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The Proceedings of the American Thoracic Society 2:433-439 (2005)
© 2005 The American Thoracic Society

Aging

Keith C. Meyer

Department of Medicine, University of Wisconsin Medical School, Madison, Wisconsin

Correspondence and requests for reprints should be addressed to Keith C. Meyer, M.D., K4/930 Clinical Sciences Center, 600 Highland Avenue, Madison, WI 53792-9988. E-mail: kcm{at}medicine.wisc.edu

ABSTRACT

Respiratory tract infections are a leading cause of morbidity and mortality in the elderly. Many factors, such as malnutrition and the presence of structural lung disease, increase the risk of respiratory infection in older individuals. Aging is also accompanied by a gradual decline in many aspects of immune function, and waning immunity is thought to be an important risk factor for pneumonia in the elderly. Although a generalized decline in both the cell-mediated and humoral aspects of acquired immunity have been described in otherwise normal elderly populations, relatively little is known about the effect of age on compartmentalized pulmonary immune surveillance and immune responses to a challenge with a respiratory pathogen. Changes in immune cell profiles and acellular components of bronchoalveolar secretions have been detected by bronchoalveolar lavage, but the impact of these changes on host defense against respiratory infections is unknown. An improved understanding of the age-associated changes in pulmonary host defense mechanisms and how these might be manipulated to reduce the susceptibility of the elderly to respiratory tract infections may reduce the possibility of severe debilitation and death and the considerable health care burden posed by the increased incidence of pneumonia in this at-risk population.

Key Words: elderly • immunity • pneumonia

Population demographics of the United States and other industrialized countries are gradually shifting toward an increased percentage of elderly adults. Life expectancy in the United States at birth has gone from 48.3 yr in 1900, to 71.1 yr in 1950, to 79.9 yr in 2002, while the total United States population has grown from 151 million in 1950 to 288 million in 2002 (1). The number of adults age 65 yr and older has gone from 12 million in 1950 (8% of the total population) to 36 million (12% of the total population) in 2002, and there has been a threefold increase in persons age 65 yr and older and an eightfold increase in persons age 85 yr and older from 1950 to 2002.

In 2002, influenza and pneumonia together were the seventh leading cause of death for all persons in the United States and the fifth leading cause for persons age 65 yr and older (1). Influenza and pneumonia accounted for 1% of deaths from all causes in persons 25 to 44 yr of age versus 3.2% of deaths for persons age 65 yr or older, and pneumonia is the leading cause of death from infection in the elderly. These statistics indicate that lower respiratory tract infection is a leading cause of death in the elderly, and bacterial pneumonia is quite capable of causing premature death or serious and sustained disability in previously healthy, elderly adults who had been leading productive lives before their episode of respiratory infection. Nonetheless, despite statistics that show that the elderly are more likely to develop pneumonia and have a fatal outcome of their infection, advanced age by itself does not signify an immunodeficient state that predisposes all elderly persons to lower respiratory tract infection. Indeed, healthy elderly individuals and even centenarians can have robust immune responses (2). Advancing age is, however, associated with a generalized waning of some immune responses that have been linked to the increased susceptibility to pulmonary infection displayed by elderly populations. Although advanced age has been associated with a decline in immune defenses and predisposition to respiratory infection, various disease states or the treatments for these disorders can affect immunity against respiratory infection regardless of age and further increase the risk of pneumonia in the elderly. In addition, changes in lung structure and function occur as a consequence of normal aging and may contribute significantly to predisposition of the elderly to lower respiratory tract infection.

AGE-ASSOCIATED CHANGES IN LUNG STRUCTURE AND FUNCTION

As immune responses wane with advancing age, changes in lung structure and function also occur (3) and may play a role in host responses to a respiratory infection (Table 1). These changes affect both the lung itself and the "respiratory pump." Lung matrix becomes remodeled as the structure and turnover of elastin and collagen are altered and accompanied by a decline in lung elastic recoil. A homogeneous increase in distal airspace (alveolar ducts and alveoli) cross-sectional diameter occurs along with a loss of alveolar gas exchange surface area and a decline in the number of capillaries per alveolus. This is accompanied by decreased tethering of small airways, which leads to a decrease in their diameter and a tendency for them to close more readily at a given lung volume, leading to a decrease in expiratory flow rates and gas trapping as the airways close during expiration, causing an increase in residual volume at the expense of vital capacity.


