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The Second Fifty Years: Promoting Health and Preventing Disability 5 Risk Factors for Infection in the Elderly There appears to be a direct relationship between increasing age and susceptibility to infections, although the documentation is weak for many specific infectious diseases.18,47,55 Factors that may contribute to the predisposition of the elderly to infections include impaired immune function,47,55 anatomic and functional changes,8 and degree of exposure to infections. Certain infections are important risk factors for the elderly because the illnesses they cause reduced quality of life during the infection and are at times fatal. The environment of an elderly individual can also influence his or her exposure to infections, with long-term care facilities28 and hospitals47 bringing greater risk than living at home. Data on community-acquired infections (i.e., acquired in "the community" rather than in institutions) are more limited than data from institutional settings.47 The range of infections that present serious risks for the elderly is great and includes the following: respiratory infections including pneumonia,17 influenza,47 and tuberculosis;18 bacteremia;18 and nosocomial (hospital-acquired) infections.47 Other types of infections also have been cited as particular problems for the elderly including urinary tract infections, salmonellosis, and hepatitis.18 Undoubtedly, there are other infectious diseases that present risks for the elderly, but limited data preclude their identification at this time. Given existing knowledge of the burdens caused by infections and the limited range of current preventive measures, only a few of the infection categories mentioned above can be given priority for
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The Second Fifty Years: Promoting Health and Preventing Disability prevention at the present time. Thus, in this chapter, the committee has chosen to highlight pneumococcal infections, influenza, and nosocomial infections. Each deserves high priority for prevention because each is a serious risk factor for the elderly and can be prevented to a great extent with existing interventions. PNEUMOCOCCAL DISEASE Pneumococcal disease has long been recognized as an important risk factor for the elderly. This category includes pneumonia, bronchitis, bacteremia, and meningitis caused by any one of the 83 serotypes of Streptococcus pneumoniae. Pneumococcal pneumonia is the most common form of community-acquired pneumonia in the elderly, accounting for up to 60 percent of cases14,34,35,36,37,52 and for up to 20 percent of nosocomial pneumonias.10,52 Pneumococcal bacteremia, which is more easily proven than pneumococcal pneumonia, occurs in up to one-quarter of cases of pneumococcal pneumonia. Population-based studies have shown that the elderly sustain the highest pneumococcal bacteremia rates of any population group—50 per 100,000 persons over the age of 65,36,37 which is more than three times greater than the rates for younger persons. The costs of pneumococcal diseases are great because the elderly require hospitalization and the illnesses often cause complications.26,32 Although pneumococcal pneumonia does not result in permanent lung damage, complications from bacteremia and meningitis are common and can damage other organ systems. Death rates from pneumococcal bacteremia range from 20 to 80 percent, increasing with age and complications.10,26,36,37 Although antibiotics are considered to be effective in the treatment of pneumococcal diseases, deaths and complications often occur despite the prompt use of effective antibiotics. Further reductions in morbidity and mortality from pneumococcal diseases require that preventive measures be used. Pneumococcal polysaccharide vaccine is the only currently available preventive measure. This vaccine was first developed in the 1940s but was temporarily abandoned with the advent of antibiotics. With growing recognition of the limitations of antibiotics, the vaccine was again introduced in the late 1970s. Some of the controlled studies of the vaccine have not demonstrated a protective effect;16,48 other research, including case-control studies, have shown pneumococcal vaccine to be both immunogenic43,44 and safe,15 and to provide up to 70 percent efficacy in the elderly.50,51 A vaccine works by providing protective levels of type-specific antibodies. Confidence in the effectiveness of the current 23-valent pneumococcal
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The Second Fifty Years: Promoting Health and Preventing Disability polysaccharide vaccine—that is, the assurance factor for its efficacy—is high. This vaccine has also been judged most useful for the elderly in terms of cost-effectiveness and has been recommended for all elderly persons by the Centers for Disease Control as well as the American College of Physicians.11,40,42,53 The committee thus recommends that 23-valent vaccine be given to all elderly persons, particularly those 65 years of age or older. Because antibodies resulting from vaccine are long-lasting, the vaccine will only need to be given once to most persons. It should be strongly considered for anyone 50 years of age or older with underlying disease (e.g., a heart condition). Revaccination should be considered for elderly persons who received only 14-valent vaccine. Medicare Part B currently pays for the vaccine and the costs of administration, but there has been little promotion of this benefit and many are unaware of its existence. Because pneumococcal vaccine is less effective in immunosuppressed persons, the committee urges that more immunogenic vaccines be developed. (The conjugated H. influenza vaccine currently available could be used as the prototype.) There is also a great need for more education of physicians, public health agencies, and the elderly themselves regarding the benefits of pneumococcal vaccine. Medicare should promote the vaccine more actively (an individual's Medicare card could indicate whether he or she had received the vaccine), and industry and government should promote or conduct research aimed at improving the existing versions. There should also be incentives provided by third-party payers for persons to be immunized. Giving vaccine on entry to long-term care or at the time of discharge from a hospital are other ways to increase the vaccine's use. INFLUENZA Influenza, a respiratory infection caused by any of the strains of the antigenically variable influenza A and B viruses, is one of the major risk factors for the elderly. Influenza epidemics occur every year, usually during the winter months. Estimates of the costs of such epidemics cite staggering figures derived from medical costs, hospitalizations, loss of productivity, and mortality.30,31,54 Household survey data suggest that influenza leads all other illness categories in terms of restricted activity and bed days,1 whereas viral surveys have demonstrated that the elderly consistently have the highest hospitalization and death rates from influenza of any population group.3,5,6,7,13,20,33,41 Even in winters with ''limited" influenza activity, there are more
