Clinical consensus on COPD

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Conference

Clinical consensus on COPD Compared to other public-enemy diseases things could hardly be worse for COPD patients, carers and COPD-focused healthcare professionals. The body count continues to rise—2.75 million deaths documented in 2002, with an untold number unrecognised, and this will certainly get worse as the trend for smoking in S.E. Asia manifests itself in a wave of COPD. Moreover, the gender gap will start to close as women catch up with men as a result of lifestyle and workplace equality. At a recent conference in London,1 over 800 healthcare professionals and clinical experts from across primary and secondary care gathered to discuss and debate the latest advances in managing the causes and clinical outcomes for COPD patients.

COPD: The burden of disease In Europe alone, the estimated yearly cost of COPD is h39 billion, of which h3 billion is directly hospital-related. Mortality is rising especially fast in women (more women died in the USA from COPD than men in the period 1980–2000), yet according to the latest GOLD definition in November 2006, COPD is both preventable and treatable (S. Buist). In 1990, it was the sixth leading cause of death—and this is set to become the third by 2020 if trends continue—yet many countries are completely unaware of the disease! In Japan, a study found that 91% of patients with chronic obstruction were undiagnosed by the Ministry of Health and Welfare. Using strictly standardised measurements, the BOLD and PLATINO initiatives were designed to look at the prevalence of COPD in 23 countries to assess this burden and to try to correlate it with known risk factors. Occupational exposure, even in developed countries like the USA, is a causative risk factor for COPD, and it doesn’t take much to extrapolate this finding to the impact on people in poorer, developing countries. One surprise was the much lower prevalence in Hannover, Germany, versus Salzburg, not that far way, both in terms of distance and culture, in Austria. These studies are crucial to further GOLD staging guidelines

and the Chinese statistics illustrate how important it is to normalise/standardise ‘‘symptomology’’—the BOLD study in China took place just after the SARS epidemic, and ‘‘nobody would admit to having any symptoms’’.

Disease mechanisms COPD is characterised by small-airway inflammation and peribronchiolar fibrosis in the lung, and we are beginning to understand the mechanisms behind each of these phenomena (P. Barnes, London; I. Adcock, London). Critically, there is a COPD-specific pattern of inflammation, different to that of asthma. Cigarette smoke stimulates the alveolar macrophages to release TNFa, which leads to NF-kB production and subsequently IL-8, which activates neutrophils. The latter is well known as an activator of many inflammatory genes, but it also activates the gene for MMP9, an enzyme that destroys elastin, which is never replaced. TGFb is also released in COPD patients, and this causes fibrosis of the small airways, explaining one of the paradoxes of COPD, in that the loss of elastin structure is accompanied by a thickening of small airway epithelia. IL-8 binds to the CXCR2 receptor on neutrophils with high affinity, as does GROa, a chemoattractant found in COPD sputum, and thought to play an important role in the chemotaxis of monocytes to the COPD lung, which then differentiate into macrophages. There is a strong correlation between the number of CD8+ lymphocytes in the lung and disease severity, again indicative of an ongoing inflammatory process. Alveolar cells play a crucial role in orchestrating this inflammatory response and, in COPD, this inflammation is largely resistant to steroids. Why is this, is there an active steroid resistance mechanism in COPD? A model is emerging in which histone deacetylation by HDAC2 (activated by steroids) normally switches off inflammatory genes, but shows reduced activity in COPD patients (in stage 4 COPD, its activity is reduced by 93%). At the same time it has been

1 The conference ‘Clinical Consensus on COPD’ was held March 2nd–3rd 2007 at the Novotel West Conference Centre in London, UK. For further details go to: www.clinical-consensus-copd.com. doi:10.1016/j.rmedu.2007.03.001

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found that histone acetylation within the IL-8 gene is increased. It is thought that the mechanism behind this is that oxidative stress creates peroxynitrite, which attacks a tyrosine residue on HDAC2, effectively labelling it for destruction in the peroxisome. This also neatly explains why theophyllines are effective in reducing some inflammatory aspects of COPD. Long known as an anti-inflammatory at very low doses, it inhibits PI3 kinase d, thereby activating HDACs. Theophylline in fact reverses steroid resistance in COPD cells of smoking mice. An explanation of why steroids have some effectiveness in treating acute exacerbations might be due to the accompanying reduction in oedema.

