Sustained IL-6 and sTNF-αR1 levels after hip fracture predict 5-year mortality: A prospective cohort study from the Baltimore Hip Studies

Abstract

Background: Persistent inflammation is associated with adverse health outcomes, but its impact on mortality has not been investigated previously among hip fracture patients. This article aims to investigate the influence of changes in levels of cytokines in the 2 months after a hip fracture repair on 5-year mortality.

Methods: This is a prospective cohort study from the Baltimore Hip Studies (BHS) with 191 community-dwelling older men and women (≥65 years) who had recently undergone surgical repair of an acute hip fracture, with recruitment from May 2006 to June 2011. Plasma interleukin-6 (IL-6), soluble tumor necrosis factor alpha receptor1 (sTNFα-R1), and interleukin-1 receptor agonist (IL-1RA) were obtained within 22 days of admission and at 2 months. All-cause mortality over 5 years was determined. Logistic regression analysis tested the associations between the cytokines' trajectories and mortality over 5 years, adjusted for covariates (age, sex, education, body mass index, lower extremity physical activities of daily living, and Charlson comorbidity index).

Results: High levels of IL-6 and sTNFα-R1 at baseline with small or no decline at 2 months were associated with higher odds of 5-year mortality compared with those with lower levels at baseline and greater decline at 2 months after adjustment for age, and other potential confounders (OR = 4.71, p = 0.01 for IL-6; OR = 15.03, p = 0.002 for sTNFα-R1). Similar results that failed to reach significance were found for IL-1RA (OR = 2.40, p = 0.18). Those with higher levels of cytokines at baseline with greater decline did not have significantly greater mortality than the reference group, those with lower levels at baseline and greater decline.

Conclusion: Persistent elevation of plasma IL-6 and sTNFα-R1 levels within the first 2 months after hospital admission in patients with hip fracture is associated with higher 5-year mortality. These patients may benefit from enhanced care and earlier intensive interventions to reduce the risk of death.

Keywords: cytokine; fragility fractures; mortality; older adults.

FIGURE 1

Visual representation of the IL-1RA (A), IL-6 (B), and sTNF-αR1 (C) mean trajectories from baseline to 2 months after hospital admission after a hip fracture (N = 191). IL-1RA, interleukin-1 receptor antagonist; IL-6, interleukin-6; sTNF-αR1, soluble tumor necrosis factor alpha receptor 1. There is one missing value for sTNF-αR1.

FIGURE 2

Percentage of deaths over 5 years after the hip fracture according to the cytokines’ trajectories from baseline to 2 months. IL-1RA, interleukin-1 receptor antagonist; IL-6, interleukin-6; sTNF-αR1, soluble tumor necrosis factor alpha receptor 1. The percentages for the “low-decreased,” “low-small change,” “high-decreased,” and “high-small change” groups represent 15, 33, 40, and 20 participants respectively for IL-1RA; 13, 32, 37, and 26 participants for IL-6; 13, 32, 34, and 28 participants for sTNF-αR1. *p < 0.05 for the high-small change group compared with all other groups.

FIGURE 3

Overall survival of patients according to the cytokine trajectory groups: (A) interleukin-1 receptor antagonist (IL-1RA); (B) interleukin-6 (IL-6); and (C) soluble tumor necrosis factor alpha receptor (sTNF-αR1).