This study investigated changes in fat free mass and skeletal muscle strength in a cohort of patients with COPD over one year's follow up. Skeletal muscle depletion was common at baseline and was associated with a more severe impairment in gas transfer. During follow up, decline in fat free mass was independently associated with more marked gas trapping, a higher FFM at baseline and use of maintenance oral corticosteroids, whereas FFM increased in patients who stopped smoking. An association between frequent exacerbations and decline in FFM was not retained as an independent correlate.
At baseline, quadriceps weakness was most marked in those with reduced fat free mass and declined further over the course of a year. The only parameter predicting decline in QMVC during follow up was QMVC at baseline. Of note the mean decline in QMVC was 4.3% which is significantly more than the 1–2% per annum anticipated in a healthy aging population [
25‐
27]. This greater decrease is of considerable interest given that an association has been demonstrated between quadriceps strength and mortality in studies of healthy elderly subjects [
28,
29]. In the former study a reduction in quadriceps force of 38 NM (about twice that observed in our study) was associated with a hazard ratio for death of 1.51 in men and 1.65 in women. Recently an association between quadriceps strength and mortality has also been found in patients with COPD which was independent of lung function [
11].
Methodological issues
Follow up data was not available for all of the patients studied at baseline which could be a source of bias. Even in shorter term studies of muscle strength in COPD follow up has been problematic [
15]. A number of arguments can be made to offset the significance of this however. Since the purpose of the study was to examine the natural history of decline in patients with COPD, we excluded those who developed significant co morbidity such as cancer or cardiovascular disease which would themselves have influenced strength or fat free mass. Moreover in a significant proportion of those not followed up the reasons were logistical, to do with coordinating laboratory visits with clinic appointments and therefore 'random' and unlikely to be a source of bias. It is acknowledged that a proportion of patients declined to have further tests but this group did not differ at baseline significantly from those followed up so it is unlikely that this was a significant source of confounding. In particular it should be noted that a similar proportion of those followed up (36%) and those not followed (37%) had fat free mass depletion at baseline. We think it is unlikely therefore that the findings of this study would have been skewed by an uneven pattern of drop out.
We chose to define exacerbations as episodes of worsening of disease sufficient to cause patients to seek medical assistance and receive a prescription for antibiotics. This definition can therefore to some extent be criticized as dependent on behaviour. On the other hand it has the merit of incorporating an element of 'clinical significance'. Other definitions and techniques such as diary cards have been used and this remains an area of controversy, but to date no consensus exists in the literature as to which is the 'gold standard'. It seems unlikely that a different definition would have caused any systematic difference in the results obtained. In addition it was possible in most patients to correlate their reports of exacerbations with the medical notes relating to clinic attendances in the intervening year to increase accuracy. As part of their routine clinical care at clinic visits during the year patients had been asked to recall exacerbations treated at home. Thus at the end of the year a 'contemporary' record of events was available to correlate with patients' recollection.
Bioelectrical impedance analysis has been shown to be highly repeatable on consecutive days in patients with COPD [
30]. In healthy subjects, isometric quadriceps force had a 95% repeatability coefficient of 7.6 kg in a study of healthy controls with a mean strength of 93 kg [
31]. Limited data are available about the repeatability of measures of quadriceps strength in this patient group. QMVC measured on two occasions within 2 weeks of each other in our lab in a group of 15 patients with COPD was 28.8(9.2) at baseline and 29.9(9.8) at 2 week follow up with a Bland Altman coefficient of repeatability (1.96 times the SD of the difference between the measurements) of 6.0 kg [
32]. Given the gap between study visits it is unlikely that there would have been a significant learning effect to bias the results.
Activity levels might also be expected to impact on changes in strength and body composition but these data were not collected in this study.
Significance of findings
To our knowledge this is the first prospective study looking at skeletal muscle impairment in patients with COPD over a significant period of follow up. Other studies have been short term [
33,
34], or where the effect of a therapeutic intervention such as growth hormone or anabolic steroids has been studied, the control group has also undergone pulmonary rehabilitation [
35‐
37].
Exacerbations of COPD are known to be associated with negative nitrogen balance and elevated levels of cytokines [
15] and an association between systemic inflammation and fat free mass depletion has previously been noted in clinically stable COPD [
38]. However frequent exacerbations were not retained as an independent predictor of FFM decline. This may be because mechanistically it is in fact the prevailing 'stable state' that is more important than these acute episodes. Patients with a higher FRC are likely to have a greater work of breathing continually and to be more limited by breathlessness. Alternatively, since exacerbations tend to occur more frequently in more severe disease it may be that our study was not large enough to pick up a discrete exacerbation 'signal' among other co-varying markers of disease severity such as FEV
1, SGRQ and in particular FRC.
Oral corticosteroids have been proposed as a significant cause of skeletal muscle impairment in COPD [
12] although other studies have not found a correlation with strength [
13,
39‐
41] and short courses in stable patients do not appear to have any significant effect on muscle function [
32]. Our study adds to the evidence that maintenance oral steroid treatment may be harmful in COPD with a significantly greater decline in FFM in this group. Maintenance therapy has been shown to attenuate the improvement in muscle bulk occurring with nutritional supplementation during pulmonary rehabilitation [
42] and to increase the risk of death [
43,
44]. In the group as a whole, who mostly received only short burst treatment with corticosteroids, there was no association between steroid exposure and fat free mass or strength, either at baseline or during the follow up period, suggesting that the latter strategy is less harmful. It remains possible that maintenance corticosteroid treatment was a surrogate for a history of frequent exacerbations.
The benefits of smoking cessation on decline in lung function are well established [
45]. Our data suggests an additional benefit with a significant increase in FFM occurring in the quitter group. Although weight gain following smoking cessation is commonly described we are not aware of any data showing an increase in FFM in COPD patients who quit. The mechanism for this benefit apart from increased appetite or exercise could be a reduction in the systemic inflammation that is present even in apparently healthy smokers [
46].
Sniff nasal inspiratory pressure did not decline during the course of this study. The diaphragm in COPD experiences an increase in loading in contrast to the lower limb muscles where disuse is an important feature. Our findings are consistent with the view that systemic factors such as inflammation are relatively unimportant in the aetiology of muscle weakness or else that they have a synergistic effect with disuse which spares the inspiratory muscles but impacts on muscles of locomotion.
It should be noted that by the time patients were enrolled in this study they had already developed significant weakness with mean QMVC only 66 percent predicted. In addition more than a third of them had significant nutritional depletion. Given that baseline FFM was strongly correlated with quadriceps strength at baseline, these two factors are clearly linked even if change over the period of follow up appeared to be dependent on different factors.
A further question will be to investigate the interaction between COPD and other co morbidities that occur frequently in these patients and also impact on skeletal muscle such as heart failure and vascular disease.
Conclusion
This study demonstrates a reduction in quadriceps strength over one year of follow up greater than would be anticipated in a healthy population. We do not know if there is early rapid loss of strength which then slows or if the decline is steady or if it is stepwise, perhaps in the context of exacerbations. The pattern of decline may well differ in different disease phenotypes. Our model explained only 46% of the decline in fat free mass over one year. Because our patients were recruited from hospital rather than primary care the population was inevitably weighted towards patients with more severe disease and it is clear that in order fully to understand the aetiology of muscle weakness and fat free mass depletion, future studies will need to enrol patients at an earlier point in the disease process and for longer periods of follow up. This should make it possible to understand better the role of factors such as systemic inflammation or hormonal depletion.