Diet and vitamin D as risk factors for lung impairment and COPD

REVIEW ARTICLE Diet and vitamin D as risk factors for lung impairment and COPD CORRINE HANSON, ERICA P. A. RUTTEN, EMIEL F. M. WOUTERS, and STEPHEN RENNARD OMAHA, NEB; AND MAASTRICHT, NETHERLANDS

Epidemiologic and observational studies have shown an association between increased intakes of certain micronutrients and higher levels of lung function and health. The National Health and Nutrition Examination Surveys of the U.S. population have demonstrated repeatedly that increased intakes or serum levels of some micronutrients, including the vitamins E, D, C, and A, and carotenes are associated positively with forced expiratory volume in 1 second (FEV1). These findings are complemented by other observational studies, including the MORGEN study as well as the Seven Countries Study, both of which found micronutrient status had positive correlations with pulmonary function. In addition, epidemiologic studies have demonstrated that dietary intake patterns with increased intakes of fruit, vegetables, fish, vitamin E, and whole grains have been associated with a decreased development of chronic obstructive pulmonary disease (COPD) in smokers and nonsmokers, higher levels of FEV1, and decreased long-term COPD mortality. Diets high in refined food have been associated with accelerated longitudinal decline in FEV1 over 5 years. Taken together, these results suggest that micronutrient status may impact lung function, and that nutrition interventions could be a useful tool in a public health campaign aimed at the prevention of lung disease. Future research should focus on the effect of nutrition interventions on the natural history of lung disease. (Translational Research 2013;-:1–18) Abbreviations: 25(OH)D ¼ 25 hydroxyvitamin D; ATBC ¼ Alpha-tocopherol, Beta-Carotene Cancer Prevention; CI ¼ confidence interval; COPD ¼ chronic obstructive pulmonary disease; DINHAL ¼ Cumulative Index of Nursing and Allied Health Literature; EMBASE ¼ Excerpta Medica Database; FEV1 ¼ forced expiratory volume in 1 second; FFQ ¼ food frequency questionnaire; FVC ¼ forced vital capacity; MESH ¼ Medical Subject Headings; NHANES ¼ National Health and Nutrition Examination Survey; OR ¼ odds ratio; SD ¼ standard deviation From the Division of Medical Nutrition Education, School of Allied Health Professions, University of Nebraska Medical Center, Omaha, Neb; Program Development Centre, Centre of Expertise for Chronic Organ Failure (CIRO), Horn, The Netherlands; Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, The Netherlands; Division of Internal Medicine, University of Nebraska Medical Center, Omaha, Neb.

the following: as a consultant: Align2Action, GlaxoSmithKline, Almirall, HealthStar, Boehringer, Ingelheim, Lek, Under Decision Resources, McKinsey, Dunn Group, Navigant, Easton Associates, Penn Technology, Elevation Pharma, Strategic North, Forest, Synapse, Gerson, and Telecon SC; as a speaker: CME Incite, Nuvis, Forest, ProiMed, Incite, Takeda, and IntraMed (Forest); on an advisory board: AstraZeneca, Pearl, Forest, Pfizer, and Johnson & Johnson.

Conflict of Interest: All the authors have read the journal’s policy on disclosing potential conflicts of interest. S. Rennard discloses that he has had or currently has a number of relationships with companies that provide products and/or services relevant to outpatient management of chronic obstructive pulmonary disease. These relationships include serving as a consultant, advising regarding clinical trials, speaking at continuing medical education programs, and performing funded research both at basic and clinical levels. He does not own any stock in any pharmaceutical companies. Specific companies and institutions with whom he has had relationships as of 2012 include

Submitted for publication February 21, 2013; revision submitted April 23, 2013; accepted for publication April 24, 2013. Reprint requests: Corrine Hanson, Division of Medical Nutrition Education, School of Allied Health Professions, 4045 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 681984045; e-mail: [email protected]. 1931-5244/$ - see front matter Ó 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.trsl.2013.04.004

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In recent years, diet and nutrition have been implicated in the prevention, development, and progression of many chronic diseases. In addition to conditions such as heart disease and cancer, there is evidence that nutrition may play a pathophysiological role in pulmonary health. Lung diseases are a major public health problem; chronic obstructive pulmonary disease (COPD) is the major chronic cause of respiratory morbidity and is the third leading cause of death in the United States.1 Lung function is measured readily by spirometry, including forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC). Measurements of FEV1 are often used as an indicator of disease severity and to describe lung function in epidemiologic studies. Of the diseases that are characterized by airflow obstruction, COPD and asthma are the most common. COPD, which includes both chronic bronchitis and emphysema, is characterized by the presence of airflow obstruction and a chronic, progressive decline in FEV1. Asthma is defined as a chronic inflammatory airway disorder with variable and reversible airflow limitation.2 The relationship between diet and asthma has been the topic of several comprehensive reviews.3,4 Lung function is an important predictor of mortality in the general population as well as in patients with lung disease5,6; therefore, it is critical to identify strategies to improve lung function in the general population as well as in populations of people with lung disease. Smoking cessation is a primary target for improving lung health; however, it is becoming clearer that other lifestyle factors, such as diet, may play a role in preserving lung function. There is evidence of a relationship between certain micronutrients, especially those with antioxidant properties, and measures of lung function. The lungs exist in a high-oxygen environment, and exposures and inflammation can increase the burden of oxidants further. The balance between these potentially toxic substances and the protective actions of antioxidant defenses, including those derived from the diet, may play an important role in the pathogenesis of lung disease and loss of lung function over time.7,8 It is possible that intake of micronutrients may modulate these effects. Increased intake of nutrients such as vitamin E, beta-carotene, vitamin C, and vitamin D have been associated positively with FEV1,9-13 and diet patterns with an increased consumption of fruit, vegetables, fish, and whole grains have been associated with a decreased development of COPD in both smokers and nonsmokers, increased FEV1, and decreased longterm COPD mortality.14-19 Diets high in refined food have been associated with accelerated longitudinal decline in FEV1 over 5 years.20 The purpose of this article is to provide a review of the literature regarding the

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association between vitamin A, carotenes, vitamin C, vitamin E, and vitamin D, including the intake and serum levels of these micronutrients and dietary patterns that affect intake with lung health. METHODS OF DIETARY INTAKE ASSESSMENT

There are several methods that can be used to assess dietary exposures. The most commonly used in epidemiologic studies is a food frequency questionnaire (FFQ). These questionnaires have the advantage of being able to assess long-term intake and are useful in large cohorts. They are also useful in longitudinal studies because the ease of administration allows for repeated measurements, and they are used in general for ranking subjects according to food or nutrient intake rather than for estimating the absolute level of intake. FFQs must be validated in the population in which they are administered. Limitation of FFQs include substantial amounts of measurement error in the estimated portion sizes of foods, and inaccuracies that result from incomplete listings of all possible foods, and the estimation of tasks required for analysis can be complex and time-consuming.21 Other methods involve 24-hour recalls and diet records. Twenty-four-hour recalls are relatively precise and can contain rich detail about the types and amounts of foods consumed. However, they may not reflect long-term intake and have been noted to have high variability.22 Diet records, such as 3-day diet dairies, can also be precise; however, some bias is introduced as a result of their prospective nature, and a high level of motivation and literacy on the part of the subjects is required for accurate data collection.3,21 These methods are based on actual intake and can be used to estimate absolute rather than relative intake of nutrients. This method is also open-ended, which has the advantage of accommodating any food or food combinations reported by the subject, providing a high level of specificity not available in structured questionnaires.21 In addition, this methodology has the advantage of not relying on memory, and portion sizes can be measured rather than estimated.21 MICRONUTRIENTS OF RELEVANCE