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Except for the fact that there is no murine equivalent of MMP-1 and the difficulty of surgery, mouse models of COPD are successful (McG. Houghton, Pittsburgh). Driven by etiology (i.e. smoking) the models show that inhibition of MMP-12, the mouse elastase, reduces the presence of cytokines. CD8knockout mice are protected from smoke-induced emphysema, and PDE4 inhibitors have even reversed emphysema in smoking mice. Lumenal content, measurable airway thickening and exercise capacity are all metrics that show heterogeneity in COPD patients and it is very important to distinguish the subphenotypes in order to identify those particularly responsive to intervention (F. Sciurba, Pittsburgh).

Genetic basis of COPD

Diagnosis is critical, but not always easy a1-antitrypsin deficiency, caused by the mutation of 342Glu to Lys, affects one in 1700 north Europeans. The protein polymerises and 85% of it is retained in the liver, causing cirrhosis and excessive inflammation. a1-antitrypsin is a strong and specific inhibitor of elastase, and apart from destroying elastin, the active enzyme also stimulates macrophages to secrete LTB4, a chemoattractant. Augmentation of a1-antitrypsin as a therapy was not shown to work in the large NIH study NHLBI (R. Stockley, Birmingham), but there are several other studies ongoing. The search is on for small molecules that block this polymerisation, but only 1–2% of COPD patients have this condition, begging the question—are there other genetic factors in COPD? There is evidence for COPD clusters within families—a major study looked at COPD markers among siblings, revealing that the familial emphysema clusters were not well correlated to pack-years smoked (D. Lomas, Cambridge). Small-airway thickness measurements clustered similarly. Recent association studies have revealed several candidate genes as biomarkers, including TGF-b, heme oxygenase-1, superoxide dismutase, glutathione S transferase, and (the one to watch, apparently) SERPINE 2. Using CT scans and image analysis, strong genetic linkage has been localised to areas on chromosomes 1p, 2q, 4p and 13q. We still have no idea ‘‘what’’ COPD is in non-smokers and there is an urgent need to characterise mechanisms in COPD patients who have never smoked. It is quite possible that, independent of smoking, some people are born with a ‘‘proinflamatory genotype’’—understanding the genetics of disease susceptibility will aid evidence-based therapies (A. Agusti, Palma de Mallorca).

Inflammatory biomarkers In the search for inflammatory biomarkers in COPD, a largely unmet need, a combination of profiling and single marker approaches is needed (S. Kharitonov, London). Of two notable markers under development, nitric oxide (NO) is simple and reproducible, such that sensitive technologies are able to distinguish between alveolar NO (typical of asthma) and bronchial NO (found in COPD). A reduced forced expiratory volume at 1 s (FEV1) is strongly associated with aortic stiffness, and this can be accurately quantified by measuring the speed of the reflected pulse from the heart beat.

The level of undiagnosed COPD is a factor that obscures an accurate assessment of the overall disease burden and prevents the benefits of early treatment being realised. But just how much of the iceberg is beneath the surface? The Dutch study on Detection, Intervention and Monitoring of Asthma and COPD (DICMA) suggests that up to 7% of the general population have obstructive respiratory symptoms, two-thirds of whom have never presented themselves to their GP (C. van Schayck, Maastricht). Furthermore, of those who had presented themselves to their GP one-in-five had still not been diagnosed with obstructive airway disease. Effective application of spirometry is the best weapon in the GP armoury when patients present in the practice with symptoms of cough. However, from a practical standpoint, COPD-directed case finding is realistic only if smokers are screened in the GP clinic, rather than all patients with cough. The age of smokers is also an important criteria for selection of those in whom to use spirometry. Some of the contributing factors in the failure to properly diagnose can be assigned to poor perception by sufferers of their own early symptoms, as well as resistance of sufferers with obvious symptoms to present themselves—fearing that they will be told to stop smoking. COPD sufferers avoid the clinic (so-called cognitive dissonance). To further compound the issue, once a diagnosis of COPD has been made and treatment initiated, patients continue to under-report the occurrence of acute exacerbations by as much as 50%, thus worsening their own long-term prognosis. A vicious cycle indeed. Screening for COPD-related systemic disease in general practice is also a considerable challenge, since COPD sufferers may be poorer at perceiving or presenting comorbid symptoms than non-smokers, especially where these may be undifferentiated from their respiratory issues (C. van Weel, Nijmegen). Where the comorbidity appears to the patient to be unconnected with smoking, e.g. diabetes, depression or joint pain, the COPD sufferer may end up in the GP clinic and this is where the GP needs to seize the opportunity to make a full diagnosis. As always, spirometry is a great tool to apply in such cases. However, once inside the GP clinic an accurate diagnosis does not always result, even if respiratory distress is obvious. When faced with complex patient history and overlapping

