Tiffanie Hammond, Amrita Ford, MA, Brandel France de Bravo, MPH, and Jessica Cote, Cancer Prevention and Treatment Fund

What is COPD, and What Causes It?
Gender Differences in COPD
How is COPD Diagnosed?
Not Everyone Defines COPD the Same Way
The Controversy Surrounding COPD Screening
Treatment Options and Prognosis
What Does This Have To Do with Lung Cancer?
How are COPD and Lung Cancer Linked?
Could COPD Patients be the Best Candidates for Lung Cancer Screening?
You Think You Might Be at Risk for COPD and/or Lung Cancer. Now what?

Did you know that more than half of all people with lung cancer have chronic obstructive pulmonary disease (COPD)? In fact, depending on the way COPD is diagnosed, 50-90% of lung cancer patients suffer from COPD.[1] Some people with lung cancer don’t find out that they have COPD until they’ve already been diagnosed with cancer. Could testing for COPD be a way of catching lung cancer earlier? We know that smokers with COPD are much more likely to develop lung cancer than smokers without it, but what about people who don’t smoke—can they get COPD, and if so, are they also at increased risk of developing lung cancer?

If you’ve never touched a cigarette in your life and have lung cancer, there is a chance it’s because you have COPD. A 2008 study published in the Archives of Internal Medicine estimated that COPD was responsible for 10% of lung cancer cases among people who don’t smoke.[2] COPD is the third leading cause of death in the U.S., and there are over 12 million people currently diagnosed with the disease.[3] Experts believe that the real number of people with COPD is twice that.[4]

While cigarette smoking is the leading cause of COPD, people who have never smoked make up 20% or more of all COPD cases[5] Interestingly, 4 out of 5 non-smokers with COPD are women. People who never smoked make up approximately 15% of diagnosed cases of lung cancer, and as with COPD, the majority of lung cancer patients who never smoked are women.  One out of 5 women diagnosed with lung cancer have never smoked whereas in men who develop lung cancer, only 1 out of 12 have never smoked.[6,7]

What is COPD, and What Causes It?

COPD is a progressive disease that causes airflow obstruction, making it more difficult for a person to breathe. COPD can take the form of chronic bronchitis or emphysema. Chronic bronchitis is the inflammation and scarring of the lung’s bronchial tubes, or air passages, which results in frequent coughing and the formation of thick mucus in the airways.  In emphysema, the walls of the tiny air sacs in the lungs are damaged and destroyed over time which leads to reduced gas exchange in the lungs.  Most people with COPD have a combination of both chronic bronchitis and emphysema.

COPD can’t be cured but its symptoms can be managed and controlled through various treatments, including medicines and pulmonary rehabilitation. Pulmonary rehabilitation includes exercise training, counseling, breathing strategies, and energy conservation techniques.

The leading cause of COPD is smoking;[8] smokers’ risk for the disease ranges from 35% to as high as 50%.[9] Second-hand smoke is also a major risk factor. A 2012 Norwegian study suggests that childhood exposure to tobacco smoke doubles the risk of girls developing COPD as adults.[10] Men exposed to tobacco smoke as children did not share the same heightened risk as women, but early exposure to tobacco smoke increases the risk of certain COPD symptoms in men, such as chronic cough. Other COPD risk factors include age, environmental and occupational exposures to pollution, dust and chemical fumes, a family history of COPD, a prior diagnosis of asthma, cooking with fire without proper ventilation, and in rare cases, having a genetic condition called alpha-1-antitrypsin (AAT) deficiency. AAT is a naturally occurring protein that protects the lungs from damage. People who don’t have enough of the protein are more likely to develop emphysema.[11]

Gender Differences in COPD

From 1998-2009, more women were diagnosed with COPD than men. Although overall death rates from COPD were lower in women than men, death rates in men decreased during this time period while death rates among women stayed the same.[12] No one is certain why this is, but there are differences in the way men and women are diagnosed and treated for COPD that may contribute to the disparity.

Even when they have the same symptoms, women with COPD are often misdiagnosed initially as having asthma, are less likely to be referred to specialists, and are therefore less likely to be treated quickly, accurately, and effectively for COPD compared to men. Women with COPD also report more severe symptoms and experience a lower quality of life. Women who are dependent on oxygen have a 50% increased risk of death from COPD as opposed to men on oxygen.[13]

How is COPD Diagnosed?

