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Aging

Keith C. Meyer

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

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 respiratoryinfection in older individuals. Aging is also accompanied by a grad-ual decline in many aspects of immunefunction, and waning immu-

nity is thought to be an important risk factor for pneumonia in theelderly. Although a generalized decline in both the cell-mediated

and humoral aspects of acquired immunity have been described inotherwise normal elderly populations, relatively little is known

about the effect of age on compartmentalized pulmonary immunesurveillance and immune responses to a challengewith a respiratory

pathogen. Changes in immune cell profiles and acellular compo-

nents of bronchoalveolar secretions have been detected by bron-

choalveolar lavage, but the impact of thesechangeson hostdefenseagainstrespiratory infectionsis unknown.An improvedunderstand-ing of the age-associated changes in pulmonary host defense mech-

anisms andhow these might be manipulated to reducethe suscepti-

bility of the elderly to respiratory tract infections may reduce thepossibility of severe debilitation and death and the considerablehealth care burden posed by the increased incidence of pneumonia

in this at-risk population.

Keywords: elderly; immunity; pneumonia

Population demographics of the United States and other indus-trialized countries are gradually shifting toward an increased per-centage of elderly adults. Life expectancy in the United States atbirth has gone from 48.3 yr in 1900, to 71.1 yr in 1950, to 79.9 yrin 2002, while the total United States population has grown from151 million in 1950 to 288 million in 2002 (1). The number ofadults 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 inpersons age 65 yr and older and an eightfold increase in personsage 85 yr and older from 1950 to 2002.

In 2002, influenza and pneumonia together were the seventhleading cause of death for all persons in the United States andthe fifth leading cause for persons age 65 yr and older (1). Influ-enza and pneumonia accounted for 1% of deaths from all causesin persons 25 to 44 yr of age versus 3.2% of deaths for personsage 65 yr or older, and pneumonia is the leading cause of deathfrom infection in the elderly. These statistics indicate that lowerrespiratory tract infection is a leading cause of death in the elderly,and bacterial pneumonia is quite capable of causing prematuredeath or serious and sustained disability in previously healthy,elderly adults who had been leading productive lives before their

episode of respiratory infection. Nonetheless, despite statisticsthat show that the elderly are more likely to develop pneumoniaand have a fatal outcome of their infection, advanced age by itselfdoes not signify an immunodeficient state that predisposes all

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

Correspondence and requests for reprints should be addressed to Keith C. Meyer,

M.D., K4/930Clinical Sciences Center, 600 HighlandAvenue,Madison,WI 53792-

9988. E-mail: kcm@medicine.wisc.edu

Proc Am Thorac Soc Vol 2. pp 433439, 2005DOI: 10.1513/pats.200508-081JSInternet address: www.atsjournals.org

elderly persons to lower respiratory tract infection. Indeed,healthy elderly individuals and even centenarians can have ro-bust immune responses (2). Advancing age is, however, associ-ated with a generalized waning of some immune responses thathave been linked to the increased susceptibility to pulmonaryinfection displayed by elderly populations. Although advancedage has been associated with a decline in immune defenses andpredisposition to respiratory infection, various disease states orthe treatments for these disorders can affect immunity againstrespiratory infection regardless of age and further increase therisk of pneumonia in the elderly. In addition, changes in lungstructure and function occur as a consequence of normal agingand may contribute significantly to predisposition of the elderlyto lower respiratory tract infection.

AGE-ASSOCIATED CHANGES IN LUNG STRUCTUREAND FUNCTION

As immune responses wane with advancing age, changes in lungstructure and function also occur (3) and may play a role in hostresponses to a respiratory infection (Table 1). These changesaffect both the lung itself and the respiratory pump. Lungmatrix becomes remodeled as the structure and turnover ofelastin and collagen are altered and accompanied by a declinein lung elastic recoil. A homogeneous increase in distal airspace(alveolar ducts and alveoli) cross-sectional diameter occurs alongwith a loss of alveolar gas exchange surface area and a declinein the number of capillaries per alveolus. This is accompaniedbydecreased tetheringof small airways,which leads to a decreasein their diameter and a tendency for them to close more readily

at a given lung volume, leading to a decrease in expiratory flowrates and gas trapping as the airways close during expiration,causing an increase in residual volume at the expense of vitalcapacity.

Respiratory function is also altered by changes in the chestwall, respiratory muscles, and control of breathing. As lung com-pliance increases because of changes in lung elasticity, chest wallcompliance progressively declines and is presumed to be causedby decreased mobility of costovertebral joints accompanied bynarrowing of intervertebral disk spaces, calcification of intercos-tal cartilages, and the gradual appearance of varying degrees ofkyphoscoliosis (4). Respiratory muscle performance also de-clines; maximal diaphragmatic force is reduced, and respiratoryintercostal muscles lose cross-sectional area and are less able tocontribute to ventilation as the chest wall loses compliance (5).Changes in the control of breathing also occur in both the awakeand sleep states with blunted ventilatory responses to hypoxiaand 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 signifi-cant respiratory dysfunction in healthy elderly individuals, theymay have a significant impact on morbidity and mortality whena stress, such as lower respiratory tract infection, occurs.

