Introduction
Complex gene–environmental interactions play a key role in the development of asthma and rhinitis. Other factors are early-life sensitization to aeroallergens, presence of atopic dermatitis or allergic rhinitis, lower respiratory tract infections with respiratory syncytial virus and potentially with other viruses (including rhinovirus and metapneumovirus), among others. Maternal smoking during pregnancy and children's exposure to environmental tobacco smoke (ETS) could be among nonallergic factors associated with an increased risk for development of and enhanced morbidity in persistent asthma or rhinitis or both [1].
Tobacco smoke is a major component of indoor air pollution, and ETS contains the same toxic substances as identified in mainstream tobacco smoke. Secondhand smoke contains at least 250 chemicals known to be toxic, including more than 50 that can cause cancer.
Cigarette smoking is associated with a 10-fold increase in the risk of dying from chronic obstructive lung disease. About 90% of all deaths from chronic obstructive lung diseases are attributable to cigarette smoking in the United States (www.cdc.gov/tobacco/). According to the World Health Organization (WHO), currently 5.1 million people die every year globally from tobacco use, out of which 1.2 million die in the south-east Asia region alone (www.searo.who.int/en).
Approximately 38% of children are exposed to ETS in the home, whereas 23.8% were exposed by maternal smoking during pregnancy [2]. About 9% of children between 9 and 15 years are active smokers in the UK. More than 3 million children under the age of 18 in the United States are current tobacco users. Nationwide, one in five high-school students (grades 9–12) is current smoker, and 7.1% of eighth graders currently smoke (www.cdc.gov/mmwr/pdf/ss/ss5704). Smoking is quite prevalent among teenagers attending high school in Argentina, with 20% of eighth graders and 43% of 11th graders reporting themselves to be smokers [3]. More recently, as a part of the International Study of Asthma and Allergies in Childhood (ISAAC) Argentina study, we have shown that half of total sample had parental smokers at home, and 13.4% of students smoked at least one cigarette/day in past 6 months [4].
In an inner-city children cohort, the major tobacco exposure has been associated with lower education, socio-economic status and depression [5•]. The smoking habit would begin even in primary school particularly in low and middle-income groups. This is relevant from the public health point of view, particularly in low and middle-income (L/MI) countries, as a meta-analysis showed that ETS causes adverse respiratory health such as either a serious lower tract respiratory illness (LRTI) or hospitalization for LRTI. ETS exposure increases at least two times the risk of having LRTI [6].
Immunological effects of tobacco smoke
There is now evidence demonstrating the detrimental effects of exposure to tobacco smoke on the immune system. Evidence that ETS can influence early immune function is becoming available.
Preliminary studies have shown that newborns of smoking mothers not only have altered cellular immune function but also the innate immunity [7]. Toll-like receptors (TLRs) are essential for proper innate responses against microbes as well as for regulatory pathways inhibiting the allergic immune responses. TLRs are found on many cells involved in immediate host defense including antigen-presenting cells (APCs) and CD4+/CD25+ T-regulatory cells. Newborns of smoking mothers may have altered signaling through TLRs. Maternal smoking in pregnancy resulted in a diminished innate production of antigen-presenting cell (APC) cytokines, as well as an impaired response to TLR ligands. These involved TNFa response through TLR-2, 3 and 4 ligands, also a decreased IL-6 production through TLR-2 and 9, and a decreased IL-10 production via TLR-2 activation [8••,9]. It has been described before the progressive diminished production of IL-10 by dendritic cells of babies exposed to ETS in the first 5 months of their life [9,10]. These studies suggest that infants born to smoking mothers have a significant impairment of their innate immunity. Taken together, not only a resulting increased susceptibility to microbial infections but also a weak Th1 stimulation pathway could favor the development of Th2 allergic diseases.
Endotoxin (lipopolysaccharides, LPS) is one of the most potent inflammatory agents known. Exposure to tobacco smoke offers endotoxin levels in huge amounts, more than hundred times compared with nonsmoking environment; these high levels could contribute to an elevated IgE and the subsequent development of atopic diseases and asthma. CD14 is the receptor for LPS and other bacterial wall-derived components. An interaction between CD14 genotypes and asthma severity (pre-FEV1) and IgE levels in the presence of ETS has been demonstrated [11,12].
