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Zinc plays an important role in immune function. The association between serum zinc and pneumonia in the elderly has not been studied.
To determine if serum zinc concentrations in nursing home elderly are associated with incidence and duration of pneumonia, total and duration of antibiotic use, and pneumonia-associated and overall deaths.
This observational study was conducted in residents from 33 nursing homes in Boston, MA, who participated in a one-year randomized, double-blind, and placebo controlled vitamin E supplementation trial; all were given daily doses of ½ RDA of essential vitamins and minerals including zinc. Participants with baseline (N=578) or final (N=420) serum zinc concentrations were categorized as having low (<70 μg/dL) or normal (≥70 μg/dL) serum zinc concentrations. Outcome measures included incidence and number of days with pneumonia, number of new antibiotic prescriptions, days of antibiotic use, death due to pneumonia, and, all-cause mortality.
Subjects with normal final serum zinc concentrations had lower pneumonia incidence, total antibiotic use (by almost 50%), and shorter duration of pneumonia and antibiotic use (by 3.9 and 2.6 days, respectively) (all p-values ≤0.004) relative to those with low zinc concentrations. Normal baseline serum zinc concentrations were associated with decreased all-cause mortality (p=0.049).
Normal serum zinc concentrations in nursing home elderly were associated with decreased incidence and duration of pneumonia, and decreased use and duration of antimicrobial therapy. Zinc supplementation to maintain normal serum zinc concentrations in the elderly may help reduce pneumonia incidence and associated morbidity.
Pneumonia is a major public health problem in the elderly (1). An important predisposing factor to the increased incidence of infections such as pneumonia in the elderly is the age-associated decline in immune function (2). Such changes in immune response with age, in addition to malnutrition, contribute to the increased frequency and severity of pneumonia, as well as mortality due to pneumonia in the elderly (1-4).
Zinc has been shown to play an important role in regulation of the immune response particularly T cell-mediated function (5-7). Zinc deficiency has been shown to cause thymus involution and to depress lymphocyte proliferation, interleukin-2 (IL-2) production, delayed type hypersensitivity skin responses, and antibody response to T cell-dependent antigens (5, 8). Similar defects in T cell function have been observed with aging (2). Several investigators have reported low zinc status or decreased intake in elderly subjects (9-11). Furthermore, low zinc status in the elderly has been shown to contribute to age-associated dysregulation of the immune response (3, 12) and zinc supplementation has been shown to improve T cell mediated function in elderly (9, 12-15) . In children, low concentrations of circulating zinc have been shown to be associated with an increased risk of respiratory morbidity (16), and zinc supplementation has been shown to reduce both the risk and duration of pneumonia and deaths due to pneumonia in children (17, 18). The association between serum zinc and pneumonia in the elderly, however, has not been studied.
From April 1998 to August 2001, a randomized controlled trial was carried out in order to investigate the effect of vitamin E supplementation on respiratory infections in a nursing home elderly population (19). We found a high proportion (about 30%) of nursing home elderly with low serum zinc concentrations at baseline, and after a year of follow up despite all participants' receiving ½ RDA of essential vitamins and minerals, including zinc, during the trial. Because recently published studies in children (17, 18) have shown zinc supplementation to be beneficial in reducing morbidity and mortality from pneumonia and past research has demonstrated the negative impact of zinc deficiency on immune function in the elderly, we examined the relationships between serum zinc concentration and the incidence and duration of pneumonia, total antibiotic use, and duration of antibiotic use and death due to pneumonia, as well as overall deaths in this population of elderly nursing home residents.
A total of 617 subjects was enrolled (approximately 1/3 enrolled in each of 3 successive years) into a randomized, double-blind, placebo-controlled trial of the effect of one-year vitamin E supplementation (200 IU/day) on respiratory infections in a nursing home population (19). The Tufts-New England Medical Center Institutional Review Board approved the study protocol and informed consent form.