There are several nutrients that have been associated with lung function, including the provitamin A carotenoids, vitamin C, vitamin E, and vitamin D. The provitamin A carotenoids function as sources of vitamin A and can prevent vitamin A deficiency. The beneficial effects of carotenoids are most likely a result of their role as antioxidants; studies have shown an association between serum carotenoid levels in the serum and the extent of lipid oxidizability.23 Many provitamin A carotenoids are found in nature, and several have provitamin A

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nutritional activity, but nutritional data are only available for 3 of them: alpha-carotene, beta-carotene, and betacryptoxanthin.24 Blood concentrations of carotenoids are considered to be the best biologic marker for consumption of fruits and vegetables.24,25 Vitamin C or ascorbic acid functions as a cofactor for enzymes (eg, prolyl hydroxylases) and also directly neutralizes free radicals and suppresses macrophage secretion of superoxide anions in vitro.11 It has very high redox potential and can reduce most reactive oxygen species present in human tissues. Vitamin C contributes to cellular aqueous-phase antioxidant capacity.26 Smokers experience increased oxidative stress and metabolic turnover of vitamin C; therefore, their vitamin C requirement is increased over the general population.24 Vitamin C and vitamin E are both found in the lung, where they protect against oxidative damage, and there is a strong interaction between them because vitamin C also functions to recycle the antioxidant capacity of oxidized vitamin E.27 Vitamin E is a lipid-phase antioxidant. It functions as a chain-breaking oxidant that is particularly important because lipid peroxidation can proceed as a chain reaction, and this is prevented by vitamin E.24 Vitamin D status, as measured by 25 hydroxyvitamin D (25(OH)D) levels, has also been associated with measures of lung function both in the general population and in patients with impaired lung function.10,28 In addition to an association with pulmonary function measures, vitamin D could potentially augment anti-inflammatory defenses, and vitamin D supplementation has been associated with reduced concentration of markers of systemic inflammation.29 The possible role of these nutrients in relation to lung health is presented in Table I. SEARCH STRATEGY

A research librarian was consulted to help with the literature search. The search included the following Medical Subject Headings (MESH) terms and combinations of these terms: antioxidants/administration and dosage, antioxidants/therapeutic use, pulmonary disease, chronic obstructive, pulmonary disease, chronic obstructive/prevention and control, vitamin E, vitamin C, vitamin D, carotenes, and selenium. Excerpta Medica Database (EMBASE) and Cumulative Index of Nursing and Allied Health Literature (CINAHL) databases were searched. Abstracts were read, and studies that identified lung function as an outcome were considered relevant. Further articles were identified from the reference lists of the included articles. The effect of macronutrient intake on COPD was not included in this review. Filters included human studies and papers published in English. Asthma was considered a separate topic and was excluded from this review.

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RESULTS Observational studies of nutrient intake and lung function. Epidemiologic and observational studies of

nutrient intake have shown that higher intakes of certain micronutrients are associated with higher levels of lung function. Observational studies examining the relationships among vitamin C, vitamin E, carotenes, and vitamin D are summarized in Tables II–V. An analysis of the Third National Health and Nutrition Examination Survey (NHANES III) of the U.S. population demonstrated that increased intakes of vitamin E, vitamin C, and total carotenes were all associated positively with FEV1.9 The increase in FEV1 (given a height of 1.7 m) for 1-standard deviation (SD) increase in vitamin C, vitamin E, and carotene intake was 9.5 mL, 16.4 mL, and 18.2 mL, respectively.9 When all 3 nutrients were considered together, the increase in FEV1 for 1-SD increase in all 3 antioxidants was 24.6 mL. Other epidemiologic studies concur with this finding, including the MORGEN study, which was conducted in 6555 Dutch adults. Subjects in this study with a high intake of vitamin C had a 53-mL (95% confidence interval [CI], 23–83) higher FEV1 and a 79-mL (95% CI, 40–110) higher FVC value than those with a low vitamin C intake. Subjects with a high intake of beta-carotene had a 60-mL (95% CI, 31–89) higher FEV1 and a 75mL (95% CI, 40–110) higher FVC value than those with a low intake of beta-carotene.30 These associations remained after adjustment for age, sex, smoking status, and energy intake. There was no association between vitamin C intake and respiratory symptoms in this study; however vitamin E showed a positive association with productive cough, and beta-carotene intake showed a positive association with wheeze. A comparable study conducted in the general adult population in Nottingham found that intakes of both vitamins C and E were associated independently with measures of lung function.31 For vitamin C, a 1-SD increase in intake was associated with a 25-mL (95% CI, 5.2–44.8, P 5 0.01) higher FEV1 and a 23.3-mL (95% CI, 0.94–45.7; P 5 0.04) higher FVC value. Each 1-SD increase of vitamin E was associated with a 20.1-mL (95% CI, 1.3–40.4; P 5 0.04) higher FEV1 and a 23.1-mL (95% CI, 1.0–45; P 5 0.04) increase in FVC, after adjusting for confounders. However, in that study, vitamin C and vitamin E intakes were correlated (r 5 0.29, P , 0.001), and the effect of vitamin E was no longer significant after adjustment for vitamin C intake.31 One explanation for this effect is that the function of aqueous vitamin C is to maintain reserves of reduced vitamin E sequestered in cell membranes and

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Hanson et al

Table I. Selected micronutrients of relevance in lung health Nutrient

Role in lung health

Correlations between intake and serum levels

Vitamin A

Plays a role in the differentiation of epithelial cells

Carotenes

The antioxidant activity of carotenes may be more important than vitamin A; scavenges O2 and reduces lipid peroxidation

Vitamin C

Appears to be the most abundant antioxidant substance in extracellular lung fluid; scavenges superoxide radicals; contributes to the regeneration of membrane-bound, oxidized vitamin E Breaks the lipid peroxidation chain reaction, representing the primary defense of cellular membranes against oxidative damage

Vitamin E

Vitamin D

May regulate the expression of genes in bronchial smooth muscle cells; deficiency may increase levels of matrix metalloproteinases, which aggravate inflammatory injury and contribute to changes in lung structure

Serum concentrations of retinol do not appear to be related to observed levels of usual intake; hepatic vitamin A stores may be more reflective of nutrient adequacy Correlation between intake and serum concentrations has been shown to range from 0.21 to 0.52 (P , 0.05); serum concentrations are considered the best biologic marker of intakes of fruits and vegetables Body tissue stores are maintained at higher concentrations than serum concentrations; correlation between intake and serum concentrations has been shown (r 5 0.28–0.56, P , 0.05) Intake of vitamin E correlates with serum vitamin D (r 5 0.07, P , 0.001); dietary vitamin E correlated with serum vitamin E-to-cholesterol ratio after adjustment for age, sex, body mass index, alcohol, and smoking (r 5 0.11, P , 0.001); intakes of alpha- and gamma-tocopherols correlate with serum levels of tocopherols (r 5 0.03–0.55, P , 0.05) Serum levels of 25(OH)D have been established as the marker of vitamin D intake, in the form of diet or sun exposure, by the Institute of Medicine

