Funding i n j u r y , COVID-19, as a representative model of viral sepsis, has advanced the concept of a storm network composed of i m m u n

The gap

Evidence profile

Sourced from the future work of the source papers, classified as general, drawn from work published between 2024 and 2026, spanning 3 journals. Those papers have been cited 335 times in total.

Supporting evidence — 3 representative gaps

• The pathophysiology of sepsis and precision-medicine-based immunotherapy (2024) · Nature Immunology · cited 315× · doi

  Sepsis is a major challenge in healthcare, both in low- to middle-income and high-income countries, representing one of the diseases with the highest burden for society10. Much has been learned in the past few decades about the heterogeneity of the pathophysiology of sepsis in people, resulting from the interaction of a variety of pathogenic microorganisms with a highly regulated immune response. A complex picture has emerged in which the immune-based pathophysiological disturbances that are crucial for the outcome of sepsis can vary between people and during the disease, from a hyperinflammatory status to defective immune paralytic conditions. This heterogeneity is one of the main causes for the failure in the 1990s and 2000s of one-size-fits-all approaches to immunotherapies, which led to a lack of investment in the immune-based treatment of sepsis. The past decade has led to the application of the latest tech- nological developments in the study of sepsis, with omics-based approaches playing a major role in the identification of immune endotypes in the condition. This opens the door to enrichment of cohorts and precision-medicine approaches to immunotherapy of sepsis, based on novel diagnostics and therapies. However, many challenges remain. In line with this, the gap between the ambitions of systems-medicine-based technologies and the challenges of clinical practice should be bridged: pragmatic approaches should be explored to translate cutting-edge omics-based technologies into ready-to-use diagnostics. Subsequently, complex systems-medicine approaches should aim to provide pragmatic and realistic combinations of new biomarkers and immunotherapeutic approaches for future clinical practice at the bedside of the patients in each hospital, not only in highly specialized academic centers. Only such an approach has a chance of leading to the establishment of immunotherapy as a success- ful pillar in the treatment of sepsis for future generations. Nature Immunology | Volume 25 | January 2024 | 19–28 24 Review articlehttps://doi.org/10.1038/s41590-023-01660-5References 1. Singer, M. et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). J. Am. Med. Assoc. 315, 801–810 (2016). 2. Kaukonen, K. M., Bailey, M., Suzuki, S., Pilcher, D. & Bellomo, R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000–2012. JAMA 311, 1308–1316 (2014). 3. Shankar-Hari, M. et al. Developing a new definition and assessing new clinical criteria for septic shock: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315, 775–787 (2016). 4. Bone, R. C. et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/ SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 101

  generalfuture work
  Keywords: sepsis based approaches immune medicine septic shock clinical consensus definitions major income society past heterogeneity
• The endothelial-immunothrombotic storm in viral sepsis: lessons from COVID-19 (2026) · Frontiers in Immunology · cited 8× · doi

  Funding i n j u r y , COVID-19, as a representative model of viral sepsis, has advanced the concept of a storm network composed of i m m u n e a m p l i fi c a t i o n , a n d e n d o t h e l i a l immunothrombosis into a mechanistically defined framework, establishing it as a central pathological pathway leading to organ failure. Compared with bacterial sepsis, viral sepsis demonstrates receptor dependent tissue tropism, interferon dysregulation driven immune dynamics, and microcirculatory dysfunction dominated by hypercoagulability and in situ immunothrombosis. These features underscore the upstream role of disrupted endothelial homeostasis in disease progression. Future research should focus on developing multidimensional biomarker panels that capture storm activity to enable precise early risk stratification and dynamic disease monitoring. It is also essential to identify the subgroups most likely to benefit and the optimal therapeutic windows for anti-inflammatory, anticoagulant, immunomodulatory, and endothelial protective interventions. Pathways involving NETs, complement activation, and endothelial regulation represent promising therapeutic nodes that merit further investigation because of their potential relevance to both acute outcomes and long term sequelae. Overall, elucidation of the mechanisms underlying the endothelial immune thrombotic storm has deepened understanding of viral sepsis and provided a theoretical foundation for improving the diagnosis and treatment of sepsis and other diseases characterized by inflammation and coagulation interplay. Transforming these mechanistic insights into accessible clinical tools represents one of the most critical challenges and opportunities for the future. The author(s) declared that financial support was received for this work and/or its publication. This study was financially supported by the National Natural Science Foundation of China (Grant No.82360372), the Key Research & Development Program of Guangxi (Grant No. GuiKeAB22080088), the Joint Project on Regional High-Incidence Diseases Research of Guangxi Natural Science Foundation (Grant No. 2023GXNSFDA026023), and the First-class Discipline Innovation-driven Talent Program of Guangxi Medical University. Conflict of interest The authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

