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  • Chronic obstructive pulmonary disease (COPD) is a lung condition, which makes it hard to breathe, but is often preventable and treatable   
  • COPD affects some 210m people worldwide, its prevalence is increasing, and it costs billions in treatment and lost production
  • By 2020 COPD is projected to be the 3rd leading cause of death worldwide
  • Recently, scientific advances have benefitted COPD research
  • But COPD researchers are challenged to provide compelling data in support of their studies
  • COPD research would benefit from smart online communications strategies
  • This could strengthen collaboration among globally dispersed scientists and people living with COPD, and expand the geographies from which COPD data are retrieved
  
Chronic Obstructive Pulmonary Disease (COPD) and the battle for breath
 
Chronic Obstructive Pulmonary Disease (COPD) is a common, preventable and treatable disorder, which affects 210m people worldwide. Its prevalence is increasing globally, and each year it causes some 3m deaths. Although COPD therapies have improved substantially in recent years, and benefit from advancing science, researchers are still challenged to provide compelling data in support of their studies. There is no definitive treatment for COPD, and more research is needed to improve the condition’s clinical management. There are regions of the world where the prevalence of COPD is increasing significantly, but where information about the disorder is sparse. This Commentary suggests that COPD research could benefit by enhancing the connectivity of globally dispersed scientists and people living with the disorder, and expanding the geographies from where COPD data are retrieved. Before suggesting ways to achieve this, let us describe COPD, and its vast and escalating burden.
 
Chronic Obstructive Pulmonary Disease (COPD)
 
COPD is an umbrella term used to describe common progressive lifetime diseases, which damage the lungs and airways, and make breathing difficult. Its prevalence is increasing especially in developing countries. It is the 4th leading cause of death worldwide and projected to be the 3rd by 2020. The causes of COPD are well known, but the nature of the condition is still not fully understood even though COPD therapies have improved significantly in recent years. The effects of COPD are persistent and progressive, but treatment can relieve symptoms, improve quality of life and reduce the risk of death. COPD impacts people differently, medications affect patients differently, and such differences make it challenging for doctors to identify patients who are at risk of a more rapidly progressing condition.

Although COPD is complex with different etiologies, pathogens and physiological effects, there are two main forms: (i) chronic bronchitis, which involves a long-term cough with mucus, and (ii) emphysema, which involves damage to the lungs over time. COPD also has significant extra-pulmonary effects, which include weight loss, nutritional abnormalities, skeletal muscle dysfunction, and it is also a major cause of psychological suffering. Further, COPD may promote heart failure because obstruction of the airways and damage to the lining of the lungs can result in abnormally low oxygen levels in the vessels inside the lungs. This creates excess strain on the right ventricle from pulmonary hypertension, which can result in heart failure.

In developed countries, the biggest risk factor for the development of COPD is cigarette smoking, whereas indoor pollutants are the major risk factor for the disease in developing nations. Not all smokers develop COPD and the reasons for disease susceptibility in these individuals have not been fully elucidated. Although the mechanisms underlying COPD remain poorly understood, the disease is associated with chronic inflammation, which is usually corticosteroid resistant, destruction of the airways, and lung parenchyma (functional tissue). There is no cure for COPD, but it is sometimes partially reversible with the administration of inhaled long-acting bronchodilators, and its progression can be slowed through smart maintenance therapy, in particular a cessation of smoking. People with stage 1 or 2 COPD lose at most a few years of life expectancy at age 65 compared with persons with no lung disease, in addition to any years lost due to smoking. Current smokers with stage 3 or 4 COPD lose about 6 years of life expectancy, in addition to the almost 4 years lost due to smoking.
 
The economic burden of COPD is vast and increasing, with attributed costs for hospitalizations, loss of productivity, and disability, in addition to medical care. In 2010, the condition’s annual cost in the US alone was estimated to be approximately US$50bn, which includes $20bn in indirect costs, and $30bn in direct health care expenditures. COPD treatment costs the UK more than £1.9bn each year. Over the past decade in the UK progress in tracking the disease has stagnated, and there is a wide variation in the quality of care.

