Infection Hospitalization Increases Risk of Dementia in the Elderly* Judith A. Tate, PhD1, Beth E. Snitz, PhD2, Karina A. Alvarez, MA3, Richard L. Nahin, PhD4, Lisa A. Weissfeld, PhD3,5, Oscar Lopez, MD2, Derek C. Angus, MD5,6, Faraaz Shah, MD7, Diane G. Ives, MPH8, Annette L. Fitzpatrick, PhD9, Jeffrey D. Williamson, MD10, Alice M. Arnold, PhD11, Steven T. DeKosky, MD12; Sachin Yende, MD5,6, for the GEM Study Investigators *See also p. 1282. 1 Department of Acute and Tertiary Care, School of Nursing, University of Pittsburgh, Pittsburgh, PA. 2 Department of Neurology, University of Pittsburgh, Pittsburgh, PA. 3 Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA. 4 National Center for Complementary and Alternative Medicine (NCCAM), National Institutes of Health, Bethesda, MD. 5 The Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, University of Pittsburgh, Pittsburgh, PA. 6 Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA. 7 Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA. 8 Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA. 9 Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA. 10 Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC. 11 Department of Biostatistics, University of Washington, Seattle, WA. 12 School of Medicine, University of Virginia, Charlottesville, VA. Dr. Tate had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). The GEM Study Investigators are listed in Appendix 1. Gingko Effect on Memory study was supported by grant U01 AT000162 from the National Center for Complementary and Alternative Medicine and the Office of Dietary Supplements and National Institute on Aging; National Heart, Lung, and Blood Institute; University of Pittsburgh Alzheimer’s Disease Research Center (P50AG05133); Roena Kulynych Center for Memory and Cognition Research; Wake Forest University School of Medicine; and National Institute of Neurological Disorders and Stroke. Dr. Tate is funded by T-32 (MH19986—principal investigator [PI] Reynolds). Dr. Tate’s institution received grant support from the National Institute of Mental Health (T32-MH19986—PI Reynolds). Dr. Tate received support for article research from the National Institutes of Health (NIH) (T-32 MH19986—PI Reynolds). Dr. Snitz is supported by National Institute on Aging (NIA 5K23AG038479). Dr. Snitz’s institution received grant support from the NIH. Dr. Snitz received support for article research from the NIH. Dr. Nahin is employed by the NIH. Dr. Lopez consulted for Grifols, Lilly, and Baxter. Dr. Lopez’s institution received grant support (NIA: P50 AG05133-27). Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000123
Critical Care Medicine
Dr. Ives’ institution received grant support and support for travel from National Center for Complementary and Alternative Medicine/NIH. Dr. Ives is employed by the University of Pittsburgh and received support for article research from the NIH. Dr. Fitzpatrick and her institution received grant support from the NIH and Centers for Disease Control and Prevention (CDC). Dr. Fitzpatrick received support for article research from the NIH and CDC. Dr. Williamson’s institution received grant support and support for travel from the NIH. Dr. Williamson received support for article research from the NIH. Dr. Arnold and her institution received grant support from the NIH. Dr. Arnold received support for travel and support for article research from the NIH. Dr. DeKosky’s institution received grant support from the NIH, support for travel from the NIH, and the active Gingko Extract and the placebo tablets for the original Gingko Effect on Memory trial from Schwabe Pharamaceuticals. Dr. DeKosky received support for article research from the NIH. Dr. Yende’s institution received grant support from the NIH. Dr. Yende received support for article research from the NIH and National Institute of General Medical Sciences (K23GM083215). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: [email protected]
Objectives: Severe infections, often requiring ICU admission, have been associated with persistent cognitive dysfunction. Less severe infections are more common and whether they are associated with an increased risk of dementia is unclear. We determined the association of pneumonia hospitalization with risk of dementia in well-functioning older adults. Design: Secondary analysis of a randomized multicenter trial to determine the effect of Gingko biloba on incident dementia. Setting: Five academic medical centers in the United States. Subjects: Healthy community volunteers (n = 3,069) with a median follow-up of 6.1 years. Interventions: None. Measurement and Main Results: We identified pneumonia hospitalizations using International Classification of Diseases, 9th Edition— Coding Manual codes and validated them in a subset. Less than 3% of pneumonia cases necessitated ICU admission, mechanical ventilation, or vasopressor support. Dementia was adjudicated based on neuropsychological evaluation, neurological examination, and MRI. Two hundred twenty-one participants (7.2%) incurred at least one hospitalization with pneumonia (mean time to pneumonia = 3.5 yr). Of these, dementia was developed in 38 (17%) after pneumonia, with half of these cases occurring 2 years after the pneumonia hoswww.ccmjournal.org
1037
Tate et al pitalization. Hospitalization with pneumonia was associated with increased risk of time to dementia diagnosis (unadjusted hazard ratio = 2.3; CI, 1.6–3.2; p 3 yr). Prior studies that assessed the association between infection Dementia is a chronic degenerative disease and the patho- and cognitive dysfunction examined changes in cognitive physiologic changes of dementia were likely to be underway function alone rather than diagnosis of dementia (16–20). prior to the occurrence of pneumonia in our study. Our results Our primary endpoint was all-cause dementia and was adjusuggest that an episode of infection accelerates dementia. A dicated based on detailed neuropsychological assessment, potential mechanism to explain this association could be perneurological and medical evaluation, and MRI of the brain sistent inflammation in the systemic circulation or in the brain using previously validated approaches (26–29). Finally, or due to activation of other aspects of the innate immune prior studies either used a case-control design or conducted response, as evidenced in observational human studies (4–9, a within-person analysis of infection patients alone (16– 13–15) and in animal models (10–12, 45). For example, a single 20). By contrast, we used a cohort design and propensitylipopolysaccharide injection in animals causes chronic neuro- matched analysis and compared risk among several different inflammation and long-term cognitive deficits and accelerates groups, including those hospitalized with pneumonia, other neurodegenerative conditions (10–12). Epidemiologic studies infections, and for other reasons. in individuals without an infection have shown that a small Our study has limitations. First, we used ICD-9 codes and increase in circulating inflammatory mediators was associated text field searches to identify pneumonia hospitalization. Prior with dementia (7) and in those with an infection have shown studies suggest that these approaches have good accuracy (35), increased and in some cases persistent circulating inflammation. and chart review of participants in our study showed that over Although our study primarily focused on less severe infec90% of cases met clinical and radiologic criteria for pneumotions, recent work by our group suggests that the risk of nia. Second, we did not have data regarding outpatient infecdementia is similar regardless of the severity of infection (46). tions, and whether infections occurring in the outpatient setting Furthermore, the risk of dementia in this study was similar to have a similar effect on dementia is not known. Third, we do not the risk of dementia observed in patients with severe pneumoknow the percentage of participants who experienced delirium nia and severe sepsis. Thus, our results could be generalized or received psychoactive medications, factors that may contribto patients hospitalized with infection in different countries, ute to increased risk of dementia. Finally, we did not use a formal whose illness severity may be different from those in the index of frailty. Instead, we used decline in physical and cogniUnited States. tive function scores over time as an approximation for frailty. 1044
www.ccmjournal.org
May 2014 • Volume 42 • Number 5
Feature Articles
In conclusion, episodes of pneumonia are associated with higher risk of dementia diagnosis. Future studies should examine mechanisms underlying this association.
