This article is an excerpt from The GOLD Report 2013. The GOLD Report 2013 is an excellent work stating the current position on COPD from a worldwide perspective. This article is the best that I’ve seen describing how the disease progresses for most people. I do appreciate that it is a hard read, but do bear in mind that it was written by professionals for professionals worldwide. The authors come from many countries, and we have to bear in mind that environmental factors differ from one country to another. Poverty is an important indirect cause in many places, and not necessarily just in Third World Countries.
I hope you find it relevant, and not too hard going.
Although cigarette smoking is the best-studied COPD risk factor, it is not the only one and there is consistent evidence from epidemiologic studies that nonsmokers may also develop chronic airflow limitation. Much of the evidence concerning risk factors for COPD comes from cross-sectional epidemiological studies that identify associations rather than cause-and-effect relationships. Although several longitudinal studies of COPD have followed groups and populations for up to 20 years, none has monitored the progression of the disease through its entire course, or has included the pre-and perinatal periods which may be important in shaping an individual’s future COPD risk. Thus, current understanding of risk factors for COPD is in many respects still incomplete. COPD results from a gene-environment interaction. Among people with the same smoking history, not all will develop COPD due to differences in genetic predisposition to the disease, or in how long they live. Risk factors for COPD may also be related in more complex ways. For example, gender may influence whether a person takes up smoking or experiences certain occupational or environmental exposures; socioeconomic status may be linked to a child’s birth weight (as it impacts on lung growth and development and in turn on susceptibility to develop the disease); and longer life expectancy will allow greater lifetime exposure to risk factors. Understanding the relationships and interactions among risk factors requires further investigation.
The genetic risk factor that is best documented is a severe hereditary deficiency of alpha-1 antitrypsin, a major circulating inhibitor of serine proteases. Although alpha-1 antitrypsin deficiency is relevant to only a small part of the world’s population, it illustrates the interaction between genes and environmental exposures leading to COPD. A significant familial risk of airflow limitation has been observed in smoking siblings of patients with severe COPD, suggesting that genetic together with environmental factors could influence this susceptibility. Single genes such as the gene encoding matrix metalloproteinase 12 (MMP12) have been related to decline in lung function. Although several genome-wide association studies indicate a role of the gene for the alpha-nicotinic acetylcholine receptor as well as the hedge-hog interacting protein gene and possibly one or two others, there remains a discrepancy between findings from analyses of COPD and lung function as well as between genome-wide association study analyses and candidate gene analyses.
Age and Gender
Age is often listed as a risk factor for COPD. It is unclear if healthy aging as such leads to COPD or if age reflects the sum of cumulative exposures throughout life. In the past, most studies showed that COPD prevalence and mortality were greater among men than women but data from developed countries show that the prevalence of the disease is now almost equal in men and women, probably reflecting the changing patterns of tobacco smoking. Some studies have even suggested that women are more susceptible to the effects of tobacco smoke than men.
Lung Growth and Development
Lung growth is related to processes occurring during gestation, birth, and exposures during childhood and adolescence. Reduced maximal attained lung function (as measured by spirometry) may identify individuals who are at increased risk for the development of COPD. Any factor that affects lung growth during gestation and childhood has the potential for increasing an individual’s risk of developing COPD. For example, a large study and meta-analysis confirmed a positive association between birth weight and FEV1 in adulthood, and several studies have found an effect of early childhood lung infections. A study found that factors in early life termed “childhood disadvantage factors” were as important as heavy smoking in predicting lung function in early adult life.
Exposure to Particles
Across the world, cigarette smoking is the most commonly encountered risk factor for COPD. Cigarette smokers have a higher prevalence of respiratory symptoms and lung function abnormalities, a greater annual rate of decline in FEV1, and a greater COPD mortality rate than nonsmokers. Other types of tobacco (e.g., pipe, cigar, water pipe) and marijuanaare also risk factors for COPD. Passive exposure to cigarette smoke (also known as environmental tobacco smoke or ETS) may also contribute to respiratory symptoms and COPD by increasing the lung’s total burden of inhaled particles and gases. Smoking during pregnancy may also pose a risk for the foetus, by affecting lung growth and development in utero and possibly the priming of the immune system.
Occupational exposures, including organic and inorganic dusts and chemical agents and fumes, are an under appreciated risk factor for COPD. An analysis of the large U.S. population-based NHANES III survey of almost 10,000 adults aged 30-75 years estimated the fraction of COPD attributable to work was 19.2% overall, and 31.1% among never-smokers. These estimates are consistent with a statement published by the American Thoracic Society that concluded that occupational exposures account for 10-20% of either symptoms or functional impairment consistent with COPD. The riskfrom occupational exposures in less regulated areas of the world is likely to be much higher than reported in studies from Europe and North America.
Wood, animal dung, crop residues, and coal, typically burned in open fires or poorly functioning stoves, may lead to very high levels of indoor air pollution. Evidence continues to grow that indoor pollution from biomass cooking and heating in poorly ventilated dwellings is an important risk factor for COPD. Almost 3 billion people worldwide use biomass and coal as their main source of energy for cooking, heating, and other household needs, so the population at risk worldwide is very large.