Many respiratory disorders are more likely to make theirappearance in the elderly, and various nonrespiratory, age-associated factors can contribute to impaired pulmonary func-tion in the elderly. The most prominent respiratory disordersthat tend to appear in older individuals are those that involve

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

Structural and anatomic changes in the lungs

Disruption and loss of elastin fibers

Altered cros s-linking of matrix (elastin and collagen)

Decrease in diameter of small bronchioles

Enlargement of terminal airspaces

Increased number of pores of Kohn

Loss of total alveolar surface area

Decrease in number of capillaries per alveolus

Other respiratory system changesDecrease in mucociliary clearance efficiency

Decrease in respiratory muscle function

Decrease in chest wall compliance plus altered chest wall contour

Changes in lung physiology and function

Decrease in lung elastic recoil (increased lung compliance)

Increase in residual volume and FRC

Decrease in FVC and forced expiratory flows (FEV1, FEF2575)

Decrease in inspiratory capacity

Decrease in DLCODecrease in PaO2Decrease in maximal oxygen consumption with exercise

remodeling of airways or distal lung parenchyma (asthma,chronic obstructive pulmonary disease, idiopathic pulmonaryfibrosis), and the prevalence of obstructive lung disease is likelygreatly underestimated and underdiagnosed in the elderly (911).Elderly individuals with these respiratory disorders are at greatlyincreased risk for respiratory tract infections versus those whodo not have structural lung disease, particularly if they smokeor have developed advanced chronic obstructive pulmonarydisease.

ADVANCING AGE, IMMUNITY, AND PULMONARYHOST DEFENSE MECHANISMS

The immune system is generally described as having two rela-tively distinct but interacting major components. Adaptive (ac-

quired, clonotypic) immunity is antigen-specific and mediatedby lymphocytes derived from fetal liver andbonemarrow precur-sors in the developing embryo, and the thymus gland and othercollections of lymphoidtissue (spleen, lymph nodes, and mucosa-associated lymphoid tissue) play key roles in generating adaptiveresponses (12, 13). Adaptive immunity can be considered a moresophisticated form of defense, in contrast to the other majorcomponent, innate immunity, which has been highly conservedamong organisms that range from invertebrates to primates (14).The innate immune system uses numerous receptors, cytokines,and chemokines but does not rely on immunologic memoryand proliferation of memory lymphocytes to respond to a nonself-challenge (15). The innate immune system can respondimmediately to a microbial challenge by pathogen-specific,

pattern-recognition receptors, which bind determinants (e.g., lipo-polysaccharide, lipoteichoic acids, mannans, peptidoglycans,glucans, or bacterial DNA) borne by infectious agents. Stimula-tion of signal receptors can then trigger the production andrelease of cytokines and costimulatory molecules. The pathogen-associated molecular patterns recognized by pattern-recognitionreceptors are shared by large classes of microorganisms, highlyconserved, and absent from mammalian tissues (15, 16). Al-though innate immune responses alone may be adequate to dealwith a microbial challenge, a significant innate response cantrigger and augment adaptive immune responses (e.g., by costi-mulatory molecules) as needed to meet an infectious challenge.Other important components of the innate immune responseinclude dendritic cells; phagocytic cells; the alternate comple-

ment pathway; and antimicrobial molecules, such as nitric oxide,defensins, and collectins. Indeed, dendritic cells play a majorimmunoregulatory role and provide a key link between innateand adaptive immune responses. As antigen-presenting cells,they can stimulate primary T-cell responses and T-cell differenti-ation by production of costimulatory molecules and cytokineproduction.

The lung has by far the greatest epithelial surface area ofany 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 ofinnate immune surveillance are constantly active in the lung todeny access by pathogens and prevent infection. Mucins, muco-ciliary clearance, antibacterial peptides (e.g., defensins), col-lectins, and alveolar macrophages (AM) play a key role in pre-venting potential pathogens that gain transient access to thelower respiratory tract from causing an infection. Augmentedinnate immune responses and triggering of adaptive responsesare not required unless a potential pathogen eludes routine de-fenses and initiates an infection (16, 17). AMs in concert withother elements of innate defenses can clear foreign particles andinconsequential amounts of bacterial pathogens from airspacesurfaces, but augmented innate and specific adaptive immuneresponses may need to be recruited to clear virulent or encapsu-latedbacteria, viruses, or intracellular pathogens that are capableof surviving within AM.

Many age-associated changes in the immune response havebeen described (Table 2), but most of the senescence-associatedchanges that have been described in the literature pertain toadaptive immune responses because various components of theinnate response have not been studied as well (18, 19). It is clearthat the thymus gland begins gradually to involute shortly afterbirth and undergoes replacement by fatty tissue that is nearlycomplete by the age of 60 yr, and absolute numbers of CD3,CD4, and CD8 T cells decrease with advancing age. A declinein naive T-lymphocyte populations gradually occurs, and memoryT cells (CD45RO) eventually predominate, although memory

