Issuu

Volume 11.1

October 2023

Respiratory

Review of

ERS International Congress 2023 Interview

Feature

High-Flow Nasal Cannula Oxygen Therapy in Adult Acute Care: Beyond Clinical Indications and Patient Selection

Luca Bertolaccini shares insights into his career and research in lung cancer surgery

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Contents 4

Editorial Board

Welcome

Foreword

Congress Review Review of the European Respiratory Society (ERS) International Congress 2023, 9th–13th September

Congress Features Managing Spontaneous Pneumothorax and Treating Severe Community-Acquired Pneumonia Robin Stannard

Precision Medicine in Airway Diseases: What Can We Offer in the Clinic? Abigail Craig

Congress Sessions Review Prioritising Patient Outcomes and Reducing Environmental Burden: How Both Are Achievable in Respiratory Care

Symposium Reviews Shaping the Future in Rare Lung Diseases: From Imaging to Patient Management

Breathing New Life Into Acute Respiratory Care: Proactively Improving Long-Term Outcomes

Exploring Type 2 Inflammation in Chronic Obstructive Pulmonary Disease

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Poster Review Efficiency Assessment of 15 Nebuliser Systems by the Respirable Drug Delivery Rate: A Comparable Quality Parameter

Abstract Reviews The Clinical Presentation of Tuberculosis in English Primary Care Kidy and Haroon

Deep Learning-Based Quantification of Traction Bronchiectasis Severity For Predicting Outcome in Idiopathic Pulmonary Fibrosis Felder et al.

79 88 95

Abstract Highlights Interview Luca Bertolaccini

Feature High-Flow Nasal Cannula Oxygen Therapy in Adult Acute Care: Beyond Clinical Indications and Patient Selection Scott and Kaur

Articles Chronic Obstructive Pulmonary Disease: Biofilm Mediated Exacerbation and Innovative Therapeutic Approaches Berger et al.

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Resolution of Resorptive and Compressive Atelectasis without Invasive Manoeuvres: A Case Report Ielo et al.

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Five Segments of the Right Upper Lobe Bronchus on Bronchoscopic Anatomy: A Rare Case Report and Review of Literature Sharma et al.

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Editorial Board Editor-in-Chief Dr Antonio Rossi

IQVIA, Milan, Italy

Editorial Board Dr Martin Balzan

University of Malta, Malta

Dr Catharina Belge

University Hospitals Leuven, Belgium

Prof Dr Jacques Bouchard

Université Laval, Canada

Prof Andrew Bush

Imperial College London, UK

Prof Giorgio Walter Canonica

Humanitas Research Hospital, Italy

Prof Enrico Clini

University of Modena, Italy

Prof Dr Oliver Eickelberg

University of Pittsburgh, USA

Dr Atul Gupta

King's College London, UK

Prof Dr Nicholas Hill

Tufts University School of Medicine, USA

Dr Neil Holden

University of Lincoln, UK

Dr Islam Ibrahim

University of California, USA

Prof Dario Olivieri

University of Parma, Italy

Dr Paraschiva Postolache

Grigore T. Popa University of Medicine and Pharmacy, Romania

Prof Mohammad Azizur Rahman

Dhaka University, Bangladesh

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Aims and Scope EMJ is an online only, peer-reviewed, open access general journal, targeted towards readers in the medical sciences. We aim to make all our articles accessible to readers from any medical discipline. EMJ allows healthcare professionals to stay abreast of key advances and opinions across Europe. EMJ aims to support healthcare professionals in continuously developing their knowledge, effectiveness, and productivity. The editorial policy is designed to encourage discussion among this peer group. EMJ is published quarterly and comprises review articles, case reports, practice guides, theoretical discussions, and original research. EMJ also publishes 18 therapeutic area journals, which provide concise coverage of salient developments at the leading European congresses. These are published annually, approximately 6 weeks after the relevant congress. Further details can be found on our website: www.emjreviews.com Editorial Expertise EMJ is supported by various levels of expertise: • • • •

Guidance from an Editorial Board consisting of leading authorities from a wide variety of disciplines. Invited contributors are recognised authorities from their respective fields. Peer review, which is conducted by EMJ’s Peer Review Panel as well as other experts appointed due to their knowledge of a specific topic. An experienced team of editors and technical editors.

Peer Review On submission, all articles are assessed by the editorial team to determine their suitability for the journal and appropriateness for peer review. Editorial staff, following consultation with either a member of the Editorial Board or the author(s) if necessary, identify three appropriate reviewers, who are selected based on their specialist knowledge in the relevant area. All peer review is double blind. Following review, papers are either accepted without modification, returned to the author(s) to incorporate required changes, or rejected. Editorial staff have final discretion over any proposed amendments. Submissions We welcome contributions from professionals, consultants, academics, and industry leaders on relevant and topical subjects. We seek papers with the most current, interesting, and relevant information in each therapeutic area and accept original research, review articles, case reports, and features.

We are always keen to hear from healthcare professionals wishing to discuss potential submissions, please email: editorial.assistant@emjreviews.com To submit a paper, use our online submission site: www.editorialmanager.com/e-m-j Submission details can be found through our website: www.emjreviews.com/contributors/authors Reprints All articles included in EMJ are available as reprints (minimum order 1,000). Please contact hello@emjreviews.com if you would like to order reprints. Distribution and Readership EMJ is distributed through controlled circulation to healthcare professionals in the relevant fields across Europe. Indexing and Availability EMJ is indexed on DOAJ, the Royal Society of Medicine, and Google Scholar®; selected articles are indexed in PubMed Central®. EMJ is available through the websites of our leading partners and collaborating societies. EMJ journals are all available via our website: www.emjreviews.com Open Access This is an open-access journal in accordance with the Creative Commons Attribution-Non Commercial 4.0 (CC BY-NC 4.0) license. Congress Notice Staff members attend medical congresses as reporters when required. This Publication ISSN 2054-3166 EMJ Respiratory is published once a year. For subscription details please visit: www.emjreviews.com All information obtained by EMJ and each of the contributions from various sources is as current and accurate as possible. However, due to human or mechanical errors, EMJ and the contributors cannot guarantee the accuracy, adequacy, or completeness of any information, and cannot be held responsible for any errors or omissions. EMJ is completely independent of the review event (ERS 2023) and the use of the organisations does not constitute endorsement or media partnership in any form whatsoever. Front cover and contents photograph: Milan, Italy home of the ERS 2023 © Ivan Floriani / stock.adobe.com

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Welcome letter Editor Evgenia Koutsouki Editorial Manager Anaya Malik Copy Editors Noémie Fouarge Kirsty Hewitt, Jaki Smith

Evgenia Koutsouki

Editorial Co-ordinators Natasha Meunier-McVey, Robin Stannard Editorial Assistants Victoria Antoniou, Abigail Craig, Evan Kimber, Darcy Richards Head of Publishing Operations Tian Mullarkey Design Manager Stacey Rivers Senior Designer Roy Ikoroha Designer Steven Paul Junior Designers Dillon Benn Grove, Shanjok Gurung Head of Sales Robert Hancox Business Unit Leader Billy Nicholson Director of Performance Keith Moule Chief Operating Officer Dan Scott Chief Commercial Officer Dan Healy Founder and Chief Executive Officer Spencer Gore

Editor Dear Readers, Welcome to the 2023 issue of EMJ Respiratory, bringing you highlights from the European Respiratory Society (ERS) International Congress 2023. A prevailing theme in the congress was the correlation between respiratory problems and the environment, which will undoubtedly dominate the research agenda for the foreseeable future. The congress hosted a plethora of sessions. Among the findings presented was a study demonstrating the positive association between improved walking distance with survival after pulmonary rehabilitation, as well as the sustainability of virtual wards in respiratory medicine, which you can read about in our abstract highlights section. Among our congress content, you can find the review of a congress session that focused on the first European guidelines for the management of primary spontaneous pneumothorax. The session covered new recommended approaches to acute pneumothorax, the optimal management of persistent air leak, and analysed the evidence for the changing use of co-adjuvants in severe community-acquired pneumonia. We also spotlight a session on precision medicine in airway diseases, which discussed the value of ‘omics’, and the identification of treatable traits in improving patient care. We are proud to feature an article highlighting important clinical and technical considerations for high-flow nasal cannula oxygen therapy. You will also find a review exploring innovative approaches to the inhibition and eradication of biofilms in chronic obstructive pulmonary disease. I would like to take this opportunity to thank our Editorial Board, peer reviewers, and contributors for another excellent issue. We look forward to next year’s congress and, of course, to the publication of our sister journal, Respiratory The American Medical Journal, covering the American Thoracic Society Congress, in 2024!

Contact us Editorial enquiries: editor@emjreviews.com Sales opportunities: salesadmin@emjreviews.com Permissions and copyright: accountsreceivable@emjreviews.com Creative Commons Attribution-Non Commercial 4.0

Reprints: info@emjreviews.com Media enquiries: marketing@emjreviews.com

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ALPHA 1 ANTITRYPSIN DEFICIENCY (AATD) THERAPIES.

THEY ARE NOT ALL THE SAME. 4 g and 5 g vials available with administration set*

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The first and only AAT therapy proving disease modification (RAPID trial)1,2 Early treatment option regardless of FEV1 percentage3 Well tolerated2 and high purity4,# Short infusion time (~ 15 min) and low volume3,5,6,# Innovative MyAlpha1™ self-administration programme empowers HCPs and patients**

* Available in select markets only. ** MyAlpha1™ is available in select markets, please request further information from our respective local affiliate. # Compared to Prolastin® and Alfalastin®. Alfalastin® is only approved in France.6 Prolastin® is a registered trademark of Grifols Therapeutics Inc. and is registered in multiple jurisdictions. Alfalastin® is a registered trademark in France of LABORATOIRE FRANCAIS DU FRACTIONNEMENT ET DES BIOTECHNOLOGIES, S.A.

CMD-RPZ-0181

References: 1. Chorostowska-Wynimko J. Disease Modification in Emphysema Related to Alpha-1 Antitrypsin Deficiency, COPD: Journal of Chronic Obstructive Pulmonary Disease. 2016;13(6):807– 815; doi: 10.1080/15412555.2016.1178224. 2. Chapman KR, Burdon JGW, Piitulainen E, et al; Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;386(9991):360 – 368; doi: 10.1016/S01406736(15)60860 – 1 3. Respreeza® SPC, May 2020 4. Boerema DJ, An B, Gandhi RP, et al.; Biochemical comparison of four commercially available human α1-proteinase inhibitors for treatment of α1-antitrypsin deficiency. Biologicals. 2017;50:63 –72. doi: 10.1016/j.biologicals.2017.08.010. 5. Prolastin® SPC, March 2021, Licence_PA1405-002-001_17112021131149.pdf (hpra.ie) 6. Alfalastin® SPC, May 2021, http://agence-prd.ansm.sante.fr/php/ecodex/extrait.php?specid=60153239 RESPREEZA®. 1,000, 4,000 or 5,000 mg powder and solvent for solution for infusion. Qualitative and quantitative composition: Highly purified, lyophilized human plasma A1-PI concentrate. 1,000, 4,000 or 5,000 mg, respectively, of A1-PI per vial. Purity ≥90% A1-PI. After reconstitution with sterile water for injections: 50 mg/ml of A1-PI. Other ingredients: sodium chloride, sodium dihydrogen phosphate monohydrate, mannitol. No preservatives. Therapeutic indications: Maintenance treatment in adults with severe A1-PI deficiency and clinical evidence of emphysema. Not indicated as therapy for lung disease patients in whom severe A1-PI deficiency has not been established. Contraindications: History of anaphylaxis or severe systemic reactions to the active substance/excipients. In IgA-deficient patients with antibodies against IgA due to the risk of severe hypersensitivity. Special warnings and precautions for use: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Recommended infusion rate is to be followed. Hypersensitivity/Anaphylaxis: Caution in patients with known allergies to an A1-PI product. Patients with selective or severe IgA deficiency can develop antibodies to IgA and have a greater risk of developing potentially severe hypersensitivity/anaphylactic reactions. Suspected allergic or anaphylactic type reactions may require immediate discontinuation of the infusion. In case of shock, emergency medical treatment to be administered. Transmissible agents: the possibility of transmitting infective agents cannot be excluded. The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) and for the non-enveloped hepatitis A (HAV) and parvovirus B19 virus. Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeated receipt of Please always refer to your national SPC.

Respreeza. Respreeza contains approximately 1.9 mg (<1 mmol) sodium per ml of reconstituted solution. That should be taken into consideration for patients on a controlled sodium diet. Interactions: Not known. Fertility, pregnancy and lactation: A1-PI is an endogenous human protein and it is considered unlikely that Respreeza will cause harm to the foetus/neonate when given at recommended doses to mothers. However, Respreeza should be given with caution to pregnant/lactating women. Effects on ability to drive and use machines: Minor influence on the ability to drive and use machines (e.g. dizziness may occur). Undesirable effects: Blood and lymphatic system disorders. Unknown: Lymph node pain. Immune system disorders. Uncommon: Hypersensitivity reactions (including tachycardia, hypotension, confusion, syncope, oxygen consumption decreased and pharyngeal oedema); Very rare: Anaphylactic reactions. Nervous system disorders. Common: Dizziness, headache; Uncommon: Paraesthesia; Very rare: Hypoaesthesia. Eye disorders. Unknown: Eye swelling. Vascular disorders. Uncommon: Flushing. Respiratory, thoracic and mediastinal disorders. Common: Dyspnoea. Gastrointestinal disorders. Common: Nausea; Not known: Lip swelling. Skin and subcutaneous tissue disorders. Uncommon: Urticaria, rash (including exfoliative and generalized); Very rare: Hyperhidrosis, pruritus; Not known: Face swelling. General disorders and administration site conditions. Uncommon: Asthenia, infusion-site reactions (including infusion site hematoma); Very rare: Chest pain, chills, pyrexia. Overdose: Consequences of overdose are unknown. In the event of overdose, the patient should be observed closely for the occurrence of adverse reactions and supportive measures should be available as necessary. Prescription status: Prescription-only drug. Manufacturer: CSL Behring GmbH, Emil-von-Behring-Strasse 76, D-35041 Marburg, Germany. Date of information: May 2020. CSL Behring GmbH, Emil-von-Behring-Strasse 76, 35041 Marburg, Germany

Foreword Dear Colleagues, It is my pleasure to introduce the latest issue of EMJ Respiratory. In this edition, you will find peer-reviewed articles alongside a review of the European Respiratory Society (ERS) International Congress 2023, which took place in Milan, Italy, between the 9th–13th September. The hybrid event saw experts from around the globe come together to present research findings and key updates across a variety of disciplines within respiratory medicine. The theme for this year’s congress was pollution, climate change, and sustainable developments, with the programme including several sessions on these topics. Moreover, Zorana Jovanovic Andersen, Professor at the University of Copenhagen, Denmark, and Chair of the ERS Environment and Health Committee, poignantly delivered the ERS statement on the results of the European Parliament vote on revision of the Ambient Air Quality Directive. In addition to climate change, other key topics highlighted by ERS’ leadership included digital innovation and precision medicine, as well as the Sadoul Lecture series, which focused on lung infection and host responses. In keeping with these topics, an interesting and pertinent

article by Loewy et al., reviewing biofilmmediated exacerbations of chronic obstructive pulmonary disease, and how innovations in microbial quorum sensing may help determine new therapeutic targets for its management, is included in this issue. Furthermore, our congress review includes coverage of a well-attended and engaging session on precision medicine in airways disease. Additionally, you can find an insightful feature article discussing the use of high flow nasal cannula O2 therapy in acute respiratory failure, which covers a range of factors, including the clinical applications, flow settings, aerosol delivery, and physiological effects of this therapy. This issue also features an interview with Luca Bertolaccini, Department of Thoracic Surgery, IEO, European Institute of Oncology IRCCS, Milan, Italy, which explores the field of lung cancer surgery, as well as up-to-date research from abstracts presented at the Congress. I would like to take this opportunity to thank all of those who have contributed to this issue, including all the authors, peer reviewers, interviewees, and Editorial Board. I hope you enjoy reading this journal.

Antonio Rossi Senior Medical Director, Oncology Center of Excellence, Therapeutic Science & Strategy Unit, IQVIA, Milan, Italy

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ERS 2023 Review of the European Respiratory Society (ERS) International Congress 2023

Location:

Milan, Italy

Date:

9th–13th September 2023

Citation:

EMJ Respir. 2023;11[1]:10-21. DOI/10.33590/emjrespir/10304133. https://doi.org/10.33590/emjrespir/10304133.

Milan, Italy, best known for its fashion week and football team, was home to the European Respiratory Society (ERS) International Congress 2023 between 9th–13th September 2023. This year’s congress kicked off with a live performance of jazz, and with the Congress Chairs 2023, Marisa Bonsignore and Sergio Harari, welcoming the attendees to the hybrid congress. After 3 years without an opening ceremony, Bonsignore expressed her pleasure to be with the attendees at the beginning of the congress. Harari continued by listing the wonderful work that Milan has done, and will do, to help the environment. The city is currently reforesting, with plans to plant more than 3 million trees by 2030. These efforts are all to keep air pollution down, which was one of the main themes of the congress, along with climate change and sustainable development. Bonsignore continued by stating that the congress will look at environmental issues related to respiratory problems, and she awarded Francesco Forastiere, Imperial College London, UK, the ERS Congress Chair Award, for his dedication in studying the effects of air pollution on the respiratory system.

ERS President, Carlos Robalo Cordeiro, was then welcomed to the stage, where he expressed his solidarity with the Moroccan people after being hit by a terrible earthquake.

"Welcome back to an opening session of the ERS International Congress." “Welcome back to an opening session of the ERS International Congress,” Cordeiro said, before stating his pleasure at sharing the ERS’s ongoing initiatives, as well as their new commitment to reducing their emissions, and being in line with the United Nation’s (UN) Sustainable Development Goals. Cordeiro emphasised the congress themes, and how, along with the charity myclimate, the ERS have identified means to offset congress CO2 emissions by 425,000 tonnes. After the pandemic, the ERS have updated their strategy by anticipating the future, evaluating performance, identifying areas of improvement, and refining the vision and purpose of the ERS. Cordeiro encouraged the audience to attend the ERS Congress 2024 in Vienna, Austria, where updates will be presented.

"Bonsignore continued by stating that the congress will look at environmental issues related to respiratory problems."

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A special video message from Tedros Adhanom Ghebreyesus, Director-General of the World Health Organization (WHO), emphasised the importance of prevention by improving living conditions, reducing exposure to excessive air pollution, reducing tobacco use, and improving the climate crisis; treatment for those who need it most, including migrants and lowincome countries; and filling knowledge gaps for respiratory disease. Ghebreyesus ended by thanking the ERS for their partnership and commitment for a healthier, safer, and fairer world. This year’s congress welcomed more than 20,000 people, in-person and online, who could attend a total of 11,272 sessions. Of these, 4,590 were abstracts, with 2,059 presentations and 4,067 e-Posters. Along with Forastiere, a number of other respiratory specialists received awards, including Athol Wells, Imperial College London and Royal Brompton Hospital, both in London, UK, who received the ERS Presidential Award for his contribution to respiratory medicine in interstitial lung diseases and idiopathic pulmonary fibrosis. Those who achieved the ERS Mid-Career Gold Medal include Bianca Schaub, University Children’s Hospital, Ludwig Maxmilian University (LMU) of Munich, Germany; Martijn Nawijn, University of Groningen Medical Center

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(UMCG), the Netherlands; Imran Satia, McMaster University and Firestone Institute for Respiratory Health (FIRH), both in Hamilton, Canada; Danny Eckert, Flinders University, Adelaide, Australia; Chin-Chung Shu, National Taiwan University Hospital, Taiwan; and Merel Hellemons, Erasmus University Medical Center (MC), Rotterdam, the Netherlands. The ERS Educational Award was given to Felix Herth, Thoraxklinik, University of Heidelberg, Germany, while the ERS Sadoul Lecture Award went to Tobias Welte, Hannover Medical School, Germany. ERS Teaching Awards were presented to Marieke Duiverman, UMCG, the Netherlands; Najib Rahman, Nuffield Department of Medicine, University of Oxford, UK; and Nicole Beydon, University Hospital Armand Trousseau, Paris, France. Finally, ERS Lifetime Achievement Awards were bestowed to Heather Joy Zar, Red Cross Childrens Hospital, University of Cape Town, South Africa; Martijn A. Spruit, Maastricht University, the Netherlands; Joanna Pepke-Zaba, Royal Papworth Hospital, Cambridge, UK; and Stefano Gasparini, Università Politecnica delle Marche Medical School, Ancona, Italy. Next year’s congress will be held in Vienna, Austria, from 7th–11th September. Until then, enjoy our key insights from the ERS International Congress 2023. ●

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Air Pollution Linked to Lower Birthweight PREGNANT females who are exposed to air pollution give birth to smaller babies, but living in a greener area may counteract these effects. This research was presented by Robin Mzati Sinsamala, University of Bergen, Norway, at the ERS International Congress 2023. Birthweight is strongly associated with lung health, as low birthweight increases risk of asthma and chronic obstructive pulmonary disease as children grow older.

Results showed that higher air pollution levels were associated with lower birthweight. This effect was reduced when taking greenness into account. Researchers further noted that mothers from greener areas had babies with a higher birthweight, compared with those living in less green areas. Sinsamala explained that this could be due to lower amounts of traffic, plants that clear the air of pollution, or higher amounts of physical activity in greener areas.

The study is part of a wider research programme investigating the effects of air pollution and greenness on lung health in generations of Europeans over the long-term. The team analysed data from the RHINE study, including 4,286 children from five European countries. Greenness of the area people lived in during pregnancy was gauged through satellite images and density of vegetation, including forests, farmlands, and parks. They further collected data on five pollutants, and compared this information with birthweight. Factors that can affect birthweight, such as mother’s age, smoking, or other health conditions, were taken into account.

ERS Advocacy Council Chair Arzu Yorgancioğlu, who was not involved in the research, stated: “This study adds to a growing body of evidence on the damage that air pollution is having on our health, especially in vulnerable babies and young children. Women who are pregnant will want to protect their babies from potential harm. However, as individuals, it can be difficult to reduce our exposure to air pollution or make our neighbourhoods greener.” They further stressed the importance of putting pressure on governments and policy-makers to lower air pollution levels. ●

"This could be due to lower amounts of traffic, plants that clear the air of pollution, or higher amounts of physical activity in greener areas."

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Using Phlegm Colour to Predict Prognosis in Patients with Bronchiectasis NEW research presented at the ERS International Congress 2023 suggests that the colour of phlegm amongst patients with the lung disease bronchiectasis has the potential to be used in order to predict future outcomes, as well as monitor symptoms of the disease. One of the most prevalent chronic inflammatory airway diseases, bronchiectasis, has no known cure. The condition is caused by a widening of the bronchi, leading to a build-up of mucus, and making the lungs more susceptible to infection. The disease affects between 67 to 566 per 100,000 individuals of all ages in Europe and North America. One of the most common symptoms is a productive cough, with the majority of patients producing phlegm (also known as sputum), which can be classified into four increasingly severe categories: mucoid, mucopurulent, purulent, and severe purulent. Presented at ERS by Megan Crichton, postdoctoral researcher at the University of Dundee, UK, this study involved 19,324 patients with bronchiectasis from 31 countries around the world. Of this group, 13,484 patients coughed up sputum regularly, the colour of which was monitored by Crichton and colleagues, with follow-ups for 5 years in order to track the

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number of exacerbations they had, their severity, and the mortality rates. Crichton reported that when patients developed chest infections, their sputum colour would darken as a result of the inflamed cells releasing the protein myeloperoxidase, meaning that sputum colour can be used to indicate inflammation. Additionally, Crichton reported an increased risk of exacerbations, hospitalisations, and death with more purulent sputum. It was found that for each one-point increase in sputum purulence, there was a 12% increase in the risk of death.

"One of the most prevalent chronic inflammatory airway diseases, bronchiectasis, has no known cure." Crichton and colleagues concluded that their research, conducted with a large sample size over a period of time, shows that sputum colour is able to reflect prognosis. Analysing sputum colour proves a non-invasive, easy-to-interpret method for monitoring disease progression, simplifying management of bronchiectasis for clinicians and patients alike. ●

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Healthy Diverse Guts Linked with Less Wheezing and Asthma INFANTS with more mature communities of bacteria in their gut are less likely to develop allergy-related wheezing and asthma, according to research presented at the ERS International Congress in Milan, Italy. The microbiota under scrutiny, developing during the early years of life, are largely comprised of bacteria acquired from the mother when first born. With age and exposure to different sources, the diversity of this microbiota increases and matures. Yuan Gao, Deakin University, Australia, who presented this study, stated: “We then hypothesised that advanced maturation of the infant gut microbiota in early life is associated with decreased risk of allergy-related wheeze in later childhood.” She went on to explain: “A more mature infant gut microbiota at 1 year of age was associated with a lower chance of developing food allergies and asthma in childhood.” The current research was conducted using the Barwon Infant Study (BIS), running in Australia since 2010, including 1,074 babies who were recruited between 2010–2013. Following the infants, Gao and colleagues analysed the bacteria in faecal samples collected 1 month, 6 months, and 1 year after birth. Postnatal reviews were conducted at 1 year and 4 years, whereby parents were asked to report on whether their children had developed allergy-related wheeze or asthma in the last 12 months. Skin-prick tests were also conducted to see if children had allergic reactions to any of 10 foods or airborne substances, such as rye grass or dust. A randomly selected subgroup of 323 children were subject to DNA sequencing in order to identify and characterise gut microbiota, in the form of calculating ‘microbiota-by-age z-score'

(MAZ), a mathematical estimate of the maturity of children’s gut microbiota. Gao highlighted: “We found that if babies had more mature gut microbiota when they were 1 year old, they were less likely to have an allergy-related wheeze at 1 and 4 years old,” and, “in other words, the more mature the gut microbiota, the less likely were the children to have allergy-related wheeze.” In explanation of the mechanism by which mature gut microbiota contribute to this, she said: “Given the complex origins and development of both gut microbiota and the infant immune system, it is likely that the protective effect of a healthy gut microbiota occurs as a result of communities of bacteria acting in multiple different ways, rather than via one particular mechanism.”

"The more mature the gut microbiota, the less likely were the children to have allergy-related wheeze."

A limitation to the study includes the inability of the DNA methods used to characterise the gut microbiota in providing insights into the function of the bacteria. Researchers are planning to recruit 2,000 children in Australia and New Zealand in an upcoming clinical trial, ARROW, in order to take this work further. This will study if giving children a mixture of dead bacteria orally can protect them from wheezing illness or asthma by boosting healthy immune response to viral infections, the most common cause of childhood illness. ●

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Obstructive Sleep Apnoea Treatment Prevents Heart Disease Deaths INDIVIDUALS with obstructive sleep apnoea (OSA) can reduce their cardiovascular disease mortality risk by using a continuous positive airway pressure (CPAP) machine during sleep, as indicated by research unveiled at the ERS International Congress 2023 in Milan, Italy. CPAP machines are prescribed to individuals with OSA to improve their sleep quality. These devices function by delivering a continuous stream of air through a facial mask, preventing the airways from collapsing during sleep. Nonetheless, research investigating the impact of CPAP therapy on cardiovascular disease has yielded inconsistent findings. Jordi de Batlle, Institut de Recerca Biomèdica de Lleida (IRBLleida), Spain, and colleagues, conducted a study involving 3,638 patients with OSA in Catalonia who ceased using CPAP in 2011. This group was compared with a parallel cohort of 3,638 patients with OSA who

persisted with CPAP treatment until at least 2015 or until their death. When comparing the two groups, it was revealed that individuals who adhered to CPAP treatment experienced a 40% reduced risk of mortality from any cause, a 36% diminished risk of cardiovascular disease-related mortality, and an 18% lower likelihood of being hospitalised due to cardiovascular disease. De Batlle noted that their findings imply that CPAP treatment can be highly beneficial for the majority of patients with OSA by preventing cardiovascular issues like heart disease and strokes. This is particularly advantageous given that CPAP treatment already provides substantial benefits for most patients with OSA by reducing daytime sleepiness, and enhancing their overall quality of life. Consequently, these results underscore the importance of encouraging individuals with OSA to continue using their CPAP machines. ●

"It was revealed that individuals who adhered to CPAP treatment experienced a 40% reduced risk of mortality from any cause."

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Could Progenitor Cell Transplantation Cure Chronic Obstructive Pulmonary Disease? AUTOLOGOUS P63+ lung progenitor cells show potential in repairing damaged lung tissue in patients with chronic obstructive pulmonary disease (COPD), according to the results of a Phase I trial funded by Regend Therapeutics Ltd, China, presented at the ERS International Congress 2023, in Milan, Italy. Wei Zuo, School of Medicine, Tongji University, Shanghai, China, and Chief Scientist, Regend Therapeutics Ltd, China, and colleagues, collected P63+ lung progenitor cells from the airways of patients with COPD, cloned these in the laboratory, and then used bronchoscopy to transplant the cells back into the corresponding patient lungs. The study included 20 patients, 17 of whom received the autologous P63+ lung progenitor transplant, with the remaining three patients comprising the control group. Zuo reported that 35% of the patients had severe COPD, and 53% had extremely severe COPD. Patients were followed up for 24 weeks to assess treatment tolerance and efficacy. The authors reported that the treatment was well tolerated by all patients, and that after 12 weeks, median diffusing capacity of the lung increased from 30.0% to 39.7% in the treatment group.

By 24 weeks, median diffusing capacity of the lung had increased to 40.3%. Two patients with mild emphysema displayed repair of damaged lung tissue following treatment. The researchers also measured the 6-minute walk distance test (6MWD) at baseline and at 24 weeks, and found that the median distance covered during the 6MWD increased from 410 m to 447 m. Furthermore, scores for the St George’s Respiratory Questionnaire (SGRQ), used to assess quality of life, reduced by seven points in the treatment group, indicative of improved quality of life following treatment. Zuo stated that P63+ progenitor cell transplantation “not only improved the lung function of patients with COPD, but also relieved their symptoms, such as shortness of breath, loss of exercise ability, and persistent coughing.” A noted limitation of the study is that transplanted progenitor cell uptake is uncontrolled. There is hope that further studies will provide clarity on this. Looking towards the future, the researchers are planning a Phase II trial to evaluate efficacy of the treatment in a larger cohort, which has been approved by China’s National Medicinal Products Administration (NMPA). ●

"After 12 weeks, median diffusing capacity of the lung increased from 30.0% to 39.7% in the treatment group."

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Exposure to Air Pollution During Pregnancy Linked with Changes to Cell Processes in Newborns ALTERATIONS in proteins have been detected in babies with mothers exposed to air pollution during pregnancy. Cell processes, such as autophagy, are affected by these changes, and a study investigated the different responses babies encountered based on their mothers’ exposure, with results presented at the ERS International Congress 2023 in Milan, Italy. Olga Gorlanova, University of Basel, Switzerland, led this research to build on a previous study analysing air pollution in pregnancy and how this affects lung function and the immune system in newborns. Healthy newborn babies had individual and different responses to their mothers’ exposure to air pollution during pregnancy, which could mean some babies were more vulnerable than others. In total, 11 proteins were measured in the cord blood of 449 healthy babies, specifically documenting the proteins involved in autophagy, ageing, and cell remodelling to see how prenatal exposure to air pollution affects these processes. The current study involved measuring the mothers’ exposure to nitrogen dioxide (NO2), and tiny particles of particulate matter (PM10) measuring 10 microns or less in diameter. Vehicle emissions, tyre and brake wear, and smoke are among these pollutants. NO2 and PM10 were both linked to changes in proteins involved in autophagy, with exposure to NO2 linked with decreased activity of the proteins SIRT1 and IL-8, and increased levels of the Beclin-1 protein. Gorlanova described the findings: “Our results

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indicate that NO2, a pollutant formed mainly from traffic emissions, is associated with increased levels of Beclin-1 protein, which is central to initiating autophagy. Exposure to higher NO2 was also linked to decreased levels of SIRT1, which is a protein that plays a protective role in stress resistance, inflammation, and ageing. IL-8 is a protein active in certain inflammatory cells.”

"Our findings suggest that healthy newborns have an individual response pattern to air pollution." “Our work adds to the growing body of evidence that autophagy-related mechanisms may be involved in how human cells react to air pollution. The findings are consistent with evidence from tissue and animal research. Further exploration of these mechanisms may help to better understand the deleterious effects of pollution on infants,” was how Gorlanova hinted at the usefulness of this study. Next steps in this field will involve examining whether babies with distinct protein response patterns to air pollution will suffer from more breathing problems during infancy and childhood, compared to those who do not show the same protein responses. Gorlanova summarised this research: “Our findings suggest that healthy newborns have an individual response pattern to air pollution. We think that this may be an indication that some babies are more vulnerable to it than others.” ●

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Smoking-Induced Leucocyte Telomere Shortening Accelerates Ageing RESULTS from a retrospective study presented at the ERS International Congress 2023 in Milan, Italy, spotlighted an association between smoking and reduction in leucocyte telomere length. Siyu Dai, School of Clinical Medicine, Hangzhou Normal University, China, and Department of Paediatrics, The Chinese University of Hong Kong, Hong Kong; and Feng Chen, The Chinese University, Hong Kong, analysed the genetic and health information of 472,174 UK Biobank participants to determine smoking status (current smoker, previous smoker, and never smoked); level of addiction to smoking cigarettes; pack year history; and leucocyte telomere length. Mendelian randomisation across 113 single nucleotide polymorphisms related to smoking status (15 for current smokers, 20 for previous smokers, and 78 for never smokers) was applied to investigate if a causal link between smoking and leucocyte telomere shortening could be inferred. The analysis found smoking status was significantly associated with shorter leucocyte telomere length. Despite a trend towards shorter leucocyte telomere length in ex-smokers, the association was not found to be statistically significant. Additonally, participants who had

never smoked did not show significantly shorter leucocyte telomere length.

"Smoking status was significantly associated with shorter leucocyte telomere length." The findings show that smoking may cause leucocyte telomere shortening, with a doseresponse effect. Dai stated: “Our study shows that smoking status and cigarette quantity can result in the shortening of leucocyte telomere length, which is an indicator of tissue selfrepair, regeneration, and ageing. In other words, smoking can accelerate the process of ageing, while quitting may considerably decrease the related risk.” In addition to this, Dai advocated that smoking cessation support and treatment should be included into daily clinical practice to help create a “smoke-free environment for the next generation.” With this in mind, Dai and Chen hope to not only conduct further research to validate the findings from this study, but also investigate the effects of passive smoking on tissue self-repair, regeneration, and ageing. ●

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City Living and the Risk of Respiratory Infections in Babies and Young Children RESULTS from a study presented at the ERS International Congress 2023 in Milan, Italy, suggest that young children growing up in towns and cities experience more respiratory infections than those growing up in the countryside. Further research presented at the congress suggests factors such as attending daycare, and living in a damp home or near dense traffic, increase the risk of chest infections in young children. Meanwhile, breastfeeding has been shown to reduce this risk. The first study, presented by Nicklas Brustad, University of Copenhagen, Denmark, included 663 children and their mothers. Participants were investigated from pregnancy until the children were 3 years old. Children living in an urban area had an average of 17 respiratory infections before the age of 3 years, compared with an average of 15 for those living in rural areas. Furthermore, children living in urban areas had differences in their immune systems compared with those living in rural areas. Brustad said: “Our findings suggest that urban living is an independent risk factor for developing infections in early life when taking account of several related factors, such as exposure to air pollution and starting day care.”

The second study, presented by Tom Ruffles from University Hospitals Sussex NHS Foundation Trust, Brighton, UK, included data from 1,344 mothers and their children living in Scotland and England. Questionnaires were completed when the children were 1 year and again when they were 2 years old. Breastfeeding for longer than 6 months helped protect babies and children from infections, while attending daycare increased the risk. Furthermore, children living in homes with visible damp were twice as likely to need treatment with an inhaler and twice as likely to require a steroid inhaler. Finally, living in an area of dense traffic increased the risk of chest infections. Ruffles said: “This research provides some important evidence about how we can help reduce chest infections in babies and toddlers. The benefits of breastfeeding are wellestablished, and we should continue to support mothers who want to breastfeed their babies.” Overall, these studies highlight the importance of understanding factors that can contribute to respiratory conditions in children, especially those related to where they live and are cared for. It is crucial to protect the developing lungs of young children. ●

"It is crucial to protect the developing lungs of young children."

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Dust Microbiota in Daycare Linked to Wheezing in Early Childhood BACTERIA present in dust at daycares are associated with wheezing in young children, which is an early sign of asthma. This is according to data presented at the ERS International Congress 2023 by Annabelle Bédard, from the French National Institute of Health and Medical Research, Paris, France. Bédard stated: “We find mixtures of different bacteria and other microbes living everywhere: outside, inside our homes, on our skin, and even inside our bodies. These communities of bacteria, known as microbiota, can have beneficial or harmful effects on our health.” This research sheds light on why children’s lung health could be affected by daycare, and may help the search for ways to lower the risk of asthma. The team collected samples of dust found on the floor of 103 daycare settings using an adapted vacuum cleaner. They then identified the bacteria found in the samples using 168 rRNA gene sequencing. Parents of 515 children attending these facilities were also asked whether the child showed respiratory symptoms, including wheezing. In total, 29% reported wheezing. Researchers identified four broad categories of microbiota: Streptococcus, Neisseria, Haemophilus and Prevotella; Streptococcus and Lactococcus; mixed with rare; and Lactococcusdominant. The second profile was associated with a higher risk of wheezing; however, no association was found in the other categories. The team concluded that there is an association between composition of dust microbiota in daycare and risk of wheezing in early childhood. The team’s next step will be to try to understand factors that influence the dust microbiota, in order to determine how to improve conditions, and prevent chronic respiratory diseases. They will also continue their research with the children to determine whether they develop asthma in later childhood. ●

"These communities of bacteria, known as microbiota, can have beneficial or harmful effects on our health.”

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Managing Spontaneous Pneumothorax and Treating Severe Community-Acquired Pneumonia Authors:

Robin Stannard, EMJ, London, UK

Citation:

EMJ Respir. 2023;11[1]:22-24. DOI/10.33590/emjrespir/10308211. https://doi.org/10.33590/emjrespir/10308211.

THE FIRST European guidelines for the management of primary spontaneous pneumothorax (PSP) were presented in a symposium session delivered at the European Respiratory Society (ERS) International Congress 2023 on the 9th–13th of September in Milan, Italy. The novel guidelines covered new recommended approaches to acute pneumothorax, optimal management of persistent air leak (PAL), and analysed the evidence for the changing use of co-adjuvants in severe community-acquired pneumonia (SCAP).

MEDICAL MANAGEMENT OF PNEUMOTHORAX Steven Walker, University of Bristol, UK, delivered the first session, where he introduced and detailed the inaugural European guidelines on the management of spontaneous pneumothorax. The guidelines include recommendations for the optimal management of both acute pneumothorax and PAL, focusing on optimal practice for recurrence prevention. The novel guidelines, which will be published later this year, were created by 25 world-leading experts who devised 12 clinical questions to be answered. Literature reviews, meta-analyses, and research studies were analysed, and then graded against a process of evidence decision frameworks, providing 12 recommendations in response to the 12 clinical questions.

