Systemic Inflammation and COPD: The Framingham Heart Study

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Systemic Inflammation and COPDThe Framingham
Heart Study

• Ashwin Basavaraj, M.D.
• Georgetown University GIM Journal Club
• February 19, 2008

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COPD

• An inflammatory disorder of the airways.
• Environmental challenges, including smoking,
  cause local inflammation, which intensifies with
  progression of disease.
• Mediated by cytokines, which recruit inflammatory
  cells, propogating the inflammatory cascade and
  oxidant injury.
• Inflammation and oxidant injury leads to
  development of airway narrowing, fibrosis, and
  obstruction.
• Interaction between local and systemic
  inflammation?

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Active Research

• Big boom in systemic inflammation-related
  research in COPD
• PUBMED search using keywords of COPD and
  Systemic Inflammation yields over 250
  citations, mostly after 2005.
• Owing to
• 1. Ease of procurement
• 2. Standardization in measurement techniques
• 3. Ready access to large biobanks of frozen
  serum and
• plasma (collected for reasons other than COPD)

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Why is this area important?

• Understand better the mechanisms of COPD for
  targeting treatment.
• Disease processes that occur secondary to
  systemic inflammation
• 1. Skeletal muscle apoptosis
• 2. Osteoporosis
• 3. Depression
• 4. Pulmonary HTN
• 5. CAD

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Previous research has shown

• C-reactive protein- A biomarker of systemic
  inflammation
• CRP levels appear to decline with inhaled
  corticosteroid treatment for COPD.
• Specific role of CRP is not completely understood
• Other biomarkers are known to influence
  mechanisms in COPD, however there are a limited
  number of reports.

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Biomarkers involved in pathogenesis of COPD

• Intercellular adhesion molecules (ICAM)-1
  activates and recruits monocytes
• Monocyte Chemoattractant protein(MCP)-1
  activates and recruits monocytes
• P-selectin Promotes neutrophil recruitment
• CD40 ligand found on activated T cells,
  contributes to activation of B and T cells, as
  well as macrophages
• IL-6 Induces T-cell differentiation
• Myeloperoxidase(MPO) Aids in bactericidal
  activities

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Walter, R., MD, et al. Systemic inflammation and
COPD The Framingham Heart Study. Chest. 2008
Jan133(1)19-25.

• Hypothesis Systemic inflammation contributes to
  intraparenchymal processes resulting in COPD.
• Systemic inflammatory profile in smokers with
  impaired lung function differs from non-smokers
  with impaired lung function
• Goal Showcase that higher concentrations of
  biomarkers were associated with lower levels of
  lung function, and this relation is modified by
  long-term smoking.

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Methods

• Participants attending the most recent
  examination of the Offspring Cohort in the
  Framingham heart study were eligible for
  inclusion (approximately 2,500).
• Phlebotomy drawn in early morning after overnight
  fast.
• Enzyme-linked immunosorbent assays were used to
  measure serum concentrations of IL-6, ICAM-1,
  MCP-1, CD40L, and plasma concentrations of
  P-selectin and MPO.
• Spirometry without bronchodilator testing was
  performed.

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Statistical Analysis

• Linear regression- Examining the response of a
  dependent variable to an independent variable
  (assumed to be a linear relationship) (FEV1)
• Usually include several variables in the analysis
  in an effort to remove factors that might produce
  spurious correlations.
• Logistic regression Model used for prediction
  of the probability of occurrence of an
  event.(COPD)
• Examined relation of biomarkers to residual FEV1
  and COPD adjusting for age, sex, BMI, current
  smoking, and pack-years.
• COPD FEV1/FVC lt0.70, FEV1lt80 predicted.