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symptoms, the critical issue can often be whether to diagnose and treat asthma or COPD (R. Buhl, Mainz). Age at onset of disease and smoking history are obviously important, but critical features to use in differentiating the two are the paroxysmal nature of dyspnoea in asthma versus persistent, exercise-limiting dyspnoea in COPD. Bronchial hyper-reactivity is more indicative of asthma, whereas a history of one or more acute exacerbations makes COPD likely, as does green or yellow sputum. If possible, spirometry should be used to confirm a diagnosis by establishing a less-than 15% improvement in FEV1 post bronchodilator. By combining scores against each type of symptom, a general practitioner may increase their confidence of making an accurate diagnosis. Further (although more-expensive) tests for blood gases and allergic responses can clarify difficult cases, but there will be a small set of patients in whom both diseases are present. It is worth making a final word of caution—after all symptoms are taken into account, if you are still unsure then treat the patient for asthma. This is the safest path should the diagnosis be wrong.

Assessing the loss of lung function in COPD As with many diseases, COPD has a natural history that is reproduced in each patient independently of external factors. Unlike other diseases, the key milestones for COPD are poorly mapped out such that treatment options and disease management goals are often unclear. The classic 1977 Fletcher and Peto study on the link between smoking, COPD and mortality colours much of our thinking as to the prevalence of COPD amongst smokers—often being paraphrased to indicate that ‘‘yonly 15% of heavy smokers develop COPD’’. This is simply wrong (J. Soriano, Illes Balears). The Fletcher and Peto study merely stated that, in order to study susceptibility to COPD amongst all smokers, it would be useful to compare the 15% of smokers with the lowest FEV1 (i.e. COPD susceptible) against those with the highest FEV1 (non-susceptible). In reality, above 60 years of age 40% of smokers will have COPD by GOLD criteria, rising to 50% above age 75. Progression through the natural history of COPD is slowed by several factors, including drug treatment, pulmonary rehabilitation, oxygen therapy and lung volume reduction strategies. However, the most important modifier is to quit smoking. Lung hyperinflation is the main determinant of exercise capacity for COPD sufferers and is therefore a very useful clinical indicator of disease progression (N. Koulouris, Athens). There is a vibrant debate as to the transition from peripheral airway disease to overt COPD in smokers, characterised by three sequential stages in which expiratory flow limitations (EFL) during tidal breathing plays a central role. In stage I, the closing volume (CV) eventually exceeds the functional residual capacity; in stage II, EFL first develops as a result of sequential dynamic heterogeneous compression of the peripheral airways during expiration and re-expansion during inspiration, and; stage III, during which dynamic hyperinflation (DH) progressively increases leading to dyspnoea and exercise limitation.