COPD is estimated to be undiagnosed or misdiagnosed in about 50% of the 24 million men and women estimated to have COPD in the U.S. Many people are not aware they have it until symptoms such as coughing, shortness of breath (dyspnea), increased mucus production, and wheezing develop slowly over time. Many patients fail to report symptoms to their doctors because they assume these symptoms are a normal part of aging and are unaware of the symptoms of COPD. Many smokers just assume that the symptoms they are experiencing are due to smoking and not to something more serious.[14] However, diagnosing patients with COPD from symptoms alone leads to errors of overdiagnosis. Studies have shown that the best method for diagnosing COPD is spirometry, which is a common and inexpensive office test that measures lung capacity. Spirometry can detect COPD even before symptoms become apparent and can be used to track the progression of COPD and determine if a treatment is working. Other methods used to diagnose COPD include chest x-rays, computed tomography (CT) scans, listening to the lungs with a stethoscope, and arterial blood gas tests that determine oxygen and carbon dioxide levels in the blood. In general, spirometry is used to detect airflow obstruction and low-dose CT is used to diagnose emphysema. Spirometry is usually used for standard COPD screening because it’s safe and inexpensive, but CT screening is sometimes necessary to diagnose people with emphysema who don’t also have airflow obstruction.

Over the years, various evidence-based guidelines for the prevention, diagnosis and management of COPD have been developed to assist healthcare professionals in their management of the disease. In 2001, the Global Initiative for Chronic Obstructive Lung Disease (GOLD), in conjunction with experts from the National Heart, Lung, and Blood Institute and the World Health Organization, published guidelines for physicians based on the latest research and recommendations.[15] The GOLD guidelines were updated in 2006 and again in 2011. Professional societies like the American Thoracic Society, the European Respiratory Society, and others have also published their own COPD guidelines, all with the same goal of educating healthcare professionals and improving COPD outcomes.[16]

Despite the availability of these guidelines for COPD, one of the most significant barriers to diagnosing COPD is a lack of knowledge among primary care professionals. A survey conducted in 2008 by Barbara Yawn and Peter Wollan at Olmsted Medical Center found that fewer than half of primary care professionals (family physicians, nurse practitioners and physicians assistants) knew about or used accepted guidelines for diagnosing COPD. A little over 20% reported using no COPD guidelines, 10% were unaware of what the current COPD guidelines are, 11% admitted using guidelines for asthma to diagnose and treat COPD, and only 7% tested for alpha-1-antitrypsin deficiency regularly. Even when these primary care physicians had spirometry in their offices, only 31% used it on suspected cases of COPD. Furthermore, only 1 in 5 primary care professionals referred all or most of their COPD patients to lung specialists.[17] This is alarming because lung specialists tend to follow the established COPD guidelines more closely than primary care physicians, and without their seeing COPD patients, the opportunity for early diagnosis and treatment may be lost.[18]

Too many primary care providers are unable to distinguish asthma from COPD and don’t recognize that women are at higher risk for COPD than men. Over a third (38%) of primary care physicians felt it was difficult to distinguish COPD from asthma, and 78% thought COPD was primarily a disease that affects men. When COPD symptoms are misdiagnosed as asthma, women receive the wrong treatment, and the correct COPD treatment is delayed.

Perhaps one of the biggest barriers to diagnosis, though, is the failure of patients to report symptoms to their doctor. People who feel guilty about smoking may decide not to tell their doctor about symptoms, or like non-smokers with COPD who think their symptoms are due to getting older, they may simply cut back on physical activity.⁴ When patients adapt to their increasing breathlessness and don’t mention it to their doctors, an opportunity to educate primary care providers about COPD—how widespread it is and whom it affects—is lost. This hurts people suffering from COPD and medical professionals alike.

Not Everyone Defines COPD the Same Way

There is no single standard for defining COPD with spirometry, which may account for some of the misdiagnosis of the disease. The GOLD definition of COPD is widely accepted: a FEV1/FVC of less than 0.70, which is the ratio of how much air a patient is able to exhale in 1 second (FEV1) to the total volume of air a patient can exhale in one breath (FVC).[19] The GOLD guidelines also classify COPD into 4 stages from mild to very severe based on other calculations.

