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Nutritional Epidemiology

Vitamin Intake Is Not Associated with Community-Acquired Pneumonia in U.S. Men¹

Anwar T. Merchant^*,,2, Gary Curhan^**,, Adrianne Bendich, Vishwa N. Singh, Walter C. Willett^*,**, and Wafaie W. Fawzi^*,**

^* Department of Nutrition, Harvard School of Public Health, Boston, MA 02115; Department of Oral Health Policy and Epidemiology, Harvard School of Dental Medicine, Boston, MA 02115; ^** Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115; The Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA 02115; GlaxoSmithKline Consumer Healthcare, Parsippany, NJ; and Roche Vitamins Incorporated, Parsippany, NJ

²To whom correspondence should be addressed. E-mail: anwar.merchant{at}post.harvard.edu.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
The age-related decline in immune function may predispose individuals to increased infection risk. Nutrition is an important determinant of immunocompetence, but vitamin supplementation in relation to infection has not been evaluated extensively in well-nourished populations. We evaluated the associations between intakes of antioxidants and B vitamins and risk of community-acquired pneumonia in well-nourished, middle-aged and older men. This was a prospective study conducted between 1990 and 2000 among 38,378 male, U.S. health professionals, aged 44 to 79 y in 1990. Participants answered a detailed 131-item FFQ to assess diet and also provided information on vitamin supplement use. We included those who at the onset had no history of pneumonia, myocardial infarction, stroke, other heart disease, arterial surgery, cancer or asthma, and also had complete dietary data. There were 446 new cases of nonfatal community-acquired pneumonia during 145,878 person-years of follow-up. After adjustment for age, smoking, BMI, alcohol use, physical activity, diabetes and total energy intake, there were no associations between total intakes of antioxidants or B vitamins and pneumonia risk. After excluding men who took vitamin E supplements, vitamin E intake from food sources only was inversely associated with pneumonia risk (multivariate relative risk comparing extreme quintiles = 0.58, 95% CI, 0.39–0.86, P-value test for trend = 0.01). Vitamin supplements are unlikely to reduce pneumonia risk in well-nourished, middle-aged and older men.

KEY WORDS: • multivitamin supplements • community acquired pneumonia • prospective study • middle-age • older men

The age-related decline in immune function may predispose individuals to infections, especially respiratory infections (1,2). Malnutrition was a common presentation of elderly persons with community-acquired pneumonia in several studies (3) and could play a role in the etiology of infection. Micronutrients can improve cell-mediated immunity (1) and reduce oxidative stress (4). Vitamin E supplementation in healthy, well-nourished seniors increased delayed hypersensitivity responses, responses to hepatitis B vaccine, lymphocyte proliferation, and decreased formation of immunosuppressive prostaglandins. Vitamin C regenerates the antioxidant form of vitamin E and is critical for the killing of pathogens by neutrophils. Vitamin B-6 (pyridoxine) supplementation enhanced lymphocyte proliferation and interleukin-2 levels in young women (5). Supplementation with a combination of vitamins and minerals in free living, older Canadians increased the number of T-cell subsets and natural killer cells, lymphocyte proliferation response to mitogens, interleukin-2 production and antibody response to natural killer cell activity (1). The results of studies evaluating the relation between micronutrient status to infections in adults have been variable (6). Moreover, most previous studies evaluated either multivitamin tablets or high doses of specific nutrients (for example, vitamin E) in relation to infection risk. In this study, we examined prospectively the associations between individual micronutrients commonly found in multivitamin supplements and the risk of community-acquired pneumonia in well-nourished, middle-aged and older men. Specifically, we examined the associations with intakes of antioxidants (vitamins A, C, and E, -carotene, ß-carotene, ß-cryptoxanthin, lycopene, lutein and zeaxanthin) and B vitamins [thiamine, riboflavin, niacin, pyridoxine (vitamin B-6), cobalamin (vitamin B-12) and folate].