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  		TABLE 1. RESPIRATORY SYSTEM CHANGES IN STRUCTURE AND FUNCTION ASSOCIATED WITH ADVANCING AGE

 
Respiratory function is also altered by changes in the chest wall, respiratory muscles, and control of breathing. As lung compliance increases because of changes in lung elasticity, chest wall compliance progressively declines and is presumed to be caused by decreased mobility of costovertebral joints accompanied by narrowing of intervertebral disk spaces, calcification of intercostal cartilages, and the gradual appearance of varying degrees of kyphoscoliosis (4). Respiratory muscle performance also declines; maximal diaphragmatic force is reduced, and respiratory intercostal muscles lose cross-sectional area and are less able to contribute to ventilation as the chest wall loses compliance (5). Changes in the control of breathing also occur in both the awake and sleep states with blunted ventilatory responses to hypoxia and hypercapnia (6), a blunted response to resistive loads (7), and an increased prevalence of sleep-disordered breathing (8). Although these changes are unlikely to lead to clinically significant respiratory dysfunction in healthy elderly individuals, they may have a significant impact on morbidity and mortality when a stress, such as lower respiratory tract infection, occurs.

Many respiratory disorders are more likely to make their appearance in the elderly, and various nonrespiratory, age-associated factors can contribute to impaired pulmonary function in the elderly. The most prominent respiratory disorders that tend to appear in older individuals are those that involve remodeling of airways or distal lung parenchyma (asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis), and the prevalence of obstructive lung disease is likely greatly underestimated and underdiagnosed in the elderly (9–11). Elderly individuals with these respiratory disorders are at greatly increased risk for respiratory tract infections versus those who do not have structural lung disease, particularly if they smoke or have developed advanced chronic obstructive pulmonary disease.

ADVANCING AGE, IMMUNITY, AND PULMONARY HOST DEFENSE MECHANISMS

The immune system is generally described as having two relatively distinct but interacting major components. Adaptive (acquired, clonotypic) immunity is antigen-specific and mediated by lymphocytes derived from fetal liver and bone marrow precursors in the developing embryo, and the thymus gland and other collections of lymphoid tissue (spleen, lymph nodes, and mucosa-associated lymphoid tissue) play key roles in generating adaptive responses (12, 13). Adaptive immunity can be considered a more sophisticated form of defense, in contrast to the other major component, innate immunity, which has been highly conserved among organisms that range from invertebrates to primates (14). The innate immune system uses numerous receptors, cytokines, and chemokines but does not rely on immunologic memory and proliferation of memory lymphocytes to respond to a non– self-challenge (15). The innate immune system can respond immediately to a microbial challenge by pathogen-specific, pattern-recognition receptors, which bind determinants (e.g., lipopolysaccharide, lipoteichoic acids, mannans, peptidoglycans, glucans, or bacterial DNA) borne by infectious agents. Stimulation of signal receptors can then trigger the production and release of cytokines and costimulatory molecules. The pathogen-associated molecular patterns recognized by pattern-recognition receptors are shared by large classes of microorganisms, highly conserved, and absent from mammalian tissues (15, 16). Although innate immune responses alone may be adequate to deal with a microbial challenge, a significant innate response can trigger and augment adaptive immune responses (e.g., by costimulatory molecules) as needed to meet an infectious challenge. Other important components of the innate immune response include dendritic cells; phagocytic cells; the alternate complement pathway; and antimicrobial molecules, such as nitric oxide, defensins, and collectins. Indeed, dendritic cells play a major immunoregulatory role and provide a key link between innate and adaptive immune responses. As antigen-presenting cells, they can stimulate primary T-cell responses and T-cell differentiation by production of costimulatory molecules and cytokine production.

The lung has by far the greatest epithelial surface area of any organ and is constantly at risk for exposure to microbes inhaled from ambient air or aspirated from the upper airway. Nonspecific clearance mechanisms and various components of innate immune surveillance are constantly active in the lung to deny access by pathogens and prevent infection. Mucins, mucociliary clearance, antibacterial peptides (e.g., defensins), collectins, and alveolar macrophages (AM) play a key role in preventing potential pathogens that gain transient access to the lower respiratory tract from causing an infection. Augmented innate immune responses and triggering of adaptive responses are not required unless a potential pathogen eludes routine defenses and initiates an infection (16, 17). AMs in concert with other elements of innate defenses can clear foreign particles and inconsequential amounts of bacterial pathogens from airspace surfaces, but augmented innate and specific adaptive immune responses may need to be recruited to clear virulent or encapsulated bacteria, viruses, or intracellular pathogens that are capable of surviving within AM.

Many age-associated changes in the immune response have been described (Table 2), but most of the senescence-associated changes that have been described in the literature pertain to adaptive immune responses because various components of the innate response have not been studied as well (18, 19). It is clear that the thymus gland begins gradually to involute shortly after birth and undergoes replacement by fatty tissue that is nearly complete by the age of 60 yr, and absolute numbers of CD3+, CD4+, and CD8+ T cells decrease with advancing age. A decline in naive T-lymphocyte populations gradually occurs, and memory T cells (CD45RO+) eventually predominate, although memory cell responses gradually wane with aging (20). T- and B-cell receptor repertoire diversity seems to diminish (21, 22), and T helper cell activity declines (23). Reduced proliferative responses to mitogens and antigens (24, 25), a shift of Th1 to Th2 cytokine profiles (26), a decline in Fas-mediated T-cell apoptosis (27), and increased DR expression on T lymphocytes (28) have also been observed. Antibody production is also less efficient with advancing age, and antibodies tend to have reduced affinity for specific antigens (29).


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  		TABLE 2. ALTERATIONS IN SYSTEMIC IMMUNITY ASSOCIATED WITH ADVANCED AGE

 
Franceschi and coworkers (14, 30) have likened immunosenescent changes to a remodeling of the immune system in which sustained, lifelong exposure to a plethora of antigens (bacterial, viral, exogenous, self) leads to a gradual decline of naive T cells; an accumulation of memory T cells and effector CD8+/CD28– T cells; and deterioration of clonotypic (acquired) immunity (decline in T-cell repertoire). In contrast, many aspects of innate (ancestral) immunity, such as phagocyte and natural killer cell function, tend to show relatively little decline and may become progressively more important to aged individuals as a means to fill the "immunologic gap" that appears as adaptive immunity wanes. Furthermore, some observations suggest that as many components of immunity decline with advanced age because of sustained antigenic stress over an individual’s lifespan, there is a shift to a chronic, proinflammatory state as effector and memory cells gradually replace naive cells and expanded effector and memory T cells secrete increased amounts of proinflammatory cytokines, such as IL-6 (30). Interestingly, prolonged survival seems to correlate with fairly well-preserved immune responses in the very old (2), whereas decreased survival in a longitudinal study in a Swedish population was associated with the "immune cluster parameter" of impaired T-cell proliferative response to mitogenic stimulation, increased numbers of CD8+ cytotoxic-suppressor cells, and low numbers of CD4+ T cells and CD19+ B cells (31). Similarly, a study in Holland identified peripheral blood CD4+ T-cell lymphopenia (< 400/µl) as a significant risk for mortality (32). Other important modulators of immune function that can have a significant effect on the elderly include neuroendocrine system responses to stress (33). Elderly individuals display a gradual increase in endogenous glucocorticoids with age, which can impair immune function yet cause an exaggerated response to stressors, such as infection.

Although there is considerable information concerning systemic immune responses and how these change with aging, relatively little is known about compartmentalized immune surveillance and innate immune responses in the lung. Studies in normal human volunteers (Table 3) have shown a modestly increased number of lymphocytes and neutrophils in bronchoalveolar lavage (BAL) fluid for healthy, never-smoking elderly subjects versus younger individuals (34–36). This is accompanied by a shift in T-cell subsets and activation markers, increased immunoglobulin and IL-6 concentrations, increased AM oxyradical production, and decreased vascular endothelial growth factor concentrations (34–38). These changes may be beneficial for immune surveillance and resisting infection, but they may also reflect dysfunctional immunoregulation, altered responses to environmental factors, an effect of age-associated structural lung changes, an increased predisposition to aspiration, and a decline in efficacy of mucociliary clearance. These changes may also contribute to age-associated changes in matrix components and the decrease in elastic recoil and structural changes observed in the aging human lung.