The GOLD definition tends to over-diagnose COPD in the elderly since one value in the FEV1/FVC ratio decreases with age more rapidly than the other. An alternative definition is the lower limit of normal (LLN) definition of COPD, which takes age into consideration and compares the FEV1/FVC ratio of a patient to that of a healthy person who is the same age. Researchers found that while the GOLD definition tended to over-diagnose COPD, the LLN definition under-diagnosed COPD in some symptomatic patients.[20] Collecting more information during spirometry readings, such as total lung capacity (TLC), reduced the number of misdiagnoses. Another study found that sex differences in diagnoses are influenced by the COPD definition used.[21] When the GOLD definition of COPD was used, men had a higher risk of COPD, but among smokers, women were more likely to be diagnosed with COPD due to their increased susceptibility to cigarette smoke. However, when the LLN definition was used, there was no significant difference between male and female risk for COPD and no evidence of increased susceptibility to COPD among female smokers. Without an agreed upon standard for defining COPD, it is difficult to diagnose COPD definitively or to understand the different risk factors.

The Controversy Surrounding COPD Screening

In 2000, the National Lung Health Education Program (NLHEP) recommended that all smokers age 45 and older be screened using lung function tests, like spirometry, to identify undiagnosed COPD.[22] This led to widespread screening and spirometers in doctors’ offices everywhere. However in 2007, the American College of Physicians recommended that only patients with respiratory symptoms be screened with spirometry and not asymptomatic individuals, regardless of smoking history or age.[23]  In 2008, the U.S. Preventive Services Task Force followed suit and recommended against screening healthy adults without any respiratory symptoms for COPD using spirometry, stating that it had no overall benefit. The recommendation does not apply to individuals who have symptoms such as wheezing and chronic cough or people with a family history of alpha-1-antitrypsin deficiency who should be screened. (Few people are aware of whether they or their relatives have alpha-1-antitrypsin deficiency, but the test to screen for it is very inexpensive.)

The Task Force determined that the harms of spirometry screening, which include misdiagnoses and adverse effects from unnecessary treatment, outweighed the possible benefits of treatment and pulmonary rehabilitation. Spirometry can result in substantial over-diagnosis of COPD in never-smokers aged 70 and older, but there are fewer false-positives in other healthy adults who are screened. The Task Force found that although treatments can prevent COPD from worsening, patients with severe COPD die at the same rate whether or not they receive treatment. COPD treatments have also been associated with negative side effects in some patients, such as elevated heart rate and infections. Unfortunately, the Task Force found that providing smokers with their spirometry results did not necessarily result in more smokers quitting, and a favorable spirometry reading could actually discourage smokers from quitting.

According to the Task Force recommendation, patients with severe or very severe COPD who would stand to gain the most from screening make up less than 10% of those identified as having COPD using current diagnostic criteria. This means that hundreds of smokers would have to be screened to identify one person who would benefit. The Task Force concluded that widespread spirometry screening is likely to identify many patients with mild to moderate COPD who would not experience any substantial benefits from being diagnosed and treated. However, no one really knows if that is true: patients with mild or moderate COPD and patients without symptoms are rarely included in drug trials for COPD treatments, and without studies there is no evidence one way or the other.[24]

While the USPSTF has weighed in against widespread screening, there is no evidence that spirometry itself causes any significant adverse effects. Spirometry is noninvasive, low cost, and a fast way to determine lung function. Current or former smokers should speak with their physicians about the risks and benefits of being screened and see if their insurance will cover it.

Spirometry in combination with other clinical methods has been shown to be an effective COPD screening in some studies. In 2008, the National Heart Lung and Blood Institute and the COPD Foundation developed a 3-part approach to screening the general population for COPD.[25] First, a patient would answer a brief questionnaire about exposure to COPD risk factors and possible symptoms. Peak expiratory flow (the maximum amount of air that a person can forcibly exhale) would then be measured in the patient. If the peak expiratory flow was less than 70% of the predicted value, only then would spirometry be performed. The study found that the 3-step approach was useful for ruling out COPD in the general population and preventing false-positive results. However, the approach was not as accurate at detecting COPD in patients who had it. Another study looked at a validated COPD assessment test (CAT), which is a questionnaire asking about symptoms in their daily lives, on a random sample of the population.[26] The researchers found that smoking history, age (55 and older), and the presence of breathlessness were all key factors in identifying individuals at risk for COPD who would benefit from spirometry screening.