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Study population. The Health Professionals Follow-up Study began in 1986 when 51,529 male U.S. health professionals, aged 40–75 y returned questionnaires about their lifestyle and medical history (7). Every 2 y, they were sent follow-up questionnaires to update lifestyle information and identify new major illnesses. Deaths were reported by family members, the Postal Service, or were ascertained through state registries or the National Death Index. Information about pneumonia was first collected in 1990. We excluded men who reported pneumonia or conditions that may have prompted them to change their diet or supplement use and that may have increased their pneumonia risk (myocardial infarction, stroke, other heart disease, arterial surgery, cancer or asthma) before 1990. Men who left 70 or more items blank on the FFQ and those who reported food intakes that were deemed to be implausible were also excluded. Data from 38,378 men were included in these analyses. Ascertainment of death was >98% complete (8). This study was approved by the Harvard School of Public Health’s Human Subjects Committee.

    Case ascertainment. The end point of this study was nonfatal, incident, community-acquired pneumonia occurring between 1990 and 2000. If a participant reported that he had pneumonia during this period, we requested permission to review his medical record to confirm the diagnosis and date of occurrence of disease. The person who reviewed the medical records was unaware of the risk factor status of the participant. A case was considered confirmed if the medical record contained a diagnosis of community-acquired pneumonia by a physician based on a chest X-ray. Because this information was not available for all fatal cases, we excluded them to focus on cases that were diagnosed in the same way to reduce the chance of misclassification or bias. If a participant had more than one episode of pneumonia, we considered only the first. We excluded aspiration pneumonia, hospital-acquired pneumonia and deaths due to pneumonia in this analysis.

    Diet ascertainment. Diet was assessed by a validated FFQ every 4 y starting in 1986 (9). To estimate intakes of vitamins, participants were asked how often on average in the past year they ate a unit or portion size of each food [for example, an apple or 1 cup (240 mL) of cooked spinach]. There were nine possible responses ranging from never or less than once a month to six or more times a day. Nutrient intakes were estimated by multiplying the number of times the food was eaten by the average nutrient content of the portion or unit of food. The nutrient content of foods was estimated from the Harvard University Food Composition database, U.S. Department of Agriculture sources and information from manufacturers (10). Because we asked the men about vitamin supplement use, we were able to determine total vitamin intake. The questionnaire included information on the brand names of supplements used so that nutrient content could be estimated from the manufacturers’ information. If dietary data were missing for one questionnaire, we used the value derived from the immediately preceding questionnaire. We adjusted nutrients for total energy by regression analysis to estimate total vitamin intake and intake from foods alone (11). Energy-adjusted intake of vitamin C, for example, can be interpreted as the composition of vitamin C in the diet independent of the total quantity of food eaten. To estimate supplemental vitamin intake we subtracted the estimated food intake from total vitamin intake.

The reproducibility and validity of our semiquantitative FFQ were reported elsewhere (9). Compared with diet records, the FFQ was a good measure of total intakes of vitamin C (deattenuated correlation, 0.76) (12), thiamine (r = 0.86), riboflavin (r = 0.88), vitamin B-6 (r = 0.85), vitamin B-12 (r = 0.56) and folate (r = 0.77) (13). The correlations of intakes of nutrients estimated from FFQ compared with plasma levels ranged from 0.11 to 0.52 for carotenoids (14), and was 0.51 for vitamin E (15).

    Statistical analysis. Person-time of follow-up was calculated from the return of the 1990 questionnaire to the first report of community-acquired pneumonia, death or January 31, 2000, whichever came first. Men who developed myocardial infarction, stroke, other heart disease, cancer (except nonmelanoma skin cancer), asthma, or who underwent arterial surgery were excluded from further follow-up.

Dietary variables were first measured in 1986 and updated in 1990 and 1994. The most recent dietary intake at the start of each 2-y follow-up interval was related to subsequent pneumonia risk. We used the Cox proportional hazards model (16) to estimate multivariate relative risks (RR) and CI. Failure time was measured by age in months, which allowed fine control of confounding by age. The Anderson-Gill data structure was used to handle time-varying covariates (17). We examined the relationship of total nutrient intake (foods plus supplements) and also nutrients from food alone. We analyzed nutrients from food in the following two ways: 1) by including as separate terms nutrients from food sources and nutrients from supplement sources simultaneously in the model, and 2) by excluding men who took supplements of the nutrients of interest, and examining the relation between nutrient intake (which is by definition limited to food sources) and the outcome. We also evaluated current use of supplemental multivitamins, and vitamins E and C and pneumonia risk.

The enrollment and follow-up questionnaires included information on age, smoking, diabetes mellitus, weight and physical activity. Metabolic equivalents (MET), a measure of energy expenditure were calculated on the basis of reported type and duration of a variety of physical activities (e.g., walking, running or swimming). BMI was computed by dividing weight in kilograms by the square of the height in meters. All time-varying covariates were updated every 2 y.

