COPD in the Never-Smoker

By David M. Mannino, MD, FCCP; and Kathryn Marie McGonigle

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Intrinsic Factors in COPD Pathogenesis

Asthma and bronchial responsiveness. Asthma and COPD have traditionally been defined as separate diseases owing to their distinct pathogenesis and reversibility of airway obstruction, although in the GOLD definition of COPD, asthma with lung function impairment that is not fully reversible is a subtype of COPD. Asthma and allergy have been shown to be important factors in the pathogenesis of COPD.^12,20 Other longitudinal studies, however, have shown that there are differences in survival and pulmonary function decline in subjects with decreased lung function at baseline who have asthma vs those without asthma, with survival being much better and lung function decline being less marked in the asthmatic patients.²¹

Although the symptoms in asthma and other subtypes of COPD can be similar, there are physiologic differences in the inflammatory processes leading to these conditions.^3,11 The bronchitic subtype of COPD is primarily a neutrophilic inflammation, with increases in macrophages and CD8+ T lymphocytes and the inflammatory mediators tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8), and leukotriene B₄. Resultant epithelial squamous metaplasia, parenchymal destruction, glandular hyperplasia, and mucous metaplasia lead to airway narrowing, fibrosis, and permanent remodeling of the lung parenchyma and airways. Asthmatic inflammation comprises primarily eosinophils, CD4+ T lymphocytes, and mast cells, with leukotriene D₄, IL-4, and IL-5 as the main inflammatory mediators. Inflammation results in a fragile epithelium, a thickened basement membrane, glandular hyperplasia, and mucous metaplasia (Table 2).

Table 2ÑCharacteristics of Inflammation in COPD and Asthma*

	COPD	Asthma
Cells	Neutrophils	Eosinophils
	Large increase in macrophages	Small increase in macrophages
	Increase in CD8+ T lymphocytes	Increase in CD4+ Th2 lymphocytes
		Activation of mast cells
Mediators	Leukotriene B4	Leukotriene D4
	IL-8	IL-4, IL-5
	TNF-α	(Plus many others)
Consequences	Squamous metaplasia of epithelium	Fragile epithelium
	Parenchymal destruction	Thickening of basement membrane
	Mucus metaplasia	Mucus metaplasia
	Glandular enlargement	Glandular enlargement
Response to treatment	Glucocorticoids have little or no effect	Glucocorticoids inhibit inflammation
Reprinted from GOLD.3

Airway hyperresponsiveness, which is the bronchoconstrictive response to a nonspecific stimulus such as methacholine or cold air, is associated both with impaired growth of the lungs during childhood and hastened decline of lung function during adulthood.^11,12 There is some evidence that there may be less airway responsiveness in patients with the bronchitic form of COPD compared with subjects who have asthma¹²; whether this observation is related to airway caliber rather than bronchial responsiveness is unknown.²² The relationship between bronchodilator reversibility, bronchial responsiveness, and lung function decline is complex, with different studies showing conflicting results.¹² Intuitively, a higher degree of reversibility suggests that less remodeling has occurred, suggesting that with appropriate interventions these patients might have better prognoses.

Genetics. Both asthma and COPD have genetic determinants, although only α₁-antitrypsin deficiency (PiZZ) has been shown definitively to be a risk factor for the development of the emphysematous form of COPD.⁹ Even among subjects with severe deficiency, however, there is considerable variability in the degree of lung function impairment, suggesting that other environmental or genetic factors are important in disease development and progression. Several different genetic factors probably contribute to the development of COPD in the never-smoker. Important determinants include mucociliary clearance rates, responses to hypoxia and hypercapnia, modulators of the pulmonary inflammatory response, antiproteases, modulators of cellular repair in the lung, enzymes that metabolize pulmonary toxicants, variability in proteolytic enzymes, and other unknown factors.^23-26 In addition, factors that influence asthma prevalence, severity, and response to therapy may also be important. Table 3 lists candidate genes that have been investigated for both asthma and COPD.^25,26 Currently, the only genes appearing on both lists are those for TNF-α and human leukocyte antigen.

Table 3ÑCandidate Genes That Have Been Associated With COPD or Asthma/Atopy in Various Studies*

COPD	Asthma / Atopy
PiMZ α1-antitrypsin deficiency	TNF-α
TNF-α	Human leukocyte antigen
Microsomal epoxide hydrolase	Interleukin-4
Glutathione S1-transferase	Interleukin-9
Heme oxygenase-1	β2-Adrenergic receptor
Taq-1 polymorphism of α1-antitrypsin	5-Lipooxygenase
α1-Antichymotrypsin	High-affinity receptor for IgE (FcεR1β)
Vitamin D binding protein	T cell receptor α/δ
ABO blood group	Clara cell protein (CC16)
ABH secretor status
Cystic fibrosis transmembrane regulator
Human leukocyte antigen
Cytochrome P450
*Modified from Lomas and Silverman25 and Hall.26

Sex. The role of sex in the development and progression of COPD is currently the subject of several studies.^15,27 Recent data have shown that in 2000, more women than men in the United States reported that they had COPD, were hospitalized for COPD, and died from COPD.⁴ While much of this finding is probably related to smoking trends over time in women,^27,28 it is also possible that hormonal or other factors, such increased bronchial responsiveness or different patterns in usage of medical care, may also be important. Other data, however, show that similar proportions of men and women, stratified by smoking status, have evidence of airflow limitation.⁵ In developing countries, where cigarette smoking is typically less prevalent in women, increased rates of COPD have been found in women who use wood-burning stoves for heating and cooking.²⁹ It is currently unclear whether women are more or less likely than men to develop COPD, given similar exposures.

Aging. Aging leads to a natural deterioration of many vital body functions, including lung function. Numerous studies have shown that lung function deteriorates with increasing age in both smoking and nonsmoking populations, although the decline is more rapid in smokers.^5,30 Both asthma and the presence of respiratory symptoms have been shown to increase the FEV₁ decline associated with aging.³¹ The specific factors leading to this deterioration are not well defined, but may be related to changes in the immune system, long-term exposures to pollutants, comorbid conditions, or other undefined factors.

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