Nursing home residents have a heterogeneous intake of micronutrients (20), some of which are necessary for proper immune function. To reduce variability in the vitamin E trial, all subjects received a daily capsule containing 50% of the Recommended Dietary Allowance (RDA) (21) for essential micronutrients, including zinc. Fifty percent RDA was selected since few subjects meeting our eligibility criteria would have dietary intakes <50% of the RDA for micronutrients (22).
At baseline as well as at follow-up, about 30% of subjects were found to be deficient in zinc. Other micronutrient deficiencies were much less prevalent at baseline (from 0 to 10%) and their prevalence did not significantly change at follow up (19).
Detailed information on the screening and recruitment of participants has been described previously (19). The eligibility criteria included age ≥65 y, life expectancy >6 months, no anticipated discharge within 3 months, not room-bound for the past 3 months, body mass index (BMI) ≥16 kg/m2, serum albumin ≥3.0 g/dL, ability to swallow pills, and willingness to receive influenza vaccine and provide informed consent. Exclusion criteria included active neoplastic disease, tube feeding, kidney dialysis, intravenous or urethral catheters for the last 30 days, tracheostomy or chronic ventilator use, chronic steroid treatment >10 mg/d, use of immunosuppressive drugs, use of antibiotics within the prior 2 weeks, and >RDA level supplements of vitamins E, C, B6, selenium, zinc, β-carotene, or fish oil.
The current analyses include all enrolled subjects with baseline (N=578) or end of study zinc measurements (N=420, including 7 subjects with only end of study zinc values). For the purposes of this study, subjects were categorized by serum zinc concentrations using cutoffs of <70 μg/dL to indicate low serum zinc concentrations and ≥70 μg/dL to indicate normal serum zinc concentrations (23).
Pneumonia-related outcomes included incidence of and number of days with pneumonia, new antibiotic prescriptions for pneumonia, days of antibiotic use for treatment of pneumonia, and death due to pneumonia. We also examined all-cause mortality.
Information regarding subject characteristics, baseline diseases and medications, and vaccination history was obtained from medical records. Fasting blood was collected at baseline and at study completion for clinical chemistries, complete blood count, and nutritional status as previously described (19). Serum samples were collected using trace metal-free tubes and serum zinc concentrations were measured using the Perkin Elmer flame atomic absorption spectrometer (24) at the Nutrition Evaluation Laboratory, Human Nutrition Research Center on Aging at Tufts University.
Study nurses were trained by a study physician to identify relevant respiratory symptoms and to perform a focused physical examination of the respiratory tract. Supervised practice evaluations were repeated throughout the study to reinforce the nurses' clinical skills and to ensure consistency of the pneumonia data collection. The study nurses collected information weekly relating to infection, including symptoms of respiratory infections, temperature, respiratory and heart rate, and a physical examination focused on the respiratory system. The nurses reviewed each participant's chart for documentation of laboratory analyses, radiography, medications, micronutrient supplementation, weight, and nursing or physician descriptions of symptoms and signs relating to pneumonia and other respiratory infections. At the end of the study, data collected from the subjects were randomly assigned, by nursing home, to the two study physicians for diagnosis of infections. Infection data from any one subject were evaluated by only one physician, except for 18 subjects whose records were used to determine the concurrence of diagnoses between physicians.
Details on how the study physicians evaluated the data to determine incidence and duration of pneumonia have been described previously (19). Briefly, clinical definitions of pneumonia were developed based on accepted definitions (25). In order to increase the specificity of the definitions, a diagnosis of pneumonia had to include at least one physical sign and thus could not be made on symptoms alone. An episode was considered resolved when all symptoms ceased. A new infection was defined as one occurring after 7 symptom-free days. Pneumonia symptoms could include cough with or without sputum production, chest pain, dyspnea, and fever. Signs of infection included elevated temperature (≥38°C), tachycardia, tachypnea, abnormal breath sounds, and dullness to percussion of the chest. The diagnosis required radiological findings of 1 or more new pulmonary infiltrates.
The demographic and clinical characteristics of participants in the low and normal serum zinc groups were compared by using Student's t-test for independent samples (continuous measures) and Fisher's exact test (categorical measures).
