The environmental tobacco smoke (ETS) exposure increases the risk of lower respiratory tract infections (LRTI) in children.
1. Introduction
Acute bronchitis, one of the most common diagnoses in ambulatory care medicine, accounted for approximately 2.5 million visits to U.S. physicians in 1998 (Slusarcick & McCaig, 2000). This condition consistently ranks as one of the top ten diagnoses for which patients seek medical care, with cough being the most frequently mentioned symptom necessitating office evaluation (Knutson & Braun, 2002; Saldías et al., 2007). The diagnosis is based on clinical findings, without standardized diagnostic signs and sensitive or specific confirmation laboratory tests (Oeffinger et al., 1997).
Acute bronchitis is usually caused by a viral infection, especially by influenza, parainfluenza and respiratory syncytial virus, it is also caused by adenovirus, coronavirus and rhinovirus (Marrie, 1998). When microbiological studies are performed, less than 10-20% of patients will have evidence of acute bacterial infection (Macfarlane et al., 2001). Thus,
The devastating health impact of cigarette smoking is well known (Kuper et al., 2002; Stewart et al., 2008). Despite ongoing efforts to reduce smoking prevalence, over 1.1 billion people continue to smoke, representing one-sixth of the world’s population (Jha et al., 2002). Cigarette smoking is a major risk factor for premature mortality due to cancer, cardiovascular and cerebrovascular disease, and chronic obstructive pulmonary disease (Dye & Adler, 1994). About half of all smokers will develop a serious smoking-related illness, such as chronic obstructive pulmonary disease (COPD), which is characterized by irreversible airway obstruction, or cardiovascular disease. Furthermore, about 1–5% of smokers will develop a smoking-related malignancy, mostly lung adenocarcinoma or other epithelial cell tumours. But cigarette smoking also appears to be a major risk factor for respiratory tract infections (Marcy & Merrill, 1987). Both active and passive cigarette smoke exposure increase the risk of infections. Passive exposure to tobacco smoke in children contributes significantly to morbidity and mortality (Cheraghi & Salvi, 2009). Children in particular, seem to be the most susceptible population for the harmful effects of environmental tobacco smoke (ETS). Exposure to ETS amongst children at homes have been reported to vary from 27.6% in Africa, 34.3% in South East Asia, 50.6% in Western Pacific, and up to 77.8% in Europe (Warren et al., 2008). The morbidity and mortality of infectious diseases associated to smoking are not widely appreciated by physicians. The mechanism of increased susceptibility to infections in smokers is multifactorial and includes alteration of the structural (Dye & Adler, 1994; Marcy & Merrill, 1987) and immunologic host defenses (Sopori et al., 1994; Sopori et al., 1998). We reviewed the epidemiology of smoking-related lung infections and the mechanisms by which smoking increases the risk of infection.
2. Mechanisms by which cigarette smoking may predispose to respiratory infections
The specific mechanisms by which cigarette smoking increases the risk of respiratory infections are incompletely understood (Saldías et al., 2007; Domagala-Kulawik, 2008). They are multifactorial and probably interactive in their effects. Mechanisms by which smoking increases the risk of infections include structural changes in the respiratory tract (Dye & Adler, 1994) and a decrease in immune response (Sopori et al., 1998).
2.1. Structural changes caused by smoking
The ciliated respiratory epithelium, the main target of most respiratory viruses, is the first line of defense against harmful environmental agents and protects by sweeping particles away in the overlying mucus gel layer, phagocytosing and killing some pathogens, maintaining a barrier through tight junctions and priming, activating and recruiting other immune cells. Cigarette smoke and many of its components produce structural changes in the respiratory tract. These changes include peribronchiolar inflammation and fibrosis, increased mucosal permeability, impairment of the mucociliary clearance, changes in pathogen adherence, and disruption of the respiratory epithelium (Dye & Adler, 1994). These changes are thought to predispose to the development of upper and lower respiratory tract infections, which may amplify the cigarette smoke–induced lung inflammation. A number of components of cigarette smoke, including acrolein, acetaldehyde, formaldehyde, free radicals produced from chemical reactions within the cigarette smoke, and nitric oxide, may contribute to the observed structural alterations in the airway epithelial cells (Marcy & Merrill, 1987).