In the multivariate models, we adjusted for age in months, smoking (never, past, and current smokers who smoked 1–14, 15–24 or 25 cigarettes/d), BMI (<21 to 21–22.9, 23–24.9, 25–29.9 and 30+ kg/m²), alcohol use (never, 0.1–4.9, 5.0–14.9 15.0–29.9 and 30+ g/d), physical activity (quintiles of MET), diabetes (dichotomous) and total energy intake (continuous). We used the Mantel extension test to calculate tests for trend for across quintiles of intake using the respective median values (18).

To assess possible confounding by other dietary or lifestyle variables, we further adjusted for intakes of saturated fat, fruits, vegetables and multivitamins. We also stratified the results by age (>65 y), BMI (25 kg/m²), current smoking (yes/no), physical activity (third quintile of MET or higher/ second quintile of MET or lower), use of vitamin E supplements (yes/no) and diabetes (yes/no). We evaluated whether these characteristics modified the relation between nutrient intake and pneumonia risk by using the Wald test for the interaction term included in the multivariate models. SAS statistical software was used for all analyses (19). P-values <0.05 were considered to be significant for the main effects.

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Men with higher total intakes of carotenoids, vitamin C and E and B vitamins were generally less likely to smoke and consume alcohol, had a lower BMI and exercised more than those consuming less of these nutrients. Men who consumed more vitamin B-12 were more likely to be current smokers than those who consumed less (Table 1).

Vitamin C from foods was not associated with pneumonia risk in multivariate analyses adjusting for vitamin C from supplements (RR comparing extreme quintiles = 1.07, 95% CI, 0.79–1.45, P-value test for trend = 0.78), or after excluding vitamin C supplement users (RR comparing extreme quintiles = 1.12, 95% CI, 0.72–1.75, P-value test for trend = 0.73). The relationship between total carotenoids from foods and pneumonia risk was similar (RR comparing extreme quintiles = 1.04, 95% CI, 0.77–1.40, P-value test for trend = 0.78) in the model adjusting for carotenoids from supplements, and (RR comparing extreme quintiles = 1.20, 95% CI, 0.64–2.26, P-value test for trend = 0.73) in the model excluding carotenoid supplement users.

Vitamin supplement use was not associated with pneumonia risk. The multivariate RR comparing supplement users with nonusers was 1.06 (95% CI, 0.87–1.30); the multivariate RR comparing vitamin E supplement users to nonusers was 1.16 (95% CI, 0.93–1.44); the multivariate RR comparing vitamin C supplement users to nonusers was 1.10 (95% CI, 0.91–1.33); and the multivariate RR comparing men who used both vitamins C and E supplements to nonusers of both was 1.19 (95% CI, 0.93–1.52).

There was no association between any of the nutrients and pneumonia risk when we stratified the results by age (>65 y), BMI (>25 kg/m²), current smoking, physical activity, use of vitamin E supplements, or restricted the analyses to nondiabetics (all tests for interaction P-values >0.20). Further adjustment for fruits and vegetables, saturated fat and multivitamin supplements did not materially change the associations.

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
We did not find any meaningful association between intakes of antioxidants or B vitamins and community-acquired pneumonia risk in this large prospective cohort of healthy, well-nourished, middle-aged and older men. We found no relationship between the intakes of vitamin C or carotenoids and pneumonia risk. The results were similar for total vitamin C intake and vitamin C from foods alone. This is consistent with several studies in which vitamin C use was not associated with a reduction in infection risk (20).

There was also no association between total vitamin E intake and pneumonia risk, but vitamin E intake from foods was inversely associated with pneumonia risk when we excluded vitamin E supplement users (25% of the men). The results of other studies evaluating vitamin E intake and infection risk are inconsistent. Supplemental vitamin E (200 IU/d for 4 mo) improved cell-mediated immunity among free-living U.S. adults 65 y old compared with placebo (21), but a Dutch study did not find any effect of multivitamins on infection risk, and an adverse effect of vitamin E supplements on acute respiratory symptoms was seen among free-living elderly Dutch individuals (22). The limitations of that study were that the outcome combined allergy and infection, and the group receiving vitamin E had more people with chronic obstructive pulmonary disease, asthma, allergy and smokers than the placebo group.

