PracticeUpdate Conference Series: ERS 2018

ISSN 2208-150X (Print) ISSN 2208-1518 (Online)

EUROPEAN RESPIRATORY SOCIETY INTERNATIONAL CONGRESS 2018 15–19 SEPTEMBER 2018 • PARIS, FRANCE

THE BEST OF ERS 2018 ANA Prevalent in Idiopathic Pulmonary Fibrosis • AI Improves Testing and Diagnosis of Lung Disease • Three Exosomal miRNAs May Be Key Drivers of COPD • Soot From Polluted Air Reaches the Placenta • Numbers of BALF Neutrophil-Derived Microvesicles Correlate With Severity of COPD for Alopecia Areata

The production and distribution of this publication is sponsored by AstraZeneca Australia.

*FASENRA significantly reduced annual exacerbation rate by 51% and 28% vs placebo (p<0.0001, p=0.0188; SIROCCO and CALIMA trials) 1,2 POWER TO REDUCE EXACERBATIONS IN SEVERE EOS INOPHI L IC ASTHMA *

75 % REDUCTION IN MEDIAN OCS DOSE from baseline with FASENRA vs 25% with placebo (p<0.001; week 28; ZONDA study) 3

8 DOSING † WEEKLY † after three doses 4-weekly 4

FASENRA is indicated as add-on therapy in patients aged 12 years and over with severe eosinophilic asthma (blood eosinophil count ≥300 cells/μL or ≥150 cells/μL if on oral corticosteroid treatment) 4

References: 1. Bleecker ER, et al. Lancet 2016;388(10056):2115–27. 2. FitzGerald JM, et al. Lancet 2016;388(10056):2128–41. 3. Nair P, et al. N Engl J Med 2017;376(25):2448–58. 4. Fasenra (benralizumab) Product Information. April 2018. FASENRA ® is a registered trademark of the AstraZeneca group of companies. Registered user AstraZeneca Pty Ltd. ABN 54 009 682 311. 66 Talavera Road, Macquarie Park, NSW 2113. www.astrazeneca.com.au. For Medical Information enquiries: 1800 805 342 or medinfo.australia@astrazeneca.com.To report an adverse event: 1800 805 342 or via https://aereporting.astrazeneca. com. AU-4639 ASTR0072/EMBC Date of preparation: July 2018 FASENRA ® (benralizumab) 30 mg in 1 mL, prefilled syringe for subcutaneous injection. THERAPEUTIC INDICATION: Fasenra is indicated as an add-on therapy in patients aged 12 years and over with severe eosinophilic asthma (blood eosinophil count ≥ 300 cells/µL or ≥ 150 cells/µL if on oral corticosteroid treatment). DOSE AND METHOD OF ADMINISTRATION: Fasenra should be prescribed by a healthcare professional in consultation with a specialist physician experienced in the diagnosis and treatment of severe asthma. Treatment with high-dose ICS and LABA should be optimised prior to commencement of treatment with Fasenra. The recommended dose is 30 mg of Fasenra by subcutaneous injection every 4 weeks for the first 3 doses, and then every 8 weeks thereafter. Fasenra should be administered by a healthcare professional, and is not for self-administration by the patient. CONTRAINDICATIONS: Hypersensitivity to benralizumab or any of its excipients. PRECAUTIONS: Fasenra should not be used to treat acute asthma exacerbations. Reduction in OCS dose, if appropriate, should be gradual and performed under the supervision of a physician. Abrupt discontinuation of OCS after initiation of Fasenra therapy is not recommended. Hypersensitivity reactions (eg urticaria, urticaria papular, rash) have occurred following administration of Fasenra. These reactions generally occur within hours of administration, but in some instances have a delayed onset (ie days). In the event of a hypersensitivity reaction, Fasenra should be discontinued. Parasitic (helminth) infections: treat patients with pre-existing helminth infections before initiating therapy with Fasenra. If patients become infected while receiving treatment with Fasenra and do not respond to antihelminth treatment, discontinue treatment with Fasenra until infection resolves. Children under 12; pregnancy (category B1); lactation. ADVERSE EFFECTS: Common ( ≥ 3% frequency): headache, pharyngitis, arthralgia, cough; Less common ( ≤ 3% frequency): hypersensitivity reactions, pyrexia, injection site reactions. See full PI for details. Date of first inclusion in the ARTG: 2 April 2018. Date of most recent amendment: 2 April 2018. BEFORE PRESCRIBING PLEASE REVIEW FULL PRODUCT INFORMATION AVAILABLE ON REQUEST FROM ASTRAZENECA ON 1800 805 342 OR www.astrazeneca.com.au/PI PBS Information: This product is not listed on the PBS.

