Key Point

In a well-functioning elderly population, systemic tumor necrosis factor and interleukin-6 levels were both indicators of the risk of subsequent hospitalization for community-acquired pneumonia.

PITTSBURGH—Although years have passed since cytokines were shown to facilitate bacterial invasion leading to pneumonia, it remains unclear whether preinfection elevations of circulating cytokines predict pneumonia. Thus, the effect of preinfection tumor necrosis factor (TNF), interleukin-6 (IL-6), and C-reactive protein (CRP) levels on the risk of community-acquired pneumonia (CAP) requiring hospitalization was evaluated recently in a prospective study of 3,075 well-functioning elderly volunteers ages 70 to 79.¹

In the presence of comorbid conditions, elevated preinfection TNF and IL-6 levels significantly raised the risk, especially among participants with levels in the highest tertile. "Our findings may help to improve the stratification of pneumonia risk in the elderly, akin to similar work done with inflammatory markers in coronary artery disease," lead author Sachin Yende, MD, told Pulmonary Reviews. Instead of stratifying the risk by age and clinical factors alone, as is currently done, it may be more precise to also use specific inflammatory markers, explained Dr. Yende, Instructor in the Department of Critical Care Medicine at the University of Pittsburgh.

THE RATE OF CAP—5.2%

During the 6.5-year study, 161 of the volunteers were hospitalized for CAP at least once. "Only 19 participants had more than one episode of CAP," the authors related.

Compared to the participants who were not hospitalized for CAP, those with CAP were more likely to be male and current or past smokers. They had a higher frequency of comorbid conditions such as congestive heart failure, diabetes, and a reduced FEV₁ and were more likely to be using oral steroids. "TNF, IL-6, and CRP levels measured in blood at the time of entry into the study (ie, in the absence of infection) were higher among participants who experienced subsequent CAP," the authors pointed out.

Notably, among the study population, the overall rate of pneumococcal vaccination was only 29%. However, the rates were similar between the groups with and without CAP.

Linear dose-effect relationships between TNF and IL-6 tertiles and CAP risk were observed. However, only the highest tertiles of TNF (> 3.7 pg/mL) and IL-6 (> 2.4 pg/mL) significantly increased the risk of being hospitalized for CAP. It is interesting to note that these concentrations associated with increased risk of CAP are very low and detected only by sensitive cytokine assays.

After adjustment for demographics and comorbid conditions, the highest tertiles of TNF and IL-6 were associated with odds ratios of 1.6 and 1.7, respectively, for CAP requiring hospitalization. The exclusion of the 188 individuals who reported having had a respiratory tract infection two weeks before the blood tests for circulating cytokines did not alter those findings.

MARKERS ACTED SYNERGISTICALLY

"Because the highest tertiles of TNF and IL-6 were independently associated with risk of CAP, we ascertained the combined effect of these inflammatory markers," related the authors. "The risk increased substantially for participants with two versus one baseline inflammatory marker level in the highest tertile (odds ratio, 2.8 vs 1.6). Furthermore, the interaction between TNF and IL-6 levels in the highest tertile and risk of CAP was also significant, suggesting a synergistic effect for the combination."

The presence or absence of comorbidities was a major influence on CAP risk in the study population. The rate of CAP requiring hospitalization was only 2.9% among participants without comorbid conditions versus 7% for those with one and 10.7% for those with two or more comorbid conditions. There was no statistical association between cytokine levels and CAP in those with no comorbidities.

The odds ratio for hospitalization due to CAP when the TNF and IL-6 levels were both in the highest tertile was 8.1 among participants with two or more comorbidities and 4.0 for those with one comorbid condition; those odds ratios were 4.0 and 3.6 when only one cytokine was in the top tertile. The comorbid condition that conferred the highest adjusted CAP risk was a predicted FEV₁ of 50% or less, which increased 3.6-fold the odds of hospitalization for CAP.

"Obviously, we have not shown causality in this study," Dr. Yende stressed. A cause-effect relationship between circulating cytokines and CAP would be more certain, he said, if the study findings were confirmed by investigations in which inflammatory markers were measured in the months preceding CAP or measured over time. The findings also raise the question of whether it might be possible to better prevent CAP with medications that target the appropriate cytokines.

—Timothy Begany

Reference
1. Yende S, Tuomanen EI, Wunderink R, et al. Preinfection systemic inflammatory markers and risk of hospitalization due to pneumonia. Am J Respir Crit Care Med. 2005;172: 1440-1446.

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