Abbreviation: 25(OH)D, 25 hydroxyvitamin D.

other lipid structures, and the biologic availability of reduced vitamin E is dependent not only on intake of vitamin E, but also on intake of vitamin C.31 Another study32 in a Dutch population evaluating the effect of functional polymorphisms in glutamate-cysteine ligase (GCL) gene subunits, with vitamin C intake and smoking as interactive factors on pulmonary function, confirmed once again that vitamin C intake was associated with FEV1 and FVC. Of interest in this study was the modification of both genetic risk factors and smoking on lung function by vitamin C intake.32 Intake of vitamin C has been associated with lung function in other ethnic populations as well. In a cross-sectional study in rural China, Hu et al.26 calculated an increase of 21.6 mL in FEV1 (95%CI, 20.4 to 43.5) and of 25 mL for FVC (95% CI, 0.2–49.6) for every 100 mg/ d greater vitamin C intake. Intake of vitamin C in this population was provided primarily by vegetables alone, and was 50% higher than vitamin C intakes in the United States, where vitamin C is provided primarily by fruits and vegetables together.26,32 Longitudinal studies. Although most studies evaluating the relationship between micronutrients and lung function are cross-sectional in nature, there is a small number of longitudinal studies available. In one such study,20 dietary intake by FFQ, FEV1, and respiratory symptoms were measured in a cross-sectional study of 2,633 adults. Nine years later, these measures were repeated in 1346 of the subjects. Higher intakes of vitamin C were associated with higher levels of

FEV1 at both points in time, and in the longitudinal analysis with adjustment for confounders, decline in FEV1 was lowest among those with higher average vitamin C intake by 50.8 mL/5 y (95% CI, 3.8–97.9) for each 100 mg of vitamin C a day.20 However, another study, which measured habitual food intake and the development of chronic nonspecific lung disease over a period of 25 years, found no association between baseline intake of beta-carotene, vitamin C, selenium, and future lung disease. However, a low baseline intake of both solid fruit (apples and pears) and total fruit was significantly lower among the future lung disease cases.33 These associations remained statistically significant after adjustment for smoking, age, body mass index, and energy intake (P , 0.05). Higher intakes of vitamin D have been associated with better lung function and a lower prevalence of COPD. Vitamin D intake in a population of patients with COPD is concerning because median intake that was roughly half of current recommendations has been reported.34 Because COPD patients spend less time outdoors,35 they would be expected to have decreased sun exposure, which places them at high risk for vitamin D deficiency. Intake of vitamin D has been shown to be associated positively with FEV1 (difference in FEV1 between top and bottom quintiles of intake, 0.079 L; 95% CI, 0.02–0.14; P for trend 5 0.007) ratio of FEV1 to FVC (P 5 0.008), and associated negatively with COPD (odds ratio [OR]

Reference

Design

Dietary intake methodology/nutrient assessment method

Outcomes

Hu and Cassano9

Cross-sectional analysis of NHANES III

24-Hour recalls

FEV1

Grievink et al30

Cross-sectional analysis of 6555 adults in the MORGEN study

FFQ

Respiratory symptoms, FEV1, FVC

Britton et al31

Cross-sectional

FFQ

FEV1, FVC

Hu et al26

Cross-sectional

3-Day weighed record of food intake

FEV1, FVC

Schwartz and Weiss12

Secondary analysis of NHANES II

24-Hour recalls

Respiratory symptoms of bronchitis and wheezing

McKeever et al37

Secondary analysis of NHANES III

24-Hour recalls

FEV1

Canova et al38

209 patients admitted to hospital for asthma or COPD were recruited

Serum levels of vitamins A, C, and E

Admission of COPD or asthma exacerbation (levels of PM at time of admit were compared with PM levels 14 days before and after the event)

Association

Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FFQ, food frequency questionnaire; FVC, forced vital capacity; NHANES, National Health and Nutrition Examination Survey; OR, odds ratio; PM, particulate matter; SD, standard deviation. *For a person 1.7 m tall.

Hanson et al

Each 111 mg in vitamin C intake was associated with a 9.5-mL increase in FEV1 (95% CI, 20.2 to 19.2)*; each 1-SD increase in serum vitamin C level was associated with a 28.1 increase in FEV1 (95% CI, 18.7– 37.6) Subjects in the highest category of vitamin C intake had a 53-mL (95% CI, 23–83) higher FEV1 and a 79-mL (95% CI, 40–110) higher FVC than those with a low vitamin C intake A 1-SD increase in vitamin C intake was associated with a 25.0-mL (95% CI, 5.2–44.8; P 5 0.01) increase in FEV1 and a 23.3-mL (95% CI, 0.94– 45.7; P 5 0.04) increase in FVC Each 100-mg increase in intake of vitamin C was associated with an increase of 21.6 mL (95% CI, 20.4 to 43.5) in FEV1 and a 24.9-mL (95% CI, 0.2–49.6) increase in FVC After adjustment for confounders, serum vitamin C was related to bronchitis (OR, 0.65; 95% CI, 0.48– 0.88) and wheezing (OR, 0.71; 95% CI, 0.58–0.88) (OR are for a 2-SD change) After adjustment for confounders, a 1SD increase in serum vitamin C level was associated with a 17.9-mL increase in FEV1 (95% CI, 7.5–28.2) Serum vitamin C levels modified the effect of PM on exacerbations of COPD or asthma (OR for serum levels for .13 mmol compared with ,13 mmol, 2.17; 95% CI, 1.38–3.43, P 5 0.007)

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Table II. Observational studies evaluating vitamin C and lung function

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Table III. Observational studies evaluating vitamin E and lung function Reference

Design

Dietary intake methodology/nutrient assessment method

Outcomes

Hu and Cassano9

Cross-sectional analysis of NHANES III

24-Hour recalls

FEV1

De Batlle et al39

Cross-sectional analysis

FFQ

Tabak et al13

Cross-sectional

Cross-check diet history

Measures of oxidative stress (serum carbonyls, nitrotyrosine, malondialdehyde, reduced glutathione) FEV1

Walda et al17

Observational longitudinal

Cross-check diet history

COPD mortality

McKeever et al37

Secondary analysis of NHANES III

24-Hour recalls

FEV1

Schunemann et al40

Cross-sectional study of 1616 subjects free of lung disease

Serum levels of vitamins C, E, retinol, and carotenoids

FEV1, FVC

Association

Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FFQ, food frequency questionnaire; FVC, forced vital capacity; NHANES, National Health and Nutrition Examination Survey; SD, standard deviation.