TABLE 2. ALTERATIONS IN SYSTEMIC IMMUNITY ASSOCIATEDWITH ADVANCED AGE

Adaptive (antigen-specific) immunity

Cell-mediated immunity

Thymus involution

Decrease in naive T-lymphocyte production

Altered memory T-cell function

Increase in peripheral memory T lymphocytes

Decrease in proliferative responses to antigens and mitogens

Th1 to Th2 cytokine shift

Increase in HLA-DR expression

Decrease in diversity of T-lymphocyte receptor repertoire

Decrease in Fas-mediated T-cell apoptosis

Humoral immunity

Decrease in B cell numberDecrease in germinal center formation

Altered antibody responses to specific antigens

Decrease in B-lymphocyte receptor repertoire

Dysfunctional generation of primary B lymphocytes

Impaired production of memory B cells

Decrease in generation of protective antibodies with high affinity for antigen

Increase in IgA and IgG

Increase in autoantibodies

Innate immunity

Decrease in natural killer activity in association with impending morbidity

Decrease in T cell proliferation and number

Decrease in efficiency of antigen presentation by dendritic cells

Dysregulated cytokine production

Decrease in macrophage and neutrophil function

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cell responses gradually wane with aging (20). T- and B-cellreceptor repertoire diversity seems to diminish (21, 22), andT helper cell activity declines (23). Reduced proliferative re-sponses to mitogens and antigens (24, 25), a shift of Th1 to Th2cytokine profiles (26), a decline in Fas-mediated T-cell apoptosis(27), and increased DR expression on T lymphocytes (28) havealso been observed. Antibody production is also less efficientwith advancing age, and antibodies tend to have reduced affinityfor specific antigens (29).

Franceschi and coworkers (14, 30) have likened immunosen-escent changes to a remodeling of the immune system in whichsustained, 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 cellfunction, tend to show relatively little decline and may becomeprogressively more important to aged individuals as a means tofill the immunologic gap that appears as adaptive immunitywanes. Furthermore, some observations suggest that as manycomponents of immunity decline with advanced age because ofsustained antigenic stress over an individuals lifespan, there isa shift to a chronic, proinflammatory state as effector and mem-ory cells gradually replace naive cells and expanded effector andmemory T cells secrete increased amounts of proinflammatorycytokines, such as IL-6 (30). Interestingly, prolonged survivalseems to correlate with fairly well-preserved immune responsesin the very old (2), whereas decreased survival in a longitudinalstudy in a Swedish population was associated with the immunecluster parameter of impaired T-cell proliferative response tomitogenic 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 peripheralblood CD4 T-cell lymphopenia (400/l) as a significant riskfor mortality (32). Other important modulators of immune func-tion that can have a significant effect on the elderly includeneuroendocrine system responses to stress (33). Elderly indi-

viduals display a gradual increase in endogenous glucocorticoidswith age, which can impair immune function yet cause an exag-gerated response to stressors, such as infection.

Although there is considerable information concerning sys-temic immune responses and how these change with aging, rela-tively little is known about compartmentalized immune surveil-lance and innate immune responses in thelung. Studies in normalhuman volunteers (Table 3) have shown a modestly increasednumber of lymphocytes and neutrophils in bronchoalveolar la-vage (BAL) fluid for healthy, never-smoking elderly subjectsversus younger individuals (3436). This is accompanied by a

TABLE 3. CHANGES IN BAL IMMUNE PARAMETERSASSOCIATED WITH ADVANCED AGE

Adaptive immunity

Increase in CD4/CD8 T-lymphocyte ratio

Increase in total lymphocytes

Increase in HLA-DR T cells

Decrease in B lymphocytes

Increase in IgM, IgA, and IgG concentrations

Innate immunity

Increase in neutrophils

Increase in IL-6 and IL-8

Increase in superoxide anion production by alveolar macrophages

Other changes

Increase in total protein and 1-antitrypsin

Decrease in vascular endothelial growth factor

shift in T-cell subsets and activation markers, increased immuno-globulin and IL-6 concentrations, increased AM oxyradical pro-duction, and decreased vascular endothelial growth factor con-centrations (3438). These changes may be beneficial for immunesurveillance and resisting infection, but they may also reflectdysfunctional immunoregulation, altered responses to environ-mental factors, an effect of age-associated structural lungchanges, an increased predisposition to aspiration, and a declinein efficacy of mucociliary clearance. These changes may also

contribute to age-associated changes in matrix components andthe decrease in elastic recoil and structural changes observed inthe aging human lung.

Because the AM figures prominently in inflammatory re-sponses and pulmonary host defense, various aspects of AMfunction have been evaluated to some degree in elderly popula-tions and animal models. Examination of macrophage popula-tions in aged animals and in humans have suggested that agingis associated with a decline in numerous macrophage functionsthat include the expression of certain pattern-recognition recep-tors, such as Toll-like receptors, a reduced capacity for phagocyto-sis, decreased generation of nitric oxide, and impaired secretionof certain cytokines and chemokines (39). Because Toll-like recep-tors are key receptors for macrophage responses to pathogens andfor the initiation of both innate and adaptive immune responses,impaired Toll-like receptor expression and function by AM mayplay a key role in susceptibility to respiratory infections in theelderly. In addition to the demonstration that macrophages fromaged mice have reduced Toll-like receptor expression (40), AMfrom aged rats have been shown to have impaired nitric oxideproduction in response to concanavalin A (41) and impairedtumor necrosis factor- release on stimulation by LPS thatseemed to be linked to decreased protein kinase C activationand translocation (42). Although little is known about the effectsof advanced age on AM function in humans, Zissel and cowork-ers (43) have shown a decrease in human AM accessory cellfunction that correlated with advanced age but could not demon-strate an effect of age on spontaneous release of tumor necrosisfactor-, transforming growth factor-, or IL-6. Antiinflamma-

tory cytokine production by AM in response to proinflammatorystimuli may also be impaired and may have important conse-quences for resolution of inflammation induced by infectionor noninfectious injurious agents. Corsini and coworkers (44)recently demonstrated that AM from aged rats that were ex-posed to carrageenan displayed impaired production of IL-10,which correlated with an accentuated inflammatory response inthe lungs of aged rats following carrageenan challenge whencompared with young rats. Interestingly, the Leiden 85-plusstudy (45) demonstrated that impaired production of both proin-flammatory and antiinflammatory cytokines by ex vivo wholeblood samples from 85-yr-old subjects predicted a greater thantwofold increase in overall mortality risk that was independentof the presence of chronic illnesses, and these authors speculate

that impaired innate immunity, as reflected by impaired produc-tion of cytokines produced by cellular components of the innateimmune system, is predictive of frailty and increased risk ofmortality in the elderly.

