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1 From the Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada (ATM); the Department of Oral Health Policy and Epidemiology, Harvard School of Dental Medicine, Boston, MA (ATM); the Departments of Epidemiology (GCC, EBR, WCW, and WWF) and Nutrition (EBR, WCW, and WWF), Harvard School of Public Health, Boston, MA; and The Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA (GCC, EBR, and WCW)
2 Supported by National Institutes of Health research grants CA55075 and HL35464. 3 Address reprint requests to AT Merchant, McMaster University, Clinical Epidemiology and Biostatistics, Population Health Research Institute, 237 Barton Street East, Hamilton, ON L8L 2X2, Canada. E-mail: merchant{at}ccc.mcmaster.ca.
ABSTRACT
Background: Essential fatty acids modulate inflammation and glucose metabolism and may alter infection risk.
Objective: We examined the association between intakes of n–6 and n–3 fatty acids and fish and the risk of community-acquired pneumonia.
Design: We prospectively evaluated 38 378 male US health professionals aged 44–79 y at the outset. We updated medical and lifestyle information biennially through questionnaires and diet every 4 y with the use of a validated food-frequency questionnaire. We excluded men who reported pneumonia, myocardial infarction, stroke, other heart disease, arterial surgery, cancer, or asthma before 1990 or those with incomplete dietary data. Community-acquired pneumonia was determined by blinded medical record review of chest radiographs.
Results: During 10 y of follow-up, there were 441 new cases of nonfatal community-acquired pneumonia. Pneumonia risk was lower in men in the highest energy-adjusted quintiles of intake than in men in the lowest quintiles of intake of linoleic acid [multivariate relative risk (RR): 0.70; 95% CI: 0.51, 0.96; P for trend = 0.01] and -linolenic acid (multivariate RR: 0.68; 95% CI: 0.50, 0.93; P for trend = 0.01). Pneumonia risk decreased 4% for every 1-g/d increase in linoleic acid intake (multivariate RR: 0.96; 95% CI: 0.93, 0.99). Pneumonia risk was reduced by 31% for every 1-g/d increase in -linolenic acid intake (multivariate RR: 0.69; 95% CI: 0.51, 0.93). Intakes of eicosapentaenoic acid and docosahexaenoic acid were not significantly related to pneumonia risk.
Conclusion: Higher intakes of -linolenic and linoleic acids and possibly of fish may reduce the risk of pneumonia.
Key Words: n–6 Fatty acids • n–3 fatty acids • fish • prospective study • community-acquired pneumonia
INTRODUCTION
Pneumonia and influenza are the fifth leading causes of death in the United States in men over the age of 65 y (1). Smoking, weight gain, physical activity (2), and alcohol use (3) are the only known potentially modifiable risk factors for community-acquired pneumonia. Polyunsaturated fatty acids have been hypothesized to modulate inflammation and immunity (4), and they constitute 19–22% of the energy intake from fats in US adults (5). Between 84% and 89% of polyunsaturated fatty acid intake consists of linoleic acid, and 9–11% is -linolenic acid; eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the long chain n–3 fatty acids from fish, make up <1% of total intake (5). Increasing intakes of n–3 fatty acids reduces inflammation associated with autoimmune diseases (6), and increased intakes of n–3 and n–6 fatty acids decreases the incidence and duration of infections in children (7). Supplementation increases the n–6 and n–3 fatty acid content of the cell walls of leukocytes and results in enhanced immune function (8). Diets supplemented with n–3 (ethyl-EPA) and n–6 (ethyl-gamma-linolenic) fatty acids reduced prostaglandin E2 production in rats put under stress (9), and EPA and DHA were shown to reduce lipopolysaccharide-induced inflammation through a pathway dependent on peroxisome proliferator-activator receptor- (10). We therefore prospectively examined the association between n–6 and n–3 fatty acids and fish intake and the risk of community-acquired pneumonia among men in the United States.
