COPD: Determination of Energy Needs (2007)


Broekhuizen R, Wouters EF, Creutzberg EC, Schols AM.  Raised CRP levels mark metabolic and functional impairment in advanced COPD.  Thorax 2006;61(1):17-22.

PubMed ID: 16055618
Study Design:
Case-Control Study
C - Click here for explanation of classification scheme.
Quality Rating:
Neutral NEUTRAL: See Quality Criteria Checklist below.
Research Purpose:
To investigate whether an increased concentration of high sensitivity CRP is related to the degree of lung function impairment, systemic inflammation, body composition, exercise capacity, energy metabolism, and quality of life in patients with advanced COPD.
Inclusion Criteria:
  • Met American Thoracic Society guidelines for COPD
Exclusion Criteria:


  • Had concurrent diseases such as malignancies, GI or kidney abnormalities, metabolic or endocrine diseases, and inflammatory diseases that may also result in raised CRP levels


  • Had no lung impairment, cardiovascular disease, diabetes or other diseases
Description of Study Protocol:


Patients consecutively admitted to an inpatient pulmonary rehab centre.  Controls were recruited from an advertisement in a local newspaper for baseline cytokine measurement.


Case-Control Study.

Blinding used (if applicable)

Not applicable.

Intervention (if applicable)

Not applicable.

Statistical Analysis

Differences between groups were analyzed using Student's t test for independent samples and Mann-Whitney U test when not normally distributed.  Regression analysis adjusting for FFM, lung function, age and sex was used to establish the variables that were influenced by log transformed CRP presented as regression coefficient beta with 95% confidence intervals.  Stepwise regression was used to select the variables that influenced log transformed CRP.  Correlations between parameters were calculated with either Pearson or Spearman correlation test. 

Data Collection Summary:

Timing of Measurements

Measurements made between subjects and controls and compared.

Dependent Variables

  • Blood samples evaluated for plasma CRP levels, interleukin-6 levels, soluble tumor necrosis factors 55 and 75 
  • Body composition measured using bioelectrical impedance 
  • Resting energy expenditure measured using indirect calorimetry 
  • Exercise capacity measured through an incremental and submaximal bicycle ergometry tests and 6 minute walking distance
  • Health related quality of life measured using St. George's Respiratory Questionnaire
  • Lung function:  FEV1, FVC and IVC calculated from flow-volume curve using spirometry, carbon monoxide transfer factor determined using single breath method, arterial oxygen and carbon dioxide tensions analyzed with a blood gas analyzer 

Independent Variables

  • Presence of COPD

Control Variables

  • FEV1
  • FFM
  • Age
  • Sex
Description of Actual Data Sample:

Initial N: 102 patients with clinically stable COPD (GOLD stage II - IV, 71 men, 31 women), 20 healthy controls

Attrition (final N):  102 patients, 20 controls

Age: mean age patients:  63 +/- 9 years

Ethnicity: not mentioned

Other relevant demographics:

Anthropometrics:  Controls were age and sex matched

Location:  The Netherlands


Summary of Results:

Inflammatory Markers in Patients with Normal and Raised CRP Levels and in Healthy Controls


Normal CRP (n=54)

Raised CRP (n=48)

Controls (n=20)

TNF-alpha (pg/ml)

1.25 (0.60 - 3.42)

1.31 (0.43 - 3.19)

1.23 (0.74 - 2.70)

sTNF-R55 (ng/ml)

0.87 (0.54 - 2.51)

1.00 (0.59 - 2.20), p < 0.03

0.88 (0.59 - 1.46)

sTNF-R75 (ng/ml)

1.42 (0.81 - 3.39)

1.54 (0.84 - 3.33), p < 0.05

1.14 (0.68 - 1.82)

IL-6 (pg/ml) 2.60 (1.00 - 11.45), p < 0.05 6.45 (0.90 - 12.85), p < 0.03 1.76 (0.81 - 6.00)

Other Findings

Median of healthy CRP of healthy controls was 1.82, with a range of 0.16 - 7.09 mg/l.  The cutoff point of normal versus raised CRP levels was determined at 4.21 mg/l which was the 95th percentile of the CRP values of healthy controls.

CRP levels were raised (higher than 4.21 mg/l) in 48 of 102 patients.  Median CRP level was 3.47 (range 0.36 - 75.60) mg/l.

In these patients, IL-6 (p < 0.001) and REE (adjusted for fat free mass, p = 0.002) were higher while maximal (p = 0.040) and submaximal exercise capacity (p = 0.017) and 6 minute walking distance (p = 0.014) were lower.

The SGRQ symptom score (p = 0.003) was lower in patients with raised CRP levels, as were post-bronchodilator FEV1 (p = 0.031), and reversibility (p = 0.001).

Regression analysis also showed that, when adjusted for FEV1, age and sex, CRP was a significant predictor for body mass index (p = 0.044) and fat mass index (p = 0.016).  

Author Conclusion:
The main findings were that irrespective of FEV1, COPD patients with a raised plasma level of high sensitivity CRP had more impaired energy metabolism, increased disability as defined by impaired exercise capacity, and more distress due to respiratory symptoms than patients with normal CRP levels.  In addition, patients with raised CRP levels had lower post-bronchodilator FEV1 related to less reversibility in FEV1 after inhalation of a beta agonist than patients with normal CRP levels.
Funding Source:
Reviewer Comments:
Small number of controls compared to subjects - controls not well described.  Cut off point for raised CRP levels of 4.21 was still within range for normal controls at 0.16 - 7.09 mg/l.  Authors note that 5 mg/l is standard cutoff point used in clinical practice.
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) N/A
  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) N/A
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? ???
  2.4. Were the subjects/patients a representative sample of the relevant population? ???
3. Were study groups comparable? ???
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? ???
  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.) ???
  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? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  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%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  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? N/A
  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? Yes
  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? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? Yes
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? N/A
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? N/A
  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? ???
  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? ???
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? N/A
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? ???
  7.5. Was the measurement of effect at an appropriate level of precision? ???
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  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? Yes
  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? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes