63 Hyperferritinemia in patients with pneumonia Introduction Ferritin, a protein secreted mainly by hepatocytes, macrophages and Kupffer cells, is a well-known acute phase reactant of which circulating levels increase in response to infection and other inflammatory conditions [1–4]. Hyperferritinemia has also been reported in more chronic disorders such as cancer, liver diseases, metabolic syndrome and kidney disease [5, 6]. In the clinic serum ferritin is mainly used as an indicator for iron status, where low ferritin levels indicate iron deficiency and elevated ferritin levels can be caused by multiple blood transfusions, hemochromatosis or rare diseases such as hereditary hyperferritinemia. Very high levels are suggestive of Still’s disease and hemophagocytic lymphohistiocytosis [1, 7–9]. In patients with sepsis, ferritin has been proposed as a biomarker for “macrophage activating-like syndrome” or MALS, a hyperinflammatory condition associated with increased mortality [1, 10]. Community-acquired pneumonia (CAP) is the world’s leading infectious killer and the most common cause of sepsis [11, 12]. We recently reported that 83% of critically ill patients with sepsis caused by CAP have elevated plasma ferritin concentrations upon admission to the Intensive Care Unit (ICU) [4]. Ten percent of CAP patients admitted to the ICU had ferritin concentrations above 4420 ng/ml [4], the suggested cut-off level for the diagnosis of MALS [1, 10]. In patients with CAP caused by SARS-CoV-2, the cause of coronavirus disease 2019 (COVID-19), circulating ferritin has been used to classify hyperinflammation and is a predictor of a favorable response to treatment with recombinant interleukin (IL)-1 receptor antagonist (RA) [13]. Therefore, hyperferritinemia is used as an inclusion criterion to select COVID-19 patients with exaggerated systemic inflammation; many trials use a ferritin level of 500 ng/ml or higher to identify patients that might benefit from anti-inflammatory therapy (clinicaltrials.gov identifiers NCT04530578, NCT04341675, NCT04443881). Knowledge of the incidence of hyperferritinemia in (non-ICU) patients presenting to the hospital with CAP and its association with activation of distinct proinflammatory host response mechanisms is limited. We here sought to determine the association of hyperferritinemia in CAP patients admitted to a general hospital ward with their clinical presentation, outcome and aberrations in key host response pathways implicated in the immunopathology of pneumonia and sepsis. Methods Study population and sample collection Patients were recruited as part of the ELDER-BIOME study (clinicaltrials.gov identifier NCT02928367) or OPTIMACT study (Dutch Trail Register identifier NTR6163), both approved by the medical ethical committees of the participating hospitals in the Netherlands: Amsterdam University Medical Centers, BovenIJ Hospital and Spaarne Gasthuis Hospital [14–16]. Consecutive patients older than 18 years admitted between October 2016 and July 2018 in one of the three hospitals were screened by trained (research) physicians. Patients were included if they were admitted with an acute infection of the respiratory tract, defined as at least one respiratory symptom (new cough or sputum production, dyspnoea, chest pain, tachypnoea, or abnormal lung examination) and one systemic symptom (fever (>38°C) or hypothermia (<35.5°C), leukocytosis (>12x109/L) or leukopenia (<4x109/L), or elevated C-reactive protein (CRP); 4
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