This page intentionally left blank 89 Chapter 5 Chronic obstructive pulmonary disease Chapter contents 5.1 COPD genetics and epidemiology 90 5.2 COPD pathophysiology 92 5.3 Investigations in COP D 98 5.4 Pharmacological therapy (including cor pulmonale) 100 5.5 Non-pharmacological mana gement for COPD 106 5.6 Management of an exacerbation of COPD 112 5.7 Surgery for COPD 116 5.8 Alpha-1-antitrypsin de \201 ciency 120 J DODD & B PATEL 90 5.1 COPD genetics and epidemiology Background The air \202 ow obstruction in smoking-related COPD is the result of small airw ays disease (obstructive bronchiolitis) and alveolar destruction (emphysema). These are dis crete pathological processes, each of which may make an inde- pendent contribution to the o verall burden of air \202 ow obstruction in an affected individual. Irreversible air \202 ow obstruction may develop in a number of other respiratory disease including chronic asth ma, bronchiectasis (and cystic \201 brosis), obliterative bronchiolitis and sarcoidosis. These diseases have a different etiology, pathology and natural history and therefore it is essential that they are consid- ered as separate conditions to COPD. in later life amongst childhood smokers is mainly the result of extra pack years smoked. Th e recognition that not all smokers are equally suscepti- ble to the development of COPD and the identi \201 cation of a subgroup of susceptible smokers means that other fac- tors, e nvironmental or genetic, must interact with cigarette smoke to predispose some individuals to developing COPD. AUTHOR \200\231S TIP Smoking is the major risk factor for COPD but variation in susceptibil ity between smokers means other factors are important. Epidemiology Cigarette smoking is the major environmental risk factor for the development o f COPD. The exact prevalence of COPD is unknown as the disease may be asymptomatic in its e arly stages, however: \200 In 1996 COPD accounted for more than 2 million deaths Environmental exposures A number of environmental exposures other than smoking have been as sociated with a reduced FEV1 or air \202 ow obstruction. These include: \200 occupationa l exposures (e.g. underground tunnel worldwide workers); \200 domestic fuels; \200 low birth weight; \200 childhood exposure to pass ive smoking; \200 viral respiratory tract infections; \200 social economic class. Sever al population-based studies have shown an inverse association between dietary antioxidants (found in fruit and vegetables), lung function and/or symptoms. It is pos- tulated that the se antioxidants may provide protection against harmful free radicals in cigarette smoke. Ho wever, there is no evidence to suggest that increasing intake of dietary antioxidants prote cts against smoking-related COPD. Compared to the effect of cigarette smoking, the effect o f other identi \201 ed environmental exposures is rela- tively weak and none of the curren tly identi \201 ed environ- mental exposures adequately explains the variation in suscepti bility to COPD seen amongst smokers. In 2004 more than 26,000 deaths in the UK were attrib- uted to COPD The prevalence of COPD in the UK may be as high as 1 million. In the USA it is estimated that 6.6% of the adult popula- tion have spirometrically de \201 ned COPD. The prevalence of COPD amongst women has risen because of the increased number of women who smoke. With the increased prevalence of cigarette smoking in China and developing countrie s it has been predicted that the global prevalence of COPD will increase so that by 2020 it will account for more than 4.5 million deaths, mak- ing it the third most common cause of death worldwide. COPD and smoking \200 Cigarette smoking is the single greatest risk factor for COPD. The relationship between cumulative smoking and forced expiratory volume in 1 second (FEV1) is relatively weak within a population, with less than 10% of variation in FEV1 explained by differences in pack years smoked (one pack year is equivalent to 20 cigarettes a day for a year). Genetic factors To date the only identi \201 ed genetic risk factor for the devel- opment of COPD is de \201 ciency of 1-antitrypsin ( 1-AT). This is an important inhibitor of t he enzyme neutrophil elastase, and homozygotes for 1-AT de \201 ciency are at an increas ed risk of developing emphysema if they smoke. However, 1-AT de \201 ciency accounts for only 1 \200\2232% of all cases of COPD seen in clinical practice. Studies which have recru ited families through the identi \201 cation of an individual with early onset COPD in the absence of 1-AT de \201 ciency (referred to as a proband), have shown that smoking sib- lings of the proband have a 3 \200\2234-fold greater risk of COPD than unrelated smokers. The non-smoking siblings of these