High baseline C-reactive protein (CRP) levels are linked to significantly increased late mortality in COPD, according to a systematic review and meta-analysis published online on January 30, 2017 in the European Respiratory Review.1
“The pooled estimates of the present meta-analysis revealed a consistent and significant association between elevated baseline CRP levels and mortality in patients with COPD,” wrote first author Giovanni Leuzzi, MD, of the IRCCS Istituto Nazionale dei Tumori Foundation, Milan, Italy, and colleagues.
No optimal marker exists for predicting mortality in COPD. Though some studies have suggested that CRP could serve such a role, the idea has provoked controversy. At least one past meta-analysis has failed to find a significant link between elevated CRP levels and COPD mortality. That meta-analysis included four studies examining the potential link and covered 460 individuals.2 The new meta-analysis expands on the previous one, and includes more than five times as many studies and more than twice as many patients.
In the study, researchers searched PubMed for studies published in English only from inception through May 2016. The overall analysis included 26 articles covering 17,890 patients (five retrospective, 21 prospective). Analyses on late mortality in COPD included 15 studies covering 11,180 patients. Subgroup analyses stratified patients by geographic area and CRP cut-off values.
• Elevated baseline CRP linked to 53% increased risk of late mortality (HR 1.53, 95% CI 1.32–1.77, p<.001)
• Nonsignificant link between CRP levels and early mortality (RR 1.15, 95% CI 0.94–1.42)
• A CRP cutoff of 3 mg/L was linked to higher risk of COPD mortality, compared to lower cutoffs (HR 1.61, 95% CI 1.12–2.30)
• Asian populations had higher risk of COPD mortality (HR 3.51, 95% CI 1.69–7.31)
The authors mentioned two possible mechanisms for systemic inflammation in COPD:
First, chronic lung inflammation may lead to a systemic inflammatory response, which in turn promotes airway inflammation in a vicious cycle leading to COPD progression.
Second, systemic inflammation may be a sign of cardiovascular disease or cancer, both of which are commonly comorbid with COPD and both of which are common causes of death in COPD patients.
The results also suggest possible therapeutic directions in COPD, according to the authors. Drugs that may need further evaluation include modulators of systemic inflammation, β2 agonists, anticholinergics, and theophylline. Statins, in particular, may be promising because of their combined anti-inflammatory and lipid-lowering effects. Studies have suggested a mortality advantage in COPD patients on long-term statin therapy.3
The authors concluded: “Systemic inflammation plays an important role in COPD pathogenesis, disease progression, and mortality. Although CRP is associated with several conditions related to the natural history of COPD, its level may also be used to assess the outcome in COPD patients. Based on our analysis, CRP levels could be used, in combination with other biochemical markers, to target preventive and therapeutic strategies in this disease. Further prospective studies should be performed to confirm the clinical value of CRP.”
The meta-analysis did not include randomized controlled trials, which may have limited the ability to discern the true prognostic role of CRP. Also, included studies lacked data on the cause of death, making it difficult to know whether elevated CRP levels were linked to deaths due to comorbidities or to COPD itself. Finally, different studies used different cut-offs for CRP, which complicated comparison between studies.
Take Home Points
• Systematic review and meta-analysis found that elevated baseline CRP is linked to 53% increased risk of late mortality in COPD
• Asian populations and individuals with CRP >3 mg/L had higher risk of COPD mortality
• Systemic immune modulators and statins may have a role in treating systemic inflammation in COPD, though more research is needed
The authors report no conflicts of interest.
1. Leuzzi G, Galeone C, Taverna F, et al. C-reactive protein level predicts mortality in COPD: a systematic review and meta-analysis. Eur Respir Rev. 2017 Jan 31;26. pii: 160070. doi: 10.1183/16000617.0070-2016. Print 2017 Jan. http://err.ersjournals.com/content/26/143/160070.long
2. Lomholt FK, Laulund AS, Bjarnason NH, et al. Meta-analysis of routine blood tests as predictors of mortality in COPD. Eur Clin Respir J 2014; 1 [DOI: 10.3402/ecrj.v1.24110]
3. Young RP, Hopkins R, Eaton TE. Pharmacological actions of statins: potential utility in COPD. Eur Respir Rev 2009; 118: 222–232.