One other aspect of innate immune function in the elderlythat may have important consequences for preventing or limitingbacterial pneumonia is neutrophil function. Although neutrophilchemotaxis remains essentially intact and N-formyl-methionyl-leucyl-phenylalanine,(fMLP)-induced superoxideanion produc-tion is relatively unaltered, the phagocytic ability of peripheralblood neutrophils from elderly donors for opsonized bacteria oryeast has been shown to be impaired (33), which may, in part,be explained by age-associated reduction in the expression of cellsurface CD16 (46). Additionally, de Martinis and coworkers (47)

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have recently demonstrated reduced expression of CD62L oncirculating peripheral blood neutrophils from elderly donors,which could cause impaired neutrophil adhesion to endothelialsurfaces in the microvasculature of an acutely inflamed focus ofinfection.

FACTORS THAT INCREASE THE RISK OF LOWERRESPIRATORY TRACT INFECTION IN THE ELDERLY

There is no simple explanation for the increased susceptibilityof elderly individuals to pneumonia. Many age-associatedchanges are thought to increase the risk of the elderly for lowerrespiratory tract infection (Table 4). These include systemic dis-eases, such as diabetes or rheumatologic disorders; structural lungdiseases; or cardiac disease in addition to various age-associatednormal changes in lung structure and function accompanied byage-associated alterations in immunity. Although immunosenes-cence likely plays a very important role, there is considerableinterindividual variationin immune function in the elderly, whichmay not only be genetically determined but also affected byrandom epigenetic changes in gene expression that occur overones lifetime (48).

Protective reflexes, oral clearance, and mucociliary clearancemust be intact to prevent potential pathogens in the upper airway

or foreign material from gaining access to the tracheobronchialtree. Oral clearance by salivation and swallowing allow normalindividuals to clear over 90% of gram-negative bacilli from theoropharynx when salivary flow is normal and swallowing mecha-nisms are intact (49). Although oral clearance is maintained inadvanced age when individuals are colonized only by normalflora (50), the appearance of pathogenic bacteria in the mouth isassociated with a significant decrease in oropharyngeal clearance(51). Patients who have xerostomia because of disease processesor who are receiving medications that disrupt salivary flow (e.g.,antidepressants, antihistamines, antiparkinsonian agents) arepredisposed to upper airway colonization by pathogens, as areelderly patients who are malnourished, immunosuppressed, orinstitutionalized (5052).

Predisposition to aspiration is particularly problematic forpatients with neurologic dysfunction. Glottic protective reflexes

TABLE 4. RISK FACTORS FOR BACTERIAL PNEUMONIAIN THE ELDERLY

Dysfunctional immune defense mechanisms

Immune suppression

Drugs (e.g., corticosteroids)

Systemic disease (e.g., malignancy, renal failure)

Age-associated decline

Predisposition to aspiration of upper airway or oral secretions

Central nervous system dysfunction

Swallowing disorders

Sedating medications

Depressed clearance mechanismsMechanical reflexes (cough)

Oral clearance (salivary flow)

Mucociliary clearance

Admission to a medical care facility

Recent hospitalization

Long-term care facility

Organ system dysfunction

Parenchymal lung disease

Other (cardiac, renal, hepatic)

Chronic disease (diabetes, rheumatologic)

Protein-calorie malnutrition or hypoalbuminemia

Tobacco smoking

Alcoholism

Viral infection

must be intact to prevent aspiration of upper airway contents,and patients with Alzheimers disease or other central nervousproblems, such as stroke, are at greatly increased risk of aspira-tion of contaminated material from the upper airway. The coor-dination of swallowing and airway protective mechanisms seemto be preserved in the elderly when no neurologic disorder ispresent that affects deglutition (53), however, although largervolumes of liquid are required to stimulate pharyngoglottal clo-sure in healthy elderly as compared with younger subjects (54).

Silent aspiration is common in the elderly, and it has been linkedto chronic bronchiolar inflammation (55, 56). Kikuchi and co-workers (55) demonstrated evidence of aspiration in 71% ofelderly patients versus 10% of control subjects by affixing gauzecontaining indium-111 to the teeth before sleep and scanningthe thorax the following day. Important determinants of infec-tion risk with aspiration may be volume and acidity of aspiratedsecretions. Small amounts of gastric secretions may be rapidlyneutralized, but exposure of human tracheal epithelial cells topH 3 to 5 has been shown to inhibit -defensin-2 productionand reduce bactericidal activity in epithelial surface liquid (57).

The early onset of chronic upper and lower respiratory tractinfection in individuals with congenital defects in ciliary functiondemonstrates the importance of mucociliary clearance in pre-venting lung infection. Aged rats display decreased clearancecompared with younger animals (58), and mucociliary clearancein humans has been shown to become less effective with advanc-ing age (59). Ho and coworkers (60) have shown that cilia onnasal epithelial cellsfrom normal elderly individuals have a lowerbeat frequency and increased microtubular abnormalities, andthese abnormalities were associated with decreased nasal muco-ciliary clearance times. Because nasal ciliary beat frequency cor-relates well with that of tracheal epithelium (61), these studiessuggest that ciliary abnormalities appear with advancing age andmay increase susceptibility to respiratory infection if inhaled oraspirated pathogens are not quickly and effectively transportedproximally to the glottis because of decreasedefficacy of mucocil-iary clearance.