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The Second Fifty Years: Promoting Health and Preventing Disability than 20,000 excess deaths from influenza in the United States, 80 to 90 percent of which occur among the elderly. Influenza can lead to such complications as pneumonia, both viral and bacterial, and cardiac respiratory failure. It can also aggravate preexisting conditions such as diabetes or asthma. Lengthy periods are needed to recover from influenza. Morbidity and mortality from influenza are largely unnecessary because effective preventive measures in the form of safe, effective vaccines became available in the late 1960s. Modern vaccines are trivalent, with two type A and one type B strains, and contain egg-grown viruses. (Vaccines are contraindicated in persons allergic to eggs.) All current influenza vaccines contain only inactivated (killed) viruses and must be given every year because of changing viruses and declining antibody levels. In field studies, vaccines have proven to be approximately 70 percent effective in preventing influenza illness, with the remaining 30 percent of vaccinees suffering a milder illness than that acquired by unvaccinated persons. Vaccines are effective in elderly persons living in the community24, 27 as well as those in long-term care,38, 39 although they are less immunogenic in the immunosuppressed elderly. For immunized immunosuppressed persons and for persons unable to take vaccines, antiviral prophylaxis or treatment (or both) with amantadine is effective against influenza A strains.2 However, vaccines are the only protection against type B influenza viruses. Influenza vaccine can be effectively given even during an epidemic if the vaccinee is also given prophylactic doses of amantadine for the 14 days required for vaccine-induced antibodies to develop. The assurance factor for influenza vaccines and the antiviral amantadine is high. The costs and benefits of influenza vaccine have been estimated. 30,31,54 Because vaccines, although safe and relatively inexpensive, must be given to millions of high-risk elderly each year, it was concluded that influenza vaccines were not cost-saving. They were considered cost-effective, nevertheless, because they produced substantial health benefits for low unit costs.30,31,54 The committee strongly endorses the use of influenza vaccine and, where indicated, amantadine for the elderly. Amantadine should be used as prophylaxis during epidemics for persons allergic to eggs. The committee also considers the recent Health Care Financing Administration (HCFA) initiative (to conduct pilot studies for determining whether Medicare should fund influenza immunization) to be a positive step. (Presumably, if the pilot studies can demonstrate cost reductions for Medicare claims, HCFA will deem influenza vaccine to be beneficial and affordable.) Furthermore, the
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The Second Fifty Years: Promoting Health and Preventing Disability committee urges increased education for the elderly, for physicians and other health care workers, and for persons having close contact with the elderly regarding the safety and benefits of influenza vaccine. In short, the committee believes health policymakers should recognize the severe impact of influenza and its preventability. Much research is needed to improve existing means of controlling influenza. There are currently several candidate live virus vaccines that are safe, easy to administer, and capable of longer-lasting protection. However, resources are required to conduct the necessary large-scale trials prior to licensure. In addition, better antiviral drugs are needed. Rimantadine,38 a derivative of amantadine that is safer for the elderly and easier to use, should be made available. An antiviral agent effective against influenza B virus is also needed. Innovative means are required to make delivery of the current vaccines easier. Regardless of the delivery means or vehicle used, however, influenza vaccines should be required for all nursing home residents and personnel and should be given to any elderly person discharged from the hospital during the fall or winter.* Influenza and pneumococcal vaccines should be promoted together because unlike some combinations they are still safe and effective when given simultaneously. The promotion and marketing of such vaccines by the pharmaceutical industry would be helpful. NOSOCOMIAL INFECTIONS Nosocomial infections are infections of any type that are not present on admission to a hospital but develop after the third hospital day. They are unlike the previous risk factors discussed in this chapter in that they are not one specific infection; nevertheless, they constitute an important risk for the elderly. The incidence of nosocomial infections is greater in the elderly than in any other population groups; the elderly have the highest rates of nosocomial urinary tract infections, infected surgical wounds, and nosocomial pneumonia and bacteremia.17,23,25,46 In addition, the incidence rates for these infections increase with each day in the hospital.45 The costs resulting from nosocomial infections are also great because they prolong hospital stays and often require separate treatment.9,51 These infections cause severe morbidity and may result in death.21,22 Much progress has been made in preventing nosocomial infections, * For elderly individuals living at home, vaccines also should be administered to their contacts (e.g., children, grandchildren, or household contacts who could expose the elderly person to influenza).
