Diet and COPD 2002

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ORIGINAL COMMUNICATION

Diet and 20-year chronic obstructive pulmonary

disease mortality in middle-aged men from threeEuropean countries

IC Walda1,2, C Tabak1,2*, HA Smit1, L Rasanen3, F Fidanza4, A Menotti1,5, A Nissinen6,7,EJM Feskens1 and D Kromhout8

1Department of Chronic Disease Epidemiology, National Institute of Public Health and the Environment, Bilthoven, TheNetherlands; 2Institute for Risk Assessment Sciences, Division Environmental and Occupational Health, Universiteit Utrecht,Utrecht, The Netherlands; 3Division of Nutrition, University of Helsinki, Helsinki, Finland; 4Nutrition Section, Department of

Internal Medicine and Endocrinological and Metabolical Sciences, University of Perugia, Perugia, Italy; 5Division of Epidemiology,

School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA;6

Department of Public Health and GeneralPractice, University of Kuopio, Kuopio, Finland; 7Department of Neurology, Kuopio University Hospital, Kuopio, Finland; and8Division of Public Health Research, National Institute of Public Health and the Environment, Bilthoven, The Netherlands

Objective: To investigate the relation of baseline antioxidant, fruit, vegetable and fish intake with 20 y chronic obstructivepulmonary disease (COPD) mortality in middle-aged men from three European countries.Design: Prospective study (1970 1990).Setting: Five population-based cohorts of middle-aged men from Finland, Italy and The Netherlands.Subjects: A total of 2917 men aged 50 69 y at baseline.Methods: Baseline information on diet was collected using the cross-check dietary history method. After 20 y of follow-up theunderlying cause of death of those who died was established centrally. Survival analyses were performed using the CoxProportional Hazards Model.Results: After adjustment for age, smoking and country, we observed an inverse trend (P-trend

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may protect the airways against oxidant-mediated damage

leading to COPD (Smit et al, 1999; Tabak et al, 1999, 2001a;

Butland et al, 2000). Only three longitudinal studies on the

relation between diet and COPD-related outcomes have been

published. In the Zutphen Study an inverse relationship was

observed between baseline consumption of total and solid

( apples, pears) fruit and 25 y incidence of chronic lung

disease (Miedema et al, 1993). However, Miedema and co-

workers did not observe a relationship with intake of anti-

oxidants (vitamin C and b-carotene). Follow-up in the other

two studies was relatively short (5 7 y). Butland et al (2000)

observed no statistically significant longitudinal relationship

between vitamin C, vitamin E or apple intake with pulmon-

ary function. However, baseline apple consumption did tend

to be inversely related to change in FEV1. Carey et al (1998)

observed no relation between average level of fresh fruit

intake during follow-up and change in pulmonary function.

In addition to the above-mentioned dietary factors with

antioxidant capacities, a protective effect against develop-

ment of COPD has been suggested for fish consumption. Fish

oils are thought to have anti-inflammatory effects, becauseof the influence of the n-3 polyunsaturated fatty acids

eicosapentaenoic acid (EPA) and docosahexaenoic acid

(DHA) on arachidonic acid metabolism (Sperling, 1991).

Results of cross-sectional studies on this topic are inconclu-

sive. Cross-sectional studies published in 1990 and 1994

suggested an inverse association between fish consumption

and COPD related outcomes (Smit et al, 1999). However, all

cross-sectional studies published in later years reported nega-

tive findings (Cook et al, 1997; Fluge et al, 1998; Tabak et al,

1999, 2001a; Butland et al, 2000). In the only individual-

level longitudinal study, no association of fish consumption

with 25 y incidence of chronic lung disease was observed

(Miedema et al, 1993).To gain more insight into the longitudinal relationship

between diet and COPD, we studied baseline antioxidant,

fruit, vegetable and fish intake in relation to 20y COPD

mortality in 2917 middle-aged men. Data of the Finnish,

Italian and Dutch cohorts of the Seven Countries Study were

combined to provide a wide range in dietary intake.

Materials and methodsStudy population

From 1958 to 1964, 16 population samples of middle-aged

men (40 59y) from seven countries were enrolled and

examined at baseline for the Seven Countries Study (Keyset al, 1967). During the second and third rounds (5 and 10 y

of follow-up, respectively), dietary data were obtained in the

Finnish, Italian and Dutch cohorts. Also 20 y follow-up

mortality data were collected.

