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

Crit Care Med. 2021 Nov 1;49(11):1901-1911. doi: 10.1097/CCM.0000000000005072.


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.

Trial registration: NCT01905033 NCT02928367 NCT04324021 NCT04330638.

Publication types

  • Observational Study

MeSH terms

  • Aged
  • Biomarkers / blood
  • Cohort Studies
  • Community-Acquired Infections / blood*
  • Community-Acquired Infections / therapy
  • Critical Illness / therapy*
  • Ferritins / blood*
  • Humans
  • Intensive Care Units
  • Macrophage Activation*
  • Male
  • Middle Aged
  • Netherlands
  • Pneumonia, Bacterial / blood*
  • Pneumonia, Bacterial / therapy
  • Prospective Studies
  • Severity of Illness Index


  • Biomarkers
  • Ferritins

Associated data