Treatment Options and Prognosis

There is no cure for COPD but symptoms can be managed through several treatment options, none of which have been shown to make people with COPD live longer.  Medications, such as bronchodilators which relax the airway muscles to make breathing easier, are administered using an inhaler.

• Bronchodilators. There are two types of bronchodilators: B2 agonists and anticholinergics. Each type can be short-acting (taken only when needed and not more than every 4-6 hours) or long-acting (taken every 12 hours or more, everyday), and some people use both types. Both B2 agonists and anticholinergics improve symptoms and lung function, but neither extends patients’ life span. Anticholinergics have been shown to be more effective in preventing symptoms from getting worse compared to long-acting B2 agonists (LABAs). LABAs appear to cause more side effects than anticholinergics, but some people find that LABAs offer them more relief than anticholinergics.[27]
• Inhaled Glucocorticosteroid. These reduce the body’s immune response and so, decrease inflammation. People who have moderate or severe COPD or are experiencing flare ups or worsening symptoms may be prescribed an inhaled glucocorticosteroid. A patient taking one of these will continue to have a declining quality of life but a slower decline than without the inhaled steroid. A patient’s breathing capacity will continue to deteriorate but the glucocorticosteroids allow the patient to be less bothered or limited by the decline. Side effects of glucocorticosteroids include hoarseness and “thrush,” a mucosal infection from yeast (oropharyngeal candidiasis).[28]
• Pill or Intravenous Steroids.  Whether inhaled or taken some other way, steroids can be very effective in the short term but have many serious side effects over the long term, including increased blood pressure, an increased risk of type 2 diabetes, weakened bones, and cataracts.[29]

In addition to controlling symptoms with medication, patients are encouraged to be vaccinated against pneumonia and the flu, both of which can worsen COPD symptoms.

Another treatment option is pulmonary rehabilitation, which can improve the health and quality of life of those who suffer from COPD. Rehab programs include exercise to maintain muscle strength, disease management training, nutritional counseling to prevent muscle wasting and maintain a healthy weight, and psychological counseling to deal with depression. Oxygen therapy is another option but is usually reserved for patients with severe COPD. It can improve quality of life by allowing patients to perform certain tasks or engage in physical activity that they otherwise couldn’t do. Oxygen therapy also helps to reduce symptoms, improve sleep, and increase overall survival in some patients.

In a small study in Japan, researchers found that acupuncture improved shortness of breath in COPD patients taking medications.[30] Patients were better able to tolerate exercise and experienced less shortness of breath during exercise, which is usually a debilitating problem for COPD sufferers. Acupuncture has previously been shown to improve shortness of breath in cancer patients. Although this alternative approach seems promising, larger studies are needed to demonstrate the efficacy of acupuncture and determine if it’s a reasonable treatment option for COPD patients.

Although rare, surgery is a last resort for cases of severe COPD where medications, pulmonary rehabilitation, oxygen therapy, and alternative medicines don’t work. Surgery can range from removing parts of the diseased lung to a complete lung transplant.

Just as there are barriers to diagnosing COPD, there are barriers to treating it, too.  According to a study of knowledge and attitudes among primary care providers, only 15% believed COPD treatment was useful for improving symptoms. Among those with access to pulmonary rehabilitation, 3% believed it was useful and 16% were neutral about its benefits.

How quickly COPD progresses varies with each patient and therefore it is hard to predict how long someone with COPD will live. One study, however, showed that inflammation measured by testing urine, blood, sputum (spit), tissue samples, and even exhaled air may help predict death in COPD patients within the next three years.[31] In the 3-year ECLIPSE study, inflammation was associated with an increased risk of death from COPD.

What Does This Have To Do With Lung Cancer?

COPD is a lung disease that often co-exists with lung cancer and is estimated to affect 40-70% of lung cancer patients (depending on the diagnostic criteria used). Similarly, the Lung Health Study Research Group found that the most common cause of death among patients with airflow obstruction was lung cancer. [32,33] One study which looked at the prevalence of COPD in lung cancer patients, independent of age, sex, or smoking history, concluded that the prevalence of COPD in newly diagnosed lung cancer cases was six-times greater than in smokers without lung cancer: 50% of newly diagnosed lung cancer patients had COPD whereas only 8% of smokers without lung cancer had COPD. Lung cancer is much more likely in smokers with previously diagnosed COPD and poor lung function compared to smokers with normal or near normal lung function. It is estimated that 20% of all long-term smokers will eventually develop COPD over the course of a lifetime. The results suggest that impaired lung function may be more important than age or even smoking history as a predictor of lung cancer.