A possible reason for observing an association with vitamin E from foods but not total intake is that foods containing vitamin E have some other beneficial nutrient that could be inversely associated with community-acquired pneumonia risk. Vitamin E–rich foods (nuts for example) also contain a number of biologically active substances including essential fatty acids. Essential fatty acids have been hypothesized to enhance immune function and reduce inflammation (23), thereby decreasing infection risk. Total vitamin E intake would result in misclassification of vitamin E intake from foods and attenuate any association with pneumonia risk.

Multivitamin supplementation was found to reduce infection risk in older adults in some studies, particularly those with some nutritional deficiencies. Multivitamin supplements compared with placebo improved cell-mediated immune response and resulted in fewer days with infection among Caucasian Canadian adults 65 y old with higher than median incomes (1). U.S. adults 45 y old receiving multivitamin supplements reported fewer infections (upper respiratory tract infection, lower respiratory tract infection, influenza-like syndrome, gastrointestinal infection and urinary tract infection) compared with those receiving placebo (24). The effect was particularly marked among diabetics (24).

We did not observe any association between intake of B vitamins, antioxidants and pneumonia risk. This could be because a very small proportion of our study population was deficient in vitamins. Multivitamin use was reported by 52% of the men in 1986, 38% in 1990 and 48% in 1994. In a French study conducted among free-living adults 60 y old with few underlying deficiencies, multivitamin supplements did not result in fewer infections compared with placebo (25). Canadian and U.S. studies also suggest the benefit may be limited to those with nutritional deficiencies. In the Canadian study, the nutrient deficiency was reduced significantly after supplementation and corresponded to improved immune response. In the U.S. study by Barringer et al. (24), diabetics were more likely to be nutritionally deficient than nondiabetics, and the greatest reduction in infection from multivitamins was seen in that group. We did not have enough diabetic cases of community-acquired pneumonia to evaluate meaningfully the associations in that group.

Most of the trials of vitamins and infection risk were conducted among older adults. Our study population consisted of middle and older-aged men, but we did not have sufficient power to evaluate the association in the higher age group. Among men > 65 y old, we had powers of 52 and 67% to detect relative risks of 0.70 and 0.65, respectively, with an error of 0.05, assuming an ordinal trend across quintiles of intake (26).

The results were consistent in men who were younger and older, current smokers and past and never smokers, overweight and normal weight, physically active and inactive, multivitamin users and nonusers. We adjusted for a number of possible confounders in this study, but the results did not change materially. Recall bias would not explain the results because of the prospective study design, and selection bias is unlikely because the follow-up rate exceeded 90% (27). It is possible that men who perceived they were more susceptible to infection took supplements and subsequently were diagnosed with pneumonia. The positive nonsignificant association (P = 0.46) between vitamin intake and pneumonia risk particularly with the B vitamins may reflect this. It is unlikely to explain the results, however, because little is known about other susceptibility factors, and we used stringent exclusion criteria to eliminate other comorbid conditions. We did not have information about pneumococcal or influenza vaccination for these men. To the best of our knowledge, there is no association reported between vaccination and diet. If, however, men who received vaccination had higher vitamin intakes, then we would have expected an inverse association between nutrient intake and pneumonia risk, something we did not observe. We estimated dietary intake by a previously validated FFQ (10). To estimate -carotene intake, for example, we used average values assigned by the USDA for its content in different types of foods. The questionnaires also asked about use of vitamin supplements, from which we estimated their nutrient content. There was, therefore, some unavoidable misclassification of exposure that was most likely random, which would attenuate the results. Misclassification of exposure, however, is not the most likely explanation of the results because there was a wide range of intake. Moreover, the association between vitamin E intake from foods and pneumonia risk was significant even after we excluded men who took vitamin E supplements.

In conclusion we did not observe any association between intakes of antioxidants, B vitamins and pneumonia risk in a large prospective investigation of well-nourished middle-aged and older men. Vitamin supplements are unlikely to reduce the risk of pneumonia in well-nourished men.

	FOOTNOTES

 
¹ Supported by National Institutes of Health research grants CA55075 and HL35464, Roche Vitamins Incorporated.

Manuscript received 24 September 2003. Initial review completed 21 October 2003. Revision accepted 27 October 2003.

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TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

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