may also allow patients to reach optimal FEV1.

Pharmacological therapies Pharmacological therapies are described in the GOLD Guidelines 2019, with a stepwise treatment approach, aiming to escalate or downgrade treatments as time progresses.

LAMA are a well-established treatment in COPD. Many studies have shown that LAMA, including tiotropium, improve FEV1, improve patient-reported qualityof-life, as well as decreasing rates of exacerbation and decreasing mortality.

Despite this, more than 50 per cent of patients treated with LAMA monotherapy still experience breathlessness, regardless of disease severity. Meta-analysis has shown that LABA/LAMA in combination is superior to LAMA monotherapy in treating breathlessness. When compared to treatment with a combination of LABA/ ICS (inhaled corticosteroids), LABA/ LAMA therapy has also shown dual bronchodilator therapy is much more effective in reducing exacerbations.1 Addition of ICS to LABA/LAMA therapy has been shown to reduce patient symptoms and reduces moderate or severe exacerbations requiring hospitalisation, in those with an FEV1 <50 per cent, despite a small risk in community-acquired pneumonia. These findings are more prevalent in those patients with blood eosinophilia.

ICS use in COPD has been shown to reduce annual exacerbation rates, improve quality-of-life, improve FEV1 and lead to a reduction in all-cause mortality across several studies.

Non-pharmacological therapies Lung volume reduction surgery This invasive therapy has been shown to convey a survival benefit in those with severe upper lobe emphysema, with low exercise tolerance.

Endobronchial valve therapy This uses one-way stents, which allow air to escape during exhalation, while allowing no influx of air with inhalation, thereby allowing expansion of normal lung, with deflation of hyper-expanded bullous lung.

These significantly increase FEV1, FVC and six-minute walk tests in patients with severe emphysema, with a resulting improvement in quality-of-life questionnaires.

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to diagnose pre-COPD, or early COPD, as well as to assess rate of decline. A focus must also be placed on identifying non-smokers with COPD, as up to onein-four patients in Ireland with COPD will have never smoked. It is crucial that an emphasis on primary prevention of disease rather than treatment of late stage disease is enforced going forward.

Therapies currently include a combination of lifestyle modification, and inhaled therapies, which are added in a step-wise fashion, with inhaled steroids addition guided by patient eosinophil count, as well as treatments including pulmonary rehabilitation, with the ultimate goal of minimising patient symptom burden, decreasing exacerbation rates, and thus slowing decline in FEV1. ■

References 1.

Despite a global decrease in smoking trends, COPD remains among the most common causes of death both in Ireland and internationally

2.

3.

4.

Pulmonary rehabilitation This is a well-established treatment, which has been shown to reduce dyspnoea, improve exercise tolerance and patient-reported quality-of-life in patients with COPD.5 5.

Summary As such, the GOLD Guidelines 2019 now recommend peripheral blood eosinophils as a biomarker for the addition of ICS, with little effect in those with eosinophils 100cells/μl.2 Those with eosinophil levels of 100cells/μl typically respond well to the addition of ICS to their inhaled therapeutic regimen.

exacerbation rates. Efforts to do this must include serial FEV1 monitoring

Despite a global decrease in smoking trends, COPD remains among the most common causes of death both in Ireland and internationally. It is a public health emergency, and going forward a focus must be placed on early detection of disease, to allow early interventions to slow decline in FEV1, and to reduce

Celli BR, Wedzicha JA. Update on Clinical Aspects of Chronic Obstructive Pulmonary Disease. Drazen JM, editor. N Engl J Med. 2019 Sep 26;381(13):1257–66.

GOLD-2019-v1.7-FINAL-14Nov2018WMS.pdf [Internet]. [cited 2020 Oct 20].

Available from: https://goldcopd.org/ wp-content/uploads/2018/11/GOLD2019-v1.7-FINAL-14Nov2018-WMS.pdf Lange P, Celli B, Agustí A, Boje Jensen G, Divo M, Faner R, et al. Lung-Function Trajectories Leading to Chronic Obstructive Pulmonary Disease. N Engl J Med. 2015 Jul 9;373(2):111–22 OECD, European Union. Health at a Glance: Europe 2018: State of Health in the EU Cycle [Internet]. OECD; 2018 [cited 2020 Oct 10]. (Health at a Glance: Europe). Available from: https://www.oecd-ilibrary.org/socialissues-migration-health/health-at-aglance-europe-2018_health_glance_ eur-2018-en ICGP. Quick Reference Guide: Chronic Obstructive Pulmonary Disease.

December 2019. [cited 2020 Oct 19]. Available from: https://www. icgp.ie/index.cfm?spPath=in_the_ practice/quick_reference_guides/ quick_reference_guides_ qrg_&resetcache=1&cachelist =page_in_the_practice_quick_ reference_guides_quick_reference_ guides_qrg_

Volume 6 | Issue 9 | 2020 | Respiratory Medicine

Recent updates in interstitial lung disease AUTHORS: Dr Abhilash Sahadevan, MB;1,2 Dr Emmet McGrath, MB PhD;1 and Dr Cormac McCarthy, MB PhD;1,2, 1 Department of Respiratory Medicine, St Vincent’s University Hospital, Dublin; 2School of Medicine, University College Dublin Interstitial lung diseases (ILD) are a heterogeneous group of disorders. There have been numerous important advances in this area over recent years and knowledge regarding pathogenesis and therapy continues to expand.

Here we summarise four recent important papers on ILD: Raghu et al. Diagnosis of hypersensitivity pneumonitis in adults. An official ATS/JRS/ ALAT clinical practice guideline¹

FIGURE 1: Three-density sign Image courtesy of Dr David Murphy, SVUH, Dublin

Hypersensitivity pneumonitis (HP) is defined as an immune-mediated disease that manifests as ILD in susceptible individuals after exposure to an identified or unidentified factor. The clear inclusion of an ‘unidentified factor’ is crucial as it is important to highlight the possibility that HP can occur in the absence of a known inhalational exposure. Despite rigorous investigations in ILD centres, the guidelines assert that antigen and inciting exposure are not identified in approximately 60 per cent of patients. This guideline stresses the importance of taking a thorough history to allow removal of potential exposures and sources in the patient’s environment, which have been linked to cause HP (Table 1). When considering HP, the high resolution CT (HRCT) scanning protocol should consist of two series of images obtained in the supine position: One at deep inspiration and then one second after prolonged expiration. The expiratory series is particularly important to characterise air trapping if present. Intravenous contrast is only recommended during an acute decline in respiratory function where pulmonary embolism is a potential cause.

If CT angiography is done, then it should be done after the non-contrast inspiratory and expiratory series of images, to allow detection of new ground glass changes that help identify an acute exacerbation of HP

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as opposed to chronic fibrosing HP. A new term ‘three-density pattern’ was coined to describe the severe bronchiolar obstruction seen in fibrotic HP (previously known as the ‘headcheese sign’). This term combines three attenuations seen on inspiratory HRCT images (normal appearing lung, groundglass opacification or high attenuation, and finally regions of decreased attenuation and decreased vascular sections or lucent lung) (Figure 1). Although this guideline suggests performing serum IgG testing against potential antigens, bronchoalveolar lavage (BAL) cellular analysis for lymphocytic dominance, and lung biopsy, the consensus was that there was very low confidence in the expected diagnostic yield from any of these diagnostic tests, hence it remains paramount that diagnosis is guided by multidisciplinary discussion.

Wells et al. Nintedanib in patients with progressive fibrosing interstitial lung diseases – subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: A randomised, double-blind, placebo controlled, parallel-group trial² Maher et al. Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: A double-blind, randomised, placebo-controlled, phase 2 trial ³

The INBUILD study examined the use of nintedanib in patients with progressive fibrosing ILD that did not include idiopathic pulmonary fibrosis (IPF). A total 663 patients were randomised to receive either nintedanib 150mg twice daily or a placebo. After 52 weeks, oral nintedanib slowed the rate of forced vital capacity (FVC) decline in patients with ILD who had previously demonstrated a progressive phenotype. This is one of the first clinical trials which ‘lumped’ fibrosing diseases based on their clinicopatho-radiological progression rather than differing ILD subgroups. Despite nine subgroups of ILD enrolled in the trial, 62 per cent of the patients had a usual interstitial pneumonia (UIP)-like fibrotic pattern on high resolution CT thorax.

A similar study3 of pirfenidone (three 267mg tables thrice daily) was shown to slow disease progression indicated by FVC decline after 24 weeks of therapy in patients with progressive fibrosing unclassifiable ILD. (Unclassifiable referring to fibrosing ILD which could not be classified under any ILD subtype by a multidisciplinary meeting with moderate or high certainty.) This trial highlighted the importance of close monitoring of all ILD patients including the non-IPF ILD cohort as their placebo arm of patients with unclassifiable ILD had a significant mean decline of 113mls of FVC by week 24.

Therapeutic options have been limited in both of these cohorts of patients, usually involving a trial of immunosuppression or continued observation. Neither trial revealed any new safety signals from previously recognised side effects with either nintedanib (diarrhoea, nausea, vomiting and liver enzyme elevations) or pirfenidone (photosensitivity, rash, and gastrointestinal disorders). The INBUILD study also allowed treatment interruptions following non-medication side effects allowing easy translation into real-life

Respiratory Medicine | Volume 6 | Issue 9 | 2020

Organisation criteria for obesity. Obese BMI as a risk factor was reported with caution due to approximately 20 per cent of the ILD cohort missing data during this audit’s data collection phase. Despite the incomplete data from this study, it is likely being obese and having ILD does result in increased morbidity and mortality due to strong evidence of increased BMI being a major risk factor from several other Covid-19 population studies.6 This study reiterates the importance of having measures in place to protect the most vulnerable patients, as this population appears extremely high-risk of poor outcome from SARS-CoV-2. ■

CONDITION

ANTIGEN

Bird fanciers’ lung

Avian droppings, serum, and feathers

Farmer’s lung

Contaminated plant material (fungi including aspergillus, alternaria, fusarium, etc)

Drug-related hypersensitivity pneumonitis

Penicillins, cephalosporins, methotrexate, interferon, lenalidomide, pravastatin, venlafaxine, temozolomide

Baker’s lung

Aspergillus enzyme in baking agents

Humidifier lung

Contaminated humidifiers and air-conditioning systems (amoebae, nematodes)

Hot tub lung

Contaminated water (nontuberculous mycobacteria)

Woodworker’s lung

Sawdust

Acid anhydride alveolitis

Spray paints, glues, polyurethane foams, imitation leather, car parts, mattresses, electrical insulations (acid anhydrides)

References

Painter’s lung

Powder paints (triglycidyl isocyanurate)

1.

Malt worker’s lung

Organic wastes (fungi including aspergillus, alternaria, fusarium, etc)

Mushroom worker’s/ grower’s lung

Mushrooms

Bagassosis

Fibrous cane sugar residue or mouldy molasses ‘bagasse’

Compost lung

Compost

Heiner syndrome

Cow milk

2.

TABLE 1: Hypersensitivity pneumonitis commonly seen in Ireland and the antigenic cause clinical practice. In conclusion, these trials offer new therapeutic strategies for progressive fibrosing lung diseases regardless of cause, however, despite therapy now being available for these conditions, there remains a need to thoroughly investigate each individual to determine potential underlying cause, and multidisciplinary discussion remains essential.

Drake et al. Outcome of hospitalisation for Covid-19 in patients with interstitial lung disease: An international multicentre study 4 Despite the concern during the initial phase of the SARS-CoV-2 pandemic that patients with pre-existing lung conditions would be at greater risk from Covid-19, there had been little data to support this theory for ILD. There has been numerous publications showing asthma is not a risk factor for

severe Covid-19.5 In Ireland, the Irish Lung Fibrosis Association and respiratory physicians advised all patients with ILD to limit their personal contacts early on in the pandemic. This recent study confirms the concerns regarding the prognosis of patients with ILD admitted to hospital with Covid-19. Following hospitalisation with Covid-19, patients with any form of ILD were at higher risk of death when compared to patients without ILD. Nearly one in every two patients with ILD (79/161 patients) hospitalised from Covid-19 died (HR 1.60, CI 1.17-2.18). A limitation of this international multicentre audit covering six countries was that it did not capture patients with ILD who were not admitted despite having Covid-19. Risk factors for poor outcome in this ILD cohort were, male patients with poorer lung function; FVC less than 80 per cent and BMI meeting the World Health

3.

4.

5.

6.

Raghu G, Remy-Jardin M, Ryerson CJ, Myers JL, Kreuter M, Vasakova M, et al. Diagnosis of hypersensitivity pneumonitis in adults. An official ATS/JRS/ALAT clinical practice guideline. American Journal of Respiratory and Critical Care Medicine.

2020;202(3):e36-e69 Wells AU, Flaherty KR, Brown KK, Inoue Y, Devaraj A, Richeldi L, et al. Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: A randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Respir Med. 2020;8(5):453-60 Maher TM, Corte TJ, Fischer A, Kreuter M, Lederer DJ, Molina-Molina M, et al. Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: A double-blind, randomised, placebocontrolled, phase 2 trial. Lancet Respir Med. 2020;8(2):147-57 Drake TM, Docherty AB, Harrison EM, Quint JK, Adamali H, Agnew S, et al.

Outcome of hospitalisation for Covid-19 in patients with interstitial lung disease: An international multicenter study.

American Journal of Respiratory and Critical Care Medicine. 2020 Butler MW, O’Reilly A, Dunican EM, Mallon P, Feeney ER, Keane MP, et al. Prevalence of comorbid asthma in Covid-19 patients. The Journal of Allergy and Clinical Immunology.

2020;146(2):334-5 Williamson EJ, Walker AJ, Bhaskaran K, Bacon S, Bates C, Morton CE, et al. Factors associated with COVID19-related death using OpenSAFELY. Nature. 2020;584(7821):430-6

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The latest Irish and international research on risks of e-cigarettes AUTHOR: Priscilla Lynch

E-CIGARETTE USAGE IN IRELAND The Health Ireland survey* for 2019 shows that:

A new Health Research Board (HRB) review into e-cigarette use has found that e-cigarettes are associated with adolescents starting to smoke tobacco cigarettes; with adolescents who had ever used e-cigarettes between three and five times more likely to start smoking compared to those who never used e-cigarettes.

Key findings include: E-cigarettes are no more effective than approved and regulated nicotine replacement therapies (NRTs) to help people stop smoking. However, e-cigarettes as a smoking cessation device are not regulated or approved and their safety beyond 12 months is not yet known.  E-cigarettes acute effects include poisonings, burns, blast injuries, lung injury and asthmatic attacks. Some of the chemicals in e-cigarettes are thought to cause tissue and cell damage and some are agents that may cause cancer in the longterm. The long-term health effects beyond 24 months are not researched.  Dual use of both e-cigarettes and conventional tobacco cigarettes was not less harmful than smoking tobacco cigarettes alone, which raises questions about the smoking reduction benefit of e-cigarettes. 

Dr Jean Long, Head of the Evidence Centre at the HRB said the findings would have to be considered as part of any smoking harm reduction strategy. “Our findings highlight that it is important more is done to promote NRT and protect the health of adolescents and vulnerable groups before considering the role of unregulated e-cigarettes as a harm reduction approach.”

Chief Executive of the HRB, Dr Mairéad O’Driscoll, said: “Independent and credible evidence is vital to help inform policy decisions. This HRB review is already

30

 5 per cent of the population use e-cigarettes and a further 12 per cent have tried them at some point.  Use is higher in more deprived areas (7 per cent), than in more affluent areas (4 per cent).

10 per cent of current smokers use e-cigarettes, with 13 per cent of ex-smokers using them. 

 38 per cent of those who made an attempt to quit smoking used e-cigarettes during this attempt.

25 per cent of those aged between 25 and 34 have tried e-cigarettes, with 8 per cent currently using them. 

20 per cent of men have tried e-cigarettes compared to 14 per cent of women.



5 per cent of men and 3 per cent of women currently use e-cigarettes.



A Health Behaviour in School Children survey found that e-cigarette use is about twice as common as tobacco smoking: More than one-in-five of 12 to 17-year-old children report that they have ever used e-cigarettes.



Boys (one-in four or 26 per cent) are more likely than girls (under one-in-five or 18 per cent) to report that they have ever used e-cigarettes.



TOBACCO SMOKING IN IRELAND: PEOPLE AGED 15 YEARS AND OVER The results for 2019 Healthy Ireland survey* show that: Smoking has declined from 23 per cent in 2015 to 17 per cent in 2019.



17 per cent of respondents are current smokers: 14 per cent smoke daily and 3 per cent smoke occasionally.



current smokers.

Smoking rates are higher in more disadvantaged areas (24 per cent) than in more affluent areas (14 per cent).



Smoking rates are also higher for those who are unemployed (40 per cent) and those with no third level education (20 per cent), than they are for those in employment (18 per cent) and those with degree level education (11 per cent).



Men are more likely to smoke than women:19 per cent of men are current smokers, compared to 16 per cent of women.





Smoking rates are highest among those

aged 25 to 34: 26 per cent of this age group are



28 per cent of respondents are ex-smokers.

* The 2019 Healthy Ireland survey involved 7,413 interviews conducted with a representative sample of the population aged 15 and older living in Ireland

informing forthcoming HSE good practice guidelines to help people stop smoking and these will take into consideration the place of the e-cigarette when trying to stop smoking. The Department of Health have also prepared legislation, which will look at licensing of retail outlets and banning e-cigarettes for young people under 18 years of age.”

Meanwhile, separate research presented at the 2020 European Respiratory Society (ERS) International Congress found that flavourings combine with solvents in e-cigarettes to produce new toxic chemicals that irritate the airways, triggering

reactions that can lead to breathing and heart and blood vessel problems.

Researchers consistently observed that the new chemicals formed from the flavours and e-liquid solvents were more toxic than either of their parent compounds.

The new chemicals also activated sensory irritant receptors in nerve endings in the bronchi called TRPV1 and TRPA1, which are responsible for a range of inflammatory responses. The researchers showed for the first time that even low concentrations of the newly-formed chemicals caused the cells lining the bronchi to die. 

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Patient advocacy – improving the lives of people with lung fibrosis AUTHOR: Ms Nicola Cassidy, on behalf of the Irish Lung Fibrosis Association The Irish Lung Fibrosis Association (ILFA) is a patient organisation founded to support individuals with lung fibrosis and their families. Lung fibrosis is an underlying pathology in a number of interstitial lung diseases (ILD), the most prevalent of which is idiopathic pulmonary fibrosis (IPF). ILD is thought to affect around 1,000 patients in Ireland – only slightly less than those diagnosed with cystic fibrosis. It is characterised by increasing breathlessness with progressive impacts on patients’ abilities to engage in normal activities of daily living and deterioration in qualityof-life. With a median survival time from diagnosis of 4.5 years, the prognosis for patients with IPF is worse than many cancers. And yet despite the prevalence and the seriousness of ILD, many healthcare professionals, let alone lay people, remain unaware of this condition. Poor recognition is a considerable factor in the late diagnosis of ILD, which in turn affects patients’ ability to access timely pharmaceutical treatments, which can slow the progression of the disease and holistic treatments to maximise quality-of-life.

A critical part of ILFA’s work is patient advocacy; as an organisation we can have a greater voice than individual patients alone. There are many inadequacies in the diagnosis and management of ILDs and through engagement with multiple stakeholders, including politicians, healthcare professionals, the health service, industry representatives and more, we hope to address these unmet needs to improve the lives of those affected by ILDs. We have recently had success in ensuring that ILD is recognised as a serious lung condition for the categorisation of people who are highly medically vulnerable to Covid-19. Lack of inclusion of ILD in the initial Health Protection Surveillance

32

Centre (HPSC) and HSE guidelines on cocooning reflects the poor awareness of this condition. Lobbying on behalf of patients, families, and healthcare professionals resulted in revision of the HPSC guidance. Research has shown that patients with ILD are at significant risk of serious illness due to Covid-19 and it is essential for protection of patients that guidelines on cocooning reflect this.

Clinical care programme A current focus of our ongoing work is to advocate for a HSE clinical care programme for lung fibrosis, as currently exists for COPD, asthma and cystic fibrosis and other conditions. Clinical care programmes provide benefits for patients and healthcare providers in clearly setting out a model for the provision of highquality care. National programmes ensure equity and timely access to appropriate care regardless of the patient’s location.

Without such a unified approach, there are currently large discrepancies in the healthcare experiences of patients with ILD. Our research indicates that this is a priority area for ILFA’s advocacy work for patients, families, and healthcare providers working in this specialty, including the Irish Thoracic Society.

Transplantation We are also engaged in work to support the enactment of legislation which would give more patients the opportunity to access lung transplantation, an effective ILD treatment for those eligible.

Enactment of the Human Tissue Bill would introduce a system whereby everyone will be considered a potential organ donor unless they have registered their objection. Opt-out legislation has the potential to increase the number of organ donors and life-saving transplant operations that can take place. Additional

funding to support staffing, infrastructure and resources for the national transplant centres is crucial as well as an ongoing national awareness campaign.

IPF registry Another advocacy priority is lobbying for adequate national funding to support the National IPF Registry. The objective of the IPF Registry is to characterise the true incidence of IPF in Ireland, in order to plan for future healthcare needs. In addition, ILFA recently contributed to the public consultation on the Draft Recommendations on the Implementation of a National Electronic Patient Summary.

Long Covid Lung fibrosis has been identified as one of the long term consequences of Covid-19 infection, so called ‘long Covid’. Research to characterise the relationship between Covid-19 and lung fibrosis is in its infancy, but available evidence suggests that there may be significant population morbidity arising from the persistent respiratory complications of Covid-19. ILFA may well be advocating for a rapidly growing patient population in light of this, giving our current work even greater urgency.

We would like to take this opportunity to thank all of those who support ILFA, most of whom are volunteers, and many who balance these commitments with busy jobs, for their work and dedication to improving the lives of people affected by lung fibrosis.

We also wish to acknowledge the great work being done by respiratory healthcare professionals in supporting lung fibrosis patients in these challenging times. n For more information please visit www.ilfa.ie References available on request

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Quadrivalent live attenuated influenza (LAIV) nasal vaccine for children AUTHOR: Dr Tom Barrett, MB Dch MRCOG, Senior Medical Officer, HSE National Immunisation Office This year the seasonal influenza vaccination programme has been extended to all children aged two-to-12 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 quadrivalent 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).