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  		TABLE 3. CHANGES IN BAL IMMUNE PARAMETERS ASSOCIATED WITH ADVANCED AGE

 
Because the AM figures prominently in inflammatory responses and pulmonary host defense, various aspects of AM function have been evaluated to some degree in elderly populations and animal models. Examination of macrophage populations in aged animals and in humans have suggested that aging is associated with a decline in numerous macrophage functions that include the expression of certain pattern-recognition receptors, such as Toll-like receptors, a reduced capacity for phagocytosis, decreased generation of nitric oxide, and impaired secretion of certain cytokines and chemokines (39). Because Toll-like receptors are key receptors for macrophage responses to pathogens and for the initiation of both innate and adaptive immune responses, impaired Toll-like receptor expression and function by AM may play a key role in susceptibility to respiratory infections in the elderly. In addition to the demonstration that macrophages from aged mice have reduced Toll-like receptor expression (40), AM from aged rats have been shown to have impaired nitric oxide production in response to concanavalin A (41) and impaired tumor necrosis factor-{alpha} release on stimulation by LPS that seemed to be linked to decreased protein kinase C activation and translocation (42). Although little is known about the effects of advanced age on AM function in humans, Zissel and coworkers (43) have shown a decrease in human AM accessory cell function that correlated with advanced age but could not demonstrate an effect of age on spontaneous release of tumor necrosis factor-{alpha}, transforming growth factor-ß, or IL-6. Antiinflammatory cytokine production by AM in response to proinflammatory stimuli may also be impaired and may have important consequences for resolution of inflammation induced by infection or noninfectious injurious agents. Corsini and coworkers (44) recently demonstrated that AM from aged rats that were exposed to carrageenan displayed impaired production of IL-10, which correlated with an accentuated inflammatory response in the lungs of aged rats following carrageenan challenge when compared with young rats. Interestingly, the Leiden 85-plus study (45) demonstrated that impaired production of both proinflammatory and antiinflammatory cytokines by ex vivo whole blood samples from 85-yr-old subjects predicted a greater than twofold increase in overall mortality risk that was independent of the presence of chronic illnesses, and these authors speculate that impaired innate immunity, as reflected by impaired production of cytokines produced by cellular components of the innate immune system, is predictive of frailty and increased risk of mortality in the elderly.

One other aspect of innate immune function in the elderly that may have important consequences for preventing or limiting bacterial pneumonia is neutrophil function. Although neutrophil chemotaxis remains essentially intact and N-formyl-methionyl-leucyl-phenylalanine, (fMLP)-induced superoxide anion production is relatively unaltered, the phagocytic ability of peripheral blood neutrophils from elderly donors for opsonized bacteria or yeast has been shown to be impaired (33), which may, in part, be explained by age-associated reduction in the expression of cell surface CD16 (46). Additionally, de Martinis and coworkers (47) have recently demonstrated reduced expression of CD62L on circulating peripheral blood neutrophils from elderly donors, which could cause impaired neutrophil adhesion to endothelial surfaces in the microvasculature of an acutely inflamed focus of infection.

FACTORS THAT INCREASE THE RISK OF LOWER RESPIRATORY TRACT INFECTION IN THE ELDERLY

There is no simple explanation for the increased susceptibility of elderly individuals to pneumonia. Many age-associated changes are thought to increase the risk of the elderly for lower respiratory tract infection (Table 4). These include systemic diseases, such as diabetes or rheumatologic disorders; structural lung diseases; or cardiac disease in addition to various age-associated normal changes in lung structure and function accompanied by age-associated alterations in immunity. Although immunosenescence likely plays a very important role, there is considerable interindividual variation in immune function in the elderly, which may not only be genetically determined but also affected by random epigenetic changes in gene expression that occur over one’s lifetime (48).


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  		TABLE 4. RISK FACTORS FOR BACTERIAL PNEUMONIA IN THE ELDERLY

 
Protective reflexes, oral clearance, and mucociliary clearance must be intact to prevent potential pathogens in the upper airway or foreign material from gaining access to the tracheobronchial tree. Oral clearance by salivation and swallowing allow normal individuals to clear over 90% of gram-negative bacilli from the oropharynx when salivary flow is normal and swallowing mechanisms are intact (49). Although oral clearance is maintained in advanced age when individuals are colonized only by normal flora (50), the appearance of pathogenic bacteria in the mouth is associated with a significant decrease in oropharyngeal clearance (51). Patients who have xerostomia because of disease processes or who are receiving medications that disrupt salivary flow (e.g., antidepressants, antihistamines, antiparkinsonian agents) are predisposed to upper airway colonization by pathogens, as are elderly patients who are malnourished, immunosuppressed, or institutionalized (50–52).