Smoke directly compromises the integrity of this physical barrier, increases the permeability of the respiratory epithelium and impairs mucociliary clearance (Dye & Adler, 1994; Jones et al., 1980; Burns et al., 1989). Although cigarette smoke has been shown to activate epithelial cells to produce pro-inflammatory mediators (Mio et al., 1997), it attenuates the
2.2. Effect of cigarette smoke on the lung and systemic immunity
Cigarette smoke has been shown to affect a wide range of host defense mechanisms (Sopori et al., 1994). However, findings between studies can be controversial and sometimes contradictory, probably because of differences in smoking history, genetic susceptibility and socioeconomic status (such as exercise, nutrition, occupation and ambient air quality, which can modify disease). Similar issues apply to animal models and
2.2.1. Cell-mediated immune responses
Reports of the effects of smoking on the different subsets of lymphocyte T cells are conflicting. Light to moderate smokers were reported to have a significant increase in CD3+ and CD4+ counts and a trend toward increased CD8+ lymphocyte count (Miller et al., 1982; Hughes et al., 1985; Tollerud et al., 1989; Mili et al., 1991). By contrast, studies of heavy smokers (over 50 pack-years) reported a decrease in CD4+ and a significant increase in CD8+ cell counts. Thus, the decrease observed in the ratio of CD4+ to CD8+ lymphocytes in heavy smokers was due predominantly to an increase of CD8+ cells (Ginns et al., 1982). These effects appeared to be reversible as soon as 6 weeks after smoking cessation (Miller et al., 1982). Other studies have reported no difference in the CD4+ and CD8+ lymphocyte counts among moderate smokers (Costabel et al., 1986). Since CD4+ cells facilitate B-cell proliferation and differentiation and immunoglobulin synthesis, the decrease in this subset observed in heavy smokers might contribute to the increased susceptibility to infections in this population.
The retention of CD8+ T cells in the lungs of chronic smokers warrants particular attention as it is a hallmark of COPD and it is known that these cells can activate alveolar macrophages to produce matrix metalloproteinase 12, a potent elastin-degrading enzyme that has been linked to emphysema (Hautamaki et al., 1997; Grumelli et al., 2004). Furthermore, CD8+ T cells are required for inflammation and tissue destruction in smoke-induced emphysema in mice (Maeno et al., 2007). Cigarette smoke has also been found to promote the retention of virus-specific CD8+ memory effector T cells, but to weaken their defensive ability (Gualano et al., 2008).
Smoking is also associated with significant increases in the percentage of macrophages in bronchoalveolar lavage fluid (Wewers et al., 1998). Owing to their strategic positioning within the alveolar space, alveolar macrophages have a key role in sensing and eliminating microbial agents early in the course of an infection. Cigarette smoking increases the number of alveolar macrophages (Sopori et al., 1998) and activates them to produce pro-inflammatory mediators, reactive oxygen species and proteolytic enzymes (de Boer et al., 2000; Russell et al., 2002), thereby providing a cellular mechanism that links smoking with inflammation and tissue damage. Similar to its effects on the respiratory epithelium, cigarette smoke compromises the ability of alveolar macrophages to phagocytose bacteria (King et al., 1988; Berenson et al., 2006) and apoptotic cells (Hodge et al., 2007) and to sense PAMPs (Drannik et al., 2004; Chen et al., 2007; Gaschler et al., 2008). Importantly, cigarette smoke may not simply suppress the function of alveolar macrophages as previously suggested, but instead might skew their inflammatory mediator profile. The nature of the skewing may be a determinant of disease susceptibility. Accordingly, one study reported a distinctive state of activation of alveolar macrophages in smokers that distinguished them from those in non-smokers (Woodruff et al., 2005). This highlights a key emerging concept — smoke may induce partial M1 deactivation or partial M2 activation of macrophages. The balance and intensity of this skewing has direct implications for the immune system and its response to disease because effective host defense requires a macrophage activation programme that is appropriate for the particular type of pathogen and because M1-type macrophages can cause marked lung damage (emphysema), whereas M2-type macrophages are linked to tumour progression. The molecular mechanisms of altered alveolar macrophage responsiveness and skewing are not presently understood but they are at least partially reversible by exposure to the reduced form of glutathione, which implicates oxidative damage of effector pathways. The infection risk is compounded by host deficiencies or polymorphisms in innate and adaptive immune response genes, in particular those encoding pattern recognition receptors, such as mannose-binding lectin, and their signal transduction intermediates (Becker & O’Neill, 2007).
In the lungs, dendritic cells (DCs), which are the most potent antigen-presenting cells and are indispensable for the initiation of T cell-mediated immune responses (Mellman & Steinman, 2001), are probably highly susceptible to smoke-induced effects because of their anatomical position (in the lumen and directly beneath the epithelium of the lung) (McComb et al., 2008). Although it is known that the DC-directed chemokine CX3CL1 is upregulated in emphysema (McComb et al., 2008), there are only a few studies assessing the effects of smoking on lung DCs in humans and animal models (Tsoumakidou et al., 2008). Clinical studies suggest that the number of mature DCs is reduced in the large airways of patients with COPD who smoke (Jahnsen et al., 2006). Following smoking cessation, the numbers of mature DCs increase and are similar to non-smoking healthy controls. By contrast, the number of immature DCs is increased in the small airways of patients with COPD compared with individuals who have never smoked and individuals who smoke but do not have COPD (McComb et al., 2008). These data indicate that smoking behavior may affect DC numbers and maturity state.
Mounting evidence suggests that natural killer cells have an important role in innate host defense against microbial agents and in protective antitumour immune surveillance. This is achieved by direct cytotoxicity through perforin and granzymes, CD95 ligand-induced apoptosis and pro-inflammatory cytokine and chemokine release (Tollerud et al., 1989; Hamerman et al, 2005). Several studies have shown that NK cell numbers and activity are decreased in smokers compared with non-smokers (Swann et al., 2007). Exposure to cigarette smoke attenuates the cytotoxic activity and cytokine production of NK cells in humans and mice (Lu et al., 2006; Mian et al., 2008), thereby linking NK cell defects to increased infection risk and cancer.
Animal studies have shown that nicotine inhibits the antibody-forming cell response through impairment of antigen-mediated signalling in T cells and suppression of intracellular calcium response (Geng et al., 1995; Geng et al., 1996; Sopori et al., 1998). It has been suggested that nicotine through activation of protein tyrosine kinases and depletion of inositol-1,4,5-trisphosphate-sensitive calcium stores in T cells could be a major immunosuppressive component in cigarette smoking (Kalra et al., 2000).
2.2.2. Humoral immune system
Autoimmunity has been proposed as a cause of smoke-induced lung disease. B cells are abundant in smoke-induced lung disease, and their roles, although obscure, are probably greatly underestimated. Cigarette smoke serves as an adjuvant, possibly because it is a potent inducer of granulocyte/macrophage colony-stimulating factor production in the lungs, which enhances the ability of DCs to present antigen and probably to induce TH2 type-biased immune responses (Trimble et al, 2009).
3. Smoking and respiratory infections
Given the complex nature of the immune system, in which unaffected defense mechanisms may compensate for local deficiencies, it is difficult to predict how the impact of cigarette smoke on specific host defense pathways affects the overall responses to microbial agents (Domagala-Kulawik, 2008). Specifically, it is unclear whether the increased risk of infection observed in smokers is due to increased susceptibility to microbial agents, an inability to effectively clear infectious agents or exaggerated pro-inflammatory responses to microbial agents (owing to changes in immune homeostasis), thereby evoking symptoms of infection. Similar considerations apply to acute exacerbations of COPD that are due to bacterial and viral infections (Sethi & Murphy, 2001; Wedzicha, 2004; Papi et al., 2006) and to microbial colonization of the airways, which occurs in approximately one third of patients with COPD (Patel et al., 2002).
3.1. Viral infections
Environmental tobacco smoke exposure increases significantly the risk of lower respiratory tract infections in children, especially maternal smoking (Table 1). Using mouse models, it has been investigated the effects of cigarette smoke on inflammatory processes, viral clearance and secondary immune protection following influenza virus infection (Robbins et al., 2006; Gualano et al., 2008; Kang et al., 2008). Cigarette smoke exposure was found to be associated with exacerbated pro-inflammatory responses to influenza virus, although neither the rate of viral clearance nor the development of influenza virus-specific memory responses were compromised. Hence, cigarette smoke mainly affects primary antiviral inflammatory processes, whereas secondary immune protection remains intact (Robbins et al., 2006). The heightened inflammatory response was associated with increased production of pro-inflammatory mediators and mortality. Furthermore, one study (Kang et al., 2008) showed that increased inflammation led to accelerated emphysema formation and airway fibrosis, providing evidence that altered responsiveness to viral agents may contribute to the pathogenesis of emphysema.