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The Second Fifty Years: Promoting Health and Preventing Disability which contributes not only to the health of patients but also to cost-effective health care provision. Rigorous infection control practice emphasizes infection surveillance, isolation practices, handwashing, sterile techniques, and other procedures, all of which can reduce the occurrence and spread of nosocomial infections.29 Many of these practices are appropriate for long-term care facilities as well. The trend toward shortened hospital stays and outpatient alternatives to hospitalization has reduced the opportunity for nosocomial infections to occur. In addition, the assurance factor for good infection control practice is very high. INFECTIONS IN LONG-TERM FACILITIES Preventing nosocomial infections in long-term care facilities is a challenge, in large part because discharging patients is not an option for control. The vaccines mentioned above for influenza and pneumococcal disease, as well as good infection control practice, are crucial for the prevention of infection in nursing homes. Other preventive measures in long-term care include ongoing surveillance to identify problems, monitored hygienic practices in the kitchen to avoid salmonella and other diarrheas, skin care to avoid decubitus ulcers, and proper use of Foley catheters. Proper protective isolation is needed for anyone with infectious diarrhea. In instances in which tuberculosis has been recognized, tuberculin skin testing of residents and staff is needed to identify the spread of infection; in addition, isoniazid prophylaxis should be considered for infected persons. *The two-step tuberculin test is needed for most persons over age 50. The administration of tetanus vaccine should be considered for injury-prone residents as most elderly individuals have not been previously immunized.† The committee recommends that accrediting agencies require the institution of proper infection control practices as part of nursing home licensure standards. In addition, efforts should continue to avoid unnecessary hospitalizations and to encourage shorter hospital stays. Research into ways to reduce infection in long-term care facilities is also needed, as are standards for infection control. * Tuberculosis can present as a pneumonia; therefore, any pneumonia in the long-term care setting should be considered potentially as a case of tuberculosis. Skin testing should utilize the two-step technique if negative on the original test. Employees in long-term care should be screened for tuberculosis. † Methicillin-resistant Staphylococcus aureus infections are becoming more common in nursing home patients, requiring vancomycin treatment when these infections cause disease. Unfortunately, prevention of these infections has been an elusive goal and remains problematic.