The findings of Victor Kiri and colleagues at PAREXEL International (a pharmaceutical clinical research firm) suggest that while lung cancer survival in general is very low, survival is even lower among patients with a previous diagnosis of COPD.[34] In the study, 26% of lung cancer patients without COPD were still alive 3 years after their diagnosis compared to just 15% of lung cancer patients with COPD. A 2005 meta-analysis, which is a combined analysis of several different but comparable studies, concluded that even a small reduction in airflow significantly predicted lung cancer.[35] Another study demonstrated that just a 10% reduction in lung function (as measured by a spirometer using forced expiratory volume in 1 second or FEV1%) was associated with an almost 3-times greater lung cancer risk.[36]

The link between emphysema and lung cancer has been illustrated in several studies. Lifelong non-smokers with a history of emphysema were more likely to be diagnosed with lung cancer and died earlier than other lifelong non-smokers.[37] In another study, current and former smokers whose CT scans showed emphysema were more likely to develop lung cancer than current and former smokers whose CT scans showed no evidence of emphysema. This was true regardless of whether spirometry testing indicated airflow obstruction among the smokers, which is also a predictor of lung cancer.[38] Lung cancer occurred most frequently in patients with both airflow obstruction and emphysema—regardless of how much tobacco exposure they had. On the other hand, the more severe the case of emphysema a patient had (severity increases with the number of cigarettes smoked per day), the greater the risk of lung cancer.

How are COPD and Lung Cancer Linked?

Genetic link

The above findings strongly suggest that COPD may be an important, independent risk factor for lung cancer. Some researchers believe that COPD and lung cancer have common origins in inflammation and also share some of the same genetic predispositions and environmental risk factors, with exposure to tobacco smoke being the primary risk factor.[39] It is well known that tobacco smoke can cause inflammation leading to chronic bronchitis and COPD. It is possible that chronic inflammation of the airways and lungs could result in repeat injury and repair of cells, uncontrolled cell growth, and eventually the development of lung cancer.[40] Chronic inflammation among people with COPD may activate the proteins that help cancer grow.[41] At the same time, the proteins needed to repair DNA in some of the lung’s cells are deactivated when COPD is present. COPD may also reduce the expression of key genes, preventing them from being involved in the detoxification of cigarette smoke. This can make cigarette smoke even more toxic and lead to the spread of malignant tumors beyond the lungs to other parts of the body. No one understands exactly how or why this happens, but studies reveal that genetic or biological changes could be responsible.

Sex hormones

Female sex hormones affect lung cancer, COPD, and asthma, which are the three most common lung diseases in women. The role of female hormones may explain why women (smokers and non-smokers) are more likely to develop lung cancer and COPD than men (smokers and non-smokers) (see Lung Cancer is a Women’s Health Issue).

Some studies suggest that female sex hormones, such as estradiol, inflame a smoker’s airways which could lead to lung cancer. Estradiol is the type of estrogen found in pre-menopausal women who are not pregnant. Its levels are low during menstruation and high during ovulation, and it causes an increase of certain proteins in the lungs which make the lungs more susceptible to damage from cigarette smoke.[42] This could be the reason why women smokers are more likely to develop COPD than male smokers—even when they smoke fewer cigarettes and for fewer years (called “pack-years” of smoking). Other studies suggest that estrogen may speed up the metabolism of cigarette smoke, which would increase cellular stress and damage in the lungs and ultimately lead to a higher chance of getting lung disease and COPD for women smokers.[43]

In addition to estrogen produced by the body, estrogen taken as hormone therapy also affects lung function. Research suggests that estrogen may help certain lung cancer cells spread throughout the lungs. A 2009 study based on the Women’s Health Initiative showed that post-menopausal women who took estrogen and progesterone combined hormone therapy had an increased risk of dying from lung cancer, regardless of whether or not they were smokers (although smokers had a higher risk of death than non-smokers).[44] A study published in 2010 showed that post-menopausal women who took estrogen hormone therapy for more than 10 years had a higher risk of developing lung cancer than women who didn’t take estrogen.[45] The use of hormone treatment after menopause does not appear to independently increase the risk of COPD, however.[46]