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After adjusting for confounders, vitamin E intake was associated positively with FEV1; for each 9.1 increase in alpha-tocopherol equivalents per day, FEV1 increased by 49.1 mL (95% CI, 37.4–60.7) Intake of vitamin E was associated with reduced serum levels of carbonyls and increased levels of glutathione (P 5 0.05) After adjustment for confounders, FEV1 was associated positively with vitamin E in Finland, with each 1 SD in vitamin E intake associated with a 22.1-mL increase in FEV1 (95% CI, 0.5–43.8; P , 0.05) Inverse relationship between COPD mortality and baseline vitamin E (P , 0.05) After adjustment for confounders, higher serum levels of vitamin E were associated with higher FEV1; each 1-SD increase in serum vitamin E was associated with a 25.3-mL increase in FEV1 (95% CI, 12.3– 38.4, P , 0.001) After adjusting for confounders, serum vitamin E was associated significantly with FEV1; the differences in FEV1 associated with a reduction of 1 SD of serum vitamin E were equivalent to 1–2 years of aging

Reference

Dietary intake methodology/nutrient assessment method

Design

Hu and Cross-sectional analysis of Cassano et al9 NHANES III

24-Hour recalls

Outcomes

FEV1

Grievink et al30

Cross-sectional analysis of 6555 adults in the FFQ MORGEN study

Respiratory symptoms, FEV1, FVC

Tabak et al13

Cross-sectional

Cross-check diet history method

FEV1

McKeever et al37 Secondary analysis of NHANES III

24-Hour recalls

FEV1

Schunemann et al40

Cross-sectional study of 1616 subjects free of lung disease

Serum levels of vitamin C, vitamin E, retinol, and carotenoids

FEV1, FVC

Semba et al41

Cross-sectional analysis of 631 moderately to severely disabled women ages 65 and older participating in the Women’s Health and Aging Study

Serum levels of carotenes, lutein/zeaxanthin, FEV1, FVC and lycopene

Morabia et al42

Cross-sectional analysis of serum and PFTs from 83 men

Serum retinol and carotenoids

Pulmonary function tests

Association

Hanson et al

After adjusting for confounders, intake of betacarotene was associated positively with FEV1, with each 1017 increase in retinol equivalents/d associated with a 27.5-mL increase in FEV1 (95% CI, 16.1–39.0) Beta-carotene was associated with lung function, with those with high intakes of beta-carotene having 60 mL (95% CI, 31– 89) higher FEV1 and 75 mL (95% CI, 40– 110) higher FVC than those with a low intake of beta-carotene After adjustment for cofounders, FEV1 was associated positively with beta-carotene in the Netherlands, with each 1-SD increase in beta-carotene intake associated with a 141.1-mL increase in FEV1 (95% CI, 27.4–254.7) After adjustment for confounders, higher serum levels of vitamin A and betacryptoxanthin were associated with higher FEV1 (b 5 33.1; 95% CI, 23.7–42.6; P , 0.001 per SD change in serum vitamin A; for beta-cryptoxanthin, P 5 0.004 between the highest and lowest quintile) Significant associations were found with betacryptoxanthin, lutein, beta-carotene, and retinol with percent FEV1 after adjustment for confounders Total serum carotenoids were associated with FEV1 (P 5 0.08) and FVC (P 5 0.06), and higher serum alpha-carotene and betacarotene were associated positively with FEV1 and FVC (P , 0.05) after adjustment for confounders A statistically significant increase in the odds of airway obstruction with decreasing serum levels of retinol (adjusted OR for middle tertile compared with high, 3.1; adjusted OR for low compared with high, 4.3; P 5 0.04) (Continued )

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Table IV. Observational studies evaluating carotenes and lung function

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Abbreviations: CI, confidence interval; FEV1, forced expiratory volume in 1 second; FFQ, food frequency questionnaire; FVC, forced vital capacity; NHANES, National Health and Nutrition Examination Survey; OR, odds ratio; PFTs, pulmonary function test; SD, standard deviation.

Respiratory symptoms, Serum levels of beta-carotene attenuated the lung function, FEV1, FVC peak expiratory flow decrements resulting from air pollution in subjects with chronic respiratory symptoms; serum levels of alpha-carotene, beta-carotene, and lycopene were associated significantly with lung function; subjects with higher serum levels of beta-carotene tended to have higher FVC values (P 5 0.05) 227 subjects included in a study conducted as Serum levels of beta-carotene and alphapart of an observational study of exposure tocopherol, serum carotenoids, serum to winter air pollution and respiratory levels of beta-carotene and alphahealth44; a secondary analysis of 538 tocopherol subjects participating in surveys on lifestyle and health among noninstitutionalized Dutch ages 65–8543; a random sample (n 5 367), ages 20–59, of the MORGEN study45 Grievink et al43-45

Outcomes Dietary intake methodology/nutrient assessment method Design Reference

Table IV. (Continued )

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Hanson et al

Association

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comparing top and bottom quintiles, 0.57; 95% CI, 0.38–0.87; P 5 0.02).36 However, as a result of a lack of correlation between plasma 25(OH)D levels and lung function in that study, the authors felt that the relationship between intake of vitamin D and lung function was likely explained by other highly correlated nutrients in the diet, such as antioxidants. Intake of dairy products, but not specifically vitamin D intake, has been associated with less severe measures of emphysema (defined by computed tomographic lung density) in 3271 subjects enrolled in the MultiEthnic Study of Atherosclerosis (P 5 0.02 and P 5 0.01 for alpha, a measure of emphysema, and apical vs basilar distribution of emphysema, respectively).46 This association was observed primarily for low-fat dairy intake, not high-fat dairy intake, and may have been confounded by other lifestyle factors, because those who choose low-fat dairy products may make different lifestyle choices compared with those who choose high-fat dairy products. The usefulness of evaluating the effect of vitamin D intake from diet may have limited value, given the overall minor contribution of dietary intake to vitamin D status, because the major source for vitamin D is outdoor sun exposure. Attempts have also been made to quantify the effect of intake of certain nutrients on markers of oxidative stress and inflammation, which may play a role in the pathogenesis of declining lung function. Increased intake of vitamin E (and olive oil, which is rich in vitamin E) were shown to be related directly to decreased serum levels of carbonyls (a marker of oxidative stress) and increased levels of glutathione (a major antioxidant; P 5 0.05 and P 5 0.01, respectively),39 in one of the few studies to measure the effect nutritional antioxidants on inflammation directly. Although the finding between vitamin E and glutathione was not replicated in a 2006 study, these investigators did find a significant association between beta-cryptoxanthin and glutathione (r 5 0.14, P , 0.05). Dietary intake of beta-carotene, beta-cryptoxanthin, vitamin C, and lutein were positively associated with FEV1 (P , 0.05 for all associations) in this study.47 Plasma levels of nutrients and lung function. Although many studies have evaluated the impact of nutrient intake on measures of lung function, other studies have attempted to define this relationship by measuring the effect of serum levels of nutrients. This approach provides different information because serum levels of nutrients may or may not be reflective of intake levels of the nutrient. In the case of vitamin D, serum 25(OH)D levels have been designated by the Institute of Medicine as the functional marker of vitamin D status, and these levels are considered reflective of intake in the form of

Reference 36

Design

Dietary intake methodology/nutrient assessment method

Outcomes

Association

Shaheen et al

Cross-sectional

FFQ for vitamin D intake

FEV1, FVC, dx of COPD

Black and Scragg10

Secondary analysis of NHANES

Serum 25(OH)D

FEV1, FVC

Janssens et al28

Cross-sectional analysis of 414 ex-smokers older than 50 years

Serum 25(OH)D levels, DBP polymorphisms

FEV1, FVC

Wood et al51

Cross-sectional study of 471 subjects with a1-antitrypsin deficiency, 140 subjects with COPD, and 480 control subjects Longitudinal study of 973 participants with COPD in a 1-year study, and baseline 25(OH)D levels were compared with risk of COPD exacerbation54; case-control study of 196 smokers in the Lung Health Study 3 cohort53 Cross-sectional analysis of 2943 subjects 59 years–73 years of age in the Hertfordshire Cohort Study 626 men from the Normative Aging Study had 25(OH)D levels measured at 3 different time points between 1984 and 2003 with concurrent spirometry

