Large clinical trials testing hydrocortisone therapy in septic shock have produced
conflicting results. Subgroups may benefit of hydrocortisone treatment depending on
their individual immune response. We performed an exploratory analysis of the database
from the international randomized controlled clinical trial Corticosteroid Therapy of Septic
Shock (CORTICUS) employing machine learning to a panel of 137 variables collected
from the Berlin subcohort comprising 83 patients including demographic and clinical
measures, organ failure scores, leukocyte counts and levels of circulating cytokines. The
identified theranostic marker was validated against data from a cohort of the Hellenic
Sepsis Study Group (HSSG) (n = 246), patients enrolled in the clinical trial of Sodium
Selenite and Procalcitonin Guided Antimicrobial Therapy in Severe Sepsis (SISPCT, n
= 118), and another, smaller clinical trial (Crossover study, n = 20). In addition, in vitro
blood culture experiments and in vivo experiments in mouse models were performed to
assess biological plausibility. A low serum IFNg/IL10 ratio predicted increased survival in
the hydrocortisone group whereas a high ratio predicted better survival in the placebo
group. Using this marker for a decision rule, we applied it to three validation sets and
observed the same trend. Experimental studies in vitro revealed that IFNg/IL10 was
negatively associated with the load of (heat inactivated) pathogens in spiked human blood
and in septic mouse models. Accordingly, an in silico analysis of published IFNg and
IL10 values in bacteremic and non-bacteremic patients with the Systemic Inflammatory
Response Syndrome supported this association between the ratio and pathogen burden.
We propose IFNg/IL10 as a molecular marker supporting the decision to administer
hydrocortisone to patients in septic shock. Prospective clinical studies are necessary
and standard operating procedures need to be implemented, particularly to define a
generic threshold. If confirmed, IFNg/IL10 may become a suitable theranostic marker for
an urging clinical need.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:84291 |
| Date | 24 March 2023 |
| Creators | König, Rainer, Kolte, Amol, Ahlers, Olaf, Oswald, Marcus, Krauss, Veiko, Roell, Daniela, Sommerfeld, Oliver, Dimopoulos, George, Tsangaris, Iraklis, Antoniadou, Eleni, Jaishankar, Neeraja, Bogatsch, Holger, Löffler, Markus, Rödel, Markus, Garcia-Moreno, Marina, Tuchscherr, Lorena, Sprung, Charles L., Singer, Mervyn, Brunkhorst, Frank, Oppert, Michael, Gerlach, Herwig, Claus, Ralf A., Coldewey, Sina M., Briegel, Josef, Giamarellos-Bourboulis, Evangelos J., Keh, Didier, Bauer, Michael |
| Publisher | Frontiers Research Foundation |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 1664-3224, 607217 |
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