Systemic inflammation and progression of COPD

Short abstract

The role of C‐reactive protein

C‐reactive protein (CRP) is considered one of the key markers of systemic inflammation in chronic obstructive pulmonary disease (COPD) and currently receives a lot of attention. In their systematic review of systemic inflammation in COPD, Gan et al showed that CRP was associated with the level of forced expiratory volume in 1 s (FEV₁) in the five studies included in the review,¹ and two recent studies using fairly large populations of well‐characterised patients with COPD have shown a strong association between increased CRP levels and prognosis.²,³ Sin and Man have previously shown that raised levels of CRP were associated with cardiac injury in COPD⁴ but, in the two recent studies, the association between CRP and mortality was not merely driven by an associated risk of cardiovascular deaths.²,³

In this issue of Thorax (see p 515) Fogarty et al examine the association between CRP and FEV₁ in more detail.⁵ Using data on 2633 randomly selected adults from Nottingham in 1991 and followed up in 2000, they looked at both cross‐sectional and longitudinal associations between CRP and FEV₁. At both the 1991 and 2000 survey there was a clear inverse association between the level of FEV₁ and CRP, with a difference in FEV₁ between the highest and lowest deciles of CRP of 381 ml and 259 ml in 1991 and 2000, respectively. The association was strongest in underweight subjects, defined as those with a body mass index (BMI) <20 kg/m². Data from 1343 subjects were available for analyses of FEV₁ decline and, in this population, there was no association between CRP at either time point and 9 year change in FEV₁.

There are currently only limited data with which to compare these findings. In a smaller French study of 531 subjects, there was a tendency towards a steeper decline in FEV₁ over the 8.5 year follow‐up in the tertile with highest CRP at baseline (p = 0.14).⁶ In this study by Shaaban et al, subjects with increasing CRP levels during follow‐up had steeper declines in FEV₁ than those with stable or decreasing CRP levels, but it is not possible to imply causality from associations between parallel changes. Other markers of systemic inflammation do not seem to help us much. Dahl et al⁷ looked at fibrinogen in a Danish cohort and found an association between fibrinogen level and level of FEV₁, preceding decline in FEV₁ and subsequent hospital admission. In fact, based on these findings it would be tempting to look at systemic inflammation more as a consequence of COPD than an active component alongside inflammation in the airways and lung parenchyma. An indicator of an effect of systemic inflammation on decline in lung function comes from a clinical study of COPD patients with and without hepatitis C.⁸ In this study, Kanazawa et al found a steeper decline in FEV₁ in patients with hepatitis C than in uninfected controls, independent of smoking habits. In addition, patients with hepatitis responding to interferon‐α treatment had slower declines than those not responding, a response defined as disappearance of HCV RNA. Although the number of patients was very limited (59 in total), these findings leave open the possibility that systemic inflammation may be linked to progression of airflow limitation.

The systemic effects of COPD are more straightforward than the role of systemic inflammation on disease progression. In particular, weight loss and loss of fat‐free mass become increasingly apparent with increasing severity of COPD, and both a low BMI and a low fat‐free mass index have been shown to be strong predictors of mortality in COPD.⁹,¹⁰,¹¹ Studies have linked systemic inflammation with loss of both body mass and fat‐free mass¹¹,¹²,¹³,¹⁴ but, in the largest study,¹¹ the association did not seem impressive and it is likely that other factors also play a role for weight loss. Bolton et al¹⁵ found a strong association between markers of systemic inflammation and loss of fat‐free mass as well as bone density, but the severity of the patients studied (mean FEV₁ 1.0 litres) makes it difficult to determine whether the findings seen are anything but the consequences of disease progression. Whether the fact that fat‐free mass depletion is seen even in early disease¹¹ indicates a role for systemic inflammation earlier than suggested above—at least in a subgroup of patients—remains to be seen.

In the most recent GOLD guidelines there has been more emphasis on extrapulmonary effects as part of COPD, and systemic features are included in the chapter on pathology, pathogenesis and pathophysiology. It is very likely that systemic inflammation plays a key role in the development of systemic manifestations of COPD and that this should impact on our approach to the disease as suggested in a recent review.¹⁶ However, as the study by Fogarty et al shows, we are still far from fully understanding the role of systemic inflammation in COPD.