Acute Presentation of Pneumothorax

Walker presented the guidelines on acute pneumothorax by introducing the audience to a patient case study. The patient was a 23-year-old, who had been short of breath for 2 days, with no signs of cardiac compromise, comfortably mobile, and with no medical history of pneumothorax. Chest X-ray showed a large

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right-side pneumothorax. Walker provided the audience with four options for patient management analysed by population of interest, intervention, comparator (standard of care [SoC]), and outcomes (clinical and patientrelated). The interventions were compared against the current SoC for acute pneumothorax, which is a chest drain.

"This newly developed decision aid weighs up the different options for acute PSP management." The first intervention was conservative management, an observational approach that allows the lung to inflate by itself. Analysis of literature reviews found that, compared with SoC, this approach was associated with a shorter length of hospital stay (4.5 days fewer), a lower rate of recurrence (81 fewer per 1,000), and fewer further procedures (152 fewer per 1,000). Based on this evidence, the new guidelines recommend conservative management for PSP in select cases, regardless of pneumothorax size, where there is minimal breathlessness, and clinical and radiological stability.

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Needle aspiration was the most robustly studied intervention, with six randomised controlled trials. Compared with SoC, needle aspiration resulted in a reduced length of hospital stay (2.2 days fewer), and decreased symptom scores (1.21 lower). The panel recommended needle aspiration over chest drain for the initial treatment of PSP. Ambulatory management involved the use of an inserted Heimlich device, which allows the patient to mobilise, and potentially go home while the air leak is being managed. Analysis found this had a shorter hospital stay (3 days fewer), reduced recurrence (39 fewer per 1,000), and 148 fewer further procedures per 1,000 patients. The guidelines advised ambulatory management for PSP, adding the caveat that this should only be used in centres where there is appropriate expertise, and procedures to manage patients as outpatients. Early surgery had been previously reserved as a recurrence prevention technique in patients who have experienced more than one pneumothorax; however, the experts examined the role of the procedures in first-line management. They found a lower rate of recurrence (271 fewer per 1,000), and a decrease in complications (95 fewer per 1,000). The panel recommended considering early surgery in patients with PSP who prioritise recurrence prevention. Walker praised this recommendation for the strong element of patient choice that is included here. This newly developed decision aid weighs up the different options for acute PSP management, allowing physicians and patients to collaboratively select the optimal approach.

Optimal Management of Persistent Air Leak

Walker also presented the novel recommendations for PAL management through the lens of a patient case study. The patient was a 73-year-old with known chronic obstructive pulmonary disease, who had a chest drain inserted 3 days prior that was still bubbling. Surgeons did not feel the patient was a good candidate for surgical management due to numerous comorbidities. The patient had a leftsided secondary spontaneous pneumothorax and PAL. Walker again compared three different management options using the novel evidence, and recommendations of the guidelines.

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"Persistent inflammatory responses are associated with higher mortality." The first option considered was an autologous blood patch, a procedure that instils the patient’s own blood via a chest drain to reduce an air leak. Analysis has shown that this intervention reduces length of hospital stay (2.37 fewer days) and increases leak resolution (222 more per 1,000). The guidelines concluded that autologous blood patch can be considered in PAL when patients are not fit for surgery. Walker secondly analysed bronchial valves as an intervention. These are unidirectional valves inserted through bronchoscopy into the bronchial tree. Analysis has demonstrated a shorter air leak duration (3.18 days fewer) and an increased number of resolutions (240 more per 1,000). However, the panel made no formal recommendations for or against bronchial valves, due to the lack of conclusive evidence. The final intervention considered was thoracic suction, which is the application of suction to a chest drain to re-expand a lung, reducing the air leak. The evidence analysed found no significant difference in outcomes, resulting in the panels making no recommendations for or against the use of this intervention. Concluding his presentation, Walker highlighted the multiple treatment avenues available for patients with PSP, while acknowledging the lack of evidence currently available for secondary patients with PAL. He highlighted the importance of additional research and funding to address these questions.

CO-ADJUVANT TREATMENTS FOR SEVERE COMMUNITY-ACQUIRED PNEUMONIA The second guidelines presentation, given by Antoni Torres Martí, University of Barcelona, Spain, delved into new findings surrounding the use of anti-inflammatory medicines, specifically corticosteroids in treating SCAP. Patients with SCAP have a very high mortality rate and, therefore, require more effective and targeted

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treatments. A previous study examining systemic inflammatory responses in 38 patients with SCAP measured inflammatory markers every 2 days. The study found that patients with persistent inflammatory responses died more frequently. Corticosteroids work to reduce inflammation through the inhibition of nuclear factor κ-light-chain-enhancer of activated B cells, a transcription factor involved in multiple inflammatory processes. Martí highlighted lessons learnt from the COVID-19 pandemic that persistent inflammatory responses are associated with higher mortality, explaining the rationale for the use of corticosteroids that downregulate local and systemic immunity in CAP and SCAP. Previous guidelines published in 2019 did not recommend corticosteroids for the treatment of SCAP; however, they have now become part of standard care. A 2015 study on the effect of corticosteroids on treatment failure among patients hospitalised with SCAP found that corticosteroids demonstrated a reduction in late treatment failure described as radiographic progression, severe respiratory failure, or death. Martí highlighted an additional study examining the efficacy and safety of adjunctive corticosteroid therapy in patients with SCAP, which found that hydrocortisone was inferior to methylprednisolone for patient outcomes. A novel study found patients with SCAP on prolonged low-dose methylprednisolone treatment did not demonstrate significantly reduced 60-day mortality; however, patients did overall require 3 fewer days of mechanical ventilation.

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In the 2023 guidelines, outlined by Martí in his presentation, the panel recommended the use of corticosteroids in patients with SCAP when shock is present; however, Martí emphasised that this is a conditional recommendation, with a low quality of evidence. The guidelines further recommend the use of methylprednisolone, based on the balance of the evidenced literature. Methylprednisolone is, therefore, recommended for use in septic shock and shock not related to sepsis to decrease mortality in patients with SCAP. Martí highlighted that guidelines are not always correct, and that they must be constantly updated based on emerging evidence. He also underlined to the audience the need for further randomised controlled trials focusing on steroid dosage and duration, viral versus bacterial pneumonia, and implications for immunosuppressed populations, as well as better endo/genotyping exploring glucocorticosteroid resistance.

CONCLUSIONS The analysis of the novel guidelines highlighted areas with large amounts of evidence, such as the management of PSP, where multiple treatment options are recommended for different situations, enabling the patients’ preference and priorities to be considered. However, the guidelines also underline areas where evidence, research, and, therefore, treatment options are limited, including secondary pneumothorax with PAL, and understanding optimal usage of corticosteroids to improve the outcomes of patients with SCAP, which is currently associated with very poor prognosis, and high mortality rates. ●

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Precision Medicine in Airway Diseases: What Can We Offer in the Clinic? Authors:

Abigail Craig, EMJ, London, UK

Citation:

EMJ Respir. 2023;11[1]:25-27. DOI/10.33590/emjrespir/10301711. https://doi.org/10.33590/emjrespir/10301711.

AN EXCITING session, delivered at the European Respiratory Society (ERS) International Congress 2023, held in Milan, Italy, saw field experts present recent research surrounding precision medicine in airway diseases. Chaired by Apostolos Bossios, Karolinska University Hospital, Stockholm, Sweden; Emer Kelly, St. Vincent’s University Hospital, Dublin, Ireland; and Omar Usmani, National Heart and Lung Institute (NHLI), Imperial College London, UK, presentations discussed the value of ‘omics’, cellular signatures, novel chronic obstructive pulmonary disease (COPD) classifications, and the identification of treatable traits in improving patient care.

EARLY DIAGNOSTICS: OMICS AND CELLULAR SIGNATURES Sanjay Haresh Chotirmall, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, began the session by considering the value of omics and cellular signatures in the early diagnosis of airway diseases. He emphasised the need for new approaches in this field, suggesting that multi-omic technologies and cellular signatures show promise. Specifically, these technologies could aid in classifying patients based on their clinical phenotypes, subphenotypes, endotypes, and treatable traits, thus generating patient sub-groups with a common characteristic that could be successfully targeted by intervention. Explaining how multi-omics can help in the clinic, Chotirmall highlighted the very clear endotypes that have been identified through this technology. Novel phenotypes of bronchiectasis and COPD were presented, with the crucial role played by multi-omics in these discoveries highlighted. When considering the value of multi-omics in constructing novel-phenotypes in airway diseases, the U-BIOPRED cohort led the way through the integration of multi-omic data related to the molecular phenotypes of asthma onto one common platform.

Chotirmall also suggested that multi-omics could help in the clinic through biomarker discovery, through the identification of new mechanisms, and by permitting a more in-depth analysis of overlap patients. For example, a recent publication including 100 patients with COPD utilised a range of ‘omic’ technologies to validate key pathways in neutrophilic dominant COPD. Multi-omic technologies have already made a dramatic difference to therapy when considering, for example, the treatment of cystic fibrosis, in which, according to Chortimall, we have now revolutionised the treatment through the use of potentiators and correctors based on genomics. Finally, Chotirmall hypothesised that multi-omics would aid in the stratification (prognosis, prediction, and progression) of patients. By understanding all these data, clinicians can more easily identify patients whose data is going to progress. For example, in a cohort of patients with COPD, data on lung microbiota was combined with metabolomics to successfully identify disease progression. Chotirmall concluded by addressing some of the challenges associated with bringing multi-omics to the bedside, namely cost, lack of facilities and expertise, standardisation, and clinical utility and validation across cohorts, before stressing that emerging technologies show great promise.

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ARE NOVEL CHRONIC OBSTRUCTIVE PULMONARY DISEASE CLASSIFICATIONS HELPFUL? Shyamali Dharmage, University of Melbourne, Australia, discussed novel COPD classifications and whether they are helpful in offering better care for patients. The definition of COPD has undergone substantial changes since it was first defined in 1969. Recently, a number of subclassifications have been developed with subtypes and aetio-types, based on risk factors that can occur at any age, which were introduced in 2023. They emphasised that, with five subtypes proposed, each associated with different risk factors and aetiologies, COPD is not just a smoker’s disease. Dharmage continued by discussing the evolving taxonomy of pre-COPD. Using repeated lung function data between the ages of 7–53 years, a report was able to generate lung function trajectories. The patterns reveal three types of trajectory in each measure that can

contribute to the development of COPD by middle-age. Overall, this suggested that there is a long lag of deteriorating lung function before reaching the diagnostic cut-off for COPD. Pre-COPD was first defined as a stage of increased risk in 2020, and the pre-COPD framework has since been formalised. Lastly, Dharmarge explained the usefulness of these classifications. As the classifications are currently conceptual, they lack precision. Furthermore, this system for sub-grouping patients is inherently flawed as the subtypes do not consider the multifactorial nature of COPD or the interactions between risk factors. However, these classifications provide opportunity to promote the multifactorial nature of COPD, strengthen the case for prevention and early diagnosis, and suggest a way forward in identifying endotypes of early disease. A decision support tool, currently under development, aims to help clinicians understand which patients in the pre-COPD stage are at risk of developing COPD.

"With five sub-types proposed, each associated with different risk factors and aetiologies, COPD is not just a smoker’s disease."

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NON-TYPE 2 ASTHMA: THE UNMET NEED Richard Costello, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland, sought to review the clinical, physiological, and immunologic features of Type 2 (T2) low asthma. Currently, T2 high asthma is well characterised as airway injury resulting in physiological changes and the production of IL-4, IL-5, and IL-13 by T helper 2 cells and T2 innate lymphoid cells lymphocytes. The definition of T2 low asthma is rather unsatisfactory; limited to an absence of T2 inflammation. Costello subsequently suggested that there is little mechanistic evidence to support the concept of T2 low asthma as an independent condition.

"The definition of T2 low asthma is rather unsatisfactory; limited to an absence of T2 inflammation." Costello stressed that previous exposure to corticosteroids could affect T2 status of the patient. Looking at cross-sectional data from several studies, between 40–50% of patients were T2 low. In contrast, when researchers record T2 status over time, between 70–90% of patients were T2 high at some point. Costello then highlighted the results of INCA SUN, a multicentre study of patients with severe asthma, recorded over 32 weeks. The researchers investigated whether clinician decision making would be altered by using digital data rather than traditional prescription data. Importantly, exposure to inhaled corticosteroids was precisely measured throughout this study. Across the study period, patients were most commonly T2 high, but when considering individuals over time at successive visits, the percentage of patients that were T2 high increased.

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When considering this result in tandem with corticosteroid use, T2 low status was significantly associated with higher inhaled corticosteroids (p=0.011). Thus, knowing the patient’s previous corticosteroid exposure is crucial in understanding their T2 status. Costello concluded that this evidence suggests there is very little mechanistic evidence to support the concept of T2 low asthma as an independent condition. In fact, most T2 asthma can be explained through the combined effects of corticosteroid treatment and the non-specific nature of asthma symptoms. He stressed that the recognition of one type of asthma, caused by damage to the airway resulting in inflammation and a change in the airflow, will make patient management easier. The final talk, delivered by Clémence Martin, Cochin Hospital, Paris, France, considered treatable traits in bronchiectasis. Following diagnosis, patient management is centred around treatable traits, such as the underlying cause, infection, breathlessness, comorbidities, and exacerbations. Martin concluded that precision medicine will aid in patient characterisation, which in turn will improve treatment and selection for clinical studies. Regarding bronchiectasis, cystic fibrosis transmembrane conductance regulators and other ion channels show promise as therapeutic targets.

CONCLUDING REMARKS It is clear that the application of precision medicine in airway disease will have a largely positive impact in the clinic, offering opportunities for improved patient classification and the early identification of disease. ●

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Congress Review

Prioritising Patient Outcomes and Reducing Environmental Burden: How Both Are Achievable in Respiratory Care This congress review is based on sessions that took place at the European Respiratory Society (ERS) International Congress 2023, held 9th–13th September 2023 in Milan, Italy Chairpeople:

John Hurst,1 Helen Reddel2

Speakers:

Christine Jenkins,3 Ekaterina Maslova,4 Alberto Papi,5 Omar Usmani,6 Tonya Winders7 1. Department of Respiratory Medicine, University College London (UCL), UK 2. Clinical Management Group, Woolcock Institute of Medical Research, Sydney, Australia 3. Medicine and Health, University of New South Wales (UNSW), Sydney, Australia 4. BioPharmaceuticals Medical, AstraZeneca, Cambridge, UK 5. Department of Translational Medicine and for Romagna, University of Ferrara, Italy 6. National Heart and Lung Institute (NHLI), Faculty of Medicine, Imperial College London, UK 7. Allergy & Asthma Network, Global Allergy and Airways Patient Platform (GAAPP), Vienna, Virginia, USA

Disclosure:

Hurst has received grant funding from AstraZeneca, GlaxoSmithKline (GSK), and Novartis; has served on the advisory board for AstraZeneca, Chiesi Farmaceutici, GSK, Novartis, and Sanofi; has served as a consultant for AstraZeneca, Chiesi Farmaceutici, and Novartis; and has received speaker and/or travel honoraria from Alkem Laboratories, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Getz Pharma, GSK, and Teva Pharmaceuticals. Reddel is Chair of the Global Initiative for Asthma (GINA) Science Committee; has received grant funding from AstraZeneca, GSK, and Novartis; has served as a consultant or on the advisory board for AstraZeneca, Chiesi Farmaceutici, GSK, Novartis, and Sanofi; and has received speaker honoraria from Alkem, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Getz Pharma, GSK, and Teva Pharmaceuticals. Jenkins has received grant funding from GSK, and Sanofi; has served on the advisory board for AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GSK, and Novartis; has served as a consultant for AstraZeneca, Boehringer Ingelheim, GSK, and Novartis; and has received speaker and/or travel honoraria from AstraZeneca, Boehringer Ingelheim, GSK, Menarini, Mundipharma, Novartis, and Sanofi. Maslova is both an employee of, and a stockholder in, AstraZeneca. Papi has received grant funding from AstraZeneca, Chiesi Farmaceutici, Fondazione Salvatore Maugeri, GSK, and Sanofi; has served as a consultant or on the advisory board for Avillion, AstraZeneca, Chiesi Farmaceutici, GSK, Edmond Pharma, Moderna, Mundipharma, Novartis, Sanofi/Regeneron, Roche, and Zambon; has received speaker fees from AstraZeneca, Cipla, Chiesi Farmaceutici, GSK, Menarini, Mundipharma, and Zambon; and has served on European Medicines Agency

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(EMA) and Agenzia Italiana del Farmaco (AIFA) panels for registration of drugs for asthma. Usmani has received grant funding and/or personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Cipla, Covis Pharma, DEVA, Edmond Pharma, GSK, Kamada, KYORIN Pharmaceutical, Menarini, Mereo BioPharma, Mundipharma, Napp Pharmaceuticals, Novartis, Orion Pharma, Sandoz, Takeda Pharmaceuticals, Trudell Medical, and UCB. Winders has received personal fees from AstraZeneca, GSK, Novartis, Roche, and Sanofi Regeneron. Acknowledgements:

Medical writing assistance was provided by Hannah Moir, EMJ, London, UK, and Jennifer Taylor, London, UK.

Disclaimer:

The purpose of the symposium presentation was for disease state awareness and is not meant to imply efficacy or safety of any AstraZeneca products or other medications. The information is intended for healthcare professionals only.

Support:

The symposium presentations and publication of this article were organised, developed, and funded by AstraZeneca.

Keywords:

Asthma, CO2 equivalent (CO2e), carbon footprint, chronic obstructive pulmonary disease (COPD), greenhouse gas (GHG) emissions, inhaler, pressurised metered-dose inhaler (pMDI), respiratory care, short-acting β-agonist (SABA).

Citation:

EMJ Respir. 2023;11[1]:29-40. DOI/10.33590/emjrespir/10305679. https://doi.org/10.33590/emjrespir/10305679.

Meeting Summary Patient outcomes must take precedence when considering environmental legislation related to the availability of inhaler devices, which are essential for the care of patients with respiratory diseases. This article reviews presentations and abstracts from the European Respiratory Society (ERS) International Congress 2023, held in Milan, Italy, in September 2023. The sessions focused on healthcare inequality and patient outcomes, highlighting the need for stakeholders to make patient-centric decisions in order to ensure access to essential inhaled medicines are prioritised. This is especially important during a period when there is an increasing need to reduce the carbon footprint associated with respiratory care. During a satellite symposium, co-chairs John Hurst, Professor of Respiratory Medicine at University College London (UCL), UK, and Helen Reddel, Research Leader at the Woolcock Institute of Medical Research, Sydney, Australia, emphasised the necessity of addressing environmentally sustainable respiratory care while prioritising patient outcomes. Christine Jenkins, Clinical Professor of Respiratory Medicine at the University of New South Wales (UNSW), Sydney, Australia, discussed the association between health inequity and uncontrolled chronic obstructive pulmonary disease (COPD) and asthma, and how that relates to the carbon footprint of treatment. Alberto Papi, Full Professor of Respiratory Medicine at the University of Ferrara, Italy, examined how implementing evidence-based guidelines can improve patient outcomes and reduce the carbon footprint of respiratory care, and the progress being made in the transition to near-zero propellants in pressurised metered-dose inhaler (pMDI)

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devices. Omar Usmani, Professor of Respiratory Medicine at the National Heart and Lung Institute (NHLI), Imperial College London, UK, stressed that pMDIs contain essential medicines, and inhaler regimens should not be considered readily interchangeable. He urged the respiratory community to ensure that their voice is heard in decisions where it relates to the environment regarding COPD and asthma care. The symposium emphasised the opportunities to reduce the environmental impact of respiratory care whilst prioritising patient outcomes. By supporting the transition to climate-friendly propellants in pMDI devices, and implementing guidelines to improve patient outcomes, the overall carbon footprint of respiratory care can be reduced. However, this must be done without limiting access to essential medicines, or increasing adverse health outcomes. The symposium identified pathways towards achieving patient-centric, sustainable respiratory care by improving outcomes, harnessing innovation, and promoting multi-stakeholder collaboration.

Introduction

not compromise the quality of patient care,10 and unintended consequences of jeopardising improvements in outcomes.11

John Hurst Hurst set the scene by highlighting that policymakers face significant challenges in addressing the post-COVID-19 priorities of resolving health inequity, building system resilience, and reducing greenhouse gas (GHG) emissions.1 Improvements in respiratory care have stalled in recent years.2 He noted that this slow-down has not occurred universally amongst all patients living with respiratory disease; rather, a disproportionate burden of mortality and morbidity due to respiratory disease occurs in people from socioeconomically deprived areas.3,4 The problem is getting worse, as an ageing population is contributing to rising disease prevalence.5 In parallel, there is climate change. Hurst stated that if the global healthcare sector were a country, it would be the fifth-largest emitter on the planet.1 Respiratory disease is a key driver of the healthcare sector’s GHG emissions. Nonetheless, inhaled medicines are essential for patients living with COPD and asthma.6 Hurst emphasised that pMDIs are the most commonly used inhaler device,7 and the sole available option for children and for many of those living with COPD. However, pMDIs have faced scrutiny, as the propellants they contain have a high global warming potential (GWP).8,9 As a result, Hurst highlighted calls, including legislative proposals, seeking to reduce their use. However, he emphasised that lower-emission solutions should

This congress review highlights the factors driving carbon emissions in respiratory treatment, and examines the links between socioeconomic inequalities, poor disease control, and environmental impact. The review also shines a spotlight on how the respiratory community must use its voice to ensure that patients remain central to any decisions that may impact the availability of treatments.

Facing the Challenges for Healthcare in the 21st Century: Health Equity, System Resilience, and the Environment Christine Jenkins There is a high burden of uncontrolled disease in those living with COPD and asthma around the world. Jenkins highlighted that in 2019, COPD was the third most common cause of death globally, accounting for approximately 3 million deaths.12 In the UK, COPD is the second most common cause of emergency admissions.13 For those with asthma, approximately 40% of patients across countries, regardless of their severity of asthma, are potentially over-reliant on short-acting β-agonist (SABA) relievers, which is associated with severe exacerbation risk, independent of inhaled corticosteroid maintenance use.14 Additionally, a short course

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of systemic corticosteroids every 1–2 years is associated with an increased risk of adverse health conditions, such as osteoporosis, cataracts, and diabetes.15 A high proportion of the burden of COPD and asthma lies in low- and middle-income countries (LMIC), where access to good care is limited,16-18 while in high-income countries (HIC), socioeconomic disparities also contribute to poor outcomes.3,4 Jenkins noted that for asthma, 90% of the burden of disease is borne by people living in LMICs,16 and steroid inhalers are only available in one-third of public primary healthcare facilities in LMICs.18 In many low-income countries, the availability of asthma medicines is low, with only 30.1% in the public healthcare system and 43.1% in private sectors receiving medications.17 Jenkins pointed out that social deprivation is associated with worse outcomes from respiratory conditions, both in terms of morbidity and mortality. In LMICs, COPD mortality is most prevalent in regions with limited resources, particularly in countries with a yearly gross national income of less than 20,000 USD per capita.19 However, HICs are not immune, with social deprivation having an impact on outcomes. COPD data from the USA show that the most deprived areas exhibit the highest likelihood of exacerbations, and an increased incidence of severe exacerbations.3 In one study from Germany, more than one-third of patients with COPD did not receive maintenance therapy following either one severe or multiple exacerbations.20 For patients with asthma, data from the UK show an elevated likelihood of emergency admissions and longer length of hospital stay with increasing deprivation.4 Jenkins highlighted how the prevalence of respiratory disease increases in both males and females in later life, especially from the age of 60 years.5 This is relevant since, according to the World Health Organization (WHO), the global population aged 60 years and older is expected to double, from 1.0 billion in 2020 to 2.1 billion by 2050.21 An even greater burden of chronic respiratory disease is, therefore, anticipated in both LMICs and HICs. This emphasised all the more the urgency to address the already considerably high prevalence of respiratory disease globally.

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The Carbon Footprint Across Healthcare

All aspects of healthcare possess a carbon footprint, with one-quarter of these GHG emissions related directly to the delivery of care.9 Therefore, the choices made in patient care have a direct impact on healthcare emissions.9 In the UK, the GHG emissions associated with healthcare activities, including travel, have been defined.22 The GHG emission associated with a general practitioner visit amounts to 1.1 kg of CO2 equivalent (CO2e).22 This figure rises progressively with the increasing intensity of treatment; for instance, if patients require emergency department care (14 kg CO2e), or if they require a hospital stay in a low- or high-intensity bed ward (38 and 90 kg CO2e, respectively).22 Jenkins emphasised that healthcare-related GHG emissions would, therefore, be amplified for those with poorlycontrolled disease who require urgent or emergency care. Jenkins presented data from around the world, illustrating the high proportion of SABA reliever medication use in many countries, which the authors had highlighted is indicative of suboptimal management of respiratory disease being commonplace. This has a consequence in terms of GHG emissions. The SABA CARBON (Healthcare-based Carbon Cost of Treatment) Europe and Canada observational study by Janson et al.8 reviewed inhaler sales data obtained from the IQVIA (Durham, North Carolina, USA) quarterly MIDAS® database as a surrogate for inhaler use (MDIs and dry powder inhalers), for SABA and controller medications (inhaled corticosteroid [ICS]-containing drugs, long-acting β2-agonists [LABA], long-acting muscarinic antagonists [LAMA], and LAMA/ LABA combinations). Across the 21 countries included, SABA use was common.8 The study identified that SABAs accounted for two-thirds of the total GHG emissions, contributing 2 million tonnes of CO2e, while the use of controller inhalers resulted in approximately 1 million tonnes of CO2e (Figure 1).8 In six countries (Canada, Germany, Italy, Poland, Sweden, and the UK), analyses showed that between 69–94% of SABA prescribing/dispensing in asthma were for patients who required three or more reliever inhalers in a 12-month period, and who were potentially uncontrolled.8 This had an environmental consequence of between 78–864 tonnes of CO2e per 10,000 persons per

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Figure 1: Inhaler sales data, as a surrogate for inhaler use, for short-acting β-agonist and controller medications, across all respiratory uses, from the IQVIA (Durham, North Carolina, USA) quarterly MIDAS® database Q3 2019 (September 2018–September 2019).8

SABA as a proportion of total inhaler greenhouse gas emissions (%)

SABA as a proportion of total inhaler use (%)

Sweden

47%

41%

the Netherlands

47%

Finland

49%

45%

Czechia

49%

37%

Poland

53%

37%

Belgium

53%

33%

Italy

55%

46%

Denmark

58%

50%

Norway

59%

51%

Greece

62%

45%

Bulgaria

63%

47%

Hungary

64%

56%

Croatia

64%

53%

Germany

67%

54%

68%

70%

Spain

69%

59%

Switzerland

72%

51%

Canada

72%

71%

France

73%

63%

Ireland

75%

71%

Romania

80%

68%

Adapted from Janson et al.8 Q: Quarter; SABA: short-acting β-agonist.

year.8 Any additional healthcare demand arising from the consequences of uncontrolled asthma would be associated with a carbon footprint.8 This is true globally, with data from the SABA CARBON International study, conducted in Africa, Asia Pacific, Latin America, and the Middle East, showing the same pattern.23 For example, in Australia, SABAs represent 83% of use and 87% of the GHG emissions of inhalers.23 Jenkins highlighted that if these patients’ symptoms could be better controlled, then this would

reduce the requirement for SABA, with the attendant environmental benefits. The SABINA CARBON study looked at all aspects of asthma healthcare, scaled to the UK asthma population.24 This included healthcare resource utilisation (HCRU) and prescribing. It found that patients who were uncontrolled in their asthma disease, as defined by recent exacerbation history or over-reliance on reliever (SABA) prescribing, had a three-fold higher carbon

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footprint than those who were well-controlled.24 Treating the consequences of poor control accounted for 45% of the total carbon footprint, 303,874 tonnes of CO2e per year, which is equivalent to emissions from more than 124,000 houses in the UK.25 A further analysis from SABINA CARBON investigating socioeconomic disparities and the carbon footprint of asthma care was presented as a poster at ERS, by Ekaterina Maslova, Director of Epidemiology at AstraZeneca, Cambridge, UK. The findings demonstrated that the carbon footprint of asthma care in the UK increased with higher socioeconomic deprivation.26 Specifically, patients with a higher Index of Multiple Deprivation (IMD) score (where scores range from least to most deprived, and higher scores are indicative of higher deprivation) exhibited GHG emissions that were approximately two-fold higher compared with those with a lower IMD score.26 This suggests that there is an environmental consequence that comes from socioeconomic disparities, in addition to the previously reported observations of higher carbon footprint in patients who are uncontrolled. The study also showed that overall GHG emissions per capita related to asthma care were driven by the prescription of SABA, underscoring the need to proactively optimise maintenance therapy in accordance with current evidence-based recommendations, to reduce reliance on reliever inhalers.26 By effectively implementing treatment recommendations that prefer the use of anti-inflammatory relievers to improve control of symptoms and prevent exacerbations, healthcare systems could achieve improved and sustained clinical outcomes, subsequently reducing the overall carbon footprint of asthma care.26 The authors concluded that targeting quality improvement programmes to areas of higher deprivation, with the goal of removing disparities in care and improving patient outcomes, could also be an important route for greater savings in the CO2e emissions associated with asthma care. Jenkins also illustrated the relationships between COPD exacerbations, HCRU, and carbon footprint. A history of COPD exacerbation increases the likelihood of a future exacerbation. For those with a severe exacerbation, this risk is higher still, so it is crucial that patients who are hospitalised are discharged on the appropriate

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medication to reduce the risk of recurrence. However, a study in Germany showed this continuity in care was not experienced by over one-third of patients.20 A total of 37% of patients did not receive appropriate guidelinedirected controller medications (LAMA, LABA, or ICS), following either one severe or multiple (regardless of severity), COPD exacerbations.20 She emphasised that people are being “grossly undertreated for a very serious disease.” Data from the SHERLOCK study showed that even one moderate exacerbation increases the risk for subsequent exacerbations, compared with having no recent exacerbation.27 For patients with COPD who experience a severe, or multiple exacerbations, the risk was higher still.27 A subsequent analysis of the GHG emissions associated with the HCRU and SABA prescribing from SHERLOCK CARBON showed that these, too, increased.28 Compared with patients with no history of exacerbations in the baseline year, a history of ≥2 moderate and/or severe exacerbations increased GHG emissions by 51%, 51%, and 44% at 12, 24, and 36 months, respectively.28 Jenkins noted that this indicates the potential that prompter intervention following COPD exacerbations may have, not just in reducing future exacerbations, but also by reducing the GHG emissions associated with care. In conclusion, Jenkins illustrated the links between health inequalities, uncontrolled respiratory disease, and carbon footprint. She identified that all elements of healthcare contribute to the carbon footprint, and that SABA relievers account for the majority of GHG emissions from inhalers. Attention should be directed towards evidence-based approaches and guideline implementation, such as controller medications, to prioritise disease management and improve patient outcomes, whilst supporting a reduction in the carbon footprint of care.8

Paving the Way for Environmentally Sustainable Respiratory Care Alberto Papi Papi highlighted the opportunities for reducing carbon emissions of respiratory conditions.

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Two main areas were discussed: implementing recommendations and evidence-based approaches to improve outcomes in patients with COPD and asthma,29-32 and transitioning to more climate-friendly pMDI inhaler medicines.

Implementing Evidence-Based Approaches and Recommendations

There are clear evidence-based treatment recommendations for asthma and COPD, as published by the Global Initiative for Asthma (GINA) and Global Initiative for Chronic Obstructive Lung Disease (GOLD).33,34 These recommendations aim for personalised treatment by assessing patient status and adjusting therapy.33,34 Papi identified that implementation of these recommendations is important to improve outcomes and, as a consequence, would be expected to reduce the CO2 emissions associated with care. For instance, acute exacerbations of COPD are associated with frequent readmissions.29 An approach to reduce readmissions of patients with COPD discharged from hospital was implemented in Canada.29 Patients were provided with a simple seven-item tool (including, for example, inhaler technique, treatment optimisation, and smoking cessation) to facilitate care continuity.29 Patients receiving the transition bundle were 83% less likely to be readmitted within 7 days (relative risk: 0.17; 95% confidence interval: 0.07–0.35; p<0.001), and 26% less likely to be readmitted within 30 days of discharge (relative risk: 0.74; 95% confidence interval: 0.60–0.91; p=0.06) compared with the usual care cohort.29 PRIMUS, a retrospective observational study utilising USA healthcare insurance claims data (N=24,770), demonstrated that the prompt initiation (≤30 days post-index) of GOLDrecommended triple therapy (comprising ICS, LABA, and LAMA) following one severe or ≥two moderate COPD exacerbations, was associated with a reduced risk of future COPD exacerbations (occurrence and number of exacerbations), decreased morbidity, and a reduction in COPDrelated costs during the 12-month follow-up period compared to delayed (31–180 days) or very delayed (181–365 days) triple therapy.30 The study indicated that implementation of management guidelines is warranted to prevent future exacerbations, and to reduce the

economic burden among patients with COPD.30 Papi said that implementing guidelines minimises the impact of exacerbations, future demand on healthcare, and would impact the associated carbon emissions, too. Papi believed that implementing GOLDrecommended treatment has the potential to impact the resilience of healthcare systems and enhance patient outcomes. The PROMETHEUS study, a simulation-based projection utilising a modelled USA COPD population with 1,000 simulations of patient progression, was designed to estimate the long-term exacerbation and mortality benefits of implementing fixed triple therapy.31 The study predicted that implementation would reduce COPD exacerbation-associated hospitalisations by 2 million, extending the average life expectancy of patients by 2.2 years, and contributing to an additional 3 million years of life to the USA population over the span of 10 years.31 In addition to the obvious benefit to patients and demand on emergency care, the improvements would also be expected to have an environmental benefit. Regarding asthma care, the ongoing SENTINEL programme aims to reduce SABA overuse through the supported implementation of a local adult asthma guideline, which advocates a SABA-free, maintenance and reliever therapypreferred strategy for patients with uncontrolled asthma.32 The study was designed to improve asthma outcomes, decrease SABA overuse, and reduce the environmental impact of asthma and its treatment. The study is being conducted in a network of practices in one of the most deprived areas in England, which was in the 90th decile of SABA prescribing.32 Patients are prioritised for asthma review based on risk, which includes the level of SABA prescribing (n=2,571).32 After 12 months, the patient-tailored approach was associated with improved asthma outcomes; a reduction of high SABA overuse (≥6 SABA prescriptions in 12 months) from approximately 30% to 13%; and, for those who underwent treatment optimisation, there was a 30% reduction in the proportion of patients experiencing one or more exacerbations.32 Importantly, the authors believe this is the first prospectively designed study to investigate both a change in outcomes and GHG emissions resulting from quality improvement.32 The full analysis of the

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GHG emissions associated with care is pending; however, interim data are available for the impact of the programme on SABA prescribing.35 In the first 12 months following the inclusion of the last site to participate in the quality improvement programme, there were an estimated 44,275 fewer SABA relievers issued for the treatment of asthma, which amounts to a saving of 1,240 metric tonnes of CO2e, the equivalent to 1,550 transatlantic flights from Leeds, UK, to New York, USA.35 A fuller picture of the carbon reduction associated with guideline-recommended treatment will be revealed in future analyses, which will account for the GHG emissions linked with the fewer asthma exacerbations.

Transitioning to Next-Generation Propellants That Are More Climate-Friendly

before degrading. For the older propellants, HFA-227ea and HFA-134a, this is 36 and 14 years, respectively, compared with 1.6 years for HFC-152a, and 19 days for HFO-1234ze(E).36 For pMDIs using HFO1234ze(E), the carbon footprint of the device would be similar to a drypowder inhaler (DPI). From 2025 onwards, pMDIs containing these next-generation propellants will become available.38

Ensuring Access to Essential Medicines: Why Partnership with Governments and Authorities is the Only Way to Achieve Patient-Centric Environmentally Sustainable Respiratory Care Omar Usmani

Papi then moved on to describe the ongoing work to reduce the carbon footprint associated with pMDIs. All pMDIs contain a propellant, and those currently approved have a high GWP, meaning they are greenhouse gases. Hydrofluoroalkane (HFA)-227ea and HFA134a, have a 100-year GWP of 3,140 and 1,360, respectively.36 However, next-generation propellants are in development, which have either low or near-zero GWP, and with a reduction of up to 99.9% GWP compared with propellants in use currently.37 A reason for the reduced GWP was shown to be the time the gaseous propellant is present in the atmosphere

The carbon footprint associated with pMDIs has prompted some individuals and groups to call for limits to their availability.39 However, although the impact of pMDIs on global GHG emissions is important,38 they are a relatively small generator of anthropogenic CO2, contributing <0.04% (Figure 2).40 Usmani stressed the need for a pragmatic approach that puts patients first, and ensures that they have uninterrupted access to essential inhaler medicines. In that regard, making the transition to environmentally-friendly propellants in pMDI devices is important to securing the continuity of patient care.41

Figure 2: The share of medical aerosols in the total global greenhouse gas emissions (data from United Nations Environment Programme, The Montreal Protocol, 2016).40

Methane, 16%

Foams, 0.14%

Nitrous oxide, 6%

CO2, 76%

Refrigeration, air conditioning and heat pumps, 1.72%

F-gases, 2%

Aerosols, 0.08%

Fire protections, 0.06%

Adapted from Emeryk et al.40

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Medical aerosols, 0.032% Technical aerosols, 0.048%

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Switching Inhaler Regimens is a Complex Issue

Usmani said that the impact of inhalers on the environment is more complex than just considering carbon emissions. There are multiple ways that inhaler devices impact the environment that go beyond their GHG emissions alone, and where, across a number of factors, a DPI has a greater impact. Jeswani and Azapagic42 showed that the transition of pMDIs to a nextgeneration propellant would have a less harmful impact on the environment than switching to dry powder inhalers when considering these factors together. The alternative of switching from pMDIs to DPI to would lead to a greater environmental impact on factors, such as photochemical oxidants formation, fossil depletion, and marine ecotoxicity, which contribute to terrestrial pollution and marine eutrophication.42 These effects occur throughout the lifecycle of inhalers, from the manufacturing process to their disposal.42 Usmani noted that the delivery of drugs by inhalation is an integral component in the management of patients with COPD and asthma, and emphasised the importance of the “voice of the patient.” The correct use of inhalers, and adherence to prescribed regimens, are key aspects in achieving better clinical control and enhanced quality of life.43 Personalising treatments, with the tailored selection of devices, enhances patient satisfaction,44 treatment adherence, and clinical outcomes,45 where the choice of an inhaler device is as important as the choice of medications it contains.46 Patient empowerment is key to optimal management and disease control, whereby patients who are consulted and satisfied with their device are more likely to use it, and benefit from the therapy.47 Usmani noted that pMDIs play a critical role in respiratory medicine, representing the majority of inhaler usage. Certain groups of patients have no alternative to pMDIs. Children, for example, are often solely dependent on pMDIs as indicated treatment.48 In the emergency setting, pMDIs are prioritised for use by GOLD and GINA.33,34 Inhaled medicines delivered by pMDIs are included on the WHO Essential Medicines List.6 This is particularly important for LMICs. A study presented at the American Thoracic Society (ATS) International

Conference, in May 2023, assessed pMDI use as a proportion of all inhalers, in 53 countries spanning six geographical regions.49 It showed that pMDI use accounted for 78% of all inhaler use, and represented the majority of inhaler use in 49 countries.49 In 17 of 20 European countries studied, pMDIs accounted for 75.6% of all inhaler use, rising to more than 90.0% in countries including Colombia and Peru.49 Usmani highlighted that switching inhaler regimens, advocated by some, is a complex issue, with variable clinical and patient-related consequences.50 He pointed out that inhaler regimen switches can be detrimental to the patient–healthcare professional relationship, especially when the switches are nonconsented.11 Furthermore, he made the point that patients who experience a severe COPD exacerbation have a similar mortality prognosis to those with heart failure, acute myocardial infarction, or bladder cancer, who would not be denied effective treatments on the basis of carbon footprint.