The early exposure to ETS, both prenatal and postnatal, increases the risk of IgE sensitization to indoor inhalant and, in particular, food allergens [13••,14] and subsequently may have effects on atopy and airway hyperresponsiveness, with the consequent presence of atopic diseases [15,16].
More studies are needed to gain insight in the relationship between tobacco smoking, ETS and the immune response and inflammatory lower and upper respiratory illnesses.
Environmental tobacco smoke and rhinitis
Although having several reports on ETS as risk factor for having allergic diseases, very scarce information is available regarding allergic rhinitis.
As part of ISAAC in Singapore, a cross-sectional study was conducted on 6794 children. Home ETS exposure was associated with increased risks of current symptoms of rhinitis [prevalence ratio (PR) 1.23; 95% confidence interval (CI) 1.01–1.50] and rhino-conjunctivitis (PR 1.79; 95% CI 1.26–2.54). A higher prevalence of wheeze and doctor-diagnosed asthma was also found. Maternal smoking was associated with the outcomes mentioned above more than father's smoking [17].
In a French epidemiological study, 20% of 7798 children were exposed to tobacco in utero and, as it has been described earlier, maternal exposure had a greater impact than paternal exposure on children's allergic sensitization. Prenatal exposure was more associated with sensitization than postnatal exposure. Children with maternal allergies and exposure to maternal ETS during pregnancy were at higher risk for sensitization to house dust mite [25.7 vs. 14.0%; odds ratio (OR) 1.95; 95% CI, 1.19–3.18; P = 0.006]. It seems to be some sort of synergistic effect between allergy in the mother, prenatal tobacco exposure and ETS [18].
Different aspects of nonallergic rhinitis (NAR) have been reviewed recently, including the association with environmental factors such as ETS. This pollutant has been found involved in nasal obstruction and alterations in muco-ciliary clearance. Even though the features of the nasal response to allergens are similar to that produced by ETS and other irritants, the underlying mechanism appears to differ [19].
A British survey corroborates the tendency in active smokers only, as passive exposure was not significantly associated [20]. The different effect of active and passive smoking described in this article highlights some controversy, as well as another report that states that adolescents exposed to passive smoking have fewer rhinitis symptoms [21].
We evaluated the independent and additive effect of both personal and parental tobacco smoke exposure on symptoms of both asthma and rhinitis in 13 to 14-year-old children from Salta, a city located in Northern Argentina. We found a trend toward an association of passive smoking with current symptoms of rhinitis and physician-diagnosed hay fever [4].
Environmental tobacco smoke and asthma
The influence of ETS on the presence and severity of asthma has been well documented [22,23]. Whether smoking causes asthma or only exacerbates latent and controlled symptoms remains controversial. However, longitudinal and case–control studies have described smoking as a risk factor for developing asthma [24–27].
Infants of mothers who smoke have reduced respiratory function and are more likely to develop wheezing. Lower values of peak tidal expiratory flow as a proportion of total expiratory time (tPTEF/tE) were independently associated with maternal smoking during pregnancy [>10 cigarettes daily; beta coefficient −0.049 (0.022), P < 0.05] and a family history of asthma [−0.028 (0.014), P < 0.05]. This study suggested that in-utero smoke exposure and a family history positive for asthma are associated with reduced lung function after birth. These factors could adversely affect lung development in utero[28]. In another study looking at the effect of tobacco exposure in utero, it was found that the in-utero exposure to maternal smoking was associated with increased risk for asthma diagnosed in the first 5 years of life and for persistent asthma. Interestingly, grand-maternal smoking during the mother's fetal period was also associated with increased asthma risk in her grandchildren (OR 2.1; 95% CI 1.4–3.2). Therefore, not only maternal but also grand-maternal smoking during pregnancy may increase the risk of childhood asthma [29].
Besides, a recent meta-regression explored the relationship between tobacco exposure and the induction of childhood asthma, selecting a total of 38 recent studies and previous meta-analysis in the field. The significant reported relative risk (RR) for secondhand smoking and ever, current and incident asthma were 1.48 (95% CI 1.32–1.65), 1.25 (1.21–1–30) and 1.21 (1.03–1.36), respectively [30].
