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Communications to the Editor |

The Puzzling Relationship Between Cigarette Smoking, Reduced Respiratory Function, and Systemic Inflammation FREE TO VIEW

Valeria Asero, MD; Antonio Mistretta, MD; Giuseppe Arcidiacono, MD; Riccardo Polosa, MD
Author and Funding Information

Affiliations: Specialistica Università di Catania, Catania, Italy,  Department of Medicine, University of British Columbia, Vancouver, Canada

Correspondence to: Riccardo Polosa, MD, Dipartimento di Medicina Interna e Specialistica, Università di Catania, Presidio Ospedaliero Ascoli-Tomaselli, Via Passo Gravina 187, 95125 Catania, Italy



Chest. 2005;128(5):3772-3773. doi:10.1378/chest.128.5.3772
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To the Editor:

In their cross-sectional survey, Gan et al1 investigated the possible relationship between cigarette smoking, reduced respiratory function, and systemic inflammation. However, there is not sufficient evidence to support their conclusion that, independent of active smoking, poor lung function is an important risk factor for low-grade systemic inflammation.

Firstly, the cross-sectional methodology does not allow exploring the temporal nature of the relationship between cigarette smoking, reduced respiratory function, and systemic markers of inflammation. The authors provide some evidence for a dose-response relationship, but the strength of evidence is usually developed from prospective cohort studies.

Another problem is the apparent lack of biological plausibility to explain the relationship between reduced lung function and systemic markers of inflammation. The accepted biological paradigm is that of cigarette smoking causing a widespread neutrophilic airway inflammation that leads to chronic bronchitis and emphysema with associated reduced lung function.2Besides, cigarette smoking per se is an important cause of systemic inflammation by means of endothelial activation/injury with ensuing stimulation of the clotting cascade3; activation of the endothelial/coagulation system is likely to explain the presence of low-grade systemic inflammation and the pathogenetic link between cigarette smoking and cardiovascular disease.3The authors failed to consider endothelial activation as an important confounding factor in their analyses. Furthermore, other neglected confounding factors, such as the presence of atopy and of subclinical bronchial hyperresponsiveness (known to be present in most smokers and linked to decline in respiratory function45), might have explained the observed relationship; in a recent study6 increased C-reactive protein (CRP) levels were strongly and independently associated with bronchial hyperresponsiveness.

Perhaps the most worrying aspect in the study of Gan et al1 is that of CRP misclassification. According to the study criteria, detectable levels of CRP were categorized as “elevated” (ie, CRP > 2.1 mg/L is considered elevated). This is clearly inaccurate, as there will be a large number of measurements > 2.1 mg/L but less than the normal value of 10.0 mg/L that will be erroneously categorized as elevated. It would be interesting to repeat all the analyses taking this into account.

Gan, WQ, Man, SF, Sin, DD. (2005) The interactions between cigarette smoking and reduced lung function on systemic inflammation.Chest127,558-564. [CrossRef] [PubMed]
 
Rennard, SI, Daughton, DM Cigarette smoking and disease Elias, JA Fishman, JA Grippi, MAet al eds.Pulmonary diseases and disorders1997,697-708 McGraw-Hill. New York, NY:
 
Ross, R Atherosclerosis: an inflammatory disease.N Engl J Med1999;340,115-126. [CrossRef] [PubMed]
 
O’Connor, GT, Sparrow, D, Weiss, ST. A prospective longitudinal study of methacholine airway responsiveness as a predictor of pulmonary-function decline: the Normative Aging Study.Am J Respir Crit Care Med1995;152,87-92. [PubMed]
 
Rijcken, B, Schouten, JP, Xu, X, et al Airway hyperresponsiveness to histamine associated with accelerated decline in FEV1.Am J Respir Crit Care Med1995;151,1377-1382. [PubMed]
 
Kony, S, Zureik, M, Driss, F, et al Association of bronchial hyperresponsiveness and lung function with C-reactive protein (CRP): a population based study.Thorax2004;59,892-896. [CrossRef] [PubMed]
 
To the Editor:

We agree with Asero and colleagues that cross-sectional studies such as ours cannot determine the temporality nor the natural history of the relationship between smoking (or reduced lung function) and systemic inflammation, an important limitation of the study, which we pointed out in the limitation section of our article.1However, cross-sectional studies can ascertain risk factors through measures of association.2 Thus, the statement that “reduced lung function is a risk factor” is fully justified by the methodology we used.12 We also agree that factors such as airway hyperresponsiveness (AHR), endothelial activation, and neutrophil recruitment may be involved in effecting systemic inflammation in smokers and nonsmokers with reduced lung function. However, these factors may not be confounders; rather, they may be part of the causal pathway(s) linking reduced lung function with systemic inflammation. For example, in the Lung Health Study,3which evaluated > 4,200 participants with mild COPD with serial methacholine challenge tests over 5 years, the investigators found that even among participants who stopped smoking, airway responsiveness increased during the follow-up period. This indicates that there are factors other than cigarette smoking that are responsible for AHR in individuals with reduced lung function. There are good experimental data to indicate that airway inflammation and remodeling are important determinants of AHR.45 Airway inflammation may also relate to systemic inflammation.6Thus, it would be misleading and erroneous to consider AHR as a confounder in the relationship between reduced lung function and systemic inflammation; it is likely to be part of its causal pathway. Finally, we disagree with the assertion of Asero et al that there was C-reactive protein (CRP) misclassification because we considered CRP levels > 2.1 mg/L to be elevated. In the general population, the geometric mean of CRP for individuals 55 to 64 years of age is between 1.6 and 2.2 mg/L.7By taking 2.1 mg/L as the cutoff threshold, we in effect used the median CRP value of the general population in dichotomizing the study sample, an approach that is widely accepted and commonly used to dichotomize continuous variables for analytic purposes in the medical literature.8 This approach strikes a reasonable balance between validity and efficiency. If we were to take the suggestion of Asero et al and use 10 mg/L as the cutoff value, we would significantly compromise the statistical power and the efficiency of the study without improving the validity of the findings.8 This approach therefore is best avoided.