probands have relatively normal lung function, which sug- gest that it is not shared environment that is the cause of this familial clustering. The increased prevalence of COPD among smoking siblings of probands is independent of pack year s smoked and supports the hypothesis that there are other, as yet unidenti \201 ed, genes that predispose to the development of COPD. A large number of studies have aimed to identif y genes that predispose to the develop- ment of COPD: the most common types of studies are candidate gene studies and linkage analysis. In their longitudinal study of middle age smokers, Fletcher and Peto identi \201 ed a sub- group of smokers who showed an accelerated decline in FEV1. These \200\230susceptible smokers \200\231 represented about 15% of the smoking population. This data is often misinterpreted as suggesting that the prevalence of COPD among smokers i s 15%. This is not the case. The prevalence of spirometrically-de \201 ned COPD in older populations of smokers is sign i \201 cantly greater than 15%. The most susceptible individuals may have more advanced disease at an earlier age. People who start to smoke in childhood may not achieve their maximum FEV1 in adulthood and therefore may be sus- ceptible to even a modest increase in rate of decline in FEV1. Curren t evidence suggests that the increased risk of COPD CHAPTER 5.1 COPD genetics and epidemiology 91 and genes, increasing the risk of a type I statistical error if a p value of 0.05 is used. AUTHOR \200\231S TIP 1-AT de \201 ciency is currently the only proven genetic risk facto r for COPD and can be screened for by blood levels. Linkage analysis Linkage analysis is a more complex method of identify- ing areas of the ge nome that segregate with the disease phenotype within a population. This has been made poss i- ble through the identi \201 cation of a large number of single nucleotide polymorphisms (SNPs) throughout the human genome. Linkage analysis studies have the advantage that they may allow the identi \201 cation of previously unidenti \201 ed genes that may be associa ted with COPD. For example, Silverman and colleagues identi \201 ed linkage of FEV1/FVC to a region on chromosome 2q. These studies may provide important future insights into the ge netic basis of COPD. Candidate gene studies Candidate gene studies are popular because they are rela- tively sim ple to undertake. In brief, investigators identify a gene that they hypothesize may be impo rtant in the devel- opment of COPD and compare the prevalence of a muta- tion in this candi date gene in individuals with COPD with the prevalence in individuals without COPD. If a mu tation or polymorphism is more prevalent in the COPD popula- tion, it supports the hypothes is that the gene may predis- pose to COPD. These studies rely on the identi \201 cation of possible candidate genes. Most genes that have been studied have coded for proteins that a re antioxidants, antiproteinases or mediators of in \202 ammation, in keeping with current hypotheses on the mechanism of COPD pathogenesis. Effect of phenotype de \201 nition A limitation of current studies is that they usually de \201 ne the COPD phenotype by the presence of irreversible air- \202 ow obstruction. CO PD is itself a heterogeneous disease, in which air \202 ow obstruction is the result of em physema and small airways disease. If each of these components has a separate genetic predi sposition then failure to adequately de \201 ne the phenotype will reduce the power of the study to identify signi \201 cant genes. The advent of high resolution CT scanning has en abled further re \201 nement of the COPD phenotype by allowing quanti \201 cation of emph ysema. This re \201 nement of the COPD phenotype may help in identify- ing susceptibility genes for emphysema and small airways disease. Examples of candidate genes Antioxidants \200 GSTP1, GSTM1. \200 EPHX1. \200 HMOX1. P rotease/antiprotease \200 MMP1, 9 & 12. \200 SERPIN A3. In \202 ammation \200 Tumor necrosis factor alpha (TNF- ). \200 Transforming growth factor beta. \200 Vitamin D bi nding protein. \200 Interleukin 13. Glutathione S transferase (GST) and microsomal epoxid e hydrolase (EPHX) genes code for enzymes that can detoxify the harmful substances in tobac co smoke whilst haem oxy- genase-1 (HMOX) is an enzyme which results in the gen- eration of anti-oxidants. Matrix metaloproteinases (MMP) are zinc dependant enzymes that degrade coll agen, inacti- vate 1-AT and activate TNF . MMP inhibitors are possi- ble future therapeu tic agents in the management of COPD. There are a number of limitations to the candidate ge ne approach, not least of which is the ability to only study genes that have been previousl y identi \201 ed, therefore elimi- nating the