TY - JOUR
TI - Use of IFNγ/IL10 Ratio for Stratification of Hydrocortisone Therapy in Patients With Septic Shock
AU - König, R.
AU - Kolte, A.
AU - Ahlers, O.
AU - Oswald, M.
AU - Krauss, V.
AU - Roell, D.
AU - Sommerfeld, O.
AU - Dimopoulos, G.
AU - Tsangaris, I.
AU - Antoniadou, E.
AU - Jaishankar, N.
AU - Bogatsch, H.
AU - Löffler, M.
AU - Rödel, M.
AU - Garcia-Moreno, M.
AU - Tuchscherr, L.
AU - Sprung, C.L.
AU - Singer, M.
AU - Brunkhorst, F.
AU - Oppert, M.
AU - Gerlach, H.
AU - Claus, R.A.
AU - Coldewey, S.M.
AU - Briegel, J.
AU - Giamarellos-Bourboulis, E.J.
AU - Keh, D.
AU - Bauer, M.
JO - Frontiers in Immunology
PY - 2021
VL - 12
TODO - null
SP - null
PB - Frontiers Media S.A
SN - null
TODO - 10.3389/fimmu.2021.607217
TODO - corticotropin;  epinephrine;  gamma interferon;  HLA DR antigen;  hydrocortisone;  immunoglobulin G;  interleukin 10;  interleukin 17;  molecular marker;  noradrenalin;  sodium selenite;  tumor necrosis factor;  antiinflammatory agent;  biological marker;  gamma interferon;  hydrocortisone;  interleukin 10;  lactic acid, antimicrobial therapy;  APACHE;  Article;  bacterial meningitis;  birth weight;  cohort analysis;  colony forming unit;  community acquired pneumonia;  computer model;  cytokine response;  disease severity;  Enterococcus faecalis;  Enterococcus faecium;  enzyme linked immunosorbent assay;  flow cytometry;  hospitalization;  human;  hypotension;  immune response;  immunotherapy;  intensive care;  intensive care unit;  leukocyte count;  limit of detection;  lymphocyte count;  machine learning;  neutrophil;  organ dysfunction score;  pathogen load;  peritoneal dialysis;  propensity score;  septic shock;  validation process;  adult;  aged;  animal;  blood;  clinical decision making;  disease management;  disease model;  female;  hemodynamics;  male;  middle aged;  mortality;  mouse;  odds ratio;  prognosis;  septic shock;  treatment outcome, Adult;  Aged;  Animals;  Anti-Inflammatory Agents;  Biomarkers;  Clinical Decision-Making;  Disease Management;  Disease Models, Animal;  Female;  Hemodynamics;  Humans;  Hydrocortisone;  Interferon-gamma;  Interleukin-10;  Lactic Acid;  Male;  Mice;  Middle Aged;  Norepinephrine;  Odds Ratio;  Prognosis;  Propensity Score;  Shock, Septic;  Treatment Outcome
TODO - 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 IFNγ/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 IFNγ/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 IFNγ 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 IFNγ/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, IFNγ/IL10 may become a suitable theranostic marker for an urging clinical need. © Copyright © 2021 König, Kolte, Ahlers, Oswald, Krauss, Roell, Sommerfeld, Dimopoulos, Tsangaris, Antoniadou, Jaishankar, Bogatsch, Löffler, Rödel, Garcia-Moreno, Tuchscherr, Sprung, Singer, Brunkhorst, Oppert, Gerlach, Claus, Coldewey, Briegel, Giamarellos-Bourboulis, Keh and Bauer.
ER -