Infection and immune response in the elderly

Infection

and Immune

Philip W. Smith,

Response

MD, J ane S. Roccaforte,

in the Elderly MD, and Pamela B. Daly, PhD

A number of immunologic functions have been shown to decline in an age-related fashion, particularly cell-mediared immunity and antibody response to an immunogen. Underlyingdegenerative diseases and medications further contribute to the immunologic abnormalities noted in the elderly. The elderly in hos@als and nursing homes are a particularly vulnerable subset, with a high incidence of institutionally acquired infection. Aspects of disease prevention in the elderly are discussed. Ann Epidemiol 1992;2:813-822. KEY WORDS:

Elderly, immunity,

infection, immunosenescence.

INTRODUCTION elderly have been shown to have an increased incidence of many infectious diseases, accompanied by increases in morbidity and mortality. Factors contributing to this phenomenon include an age-related decline in immunologic function, breaches in local defenses, malnutrition, and the effects of a number of age-related underlying diseases.

The

IMMUNITY

IN THE ELDERLY Several studies have evaluated the phenomenon of immunosenescence (Table 1). Investigators agree that with age there is a measurable decline in both T-lymphocyte and antibody function, while polymorphonuclear leukocyte (phagocytic) function and serum complement levels are relatively unaffected.

Cell-Mediated Immunity Although there have been inconsistent findings among studies of circulating T-lymphocyte numbers in the elderly, studies are in agreement that lymphocyte function does diminish with age, including decreased proliferation and synthesis of interleukin-2, ( 1, 2). Elderly individuals have also been found to react to fewer cutaneous hypersensitivity antigens (3). In one study, decreased reaction to skin test antigens was associated with increased mortality in a nursing home population (4); the surviving and the deceased resident groups had similar mean ages, but the study did not control for underlying conditions. These findings must be interpreted with caution since they employ cross-sectional designs that limit the generalizability of their findings. One particularly intriguing longitudinal study of 105 healthy elderly men described a statistically significant correlation between a decline in absolute number of peripheral

From Clarkson Hospital (P.W.S.), Immanuel Medical Center (J.S.R.), and the Department of Internal Medicine (P.W.S., J.S.R.) and Meyer Rehabilitation Institute (P.B.D.), University of Nebraska Medical Center, Omaha, NE. Address reprint requests to: Philip W. Smith, MD, Associate Professor, Department of Internal Medicine, University of Nebraska Medical Center, 4242 Famam Street, Omaha, NE 68131. Received February 8, 1991; revised June 28, 1991. 0 1092 Elzevier Science Puhlishmg Co., Inc.

1047-27971921$05.00

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Smith et al. INFECTION

AND IMMUNE RESPONSE

TABLE

1

Immunologic

function

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IN THE ELDERLY

in the elderly

Immune parameter T-lymphocyte function Cell-mediated immunity Serum antibody levels Antibody response to immunization or infection Complement activity White blood cell activity Febrile response to infection

Age-related change

References

Decreased Decreased Variable Decreased

I,2 384 5

Stable Stable Decreased

5

637

58 9

blood lymphocytes and subsequent death (10). This population did not die primarily from infectious diseases; rather, the causes of death were similar to those in the general population, with a predominance of cardiovascular deaths. In this study (lo), as in the nursing home anergy study (3), the authors concluded that the immunologic abnormality appears to be a marker for failing health rather than a predictor of an impending infectious disease. While the study did control for smoking history and the presence of heart disease (lo), a study controlling for all significant confounding variables has not yet been done.

Antibody Production B-lymphocyte numbers and antibody function decline with age, although they appear to be less profoundly affected than the T-lymphocyte line. The various antibody classes are affected differently by the aging process. Serum IgM levels decrease with age, although total serum IgA and IgG levels are relatively unchanged (5). Antibody function is more profoundly affected than measurements of total circulating serum IgG suggest. Less antibody is produced appropriately in response to an antigen (6, 7), thus placing the individual at increased risk of infection with encapsulated bacteria (e.g., Streptococcus pneumonias). As might be expected, the elderly also make less antibody in response to immunization with vaccines such as tetanus toxoid and the pneumococcal vaccine (6).

Other Immunologic Functions In general, the number of polymorphonuclear leukocytes in the elderly is unchanged and phagocytic function is relatively normal, although minor age-related dysfunctions have been detected (8). Although data are quite limited, the elderly do not appear to have an age-related complement dysfunction (5). The elderly frequently have an absent or blunted febrile response to infection, yet another manifestation of immunosenescence (9).