possibility of identifying novel genes that may predispose to the development of COPD. Ideally the stud- ies would also use control sub jects who are identical to the cases in every way (including smoking history and originat- ing from the same population) except that they do not have COPD. This is rarely achieved an d therefore it can be dif \201 cult to determine if positive associations are the result o f selection bias. Consequently many of the positive asso- ciations of candidate genes descr ibed above have not been reproducable. Finally, studies often include many alleles Conclusion Cigarette smoking is the major risk factor for developing COPD. There is however increasing evidence that there may be genetic susceptibility to COPD. Further reading British Thoracic Society 2003, The burden of lung disease. A statistics report from the British Thoracic Society. Fletcher C, Peto R. The natural history of chronic air \202 ow obstruc- tion. Br Med J 1977; 1 (6077): 1645 \200\2231648. Lomas DA, Silverman EK. The genetics of chronic obstructive pul- monary disease. Resp Res 2001; 2(1): 20 \200\22326. Lundb ck B, Lindberg A, Lindstr m M, et al. Not 15 but 50% of smoker develop COPD? Report from the Obstructive Lung Disease in Northern Sweden Studies. Respir Med 2003; 97(2):115 \200\223122. McCloskey SC, Patel D, Stephenson TJ, et al. Siblings of patients with severe COPD have a signi \201 cant risk of air \202 ow obstruction. Am J Respir Crit Care Med 20 01; 164(8 Pt 1): 1419 \200\2231424. Murray CJ, Lopez, AD. Alternative projections of mortality and dis- ability by cause 1990 \200\2232020: Global Burden of Disease Study. Lancet 1997; 349(9064):1498 \200\2231504. Patel BD, Coxson HO, Pillai SG, et al. Airway wall thickening and emphysema show independen t familial aggregation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008; 178; 500 \200\223505. Silverman EK, Palmer LJ. Case-control association studies for the genetics of complex respi ratory diseases. Am J Respir Cell Mol Biol 2000; 22(6): 645 \200\223648. Silvermann EK, Palmer L J. Genomewide linkage analysis of quanti- tative spirometric phenot ypes in severe early-onset chronic obstructive pulmonary disease. Am J Hum Genet 2002; 70(5 ): 1229 \200\2231239. D HALPIN 92 5.2 COPD pathophysiology In A-1 antitrypsin de \201 ciency panacinar emphysema is generally maximal at the base. Th e pattern of emphysema has no effect on the clinical symptoms it produces, but the two form s of emphysema have distinct mechanical properties and distinct peripheral airway involveme nt. Lung compliance is greater in panaci- nar than in centrilobular emphysema, leading to a greater contribution to air \202 ow limitation from loss of elastic recoil. Bullae are ar eas of emphysema larger than 1cm in diameter that are locally over distended. Small airway obstruction The air \202 ow obstruction that characterizes COPD is located primarily in th e small peripheral airways. Pathologically, the changes in these airways are subtle but inc lude: \200 loss of alveolar attachments that act like guy ropes to The pathological changes of COPD are complex and cor- relate poorly with the physiological abnormalities. COPD is an in \202 ammatory disease with pulmonary and systemic effects. Ph ysiologically it is characterized by air \202 ow limitation, impaired gas exchange, hyperi n \202 ation and reduced ef \201 - ciency of the respiratory muscles. hold open the airway; increased surface tension as a result of replacement of surfactant by in \202 ammatory exudate; \200 occlusion of the lumen by exudate; \200 o edema and in \202 ammation of the mucosa; \200 bronchoconstriction. Vascular and systemi c effects As well as the changes in the airways and lung parenchyma, there are changes in t he pulmonary vessels, leading to pul- monary hypertension, and systemic effects leading to skel- etal muscle dysfunction, weight loss, osteoporosis and cardiac disease. In hypoxaemic patients with COPD characteristic changes occur in peripheral pulmonary arteries: the inti ma of small arteries develops accumulations of smooth muscle; and muscular arteries develop medial hypertrophy. Cellular pathology In \202 ammation in COPD is distinct from that in asthma and is charact erized by a predominance of CD8+ cells at all airway levels, and in the lung parenchyma. In \202 ammatory changes are seen in the airways of young smokers before structural changes are present, but in general, there is a further enhancement of the in \202 ammatory respon se with increasing severity of COPD. Smoking cessation does not stop the inflammatory respo nse in the airways, particularly in advanced COPD. The molecular mechanisms for this remain unclear but it has been proposed that transcription factor activation and chromatin remode ling, perhaps as a result of increased oxi- dative stress, might be responsible for perpetu ating the in \202 ammatory process. Fig. 5.2.1 Schema of a normal bronchial (A) and the changes seen in the airways in COPD (B) 1. Mucus gland hypertrophy. 