Hyperferritinemia in Critically Ill Patients*

Abstract

Objective: Hyperferritinemia is frequently seen in critically ill patients. A rather rare though life-threatening condition related to severely elevated ferritin is hemophagocytic lymphohistiocytosis. We analyze ferritin levels to differentiate hemophagocytic lymphohistiocytosis from other causes of hyperferritinemia in a mixed cohort of critically ill patients. Design: Retrospective observational study. Setting: Adult surgical, anesthesiologic, and medical ICUs of a university hospital. Patients: Critical care patients (≥ 18 yr old) admitted to any of the adult ICUs at Charité – Universitätsmedizin Berlin between January 2006 and August 2018 with at least one ferritin value and hyperferritinemia (≥ 500 µg/L). Interventions: None. Measurements and Main Results: Patients were categorized into hemophagocytic lymphohistiocytosis, sepsis, septic shock, and other diagnoses. These were further categorized into 17 subgroups. Hemophagocytic lymphohistiocytosis diagnosis was based on Hemophagocytic Lymphohistiocytosis-2004 criteria and the HScore. Of 2,623 patients with hyperferritinemia, 40 were considered to have hemophagocytic lymphohistiocytosis (1.52%). Maximum ferritin levels were highest in hemophagocytic lymphohistiocytosis patients compared with all other disease groups (each p < 0.001). Sepsis and septic shock patients had higher maximum ferritin levels than patients with other diagnoses (each p < 0.001). A maximum ferritin value of 9,083 µg/L was at 92.5% sensitivity and 91.9% specificity for hemophagocytic lymphohistiocytosis (area under the curve, 0.963; 95% CI, 0.949–0.978). Of all subgroups with other diagnoses, maximum ferritin levels were highest in patients with varicella-zoster virus, hepatitis, or malaria (median, 1,935, 1,928, and 1,587 µg/L, respectively). Maximum ferritin levels were associated with increased in-hospital mortality (odds ratio, 1.518 per log µg/L [95% CI, 1.384–1.665 per log µg/L]; p < 0.001). Conclusions: This is the largest study of patients with ferritin available in a mixed ICU cohort. Ferritin levels in patients with hemophagocytic lymphohistiocytosis, sepsis, septic shock, and other conditions were distinctly different, with the highest ferritin levels observed in hemophagocytic lymphohistiocytosis patients. Maximum ferritin of 9,083 µg/L showed high sensitivity and specificity and, therefore, may contribute to improved diagnosis of hemophagocytic lymphohistiocytosis in ICU. The inclusion of ferritin into the sepsis laboratory panel is warranted.

Sustained Immunoparalysis in Endotoxin-Tolerized Monocytic Cells

“…One additional aspect of interest, which has to be examined in future projects, is the host iron metabolism. By deregulating glucose metabolism, this mechanism has been shown to compromise the establishment of disease tolerance to sepsis [37,38].…”

COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy

“…For example, HFC in vitro directly binds chemokine receptor 4 (CXCR4) and affects CXCR2-mediated ERK1/2 activation [ 65 ]. Despite the acute rise of blood value of ferritin as part of the normal systemic response to inflammation, a hyperferritinemic response is associated with a significantly increased mortality in septic patients [ 24 , 27 ]. Although the main modulator of ferritin levels is iron availability, its synthesis may also be regulated by different inflammatory cytokines such as IL-1β and IL-6 [ 66 , 67 ].…”

Interdisziplinäres COVID-Board bei SARS-CoV-2-getriggerter hyperferritinämischer Inflammation

“…Ergänzend zeigte als Surrogat der lymphozytären Aktivierung der sIL2R eine im Median 2‑fache Erhöhung über den oberen Normwert (1519 U/ml (285–7192)). Beide, Ferritin und sIL2R, lagen damit deutlich unterhalb der für die hämophagozytische Lymphohistiozytose oder das Makrophagen-Aktivierungssyndrom bekannt exzessiv erhöhten Werte [ 4 ], reihen sich jedoch gut in hyperferritinämische Inflammation bei Sepsispatienten ein [ 18 ].…”