REFERENCES
1. Brookmeyer R, Johnson E, Ziegler-Graham K, et al: Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement 2007; 3:186–191 2. Thies W, Bleiler L: 2011 Alzheimer’s disease facts and figures. Alzheimers Dement 2011; 7:208–244 3. Weaver JD, Huang MH, Albert M, et al: Interleukin-6 and risk of cognitive decline: MacArthur studies of successful aging. Neurology 2002; 59:371–378 4. Yaffe K, Lindquist K, Penninx BW, et al: Inflammatory markers and cognition in well-functioning African-American and white elders. Neurology 2003; 61:76–80 5. Ravaglia G, Forti P, Maioli F, et al: Blood inflammatory markers and risk of dementia: The Conselice Study of Brain Aging. Neurobiol Aging 2007; 28:1810–1820 6. Engelhart MJ, Geerlings MI, Meijer J, et al: Inflammatory proteins in plasma and the risk of dementia: The Rotterdam study. Arch Neurol 2004; 61:668–672 7. Schmidt R, Schmidt H, Curb JD, et al: Early inflammation and dementia: A 25-year follow-up of the Honolulu-Asia Aging Study. Ann Neurol 2002; 52:168–174 8. Yende S, D’Angelo G, Kellum JA, et al; GenIMS Investigators: Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis. Am J Respir Crit Care Med 2008; 177:1242–1247 9. Kale S, Yende S, Kong L, et al; GenIMS Investigators: The effects of age on inflammatory and coagulation-fibrinolysis response in patients hospitalized for pneumonia. PLoS One 2010; 5:e13852 10. Richwine AF, Parkin AO, Buchanan JB, et al: Architectural changes to CA1 pyramidal neurons in adult and aged mice after peripheral immune stimulation. Psychoneuroendocrinology 2008; 33:1369–1377 11. Qin L, Wu X, Block ML, et al: Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 2007; 55:453–462 12. Chen J, Buchanan JB, Sparkman NL, et al: Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav Immun 2008; 22:301–311 13. Brydon L, Harrison NA, Walker C, et al: Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans. Biol Psychiatry 2008; 63:1022–1029 14. Krabbe KS, Reichenberg A, Yirmiya R, et al: Low-dose endotoxemia and human neuropsychological functions. Brain Behav Immun 2005; 19:453–460 15. Reichenberg A, Yirmiya R, Schuld A, et al: Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 2001; 58:445–452 16. Iwashyna TJ, Ely EW, Smith DM, et al: Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 2010; 304:1787–1794 17. Jackson JC, Hart RP, Gordon SM, et al: Six-month neuropsychological outcome of medical intensive care unit patients. Crit Care Med 2003; 31:1226–1234 18. Hopkins RO, Weaver LK, Chan KJ, et al: Quality of life, emotional, and cognitive function following acute respiratory distress syndrome. J Int Neuropsychol Soc 2004; 10:1005–1017 19. Hopkins RO, Weaver LK, Collingridge D, et al: Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome. Am J Respir Crit Care Med 2005; 171:340–347 20. Ehlenbach WJ, Hough CL, Crane PK, et al: Association between acute care and critical illness hospitalization and cognitive function in older adults. JAMA 2010; 303:763–770 21. Fry AM, Shay DK, Holman RC, et al: Trends in hospitalizations for pneumonia among persons aged 65 years or older in the United States, 1988-2002. JAMA 2005; 294:2712–2719
Critical Care Medicine
22. Hebert PL, McBean AM, Kane RL: Explaining trends in hospitalizations for pneumonia and influenza in the elderly. Med Care Res Rev 2005; 62:560–582 23. Wier LM, Pfuntner A, Maeda J, et al: HCUP Facts and Figures: Statistics on Hospital-Based Care in the United States, 2009. Rockville, MD, Agency for Healthcare Research and Quality, 2011 24. DeKosky ST, Fitzpatrick A, Ives DG, et al; GEMS Investigators: The Ginkgo Evaluation of Memory (GEM) study: Design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia. Contemp Clin Trials 2006; 27:238–253 25. DeKosky ST, Williamson JD, Fitzpatrick AL, et al; Ginkgo Evaluation of Memory (GEM) Study Investigators: Ginkgo biloba for prevention of dementia: A randomized controlled trial. JAMA 2008; 300:2253–2262 26. McKhann G, Drachman D, Folstein M, et al: Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34:939–944 27. Erkinjuntti T: Clinical criteria for vascular dementia: The N INDS-AIREN criteria. Dementia 1994; 