Local Defenses Local defenses play an important role in protecting the host from infection, but are more difficult to quantify for analysis of age-related changes. For example, the decrease in gastric acidity noted in the elderly is believed to predispose them to gastrointestinal infections (11). Age-associated decreases in respiratory mechanics, mucociliary transport, and bacterial clearance contribute to the increased incidence of and mortality rates for pneumonia in the elderly (12). Age-associated changes in the skin of the elderly include thinning of the skin, loss of dermal thickness, and reduction in vascular

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TABLE

INFECTION

2

Infections

of major

AND IMMUNE RESPONSE

importance

Smith et al. IN THE ELDERLY

815

in the elderly

Pneumococcal pneumonia Tuberculosis Influenza Urinary tract infections Bacteremia Intra-abdominal infections Skin and soft tissue infections Herpes zostet Hospital-acquired infections Nursmg home-acquired infections

supply (13). These factors predispose to breaks in the skin, poor wound healing and secondary infections.

EFFECTS

OF UNDERLYING

DISEASES

(14),

ON IMMUNITY

A variety of underlying degenerative diseases that occur with increased frequency in the elderly further predispose to infectious diseases, and are a major confounder in research and clinical efforts to distinguish between immune depression due to aging and that due to illness. Patients with chronic bronchitis or obstructive pulmonary disease are at risk of pulmonary infections because of impaired bacterial clearance mechanisms. Other local conditions (pulmonary neoplasm) and diseases of mentation (dementia) also predispose the elderly to bacterial pneumonia (15). Atherosclerosis and venous insufficiency are risk factors for skin breakdown and secondary infection; the demented patient is particularly at risk for pressure sores or decubitus ulcers ( 11). Diabetes mellitus is associated with an increased incidence of a number of infectious diseases due to the adverse metabolic effects of diabetes on white blood cells or end-organ complications such as diabetic neurogenic bladder (16). Malnutrition, a common state in the elderly, diminishes T-lymphocyte function, making it another factor contributing to the susceptibility of the elderly to infection (17). Finally, the elderly often take a variety of medications, some of which alter immune responsiveness (18). Examples include corticosteroids (decreased T-lymphocyte function), chemotherapeutic drugs (decreased T-lymphocyte function and numbers of circulating polymorphonuclear leukocytes), and antibiotics (suppression of the body’s normal protective bacterial flora).

INFECTIOUS

DISEASES

IN THE ELDERLY

A wide variety of infectious diseases occur more commonly in the elderly ( 11, 18, 19); some of the most important of these are listed in Table 2. Although population-based data on the relative incidence of various infections in the elderly are lacking, some data are available on serious infections requiring hospitalization in this age group. Two studies of elderly patients admitted to hospitals from nursing homes and the community found the most common cause of transfer to the hospital to be infectious diseases, especially pneumonia, urinary tract infections, skin infections, and gastroenteritis (20, 21).

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The most common cause of pneumonia in the elderly is S. pneumoniae. The mortality rate from pneumococcal pneumonia and bacteremia is increased in the elderly compared to younger populations (22, 23). Finkelstein and colleagues (22) found a 44% mortality rate for pneumococcal bacteremia in patients over 65 years old compared to 14% in patients aged 20 to 49 years. This is not unexpected in view of the fact that the immune response to the pneumococcus is primarily antibody-mediated, and antibody function declines with age. The prevalence of tuberculosis increases steadily with age (24). This is due in part to the accumulation of patients with positive tuberculosis skin test results, who tend to remain skin test-positive for life. The majority of patients with active, clinical tuberculosis are older adults; the immunologic impairment in the elderly described above predisposes to reactivation of latent tuberculosis. The highest mortality rates for influenza occur in infants and in the elderly (25). The excess hospitalization and mortality rates from influenza have been noted for elderly both with and without underlying high-risk disorders such as emphysema or heart disease (26). Influenza and pneumonia together are the leading cause of excess seasonal mortality among the elderly. The prevalence of urinary tract infections increases gradually with age in women, but rises rather sharply after age 50 in men (27). These changes reflect age-related risk factors. Incontinence and diabetes predispose to urinary tract infection, and underlying conditions such as neurogenic bladder may require the placement of indwelling urinary catheters, a major risk factor for infection. In elderly men, prostatitis is common and is the leading antecedent to urinary tract infection. Bacteremia, or bloodstream infection, is an important cause of morbidity in the elderly, and is associated with a higher mortality rate in this population (28, 29). McCue found a mortality rate of 9.1% in a group of patients aged 70 and older with nonfatal and ultimately fatal underlying diseases, compared to 2.9% in a similarly classified group of patients under 70 years old, a statistically significant difference. No significant difference was seen between the two age groups in patients with rapidly fatal underlying diseases (28). Bacteremia is frequently related to an intra-abdominal perforated gastric ulcer, diverticulitis, infection, and diseases such as cholelithiasis, and ischemic bowel disease are common problems in the elderly (18). Skin and soft tissue infections are common in the elderly. Two reasons for this include