SUBJECTS AND METHODS
Study population
The Health Professionals Follow-up Study began in 1986 when 51 529 male US health professionals aged 40–75 y returned questionnaires about their lifestyle and medical history (11). The men were then sent biennial follow-up questionnaires to update their lifestyle information and identify new major illnesses. Deaths were reported by family members or the US Postal Service or were ascertained through state registries or the National Death Index. Information about pneumonia was first collected in 1992. 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 risk of pneumonia (myocardial infarction, stroke, other heart disease, arterial surgery, cancer, or asthma) before 1990. Men who left 70 or more items blank on the food-frequency questionnaire 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 (12). This study was approved by the Harvard School of Public Health's Human Subjects Committee.
Case ascertainment
The endpoint 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 did not have knowledge of the exposure status of the participant. A case was considered confirmed if the medical record contained a diagnosis of community-acquired pneumonia by a physician on the basis of a chest radiograph. We excluded cases of aspiration pneumonia and hospital-acquired pneumonia in this analysis as determined from medical records. We excluded fatal cases for whom this information was not available. If a participant had more than one episode of pneumonia, we considered only the first one.
Diet ascertainment
The reproducibility and validity of the semi-quantitative food-frequency questionnaire used to assess diet in this study has been reported elsewhere (13). To estimate intakes of fish and other nutrients, participants were asked how often on average in the past year they ate a unit or portion size of each food (an egg or 6–8 oz of fish, for example). There were 9 possible responses ranging from never or less than once per month to 6 or more times per 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, US Department of Agriculture sources (14), and information from manufacturers (15). We asked on the questionnaire whether the participants used fish oil supplements and took this information into account when estimating total n–3 fatty acid intake. -Linolenic acid intakes were corrected for gamma linolenic acid to reduce misclassification as described elsewhere (16). We adjusted nutrients for total energy by regression analysis (17). For example, the energy-adjusted intake of linoleic acid is interpreted as the composition of this nutrient in the diet independent of the quantity of food eaten.
The correlation coefficients for comparing intake assessed by the food-frequency questionnaire and fat aspirates was 0.50 for polyunsaturated fats, 0.48 for linoleic acid, 0.47 for eicosapentaenoic acid (18), and 0.34 for linolenic acid (19). For fish intake assessed by the food-frequency questionnaire compared with diet records, the correlations were 0.73 for canned tuna and 0.58 for dark meat fish (20). Dietary variables were first measured in 1986 and were updated in 1990 and 1994. If dietary data for 1990 were missing, we used the value from the 1986 measurement. We related dietary data measured in 1990 to cases of pneumonia developing between 1990 and 1994. For cases developing subsequently, we used diet measured in 1994.
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 31 January 2000, whichever came first. Men who developed myocardial infarction, stroke, other heart disease, arterial surgery, cancer (except nonmelanoma skin cancer), or asthma were excluded from further follow-up.
Most recent dietary intake at the start of each 2-y follow-up interval was related to subsequent pneumonia risk. We evaluated linoleic acid, -linolenic acid, total fats, and polyunsaturated fats in quintiles and as continuous variables. Because the main source of long-chain n–3 fatty acids in the diet is fish, we assessed fish intake in categories of <1 serving/mo, 1–3 servings/mo, 1 serving/wk, 2–4 servings/wk, and 5 servings/wk. We classified intake of long-chain n–3 fatty acids (EPA and DHA) as <0.05, 0.05 to <0.2, 0.2 to <0.4, 0.4 to <0.6, and 0.6 g/d to approximately correspond with these categories of fish intake as described elsewhere (21).
We used Cox proportional hazards models to estimate multivariate relative risks (RRs) and CIs. Failure time was measured as age in months, which allowed fine control of confounding by age. The Anderson-Gill data structure was used to handle time-varying covariates. Other variables in the model included smoking (never, past, and current smokers who smoked 1–14, 15–24, or 25 cigarettes/d), body mass index (BMI, in kg/m2: <21, 21–22.9, 23–24.9, 25–29.9, and 30), alcohol use (never, 0.1–4.9, 5.0–14.9, 15.0–29.9, and 30 g/d), physical activity [quintiles of metabolic equivalents (METs)], diabetes (dichotomous), and total energy intake (continuous). We further evaluated this multivariate association by additional adjustment for intakes of saturated fat, nuts, fruit, vegetables, and multivitamins to assess possible confounding by other dietary or lifestyle variables. We used the Mantel extension test to calculate tests for trend for categorical variables by using their respective median values.