As noted above, all subjects received a capsule containing 50% of the RDA for essential micronutrients, including zinc. Because of this supplementation, the baseline zinc concentrations might not reflect the usual zinc status during the entire study period. Therefore, we also used zinc concentrations measured at the final study visit as a marker of zinc status. However, analyses based on final zinc concentrations were necessarily limited to those who survived or completed the trial.
Rate ratios and their confidence intervals for incidence of pneumonia and number of antibiotic prescriptions per year were modeled using Poisson regression with the natural logarithm of time as an offset (26). None of the deviance statistics from the Poisson regressions exceeded 1, which suggests that there was no overdispersion. Multiple linear regression analyses were used to determine the association between serum zinc and duration of pneumonia and antibiotic use due to pneumonia. Cox-proportional hazards models using baseline zinc concentrations were fitted to determine the hazards ratio for deaths due to pneumonia or overall deaths using baseline zinc concentrations. Except for the proportional hazards analyses, these analyses were performed by using both baseline and final zinc concentrations as predictors. Although the original study did not show a significant difference in the rate of pneumonia between the vitamin E and placebo groups (19), we nevertheless controlled for allocation to treatment and placebo groups in these analyses. We also adjusted for year of enrollment, as well as age, sex, baseline BMI, current smoking, diabetes mellitus, and chronic obstructive pulmonary disease (including bronchial asthma), which have been shown to be associated with increased risk of pneumonia and/or pneumonia-associated death (1, 27, 28). Analyses done comparing those with low compared to normal final serum zinc concentrations were also controlled for change in BMI between baseline and follow-up values. Additionally, in separate analyses, we also controlled for baseline serum albumin and change in serum albumin concentrations between baseline and follow-up in these models. Two-sided observed significance concentrations (p values) <0.050 were considered to be statistically significant. All calculations were performed by using SAS for Windows, version 9.1.2 (SAS Institute Inc, Cary, NC, USA).
The demographic and clinical characteristics of participants with baseline zinc (N=578) and those with final study zinc concentrations (N=420) were similar (Table 1). These characteristics were also similar in distribution to those of our original overall study population (N=617) (19).
Of the characteristics listed in Table 1, only the difference in age between those with low and normal baseline serum zinc concentrations was statistically significant (mean ± SD were 86 ± 8 and 84 ± 7 years, respectively; p<0.001). Elderly with low final serum zinc concentrations were older at baseline (86 ± 8 versus 84 ± 7 years; p=0.014), and were more likely to have had coronary artery disease (39% versus 28%; p =0.042) at baseline compared to those with normal final zinc concentrations. All subjects received influenza vaccine and there was no difference between the two groups in the proportion of subjects who had pneumococcal immunization.
When participants with low and normal baseline zinc concentrations were compared, differences in the incidence and duration of pneumonia, and total amount and duration of antibiotic use due to pneumonia (Table 2) were not statistically significant. Deaths due to pneumonia were 53% lower in those with normal compared to low baseline serum concentrations of zinc, but this association was not statistically significant (p=0.198). All-cause mortality rate was 39% lower in those with normal versus lower baseline zinc concentrations (p=0.049) (Table 2).
End of study serum zinc concentrations were strongly associated with the incidence and duration of pneumonia as well as antibiotic use and duration of antimicrobial therapy (Table 3; p≤0.004 in all cases). The incidence of pneumonia and the total number of antibiotics used for treatment of pneumonia were about 50% lower in those with end serum zinc concentrations ≥70 μg/dL compared to those with concentrations <70 μg/dL. In addition, the duration of pneumonia was lower by 3.9 days and the duration of antibiotic use by 2.6 days in those with end serum zinc in the normal range compared to those with low concentrations (Table 3). Controlling for coronary artery disease in our multiple regression analyses model did not change the statistical significance of the differences observed. In addition, differences remained statistically significant after controlling for baseline serum albumin and change in serum albumin concentrations between baseline and follow-up. The 310 subjects with normal end zinc concentrations at completion suffered 78 cases of pneumonia while the 110 with low end zinc concentrations suffered 51. The fraction of pneumonias occurring in the final 2 months of the study was similar in those subjects with normal (14 cases out of 78) and low (8 cases out of 51) end serum zinc concentrations, i.e., 18% vs 16%, respectively.