age-associated

an entry elderly

point

individuals

the incidence

changes

for bacteria,

with mental

of another

without

diseases

NOSOCOMIAL

INFECTIONS

Hospital-Acquired

to breaks (pressure

There

Examples

that include

in the skin,

sores),

is a direct

seen

normal

and increas-

prevents

syncytial

in

between

is the reappearance

immunity

respiratory

providing

primarily

correlation

herpes zoster (shingles),

of immunosenescence

diseases

type b disease

IN THE

ulcers

changes.

manifestation

disorders.

influen~uae

predispose

skin infection,

in the elderly,

underlying

Haemo&ilus

status

important

ing age (30). Finally, an intriguing childhood

(13) that

and decubitus

virus

of

in adults (31) and

(32).

ELDERLY

Infections

Those in the geriatric age group are particularly susceptible to institutionally acquired (nosocomial) infection; approximately two-thirds of all nosocomial infections at a New Jersey medical center occurred in those over 60 years old (33). The decade-specific

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risk of nosocomial infection has been found to be constant up to the age of 49 but thereafter rises logarithmically to a peak of greater than 100 nosocomial infections per 1000 hospital discharges after 70 years (33). Thus, the patient over 70 years old has a tenfold greater risk of nosocomial infection than the patient between the ages of 40 and 50 years. This increased incidence of nosocomial infections by decade has been noted for virtually all infection sites including the urinary tract, the respiratory tract, surgical wounds, and the bloodstream (33-35). Several studies have examined the effect of age on nosocomial infection rate per hospital day, to control for the longer length of stay experienced by the elderly. Freeman and McGowan found that age was a significant risk factor for nosocomial infection, with age greater than 65 years having a relative risk of nosocomial infection per hospital day of 2.9 (36). Saviteer and associates (37) demonstrated a steadily increasing nosocomial infection rate with increasing age, with a relative risk of 1.49 (95% confidence interval, 1.40 to 1.59) for patients over the age of 60. The authors further examined the risk of infection for specific hospital days by using life-table techniques, and noted that the increased infection rate for patients over 60 did not become significant until the eighth hospital day. Goonatilake developed a mathematic model depicting the relationship between age and nosocomial infection, and found a good fit between the model and postoperative wound infection rates (correlation coefficient R = 0.97). The model depicted a log-linear relationship between wound infection rate and patient age that was independent of patient-related parameters such as sex and type of operation (38). The elderly have not only a disproportionate share of nosocomial infections, but also a disproportionate share of the mortality attributable to nosocomial infections. Based on data from national discharge and infection surveillance, patients 65 years and older account for approximately 34% of hospital discharges, 46% of nosocomial infections, and 55% of total deaths caused by nosocomial infections (35).

Nursing Home-Acquired

Infections

The elderly in nursing homes constitute a subset of individuals who are immunologically compromised compared to the elderly in the community. The median age of nursing home residents is 85, and most surveys show that these residents have an average of three to four underlying diseases that increase their susceptibility to infection (39). Demographic information on infections in nursing homes comes from a number of incidence and prevalence surveys, revealing infection rates of 2.7 to 32.7 infections per 100 resident months or 2.6 to 6.7 infections per 1000 resident days (40-53). Rates have varied widely because of differences in definitions of infection, data collection protocols, and nursing home resident acuity levels. The leading nosocomial infections in nursing homes are (a) urinary tract infections (usually related to an indwelling urinary catheter), (b) respiratory tract infections (especially pneumonia, influenza, and tuberculosis), (c) soft tissue infections (especially infected pressure sores or decubitus ulcers), and (d) infectious gastroenteritis. Epidemic infectious diseases are frequent in this setting, particularly outbreaks of tuberculosis, influenza, infectious gastroenteritis, conjunctivitis, and scabies (39). When considering the predisposition of the elderly to infections acquired in the nursing home, it is difficult to dissociate the effect of immunosenescence from the effect of underlying diseases. There is a clinical impression that the contributions of underlying diseases and breaks in local defenses (indwelling urinary catheters, intravenous catheters, and pressure sores) are more important than the age-related decline significant in immunologic function (11). Several authors have found statistically

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correlations between resident factors (immobility, age, diabetes, incontinence, indwelling urinary catheter, antibiotic administration prior to infection) or institutional factors (staff absenteeism) and infection risk (45, 46, 48, 49, 52). Nevertheless, there are no data dissociating the effects of the various factors, nor is there a model to identify factors that predict infection risk in this setting.

