Prospective Study of Cured Meats Consumption and Risk of COPD in Men

Discussion

In this large prospective cohort of US men during 12 years of follow-up, the risk of newly diagnosed COPD increased with a greater consumption of cured meats after adjustment for many important confounders. Among the individual cured meats, consumption of processed meats was significantly associated with the risk of newly diagnosed COPD, and a borderline significant association was found for bacon. In contrast to the COPD findings, there was no association between consumption of cured meats and risk of adult-onset asthma.

The sodium salts of nitrate (NaNO₃) and nitrite (NaNO₂) are used in the curing and preserving of processed meats. They are used for three purposes: to preserve color, especially the pink color for hot dogs and other cured meats; to enhance flavor by inhibiting rancidity; and to protect against bacterial growth.^[2] Regulations controlling the use of curing agents were established in the United States in 1926, and the same rules are in effect at present, with slight modification. The critical feature of these rules is that a maximum-use level of sodium nitrite is defined: No more than one-fourth ounce (7.1 g) may be used per 100 pounds (45.4 kg) of meat. Bacon has been a focus of special attention. Because it is so widely consumed and the risk of infection with anerobic Clostridium botulinum is relatively high,^[2] the regulations were changed for bacon with ingoing nitrite targeted at 200 ppm. A similar regulation was applied to other cured meats, such as ham, sausages, and corned beef.

In an inflammatory microenvironment, exaggerated production of nitric oxide in the presence of "oxidative stress" may produce the formation of strong oxidizing reactive nitrogen species, such as peroxynitrite, leading to nitration that provokes DNA damage, inhibition of mitochondrial respiration, protein dysfunction, and cell damage ("nitrosative stress")^[21,22]. Reactive nitrogen species have been implicated in the pathogenesis of COPD.^[4] The level of nitrotyrosine immunoreactivity, a marker or production of reactive nitrogen species, was higher in COPD patients than in healthy subjects^[23] and correlated with the level of obstruction in COPD patients,^[24] suggesting that nitrosative stress might be involved in both the risk of COPD and the progression of the disease. These findings are also consistent with animal studies reporting that rats drinking water enriched with sodium nitrite for 2 years developed pulmonary emphysema.^[25]

The hypothesis that frequent consumption of cured meats might be associated with increased risk of COPD was first tested in a cross-sectional study of 7,432 men and women in the Third National Health and Nutrition Examination Survey.^[10] Jiang et al.^[11] reported that frequent consumption of cured meats was associated with low lung function (forced expiratory volume in 1 second (FEV₁)) and with an increased risk of COPD. To address a possible reverse causation due to the cross-sectional design, Jiang et al. then tested the association in a longitudinal study from 1984 to 2000 of more than 71,000 US women. The longitudinal analysis supported the hypothesis that frequent consumption of cured meats was positively associated with the risk of newly diagnosed COPD in women.

Prior epidemiologic studies suggested a beneficial association between foods rich in antioxidants and COPD status or FEV₁ level.^[9] Most of these epidemiologic studies are cross-sectional,^[2629] but the few longitudinal studies also have reported a negative association between intake of fruits, vegetables, and vitamin C and the decline of FEV₁.^[3032] Previously in this male cohort, a strong association between the prudent dietary pattern and the risk of newly diagnosed COPD was reported.^[16] Adjustment for this "protective" diet did not affect our finding of a strong, independent, positive association between cured meat consumption and COPD risk. Also previously reported was a strong positive association between the Western dietary pattern and COPD risk.^[16] Because the Western pattern was highly loaded by the cured meats food group, a new pattern was derived in the present analysis to exclude this food group. The association between cured meat and the risk of newly diagnosed COPD remained, although with wider confidence intervals and marginal significance, after taking into account the "modified Western pattern." The Western pattern was also loaded by refined grains, red meats, desserts and sweets, and French fries and, among all these food groups, only cured meats increased the risk of COPD. We also note that the "modified Western pattern" remained strongly associated with the risk of newly diagnosed COPD after adjustment for cured meats and that both the "modified Western diet" and cured meat contributed independently to the risk of COPD.

The study has several potential limitations. First, we acknowledge that the association between cured meats and newly diagnosed COPD may be due, in part, to a residual confounding by cigarette smoking. To minimize this possibility, multivariate models were adjusted with multiple measures of tobacco exposure (smoking habits, pack-years, and pack-years squared) and, despite the small numbers of cases, stratified analysis according to smoking status yielded comparable results. Nevertheless, the residual confounding effect by smoking remains an issue. Furthermore, we were not able to adjust for environmental tobacco smoke, which remains an important risk factor for COPD.^[33] Nevertheless, adjustment of cured meats and COPD analyses in the Nurses' Health Study for environmental tobacco smoke did not attenuate the association.^[11]

Second, newly diagnosed COPD was defined by a self-reported physician diagnosis of COPD, and no lung function results were available. Nevertheless, validation of an ident ical, questionnaire-based definition of newly diagnosed COPD in a similar study of female health professionals showed that 80 percent of a random sample of cases meeting this definition had medical record documentation of COPD, and the mean FEV₁ among those with available spirometry reports was 50 percent of predicted.^[15] In addition, since the main source of misclassification of COPD reported by health professionals was misdiagnosis with asthma, we examined the association of cured meats and the risk of adult-onset asthma. The complete lack of association of cured meat intake with asthma suggests that our findings are unlikely to be due to misclassification with asthma. While we acknowledge the potential for some misclassifications, the Health Professionals Follow-up Study data allowed us to investigate the relation between cured meats and COPD in a very large population, with repeated measurements of both diet and COPD status.

Even if diet is assessed every 4 years with accurate food frequency questionnaires, we lacked a specific measure of nitrite intake to more specifically examine the biologic mechanism that we believe explains our results. However, cured meats contain thousands of biologically active phytochemicals other than nitrites, and it remains possible that they too might be involved in the increased risk of COPD. For example, cured meats are rich in sodium, and experimental studies suggest that a high intake of sodium may increase bronchial hyperresponsiveness, although the association with other respiratory endpoints such as medication use and lung function was not consistent.^[34]

In summary, the consumption of cured meats was positively associated with the risk of newly diagnosed COPD. Although several compounds may be responsible for this finding, we believe that nitrites provide a very plausible biologic mechanism. Because of emerging evidence regarding the deleterious effect of cured meats in other diseases (e.g., cancer^[35] and diabetes^[36]), we recommended reduced daily intake of cured meats. For COPD prevention, the most important public health message remains smoking cessation, but our data suggest that diet, another modifiable risk factor, might influence COPD risk. Future studies of actual levels of nitrite intake and COPD risk would be useful, as well as the examination of this novel association in other data sets.

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