Enhanced bacterial adherence has been documented for respiratory cells infected, with influenza A virus being responsible for viral-bacterial combination pneumonia (Hament et al., 1999). Studies have suggested that inflammatory activation of platelet-activating factor is an important factor in the attachment and invasion of cells by pneumococcal strains. Cigarette smoking alters platelet-activating factor metabolism and may contribute to the increased incidence of bacterial superinfection in people who develop influenza (Miyaura et al., 1992; Ichimaru & Tai, 1992).
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Although influenza was more severe in smokers, antibody levels to A(H1N1) antigen were not significantly higher than those of nonsmokers. Moreover, influenza antibodies wane more rapidly in smokers than in nonsmokers (Finklea et al., 1971). This finding suggests that smokers are not only at a high risk of influenza, but have an increased susceptibility to new attacks afterward (Kark et al., 1982). Influenza rates are similar in vaccinated smokers and nonsmokers. However, influenza vaccination can be considered to be more efficacious in smokers than nonsmokers because the infection rates are higher in unvaccinated smokers (Cruijff et al., 1999).
3.2. Bacterial infections
Similarly, cigarette smoke exposure was also found to be associated with increased inflammation following challenge with bacterial agents such as
A population based case-control study (Nuorti et al., 2000) showed that smoking was the strongest independent risk factor for invasive pneumococcal disease among immunocompetent adults. The OR was 4.1 (95% CI, 2.4-7.3) for active smoking and 2.5 (95% CI, 1.2-5.1) for passive smoke exposure in nonsmokers compared with nonexposed nonsmokers. The attributable risk in this population was 51% for cigarette smoking and 17% for passive smoking. The risk of pneumococcal disease declined to nonsmoker levels 10 years after cessation. In another case-control study, current smoking was associated with a nearly 2-fold risk of community-acquired pneumonia (OR: 1.88; 95% CI, 1.11-3.19), where 32% of the risk was attributable to cigarette smoking (Almirall et al, 1999). There was a trend toward a dose-response relationship: A 50% reduction in the OR was reported 5 years after cessation of smoking.
In vitro adherence of
A large case-control study in India examined smoking and tuberculosis in men between 35 and 69 years of age (Gajalakshmi et al., 2003). The tuberculosis prevalence risk ratio was 2.9 (95% CI, 2.6-3.3) for ever-smokers compared with never-smokers, and the prevalence was higher with a higher level of cigarette consumption. The authors found that the smoking attributable fraction of deaths from tuberculosis was 61%, greater than the fraction of smoking-attributable deaths from vascular disease or cancer. In a study among children living with a patient with active pulmonary tuberculosis, passive smoking confirmed by measurement of urinary cotinine levels was a strong risk factor for the development of active tuberculosis (OR: 5.39; 95% CI, 2.44-11.91) (Altet et al., 1996).
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The biological basis by which tobacco smoking increases tuberculosis risk may be through a decrease in immune response, mechanical disruption of cilia function, defects in macrophage immune responses, and/or CD4+ lymphopenia, increasing the susceptibility to pulmonary tuberculosis (Rich & Ellner, 1994; Onwubalili et al., 1987).
4. Conclusion
Smoking appears to be an important risk factor for the acquisition of a lower respiratory tract infection (bronchitis, influenza, pneumonia, tuberculosis). This link is likely mediated by smoking’s adverse effects on respiratory defenses (structural and immune system changes induced by smoking). Considering the high rates of morbidity and mortality from pneumonia, tuberculosis and influenza, as well as the economic consequences of work days lost from lesser respiratory infections, the merits of smoking cessation are clear. The fact that smokers have been shown to be less likely than nonsmokers to undergo vaccination and yet are probably at higher risk for influenza and pneumococcal infections highlights the importance of targeting this group for vaccination. The available epidemiological evidence, from studies worldwide, indicates a dose-response relationship between smoking and tuberculosis and that the association is likely to be a causal one. This provides a compelling reason for smoking cessation measures to be undertaken to combat the scourge of tuberculosis, particularly in developing countries. Physicians should educate their smoking patients about their increased risk of respiratory infections, the importance of appropriate vaccinations, and the benefits of smoking cessation.
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