From the Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Received for publication October 18, 2002; accepted for publication March 21, 2003.
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ABSTRACT |
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antioxidants; ascorbic acid; child; diet; respiratory function tests; vitamin A; vitamin E
Abbreviations: Abbreviations: CI, confidence interval; FEF2575, forced expiratory flow between 25 and 75 percent of forced vital capacity; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.
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INTRODUCTION |
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Few population-based studies have investigated the relation between intake of antioxidants and lung function during childhood (3, 14, 21). The existing evidence among children is consistent with the findings in adults, but it suggests that the assessment of the source of antioxidant intake may be important in defining the role of specific antioxidant vitamins, including vitamin C. In a cross-sectional study of 2,650 school-age children in England and Wales, the level of FEV1 was positively associated with the frequency of fresh fruit consumption and more weakly associated with green vegetables and salad consumption (3). However, FEV1 was not associated with serum levels of vitamin C, suggesting that other micronutrients in fruit were important. Studies that consider dietary and total nutrient intake that include intake from food and vitamin supplements may be informative for determining whether consumption of the package of antioxidants in whole foods or of specific vitamins is important. Using the evidence available for adults and children, we hypothesized that a low intake of fruits, vegetables, and juices, as well as an inadequate daily total intake of antioxidant vitamins A, C, and E, is associated with deficits in childhood FVC, FEV1, and forced expiratory flow between 25 and 75 percent of forced vital capacity (FEF2575) (22). The Childrens Health Study offered an opportunity to investigate the role of inadequate dietary and total antioxidant vitamin, fruit, vegetable, and juice intake on childrens lung function (23, 24).
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MATERIALS AND METHODS |
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Pulmonary function testing
Maximum forced expiratory flow-volume maneuvers were recorded using rolling-seal spirometers (Spiroflow; P. K. Morgan, Ltd., Gillingham, United Kingdom). Spirometer calibrations and room temperatures were measured just before, during, and just after each testing session using flow-volume syringes (Jones Medical Instrument Co., Oak Brook, Illinois), and lung function measures were corrected for changes in calibration or internal temperature. Testing and data management procedures have been reported previously (25).
Dietary information
Dietary intake was assessed using the Youth/Adolescent Questionnaire, a validated food frequency questionnaire developed by Rockett et al. in 1997 for use in older children and adolescents (26, 27). The questionnaire has 131 food items including snacks and is a modified version of the validated Nurses Health Study food frequency questionnaire (28). Nutrient intake was estimated for diet without supplements and diet plus supplements, and total energy intake was quantified for each individual. Of the 2,633 children who completed both the food frequency questionnaire and lung function tests, 67 children with a total energy intake below 500 calories or above 5,000 calories were excluded from analyses, resulting in a final sample size of 2,566 children aged 1119 years. Because vitamin intake depended on gender and total caloric intake, we used sex-specific means and deciles for descriptive analyses of antioxidant vitamin intake. On the basis of our hypotheses that the effects of antioxidant vitamin intake on lung function result from an inadequately low intake, we compared a low intake (10th percentile) with a higher intake (>10th percentile) in the models. Fruits and vegetables were examined as servings per day of individual items and grouped by summing the intake per day of individual members of each group. Food frequency questionnaire items assessed orange juice and other juices including apple juice. Juices were categorized as any intake of juice, intake of either category of juice, or no intake of juices. Total juice intake summed the daily servings of orange, apple, and other juices. Magnesium intake was also assessed using the food frequency questionnaire and categorized into quintiles of intake.
Sociodemographic, medical history, and exposure data
The Childrens Health Study questionnaires provided information on sociodemographic factors, history of respiratory illness and associated risk factors, exposure to environmental tobacco smoke, and maternal smoking history during pregnancy. Ethnicity was defined as non-Hispanic White, Hispanic, African American, Asian, and other/mixed ethnicity, on the basis of self-report. Health insurance was defined as any insurance coverage reported for the participants family. Self-report of physician-diagnosed asthma during follow-up lung function testing sessions was used to categorize childrens asthma status at the time of food frequency questionnaire completion. Personal smoking was defined as a history of the participants reporting having ever smoked more than 100 cigarettes.
Participants height and weight were measured using a standardized protocol, and any respiratory infection within 1 month of testing and exercising within 30 minutes of testing were documented by trained field staff immediately prior to lung function testing. Body mass index was calculated as weight (kg)/height (m)2 and categorized into age- and sex-specific quintiles.
Statistical analyses
We assessed the effect of low vitamin, fruit, vegetable, and juice intakes on lung function by using regression splines to capture the nonlinear relation among pulmonary function, age, and height (2933). Initially, a knot was placed at each integer age. The final models were fit by using knots at the ages of 13 and 17 years, leading to a more parsimonious model with essentially the same results.