Advocating for Patient Wellbeing During Policy Development

Advocacy by the respiratory community has an important role in evidence-based policy development. Incentivisation to switch inhalers was stopped in the UK in April 2023, which Usmani said may have been partly due to the respiratory community explaining to the government and policymakers that switching may be inappropriate.51 He added that the greenest inhaler is the one that the patient can, and will, use correctly.52 An expert consensus poster was presented at ERS by Tonya Winders, President and CEO of Global Allergy and Airways Patient Platform (GAAPP), Vienna, Virginia, USA. The aim was to develop global consensus quality statements on how and when to implement an appropriate inhaler regimen switch to inform clinical practice and health system policy around regimen switching.53 The consensus highlighted that the most important factors that should inform an inhaler regimen switch should be clinical and patient-led factors, such as inadequate disease control, non-adherence to regimens, and patient preferences, as well as proper implementation procedures, and inhaler technique.53 The

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consensus view was that a median of 35 minutes per patient was required for an effective inhaler switch consultation.53 This encompasses tasks such as identifying the need to switch, conducting assessments, providing training, documenting the switch, planning monitoring reviews, and allocating review time.53 The consensus emphasised that switches should be only initiated and implemented by qualified healthcare professionals.53 Usmani asserted that advocacy by the respiratory community has an important role in supporting evidence-based policy development. He pointed to the 30 individuals and groups who provided responses to the public consultation to the draft F-Gas Regulation legislation.51 This had been pivotal, he believed, in shaping the public positions of the European bodies, and the recognition of the importance of safeguarding access to essential medicines during the transition to low, or near-zero, GWP propellants. Usmani urged legislators to safeguard respiratory patients from the unintended consequences of any environmentally-led restrictions on essential medicines. Usmani then highlighted a proposal submitted by five European Union (EU) countries to the European Chemicals Agency (EHCA), calling for restrictions on the manufacture and use of per- and polyfluoroalkyl substances (PFAS) from 2026.54 This proposal aims to minimise the release of molecules with long environmental persistence to protect against potential negative effects on the environment and human health in the future.55 However, PFAS molecules are used across many medicines’ lifespans, and play a role in the research, development, and manufacturing of lifesaving medicines.56,57 As such, they are already tightly controlled by health authorities.58 In particular, there is a risk to HFO-1234ze(E), which has been classified as a PFAS based on chemical structure, despite it possessing none of the properties that are the reason for the ban, i.e., it is non-persistent, non-bioaccumulative, and non-toxic.59 Usmani emphasised the importance of communicating to policymakers that transitioning to climate-friendly propellants is crucial for both patient care, and for addressing climate change.36,37 In conclusion, respiratory clinicians must remain vigilant to the unintended consequences of wellmeaning environmental legislation, and should

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advocate for patients with local authorities, governments, policymakers, and stakeholders.

Summary and Closing Helen Reddel Selecting inhalers, and considering their impact on the environment, is intertwined with patient wellbeing, clinical outcomes, and global sustainability. While it is important to consider the environmental impact of pMDI devices, it is essential to prioritise personalised treatment based on an individual’s need.10 Reddel highlighted the importance of access to inhaled asthma medications, especially those in LMICs, who already experience limited access to these therapies.10 Shared decisionmaking between healthcare professionals and patients should focus on control of symptoms and reducing the risk of poor outcomes. Better control of disease impacts reliever use and HCRU, both of which have a carbon consequence.10 Reddel emphasised that patients in LMICs, underserved areas, and the elderly are the most affected by respiratory disease and climate change. Therefore, urgent action is required to improve individual patient management, which can influence the burden of disease experienced by patients, and their likelihood of requiring emergency healthcare. New propellants for inhaler devices are currently under development. However, it is crucial that legislation does not deter innovation, and that there is collaboration among stakeholders to achieve sustainable respiratory care without compromising patient access or health outcomes. Reddel urged attendees to provide a submission to the PFAS public consultation, and to continue advocating for, and with, patients to maintain inhaler options for those with asthma, COPD, and other respiratory conditions. This will not only improve the health of patients, but also of the planet. This underscores the significance of ensuring the respiratory community’s voice is heard, preventing the unintended consequences that may arise from otherwise well-meaning and important legislation.

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References 1.

Health Care Without Harm. Health care’s climate footprint: how the health sector contributes to the global climate crisis and opportunities for action. Health Care Without Harm Climate-smart health care series green paper number one. 2019. Available at: https://noharm-global.org/sites/default/files/ documents-files/5961/HealthCaresClimateFootprint_092319. pdf. Last accessed: 21 September 2023. Organisation for Economic Co-operation and Development (OECD). Health care quality indicators. 2023. Available at: https://stats.oecd.org/Index. aspx?DataSetCode=HEALTH_ HCQI. Last accessed: 21 September 2023. Galiatsatos P et al. The association between neighborhood socioeconomic disadvantage and chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2020;15:981-93. Alsallakh MA et al. Association of socioeconomic deprivation with asthma care, outcomes, and deaths in Wales: a 5-year national linked primary and secondary care cohort study. PLoS Med. 2021;18(2):e1003497. GBD Chronic Respiratory Disease Collaborators. Prevalence and attributable health burden of chronic respiratory diseases, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Respir Med. 2020;8(6):585-96. World Health Organization (WHO). WHO model list of essential medicines - 22nd list 2021. Available at: https://www.who.int/ publications/i/item/WHO-MHPHPS-EML-2021.02. Last accessed: 21 September 2023. Lavorini F et al.; Aerosol Drug Management Improvement Team. Retail sales of inhalation devices in European countries: so much for a global policy. Respir Med. 2011;105(7):1099-103. Janson C et al. The carbon footprint of respiratory treatments in Europe and Canada: an observational study from the CARBON programme. Eur Respir J. 2022;60(2):2102760. Tennison I et al. Health care’s response to climate change: a carbon footprint assessment of the NHS in England. Lancet Planet Health. 2021;5(2):e84-92.

10. Levy LM et al. Global access and patient safety in the transition to environmentally friendly respiratory inhalers: the Global Initiative for Asthma perspective. Lancet. 2023;402(10406):1012-6. 11. Doyle S et al. What happens to patients who have their asthma device switched without their consent? Prim Care Respir J. 2010;19(2):131-9. 12. World Health Organization (WHO). The top 10 causes of death. 2020. Available at: https://www.who.int/ news-room/fact-sheets/detail/ the-top-10-causes-of-death. Last accessed: 21 September 2023. 13. Lane N et al. Specialist emergency care and COPD outcomes. BMJ Open Respir Res. 2018;5(1):e000334. 14. Quint JK et al.; SABINA North American and European Study contributors. Short-acting beta2-agonist exposure and severe asthma exacerbations: SABINA findings from Europe and North America. J Allergy Clin Immunol Pract. 2022;10(9):2297-2309.e10. 15. Price DB et al. Adverse outcomes from initiation of systemic corticosteroids for asthma: long-term observational study. J Asthma Allergy. 2018;11:193-204. 16. Mortimer K et al. Asthma management in low and middle income countries: case for change. Eur Respir J. 2022;60(3):2103179. 17. Bissell K et al. Access to essential medicines to treat chronic respiratory disease in low-income countries. Int J Tuberc Lung Dis. 2016;20:717-28. 18. World Health Organization (WHO). Asthma. 2023. Available at: https://www.who.int/news-room/ fact-sheets/detail/asthma. Last accessed: 21 September 2023. 19. Beran D et al.; Forum of International Respiratory Societies working group collaboration. Burden of asthma and chronic obstructive pulmonary disease and access to essential medicines in low-income and middle-income countries. Lancet Resp Med. 2015;3(2):159-70. 20. Vogelmeier CF et al. COPD exacerbation history and impact on future exacerbations – 8-year retrospective observational database cohort study from Germany. Int J Chron Obstruct Pulmon Dis. 2021;16:2407-17. 21. World Health Organization (WHO).

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Ageing and health. 2022. Available at: https://www.who.int/newsroom/fact-sheets/detail/ageingand-health. Last accessed: 21 September 2023. 22. Coalition for Sustainable Pharmaceuticals and Medical Devices (CSPMD). Care pathways: guidance on appraising sustainability. 2015. Available at: https://shcoalition.org/wp-content/ uploads/2019/10/SustainableCare-Pathways-GuidanceSummary-Oct-2015.pdf. Last accessed: 21 September 2023. 23. Alzaabi A et al. Greenhouse gas emissions from respiratory treatments: results from the SABA CARBON international study. Adv Ther. 2023;DOI:10.1007/s12325023-02663-2. 24. Wilkinson A et al. Greenhouse gas emissions associated with asthma care in the UK: results from SABINA CARBON. Eur Respir J. 2021;58(Suppl 65):OA76. 25. Wilkinson AJK et al. Greenhouse gas emissions associated with suboptimal asthma care in the UK: the SABINA healthCARe‒Based envirONmental cost of treatment (CARBON) study. Chest. In press. 26. Maslova E et al. Socioeconomic disparities in the carbon footprint of asthma care in the UK: results from SABINA CARBON. Abstract 2382. European Respiratory Society (ERS) International Congress 2023, 9-13 September, 2023. 27. de Nigris E et al. Short- and long-term impact of prior chronic obstructive pulmonary disease exacerbations on healthcare resource utilization and related costs: an observational study (SHERLOCK). COPD. 2023;20(1):92-100. 28. Bell JP et al. Greenhouse gas emissions associated with COPD care in the UK: results from SHERLOCK CARBON. Eur Respir J. 2021;58(Suppl 65):PA3551. 29. Atwood CE et al. Optimizing COPD acute care patient outcomes using a standardized transition bundle and care coordinator: a randomized clinical trial. Chest. 2022;162(2):321-30. 30. Tkacz J et al. PRIMUS – prompt initiation of maintenance therapy in the US: a real-world analysis of clinical and economic outcomes among patients initiating triple therapy following a COPD exacerbation. Int J Chron Obstruct

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Pulmon Dis. 2022;17:329-42. 31. Criner G et al. PROMETHEUS: longterm exacerbation and mortality benefits of implementing singleinhaler triple therapy in the US COPD population. J Health Econ Outcomes Res. 2023;10(1):20-7. 32. Crooks MG et al. Improving asthma care through implementation of the SENTINEL programme: findings from the pilot site. ERJ Open Res. 2023;9(3):00685-2022. 33. Global Initiative for Chronic Obstructive Lung Disease (GOLD). 2023 GOLD report. Available at: https://goldcopd.org/2023gold-report-2/. Last accessed: 21 September 2023. 34. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. 2023. Available at: https:// ginasthma.org/wp-content/ uploads/2023/05/GINA-2023Full-Report-2023-WMS.pdf. Last accessed: 21 September 2023. 35. The Sentinel Project. Available at: https://sentinelplus.info/thesentinel-project. Last accessed: 21 September 2023. 36. World Meteorological Organization (WMO). Scientific assessment of ozone depletion: 2018. Global ozone research and monitoring project–report no. 58. Available at: https://ozone.unep.org/sites/ default/files/2019-05/SAP-2018Assessment-report.pdf. Last accessed: 21 September 2023. 37. Hargreaves C et al. S60 A new medical propellant HFO-1234ze(E): reducing the environmental impact of inhaled medicines. Thorax. 2022;77:A38-9. 38. Pritchard JN. The climate is changing for metered-dose inhalers and action is needed. Drug Des Devel Ther. 2020;14:3043-55. 39. National Health Service (NHS) North & East Devon Formulary and Referral. The environmental impact of inhalers. 2022. Available at: https://northeast. devonformularyguidance.nhs.uk/ formulary/chapters/3.-respiratory/ the-environmental-impactof-inhalers. Last accessed: 21 September 2023. 40. Emeryk AW et al. Impact of inhalers used in the treatment of respiratory diseases on global

warming. Adv Respir Med. 2021;89(4):427-38. 41. Pernigotti D et al. Reducing carbon footprint of inhalers: analysis of climate and clinical implications of different scenarios in five European countries. BMJ Open Respir Res. 2021;8(1):e001071. 42. Jeswani HK, Azapagic A. Life cycle environmental impacts of inhalers. J Clean Prod. 2019;237:117733. 43. Ilic AD et al. Influence of inhaler technique on asthma and COPD control: a multicenter experience. Int J Chron Obstruct Pulmon Dis. 2016;11:2509-17. 44. Price D et al. Establishing the relationship of inhaler satisfaction, treatment adherence, and patient outcomes: a prospective, realworld, cross-sectional survey of US adult asthma patients and physicians. World Allergy Organ J. 2015;8(1):26. 45. Sanaullah T et al. Inhaler use technique in chronic obstructive pulmonary disease patients: errors, practices and barriers. Cureus. 2020;12(9):e10569. 46. Lavorini F, Fontana GA. Inhaler technique and patient's preference for dry powder inhaler devices. Expert Opin Drug Deliv. 2014;11(1):1-3. 47. Small M et al. Importance of inhaler-device satisfaction in asthma treatment: real-world observations of physicianobserved compliance and clinical/ patient-reported outcomes. Adv Ther. 2011;28(3):202-12. 48. Laube BL et al; European Respiratory Society; International Society for Aerosols in Medicine. What the pulmonary specialist should know about the new inhalation therapies. Eur Respir J. 2011;37(6):1308-31. 49. Bell JP et al. An assessment of pressurized metered-dose inhaler use in countries in Europe and the rest of the world. Am J Respir Crit Care Med. 2023;207:A6315. 50. Usmani OS et al. Real-world impact of nonclinical inhaler regimen switches on asthma or COPD: a systematic review. J Allergy Clin Immunol Pract. 2022;10(10):262437. 51. European Commission. EU legislation to control F-gases.

Available at: https://climate. ec.europa.eu/eu-action/ fluorinated-greenhouse-gases/ eu-legislation-control-f-gases_en. Last accessed: 21 September 2023. 52. Pritchard J, Usmani O. The greenest inhaler: a patientcentric approach. EMJ Respir. 2022;10(Suppl 2):2-7. 53. Winders T et al. Late breaking abstract - consensus quality standard for implementing an inhaler regimen switch in patients with respiratory disease. Abstract 4607. European Respiratory Society (ERS) International Congress 2023, 9-13 September, 2023. 54. European Chemicals Agency (ECHA). ECHA publishes PFAS restriction proposal. 2023. Available at: https://echa. europa.eu/-/echa-publishespfas-restriction-proposal. Last accessed: 21 September 2023. 55. European Chemicals Agency (ECHA). Annex XV restriction report. 2023. Available at: https:// echa.europa.eu/documents/10162/ f605d4b5-7c17-7414-8823b49b9fd43aea. Last accessed: 6 July 2023. 56. American Chemistry Council (ACC). PFAS: integral to lifesaving drugs. Available at: https:// www.americanchemistry.com/ chemistry-in-america/chemistries/ fluorotechnology-per-andpolyfluoroalkyl-substances-pfas/ pfas-integral-to-life-saving-drugs. Last accessed: 21 September 2023. 57. Glüge J et al. An overview of the uses of per- and polyfluoroalkyl substances (PFAS). Environ Sci Process Impacts. 2020;22:234573. 58. European Chemicals Agency (ECHA). Per- and polyfluoroalkyl substances (PFAS). 2023. Available at: https://echa.europa.eu/hottopics/perfluoroalkyl-chemicalspfas. Last accessed: 21 September 2023. 59. Wallington TJ et al. Atmospheric chemistry of short-chain haloolefins: photochemical ozone creation potentials (POCPs), global warming potentials (GWPs), and ozone depletion potentials (ODPs). Chemosphere. 2015;129:135-41.

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Shaping the Future in Rare Lung Diseases: From Imaging to Patient Management This industry symposium took place during the European Respiratory Society (ERS) International Congress held in Milan, Italy, 9th–13th September 2023 Chairpeople:

Simon Walsh,1 Marlies S. Wijsenbeek2

Speakers:

Filipa Costa,3 Elizabeth Estes,4 Noel G. McElvaney,5 Luca Richeldi,6 Simon Walsh,1 Marlies S. Wijsenbeek2 1. National Heart and Lung Institute, Imperial College London, UK 2. Erasmus Medical Centre, Rotterdam, the Netherlands 3. Coimbra Hospital and University Centre, Portugal 4. Open Source Imaging Consortium (OSIC), Saugatuck, Michigan, USA 5. Royal College of Surgeons in Ireland (RCSI), University of Medicine and Health Sciences, Dublin, Ireland 6. A. Gemelli Hospital and Catholic University of the Sacred Heart, Rome, Italy

Disclosure:

Walsh has received grants, research funding, honoraria, consultation/speaker fees, and/or has a financial interest in Boehringer Ingelheim, Bracco, Bristol Myers Squibb (BMS), FLUIDDA, Galapagos, Medscape, the National Institute for Health and Care Research (NIHR), OncoArendi Therapeutics, the Open Source Imaging Consortium (OSIC), Roche, and Sanofi-Genzyme. Wijsenbeek has received research funding from AstraZeneca-Daiichi, Boehringer Ingelheim, The Dutch Pulmonary Fibrosis Patients Association (Longfonds), The Netherlands Organisation for Health Research and Development (ZonMw), Roche, and The Thorax Foundation – Erasmus MC; and speaker and/or consultancy fees from Boehringer Ingelheim, BMS, CSL Behring, Galapagos, Galecto, GSK, Horizon Therapeutics, Kinevant Sciences, Molecure, NeRRe Therapeutics, Novartis, PureTech Health, Respivant, Roche, Thyron, Trevi, and Vicore. Costa is affiliated with, has a financial interest in, or has received grants or research support from Boehringer Ingelheim, CSL Behring, and Grifols; has received honoraria or consultation fees from AstraZeneca, Boehringer Ingelheim, CSL Behring, Grifols, Novartis, and Tecnifar; has participated in a company-sponsored bureau for AstraZeneca, Bial, Boehringer Ingelheim, CSL Behring, Grifols, Linde, Novartis, and Tecnifar; and has received meeting travel support from CSL Behring. Estes declares no conflicts of interest that relate to this presentation. McElvaney is affiliated with, has a financial interest in, or has received grants or research support from Chiesi, CSL Behring, Grifols, Kamada, pH Pharma, and Vertex; and has received honoraria or consultation fees from Dicerna, Inhibrx, Intellia, and Vertex. Richeldi is affiliated with, has a financial interest in, or has received grants or research support from Acceleron, Bayer, Biogen, Boehringer Ingelheim, BMS, Celgene, Chiesi, CSL Behring, DevPro, FibroGen, Galapagos, Gilead, Nitto, Novartis, Pliant Therapeutics, Promedior, Prometic, Respivant, Roche, Sanofi-Aventis, Takeda, UCB, Veracyte, and Zambon; and has received honoraria or consultation fees from Boehringer Ingelheim, Cipla, CSL Behring, Roche, and Zambon.

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Acknowledgements:

Writing assistance was provided by Nicola Humphry, Nottingham, UK.

Support:

The publication of this article was funded by CSL Behring. The views and opinions expressed are exclusively those of the speakers.

Keywords:

Alpha 1 antitrypsin deficiency (AATD), pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), rare lung diseases.

Citation:

EMJ Respir. 2023;11[1]:41-51. DOI/10.33590/emjrespir/10304494. https://doi.org/10.33590/emjrespir/10304494.

Meeting Summary This symposium was held during the 2023 European Respiratory Society (ERS) International Congress in Milan, Italy. The main objective was to discuss unmet needs in the diagnosis and management of rare lung diseases, with a particular emphasis on alpha 1 antitrypsin deficiency (AATD) and idiopathic pulmonary fibrosis (IPF). Presentations focused on promising approaches to meet these needs, including the feasibility of genomic diagnosis, the development of improved biomarkers of disease progression, such as quantitative CT and novel blood biomarkers, the use of digital lung auscultation, and increased screening for AATD in vulnerable populations. The overarching message from the symposium was that advancements in technology, multidisciplinary collaboration, and partnerships between academic institutions, patient associations, and industry are crucial to the continued improvement of patient management in rare diseases, and that the education of healthcare professionals is vital to enhance the understanding and awareness of these conditions.

Identifying Unmet Needs in Rare Lung Diseases

testing, and one-third of children with a rare disease die before their fifth birthday, presenting a clear unmet medical need.1

Luca Richeldi Luca Richeldi, Professor of Respiratory Medicine at the Catholic University of the Sacred Heart and Head of Pulmonology at the A. Gemelli Hospital in Rome, Italy, explained that rare diseases represent a worldwide healthcare challenge, with approximately 10,000 disorders affecting 6% of the population in Western societies.1 Over 80% of rare diseases have a genetic component, which makes these conditions particularly disabling and expensive to manage in terms of genetic testing and comprehensive management.1 Most patients with a rare disease do not receive a correct diagnosis after standard diagnostic

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As an example of the obstacles associated with identifying a rare disease, Richeldi described the vast number of conditions that can cause bronchiectasis, including three congenital disorders: cystic fibrosis, primary ciliary dyskinesia, and AATD.2 Richeldi explained that the identification of a condition causing bronchiectasis can require a multitude of different diagnostic tools, such as sweat chloride testing and CFTR mutational analysis if cystic fibrosis is suspected, and alpha 1 antitrypsin (AAT) levels and phenotyping if AATD is suspected.2 Richeldi stressed that research into rare lung diseases often has value beyond the rare disease itself.3-5 For example, the pathogenesis of AATD

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can be seen as a paradigm of conformational diseases,3 and research into IPF has led to a greater understanding of the spectrum of pulmonary fibrosis.4,5 Richeldi emphasised that many rare diseases have a genetic component, and recent research in the UK and Ireland has indicated that genomic diagnosis of rare paediatric disease is feasible.6 However, this same study showed that the diagnosis of these disorders is significantly less likely in patients of African descent than those of European descent (odds ratio [OR]: 0.51).6 In conclusion, Richeldi identified five unmet needs in rare disease: a lack of precise and widely available diagnostic tools; a lack of prognostic tools; the challenges in designing, performing, interpreting, and funding randomised clinical trials; the heterogeneity in rare disease, which makes it difficult to target them as a single entity; and a high risk of disparities in diagnosis and treatment for ethnic and socio-economic minorities.

Challenges and Progress in Predicting Disease Trajectories Noel G. McElvaney Alpha 1 Antitrypsin Deficiency

AATD is a hereditary condition that predisposes patients to early-onset chronic obstructive pulmonary disease (COPD), liver cirrhosis, neutrophilic panniculitis, and systemic vasculitis.7 The AAT gene, SERPINA1, has two alleles, with most individuals carrying the Pi*MM genotype (where Pi* is an alias for SERPINA1). Patients with AATD generally present with genotypes Pi*MS, Pi*SS, Pi*MZ, Pi*SZ, or Pi*ZZ, and the majority (96%) of individuals with AATDassociated disease exhibit the Pi*ZZ allele in clinical practice.7 Noel G. McElvaney, Head of the School of Medicine at the Royal College of Surgeons in Ireland (RCSI), University of Medicine and Health Sciences in Dublin, Ireland, presented data from the long-term follow-up of Irish patients included in the RAPID and RAPID extension (RAPID-OLE) studies. The RAPID study was a multicentre,

randomised, double-blind trial comparing the efficacy and safety of AAT treatment with placebo over 24 months (N=180).8 At the end of the RAPID study, 140 patients entered the open-label, 24-month RAPID-OLE study.8,9 After 24 months, AAT treatment was associated with a significantly lower reduction from baseline in lung density at total lung capacity compared with placebo (-1.51 g/L/year versus -2.26 g/L/year [p=0.021]).9 Those patients remaining on AAT treatment in the RAPID-OLE study continued to show a similar rate of lung density decline over the following 24 months (-1.63 g/L/ year), whereas those patients who switched from placebo to AAT showed a showed a significantly reduced rate of decline (-1.26 g/L/year) compared with prior placebo treatment (mean treatment difference: 0.52 g/L/year; p=0.008).9 McElvaney explained that since the few patients who reached a terminal event during the RAPID study did so at a lung density of approximately 20 g/L, delaying the decline in lung density with AAT treatment could potentially extend survival in patients with AATD by approximately 5–6 years.9 To investigate this hypothesis, a study is being conducted in Ireland to follow up patients with AATD over a period of 10 years.10 The treatment cohort includes patients with AATD (Pi*ZZ) who participated in the RAPID/RAPID-OLE studies (n=19), and who have continued AAT therapy for up to 10 years after study cessation. Matched controls include patients with the Pi*ZZ genotype (n=19) who have not received AAT, and patients with the Pi*MM genotype (n=20) who had a similar disease severity to the treatment group at baseline.10 Interim results from this study indicate that spirometry, quality of life, and the diffusing capacity of the lungs for carbon monoxide are of limited use in AATD to detect progression over time. These findings are in line with an analysis of long-term registry data from Ireland, Switzerland, and Austria, in which 431 lung index cases and 178 non-lung index cases showed a plateau in forced expiratory volume decline in their late 40s.11 That study reported a significantly lower mortality during follow-up time among those who received AAT therapy compared with those who did not (p=0.00076; Figure 1).

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Figure 1: Kaplan–Meier survival analysis by alpha 1 antitrypsin therapy status.

Survival probability

1.00

0.75

0.50

0.25

p=0.00076 Placebo AAT treatment

0.00 0

Yes

364

139

213

115

Number at risk AAT therapy

Years followed

Reproduced with permission from Fraughen et al.11 AAT: alpha 1 antitrypsin.

McElvaney concluded that lung function parameters are not informative to predict disease progression, and are largely decoupled from mortality.10,11 However, it is possible that imaging biomarkers such as high-resolution CT (HRCT) lung density will be better able to monitor disease progression in patients with AATD, and may also provide further insights into an individual patient’s prognosis. McElvaney explained that healthcare systems may need to extend the diagnostic reach for AATD beyond White, European populations, to produce diagnostic algorithms for general practitioners, to consider neonatal screening, and to increase access to treatments, such as plasma-purified AAT, around the world. McElvaney emphasised that AATD may not necessarily be a truly rare condition, but one that is diagnosed rarely. Finally, McElvaney stressed that AATD is probably the best clue that clinicians have for what causes COPD, and that a better understanding of AATD will lead to a better understanding of the pathophysiology and the mechanistic causes of COPD.

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Idiopathic Pulmonary Fibrosis Marlies S. Wijsenbeek IPF is a rare interstitial lung disease (ILD) characterised by worsening dyspnoea and progressive loss of lung function, which arises from progressive scar formation in the lungs.12 Marlies S. Wijsenbeek, a pulmonologist and Chair of the ILD centre at the Erasmus Medical Centre (MC) in Rotterdam, the Netherlands, explained that patients with IPF experience a significant decline in lung function of approximately 200 mL per year.12 However, the disease course varies considerably, with some patients experiencing a rapid decline in lung function, some a more gradual decline, and some patients experiencing acute exacerbations associated with a high rate of mortality.12,13 Predicting the disease course and prognosis in IPF is important because treatment is intended to slow the decline of progressive disease, and the frequency of follow-up often depends on the rate of lung function decline. Similarly, Wijsenbeek explained that patient prognosis has an impact on lung transplant referral, advanced

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care planning, and clinical trial inclusion. For the patient with IPF, their prognosis has an impact on how they weigh treatment decisions, make plans for their future, and prioritise different aspects of their lives. One of the first clinical measures used to predict mortality in IPF was the gender-age-physiology (GAP) index.14 However, since the development of the index, the diagnostic criteria for IPF and the treatments available have advanced, and Wijsenbeek explained that the original GAP score now overestimates mortality. Several novel clinical predictors of survival have been explored, and univariate analysis found that 6-minute walk distance (6MWD) and the presence of exertional hypoxia each outperformed the predictive value of the GAP index and remained independently associated with mortality in the multivariate analysis (hazard ratio [HR]: 2.49 [p<0.001]; HR: 2.92 [p<0.001]; and HR: 1.23 [p=0.022], respectively; N=562).15 Patient-reported outcomes predictive for survival in IPF include change in the Living with Pulmonary Fibrosis (L-PF) questionnaire dyspnoea score16 and change in body weight.17 Events such as a forced vital capacity loss ≥10% per year,18 acute exacerbations,18 and worsening respiratory symptoms requiring hospitalisation have also been shown to be predictive of mortality in patients with IPF.19,20 Wijsenbeek explained that advanced techniques are being developed to support the interpretation, and therefore predictive value, of HRCT scans, such as deep learning-based algorithms.21 In addition, blood biomarkers have been identified that can help to predict progression in IPF, including epitheliumderived biomarkers and monocyte counts,22,23 and proteomic biomarker panels have been developed.24,25 Short telomere length has also been found to be associated with disease progression in both IPF and other forms of progressive pulmonary fibrosis.26 Finally, an experienced clinician’s opinion regarding disease prognosis is of considerable value. In a prospective study of 140 patients, clinicians were asked the ‘surprise’ question: “Would you be surprised if this patient died within the next year?” The study found that a

clinician’s response was of significant value in predicting 1-year mortality in patients with IPF (OR: 3.69; p=0.019).27 While advances have been made in predicting mortality, Wijsenbeek emphasised that it remains challenging to predict disease progression for the individual patient with IPF,28 and better tools are needed to address this challenge to guide patient treatment and care.

Camouflage: How Asthma Obscures the Diagnosis of Alpha 1 Antitrypsin Deficiency Filipa Costa The symptoms of AATD, such as wheezing, phlegm, and dyspnoea, appear at a young age,29,30 are non-specific, and overlap with more common diseases such as asthma.31,32 Asthma is the most common respiratory misdiagnosis prior to diagnosis of AATD,33 and most patients with AATD are initially treated for asthma.31 Filipa Costa, a respiratory physician at the Coimbra Hospital and University Centre in Portugal, stressed that AATD and asthma are distinct disease entities. While asthma is characterised by reversible airflow obstruction, and inflammation and hyper-reactivity of the airway, AATD is characterised by non-reversible airflow obstruction, and responds poorly to inhaled steroids used in the treatment of asthma.31 However, there remains significant overlap between the pathobiology, symptoms, functional characteristics, and key clinical features of these two conditions,33-36 contributing to misdiagnosis. In addition, it has been suggested that these two diseases may merge to form an overlapping syndrome.37 Although the prevalence of asthma in patients with AATD is variable, 14% of patients with AATD have been reported to have a concomitant diagnosis of asthma.38,39 The presence of coexisting asthma and AATD has been shown to exacerbate symptoms, and these patients are at increased risk of more severe disease,40 suggesting that AATD may represent a risk factor for both developing asthma and for worsening its course.41

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Although the biological mechanisms linking these two conditions are not fully understood,42 both conditions are associated with an excess of neutrophil elastase, suggesting a shared pathway of inflammation.37,43 In addition, AAT has important anti-inflammatory and immunomodulatory effects,37 and reduced AAT levels in patients with AATD could potentially lead to chronic airway inflammation and susceptibility to asthma.31,42 Costa explained that distinguishing AATD from asthma based on presentation and clinical evaluation is not possible due to overlapping clinical features.32 However, improving diagnosis in this population is fundamental to the optimisation of clinical management,32 since AATD is treated with AAT replacement therapy, whereas asthma treatments aim to reduce bronchial hyper-responsiveness and inflammation.37

However, Costa stressed that despite recommendations, most patients who are candidates for screening are not tested for AATD.31 While screening for AATD should be performed in all adolescents and adults with asthma,44,45 Costa described several disease features that should alert clinicians to a suspicion of AATD, including late-onset and/or difficult-tomanage asthma; atypical findings in lung function tests; evidence of hyperinflation on chest radiographs or emphysema on HRCT; presence of liver disease; and a family history of COPD or liver disease.

Imaging Challenges in Lung Fibrosis Simon Walsh

Current guidelines recommend screening for AATD in all patients with COPD, and adults and adolescents with asthma,44,45 and studies indicate that screening may result in the detection of more patients with AATD at a younger age, allowing for implementation of earlier lifestyle changes and therapy.31,46,47 Screening for AATD requires a simple blood test for serum AAT levels.31,32 An AAT level in the normal range rules out AATD, whereas low AAT levels should prompt phenotyping or genotyping for common mutations (Figure 2).

Simon Walsh, a thoracic radiologist and National Institute for Health and Care Research (NIHR) Clinician Scientist at the National Heart and Lung Institute, Imperial College London, UK, described three challenges to the management of patients with pulmonary fibrosis: diagnostics, disease behaviour prediction, and early detection, all of which relate to imaging, and all of which are, in principle, amenable to deep learning solutions.48

Diagnosis relies exclusively on laboratory assays1 Figureof2:AATD Diagnostic flow diagram for the screening of alpha 1 antitrypsin deficiency in patients

with asthma.

Diagnostic testing, while available, is very rarely performed during asthma diagnostic investigations, even in patients with highly suggestive AATD symptoms2

Asthma patient Wheezing Dyspnoea Chest tightness Cough Allergies

Suspect AATD particularly if: Late-onset asthma Difficult-to-manage asthma Atypical findings in LFTs Emphysema Liver disease Family history

Measure AATD serum levels and CRP

Take blood sample

Normal AAT serum levels

Low AAT serum levels

Continue asthma treatment

Phenotyping or genotyping for common mutations

AATD ruled out

Consider gene sequencing if serum levels are not consistent with phenotype/genotype

Reproduced with permission from Costa. AAT: alpha 1 antitrypsin; AATD: alpha 1 antitrypsin deficiency; CRP: C-reactive protein; LFT: lung function test.

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Challenge 1: Diagnostic Agreement

While guidelines are available for the evaluation of pulmonary fibrosis from HRCT scans,49 visual assessment of fibrosis can be associated with poor reproducibility, interobserver variability, and insensitivity to marginal progression.48,50 For example, interobserver agreement for these histopathologic patterns across 150 HRCTs of patients with pulmonary fibrosis indicated a median κ coefficient of 0.48–0.52 across 112 radiologists50 (where 1.00 is perfect agreement, 0.40 is generally considered to be clinically acceptable, and 0.00 is agreement by chance).

Challenge 3: Early Detection of Pulmonary Fibrosis

Patients are typically diagnosed when they present with symptoms, yet Walsh emphasised that disease is present well before this occurs. Incidentally detected interstitial lung abnormalities have been associated with IPF,48 yet only a small proportion of patients with these abnormalities go on to develop IPF.48,53,54 The difficulty lies in how to predict progressive pulmonary fibrosis based on subclinical CT abnormalities like these, a challenge that may be amenable to computer-based CT analysis.48

To investigate the potential for computer-based diagnostic support in the setting of pulmonary fibrosis, deep learning was used to develop an algorithm able to categorise histopathologic patterns on HRCT (the Systematic Objective Fibrotic Imaging Analysis Algorithm [SOFIA]).51 Interobserver agreement between the algorithm and consensus radiologist opinion (across 91 thoracic radiologists) was assessed in 150 HRCT scans.51 The individual radiologists’ interobserver agreement with the consensus opinion reached a median κ coefficient of 0.67, and the agreement of the algorithm with the consensus opinion reached a κ of 0.69, showing that the algorithm outperformed radiologists in this study. In addition, the algorithm provided equivalent prognostic discrimination between usual interstitial pneumonia and non-usual interstitial pneumonia patterns to the consensus opinion of the thoracic radiologists.51

Walsh explained that the scarcity of CT data for progressive pulmonary fibrosis presents a challenge to algorithm training.48 While generative artificial intelligence (AI) and synthetic data can be used to train deep learning algorithms,55 the ideal solution is to collate sufficiently large datasets, such as the vast repository of ILD data that are being gathered by the Open Source Imaging Consortium (OSIC).56

Challenge 2: Identification of Progressive Pulmonary Fibrosis

Elizabeth Estes

Walsh explained that, once disease is established, it is not currently possible to reliably predict which patients will develop progressive fibrosis and which will remain stable from baseline information alone.48 SOFIA was able to provide probabilities for the occurrence of each of the pulmonary fibrosis diagnostic categories across a large cohort of patients with progressive pulmonary fibrosis. Analysis showed that SOFIAbased probabilities, but not expert radiologist consensus, were predictive of mortality (HR: 1.75; p<0.0001), and that this was independent of disease extent (n=83).52

In closing, Walsh reiterated that AI is intended to supplement the expertise of radiologists, rather than replace them, in the manner of automated decision support, with a view to improving the diagnosis and management of pulmonary fibrosis.

New Tools to Advance Imaging in Rare Lung Diseases

Elizabeth Estes, Executive Director of the OSIC in Saugatuck, Michigan, USA, explained that the mission of OSIC-ILD is to make radical progress on behalf of people living with ILDs, their families, and their caregivers. The OSIC aims to become the largest and most diverse digital image biobank for ILDs and other rare lung diseases in the world, with the intention of driving technological innovation in a clinically meaningful way.56 By developing a large collective of real-world data, the OSIC will support the development of technology to speed diagnosis, and improve prognosis and response to therapy, in ILD and other diseases. The OSIC-ILD repository includes

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a total of 20,752 committed datasets,56 with 4,924 anonymised patients and 6,322 anonymised CT scans (OSCILD.org, unpublished data). OSIC’s large repository of CT scans is intended to overcome challenges to the development of deep learning algorithms; these include an insufficient number of available lung CT scans, primarily homogeneous populations, and limited collaboration between study groups. The OSIC repository aims to improve the accuracy of generative AI algorithms and help to remove variability from image analysis.56,57 The OSIC also plans to test the multitude of member algorithms against a similar, locked dataset from the OSIC, to encourage sharing and debate among scientists. The data contained in the OSIC repository will also support the identification of novel biomarkers in ILD.56 The next steps for the OSIC-ILD include increasing the number of longitudinal scans and clinical follow-up of patients with ILD in the database, and adding scans and clinical data from patients with AATD and sarcoidosis. Estes encouraged all clinicians to consider the way in which data need to be captured in the clinic to maximise the contribution to algorithmbased research, and to support the OSIC to get newly developed and validated tools into the clinic, where they can support patients.

Implications of Unmet Needs in Rare Disease for Management of Rare Lung Diseases

lung auscultation in the diagnosis of IPF. Lung auscultation can be used to detect bibasilar inspiratory (‘velcro-type’) crackles, and guidelines indicate that the presence of this clinical sign should lead clinicians to suspect IPF.49,58 The presence of bibasilar inspiratory crackles has been shown to predict the radiologic HRCT features of fibrosis (OR: 6.24), traction bronchiectasis (OR: 4.37), reticulation (OR: 2.57), honeycombing (OR: 2.39), and ground glass opacities (OR: 2.13), each p<0.001.59 In addition, quantitative analysis of lung sounds (producing reproducible, distinct digital acoustic features) showed that the specificity and sensitivity of acoustic features to identify fibrosis of ≥50% on HRCT were similar to that of a composite physiological index, which incorporates physiology and imaging data (area under the curve: 0.73 and 0.69, respectively; Figure 3).60 These studies indicate that digital lung auscultation may be relevant for the screening and early detection of patients with IPF and other forms of pulmonary fibrosis, and that it may represent a cost-effective way to monitor disease progression.61 Richeldi explained that advancements in technology and multidisciplinary collaboration will undoubtedly help to address unmet needs in rare disease. Partnership between academic institutions, patient associations, and industry is also crucial, but can pose a challenge because of the different agendas and driving forces among these groups. Finally, Richeldi stressed that education remains the most critical factor in addressing the unmet needs in rare disease.