High levels of urban air pollution are harmful to individuals with existing heart or lung disease. The role of outdoor air pollution in causing COPD is unclear, but appears to be small when compared with that of cigarette smoking. It has also been difficult to assess the effects of single pollutants in long-term exposure to atmospheric pollution. However, air pollution from fossil fuel combustion, primarily from motor vehicle emissions in cities, is associated with decrements of respiratory function. The relative effects of short-term, high-peak exposures and long-term, low-level exposures are yet to be resolved.
Poverty is clearly a risk factor for COPD but the components of poverty that contribute to this are unclear. There is strong evidence that the risk of developing COPD is inversely related to socioeconomic status. It is not clear, however, whether this pattern reflects exposures to indoor and outdoor air pollutants, crowding, poor nutrition, infections, or other factors that are related to low socioeconomic status.
Asthma/Bronchial Hyper reactivity
Asthma may be a risk factor for the development of COPD, although the evidence is not conclusive. In a report from a longitudinal cohort of the Tucson Epidemiological Study of Airway Obstructive Disease, adults with asthma were found to have a twelve-fold higher risk of acquiring COPD over time than those without asthma, after adjusting for smoking. Another longitudinal study of people with asthma found that around 20% of subjects developed irreversible airflow limitation and reduced transfer coefficient, and in a longitudinal study self-reported asthma was associated with excess loss of FEV1 in the general population. In the European Community Respiratory Health Survey, bronchial hyper responsiveness was second only to cigarette smoking as the leading risk factor for COPD, responsible for 15% of the population attributable risk (smoking had a population attributable risk of 39%). The pathology of chronic airflow limitation in asthmatic nonsmokers and non-asthmatic smokers is markedly different, suggesting that the two disease entities may remain different even when presenting with similarly reduced lung function. However, clinically separating asthma from COPD may not be easy.
Bronchial hyper reactivity can exist without a clinical diagnosis of asthma and has been shown to be an independent predictor of COPD in population studies as well as an indicator of risk of excess decline in lung function in patients with mild COPD.
In the seminal study by Fletcher and co-workers, chronic bronchitis was not associated with decline in lung function. However, subsequent studies have found an association between mucus hyper-secretion and FEV1 decline, and in younger adults who smoke the presence of chronic bronchitis is associated with an increased likelihood of developing COPD.
A history of severe childhood respiratory infection has been associated with reduced lung function and increased respiratory symptoms in adulthood. Susceptibility to infections plays a role in exacerbations of COPD but the effect on the development of the disease is less clear. HIV infection has been shown to accelerate the onset of smoking-related emphysema. Tuberculosis has been found to be a risk factor for COPD. In addition, tuberculosis is both a differential diagnosis to COPD and a potential comorbidity.
Inhaled cigarette smoke and other noxious particles such as smoke from biomass fuels cause lung inflammation, a normal response that appears to be modified in patients who develop COPD. This chronic inflammatory response may induce parenchymal tissue destruction (resulting in emphysema), and disrupt normal repair and defense mechanisms (resulting in small airway fibrosis). These pathological changes lead to air trapping and progressive airflow limitation. A brief overview follows of the pathological changes in COPD, their cellular and molecular mechanisms, and how these underlie physiologic abnormalities and symptoms characteristic of the disease.
Pathological changes characteristic of COPD are found in the airways, lung parenchymal, and pulmonary vasculature. The pathological changes include chronic inflammation, with increased numbers of specific inflammatory cell types in different parts of the lung, and structural changes resulting from repeated injury and repair. In general, the inflammatory and structural changes in the airways increase with disease severity and persist on smoking cessation.
The inflammation in the respiratory tract of COPD patients appears to be a modification of the inflammatory response of the respiratory tract to chronic irritants such as cigarette smoke. The mechanisms for this amplified inflammation are not yet understood but may be genetically determined. Patients can clearly develop COPD without smoking, but the nature of the inflammatory response in these patients is unknown. Oxidative stress and an excess of proteinases in the lung further modify lung inflammation. Together, these mechanisms lead to the characteristic pathological changes in COPD. Lung inflammation persists after smoking cessation through unknown mechanisms, although autoantigens and persistent microorganisms may play a role.
Oxidative stress may be an important amplifying mechanism in COPD. Biomarkers of oxidative stress (e.g., hydrogen peroxide, 8-isoprostane) are increased in the exhaled breath condensate, sputum, and systemic circulation of COPD patients. Oxidative stress is further increased in exacerbations. Oxidants are generated by cigarette smoke and other inhaled particulates, and released from activated inflammatory cells such as macrophages and neutrophils. There may also be a reduction in endogenous antioxidants in COPD patients as a result of reduction in a transcription factor called Nrf2 that regulates many antioxidant genes.
There is compelling evidence for an imbalance in the lungs of COPD patients between proteases that break down connective tissue components and anti proteases that protect against this. Several proteases, derived from inflammatory cells and epithelial cells, are increased in COPD patients. There is increasing evidence that they may interact with each other. Protease-mediated destruction of elastin, a major connective tissue component in lung parenchyma, is believed to be an important feature of emphysema and is likely to be irreversible.