All models were fit separately for males and females, because their smoothed shapes for the relation between lung function and age are different. The gender-specific regression model is
E{log(PFT)} = µ + S1 (AGE) + S2 (AGE) x log(HT) + Xß,
where "PFT" is a pulmonary function test such as the FVC or FEV1, "µ" is the overall mean, "AGE" is age at visit, "HT" is the residual of height at visit after smoothing height on age, and "X" is a vector of covariates including vitamin intake or food group of interest and a set of adjustment variables including cohort, community, technician, spirometer, race/ethnicity, barometric pressure, and other possible confounders (34). We used natural cubic splines that impose the additional constraint that the function be linear beyond the boundary knots. Flexible models were fitted that included servings of fruit and vegetable groups and sex-specific deciles of dietary and total vitamin intake and variables for cohort, community, ethnicity, spirometer, spirometer temperature, technician, and barometric pressure. Note that the models are additive on the log scale, and the results are presented as the differences in percentage from the reference curve, at the mean age. The primary parameters of interest are the main effects for low vitamin or food group intake, which characterize a parallel difference in percentage in pulmonary function compared with the baseline group of high vitamin intake. Separate models were fitted for dietary intake with and without vitamin supplements. All models were adjusted for total energy intake. We assessed parental education, household income, body mass index, age- and sex-specific quintiles, insurance status, personal smoking, environmental tobacco smoke exposure, and respiratory illness at lung function testing as potential confounders. Covariates were included in models if the adjusted estimates for intake changed by 10 percent or more compared with the unadjusted estimates. Because the lung function level is associated with magnesium intake, which is contained in foods with antioxidant vitamins, we conducted sensitivity analyses to assess the independent effects of each vitamin by adjusting for magnesium intake. We also fit multinutrient models to assess the joint effects of vitamin intake. Subjects with missing data for a given covariate were excluded from the analyses involving that covariate.
To assess the modifying effect of asthma on the relation between low vitamin and lung functions, we conducted gender-specific stratified analyses for children with and without asthma. We tested the statistical significance of interaction terms between asthma status and vitamin intake (or food groups) using likelihood ratio tests. All analyses were conducted by using generalized linear models in the S-Plus statistical software package (35).
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RESULTS |
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Fruit, juice, and vegetable intakes were relatively low among Childrens Health Study participants compared with recommendations for five servings of fruit and vegetables per day (table 3). On average, boys and girls consumed 1.52 servings of vegetables per day, about one serving of fruit per day, and 0.8 servings of fruit juice per day. On average, boys and girls consumed 3.2 and 3.5 servings per day of fruits, vegetables, and juices combined, respectively.
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Low dietary vitamin A intake was associated with a substantial reduction in FEF2575 in girls. Overall, vitamin A intake was not strongly associated with lung function in boys; however, boys with asthma who had low intake showed deficits in airflows, especially FEF2575, that were significantly larger than the deficits in boys without asthma (table 5). Girls with asthma and low vitamin A intake had larger deficits than girls without asthma, but the difference in deficits was not statistically significant (data not shown). The magnitude of the lung function deficits did not increase with increasing vitamin A intake above the 10th decile (data not shown). Adjustment for magnesium intake had little effect on the deficits associated with low vitamin A intake. We found no associations of lung function level with intake of total carotenoids.
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Low intakes of all fruit juices, orange juice, and other fruit juices were associated with significant deficits in FVC and FEV1 among boys (table 6). Among girls, the deficits were slightly smaller and did not achieve statistical significance. Low intakes of either fruits or vegetables, as well as their combined intake, were not associated with lung function level in either boys or girls. Individual food items were examined, and no consistent associations were observed for specific vegetables or fruits, including carrots and apples. We found no evidence that asthma affected the associations of fruits, vegetables, and juice intake with lung function and no confounding by family income, parents education, health insurance status, or other sociodemographic variables. We had an insufficient number of smokers to assess interactions between food groups and smoking.
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DISCUSSION |
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Our findings showing lung function deficits with inadequate intake of vitamin C are consistent with those of studies in adults showing that lower levels of FVC and FEV1 are associated with a lower intake of vitamin C, but they are inconsistent with the only reported investigation of the relation between vitamin C and lung function during childhood (3, 9, 10, 12, 16, 19, 20). In the cross-sectional study of 2,650 school-age children in England and Wales, Cook et al. (3) reported that FEV1 was positively associated with the frequency of fresh fruits, green vegetables, and salad consumption but was not associated with serum vitamin C levels, suggesting a role for other nutrients in fruit. Several studies in adults have also reported the protective effects of fruit intake on lung function or obstructive airway diseases (10). The differences in findings in the Childrens Health Study may reflect variation in diet habits among the populations or diet assessment methods. In the Childrens Health Study population, fruit juices, which were the leading contributor to vitamin C intake, were positively associated with lung function. Fresh fruit is also an important source of vitamin C, and the study population from the United Kingdom may have consumed more fresh fruits as a source of vitamin C than fruit juices during the period of the study; however, we could not assess this possibility because the consumption of fruit juices was not included in the published report by Cook et al. Additional information about fruit juice intake may contribute to understanding the differences between the studies. Cook et al. did not find an association between serum vitamin C levels and childhood lung function. Although dietary assessment of vitamin intake using food frequency questionnaires is imprecise, the lack of association may also be the result of a mismatch between the time scale of the cross-sectional studies of lung function level that integrates growth over the life course and serum levels of vitamin C, which is a water-soluble vitamin with a relatively short half-life (3). Short-term biomarkers, such as serum levels, may provide less accurate estimates of the average levels during childhood than those provided by questionnaire methods that characterize usual intake, such as the food frequency questionnaire method.