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The Second Fifty Years: Promoting Health and Preventing Disability OTHER INFECTIONS The infections discussed thus far—pneumococcal disease, influenza, and nosocomial infections—deserve priority among prevention efforts for the elderly because they are risk factors with known prevalence and with severe impacts; moreover, they have well-understood prevention methods with high assurance factors. Other high-risk infections also deserve some mention, however.12,19 For example, tuberculosis remains a problem for elderly individuals. Detecting cases in the older population is difficult; in addition, isoniazid prophylaxis has greater risks for the elderly than for younger persons. Safer preventive therapy and better early case detection is particularly needed for older individuals. Fever of unknown origin is not unusual for the elderly and often results in lengthy and costly evaluations. More expedient and less expensive methods of diagnosing the causes of such fevers are needed. Infectious diarrhea, endocarditis, meningitis, urosepsis, and pressure sores are other examples of infections in the elderly for which better methods of prevention are needed. Any elderly person with valvular heart conditions known to predispose an individual to endocarditis should receive antibiotic prophylaxis for any procedure known to cause bacteremia. All elderly individuals with a known risk factor for the acquired immune deficiency syndrome (AIDS) (e.g., homosexuality, intravenous drug abuse, prior blood transfusions, or hemophilia) should be screened and counseled about human immunodeficiency virus infection. RECOMMENDATIONS Services All elderly persons, particularly those aged 65 and older, should receive 23-valent pneumococcal polysaccharide vaccines. Revaccination of elderly persons should be considered for those who have received only 14-valent pneumococcal vaccine. All persons aged 65 and over should receive influenza vaccination annually. Consideration should be given to using amantadine as prophylaxis for those individuals with an allergy to eggs. Pneumococcal and influenza vaccines should be given to all nursing home residents. Vaccination should be considered for all elderly persons discharged from hospitals during the fall and winter. Good infection control practices should be implemented in all institutions but especially in long-term care facilities to combat nosocomial infections. Accrediting agencies should demand proper infection control practices for nursing home licensure.
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The Second Fifty Years: Promoting Health and Preventing Disability Research Industry and government should promote or conduct research to improve existing pneumococcal and influenza vaccines. Because these vaccines are less effective in immunosuppressed persons, special attention should be given to improving their immunogenicity. More research is needed to develop better antiviral drugs. Education Medicare should promote the use of pneumococcal and influenza vaccines more actively. Because these vaccines can be administered safely and effectively at the same time, they should be promoted jointly. Programs should be developed to educate physicians, public health agencies, and the elderly themselves regarding the benefits of the vaccines. REFERENCES 1. Adams, P. F. Acute conditions and restricted activity during the 1985-86 influenza season. National Center for Health Statistics, Advance Data No. 132, pp. 1-4, 1987. 2. Arden, N. H., Patriarca, P. A., Fasano, M. B., Liu, K. J., Harmon, M. W., Kendal, A. P., and Rimland, D. The roles of vaccination and amantadine prophylaxis in controlling an outbreak of influenza A(H3N2) in a nursing home. Archives of Internal Medicine 1988; 148:865-868. 3. Barker, W. H., and Mullooly, J. P. Influenza vaccination of elderly persons: Reduction in pneumonia and influenza hospitalizations and deaths. Journal of the American Medical Association 1980; 244:2547-2549. 4. Barker, W. H., and Mullooly, J. P. Impact of epidemic Type A influenza in a defined adult population. American Journal of Epidemiology 1980; 112:798-813. 5. Barker, W. H., and Mullooly, J. P. Underestimation of the role of pneumonia and influenza in causing excess mortality. American Journal of Public Health 1981; 71:643-645. 6. Barker, W. H., and Mullooly, J. P. Pneumonia and influenza deaths during epidemics. Implications for prevention. Archives of Internal Medicine 1982; 142:85-89. 7. Barker, W. H. Excess pneumonia and influenza associated hospitalization during influenza epidemics in the United States, 1970-78. American Journal of Public Health 1986; 76:761-765. 8. Beeson, P. B. Alleged susceptibility of the elderly to infection. Yale Journal of Biology and Medicine 1985; 58:71-77. 9. Brachman, P. S., Dan, B. B., Haley, R. W., Hooton, T. M., Garner, J. S., and Allen, J. R. Nosocomial surgical infections: Incidence and cost. Surgical Clinics of North America 1980; 60:15-25. 10. Chang, J. I., and Mylotte, J. M. Pneumococcal bacteremia: Update from an
