Martin-Loeches, I. | bioRxiv Science

bioRxiv2024

International multi-cohort analysis identifies novel framework for quantifying immune dysregulation in critical illness: results of the SUBSPACE consortium

Progress in the management of critical care syndromes such as sepsis, Acute Respiratory Distress Syndrome (ARDS), and trauma has slowed over the last two decades, limited by the inherent heterogeneity within syndromic illnesses. Numerous immune endotypes have been proposed in sepsis and critical care, however the overlap of the endotypes is unclear, limiting clinical translation. The SUBSPACE consortium is an international consortium that aims to advance precision medicine through the sharing of transcriptomic data. By evaluating the overlap of existing immune endotypes in sepsis across over 6,000 samples, we developed cell-type specific signatures to quantify dysregulation in these immune compartments. Myeloid and lymphoid dysregulation were associated with disease severity and mortality across all cohorts. This dysregulation was not only observed in sepsis but also in ARDS, trauma, and burn patients, indicating a conserved mechanism across various critical illness syndromes. Moreover, analysis of randomized controlled trial data revealed that myeloid and lymphoid dysregulation is linked to differential mortality in patients treated with anakinra or corticosteroids, underscoring its prognostic and therapeutic significance. In conclusion, this novel immunology-based framework for quantifying cellular compartment dysregulation offers a valuable tool for prognosis and therapeutic decision-making in critical illness.

immunology↗

bioRxiv2017

The Protective Association Of Endogenous Immunoglobulins Against Sepsis Mortality Is Restricted To Patients With Moderate Organ Failure.

Backgroundpre-evaluation of endogenous immunoglobulin levels is a potential strategy to improve the results of intravenous immunoglobulins in sepsis, but more work has to be done to identify those patients who could benefit the most from this treatment. The objective of this study was to evaluate the impact of endogenous immunoglobulins on the mortality risk in sepsis depending on disease severity.\n\nMethodsthis was a retrospective observational study including 278 patients admitted to the ICU with sepsis fulfilling the SEPSIS-3 criteria, coming from the Spanish GRECIA and ABISS-EDUSEPSIS cohorts. Patients were distributed into two groups depending on their Sequential Organ Failure Assessment score al ICU admission (SOFA < 8, n = 122 and SOFA [≥] 8, n = 156) and the association between immunoglobulin levels at ICU admission with mortality was studied in each group by Kaplan Meier and multivariate logistic regression analysis.\n\nResultsICU / hospital mortality in the SOFA < 8 group was 14.8% / 23.0%, compared to 30.1 % / 35.3% in the SOFA [≥] 8 group. In the group with SOFA < 8, the simultaneous presence of total IgG <407 mg/dl, IgM < 43 mg/dl and IgA < 219 mg/dl was associated to a reduction in the survival mean time of 6.6 days in the first 28 days, and was a robust predictor of mortality risk either during the acute and the post-acute phase of the disease (OR for ICU mortality: 13.79; OR for hospital mortality: 7.98). This predictive ability remained in the absence of prior immunosupression (OR for ICU mortality: 17.53; OR for hospital mortality: 5.63). Total IgG <407 mg/dl or IgG1 < 332 mg/dl was also an independent predictor of ICU mortality in this group. In contrast, in the SOFA [≥] 8 group, we found no immunoglobulin thresholds associated to neither ICU nor to hospital mortality.\n\nConclusionsendogenous immunoglobulin levels may have a different impact on the mortality risk of sepsis patients based on their severity. In patients with moderate organ failure, the simultaneous presence of low levels of IgG, IgA and IgM was a consistent predictor of both acute and post-acute mortality.

immunology↗