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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 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.
Keywords: 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, inuenza and pneumonia together were the seventh
leading cause of death for all persons in the United States and
the fth leading cause for persons age 65 yr and older (1). Inuenza 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 immunodecient 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., K4/930 Clinical Sciences Center, 600 Highland Avenue, Madison, WI 537929988. E-mail: kcm@medicine.wisc.edu
Proc Am Thorac Soc Vol 2. pp 433439, 2005
DOI: 10.1513/pats.200508-081JS
Internet address: www.atsjournals.org

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 signicantly 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 ow
rates and gas trapping as the airways close during expiration,
causing an increase in residual volume at the expense of vital
capacity.
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, calcication 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 signicant respiratory dysfunction in healthy elderly individuals, they
may have a signicant 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, ageassociated 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

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TABLE 1. RESPIRATORY SYSTEM CHANGES IN STRUCTURE AND
FUNCTION ASSOCIATED WITH ADVANCING AGE
Structural and anatomic changes in the lungs
Disruption and loss of elastin fibers
Altered cross-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 changes
Decrease 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 DLCO
Decrease in PaO2
Decrease in maximal oxygen consumption with exercise

remodeling of airways or distal lung parenchyma (asthma,


chronic obstructive pulmonary disease, idiopathic pulmonary
brosis), and the prevalence of obstructive lung disease is likely
greatly underestimated and underdiagnosed in the elderly (911).
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-specic 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 mucosaassociated 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-specic,
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 pathogenassociated 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 signicant 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 comple-

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ment 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.
Nonspecic 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 specic 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

TABLE 2. ALTERATIONS IN SYSTEMIC IMMUNITY ASSOCIATED


WITH 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 number
Decrease 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

Meyer: Aging

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 proles (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 efcient
with advancing age, and antibodies tend to have reduced afnity
for specic antigens (29).
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
ll 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 individuals lifespan, there is
a shift to a chronic, proinammatory state as effector and memory cells gradually replace naive cells and expanded effector and
memory T cells secrete increased amounts of proinammatory
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 cytotoxicsuppressor cells, and low numbers of CD4 T cells and CD19
B cells (31). Similarly, a study in Holland identied peripheral
blood CD4 T-cell lymphopenia ( 400/l) as a signicant risk
for mortality (32). Other important modulators of immune function that can have a signicant 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) uid for healthy, never-smoking elderly subjects
versus younger individuals (3436). This is accompanied by a

TABLE 3. CHANGES IN BAL IMMUNE PARAMETERS


ASSOCIATED 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

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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 (3438). These changes may be benecial for immune
surveillance and resisting infection, but they may also reect
dysfunctional immunoregulation, altered responses to environmental factors, an effect of age-associated structural lung
changes, an increased predisposition to aspiration, and a decline
in efcacy 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.
Because the AM gures prominently in inammatory 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- 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-, transforming growth factor-, or IL-6. Antiinammatory cytokine production by AM in response to proinammatory
stimuli may also be impaired and may have important consequences for resolution of inammation 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 inammatory 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 proinammatory and antiinammatory 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 reected 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-methionylleucyl-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)

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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 inamed 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
ones lifetime (48).
Protective reexes, 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 ow is normal and swallowing mechanisms are intact (49). Although oral clearance is maintained in
advanced age when individuals are colonized only by normal
ora (50), the appearance of pathogenic bacteria in the mouth is
associated with a signicant decrease in oropharyngeal clearance
(51). Patients who have xerostomia because of disease processes
or who are receiving medications that disrupt salivary ow (e.g.,
antidepressants, antihistamines, antiparkinsonian agents) are
predisposed to upper airway colonization by pathogens, as are
elderly patients who are malnourished, immunosuppressed, or
institutionalized (5052).
Predisposition to aspiration is particularly problematic for
patients with neurologic dysfunction. Glottic protective reexes

TABLE 4. RISK FACTORS FOR BACTERIAL PNEUMONIA


IN 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 mechanisms
Mechanical 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