Luca Richeldi Richeldi reiterated that key unmet needs in rare disease include a lack of diagnostic/predictive tools and a high risk of inequality in diagnosis and treatment. Richeldi stressed that patients with IPF may be asymptomatic, which can make cases challenging to identify,49 and this underlines the need for inexpensive and widely available diagnostic tools that can be used in all parts of the world. As an example of a widely available diagnostic tool that could help to identify patients with rare disease, Richeldi described the value of

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Summary and Closing Remarks The main improvements needed in the field of rare lung diseases relate to diagnostic and prognostic tools, disparities in diagnosis and treatment for minority populations, education of the medical community, and collaboration within multidisciplinary teams. The symposium presenters discussed promising developments in the evaluation of lung disease, such as novel biomarkers; short telomere length; digital lung auscultation; patient-reported

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Figure 3: Receiver operating characteristic curves of acoustic features and/or composite physiological index for identification of extent of fibrosis ≥50% on high-resolution CT scans.

Receiver operating characteristic curves of different models 1.0

Sensitivity

0.8

0.6

0.4 Acoustic features CPI Acoustic features+CPI Reference line

0.2

0.4

0.6

0.8

1.0

Specificity Reproduced with permission from Sgalla et al.60 CPI: composite physiological index.

outcomes; and reproducible, quantitative HRCT scan measures, which can take advantage of deep learning-based automated decision support. The OSIC may be of benefit in this regard since it provides an umbrella group to standardise HRCT scans. It was also noted that while forced expiratory volume decline tends to plateau in patients with AATD, AAT therapy continues to provide a survival advantage in this population.

References 1.

2018;378(19):1811-23.

Smedley D et al. 100,000 Genomes pilot on rare-disease diagnosis in health care - preliminary report. N Engl J Med. 2021;385(20):186880.

O’Donnell AE. Bronchiectasis - a clinical review. N Engl J Med. 2022;387(6):533-45.

Emwas AH et al. Living with the enemy: from protein-misfolding pathologies we know, to those we want to know. Ageing Res Rev. 2021;70:101391.

The presenters also emphasised the importance of screening for rare lung disease, such as screening for AATD in with adult-onset asthma, and the potential for genomic screening in the diagnosis of paediatric rare diseases in the future.

Lederer DJ, Martinez FJ. Idiopathic pulmonary fibrosis. N Engl J Med.

Wijsenbeek M, Cottin V. Spectrum of fibrotic lung diseases. N Engl J Med. 2020;383(10):958-68.

Wright CF et al. Genomic diagnosis of rare pediatric disease in the United Kingdom and Ireland. N Engl J Med. 2023;388(17):1559-71.

Blanco I et al. Alpha-1 antitrypsin Pi*Z gene frequency and Pi*ZZ genotype numbers worldwide: an update. Int J Chron Obstruct Pulmon Dis. 2017;12:561-9.

Chapman KR et al. Intravenous augmentation treatment and lung density in severe α1 antitrypsin

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deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;386(9991):3608. 9.

McElvaney NG et al. Longterm efficacy and safety of α1 proteinase inhibitor treatment for emphysema caused by severe α1 antitrypsin deficiency: an openlabel extension trial (RAPID-OLE). Lancet Respir Med. 2017;5(1):5160.

10. Roche S et al. Long-term followup of Pi*ZZ alpha-1 antitrypsin deficient patients receiving intravenous alpha-1 antitrypsin augmentation therapy. Poster

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PA3310. ERS 2023, 9-13 September, 2023. 11. Fraughen DD et al. Augmentation therapy for severe alpha-1 antitrypsin deficiency improves survival and is decoupled from spirometric decline - a multinational registry analysis. Am J Respir Crit Care Med. 2023; DOI:10.1164/rccm.2023050863OC. 12. Raghu G. Idiopathic pulmonary fibrosis: lessons from clinical trials over the past 25 years. Eur Respir J. 2017;50(4):1701209. 13. Ley B et al. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;183(4):431-40. 14. Ley B et al. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med. 2012;156(10):684-91. 15. Chandel A et al. Derivation and validation of a simple multidimensional index incorporating exercise capacity parameters for survival prediction in idiopathic pulmonary fibrosis. Thorax. 2023;78(4):368-75. 16. Wijsenbeek MS et al. Do worse scores on patient-reported outcomes predict the progression of interstitial lung disease (ILD)? Eur Respir J. 2021;58(Suppl 65):PA3748. 17. Nakatsuka Y et al. The clinical significance of body weight loss in idiopathic pulmonary fibrosis patients. Respiration. 2018;96(4):338-47. 18. Paterniti MO et al. Acute exacerbation and decline in forced vital capacity are associated with increased mortality in idiopathic pulmonary fibrosis. Ann Am Thorac Soc. 2017;14(9):1395-402. 19. du Bois RM et al. Ascertainment of individual risk of mortality for patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;184(4):459-66. 20. Durheim MT et al. Association of hospital admission and forced vital capacity endpoints with survival in patients with idiopathic pulmonary fibrosis: analysis of a pooled cohort from three clinical trials. Lancet Respir Med. 2015;3(5):38896. 21. Walsh SLF et al. Deep learningbased outcome prediction in progressive fibrotic lung disease using high-resolution computed tomography. Am J Respir Crit Care Med. 2022;206(7):883-91.

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22. Maher TM et al. An epithelial biomarker signature for idiopathic pulmonary fibrosis: an analysis from the multicentre PROFILE cohort study. Lancet Respir Med. 2017;5(12):946-55. 23. Kreuter M et al. Monocyte count as a prognostic biomarker in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2021;204(1):74-81. 24. Alqalyoobi S et al. Circulating plasma biomarkers of progressive interstitial lung disease. Am J Respir Crit Care Med. 2020;201(2):250-3. 25. Bowman WS et al. Proteomic biomarkers of progressive fibrosing interstitial lung disease: a multicentre cohort analysis. Lancet Respir Med. 2022;10(6):593-602. 26. Newton CA et al. Telomere length and genetic variant associations with interstitial lung disease progression and survival. Eur Respir J. 2019;53(4):1801641. 27. Moor CC et al. The value of the surprise question to predict one-year mortality in idiopathic pulmonary fibrosis: a prospective cohort study. Respiration. 2021;100(8):780-5. 28. Ley B et al. Predictors of mortality poorly predict common measures of disease progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2016;194(6):711-8.

1997;111(2):394-403. 35. Eden E et al. Asthma features in severe alpha1-antitrypsin deficiency: experience of the National Heart, Lung, and Blood Institute Registry. Chest. 2003;123(3):765-71. 36. Tashkin DP et al. The lung health study: airway responsiveness to inhaled methacholine in smokers with mild to moderate airflow limitation. The Lung Health Study Research Group. Am Rev Respir Dis. 1992;145(2 Pt 1):301-10. 37. Izquierdo M et al. Alpha-1 asthma overlap syndrome: a clinical overview. Curr Allergy Asthma Rep. 2022;22(9):101-11. 38. Strange C et al. Results of a survey of patients with alpha-1 antitrypsin deficiency. Respiration. 2006;73(2):185-90. 39. Miravitlles M et al. Clinical and functional characteristics of individuals with alpha-1 antitrypsin deficiency: EARCO international registry. Respir Res. 2022;23(1):352. 40. DeMeo DL et al. Determinants of airflow obstruction in severe alpha-1-antitrypsin deficiency. Thorax. 2007;62(9):806-13. 41. Maule M et al. Hidden comorbidities in asthma: a perspective for a personalized approach. J Clin Med. 2023;12(6):2294.

29. Sveger T et al. Lung function in adolescents with alpha 1-antitrypsin deficiency. Acta Paediatr. 1994;83(11):1170-3.

42. Pini L et al. Alpha1-antitrypsin deficiency and asthma. Curr Opin Allergy Clin Immunol. 2021;21(1):46-51.

30. Piitulainen E, Sveger T. Respiratory symptoms and lung function in young adults with severe α1antitrypsin deficiency (PiZZ). Thorax. 2002;57(8):705-8.

43. Vignola AM et al. Increased levels of elastase and alpha1-antitrypsin in sputum of asthmatic patients. Am J Respir Crit Care Med. 1998;157(2):505-11.

31. Siri D et al. Distinguishing alpha1antitrypsin deficiency from asthma. Ann Allergy Asthma Immunol. 2013;111(6):458-64.

44. Miravitlles M et al. European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α1antitrypsin deficiency. Eur Respir J. 2017;50(5):1700610.

32. Stirpe E, Bardaro F. Alpha1antitrypsin deficiency and asthma. Monaldi Arch Chest Dis. 2022;92(4). 33. Eden E. Asthma and COPD in alpha-1 antitrypsin deficiency. Evidence for the Dutch hypothesis. COPD. 2010;7(5):366-74. 34. McElvaney NG et al. Baseline characteristics of enrollees in the National Heart, Lung and Blood Institute Registry of alpha 1-antitrypsin deficiency. Alpha 1-Antitrypsin Deficiency Registry Study Group. Chest.

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45. World Health Organization (WHO). Alpha 1-antitrypsin deficiency: memorandum from a WHO meeting. Bull World Health Organ. 1997;75(5):397-415. 46. Hernández-Pérez JR et al. Frequency of alleles and genotypes associated with alpha-1 antitrypsin deficiency in clinical and general populations: revelations about underdiagnosis. Pulmonology. 2023;29(3):214-20. 47. Lopez-Campos JL et al. Feasibility of a genotyping system for the

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diagnosis of alpha1 antitrypsin deficiency: a multinational crosssectional analysis. Respir Res. 2022;23(1):152. 48. Felder FN, Walsh SLF. Exploring computer-based imaging analysis in interstitial lung disease: opportunities and challenges. ERJ Open Res. 2023;9(4):145-2023. 49. Raghu G et al. Diagnosis of idiopathic pulmonary fibrosis: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018;198(5):e44-68. 50. Walsh SLF et al. Interobserver agreement for the ATS/ERS/JRS/ ALAT criteria for a UIP pattern on CT. Thorax. 2016;71(1):45-51. 51. Walsh SLF et al. Deep learning for classifying fibrotic lung disease on high-resolution computed tomography: a casecohort study. Lancet Respir Med.

2018;6(11):837-54.

August 2023.

52. Walsh SLF et al. Deep learningbased outcome prediction in progressive fibrotic lung disease using high-resolution computed tomography. Am J Respir Crit Care Med. 2022;206(7):883-91. 53. Nalysnyk L et al. Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature. Eur Respir Rev. 2012;21(126):35561. 54. Fernández Pérez ER et al. Incidence, prevalence, and clinical course of idiopathic pulmonary fibrosis: a population-based study. Chest. 2010;137(1):129-37. 55. Dack E et al. Artificial intelligence and interstitial lung disease. Invest Radiol. 2023;58(8):602-9. 56. Open Source Imaging Consortium (OSIC). Available at: https://www. osicild.org/. Last accessed: 22

57. Open Source Imaging Consortium (OSIC). Data repository. Available at: www.osicild.org/dr-about. Last accessed: 22 August 2023. 58. Bohadana A et al. Fundamentals of lung ausculation. N Engl J Med. 2014;370(8):744-51. 59. Sgalla G et al. “Velcro-type” crackles predict specific radiologic features of fibrotic interstitial lung disease. BMC Pulm Med. 2018;18(1):103. 60. Sgalla G et al. Quantitative analysis of lung sounds for monitoring idiopathic pulmonary fibrosis: a prospective pilot study. Eur Respir J. 2019;53(3):1802093. 61. Richeldi L et al. Digital lung auscultation: will early diagnosis of fibrotic interstitial lung disease become a reality? Am J Respir Crit Care Med. 2019;200(2):261-3.

FOR REPRINT QUERIES PLEASE CONTACT: INFO@EMJREVIEWS.COM

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Breathing New Life Into Acute Respiratory Care: Proactively Improving Long-Term Outcomes This AstraZeneca-sponsored symposium took place on 12 September 2023, as part of the European Respiratory Society (ERS) International Congress held in Milan, Italy, between 9th–13th September 2023 th

Chairpeople:

David Price1

Speakers:

Mona Al-Ahmad,2 Mohit Bhutani,3 David Price,1 Anne Marie Marley4 1. Observational and Pragmatic Research Institute, Singapore 2. Microbiology Department, College of Medicine, Kuwait University, Kuwait 3. Division of Pulmonary Medicine, Department of Medicine, University of Alberta, Edmonton, Canada 4. Belfast Health and Social Care Trust, UK

Disclosure:

Respiratory

Price has advisory board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline (GSK), Novartis, Viatris, and Teva Pharmaceuticals; consultancy agreements with AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Viatris, and Teva Pharmaceuticals; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Chiesi, Viatris, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, and UK National Health Service (NHS); payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Commune Digital, GSK, Medscape, Viatris, Novartis, Regeneron Pharmaceuticals and Sanofi Genzyme, and Teva Pharmaceuticals; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Novartis, Medscape, and Teva Pharmaceuticals; stock/stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals; owns 74.00% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 92.61% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); owns a 5.00% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GSK. Al-Ahmad has received advisory board and lecture honoraria from AstraZeneca, GSK, Novartis, and Sanofi. Bhutani has participated in speakers’ bureaux/advisory boards funded by AstraZeneca, Covis Pharma, GSK, Grifols, Pfizer, and Sanofi; has received grants or clinical trial support from Alberta Innovates Health Solutions, Alberta Lung Association, AstraZeneca, Boehringer Ingelheim, Canadian Institutes of Health Research, GSK, and Mereo BioPharma; and is President of the Canadian Thoracic Society, Past Co-chair of the Canadian Thoracic Society COPD Clinical Assembly, and Co-chair of the Royal College of Physicians and Surgeons Adult Respiratory Examination. Marley has received advisory board and lecture honoraria from AstraZeneca, GSK, Chiesi, Pfizer, and Boehringer Ingelheim.

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Acknowledgements:

Writing assistance was provided by Rachel Danks, RSD Medical Communications Ltd, Gloucestershire, UK.

Disclaimer:

The opinions expressed in this article belong solely to the named presenters.

Support:

The publication of this article was supported and funded by AstraZeneca.

Keywords:

Burden of disease, care pathway, discharge bundle, emergency department, Global Initiative for Asthma (GINA), severe asthma.

Citation:

EMJ Respir. 2023;11[1]:52-60. DOI/10.33590/emjrespir/10305242. https://doi.org/10.33590/emjrespir/10305242.

Meeting Summary Admissions due to asthma contribute substantially to the burden faced by emergency departments (ED) worldwide, with a considerable impact arising from the high number of readmissions among patients with severe asthma. Repeated ED readmittance not only places considerable demand on healthcare resources, but also increases the humanistic burden on patients through reduced lung function, decreased quality of life, and increased exposure to systemic corticosteroids (SCS) and oral corticosteroids (OCS). In addition, patients are subject to the increased morbidity and mortality risk, and quality of life deficit associated with repeated asthma exacerbations. Admission to the ED should be seen as an opportunity to break this readmission cycle and prevent further admissions, while offering patient-centric benefits, such as investigation into the underlying causes of disease, and optimisation of care to prevent further exacerbations. Actions that require no additional resource may be taken directly in the ED, including biomarker tests among routine blood tests, or teaching inhaler technique as part of patient education and safety-netting. In addition, patient discharge may be considered as an opportunity for improving guidance implementation and breaking the cycle of readmission. Unlike emergency cardiac care, where >90% of patients are discharged on secondary prevention drugs and 85% of patients are referred to follow-up rehabilitation, guidelines for care following an ED visit for asthma are not always followed. Furthermore, current tools designed to accelerate specialist referral are not always rigorously implemented following an ED visit, meaning that follow-up may be delayed. Finally, further efforts should be made to identify high-risk patients in the community earlier in the disease pathway, allowing timely intervention before further lung function impairment, or the onset of adverse events due to OCS over-exposure. This article summarises an AstraZeneca-sponsored symposium delivered on 12th September 2023, as part of the European Respiratory Society (ERS) International Congress in Milan, Italy. The faculty, consisting of David Price, Head of the Observational and Pragmatic Research Institute, Singapore; Mona Al-Ahmad, Consultant Allergist and Clinical Immunologist at the Ministry of Health in Kuwait; and Mohit Bhutani, Professor of Medicine at the University of Alberta, Edmonton, Canada, each gave a brief presentation on proactive strategies to improve longterm outcomes in acute respiratory care. During panel discussions following each presentation, Anne Marie Marley, Respiratory Nurse Consultant from Belfast Health and Social Care Trust, UK, provided examples of implementing transition of care by bridging hospital and community care settings.

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Introduction Approximately 262 million people have asthma globally, with around 1,000 asthma-related deaths every day.1 In Europe alone, the total direct cost associated with asthma, including drugs, inpatient care, and outpatient (including primary) care, is estimated to be 19.5 billion EUR (at 2011 values).2 The burden of unplanned care for chronic conditions tends to fall disproportionately on EDs, where frequent attendances can turn the ED into a critical pressure point,3-5 particularly during the winter months.6 Asthma is a major contributor to the total number of global ED visits every year,7-9 with 24% of patients (N=8,000) with asthma in 11 European countries having visited an ED in the previous 12 months.10

A disproportionate demand for emergency care is seen among the subset of patients with high-risk asthma, as these patients tend to return to the ED multiple times.11 In a longitudinal retrospective cohort study in Canada, the average number of ED visits for asthma exacerbations between April 2015–March 2020 was highest among patients with Global Initiative for Asthma (GINA) Step 5 asthma (0.5 visits/patient/year) compared with a similar rate of 0.3 visits/patient/year among GINA Steps 1–4.11 By 90 days, the readmission rate for patients with GINA Step 5 asthma was approximately 50% (Figure 1).11 The same study also showed that ED return within 7 days was highest among GINA Step 5 (28.4% of patients), compared with approximately 15% across all GINA stages, while approximately 25% of all ED visits had an outpatient visit in the preceding 30 days (from 21.4% to 35.6% among GINA 2

Figure 1: Percentage of emergency department visits with emergency department readmissions after an asthma-specific emergency department visit* (by baseline asthma severity).

A GINA 5

Time

GINA 3 ED

GINA

GINA 4

+90 days +60 days

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25%

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% of ED visits with ED readmission after an asthma-specific ED visit *All asthma-specific ED visits are included in this analysis (i.e., a patient may contribute to multiple visits over their entire follow-up). Longitudinal retrospective cohort study (April 2015–March 2020). Figure adapted with permission from Mayers et al.11 ED: emergency department; GINA: Global Initiative for Asthma.

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and GINA 5 patients, respectively).11 It should, therefore, be a matter of priority to break the cycle of ongoing readmissions in order to reduce the burden on acute respiratory care, and proactively improve long-term outcomes in severe asthma.

How Can We Address the Burden of Unplanned Hospitalisations? The ongoing burden of unplanned hospitalisations on healthcare resources remains a key healthcare challenge within the current era of precision medicine. Exacerbations can irreversibly decrease lung function in asthma, including a decline in forced expiratory volume in 1 second over the course of several years,12 while also increasing the risk of death.13 A cohort study of more than half a million patients with asthma in five European countries reported allcause mortality in the week following a severe asthma exacerbation of between 14.1–59.9/1,000 person-years.13 High rates of exacerbations lead to increased ED admissions, and a corresponding higher

exposure to OCS and SCS.14 While OCS therapy can be lifesaving in the acute setting, and is recommended in the GINA guidelines for the treatment of exacerbations in the ED,15 increased cumulative exposure to SCS/OCS through frequent ED readmissions increases morbidity among patients with asthma.16 It is concerning that the proportion of patients receiving OCS and SCS upon discharge from the ED is currently increasing.14 The known impact of cumulative OCS doses on adverse events and mortality provides a strong rationale for introducing strategies to reduce ED readmissions. However, despite the evidence of their benefit, secondary prevention measures are frequently not adequately implemented prior to, or immediately after, ED discharge.7,17 Although the ED is a resource-constrained setting focused on acute care, strategies can be integrated into ED management plans to support decision-making, early identification, and specialist input for patients at risk of exacerbations. There are a number of examples of different pathways, biomarkers, and tools that are available to improve patient outcomes (Table 1). The OCS Charter attempts to

Table 1: Potential strategies and interventions in the acute respiratory setting prior to patient discharge in high-risk asthma.

Type of strategy

Examples

Pathways

OCS charter recommendations:18 • Educate ED clinicians on specialist assessment, new treatments, and more appropriate OCS prescribing.1 • Ensure that patients are given the most appropriate treatment for their condition.

Biomarkers

ORACLE scale:19 • A risk assessment tool for future exacerbation risk based on variables, including FeNO and blood eosinophils.20

Tools

ReferID developed and funded by AstraZeneca (Cambridge, UK):21 • Web-based tool where HCPs can check if their patient should be referred to an asthma specialist.

ED: emergency department; FeNO: fractional exhaled nitric oxide; HCP: healthcare professional; OCS: oral corticosteroid; ORACLE: Oxford Asthma Attack Risk.

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help clinicians reduce reliance on OCS by recommending education on specialist assessment, new treatment options, and more appropriate OCS prescribing.18 The Oxford Asthma Attack Risk (ORACLE) scale is a tool that uses biomarker variables, such as fractional exhaled nitric oxide and blood eosinophils, to assess risk of future exacerbations, and allows treatment to be targeted appropriately.19,20 ReferID was developed and funded by AstraZeneca (Cambridge, UK) as a web-based tool that healthcare professionals can use to help identify patients with uncontrolled suspected severe asthma, and thus determine whether referral to an asthma specialist is appropriate.21

patients to confirm the diagnosis and determine management and treatment approaches, which may include OCS sparing strategies.15 In a prospective cohort study among patients with severe asthma and high OCS exposure, initiation of biologics was associated with a reduction of 0.09 in the risk of asthma-related ED visits, which is equivalent to a 65.0% reduction in comparison with patients not initiated on biologics (p=0.003; Figure 2).22 Initiation of biologic therapy following appropriate specialist referral may also have cost-saving potential, considering that the mean direct cost of treating a hospitalisation for a severe exacerbation has recently been estimated at 4,997 EUR per exacerbation.22

Given the impact that inappropriate care, both in the ED and on discharge, can have on patient morbidity and mortality, it is essential that appropriate guideline-recommended treatment is initiated at both timepoints. This includes taking steps to facilitate timely follow-up and early referral, and specialist input for appropriate

In order to improve outcomes for all patients, and to reduce the risk of readmission, the ultimate goal should be to initiate multidisciplinary team support for every patient who visits the acute respiratory setting with an exacerbation.

Figure 2: Change from baseline in asthma-related emergency department visits among patients who initiated and did not initiate biologic therapy (prospective cohort study; January 2015–February 2021).22 ED visits

Mean rate in last 12 months

2.0 1.6

-88.9%

-76.5%

1.2 1.8

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0.0 Bx initiated (n=996)

Bx not initiated (n=996) Baseline

Follow-up

Propensity score-matched, prospective cohort study using data from the International Severe Asthma Registry (January 2015–February 2021) among patients with severe asthma and high oral corticosteroid exposure. Biologic initiators were matched 1:1 with non-initiators. Figure adapted with permission from Chen et al.22 Bx: biologic therapy; ED: emergency department.

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The first panel discussion highlighted the need to improve the handover of care at the transition between the ED and the community. Marley noted that a large number of patients are lost to follow-up on discharge, and that respiratory experts should be hyperaware at the transitions between care sectors to support risk-stratified approaches to managing asthma patients, rather than all ED visits being considered the same. Bhutani commented that while emergency care focuses on immediate resolution of problems, the long-term consequences of the asthma remain unaddressed, further increasing the importance of early identification of high-risk patients in this setting. The discussion also considered the importance of communication at all stages of the care pathway. It was noted that patients may not be aware of the severity of their condition before they are admitted, and it is not clear whose responsibility it is to inform them. It is also essential that accurate communication is provided back to primary care when a person has been to the ED. Marley considered that respiratory specialists have a responsibility to work with these teams to ensure appropriate management is implemented following an ED admission.

How Can We Integrate Learnings From Cardiology to Improve Hospital Discharge and Prevent Readmission? When a patient comes into the ED with a myocardial infarction, discharge guidance includes steps to prevent recurrent myocardial infarction. This contrasts with the situation in respiratory medicine, where there is good knowledge of pharmacological and nonpharmacological strategies that can positively impact outcomes, and reduce the chance of another exacerbation; however, these approaches are not currently maximised. In addition, key checks for asthma are poorly implemented post-discharge,23 unlike the postmyocardial infarction environment where >90% of patients are discharged on secondary prevention drugs, and 85% of patients are referred to followup rehabilitation.24 Hospital admission should not be considered a failure in asthma management, but rather an

opportunity to change care and prevent further hospitalisations. There is plenty of evidence to demonstrate that specialist care can improve outcomes of patients with severe asthma, and that delayed referral is an avoidable factor related to deaths from asthma.25 The UK National Review of Asthma Deaths (NRAD) report by the Royal College of Physicians (RCP), London, UK, states that of all patients who died of asthma between February 2012–January 2013 (N=195), most (57%) were not under specialist supervision during the year prior to death.25 Furthermore, during this period, only 43% were managed in secondary or tertiary care.25 The report also found that 10% of patients had died within 28 days of hospital discharge; only 23% had been given a personal asthma action plan; and 25% were considered to have died because of a lack of knowledge of UK guidelines, as determined by expert panels. Worldwide studies have demonstrated that specialist assessment can lead to improved asthma control, reduced exacerbations, and lowered maintenance doses of OCS. For example, an analysis of 1,140 patients in the UK Severe Asthma Registry (UKSAR) reported that 1 year after specialist assessment and management, Asthma Control Questionnaire-6 (ACQ-6) score was reduced by a median interquartile range of 0.7 (0.0–1.5), while exacerbations and unscheduled secondary care were reduced by 75% (33–100%) and 100% (67–100%), respectively. In addition, forced expiratory volume in 1 second increased by a median interquartile range of 20 (-200–340) mL, and OCS dose was decreased in 67% of patients.26 The Severe Asthma Patient Charter provides recommendations for triggers for referral to an expert respiratory physician, which are if the patient has used OCS for more than 3 months, has had two or more courses of OCS treatment in the past 12 months, has been hospitalised for asthma in the past 12 months, or has impaired lung function despite optimised standard therapy.27 Many excellent tools already exist to help improve patient outcomes, including several respiratory ED and hospital discharge bundles that are available globally, but may be adapted for local use.28-31 For example, the British Thoracic Society (BTS) Asthma Discharge Care Bundle supports patient discharge from the ED,29 while the Australian Emergency

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Care Institute (ECI) and Agency for Clinical Innovation (ACI) specifies a care plan for patients being discharged from the ED.30 In addition, the American Academy of Allergy, Asthma & Immunology (AAAAI) sets out detailed requirements for an asthma discharge plan.31 While it can be difficult to implement change, there are resources available to support adoption of discharge bundles in local healthcare systems. Tips for implementing discharge protocols in chronic obstructive pulmonary disease (COPD) in real-world clinical practice have been published,32 which could also be appropriate in asthma.4,33 It is important that respiratory specialists seek opportunities to prevent recurrent exacerbations, and should make efforts to switch the perception of hospitalisation as a failure, instead regarding it as an opportunity to improve future outcomes. During the second panel discussion, Marley briefly described the care bundles that are in place following an admission for an acute exacerbation of COPD across a number of hospitals in Northern Ireland. She described how they have a well-resourced multidisciplinary team, including respiratory nurse specialists in hospitals and community teams, respiratory physiotherapists, psychologists, physiologists, dieticians, and general practitioners (GP) to champion shared ownership with patients, so that the bundle is incorporated into patient management plans. Marley described the approach taken to try to increase the recognition of COPD and asthma among commissioners and payers, by emphasising the mortality risk of poor respiratory care.

Asthma exacerbations are associated with a faster decline in lung function, particularly among younger patients.34 An historical cohort study of 109,182 patients with asthma in the Optimum Patient Care Research Database (OPCRD) reported that for each additional exacerbation, an estimated additional -1.34 L/min peak expiratory flow rate was lost per year (p<0.001). The largest effect occurred in patients aged 18–24 and 25–39 years at baseline.34 The recent ARRISA trial, funded by the UK’s National Institute for Health Research (NIHR) Health Technology Assessment Programme, aimed to identify high-risk patients with asthma by analysing anonymised, longitudinal medical records of 118,981 patients with actively treated asthma (aged 12–80 years) from UK databases.37,38 Interim 3-year data revealed predictors associated with future attacks, including baseline-year markers of attacks (acute OCS courses, emergency visits), more frequent reliever use and healthcare utilisation, worse lung function, current smoking, blood eosinophilia, rhinitis, nasal polyps, eczema, gastroesophageal reflux disease, obesity, older age, and being female.37 ARRISA demonstrates the value of identifying individuals at risk of adverse asthma events, and flagging their electronic health records, to allow primary care staff to deploy processes of care to improve management.38 Staff were also fully trained on the approach to ensure successful implementation.38

Beyond Acute Care: How Can We Prevent Emergency Department Admissions?

An ARRISA-type strategy allows the development of a register of high-risk patients who are given automatic accelerated access to healthcare appointments, provided with self-management plans, and given support for smoking cessation, access to vaccinations, and adherence monitoring. A pilot study showed a trend to reduce admissions, GP visits, steroid use, and cost of service use following the introduction of an at-risk asthma register in a GP setting (n=26).39

Finally, it is important to look beyond the acute setting, and consider ways to prevent the very first hospital admission or ED attendance. Recurrent exacerbations of asthma place a substantial humanistic burden on patients, through reduced lung function,34 decreased quality of life,35 and increased OCS/SCS use,36 while even occasional short courses of OCS can cause serious adverse effects.16

In the final discussion session following this presentation, Al-Ahmad commented that the priority now was to implement approaches such as those seen in the ARRISA trial, by educating the relevant stakeholders, providing all the necessary tools on a common standard platform, and co-ordinating the required actions. A clear call to action to the respiratory community was to utilise their leadership and identify high-risk

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patients earlier, supporting intervention before lung function is impaired, or adverse effects of OCS occur.

Conclusions The large number of ED readmissions among patients with severe asthma contributes greatly to the demand faced by EDs worldwide, leading to increased exposure to SCS and OCS, and raising the cost and clinical burden of severe asthma. ED visits should be considered an important opportunity to break the cycle of recurrent exacerbations and prevent further admissions, while reducing the impact on patients by limiting lung function decline and mortality risk. Immediate actions that may be taken in the ED to improve

References 1.

Global Asthma Network. The global asthma report. 2022. Available at: http://globalasthmareport. org/resources/Global_Asthma_ Report_2022.pd. Last accessed: 29 August 2023. European Respiratory Society (ERS). The European lung white book. 2013. Available at: https:// www.ersnet.org/the-europeanlung-white-book/. Last accessed: 29 August 2023. Kilkenny MF et al. Factors associated with 90-day readmission after stroke or transient ischemic attack: linked data From the Australian Stroke Clinical Registry. Stroke. 2020;51(2):571-8. Broderick JP, Abir M. Transitions of care for stroke patients: opportunities to improve outcomes. Circ Cardiovasc Qual Outcomes. 2015;8(6 Suppl 3):S190-2. Chiu YM et al. Persistent frequent emergency department users with chronic conditions: a populationbased cohort study. PLoS One. 2020;15(2):e0229022. Atkin C et al. Response to winter pressures in acute services: analysis from the Winter Society for Acute Medicine Benchmarking Audit. BMC Health Serv Res. 2022;22(1):17. Asthma UK. Asthma care in a crisis. Annual asthma survey 2020. Available at: https://www.

secondary prevention include training on inhaler technique, and use of biomarkers to support identification of high-risk patients. Guidance is available for the management of asthma both during and after an ED visit; however, in many cases this guidance is not being adopted. Respiratory medicine may be able to learn from other therapy areas, such as cardiology, that have reduced ED burden and readmissions by implementing care pathways and discharge bundles, looking beyond an acute/short-term focus to opportunities to treat underlying disease or causes of exacerbations. In addition, it is important to facilitate earlier identification and referral of high-risk patients from the community earlier in the disease course in order to improve patient outcomes and reduce burden.

asthmaandlung.org.uk/sites/ default/files/2023-03/aas2020_2a-1.pdf. Last accessed: 2 October 2023. 8.

Heffler E et al. The Severe Asthma Network in Italy: findings and perspectives. J Allergy Clin Immunol Pract. 2019;7(5):1462-8.

Qin X et al. Asthma-related emergency department (ED) visits and post-ED visit hospital and critical care admissions, National Hospital Ambulatory Medical Care Survey, 2010-2015. J Asthma. 2021;58(5):565-72.

10. Price D et al. Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey. NPJ Prim Care Respir Med. 2014;24:14009. 11. Mayers I et al. Rate of admission and readmission to the emergency department (ED) associated with physician visits among patients with asthma. Eur Respir J. 2022;60(Suppl 66):2306. 12. Bai TR et al. Severe exacerbations predict excess lung function decline in asthma. Eur Respir J. 2007;30(3):452-6. 13. Engelkes M et al. Multinational cohort study of mortality in patients with asthma and severe asthma. Respir Med. 2020;165:105919. 14. Hasegawa K et al. Comparison of US emergency department acute asthma care quality: 1997-2001

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and 2011-2012. J Allergy Clin Immunol. 2015;135(1):73-80. 15. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention 2023 update. Available at: https:// ginasthma.org/reports/. Last accessed: 29 August 2023. 16. Price DB et al. Adverse outcomes from initiation of systemic corticosteroids for asthma: long-term observational study. J Asthma Allergy. 2018;11:193-204. 17. Swart M et al. Secondary asthma prevention measures are not adequately addressed prior to emergency department discharge! Am J Emerg Med. 2022;53:196200. 18. Haughney J et al. A charter to fundamentally change the role of oral corticosteroids in the management of asthma. Adv Ther. 2023;40(6):2577-94. 19. Couillard S et al. Predicting the benefits of type-2 targeted antiinflammatory treatment with the prototype Oxford Asthma Attack Risk Scale (ORACLE). ERJ Open Res. 2021;8(1):00570-2021. 20. Couillard S et al. Derivation of a prototype asthma attack risk scale centred on blood eosinophils and exhaled nitric oxide. Thorax. 2022;77:199-202. 21. Beekman M et al. Breaking the vicious circle-the Asthma Referral Identifier (ReferID) tool. NPJ Prim Care Respir Med. 2022;32(1):40.

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22. Chen W et al. Impact of initiating biologics in patients with severe asthma on long-term oral corticosteroids or frequent rescue steroids (GLITTER): data from the International Severe Asthma Registry. J Allergy Clin Immunol Pract. 2023;11(9):2732-47. 23. Royal College of Emergency Medicine (RCEM). Moderate and acute severe asthma – clinical audit 2016/17. 2017. Available at: https://rcem.ac.uk/wp-content/ uploads/2021/11/Moderate_and_ Acute_Severe_Asthma_Clinical_ Audit_2016_17.pdf. Last accessed: 29 August 2023.

Ther. 2022;39(12):5307-26. 28. Shaw A et al. Using and implementing care bundles for patients with acute admission for COPD: qualitative study of healthcare professionals' experience in four hospitals in England. BMJ Open Respir Res. 2020;7(1):e000515. 29. British Thoracic Society (BTS). Asthma discharge care bundle. 2016. Available at: https://www. brit-thoracic.org.uk/media/70103/ annex-1-care-bundle-sheet-12dec-2016-v2.pdf. Last accessed: 29 August 2023.

24. National Cardiac Audit Programme. Myocardial Ischaemia National Audit Project (MINAP). 2022 summary report. Available at: https://www.nicor.org.uk/wpcontent/uploads/2022/06/NICORMINAP_2022-FINAL.pdf. Last accessed: 29 August 2023.

30. Emergency Care Institute (ECI). Asthma plan – emergency department discharge. 2020. Available at: https://aci.health. nsw.gov.au/networks/eci/clinical/ clinical-tools/respiratory/asthma/ discharge-aathma-patient. Last accessed: 29 August 2023.

25. Royal College of Physicians (RCP). Why asthma still kills: the national review of asthma deaths (NRAD). 2014. Available at: https://www. rcplondon.ac.uk/projects/outputs/ why-asthma-still-kills. Last accessed: 29 August 2023.

31. American Academy of Allergy, Asthma & Immunology (AAAAI). Asthma discharge plan. 2014. Available at: https://www.aaaai. org/Aaaai/media/Media-LibraryPDFs/Practice%20Management/ Practice%20Tools/AMA-PCPIMeasure-6_Asthma-DischargePlan.pdf. Last accessed: 29 August 2023.

26. Redmond C et al. Benefits of specialist severe asthma management: demographic and geographic disparities. Eur Respir J. 2022;60(6):2200660. 27. Menzies-Gow A et al. A renewed charter: key principles to improve patient care in severe asthma. Adv

32. Miravitlles M et al. Implementing an evidence-based COPD hospital discharge protocol: a narrative review and expert recommendations. Adv Ther. 2023;40(10):4236-63.

33. Cowie MR et al. The Optimize Heart Failure Care Program: initial lessons from global implementation. Int J Cardiol. 2017;236:340-4. 34. Soremekun S et al. Asthma exacerbations are associated with a decline in lung function: a longitudinal population-based study. Thorax. 2023;78(7):643-52. 35. Hossny E et al. Severe asthma and quality of life. World Allergy Organ J. 2017;10(1):28. 36. Busse WW et al. Uncontrolled asthma across GINA treatment steps 2 - 5 in a large US patient cohort. J Asthma. 2022;59(5):1051-62. 37. Blakey JD et al. Identifying risk of future asthma attacks using UK medical record data: a Respiratory Effectiveness Group initiative. J Allergy Clin Immunol Pract. 2017;5(4):1015-24.e8. 38. Smith JR et al. At-risk registers integrated into primary care to stop asthma crises in the UK (ARRISA-UK): study protocol for a pragmatic, cluster randomised trial with nested health economic and process evaluations. Trials. 2018;19(1):466. 39. Noble MJ et al. A controlled retrospective pilot study of an 'at-risk asthma register' in primary care. Prim Care Respir J. 2006;15(2):116-24.

Job code: Z4-59214 Date of preparation: October 2023

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Exploring Type 2 Inflammation in Chronic Obstructive Pulmonary Disease This symposium took place on 11th September 2023 as part of the European Respiratory Society (ERS) Congress held in Milan, Italy Chairperson:

Klaus Rabe1

Speakers:

Klaus Rabe,1 Stephanie Christenson,2 Dave Singh3 1. LungenClinic, Grosshansdorf, Germany 2. University of California, San Francisco, USA 3. The University of Manchester, UK

Disclosure:

Rabe has received grants and research support from the German Federal Ministry for Research and Technology (BMFT); honoraria or consultation fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GlaxoSmithKline (GSK), Menarini, Novartis, Sanofi, Regeneron, and Verona Pharma; and serves as the Director of the Airway Research Center North (ARCN) within the Deutsche Zentrum für Lungenforschung (DZL). Christenson has acted as a consultant to AstraZeneca, GSK, Glenmark, and Sanofi/Regeneron; and has provided writing services for UpToDate. Singh has received sponsorship to attend and speak at international meetings, honoraria for lecturing or attending advisory boards, and research grants from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, EpiEndo, Genentech, GSK, Glenmark, Gossamer Bio, Kinaset Therapeutics, Menarini, Novartis, Orion, Pulmatrix, Sanofi, Teva, Theravance Biopharma, and Verona Pharma.

