The association of dietary intake and supplementation of specific polyunsaturated fatty acids with inflammation and functional capacity outcomes in chronic obstructive pulmonary disease: a systematic review protocol
Authors: Atlantis Evan , Cochrane Belinda 
Published: December 2014

Review question/objective
The quantitative objectives are to identify the association of dietary intake and supplementation of specific polyunsaturated fatty acids (PUFA) with chronic inflammation and functional capacity outcomes in people with chronic obstructive pulmonary disease (COPD).
More specifically, the objectives are:
1. To identify the association of low dietary intake of omega-3 fatty acids (docosahexaenoic acid [DHA], eicosapentaenoic acid [EPA] or α-linolenic acid [ALA]) and/or omega-6 (γ-linoleic acid [GLA] and arachidonic acid [AA]) fatty acids with chronic inflammation and functional capacity outcomes in people with COPD compared with controls (high dietary intake reference group).
2. To identify the effectiveness of omega-3 fatty acid supplementation (containing predominantly one or more omega-3 fatty acids) in reducing chronic inflammation and improving functional capacity outcomes compared with placebo/no intervention in people with COPD.

Background
Chronic obstructive pulmonary disease is currently ranked the fifth leading cause of global disability (health loss).1 The BOLD (Burden of Obstructive Lung Disease) study estimates that the prevalence of COPD, defined according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria as stage 2 or higher, was 7.5% among Australian people aged 40 years or older in 2006-10.2 The prevalence of COPD was highest among people aged 75 years or older.2 A recent report by Access Economics estimates that COPD cost the Australian economy about $98 billion in 2008.3 Since Australia's population is ageing, the projected rise in the health burden of COPD will undoubtedly cause significant stress on the national healthcare system. Effective treatments to slow the progression of COPD and/or prevent exacerbations will likely result in significant health and economic benefits.
Chronic obstructive pulmonary disease is characterized by persistent airflow limitation that is usually progressive and associated with chronic inflammation in the airways and lungs from exposure to noxious particles or gases.4 A lifetime of exposure to noxious particles and gases is likely to bring about a chronic (innate and adaptive) inflammatory response in COPD patients that increases production and accumulation of mucus, infiltration of the airway walls by inflammatory cells, as well as thickening of the airway wall and narrowing of the lumen.5 The progression of COPD (i.e. an increase in the severity of airflow limitation by the GOLD grading system) is positively associated with the degree of the inflammatory response,6 and the narrowing and disappearance of the small conducting airways.7 In addition, prospective cohort studies have shown that airway and systemic inflammation, independent of smoking, increases the risk of worsening lung function and exacerbations, which, in turn, are associated with reduced survival.8 Another cohort study observed decreases in airway and systemic inflammation in COPD patients hospitalized for acute exacerbation at the time of discharge (i.e. after treatment and remission of the exacerbation).9 Although there is considerable uncertainty about the origin and role of inflammation in COPD, this body of evidence suggests that new therapies for reducing the chronic inflammatory response may improve COPD prognosis.
Low dietary intake of omega-3 fatty acids may be a reversible risk factor for chronic inflammation, and subsequent functional decline, in COPD patients through a variety of mechanisms including cell surface and intracellular receptors that control inflammatory cell signalling and gene expression.10 The major food sources of DHA and EPA omega-3 fatty acids are fish, fish oils and animal tissues (brain), whereas some plant oils contain ALA.11 Omega-6 fatty acids are predominately derived from plant oils, although small amounts of animal tissues contain GLA and AA.11 Omega-3 and omega-6 fatty acids have competitive (inhibiting) interactions that are important in controlling inflammation.12 Epidemiological evidence (cross-sectional and prospective cohort studies) consistently shows an inverse association between dietary intake of omega-3 fatty acids and systemic inflammation across different populations including people with COPD.13-16 Moreover, the most recent systematic review and meta-analysis of relevant randomized controlled trials (RCTs) shows that short-term marine-derived omega-3 supplementation significantly reduces systemic inflammatory biomarkers including C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) in different population groups.17 The effectiveness of omega-3 supplementation for lowering inflammatory markers was most evident in patients with cardiovascular risk factors which are highly prevalent in COPD patients.18 In contrast, two cross-sectional studies on omega-6 fatty acids reported opposing associations between dietary intake of AA and systemic inflammation.16,19

Although the systematic review by Li and colleagues17 is an excellent synthesis of evidence on effectiveness, none of the studies reviewed focussed on COPD patients. Furthermore, the equivocal results reported in one RCT raise questions about whether a reduction in chronic inflammation with PUFA supplementation is actually beneficial in patients with COPD.20 For instance, a cross-sectional study found no protective and several adverse associations between dietary intake of individual omega-3 and omega-6 fatty acids and airflow limitation in a regionally representative sample of Dutch adults.21 To our knowledge, there is no completed or in-progress systematic review of evidence on this topic. We therefore seek to systematically assess relevant studies on the association of dietary intake and supplementation of specific PUFA with inflammatory markers and functional capacity outcomes in COPD to inform guidelines and clinical practice.