 
Prevalence

The prevalence of COPD has increased dramatically due to a combination of aging populations, higher smoking prevalence, changing lifestyles and environmental pollution. In developed economies, COPD affects an estimated 8 to 10% of the adult population, 15 to 20% of the smoking population, and 50 to 80% of lung cancer patients with substantial smoking histories. For many years, COPD was considered to be a disease of developed nations, but its prevalence is increasing significantly in developing countries, where almost 90% of COPD deaths occur. Even though most of the research data on COPD comes from developed countries, accurate epidemiologic data on the condition are challenging and expensive to collect. There is a dearth of systematically collected COPD prevalence data from developing nations, and a paucity of COPD studies in Africa, SE Asia and the Eastern Mediterranean region. Most of the available prevalence estimates from low- to middle-income countries are not based on spirometry testing (the internationally accepted gold standard for the diagnosis of COPD, which measures lung capacity). Hence, the available COPD data from developing countries cannot be interpreted reliably in a global context, and more data from these regions are necessary to extend and support further studies.

 

Mortality
 
COPD is one of the three leading contributors to respiratory mortality in developed countries, along with lung cancer and pneumonia.  Globally, it is estimated that 3m deaths were caused by COPD in 2015, which is 5% of all deaths globally in that year. The 5-year mortality rate for people with COPD typically ranges from 40 to 70%, depending on disease severity, while the 2-year mortality rate for people with severe COPD is about 50%, which is worse than those for people with many common cancers. India and China account for 66% of the global COPD mortality with 33% of the world’s human population. Further, it has been estimated that COPD associated mortality is likely to grow by 160% in SE Asia in the coming decades, where COPD research and data are sparse.  

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Risk factors

Air pollution
Air pollution is a risk factor for COPD and other respiratory disorders. According to a 2016 World Health Organization report, about 92% of the world’s population is exposed to dirty air. The Commission on Air pollution and Health, which is the most comprehensive global analysis to-date, and published in The Lancet in October 2017, suggests each year air pollution kills over 9m people prematurely, and costs US$4.6tn, which is equivalent to more than 6% of global GDP.

Tobacco smoke
In advanced industrial economies exposure to tobacco smoke is the number one risk factor in developing COPD, where cigarette smoking is linked to 80% of all COPD deaths. In the US, for instance, approximately 25% of the adult population continue to smoke, despite aggressive smoking prevention and cessation efforts. Each year COPD claims some 134,700 American lives, and COPD is the 4th leading cause of death in the US, and expected to be the 3rd by 2020.

Biomass fuels
In developing economies COPD burden is caused more by exposure to indoor air pollution, such as the use of biomass fuels for cooking and heating. Almost 3bn people worldwide use biomass and coal as their main source of energy for cooking, heating, and other household needs. In these communities biomass fuels are often burned inefficiently in open fires, leading to high levels of indoor air pollution responsible for a greater degree of COPD risk than smoking or outdoor air pollution. Biomass fuels account for the high prevalence of COPD among non-smoking women in parts of the Middle East, Africa and Asia, where indoor air pollution is estimated to kill 2m women and children each year. COPD research and data from these regions are sparse.  

Genetics
In some people, COPD is caused by a genetic condition known as alpha-1 antitrypsin deficiency (AATD). People with AATD do not make a type of protein that helps to protect the lungs. Because not all individuals with COPD have AATD, and because some individuals with COPD have never smoked, it is suggested that there are other genetic predispositions to developing COPD. AATD is not a common cause of COPD, and few people know they have the genetic condition. In the US for example, it is estimated that only about 100,000 people have AATD.
 
Symptoms and diagnosis
 
The typical symptoms of COPD are cough, excess sputum production, and dyspnea (difficulty breathing), recurring respiratory infections, and fatigue. Because symptoms develop relatively slowly, sometimes people are unaware that they have lung problems. People with COPD are diagnosed by way of a multifactorial assessment that includes; spirometry, clinical presentation, symptomatology, and risk factors.
 