In terms of asthma, boys are more likely to be diagnosed with asthma than girls until the age of 15; after that, more women than men are diagnosed with asthma until women’s hormones decrease during the early stages of menopause. About a third of women with asthma find that symptoms worsen (and peak flow declines) in the period immediately before their menstrual cycle, presumably due to sudden changes in hormone levels.[47] Some studies suggest that a drop in estrogen levels is the problem while other studies indicate an increased risk of developing asthma when postmenopausal women take hormone therapy, which contains estrogen.[48] Despite the confusion, one thing is clear: dramatic changes in hormone levels trigger asthma and asthma symptoms in women, and asthma increases the risk for developing COPD.

Could COPD Patients be the Best Candidates for Lung Cancer Screening?

The relationship between smoking, airflow obstruction, and lung cancer is well recognized. Diseases characterized by airflow obstruction, like COPD, are associated with an increased risk of lung cancer and screening smokers for COPD as a risk factor for lung cancer could be worthwhile.

While low-dose CT screening for lung cancer has gained support in recent years, its value is still being debated (see Lung Cancer: Who is at Risk and Can They be Screened?). Most experts agree that current and former smokers are at the highest risk for lung cancer, yet not everyone agrees that they should all be screened. Smokers who have COPD could be the best candidates for lung cancer screening because they are most likely to benefit from it. Prioritizing high-risk smokers could also increase the accuracy and cost-effectiveness of CT screening. Since emphysema is usually detected with low-dose CT, it would be efficient and cost-effective to screen smokers and former heavy smokers for both emphysema and lung cancer at the same time.

The combined use of spirometry to diagnose COPD and CT to diagnose emphysema could help identify those at greatest risk for lung cancer and who would benefit the most from lung cancer screening. A diagnosis of COPD could alert patients to their elevated risk of lung cancer, just as high blood pressure does for the risk of stroke.

You Think you Might be at Risk for COPD and/or Lung Cancer. Now What?

1. If you are currently smoking, stop or at least start cutting back. 1-800-QUITNOW and Smokefree.gov are free resources you can use to help you quit. Women have a harder time quitting than men and it takes years to reverse the damage of cigarette smoke. Even then some lung damage cannot be undone. However, women who do quit recover faster from the effects of cigarette smoke than men.
2. If you have risk factors for COPD or lung cancer, discuss the risks and benefits of screening with spirometry or low-dose CT with your doctor. If you are experiencing any symptoms associated with COPD and/or lung cancer, see your doctor immediately.
3. If you are diagnosed with COPD, lung cancer or both, consider participating in clinical trials for new treatments and therapies.
4. Advocate for additional federal funding for research to investigate the link between COPD and lung cancer and discover new treatments for both diseases.

Related Content:
Screening for lung cancer: do risks outweigh benefits?
Lung cancer: who is at risk and can they be screened?
Lung cancer and African Americans

References:

