Abstract
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.
Highlights
Sepsis, defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection [1], is most frequently a result of a bacterial infection [2,3,4], whereas those of a fungal or viral nature are less common [5,6,7]
Fungal pathogens are very common in critically ill patients and are associated with an increased morbidity, necessitating a comprehensive, reliable and fast diagnosis
An next-generation sequencing (NGS)-based diagnostic approach appeared to be suitable for the detection of fungal pathogens in plasma samples of patients with septic shock
Summary
Sepsis, defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection [1], is most frequently a result of a bacterial infection [2,3,4], whereas those of a fungal or viral nature are less common [5,6,7]. The group of infected patients appears to be small, the number of severe fungal infections is escalating due to an increase in the number of immunocompromised patients, a more aggressive surgical therapy in older patients with relevant co-morbidities, and an increasing number of oncologic diseases [5,8,12,13] Within this context, three fungal species seem to be of most relevance in Europe: Candida albicans (C. albicans), Candida glabrata (C. glabrata), and Aspergillus fumigatus [14,15]. The administration of life-saving antifungal therapy may either be completely absent, or initiated with a minimum delay of 2–3 days [22] Such a delay is known to be associated with an increased mortality [23,24]. The aims of this observational, prospective clinical study were to (1) assess the incidence, risk factors and relevance with regard to the outcome of fungal infections in patients with septic shock; (2) evaluate the additional benefit of a next-generation sequencing (NGS)-based diagnostic procedure; and (3) assess the host response upon fungal infection by investigating the diagnostic value of β-D-glucan (BG), galactomannan (GM), interferon gamma (INF-γ), tumor necrosis factor alpha (TNF-α), interleukins (IL)-2, -4, -6, -10, -17A, and mid-regional proadrenomedullin (MR-proADM) in septic patients as well as by analyzing the overall host response by expression profiling of Candida spp.-infected epithelia in vitro
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