Acknowledgements:

Medical writing assistance was provided by Deborah Liao, IMsci, Stamford, Connecticut, USA.

Support:

The symposium was sponsored by Sanofi and by Regeneron Pharmaceuticals Inc., and this article was commissioned and supported by the same companies. Sanofi and Regeneron Pharmaceuticals Inc. have reviewed this article for medical accuracy.

Citation:

EMJ Respir. 2023;11[1]:61-68. DOI/10.33590/emjrespir/10306588. https://doi.org/10.33590/emjrespir/10306588.

Meeting Summary This symposium took place during the 2023 meeting of the European Respiratory Society (ERS), with a focus on targeting chronic obstructive pulmonary disease (COPD) with Type 2 inflammation, and the emerging biologic landscape. The speakers discussed the clinical consequences of COPD through an understanding of pathological changes, the spectrum of inflammatory pathways, the role of Type 2 inflammation in the pathophysiology of COPD, and the evolving clinical landscape in COPD. Klaus Rabe, Full Member (Chair), LungenClinic, Grosshansdorf, Germany, utilised hypothetical clinical scenarios to contextualise the clinical presentation of COPD as a consequence of disease pathology, specifically chronic inflammation leading to structural changes of airways and parenchymal destruction resulting

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in airflow limitation, leading to worsening symptoms, and increasing further exacerbation risk. Stephanie Christenson, Assistant Professor of pulmonology at the University of California, San Francisco, USA, followed with a discussion of the heterogeneity of inflammatory pathways, exploration of distinct inflammatory cells and cytokines, and the evolving state of the knowledge of the diverse inflammatory pathways associated with COPD. COPD inflammation can be differentiated by distinct inflammatory cells and cytokines into Type 1/Type 3 inflammation (i.e., neutrophilic inflammation) and Type 2 inflammation. However, there is potential overlap in the various inflammatory mechanisms driving COPD via the alarmins IL33 and thymic stromal lymphopoietin. In addition, the key cytokines IL-4, IL-13, and IL-5 mediate the pathophysiology of COPD with Type 2 inflammation. Altogether, the heterogeneous inflammatory pathways contribute to characteristic features of COPD, fibrosis (small airways), wall thickening, airway remodelling, and clinical features, such as shortness of breath at rest. Dave Singh, Professor of respiratory pharmacology at The University of Manchester, UK, then discussed active areas of investigation in the development of additional treatments for patients with COPD.

Contextualising Clinical Presentation of Chronic Obstructive Pulmonary Disease Through Disease Pathology Klaus Rabe Rabe began the presentation by highlighting two hypothetical patients with different ages, physiologies, and backgrounds to contextualise the clinical presentation of COPD. Leonard is a 52-year-old patient with COPD, who is uncontrolled, on double therapy (long-acting β-agonist [LABA] or long-acting muscarinic antagonist [LAMA]), and for whom inhaled corticosteroids are contraindicated. His current symptoms include shortness of breath going uphill or taking stairs, constant cough with mucus production, and disruptive anxiety about his future. His BMI is 32 kg/m2, and he is a former smoker with a 15 pack-year history. His laboratory assessments were notable for blood eosinophil count of 120 cells/µL, a forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio of 0.63, and pre-bronchodilator FEV1 of 2.2 L (70% predicted). Clara is a 71-year-old patient with COPD, who is uncontrolled, on maximum inhaled therapy, and she has elevated eosinophils. Her current symptoms include cough, chest tightness, sleep disruption, fatigue, and anxiety about having exacerbations. She thinks her symptoms are due to her age. Her BMI is 29 kg/m2, and her laboratory assessments are notable for blood eosinophil count of 480 cells/µL, FEV1/FVC ratio 0.67, and pre-bronchodilator FEV1 1.8 L (65% predicted).

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Rabe then discussed how inflammatory changes, structural changes, and dynamic changes contribute to the impairment seen in patients with COPD, which is increasingly understood to be driven by chronic inflammation and structural changes. Chronic inflammation may be triggered by tobacco smoke, toxic particles or gases, viruses or bacteria, or oxidative stress.1-3 This inflammation drives structural changes in the airways (Figure 1). Compared with healthy airways, the airways of patients with COPD are characterised by barrier disruption, goblet cell hyperplasia, airway remodelling, inflammation, and excess mucus. Chronic inflammation also results in parenchymal destruction where alveolar membranes break down, and air trapping occurs. The combination of structural changes in the airways and parenchymal destruction results in airflow limitation.1-5 Pioneering research conducted by Hogg et al. showed that small airways (<2 mm in internal diameter) are the primary site for airflow limitation in COPD.6 Compared with healthy individuals, the small airways of patients with COPD feature mucus plugging, increased synthesis of mucin genes, and goblet cell hyperplasia and mucus production.6-10 But what does the clinical presentation look like? In a hypothetical patient like Leonard, this may present as a cough with sputum and shortness of breath. In a hypothetical patient like Clara, this might present as chest tightness. Notably, current smoking is associated with goblet cell hyperplasia in patients with COPD.11

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Figure 1: Chronic obstructive pulmonary disease is driven by chronic inflammation and structural changes.

COPD: chronic obstructive pulmonary disease.

Furthermore, small airways disease has implications for dynamic hyperinflation, commonly observed in patients with COPD. In dynamic hyperinflation, small airways disease causes expiratory airflow limitation, where the inhaled volume of air exceeds the exhaled volume of air, with a progressive increase in functional residual capacity and a decrease in inspiratory capacity.12 Clinically, this may present as shortness of breath, impaired and abnormal gas exchange, respiratory and peripheral muscle dysfunction, as well as hypercapnia, respiratory acidosis, and impaired cardiopulmonary interaction due to hypoxemia and retention of carbon dioxide.12,13 In a hypothetical patient like Leonard, his chief complaints may be a cough and shortness of breath, while a hypothetical patient like Clara may exhibit symptoms like a cough and chest tightness. More importantly, there are downstream consequences like exercise avoidance and reduced health-related quality of life (HRQoL) for patients with COPD.12 Exercise avoidance and reduced HRQoL are particularly relevant in patients with COPD and persistent symptoms. Respiratory symptoms, such as breathlessness, cough, and excess sputum, are associated with a reduction in physical activity. Symptoms are also associated

with poor HRQoL, anxiety, depressed mood, and sleep disturbance.2,14-16 In addition, a reduction in physical activity has implications for HRQoL, mood, and sleep, and vice versa.14 In a hypothetical patient like Leonard, persistent symptoms of COPD may manifest as shortness of breath when climbing or using stairs, while Clara may complain of sleep disturbance and fatigue, both affecting her quality of life. The concept of COPD as a disease limited to the lungs, airways, and lung parenchyma has evolved. It is well known that systemic inflammation is present in COPD, including both pulmonary and extrapulmonary systems. Pulmonary co-existing conditions present in patients with COPD are, among others, asthma, bronchiectasis, and pulmonary hypertension. Importantly, patients with COPD have a significantly increased risk of lung cancer.2,17,18 Extrapulmonary comorbidities include, among others, cardiovascular disease, osteoporosis, sleep disorders, anxiety, depression, metabolic syndrome, renal failure, and gastrointestinal disease.2,17-19 Importantly, worsening disease leads to a vicious cycle of COPD. Starting with initiating factors, this cycle descends into chronic inflammation and structural changes, with subsequent symptoms

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and COPD exacerbations at the centre of the cycle.1-3,20 Exacerbations lead to a further decline in lung function and prolonged recovery, along with elevated risk of mortality, further perpetuating the cycle of progressive disease.2,21-26 In summary, Rabe provided a comprehensive overview of COPD, emphasising the heterogeneity in its clinical presentation, which stems from the complex interplay of underlying disease mechanisms, risk factors, and environmental exposures. He highlighted how chronic inflammation drives structural changes in the airways, which manifests as airflow limitation leading to shortness of breath, a main COPD symptom, and increased exacerbation risk. Because of the symptoms and exacerbations present in COPD, patients experience a significant impact on their activities of daily living, limitations in physical activity, worsened HRQoL, and multimorbidities, all of which worsen as their COPD worsens. From a clinical perspective, the variability in COPD presentations underscores the need for tailored management strategies that account for the diverse facets of this complex disease.

Heterogeneity of Inflammatory Pathways in Chronic Obstructive Pulmonary Disease Stephanie Christenson Increased understanding of COPD has highlighted the existence of diverse inflammatory pathways in the lungs, with inflammation that can be differentiated by distinct inflammatory cells and cytokines. Type 1/Type 3 inflammation is characterised by elevated sputum neutrophils, elevated Type 1 cytotoxic T cells, T helper (Th)1 cells, and Th17 cells; elevated group 3 innate lymphoid cells; elevated cytokines, such as IL-1β, TNF-α; and poor response to corticosteroids.27,28 Type 1/Type 3 inflammation is observed in the majority of patients with COPD.29 COPD with Type 2 inflammation is characterised by elevated sputum eosinophils; elevated Th2 cells; elevated group 2 innate lymphoid cells; elevated Type 2 cytokines, such as IL-4, IL-13, and IL-5; and responsiveness to corticosteroids.27,30-32 Type 2 inflammation is believed to comprise an estimated 30–40% of patients with COPD,

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based on sputum eosinophils ≥3% and blood eosinophils ≥2%.33,34 Notably, there is potential overlap in Type 2 and Type 1/Type 3 inflammatory mechanisms driving COPD. Figure 2 illustrates the diverse inflammatory pathways associated with COPD, recognising that COPD is a complex disease, and not all pathophysiological pathways depicted may be specific to COPD. Viruses, bacteria, smoke, and/or pollutants can cause damage to an otherwise healthy airway epithelium via oxidative stress. The exposure triggers an inflammatory response, releasing alarmins (i.e., IL-25, IL-33, and thymic stromal lymphopoietin) from the airway epithelium and blood vessel endothelium. This process is common to both COPD with Type 2 and COPD with Type 1/Type 3 inflammation, with downstream inflammatory signalling. The chronicity leads to airway remodelling and fibrosis of the small airways, wall thickening, and mucus hyperproduction, which provides, at least partially, the clinical scenario of COPD.3-5,29,35-44 Specific to Type 1/Type 3 inflammation, the release of alarmins triggers several changes. Activated dendritic cells drive Th0 differentiation into Th1 and Th17 cells. Furthermore, epidermal growth factor ligands, alarmins, and IL-17 from Th1 cells enhance macrophage activation from the non-polarised to the polarised state. These polarised macrophages release IL-1β and TNF-α and, along with IL-17 released from Th17 cells, stimulate matrix metalloproteinase (MMP) production, and increase neutrophil levels.3,18,30,36-47 This is in comparison to Type 2 inflammation associated with COPD. The initial release of alarmins triggers Th0 differentiation into Th2 cells, mediated by dendritic cells, group 2 innate lymphoid cells, and TGF-β. Subsequently, Th2 cells release key cytokines (IL-4, IL-13, and IL-5), leading to a spectrum of outcomes.3,5,29,35,36,38,39,41,43 Pathologically, these cytokines induce goblet cell hyperplasia, heightened mucus production, disruptions in barrier integrity, and basal cell metaplasia/ hyperplasia. Clinically, these pathological changes culminate in the hallmark symptoms of COPD, notably sputum production, persistent cough, and increased breathlessness. Furthermore, the key cytokines IL-4, IL-13, and IL-5 trigger elevated levels of eosinophils in both blood and airways. Moreover, they stimulate

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Figure 2: The inflammatory pathways associated with chronic obstructive pulmonary disease are diverse.

*T cell differentiation takes place in lymph nodes and is included in the schematic for the purposes of illustration only. EGF: epidermal growth factor; ILC2: group 2 innate lymphoid cell; MMP: matrix metalloproteinase; Th: T helper cell; TSLP: thymic stromal lymphopoietin.

B cell class switching, triggering increased production of IgE, which, in turn, directly and indirectly prompts mast cell degranulation, and the release of additional inflammatory mediators. Additionally, MMP production and extracellular matrix degradation, though primarily observed in mouse models, represent another facet of the pathophysiological picture. Together, these pathophysiological changes have been associated with decreased FEV1 and broad remodelling, and can contribute to the distinct clinical features of COPD, such as worsening of respiratory symptoms.3,5,29,35-39,41,43 Notably, the potential role of Type 2 cytokines in COPD with Type 2 inflammation continues to be elucidated, and IL-4, IL-13, and IL-5 have distinct and overlapping effects on cell types involved in the pathophysiology of, and clinical outcomes observed in, COPD (Figure 3). Specifically, IL-4 is the key cytokine that induces the differentiation of naïve T cells into Th2 cells. Additionally, IL-4 stimulates basophil and mast cell degranulation.45 IL-13 plays a distinct role in goblet cell

hyperplasia and mucus production.7,46,47 IL-5 has a distinct role in eosinophil activation in the bone marrow.48 IL-4 and IL-13 have overlapping effects on B cell class switching and IgE production, barrier disruption, airway remodelling (e.g., fibrosis, wall thickening, and MMP production), and alveolar destruction and airway enlargement. All three key cytokines play a role in stimulating eosinophil trafficking to tissues.39,45,49-51 Clinically, this range of effects results in the characteristic airflow limitation seen in patients with COPD. With chronic inflammation, patients experience persistent symptoms (shortness of breath, chronic cough, sputum production), progressive lung function decline, and COPD exacerbations.2 In summary, Christenson highlighted the latest knowledge on the diverse inflammatory processes and pathways; the contribution of different pathways in causing pathologic changes; and the association between inflammation, pathologic changes, and clinical presentation in COPD. While there is some overlap in the inflammatory processes in Type 1/

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Figure 3: Potential roles of Type 2 cytokines in chronic obstructive pulmonary disease with Type 2 inflammation.

COPD: chronic obstructive pulmonary disease; ILC2: group 2 innate lymphoid cell; MMP: matrix metalloproteinase; PGD2: prostaglandin D2; Th2: T helper cell Type 2; TSLP: thymic stromal lymphopoietin.

Type 3 inflammation and Type 2 inflammation, there are distinct differences that have consequences for disease presentation, clinical presentation, and potentially for management. In addition, the heterogeneity of inflammatory pathways in COPD highlights the need for continued investigation to better understand the disease, and facilitate a more targeted management approach for patients.

Dave Singh

FVC <0.7) and initial severity classification: GOLD Grade 1 defined as FEV1 ≥80% predicted; GOLD Grade 2 defined as 50–79% predicted; GOLD Grade 3 defined as 30–49% predicted; and GOLD Grade 4 defined as <30% predicted. Patients with COPD categorised as an ‘A’; are characterised by 0 or 1 moderate exacerbations (not leading to hospitalisation), and low symptoms defined by a modified Medical Research Council (mMRC) score of 0–1 and COPD Assessment Test (CAT) score <10. Patients with COPD categorised as a ‘B’ have the same exacerbation history as patients categorised as an ‘A’, but with higher scores on mMRC (≥2) and CAT (≥10). Patients with COPD categorised as ‘E’ experience ≥2 moderate exacerbations or ≥1 leading to hospitalisation, regardless of symptoms, based on mMRC or CAT score.2

The clinical landscape in COPD continues to evolve rapidly, with implications for disease management. COPD classification for treatment continues to be guided by symptoms and exacerbations, as outlined in the 2023 Global Initiative for Chronic Obstructive Lung Disease (GOLD) ABE tool for initial assessment. Lung function confirmation is mandatory for the diagnosis of COPD (post-bronchodilator FEV1/

The future is a more targeted approach, based, in addition to these features, on biological understanding and other phenotypic and endotypic characteristics, which may link to some of the heterogeneous inflammatory pathways underpinning COPD, as discussed by Christenson. Singh highlighted several possible mechanisms that are under investigation, and in various stages of clinical development. While

The Evolving Clinical Landscape in Chronic Obstructive Pulmonary Disease and Implications for Disease Management

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it is not possible to delve into the details of the numerous clinical development programmes, it is notable that these programmes do encompass diverse COPD patient groups, which is particularly relevant for patients with COPD who experience exacerbations. As highlighted in the GOLD 2023 follow-up algorithm, blood eosinophil counts can be used to identify patients for whom treatment should be escalated. For patients treated with LABA or LAMA, who exacerbate and have a blood eosinophil count of ≥300, their treatment regimen should consist of LABA plus LAMA plus inhaled corticosteroids (ICS). If these patients continue to exacerbate despite escalation, the available options are limited. For patients who experience an exacerbation and have a blood eosinophil count <300, their treatment regimen should be escalated to LABA plus LAMA. From there, if they continue to experience exacerbations with a blood eosinophil count <100, treatment options are limited. For those with a blood eosinophil count ≥100, the next step is triple therapy with LABA plus LAMA plus ICS, though

References 1.

Barnes PJ. Inflammatory mechanisms in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2016;138(1):16-27. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. 2023. Available at: https://goldcopd.org/wp-content/ uploads/2023/03/GOLD-2023ver-1.3-17Feb2023_WMV.pdf. Last accessed: 23 June 2023. Linden D et al. Respiratory viral infection: a potential "missing link" in the pathogenesis of COPD. Eur Respir Rev. 2019;28(151):180063. Aghapour M et al. Airway epithelial barrier dysfunction in chronic obstructive pulmonary disease: role of cigarette smoke exposure. Am J Respir Cell Mol Biol. 2018;58(2):157-69.

ICS can be contraindicated in some patients.2 For a hypothetical clinical scenario like Leonard, he may have another treatment option following exacerbation on triple therapy. Subsequent treatment options are limited. In a hypothetical clinical scenario like Clara’s, uncontrolled on maximum inhaled therapy and with elevated eosinophils, there is an unmet need for additional treatment options after triple therapy. Singh summarised by noting that COPD is a mixed disease with mixed pathology. For some patients, Type 2 inflammation might be the dominant feature, while for others it may not be. Rabe, Christenson, and Singh further discussed the current excitement around COPD research, the complexity of the disease, and the movement of the field towards a better understanding of patient phenotypes and endotypes. With the treatment landscape evolving, phenotyping patients will be crucial to optimising patient care. Rabe concluded the symposium by thanking his co-panellists and the audience.

obstructive pulmonary disease. N Engl J Med. 2004;350(26):264553. 7.

Alevy YG et al. IL-13-induced airway mucus production is attenuated by MAPK13 inhibition. J Clin Invest. 2012;122(12):4555-68.

Fritzsching B et al. Hypoxic epithelial necrosis triggers neutrophilic inflammation via IL-1 receptor signaling in cystic fibrosis lung disease. Am J Respir Crit Care Med. 2015;191(8):902-13.

Polosukhin VV et al. Small airway determinants of airflow limitation in chronic obstructive pulmonary disease. Thorax. 2021;76(11):107988.

10. de Oliveira Rodrigues S et al. Mechanisms, pathophysiology and currently proposed treatments of chronic obstructive pulmonary disease. Pharmaceuticals (Basel). 2021;14(10):979.

Ruysseveldt E et al. Airway basal cells, protectors of epithelial walls in health and respiratory diseases. Front Allergy. 2021;2:787128.

11. Kim V et al. Chronic bronchitis and current smoking are associated with more goblet cells in moderate to severe COPD and smokers without airflow obstruction. PLoS One. 2015;10(2):e0116108.

Hogg JC et al. The nature of small-airway obstruction in chronic

12. Usmani OS et al. Why we should target small airways disease

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in our management of chronic obstructive pulmonary disease. Mayo Clin Proc. 2021;96(9):244863. 13. Rossi A et al. Mechanisms, assessment and therapeutic implications of lung hyperinflation in COPD. Respir Med. 2015;109(7):785-802. 14. Miravitlles M, Ribera A. Understanding the impact of symptoms on the burden of COPD. Respir Res. 2017;18(1):67. 15. Kessler R et al. Patient understanding, detection, and experience of COPD exacerbations: an observational, interview-based study. Chest. 2006;130(1):133-42. 16. Jones SE et al. Pulmonary rehabilitation in patients with an acute exacerbation of chronic obstructive pulmonary disease. J Thorac Dis. 2018;10(Suppl 12):S1390-9. 17. Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J. 2009;33(5):1165-85. 18. Dal Negro RW et al. Prevalence of different comorbidities in COPD patients by gender and GOLD

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stage. Multidiscip Respir Med. 2015;10(1):24. 19. Gaddam S et al. Prevalence of chronic kidney disease in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. BMC Pulm Med. 2016;16(1):158. 20. Stolz D et al. Towards the elimination of chronic obstructive pulmonary disease: a Lancet commission. Lancet. 2022;400(10356):921-72. 21. Donaldson GC et al. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57(10):84752. 22. Garcia-Aymerich J et al. Lung function impairment, COPD hospitalisations and subsequent mortality. Thorax. 2011;66(7):58590. 23. Hansel TT, Barnes PJ. New drugs for exacerbations of chronic obstructive pulmonary disease. Lancet. 2009;374(9691):744-55. 24. Hogea SP et al. Risk factors of chronic obstructive pulmonary disease exacerbations. Clin Resp J. 2020;14(3):183-97. 25. Jamieson DB et al. Effects of allergic phenotype on respiratory symptoms and exacerbations in pa-tients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;188(2):187-92. 26. Wageck B et al. Recovery following acute exacerbations of chronic obstructive pulmonary disease - a review. COPD. 2019;16(1):93-103. 27. Barnes PJ. Inflammatory endotypes in COPD. Allergy. 2019;74(7):124956. 28. Chen L et al. The imbalance between subsets of CD8(+) peripheral blood T cells in patients with chronic obstructive pulmonary disease. PeerJ. 2016;4:e2301. 29. Yousuf A et al. T2 biologics for chronic obstructive pulmonary disease. J Allergy Clin Immunol Pract. 2019;7(5):1405-16.

production by bronchoalveolar lavage T lymphocytes in chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2006;117(6):1484-92. 31. Christenson SA et al. AsthmaCOPD overlap. Clinical relevance of genomic signatures of type 2 inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;191(7):758-66. 32. Ghebre MA et al. Biological exacerbation clusters demonstrate asthma and chronic obstructive pulmonary disease overlap with distinct mediator and microbiome profiles. J Allergy Clin Immunol. 2018;141(6):2027-36.e12. 33. Leigh R et al. Stable COPD: predicting benefit from high-dose inhaled corticosteroid treatment. Eur Respir J. 2006;27(5):964-71. 34. Singh D et al. Eosinophilic inflammation in COPD: prevalence and clinical characteristics. Eur Respir J. 2014;44(6):1697-700. 35. Arora S et al. Macrophages: their role, activation and polarization in pulmonary diseases. Immunobiology. 2018;223(4-5):383-96.

43. Poto R et al. Angiogenesis, lymphangiogenesis, and inflammation in chronic obstructive pulmonary disease (COPD): few certainties and many outstanding questions. Cells. 2022;11(10):1720. 44. Vremec D et al. Production of interferons by dendritic cells, plasmacytoid cells, natural killer cells, and interferon-producing killer dendritic cells. Blood. 2007;109(3):1165-73. 45. Gandhi NA et al. Commonality of the IL-4/IL-13 pathway in atopic diseases. Expert Rev Clin Immunol. 2017;13(5):425-37. 46. Zhu Z et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest. 1999;103(6):779-88.

36. Barnes PJ. The cytokine network in asthma and chronic obstructive pulmonary disease. J Clin Invest. 2008;118(11):3546-56.

47. Zheng T et al. Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase- and cathepsin-dependent emphysema. J Clin Invest. 2000;106(9):1081-93.

37. Christopoulou M-E et al. Matrix metalloproteinases in chronic obstructive pulmonary disease. Int J Mol Sci. 2023;24(4):3786.

48. Gandhi NA et al. Targeting key proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov. 2016;15(1):35-50.

38. Dey S et al. Pathogenesis, clinical features of asthma COPD overlap, and therapeutic modalities. Am J Physiol Lung Cell Mol Physiol. 2022;322:L64-83.

49. Cooper PR et al. Involvement of IL-13 in tobacco smoke-induced changes in the structure and function of rat intrapulmonary airways. Am J Respir Cell Mol Biol. 2010;43(2):220-6.

39. Doyle AD et al. Eosinophil-derived IL-13 promotes emphysema. Eur Respir J. 2019;53(5):1801291. 40. Freeman CM, Curtis JL. Lung dendritic cells: shaping immune responses throughout chronic obstructive pulmonary disease progression. Am J Respir Cell Mol Biol. 2017;56(2):152-9. 41. Liu M et al. Emerging biological functions of IL-17A: a new target in chronic obstructive pulmonary disease? Front Pharmacol.

30. Barczyk A et al. Cytokine

2021;12:695957. 42. Papi A et al. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med. 2006;173(10):1114-21.

50. Lee CG et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1). J Exp Med. 2001;194(6):809-21. 51. Saatian B et al. Interleukin-4 and interleukin-13 cause barrier dysfunction in human airway epithelial cells. Tissue Barriers. 2013;1(2):e24333.

MAT-GLB-2304728 v1 10/2023 FOR REPRINT QUERIES PLEASE CONTACT: INFO@EMJREVIEWS.COM

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Poster Review

Efficiency Assessment of 15 Nebuliser Systems by the Respirable Drug Delivery Rate: A Comparable Quality Parameter This poster presentation took place on 12th September 2023, at the Congress of the European Respiratory Society (ERS) held from 9th–13th September 2023 in Milan, Italy Presenter:

Ralf Fischer1 1. Medical Affairs, PARI GmbH, Starnberg, Germany

Disclosure:

Fischer is an employee of Medical Affairs at PARI GmbH.

Acknowledgements:

The presenter thanks Filip Jukic and Rosina Ledermüller for their contributions to the study. Writing assistance was provided by Nicola Humphry, Nottingham, UK.

Support:

The publication of this article was supported by PARI GmbH.

Disclaimer:

The opinions expressed in this article belong solely to the named presenter.

Keywords:

Efficiency, inhalation, nebuliser therapy, respirable drug, respiratory disease.

Citation:

EMJ Respir. 2023;11[1]:69-73. DOI/10.33590/emjrespir/10303785. https://doi.org/10.33590/emjrespir/10303785.

Meeting Summary Nebuliser therapy is a relevant therapy option for respiratory diseases, yet studies have demonstrated a wide variation in nebuliser drug delivery efficiency. This study assessed the aerosol performance of 15 commercially available nebuliser systems based on a European standard, and calculated the respirable drug delivery rate (RDDR) as an objective, clinically important measure of efficiency. Findings confirmed that the efficiency of nebuliser systems differs significantly, which could potentially impact the therapeutic success of the drug delivered. The authors of the study recommend that physicians select a device with a high RDDR to ensure that patients receive clinically effective doses in a short time and thus achieve the best possible treatment effect.

Introduction For physicians, it can be a challenge to identify the performance differences between the many nebuliser systems available on the market. Nebuliser therapy is a relevant therapy option for respiratory diseases. Studies have demonstrated a wide variation in nebuliser drug delivery efficiency.1,2 Ralf Fischer, Medical Affairs Manager

at PARI GmbH, Starnberg, Germany, stressed that sufficient and targeted drug deposition appropriate to the underlying lung disease, severity stage, and patient population is the crucial factor for clinically successful nebuliser therapy. Consequently, National Institute for Health and Care Excellence (NICE) guidelines recommend the use of a nebuliser system that is “known to be efficient.”3

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Pulmonary drug deposition is significantly influenced by aerosol characteristics, airway anatomy, and breathing pattern of the patient.1 Of these three factors, the choice of an efficient nebuliser is a rapidly effective way for a medical practitioner to optimise aerosol delivery.1 Today, clinicians can select from a vast range of jet nebuliser systems, but there are limited objective comparison data available to help them make this choice. The current European standard for nebuliser systems (EN ISO 27427) recommends that aerosol output (AO), aerosol output rate (AOR), and mass median aerodynamic diameter (MMAD) are reported by manufacturers, to allow for comparisons to be made between systems.2 However, these values are of limited relevance from a clinical point of view. For example, a high AO does not necessarily mean a high amount of drug in the lungs. Only the combination of AO with respirable fraction (RF; representing the proportion of particles <5 µm) to calculate the respirable dose (RD) indicates how much therapeutically effective aerosol potentially reaches the lungs. RD can be calculated as RD=RF×AO.2 Fischer emphasised that nebuliser efficiency depends not only on RD, but also on the rate at which the RD is delivered. Thus, the

respirable drug delivery rate (RDDR=RF×AOR) represents an objective and clinically more relevant parameter for nebuliser efficiency (Figure 1). For these reasons, a study was conducted to assess aerosol performance of commercially available nebuliser systems according to the EN ISO 27427, which provides a benchmark comparison of aerosol performance on a standardised basis. From these data, the RDDR was calculated as an objective measure of efficiency.

Methods Fifteen types of jet nebuliser systems were evaluated. For each type of nebuliser, AO, AOR, MMAD, and RF of three individual systems were measured in duplicate, providing a total of six readings. Nebulisers were filled with 2 mL of 0.1% (w/v) salbutamol. Salbutamol amount was determined by a validated ultraviolet detector-tagged highperformance liquid chromatography system. AO, AOR, and nebulisation time were measured with

Figure 1: Respirable drug delivery rate.

Low RDDR

High RDDR

Less active substance in the lungs per minute

More active substance in the lungs per minute

Reproduced with permission from PARI GmbH. RDDR: respirable drug delivery rate.

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Results

a PARI COMPAS breath simulator (PARI GmbH, Starnberg, Germany) using a tidal volume of 500 mL, 15 breaths/min, with an inhalation:exhalation ratio of 50:50. MMAD and RF were measured with a cooled (17 °C) Next Generation Impactor (Copley Scientific, Nottingham, UK) at 50% relative humidity and 23 °C ambient conditions, at a flow rate of 15 L/min. RD was calculated as the product of AO and RF. RDDR was calculated as the product of AOR and RF.

The systems with the highest AO were the Omron C28P/Omron X105 (OMRON Healthcare, Kyoto, Japan), PARI COMPACT2 (PARI GmbH), and MPV MicroDrop® Family2 (MVP Medical GmbH, Munich, Germany; 530 μL, 520 μL, and 520 μL salbutamol, respectively). The AO of these systems was almost three-times higher than the system with the lowest AO, the aponorm® Compact PLUS (Microlife, Widnau, Switzerland) on the maximum setting (190 μL; Figure 2).

Significance comparison of the mean RDDR was assessed using analysis of variance and Fisher pairwise comparisons, with a significance level of p<0.05.

Figure 2: Mean aerosol output and respirable dose across 15 jet nebuliser types.

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Error bars indicate standard deviation. Reproduced with permission from PARI GmbH. ĩɟȻͽˍʡ͝ɟ̿‫͝ڂ‬ΰͮ͝ɟ˪ aponorm® Compact Kids: Microlife, Widnau, Switzerland; aponorm® Compact PLUS: Microlife; Atomisor® Classic Aerodjinn+ 28NL0MU: DTF Medical, Saint-Etienne, France; Atomisor® Classic Aerodjinn+ NL9MP: DTF Medical; BRM-085II: Bairui Medicine Co, Guangzhou, China; MVP MicroDrop® Family2: MVP Medical GmbH, Munich, Germany; Omron C28P/OMRON X105 Advanced: OMRON Healthcare, Kyoto, Japan; Omron NE C900/COMP AIR Pro: OMRON Healthcare; PARI BOY® Classic/Pro (blue NA): PARI GmbH; PARI BOY® Junior (yellow NA): PARI GmbH; PARI BOY® Pro/Junior (red NA): PARI GmbH; PARI COMPACT2: PARI GmbH; Philips InnoSpire Deluxe: Philips, Amsterdam, the Netherlands; Philips InnoSpire Elegance: Philips; Yuwell 403H: Yuwell, Shanghai, China. AO: aerosol output; NA: nozzle attachment; RD: respirable dose.

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In terms of the more clinically relevant parameter, RD, the PARI BOY® Junior (yellow nozzle attachment [NA]; PARI GmbH), PARI COMPACT2 (PARI GmbH), and MPV MicroDrop® Family2 (MVP Medical GmbH) had the highest RD values among the evaluated nebuliser systems (363 μL, 358 μL, and 317 μL, respectively).

The RDDR, which considers the duration of nebulisation, also varied considerably. The nebuliser system with the highest RDDR displayed a value approximately three-fold higher than the system with the lowest RDDR. The PARI BOY® Junior (yellow NA; PARI GmbH), the PARI COMPACT2 (PARI GmbH), and the PARI BOY® Classic/Pro (blue NA; PARI GmbH) showed the highest RDDR values (115 μL/min, 105 μL/ min, and 99 μ/min, respectively), which differed significantly (p<0.05) from all other nebulisers tested (Figure 3).

The AO and RD data showed that a nebuliser system with a high AO does not necessarily deliver a high amount of RD. However, RD is a crucial parameter for the success of nebuliser therapy.

Figure 3: Mean respirable drug delivery rate across 15 jet nebuliser types.

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Nebuliser system

ĩɟȻͽˍʡ͝ɟ̿‫͝ڂ‬ΰͮ͝ɟ˪

ԋ Ԇԅԋ Ԇԅԋ ԐԐ Error ԐԐ bars ԏԆ indicate ԏԆ ԏԆ 95% ԏԆ confidence ԎԐ ԎԐ ԍԎ ԍԎ ԍԅ ԍԅ interval.

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Reproduced with permission from PARINebuliser GmbH. Nebuliser system system aponorm® Compact Kids: Microlife, Widnau, Switzerland; aponorm® Compact PLUS: Microlife; Atomisor® Classic Aerodjinn+ 28NL0MU: DTF Medical, Saint-Etienne, France; Atomisor® Classic Aerodjinn+ NL9MP: DTF Medical; BRM-085II: Bairui Medicine Co, Guangzhou, China; MVP MicroDrop® Family2: MVP Medical GmbH, Munich, Germany; Omron C28P/OMRON X105 Advanced: OMRON Healthcare, Kyoto, Japan; Omron NE C900/COMP AIR Pro: OMRON Healthcare; PARI BOY® Classic/Pro (blue NA): PARI GmbH; PARI BOY® Junior (yellow NA): PARI GmbH; PARI BOY® Pro/Junior (red NA): PARI GmbH; PARI COMPACT2: PARI GmbH; Philips InnoSpire Deluxe: Philips, Amsterdam, the Netherlands; Philips InnoSpire Elegance: Philips; Yuwell 403H: Yuwell, Shanghai, China. NA: nozzle attachment; RDDR: respirable drug delivery rate.

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Conclusions Findings from this study confirmed that the efficiency of commercially available nebuliser systems differs significantly. Fischer pointed out that these performance variations could potentially impact the therapeutic success of the drug delivered through the nebuliser, by underdosing or delayed symptom relief. In the case of nebulised antibiotics, for example, insufficient nebuliser efficiency has been implicated in the development of resistance.

References 1.

Vechellio L et al. Disposable versus reusable jet nebulizers for cystic fibrosis treatment with tobramycin. J Cyst Fibros. 2011;10(2):86-92. Hatley RH, SM Byrne. Variability in delivered dose and respirable delivered dose from nebulizers: are current regulatory testing guidelines sufficient to produce

In vitro studies found that less efficient nebulisers did not achieve the minimal inhibitory concentrations of antibiotics sufficient to eradicate a target organism.4 Fischer concluded that the RDDR represents an objective parameter for the efficiency of a nebuliser system. He emphasised that physicians should select a device with a high RDDR to ensure that patients receive clinically effective doses in a short time, and thus achieve the best possible therapeutic effect.

meaningful information? Med Devices (Auckl). 2017;10:17-28. 3.

National Institute for Health and Care Excellence (NICE). Chronic obstructive pulmonary disease in over 16s: diagnosis and management. 2019. Available at: https://www. nice.org.uk/guidance/ng115/ resources/chronic-obstructivepulmonary-disease-in-over-16s-

diagnosis-and-managementpdf-66141600098245. Last accessed: 7 August 2023. 4.

Moore JE et al. The role of suboptimal concentrations of nebulized tobramycin in driving antimicrobial resistance in Pseudomonas aeruginosa isolates in cystic fibrosis. Respir Care. 2021;66(9):1446-57.

041D0719 FOR REPRINT QUERIES PLEASE CONTACT: INFO@EMJREVIEWS.COM

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Abstract Reviews Featuring insightful research from the European Respiratory Society (ERS) International Congress 2023, exploring the heterogeneity in clinical presentations of tuberculosis in adults attending primary care across England and deep learning in predicting idiopathic pulmonary fibrosis outcomes.

The Clinical Presentation of Tuberculosis in English Primary Care Authors: *Farah Kidy,1 Shamil Haroon2

will only see one case of TB every 7 years. Clinical heterogeneity and a lack of information about presentation to primary care compounds the difficulty in identifying potential cases. To improve the timely diagnosis of TB, the authors aimed to describe the primary care presentation of adults with TB in England.

MATERIALS AND METHODS

1. University of Warwick, Coventry, UK 2. University of Birmingham, UK *Correspondence to f.kidy@warwick.ac.uk

Acknowledgements: The authors would like to acknowledge and thank Noel McCarthy, University of Dublin, Ireland; and Krishnarajah Nirantharakumar, University of Birmingham, UK, for sharing their expertise in data access and interpretation, and for co-authorship of the original abstract presented at the European Respiratory Society International Congress 2023.

Coded demographic information and 5 years of prediagnostic clinical data were extracted from English primary care records held by the nationally representative Clinical Practice Research Datalink (CPRD) Aurum and Gold databases.2,3 All patients aged ≥18 years and diagnosed with TB from 2011–2020 were eligible. Thirty signs and symptoms of interest were identified through a rapid literature review, followed by discussion with patients and healthcare professionals. Data were extracted and processed using the data extraction for epidemiological research (DExtER) tool.4 Summary statistics and graphical methods were used to describe patients and their signs and symptoms, using Stata v17 (Stata, College Station, Texas, USA).

Keywords: Diagnosis, primary care, symptoms, tuberculosis (TB).

RESULTS

Disclosure: Kidy is funded by the National Institute for Health and Care Research (NIHR) Doctoral Research Fellowship, grant number 300688. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Haroon has received grants from the NIHR, NIHR Clinical research network, and UK Research and Innovation (UKRI).

Citation: EMJ Respir. 2023;11[1]:74-75. DOI/10.33590/emjrespir/10301471. https://doi.org/10.33590/emjrespir/10301471.

BACKGROUND AND AIMS The incidence of tuberculosis (TB) in England has decreased annually since 2011. However, the time from symptom onset to treatment initiation remains stubbornly elevated.1 The average general practitioner in England

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In total, 14,571 cases and 67,605 symptom codes were identified. Age at diagnosis ranged from 18– 95 years, and 45% were female. Approximately one-third identified as White, and a further third identified as South Asian. Additionally, 32% came from the most deprived decile in England, 24% had pulmonary disease, 11% had extra-pulmonary disease, and site was unspecified in 65%. Cases experienced between zero (19.6% of cases) to 15 different symptoms, and 67%

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Figure 1: Distribution of Group 1, 2, and 3 symptoms and the time intervals at which they occurred.