1. Young RP, Hopkins RJ, Christmas T, Black PN, Metcalf P, Gamble GD. COPD prevalence is increased in lung cancer, independent of age, sex and smoking history. Eur Respir J. 2009; 34(2):380-6.
2. Yang P, Sun Z, Krowka MJ, Aubry MC, Bamlet WR, et al. (2008) Alpha1-antitrypsin deficiency carriers, tobacco smoke, chronic obstructive pulmonary disease, and lung cancer risk. Arch Intern Med 168: 1097–1103.
3. National Heart Lung and Blood Institute. What is COPD? National Institutes of Health. Available from: http://www.nhlbi.nih.gov/health/health-topics/topics/copd/
4. Fromer L. Diagnosing and treating COPD: understanding the challenges and finding solutions. Int J Gen Med. 2011;4:729–739.
5. Lamprecht B, McBurnie MAM, Vollmer WMM, Gudmundsson GMF, Welte T, Nizankowska-Mogilnicka EMF, et al. COPD in never smokers: Results from the population-based burden of obstructive lung disease study. Chest. 2011;139(4):752–63.
6. Han M, Postma D, Mannino DM, Giardino ND, Buist S, Curtis JL, Martinez FJ. ; Gender and chronic obstructive pulmonary disease: Why it matters. Am J Respir Crit Care Med. 2007; 176:1179-1184.
7. Belani CP, Marts S, Schiller J, Socinski MA. Women and lung cancer: epidemiology, tumor biology, and emerging trends in clinical research. Lung Cancer. 2007; 55(1):15-23.
8. Lin K, Watkins B, Johnson T, Rodriguez JA, Barton MB. Screening for chronic obstructive pulmonary disease using spirometry: summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2008; 148:535-543.
9. Vestbo J. Chronic cough and phlegm in young adults: should we worry? Am J Respir Crit Care Med. 2007; 175:2-3.
10. Johannessen A,Bakke PS, Hardie JA, Eagan TM. Association of exposure to environmental tobacco smoke in childhood with chronic obstructive pulmonary disease and respiratory symptoms in adults. Respirology. 2012; 17(3):499-505.
11. National Heart Lung and Blood Institute. What Is Alpha-1 Antitrypsin Deficiency? National Institutes of Health. Available from: http://www.nhlbi.nih.gov/health/health-topics/topics/aat/
12. Akinbami LJ, Liu X. Chronic Obstructive Pulmonary Disease Among Adults Aged 18 and Over in the United States, 1998-2009. NCHS Data Brief, Centers for Disease Control and Prevention. 2011;63.
13. Van den Berge M, Heijink HI, Van Oosterhout AJ, Postma DS. The role of female sex hormones in the development and severity of allergic and non-allergic asthma. Clin Exp Allergy. 2009; 39:1477-81.
14. Celli BR. Update on the management of COPD. Chest. 2008;133:1451-62.
15. Global Strategy for the Diagnosis, Management and Prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011. Available at: http://www.goldcopd.org/.
16. Fromer L, Cooper CB. A Review of the GOLD Guidelines for the Diagnosis and Treatment of Patients with COPD. Int J Clin Pract CME. 2008;62(8):1219-1236.
17. Yawn B, Wollan P. Knowledge and attitudes of family physicians coming to COPD continuing medical education. Int J Chron Obstruct Pulmon Dis. 2008;3(2):311–317.
18. Tsagaraki V, Markantonis SL, Amfilochiou A. Pharmacotherapeutic management of COPD patients in Greece – adherence to international guidelines. J Clin Pharm Ther 2006; 31: 369–74.
19. GOLD Spirometry Guide. The Global Initiative for Chronic Obstructive Lung Disease. Available at: http://www.goldcopd.org/uploads/users/files/GOLD_Spirometry_2010.pdf.
20. Güder G, Brenner S, Angermann CE, Ertl G, Held M, Sachs AP et al. GOLD or lower limit of normal definition? A comparison with expert-based diagnosis of chronic obstructive pulmonary disease in a prospective cohort-study. Respir Res. 2012;13(13):1-9.
21. Jordan RE, Miller MR, Lam KB, Cheng KK, Marsh J, Adab P. Sex, susceptibility to smoking and chronic obstructive pulmonary disease: the effect of different diagnostic criteria. Analysis of the Health Survey for England. Thorax. 2012; 67(7):600-5.
22. Ferguson GT, Enright PL, Buist AS, Higgins MW. Office spirometry for lung health assessment in adults: a consensus statement for the National Lung Health Education Program. Chest. 2000; 117:1146–61.
23. Enright P. Does screening for COPD by primary care physicians have the potential to cause more harm than good? Chest. 2006; 129:833-5.]  In 2008, the U.S. Preventive Services Task Force followed suit and recommended against screening healthy adults without any respiratory symptoms for COPD using spirometry, stating that it had no overall benefit.[end U.S. Preventive Services Task Force. Screening for chronic obstructive pulmonary disease using spirometry: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2008; 148:529-534.
