Concurrent Immune Suppression and Hyperinflammation in Patients With Community-Acquired Pneumonia

Abstract

Background: The nature and timing of the host immune response during infections remain uncertain and most knowledge is derived from critically ill sepsis patients. We aimed to test the hypothesis that community-acquired pneumonia (CAP) is associated with concurrent immune suppression and systemic inflammation.

Methods: Blood was collected from 79 CAP patients within 24 h after hospitalization and 1 month after discharge; 42 age- and sex-matched subjects without acute infection served as controls. Blood leukocytes were stimulated with lipopolysaccharide (LPS) or Klebsiella pneumoniae, and cytokines were measured in supernatants. Fifteen plasma biomarkers reflective of key host response pathways were compared between CAP patients with the strongest immune suppression (lowest 25% blood leukocyte tumor necrosis factor (TNF)-α production in response to LPS) and those with the least immune suppression (highest 25% of LPS-induced TNF-α production).

Results: Blood leukocytes of CAP patients (relative to control subjects) showed a reduced capacity to release TNF-α, interleukin (IL)-1β, IL-6 and IL-10 upon stimulation with LPS or K. pneumoniae, with a concurrently enhanced ability to release the anti-inflammatory mediator IL-1 receptor antagonist, irrespective of the presence of sepsis (18.9% of cases). Low (relative to high) TNF-α producers displayed higher plasma levels of biomarkers reflecting systemic inflammation, neutrophil degranulation, endothelial cell activation, a disturbed vascular barrier function and coagulation activation.

Conclusion: CAP replicates a common feature of immune suppression in sepsis. The coexistence of immune suppression and hyperinflammation in CAP argues against the theory of two distinct phases during the host response to sepsis.

Keywords: community-acquired pneumonia; immune suppression; lipopolysaccharide; sepsis; systemic inflammation.

FIGURE 1

Blood leukocytes of patients with community-acquired pneumonia show an altered cytokine production profile upon ex vivo stimulation. Whole blood leukocytes were obtained from CAP patients at admission (n = 79) and 1 month following admission (n = 55), and from non-infected age and sex-matched controls (n = 42), and stimulated for 24 h with lipopolysaccharide (LPS; 100 ng/mL) or heat-killed Klebsiella pneumoniae (equivalent of 12.5 × 10⁶ CFU/mL). Cytokines were measured in supernatants. Individual data points are displayed with the horizontal line depicting the median. Dotted lines indicate the median concentrations in medium control samples (i.e., blood leukocytes incubated without stimulus), which were all significantly altered compared to LPS and K. pneumoniae stimulation. Asterisks indicate differences between groups as indicated (*P < 0.05, **P < 0.01, ***P < 0.001). IL, interleukin; TNF, tumor necrosis factor; RA, receptor antagonist.

FIGURE 2

Cytokine production of blood leukocytes from patients with community-acquired pneumonia stratified according to TNF-α production capacity. Patients were stratified into those with the lowest 25% blood leukocyte TNF-α production (low TNF-α producers, n = 20) and those with the highest 25% blood leukocyte TNF-α production (high TNF-α producers, n = 20) following LPS stimulation. Cytokines were measured in supernatants of whole blood leukocytes stimulated for 24 h with lipopolysaccharide (LPS; 100 ng/mL) or heat-killed Klebsiella pneumoniae (equivalent of 12.5 × 10⁶ CFU/mL). Individual data points are displayed with the horizontal line depicting the median. Dotted lines indicate median concentrations in medium control samples (i.e., blood leukocytes incubated without stimulus), which were all significantly altered compared to LPS and K. pneumoniae stimulation. Asterisks indicate differences between patients with the lowest and the highest TNF-production following LPS stimulation (**P < 0.01, ***P < 0.001). IL, interleukin; TNF, tumor necrosis factor; RA, receptor antagonist.

FIGURE 3

Host response plasma biomarker levels in patients with community-acquired pneumonia with the lowest and highest blood leukocyte TNF-α production following LPS stimulation. Patients were stratified into those with the lowest 25% blood leukocyte TNF-α production (low TNF-α producers, n = 20) and those with the highest 25% blood leukocyte TNF-α production (high TNF-α producers, n = 20) following LPS stimulation. Plasma biomarkers were measured upon hospital admission. Individual data points are displayed with the horizontal line depicting the median. Dotted lines indicate median values obtained in 42 healthy age- and sex-matched subjects. Values in patients were all significantly different from those in healthy control subjects. Asterisks indicate differences between patients with the lowest 25% and the highest 25% TNF-production following LPS stimulation (Benjamini-Hochberg corrected, *P < 0.05, **P < 0.01). CRP, C-reactive protein; MPO, myeloperoxidase; NGAL, neutrophil gelatinase-associated lipocalin; sE-Selectin, soluble E-selectin; sTREM-1, soluble triggering receptor expressed on myeloid cells 1; sVCAM-1, soluble vascular cell adhesion protein 1; TFF3, trefoil factor 3.