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Therapeutic approaches in COPD Despite the apparent clarity of the GOLD guidelines, national approaches to therapy of COPD vary greatly, especially in the application of pharmacological therapies and home oxygen (B. Celli, Boston). From a physician standpoint the holy grail of COPD disease modification is to halt, or at least slow down, the rate of decline of FEV1. However, from a patient perspective the Holy Grail is simply to be able to breathe easier. The joint ATS/ERS Task Force is about to publish their study ‘‘Outcomes for COPD pharmacological trials: from lung function to biomarkers’’. At present, no surrogate markers for COPD have been identified other than FEV1. Although mortality is the gold standard to evaluate predictors and therapies as a primary endpoint, the study suggests that consideration should be given to other surrogate markers as secondary endpoints in future clinical trials (M. Cazzola, Rome). Where more than spirometry was measured, a metaanalysis of the studies available revealed five possible biomarkers: PaO2, sputum neutrophils, IL-8, and systemic TNFa and C reactive protein. The use of a multidimensional tool like the BODE index is recommended. This combines body mass index, airflow obstruction, dyspnoea and exercise capacity into one measure, thus crucially encompassing the systemic, as well as the pulmonary effects of COPD. However, it’s applicability and reliability in trials has yet to be determined. One aspect of clinical studies on COPD mortality requires much better definition—whether COPD is the cause of death or was simply present at the point of a death due to other factors (e.g. heart disease). The Copenhagen City Heart Study reveals that death certificates are not the easiest source of information on the actual cause of death—given the number and influence of other potentially contributing factors. As part of the TORCH study, an expert panel reviewed all clinical records for trial subjects who died, in order to assign the most accurate cause of death and thus document true COPD-related mortality. Thus it was possible to conclude that 35% of deaths were due to respiratory causes during the TORCH trial (P. Calverley, Liverpool). This seminal, 156-week world-wide study recruited more than 6100 patients with moderate-to-severe COPD in a trial to determine the impact of salmeterol/fluticasone propionate combination and the individual components on the survival of COPD patients. A heated debate continues around the TORCH outcomes for the difference in all-cause mortality of those on the placebo (15.2%) and those on the combination therapy (12.6%)—many arguing that this represents a 17.5% risk reduction that clinicians ignore at their peril. However, TORCH did not statistically prove that the combination of inhaled corticosteroids and long-acting beta agonists had an effect on mortality when used to treat COPD. What is not in doubt is that, as compared with placebo, the combination therapy significantly reduced the annual rate of exacerbations and improved both health status and spirometry. Importantly, a critical issue for future clinical trials is whether it is ethical to recruit a genuine placebo group from amongst severely ill patients and thus deny them potentially

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life-enhancing or life-prolonging treatment. If not, the test treatment would have to be compared against the baseline metrics of the best currently available therapy. Ethical, but likely to create more hurdles where many already exist. Triple-combinations outscore other therapies, although a trial showed a negative outcome in terms of the frequency of exacerbations. Future approaches are sure to involve safe, long-acting anticholinergics in combinations with long-acting beta agonists. The race is also on to develop safe and efficacious therapies using PDE4 inhibitors like roflumilast and cilomilast (B. O’Connor, London). However, it is unlikely that blocking any single mediator will ultimately work (e.g. the failure of anti-TNF therapy) for COPD, in contrast with rheumatoid arthritis, for example (P. Barnes, London). Although there has been much interest and hope in the potential therapy of rebuilding lung epithelia with bone marrow-derived stem cells, this approach has suffered major problems from the start—mesenchymal stem cells perfused into the lung do establish in alveoli, but unfortunately generate osteosarcomas rather than lung tissue (S. Janes, London). In theory, transdifferentiated stem cells still probably offer the greatest hope for those with end-stage respiratory disease, but this is for the future. The NETT study showed that lung volume-reduction surgery (LVRS) works in carefully selected patients with severe disease, but it is expensive (estimated at $98,000 per quality-adjusted life year) and associated with high mortality (P. Shah, London). In the hyperinflated lung, there is another option that achieves the same volume reduction, but without the trauma and expense of LVRS: valve delivery via endoscopy. A variety of valves and umbrellas, which allow secretions and air to be cleared, but prevent the entry of air into the lung segment, are being developed. The VENT trial conducted recently for this technique is now closed and the data are anticipated. Other options are to create new pulmonary channels communicating out of the chest (spiracles), the introduction of fibrosis-inducing ‘‘glues’’ into lung segments (sclerosants) and the creation of new airways (bypasses) to allow more effective emptying of the lung segment. Non-invasive ventilation (NIV) is very effective in reducing mortality during acute exacerbations in COPD, particularly in those with acidosis and hypercapnia (M. Elliott, Leeds). Although there are no robust RCT data to support the chronic use of NIV in stable COPD patients, it should be considered in a minority of cases.

The cause and impact of acute exacerbation Acute exacerbations are associated with both upper and lower airway inflammation, along with systemic inflammation. The mechanical aspects of inflammatory obstruction help create and sustain a vicious cycle that quickly involves neuropsychological stresses resulting in a downward spiral for the patient. A clear definition as to what constitutes an acute exacerbation and its severity is not easy to come by, yet this is essential to optimise primary and emergency management, and to guide physicians towards the appropriate pharmacological and non-pharmacological therapies