Our findings were specific to zinc. We did not observe similar associations in our outcome variables of interest with other micronutrients that might influence immune function such as vitamins A, B6, D, E, β-carotene, and iron (data not shown). In addition, the mean changes in weight and BMI from baseline to follow-up between subjects with low and normal zinc concentrations were not significantly different; mean weight changes were −0.80 and −0.01 kg, respectively, and BMI, −0.35 and −0.01 kg/m2, respectively.
We observed that elderly nursing home residents with low serum zinc concentrations at the end of one year of 50% RDA micronutrient daily supplementation, including zinc, had a higher risk of pneumonia and longer duration of pneumonia episodes as well as increased antibiotic use and longer duration of antibiotic use for treatment of pneumonia episodes. In addition, low baseline concentrations of serum zinc in our elderly nursing home population were associated with increased all-cause mortality.
Our finding of a significantly lower all-cause mortality rate (by 39%) between those with normal versus low baseline serum zinc concentrations among elderly in this study suggest that zinc may play a crucial role in influencing mortality in the elderly. Severe zinc deficiency can impair immunity and increase susceptibility to infectious diseases, a major cause of mortality in the elderly (1, 3, 29, 30). Indeed, the risk of mortality was reduced by 27% in participants of the Age-related Eye-Disease Study (aged 55 to 81 years) who received zinc supplements (RR: 0.73; 95% CI, 0.61−0.89) (31). In addition, zinc supplementation has been shown to reduce overall mortality by as much as 51% in children with diarrhea and 68% in infants born full-term and small for gestational age (32, 33).
When baseline serum zinc status was used as a measure of zinc to determine if low serum zinc affects susceptibility to pneumonia, differences failed to reach statistical significance. It may be that findings using baseline zinc concentrations were attenuated due to the higher risk of death among subjects with low baseline zinc concentrations or due to loss of subjects from serious illnesses and/or hospitalizations. In addition, because all study participants were provided with ½ RDA supplement that included zinc, the baseline concentrations may not reflect zinc status during much of the study period.
Because of the potential bias introduced by zinc supplementation, we performed similar analyses using final zinc concentrations, as this measure may better reflect the zinc status of subjects during the course of the study. We observe a strong association between low final zinc concentrations with increased incidence and duration of pneumonia, as well as total and duration of antibiotic use for pneumonia treatment. As described in the results, the effects observed were specific to zinc and were not observed with other micronutrients. Furthermore, the lower incidence and morbidity of pneumonia observed in subjects with normal final zinc concentrations compared to those with low final zinc concentrations were not due to differences between the two groups in changes in weight, BMI, or other micronutrients (19) during the study period.
Zinc deficiency has been suggested to be a risk factor for immune deficiency and subsequent infection relapses in the elderly (12, 29, 34). Zinc is essential for membrane integrity, DNA synthesis and cell proliferation, in addition to being a cofactor to more than 300 enzymes (5, 35).
It is essential for all highly proliferating cells in the human body, especially the immune system (36). Thymus atrophy and lymphopenia, as well as other defects in T cell function have been observed in both zinc deficiency and in the elderly (2, 5, 8).
Low zinc consumption has been reported in the elderly (10, 37). Bogden et al. reported that zinc ingestion was below the RDA in more than 90% of their 100 study subjects aged 60−89 years (37). In addition, as mentioned above, we found below normal serum zinc concentrations in approximately 30% of the nursing home elderly enrolled in our vitamin E supplementation study. This level of deficiency persisted during the study period despite giving the participants supplements with ½ RDA of zinc (19). Thus, our finding of a significant association between low serum zinc level and pneumonia could be of major importance to the health of elderly, as poor zinc status would lead to impaired immune response, which could in turn result in increased susceptibility to infections in the elderly (9, 29, 34). Supplementing with ½ RDA of zinc appeared to benefit many of the subjects with inadequate baseline zinc concentrations, but the results also showed that this supplementation was not adequate to maintain serum zinc concentrations in a significant proportion of subjects.