The 2020/2021 influenza season presents a significant challenge to the delivery of healthcare services, both in primary care and in hospitals, especially as there is now a resurgence of cases of Covid-19. At an individual level, the consequences of dual infection with influenza and Covid-19 are unclear, but worse outcomes are likely, particularly for those at-risk.

To prevent cases of influenza in children and reduce the spread of influenza to others, the National Immunisation Advisory Committee (NIAC) has recommended influenza vaccine for all children (aged twoto-17 years inclusive).1 For the 2020/2021 influenza season, the Department of Health, on NIAC advice, has extended the influenza vaccination programme to children, providing funding

to the HSE to offer quadrivalent LAIV vaccine free to all children aged two-to-12 years inclusive.2 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-12 age group (aged six months to <two years and aged 13 years and older) who have an underlying chronic medical condition should receive quadrivalent inactivated influenza vaccine (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 five-to-10 per cent of adults.3 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 less than five years had the second highest

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hospitalisation rates for influenza after those aged 65 years and older.

our health services from dual outbreaks of influenza and Covid-19.

Between the 2009/2010 and 2018/2019 influenza seasons: ▸ 4,750 children aged 0-to-14 have required hospitalisation as a result of influenza, ▸ 183 requiring critical care, and ▸ 41 children died.4

The vaccine used is quadrivalent LAIV Fluenz Tetra, manufactured by Astra Zeneca, which will be offered to all children aged two years to 12 years. It is administered intranasally.

Influenza vaccination for children in other countries Nine European countries, the US, Canada and Australia currently recommend influenza vaccine for children. The UK gives LAIV to children. Finland, the US and Canada give LAIV or QIV to children.5, 6, 7 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 11 years.

In Finland, annual inactivated influenza vaccine was recommended for children aged six-to-35 months in 2007. 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 to six years of age.

In Ireland, for the 2020/2021 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 coming influenza season, to minimise the impact on

34

LAIV for 2020/2021 influenza season:

The vaccine contains the following four vaccine virus strains as recommended by the World Health Organisation (WHO):

In Ireland, for the 2020/2021 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 1. an A/Guangdong-Maonan/SWL1536/2019 (H1N1)pdm09-like virus; 2. an A/Hong Kong/2671/2019 (H3N2)-like virus; 3. a B/Washington/02/2019 (B/Victoria lineage)-like virus; 4. 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 long-term 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 CI 69-91 per cent).8 The UK pilot primary school programme introducing LAIV was evaluated in 2014/2015 and showed: ▸ 94 per cent reduction in primary school age children GP influenza-like consultations; ▸ 74 per cent reduction in primary school age emergency department attendances with respiratory complaints; ▸ 93 per cent reduction in primary school age confirmed influenza hospitalisations; ▸ 59 per cent reduction in adults GP influenza-like illness consultations.9

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.

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Gelatin in LAIV GROUP Medically at risk

Healthy

AGE two-to-eight years

PREVIOUS VACCINATION

DOSE

Have never had any influenza vaccine

Two doses four weeks apart

Have had any influenza vaccine before

One dose

nine-to-12 years

Not relevant

One dose

two-to-12 years

Not relevant

One dose

TABLE 1: Doses of LAIV required for children aged two-to-12 years NIAC has recommended healthy children require one dose of LAIV. However, children in a medically at-risk group aged two-toeight 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.

The following are NOT contraindications ▸ Asymptomatic HIV infection. ▸ Children receiving: ● topical or inhaled corticosteroids. ● low dose systemic corticosteroids. ● replacement therapy corticosteroids (eg, adrenal insufficiency).

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 (HSCT)). ▸ 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. ▸ Those on combination checkpoint inhibitors (eg, ipilimumab plus nivolumab) because of a potential association with immune related adverse reactions. ▸ Those post cochlear implant until the risk of CSF leak has resolved – consult with the relevant specialist. ▸ Those with a cranial CSF leak.

Precautions ▸ Defer until recovered from an acute severe febrile illness. ▸ As LAIV has an ovalbumin content <0.1 micrograms 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-12 years for whom LAIV is contraindicated should be offered QIV (provided there are no contraindications to QIV).

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 (NIO) 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 postmarketing 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

Vaccinated children can shed the attenuated virus for a few days after vaccination, but the virus that is shed cannot cause infection

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HSE SEASONAL INFLUENZA VACCINATION PROGRAMME 2020/21 QUADRIVALENT LIVE ATTENUATED INFLUENZA VACCINE (LAIV) AND QUADRIVALENT INACTIVATED INFLUENZA VACCINE (QIV) LAIV

QIV

Name

Fluenz Tetra (egg-based)

Quadrivalent Influenza vaccine (split virion, inactivated) (egg-based)

Manufacturer

Astra Zeneca

Sanofi Pasteur

Who

All aged two-to-12 years (at the time of vaccination)

In a risk group aged six months to <two years, and 13-to-64 years All aged 65 and older Two-to-12 years if LAIV is contraindicated

What

1 dose (healthy children) 2 doses if: ▶ in a risk group ▶ and aged two-to-eight years ▶ and never had influenza vaccine before

1 dose 2 doses if: ▶ never had influenza vaccine before ▶ and aged two-to-eight years ▶ or post HSCT or solid organ transplant

How

Intranasal

Intramuscular

Contraindications

Anaphylaxis following a previous dose of influenza vaccine or any of its constituents (except ovalbumin) Severe neutropaenia (absolute neutrophil count less than 0.5 x 109/l) On combination checkpoint inhibitors (eg, ipilimumab plus nivolumab) 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 Concomitant use of aspirin/salicylates Influenza antiviral medication in the previous 48 hours Pregnancy Significant immunosuppression due to disease or treatment Those who live with severely immunosuppressed persons (eg, post HSCT)

Precautions

Adverse reactions

Acute severe febrile illness, defer until recovery Children who required ICU admission for a previous severe egg anaphylaxis should be given LAIV in hospital No aspirin/salicylates for four weeks after vaccine due to risk of Reye’s syndrome Avoid antiviral medication for two weeks after vaccine

Seek specialist assessment for those who required ICU admission for a previous severe egg anaphylaxis Separate QIV from PCV vaccine by at least one week for children aged 12-to-23 months

Very common or common: Nasal congestion/ rhinorrhoea, decreased appetite, malaise, fever, headache, and myalgia. (Fever rates similar to those after other childhood vaccines; generally mild and of short duration)

Very common: Injection site pain and swelling Fever, fatigue, myalgia, and irritability in young children Common: Drowsiness, sweating, and arthralgia

Very rare: Immediate allergic reactions Guillain-Barré syndrome (risk of GBS following infection is much greater than that post vaccination)

cannot cause infection. Peak incidence of shedding occurred two-to-three days postvaccination in Fluenz clinical studies.10

the recommendations in these guidelines, which are based on current expert advice from NIAC, should be followed.”

Each chapter of the the NIAC immunisation guidelines advise: “In some circumstances, advice in these guidelines may differ from that in the Summary of Product Characteristics (SmPC). When this occurs,

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

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NIAC guidelines advise that: “Children

who live with severely immunosuppressed persons requiring isolation (eg, post HSCT) should not receive the Quadrivalent Live Attenuated Influenza (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

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is living with any other person unless the adult is in isolation, eg, following a HSCT.

The www.immunisation.ie website is updated with details on the LAIV vaccine.

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

The NIO has produced information materials on LAIV for parents and for vaccinators and copies have been distributed to vaccinators with additional copies available to order.

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.

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.

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

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

The NIO has developed an e-learning module for vaccinators available at www.HSEland.ie.

The following resources on LAIV are available from the NIO: ▸ Frequently asked questions for healthcare professionals: https://www. hse.ie/eng/health/immunisation/pubinfo/fluvaccination/faqchild.pdf ▸ Algorithms on flu vaccination for children for healthcare professionals: https://www.hse.ie/eng/health/immunisation/ pubinfo/flu-vaccination/laivalgorithm.pdf ▸ Information materials for parents in different languages and easy-read guides: https://www.hse.ie/eng/health/immunisation/ pubinfo/flu-vaccination/information/ ▸ Commonly asked questions and answers on the safety of LAIV for parents: https:// www.hse.ie/eng/health/immunisation/pubinfo/ flu-vaccination/flu-vaccine-for-children/ fluvaccineqas.html

References 1.

2.

3.

4.

Summary The introduction of 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.

the influenza vaccination programme to children aged two-to-12 years aims to protect children and reduce transmission to others, thereby reducing the burden on our health services at this crucial time. n

5.

6.

Royal College of Physicians of Ireland.

Immunisation Guidelines for Ireland. Influenza Chapter https://www. hse.ie/eng/health/immunisation/hcpinfo/ guidelines/chapter11.pdf Seasonal Influenza Programme 2020/2021 https://www.hse.ie/eng/health/ immunisation/hcpinfo/fluinfo/ Burden of paediatric influenza in Western Europe: a systematic review Antonova E A, Rycroft C E et al. BMC Public Health 12, Article number: 968 (2012) Health Protection Surveillance Centre (HPSC) Annual Epidemiological Report, Influenza and Other Seasonal Respiratory Viruses in Ireland, 2018/2019 (December 2019), https://www.hpsc.ie/a-z/ respiratory/influenza/seasonalinfluenza/ surveillance/influenzasurveillancereports/ previousinfluenzaseasons surveillancereports/20182019season/ Influenza per cent202018-2019 per cent20Season_Summary.pdf The NHS national flu immunisation programme 2020/21. https:// www.england.nhs.uk/wp-content/ uploads/2020/05/national-fluimmunisation-programme-2020-2021.pdf Finnish Institute for health and welfare.

Vaccination programme for children and adolescents [online]. Available

7.

8.

9.

10.

from: https://thl.fi/en/web/vaccination/ national-vaccination-programme/ vaccinationprogramme-for-children-andadolescents Canadian Immunisation Guide. Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2020–2021 https:// www.canada.ca/en/public-health/services/ publications/vaccines-immunization/ canadian-immunisation-guide-statementseasonal-influenza-vaccine-2020-2021. html#I1 Live-Attenuated Influenza Vaccine Effectiveness in Children from 2009 to 2015–2016: A Systematic Review and Meta-Analysis. Caspard H, Mallory R M, Yu J, and Ambrose C S. Open Forum Infect Dis. 2017 Summer; 4(3): ofx111 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 Pebody RG, Green HK, Andrews N, Zhao H, Boddington N, et al. Surveillance and outbreak report https://www. eurosurveillance.org/images/dynamic/EE/ V20N39/art21256.pdf Quadrivalent Live Attenuated Influenza (LAIV), nasal, Fluenz Tetra (AstraZeneca Pharmaceuticals (Ireland) DAC) SmPC http://www.hpra.ie/docs/defaultsource/vaccines-smpcs/fluenz-tetra_ smpc_07_2020.pdf?sfvrsn=2

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Covid 19 - when to consider lung transplantation?

AUTHOR: Dr Niamh Boyle, Respiratory Registrar, and Dr Michelle Murray, Consultant Lung Transplant Physician, Mater Misericordiae University Hospital, Dublin The true impact of the Covid-19 pandemic on our healthcare system remains unknown. However, it is already clear that the field of lung transplantation medicine is faced with new challenges to overcome.