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© ERS 2018

Contents

ERS 2018 • 15–19 September 2018 • Paris, France BY THE PRACTICEUPDATE EDITORIAL TEAM

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2 ANA Prevalent in Idiopathic Pulmonary Fibrosis 3 AI Improves Testing and Diagnosis of Lung Disease 4 Azithromycin May Reduce Time to Treatment Failure in Acute Exacerbations of COPD 5 Three Exosomal miRNAs May Be Key Drivers of COPD 6 50-Minute Test for Viral Infections Reduces Hospital Admissions and Antibiotic Use 8 Targeted Lung Denervation Linked to Improvement in Symptoms of COPD 8 Nitrate Supplementation Enhances Pulmonary Rehabilitation in Patients With COPD 10 Soot From Polluted Air Reaches the Placenta

12 Green Space Near Home During Childhood Linked to Fewer Respiratory Problems in Adulthood 12 Uterine Exposure to Organochlorine Pesticides Linked to Poorer Lung Function 14 Numbers of BALF Neutrophil-Derived Microvesicles Correlate With Severity of COPD 16 Asthma Predisposes Patients to Obesity 18 Paracetamol Use in Infancy Linked to Higher Asthma Risk in Some Teenagers 19 Children With Asthma Less Likely to Finish School and to Work in Nonmanual Occupations 20 Bacteria Passed From Uterus to Fetus Linked to Premature Birth and Breathing Difficulty

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ANA Prevalent in Idiopathic Pulmonary Fibrosis Circulating ANA is prevalent among patients with IPF, though its overall clinical significance is uncertain.

C irculating antinuclear antibody (ANA) is prevalent among patients with idiopathic pulmonary fibrosis, and patients with high-titer ANA likely represent a unique subset of the overall population with idiopathic pulmonary fibrosis. This finding of an analysis of data from the recently completed, phase IIb Efficacy and Safety of SAR156597 in the TreAtment of Idiopathic pulmonary fibRosis (ESTAIR) study was reported at ERS 2018. Peter K. Wung, MD, MHS, of the Johns Hopkins Medical Institutions in Baltimore, Maryland, and colleagues set out to address these deficiencies by examining the data from a large cohort of patients with idiopathic pulmonary fibrosis. ESTAIR assessed the safety and efficacy of SAR156597 in idiopathic pulmonary idiopathic pulmonary fibrosis with high-titer ANA likely represent a unique subset of the overall population with idiopathic pulmonary fibrosis. " PRACTICEUPDATE CONFERENCE SERIES • ERS 2018 " ...patients with

ANA is used to evaluate patients with suspected idiopathic pulmonary fibrosis to exclude conditions that mimic fibrotic lung disease, but its clinical significance in patients with confirmed idiopathic pul- monary fibrosis remains to be elucidated. The significance of circulating autoan- tibodies in patients with idiopathic pulmonary fibrosis has been of clinical and scientific interest for many years. The primary concern is that these idiopathic pulmonary fibrosis autoantibody-positive patients do not suffer from idiopathic pulmonary fibrosis, but rather from some unrecognized and occult connective tis- sue disease. Surprisingly, few studies have systemat- ically examined the clinical relevance. In a cohort of 285 patients with idiopathic pulmonary fibrosis, 34% were positive for ANA (defined as ≥1:40), but no survival difference was reported between ANA- positive vs -negative patients. In another cohort of 58 patients with idiopathic pulmonary fibrosis, 41% had an ANA titer ≥1:160, and other circulating autoantibodies were found, including 7% with rheumatoid factor and 5% with anti- Sjögren's syndrome-related antigen A. No survival difference based on ANA titer was reported. SAR 156597 is an inhibitor of the interleukin-4 and -13 pathways that failed to demonstrate efficacy in a phase II,

fibrosis. The diagnosis of idiopathic pul- monary fibrosis was confirmed by central review of chest high-resolution computed tomography and lung biopsy (if per- formed). ANA was obtained at baseline. The prevalence of ANA, with its associ- ated baseline demographics and disease characteristics, was analyzed from the modified intention-to-treat population. A total of 325 patients were included in the modified intention-to-treat population. Of the 325 patients, 171 (52.6%) were ANA-negative and 105 (32.3%) harbored low-titer ANA (1:40 or 1:80). Overall, 48 (14.7%) exhibited high-titer ANA (≥1:160) at baseline. Patients with high-titer ANA were more likely to be female (35.4% vs 23.4%) and white (100% vs 91.8%), to have been diag- nosed earlier (1.68 ± 1.46 vs 1.82 ± 1.27 years), to suffer symptoms of idiopathic pulmonary fibrosis, to never have smoked (56.3% vs 32.3%), to have greater history of acute exacerbations (12.5% vs 4.7%), to require supplemental oxygen (22.9% vs 11.7%), and to demonstrate more definite features of usual interstitial pneumonia on high-resolution computed tomogra- phy (41.7% vs 31.0%) than ANA-negative patients. Dr. Wung explained that the prevalence of ANA is not well characterized in idiopathic pulmonary fibrosis.

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AI Improves Testing and Diagnosis of Lung Disease Artificial intelligence (AI) can help in the interpretation of respiratory symptoms. A rtificial intelligence (AI) has proven to be more consistent and accu- rate in interpreting respiratory test results and suggesting diagnoses than lung specialists. Interpretations were measured against gold standard guidelines from the ERS and American Thoracic Society. The expert panel considered patients’ medical histories and results of all pulmonary func- tion tests and any additional tests before agreeing on the correct interpretation and diagnosis of each patient.

