COPD: Effectiveness of Therapies (2007-2008)


Matsuyama W, Mitsuyama H, Watanabe M, Oonakahara K, Higashimoto I, Osame M, Arimura K.  Effects of omega-3 polyunsaturated fatty acids on inflammatory markers in COPDChest 2005;128:3817-3827. 

PubMed ID: 16354850
Study Design:
Randomized Controlled Trial
A - Click here for explanation of classification scheme.
Quality Rating:
Neutral NEUTRAL: See Quality Criteria Checklist below.
Research Purpose:

To compare the clinical features and the levels of inflammatory mediators between the COPD patients who received the omega-3 PUFA-rich supplement and those who received a nonrich supplement.

Inclusion Criteria:
  • All patients fulfilled the diagnostic criteria of COPD of the British Thoracic Society
  • FEV1 of all participants was <60% of predicted value
  • All were ex-smokers, but none had smoked for at least 6 months prior to study
  • None had received antibiotics or nonsteroidal anti-inflammatory drugs
  • None had reported any acute exacerbations for at least 4 weeks prior to study 
Exclusion Criteria:
  • Patients with BMI > 25 due to reported increase in mortality risk
  • Respiratory disorders other than COPD
  • Subjects treated with systemic corticosteroids
  • Those who had inhaled corticosteroids or antibiotics in 4 weeks prior to study
  • Patients with concomitant confounding diseases such as malignant disorders, GI abnormalities, rheumatoid arthritis, diabetes mellitus, acute or chronic liver disease, immunologic abnormalities that predispose to opportunistic infections, or severe endocrine disorders
  • Those who had undergone recent surgery
  • Patients with PUFA-specific preferences based on dietitian interview
Description of Study Protocol:


Recruitment methods not specified.


Randomized Controlled Trial.

Blinding used (if applicable)

Double-blind:  both investigators and patients were blinded to treatment allocation.  Unblinding did not occur until final assessment of last subject was completed.

Intervention (if applicable)

Randomly assigned to omega-3 PUFA-rich supplement (n-3) or omega-3 PUFA-nonrich supplement (n-6) for 2 years.

Statistical Analysis

Baseline parameters between 2 groups analyzed using Mann-Whitney U test.  Changes in levels of cytokines and other parameters analyzed using 2-way ANOVA on change from baseline.  Multiple regression analysis was used to identify factors most strongly related to serum and sputum cytokine concentrations, such as n-3 or n-6 group, age, smoking index, daily energy intake, BMI prior to start of study, BMI after study, side effects, compliance points, confounding parameter points, theophylline usage, and existence of acute exacerbation.

Data Collection Summary:

Timing of Measurements

Before the study and every month for 2 years, dietary intake was assessed.  Clinical features, BMI, blood gas analysis, pulmonary function testing, serologic analysis, serum cytokine levels, and cytokine levels in sputum were investigated every 3 months.  6-minute walk test was performed before the study and every 3 months.  Patients reviewed monthly in outpatient clinic for acute exacerbations.

Dependent Variables

  • Arterial oxygen saturation measured by pulse oximetry
  • Clinical symptoms assessed using St. George Respiratory Questionnaire
  • Exercise capacity measured through 6-minute walk test
  • Sputum induced and processed
  • Leukotriene B4, tumor necrosis factor-alpha and interleukin-8 levels measured using commercial ELISA kit
  • Cytokine concentrations determined by linear regression from standard curve using software

Independent Variables

  • 400 kcal per day of omega-3 PUFA-rich supplement (0.6 g n-3, 0.4 g n-6) or omega-3 PUFA-nonrich supplement (0.07 g n-3, 0.93 g n-6) for 2 years
  • Dietary intake assessed through monthly 4-consecutive-day food records, which were nutritionally analyzed and averaged
  • Subjects agreed not to consume nutritional supplements containing omega-3 or omega-6 PUFAs
  • To evaluate compliance, patients were asked to declare if they had missed consuming the supplement

Control Variables

  • Age
  • BMI
  • Daily caloric intake
  • Side effects
  • Compliance
  • Confounding parameters mentioned, but not specified
  • Use of theophylline
  • Acute exacerbations
Description of Actual Data Sample:

Initial N: 64 patients, 29 males in n-3 group, 28 males in n-6 group 

Attrition (final N):  64 patients, 32 in each group.  No dropouts reported.

Age:  n-3 group:  mean age 65.8 +/- 23.1 years, n-6 group:  mean age 66.2 +/- 24 years 

Ethnicity:  not mentioned

Other relevant demographics

Anthropometrics:  There were no significant differences between groups at baseline with respect to male/female ratio, age, smoking index, BMI, blood gas analysis, pulmonary function testing, daily caloric intake, investigated serologic factors, serum fatty acid concentrations, serum cytokine levels, and sputum cytokine levels. 