Group 3

Group 2

Group 1

Y axes are presented on different scales due to the large difference in numbers in the lead up to diagnosis.

experienced one to four symptoms (median: 2; interquartile range: 2). Older adults, females, and those with comorbidities experienced a broader range of symptoms. The three most commonly occurring symptoms were cough (seen in 5,389 cases and 16.3% of all symptoms), back pain (n=4,197; 21.7%), and abdominal pain (n=2,822; 8.5%). The three least commonly occurring symptoms were chills (n=43; 0.1%), renal masses (n=35; 0.1%), and spinal deformity (n=24; 0.1%). Symptoms normally associated with TB, such as weight loss (2.5% of symptoms), fever (3.3%), and night sweats (0.7%), were infrequent. The interval between symptom onset and diagnosis ranged from 0 days to 5 years. Symptoms grossly followed one of three patterns (Figure 1). Group 1 symptoms (e.g., haemoptysis, anorexia, etc.) were characterised by being mostly recorded 6–7 months before diagnosis. Group 2 symptoms (chest pain, fatigue, pyuria, etc.) also had a peak in recording in the months before diagnosis, but this was not as distinct from the background rate, as in Group 1 symptoms. By contrast, no such pattern was seen in Group 3 symptoms (e.g., abdominal pain and headaches).

CONCLUSION TB is a heterogenous disease. Even in a large cohort of patients, typical symptoms are rarely

recorded in primary care, and their absence cannot be interpreted as the absence of TB disease. There are also important variations in the presentation of subgroups, with distinct patterns of symptoms. The study is limited by using coded data, which may miss information about symptoms held in free text entries in electronic healthcare records.5 Further research could investigate the sequence in appearance of symptoms to further characterise the primary presentation of patients with TB. Guidelines for primary care should consider the findings of this study. ●

References 1.

UK Health Security Agency. TB incidence and epidemiology in England, 2021. 2023. Available at: https://www.gov.uk/government/publications/ tuberculosis-in-england-2022-report-data-up-toend-of-2021/tb-incidence-and-epidemiology-inengland-2021. Last accessed: 27 July 2023.

Herrett E et al. Data resource profile: Clinical Practice Research Datalink (CPRD). Int J Epidemiol. 2015;44(3):827-36.

Wolf A et al. Data resource profile: Clinical Practice Research Datalink (CPRD) Aurum. Int J Epidemiol. 2019;48(6):1740-1740g.

Gokhale KM et al. Data extraction for epidemiological research (DExtER): a novel tool for automated clinical epidemiology studies. Eur J Epidemiol. 2021;36(2):16578.

Anoop DS et al. Long Covid symptoms and diagnosis in primary care: a cohort study using structured and unstructured data in The Health Improvement Network primary care database. medRxiv. 2023;DOI:10.1101/2023. 01.06.23284202.

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Deep Learning-Based Quantification of Traction Bronchiectasis Severity For Predicting Outcome in Idiopathic Pulmonary Fibrosis Authors: *F. Felder,1 Y. Nan,1 G. Yang,1 J. Mackintosh,2 L. Calandriello,3,4 N. Goh,5-7 P. Hopkins,2,8 Y. Moodley,9 P. Reynolds,10 T. Corte,11 V. Navaratnam,12,13 S. Walsh1 1.

National Heart and Lung Institute, Imperial College London, UK 2. Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Australia 3. Department of Diagnostic Imaging, Radiotherapy, Oncology, and Hematology, Agostino Gemelli University Policlinic, Rome, Italy 4. Istituto di Ricovero e Cura a Carattere Scientifico (IRCSS), Rome, Italy 5. Department of Respiratory and Sleep Medicine, Austin Health, Melbourne, Australia 6. Institute for Breathing and Sleep, Melbourne, Australia 7. University of Melbourne, Australia 8. Faculty of Medicine, University of Queensland, Brisbane, Australia 9. School of Medicine and Pharmacology, University of Western Australia, Perth, Australia 10. Royal Adelaide Hospital Chest Clinic, Adelaide, Australia 11. Respiratory Medicine, Royal Prince Alfred Hospital, Sydney, Australia 12. Department of Respiratory Medicine, Sir Charles Gardiner Hospital, Perth, Western Australia, Australia 13. University of Western Australia Medical School, Western Australia, Australia *Correspondence to ffelder@ic.ac.uk Disclosure: Please click here for author disclosures. Acknowledgements: The authors would like to acknowledge and thank Mario Silva, University of Parma, Italy; Ian Glaspole, Alfred Hospital, Melbourne, Australia; Wendy Cooper, New South Wales Health Pathology, Sydney, Australia, Royal Prince Alfred Hospital, Sydney, Australia, and University of Sydney, Australia; Christopher Grainge, John Hunter Hospital, Australia; and Athol Wells, National Heart and Lung Institute, Imperial College London, UK, and Royal Brompton Hospital, London, UK, for their contributions to this research, and co-authorship of the original abstract presented at the European Respiratory Society International Congress 2023.

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Keywords: Artificial intelligence, high-resolution CT (HRCT), interstitial lung disease, predictor of mortality, predictor of progression, prognosis, pulmonary fibrosis, traction bronchiectasis. Citation: EMJ Respir. 2023;11[1]:76-78. DOI/10.33590/emjrespir/10307156. https://doi.org/10.33590/emjrespir/10307156.

BACKGROUND AND AIMS Idiopathic pulmonary fibrosis (IPF) is inexorably progressive. Like IPF, other fibrotic lung diseases can exhibit this progression, and these are called progressive fibrotic phenotypes. Early identification of these phenotypes is crucial to initiate treatment promptly.1-4 The severity of traction bronchiectasis, when visually assessed, is a strong predictor of mortality in patients with fibrotic lung disease. However, semi-quantitative methods have limitations, which can be addressed by the application of quantitative methods.5-7 The objective of this investigation is to explore the prognostic utility of a novel deep-learning algorithm in quantifying the severity of traction bronchiectasis in patients with IPF, who are enrolled in the Australian IPF Registry (AIPFR).

MATERIALS AND METHODS Visual evaluation of high-resolution CT (HRCT) from the AIPFR was performed by two expert thoracic radiologists evaluated. Total airway volume (TAV) was quantified using a novel 3D U-Net-based deep-learning algorithm. Systematic objective fibrotic imaging analysis algorithm (SOFIA) usual interstitial pneumonia (UIP) probability scores were obtained using a previously reported deep-learning algorithm, trained in the identification of UIP features.5 The prognostic utility of automated airway volume quantification was evaluated against conventional measures of disease severity and SOFIA-based UIP probability scores.

RESULTS AND DISCUSSION In total, 217 HRCTs were amenable to algorithmic airway volume quantification. TAV was an independent predictor of mortality

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when controlling for visual-based evaluation of total fibrosis extent (hazard ratio [HR]: 1.96; p<0.0001), % predicted forced vital capacity (FVC; HR: 2.15; p<0.0001), or the composite physiologic index (CPI; HR: 1.52; p=0.02). On bivariable analysis, both TAV (HR: 2.13; p<0.0001) and SOFIA-UIP probability (HR: 1.30; p<0.0001) independently predicted mortality. Patients were divided based on INBUILD criteria (Group 1: ‘UIP-like fibrotic pattern’, HRCT showing UIP or probable UIP, or surgical lung biopsy showing possible, probable, or definite UIP; and Group 2: ‘other fibrotic patterns’, remaining patients).1 On bivariable analysis with total fibrosis extent, TAV independently predicted mortality in Group 1 (HR: 1.50; p=0.03), and was the only predictor of mortality (HR: 5.33; p<0.0001) in Group 2. An increase in TAV of 1% of total lung volume was associated with a three-fold increased likelihood of developing progressive disease (FVC/diffusing capacity of the lungs for carbon monoxide decline of 10% and 15%, respectively, at 12 months; odds ratio: 3.04; p=0.009) when controlling for total fibrosis extent.

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IPF exhibits an unpredictable and progressive clinical course. This means that, despite treatment, IPF is inherently progressive, akin to other interstitial lung diseases categorised as progressive phenotypes. Recognising progression is crucial to avoid delaying the onset of treatment and preventing clinical deterioration, ensuring timely intervention for the disease. For IPF, progression is typically defined as a 10% or greater decline in FVC, or a 15% or greater decline in diffusing capacity of the lungs for carbon monoxide over 12 months, or sustained over 18 months, or in cases of death or transplantation.8,9 FVC is the most widely accepted marker and primary endpoint in clinical trials. However, it has limitations, like data loss, variability, and susceptibility to the influence of emphysema, prompting the exploration of alternative markers. CT holds promise as a prognostic marker. Traction bronchiectasis has proven to be a

Figure 1: Segmentation of the airway.

The terminal bronchus is shown in red, the small bronchus in green, the medium bronchi in blue, and the large bronchi in yellow.

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Nasser M et al. Progressive fibrosing interstitial lung disease: a clinical cohort (the PROGRESS study). Eur Respir J. 2021;57(2):2002718.

Takei R et al. Prevalence and prognosis of chronic fibrosing interstitial lung diseases with a progressive phenotype. Respirology. 2022;27(5):333-40.

Walsh SLF et al. Deep learning for classifying fibrotic lung disease on high-resolution computed tomography: a case-cohort study. Lancet Respir Med. 2018;6(11):83745.

Jacob J et al. Serial CT analysis in idiopathic pulmonary fibrosis: comparison of visual features that determine patient outcome. Thorax. 2020;75(8):648-54.

Walsh SLF et al. Imaging research in fibrotic lung disease; applying deep learning to unsolved problems. Lancet Respir Med. 2020;8(11):1144-53.

CONCLUSION

In IPF, automated quantification of TAV predicts mortality independently of total fibrosis extent on HRCT, and can be used to identify patients at risk of progression at 12 months. ●

Jo HE et al. Baseline characteristics of idiopathic pulmonary fibrosis: analysis from the Australian Idiopathic Pulmonary Fibrosis Registry. Eur Respir J. 2017;49(2):1601592. Erratum in: Eur Respir J. 2017;49(3):1651592.

Jo HE et al. Disease progression in idiopathic pulmonary fibrosis with mild physiological impairment: analysis from the Australian IPF registry. BMC Pulm Med. 2018;18(1):19.

powerful sign of progression. Yet, most studies evaluating them rely on semi-quantitative methods, which are susceptible to low reproducibility and inter-observer variability, and are unable to capture subtle changes over a short timeframe.5-7,10,11 TAV objectively identifies patients at risk of progression, aiding clinical decision-making and stratification of patients in clinical trials. Compared to FVC, TAV is a reliable short-term evaluation method (Figure 1).

References 1.

Flaherty KR et al.; INBUILD Trial Investigators. Nintedanib in progressive fibrosing interstitial lung diseases. New Engl J Med. 2019;381(18):1718-27. Walsh SLF et al. Deep learning-based outcome prediction in progressive fibrotic lung disease using high-resolution computed tomography. Am J Respir Crit Care Med. 2022;206(7):883-91.

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10. De Giacomi F et al. Short-term automated quantification of radiologic changes in the characterization of idiopathic pulmonary fibrosis versus nonspecific interstitial pneumonia and prediction of long-term survival. J Thorac Imaging. 2018;33(2):124-31. 11. Hwang J-H et al. Longitudinal follow-up of fibrosing interstitial pneumonia: relationship between physiologic testing, computed tomography changes, and survival rate. J Thorac Imaging. 2011;26(3):209-17.

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Abstract Highlights The following highlights spotlight selected abstracts presented at the European Respiratory Society (ERS) International Congress 2023. They cover key topics, including persistent airflow limitation in paediatric severe asthma, pulmonary rehabilitation, health-related quality of life, chronic cough and obstructive sleep apnoea, paediatric lung transplantation, dead space ventilation in acute respiratory distress syndrome, and virtual wards for remote patient monitoring. Citation:

EMJ Respir. 2023;11[1]:79-87. DOI/10.33590/emjrespir/10308482. https://doi.org/10.33590/emjrespir/10308482.

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Association Between Minimal Important Distance and Survival After Pulmonary Rehabilitation IMPROVED walking distance more than the minimal important distance (MID) is positively associated with survival after pulmonary rehabilitation (PR), according to data presented by Thomas Ward, University of Leicester, UK, at the ERS International Congress 2023. While PR has been associated with survival, it is unknown whether this is due to a direct effect or unmeasured confounding, which is why Ward and colleagues aimed to investigate this association. The team analysed data on consenting patients from PR services in England and Wales between January–April 2015, as well as mortality data until January 2017. They performed Cox proportional hazard regression, which compared time of death between achieving MID, and not achieving MID, using 35 m for the incremental shuttle walking distance, and 25 m for the 6-minute walking distance.

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In total, 3,721 out of 4,159 (89%) patients completed walk tests before and after PR (55% male; mean age: 70.3 [standard deviation: 8.8] years; forced expiratory volume 1: 1.38 [0.58] L). Mean change was 63 (2) m for incremental shuttle walking distance, and 57 (2) m for 6-minute walking distance. By January 2017, 273 patients had died. The team noted lower unadjusted and adjusted mortality rates for those who achieved the MID in either of the walk tests.

"The team noted lower unadjusted and adjusted mortality rates for those who achieved the MID." The team concluded that there was a positive association between improved walking distance more than the MID and survival, which could indicate a direct effect of completing PR. ●

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Paediatric Lung Transplantation for Children with Interstitial Lung Disease CHILDREN’S interstitial lung disease (ChILD) is a rare and heterogenous condition that can cause significant morbidity and mortality. At present, little is known about patients with end-stage ChILD who undergo lung transplantation. Research presented at the ERS International Congress 2023 analysed sub-entities of ChILD, according to the current classification, that lead to end-stage respiratory failure along with age at transplantation. Underlying diagnoses, clinical information, and outcome were also recorded for each included patient who underwent lung transplantation. Overall, 103 patients were included (52% female; mean age at transplantation: 12.0±5.1 years). During the study period, 31 patients had ChILD (35% female; mean age at transplantation: 8.0±5.7 years), with the pretransplant status being ‘ventilated’ in seven of these patients. Most patients undergoing transplantation in the programme were in the B3 category, which consists mainly of children after stem

cell transplantation with severe bronchiolitis, or children after radiation or chemotherapy for oncologic diseases. Results showed that 27 (90%) of included patients were alive after a median follow-up time of 4.11 years. In the four deceased patients, the causes of death were chronic lung allograft dysfunction, unsuccessful re-transplantation, infection, graft failure, and adenovirus infection. The authors acknowledge that the study is limited due to its short follow-up time, and use of a single centre cohort. However, there are no other cohorts available to investigate ChILD in this way. Overall, the research suggests paediatric lung transplantation is feasible for patients with ChILD and end-stage lung disease, as the overall outcome in this cohort is “excellent.” ●

"Paediatric lung transplantation is feasible for patients with ChILD and end-stage lung disease."

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Virtual Wards in Respiratory Medicine VIRTUAL wards took centre stage in the form of an abstract presentation at the ERS International Congress 2023. Sivakamasundari Narayani Ampikaipakan, Norfolk and Norwich University Hospitals (NNUH) NHS Foundation Trust, UK, described the effectiveness of a virtual ward in delivering respiratory care, and looked at whether this is a sustainable enterprise for the future. “One of the biggest changes was the use of digital technology, and the evolution of the virtual ward,” is how Ampikaipakan described their experience working at NNUH in the post COVID-19 era. The ward operates 24/7, and was established to mirror a full clinical team, featuring 40 beds, full monitoring of observations, and a daily consultant review. This research involved a retrospective review of prospectively collected data on all patients admitted to the virtual ward at NNUH, conducted between February 2021–2023. Patient inclusion criteria for the study were conditions of chronic obstructive pulmonary disease, bronchiectasis, pneumonia, empyema, COVID-19, and tuberculosis. In total, 484 patients were

put through the ward, with an average length of stay of 6.8 days, and 98.6% satisfaction rate. The bed days saved by this virtual ward was a staggering 3,282. Benefits of the virtual ward include a lower risk of hospital-acquired infections and associated issues with extended stays in hospital, as well as improved recovery and comfort for a patient receiving care in their own home environment. Ampikaipakan drew attention to the support clinicians have provided for this practice as a new and flexible way of working, especially as it promotes increased flow in a busy tertiary care hospital. Across all specialties, over 2,500 patients have made their way through the NNUH ward to date, with close to 600 coming from the respiratory bracket. This research received a lot of positive media attention as the first 24/7 virtual ward in the UK, and this success is expected to encourage more of this type of practice to spread across the UK, and internationally. Ampikaipakan concluded: “We believe that the virtual ward for respiratory medicine is indeed sustainable.” ●

"In total, 484 patients were put through the ward, with an average length of stay of 6.8 days, and 98.6% satisfaction rate."

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Severe Asthma: Impact of Symptoms on Health-Related Quality of Life DYSPNOEA is the main symptom impacting asthma health-related quality of life (HRQoL) for patients with severe asthma, findings from a cross-sectional study presented at the ERS International Congress 2023 reveal.

vital capacity (%FEV1/FVC) were measured for all participants. The mean % predicted FEV1 was 70%±19%, and mean %FEV1/FVC was 70%±12%. The mean global AQLQ was 4.0±1.4, and the Asthma Control Test (ACT) mean was 13.0±5.5.

Gilles Louis, Department of Public Health, University of Liège, Belgium, and colleagues enrolled 143 patients from the Liège University Hospital asthma clinic aged ≥18 years, with a diagnosis of severe asthma prior to commencement of biologic therapy. They aimed to assess the relationship between the five main patient-reported asthma symptoms, and asthmaHRQoL and its four dimensions (symptom, activity, emotive, and environmental).

Each of the five main asthma symptoms were found to be significantly correlated with global AQLQ. Multiple linear regression analyses were performed to identify symptoms independently associated with global AQLQ and its dimensions, after adjusting for the ACT, age, BMI, % predicted FEV1, %FEV1/FVC, and sex. This identified dyspnoea as the only symptom significantly associated with global AQLQ (p<0.0500), and an independent predictor of the activity dimension (p<0.0001). Cough was found to be an independent predictor of the environmental dimension (p<0.01), and both cough and airway secretion were found to be independent predictors with the emotive dimension (p<0.01).

The five main patient-reported symptoms were airway secretion, chest tightness, cough, dyspnoea, and wheezing. Asthma-HRQoL was measured using the mini Asthma Quality of Life questionnaire (AQLQ), and symptom intensity was measured through use of five-point Likert scales. Baseline characteristics revealed that the mean participant age was 52±16 years, mean BMI was 28.0±5.3, and 64% of patients were female. The percentage predicted forced expiratory volume in 1 second (FEV1; % predicted FEV1), and the percentage forced expiratory volume/forced

From these findings, the authors concluded that dyspnoea is the main symptom associated with global AQLQ in patients with severe asthma, and that each symptom has a variable impact on different dimensions of the AQLQ. ●

"Each of the five main asthma symptoms were found to be significantly correlated with global AQLQ."

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Dead Space Ventilation and Mortality in Acute Respiratory Distress Syndrome ACUTE respiratory distress syndrome (ARDS) is commonly linked with elevated levels of ventilation-perfusion heterogeneity and dead space ventilation. However, the precise connection between the extent of dead space ventilation and patient outcomes has remained unclear.

Incorporating a total of 28 studies into their review, they were able to include 21 of these in their subsequent meta-analysis. All but one of these studies exhibited a low risk of bias. Notably, the review primarily focused on two widely studied indices: space fraction (VD/VT) and ventilatory ratio.

At the ERS International Congress 2023, Dilip Jayasimhan, Waikato Hospital, Hamilton, New Zealand, unveiled their systematic review and meta-analysis. Their research delved into the potential of various dead space ventilation metrics to serve as predictors of mortality among patients with ARDS.

A VD/VT exceeding 0.6 showed a substantial association with elevated mortality risk (odds ratio: 3.53; 95% confidence interval: 2.22–5.58). Furthermore, for each 0.05 increment in VD/VT, there was an independent and significant increase in the odds of death (odds ratio: 1.25; 95% confidence interval: 1.06–1.48). Notably, sensitivity analysis demonstrated robustness, even in limited studies adjusting for oxygenation, lung compliance, positive end-expiratory pressure, and baseline illness severity.

Jayasimhan and colleagues systematically searched through MEDLINE Central and Google Scholar databases. Their inclusion criteria comprised studies involving adults with ARDS that reported dead space ventilation metrics and mortality rates. Utilising a random effects model, they conducted a comprehensive meta-analysis of both unadjusted and adjusted outcomes. The I2 statistic was employed to evaluate heterogeneity among the studies, while the quality in prognostic studies tool was used to assess the risk of bias.

In summary, the findings reveal that among adults with ARDS, a high dead space ventilation measure (particularly VD/VT and ventilatory ratio) is independently associated with increased mortality. ●

"Utilising a random effects model, they conducted a comprehensive metaanalysis of both unadjusted and adjusted outcomes."

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Is Chronic Cough Associated with Obstructive Sleep Apnoea? CHRONIC cough is not associated with obstructive sleep apnoea (OSA), according to a late-breaking abstract presented at the ERS International Congress 2023. Laurent Guilleminault, Toulouse University Hospital; Toulouse Institute for Infectious and Inflammatory Diseases, INSERM U1291, France; and University of Toulouse, F-CRIN CRISALIS, France, and colleagues, conducted a cohort study to investigate if an association between chronic cough and severe OSA exists. Consecutive patients undergoing nocturnal polygraphy or polysomnography for suspected OSA in two French hospitals were prospectively enrolled; in total, 822 were included in the study. OSA was defined as an apnoea-hypopnoea index (AHI) of ≥15 events/hour, and chronic cough was defined as a cough present for ≥8 weeks. The authors collected demographic data and nocturnal recording parameters. Bias introduced by confounding variables was controlled for using propensity score matching based on age; BMI; sex; and the presence of asthma, rhinosinusitis, and gastro-oesophageal reflux. The mean age of the cohort was 52.9±14.9 years, mean BMI was 30.18±7.00 kg/m2, and 44.3% were female.

Within the cohort, the mean AHI was 20.1±22.0 events/hour, and severe OSA, defined as ≥30 events/hour, was seen in 25.1%. The overall prevalence of chronic cough was 13.4%. Interestingly, the authors found no difference in AHI values and categories between those with and without chronic cough (p=0.62). Furthermore, no association between chronic cough and severe OSA was observed after applying the propensity score (p=0.84), and these findings were similar for patients with mild and moderate OSA.

"No association between chronic cough and severe OSA was observed." The researchers concluded that there was no association between chronic cough and OSA in this large cohort of patients being investigated for suspected OSA, given that AHI values were similar between those with and without chronic cough, there was no excess of OSA in those with chronic cough, and the prevalence of chronic cough was similar in patients with and without OSA. ●

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Early Life Factors and Persistent Airflow Limitation in Childhood Severe Asthma ADVERSE exposures in early life are associated with unfavourable lung function trajectories and persistent airflow limitation (PAL), according to several population-based studies. The relationship in children with severe therapy-resistant asthma (STRA) and PAL is not as well documented. New data presented by Sormeh Salehian, Imperial College London, UK, presented at the ERS International Congress 2023, aim to analyse the relationship between early life disadvantage factors and PAL in children with STRA. Salehian and colleagues carried out their research on 147 children with STRA. Of this group, 120 had spirometry data to assess PAL, which was defined as a forced expiratory volume in 1 second z-score of no more than -1.96 postbronchodilator and post-systemic steroid trial (IM triamcinolone).

PAL was identified in 30 out of 120 (25%) children with STRA. Birthweight, gestational age, infant feeding, passive smoking, and index of multiple deprivation were the early life factors assessed. The results showed that low birthweight, defined as below 2.6 kg, was associated with a lower overall forced expiratory volume in 1 second z-score of -1.553 versus -0.658 (p=0.04). However, low birthweight was not significantly associated with PAL. Furthermore, there was no significant association between PAL and gestational age or method of infant feeding. The team concluded that PAL is common in children with STRA; however, there are no associations between early life risk factors and the development of PAL. This indicates that the mechanism for PAL in children with STRA may differ to that of those with less severe asthma. ●

"The relationship in children with severe therapy-resistant asthma (STRA) and PAL is not as well documented."

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Abstract Highlights

Emphysema: Treatable Traits in Patients Eligible for Bronchoscopic Lung Volume Reduction TREATABLE traits are highly prevalent in patients with advanced emphysema who are eligible for bronchoscopic lung volume reduction (BLVR). The number of these traits is correlated with health-related quality of life (HRQoL), according to research presented at the ERS International Congress 2023. Treatable traits characterise the heterogeneity and complexity of chronic obstructive pulmonary disease. BLVR using one-way endobronchial valves (EBV) is an effective treatment in patients who have a specific phenotype with the treatable traits. This phenotype is advanced emphysema with severe hyperinflation. However, the prevalence of other treatable traits in patients with this phenotype, and the relationship of these to HRQoL, is not well understood. To overcome this, Rein Posthuma, Ciro, Horn, the Netherlands, and colleagues evaluated the spectrum of treatable traits in patients with chronic obstructive pulmonary disease eligible for BLVR-endobronchial valve treatment, to determine which of the 16 pre-defined treatable traits were associated with worse HRQoL. These treatable traits included severe dyspnoea, very severe airflow limitation, frequent exacerbations, poor exercise capacity, low physical activity, hypoxaemia, hypercapnia, underweight, obesity, low muscle mass, decreased bone mineral density, impaired handgrip force, impaired quadriceps force, severe fatigue, anxiety, and depression. HRQoL was based on the St. George’s Respiratory Questionnaire (SGRQ), and scores were split into high (SGRQ ≥60) and low (SGRQ <60). Logistic regression analysis was used to assess odds ratios for the treatable traits.

In total, 96 patients were included in the study, of whom 36.5% were male. The mean forced expiratory volume in 1 second in the cohort was 28.3%±7.8% predicted, and mean residual volume was 231.1%±39.3% predicted. Fifty-three percent of participants had an SGRQ score of ≥60 points, and the mean SGRQ score was 60±12 points. The overall mean number of treatable traits per person was 7.6±2.7, with low physical activity, severe fatigue, and low muscle mass being most prevalent. A unique combination of treatable traits was seen in 96% of patients (n=92). The findings showed that with increased numbers of treatable traits per patient, the SGRQ score was higher (r=0.527; p<0.001).

"A unique combination of treatable traits was seen in 96% of patients." In patients with an SGRQ score of ≥60 points, severe fatigue, anxiety, and depression had statistically significant odds ratios for poorer HRQoL when compared to those with an SGRQ score of <60 points. The highest odds ratio was seen for severe fatigue, measured with checklist individual strength (6.5). The team concluded that in the cohort of patients with advanced emphysema eligible for BLVR EBV, there was a high prevalence and co-occurrence of multiple treatable traits, and that having a higher number of these treatable traits correlated with poorer HRQoL. This highlights the need to study the efficacy of combined management with EBV and pulmonary rehabilitation in the future. ●

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Interview EMJ had the pleasure of interviewing Luca Bertolaccini, who shared insights into lung cancer surgery, exploring minimally invasive techniques, role of the multi-disciplinary team in lung cancer treatment, and the potential for artificial intelligence in the field. Bertolaccini also shared advice for younger clinicians hoping to specialise in thoracic surgery in the future.

Luca Bertolaccini Department of Thoracic Surgery, Istituto Europeo di Oncologia (IEO), European Institute of Oncology IRCCS, Milan, Italy EMJ Respir. 2023; DOI/10.33590/emjrespir/10302711. https://doi.org/10.33590/emjrespir/10302711.

Citation:

What led you to specialise in lung cancer surgery after completing your medical training? The decision to perform lung cancer surgery was influenced by various factors. I have a strong interest in surgical procedures and a passion for treating lung-related diseases, and lung cancer surgery can significantly impact patients’ lives and improve their wellbeing. Furthermore, lung cancer is one of the leading causes of cancerrelated deaths globally. Surgeons specialising in lung cancer can work with diverse patients, and address critical healthcare needs. There are constant advancements in surgical techniques, technologies, and treatment options for lung cancer, which also attracted me, and I am excited about staying at the forefront of medical innovation. I am also interested in clinical research.

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Lung cancer treatment often involves a multidisciplinary approach, involving medical oncologists, radiologists, pulmonologists, and other specialists. Since I enjoy collaborative patient care, I found lung cancer surgery appealing. And, finally, challenging cases can be intellectually stimulating and rewarding for surgeons who enjoy solving intricate medical puzzles.

In May of this year, you co-authored a paper, entitled ‘Next-Generation Lung Cancer Surgery: A Brief Trip into the Future of the Research’. Could you summarise the main advances discussed in the paper and your hopes for the future of lung cancer surgery? In this paper, we discussed several key advances and considerations in lung cancer surgery with Lorenzo Spaggiari, Professor and Director of the Lung Program and Division of Thoracic Surgery at the Istituto Europeo di Oncologia

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(IEO), European Institute of Oncology IRCCS Milan, Italy, such as the prevalence and need for advancement. Lung cancer is a significant global health issue with high mortality rates. Non-small cell lung cancer (NSCLC) constitutes a large portion of lung cancer cases, and, due to the lack of effective screening and low survival rates, it remains a significant focus of scientific research. Another point that we discussed is minimally invasive surgery. The standard treatment for early-stage NSCLC is anatomic lobectomy and lymph node dissection. Minimally invasive techniques, such as video-assisted thoracoscopic surgery and robotic-assisted thoracoscopic surgery (RATS), have become the norm due to better outcomes than traditional open surgery. These techniques offer benefits like shorter recovery times and reduced invasiveness. The role of sub-lobar resection (segmentectomy and wedge resections) is debated. There are studies evaluating the feasibility and safety of these approaches. Current evidence suggests that lobectomy may be preferable for early-stage NSCLC in specific patient groups, but ongoing trials aim to provide more clarity on this matter. We also discussed adequate lymphadenectomy, which is crucial for proper staging and treatment outcomes. Studies emphasise the importance of dissecting sufficient lymph nodes to ensure accurate staging and better patient prognoses. However, patients with ipsilateral and/or subcarinal mediastinal lymphatic spread (N2) Stage III NSCLC face poor prognoses. Studies suggest that post-operative radiotherapy alone, or combined with chemotherapy, can extend survival, especially in more extensive nodal disease cases. Extra-nodal extension, where cancer cells extend beyond lymph nodes, strongly predicts poor outcomes in NSCLC. Recent research highlights its significance and association with recurrence and mortality. In terms of hopes for the future of lung cancer surgery, this paper underscores the ongoing need for advancements and research due to the persistent challenges of lung cancer. We anticipate further refinements in surgical techniques, including minimally invasive approaches like RATS. We hope for an improved understanding of patient selection criteria for sub-lobar resections, and more evidence from

ongoing trials to guide treatment decisions. Advances in imaging and staging techniques like PET/CT are expected to continue, aiding in accurate diagnosis and treatment planning. Ultimately, the goal is to enhance patient outcomes and survival rates through improved surgical methods, precision in lymph node dissection, and comprehensive treatment strategies for various stages of lung cancer.

The surgical options for NSCLC include segmentectomy and lobectomy. What are the pros and cons of these, and does the current evidence indicate that one is more favourable than the other? Segmentectomy and lobectomy are surgical options for treating NSCLC, and the choice between them depends on various factors, such as the tumour’s size, location, and the patient’s overall health. Each approach has pros and cons, and deciding which is more favourable can vary based on individual circumstances. Segmentectomy can preserve lung function as it removes only a portion of the lung, preserving more healthy lung tissue than lobectomy. This can be advantageous for patients with compromised lung function. It can also lower morbidity. A smaller resection may lead to a shorter hospital stay and quicker recovery time, reducing the risk of complications, especially in patients with limited cardiopulmonary reserve. Finally, segmentectomy might be more suitable for older patients, or those with medical conditions that make a complete lobectomy riskier. However, segmentectomy can increase the risk of local recurrence. In some instances, removing a smaller portion of the lung may leave residual cancer cells behind, leading to a potentially higher risk of local recurrence. It also has limited applicability, as segmentectomy is typically suitable for smaller tumours that are located in a way that allows for the safe removal of a specific lung segment. Larger or more centrally located tumours might not be suitable for this approach. Finally, segmentectomy might not involve a thorough lymph node evaluation, potentially affecting staging accuracy in some cases. Lobectomy, on the other hand, has higher oncological radicality. Lobectomy removes the entire lung lobe containing the tumour,

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minimising the risk of local recurrence due to residual cancer cells. Lobectomy also allows for more thorough lymph node evaluation, aiding in accurate staging and treatment planning. Finally, it has a wide applicability, and can be used for a broader range of tumour sizes and locations, providing a potentially curative option for many patients. However, there is a more significant loss of lung function when removing an entire lobe, which might be a concern for patients with limited lung capacity. There is generally a longer recovery time with lobectomy, and there may be a higher risk of complications. Moreover, lobectomy might not be suitable for older patients, or those at high-risk with underlying health issues that could complicate recovery. As for the question of whether one approach is more favourable than the other, it is essential to note that the choice between segmentectomy and lobectomy is highly individualised. Current evidence suggests that segmentectomy can yield comparable survival outcomes for smaller tumours in specific locations, while preserving more lung function. However, lobectomy might be more appropriate for larger tumours, or in cases where a more aggressive approach is required. Ultimately, the decision should carefully consider the patient’s overall health and tumour characteristics, and there should be a thorough discussion between the patient and the medical team. A multidisciplinary collaboration involving surgeons, oncologists, and other specialists is crucial to determining the best treatment strategy for individuals with NSCLC.

Since starting your career, what do you think has been the most significant change in the field of lung cancer surgery? One of the most significant changes in the field of lung cancer surgery over the years has been the adoption and advancement of minimally invasive surgical techniques. These techniques, such as video-assisted thoracoscopic surgery and RATS, have revolutionised lung cancer surgeries. Adopting these minimally invasive techniques has significantly improved lung cancer surgery, improving patient outcomes, quality of life, and overall treatment experience. It is important to note that deciding to use a specific surgical approach depends on factors

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such as the patient’s medical condition, tumour characteristics, and the surgeon’s expertise.

"Adopting these minimally invasive techniques has significantly improved lung cancer surgery." Other notable advancements in lung cancer surgery include the integration of precision medicine, improvements in imaging technologies, better perioperative care protocols, and the ongoing refinement of surgical techniques to enhance patient outcomes, and minimise the impact of surgery on the patient’s life.

You have an interest in minimally invasive thoracic surgery. Are there any innovations on the horizon that you are excited for or any aspects that require further attention to improve outcomes? There are some notable advancements and areas of ongoing research, as well as some innovations on the horizon, including single-incision surgery. Advanced and enhanced imaging technologies, such as real-time 3D imaging and augmented reality, could provide surgeons with improved visualisation and navigation during minimally invasive procedures, leading to even more precise surgeries, The continued development of robotic surgical systems could lead to more sophisticated and precise movements during minimally invasive thoracic surgeries. These systems might become more widely accessible, enhancing surgeons’ capabilities. Artificial intelligence (AI)-powered tools could assist surgeons in planning procedures, analysing imaging data, and even providing real-time guidance during surgery, leading to better decision-making and outcomes. However, there are areas that require further attention. For example, there should be a focus on training and skill development. Ensuring that surgeons are adequately trained to perform these complex procedures is crucial as minimally invasive techniques evolve. Training programmes and simulation tools can help surgeons develop the skills needed for optimal outcomes. There should also be a standardisation of techniques.

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The field benefits from guidelines and best practices that ensure consistency and quality across different surgical teams and institutions. Identifying the most suitable patients for minimally invasive approaches remains essential. Tailoring the approach to individual patient characteristics can lead to better outcomes and avoid potential complications. Patients should be well-informed about the benefits, risks, and potential outcomes of minimally invasive surgery to make informed decisions about their treatment. While minimally invasive surgery has shown promising short-term outcomes, ongoing research is needed to assess its impact on long-term cancer recurrence rates and overall survival. Minimally invasive thoracic surgery is often just one aspect of a patient’s treatment journey. However, seamless collaboration among surgeons, medical oncologists, radiation oncologists, and other specialists is essential for comprehensive patient care. Furthermore, minimally invasive surgery can be cost-effective, due to shorter hospital stays and faster recovery times, but economic factors should be considered to ensure equitable access to these advanced procedures. In conclusion, the minimally invasive thoracic surgery field continues to evolve with innovations that can further improve patient outcomes and experiences. Addressing challenges, and focusing on areas requiring attention will be vital to realising the full benefits of these advancements.

Do you think there is a role for artificial intelligence in lung cancer surgery and where do you feel this would be most beneficial in clinical practice? Yes, there is a significant role for AI in lung cancer surgery, and its potential benefits span various aspects of clinical practice. AI can augment healthcare professionals’ skills, enhance decisionmaking, and improve patient outcomes. Here are some areas where AI can be particularly beneficial in lung cancer surgery. AI can provide diagnostic assistance by analysing medical images, such as CT and PET scans, and aid in detecting and characterising lung tumours. It can identify subtle patterns and anomalies that might be missed by human observers, helping in early and accurate

diagnosis. AI-powered image analysis can assist pathologists in accurately assessing tissue samples. It can identify and classify cancer cells, determine tumour margins, and provide insights into the tumour’s aggressiveness. AI-powered tools can also provide patients with personalised educational materials, explaining their condition, treatment options, and potential outcomes in an understandable manner. It can also support telemedicine consultations by providing real-time data analysis, and assist remote specialists in making decisions about treatment plans and surgical approaches. AI algorithms can also assist surgeons and oncologists in creating personalised treatment plans. By considering patient data, tumour characteristics, and medical literature, AI can recommend optimal treatment approaches, including surgery, radiation therapy, chemotherapy, or targeted therapies. It can also analyse patient data to predict outcomes based on patient characteristics, tumour characteristics, and treatment plans. This can help clinicians make informed decisions and manage patient expectations. During surgery, AI can provide real-time guidance to surgeons, helping them navigate complex anatomical structures. This can be particularly valuable in minimally invasive procedures where precise instrument placement is essential. AI can integrate with surgical imaging systems to provide augmented reality overlays, highlighting important structures, and aiding surgeons in identifying tumour boundaries, blood vessels, and critical anatomical landmarks. AI can assist in post-operative monitoring by analysing patient data, such as vital signs and laboratory results, to detect early signs of complications or recurrence. This could lead to prompt interventions and improved patient care.

"AI can assist in post-operative monitoring by analysing patient data." As AI can process and analyse vast amounts of patient data, it can contribute to research efforts and clinical trials. It can identify trends, patterns, and potential new treatment strategies based on large datasets.

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AI can improve efficiency, accuracy, and patient care in lung cancer surgery in all these areas. However, it is essential to recognise that AI is not meant to replace healthcare professionals, but instead complement their expertise. Collaboration between AI systems and skilled medical professionals can lead to more informed decisions, and better patient outcomes.

In 2018, you were awarded the Grillo Prize for the best innovative/ experimental abstract by the European Society of Thoracic Surgeons (ESTS). Can you explain the key points from the abstract, and highlight any advances made on this work since 2018? The abstract describes a systematic review and meta-analysis of randomised controlled trials that investigated the effectiveness of endoscopic lung volume reduction (LVR) using endobronchial valves for patients with severe chronic obstructive pulmonary disease and emphysema. The study evaluated whether endoscopic LVR had a significant clinical impact compared with untreated control groups. The abstract summarises the methodology, results, and conclusions of the study. The meta-analysis concluded that, in terms of forced expiratory volume in 1-second improvement, exercise performance, and complication rate, there was no clear clinical impact of endoscopic LVR. The study recommended a more extended follow-up to assess the durability of clinical benefits and effects on survival associated with endoscopic LVR. Since 2018, there have been ongoing research and developments in endoscopic lung volume reduction for severe chronic obstructive pulmonary disease and emphysema using endobronchial valves. Some potential advances and developments might have occurred since then. For example, researchers may have conducted longer-term follow-up studies to assess the durability of clinical benefits, and effects on survival after endoscopic LVR. These studies could provide insights into the longer-term impact of the procedure on patient outcomes. Advances in procedural techniques and device design may have improved patient selection, procedural success rates, and patient outcomes. Also, researchers might have explored

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combination therapies involving endoscopic LVR and other interventions, such as bronchodilators, pulmonary rehabilitation, or medical management, to enhance overall treatment efficacy. Refinement of patient selection criteria based on individual patient characteristics, lung function, and disease severity could have improved the identification of candidates most likely to benefit from endoscopic LVR. Meanwhile, new randomised controlled trials and clinical trials might have been conducted to evaluate the effectiveness and safety of endoscopic LVR, potentially providing additional insights and data beyond those available in the original metaanalysis.