Results of this exploration of AI among 120 pulmonologists from 16 hospitals were reported at ERS 2018. Marko Topalovic, PhD, of the Catholic University of Leuven inBelgium, explained that pulmonary function tests provide extensive numerical output patterns that are difficult for the human eye to under- stand, but computers can easily manage these data. Compared with diagnosis by pulmonologists, diagnosis by AI wasmore accurate in twice as many cases, which demonstrates that AI can be used as a second opinion for pulmonologists in the assessment and diagnosis process. He also noted that interpreting pul- monary function tests and diagnosing respiratory diseases is not easy for pulmonologists. To be accurate, more information and additional tests are required. However, AI-based software can be used as a powerful decision support tool for improving clinical practice. Doctors have provided very positive feedback, especially based on the assistance with identifying difficult patterns of rare diseases. According to Dr. Topalovic, the belief is that AI can be used to empower doctors to make interpretations and diagnoses earlier. AI will not replace doctors, how- ever, because doctors can see a broader perspective beyond what is presented by pulmonary function tests. AI can be used to augment the ability to accomplish more and reduce errors and redundant work. He also noted that we currently use computers for flying planes, driving cars, and guarding security. AI can be used to provide high-quality pulmonary function test interpretation regardless of location or medical coverage. The acceptance by the medical community will determine whether AI will be used widely in clinical applications. Dr. Topalovic and coinvestigators used historical data from 1430 patients from 33 Belgianhospitals. Thedatawereassessed by an expert panel of pulmonologists.

Dr. Topalovic explained that quality data is the most important factor to consider when training the AI algorithm. All results of the pulmonary function tests, additional tests, and medical information were reviewed by an expert panel who agreed on the final diagnosis. These diagnoses were used to develop the algorithm for training the AI prior to incorporating it into clinical practice at the University Hospital Leuven for validation. Ensuring that the algorithm could recognize patterns of up to nine different diseases was challenging. Then, 120 pulmonologists from 16 European hospitals in Belgium, France, The Netherlands, Germany, and Luxembourg performed 6000 interpre- tations of pulmonary function test data from 50 randomly selected patients. The AI examined the same data. Results of both were measured against gold standard guidelines the same way as during algorithm development. The researchers found that interpretation of pulmonary function tests by pulmonol- ogists matched guidelines in 74% (56% to 88%) of cases. Software interpretations based on AI matched the guidelines per- fectly (100%).Pulmonologists were able to diagnose the primary disease correctly in 45% (24% to 62%) of cases. AI diagnosed correctly in 82% of cases. Two large Belgian hospitals are using the AI-based software to improve inter- pretations and diagnoses. The AI-based software confers superior performance and may provide a powerful decision support tool to improve clinical practice. The next step will be to get more hospitals to use this technology and investigate transferring the AI technology to primary care, where the data will be captured by general practitioners to help them diagnose and refer correctly.

randomized, placebo-controlled, double- blind trial. Evidence-based 2011 clinical prac- tice guidelines for the diagnosis and management of idiopathic pulmonary fibrosis defined the disorder as pro- gressive fibrotic lung disease limited to the lungs. Interstitial pulmonary fibrosis occurs in adults without attributable sys- temic disease and environmental factors. The guidelines include precise imaging and histopathological criteria for pat- terns of usual interstitial pneumonia (the hallmark feature of interstitial pulmonary fibrosis in the lung). Since then, new evidence has changed the landscape of treatment for interstitial pulmonary fibrosis. Idiopathic pulmonary fibrosis is a fibro- proliferative interstitial lung disease of unknown etiology that results in a pro- gressive loss of lung function and median survival of 3–5 years. Dr. Wung concluded that circulating ANA is prevalent among patients with idio- pathic pulmonary fibrosis. Its overall clinical significance remains to be determined, but patients with idi- opathic pulmonary fibrosis with high-titer ANA likely represent a unique subset of the overall population with idiopathic pulmonary fibrosis.

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AzithromycinMay Reduce Time to Treatment Failure inAcute Exacerbations of COPD Themacrolide antibiotic azithromycinmay significantly reduce treatment failure during the

period of highest risk in COPD. A zithromycin may significantly reduce treatment failure during the highest-risk period of chronic obstructive pulmonary disease (COPD) requiring hospitalization. These benefits are lost, however, 6 months after discon- tinuing azithromycin. This finding of the multicenter, randomized, double-blind, placebo-controlled Belgian trial with Azithromycin for acute COPD Exacerbations requiring hospitalization (BACE) was reported at ERS 2018. Kristina Vermeersch, MS, of Universitair Ziekenhuis in Leuven, Belgium, and col- leagues set out to investigate the effect of azithromycin initiated within 48 h of hos- pital admission for an acute exacerbation of COPD (500 mg daily for 3 days) and administered subsequently for 3 months (250 mg for 2 days). BACE was a randomized, placebo-con- trolled, multicenter trial in 500 patients with COPD to determine the effectiveness and safety of azithromycin therapy in the acute setting of COPD exacerbations requiring hospital admission. Though long-term use of azithromycin is proven effective to prevent exacerbations, inherent risks outweigh the benefits. By reducing the dose and duration of azithromycin treatment and restricting it to acute periods of highest risk for treat- ment failure, benefits may counterbalance potential side effects, which may result in a new treatment strategy for these acute events. Patients were followed for 9 months, including 6 months after withdrawal of azithromycin. Time-to-treatment failure within 3 months was evaluated as a novel primary endpoint. Clinical failure was defined as the com- posite of death, treatment intensification (additional dose of systemic steroids, a switch of antibiotics for respiratory rea- sons, or a new course of systemic steroids and/or antibiotics) and an escalation in hospital care for respiratory reasons

exacerbations, relapse is common. Some patients remain at high risk of recurrent episodes for several weeks after the initial event. Failure may be related to inadequate antibiotic efficacy, but even with effec- tive bacterial eradication, or in cases of noninfectious events, increased airway inflammation may persist for a prolonged period after discharge and will likely pro- mote recurrence. Epidemiological data confirm that risk of subsequent events peaks drastically dur- ing 90 days after discharge and increases with all subsequent hospital admissions. Disrupting the vicious cycle of a severe exacerbation leading to a subsequent one is therefore promising. Ms. Vermeersch explained that azithro- mycin prevents acute exacerbations of COPD but the optimal dose, treatment duration, and target population are yet to be defined. Ms. Vermeersch concluded that azithro- mycin may significantly reduce treatment failure during the highest-risk period of acute exacerbations of COPD requiring hospitalization. These benefits are lost, however, 6 months after the discontinua- tion of azithromycin. " Epidemiological data confirm that risk of subsequent events peaks drastically during 90 days after discharge and increases with all subsequent hospital admissions. "

(from ward to intensive care unit during an index event, or from home to ward or intensive care unit [new admission] after discharge). Overall, 301 patients with COPD were randomized 1:1 to azithromycin (n=147) or placebo (n=154) in addition to stand- ard treatment with corticosteroids and antibiotics. The rate of treatment failure at 3 months was 49% in the azithromycin arm and 60% in the placebo arm (HR 0.73; 95% CI 0.53–1.01; P = .053 for time to treatment failure and change of –0.24; 95% CI –0.48 to 0.00; P = .040 for cumulative treatment failure). Treatment intensification, readmission for respiratory reasons, and mortality within 3 months were 47% versus 60% (P = .027), 13% versus 28% (P = .002), and 2% versus 4% (P = .507), respectively. Significance was lost 6 months after withdrawal of azithromycin. Though available treatments for COPD reduce the frequency of exacerbations by approximately 20% to 30%, these ther- apies are insufficient as many patients still experience at least one exacerbation a year. One-quarter of these exacerbations require hospitalization. A 2013 large European audit on COPD exacerbations in hospitalized patients revealed that these events were asso- ciated with 12% mortality and 35% risk of readmission within 3 months after discharge. Acute interventions lacking effective- ness in a substantial proportion of admissions for COPD. New interventions are warranted. Bacterial infections are responsible for approximately half of acute exacerbations of COPD. Guidelines, therefore, recommend antibiotic therapy for patients with more severe symptoms, with treatment typically lasting 5–7 days. Though such intervention has been shown to reduce the risk of subsequent

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T hree novel, differentially expressed exosomal microRNAs may be key drivers of the persistent inflammatory response in chronic obstructive pulmonary disease (COPD). Therefore, they are potential targets of future therapies. This finding of an exosome isolation study using exclusion chro- matography was reported at ERS 2018. Tom Wilkinson, MD, of the University of Southampton, UK, and colleagues set out to investigate differentially expressed microR- NAs in exosomes from bronchoalveolar lavage fluid. The goal was to study their effects on inflammatory pathways thought to be key in the pathogenesis of COPD. Exosomes were isolated frombronchoalveolar lavage fluid by size exclusion chromatography from 15 healthy ex-smokers and 20 age- and sex-matched patients withmild tomoderate COPD. Mean forced expiratory volume in 1 second was 79.9% ± 13.9% predicted. Exosomal microRNA was sequenced using the Illumina NextSeq500. Raw data was demultiplexed, trimmed, and aligned to hg19. Negative binomial generalized linear models were used to identify differentially expressed microRNAs between patients with COPD and healthy ex-smokers. An average of 2.8 million reads was obtained for each sample and the average genome mapping rate was 54.5%. A total of 513 microRNAs were detected with a median absolute deviation >1. Of these, 23 microRNAs were differentially expressed between patients with COPD and healthy ex-smokers (false discovery rate < .05). Six exhibited a fold change of >2: ƒ ƒ iR-223-3p Differentially expressed exosomal miRNAs target key inflammatory pathways in COPD. Three Exosomal miRNAs May Be Key Drivers of COPD