Declining body weight has been linked to morbidity and

mortality and seems to play an important role in lowering resis-tance to infection. Hypoalbuminemia has been shown to be arisk factor for pneumonia in the elderly (62), suggesting thatmalnutrition is an important, and potentially preventable riskfor respiratory infection. Indeed, protein energy malnutritionin the elderly has been linked to significant impairment of bothT-cell and macrophage function (63). Involuntary weight losscan 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 associatedwith increased levels of proinflammatory cytokines, such as IL-1and tumor necrosis factor-, in the peripheral circulation (64).Nutritional status can also affect leptin homeostasis. Malnutri-tion, food restriction, and starvation have all been associated

with depressed leptin levels in serum (66), and leptin-deficientmice have been shown to have impaired bacterial clearance,depressed macrophage phagocytosis, and increased mortalitywhen challenged with intratracheal Klebsiella pneumoniae(67).Additionally, altered bodycomposition and the decline in musclemass associated with aging may be linked to malnutrition andcontribute to the decrease in diaphragmatic strength that hasbeen observed in clinically normal elderly subjects.

Yet another important risk factor for pneumonia in the el-derly is residence in long-term care facilities (68, 69). Pathogensare usually introduced into such facilities by a point source (pa-tient, visitor, or caregiver), and they rapidly spread among bothresidents and staff (69). Outbreaks frequently involve atypicalpathogens, such as Legionella spp., Chlamydiae pneumoniae,

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influenza A and B, parainfluenza virus, respiratory syncytial virus,Bordetella pertussis, Hemophilus influenzae, and Mycobacteriumtuberculosis(70).

PREVENTION AND TREATMENT OF PNEUMONIA INTHE ELDERLY

When an elderly patient develops pneumonia, rapid diagnosisand prompt administration of empiric antibiotic therapy thatadequately covers likely pathogens is key to a successful out-come. Because the elderly patient frequently lacks typical symp-toms of pneumonia when a lower respiratory tract infection ispresent, medical practitioners must be aware that altered mentalstatus may be the only sign of an evolving pneumonia in elderlyindividuals (71). The rapid institution of empiric antibiotic ther-apy that follows guidelines established by the American ThoracicSociety for community-acquired pneumonia (72) while avoidingunnecessary, time-consuming diagnostic testing that can delayantibiotic administration may be life-saving and prevent pro-longed hospitalization and subsequent debilitation. Practitionersmust recognize the increased likelihood that elderly patientswith pneumonia may have drug-resistant pneumococci as thecause of their infection and give empiric therapy that is activeagainst drug-resistant Streptococcus pneumoniae (71).

The pneumococcal and influenza vaccines are recommendedfor prevention of pulmonary infection caused by these commonrespiratory pathogens (71), and prevention of pneumonia is cer-tainly preferable to trying to administer effective therapy oncepneumonia has occurred. Vaccination against these agents isthought to be safe, protective, and cost-effective. Vaccine re-sponses are generally blunted in the elderly, however, becauseimmune responses wane with advancing age. Vaccine-inducedantibodies to pneumococcal capsular polysaccharides are espe-cially likely to decline over relatively short time periods in theelderly, and revaccination 5 years after the first dose has beenadvocated (73). Although a recently published metaanalysis (74)suggests that the currently used pneumococcal vaccine againstpneumococcal capsular polysaccharides does not provide sig-

nificant protection, many smaller studies have shown benefitsfor the elderly that include a diminished risk of invasive pneumo-coccal disease. The American Thoracic Society recommends thatall people 65 yr of age or older receive the vaccine, and a recentcost-efficacy analysis suggested that those in the general popula-tion age 50 to 64 are likely to benefit and should be vaccinated(75). The influenza vaccine has been shown to be effective forthe elderly when the circulating influenza strain and the vaccineare matched, and the vaccine is recommended for individualsgreater than or equal to 50 yr of age and for younger, at-riskpopulations. Despite the potential benefit of vaccination, in 2002only 65.8% of adults 65 yr of age and over received the influenzavaccine, 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 and30.3%) 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 chronicdisease, minimizing the risk of aspiration, optimizing nutrition,avoiding institutionalization, giving neuraminidase inhibitors forearly treatment of viral influenza or for prophylaxis when out-breaks in the community or within an institution are occurring,combating poverty, and providing basic health care for all per-sons. Cigarette smoking remains a major health problem. Theestimated prevalence of smoking for high school students in 2003was 21.9% and 26.2% for students in Grade 12, and prevalencefor adult men was 24.8% and adult women 20.1%. Many of theseindividuals will develop chronic lung disease and respiratory

infections whenthey join the ranks of the elderly. Unfortunately,preventive measures that decrease the risk of lower respiratorytract infection in the elderly are often overlooked, includingsimple measures, such as optimizing nutrition and administeringvaccinations.