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Statistical Analysis

• There was a statistically significant correlation
  among biomarkers, specifically CRP to IL-6.
• Simultaneous inclusion of the entire panel of
  biomarkers may mask the relation of individual
  biomarkers to impaired lung function.
• To further characterize collinearity, a variance
  inflation factor was calculated.
• Secondary analyses were implemented including
  only single biomarkers as exposures.
• Analysis implemented on total sample and two
  subgroups, heavy cigarette smoking(at least 10 pk
  yrs) and those without heavy smoking.

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Statistical Analysis

• Tested for apparent differences between subgroups
  of cigarette smoking in associations of biomarker
  concentration to impaired lung function
• Included baseline covariates, smoking history as
  dichotomous variable(yes/no), biomarkers, and
  interaction between biomarkers and smoking.
• Two-sided p value set at lt0.05.

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Results

• Majority of patients were female and smokers.
• Those with COPD were older and more likely to be
  smokers.
• Subjects with COPD generally had higher
  concentrations of serum inflammatory markers,
  including CRP and IL-6.
• Only modest correlation found among biomarkers.

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Results

• Linear regression for FEV1, adjusting for age,
  sex, BMI, smoking.
• IL-6,CRP, P-selectin were significantly
  associated with FEV-1.
• 1 SD higher concentration of IL-6,CRP, and
  P-selectin was associated with on avg 41ml, 46ml,
  and 19ml lower of FEV1, respectively.
• Repeating analysis after separating the
  biomarkers, associations were strengthened, and
  ICAM became statistically significant.

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Results

• Using logistic regression, the relation of IL-6
  and CRP to COPD were significant
• IL-6 associated with a 15 higher odds ratio of
  COPD
• CRP associated with 20 higher odds ratio
• Separating biomarkers strengthened association.

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Results

• Examining the relations of individual biomarkers
  to COPD among smoking history, CD40L was
  significant(at least 10 yr pack history) p value
  0.01
• There were associations with biomarkers and FEV1
  among smoking strata but did not reach
  statistical significance.

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Discussion

• Significant association between biomarkers of
  systemic inflammation and impaired lung function,
  especially IL-6, CRP, and ICAM.
• Higher odds of COPD were observed with higher
  concentrations of CD40L among heavy smokers.

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Strengths

• Large sample size
• Repeated analysis with separation of biomarkers
  increased power of study.
• Used two different statistical methods which
  reached similar conclusions.
• Reached statistical significance.

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Limitations

• Relation between biomarkers and COPD are not
  completely understood, no causal link can be
  noted.
• Circulatory inflammatory markers may not
  accurately assess local pulmonary tissue
  inflammatory concentrations.
• Did not observe large differences between smoking
  strata(only CD40L)

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Future research

• Establish whether the elevation of biomarkers are
  specific to COPD or other factors
• Better understanding of mechanisms that
  contribute to COPD may help predict disease
  progression and target treatment.
• May help understand relation between these
  systemic biomarkers and other diseases.
• More research needed using IL6, CRP, and CD40L as
  avenues for research.

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References

• Hogg JC, Chu F, Utokaparch S, et al. The nature
  of
• small-airway obstruction in chronic
  obstructive
• MacNee W. Pathogenesis of chronic obstructive
  pulmonary
• disease. Proc Am Thorac Soc 2005 2258268
• Sin, Don D. MD, FCCP Man, S F. Paul MD, FCCP
  Interleukin-6 A Red Herring or a Real Catch in
  COPD? Chest. 133(1)4-6, January 2008.
• Walter, Robert E. MD, MPH Wilk, Jemma B. DSc
  Larson, Martin G. ScD Vasan, Ramachandran S. MD
  Keaney, John F. Jr MD Lipinska, Izabella PhD
  O'Connor, George T. MD, MS, FCCP Benjamin,
  Emelia J. MD, ScM Systemic Inflammation and
  COPD The Framingham Heart Study. Chest.
  133(1)19-25, January 2008.
• http//en.wikipedia.org/wiki/Linear_regression
• http//en.wikipedia.org/wiki/Logistic_regression

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