Such deregulation targeting a variety of cellular and molecular pathways such as Notch, Wnt, hypoxia-inducible factor-1α, trans- forming growth factor, Kras, and Smad may be involved in the pathogenesis of COPD. Multiple lines of evidence have indicated that extracellular ves- icles such as exosomes may carry a variety of cargos (that is, mRNAs, microRNAs, and proteins) that transfer various cellular and molecular signals to recipient cells. A variety of external factors (that is, smoking and oxidative stress) and internal factors (that is, deregulation of various growth factor ligands, interleukins, and receptor tyrosine kinase) may lead to deregulation of many cellular and molecular pathways and microRNA expression. These events are associated with small and large alterations in molecular and cellular levels and could contribute to the pro- gression of COPD. In addition to their role as therapeutic targets, microRNAs could be employed as prognostic and diagnostic biomarkers in various diseases such as COPD. The latter is a multifactorial disease, and effective diagnostic and therapeutic platforms to treat patients with chronic obstructive pulmonary disease have been sought. It has been shown that the levels of various cytokines (that is, interleukins -6, -8, -10, -17, -12p70, and -1β), cysteinyl-leukotrienes, leukotriene B4, prostaglandin E4, hydrogen peroxide, and 8-iso- prostane may be associated with the pathogenesis of COPD. Despite numerous efforts, effective diagnostic biomarkers remain rare. MicroRNAs have been shown to play a critical role in the pathogenesis of COPD, so it seems that these molecules may be used as prognostic and diagnostic biomarkers for monitoring. In 2015, Dr. Wilkinson’s team assessed the role of exosomal microRNAs in patients with COPD who suffered from skeletal muscle weakness. They found that one exosomal microRNA was upregulated in the serum of patients with COPD. Four exosomal microRNAs were downregulated in the bronchoalveolar fluid of patients with COPD. These microRNAs may exert their effects via targeting of many genes including S6K involved in the mTORC1 signaling pathway. This pathway serves as a key regulator of skeletal muscle wasting. The results indicated that exosomal microRNAs play a critical role in skeletal muscle wasting in patients with COPD and may be used as diagnostic and prognostic biomarkers for detection, treatment, and monitoring. Dr. Wilkinson concluded that these novel, differentially expressed, exosomal microRNAs may be key drivers of the persistent inflam- matory response in COPD. They are therefore potential targets of future therapies.

ƒ ƒ miR-223-5p ƒ ƒ miR-338-3p ƒ ƒ miR-1469 ƒ ƒ miR-204-5p ƒ ƒ miR-618

Kyoto Encyclopedia of Genes and Genomes pathway analysis identified disease relevant inflammatory pathways (tumor necrosis factor α, nuclear factor κ-light-chain-enhancer of activated β cells, andmitogen-activated protein kinase signaling) regulated by these microRNAs. Future in vitro modeling will validate these findings. Exosomes are nanosized vesicles that transport microRNA and alter gene expression in recipient cells. Among various bio- markers, microRNAs have emerged as new biomarkers for the prognosis and diagnosis of COPD. Deregulation of microRNAs is associated with the initiation and progression of several diseases such as stroke, cardiovascular diseases, diabetes, cancer, and inflammatory diseases.

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50-Minute Test for Viral Infections Reduces Hospital Admissions and Antibiotic Use The test can reduce unnecessary antibiotic use and hospital admissions.

A 50-minute viral test could save hospitals approximately €2500 per patient not admit- ted to hospital and could help relieve winter pressure for available beds. It may also help reduce antibiotic resistance, results of a trial including over 1000 patients report. According to Kay Roy, MD, of West Hertfordshire Hospitals National Health Service Trust, Watford, and the University of Hertfordshire in Hatfield, UK, the potential of this test was revealed through initial results of the first 1075 patients. Of these patients, 121 had viral infections, lacked evidence of bacterial infection, and had normal chest x-rays and modest inflammatory markers. Dr. Roy also noted that unnecessary antibiotics were avoided in 50% of patients and hospital admission was avoided in 25% of patients. Of those who avoided hospital admission and were not prescribed antibiotics, none experienced adverse clinical outcomes.

She also explained that the process, including obtaining the sample and receiving the result, should take 50 minutes or less. This quick turna- round may have an enormous impact on the quality of care patients receive. The patient journey will be improved through ear- lier patient management decision making with the shortened test time. Dr. Roy noted that this is the same technology used in the microbiology labo- ratory, but now the equipment is at the bedside. When samples are sent to the microbiology lab, more than 2 days may be required for analysis and reporting of the results. A swab is inserted into the patient’s nostril to collect a secretion sample from the back of the nose (1 minute). The sample is then prepared and inserted into the compact FilmArray® machine (3–5 minutes). The machine analyzes the sample and prints results within 43 minutes. Of the first 1075 patients who underwent the testing, 61% were found to harbor one or more viruses, of which 56% were influenza and 54%, other viruses such as rhinovirus, coronavirus, metapneumovirus, and adenovirus. These can cause as many respira- tory and other problems as influenza or bacterial