Finally, what advice would you give to young clinicians starting their career in thoracic surgery? Medicine and surgery are ever-evolving fields, which require continuous learning. Stay committed to lifelong learning by attending conferences and workshops, and stay updated with the latest research. Continuous education will keep you at the forefront of advancements in thoracic surgery. Develop and refine your surgical skills with dedication and diligence. Focus on achieving technical excellence, as this will be the foundation of your surgical practice. Medicine evolves rapidly. Be adaptable and willing to embrace new technologies, techniques, and treatment modalities to ensure the best care for your patients. Seek experienced mentors who can guide you through the challenges and decisions you will face. A mentor can provide invaluable insights, advice, and support as you develop your skills and career. Also, establish a solid professional network by engaging with colleagues, attending conferences, and participating in surgical societies. Networking can lead to collaboration, mentorship, and career opportunities. Thoracic surgery often involves collaboration with various healthcare professionals. Build strong relationships with pulmonologists, oncologists, radiologists, anaesthesiologists, and other specialists, to ensure comprehensive patient care. Always prioritise your patients’ wellbeing and preferences. Effective communication and

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empathy are essential in building trust, and providing patient-centred care. Uphold the highest standards of ethics and professionalism. Your patients’ trust depends on your integrity and ethical decision-making. Work with patients from diverse backgrounds. Cultural sensitivity and effective communication are crucial to personalised care that respects patients’ values and beliefs. Acknowledge your achievements and milestones. Celebrating successes, whether big or small, can provide motivation and satisfaction. However, medicine is a humbling profession. Recognise that you will encounter cases that challenge your knowledge and skills. Embrace a growth mindset and be open to learning from every experience. Thoracic surgery can be demanding, but do not neglect your wellbeing. Strive for a healthy worklife balance to prevent burnout, and to maintain physical and mental health.

Surgery can be challenging and emotionally taxing. Develop resilience to cope with the pressures of the profession. Seek support from colleagues, mentors, and resources when needed. Contribute to the field through research and innovation. Investigate clinical questions, participate in studies, and explore ways to improve patient outcomes. Surgery is a field of continuous discovery. Stay curious, ask questions, and explore intellectually to deepen your understanding of thoracic surgery, and related disciplines. Remember, the journey in thoracic surgery is a marathon, not a sprint. Embrace the growth opportunities, learning, and impact this career offers. The dedication to patient care and the advancement of the field will leave a lasting mark on the lives you touch, and the future of thoracic surgery. ●

"Strive for a healthy work-life balance to prevent burnout, and to maintain physical and mental health."

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EMJ Podcasts The EMJ Podcast aims to provoke conversations around the latest trends and innovations in healthcare, provide engaging and educational content for healthcare professionals, and hosts conversations with physician entrepreneur, Jonathan Sackier. Listen today www.emjreviews.com ●

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High-Flow Nasal Cannula Oxygen Therapy in Adult Acute Care: Beyond Clinical Indications and Patient Selection Authors:

*J. Brady Scott,1 Ramandeep Kaur1 Department of Cardiopulmonary Sciences, Division of Respiratory Care, Rush University Medical Center, Chicago, Illinois, USA *Correspondence to jonathan_b_scott@rush.edu

Disclosure:

Scott has received research funding from the American Association for Respiratory Care (AARC) and Teleflex outside of the submitted work; one-time speaking fees from Aerogen and Medline Industries outside of the submitted work; and is a content contributor for Relias Media. Kaur has declared no conflicts of interest.

Received:

27.06.23

Accepted:

23.08.23

Keywords:

High-flow nasal cannula (HFNC), hypercapnic respiratory failure, hypoxemic respiratory failure.

Citation:

EMJ Respir. 2023. DOI/10.33590/emjrespir/10300419. https://doi.org/10.33590/emjrespir/10300419.

INTRODUCTION Oxygen therapy has been used for centuries to support patients with breathing difficulties.1 Historically, oxygen therapy primarily involved using low-flow delivery devices. The long-term use of nasal high-flow oxygen was not common until more recently, as concerns about patient discomfort were associated with a lack of humidification. High-flow nasal cannula (HFNC) oxygen therapy refers to delivering heated and humidified gases at flows (between 20–60 L/min) through the nose to support patients in hypoxemic and/or hypercapnic respiratory failure. Over a relatively short period, HFNC oxygen therapy has become widely used in respiratory medicine. Much of its popularity comes from its ease of application, and the comfort it provides to patients. While evidence is still evolving regarding clinical indications and patient selection for HFNC oxygen therapy, other factors might play a role in the success of the modality. Thus, this feature article highlights important clinical and technical considerations of HFNC oxygen therapy.

CLINICAL APPLICATIONS Among all the available oxygen therapy modalities, evidence suggests that HFNC oxygen therapy is superior in improving outcomes of patients with acute hypoxemic respiratory failure. For example, in a small randomised controlled trial, Roca et al.2 compared HFNC oxygen therapy with conventional oxygen therapy via face mask among patients with acute hypoxemic respiratory failure. Their study demonstrated that HFNC oxygen therapy was associated with less dyspnoea (3.8 [1.3–5.8] versus 6.8 [4.1–7.9]: p=0.001) and mouth dryness (5 [2.3–7.0] versus 9.5 [8.0–10.0]; p<0.001), and was reported to be more comfortable (9 [8.0–10.0] versus 5 [2.3– 6.8]; p<0.001) to wear by the subjects. Additionally, HFNC oxygen therapy led to lower respiratory rates (21 [18–27] versus 28 [25–32]; p<0.001) and higher arterial blood oxygen (mmHg) levels (127 [83–191] versus 77 [64–88]; p=0.002). A meta-analysis by Rochwerg et al.3 reported that use of HFNC oxygen therapy, when compared with conventional oxygen therapy,

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lowers the risk for endotracheal intubation (risk ratio [RR]: 0.85; 95% confidence interval [CI]: 0.74–0.99) in patients with acute hypoxemic respiratory failure, but does not impact the mortality rate (RR: 0.94; 95% CI: 0.67–1.31; moderate certainty).3 A recent meta-analysis by Pitre et al.4 assessed the effectiveness of non-invasive oxygen strategies for treating acute hypoxemic respiratory failure and demonstrated with moderate certainty that HFNC oxygen therapy reduces the need for invasive mechanical ventilation (103.5 fewer events per 1,000; 95% CI: 40.5–157.5 fewer). In a meta-analysis by Li et al.5 compared HFNC oxygen therapy with conventional oxygen therapy, similar findings were reported, but their analysis showed a decrease in 28-day intensive care unit mortality rates (odds ratio: 0.54; 95% CI: 0.30–0.97; p=0.04) with the use of HFNC t herapy among adult patients with acute respiratory failure secondary to COVID-19.5 When comparing the clinical effectiveness of HFNC oxygen therapy to non-invasive ventilation (NIV), a meta-analysis by Beran et al.6 reported no difference in the intubation rate (RR: 1.01; 95% CI: 0.85–1.20; p=0.89), but improvement in the mortality rate (RR: 0.81; 95% CI: 0.66–0.98; p=0.03) among patients with COVID-19 with the use of NIV.6 Amidst the COVID-19 pandemic, non-invasive respiratory support, especially HFNC oxygen therapy, was extensively utilised to manage patients with acute respiratory failure secondary to COVID-19.7 This approach helped decrease the requirement for invasive mechanical ventilation, subsequently alleviating the strain on the availability of ventilators. When assessing the impact of HFNC therapy on hypercapnic respiratory failure, the existing evidence indicates a reduction in arterial CO2 level among patients with stable chronic obstructive pulmonary disease (COPD).8,9 A physiologic study by Rittayamai et al.10 enrolled 12 patients with hypercapnic COPD demonstrated that HFNC oxygen therapy use at a flowrate of 30 L/min provides similar clinical effect as NIV. A recent randomised controlled trial by Nagata et al.11 reported that the home use of HFNC oxygen therapy among patients with stable hypercapnic COPD resulted in a significant lower rate of moderate/severe exacerbations

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as compared with the conventional oxygen therapy (mean count 1.0 versus 2.5). Overall, the majority of the evidence available have demonstrated that using HFNC oxygen therapy to manage acute hypoxemic respiratory failure yields better patient outcomes when compared with conventional oxygen therapy; however, its application produces similar outcomes when compared with the NIV. The available data supports the adoption of HFNC oxygen for treating chronic hypercapnic respiratory failure, but its role in managing acute hypercapnic respiratory failure is currently unknown.

PHYSIOLOGICAL EFFECTS OF HIGH-FLOW NASAL CANNULA The major physiologic effects of HFNC oxygen therapy include the washout of anatomical dead-space, a ‘more stable’ delivery of fraction of inspired O2 (FIO2), adequate heating and humidification of inspired gases, and positive pressure. Washing out CO2 from the anatomical dead space improves gas exchange efficiency. This is because a more significant portion of the minute volume is actively involved in gas exchange.12 During HFNC oxygen therapy, the device can deliver flows that exceed patient peak tidal inspiratory flow (PTIF). When the PTIF is exceeded, it reduces the risk of diluting the delivered FIO2 through the entrainment of ambient air. Patients have control over their PTIF and tidal volume, so there is likely some variability in the delivered FIO2.12,13 Providing properly warmed and humidified gases offers several benefits, including improved mucociliary function, enhanced clearance of secretions, reduced airway constriction, and decreased metabolic costs of breathing.14-16 Finally, despite being an open system, HFNC oxygen therapy devices provide some positive pressure. Evidence has shown that pharyngeal pressures and end-expiratory lung volumes increase with HFNC oxygen therapy. Improved gas exchange can result from the increased alveolar recruitment due to the positive pressure generated; however, an open mouth during patient breathing complicates the positive pressure effect. Studies exploring the impact of mouth closure or openness have demonstrated considerable variation in pharyngeal pressures. Factors such as BMI, lung heterogeneity, and device flow rate may also contribute to the

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variability in lung recruitment observed with HFNC oxygen therapy.15,17–21

HIGH-FLOW NASAL CANNULA SETTINGS Flow settings impact the aforementioned physiologic effects of HFNC oxygen therapy. Surpassing the PTIF appears to maximise the benefits of HFNC oxygen therapy, if the flows do not cause patient discomfort and alveolar overdistension.22,23 However, clinicians currently face the challenge of having no commercially available device to measure PTIF directly. Furthermore, variations in PTIF occur due to patient and disease conditions, further complicating the matter.23 Without a PTIF measurement device or tool, clinicians must rely on clinical indicators to establish and adjust patient flows. A systematic review conducted by Li et al.,23 which assessed the impact of flow settings, suggested that until a PTIF measurement device becomes available, clinical findings such as patient comfort, respiratory rate and oxygenation (ROX) index, respiratory rate, and oxygenation should be utilised to personalise flow settings. This approach might help individualise and optimise flow settings without a direct PTIF measurement device.24 Patient comfort cannot be overstated, as the success of the therapy relies on patient compliance. In a prospective, randomised, crossover study by Mauri et al.,25 patient comfort appeared to be affected by temperature. A temperature of 31 °C was more comfortable than 37 °C at both 30 and 60 L/min (p<0.0001). Interestingly, the authors reported that in a subgroup of patients (those with a FIO2 >0.45), a temperature of 31 °C, and a flow of 60 L/min led to higher comfort (p<0.01). While it may be intuitive that higher flows may decrease comfort, this may not be true, at least for some patients. Clinicians should make efforts in adjusting heat and flow settings (in addition to a properly fitted nasal interface) to maximise patient comfort during HFNC oxygen therapy.

AEROSOL DELIVERY VIA HIGH-FLOW NASAL CANNULA Patients with acute respiratory failure often receive aerosol therapy in addition to the HFNC oxygen therapy. However, delivering aerosolised medications via HFNC is a relatively new technique. Traditional oxygen delivery methods require a stoppage in the therapy to be able to administer aerosolised medications. The advantages of delivering aerosol delivery via HFNC is that it allows clinicians to provide uninterrupted respiratory support to the patients.26 During HFNC oxygen therapy, aerosol particles are generated by nebulisers and get entrained within the high gas flow and carried to patient lungs. To optimise aerosol delivery through a HFNC device, clinicians should consider nebuliser type (jet or vibrating mesh), nebuliser placement, and gas flow.26 A study by Dugernier et al.27 compared aerosol delivery between jet nebuliser and vibrating mesh nebuliser through a HFNC, and found that vibrating mesh nebuliser yielded a threetimes higher lung deposition as compared to the jet nebuliser. Similarly, a bench study by Li et al.28 demonstrated that use of vibrating mesh nebuliser resulted in a higher inhaled dose as compared with the small volume jet nebuliser. Another study by Li et al.29 studied the impact of nebuliser placement on the aerosol delivery, and reported that a nebuliser placed at the humidifier level resulted in higher inhaled dose as compared to a nebulizer placed close to the patient. Lastly, the set gas flow rate of HFNC also influences the drug deposition. HFNC device gas flow is generally set at a higher rate (40–60 L/min) to meet the PTIF to maximise the physiologic effects of the modality. Alcoforado et al.30 studied the effect of HFNC flow on drug deposition and reported that lung deposition was greater for 10 L/min flowrate, as compared with 30 L/min or 50 L/min (17.2±6.8%, 5.71±2.04%, and 3.46±1.24%, respectively; p=0.0001).29 To achieve higher lung deposition when administering aerosol therapy via HFNC, it may be advantageous to use a vibrating mesh nebuliser placed close to the humidifier, and utilise lower flowrates on the device. More studies are needed to determine precisely which flows are best on the various devices that are commercially available.

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CONCLUSION HFNC oxygen therapy is a commonly used respiratory intervention to support patients with acute respiratory failure. To achieve maximum clinical benefits, clinicians need to look beyond clinical indications of the modality, and consider

References 1.

Grainge C. Breath of life: the evolution of oxygen therapy. J R Soc Med. 2004;97(10):489-93.

Roca O et al. High-flow oxygen therapy in acute respiratory failure. Respir Care. 2010;55(4):408-13.

Rochwerg B et al. High flow nasal cannula compared with conventional oxygen therapy for acute hypoxemic respiratory failure: a systematic review and meta-analysis. Intensive Care Med. 2019;45(5):563-72.

Pitre T et al. Noninvasive oxygenation strategies in adult patients with acute hypoxemic respiratory failure: a systematic review and meta-analysis. Chest. 2023;S0012-3692(23):00597-4. Li Y et al. High-flow nasal cannula reduces intubation rate in patients with COVID-19 with acute respiratory failure: a meta-analysis and systematic review. BMJ Open. 2023;13(3):e067879. Beran A et al. High-flow nasal cannula oxygen versus noninvasive ventilation in subjects with COVID-19: a systematic review and meta-analysis of comparative studies. Respir Care. 2022;67(9):1177-89. Reyes LF et al.; International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) Characterization Group. Respiratory support in patients with severe COVID-19 in the International Severe Acute Respiratory and Emerging Infection (ISARIC) COVID-19 study: a prospective, multinational, observational study. Crit Care. 2022;26(1):276. Bräunlich J et al. Effectiveness of nasal highflow in hypercapnic COPD patients is flow and leakage dependent. BMC Pulm Med. 2018;18:14. Bonnevie T et al. Nasal high flow for stable patients with chronic obstructive pulmonary disease: a systematic review and metaanalysis. COPD. 2019;16(5-6): 368-77.

10. Rittayamai N et al. Effects of high-flow nasal cannula and non-

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how settings and medication delivery strategies play a role in improving outcomes. More studies are needed, particularly in exploring the application of HFNC oxygen in addressing hypercapnic respiratory failure, as the use of the modality increases, and the technology evolves.

invasive ventilation on inspiratory effort in hypercapnic patients with chronic obstructive pulmonary disease: a preliminary study. Ann Intensive Care. 2019;9(1):122. 11. Nagata K et al. Home high-flow nasal cannula oxygen therapy for stable hypercapnic COPD: a randomized clinical trial. Am J Respir Crit Care Med. 2022;206(11):1326-35. 12. Spoletini G et al. Heated humidified high-flow nasal oxygen in adults: mechanisms of action and clinical implications. Chest. 2015;148(1):253-61. 13. Sun YH et al. Factors affecting FiO2 and PEEP during high-flow nasal cannula oxygen therapy: a bench study. Clin Respir J. 2019;13(12):758-64. 14. Dysart K et al. Research in high flow therapy: mechanisms of action. Respir Med. 2009;103(10):1400-5. 15. Drake MG. High-flow nasal cannula oxygen in adults: an evidencebased assessment. Ann Am Thorac Soc. 2018;15(2):145-55. 16. Nishimura M. High-flow nasal cannula oxygen therapy in adults: physiological benefits, indication, clinical benefits, and adverse effects. Respir Care. 2016;61(4):529-41. 17. Corley A et al. Oxygen delivery through high-flow nasal cannulae increase end-expiratory lung volume and reduce respiratory rate in post-cardiac surgical patients. Br J Anaesth. 2011;107(6):998-1004. 18. Riera J et al. Effect of high-flow nasal cannula and body position on end-expiratory lung volume: a cohort study using electrical impedance tomography. Respir Care. 2013;58(4):589-96. 19. Parke RL et al. Effect of veryhigh-flow nasal therapy on airway pressure and end-expiratory lung impedance in healthy volunteers. Respir Care. 2015;60(10):1397-403. 20. Parke RL, McGuinness SP. Pressures delivered by nasal high flow oxygen during all phases of the respiratory cycle. Respir Care. 2013;58(10):1621-4.

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21. Scott BJ. Noninvasive ventilation in adult acute care: beyond clinical indications. Relias Media. 2021;29(1):1-3. 22. Mauri T et al. Optimum support by high-flow nasal cannula in acute hypoxemic respiratory failure: effects of increasing flow rates. Intensive Care Med. 2017;43(10):1453-63. 23. Li J et al. The effects of flow settings during high-flow nasal cannula support for adult subjects: a systematic review. Crit Care. 2023;27(1):78. 24. Scott BJ. Flow settings during high-flow nasal cannula oxygen therapy. 2023. Available at: https:// www.reliasmedia.com/articles/flowsettings-during-high-flow-nasalcannula-oxygen-therapy. Last accessed: 26 June 2023. 25. Mauri T et al. Impact of flow and temperature on patient comfort during respiratory support by high-flow nasal cannula. Crit Care. 2018;22(1):120. 26. Li J, Fink JB. Narrative review of practical aspects of aerosol delivery via high-flow nasal cannula. Ann Transl Med. 2021;9(7):590. 27. Dugernier J et al. Aerosol delivery with two nebulizers through highflow nasal cannula: a randomized cross-over single-photon emission computed tomography-computed tomography study. J Aerosol Med Pulm Drug Deliv. 2017;30(5):34958. 28. Li J et al. The impact of high-flow nasal cannula device, nebulizer type, and placement on trans-nasal aerosol drug delivery. Respir Care. 2022;67(1):1-8. 29. Li J et al. In vitro comparison between inspiration synchronized and continuous vibrating mesh nebulizer during trans-nasal aerosol delivery. Intensive Care Med Exp. 2020;8:6. 30. Alcoforado L et al. Impact of gas flow and humidity on trans-nasal aerosol deposition via nasal cannula in adults: a randomized cross-over study. Pharmaceutics. 2019;11(7):320.

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Chronic Obstructive Pulmonary Disease: Biofilm Mediated Exacerbation and Innovative Therapeutic Approaches Authors:

Irene Berger,1 Adina Kagan,1 Rebecca Bock,1 *Zvi G. Loewy1,2 1. Touro University College of Pharmacy, New York, USA 2. Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, USA *Correspondence to Zvi.loewy@touro.edu

Disclosure:

The authors have declared no conflicts of interest.

Received:

07.06.23

Accepted:

14.09.23

Keywords:

Biofilm, drug delivery, exacerbation, quorum sensing, treatment.

Citation:

EMJ Respir. 2023;11[1]:99-107. DOI/10.33590/emjrespir/10305099. https://doi.org/10.33590/emjrespir/10503099.

Abstract Chronic obstructive pulmonary disease (COPD) is a leading cause of death. The prevalence of the disease and associated mortality continue to increase. Bacterial and viral infections are responsible for the transition of the disease to more severe stages, resulting in COPD exacerbation. Biofilms, communities of micro-organisms that contribute to COPD exacerbation, pose a formidable challenge for effective pharmacotherapy. This review focuses on the development of biofilms, and approaches to inhibit and eradicate biofilms.

Key Points 1. Combination therapies are beneficial in eradicating biofilms; however, they pose an increased risk of side effects, allergies, toxicity, and Clostridium difficile infections. To address the issue of toxicity often seen with dual antimicrobial therapy, topical administration of these agents is recommended. Topical administration delivers high concentrations to the target site of infection with nearly undetectable serum concentrations, thereby reducing the risk of systemic side effects. 2. Use of bacteriophages as anti-biofilm agents is showing promise. Bacteriophages can prevent biofilms from forming, and can eradicate existing biofilms. Phages work by utilising enzymes to dissolve the outer matrix of the target biofilm, and once they penetrate the tough matrix, they continue to kill the bacterial cells embedded within the host biofilm. 3. In respiratory infections involving biofilms, many clinicians choose inhaled formulations of antimicrobial agents. Inhaled antimicrobials are beneficial because they allow for a higher concentrated dosage to reach the respiratory tract. While inhaled formulations limit systemic exposure of antibiotics, it is difficult to treat biofilms with single agent antimicrobials, because biofilms can survive 1,000-fold higher concentrations of antimicrobials compared to planktonic bacteria.

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CHRONIC OBSTRUCTIVE PULMONARY DISEASE EXACERBATION Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. COPD encompasses two clinical phenotypes: emphysema and chronic bronchitis. Factors that contribute to the onset of COPD include genetic factors, pollution, cigarette smoke, and exposure to diverse chemicals. Exacerbation of COPD correlates with bacterial colonisation and respiratory viral infections. The main bacterial pathogens implicated in COPD exacerbation include Pseudomonas aeruginosa, Moraxella catarrhalis, Haemophilus influenzae, and Streptococcus pneumoniae. An important contributing factor to the virulence of bacteria associated with COPD exacerbations is their ability to form biofilms. Micro-organisms that form biofilms pose significant health challenges attributed to human and animal infections they cause. The host immune system has difficulty in eradicating the microbial complex communities, resulting in increased antimicrobial resistance. Proinflammatory cytokines implicated in the host immune response to biofilm-forming P. aeruginosa strains include IL-6, IL-8, IL-10, TNFα, and IL-1β.1 Pathogenic bacteria can survive in the lungs of patients with COPD for several months. This may be attributed to the formation of biofilms, which may also be responsible for recurring episodes of acute exacerbations.2 Exacerbations of COPD are prevalent, and the patients who suffer from exacerbations frequently experience poor quality of life, accelerated decline in lung function, increased healthcare expenses, and increased morbidity and mortality. Studies testing patients’ sputum cultures have determined that approximately 50% of COPD exacerbations are attributed to bacterial lung infections.3 Bronchial colonisation by potentially pathogenic micro-organisms is related to the course of the illness, and is associated with airflow obstruction and a poor prognosis for many patients.4 Hunt et al.5 analysed how the pathogenic micro-organisms that persist within polymicrobial biofilms contribute to the severity of COPD exacerbations. They found that in animals exposed to smoke, infection

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by non-typeable H. influenzae led to airway neutrophilia, which is commonly seen in COPD. Neutrophilia is linked to airway obstruction and decline of forced expiratory volume in patients with COPD. Infection with nontypeable H. influenzae triggered the migration of neutrophils into the lungs, and increased the levels of active neutrophil enzymes, including myeloperoxidase, matrix metalloproteinase-2, and matrix metallopeptidase 9. The neutrophils release neutrophil elastase and produce neutrophil extracellular traps, which can degrade the extracellular matrix. Neutrophil extracellular traps are also responsible for increasing mucus viscosity, and thereby contribute to disease progression by complicating infections. Results of the study demonstrated that non-typeable H. influenzae infection led to alterations in lung morphology, obstruction of bronchioles, accumulation of mucus, and thickening of airway walls. In addition, infection led to significant airway resistance and a reduction in respiratory capacity. Overall, the infections caused by bacteria that reside within biofilms trigger host responses consistent with COPD exacerbations. Treating these biofilms may help alleviate airway inflammation, and potentially mitigate disease severity and slow the progression of COPD.5 Previously, the authors presented a detailed description of therapeutic approaches for COPD, with a focus on mucoregulators, bronchodilators, and anti-inflammatory drugs.6 In this article, the authors address approaches to inhibit and eradicate biofilms implicated in COPD pathogenesis.

MATERIALS AND METHODS A meta-analysis of previously published studies was conducted. The search terms used included: “COPD exacerbation,” “anti-microbials,” “biofilms,” “quorum sensing,” “drug delivery,” etc. MEDLINE, Embase, related websites, and reference lists were searched from 2000–2023 to identify appropriate papers that addressed the objectives of this review. Publications were reviewed independently by four investigators. The investigators extracted the data and inspected each reference identified by the search and applied inclusion criteria. In cases where the same studies were reported in more than one publication, the study’s results were accounted

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for only once. The electronic search was followed by extensive hand searching, using reference lists from the identified articles. Publications written in English were reviewed exclusively. The search method used was designed to strengthen existing concepts, and to identify approaches for upcoming research studies.

BIOFILM FORMATION Biofilms are dense micro-communities, often attached to inert surfaces that are encapsulated by secreted polymers.7 The development of a biofilm is a dynamic process.8 Initially, a planktonic microbe attaches itself to a surface; it then subsequently aggregates with other microbes in the formation of a biofilm. The formation and survival of a biofilm lies in the ability of the bacteria to communicate. The bacterial cell–cell communication process, called quorum sensing (QS), involves the production, detection, and response to extracellular signalling molecules, autoinducers. QS controls genes that direct activities that are beneficial when performed by a population of bacteria acting in synchrony. Initially discovered in Vibrio fischeri, QS systems have been observed in Gram-positive and Gram-negative bacteria, as well as the fungus Candida albicans.9 The basic premise of QS is that the more cells are present, the more they can elicit a response from one another. Within the bacterial community, each individual cell produces a molecule termed an autoinducer, which exits the cell via passive diffusion in the absence of other autoinducers in the extracellular space. However, as the bacterial population grows, more autoinducers accumulate in the extracellular space, and the autoinducers begin to diffuse back down their concentration gradient, only this time, entering the cells. Once inside the cell, autoinducers bind to regulatory transcription factors in the cytoplasm or nucleus, inducing gene expression of the autoinducer synthase, which results in a positive feedback loop.10 The QS processes that occur in the bacteria that contribute to COPD exacerbation, are analogous to those seen in V. fischeri. In P. aeruginosa there are multiple known QS pathways, but two of them are nearly identical to the QS system in V. fischeri, LasI and RhlI. Similar to V. fischeri,

both systems are activated by increased cell density.11 These genes encode the autoinducer synthase in P. aeruginosa, which allows for greater amplification of the signal.11 There is also evidence to indicate that QS is somewhat regulated by small RNAs, as well as other environmental factors.12 Additionally, biofilm formation can be inhibited when the secretion of matrix components ceases, a process that occurs through a tyrosine phosphatase that is controlled by the LasI system.13 There is a third and interconnected method of QS, which is based on quinolone signalling. In this pathway, the signalling molecule is 2-heptyl3-hydroxy-4-quinolone, which is produced by multiple Pqs genes, one of which is PqsH. PqsH is under the control of the PqsH gene, and the molecule that detects the quinolone, PqsR, is encoded by the PqsR gene. The Las system induces the expression of these genes, while the Rhl system can suppress these genes.11 There is a fourth and newly discovered QS system that was discovered in P. aeruginosa, integrated QS. Although much about this system remains unknown, what is clear is that it is activated by phosphate depletion, and is controlled by Las like the quinolone system.14 The Las, Rhl, and quinolone systems function in tandem to create the functional elements of the biofilm that contribute to its stable structure and antibiotic resistant properties. One molecule that assists in keeping the biofilm intact is rhamnolipid, which creates channels between individual colonies to allow nutrients and other resources to travel amongst them. Pyoverdine is another molecule that is a product of QS, which assists in biofilm development by converting iron into stable forms so that it can be utilised by the cells within the biofilm. For maintenance of the biofilm structure, key elements are pyocyanin and pel polysaccharides. Pyocyanin causes the release of extracellular DNA into the environment, allowing it to bind the pyocyanin and pel polysaccharides, resulting in a more viscous biofilm matrix. Finally, lectin molecules are structural molecules that help hold the biofilm together and allow the biofilm to adhere to other surfaces.15

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The autoinducer feedback loop mechanism of QS is present in nearly all gram-negative bacteria.16 In H. influenzae, another gramnegative microbe that is frequently found in patients who suffer from COPD exacerbation, there is an autoinducer QS system that is like the autoinducer system of P. aeruginosa, only with different autoinducers, genes, and regulatory transcription factors. An autoinducer, termed autoinducer-2 (AI-2), acts like the autoinducers in P. aeruginosa, activating S-ribosylhomocysteine lyase (LuxS), and acting as a positive feedback loop to produce an enhanced response.16 There is another QS system in H. influenzae that is unrelated to the autoinducer/LuxS system, which is the QS Escherichia coli B/C (QseB/C). QseC is a membrane-bound sensor that phosphorylates a QseB. Only when QseB is phosphorylated can it bind to DNA and alter transcription.17 While there is information on the signalling pathways involved in H. influenzae, how these directly lead to the formation of the biofilm is not as clear.18 Moraxella catarrhalis is yet another gramnegative bacterium that can colonise the lungs in an episode of COPD exacerbation. There is not much known about biofilms that consist of M. catarrhalis alone, but there is literature that explores biofilms that develop when there is coinfection of H. influenzae and M. catarrhalis. In such a system, the AI-2 method of QS is employed, but there are different theories that suggest how this occurs. One hypothesis is simply that AI-2 is a signal that is used by many species of bacteria since many contain LuxS. In certain cases, it appears that AI-2 can influence multi-species biofilms, which can be attributed to the presence of LuxS in more than one bacterial species. Another hypothesis is that M. catarrhalis does not have its own LuxS, so it cannot produce its own AI-2. However, it is nonetheless capable of responding to the AI-2 signals from the neighbouring H. influenzae.19 The final pathogen that is involved in COPD exacerbation is S. pneumoniae, which is a Gram-positive bacterium that can cause severe infection. Generally, one difference between Gram-positive and Gram-negative bacteria QS mechanisms is the type of molecule used for the autoinducer. While Gram-negative bacteria usually utilise small molecules as autoinducers, particularly lactones, Gram-positive bacteria will usually utilise peptides in their signalling,

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although the basic process of reactivating the autoinducer is the same in both systems.14 S. pneumoniae primarily uses two QS mechanisms: one is the autoinducer/LuxS process, and the second is the Com QS system. This system is focused on the exchange of DNA within the cells of the biofilm. This system is comprised of the ComCDE operon, where comC acts as the signalling molecule, comD acts as the receptor for comC, and comE regulates the transcriptional response. The exact role that both these systems play in the formation of the biofilm structure remains unknown.

CHRONIC OBSTRUCTIVE PULMONARY DISEASE EXACERBATION TREATMENT The structure of a biofilm and the associated changes in gene expression can protect microbes from antibiotics.8 The treatment of infections in the context of chronic pulmonary disorders is limited by the biofilm mode of growth of pathogenic organisms. Compared with bacteria in their planktonic state, bacteria in biofilms can survive extremely high concentrations of antimicrobial compounds.20 A primary concern with antibiotic use in COPD is the emergence of antimicrobial resistance due to the frequent use of antimicrobials in this patient population. In addition, the COPD lung is susceptible to the formation of biofilms, thus enabling the development of antimicrobial resistance. Biofilms limit the infiltration of antibiotics and induce a heterogeneous community of bacteria that develop multidrug resistance (MDR).21 In many cases of infections involving biofilms, routinely used antibiotics, such as imipenem and colistin, reduce the biofilm, but are not successful in eradicating the biofilm completely.22 In respiratory infections involving biofilms, many practitioners resort to inhaled formulations of antimicrobial agents. Inhaled antimicrobials are beneficial because they allow for a higher concentrated dosage to reach the respiratory tract, thereby limiting systemic exposure of the antimicrobial compound. Some examples of inhaled antibiotics used to combat respiratory biofilms are ciprofloxacin, streptomycin, aztreonam, and colistin. Examples of inhaled antifungals include pentamidine and

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amphotericin B.23 While inhaled formulations limit systemic exposure of antibiotics, it is difficult to treat biofilms with single agent antimicrobials, because biofilms can survive 1,000-fold higher concentrations of antimicrobials compared with planktonic bacteria.24 The values of minimum inhibitory concentration required make antimicrobial agents less suitable for treating biofilms due to the increased risk of toxicity and side effects associated with the higher doses required.22 The MDR properties of biofilms warrant alternative approaches, such as enhancing activity of conventional antimicrobials synergistically, inhibiting biofilm formation, disrupting established biofilms, or by interrupting bacterial signalling pathways involved in biofilm formation.24 In addition, novel strategies in drug delivery have been utilised in recent years to combat biofilms implicated in respiratory infections.

ENHANCING ACTIVITY OF CONVENTIONAL ANTIMICROBIALS SYNERGISTICALLY Several studies have demonstrated that dual antimicrobial therapy was more effective than monotherapy in eradicating biofilms in respiratory infections due to the tolerance of biofilms to antimicrobial agents. A study done by GómezJunyent et al.25 demonstrated that ceftolozane/ tazobactam or meropenem used in conjunction with colistin was more effective in treating biofilms than with colistin alone. Lower bacterial counts of MDR P. aeruginosa strains were seen in the biofilm samples treated with combination therapy. Other approaches to combat biofilms include utilising non-conventional agents in conjunction with antibiotics. Results of a study done by Llamosí et al.26 revealed that when an antioxidant N-acetyl-L-cysteine (NAC) was used in combination with cefditoren, a cephalosporin antibiotic, NAC significantly enhanced inhibition and eradication of MDR S. pneumoniae biofilms. Similarly, enhanced anti-biofilm effects were seen when nitric oxide was utilised synergistically with antibiotics.27 While combination therapies are beneficial in eradicating biofilms, they pose an increased risk of side effects, allergies, toxicity, and increased risk of Clostridium difficile infections.28 To address the issue of toxicity, often seen with

dual antimicrobial therapy, topical administration of these agents is recommended. Topical administration delivers high concentrations to the target site of infection with nearly undetectable serum concentrations thereby reducing the risk of systemic side effects. For example, when nebulised tobramycin was utilised to combat P. aeruginosa biofilms in cystic fibrosis human airway cells, serum concentrations remained <1 mg/L while it reaches levels up to 1,200 mg/L in the sputum.29

INHIBITING BIOFILM FORMATION AND DISRUPTING ESTABLISHED BIOFILMS Recently there have been many advances in the utilisation of bacteriophage as an antibiofilm agent. Bacteriophages can prevent biofilms from forming and can eradicate existing biofilms as well. Phages work by utilising enzymes to dissolve the outer matrix of the target biofilm, and once they penetrate the tough matrix, they continue to kill the bacterial cells embedded within the host biofilm.30 Antimicrobial peptides, also known as host defence peptides, are compounds found in the host defence systems, which offer multimodal antimicrobial effects through various complex mechanisms.31,32 A recent study highlighted the ability of antimicrobial peptides to interfere with production of extracellular polymeric substance, inhibit QS to prevent the formation of biofilms, and to kill cells adhered in biofilms.33 An example of an AMP that has been studied in respiratory infections includes amphibian AMP Esculentin (1–21). Luca et al.34 demonstrated that in mice with pulmonary infections and sepsis, those treated with amphibian AMP Esculentin (1–21) experienced prolongedsurvival due to the antibiofilm effects of the AMP.34

QUORUM SENSING AND INTERRUPTING BACTERIAL SIGNALING PATHWAYS In recent years, QS has become an attractive target to promote the dispersion of biofilms. Recent work has highlighted that acylated homoserine lactone lactonase AiiK, a synthetic anti-QS agent, was successful in preventing P. aeruginosa pyocyanin production, and

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thereby inhibited biofilm formation.35 Another attractive target is to block nucleotide signalling; nucleotides, such as cyclic guanosine monophosphate, serve as secondary messengers involved in gene regulation and transitioning of bacteria from planktonic to sessile state in the process of biofilm formation.36 Recent work has demonstrated that a decrease in cyclic guanosine monophosphate levels, through induction of E. coli YhjH cyclic guanosine monophosphate phosphodiesterase, induced the dispersal of bacteria embedded in P. aeruginosa biofilms in mice.37 Of note, while QS inhibitors can potentially prevent the maturation of biofilms, they do not affect the planktonic bacteria cells. As a consequence, QS inhibitors in concert with antibiotics may help control biofilm infections.9

ENHANCED DRUG DELIVERY Biomaterial strategies describe the use of carriers to optimise the delivery of drugs to the target site of action. Recent work has highlighted the benefits of using nanoparticles. such as poly (lactide-co-glycolide) (PLGA), liposome, and chitosan, to enhance drug delivery when treating biofilms in the respiratory tract. These nanoparticles serve as promising advancements

in the treatment of biofilms because they allow for controlled release of antimicrobials, and increase the penetration of the compound at the site of action. Furthermore, these drug delivery polymers shield the drug from degradation by the host and thereby enhance therapeutic effects of the agent.23,38,39 A study done by Lin et al.40 demonstrated that lysostaphinencapsulated PLGA microparticles were successful in inhibiting the growth of methicillinresistant Staphylococcus aureus, P. aeruginosa, and Klebsiella, and prevented the formation of biofilms. In those mice treated with the lysostaphin-encapsulated PLGA microparticles, the biomaterial allowed for enough of the lysozyme to be delivered to the lungs of the mice to eliminate methicillin-resistant S. aureus and improve survival rates.25,29 Bacteriophages and antimicrobial peptides have also demonstrated enhanced activity in the presence of biomaterials. In a study that evaluated the effects of an inhaled formulation of PLGA microparticles on the delivery of bacteriophage, results demonstrated that the PLGA microparticles loaded with bacteriophage significantly reduced bacterial load of P. aeruginosa and improved survival outcomes in mice infected with pneumonia.40 Table 1 summarises several biofilm inhibition strategies.

Table 1: Biofilm inhibition strategies.