5:189–192 28. Rockwood K, Parhad I, Hachinski V, et al: Diagnosis of vascular dementia: Consortium of Canadian Centres for Clinical Cognitive Research consensus statement. Can J Neurol Sci 1994; 21:358–364 29. Chui HC, Mack W, Jackson JE, et al: Clinical criteria for the diagnosis of vascular dementia: A multicenter study of comparability and interrater reliability. Arch Neurol 2000; 57:191–196 30. Teng EL, Chui HC: The Modified Mini-Mental State (3MS) examination. J Clin Psychiatry 1987; 48:314–318 31. Rosen WG, Mohs RC, Davis KL: A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984; 141:1356–1364 32. Morris JC: The Clinical Dementia Rating (CDR): Current version and scoring rules. Neurology 1993; 43:2412–2414 33. Lopez OL, Becker JT, Klunk W, et al: Research evaluation and diagnosis of probable Alzheimer’s disease over the last two decades: I. Neurology 2000; 55:1854–1862 34. Lopez OL, Kuller LH, Fitzpatrick A, et al: Evaluation of dementia in the cardiovascular health cognition study. Neuroepidemiology 2003; 22:1–12 35. Guevara RE, Butler JC, Marston BJ, et al: Accuracy of ICD-9-CM codes in detecting community-acquired pneumococcal pneumonia for incidence and vaccine efficacy studies. Am J Epidemiol 1999; 149:282–289 36. Fine MJ, Smith MA, Carson CA, et al: Prognosis and outcomes of patients with community-acquired pneumonia. A meta-analysis. JAMA 1996; 275:134–141 37. Rosenbaum PR, Rubin DB: The central role of the propensity score in observational studies for causal effects. Biometrika 1983; 70:41–55 38. Austin PC: Goodness-of-fit diagnostics for the propensity score model when estimating treatment effects using covariate adjustment with the propensity score. Pharmacoepidemiol Drug Saf 2008; 17:1202–1217 39. Roy B, Pawar PP, Desai RV, et al: A propensity-matched study of the association of diabetes mellitus with incident heart failure and mortality among community-dwelling older adults. Am J Cardiol 2011; 108:1747–1753 40. Nagin DS, Odgers CL: Group-based trajectory modeling in clinical research. Annu Rev Clin Psychol 2010; 6:109–138 41. Rosenbaum PR: Sensitivity to hidden bias. In: Observational Studies. Second Edition. Rosenbaum PR (Ed). New York, NY, Springer-Verlag, 2002, pp 110–124 42. Jones BL, Nagin DS: Advances in group-based trajectory modeling and an SAS procedure for estimating them. Sociol Methods Res 2007; 35:542–571 43. Yende S, Angus DC, Ali IS, et al: Influence of comorbid conditions on long-term mortality after pneumonia in older people. J Am Geriatr Soc 2007; 55:518–525 44. Kaplan V, Angus DC, Griffin MF, et al: Hospitalized community-acquired pneumonia in the elderly: Age- and sex-related patterns of care and outcome in the United States. Am J Respir Crit Care Med 2002; 165:766–772 www.ccmjournal.org
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Tate et al 45. Cunningham C, Campion S, Lunnon K, et al: Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry 2009; 65: 304–312 46. Shah FA, Pike F, Alvarez K, et al: Bidirectional relationship between cognitive function and pneumonia. Am J Respir Crit Care Med 2013; 188:586–592 47. Rockwood K, Song X, MacKnight C, et al: A global clinical measure of fitness and frailty in elderly people. CMAJ 2005; 173:489–495
48. Morley JE, Haren MT, Rolland Y, et al: Frailty. Med Clin North Am 2006; 90:837–847 49. Sligl WI, Eurich DT, Marrie TJ, et al: Only severely limited, premorbid functional status is associated with short- and long-term mortality in patients with pneumonia who are critically ill: A prospective observational study. Chest 2011; 139:88–94 50. Sligl WI, Majumdar SR: How important is age in defining the prognosis of patients with community-acquired pneumonia? Curr Opin Infect Dis 2011; 24:142–147
APPENDIX 1. GEM Study Investigators
MD, MHS, Katherine Gundling, MD, Sharene Theroux, CCRP, Lisa Pastore, CCRP, University of California-Davis; Lewis Kuller, MD, DrPH, Roberta Moyer, CMA, Cheryl Albig, CMA, University of Pittsburgh; Gregory Burke, MD, Steve Rapp, PhD, Dee Posey, Margie Lamb, RN, Wake Forest University School of Medicine. Schwabe Pharmaceuticals: Robert Hörr, MD, Joachim Herrmann, PhD.