CONCLUSIONS

Pneumonia is a leading cause of death and debilitation for indi-viduals 65 yr of age or older. Many factors increase the risk of

pneumonia for the elderly and are not necessarily associatedwith waning immunity. Systemic immune responses, particularthe cellular and humoral components of adaptive immunity,however, gradually decline with advancing age and are thoughtto be a major risk factor for lower respiratory tract infection.This age-associated decline in immune function has providedthe rationale for vaccination against the most common bacterialand viral pathogens (pneumococcus and influenza A) as a pre-ventive measure against lower respiratory tract infection. Com-partmentalized immunity in the lung is highly dependent onintact innate immune mechanisms and their interaction, whennecessary, with adaptive immune responses. Relatively little isknown about how these immune mechanisms change in thepulmonary compartment with advancing age, however, espe-

cially components of innate immunity. Sampling of airspace se-cretions suggests that immune cell populations and profiles differbetween otherwise healthy elderly versus younger individuals,but the significance of these findings is unknown. Some investiga-tors have found various defects in AM function in aged rodentsand in humans, suggesting that pulmonary innate immunity andresistance to respiratory infection may be compromised, at leastin part, by a decline in AM immune and inflammatory responsesin elderly individuals. Identification and amelioration of riskfactors, vaccination, and prompt recognition and treatment ofpneumonia are all likely to lessen the morbidity and mortalitythat pneumonia holds for the elderly. Future research may iden-tify key changes in compartmentalized immune function in theaged lung that increase the risk of infection for the elderly andlead to strategies to modulate these changes and maintain a levelof resistance to respiratory infection that is characteristic ofyounger individuals.

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

References

1. National Center for Health Statistics. Health, United States, 2004 with

chartbook on trends in the health of Americans [Internet]. Hyattsville,

MD; 2004. Available from http://www.edc.gov .

2. Francheschi C, Monti D, Samsoni P, Cossarizza A. The immunology of

exceptional individuals: the lesson of centenarians. Immunol Today

1995;16:1216.

3. Green FHY, Pinkerton KE. Environmental determinants of lung aging.

In: Harding R, Pinkerton KE, Plopper CG, editors. The lung: develop-ment,aging and the environment. London: Elsevier; 2004. pp. 377395.

4. Peterson DD, Fishman AP. The lungsin laterlife. In: Fishman AP, editor.

Pulmonary disease and disorders: update 1. New York: McGraw-Hill;

1982. pp. 123136.

5. Enright PL, Kronmal RA, Manolio TA, Schenker MB, Hyatt RE. Respi-

ratory muscle strength in the elderly: correlates and reference values.

Am J Respir Crit Care Med1994;149:430438.

6. Peterson DD, Pack AI, Silage DA, Fishman AP. Effects of aging on

ventilatory and occlusion pressure responses to hypoxia and hyper-

capnia.Am Rev Respir Dis 1981;124:387391.

7. Tack M, Altose M, Cherniack N. Effect of aging on the perception of

resistive ventilatory loads. Am Rev Respir Dis 1982;126:463467.

8. Ancoli-Israel S, Coy T. Are breathing disturbances in elderly equivalent

to sleep apnea syndrome. Sleep 1994;17:7783.

7/25/2019 2005 - Aging

6/7

438 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 2 2005

9. Malik A, Saltoun CA, Yarnold PR, Grammer LC. Prevalence of obstruc-tive airways disease in the disadvantaged elderly of Chicago. Allergy

Asthma Proc2004;25:169173.10. Lundback B, Lindberg A, Lindstrom M, Ronmark E, Jonsson AC,

Jonsson E, Larsson LG, Andersson S, Sandstrom T, Larsson K. Ob-structive lung disease in Northern Sweden Studies: not 15 but 50% ofsmokers develop COPD? Report from the Obstructive Lung Diseasein Northern Sweden Studies. Respir Med 2003;97:115122.

11. JanssensJP, HerrmannF, MacGeeW, MichelMP. Cause ofdeathin olderpatients with anatomo-pathological evidence of chronic bronchitis oremphysema: a case-control study based on autopsy findings. J AmGeriatr Soc 2001;49:571576.

12. Delves PJ, Roitt IM. The immunesystemPart I. N EnglJ Med 2000;343:3749.

13. Delves PJ, Roitt IM. The immune systemPart II.N Engl J Med 2000;343:108117.

14. Franceschi C, Bonafe M, Valensin S. Human immunosenescence: theprevailing of innate immunity, the failing of clonotypic immunity, andthe filling of immunological space. Vaccine2000;18:17171720.

15. Medzhitov R, Janeway C Jr. Innate immunity.N Engl J Med 2000;343:338344.

16. ZhangP, Summer WR, BagbyGJ, Nelson S. Innate immunity and pulmo-nary host defense. Immunol Rev 2000;173:3951.

17. Masten BJ. Initiation of lung immunity: the afferent limb and the roleof dendritic cells. Semin Respir Crit Care Med 2004;25:1120.

18. Ginaldi L, De Martinis M, DOstilio A, Marini L, Loreto MF, QuaglinoD. Immunological changes in the elderly.Aging Clin Exp Res1999;11:

281286.19. Meyer KC. The role of immunity in susceptibility to respiratory infection

in the aging lung. Respir Physiol2001;128:2331.20. Flurkey K, Stadecker M, Miller RA. Memory T lymphocyte hyporespon-

siveness to non-cognate stimuli: a key factor in age-related immunode-ficiency.Eur J Immunol1992;22:931935.

21. NicolettiC, Borghesi-Nicoletti C, YangX, Schulze D, CernyJ. Repertoire

diversity of antibody response to bacterial antigens in aged mice. II.Phosphorylcholine-antibody in young and aged mice differ in bothVH/VL gene repertoire and in specificity. J Immunol1991;147:27502755.