ASPECTS

OF DISEASE

PREVENTION

The elderly are among the primary target groups for appropriate immunizations, including tetanus/diphtheria (administered every 10 years), pneumococcal vaccination (administered one time only), and influenza vaccination (administered annually). These immunizations are widely recommended, safe, and relatively inexpensive, although the antibody response of elderly persons to the vaccines may be suboptimal (18). An analysis of the efficacy of the two most important vaccines for the elderly underscores the problems of clinical stratification and measurement. Initial trials of pneumococcal vaccine that demonstrated vaccine efficacy were conducted with South African gold miners with extraordinarily high attack rates of pneumococcal pneumonia (54). Studies in the United States have been hampered by lower attack rates for pneumococcal pneumonia, the difficulty in making a precise diagnosis of pneumococcal pneumonia (54)) and controversy regarding the best method for measuring antibody response to the vaccine (55). Most recent studies of the vaccine have shown significant clinical efficacy (56-59), but other studies have not demonstrated efficacy (60, 61). Controlling for age, immune status, underlying diseases, and prior antibody (immunity) in vaccine studies is very difficult. Studies on the efficacy of influenza vaccine in the elderly have also found conflicting results, although the vaccine is strongly recommended for the elderly by the Immunization Practices Advisory Committee (62). The vaccine appears most efficacious in the nursing home setting, where herd immunity is a factor in prevention of epidemics (63-65). Varying measures of influenza vaccine efficacy have been used and include serum antibody levels after vaccination, reduction in length of illness, reduction in necessity of hospitalization, incidence of secondary pneumonia, and mortality (65). One of the areas where the physician may have the greatest clinical impact on infection prevention is the treatment of underlying diseases. A number of conditions that alter resistance to infection in the elderly, including diabetes mellitus, congestive heart failure, pressure sores, incontinence, malnutrition, and dehydration, are amenable to therapy. In addition, the physician may have control over medications and dietary habits that can impair the immune system in elderly individuals. Measures to enhance immune response in the elderly, such as injection of thymic hormones, are experimental and technically problematic at present (66). Prompt treatment of infections is important in the elderly because of the increased morbidity and mortality for many infectious diseases, but diagnosis may be difficult because of atypical clinical presentations in this age group. Therapeutic intervention has the additional public health benefit of preventing spread of a pathogen in the population by controlling the animate reservoir of the infectious agent. Overutilization of antimicrobials, a common phenomenon (67), has an adverse impact on the individual patient (by eliminating protective bacterial flora) and on public health (by selecting more resistant bacteria). Finally, one needs to address the control of cross-infection. Infection control

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programs in hospitals and nursing homes deal with such issues as isolation, handwashing, and air filtration. In a well-controlled, large-scale study, active hospital infection control programs with qualified staff were found to have a significant effect on lowering hospital infection rates (68). Analogous measures in the community, including handwashing and limiting exposure of the elderly to individuals with known infectious diseases, are logical but of unproved benefit.

CONCLUSION A number

of studies have described the infections that occur in the elderly in the community, hospital, and nursing home. Early work is being done on immunosenescence, specific risk factors for infection in the elderly, and preventive interventions (especially vaccines). While both diminished immune competence and increased incidence of infections are correlated with advancing age, no consistent causative factor has yet been identified. Conflicting findings among studies-particularly investigations of cell-mediated immunity changes-may be due to the prevalence of crosssectional designs with subject selection limitations that bias findings. More epidemiologic studies need to be conducted with larger numbers of subjects who are carefully characterized and stratified according to age, health status, and environmental and genetic histories to better identify confounding and effect-modifying variables.

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14. Stromberg 15. Verghese 1983;62:271-83.

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BV. Wound healing in the elderly, Geriatr Med Today. 1989;8:93-7. A, Berk SL. Bacterial pneumonia in the elderly, Medicine.