Predisposition to aspiration is particularly problematic for patients with neurologic dysfunction. Glottic protective reflexes must be intact to prevent aspiration of upper airway contents, and patients with Alzheimer’s disease or other central nervous problems, such as stroke, are at greatly increased risk of aspiration of contaminated material from the upper airway. The coordination of swallowing and airway protective mechanisms seem to be preserved in the elderly when no neurologic disorder is present that affects deglutition (53), however, although larger volumes of liquid are required to stimulate pharyngoglottal closure in healthy elderly as compared with younger subjects (54). Silent aspiration is common in the elderly, and it has been linked to chronic bronchiolar inflammation (55, 56). Kikuchi and coworkers (55) demonstrated evidence of aspiration in 71% of elderly patients versus 10% of control subjects by affixing gauze containing indium-111 to the teeth before sleep and scanning the thorax the following day. Important determinants of infection risk with aspiration may be volume and acidity of aspirated secretions. Small amounts of gastric secretions may be rapidly neutralized, but exposure of human tracheal epithelial cells to pH 3 to 5 has been shown to inhibit ß-defensin-2 production and reduce bactericidal activity in epithelial surface liquid (57).

The early onset of chronic upper and lower respiratory tract infection in individuals with congenital defects in ciliary function demonstrates the importance of mucociliary clearance in preventing lung infection. Aged rats display decreased clearance compared with younger animals (58), and mucociliary clearance in humans has been shown to become less effective with advancing age (59). Ho and coworkers (60) have shown that cilia on nasal epithelial cells from normal elderly individuals have a lower beat frequency and increased microtubular abnormalities, and these abnormalities were associated with decreased nasal mucociliary clearance times. Because nasal ciliary beat frequency correlates well with that of tracheal epithelium (61), these studies suggest that ciliary abnormalities appear with advancing age and may increase susceptibility to respiratory infection if inhaled or aspirated pathogens are not quickly and effectively transported proximally to the glottis because of decreased efficacy of mucociliary clearance.

Declining body weight has been linked to morbidity and mortality and seems to play an important role in lowering resistance to infection. Hypoalbuminemia has been shown to be a risk factor for pneumonia in the elderly (62), suggesting that malnutrition is an important, and potentially preventable risk for respiratory infection. Indeed, protein energy malnutrition in the elderly has been linked to significant impairment of both T-cell and macrophage function (63). Involuntary weight loss can occur in the elderly in the absence of an underlying disorder, such as depression, malignancy, or digestive abnormality (64, 65), and both cachexia and advancing age have been associated with increased levels of proinflammatory cytokines, such as IL-1 and tumor necrosis factor-{alpha}, in the peripheral circulation (64). Nutritional status can also affect leptin homeostasis. Malnutrition, food restriction, and starvation have all been associated with depressed leptin levels in serum (66), and leptin-deficient mice have been shown to have impaired bacterial clearance, depressed macrophage phagocytosis, and increased mortality when challenged with intratracheal Klebsiella pneumoniae (67). Additionally, altered body composition and the decline in muscle mass associated with aging may be linked to malnutrition and contribute to the decrease in diaphragmatic strength that has been observed in clinically normal elderly subjects.

Yet another important risk factor for pneumonia in the elderly is residence in long-term care facilities (68, 69). Pathogens are usually introduced into such facilities by a point source (patient, visitor, or caregiver), and they rapidly spread among both residents and staff (69). Outbreaks frequently involve atypical pathogens, such as Legionella spp., Chlamydiae pneumoniae, influenza A and B, parainfluenza virus, respiratory syncytial virus, Bordetella pertussis, Hemophilus influenzae, and Mycobacterium tuberculosis (70).

PREVENTION AND TREATMENT OF PNEUMONIA IN THE ELDERLY

When an elderly patient develops pneumonia, rapid diagnosis and prompt administration of empiric antibiotic therapy that adequately covers likely pathogens is key to a successful outcome. Because the elderly patient frequently lacks typical symptoms of pneumonia when a lower respiratory tract infection is present, medical practitioners must be aware that altered mental status may be the only sign of an evolving pneumonia in elderly individuals (71). The rapid institution of empiric antibiotic therapy that follows guidelines established by the American Thoracic Society for community-acquired pneumonia (72) while avoiding unnecessary, time-consuming diagnostic testing that can delay antibiotic administration may be life-saving and prevent prolonged hospitalization and subsequent debilitation. Practitioners must recognize the increased likelihood that elderly patients with pneumonia may have drug-resistant pneumococci as the cause of their infection and give empiric therapy that is active against drug-resistant Streptococcus pneumoniae (71).

