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Background. Nowadays, invasive fungal infections (IFI) are of increasing importance and associated with an increased mortality. However, reliable diagnostic tools for the identification of patients suffering from an IFI are rare and associated with relevant weaknesses. Methods. Within this secondary analysis of an observational clinical study, an innovative biomarker panel (consisting of 62 biomarkers in total) was screened for the identification of septic shock patients suffering from an IFI. Fungal growth in blood cultures, intraoperative swabs, and Aspergillus spp. in deep respiratory tract specimens with accompanying pulmonary infiltrates were classified as infection, whereas Candida spp. in the respiratory tract or in fluids from drainages were classified as colonization. Plasma samples of 50 septic shock patients at six predefined timepoints within a period of 28 days following the onset of septic shock were available. Results. In total, 11 out of the 50 patients (22%) were shown to suffer from an IFI, whereas 22 patients (44%) presented with a fungal colonization. Within the presented biomarker panel, plasma levels of soluble intercellular adhesion molecule- (sICAM-) 1, thrombospondin-1, and vinculin were shown to be the most promising. sICAM-1 was shown to be increased in patients with an IFI, whereas thrombospondin-1 and vinculin revealed decreased plasma levels as compared to colonized patients as well as patients without any fungal findings at any time. Conclusion. Plasmatic measurements of sICAM-1, thrombospondin-1, and vinculin may help to facilitate the diagnosis of an IFI in human septic shock and to identify patients with an increased risk for an IFI. This trial is registered with DRKS00005463.

Early sepsis identification is of paramount importance for an effective therapy and the patient outcome; however, a suitable prognostic biomarker is lacking. Anti-inflammatory nonneuronal cholinergic signaling modulates the magnitude of an immune response. Serum cholinesterase (BChE), an enzyme that hydrolyzes acetylcholine, plays an important role during inflammatory response and serves as an accurate index of cholinergic activity. BChE activity was measured in septic patients using a point-of-care system, and levels of conventional inflammatory markers and the disease severity scores were obtained. We observed a strong, sustained reduction in BChE activity in patients who died within a 90-day observation period, as compared to survivors. Reduced BChE activity when measured at the ICU admission effectively differentiated between the 90-day survivor and the nonsurvivor patient groups. We estimated a critical BChE level of 1.661 kU/L (CI 0.5–0.8, 94% sensitivity, 48% specificity, AUC 0.7) to best predict patient outcome providing a benchmark criterion for early detection of potentially fatal sepsis measured at the admission. This finding suggests that the BChE activity, used in combination with the laboratory tests, clinical examination, and the disease severity scoring, could serve to identify high-risk patients at the ICU admission, the most critical time point in the sepsis treatment.

Fungi are of increasing importance in sepsis. However, culture-based diagnostic procedures are associated with relevant weaknesses. Therefore, culture- and next-generation sequencing (NGS)-based fungal findings as well as corresponding plasma levels of β-d-glucan, interferon gamma (INF-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-2, -4, -6, -10, -17A, and mid-regional proadrenomedullin (MR-proADM) were evaluated in 50 septic patients at six consecutive time points within 28 days after sepsis onset. Furthermore, immune-response patterns during infections with Candida spp. were studied in a reconstituted human epithelium model. In total, 22% (n = 11) of patients suffered from a fungal infection. An NGS-based diagnostic approach appeared to be suitable for the identification of fungal pathogens in patients suffering from fungemia as well as in patients with negative blood cultures. Moreover, MR-proADM and IL-17A in plasma proved suitable for the identification of patients with a fungal infection. Using RNA-seq., adrenomedullin (ADM) was shown to be a target gene which is upregulated early after an epithelial infection with Candida spp. In summary, an NGS-based diagnostic approach was able to close the diagnostic gap of routinely used culture-based diagnostic procedures, which can be further facilitated by plasmatic measurements of MR-proADM and IL-17A. In addition, ADM was identified as an early target gene in response to epithelial infections with Candida spp.