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Zinc may be a new risk factor for pneumonia in the elderly. In this special article, we reviewed the magnitude of the problem of pneumonia (its prevalence, morbidity and mortality) in the elderly, its etiology, and the dysregulation of the immune system associated with increasing age. In addition, we presented evidence from the literature, including work we did recently, that low zinc status (commonly reported in the elderly) impairs immune function, decreases resistance to pathogens, and is associated not only with increased incidence and duration of pneumonia, increased use and duration of antimicrobial treatment, but also with increased overall mortality in the elderly. Inadequate stores of zinc might therefore be a risk factor for pneumonia 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.
Is zinc a new risk factor for pneumonia in the elderly? In this Special Article we review the magnitude of the problem of pneumonia in the elderly (its prevalence, morbidity and mortality), especially in nursing home elderly; etiology of pneumonia; dysregulation of the immune system associated with age; and its implications for pneumonia in the elderly. In addition, we discuss the role of zinc in immune response, and the impact of low zinc status not only on increased morbidity and mortality due to pneumonia, but also on all-cause mortality in the elderly.
Pneumonia is a major public health problem in the elderly in general 1 and in nursing home (NH) residents in particular. 2 The elderly have higher morbidity and mortality from pneumonia, one of the top 5 leading causes of death in the United States for older adults.3-5 Recovery from pneumonia in the elderly takes longer, and complications and mortality are also more frequent than in younger adults. 4, 6 Pneumonia is one of the most common causes of hospitalization and decreased activities of daily living (ADL) among the elderly. 7, 8 Recent data indicate that both the incidence and mortality from pneumonia are rising in the elderly. 9 The cost associated with hospitalization due to community acquired pneumonia (CAP) including NH residents was reported in 2002 to be $4.4 billion 2; these costs were significantly greater for those admitted from NH.
Infection is a major reason for transfer of NH residents to acute care hospitals and pneumonia is the leading cause of infection requiring hospitalization. 10-12 Pneumonia-related hospitalization rates in NH residents are nearly 30 times higher than those of independently living elderly. 13 Nine to 51% of patients acquiring pneumonia in NH were transferred to hospital. 14-18 Death rates from pneumonia in NH elderly may reach as high as 57%. 4 Kaplan et al. 19 reported that death from pneumonia in elderly admitted to hospital was twice that from admission due to other causes up to 1 year after hospitalization. The difference in death rates between pneumonia and other causes could not be attributed to differences in underlying diseases. The cost of treatment in the NH for pneumonia is $480/case while the hospital cost exceeds $7000/case. 20 Given that currently there are 1.6 million nursing home residents in the USA with an average pneumonia incident rate of 0.45 per person per year, this translates into millions of dollars each year in costs associated with pneumonia therapy.
A wide range of different bacterial and viral pathogens are responsible for CAP in the elderly as well as NH-acquired pneumonia (NHP) in the U.S. Foremost among them is Streptococcus pneumoniae, which accounts for up to half of all cases.19 Other commonly encountered bacterial pathogens include Staphylococcus aureus, Haemophilus influenzae, Chlamydia pneumoniae, Moraxella catarrhalis, Legionella pneumophila, Mycoplasma pneumoniae, and gram-negative rods such as Klebsiella pneumoniae and E. coli. 13, 21 During recent years the role of viral pathogens in the etiology of acute lower respiratory tract infections (ALRI) in the institutionalized and non-institutionalized elderly has been increasingly described. 22 While influenza is well recognized as a cause of viral pneumonia in the aged, several studies in recent years have demonstrated the importance of parainfluenza virus (PIV), respiratory syncytial virus (RSV), adenovirus, and human metapneumovirus (hMPV). 23-26 Marrie and colleagues attributed a viral cause to 11 of 74 patients with NHP, 27 with etiologic agents including influenza A and B, cytomegalovirus, and PIV. PIV, hMPV, and coronavirus 229E have also been reported in 33 long-term care facilities in Boston during a 3-year period. 28
Many factors such as the presence of certain co-morbid medical conditions (e.g., chronic obstructive pulmonary disease), use of certain drugs, changes in physiochemical characteristics of the non-specific host defense system such as cilia and mucus of the respiratory tract, malnutrition, and mechanical devices contribute to an increased incidence of pneumonia among the elderly. However, an important predisposing factor to the increased incidence of infections is the well-described age-associated decline in immune responsiveness. Changes in immune response not only decrease resistance to pathogens but also contribute to increased morbidity and mortality due to infections. Adequate functioning of the immune system becomes critical in determining the outcome of infections among the elderly already compromised by the presence of disease and other physiological changes.
Considerable evidence indicates that aging is associated with impaired regulation of the immune system. 29-33 This decline in immune function contributes to the increased incidence of infectious, inflammatory and neoplastic diseases observed in elderly subjects as well as their prolonged post-illness recovery periods. Prospective studies indicate a higher incidence of morbidity and mortality in elderly subjects with low delayed-type hypersensitivity (DTH) responses, an in vivo measure of cell-mediated immune response. 34-38
Different cells of the immune system contribute to the impaired immunity of old age, but T cells have been shown to be the major contributor. 39-41 In vivo, T cell dependent functions such as DTH, 36, 42 resistance to viral and bacterial challenge 40, and response to T cell dependent vaccines 32, 43 are depressed with age. In vitro, the proliferative responses of lymphocytes to phytohemagglutinin (PHA) and concanavalin A (Con A), and anti-CD3 (T cell receptor) become depressed with age. 41, 44-47 Antigen and mitogen stimulated interleukin-2 (IL-2) accumulation declines with age and contributes to the T cell mediated defects observed with aging. 46, 48-54
The alterations in T cell function have been attributed to intrinsic changes in T cells themselves including shifts in the distribution of functionally distinct T cell subsets, 55 increases in the accumulation of memory T cells and decreases in naïve T cells, 56, 57 diminished ability of naïve cells to produce IL-2 and progress through cell cycle division, 54 changes in efficiency of early signal transduction events, 31, 46, 58-61 and the ability of T cells to produce and respond to IL-2 (T cell growth factor) and express the IL-2 receptor 46, 48-54, 62 as well as increases in prostaglandin E2 (PGE2) production. 42, 63-65
Reports on the age-associated changes in the production of other cytokines are less consistent. For example, decreases, increases or no change in the production of IL-6, tumor necrosis factor-α (TNF-α), IL-1, and interferon-γ (IFN-γ) have been noted. 66-74 Looney et al. 75 showed that peripheral blood mononuclear cells (PBMC) from old subjects produced significantly less IFN-γ compared to young subjects when stimulated with autologous dendritic cells (DC) infected with RSV, suggesting that aging may be associated with a defect in the T cell response to RSV. Humoral response to RSV tested in different adult age groups have shown that older and frail elderly adults have a lower neutralizing antibody titre than young adults, and that neutralizing antibody titre declines with age 76-78. These findings provide potential mechanisms for the increased morbidity observed with RSV infection in the elderly.