Serum 25(OH)D levels, DBP levels, and single nucleotide polymorphisms in the DBP gene

Phenotypical characteristics and alveolar macrophage activation

Serum 25(OH)D levels, baseline serum 25(OH)D levels

Acute exacerbations of COPD, rate of decline in FEV1 over 6 years

No association between baseline levels of 25(OH)D and risk of exacerbations; baseline 25(OH)D levels were not predictive of decline in lung function

Serum 25(OH)D, vitamin D intake per FFQ, vitamin D receptor polymorphisms Serum 25(OH)D levels

FEV1, FVC

No association between serum 25(OH) D and lung functions

Lung function and decline in lung function over time

A significant difference was found with a greater effect of pack-years of smoking on FEV1 decline in those with vitamin D deficiency (P 5 0.02)

Kunisaki et al52,53

Shaheen et al36

Lange et al54

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Table V. Observational studies evaluating vitamin D and lung function

Total vitamin D intake associated positively with FEV1 (P 5 0.007) and FEV1/FVC (P 5 0.02) associated negatively with COPD (OR, 0.57; 95% CI, 0.38–0.87; P 5 0.02) comparing top and bottom quintiles After adjustment for confounders, 25(OH)D levels were associated positively with FVC (P , 0.001) and FEV1 (P , 0.001) In subjects with COPD, 25(OH)D levels were associated with FEV1 (P , 0.0001) 25(OH)D levels related positively to FEV1 (P 5 0.04); DBP levels related inversely to FEV1 (P 5 0.02)

Hanson et al

Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; DBP, vitamin D binding protein; dx, diagnosis; FEV1, forced expiratory volume in 1 second; FFQ, food frequency questionnaire; FVC, forced vital capacity; NHANES, National Health and Nutrition Examination Survey; OR, odds ratio; 25(OH)D, 25 hydroxyvitamin D.

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either diet or sun exposure. However, for other nutrients, serum levels may not reflect actual intake, because correlations between intake and serum levels are affected by many factors, including age, gender, smoking and alcohol intake, and race.48-50 Studies evaluating the correlation between intakes of nutrients and serum levels of nutrients have reported coefficients that range from 0.18 to 0.53 for vitamin C, vitamin E, and carotenoids24,48-50,55-58 (Table I). Furthermore, it is possible that serum levels of a nutrient, such as vitamin C, may not be a good indicator of tissue antioxidant activity. Indeed, it has been suggested that one possible response to respiratory oxidative stress is to transfer vitamin C to the respiratory epithelial lining from the lung tissue. This localized activity in the lung may not be reflected well by serum levels, and could possibly even result in decreased serum levels.2 A small study (n 5 21) reported a Pearson correlation coefficient between serum beta-carotene levels and lung tissue beta-carotene concentrations of 0.72 compared with a correlation coefficient between beta-carotene intake and lung tissue beta-carotene concentrations of 0.54, demonstrating that serum levels may be a better marker for nutrient exposure than intake levels.58 Data from the NHANES have been used in an attempt to define the relationship between serum levels of nutrients and pulmonary health. The first analysis, conducted in 1990 using data from NHANES II, found that bronchitis and wheezing were both associated negatively with serum levels of vitamin C.12 These results were complemented in an analysis of the NHANES III. In that study, McKeever et al37 investigated the relationship between 21 serum markers of potentially relevant nutrients and FEV1 with adjustment for potential confounders. Higher serum levels of micronutrients, including vitamin A, beta-cryptoxanthin, vitamin C, vitamin E, normalized calcium, chloride, and iron, were associated with higher FEV1 values.37 Participants in another study by Schunemann et al40 demonstrated that subjects with the lowest serum values for vitamin C, vitamin E, beta-cryptoxanthin, lutein, and beta-carotene consistently had the lowest values for FEV1 and FVC (P , 0.001 for all nutrients), with vitamin E and betacryptoxanthin having the strongest correlations. The differences associated with a 1-SD reduction in either serum vitamin E or beta-cryptoxanthin were equivalent to the negative influence of approximately 1 year– 2 years of aging. Both vitamins C and E retained a significant association with FEV1 after adjustment for lifetime exposure to tobacco smoke, current smoking status, weight, education, and eosinophil count.40 These relationships were not altered significantly when stratified for smoking.9 Serum carotene levels have been

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associated with greater lung function in both community-dwelling and disabled older men42,43 and women,38,43,44 and recent findings that serum vitamin C levels can modify the effect of air pollution on COPD and asthma exacerbations,38 and that serum beta-carotene levels may attenuate the respiratory effects of air pollution44 all highlight the role nutritional factors can play in potentially modifying other risk factors of respiratory impairment. Serum levels of the marker of vitamin D status, 25(OH)D, have also been associated with lung function. Epidemiologic studies in healthy subjects have identified a quantitative relationship between vitamin D levels and pulmonary function. Analysis of the NHANES III showed a significant association between 25(OH)D levels and pulmonary function tests—specifically, FEV1 and FVC. Adjusting for variables such as age, sex, smoking history, height, ethnicity, history of asthma/bronchitis, and body mass index demonstrated a mean difference in FEV1 of 126 mL and in FVC of 172 mL (P , 0.0001) between the lowest and highest quintile of serum 25(OH)D levels. Further adjustments for leisure time activity, antioxidant intake, and dietary intake maintained a significant difference.10 There have also been longitudinal studies to evaluate the relationship between vitamin D status and associations with lung health over time. In the Lung Health Study, an analysis of rapid decliners vs slow decliners found no relationship between vitamin D levels and rate of change in FEV1, but this study included only 196 COPD subjects and no control subjects.52 Likewise, an analysis of 973 participants with COPD in a 1-year study showed no relationship between vitamin D status at baseline and risk of acute exacerbations of COPD.53 However, an analysis of 626 men from the Normative Aging Study showed more rapid rates of decline in FEV1 (P 5 0.023) per pack-year of smoking in subjects with vitamin D deficiency compared with subjects who were vitamin D sufficient.54 Dietary patterns and lung function. Dietary intake of a nutrient is always increased by increasing intake of foods high in this nutrient. However, nutrients do not occur in food in isolation; they occur simultaneously with many other compounds. It is possible that the effects associated with a certain nutrient are, in fact, a result of another compound or group of compounds—or the effects of multiple compounds could be additive, synergistic, or interact in other ways. For this reason, studies investigating a ‘‘dietary pattern’’ including foods as part of a larger group have been undertaken. Observational studies have shown that adults following a ‘‘prudent’’ diet (high in fruit, vegetables, oily fish, and whole-grain cereals) are associated positively with FEV1 (P 5 0.001 in males, P 5 0.008 in females).

