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Chronic obstructive pulmonary disease: aetiology, pathology, physiology and outcome
CHRONIC OBSTRUCTIVE LUNG DISEASE
Chronic obstructive pulmonary disease: aetiology, pathology, physiology and outcome
What’s new? C
C
Rohit Chitkara C
John R Hurst
Abstract
limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases’. The most important part of the definition relates to airflow obstruction. Airflow obstruction (low ratio of forced expiratory volume in 1 second (FEV1): forced vital capacity (FVC)) can be detected using spirometry, which is the only way to confirm a diagnosis of COPD. The severity of airflow obstruction (FEV1) is used to grade the severity of COPD. The severity classification used in the National Institute for Health and Clinical Excellence clinical guideline2 is now aligned with that of the GOLD document, and is summarized below in Table 1. Whilst other severity assessments such as the multi-dimensional ‘BODE’ index, relating body mass index, airflow obstruction, dyspnoea and exercise capacity,3 may be a better predictor of outcomes such as mortality, the inclusion of an exercise tolerance assessment in BODE means that this tool is difficult to integrate into routine clinical practice. As stated in the GOLD definition, the airflow obstruction in COPD is largely irreversible (in contrast to asthma). However, it is now recognized that patients may change from being ‘reversible’ to ‘irreversible’ on sequential tests when arbitrary classifications are used, and the presence of reversibility does not predict the clinical response to either inhaled corticosteroids or bronchodilators. For these reasons, diagnostic criteria are now based on post-bronchodilator spirometry, and routine reversibility testing is not recommended.2 When reversibility testing is performed, and the changes are large (e.g. a change in
Chronic obstructive pulmonary disease (COPD) is a physiological diagnosis made on the basis of airflow obstruction. It develops when a genetically susceptible individual encounters a sufficient environmental trigger. Genetic susceptibility is complex and determined by multiple alleles, aside from the model of emphysema caused by a-1 anti-trypsin deficiency. Cigarette smoke is the usual trigger in the developed world but globally the burning of biomass fuel in under-ventilated space is important. In those subjects genetically susceptible to the effects of smoke, there is an airway inflammatory response that is qualitatively and quantitatively different from non-susceptible subjects, predominantly composed of neutrophils, macrophages and CD8þ lymphocytes. Once established, the inflammation can persist even after exposure to smoke has ceased. Airflow obstruction in COPD results from a combination of the airway wall inflammatory response, luminal mucus, and loss of alveolareairway attachments from co-existent emphysema. Although progressive airflow obstruction is the hallmark of COPD, it is now recognized that there are other important outcomes in this condition, notably exacerbations and the development of co-morbidities.
Keywords Chronic bronchitis; chronic obstructive pulmonary disease; COPD; emphysema; exacerbation; spirometry
Definitions and diagnosis The World Health Organization Global initiative for chronic Obstructive Lung Disease (GOLD) document1 has defined chronic obstructive pulmonary disease (COPD) as: ‘a preventable and treatable disease with some significant extra-pulmonary effects that may contribute to the severity in individual patients. Its pulmonary component is characterized by airflow limitation that is not fully reversible. The airflow
Diagnosis and severity classification of COPD
1 2 3 4
Rohit Chitkara BSc is a Fourth Year Medical Student at UCL Medical School, London, UK. Conflicts of interest: none declared.
Stage
Post-bronchodilator FEV1/FVC ratio
Post-bronchodilator FEV1 (% predicted)
Mild Moderate Severe Very severe
<0.7 <0.7 <0.7 <0.7
80% 50e79% 30e49% <30% (or <50% with respiratory failurea)
COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity. a Respiratory failure is defined as a partial pressure of oxygen in arterial blood <8.0 kPa (60 mmHg) with or without a partial pressure of carbon dioxide in arterial blood >6.7 kPa (50 mmHg) breathing air.
John R Hurst PhD FRCP is a Senior Lecturer in Respiratory Medicine at UCL Medical School, London, UK. Dr Hurst has a clinical and research interest in the causes and mechanisms of exacerbations in airway diseases including COPD and bronchiectasis. Conflicts of interest: none declared.
MEDICINE 40:5
Genome-wide association studies (GWAS) have investigated genetic determinants of COPD susceptibility other than a-1 antitrypsin deficiency Susceptibility to exacerbations varies between individual patients and can be predicted by asking about previous exacerbations It is important to assess and treat co-morbidities in patients with COPD
Table 1
257
Ó 2012 Elsevier Ltd. All rights reserved.
CHRONIC OBSTRUCTIVE LUNG DISEASE
FEV1 > 400 ml), a diagnosis of asthma should be suspected. Finally, current guidelines recommend using a fixed FEV1:FVC ratio of less than 0.7. Whilst simple to use, the FEV1:FVC ratio declines with age, risking over-diagnosis of airflow obstruction in the elderly (and under-diagnosis in the young) and there is currently debate about moving to criteria using the FEV1:FVC ratio based on predicted lower limits of normal for the patient’s age, sex, race and height. COPD should not be confused with chronic bronchitis or emphysema and these terms are not synonymous. COPD, as described above, is a physiological diagnosis. Emphysema is an anatomical (pathological or radiological) diagnosis defined as ‘an abnormal and permanent enlargement of airspaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis’. Chronic bronchitis is a clinical diagnosis based on cough productive of sputum for most days of the week, in 3 or more months of 2 or more consecutive years (and the absence of another specific diagnosis such as bronchiectasis). Many patients with COPD have varying degrees of emphysema and/or chronic bronchitis and this produces heterogeneity in the disease and specific ‘phenotypes’ that have historically included emphysematous ‘pink puffers’ and bronchitic, hypercapnoeic ‘blue bloaters’. Our understanding of phenotypes in COPD, and our ability to define them is now much more sophisticated. This is clinically important in predicting treatment response. For example, lung volume reduction surgery (LVRS) would be recommended only for patients with COPD who have upper-lobe predominant emphysema, and a poor response to pulmonary rehabilitation.4 Many cigarette smokers may fulfil the definition of chronic bronchitis without having airflow obstruction (COPD), and this is termed simple chronic bronchitis. Finally, some patients with chronic asthma may develop fixed airflow obstruction that is clinically indistinguishable from COPD.
COPD (1% in the UK). Recent genome-wide association studies in COPD have suggested further candidate susceptibility genes,5 but the effect of individual polymorphisms is small; susceptibility to COPD remains poorly explained and is probably determined by many alleles. Historically, the aetiology of COPD was described by two hypotheses: a ‘British hypothesis’ that airflow obstruction results from multiple episodes of airway infection in patients with chronic bronchitis, and a ‘Dutch hypothesis’ that placed COPD on a spectrum of airway disorders with asthma. Components of both theories remain valid. The fact that COPD requires a sufficient exposure to respiratory insults highlights that COPD is a preventable disease. Longterm efforts to reduce the global and individual burden of COPD require effective tobacco control measures.
