Coffee Drinking and Prevalence of Bronchial Asthma

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preliminary report Coffee Drinking and Prevalence of Bronchial Asthma Romano Pagano, Ph.D.;* Eva Negri, Sc.D.;t,+ Adriano Decarli, Sc.D.;§

and Carlo La Vecchia, M.D.+

The relationship between coffee consumption and the prevalence of bronchial asthma has been evaluated using data from the 1983 Italian National Health Survey, based on 72,284 individuals aged over 15 years randomly selected within strata of geographic area, size of the place of residence and of the household in order to be representative of the whole Italian population. The prevalence of bronchial asthma was inversely related with the level of coffee intake. Compared with subjects who did not drink coffee, the ageand sex-adjusted relative risks were 0.95 for one cup, O. 77 for two and O.72 for three or more cups per day This inverse relation was of comparable magnitude at younger and older ages, not explainable through selection, since the sample was representative of the general Italian population and the participation rate was 93.4 percent, or through

confounding by several identified potential distorting factors. Thus, the results of this survey provide epidemiologic confirmation of previous clinical observations that caffeine intake has a bronchodilator effect in asthma, and indirectly suggest that long-term moderate coffee consumption may not only reduce symptoms, but also prevent the clinical manifestation of bronchial asthma. An alternative explanation of these findings is that subjects receiving treatment for asthma might tend to reduce their coffee consumption, in consequence of the side effects shared by sympathomimetics, theophylline and caffeine. Thus, further studies taking simultaneously into account methylxanthine intake from beverages and drug treatments are required before considering causal the apparent protection which emerged.

Caffeine and theophylline are methylxanthines that share several pharmacologic effects, including bronchodilation;'-" although the mechanism of action is still not completely understood. Many of their effects may be mediated through adenosine, a component of ATP and nucleic acids. The action of adenosine, which is opposite that of caffeine, tends to slow body function. Methylxanthines have been found to act as competitive antagonists for adenosine receptors on cell surfaces.F' Many studies exist on the pharmacologic effects of caffeine on respiratory renal, cardiovascular, and other systems, but few effects have been demonstrated to occur at levels attained from dietary intakes." Concerning the respiratory effects of caffeine, early studies reported that respiration was stimulated, both in human volunteers and patients with chronic obstructive pulmonary diseases. 2 Subsequently controlled clinical studies of pulmonary function tests after administration of caffeine showed significant improvements of forced vital capac-

ity forced expiratory volume in one second and forced expiratory flow rates one to six hours after administration of caffeine tablets. The bronchodilator effect of caffeine was comparable to that of theophylline, but peak serum levels were reached earlier with caffeine (1 vs 2.2 hours)." Further studies indicated that coffee intake affects forced expiratory volume and that three cups of coffee (ie, about 450 mg of caffeine) have a bronchodilator effect similar to 200 mg of theophylline." These studies, however consistent, were based on limited numbers of selected subjects. Thus, there is at present no information on the potential public health implications of these findings. The availability of data on coffee consumption and prevalence of bronchial asthma in (he 1983 National Health Survey conducted by the Italian Central Institute of Statistics'v? provided the opportunity to examine this topic in a large sample representative of the whole Italian population.

*From the Istituto Centrale di Statistica, Rome; tConsorzio Interuniversitario Lombardo per l'Elaborazione Automatica, Milan; :I:Istituto di RicercheFarmacologiche "Mario Negri," Milan; and §Istituto di Biometria e Statistica Medica, Universita di Milano, Istituto Nazionale dei Tumori, Milan, and Istituto di Statistica e Ricerca Operativa, Universita di Trento, Trento, Italy Reprint requests: Dr. DeCarli, Institute of Medical Statistics, University of Milan, Via Venezian I~ Milan, Italy 20133

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MATERIAL AND METHODS

The 1983 National Health Survey The second National Health Survey's? was conducted by the Central Institute of Statistics during the week between November 28 and December 3, 1983. A sample of 31,025 households (for a total of 89,753 individuals) was randomly selected within strata of geographic area (region), size of municipality and of the household, in order to be representative of the general Italian population. Coffee Drinking and Bronchial Asthma (Pagano at al)

