Potential new treatment combats COPD and other lung diseases

New research published online in The FASEB Journal reveals a potential drug to combat the life-threatening effects of chronic obstructive pulmonary disease (COPD). Specifically, the study investigated the efficacy of a receptor for advanced glycan end-products (RAGE)-specific antagonist chemical compound, FPS-ZM1, in mice, and found that this compound reverses the inflammatory response and has a protective role in COPD.

"RAGE disturbances in pulmonary disorders are precise and effective strategies with beneficial clinical effects," said Se-Ran Yang, D.V.M., Ph.D., a researcher involved in the work and an associate professor at the Department of Thoracic and Cardiovascular Surgery in the School of Medicine at Kangwon National University in Gangwon, Korea. "Blockade of RAGE as a novel clinical therapeutic for COPD ameliorates emphysema/COPD development and progression."

In their study, Yang and colleagues investigated the efficacy of RAGE-specific antagonist FPS-ZM1 administration in both in vivo and in vitro COPD models to determine the molecular mechanism by which RAGE influences COPD. The researchers injected mice with an in vivo COPD inducer and the RAGE antagonist FPS-ZM1. Then they assessed the infiltrated inflammatory cells and their production of cytokines. Cellular expression of RAGE, initiating inflammatory response, and soluble RAGE, acting as a "decoy," was determined in protein, serum, and bronchoalveolar lavage fluid in the mice, as well as in the serum of human donors and patients with COPD. They analyzed downstream damage-associated molecular patterns (DAMPs) and danger signals in vivo and in vitro and in patients with COPD, and found that RAGE was associated with the up-regulation of DAMP-related signaling pathways via Nrf2 (a master regulator of the total antioxidant system in humans). FPS-ZM1 administration also significantly reversed emphysematous lung symptoms in mice.

"No one expected the pathogenic roots of COPD to be simple, and this study gives us an indication of the complexity involved.," said Thoru Pederson, Ph.D., Editor-in-Chief of The FASEB Journal. "The current pharmacological armamentarium is limited, and studies like this are thus extremely valuable as a foundation."

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Federation of American Societies for Experimental Biology.

New hope for patients with severe lung disease

Patients suffering from severe lung disease could see their lives transformed thanks to a 'game-changing' clinical trial carried out by UK experts and led by the team from the Lane Fox Respiratory Service based at Guy's and St Thomas' in London.

The HOT-HMV trial (Home Oxygen Therapy-Home Mechanical Ventilation), which involved giving selected patients a breathing machine to be used in their home in addition to oxygen therapy, was found to reduce readmissions to hospital following an acute infection.

The results of the trial, which have been published in the Journal of the American Medical Association (JAMA), were announced at the American Thoracic Society's annual conference in Washington, DC.
In the UK alone, approximately 30,000 people die from Chronic Obstructive Pulmonary Disease (COPD) every year. The World Health Organisation (WHO) estimates that COPD will be the world's third largest killer disease by 2020.

Chronic Obstructive Pulmonary Disease (COPD) is an umbrella term used to describe progressive lung diseases including emphysema, chronic bronchitis, refractory (non-reversible) asthma, and some forms of bronchiectasis. This disease is characterized by increasing breathlessness.

Respiratory experts Professor Nicholas Hart and Dr Patrick Murphy, who co-ordinated the UK-wide trial from St Thomas' Hospital, said the trial results could pave the way for a complete change in the way that the most severely affected COPD patients across the world are treated.

Professor Hart explains: "The only current treatment we have to give these patients is oxygen therapy, but now we can give them oxygen as well as a ventilator in their home. We have managed to reduce the likelihood of readmission to hospital by almost 50%.

"In the trial we used a home ventilator that co-ordinates itself with the individual patient's breathing. The mask ventilator machine works by blowing in air and oxygen to keep oxygen levels high and carbon dioxide, the waste gas, low."

The trial was carried out thanks to funding and equipment from manufacturers Philips Respironics and ResMed, and Guy's and St Thomas' Charity.

COPD, or Chronic Obstructive Pulmonary Disease, is one of the world's biggest killers, but the addition of a home ventilator to oxygen treatment reduces admissions to hospital as well as maintaining quality of life.
Ronnie Ward, 74, from Brighton, has suffered from COPD for five years and uses his home ventilator every night, to support his breathing. Since being recruited for the trial, he and his wife Julie, 55, have had to make far fewer trips to hospital.

"Ronnie was in and out of hospital, sometimes spending weeks and months on the wards. Coming back and forth and spending so much time in hospital was stressful and very demoralising," she says.

"We were finding that just weeks after he'd been discharged from hospital, Ronnie would need to be readmitted because he was struggling to breathe again. Using the breathing machine every night has taken a lot of pressure off us."

Meanwhile, the trial follow up will continue, as patients are monitored for survival rates over the next three and five years.

"These results are extremely promising but the work will continue. So far we have found that patients using home oxygen with a home ventilator device are two-thirds less likely to be readmitted within 28 days," says Professor Hart.