Several mechanisms for the protective effects of vitamin C on lung function have been investigated. Vitamin C is an important antioxidant in the extracellular respiratory lining fluid that protects proteases, antiproteases, epithelial, and immune cells from oxidant attack, and low levels may leave the lung relatively unprotected from oxidant stress. The importance of vitamin C to antioxidant defenses is illustrated by trials that document the protective effects of vitamin C supplementation on short-term changes in lung function in free-living subjects exposed to high levels of oxidant air pollutants (16, 19, 38). Vitamin C may contribute to lung growth and development and reduce airway hyperreactivity, both of which are determinants of childhood and adult lung function (16, 39). Whether the association of flows with the antioxidant vitamins and juice intake results from enhancement of lung growth, protection against bronchospasm, or reduced airway hyperreactivity in children from the Childrens Health Study is presently unknown because this analysis was cross-sectional and we cannot differentiate between acute and chronic deficits in lung function. Future longitudinal follow-up of the cohort may be informative about the acute and chronic effects on lung function growth and maximum attained lung function at maturity.
The present study findings show that deficits in lung function are associated with low vitamin A intake. The findings are supported by results in the single published report concerning the effects of low levels of vitamin A on childrens lung function (21). Among 702 rural Ethiopian children aged 69 years, FEV1 was 48.8 ml (p = 0.006) lower in children with inadequate vitamin A reserves than in those with adequate reserves. The evidence for a protective effect of vitamin A has been inconsistent in adults (10, 19). The biologic plausibility for the association of lung function with vitamin A is provided by evidence that vitamin A is involved in critical pathways for normal lung function growth in early life, including lung development, normal respiratory epithelial differentiation, pulmonary immune function, resistance to respiratory infections, and antioxidant defenses (40). Our finding that deficits in flow were larger in boys with asthma than in those without asthma warrants further research.
The evidence that vitamin E is associated with lung function is less consistent than for vitamin C (10). Studies in adults suggest that vitamin E intake is positively correlated with lung function; however, the associations appear to be accounted for by correlations with vitamin C or other nutrients (16, 19). No studies of the associations of vitamin E intake with lung function have been reported in children. We found that low vitamin E intake was associated with deficit in FEF2575, a measure of small airway flow that has not been routinely reported in other epidemiologic studies of nutritional determinants of lung function. It may be that vitamin E plays a role in protecting small airway function, and measures such as FEV1 may be less sensitive for the effects. Because vitamin E intake and levels may not be measured precisely by food frequency questionnaire methods, our estimates may be biased toward no effect of vitamin E intake.
There are several limitations that arise from our study design and methods. Our data were cross-sectional and were subject to problems with temporality and selection bias. This cross-sectional study cannot distinguish between children who had low lung function as a result of low intake of antioxidant vitamins and children who had respiratory problems that lead to reduced lung function that leads to diet changes. Because deficits were observed in children with and without asthma, it is unlikely that disease-related dietary changes explain our findings. Only a subset of Childrens Health Study participants remained enrolled in schools in the 19971998 school year. The 10th graders enrolled in the cohort in 1993 had graduated by 1997. The primary reason for not completing the dietary assessment was family relocation to a new residence outside a participating school district. We assessed the reason for moves using a telephone interview and found that moves were almost entirely due to changes in the parents employment, which were more common in lower income families with lower educational attainment. Because education and income may affect diet and lung function, we adjusted for these factors in sensitivity analyses and found no evidence of bias. We used a validated food frequency questionnaire designed to assess usual dietary intake in children and adolescents; however, measurement error remains an unresolved problem for diet assessment, and the effect estimates for micronutrients are likely to be biased toward no effect. Repeated food frequency questionnaires or repeated serum level measurements in longitudinal studies of lung function have the potential to reduce the bias from measurement errors.
In summary, low intakes of antioxidant vitamins were associated with deficits in pulmonary function levels among boys and girls in the Childrens Health Study. The deficits were large enough among boys with asthma to be potentially clinically significant. Low intake during childhood may contribute to risk for obstructive lung diseases during adulthood as well as increased morbidity and mortality associated with low FEV1. Future longitudinal analyses, as follow-up of the Childrens Health Study cohort continues and additional nutrient data are collected, will allow better assessment of the temporal relation between dietary intake and lung function.
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ACKNOWLEDGMENTS |
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The authors thank Dorothy Starnes for providing technical support in the preparation of this manuscript.
The statements and conclusions in this report are those of the investigators and not necessarily those of the California Air Resources Board, the Environmental Protection Agency, or the National Institute of Environmental Health Sciences. The mention of commercial products, their source, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products.
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NOTES |
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REFERENCES |
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