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The prudent diet was also associated with a significant reduction in the OR for COPD in males (P 5 0.012), with males in the top quintile being 54% less likely to have COPD when compared with the lowest quintile.15 In a 5-year longitudinal study to evaluate the effect of dietary patterns categorized as ‘‘traditional’’ (higher intakes of meat and potatoes, lower intake of soy and cereal), ‘‘cosmopolitan’’ (higher intake of chicken, fish, and vegetables), and a ‘‘refined foods diet’’ (higher intakes of mayonnaise, salty snacks, candy, high-sugar beverages, white bread), none of the dietary patterns appeared to be related to decline in lung function over time. However, the traditional diet was associated with lower FEV1 (P , 0.001) and an increased prevalence of COPD, and the highest quintile of the refined food diet had a significantly greater decline in lung function over 5 years (248.5 mL; 95% CI, 280.7 to 216.3) when compared with the lowest quintile of the refined food diet.20 Intake of fruit and vegetables has been shown to be lower in cases with a diagnosis of COPD when compared with control subjects.59 In addition to associations between dietary patterns and lung function in the general population, dietary intake patterns with an increased consumption of fruit, vegetables, fish, vitamin E, and whole grains have been associated with a decreased development of COPD in smokers and nonsmokers, increased FEV1, and decreased long-term COPD mortality.14-19,60,61 Indeed, 1 study showed that a 100-g increase in fruit intake at baseline was associated with a 24% lower COPD mortality risk.17 Analysis of the Seven Countries Study, a population-based cohort of 12,763 men, calculated that fruit and fish intake together explained about 67% of the variation in COPD mortality rates after 25 years.14 Studies evaluating the relationship between dietary patterns and lung function are described in Table VI. There are studies that show conflicting results between diet and lung function. One study of 2512 males showed that intake of hard fruit, such as apples, was associated with FEV1, but intake of citrus fruits, which are high in vitamin C, was not.62 This is, however, consistent with other studies that have shown that higher intakes of solid fruit are associated with FEV1.33 One possible explanation for this may be the high concentration of flavonoids that are present in solid fruits such as apples.63 Flavonoids are strong antioxidants; thus, these findings may support the theory of a protective effect of antioxidant intake.64 Likewise, the associations between intake of specific nutrients and lung function were inconsistent across countries in a study conducted in 3 European countries.13 FEV1 was associated positively with vitamin E intake in Finland, fruit intake in Italy, and beta-carotene intake in the Netherlands. How-

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ever, a high intake of fruit and vegetables was associated positively with lung function in all 3 countries.13 From another study, it is possible to speculate that the relationship between fruit intake and lung function has a dose-response relationship, given the results of a study in 2010 that showed a 132-mL difference in FEV1 between those eating fresh fruit less than once a month and those eating fruit daily.65 Interventional studies. There have been very few interventional studies designed to test the relationship between micronutrient intake and lung function. One such study was conducted in a population of subjects with known COPD. In that study, 120 patients were randomized to follow either a diet based on a high consumption of fruit and vegetables or a usual diet for 3 years. The COPD patients who followed a diet with a high intake of fruits and vegetables showed an annual increase in the percentage predicted FEV1 compared with patients on their usual diet, who showed a decrease in FEV1 over 3 years (P 5 0.03).19 Interaction of micronutrient intake and smoking. Smoking can be a strong confounder in the as-

sociation between nutritional effects and lung function for several reasons. The burden of antioxidants differs between smokers and nonsmokers, and smokers will carry not only a burden of general oxidants, but also a burden of oxidants generated from cigarette smoke directly, and from the inflammation that smoking induces. The relationship between specific micronutrients and the many oxidants and other toxins in smoke is unknown, which complicates interpretation of the available data. The association of serum beta-carotene and FEV1 has been shown to be weaker in smokers when compared with nonsmokers, and the strength of the relationship decreased as the amount of smoking increased.9 A small study (n 5 12) of smokers assigned randomly to 1000 retinol equivalents/d or placebo for 1 month showed 22.9% improvement in FEV1 in the supplemented group (P 5 0.004), with a return to baseline values after the withdrawal of supplementation.66 However, in a larger study of 29,133 male smokers enrolled in the Alphatocopherol, Beta-Carotene Cancer Prevention (ATBC) study, supplementation of beta-carotene and/or alphatocopherol showed no effect on the incidence of chronic cough, phlegm, bronchitis, or dyspnea.67 Interestingly, in that study, high baseline intake of beta-carotene and vitamin E were associated with low prevalence of chronic bronchitis (OR, 0.78; 95% CI, 0.73–0.83; OR, 0.87; 95% CI, 0.83–0.93, respectively) and dyspnea (OR, 0.67; 95% CI, 0.62–0.71; OR, 0.78; 95% CI, 0.73–0.83, respectively). High serum levels of beta-carotene and alpha-tocopherol were also associated with low prevalence of chronic bronchitis

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symptoms (OR, 0.59; 95% CI, 0.55–0.62; OR, 0.76; 95% CI, 0.71–0.80, respectively) and dyspnea (OR, 0.62; 95% CI, 0.58–0.66; OR, 0.80; 95% CI, 0.75– 0.85, respectively) at baseline.67 Both circulating vitamins A and E showed significant associations with FEV1. Excluding participants diagnosed with COPD from the study resulted in effect sizes that were slightly reduced, implying that perhaps the effect was greater in the participants with COPD. Several studies have reported that smokers have lower plasma carotenoid concentrations compared with nonsmokers.68,69 Greater numbers of cigarettes per day led to a corresponding decrease in serum carotenoids in a dose-dependent manner.68 Whether this is a result of a decreased intake of carotenoids is unknown; tobacco smoke is highly oxidative, and has been shown to destroy beta-carotene and other carotenoids in human plasma in vitro,70 which may contribute to a reduction in serum levels. Use of supplements for repletion is controversial. The ATBC study showed a significantly greater incidence of lung cancer in current smokers supplemented with 20 mg/ d beta-carotene for 5 years–8 years (relative risk, 1.18; 95% CI, 1.03–1.36).71 The bioavailability of betacarotene in supplement form is much higher than the bioavailability from food, and 20 mg of beta-carotene in supplement form will have a much larger impact on serum beta-carotene levels than the corresponding amount from food. Hence, the serum concentrations of beta-carotene in the ATBC trial were well beyond serum levels from dietary intake in the populationbased NHANES study.24 Thus, any recommendation to smokers regarding nutrient intake needs to state clearly that individuals who smoke might benefit from a higher beta-carotene intake from food, not in supplement form, should they choose to increase their carotene intake. Supplementation of micronutrients. Although a summary of the epidemiologic data generally suggests a beneficial effect of micronutrients, data from clinicaltrials are lacking and the information is often conflicting. There are many reasons why trials of micronutrient supplementation may have mixed results on lung function outcomes. There is a large amount of heterogeneity in the vitamins supplemented, dosages, and duration of supplementation among the studies. Poor bioavailability of nutrients and antioxidants to lung tissue could be a potential limitation, as well as the interaction between nutrients and smoking. Nutrients must be absorbed from food, which is often a competitive process based on the composition of the diet, the bioavailability of the nutrient, and the requirements of the host. The compounds must then pass through the gut lumen into the circulation, and be