24. Lin K, Watkins B, Johnson T, Rodriguez JA, Barton MB. Screening for Chronic Obstructive Pulmonary Disease Using Spirometry: Summary of the Evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2008; 148: 535-543.
25. Nelson SB, LaVange LM, Nie Y, Walsh JW, Enright PL, Martinez FJ, Mannino DM, Thomashow BM. . Questionnaires and pocket spirometers provide an alternative approach for COPD screening in the general population. Chest. 2011; 142(2):358-66.
26. Raghavan N, Lam YM, Webb KA, Guenette JA, Amornputtisathaporn N, Raghavan R et al.. Components of the COPD assessment test (CAT) associated with a diagnosis of COPD in a random population sample. COPD. 2012; 9(2):175-83.
27. Chong J, Karner C, Poole P. Tiotropium versus long-acting beta-agonists for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;9:CD009157.
28. Yang IA, Clark MS, Sim EH, Fong KM. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012, 7:CD00291.
29. Walters JA, Walters EH, Wood-Baker R. Oral corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2005;3:CD005374.
30. Suzuki M, Muro S, Ando Y, Omori T, Shiota T, Endo K et al. A randomized, placebo-controlled trial of acupuncture in patients with chronic obstructive pulmonary disease (COPD): the COPD-acupuncture trial (CAT). Arch Intern Med. 2012; 172(11):878-86.
31. Celli BR, Locantore N, Yates J, Tal-Singer R, Miller BE, Bakke P et al.. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012; 185(10):1065-72.
32. Anthonisen NR, Skeans MA, Wise RA, Manfreda J, Kanner RE, Connett JE; Lung Health Study Research Group. The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann Intern Med. 2005; 142:233–239.
33. Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med. 2000; 343:1902–1909.
34. Kiri V, Soriano J, Visick G, Fabbri L. Recent trends in lung cancer and its association with COPD: an analysis using the UK GP Research Database. Prim Care Respir J. 2010; 19(1):57-61.
35. Wasswa-Kintu S, Gan WQ, Man SFP, Pare PD, Sin DD. Relationship between reduced forced expiratory volume in one second and the risk of lung cancer: a systematic review and meta-analysis. Thorax. 2005;60:570–575.
36. Calabro E, Randi G, La Vecchia C, Sverzellati N, Marchiano A, Villani M et al. Lung function predicts lung cancer risk in smokers: a tool for targeting screening programmes. Eur Respir J. 2010; 35(6):146-151.
37. Turner MC,Chen Y, Krewski D, Calle EE, Thun MJ. Chronic obstructive pulmonary disease is associated with lung cancer mortality in a prospective study of never smokers. Am J Respir Crit Care Med. 2007; 176(3):285-290.
38. Wilson DO, Weissfeld JL, Balkan A, Schragin JG, Fuhrman CR, Fisher SN et al. Association of radiographic emphysema and airflow obstruction with lung cancer. Am J Respir Crit Care Med. 2008; 178(7): 738-744.
39. Barnes PJ. New concepts in chronic obstructive pulmonary disease. Annu Rev Med. 2003; 54:113–129.
40. Pages V, Fuchs RPP. How DNA lesions are turned into mutations within cells? Oncogene. 2002; 21:8957–8966.
41. Barnes PJ, Adcock IM. Chronic obstructive pulmonary disease and lung cancer: a lethal association. Am J Respir Crit Care Med. 2011; 184(8):866-867.
42. Tam A, Morrish D, Wadsworth S, Dorscheid D, Man SFP, Sin DD. The role of female hormones on lung function in chronic lung diseases. BMC Women’s Health. 2011; 11:24.
43. Sin DD, Cohen SBZ, Day A, Coxson H, Pare PD. Understanding the Biological Differences in Susceptibility to Chronic Obstructive Pulmonary Disease between Men and Women. Proc Am Thorac Soc. 2007; 4(8): 671-674.
44. Chlebowski RT, et al.  Oestrogen plus progestin and lung cancer in postmenopausal women (Women’s Health Initiative trial): a post-hoc analysis of a randomised controlled trial. Lancet. 2009; 374(9697):1243-1251.
45. Slatore CG, et al. Lung cancer and hormone replacement therapy: association in the vitamins and lifestyle study. J Clin Oncol. 2010;28(9):1540-1546.
46. Barr GR, Wentowski CC, Grodstein F, Somers SC, Stampfer MJ, Schwartz J et al. Prospective study of postmenopausal hormone use and newly diagnosed asthma and chronic obstructive pulmonary disease. Arch Intern Med. 2004; 164(4):379-386
47. Shames RS, Heilbron DC, Janson SL, Kishiyama JL, Au DS, Adelman DC. Clinical differences among women with and without self-reported perimenstrual asthma. Ann Allergy Asthma Immunol. 1998; 81:65–72.
48. Skobeloff EM, Spivey WH, Silverman R, Eskin BA, Harchelroad F, Alessi TV. The effect of the menstrual cycle on asthma presentations in the emergency department. Arch Intern Med. 1996;156(16):1837-1840