COPD management

The heterogeneous nature of COPD, and the fact that it affects different people differently, and different therapies impact the condition differently, presents challenges for clinicians. There are several types of drugs, which can be used for the condition based on whether the drug is intended to improve airflow obstruction, provide symptom relief, modify or prevent exacerbations, (a worsening of symptoms often precipitated by infection), or alter the progression of the disease. It is possible that a drug may affect only one aspect of the condition or that it may act on many. It is also possible that a drug may benefit COPD patients in other meaningful ways.

View from a leading pulmonologist
Some treatments for COPD overlap with asthma,” says Murali Mohan, Consultant Pulmonologist from Narayana Health City in Bangaluru, India.  “The foundation for treating COPD is inhaled long-acting bronchodilators, whereas corticosteroids are beneficial primarily in patients who have coexisting features of asthma, such as eosinophilic inflammation and more reversibility of airway obstruction.  . . . An important part of COPD management is for smokers to stop, and to reduce a patient’s exposure to pollutants both in the home and at work. Vaccines are used to prevent serious infections . . . . . .  People with COPD tend to eat less, and become breathless when they eat. There is a lot of systemic inflammation, which causes patients to lose weight, but being overweight is just as bad. So we ensure that COPD patients adopt a healthy diet and exercise. This is to obtain an ideal body weight, and to supplement muscle strength, which is very important because it’s the muscles that move the lungs and gets the air in and out of the chest . . . . Often we recommend psychotherapy because a lot of people with COPD are depressed. More research is needed to better understand the conditions mechanisms, and to develop new treatments that reduce disease activity and progression,” says Mohan, see videos below.
 
What are the treatments for COPD?
 
 COPD market and changing treatment landscape
 
Given the vast and escalating global prevalence of COPD, the market for therapies is also huge, global, and rapidly growing, and giant pharmaceutical companies aggressively compete for market share. The current size of the COPD market is estimated to be US$17bn. The overall respiratory therapeutics market, which in addition to COPD, includes, asthma, idiopathic pulmonary fibrosis (IPF), and cystic fibrosis, is about US$30bn and projected to grow to US$47bn by 2022. Currently, there are some 900 drugs in development for all types of respiratory disorders. The sheer size and rate of growth of this market, plus the fact that there is still no definitive treatment for COPD, motivates pharmaceutical companies to commit millions to its research. Notwithstanding, the overwhelming majority of current research data are derived from a relatively narrow band of developed nations.
 
COPD research

Influence of cigarette smoking on COPD research
For many years COPD research concentrated on the condition’s association with cigarette smoking. This led to the early discovery that a subgroup of patients with emphysema was genetically deficient in an inhibitor of an enzyme that breaks down proteins and peptides. Although this explanation captures key elements of COPD, it has neither led to a reduction in its prevalence or morbidity, nor to the development of any therapy proven to modify the disease process itself, or to an adequate understanding of how risk factors other than cigarette smoking may contribute to COPD pathogenesis.
 
Biologics
Although research has improved and our understanding of COPD has advanced, there remain challenges for researchers. Contributing to these is a broader array of mechanisms implicated in COPD’s pathogenesis compared to many other respiratory disorders. Notwithstanding, there has been a determined focus on a range of targeted biologic agents as potential therapies for the condition, which has led to an improved understanding of the pathophysiology and clinical manifestations of COPD; and the increased awareness of the importance of inflammation.
 
Although, innovative sampling techniques have led to the identification of several pulmonary biomarkers, (measurable substances that signal the presence of disease in the blood or tissues), which potentially could provide an enhanced insight into the pathophysiological mechanisms of exacerbation, sampling methods still could be improved because the utility of current methods is not yet established, and they have yet to provide compelling data in support of their use in COPD. This suggests a need for more research directed toward identifying the bases of COPD exacerbations, and clarifying the pathophysiological processes that contribute to worsening of symptoms. Other research studies focus on the underlying genetics of COPD in order to find better ways of identifying which smokers are more likely to develop COPD.
 
Challenge of COPD data
 
When recruiting patients for COPD studies, it is impossible to determine the speed at which the lung function will deteriorate in any given individual. This raises methodological challenges particularly with regard the size and nature of a cohort at the beginning and end of a study. Further, longitudinal studies require regular, and systematic collection of patient data, which may be a combination of self-reporting, electronic patient records (EPR), and results of tests undertaken by health professionals. Collecting longitudinal patients’ perceptions of the status of their COPD from a dispersed patient cohort is challenging because of different distributions of the disease, and the variation in the availability and quality of significant events, such as exacerbations.
 