COPD is characterized by a specific pattern of inflammation involving increased numbers of CD8+ (cytotoxic) Tc1 lymphocytes present only in smokers that develop the disease. These cells, together with neutrophils and macrophages, release inflammatory mediators and enzymes and interact with structural cells in the airways, lung parenchyma and pulmonary vasculature.
The wide variety of inflammatory mediators that have been shown to be increased in COPD patients attract inflammatory cells from the circulation (chemotactic factors), amplify the inflammatory process (pro inflammatory cytokines), and induce structural changes (growth factors).
Differences in Inflammation Between COPD and Asthma.
Although both COPD and asthma are associated with chronic inflammation of the respiratory tract, there are differences in the inflammatory cells and mediators involved in the two diseases, which in turn account for differences in physiological effects, symptoms, and response to therapy. Some patients with COPD have features consistent with asthma and may have a mixed inflammatory pattern with increased eosinophils.
There is now a good understanding of how the underlying disease process in COPD leads to the characteristic physiologic abnormalities and symptoms. For example, inflammation and narrowing of peripheral airways leads to decreased FEV1. Parenchymal destruction due to emphysema also contributes to airflow limitation and leads to decreased gas transfer
Airflow Limitation and Air Trapping.
The extent of inflammation, fibrosis, and luminal exudates in small airways is correlated with the reduction in FEV1 and FEV1/FVC ratio, and probably with the accelerated decline in FEV1 characteristic of COPD. This peripheral airway obstruction progressively traps air during expiration, resulting in hyperinflation. Although emphysema is more associated with gas exchange abnormalities than with reduced FEV1, it does contribute to gas trapping during expiration. This is especially so as alveolar attachments to small airways are destroyed when the disease becomes more severe. Hyperinflation reduces inspiratory capacity such that functional residual capacity increases, particularly during exercise (dynamic hyperinflation), resulting in increased dyspnea and limitation of exercise capacity. These factors contribute to impairment of the intrinsic contractile properties of respiratory muscles; this results in up regulation of local pro-inflammatory cytokines. It is thought that hyperinflation develops early in the disease and is the main mechanism for exertional dyspnea. Bronchodilators acting on peripheral airways reduce air trapping, thereby reducing lung volumes and improving symptoms and exercise capacity.
Gas Exchange Abnormalities.
Gas exchange abnormalities result in hypoxaemia and hypercapnia, and have several mechanisms in COPD. In general, gas transfer for oxygen and carbon dioxide worsens as the disease progresses. Reduced ventilation may also be due to reduced ventilatory drive. This may lead to carbon dioxide retention when it is combined with reduced ventilation due to a high work of breathing because of severe obstruction and hyperinflation coupled with ventilatory muscle impairment. The abnormalities in alveolar ventilation and a reduced pulmonary vascular bed further worsen the VA/Q abnormalities.
Mucus Hyper secretion.
Mucus hyper secretion, resulting in a chronic productive cough, is a feature of chronic bronchitis and is not necessarily associated with airflow limitation. Conversely, not all patients with COPD have symptomatic mucus hyper secretion. When present, it is due to an increased number of goblet cells and enlarged submucosal glands in response to chronic airway irritation by cigarette smoke and other noxious agents. Several mediators and proteases stimulate mucus hyper secretion and many of them exert their effects through the activation of epidermal growth factor receptor (EGFR).
Pulmonary hypertension may develop late in the course of COPD and is due mainly to hypoxic vasoconstriction of small pulmonary arteries, eventually resulting in structural changes that include intimal hyperplasia and later smooth muscle hypertrophy/hyperplasia. There is an inflammatory response in vessels similar to that seen in the airways and evidence of endothelial cell dysfunction. The loss of the pulmonary capillary bed in emphysema may also contribute to increased pressure in the pulmonary circulation. Progressive pulmonary hypertension may lead to right ventricular hypertrophy and eventually to right-side cardiac failure.
Exacerbations of respiratory symptoms often occur in patients with COPD, triggered by infection with bacteria or viruses (which may coexist), environmental pollutants, or unknown factors. Patients with bacterial and viral episodes have a characteristic response with increased inflammation. During respiratory exacerbations there is increased hyperinflation and gas trapping, with reduced expiratory flow, thus accounting for the increased dyspnea. There is also worsening of VA/Q abnormalities, which can result in hypoxaemia. Other conditions (pneumonia, thromboembolism, and acute cardiac failure) may mimic or aggravate an exacerbation of COPD.
It is increasingly recognized that many patients with COPD have comorbidities that have a major impact on quality of life and survival. Airflow limitation and particularly hyperinflation affect cardiac function and gas exchange. Inflammatory mediators in the circulation may contribute to skeletal muscle wasting and cachexia, and may initiate or worsen comorbidities such as ischemic heart disease, heart failure, osteoporosis, normocytic anaemia, diabetes, metabolic syndrome, and depression.