The ability of antigen presenting cells [macrophages (M) and DC] to process and present antigen to T cells is for the most part maintained in older individuals 79. Innate immunity, consisting of phagocytic cells and natural killer (NK) cells, continues to function reasonably well. 80 Most studies indicate that the chemotaxis, adherence and phagocytic ability of monocytes, M, and polymorphonuclear cells (PMNs) are not affected by aging, 39 although a decrease in the respiratory burst of monocytes, PMN production of reactive oxygen species, and chemotaxis in elderly compared to young subjects has been reported. 81
Zinc, in addition to being a cofactor to more than 300 enzymes, 82, 83 is essential for membrane integrity, DNA synthesis and cell proliferation, and thus is needed for all highly proliferating cells, especially the immune cells. 84 Zinc has been shown to play an important role in regulation of the immune response, particularly T cell-mediated function. 85-87 Similar to changes observed in the elderly immune response, zinc deficiency is associated with thymus involution, and reductions in lymphocyte proliferation, DTH, and antibody response to vaccines, 88 naïve to memory CD4 T cells, and Th1/Th2 ratios as indicated by lower IL-2 and IFN-γ production. 88, 89 Reports on the effect of zinc on other cells of the innate immune system are less consistent. Decreases 90, 91, increases, or no change in M and PMN functions have been reported due to changes in zinc status. 84, 92-95 Like the elderly, zinc deficient subjects have greater susceptibility to a variety of pathogens. 96
Several investigators have reported low zinc status or decreased intake in elderly subjects. 97-99 Furthermore, low zinc status in the elderly contributes to age-associated dysregulation of the immune response 100, 101 and zinc supplementation has been shown to improve T cell function in elderly. 97, 101-104 Thus, zinc deficiency was indicated as a risk factor for immune deficiency and susceptibility to infection in the elderly. 101, 105, 106 Zinc supplementation may therefore play an important role in the prevention of infectious diseases in the elderly. 97, 100, 103, 106 Various studies on zinc supplementation in the elderly have observed increased circulating zinc concentrations 102, 103 as well as enhanced immune status including improved cell-mediated immune response, IL-2 production, and increased response to DTH.101, 104, 107
In a randomized, double-blind, placebo-controlled clinical trial (N=81), institutionalized elderly (>65 years) had a significant decrease in the mean number of respiratory infections during a 2- year supplementation period with micronutrients containing 20 mg of zinc and 100 μg of selenium (as zinc sulfate and selenium sulfide, respectively), but not vitamins. 108 In another, larger (N=725), randomized, double-blind, placebo-controlled intervention study, low-dose zinc and selenium supplementation (20mg as zinc sulfate and 100 μg as selenium sulfide, respectively) significantly increased the humoral response in institutionalized elderly (aged 65 to 103 years) after vaccination. 109 The number without respiratory infections during the study was also found to be higher in elderly, who received trace elements over a 2-year period. 109 While these studies suggest a protective effect of zinc against respiratory tract infections, contribution from other nutrients present in the mixture cannot be ruled out. A recent study by Prasad et al. 110 showed that supplementation with 45 mg/day of elemental zinc in the gluconate form for 12 months in a small number of elderly (aged 55 to 87 years; 24-25/group) significantly reduced the incidence of all infections, including respiratory infections. The effect on pneumonia could not be evaluated due to the low rate of events. The authors concluded that while these results are encouraging they need to be repeated with a larger number of participants. The decrease in infection by zinc supplementation was suggested to be due to improvement in T cell mediated function as shown by an increase in IL-2 mRNA levels. In addition, in this study zinc supplementation was associated with a decrease in production of the pro-inflammatory cytokine, TNF-α, and DNA and lipid oxidation.
We recently showed, in an observational study, that 29% of NH residents (≥65 years) have low serum zinc levels (<70 μg/dL) despite supplementation with 7 mg/day of zinc (in the sulfate form) over a period of one year. 111 All-cause mortality was 39% lower (RR= 0.61; CI=0.37-1) in those with normal (≥70 μg/dL) versus low (<70 μg/dL) pre-intervention or baseline serum zinc concentrations (p=0.049) (Table 1). Controlling for comorbidities, other risk factors of pneumonia, and other variables found to be significantly different between those with low and normal baseline serum zinc concentrations in the model did not materially change the statistical significance of the difference observed. Our finding suggests that zinc may play a crucial role in influencing all-cause mortality in the elderly. Similarly, the risk of mortality was reduced by 27% in participants of the Age-Related Eye-Disease Study (AREDS) (aged 55 to 81 years) who received high dose zinc (80 mg/day of zinc oxide during median follow-up of 6.5 years (RR: 0.73; 95% CI, 0.61–0.89). 112 However, the authors also noted increased hospital admissions among those who received this high dose zinc due to genitourinary complications. 113.
In our observational study, subjects with normal post-intervention or final serum zinc concentrations had lower pneumonia incidence, reduced 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 final zinc concentrations (Table 1). 111 Controlling for known pneumonia risk factors and other variables found to be significantly different between those with low and normal final serum zinc concentrations such as age, percent lymphocyte, serum albumin concentration, coronary artery disease, 1, 114, 115 or statin use 116 in a multiple regression analyses model did not materially change the statistical significance of the differences observed.
In that study, we were not able to show significant differences in susceptibility to pneumonia using pre-intervention or baseline serum zinc concentrations as a measure of zinc status. It is likely that the higher risk of death among subjects with low baseline zinc concentrations or due to loss of subjects from serious illnesses and/or hospitalizations may have attenuated these findings. Additionally, the baseline zinc concentrations may not reflect zinc status during much of the study period because all study participants [i.e., those in both the treatment (200 IU/day vitamin E) or placebo (4 IU/day vitamin E) groups] were provided with ½ RDA supplement that included, as mentioned above, 7mg/day of zinc (as zinc sulfate). The effects observed were specific to zinc, but not with other micronutrients. Additionally, 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 micronutrients117 during the study period. The low final serum zinc levels were also not due to higher incidence of pneumonia in the last few months of the study, nor to higher C-reactive protein (CRP) or lower albumin levels.
In some of the studies on the role of supplemental zinc on immune parameters and infections in the elderly, other micronutrients were given in addition to zinc. While all of the improvements in immune response and infections in these studies cannot be attributed to zinc alone, a number of studies have been done in children and the elderly that have clearly demonstrated the beneficial impact of supplementation with zinc alone on immune function and the prevention of infections. 104, 107, 110, 118-120
Further, we found that several viruses are detectable in 157 NH residents in the Boston area 28. These viruses were detected with significantly higher frequency in those with ALRI including pneumonia. Our data indicate that multiple viral pathogens circulate in NHs during and are likely associated with clinically significant illnesses. Furthermore, significantly more RSV infections [11% vs. 5% (p=0.04)] were noted in those with low zinc levels (Falsey et al., unpublished data). A similar trend was noted for PIV infections, although this did not reach statistical significance.
The results from our observational study, 111 in addition to findings by other studies described above, suggest that having inadequate stores of zinc might be a risk factor of pneumonia in the elderly. Elderly with low serum zinc concentrations might therefore benefit from zinc supplementation. Such a measure has the potential to reduce not only the number and duration of pneumonia episodes and the total amount and duration of antibiotic use due to pneumonia, but also all-cause mortality in the elderly. Based on our careful review of the literature and given the upper safe limit of zinc a, dose of 30 mg elemental zinc per day might be adequate to improve immune function, and reduce the risk of infections. However, it needs to be emphasized that in order to provide conclusive evidence to support this recommendation, and to substantiate the findings described above, randomized, double blind, controlled studies, with adequate number of participants, 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. The results of such studies have the potential to significantly improve the health span and quality of life for the elderly, and to result in substantial savings on the order of millions of dollars, which might be saved in costs associated with the health care of the elderly, in particular elderly residing in NHs.
Funding All financial and material support related to the work must be clearly identified in the form of an acknowledgment at the end of the text.
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.
Junaidah B. Barnett, The Nutritional Immunology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, the Nutrition/Infection Unit, Department of Public Health and Family Medicine, Tufts University School of Medicine, the Friedman School of Nutrition Science and Policy at Tufts University, and Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts.
Davidson H. Hamer, The Nutritional Immunology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, the Friedman School of Nutrition Science and Policy at Tufts University, Department of Medicine, Boston University School of Medicine, and the Center for International Health and Development, Boston University School of Public Health, Boston, Massachusetts.
Simin N. Meydani, The Nutritional Immunology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, the Department of Pathology, Sackler Graduate School of Biochemical Sciences, Tufts University, and the Friedman School of Nutrition Science and Policy at Tufts University, Boston, Massachusetts.