"This is very important because not only does it maintain a patient's quality of life but also it has the potential to significantly increase our ability to care for these patients without the need for a hospital stay. At Guy's and St Thomas' around 1,000 patients are admitted each year with COPD. If we can keep them comfortable at home for longer, this will have a big impact."

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NIHR Biomedical Research Centre at Guy's and St Thomas' and King's College London

Chronic obstructive pulmonary disease increases the risk of sudden cardiac death

People suffering from the common lung disease, chronic obstructive pulmonary disease (COPD), have an increased risk of sudden cardiac death (SCD), according to new research published online in the European Heart Journal.

When compared with people of the same age and sex who do not have the disease, those with COPD have a 34% increased risk of SCD overall, but their risk almost doubles more than five years after first being diagnosed with COPD. In COPD patients who have frequent exacerbations (sudden worsening of their symptoms, such as shortness of breath and cough), the risk of SCD increases more than three-fold after five years.

The Rotterdam study of nearly 15,000 people aged 45 and older is the first to show that COPD is associated with an increased risk of SCD in the general population and that this remains the case even when taking into account the fact that COPD is known to increase the risk of death from any cause.

The researchers say that their findings should help doctors to assess their patients' risk of SCD more accurately, as well as suggesting directions for further research into how to target preventive action more effectively for patients with COPD. Preventive treatments could include beta-blockers, implantable cardioverter defibrillators (ICD) to regulate heartbeat, or the withdrawal of drugs that prolong the interval between the two waves (Q and T) of the heart's electrical cycle, such as adrenaline, various cold remedies, some antibiotics and anti-depressants.

"Sudden cardiac death (SCD) is a major health problem; however, risk stratification remains difficult and probably not all risk indicators have been identified," they write in their EHJ paper. "Chronic obstructive pulmonary disease (COPD) has been associated with an increased risk of cardiovascular disease and with SCD in specific high-risk patient populations. This study shows that COPD is a risk indicator for SCD in the general population and that the risk increases with COPD severity. This provides directions for further measures to prevent SCD."

Dr Lies Lahousse, who led the research and is a post-doctoral researcher in the Department of Respiratory Medicine at Ghent University Hospital, Belgium, said: "We are carrying out further research to explore the mechanisms that could explain the high risk of SCD in patients with COPD. We are also looking at the links between the causes of arrhythmias -- irregular heart beats -- and SCD and COPD."

A co-author of the paper, Dr Marieke Niemeijer, a medical doctor and PhD student in the Department of Epidemiology at Erasmus Medical Centre, Rotterdam, The Netherlands, said: "The most important way to prevent COPD and SCD is not to smoke and to have a healthy lifestyle. If a person does develop COPD, then this is even more important, as smoking, an unhealthy and a sedentary lifestyle have been proven to increase the risk of SCD. Therefore, smoking cessation is not only important for the course of COPD but also for the development of heart problems and, subsequently, the occurrence of SCD."

SCD is a sudden, unexpected death caused by the heart ceasing to work. It is responsible for approximately half of all the four to five million heart disease deaths worldwide. It has a number of causes, which makes it difficult to assess adequately a person's risk and to plan prevention strategies. COPD is the world's third leading cause of death, with smoking as the most significant cause of the disease. It is also more likely to develop as people age. Chronic inflammation in the airways and lungs leads to progressive limitation of airflow, and patients have a two- to three-fold higher risk of developing diseases of the heart and blood vessels.

The ongoing Rotterdam study, which started in 1990 in The Netherlands, has been following 14,926 people living in the community, aged 45 and older, for up to 24 years. The participants have regular medical examinations and are continuously monitored so that deaths and medical conditions and diseases are recorded.

The researchers in The Netherlands and Belgium included 13,471 people from the study in their analysis; of these, 1615 were diagnosed with COPD. Of the 5197 (39%) study participants who died, 551 died due to SCD during the follow-up period and of these 82 (15%) had COPD and 469 (85%) did not. People with COPD who died due to SCD were more likely to die during the night.

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European Society of Cardiology.

New genetic markers for COPD discovered

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States, yet there are no effective medicines that improve mortality from the disease. While smoking remains the single most important risk factor for COPD, genetics also play an important role. In a new Research Letter published in Nature Genetics on Feb. 6, 2017, investigators describe 13 new genetic regions associated with COPD, including four that have not previously been associated with any type of lung function. The researchers also found overlap of the genetic risk of COPD with two other lung diseases, asthma and pulmonary fibrosis. These findings create an improved understanding of the genetic basis for this deadly disease.

"We are excited about these findings because we have not only uncovered new genetic risk factors for COPD, but also shown overlap of COPD genetic risk with the risk to asthma and pulmonary fibrosis," said lead author Brian Hobbs, MD, MMSc a physician-researcher in the Channing Division of Network Medicine and Pulmonary and Critical Care Division of BWH. "This is the first step in a longer process in which we hope to better understand the genetic basis for COPD, or what may be several different diseases that present as COPD. Now that we know there are new regions of the genome associated with COPD, we can build on this research by probing new biological pathways with the ultimate goal of improving therapies for our patients with this disease."