Questions are being raised about the potential role of lung transplantation post SARS-CoV-2 lung infection.

However, as the disease course is yet to be fully elucidated, the indications and considerations for lung transplantation are uncertain. It is well-known that SARSCoV-2 can cause acute respiratory failure and acute respiratory distress syndrome (ARDS), however, whether it can cause worsening of a pre-existing respiratory disorder or lead to pulmonary fibrosis has not been fully established. Many respiratory viruses are known to cause ARDS and while we are familiar with lung recovery rates and survival in influenza viruses, ARDS secondary to SARS-CoV-2 infection poses a remarkable challenge.

SARS-CoV-2 infection Uncertainty exists as to whether transplantation should be considered for either acute Covid-19 disease or for the potential sequelae. The manifestation of Covid-19 in the acute setting varies from a mild disease course to ARDS requiring intensive care admission. Approximately 10 per cent of patients will develop ARDS. In this group, mortality rates of 60 per

cent have been reported. The long-term manifestations will become apparent in time. However, extrapolating from the acute findings and the experience with ARDS, post SARS-CoV-2 fibrosis is a potential complication, particularly in those with an underlying lung disease or those who have survived an ICU admission.

Cases of lung transplantation as a therapy for patients with acute SARS-CoV-2 respiratory failure have been reported in China, Europe, and the US

Acute setting Lung transplantation is seldom an option for acutely critically ill patients and in this setting the long-term prognosis is likely to be poor. Cases of lung transplantation as a therapy for patients with acute SARS-CoV-2 respiratory failure have been reported in China, Europe and the US. While initial reports have been acceptable, it is likely that more transplantations have occurred, but have not been reported due to poor outcomes and related publication bias. Nevertheless, these initial cases

highlight the challenges associated with transplantation in the acute setting.

Firstly, many of the patients who progress to respiratory failure requiring ICU admission secondary to SARS-CoV-2 have multiple co-morbidities including elevated body mass index (BMI), coronary artery disease and diabetes mellitus. These conditions can increase their risk of posttransplant complications and preclude them from transplantation irrespective of SARS-CoV-2 infection. These patients with advanced respiratory failure requiring ventilatory or extra-corporeal membrane oxygenation (ECMO) support are at a particular risk for complications such as muscle wasting, malnutrition, renal disease, and multi-organ damage, which renders them an unsuitable transplant candidate. Older frail patients also have a poor prognosis from lung transplantation in this setting.

Secondly, transplantation should only be considered in end-stage lung disease.

At present, the recovery time for Covid19-related ARDS is unknown. Emerging reports suggest it is similar to ARDS due to other causes. It is well known that nonfunctioning lungs can recover after weeks to months of ECMO support following infection with influenza or a bacterial pneumonia. Thus, adequate time should

Acute illness Severe, refractory ARDS Standard Transplant Considerations

Age

Physical Rehab

Other Organ Dysfunction

FIGURE 1: Transplant Covid-19 testing protocol

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Specific COVID-19 Considerations

Social Support

BMI

Timing

Reversibility

Transplant Consent

Sars-Co-V PCR

Center Experience

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be given to allow for lung recovery prior to deeming the SARS-CoV-2 related lung disease irreversible. The International Society of Heart and Lung Transplantation (ISHLT) suggests lung transplantation could be considered after at least 28 days from the onset of lung injury. While transplant may initially appear as a panacea, the longterm survival rates of transplantation are approximately 60 per cent at five years, thus if native organ function can recover, this is often preferable.

In addition, the rapid spread and high infectivity rate of SARS-CoV-2 represents a complex challenge which has important implications across the entire field of transplantation. Transmission of infection to the clinical team is a distinct possibility, especially in the setting of lung transplantation, in which organ retrieval and transplant surgery are considered aerosol-generating procedures. It requires a significant change in practice for teams involved in organ procurement and recipient hospitals carrying out the transplant surgery.

At all stages in the transplant pathway, safety of staff should be paramount. The ISHLT consensus recommends waiting at least 14 days after the confirmation of SARS-CoV-2 and two negative PCR tests 48 hours apart, prior to transplantation. A significantly higher mortality in PCR-positive patients, even in the absence of symptoms, has also been reported. The Department of Cardiothoracic Surgery and Transplant Medicine in the Mater has continued to perform heart and lung transplantation safely during the current pandemic by devising protocols for patients awaiting transplantation. See Figure 1.

Finally, of the reported cases of lung transplantation in the literature to date, all of the patients were bridged with ECMO. Many transplant centres have experience with ECMO-bridging, which is considered high-risk transplantation, and as such outcomes are intimately related to centre volume. Many centres have shown that outcomes are worse for patients who are elderly or non-ambulatory whilst on ECMO. Overall in the acute setting, in

Active transplant recipient at home/called in for transplant

Negative COVID-19 swab

Positive COVID-19 swab

Proceed with Transplant

Temporarily suspend from the active transplant list

Recovered and symptom free for 28 days

Positive Covid-19 swab

Two negative nose/throat swabs 24 hours apart

Remain suspended from the active transplant list

Relist for Transplant

Weekly Gene Xpert and Flow Flex PCR testing

Two negative NP 24-48 hours apart Relist for transplant after MDT discussion

Covid testing on all potential recipients If negative; proceed with transplant If positive; defer transplant

FIGURE 2: Transplant pathway

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patients with ARDS secondary to SARSCoV-2, consideration for potential lung transplantation should only be considered in those who are likely to have a good postoperative outcome. As such, both standard transplantation considerations and SARSCoV-2 specific considerations need to be assessed. See Figure 2.

ISHLT and Cypel M et al have outlined important considerations, which take into account candidate, disease and transmissibility factors in addition to rehabilitation potential, centre experience and equity of access to an organ: Candidates 1. Should be under 65 years of age; 2. Should have single organ disease; 3. Should not have any other co-morbidities precluding from transplant; 4. Should be able to give informed consent.

Disease 5. Appropriate time should be given for lung recovery; 6. Radiology should suggest irreversibility.

lung disease. The spectrum of fibrotic disease observed with SARS-CoV-2 ranges from fibrosis associated with organising pneumonia to severe acute lung injury with progression to extensive fibrotic change.

Two studies from China provide us with some early figures following discharge.

Functionally, 47 per cent of patients had impaired gas transfer and 25 per cent had reduced total lung capacity after discharge which correlated with disease severity.

Overall in the acute setting, in patients with ARDS secondary to SARS-CoV-2, consideration for potential lung transplantation should only be considered in those who are likely to have a good post-operative outcome

Rehabilitation 7. Candidate should be ambulatory with good rehabilitation potential.

Radiographically, 65 per cent of patients had complete resolution of radiographic findings four weeks post-discharge.

Infection 8. Candidate should have negative PCR result or sample showing absence of viable virus.

Until robust long-term data is available, we can only draw from prior experience with ARDS and other strains of the coronavirus; Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV, SARS) and Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV, MERS). Studies have reported up to 30 per cent of patients with SARS and MERS with interstitial abnormalities radiologically and physiologically. A study of 71 patients with SARS showed that interstitial abnormalities and functional decline recovered two years post infection and at 15 years, 4.6 per cent of patients had persistent abnormalities. In a study of 36 patients who had recovered from MERS, chest radiographs approximately one month after hospital discharge showed abnormalities in one-third of patients. These results may appear reassuring, however, long-term outcomes

Centre 9. Should have experience in ECMObridging for ARDS; 10. Should have access to broad donor pool with a low wait-list mortality rate.

Post-acute setting Pulmonary fibrosis is a well-recognised complication of ARDS with a substantial proportion of patients experiencing residual pulmonary function impairment and radiographic evidence of pulmonary fibrosis. Emerging reports suggest that some patients who survive the acute insult from SARS-CoV-2, may go on to develop pulmonary fibrosis resulting in end stage

40

secondary to SARS-CoV-2 may not be comparable. The population with severe SARS-CoV-2 respiratory disease have more co-morbidities and an older age profile than those that were enrolled in these longitudinal studies.

The trajectory of pulmonary fibrosis is variable. Some patients have a rapidly progressive disease course. It is postulated that aberrant immune pathways promote pulmonary fibrosis, possibly as the end result of a cytokine storm, however, the factors that determine which patients develop fibroproliferative ARDS are not well understood. Interestingly, the risk factors for severe SARS-CoV-2 are similar to those of idiopathic pulmonary fibrosis; male gender and advanced age. We must identify patients at risk of pulmonary fibrosis as there is evidence that the magnitude of the fibroproliferative response is related to long-term healthrelated quality-of-life.

Conclusion The Covid-19 pandemic is uncharted territory. Transplant programmes around the world are endeavouring to continue to assess typical candidates with reduced elective beds, to perform life-saving surgery with limited critical care capacity and to safely deliver post-transplant care.

While striving to continue usual care, new clinical questions arise. What is the optimal management of SARS-CoV-2 in transplanted patients and is there a therapeutic role for transplant in severe SARS-CoV-2-related lung disease? With these unanswered questions, comes the need to establish systems of care and resources to deal with the expected increase in referrals to transplant centres and programmes, such as pulmonary rehab, to optimise potential candidates. Should lung transplant be added to the armamentarium of treatments for patients with SARS-CoV-2 related ARDS or pulmonary fibrosis? Only time will tell, but hopefully understanding the complexities related to this will be beneficial to referring physicians now. â&#x2013; References on request

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Acute respiratory viral infections AUTHOR: Dr Amy Rigby, Consultant in Respiratory and General Internal Medicine, Beacon Hospital, Dublin Acute respiratory tract infections are the cause of significant morbidity and mortality worldwide and are rivalled only by diarrhoea as the leading cause of death in developing countries. An adult may experience two-to-four upper respiratory infections a year, and a child may suffer up to 10. Thus the burden of viral respiratory tract infections, both clinical and economic, is significant. Viral respiratory pathogens may cause a number of clinical syndromes. Except for a few notable cases (adenoviruses, coronavirus) and rare cases of extrapulmonary dissemination of other respiratory viruses, replication of respiratory viruses generally occurs only in the respiratory mucosa of humans. Acute respiratory tract infections usually start in the upper respiratory tract; spread to the lower airways occurs in two-to-four days either by continuous spread or by inhalation of aerosols.

of chemical inflammation mediators (prostaglandins and bradykinin) that stimulate pain nerve endings rather than a true pharyngitis, although cytomegalovirus (CMV) and Epstein–Barr virus (EBV) can cause true pharyngitis (infection and inflammation of the pharynx itself).

Viral pharyngitis Mucosal infection of the lower respiratory tract leads to destruction of epithelial cells, submucosal hyperaemia, oedema of airways, and may cause a degree of haemorrhage; these will result in the clinical syndrome of viral pneumonia. For a pathogen to cause pneumonia, it must reach the alveolar space and have a large enough inoculum, or overwhelm the host’s already impaired immune system.

Common cold

Viral pharyngitis

The sore throat that results from the common cold is caused by excretion

Diagnosis Identifying the causative pathogen in viral respiratory tract infections can be problematic. Novel viruses continue to be identified, including bocavirus, WU/KI polyomaviruses, and of course the novel coronavirus, Covid-19.