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The Second Fifty Years: Promoting Health and Preventing Disability adult hospital with a high rate of nosocomial cases. Journal of the American Geriatrics Society 1987; 35:747-754. 11. Committee on Immunization. Guide for Adult Immunization. Philadelphia: American College of Physicians, Council of Medical Societies, 1985. 12. Cunha, B. A. (ed.), Infectious Diseases in the Elderly. Littleton, Mass.: PSG Publishing Company, 1988. 13. Eickhoff, T. C., Sherman, I. L., and Serfling, R. E. Observations on excess mortality associated with epidemic influenza . Journal of the American Medical Association 1961; 176:104-110. 14. Filice, G. A., Darby, C. P., and Fraser, D. W. Pneumococcal bacteremia in Charleston County, South Carolina. American Journal of Epidemiology 1980; 112:828-835. 15. Fiumara, N. J., and Waterman, G. E. Statewide geriatric immunization program with polyvalent pneumococcal vaccine. Current Therapeutic Research 1979; 25:185-192. 16. Forrester, H. L., Jahnigen, D. W., and LaForce, F. M. The efficacy of pneumococcal vaccine in a high-risk population. American Journal of Medicine 1987; 83:425-430. 17. Freeman, J., and McGowan, J. E. Risk factors for nosocomial infections. Journal of Infectious Diseases 1978; 138:811-819. 18. Gardner, I. D. The effect of aging on susceptibility to infection. Reviews of Infectious Disease 1980; 2:801-810. 19. Gleckman, R. A., and Gantz, N. M. (eds.), Infections in the Elderly. Boston: Little, Brown and Company, 1983. 20. Glezen, W. P. Serious morbidity and mortality associated with influenza epidemics. Epidemiologic Reviews 1982; 4:25-44. 21. Gross, P. A., Neu, H. C., Aswapokee, P., Antwerpen, C. V., and Aswapokee, B. Deaths from nosocomial infections: Experience in a university hospital and a community hospital. American Journal of Medicine 1980; 68:219-223. 22. Gross, P. A., and Antwerpen, C. V. Nosocomial infections and hospital deaths. A case-control study. American Journal of Medicine 1983; 75:658-662. 23. Gross, P. A., Rapuano, C., Adrignolo, A., and Shaw, B. Nosocomial infection: Decade-specific risk. Infection Control 1983; 4:145-147. 24. Gross, P. A., Quinnan, G. V., Rodstein, M., LaMontagne, J. R., Kaslow, R. A., Saah, A. J., Wallenstein, S., Neufeld, R., Denning, C., and Gaerlan, P. Association of influenza immunization with reduction in mortality in an elderly population. Archives of Internal Medicine 1988; 148:562-565. 25. Haley, R. W., Hooton, T. M., Culver, D. H., Stanley, R. C., Emori, T. G., Hardison, C. D., Quade, D., Shachtman, R. H., Schaberg, D. R., Shah, B. V., and Schatz, G. D. Nosocomial infections in U.S. hospitals, 1975-1976. Estimated frequency by selected characteristics of patients. American Journal of Medicine 1981; 70:947-959. 26. Hook, E. W., Horton, C. A., and Schaberg, D. R. Failure of intensive care unit support to influence mortality from pneumococcal bacteremia. Journal of the American Medical Association 1983; 249:1055-1057. 27. Howells, C. H. L., Vesselinova-Jenkins, C. K., Evans, A. D., and James, J. Influenza vaccination and mortality from bronchopneumonia in the elderly. Lancet 1985; 1:381-383. 28. Jackson, M. M., and Fierer, J. Infections and infection risk in residents of long-term care facilities: A review of the literature, 1970-1984. American Journal of Infection Control 1985; 13:63-77.
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The Second Fifty Years: Promoting Health and Preventing Disability 29. Joint Commission on the Accreditation of Hospitals. Infection control. In: AMH/84 Accreditation Manual for Hospitals. Chicago: Joint Commission on the Accreditation of Hospitals, 1983, p. 69. 30. Kavet, J. Influenza and public policy. Doctoral dissertation, Harvard School of Public Health, 1972. 31. Klarman, H. E., and Guzick, D. Economics of influenza. In: P. Selby (ed.), Influenza: Virus, Vaccines, and Strategy. New York: Academic Press, 1976, pp. 255-270. 32. Lipsky, B. A., Boyko, E. J., Inui, T. S., and Koepsell, T. D. Risk factors for acquiring pneumococcal infections. Archives of Internal Medicine 1986; 146:2179-2185. 