We assessed interaction by age (65 versus >65 y), BMI (<25 versus 25), current smoking, physical activity [inactive (reported METs less than median quintile) versus active (reported METs at the median quintile and higher)], use of vitamin E supplements (yes, no), and diabetes. To assess interaction, we classified fish intake in 3 categories (1 serving/mo, >1 serving/mo to 4 servings/wk, and 5 servings/wk) and grouped -linolenic acid and linoleic acid into tertiles in the main analyses. Tests for interaction were done by use of the Wald test with multiplicative terms of intakes of fish and fatty acids. We used SAS version 8.2 (SAS Institute Inc, Cary, NC) for all the analyses.
RESULTS
Men consuming more -linolenic and linoleic acids drank less alcohol and ate fewer carbohydrates and monounsaturated fats and more polyunsaturated fat but otherwise were similar to those who consumed less of these fatty acids (Tables 1 and 2).As described elsewhere, men eating more fish and long-chain n–3 fatty acids were less likely to be current smokers or overweight and were more likely to be physically active, eat more fruit and vegetables, and use multivitamin supplements (21).
View this table:
TABLE 1. Characteristics of men in selected quintiles (Q) of intake of -linolenic and linoleic acids1
View this table:
TABLE 2. Mean intakes of nutrients by men in selected quintiles (Q) of intake of -linolenic and linoleic acids1
During 10 y of follow-up (145 910 person-years), there were 441 new cases of nonfatal community-acquired pneumonia. Increased -linolenic acid intake was associated with a reduced risk of pneumonia. As shown in Table 3, the risk of pneumonia was 32% lower among men in the top quintile of intake of -linolenic acid (median of quintile = 1.53 g/d) than in men in the bottom quintile (median of quintile = 0.71 g/d; multivariate RR: 0.68, 95% CI: 0.50, 0.93; P for trend = 0.01). The risk of pneumonia decreased by 31% for every 1-g/d increase in -linolenic acid intake (RR: 0.69, 95% CI: 0.51, 0.93).
View this table:
TABLE 3. Intakes of -linolenic and linoleic acids and pneumonia risk1
We found a significant inverse linear trend for linoleic acid intake and pneumonia risk. Men in the highest category of linoleic acid intake (median intake of category = 15.8 g/d) had a 30% lower risk of pneumonia than did men in the lowest category of linoleic acid intake (median intake of category = 7.6 g/d; multivariate RR: 0.70, 95% CI: 0.51, 0.96; P for trend = 0.01; Table 3). There was a 4% decline in community-acquired pneumonia risk for every g/d increase in linoleic acid intake (multivariate RR: 0.96, 95% CI: 0.93, 0.99). There was no relation between pneumonia risk and intakes of total fat (multivariate RR: 0.93, 95% CI: 0.67, 1.28; P for trend = 0.49) or polyunsaturated fatty acids (multivariate RR: 1.23, 95% CI: 0.85, 1.69; P for trend = 0.28).
The relation between fish intake and pneumonia risk was inverse but nonsignificant. The multivariate RR of community-acquired pneumonia for men eating fish 5 or more times per week compared with those eating fish less than once per month was 0.59 (95% CI: 0.34, 1.02; P for trend = 0.18; Table 4). The association between long-chain n–3 fatty acid intake and pneumonia risk was not significant. The multivariate RR of community-acquired pneumonia comparing men in the extreme quintiles of long-chain n–3 fatty acid intake was 0.77 (95% CI: 0.44, 1.36; P for trend = 0.41; Table 4).