Rhinovirus and coronavirus generally do not cause significant damage to the airway cells; thus the common cold is associated with little coughing, whereas the influenza

Syndrome

Pathogenicity of a particular virus depends on how a number of factors interact, in particular the number of infectious particles, how they reach the target tissue, the rate of multiplication, the effect of the virus on cell functions, and the host’s immune response. There is significant overlap in aetiology and symptoms of infections, so that even defining the exact syndrome (eg, common cold or influenzalike illness) can be difficult.

virus may cause more significant damage to the respiratory epithelium (resulting in increased cough with influenza infection).

Croup

Causative viruses ▸ Rhinovirus/coronavirus ▸ Influenza, parainfluenza, enteroviruses, adenoviruses, human metapneumovirus (HMPV), RSV ▸ Parainfluenza viruses ▸ Influenza, RSV

Influenzalike illness

▸ Influenza viruses

Pneumonia

▸ Influenza viruses/RSV/ adenoviruses

▸ Parainfluenza viruses, adenoviruses

▸ Parainfluenza viruses, enteroviruses, rhinoviruses, HMPV, coronaviruses TABLE 1: Acute respiratory tract infections

Rapid point of care tests are available, but only for a select few viruses (influenza and respiratory syncytial virus (RSV)), and these are antigen-based. They are less sensitive than laboratory tests.

PCR-based testing may be performed as a multiplex panel or individually (influenza, RSV, herpes simplex virus (HSV) and CMV). This is more sensitive than point of care tests.

For viruses that can be shed for prolonged periods (such as bocavirus, rhinoviruses, and some adenoviruses) or are latent and can reactivate (HSV and CMV), it is again more difficult to confirm a causal role. Thus demonstration of increasing viral load by quantitative PCR may be necessary should the pathogenic role of the virus need to be confirmed. Many viruses may be detected via ELISA (rapid antigen testing) but this may not indicate active disease, and these may coexist with bacterial pathogens.

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Treatment Treatment for viral respiratory infections is usually supportive. Occasionally specific antiviral therapy exists, such as oseltamivir/ zanamivir for influenza (given within the first 48 hours, longer if the illness is severe or the patient immunocompromised) and ribavirin for RSV in immunocompromised patients. Pleconaril was developed for the common cold, but its side effects outweighed the benefits.

Influenza treatments target neuraminidase, an enzyme of the viral capsid that is required for intercellular viral propagation. Oseltamivir and zanamivir are selective inhibitors of this enzyme and may contain infection during peak viral replication period (the first 24-72 hours), thus improving clinical symptoms and reducing morbidity and mortality.

Particularly within the immunocompromised population, ribavirin has been used also against metapneumovirus, and intravenous acyclovir may be considered for treatment of varicella zoster pneumonia in this population.

Antibiotics should not be used as prophylaxis against secondary bacterial infection, with the exception being given to those with chronic lung conditions.

Viral pneumonia Viruses are the most commonly identified pathogens in severe communityacquired respiratory infections, with 25 per cent of community-acquired pneumonia being viral (this proportion is higher in children due to large proportion of RSV). It is most common in those at extremes of age and in the immunocompromised. It is also of particular concern during pregnancy due to the increased mortality rate even in otherwise healthy women. It is no longer a diagnosis of exclusion, as identification of the causative pathogen may often be obtained via PCR/ELISA testing. Cultures are gold standard but it may take weeks to get a result.

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The epidemiology of pneumonia is changing due to a number of factors, including introduction of the pneumococcal conjugate vaccine and declining rates of cigarette smoking (both associated with a reduction in the number of pneumococcal pneumonias), and an ageing population (age being a risk factor for viral pneumonia). Older people are 10 times more likely to develop viral pneumonia, which is associated with increased morbidity/mortality.

Additionally, viral respiratory pathogens have an increased role in pathogenicity

Chest x-ray of Pneumocystis jirovecii pneumonia in an immunocompromised patient and as cofactors with bacterial pneumonia in the immunocompromised. It is vital to remember that viral pneumonia in the immunocompromised may present very differently, and that imaging may be much more dramatic than in the immunocompetent patient.

The US Centers for Disease Control and Prevention (CDC) Etiology of Pneumonia in the Community (EPIC) study found that 23 per cent of hospitalised patients were positive for viruses, and ICU studies identify viruses in 18-41 per cent of patients.

A systematic review including over 10,000 patients identified viral infections in 25 per cent of those with community-acquired pneumonia; this number increased to 44 per cent in studies where >50 per cent had a lower respiratory sample obtained.

Viral pneumonia has multiple aetiologies.

It may occur with severe measles/varicella

or secondary to generalised infection with EBV or CMV. Influenza is the most common cause across the population.

Rhinovirus is commonly identified in patients admitted with community-acquired pneumonia, but the significance of this remains unclear.

Although there are features suggestive of bacterial versus viral aetiology (adult age group, raid onset of illness, elevated white cell count and neutrophilia are suggestive of bacterial aetiology, whereas interstitial bilateral infiltrates rather than lobar alveolar infiltrates suggest a viral cause), there is such significant overlap that these features are not clinically useful.

As testing improves, the question becomes if/when/how to test. Does testing improve antimicrobial stewardship and allow early commencement of antiviral therapy? Or merely identify pathogens of uncertain clinical significance and increase costs? In multiple observational studies of influenza patients, viral testing was infrequently found to alter management. In one study 75 per cent of patients with PCR-confirmed influenza continued to receive antibiotics, and in another over 60 per cent of low-risk patients with a positive rapid viral test continued to receive antibiotics. The clinical significance of a positive respiratory viral test result remains unclear.

Rapid tests for biomarkers of bacterial versus viral infection are increasingly being looked to in an attempt to address these issues. These include: ▸ CRP; ▸ Procalcitonin; ▸ TNF-related apoptosis-inducing ligand (TRAIL); ▸ IP-10; ▸ Myxovirus resistance A (MxA).

CRP CRP is an acute phase reactant. Its production is stimulated during infection or tissue inflammation, when interleukin-6 (IL-6), interleukin-1b (IL-1b), and tumour necrosis factor-alpha (TNF-a) stimulate hepatocytes to synthesise CRP.

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CRP levels tend to be much higher in bacterial infections than in those of viral aetiology, and due to its short half-life serial measurements may also be used to ensure appropriate response to therapy.

However, a moderately elevated CRP (1060mg/l) may also be seen in viral infections (particularly those caused by influenza virus and adenovirus), and as such there is significant overlap between viral and bacterial aetiologies. In systematic reviews it has been found to be neither sufficiently sensitive to rule out nor sufficiently specific to rule in a bacterial cause for an infiltrate on chest x-ray. CRP peaks between three-tofive days after a viral challenge; thus raised CRP values from viral infection during the first seven days may lead to mistaken prescription of antibiotics. However, CRP may also be more specific for predicting bacterial aetiology after the first week, when elevated levels may suggest secondary bacterial confection.

Procalcitonin Procalcitonin is an acute phase reactant released by leukocytes. As viral infections are less likely to result in a leukocytosis, acute phase reactants are thought to be a marker of bacterial aetiology. Production of procalcitonin requires circulating tumour necrosis factor (TNF-alpha); in viral infections, macrophages produce interferon-alpha (INF) that can inhibit TNF-alpha and so suppress elevation of procalcitonin; thus viral infections tend not to increase procalcitonin.

However, a meta-analysis of 12 studies (over 2,000 patients) found that both sensitivity and specificity of procalcitonin as a determinant of viral versus bacterial aetiology were too low and too variable to be used for decision-making.

TRAIL and IP-10 TNF-related apoptosis-inducing ligand (TRAIL) and interferon-gamma-inducedprotein-10 (IP-10) have been shown to predict viral infection, particularly in combination.

Both are induced in viral infection and suppressed in bacterial infection, thus elevated levels are suggestive of viral aetiology.

Myxovirus A (MxA) Myxovirus resistance genes mx1 and mx2 belong to the class of IFN-stimulated genes that are induced by viruses. After viral infection, IFNs bind with their receptors on the surface of uninfected cells, which activates mx1 and mx2. These then produce antiviral proteins MxA and MxB. The MxA protein is selectively increased in patients with viral infections and may therefore be useful biomarkers for viral infection.

Combination tests Newer combinations of viral-induced proteins that complement routinely used bacterial-induced proteins (such as CRP and procalcitonin) are being developed to increase capacity to accurately distinguish between viral and bacterial aetiologies.

Studies of combinations of MxA and CRP have demonstrated the capacity to correctly identify 92 per cent of patients without infection, 80 per cent of patients with confirmed bacterial infection, and 70 per cent of patients with established viral infection. A combination of CRP + TRAIL + IP-10 has been shown in several studies to have a significantly greater efficacy in the differential diagnosis of bacterial and viral infections than not only individual biomarkers (CRP, procalcitonin, white cell count, IL-6), but also currently used combinations of these biomarkers.

in susceptible individuals may continue even after the acute viral infection has resolved. Viral respiratory tract infections may cause wheeze in many asthmatics and are the underlying cause for more than half of acute exacerbations of asthma. Even following a simple rhinovirus infection, allergen-induced production of histamine and late-phase reactions secondary to eosinophil activation may persist for fourto-six weeks.

Pure post-viral cough remains a diagnosis of exclusion. Imaging will be normal.

Treatment (if required), includes an antihistamine, bronchodilators, and inhaled corticosteroids. Occasionally oral corticosteroids may be trialled.

Post-viral cough Viral infections result in an immune response that in particular stimulates T-lymphocytes. Th2 response leads to wheeze and airway inflammation. Postviral cough is a very common complaint presenting to medical practitioners. It may last three-to-eight weeks, and is the result of the inflammatory response, resulting in bronchial hyper-responsiveness, mucus hypersecretion, and impaired mucociliary clearance. When the larynx is inflamed and hyperreactive, coughing may continue to occur in response to stimuli that would not generally cause coughing (such as cold air). A spectrum exists between viral-induced post-viral cough and exacerbations of asthma following viral infection. Stimulation of allergic pathways

Summary Multiple viruses exist that may cause a number of syndromes. Diagnosis is usually clinical, although there is an increasing push for a specific diagnosis in order to reduce the use of antibiotics. Significant cross over exists between viral and bacterial aetiologies, and current research is focused on ways to differentiate between the two.

Unusual presentations may occur in the immunocompromised. Few treatment options are available other than supportive care. Finally, post-viral cough is common and may present similarly to asthma, although it should resolve completely (but may take several months). n References on request

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Positive developments within the field of cystic fibrosis AUTHOR: Sarah Tecklenborg, Senior Research and Policy Coordinator, Cystic Fibrosis Ireland

related quality-of-life (HRQOL) among a sample of adolescents and adults with CF aged >14 years in Ireland. The study found that mental health variables, specifically depression and anxiety, were more strongly associated with HRQOL than physical variables. The results indicate that as CF disease progresses and physical health declines, maintaining mental health is essential to ensure people with CF have the highest HRQOL possible.

At the recent European Cystic Fibrosis Society conference, held online on 24-25 September, Prof Ed McKone, Consultant Respiratory Physician, St Vincentâ&#x20AC;&#x2122;s University Hospital, Dublin, outlined the evolving natural history of cystic fibrosis (CF) in Ireland, the clinical characteristics of CF at the different life phases and the treatment challenges that arise therein.