Interviews were arranged and conducted by civil servants (appointed by each municipality included in the study) within the houses of the families identified. Impossibility of tracing or refusal of the interview led to the substitution of 2,058 households, thus giving an overall participation rate for the original sample of 93.4 percent. Proxy interviews were permitted for members not present in the house (8.3 percent of the sample considered). Information was collected on socio-demographic characteristics, current health status, prevalence of 19 chronic diseases or groups of diseases (including major cardiovascular conditions, respiratory and digestive tract disorders, renal and urinary tract diseases, arthritis and nervous disorders), health service utilization during the month (for outpatient procedures) or the year (for inpatient procedures) preceding the interview; smoking habits (smoking status, age at starting and for ex-smokers at stopping, current number of cigarettes or pipe/cigars smoked per day), coffee and alcohol consumption. Information on prevalence of diseases was based on the responders' answer only and no independent check was available on reliability of diagnoses. We obtained from the Central Institute of Statistics copies of the original computer tapes including all available information for each subject. The total numbers of subjects included in the present analysis, stratified for sex and broad age group, are reported in Table 1. Subjects below age 15 were not considered, leaving a total of 34,787 males and 37,497 females.

Data Analysis and Control of Confounding We estimated the relative risks (RR) of bronchial asthma, together with their 95 percent approximate confidence intervals," according to the level of coffee consumption (in cups per day) from data stratified for sex and age in decades by means of the usual MantelHaenszel procedure." The significance of the trends in risk was assessed by the test described by Mantel.'? Further, multiple logistic regression analysis, fitted by the method of maximum likelihood," was used to estimate relative risks and corresponding confidence limits simultaneously adjusted for sex, age (as a continuous variable), geographic area (North/Center/South and Islands), education, cigarette smoking and alcohol consumption. RESULTS

Table 1 gives absolute numbers and estimated prevalences in percentages for bronchial asthma, cof-

fee consumption and smoking habits in separate strata of age and sex. The overall estimated prevalence of bronchial asthma was 4.0 percent for males and 2.5 percent for females aged 15 or over. In both sexes, the reported prevalence increased with advancing age. Among the 34, 787 males included in this study 21 percent did not drink coffee, 24 percent drank one, 28 percent two, and 27 percent three or more cups per day Corresponding figures for the 37,497 females were 23 percent, 27 percent, 28 percent and 22 percent. In both sexes, coffee consumption was greater in middle age (45 to 64 years). Females drank slightly less coffee than males in all age groups considered (Table 1). In relation to smoking, 41.1 percent of males were never-smokers, 13.8 ex-smokers, 1.0 percent smoked pipe or cigars, 15.8 percent less than 15 cigarettes per day and 28.2 percent 15 or more cigarettes per day Corresponding figures among females were 79.6 percent, 2.5 percent, 0.2 percent, 12.0 percent and 5.7 percent. In this study there was no relation between current smoking and bronchial asthma, the estimated prevalence of the disease in males being 2.6 percent for never smokers and 3.0 for heavy smokers, and in females 2.5 percent and 1.6 percent, respectively Exsmokers, by contrast, showed a substantial excess prevalence (9.2 percent in males, 4.3 percent in females), indicating that the presence of such severe respiratory condition selectively influences cessation of smoking. The prevalence of bronchial asthma was inversely related to the level of coffee intake. Compared with subjects who did not drink coffee, the estimated relative risks were 0.95 for one cup, O. 77 for two, and O. 72 for three or more cups per day when allowance was made for age and sex only Separate analyses in

Table I-Numbers of Subjects Included in the 1983 Italian National Health Survey by the Central Institute of Statistics (ISTAT)6,7 According to Sex, Age Group, Prevalence of Asthma, Coffee Drinking and Smoking Habits Males, age

Prevalence of asthma Coffee drinking (cups per day) 0 1 2 2::3 Smoking habits Never smokers Ex-smokers Pipe/cigar smokers Cigarette smokers <15 cigarettes/day ~15 cigarettes/day Total no. of subjects

Females, age

15-44 No(%)

45-64 No(%)

2::65 No(%)

15-44 No(%)

45-64 No(%)

2::65 No(%)

246 (1.3)

567 (5.2)

592 (11.5)

209(1.1)

314 (2.7)

406 (6.1)

4,098 4,020 5,219 5,377

(21.9) (21.5) (27.9) (28.7)

1,834 2,678 3,306 3,115

(16.8) (24.5) (30.2) (28.5)

1,369 1,646 1,356 769

(26.6) (32.0) (26.4) (15.0)

4,310 4,494 5,474 4,821

(22.6) (23.5) (28.7) (25.2)

2,295 3,317 3,492 2,606

(19.6) (28.3) (29.8) (22.3)

2,145 2,240 1,520 783

(32.1) (33.5) (22.7) (11.7)