  generalfuture work
  Keywords: sepsis endothelial viral storm foundation grant guangxi immunothrombosis driven immune disease future therapeutic potential diseases
• Extracorporeal Cytokine Adsorption in Sepsis: Current Evidence and Future Perspectives (2025) · Biomedicines · cited 12× · doi

  The future of extracorporeal cytokine adsorption in sepsis lies in several key areas of development (Figure 2). Biomedicines 2025, 13, 1684 10 of 16 Figure 2. Future directions of extracorporeal cytokine adsorption in sepsis: towards personalized treatment. This infographic illustrates the four core elements driving the future of extracorporeal cytokine adsorption in sepsis management: (1) biomarker-guided therapy, using biomarkers such as IL-6, cfDNA, mHLA-DR, and LPS to identify immune states and guide treatment initiation; (2) selective adsorption technologies, designed to target specific inflammatory or anti-inflammatory mediators, thereby minimizing off-target effects; (3) sepsis phenotyping, enabling the stratification of patients based on immune profiles (e.g., hyper-inflammatory vs. immunosuppressed); and (4) pharmacokinetic considerations, to optimize therapy while avoiding unintended adsorption of essential medications. Together, these pillars support a precision medicine approach aiming to tailor extracorporeal therapy to individual patient needs. Note: Cell-free DNA; mHLA-DR: Monocyte human leukocyte antigen-DR; LPS: Lipopolysaccharide. First, the identification of reliable biomarkers, such as mHLA-DR expression and cytokine profiles, could enable more targeted therapies, allowing clinicians to select pa- tients who would benefit most from this intervention. This personalized approach could optimize the timing and effectiveness of treatment. Among the most studied biomark- ers, IL-6 is widely used to assess the inflammatory burden and monitor the response to treatment [16]. LPS levels, measured via endotoxin activity assays, are particularly relevant for endotoxin-targeting devices, such as Toraymyxin [17]. The mHLA-DR is a marker of immune competence, with low expression indicating immunosuppression and increased risk of secondary infections [8]. However, its measurement requires flow cytometry and is not yet standardized for routine clinical use. Cell-free DNA (cfDNA),  Biomedicines 2025, 13, 1684 11 of 16 released during cellular damage, has also emerged as a potential marker of disease severity and may correlate with cytokine levels [23]. Despite their promise, these biomarkers are not yet validated for guiding timing, duration, or repetition of adsorption therapy, and further studies are needed to establish their clinical utility. Second, there is a need for the development of more selective and customizable devices. Currently, existing devices often remove a broad range of molecules, which may not always be beneficial. Future devices could be designed to selectively target specific cytokines or pathogens, minimizing unintended consequences such as the removal of protective mediators. Selective adsorp- tion aims to remove harmful mediators such as IL-6, TNF-α, and IL-1β, while sparing beneficial molecules like IL-10, which has anti-inflammatory properties, and growth fac- tors such as VEGF and Epidermal Growth Factor (E

  generalfuture work
  Keywords: adsorption cytokine inflammatory future extracorporeal sepsis treatment therapy mhla devices biomarkers immune selective target mediators

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