In the present study two Finnish, two Italian and one

Dutch cohort of the Seven Countries Study are involved. In

Finland one cohort was located in the east, in Ilomantsi, a

rural area close to the Russian border. The other Finnish

cohort was situated in the south-western part of the country,

in Poytya and Mellila. Two cohorts of Italian men partici-

pated in the study. One consisted of men living in the village

of Crevalcore, which is located in the Po Valley. The partici-

pants of the other Italian cohort were inhabitants of Mon-

tegiorgio, a small country village in central Italy. The fifth

cohort was located in Zutphen, a small commercial town in

the central-east of The Netherlands.

In 1959 in Finland 1675 men were examined, about 98%

of the total eligible population of men born from 1900 to

1919 in the two areas. After 10 y, 612 men in east Finland

and 694 men in west Finland were re-examined, respectively

91 and 93% of the surviving men. Complete dietary infor-

mation was obtained from 590 men in east Finland and 670

men in west Finland. In Zutphen a random sample of four

out of each nine eligible men was drawn in 1960. Invited

were 1088 men of which 872 men participated in both the

medical examination and the dietary survey (80%). In 1970

625 men were re-examined, of whom 558 participated in

individual dietary surveys. In both Italian cohorts 99% of the

eligible men participated in 1960 (n1712). In 1970, 570

participants in Montegiorgio and 753 men in Crevalcorewere examined. From respectively 551 and 584 men com-

plete dietary information was obtained. For 36 of the 2953

subjects with complete dietary data in the three countries,

information on one or more potential confounders was

missing. The final study population therefore consisted of

2917 men.

Data collection

Individual dietary surveys were carried out around 1970 in

all cohorts, except in Montegiorgio, where this survey took

place in 1965. The dietary data gathered in 1965 in thisItalian cohort were used as an approximation for dietary

intakes in 1970. Individual dietary intake was estimated by

the cross-check dietary history method (Burke, 1947).

Although this method was adapted to the local situation in

the specific country, the methodology was comparable for

the three countries. The cross-check dietary history method

provides information about the usual food consumption

pattern during 6 12 months preceding the interview. The

first part of the method concerns questions about the foods

used at breakfast, lunch, dinner and between meals to assess

the usual food consumption pattern of a person during

weekdays and weekends. For the second part of the survey

a checklist with a number of foods was used. The frequenciesand amounts consumed were recorded for the different food

groups. The information about the food pattern was com-

pared with the information from the checklist. In all cohorts

the dietary interviews were carried out by experienced dieti-

cians and nutritionists. The food intake was converted into

energy and nutrient intake using the computerised versions

of the local food tables for the three different countries (Den

Hartog et al, 1965; Hautvast, 1975; Pekkarinen, 1981; Alberti-

Fidanza et al, 1988).

Diet and COPD mortalityIC Walda et al

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In all cohorts information on age, height, weight and

smoking status of the participants was collected in a stan-

dardised way (Keys et al, 1967). Body mass index (BMI) was

calculated from measurements of body weight (kg) and

height (m). Current smoking status was assessed using a

standardised questionnaire. Possible answers were: current

smoker, former smoker and never smoker. Current or former

smokers were asked to report the amount of cigarettes they

smoked or used to smoke daily. The number of years smoked

was estimated by assuming that in all cohorts the men

started smoking at the age of 16, as for the Dutch cohort.

Pack years of smoking were calculated as the product of the

number of years smoked and the number of packs of cigar-

ettes smoked per day. It was assumed that a pack of cigarettes

contained 20 cigarettes.

The vital status of the participants was recorded during

20 y of follow-up. The underlying cause of death from those

who died was established centrally by two investigators.

They reviewed the information from clinical records, from

family doctors, specialists and relatives and from other useful

sources collected by local investigators. Usually the officialcause of death was not considered or only used as a pre-

liminary indication. Primary mortality was coded according

to the 8th revision of the International Classification of

Diseases (ICD) of the World Health Organization (WHO,

1967). The ICD codes 491 493 refer to death from chronic

bronchitis, lung emphysema and asthma, respectively.

Statistical analyses

The Cox Proportional Hazards Model (SAS Procedure PHREG;

SAS Institute Inc., 1991) was used to assess the relationship

between the consumption of the selected dietary variables

and 20y COPD mortality, since this method takes intoaccount the unequal lengths of time that each participant

was observed.

First, dietary variables were ranked into tertiles and asso-

ciations with COPD mortality were studied after adjustment

for age and cigarette smoking (pack years) at baseline and for

country. Adjustment for country was carried out by calculat-

ing a pooled relative risk (RR), using the strata option of the

PHREG procedure that allows baseline hazards to vary

between countries. Only dietary factors showing a statisti-

cally significant trend in COPD mortality across the tertiles

(P-trend

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No association was observed for vegetables, fish and b-car-

otene. After adjustment for country, age and smoking the

trend remained statistically significant for fruit and vitamin

E intake. The adjusted RR of the highest vs the lowest tertile

of intake was 0.49 (95% CI0.26 0.93) for fruit and 0.54(95% CI0.27 1.05) for vitamin E (Table 3).

In subsequent analysis fruit and vitamin E intake were

modelled continuously (Table 4). After adjustment for coun-

try, age and smoking, a 100g increase in fruit intake was

associated with a 24% lower COPD mortality risk (RR 0.76,

95% CI0.60 0.92). Additional adjustment for BMI, energy

intake or alcohol consumption each reduced the estimated

RR slightly (to 0.79 0.80). Additional adjustment for all

three factors reduced the RR to 0.86 (95% CI 0.69 1.07,

P0.12). In these analyses vitamin E intake was not statis-

tically significantly associated with COPD mortality after

adjustment for country, age and smoking (RR per

5 mg0.77, 95% CI0.55 1.06). Of the other three poten-tial confounders energy intake had the strongest effect,

reducing the RR to 0.88 (95% CI0.62 1.25). After addi-

tional adjustment for the three factors the RR (per 5 mg) was

0.93 (95% CI0.65 1.33; Table 4).

DiscussionAfter adjustment for age, smoking and country, we

observed an inverse trend (P-trend 30 vs 1 30 g=day.


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Due to the relatively small number of men dying from COPD

(n73) in our study derived confidence intervals were rather

wide. Still, the results suggest a protective effect of a high

intake of fruit against COPD. This is in agreement with the

results of most cross-sectional studies (Smit et al, 1999; Tabak

et al, 1999, 2001a; Butland et al, 2000) and with the results of

two of the three longitudinal studies (Butland et al, 2000;

Miedema et al, 1993; Carey et al, 1998). Miedema et al (1993)

observed an inverse relation between baseline consumption

of total and especially solid fruit ( apples, pears) and 25 y

chronic lung disease incidence in the Dutch cohort of the

Seven Countries Study. Butland et al (2000) reported a non-

significant trend towards an inverse relation between base-

line apple consumption and change in FEV1. As has been

observed earlier (Tabak et al, 2001a) the effect of fruit intake

appeared to be largely independent of that of alcohol

consumption.

In none of the longitudinal studies that investigated

vitamin C intake in relation to indicators of COPD (includ-

ing our own) a clear association was observed (Miedema et al,

1993; Butland et al, 2000). This suggests that other fruitcomponents than the antioxidant vitamin C may have a

protective effect on the development of emphysema and

chronic bronchitis, eg flavonoids, which have strong anti-

oxidant capacities (Bors & Saran 1987; Hertog et al, 1993). In

a recent Dutch study, total intake of three of the six flavo-

noid subclasses (ie catechins, flavonols and flavones) was

observed to be positively associated with the FEV1 and

inversely associated with chronic cough and breathlessness.

More detailed analyses suggested that the association with

COPD was likely to be due to an effect of catechins, and not

of flavonols and flavones (Tabak et al, 2001c).

Results of cross-sectional studies on the relationship

between vitamin E intake and COPD-related outcomes areinconsistent; both results suggesting a protective and results

suggesting no effect being reported (Smit et al, 1999; Tabak et

al, 1999; Butland et al, 2000). Butland et al (2000) observed

no longitudinal relation between vitamin E intake and

pulmonary function. In our study the association was sub-

stantially weakened by adjustment for energy intake. Energy

intake is not a known risk factor for COPD. It is strongly

associated with physical activity, but physical activity, even

training, does not affect lung volumes (McArdle et al, 1991).