2. Smooth muscle hypertrophy. 3. Goblet cell hyperplasia. 4. I n \202 ammatory cell in \201 ltrate. 5. Excessive mucus. 6. Squamous metaplasia. Reproduc ed with permission from Halpin DMG. Rapid Reference to COPD. Copyright 2001 Mosby Intern ational Limited. Pathological changes Within the lungs COPD is associated with (Fig. 5.2.1): \200 an incre ase in the volume and number of submucosal glands; an increase in the number of goblet cells in the mucosa; \200 mucosal in \202 ammation; \200 emphysema (see below); \200 loss of alveolar attachments to small airway; \200 i n \202 ammatory exudate within airway lumens. Emphysema Emphysema is de \201 ned as \200 \230abnormal, permanent enlargement of airspaces distal to the terminal bronchiole accompan ied by destruction of their walls and without obvious \201 brosis \200\231. Emphysema can be classi \201 ed into: \200 panacinar; \200 centriacinar; \200 paraseptal. Centria cinar emphysema is commonest in the upper zones of both upper and lower lobes and has a clo ser relation- ship to cigarette smoking than panacinar disease. Cellular changes seen in COPD \200 Airway epithelial cells can be activated by cigarette smoke to produce in \202 ammatory mediators, including TNF , IL-1 , GMCSF and IL-8. Smoking and COPD are associated with in \201 ltration of the airway wall by CD8+ T-lymphocytes. The number of CD8+ cells correlates with the degree of air \202 ow limitation. Macrophages and neutrophils are found in the airway lumen. Cigarette smoke activates macrophages to release in \202 ammatory mediators, including TNF , IL-8 and other CHAPTER 5.2 COPD pathophysiology 93 chemokines, reactive oxygen species and proteases, including MMP-2, -9 and -12 and cathepsi ns K, L, and S. \200 Macrophages appear to recruit neutrophils by releasing Alpha-1 antitrypsin de \201 ciency In 1963 -1 antitrypsin de \201 ciency was identi \201 ed and found to be associated with the early onset of severe lower zone emphysema. It should always be considered in these cir- cumstances. It accounts for around 2% of cases of COPD. See Chapter 5.8, p.120 for more information. IL-8 and leukotriene B4. Neutrophils release proteolytic enzymes such as neutrophil elastase, cathepsins and matrix metaloproteinases, which may cause the tissue destruction seen in emphysema. Phsyiological abnormalities Pulmonary abnormalities Decreased maximal expiratory \202 ow and impaired gas exchange are fundamental to the pathophysiology of COPD. The effects of st atic airway obstruction are exacer- bated by the loss of lung recoil due to destruction of the lung parenchyma. In clinical practice, air \202 ow obstruction is usually assessed usi ng spirometry (Fig. 5.2.2). The time volume curve shows a reduced FEV1 and often a reduced FVC, but the characteristic feature is a reduced FEV1/FVC ratio (less than 0.7). FEV1, FVC and FEV1/FVC ratios must be related to predicted values based on the individual \200\231s a ge, sex and height. Neutrophils move rapidly out of capillaries, through the airway wall and into the lumen. Th e number of neutrophils correlates with disease severity and reduction in FEV1. \200 Eosi nophils are not present in the airway of patients with COPD but they do appear during exacerbations. Mechanisms of lung damage in COPD It appears that multiple mechanisms are responsible for t he development of the complex pathology found in COPD. The three principal mechanisms that have been identi \201 ed are protease \200\223antiprotease balance, oxidative stress and a poptosis, but it is likely that interactions also occur between these mechanisms. Protease \200\223antiprotease imbalance On the basis of studies of the pathogenesis of emph ysema in patients with -1 antitrypsin deficiency, protease \200\223 antiprotease imbalanc e, leading to the breakdown of con- nective tissue components, particularly elastin, has be en proposed as the key mechanism in the pathogenesis of emphysema. Whilst there is evidence that smoking may par- tially inactivate -1 antitrypsin and cause a partial \200\230func tional \200\231 de \201 ciency, and that the elastase burden could be increased in chronic smokers as a result of increases in the numbers of neutrophils and macrophages which relea se of proteases, it is clear that protease-antiprotease imbalance cannot account for all th e changes seen in COPD. As well as increased degredation as a result of protease action, ab normalities of elastin synthesis and repair may also be involved in the pathogenesis of emp hysema. Volume