Self-management

More recently, apps have been developed to encourage the self-management of COPD, but they are also potentially helpful for research. This is because apps are able to unobtrusively enter the daily lives of people with COPD. However, the utility of apps as research aids is limited because rarely are they configured to aggregate, export and share the data they collect. However, this is changing.

The large and rapid growth of the health-related apps market, and the impact it has on shaping the attitudes and expectations of millions of people about healthcare, suggests that the utility of such devices to support clinical research will increase. Helpful in this regard is the fact that apps are being configured to enable rapid remote tests, and collect, transmit, store and analyse data.
 
Data validity and patient compliance
Notwithstanding, two significant challenges associated with apps remain for COPD researchers. One concerns the technological adequacy of apps to consistently produce valid data, and another is the compliance of patients in COPD studies. Both of these concerns however are being addressed.
 
Validation
A study, published in 2017 in the journal Nature Biotechnology, provides some validation for data derived from apps to be used in clinical studies. Scientists developed an app to collect survey data from 7,600 asthma sufferers over a 6-month period on how they managed their condition. Researchers then compared these app-generated patient-reported data with similar data from traditional asthma studies and found that there were no significant differences. Although there still remains some methodological challenges associated with using apps to recruit patients for clinical studies, findings from this and other studies give scientists some degree of confidence that app-derived data can be reliable enough for clinical studies.
 
Giant tech companies and medical research
The increasing validation of app-generated health data is driving the growth in pairing wireless health apps with data monitoring, and creating an opportunity for giant global technology companies to enter the healthcare market by joint venturing with big pharmaceutical companies. Such ventures create big-data opportunities to aggregate vast amounts of patient data from millions of COPD sufferers and the efficacy of specific drugs. Such ventures also allow patients remotely to keep track of their drug usage, and for health professionals to instantly access the data to monitor an individual patient’s condition.
 
Compliance
There is some evidence to suggest that people with COPD are less compliant recording information about their condition when they are experiencing an exacerbation, or just not feeling well. A solution might be to employ techniques, which “nudges” patients to be more compliant. The genesis of nudge systems is a 2008 publication, Nudge, by US academics Cass Sunstein and Richard Thaler. The authors suggest that making small changes to the way options are presented to individuals “nudges” them to engage in behaviours that they would not normally do. Following the publication of the book, “nudge units” were set up in the White House and in 10 Downing Street to encourage people to change entrenched behaviours in order to improve occasional and unsystematic public services, while reducing costs.

The UK’s Nudge Unit has, among other things, significantly increased the rate of organ donation, and encouraged a substantial number of individuals to initiate and maintain healthier lifestyles. Minded of the successes, governments throughout the world have set up nudge units. A 2017 OEDC report suggests that nudge units have entered the mainstream,  and could be used much more widely. Also in 2017, Richard Thaler was awarded the Nobel Prize for his contribution to behavioural economics. COPD researchers might consider replacing the current “pull” techniques with nudge techniques to enhance patient compliance in COPD clinical studies.
 
Takeaways

For years COPD research was in the doldrums, but over the past decade things have changed significantly. Notwithstanding, COPD studies could benefit from more compelling data, and this could be achieved by employing smart online communications strategies that increase the connectivity of globally dispersed COPD researchers and individuals living with the condition with an eye to enhance patient compliance in COPD studies, increase the quality of research data, and expand the geographies from which COPD data are retrieved.
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  • Tobacco is a legacy recreational drug that causes cancers, and kills over 6m people each year
  • No new food, drink, recreational or over the counter drug with a similar adverse health profile would ever be approved in the modern world
  • Smoking causes 150 extra mutations in every lung cell
  • New research demonstrates that smoking causes cancers in organs not exposed to smoke such as the bladder, kidney and pancreas
  • Smoking triggers cell mutations that can cause cancer years after quitting
  • Anti-smoking campaigns have decreased the prevalence of smoking, but incidence rates have increased because of population growth
  • Identifying all the cancer genes will eventually improve treatments
 
 
Smoking is playing Russian roulette with your life
 
Tobacco is the only legal drug that kills millions when used exactly as intended by manufacturers. New research into the root causes of cancer demonstrates how tobacco smoke mutates DNA, and gives rise to more than 17 types of cancers, and surprisingly, causes cancers in organs not directly exposed to tobacco smoke.
 

