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Roundtable Proceedings

Immune Senescence: A Context for Clinical Influenza © Chris Ryan / Caiaimage / Getty Images

Thought leaders in the fields of geriatrics, cardiology, infectious diseases, internal medicine, pulmonology, critical care, family medicine, hospital-health systems, public health, and epidemiology convened at a roundtable to explore the direct and indirect consequences of influenza in older patients with multiple comorbidities. This monograph on the relationship between immune senescence and influenza is Part 2 of a series resulting from the information shared and issues discussed during the roundtable. Part 1 of the series focused on the role of influenza in the pathogenesis of cardiovascular disease.

EDITORIAL BOARD

Stefan Gravenstein, MD, MPH (Co-moderator)

Mohammad Madjid, MD, MS (Co-moderator)

Michael Baram, MD Marvin J. Bittner, MD Dale W. Bratzler, DO, MPH Donald A. Jurivich, DO Paul Kilgore, MD, MPH Martin C. Mahoney, MD, PhD Arnold Monto, MD Carlos E. Picone, MD Gregory A. Poland, MD Keith M. Ramsey, MD

Increasing dysregulation of the immune system that occurs with aging adds to the likelihood of influenza-related complications in the elderly.

A

lthough influenza affects people of all ages, older adults often bear a greater proportion of the burden of severe influenzaassociated morbidity and mortality.While individuals 65 years of age and older comprise only about 13% of the population in the United States (US),1 they represent more than 60% of influenza-related hospitalizations due to bacterial infections and pulmonary, cardiovascular, and cerebrovascular complications during a typical season,2 and about 90% of influenzarelated deaths across all age groups.3,4 For each death due to influenza, there are approximately 8 hospitalizations.5 In all, adults 65 years of age and older account for about 40% of direct medical costs and 64% of the total economic burden of seasonal influenza in the US.5 As the population ages, these burdens will increase. INFLUENZA-ASSOCIATED HOSPITALIZATIONS AND MORTALITY INCREASE WITH AGE A study performed in England and Wales during 12 consecutive influenza seasons (19892001) quantified excess hospital admissions and average bed stay for respiratory conditions during influenza outbreaks and examined the importance of age. Excess admissions related to influenza were strongly age-related, with older adults accounting for the majority of hospitalizations.6 (Figure 1) The inflection in the curve for excess bed days began at around 50 years of age and rose sharply thereafter. Similar trends for the excess burden of influenza in older patients were found using virologic, mortality, and hospitalization data from US Centers for Disease Control and Prevention (CDC) influenza-infection surveillance and the National Hospital Discharge

Survey.7 Between 1976 and 2000, influenzarelated mortality per 100,000 population was 6.3 among those 50-64 years of age and 18.5 among those 65-69 years of age; it increased sharply to 357.9 in those ≥85 years of age. Influenza-related hospitalization rates per 100,000 between 1979 and 2001 also rose sharply with increasing age, from 84 in those 50-64 years of age and 190 in those 65-69 years of age to 1195 in those ≥85 years of age.7 INFLUENZA: WHY THE HIGHER IMPACT IN OLDER ADULTS? High-risk comorbidities A number of factors influence the way in which older adults react to infection with influenza virus. Host factors, such as the accumulation of underlying disease conditions with age, play a role. The presence of high-risk comorbid conditions — such as diseases of the cardiovascular, pulmonary, renal, endocrine, or central nervous systems, and malignancy — dramatically increases the risk of influenzarelated mortality in older adults. For example, in 1 study conducted within a health maintenance organization during 2 influenza epidemics, the rate of pneumoniaand influenza-related deaths among adults 65 years of age and older increased sharply with the number of comorbid conditions.8 There were 9 deaths per 100,000 among those who had no comorbid high-risk conditions. For those with 1 comorbid condition, the mortality rate climbed to 217 per 100,000, and for those with 2 or more comorbid conditions, the rate was 306 per 100,000.8 In another study conducted in the United Kingdom during the 1989-1990 inf luenza season among nursing home residents


Excess admissions

Excess bed days

5000

4000

4000

3000

3000

2000

2000

1000

1000

0

15

2 2 3 3 4 4 5 6 5 6 7 7 8 -1 0-2 5-2 0-3 5-3 0-4 5-4 0-5 5-5 0-6 5-6 0-7 5-7 0-8 ≥85 9 4 9 9 9 9 9 4 9 4 4 4 4 4

Number of excess bed days

Number of excess admissions

5000

0

Age (years) © Crown copyright. Reproduced with permission of Public Health England.