Biofilm Strategies

MoA

Reference

Antibiotics and antifungals: cephalosporins, aminoglycosides, monobactams, polymyxins, tetracyclines, and glycylglycines

Prevent biofilm formation/bactericidal or bacteriostatic

Mirghani et al.41

Silver

Prevent adhesion

Zhang et al.42

Hydrogels

Prevent adhesion

Zhang et al.42

Triton X-100

Autolysis

Shrestha et al.43

Tween 80

Prevent adhesion

Shrestha et al.43

Surfactants

Quaternary ammonium compounds Cell lysis

Shrestha et al.43

Poloxamer

EPS modulation

Shrestha et al.43

Rhamnolipids

EPS modulation

Shrestha et al.43

EDTA

Degrades cell wall

Shrestha et al.43

Chitosan

Degrades cell wall

Shrestha et al.43

Polyamine norspermidine

EPS modulation

Shrestha et al.43

Small molecules

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Table 1 continued.

Biofilm Strategies

MoA

Reference

Secondary metabolite from citrus limonoids

QSI

Shrestha et al.43

Cyclo(l-Tyr-l-Leu)

Suppress EPS production

Shrestha et al.43

Cahuitamycins

EPS modulation

Shrestha et al.43

Phlorotannin

Cell lysis

Shrestha et al.43

Tea tree oil

Alter metabolism

Shrestha et al.43

Trypsin

Degrade eDNA

Mirghani et al.41

DNase

Degrade eDNA

Mirghani et al.41

α-amylase

EPS degradation

Shrestha et al.43

Protease

EPS degradation

Shrestha et al.43

Esp (serine protease)

EPS degradation

Shrestha et al.43

D-amino acids

Degrade biofilm

Shrestha et al.43

NAC

Inhibit synthesis of EPS

Mirghani et al.41

Benzimidazole

Inhibit synthesis of EPS

Mirghani et al.41

FABHL

Down-regulate QS receptors (LasR and RhlR)

Mirghani et al.41

CABHL

Down-regulate QS receptors (LasR and RhlR)

Mirghani et al.41

Garlic extracts

Inhibit QS

Shrestha et al.43

Chloroform extract

Inhibit QS

Mirghani et al.41

Cinnamaldehyde

Reduce motility

Shrestha et al.43

Hordenine

Reduce signalling molecules required for biofilm production

Shrestha et al.43

Isolimonic acid

Disrupt cell-to-cell signalling pathways Shrestha et al.43

AIP-I

Inhibit QS/disperse biofilms

Shrestha et al.43

RIP

Inhibit QS

Shrestha et al.43

Querentin

Inhibit QS

Shrestha et al.43

Small organic molecules

Disperse biofilms/prevent EPS formation/inhibit QS/cell lysis

Shrestha et al.43

AMPs

Membrane degradation/suppress cell wall synthesis/EPS degradation/inhibit QS

Zhang et al.42

Degradation of biofilm

Mirghani et al.41

Target capsular polysaccharide serotypes (CP5 and CP8) of the EPS

Shrestha et al.43

Secondary metabolites

Bioactive molecules and enzymes

QS system inhibitors

Natural products

Phage therapy Bacteriophages Vaccines Staphvax

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Table 1 continued.

Biofilm Strategies

MoA

Reference

Photodynamic therapy

EPS degradation/cellular destruction of biofilms

Shrestha et al.43

Nitric oxide-releasing nanoparticles

Bactericidal/enhance delivery and activity of anti-biofilm agents

Zhang et al.;42 Shrestha et al.43

Calcium fluoride nanoparticles

Bactericidal/enhance delivery and activity of anti-biofilm agents

Zhang et al.;42 Shrestha et al.43

Catalytic antimicrobial robots

Disperse biofilms/kill cells

Shrestha et al.43

Nanotechnology and nanomaterials

AIP-I: autoinducing peptide Type I; AMP: antimicrobial peptide; CABHL: N-(4-[4-chlororoanilno]butanoyl)-L-homoserine lactone; DNase: deoxyribonuclease; eDNA: environmental DNA; EDTA: ethylenediaminetetraacetic acid; EPS: extracellular polymeric substance; FABHL: N-(4-[4-fluoroanilno]butanoyl)-L-homoserine lactone; NAC: N-acetylcysteine; QS: quorum sensing; QSI: quorum sensing inhibitor; RIP: RNAIII-inhibiting peptide.

CONCLUSIONS World-wide, COPD poses significant health and economic challenges. According to the World Health Organization (WHO), 3.23 million people died from COPD in 2019.44 Direct medical costs attributed to exacerbation approximates 83% of the total healthcare costs for COPD.45 Although much progress has been made in the treatment of COPD, advancements are needed in inhibiting and eradicating biofilms implicated in COPD exacerbation.

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Short B et al. Development and characterisation of a multi-species COPD biofilm. Eur Respir J. 2020;56(Suppl 64):2053.

Pragman AA et al. Understanding persistent bacterial lung infections. Clin Pulm Med. 2016; 23(2):57-66.

Garcia-Nuñez M et al. Bronchial microbiome, PA biofilm-forming capacity and exacerbation in severe COPD patients colonized by P. aeruginosa. Future Microbiol. 2017;12:379-92.

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This review summarised the current approaches used to combat biofilm-mediated COPD exacerbation. The authors demonstrated that microbial SQ provides for attractive therapeutic targets. That said, more work is needed on strategies designed to modulate microbial behaviours. Presumably, therapies that affect microbial behaviour will not be prone to resistance as are traditional antibiotics and will thus yield promising results.

Hunt BC et al. Haemophilus

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Nadell CD et al. The sociobiology of biofilms. FEMS Microbiol Rev. 2009;33(1):206-24.

Hall-Stoodley L, Stoodley P. Development regulation of microbial biofilms. Curr Opin Biotechnol. 2002;13(3):228-33.

Berger D et al. Oral biofilms: development, control and analysis. High Throughput. 2018;7(3):24.

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Bacterial quorum sensing: its role in virulence and possibilities for its control. Cold Spring Harb Perspect Med. 2012;2(11):a012427. 11. De Kievit TR et al. Quorumsensing genes in Pseudomonas aeruginosa biofilms: their role and expression patterns. Appl Environ Microbiol. 2001;67(4):1865-73. 12. Svenningsen SL. Small RNA-based regulation of bacterial quorum sensing and biofilm formation. Microbiol Spectr. 2018;6(4):RWR001702018. 13. Wei Q, Ma LZ. Biofilm matrix and its regulation in Pseudomonas aeruginosa. Int J Mol Sci. 2013;14(10):20983-1005. 14. Lin J et al. The Pseudomonas quinolone signal (PQS): not just for quorum sensing anymore. Front

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Cell Infect Microbiol. 2018;8:230. 15. Wang J et al. Bacterial quorumsensing signal IQS induces host cell apoptosis by targeting POT1-p53 signalling pathway. Cell Microbiol. 2019;21(10):e13076. 16. Papenfort K, Bassler BL. Quorum sensing signal-response systems in Gram-negative bacteria. Nat Rev Microbiol. 2016;14(9):576-88. 17. Langereis JD, Hermans PWM. Novel concepts in nontypeable Haemophilus influenzae biofilm formation. FEMS Microbiol Lett. 2013; 346(2):81-9. 18. Unal CM et al. QseC controls biofilm formation of non-typeable Haemophilus influenzae in addition to an AI-2-dependent mechanism. Int J Med Microbiol. 2012;302(6):261-9. 19. Armbruster CE et al. Indirect pathogenicity of Haemophilus influenzae and Moraxella catarrhalis in polymicrobial otitis media occurs via interspecies quorum signaling. mBio. 2010;1(3):e00102-10. 20. Martin I et al. Approaches to targeting bacterial biofilms in cystic fibrosis airways. Int J Mol Sci. 2021; 22(4):2155. 21. Smith D et al. Prevalence, pattern, risks factors and consequences of antibiotic resistance in COPD: a systematic review. COPD. 2021;18(6):672-82. 22. Roy R et al. Strategies for combating bacterial biofilms: a focus on anti-biofilm agents and their mechanisms of action. Virulence. 2018;9(1): 522-54. 23. Sharma A et al. Advances in pulmonary drug delivery targeting microbial biofilms in respiratory diseases. Nanomedicine (Lond). 2021;16(21):1905-23. 24. Boisvert A-A et al. Microbial biofilms in pulmonary and critical care diseases. Ann An Thorac Soc. 2016;13(9):1615-23. 25. Gómez-Junyent J et al. Efficacy of ceftolozane/tazobactam, alone and

in combination with colistin, against multidrug-resistant pseudomonas aeruginosa in an in vitro biofilm pharmacodynamic model. Int J Antimicrob Agents. 2019;53(5):612-9.

26. Llamosí M et al. Combination of cefditoren and N-acetyl-l-cysteine shows a synergistic effect against multidrug-resistant streptococcus pneumoniae biofilms. Microbiol Spectr. 2022;10(6):e0341522. 27. Poh WH, Rice SA. Recent developments in nitric oxide donors and delivery for antimicrobial and anti-biofilm applications. Molecules. 2022; 27(3):674. 28. Goneau LW et al. Issues beyond resistance: inadequate antibiotic therapy and bacterial hypervirulence. FEMS Microbes. 2020; 1(1):xtaa004. 29. Ciofu O et al. Antibiotic treatment of biofilm infections. APMIS. 2017;125(4):304-19. 30. Wang X et al. Prospects of inhaled phage therapy for combatting pulmonary infections. Front Cell Infect Microbiol. 2021;11:758392. 31. Batoni G et al. Antimicrobial peptides and their interaction with biofilms of medically relevant bacteria. Biochim Biophys Acta. 2016;1858(5):1044-60. 32. Drayton M et al. Host defense peptides: dual antimicrobial and immunomodulatory action. Int J Mol Sci. 2021;22(20):11172. 33. Batoni G et al. Therapeutic potential of antimicrobial peptides in polymicrobial biofilmassociated infections. Int J Mol Sci. 2021;22(2):482. 34. Luca V et al. Esculentin(1-21), an amphibian skin membraneactive peptide with potent activity on both planktonic and biofilm cells of the bacterial pathogen Pseudomonas aeruginosa. Cell Mol Life Sci. 2013; 70(15):2773-86. 35. Jiang Q et al. Quorum sensing: a prospective therapeutic target for bacterial diseases. BioMed Res Int. 2019; 2015978.

36. Wu H et al. Strategies for combating bacterial biofilm infections. Int J Oral Sci. 2015;7(1):1-7. 37. Christensen LD et al. Clearance of Pseudomonas aeruginosa foreign-body biofilm infections through reduction of the cyclic di-GMP level in the bacteria. Infect Immun. 2013;81(8):2705-13. 38. Guo X et al. PLGA-based micro/ nanoparticles: an overview of their applications in respiratory diseases. Int J Mol Sci. 2023;24(5):4333. 39. Chee E, García AJ. Biomaterial therapeutic strategies for treatment of bacterial lung infections. Biofilm. 2023;5:100111. 40. Lin X et al. Lungtargeting lysostaphin microspheres for methicillinresistant Staphylococcus aureus pneumonia treatment and prevention. ACS Nano. 2021;15(10):16625-41. 41. Mirghani R et al. Biofilms: formation, drug resistance and alternatives to conventional approaches. AIMS Microbiol. 2022;8(3):239-77. 42. Zhang K et al. Promising therapeutic strategies against microbial biofilm challenges. Front Cell Infect Microbiol. 2020;10:359. 43. Shrestha L et al. Recent strategies to combat biofilms using antimicrobial agents and therapeutic approaches. Pathogens. 2022;11(3):292. 44. World Health Organization (WHO). Chronic obstructive pulmonary disease (COPD). 2023. Available at: https://www.who.int/newsroom/fact-sheets/detail/chronicobstructive-pulmonary-disease(copd). Last accessed: 21 September 2023. 45. Lakiang T et al. Economic impact of chronic obstructive pulmonary disease: a cross-sectional study at teaching hospital in South India. J Family Med Prim Care. 2018;7(5):1002-6.

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Resolution of Resorptive and Compressive Atelectasis without Invasive Manoeuvres: A Case Report Authors:

*Simone Ielo,1 Paolo Calò,2 Alessia Del Pizzo,2 Riccardo Cucurachi,1 Giovanni Piraino,1 Eirini Lemontzi2 1. Università Cattolica del Sacro Cuore, Rome, Italy 2. Pulmonary Rehabilitation Unit, San Raffaele Pisana Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Rome, Italy *Correspondence to simone.ielo01@icatt.it

Disclosure:

The authors have declared no conflicts of interest. Informed, written consent was obtained from the patient for the publication of this case report.

Received:

25.06.23

Accepted:

25.09.23

Keywords:

Airway clearance, case report, chest physiotherapy, lung atelectasis, mucus plugs, pulmonary rehabilitation.

Citation:

EMJ Respir. 2023;11[1]:108-114. DOI/10.33590/emjrespir/10309984. https://doi.org/10.33590/emjrespir/10309984.

Abstract A care challenge that clinicians and other healthcare professionals face very frequently is the complications of bedridden syndrome. Respiratory involvement readily occurs in these patients for whom medical therapy alone is not sufficient. In this clinical case, the authors describe the results of chest physiotherapy in an elderly patient who had developed complete atelectasis of the left lung, attributable to two mechanisms: obstructive, due to mucus plugging, and compressive, due to pleural effusion. The patient was accessed in the authors' Respiratory Rehabilitation Department, San Raffaele Pisana Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Rome, Italy, with dyspnoea at rest and high O2 requirement (venturi mask fraction of inspired O2: 40%), demonstrated by severe respiratory failure on blood gas analysis (partial pressure of O2/fraction of inspired O2: 155). Physical examination revealed marked reduction of lung sounds, especially on the left side, with diffuse rhonchi. A chest CT scan was performed to demonstrate complete left lung collapse that would have required invasive therapeutic procedures, such as bronchoscopy. However, given the high risk of periprocedural complications and the patient's refusal, a chest physiotherapy programme was started. The lung was able to re-expand 7 days later, as evidenced by X-ray and improved gas exchange. The manuscript describes the physiotherapeutic techniques used and collects the main scientific evidence on them. The main purpose is to highlight the role of respiratory physiotherapy as an effective, safe, co-adjuvant treatment, and sometimes alternative to invasive manoeuvres in the treatment of frail patients.

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Key Points 1. The article highlights the importance of respiratory physiotherapy, a safe and inexpensive therapy that avoided the use of invasive procedures in an elderly and frail patient with hypoxaemic acute respiratory failure from resorptive atelectasis. 2. Few studies exist on the effectiveness of chest physiotherapy in resolving resorptive lung atelectasis. In this case report, the authors describe the implemented treatment that resulted in the resolution of the mucosal plug. It will be essential to start randomised clinical trials in the future to compare chest physiotherapy with other treatment strategies. 3. Chest physiotherapy should be encouraged from the early stages of hospitalisation in all sufficiently co-operative patients who are elderly, bedridden, or have chronic respiratory diseases, regardless of the reason for admission. It can be considered as a preventive strategy for respiratory complications in the inpatient or as an adjuvant treatment for cases of bronchial hypersecretion.

BACKGROUND Atelectasis is a kind of lung collapse that might be induced by several factors. Depending on the cause, it can affect only certain areas of the lung (segments or lobes) or the entire lung.1 The main forms of atelectasis are resorptive (or obstructive) and compressive forms. Resorptive atelectasis results from the presence of airflow obstruction, with the distal residual volume being gradually reduced by shunt phenomena or re-absorption from the blood.2 It occurs in cases of small airway collapse, such as in mucus plugs, neoplasms that narrow the lumen of the bronchi, mediastinal tumours, or compressive lymphadenopathy.1,3 Compressive atelectasis, on the other hand, can also be the result of forces acting externally on the lung parenchyma, causing its collapse. Examples include pleural effusion, pneumothorax, or abdominal distension. A particular radiological manifestation of atelectasis is the so-called ’rounded atelectasis’. It is visible on the chest CT scan as a roundish area with connecting stripes trying to reach the lung hilum, hence the name ‘comet star sign’.4 It is usually found near a pleural thickening, as in patients with asbestosis or a history of exudative pleurisy.4 This report presents the case of an elderly patient with a double component of atelectasis (obstructive due to mucus plug and compressive

due to pleural effusion), who responded excellently to physio-kinetic respiratory treatment without recourse to invasive procedures such as bronchoscopy, usually the gold standard in bronchial unblocking.1 The mucous plug, in this case, represented an important medical emergency because it developed from the left main bronchus and resulted in minimal ventilation of the lung, as shown in chest CT. Although respiratory physiotherapy has been shown to be effective in the treatment of respiratory disease,5-8 there is limited scientific evidence to support its use in acute and emergency situations.9 In this case, chest physiotherapy represented the resolving treatment of lung collapse and was enabled by the patient’s remaining discrete performance status and by acting as early as possible. In addition, the patient declined more invasive procedures such as bronchoscopy, which would also have been a risky procedure given the concomitant diseases and the severity of respiratory failure.

CASE PRESENTATION The authors present the case of an 81-year-old female with a history of Parkinson’s disease, atrial fibrillation, and recent bedridden syndrome. Family history was negative for bronchiectasis, cystic fibrosis, or primary ciliary dyskinesia. The patient denied significant pulmonological

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history, as well as hospitalisations, including in rehabilitation institutions. The patient was transferred from the Department of General Medicine, San Raffaele Pisana IRCCS, where she had been admitted for dyspnoea, to the Pulmonary Rehabilitation Unit. Empiric antibiotic therapy was administered in the general medical ward, but within a few days the patient showed progressive deterioration of respiratory failure and underwent CT of the chest, which revealed complete atelectasis of the left lung (Figures 1 and 2). Chest CT showed both an obstructive and a compressive genesis of the lung collapse. The obstructive component was due to mucosal plugs visible in the left main bronchus and extending to the segmental branches of the lower lobe (Figure 2). The compressive component was determined by a pleural effusion that reached the lung apex. On arrival to the Pneumology Department, San Raffaele Pisana IRCCS, the patient was awake and oriented, with high O2 demand (fraction of

inspired O2 of venturi mask: 40%). Blood gas analysis during O2 therapy showed pH: 7.42; pressure of CO2: 45 mmHg; partial pressure of O2: 62 mmHg; bicarbonate: 26.5 mmol/L; and partial pressure of O2/fraction of inspired O2: 155. Although the patient did not show significant dyspnoea, she desaturated during exercise and in the absence of O2 therapy. Physical examination revealed a marked decrease in lung sounds, especially on the left side, with diffuse rhonchi. Cardiac activity was rhythmic, with a slight amplification of the second tone, but without significant additional murmurs. Dependent oedema was not present. Peripheral pulses were valid and rhythmic. The cough reflex was effective, although attenuated. The peak cough flow measured was 240 L/min, lower than normal but above critical values. Considering the patient’s age, moderate respiratory failure, concomitant diseases, and therapies (antiplatelet and anticoagulation therapy), invasive bronchoscopy was considered a risky procedure, which was also refused by the patient.

Figure 1: Chest CT scout image shows opacification of the left hemithorax.

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Figure 2: Chest CT mediastinal window (left) and lung window (right).

A and D) Atelectasis parenchyma of the left upper lobe surrounded by fluid. B and E) Hull-level scan highlighting mucous plug in the left main bronchus. C and F) Thickening of bronchial walls and obliteration of left lower lobe branches.

On the other hand, the authors considered the patient’s will and compliance with physical and rehabilitative treatments. After a multidisciplinary meeting (consisting of pulmonary physicians and physiotherapists), a plan of chest physiotherapy was developed and implemented for at least 3 hours per day by the authors’ medical team. At the same time, broad-spectrum antibiotic therapy (meropenem) was administered because of suspected nosocomial infection. The physiotherapy plan included treatments aimed at the following. Humidification of secretions with a thermal inhaler and a medical aerosol. They were performed daily at least 3

times a day. The duration of the sessions ranged from 5–10 minutes of treatment, depending on tolerance and amount of drug delivered by inhalation (salbutamol 2.5 mg in 0.5 cc; ipratropium bromide 0.25 mg in 1 cc; and beclometasone 400 mcg in 1 mL). Drainage of the same with active cycle of breathing techniques, consisting of periods of controlled breathing, thoracic expansion exercises, and forced expiration; with l’expiration lente totale glotte ouverte en décubitus latéral (ELTGOL) technique. The manoeuvres were carried out twice a day for a total of 2 hours of treatment, including breaks.

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Maintenance and improvement of bronchial clearance by positive expiratory pressures (PEP), frequent postural changes, and diaphragmatic ventilation exercises. The PEPbased treatment that has been used is the PEPbottle, which has been shown to increase lung volume and removes secretions.10 The device was left with the patient to be used independently under the supervision of the health care team. The clinical benefit of secretion drainage was immediate, respiratory failure gradually decreased, and a comparative radiograph, taken 7 days later, showed lung re-expansion (Figure 3).

DISCUSSION Recurrent pneumonia and recent development of semi-immobilisation were the causes of progressive mucus accumulation. The patient was hospitalised for a long time without mobilisation and physical therapy. This, in combination with a weakened peak cough flow caused by Parkinson’s disease, contributed to the obstruction. Humidification was necessary before any secretion drainage techniques could be initiated. Humidification techniques have included both the use of a thermal inhaler and a medical aerosol. After this first phase, chest physiotherapy played a central role in the management of this clinical case.

The techniques described have a historical origin, but are still used for patients with respiratory diseases.7 Active cycle of breathing techniques was first proposed in 1979; it consists of 3 phases.11 The phase of controlled breathing is a pause time after the next two manoeuvres, a slow but not prolonged breathing with tidal volume performed through pursed lips. The thoracic expansion exercises step involves a deep, maximal inspiration followed by a 3-second apnoea phase before the slow exhalation. This step is supported by manual chest compressions by the physical therapist or other percussion techniques. By percussion techniques, the authors mean all those manoeuvres aimed at creating a compressive force external to the chest that promotes mobilisation of secretions. These techniques can be manual, exerted directly on the patient by the physiotherapist, or performed through devices (such as those that provide vibrations and oscillations favouring drainage). Examples in the literature are thoracic percussion performed during active cycle of breathing techniques or oscillating devices that generate intra- or extra-thoracic oscillations (orally or external to the chest wall). Internally they create variable resistance within the airway, generating an oscillating positive controlled pressure that mobilises mucus. Extra-thoracic oscillations are generated by forces outside the respiratory system, for example high-frequency oscillation of the chest wall.12

Figure 3: Chest X-ray (A) and comparison after treatment (B).

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Finally, forced expiration involves open-glottis exhalation by applying a moderate-intensity force after normal inspiration. It is currently considered the gold standard in physiotherapy for promoting bronchial clearance in patients with chronic respiratory disease.8,13 A study conducted in paediatric patients has shown that a greater amount of sputum is produced in cystic fibrosis compared with conventional physiotherapy techniques.14 However, in this regard, the Cochrane Update 2023 shows no significant differences in outcomes in adult patients with cystic fibrosis between this technique and other physiotherapy treatments.15 A possible application has been hypothesised in patients with hypercapnic respiratory failure undergoing non-invasive ventilation, aimed at increasing the rate of alveolar recruitment by promoting weaning and reducing the length of hospital stay.16 The other technique used was ELTGOL. This technique represents one of the best evidencebased options for secretion removal in patients with bronchiectasis.17,18 It consists of cycles of open glottis exhalations performed in the lateral decubitus, performing breathing efforts starting from normal inhalation reaching the end of exhalation. In the authors’ case, the patient was placed in the left lateral decubitus because secretion drainage is greater in the infralateral lung (i.e., the ‘dependent’ lung), as described in the literature.19 As air passes through the secretions, shear forces are created that promote mobilisation. In a second phase of therapeutic management of this clinical case, therapies that maintained airway clearance were used, such as exercises based on positive expiratory pressure. Autogenic training and postural drainage were also continued.

References 1.

The PEP-system, like active cycle of breathing techniques, is based on collateral ventilation. The latter is provided by Kohn’s pores, which allow air to reach a given group of alveoli through adjacent ones, bypassing any obstacles. PEP exercise consists of exhaling against a resistance, creating a force that spans the mucosal plug. Postural drainage, on the other hand, involves taking a specific decubitus that takes advantage of gravity and bronchial anatomy to move secretions. Although its effectiveness in draining secretions has not been proven, it can be assumed to play a positive role in the ventilation/ perfusion ratio of West’s zones by forcing the patient to assume various decubitus positions.20

CONCLUSION In conclusion, active therapy with the patient and on the patient proved to be a successful strategy in this case, avoiding invasive manoeuvres in an elderly and frail patient. In particular, the authors believe that patients with bedridden conditions can have a great benefit from the early initiation of rehabilitation manoeuvres. Although bronchoscopy remains essential for bronchial unblocking from mucus plugs, chest physiotherapy could be an alternative to consider in selected cases. Most of the physical therapy techniques that were used in this clinical report are actually implemented in patients with chronic respiratory diseases. Scientific evidence studying chest physiotherapy in cases of lung atelectasis due to secretory obstruction is essentially absent. This clinical case opens a new therapy scenario, to be further investigated in future randomised clinical trials that may be initiated in intensive care units or pulmonology departments.

atelectasis. J Thorac Imaging. 1996;11(2):92-108.

Peroni DG, Boner AL. Atelectasis: mechanisms, diagnosis and management. Paediatr Respir Rev. 2000; 1(3):274-8.

Patel TP et al. Resorptive (obstructive) atelectasis. BMJ Case Rep. 2019;12(11):e232405.

Woodring JH, Reed JC. Types and mechanisms of pulmonary

Sobocińska M et al. Rounded atelectasis of the lung: a

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pictorial review. Pol J Radiol. 2014;79:203-9. 5.

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Battaglini D et al. Chest physiotherapy: an important adjuvant in critically ill mechanically ventilated patients with COVID-19. Respir Physiol Neurobiol. 2020;282:103529.

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Tang CY et al. Chest physiotherapy for patients admitted to hospital with an acute exacerbation of chronic obstructive pulmonary disease (COPD): a systematic review. Physiotherapy. 2010;96(1):1-13.

Stiller K. Physiotherapy in intensive care: an updated systematic review. Chest. 2013;144(3):825-47.

Zisi D et al. The effectiveness of the active cycle of breathing technique in patients with chronic respiratory diseases: a systematic review. Heart Lung. 2022;53:89-98.

Chen X et al. Chest physiotherapy for pneumonia in adults. Cochrane Database Syst Rev. 2022;9(9):CD006338.

10. Liverani B et al. An integrative review on the positive expiratory pressure (PEP)-bottle therapy for patients with pulmonary diseases. Physiother Res Int. 2020;25(1):e1823. 11. Salehi Derakhtanjani A et al. Comparison the effect of active

cyclic breathing technique and routine chest physiotherapy on pain and respiratory parameters after coronary artery graft surgery: a randomized clinical trial. Anesth Pain Med. 2019;9(5):e94654. 12. Morrison L, Innes S. Oscillating devices for airway clearance in people with cystic fibrosis. Cochrane Database Syst Rev. 2017;5(5):CD006842. 13. Lewis LK et al. The active cycle of breathing technique: a systematic review and meta-analysis. Respir Med. 2012;106(2):155-72. 14. Hristara-Papadopoulou A, Tsanakas J. Results of active cycle of breathing techniques and conventional physiotherapy in mucociliary clearance in children with cystic fibrosis. Hippokratia. 2007;11(4):202-4. 15. Wilson LM et al. Active cycle of breathing technique for cystic fibrosis. Cochrane Database Syst Rev. 2023;2(2):CD007862.

16. Inal-Ince D et al. Active cycle of breathing techniques in noninvasive ventilation for acute hypercapnic respiratory failure. Aust J Physiother. 2004;50(2):67-73. 17. Wong C et al. ELTGOL airway clearance in bronchiectasis: laying the bricks of evidence. Eur Respir J. 2018;51(1):1702232. 18. Muñoz G et al. Long-term benefits of airway clearance in bronchiectasis: a randomised placebo-controlled trial. Eur Resp J. 2018;51(1):1701926. 19. Martins JA et al. Effect of slow expiration with glottis opened in lateral posture (ELTGOL) on mucus clearance in stable patients with chronic bronchitis. Respir Care. 2012;57(3):420-6. 20. Belli S et al. Airway clearance techniques: the right choice for the right patient. Front Med (Lausanne). 2021;8:544826.

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Five Segments of the Right Upper Lobe Bronchus on Bronchoscopic Anatomy: A Rare Case Report and Review of Literature Authors:

*Priya Sharma,1 Deependra Kumar Rai,1 Manohar Kumar,1 Vatsal Bhushan Gupta1 1. Department of Pulmonary Medicine, All India Institute of Medical Sciences (AIIMS), Patna, India *Correspondence to priyasharma25292@gmail.com

Disclosure:

The authors have declared no conflicts of interest.

Acknowledgements:

All of the authors contributed equally in the data collection, analysis of the data, and writing the manuscript. All authors approved the final manuscript. Informed consent has been taken from the patient, and ethics approval taken from the authors’ institute’s ethical committee.

Received:

21.04.23

Accepted:

03.10.23

Keywords:

Anatomical variant, bronchoscopic variant, five segments, right upper lobe.

Citation:

EMJ Respir. 2023;11[1]:115-119. DOI/10.33590/emjrespir/10306996. https://doi.org/10.33590/emjrespir/10306996.

Abstract The authors present a case of a 77-year-old female, a former smoker with a history of chronic obstructive pulmonary disease who underwent bronchoscopy for evaluation of haemoptysis. The bronchoscopy revealed an anatomical variant of the right upper lobe bronchus with five branches instead of the usual three. This case report describes a peculiar anatomical abnormality in the right upper lobe. A review of the literature related to various variants in bronchial anatomy is presented. Conclusion: Awareness of this anatomical variation provides valuable information to clinicians, particularly thoracic surgeons, to plan surgical interventions, tailor procedures, and minimise complications.

Key Points 1. Right upper lobe bronchus anatomical variations may be more common than previously thought, as they may be asymptomatic and therefore go undetected. 2. Anatomical variations of the right upper lobe bronchus can lead to technical difficulties during diagnostic procedures, impact the distribution of inhaled medications, increase the risk of atelectasis or aspiration, and increase the risk of complications during surgery. 3. Radiologists and clinicians should be aware of tracheobronchial anomalies to ensure appropriate management of pulmonary disorders.

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INTRODUCTION There are various anatomical classifications of bronchial tree available in the literature, including the Jackson–Huber classification,1 the Yamashita Japanese classification,2 and the Boyden surgical anatomy classification.3 Contrary to these classifications, anatomical variance may exist that might show in a variety of ways, from being asymptomatic to exhibiting a variety of symptoms. Segmentectomies of the right upper lobe,4 as well as imaging, diagnostic and interventional endoscopy, brachytherapy, and anaesthetic tracheal intubation all require knowledge of these variances. Accurate diagnosis and effective care can be aided by close attention to not only radiological and bronchoscopy findings, but also anatomical variances. Here, the authors present a case with bronchoscopy revealing an anatomical variant of the right upper lobe bronchus with five branches, and its clinical implication with a review of the literature.

CASE REPORT A 77-year-old female presented to the outpatient department of All India Institute of Medical Sciences (AIIMS), Patna, India, with a chief complaint of shortness of breath and cough for 45 days. She was a former bidi smoker, with a history of hypertension and exposure to biomass fuel. The patient also reported history of haemoptysis in past, one episode 25 years ago. She had taken anti-tubercular treatment for 2 years on an emperical basis around 25 years ago. Family history of bronchial asthma was present. Amlodipine was being used by the patient to treat hypertension. Theophyllines, oral bronchodilators, and antihistamines were also occasionally taken by the patient for symptomatic relief, with no prior history of using inhaled drugs, or any regular therapy for obstructive airway disease. There were no relevant past interventions done as per patient’s recall, nor were there any records available. On further investigation, chest CT showed multiple sub-segmental areas of atelectasis surrounding ground-glass opacities, and sub-pleural fibrotic bands were observed, along with pleural thickening, and segmental and sub-segmental tractional bronchiectasis in bilateral upper lobes. Therefore, the authors

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proceeded to fiberoptic bronchoscopy to evaluate for any obvious site of bleeding, and to rule out infections. Although infective aetiology was ruled out, no obvious site of bleeding could be appreciated during the procedure. An uncommon anatomical variant of right upper lobe bronchus, with the right bronchus intermedius normal in its anatomy branching into the right middle and lower lobe bronchus segments (Figure 1), was observed during the procedure.

DISCUSSION Several models have been mentioned in the literature for pulmonary morphometry that were based on the concept of the pulmonary branch and airway generation to model geometry.5-9 The term right post-eparterial bronchus has been mentioned in the literature for any bronchus that emerges from the right bronchial tree at a level lower than the right upper lobe bronchus (eparterial bronchus).10 The difference in the anatomy of the airways is thought to result from a problem with lung formation, such as when too few lung buds form, or when they form at unusual locations. According to the research, tracheal bronchi and supernumerary superior segmental bronchi are the two most prevalent bronchial abnormalities, which are typically on the right side of airways.11 Traditionally, the apical segmental bronchi (B1), dorsal (B2), and ventral (B3) of the right upper lobar bronchus are separated. In the study conducted by Thiam et al.,12 only one instance exhibited quadrifurcation of the right upper lobe bronchus. There are numerous variations in bronchial segmentation that affect 43% of normal persons.13 These variants are predominately bifurcations, with a prevalence of 16.6–71.6% in the right upper lobe.13,14 Foster-Carter15 distinguished between supernumerary bronchus (the simultaneous presence of all segmental bronchi) and displaced bronchus (the location of a segmental bronchus distant from its theoretical origin). According to this, the authors’ case was a supernumerary bronchus. In the authors’ present case, the radiological presentation, adding to this that the patient had a history of former bidi smoking and biomass fuel exposure, is suggestive of diagnosis of chronic

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Figure 1: Flexible bronchoscopy showing five segmental divisions of the right upper lobe bronchus.

Fourth and fifth segmental branch of RUL (RBx and RBy)

RB1 (apical segment) RB3 (anterior segment)

RB2 (posterior segment)

RB: right bronchus; RUL: right upper lobe.

obstructive pulmonary disease and old treated pulmonary Koch’s. However, the presence of ground-glass opacities and sub-pleural fibrotic bands raises the possibility of an additional diagnosis of lung cancer or tuberculosis, given the patient’s history of anti-tubercular treatment use and haemoptysis. The bronchoscopy revealed a rare anatomical variant of the right upper lobe bronchus with five branches. Although this finding may be incidental and unrelated to the patient’s presenting symptoms, it is, however, important to note the existence of such an anatomical variant, as it may have implications for diagnostic and therapeutic interventions in the future. The majority of these anatomical variations are asymptomatic and incidental, but there are few case reports and series in literature that suggest haemoptysis as a symptom related to tracheobronchial anatomical variation.16-18

In 0.1–2.0% of bronchoscopic examinations, a tracheal bronchus, sometimes known as a pig bronchus, is discovered; it almost always develops on the right.19 This variant describes a number of abnormal bronchial patterns, including classic pre-eparterial bronchus (the trachea’s misplaced right upper lobe apical segmental bronchus), classic tracheal bronchus (tracheal apical segmental bronchus with misplaced right upper lobe), and tracheal apical segmental bronchus that are extraneous. With an overall prevalence of 1–12%, other types previously described include auxiliary cardiac bronchus,20 ectopic, and accessory bronchus.21 The right upper lobe is considered as having the largest percentage of variants by most authors.21-23 The prevalence of right upper lobe variation in these studies varies from 1.2–54.0%. The prevalence of these variations varies widely across different studies, which may be due to factors such as differences in study populations

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and methods of classification. However, the right upper lobe variant with five segments spotted by the authors was unique, as it has never been described in the past, despite a tedious literature search. Right middle and lower lobe variants have also been described in literature.24 In a study, apart from the above-mentioned variants, a few other right upper lobe bronchus variants were described, including bipartite branching at the entrance, two segmental bronchus, and four segmental bronchus.25 The clinical significance of these variations is mainly related to their potential impact on diagnosis, treatment, and outcomes. In some cases, anatomical variations of the right upper lobe bronchus can lead to technical difficulties during diagnostic procedures, such as bronchoscopy or imaging studies. Furthermore, anatomical variations of the right upper lobe bronchus can impact the distribution of inhaled medications, and the development of atelectasis or aspiration. An understanding of these variations is, therefore, important for appropriate diagnosis and management of respiratory diseases. In some conditions, such as atelectasis or lobar pneumonia, recognising anatomical variations of the right upper lobe bronchus can be essential in determining the most appropriate therapeutic approach. They can also result in complications during surgery, particularly in cases of resection of the right upper lobe. Although variations in bronchial anatomy are a rare clinical entity and are usually asymptomatic, their recognition and correct diagnosis are eminent to know, as few entities may require clinical, endobronchial, and, in some instances, surgical interventions. In conclusion, bronchoscopy is a valuable diagnostic tool to evaluate the bronchial tree and detect anatomical variations, such as the

Limitation of this case report is due to the rarity of the occurrence, and it is the first case at the authors’ institute with penta-lobe bronchus division finding of the right upper lobe. So, definite comment and implications on its clinical and surgical management is not possible. The patient was admitted for investigations, and management, and was greatly relieved of her presenting complains of shortness of breath. She was discharged with medication advice, and is continuing follow-up in outpatient department, as per advice and her schedule. She was informed of the anatomical variation of her case, and informed consent was taken for reporting her case.

CONCLUSION Overall, this case report highlights the importance of considering a wide range of differential diagnoses in patients with chronic respiratory symptoms, particularly in those with a history of smoking or biomass fuel exposure. Close attention to CT findings and bronchoscopy results, as well as knowledge of anatomical variants, can aid in accurate diagnosis and appropriate management. Further studies may be needed to investigate the prevalence and clinical significance of rare variants of the bronchial tree.

References

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Gossot D, Seguin-Givelet A. Anatomical variations and pitfalls to know during thoracoscopic segmentectomies. J Thorac Dis. 2018;10(Suppl 10):S1134-44.

Weibel ER. Principles and methods for the morphometric study of the lung and other organs. Lab Invest. 1963;12:131-55.

Horsfield K et al. Models of the human bronchial tree. J Appl Physiol. 1971;31(2):207-17.

Yamashita H (ed.). Roentgenologic Anatomy of the Lung (1978) 1st edition, Tokyo: Igaku-Shoin.

Boyden EA et al. Committee on anatomical nomenclature. Science. 1942;96(2483):116.

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penta-segmental right upper lobe bronchus. Radiologists and clinicians should be aware of this anomaly to ensure appropriate management of pulmonary disorders, particularly in patients requiring bronchoscopy or surgical interventions. Newer techniques, including virtual, mixed, and augmented reality, are in development for studying the digital anatomy of the lungs and airways.27

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Phalen RF et al. Application of an idealized model to morphometry of the mammalian tracheobronchial tree. Anat Rec. 1978;190(2):167-76.

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Case Report

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bronchopulmonary segments in the light of their variations. Dis Chest. 1949;15(6):657-68. 23. Martín-Ruiz S et al. The bronchial segmentation and its anatomical variations. A clinical-anatomic and bronchoscopy study. Ann Anat. 2021;235:151677. 24. Nagashima Tet al. Analysis of variation in bronchovascular pattern of the right middle and lower lobes of the lung using three-dimensional CT angiography and bronchography. Gen Thorac Cardiovasc Surg. 2017;65(6): 343-9. 25. Abakay A et al. Clinical and demographic characteristics of tracheobronchial variations. Lung India. 2011;28(3):180-3. 26. Uhl J-F et al., “Digital anatomy: applications of virtual, mixed and augmented reality,” Uhl J-F et al. (eds.) Anatomical to Digital Dissection: A Historical Perspective Since Antiquity Towards the Twenty-First Century (2021) 1st edition. New York: Springer, p.29.

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