The effects of age on inflammatory and coagulation-fibrinolysis response in patients hospitalized for pneumonia

Abstract

Objective: To determine whether inflammatory and hemostasis response in patients hospitalized for pneumonia varies by age and whether these differences explain higher mortality in the elderly.

Methods: In an observational cohort of subjects with community-acquired pneumonia (CAP) recruited from emergency departments (ED) in 28 hospitals, we divided subjects into 5 age groups (<50, 51-64, 65-74, 75-84, and ≥85). We measured circulating levels of inflammatory (TNF, IL-6, and IL-10), hemostasis (D-dimer, Factor IX, thrombin-antithrombin complex, antithrombin and plasminogen-activator inhibitor-1), and cell-surface markers (TLR-2, TLR-4, and HLA-DR) during the first week of hospitalization and at discharge and compared 90-day mortality. We used logistic regression to compare odds ratios (OR) for 90-day mortality between age groups, adjusting for differences in pre-infection factors alone and then additionally adjusting for immune markers.

Results: Of 2,183 subjects, 495, 444, 403, 583, and 258 subjects were <50, 51-64, 65-74, 75-84, and ≥85 years of age, respectively. Large age-related differences were observed in 90-day mortality (0.82% vs. 3.2% vs. 6.4% vs. 12.8% vs. 13.6%, p<0.01). No age-related differences in inflammatory and cell surface markers occurred during the first week. Older subjects had higher pro-coagulant markers on ED presentation and over first week (p ≤ 0.03), but these differences were modest (1.0-1.7-fold differences). Odds of death for older adults changed minimally in models incorporating differences in hemostasis and inflammatory markers (for subjects ≥ 85 compared to those <50, OR = 4.36, when adjusted for pre-infection factors and OR = 3.49 when additionally adjusted for hemostasis markers). At discharge, despite clinical recovery as evidenced by normal vital signs in >85% subjects, older subjects had modestly increased hemostasis markers and IL-6 levels (p<0.01).

Conclusions: Modest age-related increases in coagulation response occur during hospitalization for CAP; however these differences do not explain the large differences in mortality. Despite clinical recovery, immune resolution may be delayed in older adults at discharge.

Figure 1. A modest pro-coagulant response was seen in older subjects upon ED admission (Day 1) and during the first week of hospitalization.

There was an age-related increase in mean values of hemostasis markers D-dimer and thrombin-antithrombin complex (TAT) and an age-related decrease in F-IX, plasminogen-activator inhibitor-1 (PAI-1), and antithrombin (AT). Pa are p values from ANOVA or Tobit models adjusted for sex, race, comorbidity, and smoking status to compare differences in mean levels of markers on Day 1 across different age groups. Pb are p values for linear trend tests for markers on Day 1, adjusted for sex, race, comorbidity, and smoking status. Pc are p values from mixed effects model adjusted for sex, race, comorbidity, and smoking status to compare mean levels over the first week.

Figure 2. No differences were found in the mean values of inflammatory (TNF, IL-6, and IL-10) markers when stratified by age group.

Markers were measured upon presentation to the ED and over the first week of hospitalization. Pa are p values from Tobit models adjusted for sex, race, comorbidity, and smoking status to compare differences in mean levels of markers on Day 1 across different age groups. Pc are p values from mixed effects model adjusted for sex, race, comorbidity, and smoking status to compare mean levels over the first week.

Figure 3. No differences were found in expression of cell surface markers when stratified by age group.

Markers were measured upon ED presentation and at days 3 and 7. Values for cell surface markers are reported as mean channel fluorescence (MCF) of cells positive for a given cell surface marker. Pa are p values from ANOVA models adjusted for sex, race, comorbidity, and smoking status to compare differences in mean levels of markers on Day 1 across different age groups. Pc are p values from mixed effects model adjusted for sex, race, comorbidity, and smoking status to compare mean levels on Days 1, 3, and 7.