Plasma or serum zinc concentrations are also known to decrease sharply in many infections (35, 38, 39). The decline is part of a set of metabolic reactions to infection known as the acute phase response (40). Although one could argue that lower serum zinc concentrations might be due to a higher incidence of pneumonia, this is unlikely to be the case here as the acute effect of pneumonia on zinc is likely to be transient--approximately 2 weeks if effective therapy is provided (41). Given the similar incidence of pneumonia in our participants in the last months of the study, transient suppression of serum zinc by the acute phase response is unlikely to be responsible for the low end study zinc concentrations.
Zinc supplementation may play an important role in the prevention and/or modulation of infectious diseases in the elderly (3, 9, 14, 29). Various studies on zinc supplementation in the elderly have observed increased circulating zinc concentrations (13, 14), as well as enhanced immune status including improved cell-mediated immune response, serum thymulin activity, and IL-2 production, and increased response to skin-test antigens (12, 15, 42). Also, when cultures of white blood cells from elderly subjects were supplemented with 15 μM zinc (the physiologic concentration), they produced interferon-alpha in amounts comparable to those from the younger subjects (43). In a randomized, double-blind, placebo-controlled clinical trial (N=81), institutionalized elderly had a significant decrease in the mean number of respiratory infections 2 years following supplementation with micronutrients containing zinc and selenium, but not vitamins (44). In another, larger (N=725), randomized, double-blind, placebo-controlled intervention study, low-dose supplementation of zinc and selenium significantly increased the humoral response in institutionalized elderly after vaccination (45). The number without respiratory tract infections during the study was also found to be higher in elderly that received trace elements over a 2-year period (45). While these studies suggest a protective effect of zinc against respiratory infections, contribution from other nutrients present in the mixture cannot be ruled out.
The results from our current study, in addition to these earlier findings, suggest that elderly with low serum zinc concentrations might benefit from zinc supplementation. Such a measure has the potential to reduce not only the number of episodes and duration of pneumonia and the total and duration of antibiotic use due to pneumonia, but also overall deaths in the elderly. Randomized, double blind, controlled studies are needed to determine the efficacy of zinc supplementation as a potential low cost intervention to reduce morbidity and mortality due to pneumonia in this vulnerable population.
This work was supported by NIA, National Institutes of Health Grant 1R01-AG13975, and United States Department of Agriculture agreement 58−1950−9−001, and a grant for preparation of study capsules from Hoffmann-LaRoche Vitamins and Fine Chemicals Division (currently DSM) Inc. The funding organizations did not have input into the design or conduct of the study, into the collection, analysis, or interpretation of the data, or in the preparation, review, or approval of the manuscript. Dr. Meydani had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs. Meydani, Fine, Hamer and Ms. Leka were responsible for data acquisition. Drs. Meydani, Barnett, Dallal, Fine, Jacques and Hamer were responsible for the study concept and design, interpretation of study findings, and drafting of the manuscript. Dr. Dallal was responsible for statistical analyses. Drs Meydani, Barnett, Fine, Jacques and Hamer helped to direct these analyses. All authors were responsible for critical review and revision of the manuscript for important intellectual content, as well as final approval of the version to be published. All authors declare that we have no conflict of interest.
Sources of support: This work was supported by NIA, National Institutes of Health Grant 1R01- AG13975, United States Department of Agriculture agreement 58−1950−9−001, and a grant for preparation of study capsules from Hoffmann-LaRoche Vitamins and Fine Chemicals Division (currently DSM) Inc.
This work was performed at the Nutritional Immunology Laboratory, Jean Mayer USDA-HNRC at Tufts University, Boston, MA.