Association of Hyperferritinemia With Distinct Host Response Aberrations in Patients With Community-Acquired Pneumonia.

BACKGROUND: Strongly elevated ferritin levels have been proposed to reflect systemic hyperinflammation in patients admitted to the intensive care unit. Knowledge of the incidence and pathophysiological implications of hyperferritinemia in patients with acute infection admitted to a non-intensive care setting is limited. METHODS: We determined the association between hyperferritinemia, defined by 2 cutoff values (500 and 250 ng/mL), and aberrations in key host response mechanisms among patients with community-acquired pneumonia (CAP) on admission to a general hospital ward (clinicaltrials.gov NCT02928367; trialregister.nl NTR6163). RESULTS: Plasma ferritin levels were higher in patients with CAP (n = 174; median [interquartile ranges], 259.5 [123.1-518.3] ng/mL) than in age- and sex-matched controls without infection (n = 50; 102.8 [53.5-185.7] ng/mL); P < .001); they were ≥500 ng/mL in 46 patients (26%) and ≥250 ng/mL in 90 (52%). Measurements of 26 biomarkers reflective of distinct pathophysiological domains showed that hyperferritinemia was associated with enhanced systemic inflammation, neutrophil activation, cytokine release, endothelial cell activation and dysfunction, and activation of the coagulation system. Results were robust across different cutoff values. CONCLUSIONS: Hyperferritinemia identifies patients with CAP with a broad deregulation of various host response mechanisms implicated in the pathogenesis of sepsis. This could inform future therapeutic strategies targeting subgroups within the CAP population.

Plasma Ferritin as Marker of Macrophage Activation-Like Syndrome in Critically Ill Patients With Community-Acquired Pneumonia.

OBJECTIVES: Plasma ferritin levels above 4,420 ng/mL have been proposed as a diagnostic marker for macrophage activation-like syndrome in sepsis and used for selection of sepsis patients for anti-inflammatory therapy. We here sought to determine the frequency, presentation, outcome, and host response aberrations of macrophage activation-like syndrome, as defined by admission ferritin levels above 4,420 ng/mL, in critically ill patients with community-acquired pneumonia. DESIGN: A prospective observational cohort study. SETTING: ICUs in two tertiary hospitals in the Netherlands. PATIENTS: One hundred fifty-three patients admitted with community-acquired pneumonia. MEASUREMENTS AND MAIN RESULTS: Patients were stratified in community-acquired pneumonia-macrophage activation-like syndrome (n = 15; 9.8%) and community-acquired pneumonia-control groups (n = 138; 90.2%) based on an admission plasma ferritin level above or below 4,420 ng/mL, respectively. Community-acquired pneumonia-macrophage activation-like syndrome patients presented with a higher disease severity and had a higher ICU mortality (46.7% vs 12.3% in community-acquired pneumonia-controls; p = 0.002). Twenty-three plasma biomarkers indicative of dysregulation of key host response pathways implicated in sepsis pathogenesis (systemic inflammation, cytokine responses, endothelial cell activation, and barrier function, coagulation activation) were more disturbed in community-acquired pneumonia-macrophage activation-like syndrome patients. Hematologic malignancies were overrepresented in community-acquired pneumonia-macrophage activation-like syndrome patients (33.3% vs 5.1% in community-acquired pneumonia-controls; p = 0.001). In a subgroup analysis excluding patients with hematologic malignancies (n = 141), differences in mortality were not present anymore, but the exaggerated host response abnormalities in community-acquired pneumonia-macrophage activation-like syndrome patients remained. CONCLUSIONS: Macrophage activation-like syndrome in critically ill patients with community-acquired pneumonia occurs more often in patients with hematologic malignancies and is associated with deregulation of multiple host response pathways.