There have been large improvements over the last 60 years in CF survival.

Many of these improvements were being seen even before the advent of CFTR modulators â&#x20AC;&#x201C; the cystic fibrosis transmembrane conductance regulator modulator therapies, which are designed to correct the malfunctioning protein made by the CFTR gene in people with CF. Much of the improvements in survival and life expectancy have been attributed to antipseudomonal antibiotics, improved nutrition, the expertise of the multidisciplinary care teams and our ability to detect CF early and begin treatment.

New research published in the European Journal of Human Genetics has shed light on some of the outcomes over 6.5 years of the inclusion of CF in the Newborn Screening Programme in Ireland. The overall incidence of CF was found to be onein-2,570 births, with an estimated carrier frequency of one-in-25.3. This is lower than the previously reported one-in-19 carrier frequency in Ireland.

The likely cause of this decrease in incidence in the Republic of Ireland is increased ethnic diversity arising from inward migration. The authors recommended that in the case of counselling for a couple of Irish origin, the carrier rate of one-in-19 should still be

44

Prof Eileen Savage used. Ireland continues to have one of the highest incidences of CF in the world.

Transition Prof McKone noted the decline in physical markers of health experienced by people with CF in adolescence and early adulthood. The transition from paediatric to adult care and greater selfmanagement of their condition is a critical time for people with CF. This period is characterised by a decline in lung function and nutritional status, increases in the detection of pseudomonas and MRSA bacteria, and is associated with increasing rates of depression and anxiety.

In a joint Cystic Fibrosis Ireland (CFI) and Health Research Board-funded study, Vice Dean for Graduate Studies in the College of Medicine and Health in University College Cork (UCC) Prof Eileen Savage (PhD) and colleagues from UCC used a multivariate analysis to examine the association between socio-demographic variables (age, sex), physical (FEV1, BMI) and mental health variables and health-

Dr Jennifer Cronly (PhD), School of Nursing and Midwifery, UCC, and Prof Savage also investigated the role of agency in empowering young people to take control of their own disease management during adolescence.

Their research highlighted the threats negative interactions with healthcare professionals may have for this patient group in the development of agency. The authors noted the need for respect and encouragement of young people as they go through the process of transition and to allow adolescents to have an active role in the decision-making process around their own care.

Covid-19 Mental health concerns are not only prevalent during adolescence, but throughout the life course for people with long-term health conditions. The coronavirus pandemic has had an unprecedented impact on those with underlying health conditions including people with CF. In the early period of the pandemic, people with CF were considered extremely medically vulnerable and were advised to cocoon for their own safety. This caused high levels of stress and concern.

A survey undertaken by CFI in late March 2020 identified high levels of

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anxiety among people with CF and their carers, and observed major concerns about the unknown health implications of coronavirus and CF, fears of possible medication shortages or supply issues, and the mental health and practical implications of cocooning. In light of new data on the nature of Covid-19 disease and CF, people with CF are now considered high risk from Covid-19 if their CF is stable, and extremely medically vulnerable if their CF is unstable or they are post-transplant. While data has shown that coronavirus is not as severe in people with CF as originally feared, it is not a benign disease.

Data from the European Cystic Fibrosis Registries up to 18 September identified 138 cases of Covid-19 among people with CF. Where information was known, 20 per cent (n=27) of these infections were asymptomatic and 79 per cent (n=102) were symptomatic. Among symptomatic patients, 60 per cent required hospitalisation, 16 per cent of these were treated in ICU and sadly 25 per cent (n=4) of those in ICU died. The incidence of Covid-19 among people with CF in the EU was 0.2 per cent with a 2.9 per cent case fatality rate. Both of these are lower than the incidence and case fatality rate among the general population in the EU for the same time period (4.5 per cent and 0.5 per cent respectively). This may reflect the enhanced precautions taken by people with CF and their family members and carers to prevent infection.

These enhanced precautions, and the duration for which people with CF have had to endure them, may not come without consequences. Prof Patricia Fitzpatrick, Professor of Epidemiology and Biomedical Statistics in University College Dublin, is currently leading a research project to assess the impact the Covid-19 pandemic and cocooning have had on the daily lives of people with CF. The research will investigate how people with CF and their parents/carers have managed their daily lives throughout the pandemic; assess their access to hospital

visits and routine CF care; examine precautions taken by them; and report on the impact on mental health and the stress management techniques used to cope.

Ivacaftor/tezacaftor/elexacaftor While Covid-19 has cast a grey uncertainty across the future, for many people with CF the horizon is looking brighter than ever. On 21 August, it was announced that the European Commission had granted marketing authorisation for Kaftrio (ivacaftor/tezacaftor/elexacaftor) in a combination regimen with ivacaftor to

The transition from paediatric to adult care and greater self-management of their condition is a critical time for people with CF

treat people with CF aged 12 and over with one F508del mutation and one minimal function mutation, or two F508del mutations in the CFTR gene.

Thanks to the innovative ‘Portfolio Agreement’ signed in 2017 between the HSE and Vertex Pharmaceuticals, the treatment regime is now available to eligible patients in Ireland.

Ms Sally Ann Lynch and Ms Tara Clark, Department of Clinical Genetics, Children’s Health Ireland at Crumlin, suggest that up to 95 per cent of people with CF may be eligible for a modulator therapy in Ireland based on their genotypes. A recent European study using CF registry data (currently unpublished) goes further and found that up to 97.7 per cent of adults with CF in Ireland will be eligible for at least one of the modulator drugs – this would be the highest proportion of eligible adults throughout Europe.

RECOVER Ivacaftor/tezacaftor/elexacaftor has been shown to be effective in multiple clinical trials, however, the real-world impact of this drug on the lives of people with CF may be even greater. The RECOVER project, led by Prof Paul McNally, Associate Professor of Paediatrics, RCSI, will investigate the real-world effect of the new CF medications on clinical outcomes in people with CF. The project is funded by the Cystic Fibrosis Foundation in the US (€2.85 million), the CF Trust (UK) (£112,000), and Cystic Fibrosis Ireland (€100,000). RECOVER is a multi-centre cohort study, which will take place in eight sites across Ireland and the UK over a three-year period.

It will collect information on a range of health data and clinical end-points such as lung clearance index, chest CT, gastrointestinal symptoms and inflammation, and medication adherence.

‘Real-world’ studies examine how drugs impact on a broad range of patients, many of whom would have been excluded from the initial clinical trials due to poor underlying health or the existence of comorbidities. The data can confirm trial findings and shed light on the overall impact of the drug on the day-today lives of people with CF and not just on a limited range of biomarkers or a specific cohort.

With more and more people with CF living for longer, clinicians are having to detect and treat current and emerging ageing comorbidities in this group, including those already known to be associated with older age and those possibly resulting from long-term use of new therapies. People with CF are also turning their minds to the need for better educational opportunities, long-term careers and pension planning.

A normal life is becoming less of an extraordinary ambition for people with CF. Cystic Fibrosis Ireland is committed to leaving no one behind in the quest for improved quality-of-life for all people with CF. 

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Non-tuberculous mycobacteria: An overview AUTHORS: Dr David Quigley, Respiratory Registrar; and Prof Anne Marie McLaughlin, Respiratory Consultant, St James’s Hospital, Dublin

Non-tuberculous mycobacteria (NTM) are ubiquitous organisms found in the environment. NTM comprises over 160 subspecies. Data from 2013 identifies Mycobacterium avium complex (MAC) as the most frequently isolated form of NTM in Europe with a prevalence of 38 per cent of all NTM. A total 43 per cent of all NTM in Ireland represented MAC in subgroup analysis of this data, with only Sweden (67 per cent) and Germany (55 per cent) having higher levels in Europe. It predominantly affects northern European over southern European countries. Transmission is generally based on complex host-pathogen factors not yet fully understood. The (Mycobacterium) M.kansaii, M.xenopi, M.almonese, and M.abscessus subspecies are encountered less frequently in Europe but are common in other parts of the world. They have been identified in soil, shower heads and water reservoirs. There is also data for humanhuman transmission with M.abscessus in individuals with cystic fibrosis (CF). NTM have the potential to cause multisystem disease in both humans and animals.

For the purpose of this review we will be concentrating on pulmonary disease as the most common presentation of NTM and one with which we are familiar in treating.

Host genetic and immune factors are thought to play a key role in susceptibility to NTM disease. Those with underlying lung disorders are at risk, particularly those with bronchiectasis, CF and in some cases severe emphysema. Other individual risks include low socioeconomic backgrounds, poor nutritional status and HIV, particularly in disseminated disease.

It affects women significantly more than men overall. The Ontario study identified 74 per cent of cases to be women. MAC

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Host genetic and immune factors are thought to play a key role in susceptibility to NTM disease

has an even higher incidence in these patients with the overall phenotype previously referred to as ‘Lady Windermere syndrome’. These tend to be elderly, nonsmoking Caucasian females.

One study indicated patients with NTM have more low-frequency, proteinaffecting variants in immune, CFTR (cystic fibrosis transmembrane regulator), cilia, and connective tissue genes than their unaffected family members and control subjects. The authors suggest this may be related to the development of

bronchiectasis initially and subsequent development of NTM due to further acquired immunodeficiency. Genetic variations in MST1R has been identified when associated with pectus excavatum and scoliosis. Heterozygous mutations in the CFTR gene have been associated with the disease relevant to an Irish population. A modest reduction in interferon-γ production and an increase in transforming growth factor (TGF)-β levels have been described.

In terms of true incidence of NTM, regional and global geographical factors are likely at play but universally rates seem to be increasing. In Europe, a study in the UK identified a rising incidence of NTM isolation driven almost exclusively by an increase in MAC disease with incidence rising from 5.6 per 100,000 to 7.6 per 100,000 over the period 2007-2012.

Ringshausen et al reported a prevalence of 2.3 per 100,000 for NTM pulmonary

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disease in 2009 in Germany rising to 3.3 per 100,000 in 2014. A concerning incidence of up to 14.5 per cent of NTM in CF patients has been reported in one study.

Improved diagnostic methods and increased physician awareness might have led to such increase in NTM infection. It has been suggested that its incidence is increasing due to ageing populations and immunosuppression. NTM disease has been associated with immunosuppressive medications such as azathioprine, cyclophosphamide, mycophenolate and cyclosporine, as well as with anti-TNFÎą agents. This raises questions for clinicians in screening for NTM before initiation of these therapies. Data from Denmark indicates patients with COPD on inhaled corticosteroids (ICS) have three-times the risk of developing NTM than those on non-steroid based therapy. Increased risk of NTM has also been seen in patients with asthma with long-term use of ICS. Those with obstructive lung disease and worsening infective symptoms should be considered for further investigation if there is any clinical/ radiological concern for NTM.

Classification of NTM Runyon initially classified mycobacteria based on their growth patterns (rapid versus slow), whether they produced yellow pigment or not and if this was produced in the dark or only after light exposure. Class 1-3 where defined as slow growers with Class 4 rapid growers. Class 1 (photochromogens) produce a yellow pigment when exposed to light and most commonly include subtypes M.kansaii and M.simiae. Class 2 (scotochromogens) produce a yellow pigment in either light or dark with M.Gordonae the most identifiable subspecies here. Class 3 (nonchromogens) never produce pigment and includes MAC. Rapid growers include M.abscessus, which is especially pathogenic in CF patients.