Researchers conducted a genome-wide association study of risk for chronic obstructive pulmonary disease (COPD) in a large, multi-ancestry cohort (15,256 cases and 47,936 controls). This type of study allows investigators to look across a comprehensive set of genetic variants in different individuals to see if any variant is associated with disease. Top findings from this study were replicated in a second cohort. The authors also sought to understand more about their findings by examining overlap with other diseases and examining what was known about gene function in these regions. In addition to identifying 13 new genetic regions associated with COPD, they also discovered four genetic regions that were not previously associated with any lung function trait. Nine of the genetic regions have been identified as playing an important role in lung function. Two have previously shown an association with pulmonary fibrosis; however, the specific forms of these genetic variants that increase risk for COPD decrease risk for pulmonary fibrosis. All analyses accounted for the effects of age, gender, and cigarette smoking on disease risk.

"While it is extremely important that patients not smoke for many health reasons -- including the prevention of COPD -- we know that smoking cessation may not be enough to stave off the disease," said Michael Cho, MD, MPH, one of the senior authors of this manuscript and a physician-researcher in the Channing Division of Network Medicine and Pulmonary and Critical Care Division. "Many patients with COPD experience self-blame, but they may be comforted to know that genetics does play a role in who ultimately develops the disease."

The BWH group also co-authored a companion paper in the same issue of Nature Genetics, led by researchers from the University of Leicester and University of Nottingham. In this large study of lung function in the UK population, they almost doubled the number of genetic variants associated with lung function levels, and found a strong association between this combined genetic risk score and COPD.
This research was conducted by the International COPD Genetics Consortium, a collaborative research effort established in 2010 at a conference at BWH. Marike Boezen, PhD, of the University of Groningen, co-led the study with Cho. The consortium now involves more than 20 studies around the world.
"This work is representative of the importance of global collaboration and the shared goal of improving care for patients everywhere," said Cho. "We're grateful for the efforts of all of the authors, each of whom played a valuable role in this discovery."

"These findings would only be possible with the kind of large collaborative efforts that supports this study. Not only do the results build on our knowledge of COPD, but also reveal potential links with other lung diseases, like pulmonary fibrosis and asthma and can form the underpinnings of a precision medicine strategy for the treatment of more than one lung disease," said Dr. James Kiley, Director of the Division of Lung Diseases of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH).

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Brigham and Women's Hospital.

New opioid use in older adults with COPD associated with increased risk of death

Older adults with chronic obstructive pulmonary disease who start using opioids have a more than two-fold higher risk of dying from a respiratory-related complication compared to non-opioid users, St. Michael's Hospital researchers have found.

When researchers looked specifically at more potent opioids, they found the risk for respiratory-related death was five times higher for new opioid users compared to non-opioid users.

The study, published in the European Respiratory Journal, raises safety concerns about new opioid use among older adults with chronic obstructive pulmonary disease, or COPD, a progressive lung disease that causes breathing difficulty, said Dr. Nicholas Vozoris, a respirologist at St. Michael's and lead author of the study.

COPD affects approximately four to 10 per cent of the Canadian population, with the five-year mortality rate from 40 to 70 per cent, depending on the severity. The two-year mortality rate for people with severe COPD is about 50 per cent.

The researchers looked at the records of more than 130,000 adults in Ontario age 66 and older with COPD, using multiple provincial health care administrative databases at the Institute for Clinical Evaluative Sciences.

"Previous research has shown about three-quarters of older adults with COPD have been prescribed opioids, which is an incredibly high rate of new use in a population that is potentially more sensitive to narcotics," said Dr. Vozoris. "Our new findings show there are not only increased risks for respiratory-related death associated with new opioid use, but also increased risk, of visits to emergency rooms, hospitalizations and needing antibiotics or steroid pills."

Dr. Vozoris found that 68 per cent of older adults with COPD living in the community were given a new opioid prescription between April 2007 and March 2012. Opioids, such as codeine, oxycodone and morphine are prescribed frequently among older adults with COPD to help treat chronic muscle and bone pain, persisting cough and shortness of breath despite inhaler therapy, as well as insomnia.

"This is a population that has a chronic lung disease, with symptoms that can sometimes be challenging to manage," said Dr. Vozoris. "This class of drugs may offer some relief, however, there is also evidence suggesting that opioids can adversely affect breathing and lung health in people who already have chronically compromised lungs."

To lower the risks of adverse events in this population, the thinking has been to prescribe less potent or lower dosage opioids. However, Dr. Vozoris and his team still found a significantly increased risk of respiratory-related complications and death in new opioid users, regardless of dose. "This is an important finding because it has been previously thought that lower opioid doses might be safe for COPD patients," said Dr. Vozoris.

Dr. Vozoris hopes that clinicians take these findings into consideration when prescribing opioids to COPD patients. Current guidelines recommend their use to manage difficult-to-control respiratory symptoms that can often compromise a patient's quality of life, but current evidence does not support the use of opioids for chronic pain.

"Sometimes patients are looking for a quick fix for chronic pain or breathing issues and physicians may believe opioids can offer them some relief," said Dr. Vozoris. "The trade-off becomes explaining that there are risks to patients and making sure they understand that potentially alleviating their symptoms could come at a higher cost to their health."

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St. Michael's Hospital.