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" ...unnecessary antibiotics were avoided in 50% of patients and hospital admission was avoided in 25% of patients. Of those who avoided hospital admission and were not prescribed antibiotics, none experienced adverse clinical outcomes. "

infection, particularly in patients with chronic obstructive pulmonary disease. In 387 patients, test results were com- bined with other important clinical factors, such as chest x-ray findings and lack of evidence of bacterial infection. According to Dr. Roy, bed flow was improved and fewer bed closures were required as a result of viral infections when patients underwent this respiratory viral testing shortly following admission to the emergency department. She also noted that 50 cases of influenza were diagnosed in the first 2 weeks of this new service. Of these cases, 22 were diagnosed in the emergency depart- ment and 28 were diagnosed following hospital admission. Importantly, no bed moves were needed in the former group, whereas 14 were needed in the latter group. Dr. Roy noted that infection control was improved through earlier testing at the bedside in the emergency department, which also avoided bed and ward

closures and reduced the risk of infection spreading to more vulnerable patients. If admission is required, patients with an early influenza diagnosis based on point-of-care respiratory viral testing can be placed in designated beds. Importantly, the use of this test seems to provide a net cost saving by avoid- ing unnecessary admission in patients who otherwise would be admitted and prescribed antibiotics while waiting approximately 2 days for lab results, according to Dr. Roy. Dr. Roy is about to begin a randomized controlled trial in the community, in which

primary care physicians will refer patients to point-of-care respiratory viral testing. According to Dr. Roy, good antimicrobial stewardship has been hindered based on the frequent underestimation of the importance of viruses in respiratory admissions, which has resulted in other health problems such as inappropriate antibiotic use and hospital admission. She concluded by noting that the hope is that point-of-care respiratory viral testing can improve quality of care and reduce anti- biotic resistance.

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Targeted LungDenervationLinked to Improvement in Symptoms of COPD Patients with COPD suffer fewer respiratory-related problems when treated with targeted lung denervation. F irst results with targeted lung dener- vation (TLD) in patients with chronic obstructive pulmonary disease nerves interrupts their normal function. The airways then relax and widen, mucus production is decreased, and airway wall inflammation decreases as well.

Dr. Slebos noted that there was a trend toward better lung function and improved quality of life in patients who received treatment, which will significantly impact healthcare costs for these patients. He also explained that the number of patients requiring hospitalization for respiratory complications decreased by over 50% in the first year in patients receiving TLD treatment compared with those in the sham arm. TLD involves passing a catheter through a bronchoscope into the lungs. Radiofrequency energy to the airway

(COPD) have shown significantly reduced symptoms and good tolerability, reports the AIRFLOW 2 phase II clinical trial. Dirk-Jan Slebos, MD, PhD, of the University Medical Centre Groningen in The Netherlands, explained that a group of COPD patients on aggressive medical therapy has exhibited significantly reduced chronic respiratory symptoms, including disease exacerbations, shortness of breath, infections, and hospitalizations.

AIRFLOW-2 is taking place in several centers in six European countries. Patients are randomized to either TLD or a sham procedure under general anesthesia. The sham procedure also involves inserting the bronchoscope and catheter, but the radiofrequency electrical change is not delivered. TLD targets the cholinergic pathway. Anticholinergic drugs, which are often

Nitrate SupplementationEnhances Pulmonary Rehabilitation inPatientsWithCOPD Supplementation of the diet with nitrate improves pulmonary rehabilitation and exercise endurance time in patients with COPD.

I n patients with chronic obstructive pulmonary disease (COPD), dietary nitrate supplementation reduces the oxygen cost of peak exercise and raises exercise endurance time via improved skel- etal muscle blood flow and efficiency of energy metabolism and thus has the potential to augment the effect of exercise training. This conclusion, based on results of a multicenter, double-blind, placebo-controlled, parallel group comparison, was presented at ERS 2018. Matthew Pavitt, MBBS, PhD, of the Royal Brompton & Harefield National Health Service Trust in Harefield, UK, and colleagues set out to determine whether adjunctive dietary nitrate supplementation enhances the effects of pulmonary rehabilitation and exercise endurance time in stable COPD. They hypothesized that dietary nitrate supplemen- tation would enhance the gains in incremental shuttle walk test in the context of pulmonary reha- bilitation in patients with COPD versus placebo. The effect of 140 mL (12.9 mmol) of nitrate-rich beetroot juice was compared with that of matched placebo, nitrate-depleted beetroot juice. Patients consumed one of these beverages 3 hours before attending pulmonary rehabilitation sessions only (n=122).

The pulmonary rehabilitation program consisted of twice-weekly strength and endurance training over 8 weeks and education. Primary outcomes included change in distance on the incremental shuttle walk test and exercise endurance time via the endurance shuttle walk test, assessed 3 h after ingesting nitrate-rich or nitrate-depleted beetroot juice. A total of 166 patients were recruited, and 122 com- pleted the full protocol (female, 40%; age, 76 ± 11 years; body mass index, 27± 7 kg/m 2 ; forced expir- atory volume in 1 s, percent predicted 49% ± 18%; baseline distance of 284.9 ± 152.8 m on the incre- mental shuttle walk test). Nitrate supplementation increased distance on the incremental shuttle walk test significantly: nitrate- rich beetroot juice 60 m versus placebo 30 m (95% CI 10, 40), P = .008. A total of 20 patients (female 40%, age 67.6 ± 8.5 years, body mass index 25.2 ± 4.7 kg/m 2 , forced expiratory volume in 1 s percent predicted 27% ± 8.1%) completed the incremental shuttle walk test. Nitrate supplementation increased exercise endurance time significantly: beetroot juice 194.6 s (89.1–1200.0 s) versus placebo 159.1 s (78.6–785.0 s).