The pneumococcal and influenza vaccines are recommended for prevention of pulmonary infection caused by these common respiratory pathogens (71), and prevention of pneumonia is certainly preferable to trying to administer effective therapy once pneumonia has occurred. Vaccination against these agents is thought to be safe, protective, and cost-effective. Vaccine responses are generally blunted in the elderly, however, because immune responses wane with advancing age. Vaccine-induced antibodies to pneumococcal capsular polysaccharides are especially likely to decline over relatively short time periods in the elderly, and revaccination 5 years after the first dose has been advocated (73). Although a recently published metaanalysis (74) suggests that the currently used pneumococcal vaccine against pneumococcal capsular polysaccharides does not provide significant protection, many smaller studies have shown benefits for the elderly that include a diminished risk of invasive pneumococcal disease. The American Thoracic Society recommends that all people 65 yr of age or older receive the vaccine, and a recent cost-efficacy analysis suggested that those in the general population age 50 to 64 are likely to benefit and should be vaccinated (75). The influenza vaccine has been shown to be effective for the elderly when the circulating influenza strain and the vaccine are matched, and the vaccine is recommended for individuals greater than or equal to 50 yr of age and for younger, at-risk populations. Despite the potential benefit of vaccination, in 2002 only 65.8% of adults 65 yr of age and over received the influenza vaccine, and only 56% had been given the pneumococcal vaccine (1); and the vaccination rates for blacks (48.5 and 33.9%) and Hispanics (52.4 and 30.3%) were much lower than that for whites (67 and 58.4%).

Other important interventions to prevent pneumonia in the elderly include smoking cessation, optimal treatment of chronic disease, minimizing the risk of aspiration, optimizing nutrition, avoiding institutionalization, giving neuraminidase inhibitors for early treatment of viral influenza or for prophylaxis when outbreaks in the community or within an institution are occurring, combating poverty, and providing basic health care for all persons. Cigarette smoking remains a major health problem. The estimated prevalence of smoking for high school students in 2003 was 21.9% and 26.2% for students in Grade 12, and prevalence for adult men was 24.8% and adult women 20.1%. Many of these individuals will develop chronic lung disease and respiratory infections when they join the ranks of the elderly. Unfortunately, preventive measures that decrease the risk of lower respiratory tract infection in the elderly are often overlooked, including simple measures, such as optimizing nutrition and administering vaccinations.

CONCLUSIONS
Pneumonia is a leading cause of death and debilitation for individuals 65 yr of age or older. Many factors increase the risk of pneumonia for the elderly and are not necessarily associated with waning immunity. Systemic immune responses, particular the cellular and humoral components of adaptive immunity, however, gradually decline with advancing age and are thought to be a major risk factor for lower respiratory tract infection. This age-associated decline in immune function has provided the rationale for vaccination against the most common bacterial and viral pathogens (pneumococcus and influenza A) as a preventive measure against lower respiratory tract infection. Compartmentalized immunity in the lung is highly dependent on intact innate immune mechanisms and their interaction, when necessary, with adaptive immune responses. Relatively little is known about how these immune mechanisms change in the pulmonary compartment with advancing age, however, especially components of innate immunity. Sampling of airspace secretions suggests that immune cell populations and profiles differ between otherwise healthy elderly versus younger individuals, but the significance of these findings is unknown. Some investigators have found various defects in AM function in aged rodents and in humans, suggesting that pulmonary innate immunity and resistance to respiratory infection may be compromised, at least in part, by a decline in AM immune and inflammatory responses in elderly individuals. Identification and amelioration of risk factors, vaccination, and prompt recognition and treatment of pneumonia are all likely to lessen the morbidity and mortality that pneumonia holds for the elderly. Future research may identify key changes in compartmentalized immune function in the aged lung that increase the risk of infection for the elderly and lead to strategies to modulate these changes and maintain a level of resistance to respiratory infection that is characteristic of younger individuals.

FOOTNOTES

Conflict of Interest Statement: K.C.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form August 1, 2005; accepted in final form September 6, 2005)

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