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TABLE 4. Intakes of fish and long-chain n–3 fatty acids and pneumonia risk1
Further adjustment for a variety of dietary variables did not materially alter the relation between intakes of fish, intakes of n–6 and n–3 fatty acids, and pneumonia risk (ie, the beta coefficient for the multivariate RR between exposure and outcome did not change by >10%). The relations between intakes of fish, linoleic acid, and -linolenic acid were materially unchanged after additional adjustment for intakes of multivitamins, fruit, vegetables, nuts, and saturated fat. There was no significant interaction by age (>65 y versus lower), BMI (25 versus lower), current smoking, physical activity, supplemental vitamin E use (yes or no), multivitamin use, or diabetes (data not shown).
When we stratified by tertiles of -linolenic acid intake, the association between fish intake and pneumonia risk was inverse and significant only in the lowest tertile of intake (range of intake: 0.2–0.9 g/d; Table 5). The interaction between -linolenic acid and fish intake and pneumonia risk was significant (P value from Wald test = 0.02). The interaction between linoleic acid and fish intake and pneumonia risk was not significant (P value from Wald test = 0.10).
View this table:
TABLE 5. Relative risk (95% CI) for the relation between jointly classified -linolenic acid and fish intakes and risk of pneumonia1
The correlations between intakes of fish and linoleic and -linolenic acids, respectively, were 0.07 and 0.01. The respective multivariate associations between linoleic and -linolenic acid intakes and pneumonia risk did not change significantly with simultaneous adjustment for fish intake.
Because intakes of -linolenic acid and linoleic acid were highly correlated (r = 0.66), we were not able to evaluate the interaction between them or their independent effects. The ratio of linoleic acid to n–3 fatty acid (EPA, DHA, and -linolenic acid) intake was not associated with pneumonia risk (RR for extreme categories of the ratio of linoleic acid to n–3 fatty acids: 0.85, 95% CI: 0.62, 1.17; P for trend = 0.82).
DISCUSSION
In this large, prospective investigation, we observed lower risks of nonfatal community-acquired pneumonia among men in the highest categories of intakes of linoleic and -linolenic acids compared with men in the lowest categories of intakes. Among men with low n–6 and n–3 fatty acid intakes from plant sources, high fish intake was associated with reduced pneumonia risk. The main dietary sources of -linolenic and linoleic acids are canola and soybean oils, nuts, and oil-based salad dressings.
The prospective study design minimized the possibility of recall bias, and a follow-up rate of >90% reduced selection bias resulting from differential loss to follow-up. We estimated dietary intake by use of a previously validated food-frequency questionnaire (13). The estimation of linoleic acid, -linolenic acid, EPA, and DHA from foods by using average values assigned by the US Department of Agriculture may have led to some misclassification of exposure that was most likely random, thus likely attenuating the associations. Because the range of intake of foods was wide, we were able to contrast extremes of intake in relation to disease risk. Confounding by known factors was minimal because the results did not significantly change when adjusted for several variables. The results were consistent between younger men and older men, between current smokers and past and never smokers, between overweight and normal-weight men, between physically active and inactive men, between multivitamin users and nonusers, and between men with diabetes and those without. We were unable to separate the effects of -linolenic and linoleic acids because they are derived from common food sources. Also, we cannot exclude the possibility that other constituents in vegetable oils, the major source of linoleic and -linolenic acids, may be the true protective factor. We did not have information about pneumococcal or influenza vaccination in these men; however, we could not find any reports correlating vaccination and diet. If these factors were correlated, this would be a potential limitation. Even then, the influence on our results would likely be small because the effect of influenza vaccination in elderly US adults is probably overestimated (22) and the relation between pneumococcal vaccination and community-acquired pneumonia is weak (23). It is also possible that our results were due to chance.
