Mortality of elderly subjects with self-reported asthma in a French cohort, 1991±1996

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1 European Journal of Epidemiology 17: 57±63, Ó 2001 Kluwer Academic Publishers. Printed in the Netherlands. Mortality of elderly subjects with self-reported asthma in a French cohort, 1991±1996 C. Dantzer 1, J.F. Tessier 1, C. Nejjari 1,2, P. Barberger-Gateau 1 & J.F. Dartigues 1 1 INSERM U330, University of Victor Segalen, Bordeaux 2, Bordeaux Cedex, France; 2 Faculte de MeÂdecine et de Pharmacie, Casablanca, MAROC Accepted in revised form 2 April 2001 Abstract. The objective of this study is to describe the mortality of subjects with self-reported asthma aged 65 and over and to determine risk factors. PAQUID (Personnes Age es QUID) is a prospective cohort of 3777 elderly people, living at home in the South-west of France. The study of subjects with self-reported asthma started at 3 year follow-up by using three epidemiological questions: `Did you have an attack of wheezing that made you feel short of breath in the last 12 past months?', `Have you ever had asthma?', `Did you have at least one asthma attack in the previous 12 months?'. Data on mortality were available at 8-year follow-up. Among the 2348 subjects who responded to these questions, 206 reported symptoms of asthma. Two groups were de ned as `pure asthma' and `associated asthma' taking into account chronic bronchitis and smoking. Besides a gender di erence, there was no statistical di erence between those two groups so they were combined in a single group for further analysis. During the 5-year study period, 29.1% of subjects with self-reported asthma vs. 23.8% nonasthmatics died. A Cox model with delayed entry was used to calculate mortality rates. Interaction terms between each of the factors related to mortality and asthmatic status were analyzed to determine risk factors of mortality. Subjects with selfreported asthma had a higher risk of death than nonasthmatics (relative risk (RR): 1.49; 95% con dence interval (CI) 1.1±1.9; p ˆ 0.009). This risk was signi cant (RR: 1.4; 95% CI: 1.05±1.8; p ˆ 0.02) even after adjustment on morbidity variables. However no speci c mortality risk factors were found for subjects with self-reported asthma. Key words: Elderly, Mortality, Self-reported asthma Introduction Life expectancy has been increasing steadily over the last decades. Nowadays, French people aged 65 years and over represent 15.4% of the general population [1]. This trend goes along with an increase in chronic pathologies and has consequences on the management of these patients. For the last 10 years, attention has been focused speci cally on asthma. Its prevalence is increasing in industrialized countries [2], and it is responsible for 2000 deaths in France each year [3]. Since asthma is not an uncommon disease in subjects aged 65 years and over (prevalence 4±8%), it should be considered as a public health problem [4±8]. Moreover, chronic diseases are a major problem in the elderly since they can lead to disability by restraining the elderly autonomy, a ecting quality of life and leading to mortality [9]. In spite of these aspects, the consequences of asthma in the elderly in terms of mortality have been little studied. Some authors have compared mortality of asthmatic subjects to nonsick subjects aged less than 60 years old and found that these subjects were dying signi cantly more than nonsick subjects [10±12]. The risk factors of mortality of adult asthmatics found in some studies are described in three categories: psychological characteristics, such as anxiety [13] and depression, respiratory capacity and smoking [11]. It is not known whether the same applies to an elderly population [14]. Therefore, the goals of the present study were (1) to determine if elderly subjects with self-reported asthma have a higher risk of dying compared to nonasthmatics; and (2) to identify possible risk factors for mortality. Materials and methods Population Information for this study was gathered from the PAQUID (Personnes Aà geâ es QUID) cohort. The general methodology of PAQUID has been described previously [15, 16]. The target population is a cohort of 3777 subjects aged 65 years and over, living at home, and taken at random from the electoral rolls of the Gironde and Dordogne `departments' in

2 58 South-western France. A sample of 75 districts was randomly selected in these two administrative areas, with strati cation upon the size of urban units (<2000; 2000±9999; 10,000±49,999; 50,000±99,999; >100,000 inhabitants). Subjects were chosen at random from the electoral rolls of each district, with a homogeneous sampling ratio and strati cation by age and sex. Data for the present study were collected by a questionnaire lled in at home by speci cally trained psychologists. During the 3 year follow-up (1992), 2406 subjects (63.7% of the initial sample) were seen. Of these, 2348 responded to the three questions recommended to detect prevalent asthma in epidemiological studies [17]: `Did you have an attack of wheezing that made you feel short of breath in the last 12 past months?', `Have you ever had asthma?', `Did you have at least one asthma attack in the previous 12 months?'. In France, asthma is normally diagnosed according to international criteria [5]. In the present epidemiological study, identi cation of asthma was based on the subject's responses to the preceding questions. A subject was considered as asthmatic if he had responded `yes' to at least one of the three questions, and nonasthmatic if he had responded `no' to all of the three questions. Moreover, according to Fletcher's recommendation [18], subjects were considered as having `chronic bronchitis' if they responded positively to the question: `Have you had any productive cough of sputum or phlegm in the morning for at least 3 months per year for the two previous years?', and smoking history was taken into account. Subsequently, asthma was considered as `pure asthma' when negative responses on both chronic bronchitis and smoking history were obtained. If the subjects had any smoking history and/or chronic bronchitis, asthma was classi ed as `associated asthma'. Every death occurring during the follow-up was registered systematically using the ICD-9 classi cation [19]. If a subject could not be reached, he/she was checked at the proxy or his/her general practitioner. Otherwise, a letter was sent to the city administration asking if they had registered his death noti cation. Date of death was also registered. Moreover, for all subjects who were known as dead, respective physicians were contacted in order to determine the direct cause(s) of death. Data collected Table 1 presents the independent variables under study. Sociodemographic variables were age at the third year follow-up, gender, marital status and educational level (no education vs. primary level, and more). Psychosocial variables were depressive symptomatology measured by the CES-D scale [20], treatment for depression, subjective health, and Table 1. Description of the variables under study and their de nition Variables Measurement time De nition Sociodemographic Age 3-Year follow-up Quantitative Gender Inclusion Male vs. female Marital status 3-Year follow-up Married, couple vs. single, widow, separated, divorced Educational level Inclusion No diploma vs. primary school diploma Psychosocial variables Depressive symptomatology (CES-D scale) Depressed vs. nondepressed 3-Year follow-up Treatment for depression 3-Year follow-up Yes vs. no Subjective health (two analogic scales) Actual health 3-Year follow-up Good health vs. bad health Satisfaction 3-Year follow-up Satis ed vs. unsatis ed Symptoms and pathologies Dyspnoea 3-Year follow-up Yes vs. no Previous ischaemic heart disease Inclusion Yes vs. no Previous stroke 3-Year follow-up Yes vs. no Previous angina 3-Year follow-up Yes vs. no Hospitalization in the past 12 months 3-Year follow-up Yes vs. no Cognitive impairment 3-Year follow-up Quantitative Smoking Inclusion Yes vs. no Disability 3-Year follow-up Yes vs. no

3 59 cognitive impairment measured by the mini-mental status [21]. Morbidity variables were dyspnoea, previous attack of ischaemic heart disease, stroke, angina, and hospitalization in the past 12 months). Other variables were smoking and level of disability measured by the instrumental activities of daily living (IADL) scale [22]. Statistical analysis First, a descriptive analysis was performed to compare subjects with `pure asthma' and `associated asthma'. Since no statistical di erence was found between these groups, they were combined for further analysis in order to strengthen statistical power. Therefore, characteristics of subjects with selfreported asthma were compared to nonasthmatics by univariate analysis (Student test or v 2 test). The mortality analysis of subjects with selfreported asthma was performed by using a Cox model with delayed entry [23] on the whole sample (2348 subjects). Asthmatic status (self-reported asthma vs. nonasthmatic) was introduced as a covariable. This model was used to take into account age at the entrance in the cohort (left truncating) and potential confounding factors. The dependent variable was mortality event coded 1 vs. 0. In addition to age (taken already into account in the Cox model with delayed entry), independent variables, as de ned previously, were added to the model. Survival curves were realized with the Kaplan± Meier method and were compared by the Logrank test. The dependent variable was the subject's age at time of death, which was informed by the general practitioner. The study of mortality factors was performed by using a Cox model with delayed entry in two steps. First, we selected variables signi cantly associated to mortality. Then, we introduced an interaction term between each variable associated to mortality and asthmatic status to calculate the speci c relative risk of each variable. Results Among the 2406 subjects followed-up during the third year of the cohort, 2348 responded to the questions on asthma symptoms (674 men and 1374 women). The average age of the population at this time was years (range 68±100). Two hundred and six subjects (8.7% of the study population at 3 year follow-up) responded positively to one of the three questions on asthma and therefore were classi ed as having self-reported asthma, 2142 were considered as nonasthmatics. Out of these 206 subjects, 83 had `pure asthma' and 123 had `associated asthma'. Baseline characteristics of subjects with self-reported asthma and nonasthmatic subjects First, comparative analysis were performed between subjects with `pure asthma' and `associated asthma' on sociodemographic and morbidity variables (dyspnoea, ischaemic heart disease, hospitalization in the past 12 months, hospitalization causes and disability). No signi cant di erences were found between those two groups except for gender: there were more women in the `pure asthma' group (84%) than in the `associated asthma' group (30%). Therefore, these two groups were combined to compare subjects with self-reported asthma to nonasthmatics. Table 2 shows sociodemographic characteristics of these groups. Elderly subjects with self-reported asthma had a lower level of education than non- Table 2. Description of sociodemographic characteristics of the PAQUID cohort (n = 2348) Self-reported Nonasthmatics p asthma (n = 2142) (n = 206) Age (mean standard deviation) NS* Gender (%) NS Men Women Marital status (%) NS Married, couple Widow, single, divorced, separated, other Educational level (%) <0.001 No diploma Primary school diploma and more * NS ± nonsigni cant.

4 60 Table 3. Comparison of morbidity, smoking and disability variables (n = 2348) Self-reported asthma (n = 206) (%) Nonasthmatics (n = 2142) (%) Hospitalization in the past 12 months (yes vs. no) NS Hospitalizations reasons (in the past 12 months) Respiratory < Cardiac Dyspnoea (yes vs. no) <0.001 Ischaemic heart disease (yes vs. no) <0.001 Smoking (yes vs. no) Disability (IADL scale) (yes vs. no) p asthmatics (p < 0.001), were signi cantly more depressed (p ˆ 0.005), felt less in good shape (p ˆ 0.01), and were less satis ed with their quality of life (p ˆ 0.003). Morbidity, smoking and disability Descriptive analysis was also performed on morbidity, smoking and disability variables (Table 3). Subjects with self-reported asthma had more previous history of ischaemic heart disease (p < 0.001), were more often hospitalized for respiratory (p < ) and cardiac disorders (p ˆ 0.02), more dyspneic (p < 0.001), more smokers and ex-smokers (p = 0.01), and were more disabled than nonasthmatics (p ˆ 0.01). Mortality of subjects with self-reported asthma The 5-year mortality rate was 29.1% for subjects with self-reported asthma (60 out of 206) and 23.8% (510 out of 2142) for nonasthmatics. 26.5% of subjects with `pure asthma' and 28.5% of subjects with `associated asthma' died (no statistical di erence). Among the subjects with self-reported asthma who died, 45.3% were women and 54.7% were men. Moreover, among subjects who had died, subjects with self-reported asthma had been more frequently hospitalized for respiratory reasons than other subjects (p < 0.001). As shown in Table 4, there was no case of death by asthma attack, and causes of death did not di er signi cantly between the two populations (v 2 ˆ 3.8; p ˆ 0.4). In the group of subjects with self-reported asthma, ve deaths (according to the ICD-9 classi cation) were attributed to respiratory diseases: pulmonary infections, bronchial surinfections, and chronic respiratory insu ciency. A Cox model with delayed entry showed that the mortality risk for a subject with self-reported asthma was multiplied by 1.49 compared to nonasthmatics (95% CI: 1.098±1.951; p ˆ 0.009). In addition, survival curves by the Kaplan±Meier method were signi cantly di erent (Logrank test: v 2 ˆ 10.93; p < 0.001) (Figure 1). Mortality risk factors Two multivariate models were used to separate variables that are known to be related to mortality and variables that could be consequences of asthma (depression, dyspnoea and subjective health). As shown in Table 5, the risk of death for a subject with self-reported asthma was multiplied by 1.4 compared to nonasthmatics (p < 0.05) even after adjusting on gender, marital status, educational level, cognitive impairment, smoking and a previous history of ischaemic heart disease, stroke and angina. However, reporting symptoms of asthma was not a signi cant mortality factor when adjusting on depression, subjective health and dyspnoea. To nd speci c mortality risk factors for subjects with self-reported asthma, multivariate analysis was Table 4. Death causes at 8-year follow-up of subjects with self-reported asthma and nonasthmatics in the PAQUID cohort (n = 470) Mortality causes Self-reported Nonasthmatics asthma (n = 60) (n = 410) (%) (%) Cancer Cardio-vascular Stroke Respiratory a Others b and unknown a Five deaths for respiratory causes (two pulmonary infections, two bronchial surinfections and one chronic insu cient respiratory). b Others: digestive disease, accidents.

5 61 Figure 1. Survival curves of subjects with self-reported asthma and nonasthmatics (N=2348), (Kaplan-Meier method). performed using interaction terms (self-reported asthma variable). There was no signi cant interaction term. Therefore, none of the variables under study was speci c of subjects with self-reported asthma mortality. Discussion The results of the present study show that subjects in the PAQUID cohort with self-reported asthma died more than nonasthmatics (RR: 1.49; 1.1±1.9; p ˆ 0.009). This result is in accordance with data from other studies [7, 11, 12, 24]. The higher mortality risk was signi cant (RR: 1.4; p ˆ 0.02) even after adjusting on gender, educational level, marital status, cognitive impairment, smoking and a previous history of ischaemic heart disease, infarctus and cardiovascular accident. This illustrates the importance of asthma symptoms in the elderly mortality. On the opposite, the e ect of asthma symptoms on mortality disappeared when adjusting on variables that are linked to asthma such as depression, subjective health and dyspnoea. These variables appear to explain much better the elderly's mortality than asthma itself. The present study has a certain number of limits. Certainly the most important one is the de nition of asthma in the elderly population. Epidemiological evidence has suggested that it is di cult to assign precise gures to the prevalence and incidence of asthma in the elderly in the general population because there is no universally accepted de nition of the condition and because of the several pathologies associated to senescence, particularly cardiac diseases and chronic obstructive bronchitis. In general, identi cation of cases is often based on symptoms presented by patients [7]. This study used three epidemiological questions to diagnose asthma. These questions have already been validated taking the bronchial hyper-responsiveness as the reference in a sample aged 18±64 years. Direct questions on asthma Table 5. Factors associated to mortality after adjustment on a 5-year study period, Cox model with delayed entry (n = 2316; 32 subjects had missing values) Variables arr* 95% CI p Self-reported of asthma (yes vs. no) ± Gender (women vs. men) ± Marital status (alone vs. couple) ±1.4 NS Educational level (no diploma vs. primary school diploma) ±1.3 NS Cognitive impairment (continuous) ±0.95 <0.001 Smoker + ex smoker (vs. nonsmoker) ±2.01 <0.001 Previous ischaemic heart disease ± Previous stroke ±2.5 NS Previous angina ±1.8 NS * arr ± adjusted relative risk.

6 62 (symptoms in the last 12 months) have a high speci city (97%), but a moderate sensitivity (43%) [17]. In the same way, a recent study aimed at investigating the di erences in physical and psychological morbidity in older people with and without selfreported asthma, used epidemiological questions similar to those used in the present study [8]. These questions had also been validated and were reported to have a mean sensitivity of 72% and speci city of 99%. Thus, we could underestimate the number of subjects with self-reported asthma. Banerjee et al. [25] tried to detect asthma only on the objective reversibility to Salbutamol in a group of subjects aged 55 and over. More than 41% had a positive response to the reversibility test while only 7% of them were receiving respiratory-related treatment. These authors concluded that asthma is underdiagnosed or undertreated in the elderly. The hypothesis of underperceived, underdiagnosed and undertreated asthma in the elderly has also been proposed by other authors [26]. Another important point is the representativeness of the sample under study. Concerning subjects lost at follow-up, there was less than 1% of lost subjects at 8 year follow-up since initial inclusion. Overall 5-year mortality rate in this study was 25%. Considering no linear progression of mortality, it is possible to compare the mortality rate in 1 year (5%) in our sample to the 1-year mortality rate of the general population in this region, which was 7.9% at that time. The mortality rate of our study is lower than in the general population. This can be due to the fact that the PA- QUID cohort concerns only subjects aged more than 65 years who are still living at home. Therefore, a possible explanation for relatively low rate is that since subjects are living at home, they are less sick and less disabled than the general population that includes also elderly subjects who are institutionalized. Another possible bias could be that asthma may play a role in mortality earlier in life [27, 28]. In this study, there could be an overrepresentation of survivors since analysis took into account subjects that were alive at the 3-year follow-up (13% of the initial cohort had already died). Moreover, an information bias which cannot be avoided is that cognitive impairment can lead the subjects to give approximate responses because of cognitive problems. Concerning causes of death, none of the subjects died of asthma in our cohort. This is not surprising because asthma-related mortality for the subjects older than 65 is 1/10,000 [29]. For this reason, data from the present study do not allow to conclude that asthma is a major direct cause of death in the elderly people. No di erence was found between the death causes of subjects with symptoms of asthma and those of nonasthmatic subjects. This result has also been found in an adult population except for the asthma causes [12]. In this study, asthma was not signi cantly related to mortality when adjusting on disability, dyspnoea and other psychological variables. This result is not surprising since dyspnoea has already been shown to predict mortality in the same cohort [30]. We can therefore hypothesize that in the elderly, asthma is indirectly associated to mortality by the disability that it engenders, like it is the case with some other chronic diseases [9]. Finally, no speci c mortality risk factors were found for subjects with self-reported asthma. 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