Clinical presentation Clinically, patients with NTM present with pulmonary symptoms such as productive

cough, dyspnoea and occasionally haemoptysis which may give concern for TB. Constitutional symptoms include night sweats, weight loss, loss of appetite and general decline. Cavitary disease may be difficult to differentiate radiologically from TB in both conditions. Patient factors including birthplace, age, and presence of underlying lung disease have been shown to be helpful in differentiation. An interferon-gamma release assay is typically positive in TB and negative in NTM. Clinical symptoms can be minor including mild cough and mild fatigue. The NTM diagnosis may only become apparent after incidental radiological findings consistent with the disease with symptoms correlated retrospectively.

Clinically, patients with NTM present with pulmonary symptoms such as productive cough, dyspnoea and occasionally haemoptysis which may give concern for TB

Diagnosis As per the American Thoracic Society (ATS) guidelines, the diagnosis of NTM encompasses clinical (as described above), microbiological and radiological evidence.

An isolated microbiological specimen does not necessarily indicate lung disease but can reflect colonisation or specimen contamination. The microbiologic criterion includes positive culture results from either: A minimum of two separate expectorated sputum samples, one bronchial wash/lavage (BAL) or a transbronchial/other lung biopsy with mycobacterial histopathologic features.

Bronchoscopy with BAL is performed with patients off all antibiotic therapy when done for suspected NTM. If clinically suspected, NTM should be excluded before

initiating long-term macrolide therapy in those with bronchiectasis to prevent future resistance.

Radiologically, the ATS criteria requires an observation of nodular or cavitary opacities on a chest x-ray or a CT scan that shows multifocal bronchiectasis with multiple small nodules. In more recent guidelines, the radiographic criterion has been interpreted to demand one-of-two different radiographic manifestations: Fibrocavitary or nodular bronchiectatic disease. Fibrocavitary disease demonstrates cavitary lesions predominantly in the upper lobes while nodular bronchiectatic disease presents as multifocal bronchiectasis, clusters of small nodules, and branching linear structures that commonly involve the right middle lobe and the lingular segment of the left upper lobe. The latter is more common in older, thin females. Mixed patterns are also seen. CT scanning is the modality of choice for assessing the anatomical evidence of disease in detail.

Treatment In August of this year (2020) new ATS/ ERS/ESCMID/IDSA comprehensive guidelines were published. This group refer to the fact that although overall they recommend treatment in those with NTM disease, patient factors should be considered. This list is complex and nonexhaustive. Clinically, disease progression can vary amongst patients independent of perceived microbiological or radiological severity. Propensity for recurrence and reinfection despite appropriate treatment is high, especially in cases of nodular/ bronchiectatic disease, with rates of up to 50 per cent quoted in one study of 180 patients at four-year follow-up.

There is evidence from Korea that up to half of patients with stable MAC disease that had not progressed clinically or radiologically at three years become culture negative during a six-year follow up period. On subgroup analysis, younger patients with higher BMI and AFBnegative smear disease were more likely to convert spontaneously. Conversely,

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systemic symptoms including fever/fatigue, increased age, and low BMI were less likely and smear-positive patients were less likely to sputum convert.

The recent ATS/ERS/ESCMID/IDSA clinical guidelines for treatment of MAC encompass three regimens depending on clinical severity/radiological appearance (nodule versus cavitating) and previous treatment of disease. This has not changed significantly from previous ATS guidelines.

For non-severe nodular/bronchiectatic disease it is recommended a macrolide, ethambutol and rifampicin are taken three times a week. For cavitary and recurring or clinically severe disease the above medications are given daily with the recommendation for an IV aminoglycoside for the first two-tothree months.

When considering a patient for treatment the disease severity, type of infectious species and patient preferences/ characteristics are evaluated in detail.

Poor prognostic factors include cavitary disease, low BMI, low albumin, and/or elevated inflammatory markers at time of diagnosis. Cases in which severe clinical symptoms affecting overall health and functional status would be important to consider treatment. Those with baseline immunosuppression should also be considered for early intervention. Rapid radiological progression on follow up and decline in pulmonary function at follow up is also associated with poor prognosis and favours early treatment.

Duration of treatment and drug regimens vary depending on specific organism and susceptibility profile. In most cases treatment is continued until a patient is sputum negative for 12 months. In terms of specific microorganisms, more virulent and treatment-responsive forms of NTM such as M.kansaii favour a trial of treatment. In patients with M.kansasii pulmonary disease, we perform susceptibility-based treatment for rifampicin over empiric therapy as resistant disease has been associated with

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treatment failure. In patients with MAC and M.abscesses pulmonary disease a ‘watch and wait’ approach may sometimes be more appropriate.

Susceptibility-based treatment for macrolides and amikacin over empiric therapy again is favoured in all organisms based on evidence of treatment failure in resistant disease. Close liaison with microbiology colleagues is important.

Full transparency regarding the risks and benefits of treatment is important in discussion with patients. NTM poses specific difficulties due to the variable treatment response clinically, duration of treatment, and unpredictable recurrence.

Side effects of medications can be serious.

Rifampicin is associated with hepatic dysfunction and amikacin has been associated with renal dysfunction. Regular monitoring of liver and renal function tests is crucial at two-to-three monthly intervals. Macrolides can cause cardiac arrythmias, so baseline ECG is important for QTC evaluation. Visual loss and ototoxicity are reported with ethambutol/ macrolides and aminoglycosides respectively. When concerns around adherence are present due to cognitive, social or functional impairment, a watch and wait approach is more appropriate.

The risks of taking medications intermittently increases resistance profiles with no treatment preferable in these cases. Current ATS guidelines recommend treating until 12 months post-culture conversion. Sputum cultures are repeated at three-monthly intervals post treatment to ensure they remain negative, however, there is an argument that clinical and radiological improvement could be used rather as treatment endpoints.

poorly responsive to medical therapy.

Paradoxically, resistant disease is usually too widespread for surgical consideration by the time it is identified.

Inhaled amikacin can be used in treatment of NTM as per recent guidelines. Efficacy comes from five retrospective case series (138 patients) of treatment-refractory cases with no comparator arm. Sputum conversion ranged from 18-67 per cent and clinical response from 20-100 per cent depending on the series.

Novel inhaled therapies are currently being researched for NTM. Clofazimine inhalation suspension has showed promise in mouse models with concentrations in the lungs four times greater than equivalent oral dosing. Inhaled ciprofloxacin has showed some early promise in bronchiectasis treatment, but data for NTM at this stage is lacking.

Conclusion NTM is increasing in incidence worldwide and is a common presentation in our centre. We believe treatment for NTM should be made after longitudinal assessment. Despite guidelines for radiological, clinical and microbiological characteristics that would support treatment, data in the literature can be conflicting due the variable nature of the disease. The right decision for a particular patient may prove difficult depending on their demographics. Basic medical ethical principles of beneficence, non-maleficence and informed consent are particularly relevant to this illness

Key learning points NTM prevalence is increasing.

Most common subtype in Ireland is MAC infection.  Clinical/microbiological/radiological and patient criteria determine severity and need for treatment.  Novel inhaled therapies with lower side effect profiles and good efficacy may provide future options. ■  

Surgery has also been described in the literature as an adjunct treatment for NTM. ATS recommends it only for those with localised disease, limiting rate of progression, or refractory disease.

One review collaborates positive data from several studies indicating it may still have a role, however, it is mostly reserved for those with resistant disease

References on request

Respiratory Medicine | Volume 6 | Issue 9 | 2020

An overview of alpha-1 antitrypsin deficiency in Ireland AUTHORS: Dr Daniel Fraughen,1 Dr Tomás P Carroll,1,2, Geraldine Kelly,2 and Prof Gerry McElvaney,1 Irish Centre for Genetic Lung Disease, RCSI Education and Research Centre, Beaumont Hospital, Dublin; 2Alpha-1 Foundation Ireland

1

The field of alpha-1 antitrypsin deficiency (AATD) has undergone exciting new changes in recent years with two clinical trials of novel oral medicinal compounds currently being undertaken in Beaumont Hospital, Dublin, to help those most severely affected by the condition.

Alpha-1 antitrypsin (AAT) is an anti-protease, which is primarily produced in the liver and circulates in the blood (Figure 1). Its main site of action is in the lungs where it binds to neutrophil elastase (NE), inhibiting it in the process. If NE remains unbound due to AATD; it can result in premature emphysema.

This manifests clinically as chronic obstructive pulmonary disease (COPD). The risk of COPD is greatly enhanced by the presence of environmental and cigarette smoke exposure.

The production of AAT protein is controlled by the SERPINA1 gene. Each person has two copies (alleles) of the SERPINA1 gene, which is located on the long arm of chromosome 14.

The SERPINA1 alleles are co-dominant and are equally responsible for producing their own set of AAT protein. The protein produced by the normal SERPINA1 allele is called

FIGURE 1: The role of AAT in normal and deficient individuals ‘M’ AAT protein. If a person has two normal SERPINA1 alleles, then they will only produce M AAT protein – and their AAT phenotype will be MM. Over 100 mutations in the SERPINA1 gene exist and cause the production of a variety of abnormal AAT variants with some quantitatively and/or qualitatively defective (Figure 1). Abnormal variants of

the AAT protein can be analysed by a process called isoelectric focusing or ‘phenotyping’ and this is how AATD can be diagnosed (Figure 2). Simply, AAT protein variants are separated on an agarose gel by electric current. Different variants of AAT protein travel through the agarose gel at different speeds and abnormal AAT protein variants are assigned different letters based on their migration speed. Common variants include

FIGURE 2: (LEFT) Typical isoelectric focusing gel used to diagnose AATD. The six most common phenotypes are shown with ZZ causing the most severe serum AAT deficiency (reduced by 80-85%) and posing the highest disease risk. (RIGHT) List of common AAT phenotypes and simple guide to risk (Note: phenotype reported when testing is on serum, genotype reported when testing is on DNA).

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miss out on opportunities for specialist care and behavioural change, but also to engage with clinical trials that are being conducted at the National Centre of Expertise for AATD at Beaumont Hospital.

The indications for screening for AATD follow World Health Organisation (WHO) and American Thoracic Society/ European Respiratory Society (ATS/ERS) recommendations and these include:  All individuals with COPD/airflow

obstruction (regardless of age/ethnicity/ smoking status).  All individuals with unexplained liver

disease, including neonates and the elderly.  Parents, siblings and children of those

with AATD.  All individuals with asthma and airflow

FIGURE 3: Typical AATD family tree. ZZ (severe AATD), MZ (moderate AATD), and MM (unaffected) phenotypes are shown

obstruction that is incompletely reversed by treatment.

the ‘F (fast)’, ‘S (slow)’ and ‘Z’ AAT variants.

As the SERPINA1 alleles are co-dominant; this can result in a spectrum of phenotypes of AAT protein such as MS (minimal risk), MI, MZ (moderate risk), IS, SS, SZ (moderate risk) and ZZ (severely affected) phenotypes, for example, (Figure 3). It should be noted that extremely rare deficient mutations exist where no detectable AAT protein is produced and these are called ‘null’ or ‘Q0’ mutations. In Ireland, for example, we have discovered two novel null mutations, named Q0dublin and Q0cork.