In a cross-sectional study, we investigated the effect of ETS on atopy, and wheezing disorders were studied in 1737 preschool children from Austria. Up to 46% of the participating children were exposed to ETS at some stage in their life. The exposure to tobacco smoke during pregnancy was associated to a significantly increased risk for wheezing in the first year of life (OR 1.6; 95% CI 1.0–2.6), wheezing in the past 12 months (OR 1.5; 95% CI 1.0–2.4) and doctor-diagnosed asthma (OR 2.1; 95% CI 1.0–4.1). There was also an association with the socio-economic level, the lower the educational background the higher the risk of the children for having wheezing [31].
More recently, a study from the United States was published. Data from National Children's Health Survey (NCHS, 2003) were obtained from a representative sample (n = 102 000) of youths 0–17 years of age. The study showed that household smoking was associated with a statistically significant increase in risk of asthma among children (P = 0.026). This association was not influenced by outdoor air quality at the state level or socio-economic position. These results show a link between cigarette smoking in the home and childhood asthma [32].
Several deleterious effects have been described because of smoking: accelerated decline in lung function, more severe symptoms, impairment in quality of life and diminished therapeutic response to steroids [33–36]. Taking these data together, there is no doubt about the harmful effect of tobacco smoking on this regard.
There is evidence suggesting that asthma susceptibility to ETS tobacco smoking could be genetically influenced. Selected genetic polymorphism was described as being associated with early onset of asthma, but not with late onset (over 4 years old). The interaction of 17q21 chromosome variant together with ETS in early life was significantly associated to this early onset of asthma [37••].
Active smoking as risk factor for rhinitis and asthma
There is strong evidence nowadays that active smoking is a risk factor, both for the presence and severity of symptoms, and also for the development of asthma [38–40].
In a French survey, being an active smoker was associated to asthma, eczema and rhino-conjunctivitis; and the most severe symptoms were significantly related to tobacco smoking [18]. The authors concluded that having an allergic disease does not seem to be a barrier to smoke as active smoking was reported among those adolescents having concomitant lifetime asthma and hay fever.
As part of ISAAC study in north Argentina, we found that 13.4% of the adolescents reported themselves as current smokers. Active smoking was associated with the presence of asthma symptoms in the past 12 months (OR 1.83; 95% CI 1.42–2.35). We speculated that some children with rhinitis or asthma or both never started smoking because of their respiratory health condition, as then the true risk influence by active smoking could be even higher (M. Gomez, W. Vollmer, C.E. Baena-Cagnani, in preparation).
In allergic rhinitis patients, smoking was significantly related to the risk of incident asthma, both in univariate analysis (OR 2.67; 95% CI 1.70–4.19) and in multivariate analysis (OR 2.98; 95% CI 1.81–4.92). Besides, there was a dose–response association of exposure to tobacco and risk of new-onset asthma in multivariate analyses, when smoking 1–10 pack-years had an OR of 2.05 (95% CI 0.99–4.27), 11–20 pack-years had an OR of 3.71 (95% CI 1.77–7.78) and 21 or more pack-years had an OR of 5.05 (95% CI 1.93–13.20) [25]. The rigorous selection of patients without any sign of having asthma or chronic obstructive pulmonary disease (COPD) or both at the beginning of the follow-up gives this report a unique value [41••].
From the therapeutic point of view, tobacco smoking is associated with a lesser response to oral steroids [36], inhaled corticosteroids [42] and leukotrienes receptor antagonists [43••]. A school-based asthma therapy trial is proposing comprehensive school-based program with control of ETS in order to assess whether it helps to improve asthma medication efficacy [44].
All these findings suggest tobacco exposure control should be a tool in the management of asthma.
Conclusion
- Tobacco smoking provokes a strong immunological imbalance to those exposed. The innate immunity is impaired by tobacco exposure.
- As a consequence, typical allergic diseases such as rhinitis and asthma could initiate or aggravate preexisting conditions or both. Active smoking is a factor for nasal obstruction in NAR.
- Tobacco smoking (and probably ETS also) has a detrimental effect on the efficacy of inhaled corticosteroids, leukotriene receptor antagonists and on those patients in programs for controlling asthma in deprived populations.
- Robust evidence is provided in order to empower both primary and secondary prevention by physicians.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 181–182).
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