FIGURE 1. Average excess hospital admissions and excess bed days by age for respiratory conditions during 12 consecutive influenza seasons, United Kingdom, 1989-2001.6

65 years of age and older, the risk of influenzaassociated mortality was increased nearly 8-fold among residents with at least 3 underlying conditions compared with those who had only 1 condition.9 Immune senescence: The immunologic context of aging and influenza Changes occur with increasing age in both the innate and adaptive immune systems. This phenomenon, termed immune senescence, is generally defined as age-associated changes in the immune response and is a state of dysregulated immune function. Immune senescence increases susceptibility to some, but not all, infectious diseases.10 It is a common misconception that the immune system of the elderly becomes uniformly less responsive or generally nonfunctional with increasing age. Although many aspects of immunity do decline with age, the changes do not occur uniformly; some aspects of the aging immune response are preserved11 while others — such as pro-inflammatory cytokine production by macrophages — are actually enhanced.12 The age-related system ic ch ron ic inflammation that results from increases in pro-in f lam mator y cy tok ines, ca l led “inflammaging,” has been suggested as an important driver for frailty in the elderly and for the development and progression of common severe age-related diseases, including cardiovascular diseases, type 2 diabetes mellitus, and neurodegenerative diseases.12 In addition, the slower decline in inflammatory cytokines that also occurs with inflammaging is associated with a pro2

thrombotic state, which increases the risk for thromboembolic stroke and myocardial infarction in elderly patients following influenza infection.13 (Table) These changes in the immune system with age affect both the clinical presentation and the consequences of influenza. Older people produce less interferon and interleukin, which may help explain the milder initial presentation of influenza (ie, reduced prevalence of fever and malaise) with age.13,14 Unfortunately, this lack of severe symptoms can delay the clinical diagnosis of inf luenza.13 Cell-mediated immune responses also decline with age, which

may explain why influenza lasts longer in elderly patients.15 The response of elderly individuals to influenza vaccines is also impacted by immune senescence. (See page 3.) Other biologic changes with age that affect the clinical presentation and consequences of influenza In frail older patients, mucociliary function in the respiratory tract is impaired, leading to reduced cough and less efficient clearance of mucus and virus.13 Due to their poorer nutritional status, elderly patients often have depleted physiologic reserves, complicating their rehabilitation. In addition, cytokine storm secondary to influenza infection is more likely to induce delirium and other disturbances in the brains of elderly patients.13 (Table) INFLUENZA CAN ALSO LEAD TO FUNCTIONAL DECLINE IN ELDERLY PATIENTS Especially among the most fragile elderly patients, influenza can lead to a decline in major physical functions, and therefore act as a trigger for catastrophic disability.16,17 More than a third of hospitalized patients 70 years of age or older in the US are discharged from the hospital less able to perform basic activities of daily living than when they were admitted.18 Because older patients often endure more frequent and longer influenza-related hospitalizations,2 influenza likely contributes significantly to this functional loss.

Table. Biologic changes with age related to clinical consequences of influenza10,12-15 Biologic Change With Age

Clinical Implication With Infection

Reduced amplitude of cytokine response to infection

Fewer symptoms at disease onset; reduced fever  less efficient viral clearance

Impaired mucociliary function in respiratory tract

Reduced cough, less efficient viral clearance and mucus clearance

Reduced TNF-αa

Less malaise; delay in diagnosis

Delayed decline in inflammatory cytokines

Longer period during which inflammatory cytokines produce a prothrombotic state (increased risk for thromboembolic stroke, mycardial infarction)

Reduced T-cell function

Reduced protection from vaccine; reduced longevity of protection from vaccine

Poorer nutritional intake

Decreased physiologic reserve, more difficult rehabilitation

Brain aging

Cytokine storm more likely to produce delirium, sleep and appetite disturbances

a

TNF-α = tumor necrosis factor alpha.