8,891 (47.5) 1,121 (6.0) 160 (0.9)

3,460 (31.6) 2,128 (19.5) 89 (0.8)

1,961 (38.2) 1,566 (30.5) 106 (2.1)

13,860 (72.6) 488 (2.6) 60 (0.3)

9,787 (83.6) 287 (2.5) 17 (0.1)

6,213 (92.9) 146 (2.2) 13 (0.2)

2,954 (15.8) 5,588 (29.9) 18,714 (100.0)

1,701 (15.6) 3,555 (32.5) 10,933 (100.0)

856 (16.7) 651 (12.7) 5,140 (100.0)

3,235 (16.9) 1,456 (7.6) 19,099 (100.0)

1,051 (9.0) 568 (4.9) 11,710 (100.0)

221 (3.3) 95 (1.4) 6,688 (100.0)

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Table 2-Prevalence (percent) ofBronchial Asthma in Italian Males and Females According to Coffee Drinking Habits; (Datafrom 1983 National Health Survey conducted by the Central Institute of Statistics 6,7) Relative risk estimates (95% CI) Males

Females

M-H*

Multivariatet

4.89 (357)* 5.02 (419)

3.06 (268) 3.08 (310)

2

3.66 (362)

1.95 (205)

~3

2.88 (267)

1.78 (146)

1§ 0.95 (0.85-1.06) 0.77 (0.68-0.86) 0.72 (0.63-0.83) 29.30 (p
1§ 0.93 (0.83-1.04) 0.79 (0.69-0.91) 0.78 (0.69-0.88) 17.88 (p
Coffee drinking (cups per day) 0 1

xt(trend)

*Mantel-Haenszel estimates adjusted for age and sex. tEstimates from multiple logistic regression. Allowance was made for age, sex, geographical area, education, alcohol consumption and smoking habits. :I:The numbers of subjects with the disease are given in parentheses. §Reference category

different strata of smoking or adjustment for other potential distorting factors did not materially modify this inverse relation (Table 2). The trend of decreasing risk with increasing coffee consumption based on the four levels presented in Table 2 was statistically significant, but no further decrease in risk was evident when the "three or more cups" category was subdivided. The apparent reduction in bronchial asthma risk was somewhat greater at older ages, but there was no significant interaction between age and the risk of bronchial asthma in relation to coffee consumption (Table 3). DISCUSSION

The findings of the 1983 Italian National Health Survey suggest that coffee consumption is negatively related to the prevalence of bronchial asthma. The Table 3-Relative Risk ofBronchial Asthma in Various Age Groups According to Coffee Drinking Habits; (Data from the 1983 Italian National Health Survey conducted by the C entral Institute of Statistics6 , 7) Relative risk estimates (95% CI) at ages:

Coffee drinking (cups per day)

o 1 2

~3

15-44

45-64

~65

It 1.02 (0.74-1.40) 0.77 (0.56-1.06) 0.93 (0.69-1.27)

It 1.00 (0.83-1.20) 0.64 (0.53-0.77) 0.78 (0.64-1.01)

It 0.90 (0.77-1.05) 0.88 (0.74-1.04) 0.68 (0.55-0.85)

*Mantel-Haenszel estimates adjusted for age and sex. tReference category

388

estimated reduction of risk was 5 percent for one, and over 20 percent for two or more cups per day The inverse relation between asthma and coffee was consistent among strata of age and sex and not explainable in terms of potential confounding factors (geographic area, education, alcohol and smoking) included in the regression equations. Likewise, selection bias is unlikely to play an important role in this study since , the sample was large and representative of the general Italian population in terms of distribution for age, sex and region of residencer'-? participation rate was satisfactory since less than 7 percent of the households originally sampled were substituted, and proxy interviews covered less than 10 percent of the individuals. 6, 7 Thus, the major problems in the interpretation of this dataset pertain to information bias, since the questionnaires were administered by non-medically trained civil servants, and no independent check was available of reliability of diagnoses. Nonetheless, bronchial asthma is a chronic condition, easy to diagnose and whose presence should not be affected by major misclassification on the basis of patients' recall alone. Diagnostic reliability was probably lower at older age, when chronic obstructive lung disease related to smoking may possibly be misreported as "asthma." It is, however, reassuring, in this regard, that no association emerged between smoking and asthma, although smoking was strongly and positively associated with chronic bronchitis and lung emphysema or respiratory insufficiency 12 Further, even admitting a proportion of incorrect recall, there is no reason to presume a differential recall in relation to coffee consumption, since the possible relation between coffee and asthma had not gained widespread attention in the lay press in Italy (and, if it had, it would probably have led to an increase Coffee Drinking and Bronchial Asthma (Pagano et al)