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must be intact to prevent aspiration of upper airway contents,


and patients with Alzheimers 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 inammation (55, 56). Kikuchi and coworkers (55) demonstrated evidence of aspiration in 71% of
elderly patients versus 10% of control subjects by afxing 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 -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 efcacy 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 signicant 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 proinammatory cytokines, such as IL-1
and tumor necrosis factor-, 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-decient
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,

Meyer: Aging

inuenza A and B, parainuenza virus, respiratory syncytial virus,


Bordetella pertussis, Hemophilus inuenzae, 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 inuenza 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 rst 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 signicant protection, many smaller studies have shown benets
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-efcacy analysis suggested that those in the general population age 50 to 64 are likely to benet and should be vaccinated
(75). The inuenza vaccine has been shown to be effective for
the elderly when the circulating inuenza 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 benet of vaccination, in 2002
only 65.8% of adults 65 yr of age and over received the inuenza
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 inuenza 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

437

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 inuenza 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 proles differ
between otherwise healthy elderly versus younger individuals,
but the signicance of these ndings 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 inammatory responses
in elderly individuals. Identication 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.
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.

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: development, aging and the environment. London: Elsevier; 2004. pp. 377395.
4. Peterson DD, Fishman AP. The lungs in later life. 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. Respiratory muscle strength in the elderly: correlates and reference values.
Am J Respir Crit Care Med 1994;149:430438.
6. Peterson DD, Pack AI, Silage DA, Fishman AP. Effects of aging on
ventilatory and occlusion pressure responses to hypoxia and hypercapnia. 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.

438
9. Malik A, Saltoun CA, Yarnold PR, Grammer LC. Prevalence of obstructive airways disease in the disadvantaged elderly of Chicago. Allergy
Asthma Proc 2004;25:169173.
10. Lundback B, Lindberg A, Lindstrom M, Ronmark E, Jonsson AC,
Jonsson E, Larsson LG, Andersson S, Sandstrom T, Larsson K. Obstructive lung disease in Northern Sweden Studies: not 15 but 50% of
smokers develop COPD? Report from the Obstructive Lung Disease
in Northern Sweden Studies. Respir Med 2003;97:115122.
11. Janssens JP, Herrmann F, MacGee W, Michel MP. Cause of death in older
patients with anatomo-pathological evidence of chronic bronchitis or
emphysema: a case-control study based on autopsy ndings. J Am
Geriatr Soc 2001;49:571576.
12. Delves PJ, Roitt IM. The immune systemPart I. N Engl J 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: the
prevailing of innate immunity, the failing of clonotypic immunity, and
the lling of immunological space. Vaccine 2000;18:17171720.
15. Medzhitov R, Janeway C Jr. Innate immunity. N Engl J Med 2000;343:
338344.
16. Zhang P, Summer WR, Bagby GJ, Nelson S. Innate immunity and pulmonary host defense. Immunol Rev 2000;173:3951.
17. Masten BJ. Initiation of lung immunity: the afferent limb and the role
of dendritic cells. Semin Respir Crit Care Med 2004;25:1120.
18. Ginaldi L, De Martinis M, DOstilio A, Marini L, Loreto MF, Quaglino
D. Immunological changes in the elderly. Aging Clin Exp Res 1999;11:
281286.
19. Meyer KC. The role of immunity in susceptibility to respiratory infection
in the aging lung. Respir Physiol 2001;128:2331.
20. Flurkey K, Stadecker M, Miller RA. Memory T lymphocyte hyporesponsiveness to non-cognate stimuli: a key factor in age-related immunodeciency. Eur J Immunol 1992;22:931935.
21. Nicoletti C, Borghesi-Nicoletti C, Yang X, Schulze D, Cerny J. Repertoire
diversity of antibody response to bacterial antigens in aged mice. II.
Phosphorylcholine-antibody in young and aged mice differ in both
VH/VL gene repertoire and in specicity. J Immunol 1991;147:2750
2755.
22. Liu J, Wang S, Liu H, Yang L, Nan G. The monitoring biomarker for
immune function of lymphocytes in the elderly. Mech Ageing Dev
1997;94:177182.
23. Li SP, Verma S, Miller RA. Age-related defects in T cell expression of
CD40 ligand and induction of in vitro B cell activation. Aging Immunol
Infect Dis 1995;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 between TH1 and TH2 T cell subpopulations in the elderly. Mech Aging
Dev 1996;87:197209.
27. Zhou T, Edwards CK, Mountz JK. Prevention of age-related T cell
apoptosis defect in CD2-fas transgenic mice. J Exp Med 1995;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. Immune
parameters in a longitudinal study of a very old population of Swedish
people: a comparison between survivors and nonsurvivors. J Gerontol
1995;50:B378B382.
32. Remarque E, Pawelec G. T-cell immunosenescence and its clinical relevance in man. Rev Clin Gerontol 1998;8:514.
33. Butcher SK, Lord JM. Stress responses and innate immunity: aging as a
contributory factor. Aging Cell 2004;3:151160.
34. Meyer KC, Ershler W, Rosenthal N, Lu X, Peterson K. Immune dysregulation in the aging human lung. Am J Respir Crit Care Med 1996;153:
10721079.
35. Meyer KC. Neutrophils and low-grade inammation in the seemingly
normal aging human lung. Mech Aging Develop 1998;104:169181.
36. Meyer KC, Soergel P. Bronchoalveolar lymphocyte phenotypes change
in the normal aging human lung. Thorax 1999;54:697700.

PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY

VOL 2 2005

37. Thompson AB, Scholer SG, Daughton DM, Potter JF, Rennard SI.
Altered epithelial lining uid parameters in old normal individuals.
J Gerontol 1992;47:M171M176.
38. Meyer KC, Cardoni A, Xiang Z. Vascular endothelial growth factor in
bronchoalveolar lavage from normal subjects and patients with diffuse
parenchymal 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 Cell
2004;3:161167.
40. Boehmer ED, Goral J, Faunce DE, Kovacs EJ. Age-dependent decrease
in Toll-like receptor 4-mediated proinammatory cytokine production
and mitogen-activated protein kinase expression. J Leukoc Biol 2004;
75:342349.
41. Koike E, Kobayashi T, Mochitate K, Murakami M. Effect of aging on
nitric oxide production by rat alveolar macrophages. Exp Gerontol
1999;34:889894.
42. Corsini E, Battaini F, Lucchi L, Marinovich M, Racchi M, Govoni S,
Galli CL. A defective protein kinase C anchoring system underlying
age-associated impairment in TNF-alpha production in rat macrophages. J Immunol 1999;163:34683473.
43. Zissel G, Schlaak M, Muller-Quernheim J. Age-related decrease in accessory cell function of human alveolar macrophages. J Invest Med 1999;
47:5156.
44. Corsini E, Di Paola R, Viviani B, Genovese T, Mazzon E, Lucchi L,
Marinovich M, Galli CL, Cuzzocrea S. Increased carrageenan-induced
acute lung inammation 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 innate immunity
predicts frailty in old age. The Leiden 85-plus study. Exp Gerontol
2004;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 elderly humans. J Leukoc Biol 2001;70:881886.
47. De Martinis M, Modesti M, Ginaldi L. Phenotypic and functional changes
of circulating monocytes and polymorphonuclear leucocytes from elderly persons. Immunol Cell Biol 2004;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. Epigenetic
differences arise during the lifetime of monozygotic twins. Proc Natl
Acad Sci U S A 2005;102:1060410609.
49. Laforce FM, Hopkins J, Trow R, Wang WL. Human oral defenses against
gram negative rods. Am Rev Respir Dis 1976;114:929935.
50. Smaldone GC. Deposition and clearance: unique problems in the proximal airways and oral cavity in the young and elderly. Respir Physiol
2001;128:3338.
51. Palmer LB, Albulak K, Fields S, Filkin AM, Simon S, Smaldone GC.
Oral clearance and pathogenic oropharyngeal colonization in the
elderly. Am J Respir Crit Care Med 2001;164:464468.
52. Ayars GH, Altman LC, Fretwell MD. Effect of decreased salivation and
pH on the adherence of Klebsiella species to human buccal epithelial
cells. Infect Immun 1982;38:179182.
53. Shaker R, Staff D. Esophageal disorders in the elderly. Gastroenterol
Clin North Am 2001;30:335361.
54. Shaker R, Ren J, Bardan E, Easterling C, Dua K, Xie P, Kern M.
Pharyngoglottal closure reex: characterization in healthy young, elderly and dysphagic patients with predeglutitive aspiration. Gerontology 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 communityacquired pneumonia. Am J Respir Crit Care Med 1994;150:251253.
56. Matsuse T, Oka T, Kida K, Fukuchi Y. Importance of diffuse aspiration
bronchiolitis caused by chronic occult aspiration in the elderly. Chest
1996;110:12891293.
57. Nakayama K, Jia YX, Hirai H, Shinkawa M, Yamaya M, Sekizawa K,
Sasaki H. Acid stimulation reduces bactericidal activity of surface
liquid in cultured human airway epithelial cells. Am J Respir Crit Care
Med 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 after
intratracheal instillation of Listeria monocytogenes. Chest 2001;120:
240249.
59. Puchelle E, Zahm JM, Bertrand A. Inuence of age on bronchial mucociliary 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,