| Immune Senescence: A Context for Clinical Influenza


that influenza vaccination was associated with a significantly lower risk of major adverse cardiovascular events.29 In fact, the greatest treatment effect was seen among the highestrisk patients, for example, those with recent acute coronary syndrome.29 AGING AND IMPAIRED IMMUNITY: IMPLICATIONS FOR INFLUENZA VACCINE DEVELOPMENT FOR OLDER ADULTS Because most influenza-related hospitalizations and the overwhelming majority of influenza-related deaths occur in elderly persons, vaccines with improved efficacy in this age group and continued efforts to increase vaccination rates are both needed to protect this vulnerable population.30 In 2009, a higher-dose influenza vaccine with 4 times the hemagglutinin antigen content of standard inactivated influenza vaccine was licensed for use in persons 65 years of age and older based on studies demonstrating superior immunogenicity compared with a standard vaccine.31 The higher-dose vaccine also generated a significantly greater antibody response than did the standard vaccine in several studies that measured antibody titers at baseline and 28 days post vaccination.31-33 Efficacy studies comparing the higher-dose and the standard inf luenza vaccine have recently been completed.34 In older adults, influenza can cause more than “just” pneumonia, hospitalization, and

.125

.12

3

.115 2.5

.11 2 .105

Influenza deaths/100,000 population

3.5

1.5 1999Q4 2000Q1 2000Q2 2000Q3 2000Q4 2001Q1 2001Q2 2001Q3 2001Q4 2002Q1 2002Q2 2002Q3 2002Q4 2003Q1 2003Q2 2003Q3 2003Q4 2004Q1 2004Q2 2004Q3 2004Q4 2005Q1 2005Q2 2005Q3

INFLUENZA VACCINE AND PROTECTING THE ELDERLY Most studies suggest that the response to influenza vaccination in older adults is significantly reduced compared to that in young, healthy adults.4,23 For example, a study utilizing data from France’s Sentinel Network estimated vaccine effectiveness over a 7-year period at 62% to 76% in persons 15-64 years of age, but only between 26% and 52% among those 65 years of age and older.24 (Figure 3) Nevertheless, a systematic review of studies of influenza vaccine in the elderly, including data from observational trials, found a 26% reduction in hospitalization from influenza and pneumonia, and a 42% reduction in allcause mortality among community-dwelling elderly persons.25 A 2010 Cochrane review on influenza vaccine effectiveness and safety in the elderly found no convincing evidence for vaccine effectiveness against disease.26 However, a more recent study that utilized the same data as the Cochrane review but analyzed them according to “more clinically meaningful scenarios” found substantial evi-

dence for the ability of influenza vaccine to reduce the risk of influenza infection and influenza-related disease and death in the elderly.27 According to the authors of this study, “vaccination of the elderly is efficacious in reducing infection, disease, and death caused by influenza virus infection; is worthwhile as a public health intervention; and … there is a sound scientific basis for the recommendations made by the World Health Organization, and multiple international and national bodies.”27 Another recent retrospective cohort study conducted over a 15-year period among Ontario (Canada) residents 65 years of age and older linked weekly vaccination, hospitalization, and death records for 1.4 million community-dwelling persons. Excess pneumonia/influenza hospitalizations as well as excess deaths occurring within 30 days of a pneumonia/influenza hospitalization were significantly reduced by influenza vaccination, by 19% and 25%, respectively.28 The effectiveness of influenza vaccine may reflect more than just the reduced risk of respiratory infection. Evidence suggests that influenza vaccines can contribute significantly to reducing mortality secondary to acute myocardial infarction and stroke among elderly adults. A recent meta-analysis of randomized controlled trials comparing influenza vaccine with placebo or control in patients at high risk of cardiovascular disease found

Rate of ADL decline

However, the role that influenza plays in these clinical consequences is often unrecognized.16 The typical clinical presentation of influenza and influenza-like illness — abrupt onset of fever, chills, myalgias, and headache, along with sore throat and cough — may be more subtle or even entirely absent in older patients.19-21 Instead, the frail elderly, including residents of nursing homes, may have a blunted febrile response to infection and exhibit mainly a decline in functional status, such as new or increasing confusion, incontinence, falling, deteriorating mobility, reduced food intake, or failure to cooperate with the staff.20 Both a small case-control study of frail nursing home residents from a limited geographical location over 2 consecutive influenza seasons16 and a 6-year longitudinal analysis of nursing home residents from more than US 120 cities22 found that physical function outcome measures, such as the rate of decline in activities of daily living (Figure 2), weight loss, and pressure ulcers, exhibit a strong seasonal trend that corresponds to influenza mortality and severity. Seasonal influenza may also be a factor in the pathogenesis of acute cardiovascular deaths and hospitalizations; vaccination against influenza may help prevent the infection-associated increase in acute coronary syndrome. See Part 1 of this monograph series for more information.