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used to treat COPD, also target this pathway. When combined with TLD, an additional beneficial effect is observed, even in patients treated heavily with other drugs. Patients in both parts of the trial received the anticholinergic bronchodi- lator tiotropium. Dr. Slebos presented results of 82 patients. Half were male, and the aver- age age was nearly 64 years. At 3 to 6 months after treatment, 71% of patients who had received the sham treatment had experienced an adverse respiratory event related to COPD versus 32% of those who underwent TLD. None of the patients died and no TLD- related adverse side effects needed to be treated. A total of 5 patients (12%) who underwent TLD experienced stomach problems such as nausea, abdominal bloating, and digestive discomfort. These

new, under investigation since 2008. Four clinical trials have taken place in the past 6 years (Innovative Pulmonary Solutions I and II, AIRFLOW-1, and AIRFLOW-2). According to Dr. Slebos, there is a great clinical need for more effective therapies. The effectiveness of treatment should be demonstrated through a double-blind, randomized, sham-controlled trial. Daiana Stolz, MD, of the University Hospital Basel in Switzerland, who was not involved in the study, emphasized the importance of these results based on the difficulty of treatment for patients with COPD. These results demonstrate that TLD can provide significant improvements to patient health, she said. She added the results of the AIRFLOW-3 trial are highly anticipated to confirm TLD as a safe and effective treatment for patients with severe COPD.

were temporary and subsided after 6 months. Dr. Slebos explained that these issues occurred based on the effect of radiof- requency energy on nearby nerves. The process and imaging are undergoing improvements in order to improve under- standing of the location of these gastric nerves, and additional measures have been implemented to avoid these nerves in future procedures. The larger, phase III, AIRFLOW-3 trial is being planned. It is likely to be launched in carefully chosen centers of excellence in Europe in 2019. Dr. Slebos noted that AIRFLOW-3 will have a similar design but will include more patients in order to gather more evidence for the procedure. Over 300 million patients worldwide suffer from COPD, including 4% to 10% of adults in European countries. TLD is relatively

www.practiceupdate.com/c/73940

" ...dietary nitrate in association with pulmonary rehabilitation

enhanced the gains in exercise capacity in patients with COPD and increased exercise endurance time... "

Estimated treatment effect of beetroot juice vs placebo 62 s (95% CI 33, 106), P < .0001. Nitrite and nitrate levels increased sig- nificantly (beetroot juice change in nitrite 0.31 ± 0.23 µM vs placebo change in nitrite 0.03 ± 0.09 µM, P < .0001; beetroot juice change in nitrate 567.8 ± 165.1 µM vs placebo change in nitrate –4.25 ± 25.07 µM, P < .0001). Dietary nitrate supplementation reduced the oxygen cost of exercise in COPD but not endurance time. Individuals using ambulatory oxygen may show a greater response. Dr. Pavitt concluded that administration of dietary nitrate in association with pulmonary rehabilitation enhanced the gains in exercise capacity in patients with COPD and increased exercise endurance time in this cohort of patients with COPD who required ambulatory oxygen.

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Soot From Polluted Air Reaches the Placenta Evidence of soot has been found in placentas for the first time.

E vidence of tiny particles of carbon, typically created by burning fossil fuels, has been found in placentas for the first time. These pollution levels, lower than the recommended European Union annual limit, can raise the incidence of low birth weight. This finding of a microscopy study of placental tissue was reported at ERS 2018. Results of the study by Norrice Liu, MB, BCh, BAO, and Lisa Miyashita, PhD, BSc, MSc, of the Queen Mary University of London, UK, add to existing evidence on the dangers of pollution for unborn babies and suggests that when pregnant women breathe polluted air, the smallest inhaled sooty particles are able to reach the placenta via the bloodstream. In an ERS press release, Dr. Miyashita said, “We’ve known for a while that air pollution affects fetal development and can continue to affect babies after birth and throughout their lives.” She continued, “We were interested to determine whether these effects could be due to pollution particles moving from the mother’s lungs to the placenta. Until now, there has been very little

evidence that inhaled particles get into the blood from the lung. “We thought that looking at macrophages in other organs might provide direct evidence that inhaled particles move out of the lungs to other parts of the body. “We were not sure,” she continued,” whether we would find any particles and if we did, we were only expecting to find a small number of placental macrophages that contain these sooty particles. This is because most of them should be engulfed by macrophages within the airways, particularly the bigger particles, and only a minority of small-size particles would move into the circulation.” “Our results,” she said, “provide the first evidence that inhaled pollution particles can move from the lungs into the circulation and then to the placenta.” Dr. Liu added, “We do not know whether the particles we found could also move across into the fetus, but our evidence suggests that this is indeed possible. We also know that the particles do not need to get into the baby’s body to have an adverse effect, because if they have an effect on the placenta, this will have a direct impact on the fetus.”

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" This new research suggests a possible mechanismof how babies are affected by pollutionwhile being theoretically protected in the womb. This should raise awareness among clinicians and the public regarding harmful effects of air pollution in pregnant women. "

Mina Gaga, MD, of Athens Chest Hospital in Greece, who was not involved in the study, commented: “Previous research shows that pregnant women liv- ing in polluted cities are more prone to pregnancy issues such as restricted fetal growth, premature birth, and low-birth-weight babies. Increased risk of low birth weight can happen even at pollution levels lower than the recommended European Union annual limit.” She continued, “This new research suggests a possible mechanism of how babies are affected by pollution while being theoretically protected in the womb. This should raise awareness among clinicians and the public regarding harmful effects of air pollution in pregnant women. “We need stricter policies for cleaner air to reduce the impact of pollution on health worldwide because we are already seeing a new population of young adults with health issues,” she added.