FVC Normal FEV1 FVC Airflow obstruction FEV1 1 sec Oxidative stress In addition to imbalance in protease/antiprotease activity, there is now c onsiderable evidence that increased oxida- tive stress is present in smokers and may lead t o some of the changes seen in lungs in patients with COPD Increased oxidative stress can ca use direct lung injury through damage to proteins and DNA and it also induces indirect inju ry thorough activation of metabolic processes. Oxidative stress also affects the extracellu lar matrix and inhibits protec- tive mechanisms, such as surfactant and antiproteases. Oxid ative stress also appears to lead to in \202 ammation in the lungs by activating transcrip tion factors such as nuclear factor-kappa B (NF- B) and activator protein-1 (AP-1). In pat ients with COPD the protective effects of intra- and extracellular antioxidant defense syst ems may be over- whelmed by oxidative stress. Cigarette smoke is a complex mixture of many compounds, including high concentrations of free radicals and other oxidants. Components of the lung matrix (e.g. elastin and collagen) are damaged by oxidants in cigarette smoke and cigarette smoke has a detrimental effect on alveolar epithelial cell function that is, in part, oxidant mediated Time Fig. 5.2.2 Spirometry in a normal individual and a person with air \202 ow obstruction due to COPD. KEY ISSUES In older patients the results of spirometry need to be interpreted with caution as there are age-related changes in lung structure which can lead to functional changes sim ilar to those seen in COPD: \200 Loss of elastic tissue leads to dynamic airway collapse. \200 FEV1/FVC ratio falls with age. \200 FEV1/FVC ratio less than 0.7 in: \200 35% of healthy non smokers aged >70 yrs; 50% of healthy non smokers aged >80 yrs. RV increases and alveolar walls disappear leading to what has been called \200\230senile emphysema \200\231. Increased resting lung volumes are another characteristic feature of COPD. The resting volu me of the thorax is deter- mined by the balance between the elastic recoil of the lungs and the chest wall. When the lung parenchyma is destroyed in emphysema the lungs are more comp liant and thus there is less force to balance the recoil of the chest wall and thus the res ting thoracic volume is increased. This is in part responsible for hyperinflation seen in C OPD and the increase in functional residual capacity (FRC) (Fig. 5.2.3). Apoptosis It is now thought that cigarette smoke may also induce emphysema by triggering al veolar cell apoptosis as a result of blockade of the vascular endothelial growth factor (VE GF) receptor. D HALPIN 94 available to allow the end expiratory lung volume (EELV) to fall to the relaxation volume d etermined by elastic recoil. EELV is dependent on both the degree of air \202 ow limitatio n and the time available for exhalation and is thus dynamically determined. Dynamic hyperin \202 ation (DH) refers to acute and variable increase in EELV above its baseline value. D H occurs during exercise in \202 ow-limited patients as inspired tidal volume increases a nd expiratory time decreases so that the lungs are unable to de \202 ate fully prior to th e next inspiration. Development of dynamic hyperin \202 ation can be assessed by measuring the inspiratory capacity (IC) and this correlates better with the degree of exercise limit ation and dyspnoea than the FEV1. Respiratory muscles Hyperin \202 ation and the resultant increase in FRC greatly increase the work of breathing (Fig. 5.2.5). In COPD both the forc e of contraction generated by the inspiratory mus- cles and the mechanical load against whi ch they are required to act are abnormal. \200 The inspiratory load is increased as a res ult of the airway TLC IC TLC e m u o V IRV IC l VT FRC ERV FRC RV COPD Normal Fig. 5.2.3 Static lung volumes in a healthy individual and in a patient with COPD. RV resid ual volume, ERV expiratory reserve volume, VT tidal volume, IRV inspiratory reserve volume, TLC total lung capacity, FRC functional residual capacity, IC inspiratory capacity. Loss of lung recoil also means that the airways collapse ear- lier in expiration (i.e. at l arger lung volumes) increasing the amount of air trapped in the lungs and again increasing the FRC and RV. Patients with COPD are said to be \202 ow limited when unlike normal indi viduals they cannot increase the expira- tory \202 ow they generate during tidal breathin g at any given lung volume (Fig. 5.2.4) Expiratory \202 ow limitation contributes to hype rin \202 ation by preventing the exhalation of suf \201 cient volume in the time obstruction. The force of contraction is reduced as a consequence of: the effect of hyperin \202 ation altering the mechanical advan- tage of the muscles (both intercostal and diaphragmatic), ma lnutrition and, in some cases, respiratory muscle fatigue. \200 Inspiratory muscle dysfun ction is central to the develop- ment of hypercapnia. Gas exchange abnormalities Pulmonary gas exchange abnormalites may arise as a result of: \200 alveolar hypoventilation; \200 impaired alveolar-capillary diffusion; \200 ventil ation-perfusion (VA/Q) mismatching; \200 shunting. Although emphysema impairs alveolar \200\223capillary diffusion, impaired ventilation \200\223perfusion matching appears to be the major mechanism leading to impaired gas exchange in COPD. Normal w o F TLC RV l Circulatory abnormalities Pulmonary artery hypertension is an important complica- tion of C OPD and it is associated with a poor prognosis. The normal pulmonary circulation is a low-p ressure low- resistance system with low vasomotor tone. The consider- able increases seen i n cardiac output with exercise do not lead to signi \201 cant increases in pulmonary arter y pressure because they are associated with recruitment of under- perfused vessels, particu larly at the lung apex. In hypoxaemic patients with COPD the structural changes in peripher al pulmonary arteries arteries appear to be more important in the development of sustained pulmonary hypertension than hypoxic vasoconstriction. Pulmonary thrombosis may also develop , possibly second- ary to small airway in \202 ammation. Pred Rest Ex Max COPD w o F RV TLC l Ventilatory abnormalities Patients with COPD may develop dif \201 culty in excreting CO2. This appears to be due to a combination of inspira- tory muscle fatigue, ventilation perfusion mismatch and possibly alveolar hypoventilation. \200 Some patients respond to the dif \201 culty in excreting CO2 by increasing the frequency and depth of their breathing to maintain a normal arterial partial pressure of CO2 (PaCO2). Volume Fig. 5.2.4 Flow volume loops in a healthy individual and a patient with COPD showing how at rest and during exercise (Ex) expiratory \202 ow is signi \201 cantly reduced in people with COPD compared to the predicted value (Pred) and is limited by the maximum \202 ow p ossible (Max). CHAPTER 5.2 COPD pathophysiology 95 Other patients are unable to maintain adequate alveolar ventilation and there is an adaptiv e response in the control of breathing, with a reduced ventilatory response to the PaCO2. T his leads to a rise in the PaCO2 and the arterial partial pressure of oxygen (PaO2) becomes an important factor controlling breathing. hypoxia; \200 acidosis. These effects may precipitate ventilatory failure. The consequenc es of worsening airflow limitation and DH during exacerbations are summarized in Fig. 5.2.6 . Hypoxaemia during exacerbations results from: \200 worsening ventilation perfusion matc hing; \200 reduction in mixed venous oxygen tension resulting Some, but not all, of these patients hypoventilate if given too much oxygen and it is these patients who are at risk of CO2 narcosis and respiratory arrest There is a very poor relationship be tween ventilatory capac- ity (i.e. FEV1) and the development of ventilatory failure. from increased oxygen consumption. The deterioration in ventilatory mechanics and gas exchange that occur during an exacerbati on take approxi- mately 10 days to recover. Exacerbations Exacerbations are associated with increased airway in \202 am- mation which worsens air \202 ow obstruction, and reduced V/Q matching and systemic in \202 ammation w hich increases oxygen consumption and circulatory abnormalities. \200 Worsening air \202 ow limitation leads to increased static hyperin \202 ation and the effects of this are in creased by rapid breathing which leads to dynamic hyperin \202 ation. \200 These effects increase the work of breathing by forcing the respiratory muscles to operate on the \202 atter part of the pressure volume curve (Fig. 5.2.5). Systemic effects COPD is associated with important extra-pulmonary, or systemic effects. Th ere is systemic as well as pulmonary in \202 ammation in COPD and this together with syste mic oxidative stress contributes to their development. \200 Circulating levels of pro-in \202 ammatory cytokines (includ- ing tumor necrosis factor (TNF ) and interleukin 8 (I L-8)) and acute phase proteins, particularly C reactive protein (CRP) are elevated in patie nts with COPD. CRP levels are inversely related to disease severity as The additional work of breathing leads to recruitment of assessed by the FEV1. the accessory muscles. There is increased systemic oxidative stress. \200 There are increased numbers of circula ting in \202 amma- During exacerbations the ef \201 cacy of respiratory muscles is affected by: \200 additi onal elastic loading; \200 reduced resting length in the diaphragmatic muscles as a tory cells