Reprinted from Gozalo PL, et al. J Am Geriatr Soc. 2012;60(7):1260-1267,22 by permission of the American Geriatrics Society and Blackwell Publishing, Inc.

FIGURE 2. Quarterly pattern of the rate of decline of activities of daily living [ADL (n)] vs influenza mortality (s) for nursing home residents in 122 cities monitored by the CDC, 1999-2005.22 Immune Senescence: A Context for Clinical Influenza | 3


80 15-64 years of age

Vaccine effectiveness (%)

70

≥65 years of age

60 50 40 30 20 10 0 1998- 1999- 2000- 2001- 2002- 2003- 20041999 2000 2001 2002 2003 2004 2005 Influenza season

FIGURE 3. Effectiveness of influenza vaccines against influenza-like illness, by age.24

death, and the immune response to vaccine may be less robust. However, the severity of influenza and its sequelae can be reduced by immunization, even among the oldest and frailest persons, and even when vaccine fails to prevent infection.13,25,27-29 Armed with this KEY MESSAGES n  Influenza remains one of the most common preventable causes of death for older adults3,4 n  Vaccination of the elderly is efficacious in reducing disease and death caused by influenza virus infection, and therefore worthwhile as a public health intervention27 n The severity of influenza’s effects may be reduced by vaccination, even when vaccine fails to prevent infection13,25,27-29 n A higher-dose influenza vaccine formulated to help address age-associated changes in the immune response is approved for use in persons 65 years of age and older31 knowledge, health care providers must continue to take an active role in ensuring that their elderly patients are immunized against influenza. REFERENCES: 1. Department of Health & Human Services Administration on Aging. A profile of older Americans: 2010. http:// www.aoa.gov/aoaroot/aging_statistics/profile/2010/ docs/2010profile.pdf. Accessed March 7, 2014. 2. Thompson WW, Shay DK, Weintraub E, et al. Influenzaassociated hospitalizations in the United States. JAMA. 2004;292(11):1333-1340.

3. Centers for Disease Control and Prevention (CDC). Estimates of deaths associated with seasonal influenza—United States, 1976-2007. MMWR. 2010;59(33):1057-1062. 4. CDC. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices — United States, 2013–2014. MMWR. 2013;62(RR-7):1-45. 5. Molinari NM, Ortega-Sanchez IR, Messonnier ML, et al. The annual impact of seasonal influenza in the US: measuring disease burden and costs. Vaccine. 2007;25(27):5086-5096. 6. Fleming D, Harcourt S, Smith G. Influenza and adult hospital admissions for respiratory conditions in England 1989-2001. Commun Dis Public Health. 2003;6(3):231-237. 7. Thompson WW, Comanor L, Shay DK. Epidemiology of seasonal influenza: use of surveillance data and statistical models to estimate the burden of disease. J Infect Dis. 2006;194(Suppl 2):S82-S91. 8. Barker WH, Mullooly JP. Pneumonia and influenza deaths during epidemics: implications for prevention. Arch Intern Med. 1982;142(1):85-89. 9. Nguyen-Van-Tam JS, Nicholson KG. Influenza deaths in Leicestershire during the 1989-1990 epidemic: implications for prevention. Epidemiol Infect. 1992;108(3):537-545. 10. Castle SC, Uyemura K, Fulop T, Makinodan T. Host resistance and immune responses in advanced age. Clin Geriatr Med. 2007;23(3):463-479. 11. Lelic A, Verschoor CP, Ventresca M, et al. The polyfunctionality of human memory CD8+ T cells elicited by acute and chronic virus infections is not influenced by age. PLoS Pathog. 2012;8(12):e1003076. 12. Olivieri F, Rippo MR, Prattichizzo F, et al. Toll like receptor signaling in “inflammaging”: microRNA as new players. Immun Ageing. 2013;10(1):11. 13. Gravenstein S, Pop-Vicas A, Ambrozaitis A. The 2009 A/H1N1 pandemic influenza and the nursing home. Med Health R I. 2010;93(12):382-384. 14. Deng Y, Jing Y, Campbell AE, Gravenstein S. Age-related impaired type 1 T cell responses to influenza: reduced activation ex vivo, decreased expansion in CTL culture in vitro, and blunted response to influenza vaccination in vivo in the elderly. J Immunol. 2004;172(6):3437-3446. 15. McElhaney JE. Influenza vaccine responses in older adults. Ageing Res Rev. 2011;10(3):379-388.