Pathology Exposure to cigarette smoke results in an inflammatory response in the airways. In those subjects genetically susceptible to the effects of this smoke, the inflammatory response is qualitatively and quantitatively different from that seen in non-susceptible subjects. This is why the GOLD definition of COPD1 makes reference to an abnormal inflammatory response e it is, of course, normal to have an airway inflammatory response to airborne insults. Importantly, the inflammatory response in COPD can persist after smoking cessation. The major site of the physiological airflow obstruction in COPD is the small airways (defined as those <2 mm in internal diameter). Pathological changes are also seen in the large airways, and lung parenchyma. As the severity of airflow obstruction increases (higher GOLD Stage), there is an increase in the volume of inflammatory cells in the airway wall and accumulation of mucus in the airway lumen.6 The inflammatory infiltrate includes macrophages, neutrophils and CD8þ lymphocytes and, in GOLD Stages 3 and 4, lymphoid follicles (Figure 1). This suggests an adaptive response to a self or microbial antigen and could explain the persistence of inflammation after smoking cessation. The airflow obstruction that defines COPD therefore arises from a combination of an increase in volume of the airway wall, and luminal mucus filling. A further important mechanism is the loss of airway attachments resulting from destruction of alveolar septa. Alveolar destruction (emphysema) results from an imbalance between pro- and anti-inflammatory mechanisms, exemplified by a-1 anti-trypsin deficiency. This autosomal codominant condition is associated with a reduced serum concentration of a-1 anti-trypsin, the major defence against neutrophil elastase, unopposed action of which in the alveoli results in accelerated and extensive emphysema. As COPD becomes more severe, bacterial colonization becomes important. Modern molecular methods have transformed our understanding of the airway microbiome and it is now clear that the old view of the airway as sterile in health is incorrect.7 What used to be considered the development of colonization in COPD is now thought to represent a change in colonizing species. Patients colonized with bacterial species such as Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis are known to have accelerated lung function
Aetiology The GOLD definition of COPD makes reference to an abnormal inflammatory response of the lung to noxious particles or gases.1 The aetiology of COPD therefore requires an inflammatory insult to the lung. In the developed world this insult is usually cigarette smoke exposure. Globally, exposure to biomass fumes in underventilated spaces is important. Biomass is burned in stoves for cooking and heating and therefore in the developing world women may be at particular risk of COPD. It is important to enquire about other domestic, recreational and occupational exposures, too: use of drugs such as marijuana may result in accelerated disease. Historically it has been stated that only about 15% of smokers develop COPD though the figure is likely to be higher. However, this does highlight that exposure alone is not sufficient to cause disease and this only occurs in individuals with a susceptible genetic background. Some people exposed to significant environmental tobacco smoke exposure (passive smoke) may also be at increased risk, which has been a major driver for recent tobacco control legislation. COPD therefore results from the combination of a susceptible individual meeting a sufficient environmental trigger. The best-defined genetic determinant is a-1 anti-trypsin deficiency, but this is an uncommon cause of
MEDICINE 40:5
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Ó 2012 Elsevier Ltd. All rights reserved.
CHRONIC OBSTRUCTIVE LUNG DISEASE
Figure 2
Figure 1
Outcomes decline, and more frequent exacerbations. Pseudomonas aeruginosa and atypical Mycobacteria may be seen in advanced COPD.
The classic description of the natural history of COPD is derived from the work of Fletcher and Peto,8 with accelerated decline of lung function in those smokers susceptible to the effects of cigarette smoke (Figure 3). It is now acknowledged that this model does not account for insults that may affect the attainment of maximal lung capacity in early adult life, for example the commencement of smoking in adolescence (which is common), or paediatric disease, such as the bronchopulmonary dysplasia observed in survivors of pre-term birth. Those smokers unable to quit continue to experience accelerated lung function decline, associated with progressive symptoms and functional limitation, the development of respiratory failure and death. Lung function decline is not the only relevant outcome in COPD. Exacerbations are important events, characterized by
Physiology The flowevolume loop from a patient with COPD, at baseline and with additional demand such as exercise or exacerbation, is illustrated as Figure 2. The inspiratory curve is normal. However, shortly after reaching peak-expiratory flow, collapse of the small airways results in a reduction in airflow and the characteristic ‘scalloped’ shape of the expiratory limb. Dynamic hyperinflation puts additional load on the respiratory muscles, which may already be weakened due to the skeletal muscle weakness that can accompany COPD. This is one mechanism leading to Type 2 (hypercapnoeic) respiratory failure.
MEDICINE 40:5
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Ó 2012 Elsevier Ltd. All rights reserved.