References
Gan, WQ, Man, SF, Sin, DD. The interactions between cigarette smoking and reduced lung function on systemic inflammation.Chest2005;127,558-564. [CrossRef] [PubMed]
 
Grimes, DA, Schulz, KF. An overview of clinical research: the lay of the land.Lancet2002;359,57-61. [CrossRef] [PubMed]
 
Wise, RA, Kanner, RE, Lindgren, P, et al The effect of smoking intervention and an inhaled bronchodilator on airways reactivity in COPD: the Lung Health Study.Chest2003;124,449-458. [CrossRef] [PubMed]
 
Chen, H, Tliba, O, Van Besien, CR, et al TNF-[alpha] modulates murine tracheal rings responsiveness to G-protein-coupled receptor agonists and KCl.J Appl Physiol2003;95,864-872. [PubMed]
 
Yang, G, Volk, A, Petley, T, et al Anti-IL-13 monoclonal antibody inhibits airway hyperresponsiveness, inflammation and airway remodeling.Cytokine2004;28,224-232. [CrossRef] [PubMed]
 
Sin, DD, Man, SF. Chronic obstructive pulmonary disease: a novel risk factor for cardiovascular disease.Can J Physiol Pharmacol2005;83,8-13. [CrossRef] [PubMed]
 
Hutchinson, WL, Koenig, W, Frohlich, M, et al Immunoradiometric assay of circulating C-reactive protein: age-related values in the adult general population.Clin Chem2000;46,934-938. [PubMed]
 
Altman, D. Statistics in medical journals: some recent trends.Stat Med2000;19,3275-3289. [CrossRef] [PubMed]
 

Figures

Tables

References

Gan, WQ, Man, SF, Sin, DD. (2005) The interactions between cigarette smoking and reduced lung function on systemic inflammation.Chest127,558-564. [CrossRef] [PubMed]
 
Rennard, SI, Daughton, DM Cigarette smoking and disease Elias, JA Fishman, JA Grippi, MAet al eds.Pulmonary diseases and disorders1997,697-708 McGraw-Hill. New York, NY:
 
Ross, R Atherosclerosis: an inflammatory disease.N Engl J Med1999;340,115-126. [CrossRef] [PubMed]
 
O’Connor, GT, Sparrow, D, Weiss, ST. A prospective longitudinal study of methacholine airway responsiveness as a predictor of pulmonary-function decline: the Normative Aging Study.Am J Respir Crit Care Med1995;152,87-92. [PubMed]
 
Rijcken, B, Schouten, JP, Xu, X, et al Airway hyperresponsiveness to histamine associated with accelerated decline in FEV1.Am J Respir Crit Care Med1995;151,1377-1382. [PubMed]
 
Kony, S, Zureik, M, Driss, F, et al Association of bronchial hyperresponsiveness and lung function with C-reactive protein (CRP): a population based study.Thorax2004;59,892-896. [CrossRef] [PubMed]
 
Gan, WQ, Man, SF, Sin, DD. The interactions between cigarette smoking and reduced lung function on systemic inflammation.Chest2005;127,558-564. [CrossRef] [PubMed]
 
Grimes, DA, Schulz, KF. An overview of clinical research: the lay of the land.Lancet2002;359,57-61. [CrossRef] [PubMed]
 
Wise, RA, Kanner, RE, Lindgren, P, et al The effect of smoking intervention and an inhaled bronchodilator on airways reactivity in COPD: the Lung Health Study.Chest2003;124,449-458. [CrossRef] [PubMed]
 
Chen, H, Tliba, O, Van Besien, CR, et al TNF-[alpha] modulates murine tracheal rings responsiveness to G-protein-coupled receptor agonists and KCl.J Appl Physiol2003;95,864-872. [PubMed]
 
Yang, G, Volk, A, Petley, T, et al Anti-IL-13 monoclonal antibody inhibits airway hyperresponsiveness, inflammation and airway remodeling.Cytokine2004;28,224-232. [CrossRef] [PubMed]
 
Sin, DD, Man, SF. Chronic obstructive pulmonary disease: a novel risk factor for cardiovascular disease.Can J Physiol Pharmacol2005;83,8-13. [CrossRef] [PubMed]
 
Hutchinson, WL, Koenig, W, Frohlich, M, et al Immunoradiometric assay of circulating C-reactive protein: age-related values in the adult general population.Clin Chem2000;46,934-938. [PubMed]
 
Altman, D. Statistics in medical journals: some recent trends.Stat Med2000;19,3275-3289. [CrossRef] [PubMed]
 
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