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(R. Rodriguez-Roisin, Barcelona). The frequency, duration and symptomology of acute exacerbation have all factored into efforts to standardise on approach but, at this point, each physician must still fall back on their own experience when assessing options for each patient. Whether it is the presence of serum markers of infection or the winter-intensive frequency of hospital admissions, the signs are there for respiratory tract infections (RTI) to be a major contributing factor in exacerbations. Of course, the presence of existing COPD may simply predispose patients to RTI and other seasonal respiratory stresses but mounting evidence is pointing to a direct role for persistent or recurring RTI as a major cause of acute exacerbations of COPD (S. Sethi, Buffalo). This makes understanding the host-pathogen interaction a critical factor in the pathogenesis and recovery from acute exacerbation. It is known that RTI with a few strains of bacteria is common in patients with symptoms of exacerbation—these are Streptococcus pneumoniae, Moraxella cattarhalis and Haemophilus influenzae. An important hypothesis being tested is that acquisition of new strains or new strain subtypes is a driver of acute exacerbation. Certainly it is possible to show that a proportion of exacerbations follow a cycle that involves immune-mediated or antibiotic-mediated clearance of colonisation, followed by acquisition with a new strain or subtype. Viral infection is also identified as a cause of acute exacerbation, with indications that the interplay between viral and bacterial infection intensify the acute inflammation. In understanding the impact of acute exacerbations, it is acknowledged that COPD patients can be broadly divided into infrequent and frequent ‘‘exacerbators’’ (W. Wedzicha, London). Not surprisingly, frequent exacerbators have poorer outcomes for most clinical outcomes, including FEV1, dyspnoea, quality of life, incidence of comorbidities and ultimately mortality. Frequent exacerbators also suffer more common colds, in line with the RTI hypothesis, but this equally begs the chicken-andegg question as to what is cause and what is effect. Measurement of inflammatory biomarkers suggests a propensity for a more-rapid and persistent change in certain pro-inflammatory proteins, such as C-reactive protein (CRP), in frequent exacerbators but the utility of this as a real predictive indicator is not yet proven. A single acute exacerbation can result in as much lean muscle damage in the chest as three years of ageing, and may be argued to be no less serious than a myocardial infarction (L. Fabbri, Modena). Prevention and treatment is critical, but the cause of acute exacerbation is not always clear and is complicated by the need to diagnose and treat comorbid diseases such as congestive heart failure, pulmonary embolism or diabetes. Furthermore, there is no agreed classification of exacerbations, although the clinical relevance of the episode and its outcome may be ranked as—level I: treated at home, Level II: requires hospitalisation, Level III: leads to respiratory failure. Hospital at home (HaH) is possible for level 1 cases (see below), whereas therapy with oral corticosteroids, (procalcitonin-guided) use of antibiotics, increased bronchodilator therapy and non-invasive positive-pressure ventilatory support are effective approaches to treatment in more-severe cases.

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Patient-centred approaches Acute exacerbation is to COPD what myocardial infarction is to cardiovascular disease, and patients express real fear of suffocating breathlessness and the next, possibly fatal, exacerbation (M. Partridge, London). Patients do not however refer to ‘‘exacerbation’’ since 60% do not know or understand the term, rather referring to ‘‘infections’’, ‘‘attacks’’, ‘‘crisis’’ or ‘‘breathlessness’’. On the other hand, although the symptoms of exacerbation vary greatly from patient-to-patient, 85% of patients experience the same symptoms each time they have an exacerbation and two-thirds of patients are aware of when an exacerbation is imminent. Patient awareness is a critical factor in developing selfmanagement protocols for mitigating the impact and cost of exacerbations, since the earlier the intervention starts, the better the outcomes. Early intervention in exacerbation, either in hospital or at home, not only decreases the risk of hospitalisation, but leads to faster recovery and better healthrelated quality of life. For each day of delay in initiation of treatment patients will spend 0.42 additional days in hospital. Clinical studies have shown that patients with active involvement in managing their disease, including early selftreatment of signs of exacerbation with prednisone and antibiotics, have up to 40% fewer hospital admissions and medical emergency attendance (J. Bourbeau, Montreal). These protocols tend to include a component of pulmonary rehabilitation and active patient support, also proven to reduce hospitalisation, thus it is still contentious that patient self-management of exacerbations is effective in isolation. Since involving the patient in an integrated approach is preferable, the implementation of ‘‘action plans’’ is becoming more common. However, this brings its own challenges since the critical improvements in patient health and quality of life can be achieved only with training and changes in patient behaviour. This is not simple to achieve, up to 15% of patients may be functionally illiterate (M. Partridge, London) and respond better to guidelines in cartoon format. Once patient involvement is confirmed, the reductions in short and longterm hospitalisation do seem evident. It must be pointed out that not everyone is convinced, and a more-focused clinical study is needed to confirm the benefits of action plans and self-management.

