The relationship between functional status and inflammatory disease in older adults.

Abstract

Listen

Translate article

DECLINE in functional status is a profound predictor of morbidity and mortality, as previously pointed out in an editorial in the Journal (1). Decline in functional status during a hospitalization is a major predictor of risk for nursing home placement (2,3), subsequent acute illness (4), and declining quality of life (5). Functionally impaired nursing home residents tend to become more functionally impaired over time and have a higher death rate. Frailty is related to loss of instrumental activities of daily living and sarcopenia (loss of muscle mass) is strongly related to frailty and functional decline (6–9). A series of articles in the Journal suggested that loss of mobility and a decline in walking speed is related to the development of frailty (10–17). Recently a body of evidence has emerged that suggests that many of these effects are due to excess production of cytokines. Cytokines are cell-associated proteins produced and secreted by inflammatory cells that have the capacity to act at low concentrations on other cells both locally and systematically via specific cell receptors. Cytokines act principally in a paracrine fashion, and their concentrations in tissues are often several times higher than those found in the peripheral circulation. Aging is characterized by progressively increased concentrations of glucocorticoids and catecholamines and decreased production of growth and sex hormones, a pattern reminiscent of that seen in chronic stress. Plasma levels of interleukin-6 (IL-6) increase with age, probably as the result of catecholamine hypersecretion and sex-steroid hyposecretion. However, the age-associated changes in cytokine production are inconsistent (18,19). Cohen and colleagues found that IL-6 levels correlate with the functional disability of the community-dwelling elderly person (20). In 3075 older men and women evaluated in the Health ABC study, higher levels of IL-6 or tumor necrosis factor alpha (TNF-a) were associated with lower muscle mass and strength (21). This suggests that IL-6 may contribute to the increased morbidity and mortality seen in chronically stressed or physiologically aged persons. In 1723 participants older than 71 years, IL-6 and D-dimer were measured and participants were followed for 5-year mortality and functional status. The relative risk of mortality was 1.28 (95% confidence interval [CI]: 0.98–1.69; p5 .06) for those with only IL-6 levels in the highest quartile, 1.53 (95% CI: 1.18–1.97; p 5 .001) for participants with only Ddimer levels in the highest quartile, and 2.00 (95% CI: 1.53– 2.62; p 5 .0001) for those with levels of both in the highest quartile, as compared with those who were not in either of the highest quartiles. Those participants with high IL-6 and high D-dimer levels had the greatest declines in all measures of function. Thus, activation of the coagulation and inflammatory pathways was associated with mortality and decline in function, and may contribute to the development of a frailty phenotype in elderly people (22). In high-functioning healthy, nondisabled older persons, serum albumin and plasma IL-6 were measured at baseline and followed for 4 years. Among participants without evidence of IL-6-mediated inflammation, having a lower albumin level was associated with a multiply adjusted relative mortality risk of 2.1, compared with those with higher albumin. In the presence of elevated IL-6 levels, either high and low serum albumin levels had increased risk (adjusted relative risks 4.0 and 3.8, respectively) compared with the group with higher albumin and low IL-6. High serum albumin has a protective effect in healthy older persons who do not have evidence of cytokine-mediated inflammation. This protective effect is not seen in the presence of inflammation (23). In congestive heart failure (CHF) patients, elevated plasma cytokine levels are associated with poor functional status and a worse prognosis. Elevated levels of TNF-a are associated with mortality in patients with CHF (24). Cytokine levels also appear to predict the incidence of CHF in asymptomatic individuals. Among 732 elderly Framingham Study participants whose mean age was 78 years and who were free of prior myocardial infarction and CHF, 56 participants developed CHF after a mean of 5.2 years of follow-up. After adjustment for established risk factors, including the occurrence of myocardial infarction on follow-up, there was a 60% (TNF-a) to 68% (serum IL-6) increase in risk of CHF per tertile increment in cytokine concentration. An elevated serum C-reactive protein (CRP) level was associated with a 2.8-fold increased risk of CHF. Participants with elevated levels of all 3 biomarkers had a markedly increased risk of CHF (hazards ratio 4.07 [95% CI 1.34–12.37], p 5 .01) compared with the other participants. In this elderly community-based sample, a single determination of serum inflammatory markers, particularly elevated IL-6, predicted an increased risk of CHF in people without prior myocardial infarction (25).