Cell mutation and the body’s natural resistance
 
A mutation occurs when a DNA gene is damaged or changed in such a way as to alter the genetic message carried by that gene. The more mutations a cell acquires, the more likely it is to turn cancerous.
 
Decreased prevalence, but increased incidence of smoking

Globally, smoking prevalence - the percentage of the population that smokes regularly - has decreased, but the number of cigarette smokers worldwide has increased due to population growth. Today, over 1bn people worldwide smoke tobacco, which each year causes nearly 6m early deaths, many different cancers, pain, misery and grief; not to mention the huge costs to healthcare systems and the loss of productivity.  If current trends continue tobacco use will cause more than 8m deaths annually by 2030. On average, smokers die 10 years earlier than nonsmokers.
 

Cancer and the body’s natural resistance

Cancer is a condition where cells in a specific part of the body mutate and reproduce uncontrollably. There are over 200 different types of cancer. Cancerous cells can invade and destroy surrounding healthy tissue and organs. Cancer sometimes begins in one part of the body before spreading to other areas. This process is known a metastasis. The body has a capacity to naturally resist cancer, through tumor suppressor genes, which function to restrain inappropriate mutations, and stimulate cell death to keep our cells in proper balance.New therapies that boost the body’s own immune system to fight cancer are believed to be a game-changer in cancer treatment.

Cancer and the causes of cancer

Whitfield Growdon, a surgical oncologists from Harvard University Medical School and the Massachusetts General Hospital in Boston, describes cancer and the causes of cancer:
 
What is cancer?



What causes cancer?
 
Epidemiology of smoking

Today, it is widely accepted that tobacco use is the single most important preventable health risk in the developed world, and an important cause of premature death worldwide. The research of the British epidemiologists Richard Doll and Tony Bradford Hill, more than anyone else, is responsible for the link between tobacco use and lung cancer. Following reports of several case-controlled studies in the early 1950’s Doll and Hill published findings of a larger case-controlled study in 1954 in the British Medical Journal, which suggested that smoking was, "a cause, and an important cause" of lung cancer. This was followed by the publication of further research findings in 1956. Doll and Hill’s latter study confirmed their earlier case-controlled findings: that there is a higher mortality rate among smokers than in non-smokers, and a clear dose-response relationship between the quantity of tobacco used, and the death rate from lung cancer. Data also indicated a significant progressive reduction in mortality rates with the length of time following the cessation of smoking.
 
US Surgeon General Report of smoking and lung cancer

The research of Doll and Hill, along with other cohort studies published in the 1950s, formed the basis for the game-changing 1964 report of the US Surgeon General, which concluded that, "Cigarette smoking is causally related to lung cancer in men; the magnitude of the effect of cigarette smoking far outweighs all other factors". This led to groundbreaking research on tobacco use, and investments by governments and nonprofit organizations to reduce tobacco prevalence and cigarette consumption, which in some developed countries has been successful. In 2003, the Framework Convention on Tobacco Control was adopted by the World Health Organization, and has since been ratified by 180 countries.  
 
The best and the worst countries for smoking related lung cancer
 
Between 1980 and 2012 age-standardized smoking prevalence decreased by 42% for women and 25% for men worldwide. Canada, Iceland, Mexico, and Norway have reduced smoking by more than half in both men and women since 1980. The greatest health risks for both men and women are likely to occur in countries where smoking is pervasive and where smokers consume a large quantity of cigarettes. These countries include China, Ireland, Italy, Japan, Kuwait, South Korea, the Philippines, Uruguay, Switzerland, and several countries in Eastern Europe. The number of cigarettes smoked worldwide has grown to more than 6 trillion. In 75 countries: smokers consume an average of more than 20 cigarettes a day.
 