Location:  Japan


Summary of Results:


  n-3 Group:  Before n-3 Group:  After  n-6 Group:  Before n-6 Group:  After
Heart rate - baseline (beats/min) 83 +/- 8.1 82.1 +/- 8.2 81.2 +/- 9.2 83.2 +/- 9.1
Heart rate - end of test (beats/min) 113 +/- 24.1 114 +/- 25.2 113 +/- 23.1 115 +/- 23.7
Dyspnea (Borg Scale) - baseline 1.89 +/- 1.34  1.88 +/- 1.44 1.87 +/- 1.44 1.87 +/- 1.42
Dyspnea (Borg Scale) - end of test 5.88 +/- 2.11 4.99 +/- 1.99, p <0.05 from baseline 5.89 +/- 2.24 5.88 +/- 2.27

Leg Fatigue (Borg Scale) - baseline

0.34 +/- 0.13 0.34 +/- 0.11 0.31 +/- 0.12 0.32 +/- 0.11
Leg Fatigue (Borg Scale) - end of test 3.42 +/- 1.89 3.33 +/- 1.91 3.44 +/- 1.91 3.33 +/- 1.89
Fall of SpO2 (%) 10.1 +/- 2.1 8.2 +/- 1.7, p <0.05 from baseline 10.3 +/- 2.22 9.8 +/- 2.13
Distance predicted (%) 68.2 +/- 18.1 73.2 +/- 19.2 69.2 +/- 17.8 68.2 +/- 18.1
SGRQ - Symptoms 49.2 +/- 22.2 43.2 +/- 21.2 49.3 +/- 20.1 47.3 +/- 21.9
SGRQ - Activity 52.1 +/- 25.3 48.1 +/- 26.1 53.1 +/- 26.2 49.2 +/- 27.3
SGRQ - Impact 34.3 +/- 25.2 33.2 +/- 24.9 35.2 +/- 24.8 34.2 +/- 25.1
SGRQ - Total 44.2 +/- 20.2 40.2 +/- 19.1 44.3 +/- 22.2 43.2 +/- 21.9
Serum LTB4 (pg/ml) 817.7 +/- 234.2 557.6 +/- 218.5, p < 0.05 from baseline and from n-6 812.3 +/- 192.2 814.7 +/- 207.2
Serum TNF-alpha(pg/ml) 27.4 +/- 24.5 28.7 +/- 23.1 28.8 +/- 32.3 28.2 +/- 22.2
Serum IL-8 (pg/ml) 31.1 +/- 44.4 32.7 +/- 49.5 32.8 +/- 39.1 33.3 +/- 37.8
Sputum LTB4 (pg/ml) 69.9 +/- 38.4 41.5 +/- 19.4, p < 0.05 from baseline and n-6 72.5 +/- 35.9 68.6 +/- 36.2
Sputum TNF-alpha (pg/ml) 41.7 +/- 22.2 21.7 +/- 15.3, p < 0.05 from baseline and n-6 39.9 +/- 16.5 40.1 +/- 15.6
Sputum IL-8 (pg/ml) 14.1 +/- 9.1 6.4 +/- 5.3, p < 0.05 from baseline and n-6 12.2 +/- 6.4 11.1 +/- 8.5

Sputum macrophages (%)

56.7 +/- 18.2

61.2 +/- 17.3

57.1 +/- 18.1

57.8 +/- 18.9

Sputum neutrophils (%)

46.2 +/- 18.9

40.8 +/- 18.7

45.9 +/- 18.8

44.8 +/- 17.4

Other Findings

BMI, serum protein levels and serum albumin levels significantly increased in both groups (p < 0.05) but there was no significant difference between groups.

There were no significant changes in the blood gas analysis tests or pulmonary function results.

In 6-minute walk testing, the dyspnea Borg scale and decrease of arterial oxygen saturation significantly improved in the n-3 group (p < 0.05).

Leukotriene B4 levels in serum and sputum and tumor necrosis factor-alpha and interleukin-8 levels in sputum decreased significantly in the n-3 group, while there was no significant change in the n-6 group.

2 patients in the n-3 group and 3 patients in the n-6 group had mild diarrhea, and 3 patients in the n-3 group and 3 patients in the n-6 group had nausea, but their symptoms were controllable and they improved with treatment.

In summary, in the n-3 group, serum EPA levels, serum AA levels, serum LTB4 levels and sputum cytokine levels began to change at 6 months, 12 months, 15 months and 18 months after the start of the study, respectively.  The dyspnea Borg scales and the decrease in SpO2 in the n-3 group improved 24 months after the start of therapy.

Based on multiple regression analysis, the omega-3 PUFA-rich diet significantly contributed to the change in cytokine levels in this study. 

Author Conclusion:

The authors recommend nutritional support with omega-3 PUFAs for the nutritional treatment of COPD.

Funding Source:
Reviewer Comments:

The recruitment methods are not specified in the article.  Strict exclusion criteria may lead to unrepresentativeness.  P values are not listed in tables.  The authors do not discuss physical activity for possible improvement of 6-minute walk test.  Authors note that the dosage of omega-3 PUFAs used was smaller than the standard dose used to treat cardiovascular diseases, and that the sample size and time period are insufficient for reaching a definitive conclusion.

Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? ???
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? ???
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) No
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? N/A
  4.1. Were follow-up methods described and the same for all groups? N/A
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) N/A
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? N/A
  4.4. Were reasons for withdrawals similar across groups? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? ???
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? ???
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? ???
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? No
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? ???
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? ???