It is evident that the admission of some patients with sepsis and septic shock to hospitals is occurring late in their illness, which has contributed to the increase in poor outcomes and high fatalities worldwide across age groups. The current diagnostic and monitoring procedure relies on an inaccurate and often delayed identification by the clinician, who then decides the treatment upon interaction with the patient. Initiation of sepsis is accompanied by immune system paralysis following “cytokine storm”. The unique immunological response of each patient is important to define in terms of subtyping for therapy. The immune system becomes activated in sepsis to produce interleukins, and endothelial cells express higher levels of adhesion molecules. The proportions of circulating immune cells change, reducing regulatory cells and increasing memory cells and killer cells, having long-term effects on the phenotype of CD8 T cells, HLA-DR, and dysregulation of microRNA. The current narrative review seeks to highlight the potential application of multi-omics data integration and immunological profiling at the single-cell level to define endotypes in sepsis and septic shock. The review will consider the parallels and immunoregulatory axis between cancer and immunosuppression, sepsis-induced cardiomyopathy, and endothelial damage. Second, the added value of transcriptomic-driven endotypes will be assessed through inferring regulatory interactions in recent clinical trials and studies reporting gene modular features that inform continuous metrics measuring clinical response in ICU, which can support the use of immunomodulating agents.

Introduction: Sepsis remains a major contributor to critical care mortality and morbidity worldwide. Despite advances in understanding its complex immunopathology, the compartmentalized nature of immune responses across different organs has yet to be fully translated into targeted therapies. This review explores the burden of sepsis on organ-specific immune dysregulation, immune resilience, and epigenetic reprogramming, emphasizing translational challenges and opportunities. Methods: We implemented a systematic literature search strategy, incorporating data from studies published between 2010 and 2024, to evaluate the role of molecular profiling techniques, including transcriptomics and epigenetic markers, in assessing the feasibility of targeted therapies. Results: Sepsis-induced immune dysregulation manifests differently in various organs, with lung, heart, liver, and kidney responses driven by unique local immune environments. Organ-specific biomarkers, such as the Spns2/S1P axis in lung macrophages, mitochondrial dysfunction in the heart, proenkephalin for early acute kidney injury (AKI), and adrenomedullin for predicting multi-organ failure, offer promising avenues for timely intervention. Furthermore, immune resilience, particularly through regulatory T-cell modulation and cytokine targeting (e.g., IL-18), is crucial for long-term recovery. Epigenetic mechanisms, including histone modification and trained immunity, present opportunities for reprogramming immune responses but require more precision to avoid unintended inflammatory sequelae. Conclusions: A deeper understanding of compartmentalized immune responses and the dynamic immune landscape in sepsis is critical for developing precision therapies. Real-time immune monitoring and organ-targeted interventions could revolutionize sepsis management, although significant barriers remain in clinical translation. Further research is required to establish biomarkers and treatment timing that optimize therapeutic efficacy while minimizing systemic risks.

Critically ill COVID-19 patients start developing single respiratory organ failure that often evolves into multiorgan failure. Understanding the immune mechanisms in severe forms of an infectious disease (either critical COVID-19 or bacterial septic shock) would help to achieve a better understanding of the patient’s clinical trajectories and the success of potential therapies. We hypothesized that a dysregulated immune response manifested by the abnormal activation of innate and adaptive immunity might be present depending on the severity of the clinical presentation in both COVID-19 and bacterial sepsis. We found that critically ill COVID-19 patients demonstrated a different clinical endotype that resulted in an inflammatory dysregulation in mild forms of the disease. Mild cases (COVID-19 and bacterial non severe sepsis) showed significant differences in the expression levels of CD8 naïve T cells, CD4 naïve T cells, and CD4 memory T cells. On the other hand, in the severe forms of infection (critical COVID-19 and bacterial septic shock), patients shared immune patterns with upregulated single-cell transcriptome sequencing at the following levels: B cells, monocyte classical, CD4 and CD8 naïve T cells, and natural killers. In conclusion, we identified significant gene expression differences according to the etiology of the infection (COVID-19 or bacterial sepsis) in the mild forms; however, in the severe forms (critical COVID-19 and bacterial septic shock), patients tended to share some of the same immune profiles related to adaptive and innate immune response. Severe forms of the infections were similar independent of the etiology. Our findings might promote the implementation of co-adjuvant therapies and interventions to avoid the development of severe forms of disease that are associated with high mortality rates worldwide.

A common result of infection is an abnormal immune response, which may be detrimental to the host. To control the infection, the immune system might undergo regulation, therefore producing an excess of either pro-inflammatory or anti-inflammatory pathways that can lead to widespread inflammation, tissue damage, and organ failure. A dysregulated immune response can manifest as changes in differentiated immune cell populations and concentrations of circulating biomarkers. To propose an early diagnostic system that enables differentiation and identifies the severity of immune-dysregulated syndromes, we built an artificial intelligence tool that uses input data from single-cell RNA sequencing. In our results, single-cell transcriptomics successfully distinguished between mild and severe sepsis and COVID-19 infections. Moreover, by interpreting the decision patterns of our classification system, we identified that different immune cells upregulating or downregulating the expression of the genes CD3, CD14, CD16, FOSB, S100A12, and TCRɣδ can accurately differentiate between different degrees of infection. Our research has identified genes of significance that effectively distinguish between infections, offering promising prospects as diagnostic markers and providing potential targets for therapeutic intervention.

Background/Objectives: Mid-regional pro-adrenomedullin (MR-proADM) is a biomarker of endothelial dysfunction in sepsis. Its relationship with real-time microcirculatory alterations in critically ill patients remains insufficiently characterised. Methods: In a prospective cohort of 59 ICU patients with sepsis, serial sublingual microcirculation assessments were performed using sidestream dark field (SDF) imaging. Serum MR-proADM concentrations were measured with BRAHMS Kryptor assays. Automated software quantified microvascular structure and flow. Associations with disease severity and outcomes were evaluated using correlation, regression, and receiver operating characteristic (ROC) analyses (ClinicalTrials.gov Identifier: NCT05357339). Results: Higher MR-proADM concentrations at ICU admission were modestly associated with impaired microvascular perfusion (perfused number of crossings [PNOC]: ρ = −0.32; perfused De Backer density [PDBD]: ρ = −0.32; consensus proportion of perfused vessels [CPPV]: ρ = −0.26; all p < 0.05). Rising MR-proADM levels over time were strongly associated with worsening perfusion (ΔPDBD: ρ = 0.52; ΔPNOC: ρ = 0.54). MR-proADM correlated with SOFA and APACHE II scores and predicted the need for renal replacement therapy (AUC = 0.799, p = 0.041), but not ICU length of stay or hospital mortality. Conclusions: MR-proADM correlates with in vivo microcirculatory dysfunction in sepsis. Its dynamic association with microvascular impairment supports its potential role as a translational biomarker for monitoring endothelial and microcirculatory failure in critically ill patients.