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 on the island of Ireland (Carroll et al, 2011).

Extrapolating from these frequencies; it is estimated that there are 3,000 patients with ZZ AATD in Ireland and a further 12,000 with SZ AATD. Other less severe phenotype combinations of AATD exist and while these have a lower disease risk; they can be clinically significant in smokers where the risk of COPD is increased (eg, MZ) (Molloy et al, 2014). More information on this can be found at www.alpha1.ie.

symptoms or mild hepatitis, but it is important to recognise that AATD can present to an outpatient clinic or a GP practice with a number of different and interesting clinical manifestations such as panniculitis (erythema nodosum), ANCAassociated vasculitis, cirrhosis, bronchiectasis, and difficult to control asthma. In patients with these conditions, it is worth considering and out-ruling a diagnosis of AATD.

 All individuals with unexplained

bronchiectasis.  All individuals with necrotising

panniculitis.  All individuals with ANCA-associated

vasculitis (granulomatosis with polyangiitis).

A synopsis of these guidelines can be found on the Alpha-1 Foundation Ireland website at www.alpha1.ie.

AATD is very common in Ireland. It is known from prevalence data that approximately one-in-25 carry a Z mutation and onein-10 carry an S mutation on the island of Ireland

Previously conducted research in the RCSI A substantial amount of research has been conducted in the RCSI under Prof Gerry McElvaney in the past 20 years trying to understand the AAT protein and how its deficiency affects our health.

Previous family-based research has investigated to what degree AATD affects those who are not yet symptomatic. A person who is known to have AATD invites their family members to be screened and

To date in Ireland the national targeted detection programme has tested over 20,000 people for AATD. A total 380 patients with ZZ AATD have been identified through

to undergo spirometry in order to assess how AATD affects those who have not yet presented themselves to a doctor for respiratory reasons.

this programme. This means there are

Patients with AATD are classically diagnosed due to family screening, respiratory

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approximately 2,600 people with severe

These family-based studies were carried out

AATD left to be identified. These patients will

in the past with the valuable assistance of a

Respiratory Medicine | Volume 6 | Issue 9 | 2020

large community of participants with MZ

people with SZ AATD as it means their risk of

and SZ AATD. The SZ family study has led to

lung disease is not the same as a more severe

a number of very important findings about

form of the condition.

AATD. Through research carried out with the help of 44 Irish families containing at least

People with the MS phenotype of AATD were

one member with SZ AATD, it was found that

no different to people with two normal copies

SZ never-smokers demonstrated no increased

of AAT (MM). This is reassuring for the large

risk of COPD when compared to their never-

numbers of people who are MS (one-in-10

smoking MM and MS relatives (Figure 4,

in Ireland are MS) as this means there is no

left). This has led to a challenge of the historic

evidence for any increased risk of lung disease

assumption that SZ AATD was a ‘severe’

due to this type. Many of these observations

phenotype and serious enough to require

have been confirmed in other large studies

intravenous AAT replacement therapy.

outside of Ireland.

A history of smoking combines with the SZ

The RCSI is currently leading further research

genotype to significantly increase the severity

projects in Ireland in trying to clarify the

of COPD when compared to ever-smoking

exact risk AATD poses to our population’s

MM and MS relatives (Figure 4, right). This

lung health, given the myriad ways AATD can

means that smoking cigarettes (or long

affect the lungs.

periods of exposure to workplace chemicals, dusts and fumes) is required before significant

The future of AATD research

lung disease will develop.

When a patient is referred to our National Centre of Expertise for AATD, they are given expert advice about their condition and given the opportunity to take part in our AATD registry.

Furthermore, the SZ family study also found that a history of smoking alone is not associated with a greater rate of lung function decline, suggesting that stopping smoking prevents lung disease from getting worse. In real life terms, the knowledge is reassuring for

Involvement in the AATD registry is of particular benefit to patients who attend our

FIGURE 4: (LEFT) Lung function decline (both FEV1% predicted (pp) and FEV1/FVC) in never-smoking SZ AATD (red) compared to neversmoking normal risk MM and MS siblings (green) (RIGHT) Lung function decline in ever-smoking SZ AATD (red) compared to ever-smoking MM/MS siblings (green)

AATD clinic as they can be easily identified for inclusion in clinical trials that are currently being undertaken at RCSI Beaumont Hospital and worldwide.

One phase 2 clinical trial has already been completed in recent weeks in association with Vertex (VX19-814). This trial sought to increase circulating levels of AAT protein with an oral compound so it could act to prevent the damaging effects of NE in the lung.

Another phase 2 clinical trial (VX19-864) of an oral compound will be conducted in Ireland in the coming months and will be recruiting patients with ZZ AATD in the very near future.

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. We have a particular interest in patients with a ZZ AATD phenotype as they may be eligible for inclusion in current and all future trials.

It is hoped that at some point in the near future, a family-based study will be carried out involving patients with ZZ AATD and their siblings in order to establish the degree to which lung disease is present in asymptomatic ZZ AATD individuals. This will be a follow-on study from the MZ and SZ family studies. This new research will help us clarify to what extent people with ZZ AATD have disease before they present themselves to a healthcare professional with symptoms of lung disease. This will allow us to intervene very early in their disease trajectory and likely stave off some of the major complications of severe AATD. Of the 380 patients found to have ZZ AATD, we have currently recruited approximately 220 to our registry. Given the ongoing trials and upcoming family-based studies, we would encourage referral to our outpatient clinic so these patients can be identified more easily for inclusion into clinical trials. Further information can be found on www.alpha1.ie or by emailing us at alpha1@rcsi.ie. 

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Idiopathic pulmonary fibrosis and inhaled drug development AUTHOR: Dr Cian O’Leary, PhD MPSI, RCSI School of Pharmacy and Biomolecular Sciences Idiopathic pulmonary fibrosis (IPF) persists today as a devastating lung disease with a five-year survival of approximately 20 per cent, according to the European Respiratory Society. Although a rare disease in which the exact cause is unknown, its European incidence is near that of brain, stomach, and testicular cancers. For the approximate 200,000 people with IPF across Europe and North America, along with the additional 60,000 newly diagnosed cases annually, there is no current cure, with only two focused antifibrotic therapies available to slow the rate of fibrosis in the alveolar sacs and deterioration of pulmonary function: pirfenidone and nintedanib. These medications have certainly had a positive impact on the treatment of IPF and recent evidence has emerged that both confer a survival benefit, but they are not without their adverse drug reactions. In particular, gastrointestinal side effects such as nausea and diarrhoea can be significantly debilitating and lead to drug discontinuation in one in five patients. Patients can typically only tolerate one of these medications, with limited scope for combination therapy.

Photosensitivity induced by pirfenidone can limit its use for those who are regularly outdoors, while both drugs are subject to drug-drug interactions that can complicate their use in patients with co-morbidities.

Ultimately, additional therapies are needed for more effective clinical management of IPF, particularly when the condition is compared to other chronic respiratory diseases that have a vaster, versatile, armamentarium of therapies to select from.

New developments In answer to this call, many exciting drug candidates in development are advancing through clinical trials and show great promise as new drug classes for IPF management, including the autotaxin inhibitor GLPG1690, the anti-CTGF monoclonal antibody pamrevlumab, and the ROCK inhibitor

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KD025. However, the development of inhaled therapies for IPF remains relatively unpursued.

As observed in the management of conditions like asthma and COPD, inhaled therapy is effective through direct delivery of a lower drug dose to the disease site in the lungs; it also reduces systemic side effects and drug-drug interactions, facilitating combination therapy as part of an improved drug regimen. For IPF, an inhaled medicine could complement the use of oral pirfenidone and/or nintedanib, as well as other therapeutics that emerge from the clinical trial pipeline, to maximise improved patient outcomes. While lesser in number than oral or injectable therapies, several inhaled drug candidates are in the midst of clinical trials, with one of the most advanced in phase 2 trials being GB0139 by the biopharma spinout Galecto Biotech. Indeed, such is inhaled therapies’ potential to improve upon other routes of drug administration that the company Avalyn Pharma is pursuing the launch of inhaled pirfenidone, believing the same drug, delivered more efficiently, can provide better outcomes.

With all this information in mind, the logical question is why are other pharmaceutical companies not considering inhaled drug development? There are likely several factors in play here, but two prominent reasons are regulatory and clinical in nature. From a regulatory perspective, inhaled medicinal products require more extensive specification and characterisation than oral medicines, with consideration for accurate and reproducible specification for the inhaled device’s successful delivery of dose as a major hurdle. Of more concern to healthcare professionals, however, is whether it is feasible for sufferers of IPF with reduced pulmonary function to be able to inhale medicines adequately. The TOPICAL study, published last year, conducted a small trial to answer this question and show that alveolar deposition of drugs from nebulisers and pressurised metred dose inhalers (pMDI)

is possible, encouraging further research into inhaled anti-fibrotic development.

Irish research Within the School of Pharmacy and Biomolecular Sciences at the RCSI, my research group is actively exploring the development of such inhaled anti-fibrotic medicines. Our investigations are two-fold: First, to identify molecules with potential anti-fibrotic activity and to explore the therapeutic potential of these molecules when administered both as a standalone therapy and in combination with the current standard of care (pirfenidone or nintedanib); and second, to translate these molecules into an inhalable dosage form that could feasibly be used in the healthcare setting for the benefit of people with IPF. A key element of our current research programme is that we are repurposing off-patent drugs that have previously been used as oral medications for entirely different conditions, which have the advantage of decades of safety data in patients.

Our research, kindly funded by the Irish Lung Fibrosis Association (ILFA), has begun to show that several of these drugs exhibit anti-fibrotic activity in cells isolated from IPF patients, and that this activity is potentially unique to the drug’s original mechanism of action. Now, by reformulating these drug molecules into inhalables so that lung cells can be directly exposed to them, we are unearthing new possibilities in IPF for safe medicines.

Overall, the future for inhaled medicines in IPF appears bright. Inhaled medicines can improve a patient’s situation by not just providing a new possibility of improving their condition, but also a means to improve quality of life by reducing adverse drug reactions. They are unlikely to be the definitive cure for IPF at present, but as part of a therapeutic regimen, they could provide the clinical management of IPF with a breath of fresh air. 

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 1-3 to their tomorrows 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 Fictional patient, for illustrative purposes only

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

**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

Today. Tomorrow. TRELEGY. 2-3

▼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 corticosteroidrelated 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 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

Find out more here:

www.trelegy.ie or request a visit from a GSK representative

(≥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.

TRELEGY Ellipta was developed in collaboration with ©2020 GSK Group of Companies or its licensor Trademarks are owned by or licensed to the GSK Group of Companies PM-IE-FVU-ADVT-200002 | February 2020

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 1-3 to their tomorrows 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 Fictional patient, for illustrative purposes only

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

**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

Today. Tomorrow. TRELEGY. 2-3

▼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 corticosteroidrelated 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 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

Find out more here:

www.trelegy.ie or request a visit from a GSK representative

(≥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.

TRELEGY Ellipta was developed in collaboration with ©2020 GSK Group of Companies or its licensor Trademarks are owned by or licensed to the GSK Group of Companies PM-IE-FVU-ADVT-200002 | February 2020