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of COPD patients with worsening symptoms can reduce admissions by 30%, although this is most effective in larger urban units with sufficient staff to provide the screen. In smaller community-oriented hospitals, admission may be the best option initially but followed up with early supported discharge following assessment. Up to 38% of patients can be sent home early under these schemes. What does HaH really mean? In reality HaH is a ‘‘package’’ of medical tools (bronchodilators, oral steroids, antibiotics, oxygen, etc.) delivered in parallel with nursing and/or physiotherapy care along with social support (L. Davies, Liverpool). A well-trained, enthusiastic multidisciplinary team, led by a consultant respiratory physician is vital, as is effective patient screening and the right expectations on the part both of patient and team members. With experience, HaH can take a patient from presentation to the point of discharge in as few as 3.8 home visits by the team. Getting these components right can have dramatic benefits to patient quality of life and mortality, and as a bonus saves the health service money—the per-patient cost of HaH in available studies can be reduced by up to 62% of the typical cost of treating them in hospital. Obviously, even if they fit the basic clinical criteria for HaH, not all patients want to be cared for at home and some are simply unsuitable. Overall though, the clear message is that keeping patients out of hospital and supporting them at home is an important part of the modern approach to COPD management. Critically, managing patients at home requires much better communication with patients and their carers. This is especially true towards the end of life (J. Scullion, Leicester). The diagnosis of COPD is not always communicated clearly or consistently to patients, resulting in confusion about the nature and cause of their symptoms. More than one-in-three do not understand that their disease will get progressively worse, and over 50% felt they had received no advice or help on the emotional and psychological aspects of COPD. The stage at which death is likely has been mapped out through a series of clinical indicators, yet patients and carers are often not advised when they reach this. Consequently, a range of important end-of-life options and choices in regard of patient and carer support may be tacitly denied. It is unthinkable that this would happen in other terminal diseases, such as cancer, and strenuous efforts are now being made to develop a protocol that puts patients and carers at the centre of the palliative approach.

Keeping COPD patients out of hospital Of the stated components of the ERS-ATS guidelines for hospital admission for COPD patients, the clinical indicators that are likely to have most value are worsening hypoxemia and hypercapnea, accompanied by respiratory acidosis. But where these do not necessarily make medical admission unavoidable, there is a good case for treating patients at home as much as possible (R. Stevenson, Edinburgh). It frees up valuable hospital resource and is better for the patient’s sense of well-being. So-called ‘‘admission avoidance’’ and ‘‘early supported discharge’’ do work if there is both an effective screening mechanism and reliable ‘‘Hospital at Home’’ (HaH) support. Screening by pulmonary medical teams in emergency rooms

Oxygen therapy in COPD—not as straightforward as you might think The NOTT and MRC clinical trials in the 1980s confirmed that mortality could be significantly improved for COPD patients with resting hypoxemia if they received long-term oxygen therapy (LTOT). Since then, oxygen at home has been augmented with ambulatory oxygen therapy (AOT) and short-burst oxygen therapy (SBOT), and there is good evidence that each of these can provide many benefits— dyspnoea, work-rate endurance and sleep apnoea all show short-term improvement. However, the reality of oxygen therapy differs greatly from the controlled approach of the landmark studies and the setting and application for oxygen

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therapy is important to manage appropriately. Moreover, it is critical to ensure that you take the patient’s perspective into account when assessing the effectiveness and suitability of treatment—as a healthcare professional you may be convinced that it will do them good, but often as patients they are not. For patients still able to undertake exercise, either as part of their therapy or their regular daily lives, AOT and SBOT can provide benefit during exercise and on recovery, and also to help them cope with breathlessness at rest (W. Wedzicha, London). However, patient compliance is variable and there is evidence that, despite the availability in the home of AOT or SBOT, many patients rely very heavily on the standard LTOT set-up, thus negating the additional exercise-related benefits that AOT or SBOT can provide in terms of improved mobility and social activity (R. Casaburi, Los Angeles). Taking a patient-centred perspective uncovers a critical set of issues not documented by disease-centred studies. Once domiciliary LTOT is put in place patients and their carers often struggle with feelings of loss of self-worth and social identity, as well as finding it hard to cope with what LTOT really means for them—many are unclear that the role of LTOT is not short-term as part of a ‘‘cure’’, and that ultimately they are now on a therapy that will accompany them to their death (K. Clancy, Rochdale). Despite the disease-centred scientific metrics, LTOT patients and carers often perceive no benefit, rather talking of ‘‘just existing’’ with no quality to their lives. The more negative of these perceptions may be skewed towards patients who have not been hospitalised prior to being put on LTOT. Those who have had frequent admissions do seem to appreciate more the benefit that LTOT provides. Overall, two clear imperatives emerge from this: (1) a new LTOT study is needed to further define and clarify the genuine benefits of oxygen therapy, with a sufficiently large study group (3500 patients) and able to collect data over at least a 4 year period, and; (2) a better protocol for connecting patients and carers with their oxygen therapy, to help them manage feelings of isolation and loss. Combining LTOT with cognitive therapy and better palliative approaches may prove valuable here.

Pulmonary rehabilitation—by no means a walk in the park Exercise limitation is a major cause of disability in COPD and is closely linked to disease progression. If you ask a COPD patient what they want from pulmonary rehabilitation they are most likely to answer—‘‘to be able to walk further’’. If this is the criteria by which you measure success then there is no doubt that pulmonary rehabilitation works. The critical factor may be to put in place a pulmonary rehabilitation team who are able to motivate patients to participate in a well-designed programme (S. Singh, Leicester). Team performance in this regard is variable, and there is plenty of scope for further development of team skills and best-practice. Given the patients own stated goal, improvements in the 6min walking test (6MWT) or the shuttle walking test (SWT) are highly desirable outcomes, and this should be reflected in the balance between training based on endurance versus

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strength or high intensity. Strength training has health-status benefits for patients, but only endurance training improves VO2 and endurance time. Patient selection is a critical factor in successful pulmonary rehabilitation in COPD, since not everyone can or wants to undertake the training involved. If your resources are limited, you need to focus on those who are most likely to respond. Age, disability or smoking status are not good selective criteria, whereas patients who are obese or who have low motivation (and may be clinically depressed) are unlikely to benefit until these underlying factors have been addressed.

COPD is a system-wide disease It is becoming accepted that the lung inflammation in COPD is associated with a concomitant systemic inflammation (A. Agusti, Palma de Mallorca), the degree of which is a strong predictor of health status, functional status, hospitalisations and death in COPD (C. Donner, Borgomanero). An important chicken-and-egg question to answer is whether the systemic inflammation seen in COPD is result of pulmonary inflammation or vice versa. Pulmonary hypertension (PH) in COPD has been linked to ‘‘GG’’ variants in the IL-6 gene promoter (A. Chaouat, Strasbourg). It is estimated that 60,000 people are at risk in the UK, and 300,000 in the USA. Causative factors include chronic alveolar hypoxia, inflammation and emphysema, all of which produce intimal and medial thickening in the pulmonary arteries, reducing the luminal volume and thereby increasing vascular resistance. In COPD patients, the condition is usually mild to moderate, but can worsen with exercise, sleep and during exacerbations. Right-heart catheterization is the gold standard way of measuring PH but this is obviously invasive and probably only beneficial in severe cases. Other metrics include increased levels of brain natriuretic peptide, and Doppler echocardiography, although the latter can be inaccurate. New pharmacological vasodilators are needed to treat pulmonary arterial hypertension in COPD patients. Acute cardiovascular events are the primary cause of death in patients with COPD—every 10% reduction in FEV1 is associated with a 28% increase in cardiovascular mortality (W. MacNee, Edinburgh). The mechanism in COPD appears to be related to oxidative stress and systemic inflammation, thus treatment of the latter might improve patient outcomes. In a study of acute exacerbations in COPD, 67% of the patients had chest pains, which could easily be cardiovascular events. Whatever the etiology, the systemic inflammation can be linked to weight loss (cachexia), skeletal muscle dysfunction, cardiovascular disease, osteoporosis, depression, cancer and other problems (E. Wouters, Maastricht). The interplay between symptoms is complex, such that changes in FEV1 are as important as cholesterol in predicting mortality from ischaemic heart disease. Smoking itself can have systemic pro-inflammatory effects, but in COPD patients these persist following smoking cessation. Lung hyperinflation can lead to systemic inflammation, as can tissue hypoxia and abnormal exercise responses in