Project Office: Richard L. Nahin, PhD, MPH, Barbara C. Sorkin, PhD, National Center for Complementary and Alternative Medicine. Clinical Centers: Michelle Carlson, PhD, Linda Fried, MD, MPH, Pat Crowley, MS, Claudia Kawas, MD, Paulo Chaves, MD, PhD, Sevil Yasar, MD, PhD, Patricia Smith, Joyce Chabot, John Hopkins University; John Robbins,
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Dr. Ives’ institution received grant support and support for travel from National Center for Complementary and Alternative Medicine/NIH. Dr. Ives is employed by the University of Pittsburgh and received support for article research from the NIH. Dr. Fitzpatrick and her institution received grant support from the NIH and Centers for Disease Control and Prevention (CDC). Dr. Fitzpatrick received support for article research from the NIH and CDC. Dr. Williamson’s institution received grant support and support for travel from the NIH. Dr. Williamson received support for article research from the NIH. Dr. Arnold and her institution received grant support from the NIH. Dr. Arnold received support for travel and support for article research from the NIH. Dr. DeKosky’s institution received grant support from the NIH, support for travel from the NIH, and the active Gingko Extract and the placebo tablets for the original Gingko Effect on Memory trial from Schwabe Pharamaceuticals. Dr. DeKosky received support for article research from the NIH. Dr. Yende’s institution received grant support from the NIH. Dr. Yende received support for article research from the NIH and National Institute of General Medical Sciences (K23GM083215). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: [email protected]
Objectives: Severe infections, often requiring ICU admission, have been associated with persistent cognitive dysfunction. Less severe infections are more common and whether they are associated with an increased risk of dementia is unclear. We determined the association of pneumonia hospitalization with risk of dementia in well-functioning older adults. Design: Secondary analysis of a randomized multicenter trial to determine the effect of Gingko biloba on incident dementia. Setting: Five academic medical centers in the United States. Subjects: Healthy community volunteers (n = 3,069) with a median follow-up of 6.1 years. Interventions: None. Measurement and Main Results: We identified pneumonia hospitalizations using International Classification of Diseases, 9th Edition— Coding Manual codes and validated them in a subset. Less than 3% of pneumonia cases necessitated ICU admission, mechanical ventilation, or vasopressor support. Dementia was adjudicated based on neuropsychological evaluation, neurological examination, and MRI. Two hundred twenty-one participants (7.2%) incurred at least one hospitalization with pneumonia (mean time to pneumonia = 3.5 yr). Of these, dementia was developed in 38 (17%) after pneumonia, with half of these cases occurring 2 years after the pneumonia hoswww.ccmjournal.org
1037
Tate et al pitalization. Hospitalization with pneumonia was associated with increased risk of time to dementia diagnosis (unadjusted hazard ratio = 2.3; CI, 1.6–3.2; p 3 yr). Prior studies that assessed the association between infection Dementia is a chronic degenerative disease and the patho- and cognitive dysfunction examined changes in cognitive physiologic changes of dementia were likely to be underway function alone rather than diagnosis of dementia (16–20). prior to the occurrence of pneumonia in our study. Our results Our primary endpoint was all-cause dementia and was adjusuggest that an episode of infection accelerates dementia. A dicated based on detailed neuropsychological assessment, potential mechanism to explain this association could be perneurological and medical evaluation, and MRI of the brain sistent inflammation in the systemic circulation or in the brain using previously validated approaches (26–29). Finally, or due to activation of other aspects of the innate immune prior studies either used a case-control design or conducted response, as evidenced in observational human studies (4–9, a within-person analysis of infection patients alone (16– 13–15) and in animal models (10–12, 45). For example, a single 20). By contrast, we used a cohort design and propensitylipopolysaccharide injection in animals causes chronic neuro- matched analysis and compared risk among several different inflammation and long-term cognitive deficits and accelerates groups, including those hospitalized with pneumonia, other neurodegenerative conditions (10–12). Epidemiologic studies infections, and for other reasons. in individuals without an infection have shown that a small Our study has limitations. First, we used ICD-9 codes and increase in circulating inflammatory mediators was associated text field searches to identify pneumonia hospitalization. Prior with dementia (7) and in those with an infection have shown studies suggest that these approaches have good accuracy (35), increased and in some cases persistent circulating inflammation. and chart review of participants in our study showed that over Although our study primarily focused on less severe infec90% of cases met clinical and radiologic criteria for pneumotions, recent work by our group suggests that the risk of nia. Second, we did not have data regarding outpatient infecdementia is similar regardless of the severity of infection (46). tions, and whether infections occurring in the outpatient setting Furthermore, the risk of dementia in this study was similar to have a similar effect on dementia is not known. Third, we do not the risk of dementia observed in patients with severe pneumoknow the percentage of participants who experienced delirium nia and severe sepsis. Thus, our results could be generalized or received psychoactive medications, factors that may contribto patients hospitalized with infection in different countries, ute to increased risk of dementia. Finally, we did not use a formal whose illness severity may be different from those in the index of frailty. Instead, we used decline in physical and cogniUnited States. tive function scores over time as an approximation for frailty. 1044
www.ccmjournal.org
May 2014 • Volume 42 • Number 5
Feature Articles
In conclusion, episodes of pneumonia are associated with higher risk of dementia diagnosis. Future studies should examine mechanisms underlying this association.
REFERENCES
1. Brookmeyer R, Johnson E, Ziegler-Graham K, et al: Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement 2007; 3:186–191 2. Thies W, Bleiler L: 2011 Alzheimer’s disease facts and figures. Alzheimers Dement 2011; 7:208–244 3. Weaver JD, Huang MH, Albert M, et al: Interleukin-6 and risk of cognitive decline: MacArthur studies of successful aging. Neurology 2002; 59:371–378 4. Yaffe K, Lindquist K, Penninx BW, et al: Inflammatory markers and cognition in well-functioning African-American and white elders. Neurology 2003; 61:76–80 5. Ravaglia G, Forti P, Maioli F, et al: Blood inflammatory markers and risk of dementia: The Conselice Study of Brain Aging. Neurobiol Aging 2007; 28:1810–1820 6. Engelhart MJ, Geerlings MI, Meijer J, et al: Inflammatory proteins in plasma and the risk of dementia: The Rotterdam study. Arch Neurol 2004; 61:668–672 7. Schmidt R, Schmidt H, Curb JD, et al: Early inflammation and dementia: A 25-year follow-up of the Honolulu-Asia Aging Study. Ann Neurol 2002; 52:168–174 8. Yende S, D’Angelo G, Kellum JA, et al; GenIMS Investigators: Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis. Am J Respir Crit Care Med 2008; 177:1242–1247 9. Kale S, Yende S, Kong L, et al; GenIMS Investigators: The effects of age on inflammatory and coagulation-fibrinolysis response in patients hospitalized for pneumonia. PLoS One 2010; 5:e13852 10. Richwine AF, Parkin AO, Buchanan JB, et al: Architectural changes to CA1 pyramidal neurons in adult and aged mice after peripheral immune stimulation. Psychoneuroendocrinology 2008; 33:1369–1377 11. Qin L, Wu X, Block ML, et al: Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 2007; 55:453–462 12. Chen J, Buchanan JB, Sparkman NL, et al: Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav Immun 2008; 22:301–311 13. Brydon L, Harrison NA, Walker C, et al: Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans. Biol Psychiatry 2008; 63:1022–1029 14. Krabbe KS, Reichenberg A, Yirmiya R, et al: Low-dose endotoxemia and human neuropsychological functions. Brain Behav Immun 2005; 19:453–460 15. Reichenberg A, Yirmiya R, Schuld A, et al: Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 2001; 58:445–452 16. Iwashyna TJ, Ely EW, Smith DM, et al: Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 2010; 304:1787–1794 17. Jackson JC, Hart RP, Gordon SM, et al: Six-month neuropsychological outcome of medical intensive care unit patients. Crit Care Med 2003; 31:1226–1234 18. Hopkins RO, Weaver LK, Chan KJ, et al: Quality of life, emotional, and cognitive function following acute respiratory distress syndrome. J Int Neuropsychol Soc 2004; 10:1005–1017 19. Hopkins RO, Weaver LK, Collingridge D, et al: Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome. Am J Respir Crit Care Med 2005; 171:340–347 20. Ehlenbach WJ, Hough CL, Crane PK, et al: Association between acute care and critical illness hospitalization and cognitive function in older adults. JAMA 2010; 303:763–770 21. Fry AM, Shay DK, Holman RC, et al: Trends in hospitalizations for pneumonia among persons aged 65 years or older in the United States, 1988-2002. JAMA 2005; 294:2712–2719
Critical Care Medicine
22. Hebert PL, McBean AM, Kane RL: Explaining trends in hospitalizations for pneumonia and influenza in the elderly. Med Care Res Rev 2005; 62:560–582 23. Wier LM, Pfuntner A, Maeda J, et al: HCUP Facts and Figures: Statistics on Hospital-Based Care in the United States, 2009. Rockville, MD, Agency for Healthcare Research and Quality, 2011 24. DeKosky ST, Fitzpatrick A, Ives DG, et al; GEMS Investigators: The Ginkgo Evaluation of Memory (GEM) study: Design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia. Contemp Clin Trials 2006; 27:238–253 25. DeKosky ST, Williamson JD, Fitzpatrick AL, et al; Ginkgo Evaluation of Memory (GEM) Study Investigators: Ginkgo biloba for prevention of dementia: A randomized controlled trial. JAMA 2008; 300:2253–2262 26. McKhann G, Drachman D, Folstein M, et al: Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34:939–944 27. Erkinjuntti T: Clinical criteria for vascular dementia: The N INDS-AIREN criteria. Dementia 1994; 5:189–192 28. Rockwood K, Parhad I, Hachinski V, et al: Diagnosis of vascular dementia: Consortium of Canadian Centres for Clinical Cognitive Research consensus statement. Can J Neurol Sci 1994; 21:358–364 29. Chui HC, Mack W, Jackson JE, et al: Clinical criteria for the diagnosis of vascular dementia: A multicenter study of comparability and interrater reliability. Arch Neurol 2000; 57:191–196 30. Teng EL, Chui HC: The Modified Mini-Mental State (3MS) examination. J Clin Psychiatry 1987; 48:314–318 31. Rosen WG, Mohs RC, Davis KL: A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984; 141:1356–1364 32. Morris JC: The Clinical Dementia Rating (CDR): Current version and scoring rules. Neurology 1993; 43:2412–2414 33. Lopez OL, Becker JT, Klunk W, et al: Research evaluation and diagnosis of probable Alzheimer’s disease over the last two decades: I. Neurology 2000; 55:1854–1862 34. Lopez OL, Kuller LH, Fitzpatrick A, et al: Evaluation of dementia in the cardiovascular health cognition study. Neuroepidemiology 2003; 22:1–12 35. Guevara RE, Butler JC, Marston BJ, et al: Accuracy of ICD-9-CM codes in detecting community-acquired pneumococcal pneumonia for incidence and vaccine efficacy studies. Am J Epidemiol 1999; 149:282–289 36. Fine MJ, Smith MA, Carson CA, et al: Prognosis and outcomes of patients with community-acquired pneumonia. A meta-analysis. JAMA 1996; 275:134–141 37. Rosenbaum PR, Rubin DB: The central role of the propensity score in observational studies for causal effects. Biometrika 1983; 70:41–55 38. Austin PC: Goodness-of-fit diagnostics for the propensity score model when estimating treatment effects using covariate adjustment with the propensity score. Pharmacoepidemiol Drug Saf 2008; 17:1202–1217 39. Roy B, Pawar PP, Desai RV, et al: A propensity-matched study of the association of diabetes mellitus with incident heart failure and mortality among community-dwelling older adults. Am J Cardiol 2011; 108:1747–1753 40. Nagin DS, Odgers CL: Group-based trajectory modeling in clinical research. Annu Rev Clin Psychol 2010; 6:109–138 41. Rosenbaum PR: Sensitivity to hidden bias. In: Observational Studies. Second Edition. Rosenbaum PR (Ed). New York, NY, Springer-Verlag, 2002, pp 110–124 42. Jones BL, Nagin DS: Advances in group-based trajectory modeling and an SAS procedure for estimating them. Sociol Methods Res 2007; 35:542–571 43. Yende S, Angus DC, Ali IS, et al: Influence of comorbid conditions on long-term mortality after pneumonia in older people. J Am Geriatr Soc 2007; 55:518–525 44. Kaplan V, Angus DC, Griffin MF, et al: Hospitalized community-acquired pneumonia in the elderly: Age- and sex-related patterns of care and outcome in the United States. Am J Respir Crit Care Med 2002; 165:766–772 www.ccmjournal.org
1045
Tate et al 45. Cunningham C, Campion S, Lunnon K, et al: Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry 2009; 65: 304–312 46. Shah FA, Pike F, Alvarez K, et al: Bidirectional relationship between cognitive function and pneumonia. Am J Respir Crit Care Med 2013; 188:586–592 47. Rockwood K, Song X, MacKnight C, et al: A global clinical measure of fitness and frailty in elderly people. CMAJ 2005; 173:489–495
48. Morley JE, Haren MT, Rolland Y, et al: Frailty. Med Clin North Am 2006; 90:837–847 49. Sligl WI, Eurich DT, Marrie TJ, et al: Only severely limited, premorbid functional status is associated with short- and long-term mortality in patients with pneumonia who are critically ill: A prospective observational study. Chest 2011; 139:88–94 50. Sligl WI, Majumdar SR: How important is age in defining the prognosis of patients with community-acquired pneumonia? Curr Opin Infect Dis 2011; 24:142–147
APPENDIX 1. GEM Study Investigators
MD, MHS, Katherine Gundling, MD, Sharene Theroux, CCRP, Lisa Pastore, CCRP, University of California-Davis; Lewis Kuller, MD, DrPH, Roberta Moyer, CMA, Cheryl Albig, CMA, University of Pittsburgh; Gregory Burke, MD, Steve Rapp, PhD, Dee Posey, Margie Lamb, RN, Wake Forest University School of Medicine. Schwabe Pharmaceuticals: Robert Hörr, MD, Joachim Herrmann, PhD.
Project Office: Richard L. Nahin, PhD, MPH, Barbara C. Sorkin, PhD, National Center for Complementary and Alternative Medicine. Clinical Centers: Michelle Carlson, PhD, Linda Fried, MD, MPH, Pat Crowley, MS, Claudia Kawas, MD, Paulo Chaves, MD, PhD, Sevil Yasar, MD, PhD, Patricia Smith, Joyce Chabot, John Hopkins University; John Robbins,
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May 2014 • Volume 42 • Number 5