CHRONIC OBSTRUCTIVE LUNG DISEASE
Figure 4
Figure 3
mechanism may be the increased systemic inflammation seen in COPD. Such manifestations include an increased risk of cardiovascular disease, lung cancer, cachexia, osteoporosis, skeletal muscle weakness and depression. Addressing co-morbidities in COPD is important because many patients with COPD die from such conditions10 (rather than from airway disease) and (as with depression) there may be profound effects on quality of life. COPD remains a major health challenge in the UK, and more widely. COPD kills 25,000 people annually in England and Wales alone, and across the UK it is estimated that there are 835,000 patients in whom the condition has been diagnosed and perhaps 2,200,000 more in whom it remains undiagnosed.11 Understanding effective prevention, identification and management of COPD are therefore core skills required across the spectrum of primary and secondary care, in general and specialist areas. A
deteriorations in respiratory symptoms, principally increased breathlessness and/or a change in the character of expectorated sputum. Most are caused by episodes of tracheo-bronchial infection, with bacteria or respiratory viruses. Although exacerbations generally become more frequent and more severe as the severity of the underlying COPD progresses (Figure 4),9 they also occur in less severe disease. Exacerbation severity is a difficult concept, representing both the severity of the underlying disease and the exacerbation trigger. Susceptibility to exacerbations varies between patients: some appear more susceptible, and some more resistant than others. The best predictor of how many exacerbations a patient will experience this year is how many they experienced last year.9 Exacerbations, and hospitalizations are associated with much of the healthcare costs attributable to COPD. Exacerbation of COPD is one of the commonest reasons for emergency hospital admission in the UK. Patients susceptible to frequent exacerbations have a poor quality of life, accelerated decline of lung function and greater mortality. For all these reasons, prevention of exacerbations should be a key goal of COPD management strategies. The GOLD definition of COPD also makes reference to extrapulmonary effects of COPD. Because COPD is associated with cigarette smoke and increasing age, co-morbidities are very common. When co-morbidities are more common in COPD than smoking- and age-matched controls, such manifestations may be thought of as extra-pulmonary effects of COPD. A common
MEDICINE 40:5
REFERENCES 1 Global initiative for chronic Obstructive Lung Disease. Global strategy for diagnosis, management, and prevention of COPD. Available at: http://www.goldcopd.org/guidelines-global-strategy-for-diagnosismanagement.html (last accessed 22 August 2011). 2 National Institute for Health and Clinical Excellence. Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care. Available at http:// guidance.nice.org.uk/CG101/Guidance/pdf/English (last accessed 22 August 2011).
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Ó 2012 Elsevier Ltd. All rights reserved.
CHRONIC OBSTRUCTIVE LUNG DISEASE
3 Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 2004 Mar 4; 350: 1005e12. 4 Fishman A, Martinez F, Naunheim K, et al. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003 May 22; 348: 2059e73. Epub 2003 May 20. 5 Pillai SG, Ge D, Zhu G, et al. A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genet 2009 Mar; 5: e1000421. Epub 2009 Mar 20. 6 Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004 Jun 24; 350: 2645e53. 7 Erb-Downward JR, Thompson DL, Han MK, et al. Analysis of the lung microbiome in the “healthy” smoker and in COPD. PLoS One 2011 Feb 22; 6: e16384.
MEDICINE 40:5
8 Fletcher C, Peto R. The natural history of chronic airflow obstruction. Br Med J 1977 Jun 25; 1: 1645e8. 9 Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 2010 Sep 16; 363: 1128e38. 10 McGarvey LP, John M, Anderson JA, Zvarich M, Wise RA. Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee. Thorax 2007 May; 62: 411e5. Epub 2007 Feb 20. 11 Department of Health (UK). An outcomes strategy for chronic obstructive pulmonary disease (COPD) and Asthma in England. Available at http://www.dh.gov.uk/en/ Publicationsandstatistics/Publications/ PublicationsPolicyAndGuidance/DH_127974 (last accessed 24 August 2011).