16. Barker WH, Borisute H, Cox C. A study of the impact of influenza on the functional status of frail older people. Arch Intern Med. 1998;158(6):645-650. 17. Monto AS, Ansaldi F, Aspinall R, et al. Influenza control in the 21st century: optimizing protection of older adults. Vaccine. 2009;27(37):5043-5053. 18. Covinsky KE, Palmer RM, Fortinsky RH, et al. Loss of independence in activities of daily living in older adults hospitalized with medical illnesses: increased vulnerability with age. J Am Geriatr Soc. 2003;51(4):451-458. 19. Smith PW, Bennett G, Bradley S, et al. Society for Healthcare Epidemiology of America (SHEA)/Association for Professionals in Infection Control (APIC) guideline: infection prevention and control in the long-term care facility, July 2008. Infect Control Hosp Epidemiol. 2008;29(9):785-814. 20. High KP, Bradley SF, Gravenstein S, et al; Infectious Diseases Society of America. Clinical practice guideline for the evaluation of fever and infection in older adult residents of longterm care facilities: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(2):149-171. 21. Pop-Vicas A, Gravenstein S. Influenza in the elderly: a minireview. Gerontology. 2011;57(5):397-404. 22. Gozalo PL, Pop-Vicas A, Feng Z, Gravenstein S, Mor V. Effect of influenza on functional decline. J Am Geriatr Soc. 2012;60(7):1260-1267. 23. Reber AJ, Chirkova T, Kim JH, et al. Immunosenescence and challenges of vaccination against influenza in the aging population. Aging Dis. 2012;3(1):68-90. 24. Legrand J, Vergu E, Flahault A. Real-time monitoring of the influenza vaccine field effectiveness. Vaccine. 2006;24(4446):6605-6611. 25. Jefferson T, Rivetti D, Rivetti A, et al. Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review. Lancet. 2005;366(9492):1165-1174. 26. Jefferson T, Di Pietrantonj C, Al-Ansary LA, et al. Vaccines for preventing influenza in the elderly. Cochrane Database Syst Rev. 2010;(2):CD004876. 27. Beyer WE, McElhaney J, Smith DJ, et al. Cochrane rearranged: support for policies to vaccinate elderly people against influenza. Vaccine. 2013;31(50):6030-6033. 28. Ridenhour BJ, Campitelli MA, Kwong JC, et al. Effectiveness of inactivated influenza vaccines in preventing influenzaassociated deaths and hospitalizations among Ontario residents aged ≥65 years: estimates with generalized linear models accounting for healthy vaccinee effects. PLoS One. 2013;8(10):e76318. 29. Udell JA, Zawi R, Bhatt DL, et al. Association between influenza vaccination and cardiovascular outcomes in high-risk patients: a meta-analysis. JAMA. 2013;310(16):1711-1720. 30. CDC. Estimated influenza illnesses and hospitalizations averted by influenza vaccination — United States, 2012–13 influenza season. MMWR. 2013;64(49):997-1000. 31. Falsey AR, Treanor JJ, Tornieporth N, Capellan J, Gorse GJ. Randomized, double-blind controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose influenza vaccine in adults 65 years of age and older. J Infect Dis. 2009;200(2):172-180. 32. DiazGranados CA, Dunning AJ, Jordanov E, Landolfi V, Denis M, Talbot HK. High-dose trivalent influenza vaccine compared to standard dose vac­cine in elderly adults: safety, immunogenicity, and relative efficacy during the 2009-2010 season. Vaccine. 2013;31(6):861-866. 33. Robertson CA, Greenberg DP, Decker MD. Safety and immunogenicity comparison of 2011-2012 high-dose and standard intramuscular influenza vaccines in older adults (GRC48). Presented at: IDWeek 2012; October 17-21, 2012; San Diego, CA. Abstract 1527. 34. ClinicalTrials.gov. A study of Fluzone High-Dose vaccine compared with Fluzone vaccine in elderly adults. http://www. clinicaltrials.gov/ct2/show/NCT01427309. Accessed March 3, 2014.

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