in coffee consumption among asthmatics, thus reducing the strength of the inverse association). On the other hand, a further major limitation for the interpretation of the present findings is the absence of information on treatment of asthma. It is conceivable, in fact, that persons receiving pharmacologic therapy spontaneously reduce their coffee intake, since caffeine shares side effects (tremor, tachycardia and palpitations) with theophylline and sympathomimetics used in the treatment of asthma.l'':" This potential biologic interaction can be particularly important in older subjects, who may be more susceptible to the combined effects of coffee and drugs in inducing side effects, although any inference on subgroups by age in this study should be made with utmost caution, in the absence of significant differences in estimated risks for various age groups. Nonetheless, further studies taking simultaneously into account methylxanthine intake from coffee and other beverages and drug use are required before stating whether the observed association is causal, and in order to understand potential interactions between various sources of methylxanthine intake and other drugs in the treatment of asthma. With these cautions in mind, the findings of this survey should be interpreted along the lines of previous clinical observations that caffeine intake" or coffee consumption" have bronchodilator effects in asthma, and indirectly suggest that long-term moderate coffee consumption may not only reduce symptoms, but also prevent the clinical manifestation of asthma. In 1983, the estimated prevalence of asthma in the whole of Italy was 1,556,000 cases," On the basis of standard methods of calculation of attributable risk, 16 and assuming that the negative relation between coffee and asthma is real, it can be estimated that about 275,000 prevalent cases were prevented by regular coffee consumption in the whole of Italy A study conducted in California" indicated that three cups of percolator coffee are an optimal dose for a bronchodilator effect, since they provide about 450 mg of caffeine, whose biologic activity is comparable to the standard dose of 200 mg of theophylline. This is consistent, too, with the dose-effect relationship observed in this stud)', since the estimated relative risk decreased up to two or three cups of coffee per day and flattened off thereafter. It should be noted,however, that the data did not permit a distinction between the two major types of coffee preparations used in Italy "mocha" coffee (whose caffeine content is comparable with that of percolator coffee) and "espresso," whose caffeine content is considerably lower (up to 50 percent). 17

Finally because of the intrinsic limitations of available data (chiefly in terms of diagnostic definition and absence of information on treatments), the apparent protection of coffee on bronchial asthma observed in this study should at present be considered an hypothesis to be tested in further, ad hoc designed investigations. ACKNOWLEDGMENTS: This work was conducted within the framework of the CNR (Italian National Research Council) Applied Project "Preventive and Rehabilitative Medicine" (Contracts 85.00487.56 and 85.00549.56). Data processing and analysis were performed using the computing facilities of the Inter University Consortium of Lombardy for Automatic Data Processing (CILEA). The authors wish to thank Ms. Antonella Palmiero, Judy Baggott and the G.A. Pfeiffer Memorial Library for editorial assistance.

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8 Breslow NE, Day NE. Statistical methods in cancer research. IARC Sci Pub I 1980:32 9 Mantel N, Haenszel W Statistical aspects of the analysis of data from retrospective studies of disease. JNCI 1959; 22:719-48 10 Mantel N. Chi-square tests with one degree of freedom; extensions of the Mantel-Haenszel procedure. J Am Stat Assoc 1963; 58:690-700 11 Baker RJ, Nelder JA. The GLIM system, release 3. Oxford: Numerical Algorithms Group, 1978 12 La Vecchia C, Pagano R, Negri E, Decarli A. Smoking and prevalence of disease in the 1983 Italian National Health Survey Int J Epidemiol1988 (in press) 13 James JE, Stirling KE Caffeine: A survey of some of the known and suspected deleterious effects of habitual use. Br J Addiction 1983; 78:251-58 14 Shirlow MJ, Mathers CD. A study of caffeine consumption and symptoms: Indigestion, palpitations, tremor, headache and insomnia. Int J Epidemiol1985; 14:239-48 15 Grossman EM. Some methodological issues in the conduct of caffeine research. Food Chern Toxicol1984; 22:245-49 16 Cole E MacMahon B. Attributable risk percent in case-control studies. British Journal of Preventative and Social Medicine 1971; 25:242-44 17 Bonati M, Latini R, Galletti F, [oung JF, Tognoni G, Garattini S. Caffeine disposition after oral doses. Clin Pharmacol Ther 1982; 32:98-106

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