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case for glucose

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42. Garibaldi RA, Brodine A, Matsumiya S. Infections among patients in nursing homes-policies, prevalence, and problems, N Engl ] Med. 1981;305:731-5. 43. Gambert SR, Duthie EH Jr, Priefer B, Rabinovitch RA. Bacterial infections in a hospital-based skilled nursing facility, J Chronic Dis. 1982;35:781-6. 44. Farber BF, Brennen C, Puntereri A], Brody JP. A prospective study of nosocomial infections in a chronic care facility, J Am Geriatr Sot. 1984;32:499-502. 45. Nicolle LE, McIntyre M, Zacharias H, MacDonell JA. Twelve-month surveillance of infections in institutionalized elderly men, J Am Geriatr Sot 1984;32:513-9. 46. Standfast SJ, Michelsen PB, Batch AL, et al. A prevalance survey of infections in a combined acute and long-term care hospital, Infect Control. 1984;5:177-84. 47. Price LE, Sarubbi FA Jr, Rutala WA. Infection control programs in twelve North Carolina extended-care facilities, Infect Control. 1985;6:437-41. 48. Setia U, Serventi I, Lorenz P. Nosocomial infections among patients in a long-term care facility: Spectrum, prevalence, and risk factors, Am J Infect Control. 1985;13:57-62. 49. Franson TR, Duthie GH Jr, Cooper JE, Oudenhoven EV, Hoffmann RG. Prevalence survey of infections and their predisposing factors at a hospital-based nursing home care unit, J Am Geriatr Sot. 1986;34:95-100. 50. Scheckler WE, Peterson PJ. Infections and infection control among residents of eight rural Wisconsin nursing homes, Arch Intern Med. 1986;146:1981-4. 51. Alvarez S, Shell CG, Woolley TW, Berk SL, Smith JK. Nosocomial infections in long-term facilities, J Gerontol. 1988;43:M9-17. 52. Hoffman N, Jenkins R, Putney K. Nosocomial infection rates during a one-year period in a nursing home care unit of a Veterans’ Administration hospital, Am J Infect Control. 1990;18:55-63. 53. Jacobson C, Strausbaugh LJ. Incidence and impact of infection in a nursing home care unit, Am J Infect Control. 1990;18:151-9. 54. LaForce FM, Eickhoff TC. Pneumococcal vaccine: The evidence mounts, Ann Intern Med. 1986; 104: 110-2. 55. Musher DM, Luchi MJ, Watson DA, et al. Pneumococcal polysaccharide vaccine in young adults and older bronchitics: Determination of IgG responses by ELISA and the effect of absorption of serum with non-type-specific cell wall polysaccharide, J Infect Dis. 1990;161:728-35. 56. Shapiro ED, Clemens JD. A controlled evaluation of the protective efficacy of pneumococcal vaccine for patients at high risk of serious pneumococcal infections, Ann Intern Med. 1984;101:325-30. 57. Bolan G, Broome CV, Facklam RR, et al. Pneumococcal vaccine efficacy in selected populations in the United States, Ann Intern Med. 1986;104:1-6. 58. Sims RV, Steinmann WC, McConville JH, et al. The clinical effectiveness of pneumococcal vaccine in the elderly, Ann Intern Med. 1988;108:653-7. 59. Gable CB, Holzer SS, Engelhart L, et al. Pneumococcal vaccine-Efficacy and associated cost savings, JAMA. 1990;264:2910-5. 60. Simberkoff MS, Cross AP, Ibrahim M, et al. Efficacy of pneumococcal vaccine in high-risk patients-Results of a Veterans’ Administration cooperative study, N Engl J Med. 1986;315:1318-27. 61. Forrester HL, Jahnigen DW, LaForce FM. Inefficacy of pneumococcal high risk population, Am J Med. 1987;83:425-30. 62. Prevention and control of influenza, MMWR. 1990;39:1-15.

vaccine in a

63. Patriarca PA, Weber JA, Parker RA, et al. Efficacy of influenza vaccine in nursing homes-Reduction in illness and complications during an influenza A (H3N2) epidemic, JAMA. 1985;253:1136-9. 64. Gross PA, Quinnan GV, Rodstein M, et al. Association of influenza immunization with reduction in mortality in an elderly population-A prospective study, Arch Intern Med. 1988;148:562-5.

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65. Cartter ML, Renzullo PO, Helgerson SD, et al. Influenza outbreaks in nursing homes-How effective is influenza vaccine in the institutionalized elderly?, Infect Control Hosp Epidemiol. 1990; 11:473-8. 66. Felser JM, Raff MJ. Infectious diseases and aging: Immunologic perspectives, J Am Geriatr Sot. 1983;31:802-6. 67. Levy SB. Antibiotic resistance, Infect Control. 1983;4:195-7. 68. Haley RW, Culver DH, White JW, et al. The efficacy of infection surveillance and control programs in preventing nosocomial infections in US hospitals, Am J Epidemiol. 1985;121:182-205.