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transported to tissues for metabolism. For example, fat-soluble vitamins such as vitamins A, E, and D are hydrophobic and require dietary lipids to be absorbed. When fats are present in the diet, vitamin E can be packaged into chylomicrons and transported in the circulation. However, the fat content of the diet can have a significant impact on the absorption of such nutrients.24,55,72 Also, serum levels of some nutrients are under aggressive homeostatic control and supplementation may not alter serum levels. Supplementation of individual nutrients can also affect the absorption of other compounds.73 In 1 interventional study, individuals at high risk for cardiovascular events received antioxidant vitamins for 5 years (600 mg vitamin E, 250 mg vitamin C, 20 mg beta-carotene). That study failed to identify any effect on lung function, although it was measured only at the last visit, or hospitalization for nonneoplastic respiratory causes. Individuals with severe COPD, however, were excluded from that study.74 In COPD patients, studies that have shown that antioxidant levels are low in the stable COPD patient but tend to increase after episodes of stress, such as exercise or exacerbations,75 make it logical to attempt to treat COPD with antioxidant supplementation. Supplementation with antioxidants (vitamin E, vitamin C, and beta-carotene) has been shown to offer some protective effects against the decline in lung function caused by exposure to ozone.76,77 Results of other supplementation trials, however, tend to provide conflicting results. A trial of 800 IU/day vitamin E supplementation for 8 weeks did not improve clinical parameters in COPD patients; however, levels of certain endogenous antioxidants were augmented in the intervention group.78 These results were similar to the results of Daga et al79, who provided 8 weeks of vitamin E supplementation to subjects with COPD and showed improvement in serum lipid peroxidation levels after 8 weeks of vitamin E supplementation, but no improvement in lung function tests. Similarly, Wu et al80 provided supplementation of 200 mg vitamin E, 400 mg vitamin E, or 250 mg vitamin C to 35 subjects with stable COPD for 12 weeks and observed a decrease in DNA breakage from baseline, but no improvement in spirometric measurements. A recent study of vitamin D supplementation on COPD exacerbations did not demonstrate an effect of vitamin D supplementation on exacerbations in a population of 182 COPD patients; however, reduction in exacerbations was observed in a subset of these patients with severe vitamin D deficiency.81 Excessive intake of micronutrients can lead to adverse side effects. For example, carotenoid toxicity can lead to yellowing of the skin and nausea. Vitamin C supplementation greater than 2000 mg/d has been

Reference

Design

Dietary intake methodology/ nutrient assessment method

Dietary pattern

Measurements

Tabak et al14,60

Cross-sectional analysis57 and longitudinal14 of the MORGEN study, FFQ

FFQ

Fruit, whole grains, alcohol, vegetables, fish

Shaheen et al15 2010

Cross-sectional, FFQ

FFQ

Diet pattern: prudent pattern (high in fruit, vegetables, oily fish, and whole grains; low in sugar and processed meat) vs traditional (high consumption of vegetables, red meat, processed meat) Prudent pattern (fruit, vegetables, fish, whole grains) vs western pattern (refined grains, cured and red meat, desserts, French fries)

FEV1, FVC, dx of COPD

FEV1, FVC, respiratory symptoms, COPD mortality

2007 longitudinal (analysis of the Nurses Cohort Study), FFQ; 2007 longitudinal (Analysis of Health Professionals Follow-up Study), FFQ

FFQ (both studies)

Watson et al18

Case-control (control group composed of smokers with no COPD dx) Case-control (control group composed of smokers)

FFQ

Fruit, vegetables, starch, dairy, alcohol

COPD dx

FFQ

Grains, meats, dairy, vegetables, fruits, fats, black tea

COPD dx

Celik and Topcu61

New dx of COPD

Diets high in fruit, whole grains, and alcohol associated with COPD57 (P , 0.001) and FEV1 (P , 0.001); inverse associations between baseline consumption fish and fruit and COPD mortality after 25 years14 Diet pattern high in fruits, vegetables, fish, whole grains associated with improved FEV1 (P , 0.001 for males, P , 0.008 for females) and COPD (OR, 0.46; 95% CI, 0.26–0.81) For women, prudent diet associated with decreased risk of COPD dx (RR, 0.75; 95% CI, 0.58–0.98; P 5 0.02) and western diet associated with increased risk (RR, 1.31; 95% CI, 0.94–1.82, P 5 0.02); for men, prudent diet associated with decreased risk of COPD dx (RR, 0.50; 95% CI, 0.25– 0.98; P 5 0.02) and western diet associated with increased risk (RR, 4.56; 95% CI, 1.95–10.69; P 5 0.02) Intake of vegetables (.93 g/d) and fruit (.121 g/d) inversely associated with COPD Vegetable/fruit intake and black tea independently predicted COPD independently (OR, 0.86; 95% CI, 0.792–0.941; OR, 0.635; 95% CI, 1.502– 0.803, respectively) (Continued )

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Varraso et al16

Outcomes

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Table VI. Observational studies evaluating the relationship between dietary patterns and lung function

13

Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; dx, diagnosis; FEV1, forced expiratory volume in 1 second; FFQ, food frequency questionnaire; FVC, forced vital capacity; OR, odds ratio; RR, relative risk.

Fruit, vitamin D, vegetables, fish, vitamin C, beta-carotene Walda et al17

Observational longitudinal

Cross-check diet history

COPD mortality

Fruit and vegetable intake lower in cases than control subjects (P 5 0.01) before dx of COPD; vegetable intake decreased risk of COPD (P 5 0.037) and breathlessness (P , 0.001) Inverse relationship between COPD mortality and baseline intake of fruit (P , 0.05) COPD dx Vegetable and fruit consumption, fiber, carotenes, vitamin A, vitamin C, omega 3 and omega 6 fatty acids Structured questionnaire Case-control Hirayama et al59

Measurements Dietary pattern Dietary intake methodology/ nutrient assessment method Design Reference

Table VI. (Continued )

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associated with nausea and diarrhea, and antiplatelet effects and bleeding may occur with excessive doses of vitamin E.73 However, no adverse events on lung function related to excessive intake have been reported. Randomized controlled trials of dietary factors and lung function are summarized in Table VII. The effect of nutrition on the risk for lung impairment over the life course. The effect of nutrition intake on lung

function may differ during different points during the life cycle. The lung matures, and maximal lung function is achieved by age 20–25; thereafter, aging is associated with loss of lung function.82 Deficits in lung function before age 25 may predispose certain individuals to an earlier diagnosis of impaired lung function; therefore, interventions to maximize lung function early in life are of interest.83 Several studies have demonstrated the potential for nutrition modulation of lung function early in life, even in utero; however, most of these studies have used asthma or the presence of wheeze in children as an end point. A 2011 review of the literature by Patelarou et al84 reported 8 studies that demonstrated an association between antioxidant status during pregnancy and asthma in childhood. Maternal intake of vitamin D during pregnancy was associated with a lower risk of recurrent wheeze in early childhood85; and vitamin A supplementation before, during, and after pregnancy in a chronically malnourished population improved lung function in the offspring.86 Increased intake of fruits and vegetables demonstrated a beneficial effect on lung function in children 8 years old–11 years old.87 These possible beneficial effects of micronutrient intake have been shown to continue throughout the life span into middle age (40 years–55 years),9,30,60,65,88 and extending into the elderly population (.65 years of age).2,15,31,89,90 CONCLUSIONS AND FUTURE DIRECTIONS

It is always difficult to separate the direct effect of a nutrient on an outcome from the overall effects of associated lifestyle factors. However, these results suggest the possibility that the intake of certain nutrients may impact lung function and the development of lung diseases, and may help attenuate the progressive decline in lung function over time. Given the importance of inflammation and oxidant stress in lung function—and, specifically, in lung function impairment—a direct effect of nutrients that have antioxidant and antiinflammatory properties is readily plausible. Because measures of lung function are an independent predictor of mortality in the general population as well as in people with lung disease,5,6 public health initiatives to improve lung function through dietary interventions could potentially have a profound impact. In the