Smoking-related deaths in the UK and US

19% (10m) of adults in the UK, and 17% (40m), of adults in the US are current cigarette smokers, a figure, which has more than halved since the mid 1970s. Results from a 50-year study shows that half to two thirds of all lifelong cigarette smokers will be eventually killed by their habit. Death is usually due to lung cancer, chronic obstructive lung disease and coronary heart disease. Many who suffer from these diseases experience years of ill health and subsequent loss of productivity. Every year, around 96,000 people in the UK, and 480,000 people in the US, die from diseases caused by smoking. This equates to 226 and 1,300 smoking-related deaths every day in the UK and US respectively.
 
Costs

In addition to death and sickness, tobacco use also imposes a significant economic burden on society. These include direct medical costs of treating tobacco-induced illnesses, indirect costs including loss of productivity, fire damage and environmental harm from cigarette litter and destructive farming practices. Cigarettes sales contribute significant tax revenues to national coffers; the industry employs tens of thousands of people who also pay taxes. Notwithstanding, the total burden caused by tobacco products outweighs any economic benefit from their manufacture and sale.
 
Direct link between the number of cigarettes smoked and cancers

Scientists from the Wellcome Trust Sanger Institute near Cambridge, UK, the Los Alamos National Laboratory in New Mexico, and others have discovered a direct link between the number of cigarettes smoked and the number of mutations in the tumor DNA, and that smoking also causes cancers in organs not exposed to tobacco smoke.

Research published in the Journal Science in 2016 analyzed more than 5,000 cancer tumors from smokers and nonsmokers, and concluded that if you smoke even a few cigarettes a day you will erode the genetic material of most of the cells in your body, and thereby be at a significantly greater risk of cancer. "Before now, we had a large body of epidemiological evidence linking smoking with cancer, but now we can actually observe and quantify the molecular changes in the DNA due to cigarette smoking," says Ludmil Alexandrov, a theoretical biologist at Los Alamos National Labroratory and an author of the study.
 
The discovery means that people who smoke a pack of cigarettes a day for a year, develop on average, 150 extra mutations in every lung cell, and nearly 100 more mutations than usual in each cell of the voice box, 39 mutations for the pharynx, 23 mutations for mouth, 18 mutations for bladder, and 6 mutations in every cell of the liver.
 
Smoking causes cancers not exposed to smoke
 
Scientists were surprised to find that tobacco smoke caused mutations in tissues that are not directly exposed to smoke. While more than 70 of the 7,000 chemicals in tobacco smoke have long been known to raise the risk of at least 17 forms of cancer, the precise molecular mechanisms through which these chemicals mutate DNA, and give rise to tumours in different tissues have never been altogether clear, until now. The study showed that some chemicals from tobacco smoke damage DNA directly, but others found their way to different organs and tissues, and ramp up the natural speed at which mutations built up in the tissues in more subtle ways, often by disrupting the way cells function. The more mutations a cell acquires, the more likely it is to turn cancerous.
 
Why some smokers get cancer and others do not

It won’t happen to me. . . . My grandfather started smoking when he was 11, smoked 20 a day, and lived ‘til he was 90”. We have all heard this before. But we now know why some smokers get cancer and others do not. it is because of the way mutations arise. When a person smokes, the chemicals they inhale create mutations at random points in the genome. Many of these changes will be harmless, but others will not be so benign. The more smoke a person is exposed to, the greater the chance that the accumulating mutations will hit specific spots in the DNA that turn cells cancerous. Even decades after people stop smoking, former smokers are at a long-term increased risk of developing cancers.“You can really think of it as playing Russian roulette,” says Alexandrov.
 
Takeaways

Until now, it has not been fully understood how smoking increases the risk of developing cancer in parts of the body that do not come into direct contact with smoke.
 
Sir Mark Walport, director of the Wellcome Trust, says that the findings from the research described above: “will feed into knowledge, methods and practice in patient care.” Dr Peter Campbell, from the Wellcome Trust Sanger Institute says: “The knowledge we extract over the next few years will have major implications for treatment. By identifying all the cancer genes we will be able to develop new drugs that target the specific mutated genes, and work out which patients will benefit from these novel treatments.”
 
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