PI*Z individuals have a severe deficiency of alpha-1 antitrypsin (AAT) and are genetically susceptible to developing chronic obstructive pulmonary disease (COPD) (Black and Kueppers 1978; Larsson, 1978; Tobin et al 1983; Janus et al 1985; Brantly et al 1988; Silverman et al 1989) particularly with personal tobacco use (Larsson 1978; Tobin et al 1983; Janus et al 1985; Brantly et al 1988; Silverman et al 1989). Other reported risk factors include occupational exposures (Piitulainen et al 1997, 1998; Mayer et al 2000b), lower respiratory tract infections (Brantly et al 1988; Silverman et al 1989), and family history of emphysema (Silverman et al 1989). In an early study of highly symptomatic PI*Z patients, tobacco smoking was identified as a risk factor by comparing the age of symptom onset in smokers and nonsmokers (Larsson 1978). Age of symptom onset has not been well studied in relationship to other exposures.

Childhood environmental tobacco smoke (ETS) exposure has been associated with increased frequency and severity of respiratory infections (Colley et al 1974; Ware et al 1984; Fergusson and Horwood 1985; Tager et al 1993; Chen 1994; Strachan and Cook 1997), respiratory symptoms (Cunningham et al 1996; Ehrlich et al 1996; Jaakkola et al 1996; Withers et al 1998), and diminished airflow (Ware et al 1984; Tager et al 1993) in the general population. A prospective study of PI*Z children found a greater prevalence of recurrent wheezing at 4 years of age in those with two smoking parents. Lower forced expiratory volume in one second [FEV₁]/forced vital capacity [FVC] ratio was found in that group at 18 years, although no difference in FEV₁ or wheeze was seen (Piitulainen and Sveger 1998). Childhood lower respiratory infections have been associated with respiratory symptoms (Gold et al 1989) and airflow limitation (Gold et al 1989; Shaheen et al 1994; Johnston et al 1998) in the general population. An interaction between the effects of ETS exposure and respiratory infections has been postulated (Gold et al 1989; Strachan and Cook 1997).

We systematically surveyed 313 PI*Z individuals to examine the relationships of personal tobacco use, childhood ETS exposure, and respiratory infections to age of symptom onset.

Survival analyses were performed using Cox proportional hazards modeling (Elashoff 1983). The hazard rate may be thought of as the instantaneous odds of developing the symptom at a given age for those individuals who have not developed that symptom before that age. The hazard ratio (HR) is the hazard rate for those in the risk group divided by the hazard rate for those not in the risk group. A separate Cox model was created for outcomes of cough, wheeze, and dyspnea onset. Models were created using only one predictor variable at a time, as well as multivariable modeling of the predictor variables of pack-years of smoking before the development of each symptom, childhood ETS, childhood respiratory infections, and family history of emphysema. Three sets of interaction were also examined in these models. First, exposure variable by age of onset of symptom interactions were included to test for the proportional hazards assumption, ie, that the HR does not vary by age of symptom onset. Plots of differences in log cumulative hazard rates for the exposure group versus age of onset of symptom were also examined to determine if simple interaction terms were adequate to account for nonproportional hazards. Second, group by exposure variables were included to test for heterogeneity between sampling groups. None of these group interaction terms were significant. Third, exposure interactions were also examined. The main interaction of interest here was between ETS and respiratory infections, controlled for personal smoking. Interactions between personal smoking and respiratory infections, ETS and personal smoking, ETS and family history, and family history and personal smoking were also examined. None of these interactions reached a significance level of <0.1 in the final model, so results are not presented here.

Odds ratios of current symptoms and of respiratory infections given childhood ETS exposure were estimated using logistic regression techniques and chi-square test. Spearman correlation coefficients were used to assess the association between the ages of onset of cough, wheeze, and dyspnea. Differences between groups were assessed by ANOVA. All statistical tests were two-sided and were considered statistically significant at the 5% level. Statistical analyses were performed using JMP (version 3.2, SAS Institute Inc., Cary, NC) and SAS (version 6.12, SAS Institute Inc.).

In this study, we found that childhood ETS exposure was associated with earlier onset of cough in individuals with PI*Z AAT deficiency. Childhood respiratory infections and family history were associated with earlier onset of wheeze. Among those with symptoms, childhood respiratory infections were associated with earlier onset of all symptoms in both smokers and never-smokers. With personal smoking, increased risk of onset of cough and wheeze was noted within the first 10 pack-years. Earlier onset of dyspnea was seen after 10 pack-years with a dose-dependent increased risk up to 30 pack-years.

In an earlier analysis of Groups 1 and 2, we had found a statistically significant association between childhood ETS exposure and earlier age of onset of cough, wheeze, and dyspnea, adjusted for personal smoking, dichotomized as ever- or never-smoker (Mayer et al 2000a). The main reason for recruiting additional subjects for this second study was to increase sample size. We also realized that we had the ability to calculate the number of pack-years smoked before the age on onset of symptoms, thus giving a better measure of the “dose” of personal smoking. We had previously analyzed earlier age of beginning personal smoking in Groups 1 and 2, but we did not find this to be a better or additive predictor. Although there was no overall difference in the number of cigarettes smoked per day between those with and without childhood ETS, it is possible that these who began smoking earlier also smoked more intensely. A post-hoc analysis revealed this trend (p = 0.079). We continued to see a greater association between childhood ETS and age of onset of wheeze and breathlessness in Groups 1 and 2 than in Groups 3 and 4, albeit of borderline significance. It is possible that the earlier reported age of onset of cough and breathlessness could have been contributory, but our analyses for heterogeneity did not reveal any statistically significant differences between the groups.

No statistically significant interactive effect on age of symptom onset was observed between the occurrence of childhood respiratory infections and ETS exposure. It is possible that the sample size conferred inadequate power to detect such an interaction. While we were able to identify those with ETS exposure in early childhood, we lacked information regarding the age at which lower respiratory tract infections occurred, precluding us from confirming other observations (Colley et al 1974; Ware et al 1984; Fergusson and Horwood 1985) that childhood ETS exposure predisposes to infections during the first few years of life. The questionnaire did not distinguish between prenatal, postnatal maternal, or paternal smoking. There remains considerable controversy regarding the relative risk conferred by these different exposure sources (Ware et al 1984; Fergusson and Horwood 1985; Tager et al 1993; Chen 1994; Strachan and Cook 1997). Because of our relatively small sample size, we combined bronchitis and pneumonia in childhood, but these may confer differential risk. As individuals reporting ETS exposure were more likely to also report previous lower respiratory tract infections, these risk factors would be additive in those individuals.

Experimentally, it takes time for the AAT deficiency-associated pulmonary parenchymal destruction to occur (Karlinsky and Snider 1978), which is supported by the observation in epidemiologic studies that few individuals develop symptoms before age 25 (Larsson 1978; Brantly et al 1988; Silverman et al 1989). It is possible that our study participants with current chronic symptoms may have reported respiratory symptoms in childhood that had nothing to do with their genetic disease. Even if they had, a serious detriment to quality of life is posed by the presence of respiratory symptoms during childhood and teenage years in a population at increased risk for an adult life with chronic progressive pulmonary problems.

While we examined the effects of prior respiratory infections and personal tobacco use, there may have been additional effects from other unmeasured exposures or host factors. For example, increased risk of airflow limitation and chronic bronchitis has been found in smoking first-degree relatives of individuals with severe COPD without AAT deficiency (Silverman et al 1998).

Misclassification and recall bias may have affected our results. It is possible that subjects reporting childhood ETS exposure may have been more likely to recall symptoms and to ascribe them to an earlier age. However, the 6% of subjects reporting dyspnea before age 20 in this series is similar to the 7% with symptoms before age 20 in the study by Brantly and colleagues (1988), but less than the 18% reporting lung trouble before age 16 in the series by Silverman and colleagues (1989), making it less likely that our subjects significantly underestimated their age of onset of symptoms. We may have missed significant childhood ETS exposure outside of the home, biasing our results towards the null. Alternatively, individuals with earlier onset of symptoms may have been more likely to report childhood ETS exposure. This would have led to a selective misclassification of exposure, falsely implicating childhood ETS exposure or increasing the magnitude of its true effect. We attempted to minimize this bias by separating these two questions and nesting them among questions about other current symptoms and environmental exposures, respectively. As there was no real association between childhood ETS exposure and current symptoms, we do not believe current clinical status presented a significant source of bias.

Although we adjusted for personal tobacco use in the Cox proportional hazards modeling, it is possible that some confounding still occurred. Never-smokers may have had a greater tendency to recall ETS exposure than smokers. A “healthy smoker effect” is possible whereby those who chose never to smoke may somehow already have been less healthy than those who did. It is also possible that the effects of personal tobacco use outweighed and obscured the effects of childhood ETS exposure. The mean age of smoking commencement was almost 2 years earlier in those with ETS exposure compared with those without exposure. It is likely the significantly earlier age of onset of wheeze and dyspnea with childhood ETS exposure in smokers only is attributable to the earlier age of beginning smoking. However, it does not account for the earlier age of cough in the never-smokers. Multiple comparisons error is unlikely as childhood ETS exposure had a consistent effect on elevated risk of developing cough, mean age of onset of cough, and odds of currently having chronic cough.

Personal smoking was associated with elevated risk of development of dyspnea beginning after 10 pack-years and increasing in a dose-dependent manner up to 30 pack-years. Decreased risk after 30 pack-years might represent a “survivor effect” whereby those who are able to smoke that long without developing symptoms are less likely to do so in the future. Elevated risk for the development of cough and wheeze during the first 10 pack-years of smoking only was not expected. It is possible that these represent irritant symptoms rather than true AAT deficiency-related pulmonary injury and therefore might occur more quickly, if indeed they are to occur. Post-hoc analysis shows a median of cessation of smoking 7 years after the development of cough, 4 years after the development of wheeze, and 5 years after the development of dyspnea.

In order to achieve adequate statistical power, we recruited study participants from four known populations with this uncommon disorder. As such, there is an inherent risk of selection bias that may limit our ability to generalize our findings to the PI*Z population as a whole. Fewer subjects in this study reported dyspnea than in a survey of Alpha-1 Association members (90% with dyspnea at mean age 48 years) or participants in the National Heart, Lung, and Blood Institute Registry (90% at mean age 46 years). However, the prevalence of pulmonary symptoms was greater in our study population than in the Swedish Alpha-1 Registry studies (Piitulainen et al 1997, 1998). Our study subjects may have been more symptomatic than an unselected PI*Z population. Only a portion of the participant phenotypes were verified. We believe that the possible inclusion of individuals with less severe deficiency states, with their expected overall less severe clinical course, would have served only to decrease the power of our study.

In individuals with severe AAT deficiency, personal smoking was associated with earlier onset of cough, wheeze, and dyspnea. Self-reported childhood environmental tobacco smoke exposure was associated with younger age of cough. Childhood respiratory infections and family history of emphysema were associated with earlier onset of wheeze.