296 Chapter 12 Care Unit (ICU) with sepsis caused by pneumonia have elevated ferritin concentrations in their blood [8]. We studied the incidence of hyperferritinemia in non-ICU patients presenting to the hospital with pneumonia and its association with pathogenic features of pneumonia. We found that hyperferritinemia in patients with pneumonia admitted to a general ward was associated with enhanced systemic inflammation, neutrophil activation, cytokine release, endothelial cell activation and dysfunction, and activation of the coagulation system. As such, hyperferritinemia identified pneumonia patients with a broad deregulation of various host response mechanisms implicated in the pathogenesis of sepsis. This is interesting, as circulating ferritin levels have been and are used as inclusion criterion in trials evaluating immunomodulatory therapies in acute infections and may assist in identifying patients who might benefit from such therapies [9,10](clinicaltrials.gov identifiers NCT04530578, NCT04341675, NCT04443881, NCT04990232). Our study was not designed to associate hyperferritinemia with a longer length of hospital stay or transfer to the ICU. It would be interesting for future studies to investigate these clinically relevant outcome measures. Parallel to efforts for sepsis stratification, ferritin could be an easily obtainable biomarker for future theragnostic use in pneumonia subgroups. The need for biomarkers in critically ill patients might be even larger than for pneumonia patients on the general ward, given the higher morbidity and mortality, but research is also more challenging. This is due to the high complexity of disease and the many “confounding” factors that ICU care entails, such as concurrent mechanical ventilation, infusion of vasoactive medication, renal replacement therapy, and so on. With the ultimate goal of more targeted therapy for the individual patient in mind, it is extra challenging to study the host response in the ICU setting. Critically ill patients in the ICU, including those with a sepsis admission diagnosis, are vulnerable to secondary opportunistic infections. Immune suppression is implicated as a key factor placing ICU patients at risk for the development of ICU-acquired infections [11,12], however studies also show that the patients with these infections, rather than only showing signs of immune suppression, demonstrated wide-ranging disturbances across multiple pathophysiological domains as compared to patients who do not develop an ICUacquired infection [13]. In Chapter 5 we tested the hypothesis that critically ill patients, irrespective of their primary reason for admission, exhibit broad anomalies in their host response both prior to and during ICU-acquired pneumonia, and that these are distinctive from patients who do not acquire pneumonia while on the ICU. For this, we measured 19 host response biomarkers providing insight into key pathophysiological pathways in plasma samples collected in a prospective observational study in patients admitted to 30 ICUs throughout Europe with various admission diagnoses (medical, trauma, surgical) and compared patients who developed pneumonia during their ICU stay (cases) with patients who did not develop pneumonia (controls). We found that cases showed biomarker concentrations suggestive of enhanced inflammation and a more disturbed endothelial barrier function, both shortly after ICU admission and in the days prior to pneumonia diagnosis. Baseline host response biomarker aberrations were most profound in patients who developed pneumonia either shortly (<5 days) or late (>10 days) after ICU admission. While the time windows chosen are arbitrarily, possibly these groups represent distinct pathobiological phenotypes, with in the first group changes that were partially the consequence of an already evolving infectious
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