Reference

Keranis et al19 Nadeem et al78

Daga et al79

Lehouck et al81

Heart Protection Study Collaborative Group74

Agacdiken et al75

Paiva et al66

Rautalahti et al67

Wu et al80

Romieu et al76

Measurements

Outcomes

Subjects randomized to diet high in fruits and vegetables FEV1 Intervention group improved FEV1 over 3 years vs standard diet compared with control (P 5 0.03) 10 COPD patients received 400 IU vitamin E twice a day Spirometry, clinical assessment, biochemical No improvement in clinical or spirometric parameters; for 8 weeks, 14 control subjects received a placebo parameters of oxidant/antioxidant status supplemented group showed increased serum levels of sulfhydryls (P , 0.01) and red cell catalase (P , 0.05) (beneficial antioxidants) 30 COPD patients and 20 control subjects received Spirometry, serum lipid peroxidase, No improvement in lung function; supplemented group 12 weeks of 400 IU of vitamin E daily measurements, serum superoxide had reduced lipid peroxidation levels (P , 0.001) dismutase 182 subjects with moderate to severe COPD randomized COPD exacerbations No improvement in exacerbations; reduction in to 100,000 IU vitamin D or placebo every 4 weeks for exacerbations seen in a subset of severely deficient 1 year (,10 ng/mL) subjects (rate ratio, 0.57; 95% CI, 0.33– 0.98; P 5 0.042) 20,536 adults randomized to antioxidant Primary outcome was major coronary events No difference between the 2 groups in lung function and fatal or nonfatal vascular events; measures or hospitalization for nonneoplastic supplementation (600 mg vitamin E, 250 mg vitamin C, 20 mg beta-carotene daily) or placebo for 5 years secondary outcome was lung function respiratory cause (patients with severe COPD were excluded) 21 COPD patients, 10 control subjects; 10 COPD Exercise capacity, serum measures of Exercise time improved in the intervention group patients received 200 IU/day and 500 mg vitamin C for oxidative stress (6.4 1 1.8 minutes vs 8.7 1 2.1 minutes; P 5 0.01) 4 weeks 12 smokers randomized to 1000 Retinol equivalents or Lung function tests Vitamin A-supplemented group had improvement in placebo for 30 days FEV1 (22.9%) and FVC (24.5%) compared with placebo; values returned to baseline after withdrawal of vitamin A supplementation 29,133 subjects in the Alpha-Tocopherol Beta-Carotene Primary outcome was cancer; secondary Prevalence of chronic bronchitis and dyspnea at baseline Cancer Prevention Study; subjects randomized to analysis for COPD symptoms included was lower among those with high dietary intake of 50 mg/day alpha-tocopherol and 20 mg/day betachronic cough, phlegm, or dyspnea beta-carotene (OR, 0.78 and 0.67, respectively) or carotene for 5–8 years, or placebo vitamin E (OR, 00.87 and 0.77); no benefit in chronic cough, phlegm, or dyspnea seen from supplements 35 subjects with COPD randomized to placebo, 400 mg Oxidative damage to DNA of WBCs DNA breakage significantly decreased in supplemented vitamin E, or 200 mg vitamin E, or 250 mg/d vitamin C groups; from baseline, 400 mg vitamin E 5 45% (P 5 0.023) 200 mg vitamin E 5 59% (P 5 0.007), for 12 weeks 250 mg vitamin C 5 52% (P 5 0.050) 47 subjects exposed to high levels of ozone assigned FVC, FEV1 Ozone levels were associated with FVC and FEV1 in the randomly to 75 mg vitamin E, 650 mg vitamin C, 15 mg placebo group, but not the supplemented group (P , 0.01) beta-carotene or placebo 38 Dutch bikers randomized to 100 mg vitamin E and Lung function before and after exercise, The difference in ozone effect on lung function between 500 mg vitamin C for 15 weeks and exposure to ozone and particulate the supplemented and nonsupplemented groups was matter statistically significant

Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; OR, odds ratio; WBCs, white blood cells.

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Grievink et al77

Supplementation/design

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Table VII. Randomized clinical trials of nutrient supplementation on lung function

15

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future, well-designed interventional trials are needed to confirm these associations and to establish whether dietary interventions are effective in the prevention or treatment of lung impairment. Populations of subjects susceptible to a decline in lung function, such as the elderly, may provide a target population that would incur the most benefit from the results of such trials. The low cost and safety of dietary interventions, such as counseling to increase fruit and vegetable intake to maintain or improve lung function, make this a very attractive intervention for researchers as well as clinicians working with populations of patients either with or at risk for lung impairment. The authors thank Craig Boyer for his assistance in the preparation of this article. REFERENCES

1. Hughes DA, Norton R. Vitamin D and respiratory health. Clin Exp Immunol 2009;158:20–5. 2. Schunemann HJ, Freudenheim JL, Grant BJ. Epidemiologic evidence linking antioxidant vitamins to pulmonary function and airway obstruction. Epidemiol Rev 2001;23:248–67. 3. Litonjua AA. Dietary factors and the development of asthma. Immunol Allergy Clin North Am 2008;28:603–29. ix. 4. Allan K, Devereux G. Diet and asthma: nutrition implications from prevention to treatment. J Am Diet Assoc 2011;111:258–68. 5. Hole DJ, Watt GC, Davey-Smith G, Hart CL, Gillis CR, Hawthorne VM. Impaired lung function and mortality risk in men and women: findings from the Renfrew and Paisley Prospective Population Study. BMJ 1996;313:711–5. discussion 715–6. 6. Thomason MJ, Strachan DP. Which spirometric indices best predict subsequent death from chronic obstructive pulmonary disease? Thorax 2000;55:785–8. 7. Wouters EF. Local and systemic inflammation in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005;2:26–33. 8. Schols AM, Buurman WA, Staal van den Brekel AJ, Dentener MA, Wouters EF. Evidence for a relation between metabolic derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic obstructive pulmonary disease. Thorax 1996;51:819–24. 9. Hu G, Cassano PA. Antioxidant nutrients and pulmonary function: the Third National Health and Nutrition Examination Survey (NHANES III). Am J Epidemiol 2000;151:975–81. 10. Black PN, Scragg R. Relationship between serum 25hydroxyvitamin D and pulmonary function in the Third National Health and Nutrition Examination Survey. Chest 2005;128:3792–8. 11. Schwartz J, Weiss ST. Relationship between dietary vitamin C intake and pulmonary function in the First National Health and Nutrition Examination Survey (NHANES I). Am J Clin Nutr 1994; 59:110–4. 12. Schwartz J, Weiss ST. Dietary factors and their relation to respiratory symptoms: the Second National Health and Nutrition Examination Survey. Am J Epidemiol 1990;132:67–76. 13. Tabak C, Smit HA, Rasanen L, et al. Dietary factors and pulmonary function: a cross sectional study in middle aged men from three European countries. Thorax 1999;54:1021–6. 14. Tabak C, Feskens EJ, Heederik D, Kromhout D, Menotti A, Blackburn HW. Fruit and fish consumption: a possible explanation for population differences in COPD mortality (the Seven Countries Study). Eur J Clin Nutr 1998;52:819–25.

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