22. Liu J, Wang S, Liu H, Yang L, Nan G. The monitoring biomarker for

immune function of lymphocytes in the elderly. Mech Ageing Dev1997;94:177182.

23. Li SP, Verma S, Miller RA. Age-related defects in T cell expression ofCD40 ligand and induction of in vitro B cellactivation.Aging Immunol

Infect Dis1995;6:7993.24. Linton PJ, Haynes L, Tsui L, Zhang X, Swain S. From naive to effector:alterations with aging. Immunol Rev 1997;160:918.

25. Miller RA, Garcia G, Kirk CJ, Witkowski JM. Early activation defects

in T lymphocytes from aged mice. Immunol Rev 1997;160:7990.26. Cakman I, Rohr J, Schutz RM, Kirchner H, Rink L. Dysregulation be-

tween TH1and TH2T cell subpopulations in the elderly. Mech AgingDev1996;87:197209.

27. Zhou T, Edwards CK, Mountz JK. Prevention of age-related T cell

apoptosis defect in CD2-fastransgenic mice.J Exp Med1995;182:129

137.28. Jackola DR, Ruger JK, Miller RA. Age-associated changes in human

T cell phenotype and function. Aging Clin Exp Res 1994;6:2534.

29. Song H, Price PW, Cerny J. Age-related changes in antibody repertoire:contribution from T-cells. Immunol Rev 1997;160:5562.

30. Franceschi C, Bonafe M. Centenarians as a model for healthy aging.Biochem Soc Trans 2003;31:457461.

31. Ferguson FG, Wiikby A, Maxon P, Olsson J, Johansson B. Immuneparameters in a longitudinal study of a very old population of Swedishpeople: a comparison between survivors and nonsurvivors. J Gerontol1995;50:B378B382.

32. Remarque E, Pawelec G. T-cell immunosenescence and its clinical rele-

vance in man. Rev Clin Gerontol1998;8:514.33. Butcher SK, Lord JM. Stress responses and innate immunity: aging as a

contributory factor. Aging Cell2004;3:151160.34. Meyer KC, Ershler W, Rosenthal N, Lu X, Peterson K. Immune dysregu-

lation in the aging human lung. Am J Respir Crit Care Med1996;153:10721079.

35. Meyer KC. Neutrophils and low-grade inflammation in the seeminglynormal aging human lung. Mech Aging Develop1998;104:169181.

36. Meyer KC, Soergel P. Bronchoalveolar lymphocyte phenotypes change

in the normal aging human lung.Thorax1999;54:697700.

37. Thompson AB, Scholer SG, Daughton DM, Potter JF, Rennard SI.Altered epithelial lining fluid parameters in old normal individuals.

J Gerontol1992;47:M171M176.38. Meyer KC, Cardoni A, Xiang Z. Vascular endothelial growth factor in

bronchoalveolar lavage from normal subjects and patients with diffuseparenchymal lung disease. J Lab Clin Med 2000;135:332338.

39. Plowden J, Renshaw-Hoelscher M, Engleman C, Katz J, Sambhara S.Innate immunity in aging: impact on macrophage function. Aging Cell2004;3:161167.

40. Boehmer ED, Goral J, Faunce DE, Kovacs EJ. Age-dependent decreasein Toll-like receptor 4-mediated proinflammatory cytokine production

and mitogen-activated protein kinase expression. J Leukoc Biol2004;75:342349.

41. Koike E, Kobayashi T, Mochitate K, Murakami M. Effect of aging onnitric oxide production by rat alveolar macrophages. Exp Gerontol1999;34:889894.

42. Corsini E, Battaini F, Lucchi L, Marinovich M, Racchi M, Govoni S,Galli CL. A defective protein kinase C anchoring system underlyingage-associated impairment in TNF-alpha production in rat macro-phages. J Immunol1999;163:34683473.

43. Zissel G, Schlaak M, Muller-Quernheim J. Age-related decrease in acces-sory cell function of human alveolar macrophages.J Invest Med1999;47:5156.

44. Corsini E, Di Paola R, Viviani B, Genovese T, Mazzon E, Lucchi L,Marinovich M, Galli CL, Cuzzocrea S. Increased carrageenan-inducedacute lung inflammation in old rats. Immunology 2005;115:253261.

45. Van den Biggelaar AHJ, Huizinga TWJ, de Craen AJM, Gussekloo J,

Heijmans BT, Frolich M, Westendorp RGJ. Impaired innateimmunitypredicts frailty in old age. The Leiden 85-plus study. Exp Gerontol2004;39:14071414.

46. Butcher SK, Chahal H, Nayak L, Sinclair A, Henriquez NV, Sapey E,OMahony D, Lord JM. Senescence in innate immune responses:reduced neutrophil phagocytic capacity and CD16 expression in el-derly humans. J Leukoc Biol2001;70:881886.

47. De Martinis M,Modesti M, GinaldiL. Phenotypic and functional changesof circulating monocytes and polymorphonuclear leucocytes from el-derly persons. Immunol Cell Biol2004;82:415420.

48. Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML,Heine-Suner D, Cigadosa JC, Urioste M, Benitez J, et al. Epigeneticdifferences arise during the lifetime of monozygotic twins. Proc Natl

Acad Sci U S A2005;102:1060410609.49. Laforce FM, Hopkins J, Trow R,Wang WL. Human oral defenses against

gram negative rods. Am Rev Respir Dis1976;114:929935.50. Smaldone GC. Deposition and clearance: unique problems in the proxi-

mal airways and oral cavity in the young and elderly. Respir Physiol2001;128:3338.