which show evidence of activation. Exacerbations appear to increase the level of systemic result of worsening hyperin \202 ation; in \202 ammation. The origin of systemic in \202 ammation is not clear and a num- ber of mechanisms may be r esponsible. It may be due to: \200 systemic effects of tobacco smoke; \200 spillover of pulmonary inflammation, with release of cytokines produced in the lungs into the systemic circulation; Volume Normal TLC inflammation induced in systemic tissues by conse- quences of COPD such as hypoxia; an autoimmune process. Whatever the origin, it appears that systemic in \202 ammation is i mportant in the development, at least in part, of some, if not all of the systemic effects of COPD. Skeletal muscle dysfunction contributes to exercise limitation. There is a loss of muscle mass and a reduction in the proportion of type 1 \201 bres. Sedentarism, hypoxia, corticosteroid therapy, nutritional depletion and systemic in \202 ammation contribute to its development. Weight loss is another important effect. It is associated with a worse pr ognosis which changes with therapy and may be due to reductions in calorie intake, changes in intermediate metabolism and effects of systemic in \202 ammation. Cardiovascular diseas e is a frequent cause of death in COPD and coronary artery disease, left ventricular failur e and arrhythmias are systemic effects of COPD as well as co-morbidities sharing a common e tiology. Exacerbations of COPD may increase the risk of coronary events by increasing the l evel of systemic in \202 ammation. Osteoporosis is more common in COPD (even after adjusti ng for corticosteroid usage) and may be due to a combination of inactivity and the effects of systemic in \202 ammation. \210\206V \210\206EELV \210\206P RV Pressure Volume TLC COPD \210\206V \210\206EELV \210\206P RV Pressure Fig. 5.2.5 Pressure-volume curves at rest (dotted) and on exercise (solid) in a normal indi vidual and a person with COPD showing the higher residual volume (RV) and total lung capaci ty (TLC), differential change in end-expiratory lung volume (EELV) and the reduced changes in volume(ZV) for a given transpleural pressure change (ZP). D HALPIN 96 COPD exacerbation Increased ventilatory drive - d PaO2 - i PaCO2 - d pH Tachypnoea (e.g. anxiety) Worsening expiratory flow limitation Dynamic hyperinflation (i EELV, d IC) Gas exchange Mechanical disadvantage Cardiovascular effects - i Pulmonary Neuromechanical uncoupling - Dyspnoea i VD/VD due to i PEEPi - d CDYN - i Elastic/threshold loading of inspiratory muscles constraint of VT arterial pressure d RV preload - i LV afterload Inspiratory muscle dysfunction Fig. 5.2.6 The pathophysiological consequences of worsening air \202 ow limitation and dyn amic hyperin \202 ation. Reproduced with permission from Thorax 2006; 61: 354 \200\223361. COPD is also associated with systemic endothelial dysfunction and central nervous system ab normalities (including depression) which may also be due to the effects of systemic in \202 ammation. MacNee W. Pathophysiology of cor pulmonale in chronic obstruc- tive pulmonary disease. Part One. Am J Respir Crit Care Med 1994; 150(3): 833 \200\223852. Magee F, Wright JL, Wiggs BR, et al. Pulmonary vascular structure and function in chronic o bstructive pulmonary disease. Thorax 1988; 43(3): 183 \200\223189. Further reading Agusti A. Thomas A. Neff lecture. Chronic obstructive pulmonary disease: a systemic disease. Proc Am Thorac Soc 2006; 3(6): 478 \200\223481. Niewoehner DE, Kleinerman J, Rice DB. Pathologic changes in the peripheral airways of young cigarette smokers. N Engl J Med 1974; 291(15): 755 \200\223758. O \200\231Donnell DE, Parker CM. COPD exacerbations. 3: Pathophysiology. Barbera JA, Roca J, Ferrer A, et al. Mechanisms of worsening gas exchange during acute exac erbations of chronic obstructive pulmonary disease. Eur Respir J 1997; 10(6): 1285 \200\223 1291. Thorax 2006; 61(4): 354 \200\223361. Saetta M, Di Stefano A, Maestrelli P, et al. Airway eosinophilia in chronic bronchitis duri ng exacerbations. Am J Respir Crit Care Med 1994; 150(6 Pt 1): 1646 \200\2231652. Gibson GJ. Pulmonary hyperin \202 ation a clinical overview. Eur Respir J 1996; 9(12):2640 \200\2232649. Saetta M, Turato G, Maestrelli P, et al. Cellular and structural bases of chronic obstructi ve pulmonary disease. Am J Respir Crit Care Med 2001; 163(6): 1304 \200\2231309. Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airway obstruction in chronic obstruc tive lung disease. N Engl J Med 1968; 278(25): 1355 \200\2231360. Shapiro SD. The macrophage in chronic obstructive pulmonary dis- Janssens JP, Pache JC, Nicod LP. Physiological changes in respiratory function associated w ith ageing. Eur Respir J 1999; 13(1): 197 \200\223205. Jeffery PK. Comparison of the struct ural and in \202 ammatory features of COPD and asthma. Giles F. Filley Lecture. Chest 2000 ; 117 (5 Suppl 1): 251S \200\223260S. ease. Am J Respir Crit Care Med 1999; 160(5 Pt 2): S29 \200\223S32. Stockley RA. Neutrophils and protease/antiprotease imbalance. Am J Respir Crit Care Med 1999; 160(5 Pt 2): S49 \200\223S52. MacNee W, Wiggs B, Belzberg AS, et al. The effect of cigarette smoking on neutrophil kineti cs in human lungs. N Engl J Med 1989; 321(14): 924 \200\223928. This page intentionally left blank J CALVERT 98 5.3 Investigations in COPD Investigations in COPD con \201 rm a diagnosis suspected on clinical grounds. Further inve stigations are used to de \201 ne the level of physiological compromise associated with th e condition and to de \201 ne interventions to be considered as part of the management pla n. The following categories of investigation will be considered: \200 lung function testi ng; \200 imaging: plain radiology; \200 cross sectional imaging; \200 oxygen assessme nt; \200 functional assessment & anthropometry; \200 bloods; \200 cardiac investigati ons. The carbon dioxide transfer coef \201 cient is also reduced in COPD and is a marker of the severity of emphysema. Imaging Radiological investigations are not required to make a diag- nosis of COPD however all patients should have a CXR to exclude other pathologies. Typical appearances of COPD on the plain radiograph include hyper-inflated lung fields (>7 posterior ribs visible overlyi ng the lung \201 elds), \202 attening of the diaphragm, horizontal ribs and narrowing o f the mediastinum. Bullae may be visible on some \201 elds. Care must be taken not to mis interpret these as evidence of a pneumothorax (Fig. 5.3.1). Lung function testing Diagnosis of COPD is suggested by a compatible symptom and exposure h istory and is con \201 rmed by the presence of air- \202 ow obstruction on lung function testing. Current UK Guidelines (NICE)(1) suggest performing lung function measurements in p atients over the age of 35 who have smoked and who describe symptoms of regular cough, whee ze, sputum production, or exertional dyspnoea. Spirometry Air \202 ow obstruction is con \201 rmed by the presence of a FEV1 of less tha n 80% predicted (de \201 ned using reference values based on a patients height, sex and ag e) and an FEV1 to FVC ratio of 70% or less. Classi \201 cation of disease severity in guid elines is based on patients FEV1 \200\223 though this may not re \202 ect degree of funct ional impairment. The severity strati- \201 cation developed by GOLD is given in Table 5. 3.1. Table 5.3.1 MRC dyspnoea scale Fig. 5.3.1 CXR showing changes consistent with COPD. Score De \201 nition 1 Not troubled by breathlessness except on strenuous exercise High resolution CT scanning (Fig. 5.3.2) may also be con- sidered. This permits identi \201 cation of large bullae or upper zone predominant emphysematous changes which may be am enable to surgery. 2 Short of breath when hurrying or walking up a slight hill 3 Walks slower than contemporaries on the level because of breathlessness, or has to stop to catch breath when walking at own pace 4 Stops for breath after about 100m or after a few minutes on the level 5 Too breathless to leave the house, or breathless when dressing or undressing Further investigations: Where there is diagnostic uncertainty and asthma is being considere d in the differential diagnosis a peak \202 ow (PEF) diary showing greater than 20% varia bility in PEF may pro- vide additional diagnostic information. Where uncertainty still exis ts reversibility testing may be carried out using spirometry pre- and post-inhaled bron- ch odilator or steroid challenge (30mg prednisolone for 10 days). A positive test is one where FEV1 improves by >15% and the magnitude of the change is at least 150ml. Where the patient \200\231s symptoms are in excess of the meas- ured spirometry detailed lung function measu rements can be made. TLC, RV and FRC are all characteristically increased in COPD and are r elated to the degree of hyperin \202 ation of the lungs. Fig. 5.3.2 Typical appearance of emphysema on HRCT. CHAPTER 5.3 Investigations in COPD 99 A-1 antitrypsin In subjects with proven COPD aged <45 assay of -1 anti- trypsin should be considered. This is an anti-proteinase inhibitor inherited on chromosome 14. 70 variants h ave been identi \201 ed. Normal variants are labeled M. The com- monest abnormal variants are designated S and Z. Subjects inheriting 2 normal versions are designated PiMM. Abnor- m al subjects may be homozygous or heterozygous for the abnormal forms of the enzyme so enzym e activity is quoted when abnormal results are quoted. -1 AT is also present in the liver so LFTs should be checked in abnormal subjects.