Meyer: Aging

61.

62.

63.
64.
65.

66.

67.

and ultrastructure of respiratory cilia. Am J Respir Crit Care Med


2001;163:983988.
Rutland J, Penketh A, Grifn WM, Hodson ME, Batten JC, Cole PJ.
Cystic brosis serum does not inhibit human ciliary beat frequency.
Am Rev Respir Dis 1983;128:10301034.
Riquelme R, Torres A, El-Ebiary M, de la Bellacasa JP, Estruch R, Mensa
J, Fernandez-Sola J, Hernandez C, Rodriguez-Roisin R. Communityacquired pneumonia in the elderly: a multivariate analysis of risk and
prognostic factors. Am J Respir Crit Care Med 1996;154:14501455.
Lesourd BM. Nutrition: a major factor inuencing immunity in the elderly. J Nutr Health Aging 2004;8:2837.
Yeh S, Schuster MW. Geriatric cachexia: the role of cytokines. Am J
Clin Nutr 1999;70:183197.
Pamuk ER, Williamson DF, Serdula MK, Madans J, Byers TE. Weight
loss and subsequent death in a cohort of U.S. adults. Ann Intern Med
1993;119:744748.
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 and
rodent: measurements of plasma leptin and ob RNA in obese and
weight-reduced subjects. Nat Med 1995;1:11551161.
Macuso P, Gottschalk A, Phare SM, Peters-Golden M, Lukacs NW,
Huffnagle GB. Leptin-decient mice exhibit impaired host defense in
gram-negative pneumonia. J Immunol 2002;168:40184024.

439
68. Starczewski AR, Allen SC, Vargas E, Lye M. Clinical prognostic indices
of fatality in elderly patients admitted to hospital with acute pneumonia. 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 nursing
homes. CMAJ 2000;162:11331137.
70. Strausbaugh LJ, Sukumar SR, Joseph CL. Infectious disease outbreaks
in 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 in
the elderly. Drugs Aging 2004;21:851864.
72. American Thoracic Society Board of Directors. Guidelines for the management of adults with community-acquired pneumonia: diagnosis,
assessment of severity, antimicrobial therapy, and prevention. Am J
Respir Crit Care Med 2001;163:17301754.
73. Ortqvist A. Pneumococcal vaccination: current and future issues. Eur
Respir J 2001;18:184195.
74. Dear K, Holden J, Andrews R, Tatham D. Vaccines for preventing
pneumococcal infection in adults. Cochrane Database Syst Rev 2003;
4:CD000422.
75. Sisk JE, Whang W, Butler JC, Sneller V, Whitney CG. Cost-effectiveness
of vaccination against invasive pneumococcal disease among people
50 through 64 years of age: role of comorbid conditions and race. Ann
Intern Med 2003;138:960968.