33. Liu, K. J., and Kendal, A. P. Impact of influenza epidemics on mortality in the United States from October 1972 to May 1985. American Journal of Public Health 1987; 77:712-716. 34. MacFarlane, J. T., Finch, R. G., Ward, M. J., and MacRae, A. D. Hospital study of adult community-acquired pneumonia. Lancet 1982; 2:255-258. 35. Marrie, T. J., Haldane, E. V., Faulkner, R. S., Durant, H., and Kwan, C. Community-acquired pneumonia requiring hospitalization. Is it different in the elderly? Journal of the American Geriatrics Society 1985; 33:671-680. 36. Mufson, M. A. Pneumococcal infections. Journal of the American Medical Association 1981; 246:1942-1948. 37. Mufson, M. A., Oley, G., and Hughey, D. Pneumococcal disease in a medium-sized community in the United States. Journal of the American Medical Association 1982; 248:1486-1489. 38. Patriarca, P. A., Kater, N. A., Kendal, A. P., Bregman, D. J., Smith, J. D., and Sikes, R. K. Safety of prolonged administration of rimantadine hydrochloride in the prophylaxis of influenza A virus infections in nursing homes. Antimicrobial Agents and Chemotherapy 1984; 26:101-103. 39. Patriarca, P. A., Weber, J. A., Parker, R. A., Hall, W. N., Kendal, A. P., Bregman, D. J., and Schonberger, L. B. Efficacy of influenza vaccine in nursing homes. Reduction in illness and complications during an influenza A(H3N2) epidemic. Journal of the American Medical Association 1985; 253:1136-1139. 40. Patrick, K. M., and Woolley, F. R. A cost-benefit analysis of immunization for pneumococcal pneumonia. Journal of the American Medical Association 1981; 245:473-477. 41. Perrotta, D. M., Decker, M., and Glezen, W. P. Acute respiratory disease hospitalizations as a measure of impact of epidemic influenza. American Journal of Epidemiology 1985; 122:468-476. 42. Recommendations of the Immunization Practices Advisory Committee. Pneumococcal polysaccharide vaccine. Morbidity and Mortality Weekly Report 1989; 38:64-76. 43. Roghmann, K. J., Tabloski, P. A., Bentley, D. W., and Schiffman, G. Immune response of elderly adults to pneumococcus: Variation by age, sex, and functional impairment. Journal of Gerontology 1987; 42:265-270. 44. Ruben, F. L., and Uhrin, M. Specific immunoglobulin-class antibody response in the elderly before and after 14-valent pneumococcal vaccine. Journal of Infectious Diseases 1985; 151:845-849. 45. Saviteer, S. M., Samsa, G. P., and Rutala, W. A. Nosocomial infections in the elderly. Increased risk per hospital day. American Journal of Medicine 1988; 84:661-666. 46. Scheckler, W. E., and Peterson, P. J. Nosocomial infections in 15 rural
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The Second Fifty Years: Promoting Health and Preventing Disability Wisconsin hospitals: Results and conclusions from 6 months of comprehensive surveillance. Infection Control 1986; 7:397-402. 47. Schneider, E. L. Infectious diseases in the elderly. Annals of Internal Medicine 1983; 98:395-400. 48. Simberkoff, M. S., Cross, A. P., Al-Ibraham, M., Baltch, A. L., Geiseler, P. J., Nadler, J., Richmond, S., Smith, R. P., Schiffman, G., Shepard, D. S., and Van Eeckhout, J. P. Efficacy of pneumococcal vaccine in high-risk patients. Results of a Veterans Administration cooperative study. New England Journal of Medicine 1986; 315:1318-1327. 49. Shapiro, E. D., and Clemens, J. D. A controlled evaluation of the protective efficacy of pneumococcal vaccine for patients at high risk of serious pneumococcal infections. Annals of Internal Medicine 1984; 101:325-330. 50. Sims, R. V., Steinman, W. C., McConville, J. H., King, L. R., Zwick, W. C., and Schwartz, J. S. The clinical effectiveness of pneumococcal vaccine in the elderly. Annals of Internal Medicine 1988; 108:653-657. 51. Spengler, R. F., and Greenough, W. B. Hospital costs and mortality attributed to nosocomial bacteremias. Journal of the American Medical Association 1978; 240:2455-2458. 52. Verghese, A., and Berk, S. L. Bacterial pneumonia in the elderly. Medicine 1983; 62:271-285. 53. Willems, J. S., Sanders, C. R., Riddiough, M. A., and Bell, J. C. Cost effectiveness of vaccination against pneumococcal pneumonia. New England Journal of Medicine 1980; 303:553-559. 54. Willems, J. S., and Sanders, C. R. Cost-effectiveness and cost-benefit analysis of vaccines. Journal of Infectious Diseases 1981; 144:486-493. 55. Yoshikawa, T. T., Norman, D. C., and Grahn, D. Infections in the aging population. Journal of the American Geriatrics Society 1985; 33:496-503.
Representative terms from entire chapter: