What is new in COPD

David Bellamy GPwSI in COPD, Bournemouth and Poole PCT

COPD is more common than we suspect

COPD is well known to be underdiagnosed with estimates of between one in two and one in four patients being missed. In part this is due to the slow insidious onset of symptoms such as cough and breathlessness and also to the seeming reluctance of patients to visit a doctor once symptoms have developed. COPD has a prevalence of about 1.5% of the population according to data from the Quality Framework system in Primary Care but the prevalence from a recent study in Manchester (1) showed COPD in a population over 30 years of age to be 4.1 per cent and 14.7 per cent in those in the 60 – 69 age group. A surprising 63.2 per cent of those found to have COPD had no record of COPD in the practice notes including 14 of 31 whose spirometry results classified them as having severe or very severe disease.

A large study of 8045 normal people from Copenhagen (2) followed for 25 years showed an incidence of moderate and severe COPD of 20.7 per cent and 3.6 per cent respectively with no differences in men and women. They calculated that the risk of developing COPD among continuous smokers over this period was at least 25 per cent which is considerably higher than previously estimated.

These and other studies confirm COPD is a lot more common than we are diagnosing it, smokers are at high risk of developing COPD and women have caught up with men in terms of incidence. Women also seem more susceptible to the effects of smoking than men (3).

COPD is a systemic disease
There has been a good deal of published scientific data over the past few years to suggest that COPD has effects and manifestations outside the lung and that it is linked to other systemic diseases. Indeed the latest GOLD Guideline definition of COPD has added “a preventable and treatable disease with significant extrapulmonary effects that may contribute to the symptom characterised by airflow limitation that is not fully reversible”. The exact mechanisms are still to be discovered but it appears that there is evidence that at least in part the causative link may be through various chronic inflammatory substances circulating in the body.

Many of the co-morbidities linked to COPD are also related to smoking. However there is enough evidence to support a causative cross relationship in addition.

COPD is linked with:

• weight loss and cachexia
• skeletal muscle dysfunction
• cardiovascular effects
• osteoporosis
• depression
• lung cancer
• anaemia of chronic disease.
  

A meta-analysis of inflammatory markers associated with COPD was conducted by Gan et al in 2004 (4). Levels of white cells were increased as was CRP (C- reactive protein), fibrinogen and the cytokine TNF-alpha. The origin of these substances is uncertain but it is likely they do arise in the lung as their levels rise with increasing severity of COPD. Causes may include smoking, lung hyperinflation, tissue hypoxia and abnormal exercise responses in COPD which cause greater release of TNF –alpha.

These inflammatory substances may contribute to cachexia and atrophy of muscle fibres (TNF- alpha) which in turn limit exercise, cause fatigue and contribute to further decrease in exercise ability and poorer quality of life. Sedentary behaviour adds to the downward spiral and more muscle loss. The benefits of pulmonary rehabilitation become ever more important.

 The raised CRP is associated with increased risk of cardiovascular events and in many studies the cause of death in COPD patients is from cardiovascular causes.

A recent review by Young et al (5) has confirmed that a reduced FEV1 is not only a measure of COPD severity but a marker of premature death from such diverse diseases as lung cancer and cardiovascular disease.  Falling FEV1 is independently associated with cardiac events - every 10 per cent fall in FEV1 equates to an increase in cardiovascular mortality of 28 per cent - and when the raised CRP and low FEV1 are present together the risks are additive. The combination of reduced FEV1 and smoking are better predictors of future mortality from heart disease than serum cholesterol.

In lung cancer smokers with reduced FEV1 carry as much as a five fold risk of lung cancer compared with smokers with normal lung function. In the large TORCH study (6), 22 per cent of deaths were from cancer and 27 per cent from cardiovascular diseases.

Are there any treatments which help?
Quitting smoking is still the only proven intervention to slow the rate of decline in FEV1 and prolong life. Many inhalers containing long acting bronchodilators of both the beta-agonist and anticholinergic variety, corticosteroids, theophyllines and even mucolytic drugs have all been shown to reduce the frequency of exacerbations of COPD. Since exacerbations are linked with accelerated lung function decline it might be anticipated they would also have a role in prolonging life expectation. The large TORCH study (6) had all cause mortality as its main outcome with over 6000 patients followed for 3 years. The patients on the combined salmeterol /  fluticasone inhaler had a trend towards reduced mortality but this just failed to reach statistical significance at the p = 0.052 level. On the positive side the trial confirmed the major benefits to patients on the combined inhaler of large reductions in exacerbation frequency improved quality of life and improved lung function.

Of new and potential interest are some studies with COPD patients taking statins (5,7). In a non–randomised study of lung function screening in smokers those taking statins had a 85 per cent reduction in annual FEV1 decline and 35 per cent reduction in COPD related hospitalisation compared to placebo. The reduction in myocardial infarction was two fold greater in COPD patients than in other statin related cardiac prevention studies. Statins have also been linked to a reduction in lung cancer. The effect is still far from certain but appears statins may have a role in reducing the known inflammatory effects of smoking on the lung.

Conclusion

Smoking is still the major factor related to developing COPD. Some of these newer concepts surrounding chronic inflammation in the lung and other organs help in our understanding of the progression of the disease and offer hopes for finding more effective therapies.


References

1. Frank TL, Hazell ML, Linehan MF et al.  The estimated prevalence of chronic obstructive pulmonary disease in a general practice population. Prim Care Resp J  2007; 16: 169- 73.
2. Lokke A, Lange P, Scharling H, et al. Developing COPD: a 25 year follow up study of the general population. Thorax 2006; 61: 935-9.
3. Prescott E, Bjerg AM, Andersen PK, et al. Gender differences in smoking effects on lung function and risk of hospitalisation for C OPD: results from a Danish longitudinal population.  Eur Resp J 1997; 10: 822-7.
4. Gan WQ, Man SF, Senthilselvan A, et al. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and meta-analysis. Thorax 2004; 59: 574 -580.
5.  Young RP, Hopkins R, Eaton TE. Forced expired volume in one second: not just a lung function test but a marker of premature death from all causes. Eur Resp J 2007; 30: 616- 622.
6. Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. New Eng J Med 2007; 356: 775- 789.
7. Soyseth V, Brekke PH, Smith P, et al. Statin use is associated with reduced mortality in COPD. Eur Resp J 2007; 29: 279-283.