The researchers worked with five pregnant women scheduled for cesarean section. They were all nonsmokers who experienced an uncomplicated pregnancy and each gave birth to a healthy baby. The researchers were interested in placental macrophages. The team studied 3500 placental macrophage cells from the five placentas and examined them under a high-power microscope. They found 60 cells that, between them, contained 72 small black areas that they believed were carbon particles. On average, each placenta contained approximately 5 µm 2 of this black substance. They studied the placental macrophages from two placentas in greater detail using electron micros- copy and again found material they believed was tiny carbon particles. Previous research has indicated links between pregnant mothers’ exposure to air pollution and premature birth, low birth weight, infant mortality, and childhood respiratory problems. In previous research, the team used the same techniques to identify and measure these sooty particles in macrophages of subjects’ airways.

www.practiceupdate.com/c/73936

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Green SpaceNearHomeDuring Childhood Linked to Fewer Respiratory Problems inAdulthood Nearby access to green spaces reduces future respiratory problems. C hildren who have access to green spaces close to their homes have fewer respiratory problems, such as asthma and wheezing, in adulthood, reports an analysis of air pol- lution data in the Respiratory Health In Northern Europe, Spain and Australia (RHINESSA) study. “We will be conducting further analyses that include more centers taking part in RHINESSA. We also want to expand analyses to look at the effects of exposure to air pollution and greenness across generations.”

Dr. Kuiper and colleagues analyzed greenness data from 5415 participants aged 18–52 years, contributed by RHINESSA centers in Tartu, Estonia; Reykjavik, Iceland; Uppsala, Gothenburg, and Umea, Sweden; and Bergen, Norway. They also analyzed air pollution data from 4414 participants in Uppsala, Gothenburg, Umea, and Bergen. RHINESSA is a large international study that investigates lung health in children and adults in seven European countries and that collects information on residential greenness and air pollu- tion exposure from birth onward. The investigators looked at numbers of subjects who suffered from more than three respiratory symptoms, severe wheeze (in which the person experienced wheezing with breathlessness in the past year but did not have a cold), and late-onset asthma (after age 10 years). Respiratory symptoms included chest wheezing or whistling; breathlessness when wheezing; wheezing or whistling with- out a cold; tight chest on waking; being woken by an attack of shortness of breath; or by cough; asthma attack; or the need to take asthma medication.

Ingrid Nordeide Kuiper, MD, of the Haukeland University Hospital in Haukeland, Norway, said in an ERS press release, “These are preliminary results, but we found that exposure to greenness during childhood was associated with fewer respiratory symp- toms in adulthood. Exposure to air pollutants in childhood was associated with more respiratory symptoms in adulthood and with late-onset asthma. “We believe that our results,” she continued, “together with pre- vious results, will be of particular value for city planners and policymakers. With increasing population density in years to come it will be vital to include a decrease in air pollution expo- sure and an increase in access to green spaces in city plans and societal regulations. “We need to analyze these findings further before drawing any definite conclusions. However, it is likely that our findings will substantially expand our knowledge on the long-term effects of air pollution and greenness, enabling physicians, scientists and policymakers to see the importance of exposure to pollution and access to green spaces, and helping to improve public health,” noted Dr. Kuiper.

Uterine Exposure to Organochlorine Pesticides Linked to Poorer Lung Function Babies exposed to higher organochlorine levels in thewomb sufferworse lung function in childhood.

F or the first time, a link with objective meas- ures of lung strength and capacity has been demonstrated in relation to low-level uterine exposure to organochlorine compounds. This outcome of a study of pregnant mothers’ blood followed by pulmonary function testing of the child was reported at ERS 2018. Maribel Casas Sanahuja, DVM, PhD, of the Barcelona Institute for Global Health (ISGlobal), said in an ERS press release, “We already have evidence that exposure to environmental chem- icals including organochlorine compounds can have an impact on children’s health. Though this group of chemicals was banned in the 1970s, low (but detectable) levels are still present in pregnant women and in children. That means current popu- lations and future generations are still exposed to these compounds.”

She continued, “To reduce exposure to these chemicals, women of reproductive age can try to moderate their consumption of foods with high levels of organochlorine compounds, such as fatty meats and oily fish.” “We know,” she added, “that this group of chemicals can interfere with the body’s endocrine system and we also know that hormone receptors play an important role in fetal lung development, so this could be the mechanism for a link.” “Organochlorine compounds are thought to dis- rupt the endocrine system,” Dr. Casas Sanahuja noted, “and have been linked to a wide range of conditions. These include cardiovascular disorders, cancer, and low birth weight. The main source of exposure to organochlorine compounds is food, but fetuses and newborns can be exposed via the placenta and breastfeeding.”

Dr. Maribel Casas Sanahuja

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