261
Ó 2012 Elsevier Ltd. All rights reserved.
Chronic obstructive pulmonary disease: aetiology, pathology, physiology and outcome
What’s new? C
C
Rohit Chitkara C
John R Hurst
Abstract
limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases’. The most important part of the definition relates to airflow obstruction. Airflow obstruction (low ratio of forced expiratory volume in 1 second (FEV1): forced vital capacity (FVC)) can be detected using spirometry, which is the only way to confirm a diagnosis of COPD. The severity of airflow obstruction (FEV1) is used to grade the severity of COPD. The severity classification used in the National Institute for Health and Clinical Excellence clinical guideline2 is now aligned with that of the GOLD document, and is summarized below in Table 1. Whilst other severity assessments such as the multi-dimensional ‘BODE’ index, relating body mass index, airflow obstruction, dyspnoea and exercise capacity,3 may be a better predictor of outcomes such as mortality, the inclusion of an exercise tolerance assessment in BODE means that this tool is difficult to integrate into routine clinical practice. As stated in the GOLD definition, the airflow obstruction in COPD is largely irreversible (in contrast to asthma). However, it is now recognized that patients may change from being ‘reversible’ to ‘irreversible’ on sequential tests when arbitrary classifications are used, and the presence of reversibility does not predict the clinical response to either inhaled corticosteroids or bronchodilators. For these reasons, diagnostic criteria are now based on post-bronchodilator spirometry, and routine reversibility testing is not recommended.2 When reversibility testing is performed, and the changes are large (e.g. a change in
Chronic obstructive pulmonary disease (COPD) is a physiological diagnosis made on the basis of airflow obstruction. It develops when a genetically susceptible individual encounters a sufficient environmental trigger. Genetic susceptibility is complex and determined by multiple alleles, aside from the model of emphysema caused by a-1 anti-trypsin deficiency. Cigarette smoke is the usual trigger in the developed world but globally the burning of biomass fuel in under-ventilated space is important. In those subjects genetically susceptible to the effects of smoke, there is an airway inflammatory response that is qualitatively and quantitatively different from non-susceptible subjects, predominantly composed of neutrophils, macrophages and CD8þ lymphocytes. Once established, the inflammation can persist even after exposure to smoke has ceased. Airflow obstruction in COPD results from a combination of the airway wall inflammatory response, luminal mucus, and loss of alveolareairway attachments from co-existent emphysema. Although progressive airflow obstruction is the hallmark of COPD, it is now recognized that there are other important outcomes in this condition, notably exacerbations and the development of co-morbidities.
Keywords Chronic bronchitis; chronic obstructive pulmonary disease; COPD; emphysema; exacerbation; spirometry
Definitions and diagnosis The World Health Organization Global initiative for chronic Obstructive Lung Disease (GOLD) document1 has defined chronic obstructive pulmonary disease (COPD) as: ‘a preventable and treatable disease with some significant extra-pulmonary effects that may contribute to the severity in individual patients. Its pulmonary component is characterized by airflow limitation that is not fully reversible. The airflow
Diagnosis and severity classification of COPD
1 2 3 4
Rohit Chitkara BSc is a Fourth Year Medical Student at UCL Medical School, London, UK. Conflicts of interest: none declared.
Stage
Post-bronchodilator FEV1/FVC ratio
Post-bronchodilator FEV1 (% predicted)
Mild Moderate Severe Very severe
<0.7 <0.7 <0.7 <0.7
80% 50e79% 30e49% <30% (or <50% with respiratory failurea)
COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity. a Respiratory failure is defined as a partial pressure of oxygen in arterial blood <8.0 kPa (60 mmHg) with or without a partial pressure of carbon dioxide in arterial blood >6.7 kPa (50 mmHg) breathing air.
John R Hurst PhD FRCP is a Senior Lecturer in Respiratory Medicine at UCL Medical School, London, UK. Dr Hurst has a clinical and research interest in the causes and mechanisms of exacerbations in airway diseases including COPD and bronchiectasis. Conflicts of interest: none declared.
MEDICINE 40:5
Genome-wide association studies (GWAS) have investigated genetic determinants of COPD susceptibility other than a-1 antitrypsin deficiency Susceptibility to exacerbations varies between individual patients and can be predicted by asking about previous exacerbations It is important to assess and treat co-morbidities in patients with COPD
Table 1
257
Ó 2012 Elsevier Ltd. All rights reserved.
CHRONIC OBSTRUCTIVE LUNG DISEASE
FEV1 > 400 ml), a diagnosis of asthma should be suspected. Finally, current guidelines recommend using a fixed FEV1:FVC ratio of less than 0.7. Whilst simple to use, the FEV1:FVC ratio declines with age, risking over-diagnosis of airflow obstruction in the elderly (and under-diagnosis in the young) and there is currently debate about moving to criteria using the FEV1:FVC ratio based on predicted lower limits of normal for the patient’s age, sex, race and height. COPD should not be confused with chronic bronchitis or emphysema and these terms are not synonymous. COPD, as described above, is a physiological diagnosis. Emphysema is an anatomical (pathological or radiological) diagnosis defined as ‘an abnormal and permanent enlargement of airspaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis’. Chronic bronchitis is a clinical diagnosis based on cough productive of sputum for most days of the week, in 3 or more months of 2 or more consecutive years (and the absence of another specific diagnosis such as bronchiectasis). Many patients with COPD have varying degrees of emphysema and/or chronic bronchitis and this produces heterogeneity in the disease and specific ‘phenotypes’ that have historically included emphysematous ‘pink puffers’ and bronchitic, hypercapnoeic ‘blue bloaters’. Our understanding of phenotypes in COPD, and our ability to define them is now much more sophisticated. This is clinically important in predicting treatment response. For example, lung volume reduction surgery (LVRS) would be recommended only for patients with COPD who have upper-lobe predominant emphysema, and a poor response to pulmonary rehabilitation.4 Many cigarette smokers may fulfil the definition of chronic bronchitis without having airflow obstruction (COPD), and this is termed simple chronic bronchitis. Finally, some patients with chronic asthma may develop fixed airflow obstruction that is clinically indistinguishable from COPD.
COPD (1% in the UK). Recent genome-wide association studies in COPD have suggested further candidate susceptibility genes,5 but the effect of individual polymorphisms is small; susceptibility to COPD remains poorly explained and is probably determined by many alleles. Historically, the aetiology of COPD was described by two hypotheses: a ‘British hypothesis’ that airflow obstruction results from multiple episodes of airway infection in patients with chronic bronchitis, and a ‘Dutch hypothesis’ that placed COPD on a spectrum of airway disorders with asthma. Components of both theories remain valid. The fact that COPD requires a sufficient exposure to respiratory insults highlights that COPD is a preventable disease. Longterm efforts to reduce the global and individual burden of COPD require effective tobacco control measures.
Pathology Exposure to cigarette smoke results in an inflammatory response in the airways. In those subjects genetically susceptible to the effects of this smoke, the inflammatory response is qualitatively and quantitatively different from that seen in non-susceptible subjects. This is why the GOLD definition of COPD1 makes reference to an abnormal inflammatory response e it is, of course, normal to have an airway inflammatory response to airborne insults. Importantly, the inflammatory response in COPD can persist after smoking cessation. The major site of the physiological airflow obstruction in COPD is the small airways (defined as those <2 mm in internal diameter). Pathological changes are also seen in the large airways, and lung parenchyma. As the severity of airflow obstruction increases (higher GOLD Stage), there is an increase in the volume of inflammatory cells in the airway wall and accumulation of mucus in the airway lumen.6 The inflammatory infiltrate includes macrophages, neutrophils and CD8þ lymphocytes and, in GOLD Stages 3 and 4, lymphoid follicles (Figure 1). This suggests an adaptive response to a self or microbial antigen and could explain the persistence of inflammation after smoking cessation. The airflow obstruction that defines COPD therefore arises from a combination of an increase in volume of the airway wall, and luminal mucus filling. A further important mechanism is the loss of airway attachments resulting from destruction of alveolar septa. Alveolar destruction (emphysema) results from an imbalance between pro- and anti-inflammatory mechanisms, exemplified by a-1 anti-trypsin deficiency. This autosomal codominant condition is associated with a reduced serum concentration of a-1 anti-trypsin, the major defence against neutrophil elastase, unopposed action of which in the alveoli results in accelerated and extensive emphysema. As COPD becomes more severe, bacterial colonization becomes important. Modern molecular methods have transformed our understanding of the airway microbiome and it is now clear that the old view of the airway as sterile in health is incorrect.7 What used to be considered the development of colonization in COPD is now thought to represent a change in colonizing species. Patients colonized with bacterial species such as Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis are known to have accelerated lung function
Aetiology The GOLD definition of COPD makes reference to an abnormal inflammatory response of the lung to noxious particles or gases.1 The aetiology of COPD therefore requires an inflammatory insult to the lung. In the developed world this insult is usually cigarette smoke exposure. Globally, exposure to biomass fumes in underventilated spaces is important. Biomass is burned in stoves for cooking and heating and therefore in the developing world women may be at particular risk of COPD. It is important to enquire about other domestic, recreational and occupational exposures, too: use of drugs such as marijuana may result in accelerated disease. Historically it has been stated that only about 15% of smokers develop COPD though the figure is likely to be higher. However, this does highlight that exposure alone is not sufficient to cause disease and this only occurs in individuals with a susceptible genetic background. Some people exposed to significant environmental tobacco smoke exposure (passive smoke) may also be at increased risk, which has been a major driver for recent tobacco control legislation. COPD therefore results from the combination of a susceptible individual meeting a sufficient environmental trigger. The best-defined genetic determinant is a-1 anti-trypsin deficiency, but this is an uncommon cause of
MEDICINE 40:5
258
Ó 2012 Elsevier Ltd. All rights reserved.
CHRONIC OBSTRUCTIVE LUNG DISEASE
Figure 2
Figure 1
Outcomes decline, and more frequent exacerbations. Pseudomonas aeruginosa and atypical Mycobacteria may be seen in advanced COPD.
The classic description of the natural history of COPD is derived from the work of Fletcher and Peto,8 with accelerated decline of lung function in those smokers susceptible to the effects of cigarette smoke (Figure 3). It is now acknowledged that this model does not account for insults that may affect the attainment of maximal lung capacity in early adult life, for example the commencement of smoking in adolescence (which is common), or paediatric disease, such as the bronchopulmonary dysplasia observed in survivors of pre-term birth. Those smokers unable to quit continue to experience accelerated lung function decline, associated with progressive symptoms and functional limitation, the development of respiratory failure and death. Lung function decline is not the only relevant outcome in COPD. Exacerbations are important events, characterized by
Physiology The flowevolume loop from a patient with COPD, at baseline and with additional demand such as exercise or exacerbation, is illustrated as Figure 2. The inspiratory curve is normal. However, shortly after reaching peak-expiratory flow, collapse of the small airways results in a reduction in airflow and the characteristic ‘scalloped’ shape of the expiratory limb. Dynamic hyperinflation puts additional load on the respiratory muscles, which may already be weakened due to the skeletal muscle weakness that can accompany COPD. This is one mechanism leading to Type 2 (hypercapnoeic) respiratory failure.
MEDICINE 40:5
259
Ó 2012 Elsevier Ltd. All rights reserved.
CHRONIC OBSTRUCTIVE LUNG DISEASE
Figure 4
Figure 3
mechanism may be the increased systemic inflammation seen in COPD. Such manifestations include an increased risk of cardiovascular disease, lung cancer, cachexia, osteoporosis, skeletal muscle weakness and depression. Addressing co-morbidities in COPD is important because many patients with COPD die from such conditions10 (rather than from airway disease) and (as with depression) there may be profound effects on quality of life. COPD remains a major health challenge in the UK, and more widely. COPD kills 25,000 people annually in England and Wales alone, and across the UK it is estimated that there are 835,000 patients in whom the condition has been diagnosed and perhaps 2,200,000 more in whom it remains undiagnosed.11 Understanding effective prevention, identification and management of COPD are therefore core skills required across the spectrum of primary and secondary care, in general and specialist areas. A
deteriorations in respiratory symptoms, principally increased breathlessness and/or a change in the character of expectorated sputum. Most are caused by episodes of tracheo-bronchial infection, with bacteria or respiratory viruses. Although exacerbations generally become more frequent and more severe as the severity of the underlying COPD progresses (Figure 4),9 they also occur in less severe disease. Exacerbation severity is a difficult concept, representing both the severity of the underlying disease and the exacerbation trigger. Susceptibility to exacerbations varies between patients: some appear more susceptible, and some more resistant than others. The best predictor of how many exacerbations a patient will experience this year is how many they experienced last year.9 Exacerbations, and hospitalizations are associated with much of the healthcare costs attributable to COPD. Exacerbation of COPD is one of the commonest reasons for emergency hospital admission in the UK. Patients susceptible to frequent exacerbations have a poor quality of life, accelerated decline of lung function and greater mortality. For all these reasons, prevention of exacerbations should be a key goal of COPD management strategies. The GOLD definition of COPD also makes reference to extrapulmonary effects of COPD. Because COPD is associated with cigarette smoke and increasing age, co-morbidities are very common. When co-morbidities are more common in COPD than smoking- and age-matched controls, such manifestations may be thought of as extra-pulmonary effects of COPD. A common
MEDICINE 40:5
REFERENCES 1 Global initiative for chronic Obstructive Lung Disease. Global strategy for diagnosis, management, and prevention of COPD. Available at: http://www.goldcopd.org/guidelines-global-strategy-for-diagnosismanagement.html (last accessed 22 August 2011). 2 National Institute for Health and Clinical Excellence. Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care. Available at http:// guidance.nice.org.uk/CG101/Guidance/pdf/English (last accessed 22 August 2011).
260
Ó 2012 Elsevier Ltd. All rights reserved.
CHRONIC OBSTRUCTIVE LUNG DISEASE
3 Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 2004 Mar 4; 350: 1005e12. 4 Fishman A, Martinez F, Naunheim K, et al. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003 May 22; 348: 2059e73. Epub 2003 May 20. 5 Pillai SG, Ge D, Zhu G, et al. A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genet 2009 Mar; 5: e1000421. Epub 2009 Mar 20. 6 Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004 Jun 24; 350: 2645e53. 7 Erb-Downward JR, Thompson DL, Han MK, et al. Analysis of the lung microbiome in the “healthy” smoker and in COPD. PLoS One 2011 Feb 22; 6: e16384.
MEDICINE 40:5
8 Fletcher C, Peto R. The natural history of chronic airflow obstruction. Br Med J 1977 Jun 25; 1: 1645e8. 9 Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 2010 Sep 16; 363: 1128e38. 10 McGarvey LP, John M, Anderson JA, Zvarich M, Wise RA. Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee. Thorax 2007 May; 62: 411e5. Epub 2007 Feb 20. 11 Department of Health (UK). An outcomes strategy for chronic obstructive pulmonary disease (COPD) and Asthma in England. Available at http://www.dh.gov.uk/en/ Publicationsandstatistics/Publications/ PublicationsPolicyAndGuidance/DH_127974 (last accessed 24 August 2011).
261
Ó 2012 Elsevier Ltd. All rights reserved.