Energy intake may stand for another, unknown, factor asso-

ciated with diet and COPD mortality, but in this case the

factor may be an intermediate factor and not a confounder.

Therefore, it is unclear whether the results are more validafter or before adjustment for energy intake.

We did not observe a relationship between fish consump-

tion and COPD mortality. In the early 1990s a protective

effect of fish intake was suggested by several cross-sectional

studies (Smit et al, 1999). These findings were supported by a

plausible biological mechanism, ie an anti-inflammatory

effect of the n-3 fatty acids abundantly present in fish oils.

In accordance with our findings, all more recent epidemio-

logical studies observed no association of fish intake with

COPD related outcomes (Cook et al, 1997; Fluge et al, 1998;

Tabak et al, 1999, 2001a; Butland et al, 2000). It is not likely

that this is due to a higher level of fish intake in the earlier

studies. In our study, for instance, the mean daily fish intake

was 27.4 g, which is comparable to the level of intake in the

study by Shahar et al (1994; 1.9 servings=week or 85 142g

fish=week).

Of the study population 89% had ever smoked cigarettes.

Although we adjusted for smoking habits as well as possible,

residual confounding by smoking cannot be excluded. It is

known that smokers tend to eat less fruit, vegetables and

whole grain products and have lower intakes of vitamin C

and b-carotene (Margetts & Jackson, 1993). It is, however,

not necessarily so that residual confounding by smoking

leads to overestimation of the studied dietary effects. If

heavy smokers tend to under-report the number of cigar-

ettes they usually smoke, which is not unlikely, this would

even cause dilution of observed dietary effects. Possibly

even more important is the fact that in the majority of

epidemiological studies on diet and COPD, that reported on

whether observed effects varied by smoking status (smokervs non-smokers, current vs former vs never smokers or

interaction with smoking status), such variation was not

observed (Strachan et al, 1991; Schwartz & Weiss, 1994; Dow

et al, 1996; Chuwers et al, 1997; Hu et al, 1998; Butland et al,

2000). It is therefore unlikely that the observed associations

in our study are substantially biased by residual confound-

ing by smoking.

A number of other methodological issues needs to be

discussed. The validity and reproducibility of the cross-

check dietary history method has been observed to be

comparable to that of other dietary assessment methods

(Block, 1982; Bloemberg et al, 1989). Yet, random misclassi-

fication of intake of the selected dietary factors may haveoccurred, which is likely to lead to underestimation of the

relative risks. Furthermore, it may be questioned whether

food consumption around 1970 is a good indicator for

average food consumption during 20y of follow-up.

Changes in the food consumption patterns in the countries

participating in the Seven Countries Study have been

observed between 1960 and 1985 (Kromhout et al, 1989).

However, the relative position of the countries in the dis-

tribution of different foods was maintained (Kromhout et al,

1989). In survivors of our study population (from Finland,

Italy and The Netherlands) fruit intake was observed to

increase during 20 y of follow-up (Huijbregts et al, 1995).

Since this increase was highest in the reference group, thelowest fruit tertile, this may have caused underestimation of

the effect of fruit. Finally, although in our study we used the

term COPD (defined as chronic bronchitis and emphysema),

asthma does contribute to the mortality rates. However,

chronic bronchitis or emphysema was often noted as the

secondary cause of death in cases where asthma was reported

as the underlying cause of death. Also considering the fact

that the number of asthma cases was small (n4), we

decided against excluding them from the analyses.


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In summary, our results suggest a protective effect of fruit

and possibly vitamin E against dying from COPD. No effect

was observed for intake of vitamin C, b-carotene, vegetables

and fish.

Acknowledgements

The authors thank the many people that were involved inthis longitudinal study. This includes the men who took part

in the surveys and the organisers of the fieldwork in the

three countries, Professor A Menotti and Dr S Giampaoli

in Italy, Professor A Nissinen in Finland and Professor D

Kromhout in The Netherlands.

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Diet and COPD 2002