We only considered the first pneumonia case reported because community-acquired pneumonia risk increases with previous hospital admissions, previous antibiotic therapy, and pulmonary comorbidity (24). Moreover, individuals often change their diets after major illness. Including all episodes of pneumonia would have increased our number of cases but would have raised concerns of possible biases because of the above-mentioned reasons. We therefore opted for the more conservative but valid approach of considering only the first report of disease. We restricted our analyses to pneumonia that had been diagnosed on the basis of radiographic findings to minimize false-positive cases and increase internal validity. We therefore also excluded fatal pneumonia cases, because the radiographic evidence of pneumonia was often missing. It was particularly important to avoid misclassification of outcome in the case of pneumonia because in a randomized clinical trial, vitamin E supplementation did not have any effect on lower respiratory infections but was protective against upper respiratory infections (25). Even though the hypothesized mechanisms through which n–6 and n–3 fatty acids modulate pneumonia risk are likely the same in fatal and nonfatal pneumonia, we were unable to directly evaluate fatal pneumonia in this study. Our results should therefore be interpreted with this caveat.
Our results are consistent with other studies examining the relation between these fatty acids and risk of infection or immune system responsiveness. In a randomized, crossover double-blind study of 20 children aged 36–49 mo, supplementation with n–3 and n–6 fatty acids reduced infective episodes, days with fever, and days absent from school compared with placebo (7). In another study, elderly patients undergoing surgery who received an immune-enhancing preparation that included polyunsaturated fatty acids had better delayed-type hypersensitivity responses than did subjects who received placebo (26). In patients with acute respiratory distress syndrome caused by sepsis, pneumonia, trauma, or aspiration and requiring enteral nutrition, those receiving EPA and -linolenic acid added to their diets had less need for artificial ventilators, shorter lengths of intensive care unit stay, and less organ failure than did control subjects (27).
Essential fatty acid intake may decrease infection risk by reducing inflammation (4) and improving insulin sensitivity (28). Plasma concentrations of inflammatory cytokines increase with the severity of community-acquired pneumonia (29). Severe pneumonia is more likely in individuals with a genetic predisposition for inflammation (30) and in those with a defect in heat shock protein production (31). Inflammatory cytokine concentrations increase with hyperglycemia (32); hyperglycemia raises infection risk in both persons with diabetes (33) and those without diabetes (34).
n–6 Fatty acids have been hypothesized to increase inflammation because they are precursors of the proinflammatory eicosanoids (4). However, evidence is growing that intakes of n–6 together with n–3 fatty acids may reduce inflammation more than intakes of either essential fatty acid alone (9, 35). Habitual n–6 and n–3 fatty acid intakes were inversely associated with plasma inflammatory cytokines (35), and higher serum fatty acids from vegetable sources (eg, linoleic and -linolenic acids) were associated with reduced risk of impaired fasting glycemia and diabetes in middle-aged men (36). Essential fatty acids are ligands of the peroxisome proliferator-activated receptor- and have been shown to increase insulin sensitivity (28). EPA and DHA have been shown to reduce lipopolysaccharide-induced inflammation through the pathway activated by peroxisome proliferator-activator receptor- (10). Taken together, these facts are consistent with the hypothesis fatty acids may modulate community-acquired pneumonia risk through reduced inflammation and improved glycemic control.
To the best of our knowledge, this is the first study to evaluate the association between intakes of n–6 and n–3 fatty acids and risk of community-acquired pneumonia in healthy adult men. Fish and nut intakes (high in polyunsaturated fats) have been shown to be inversely associated with the risk of diabetes (37), stroke (21), and CHD (16, 38), leading to recommendations for higher intakes (39). Our data on the inverse relations between n–6 and n–3 fatty acid intake and pneumonia risk provide further support for recommendations to replace animal and partially hydrogenated fats with those foods and nonhydrogenated vegetable oils in general.
ACKNOWLEDGMENTS
We thank the participants of the Health Professionals Follow-up Study for their cooperation and participation.
ATM was responsible for data analysis. ATM, GCC, EBR, WCW, and WWF were responsible for drafting the manuscript. EBR and WCW were responsible for procuring funding. None of the authors had any conflict of interest.
REFERENCES