Date Published: June 19, 2018
Publisher: Public Library of Science
Author(s): Dominik Schaack, Benedikt Hermann Siegler, Sandra Tamulyte, Markus Alexander Weigand, Florian Uhle, Sunil K Ahuja.
Sepsis is defined as a life-threatening condition, resulting from a dysregulated and harmful response of the hosts’ immune system to infection. Apart from this, the (over-)compensating mechanisms counterbalancing the inflammatory response have been proven to render the host susceptible to further infections and increase delayed mortality. Our study aimed to unravel the heterogeneity of immune response in early sepsis and to explain the biology behind it.
A systematic search of public repositories yielded 949 microarray samples from patients with sepsis of different infectious origin and early after clinical manifestation. These were merged into a meta-expression set, and after applying sequential conservative bioinformatics filtering, an in-deep analysis of transcriptional heterogeneity, as well as a comparison to samples of healthy controls was performed.
We can identify two distinct clusters of patients (cluster 1: 655 subjects, cluster 2: 294 subjects) according to their global blood transcriptome. While both clusters exhibit only moderate differences in direct comparison, a comparison of both clusters individually to healthy controls yielded strong expression changes of genes involved in immune responses. Both comparisons found similar regulated genes, with a stronger dysregulation occurring in the larger patient cluster and implicating a loss of monocyte and T cell function, co-occurring with an activation of neutrophil granulocytes.
We propose a consistent—but in its extent varying—presence of immunosuppression, occurring as early in sepsis as its clinical manifestation and irrespective of the infectious origin. While certain cell types possess contradictory activation states, our finding underlines the urgent need for an early host-directed therapy of sepsis side-by-side with antibiotics.
Critically ill patients on intensive care units (ICU) are affected by complex and frequently interwoven medical conditions. Above others, sepsis continues to challenge worldwide modern intensive care medicine as the main contributor to mortality and critical illness on ICU.[1,2]
Since the birth of microarray technology around the end of the last millennium, an enormous number of microarray experiments have been performed on uncountable cell types, conditions, and diseases. Earlier (meta-)analysis of sepsis microarrays were often performed in a narrative approach or by the re-analysis of individual studies. Contrasting, our study systematically searched, extracted and merged samples of 949 patients with sepsis and generated to our knowledge the largest meta-expression set available.
We need to reframe our perspectives on sepsis syndrome: Highly individual predisposition and the qualitative and quantitative characteristic of the insult mount a response, which can be “late sepsis” from start or “early sepsis” for days, with divergent activation states of different immune cells. Based on this concept, we need to identify the pathological phenotypes of the cells and the corresponding host-directed therapies. Several of which might be already available from oncology, but if they project into a reduction of antibiotic use, survival and quality of life of the patients has yet to be proven.