51. Palmer LB, Albulak K, Fields S, Filkin AM, Simon S, Smaldone GC.Oral clearance and pathogenic oropharyngeal colonization in theelderly.Am J Respir Crit Care Med 2001;164:464468.

52. Ayars GH, Altman LC, Fretwell MD. Effect of decreased salivation andpH on the adherence ofKlebsiellaspecies to human buccal epithelialcells.Infect Immun 1982;38:179182.

53. Shaker R, Staff D. Esophageal disorders in the elderly. GastroenterolClin North Am2001;30:335361.

54. Shaker R, Ren J, Bardan E, Easterling C, Dua K, Xie P, Kern M.Pharyngoglottal closure reflex: characterization in healthy young, el-derly and dysphagic patients with predeglutitive aspiration. Gerontol-ogy 2003;49:1220.

55. Kikuchi R, Watabe N, Konno T, Mishina N, Sekizawa K, Sasaki H.High incidence of silent aspiration in elderly patients with community-

acquired pneumonia. Am J Respir Crit Care Med 1994;150:251253.56. Matsuse T, Oka T, Kida K, Fukuchi Y. Importance of diffuse aspirationbronchiolitis caused by chronic occult aspiration in the elderly.Chest1996;110:12891293.

57. Nakayama K, Jia YX, Hirai H, Shinkawa M, Yamaya M, Sekizawa K,Sasaki H. Acid stimulation reduces bactericidal activity of surfaceliquid in cultured human airway epithelial cells.Am J Respir Crit CareMed 2002;26:105113.

58. Antonini JM, Roberts JR, Clarke RW, Yang H, Barger MW, Ma JYC,Weissman DN. Pulmonary bacterial clearance in Fischer 344 rats afterintratracheal instillation of Listeria monocytogenes. Chest 2001;120:240249.

59. Puchelle E, Zahm JM, Bertrand A. Influence of age on bronchial mucocil-iary transport. Scand J Respir Dis 1979;60:307313.

60. Ho JC, Chan KN, Hu WH, Lam WK, Zheng L, Leung R, Tsang KW.The effect of aging on nasal mucociliary clearance, beat frequency,

7/25/2019 2005 - Aging

7/7

Meyer: Aging 439

and ultrastructure of respiratory cilia. Am J Respir Crit Care Med2001;163:983988.

61. Rutland J, Penketh A, Griffin WM, Hodson ME, Batten JC, Cole PJ.Cystic fibrosis serum does not inhibit human ciliary beat frequency.

Am Rev Respir Dis 1983;128:10301034.62. RiquelmeR, TorresA, El-Ebiary M,de laBellacasa JP,EstruchR, Mensa

J, Fernandez-Sola J, Hernandez C, Rodriguez-Roisin R. Community-acquired pneumonia in the elderly: a multivariate analysis of risk andprognostic factors. Am J Respir Crit Care Med 1996;154:14501455.

63. Lesourd BM. Nutrition: a major factor influencing immunity in the el-derly. J Nutr Health Aging 2004;8:2837.

64. Yeh S, Schuster MW. Geriatric cachexia: the role of cytokines. Am JClin Nutr1999;70:183197.

65. Pamuk ER, Williamson DF, Serdula MK, Madans J, Byers TE. Weightloss and subsequent death in a cohort of U.S. adults. Ann Intern Med1993;119:744748.

66. Maffei M, Halass J, Ravussin E, Pratlet RE, Lee GH, Zhang Y, Fei H,Kim S, Lallone R, Ranganathan S, et al. Leptin levels in human androdent: measurements of plasma leptin and ob RNA in obese andweight-reduced subjects. Nat Med 1995;1:11551161.

67. Macuso P, Gottschalk A, Phare SM, Peters-Golden M, Lukacs NW,Huffnagle GB. Leptin-deficient mice exhibit impaired host defense ingram-negative pneumonia. J Immunol2002;168:40184024.

68. Starczewski AR, Allen SC, Vargas E, Lye M. Clinical prognostic indicesof fatality in elderly patients admitted to hospital with acute pneumo-nia.Age Aging 1988;17:181186.

69. Loeb M, McGeer A, McArthur M, Peeling RW, Petric M, Simor AE.Surveillance for outbreaks of respiratory tract infections in nursinghomes.CMAJ2000;162:11331137.

70. Strausbaugh LJ, Sukumar SR, Joseph CL. Infectious disease outbreaksin nursing homes: an unappreciated hazard for frail elderly persons.Clin Infect Dis 2003;36:870876.

71. Neralla S, Meyer KC. Drug treatment of pneumococcal pneumonia inthe elderly. Drugs Aging2004;21:851864.

72. American Thoracic Society Board of Directors. Guidelines for the man-agement of adults with community-acquired pneumonia: diagnosis,assessment of severity, antimicrobial therapy, and prevention. Am JRespir Crit Care Med2001;163:17301754.

73. Ortqvist A. Pneumococcal vaccination: current and future issues. EurRespir J2001;18:184195.

74. Dear K, Holden J, Andrews R, Tatham D. Vaccines for preventingpneumococcal infection in adults. Cochrane Database Syst Rev 2003;4:CD000422.

75. Sisk JE, Whang W, Butler JC, Sneller V, Whitney CG. Cost-effectivenessof vaccination against invasive pneumococcal disease among people50 through 64 years of age: role of comorbid conditions and race. Ann

Intern Med 2003;138:960968.