Long-term mortality among adults with or without asthma in the PAARC study

Mortality rates for asthma appear to have been increasing in industrialised countries but are now considered stable 1–4. The reasons for this trend remain unclear since mortality due to many chronic diseases has decreased and physiopathological and therapeutic knowledge concerning asthma has improved 5.

Understanding concerning the long-term mortality of asthmatics is still inadequate and most studies have been unable to ascertain whether or not asthma shortens survival. Only few epidemiological data on the overall survival of adults with asthma are available. The results obtained have sometimes been contradictory. In particular, there is still controversy concerning the excessive risk of death from other lung diseases in asthmatics 6. For example, Lange et al. 7 concluded that, in the general population, self-reported asthma was associated with a slight excess of mortality, mainly due to respiratory diseases. In a community-based study, Markowe et al. 8 reported that mortality from all causes was higher in the asthmatic cohort. The predominant cause of excess mortality identified was respiratory diseases, more specifically asthma and chronic obstructive airway disease 8, 9. Silverstein et al. 10 stated that survival among patients suffering from asthma but without any other lung disease was not significantly different from that expected. Risk factors and prognoses in asthmatics are not yet well established and reducing the risk of mortality due to asthma remains difficult. Some of the inconsistencies may result from misdiagnosis of asthma. Moreover, although many studies have controlled for the effects of age, sex and smoking 7, 10, other confounding factors, such as occupational and environmental factors, may also be important 11.

The 25-yr mortality of a large French cohort was studied in order to determine whether or not mortality was premature in asthmatics and to analyse the specific causes of death.

Methods

The Pollution Atmosphérique et Affections Respiratoires Chroniques (PAARC; Air Pollution and Chronic Respiratory Diseases) study was conducted during 1974–1976 in 24 areas around seven French cities, in order to assess the relationship between chronic respiratory diseases and air pollutants. The inclusion criteria were described in a previous PAARC report 12, 13. The PAARC study included adults aged 25–59 yrs. The household family had to be French. They had to have been living in the area for 3 yrs and be of a socioeconomical status other than that of manual workers (the potential occupational exposures could exert greater effect than that expected from air pollution). The PAARC study included 20,310 adults in its initial stage but 900 were excluded because of unreliable data. Vital status was sought for all subjects born in France (16,905 subjects) over 3 yrs (1995–1998) for each place of birth and data were completed using a computerised national register (National Register of People Identification (RNIPP)). Causes of death were obtained through a specialised department (Causes of Death) of the National Institute of Health and Medical Research (INSERM). They were coded according to the International Classification of Diseases eighth and ninth revisions (ICD‐8 and ICD‐9) and pooled into four categories: cardiovascular diseases, respiratory diseases, cancer, and other causes (including endocrine diseases, blood diseases, mental troubles, nervous system disease, infectious diseases, digestive system disease, genitourinary system diseases, skin diseases, osteoarticular system diseases, congenital anomaly, other morbid symptoms, trauma and poisoning). Causes of death from among the total available causes of deaths in asthmatic and nonasthmatic subjects and then respiratory versus nonrespiratory causes of death were compared using a global Chi-squared test.

Asthmatics were defined as subjects having responded positively to either the diagnostic question “have you ever had asthma?” or the symptomatic question “have you ever had attacks of breathlessness associated with wheezing?” during a face-to-face baseline interview conducted in 1974–1976. The validity of these questions has been assessed in previous studies 14. Individual data were also collected during 1974–1976. The baseline variables studied were as follows. 1) Sex. 2) Education, defined in three levels: primary, secondary (technical school certificate) and tertiary (university). 3) Smoking habits, defined in five classes from the initial questionnaire: nonsmokers (people who had not smoked for 1 yr), former smokers (people who had stopped smoking for ≥1 month), light smokers (<10 g tobacco·day⁻¹), moderate smokers (≥10 and ≤20 g tobacco·day⁻¹) and heavy smokers (≥20 g tobacco·day⁻¹). 4) Forced expiratory volume in one second (FEV₁), measured by vitalograph mobile spirometry 12 (on the basis of at least three graphs, the best FEV₁ being selected) and expressed as a percentage of reference (predicted) values according to the recommendations of the European Respiratory Society 15. Analysis was performed using FEV₁ as a continuous variable and then categorising it according to the severity criteria of asthma (National Heart, Lung and Blood Institute (NHLBI)/World Health Organization (WHO) workshop report, 1995) as either less than or at least 80% predicted 16. 5) Occupational exposure to gas, dust or vapour, defined using a job exposure matrix 17.

The study outcome was death. Adjusted mortality relative risk (RR) was estimated using a Cox proportional hazards regression model and the model with delayed entry to take into account left-truncation 18, 19. A multivariate Cox model allowed the association between death and the different variables to be studied. Models were initially created for both sexes, then separately for males and females, and finally for nonsmokers, in order to study mortality caused by asthma rather than chronic bronchitis or smoking.

Results

Mortality

The mean age at death was similar in asthmatics and nonasthmatics. There were 224 (23.8%) deaths in asthmatics and 2,171 (16.3%) in nonasthmatics, with mean incidence rates during follow-up of 10.4 and 6.9 deaths·1,000 person-yrs⁻¹, respectively (p<1×10⁻⁴). The risk of death was significantly higher in asthmatics than nonasthmatics (p<1×10⁻⁴, log-rank test) (fig. 1⇓).

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Fig. 1.—

Survival of asthmatics (═: forced expiratory volume in one second (FEV₁) ≥80% predicted; ––––: FEV₁ <80% pred) and nonasthmatics (– - –: FEV₁ ≥80% pred; - - - - -: FEV₁ <80% pred) in the Pollution Atmosphérique et Affections Respiratoires Chroniques (Air Pollution and Chronic Respiratory Diseases) study (1974–1998). Log-rank test p<1×10⁻⁴.

Discussion

The present findings suggest excessive mortality in asthmatics, particularly due to COPD. This finding is strengthened by the fact that the data are based on a 25-yr follow-up of a large sample of the French adult population. The study could have some limitations regarding data precision due to asthma definition, which can be problematic because of difficulties in the differential diagnosis of asthma and COPD overall in adults. Similarly, smoking habits, which are likely to have changed between the 1970s and the 1990s, and mortality data depend on death certificates, the reliability of which can be uncertain 20. Moreover, selection bias must be considered when extrapolating the present results to the entire population. The study did not include people of foreign nationality, those born in foreign countries or the elderly. For some females, vital status could not be easily identified due to their change of family name after marriage. If being female, having a low educational level and being elderly make subjects more susceptible than others to death due to asthma, it is possible that this selection bias would have induced difficulty in demonstrating their effect 21.

Nevertheless, some comment can be made with regard to these potential limitations. The definition of asthma used in the present study is the one commonly used in epidemiological studies; several studies have shown that the question “do you have asthma?” is very specific 22, 23, and Vestbo et al. 24 concluded that questions on breathlessness, compared to spirometric measurements, FEV₁ in particular, provide good validity 25. Even if tobacco habits have changed between the 1970s and the 1990s, tobacco consumption has been taken into account both qualitatively (former and current smokers) and quantitatively (grams of tobacco per day). The loss of information on smoking habits was not relevant in the present study because people tend to quit smoking and it is uncommon to start smoking at the age chosen for recruitment (25–50 yrs); the strongly expected association of the smoking variables with specific causes of death (previous analysis by authors) showed the relevance of this indicator. Therefore, the analysis was restricted to nonsmokers in order to focus on asthma 26, 27 and the confusion bias reduced by controlling not only for the effects of age (left-truncated model), sex, educational level and smoking but also for other confounders such as occupational exposure. The PAARC population can be considered as representative of the urban nonmanual worker household population in France in the 1970s and provides original findings. Thus, in this 25-yr follow-up of a large sample of the French adult population, premature mortality was found in asthmatics, which could provide an answer to the questions of Ulrik 28 regarding mortality in asthma. A significant excess mortality was observed in asthmatic subjects, with an excess of death due to COPD in asthmatic subjects (ICD‐9 codes 490–496). This finding supports the hypotheses of previous studies, according to which asthma is a risk factor for COPD and COPD a risk factor for mortality in asthma 29. No significant excess in mortality from lung cancer was found among asthmatics, unlike in the studies of Boffetta et al. 6, Huovinen et al. 30 and Wu et al. 31, in which the risk of death due to lung cancer adjusted for smoking was higher in males with asthma (RR 3.2, 95% CI 1.4–7.3). However, no long-term survival studies controlled for occupational exposure. Even if FEV₁ is known to be a predictive factor of mortality, this association has rarely been described in the long-term survival of asthmatic subjects 32, 33. Like the present authors, Lange et al. 7 observed that self-reported asthma was associated with poorer survival and higher risk of death from pulmonary diseases. They also stressed the role of an FEV₁ of <80% pred as a predictor of mortality, but its role was similar in asthmatics and nonasthmatics. The mortality rate from all causes in the present study is comparable to those reported in previous studies; Markowe et al. 8 found increased mortality from all causes (RR 1.6, 95% CI 1.3–2.0) and Huovinen et al. 30 found an age-adjusted RR of 1.5 (95% CI 1.1–2.1).

In conclusion, the present study suggests excessive mortality in asthmatics, particularly due to chronic obstructive pulmonary disease. Smoking habits, social class and occupational exposure did not fully explain this excess of mortality 34, but a decrease in forced expiratory volume in one second increased the risk of death even in nonsmokers. Therefore, an implication of this study is that mortality in asthmatics could be diminished by avoiding lung function decrease, thus stressing the usefulness of monitoring forced expiratory volume in one second in asthmatics.