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COPD. In COPD-associated cachexia you can show an increase in pro-inflammatory mediators and molecules such as TNF-a, iNOS, NF-kB and nitrotyrosinated proteins. However, along with these markers, the smaller muscle fibres and apoptotic nuclei seen in COPD-associated cachexia fit the theory that the systemic inflammation seen in so-called ‘‘pink puffers’’ may be different to that in COPD patients with normal or elevated BMI. What about treating systemic inflammation? The inhaled and oral corticosteroids used to treat the pulmonary symptoms of COPD are effective in reducing serum CRP levels in patients with COPD and suggest their potential use for improving cardiovascular outcomes in COPD. This also stirs a debate as to the interplay between systemic markers of COPD and those of cardiovascular disease, and whether treatments that lower the risk of cardiovascular injury (e.g. statins) may improve outcomes in COPD. The jury seems still to be out on this. There is clearly a link between cachexia and poor health status in COPD. Moreover, there is also a case that chronically poor nutrition on its own can lead to respiratory problems. Consequently, much work has been done to establish the value of nutritional therapy. Reducing involuntary weight loss and improving muscle performance certainly improves mortality (A. Schols, Maastricht), and this approach can be implemented even during acute exacerbation. Equally, therapies that improve lung function also result in improved body mass in underweight subjects. More detailed work shows that, rather than total BMI, it is the change in the fat-free mass (FFM) that has most effect on outcomes in COPD. Thus, it is possible that overall BMI may remain unaffected but that a decrease in FFM is contributing to poor health status in some subjects.

COPD in body and mind? The physical toll that is exacted on patients with COPD is relatively easy to measure, but what about psychological effects? Clinical depression is often listed as a comorbid feature of COPD yet the published literature is equivocal on this issue, with many studies claiming that depression is no more frequent for COPD patients than non-sufferers (P. Jones, London). It is possible to correlate changes in health status to depression, but treating symptoms of depression in the short term (over a 6-week period) does not improve either the symptoms of depression or of COPD. There may be benefits to longer-term treatment (3 months and beyond) but a full-scale clinical trial would be needed to prove this. Cognitive function in COPD patients is also a topic of debate, again generating mixed opinion. Against a battery of

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cognitive tests, only slight changes can be seen in nonhypoxic COPD, with a higher incidence in hypoxic patients. The main concern in cognitive-impaired hypoxic patients would be that they became poorly compliant with their medication regime. However, this seems unavoidable since treating COPD patients for cognitive impairment makes little or no difference.

Quit smoking? I want to, buty Despite the much discussed pharmacotherapies and other support mechanisms for COPD sufferers, nobody doubts that the most effective intervention is one that results in early cessation of smoking. Simple to point out, almost impossible to achieve. Everybody knows that smoking is bad for you—really bad—and approximately 70% of all smokers say they want to quit. How best can this group be supported? The primary care clinic is the obvious place for advice, encouragement and therapy to begin, yet only 25% of primary care professionals in the UK have had specific training in smoking cessation therapy and management (K. Lewis, Swansea). Pharmacological assistance is possible, not just with nicotine-replacement therapy (NRT) but with bupropion (an anti-depressant) and varenicline (a specific anti-smoking drug) each showing a level of effectiveness in supporting those who want to quit smoking, including amongst COPD sufferers. The real success with pharmacotherapy comes if additional cognitive support is provided in the form of advice from a healthcare professional, with managed follow-up. With this regime, up to 20% of quitters can maintain abstinence over a 12-month follow up period. In terms of cost-per-life saved, this approach is stunningly effective—no more than £630. Compared to the £45,000 cost per-life-saved via prescription of ACE-inhibitors in cardiovascular disease, it is shameful that more resources aren’t allocated to such smoking cessation schemes. The goal of large-scale smoking cessation as a means of reducing all-cause mortality remains an uphill struggle. Over the last 10 years, despite the ever increasing cost of cigarettes and the ever-decreasing number of public places where smoking is permitted, there has been only a net 5% reduction in active smoking across Europe (C. van Schayck, Maastricht).

Robert Brines, Matthew Thorne C/o Reed Medical Education, Gateway House, 28 The Quadrant, Richmond, Surrey, TW9 1DN E-mail address: [email protected] (R. Brines)