Rethinking post-sepsis syndrome: linking cellular dysfunction to the clinical picture
By
Gabriel-Petre Gorecki
Andrei Bodor
Marius-Bogdan Novac
Dan-Gabriel Costea
Daniel-Ovidiu Costea
Andreea-Cristina Costea
Cătălin-Nicolae Grasa
Dana-Rodica Tomescu
October 2, 2025
Clinical Scorecard: Reevaluating Post-Sepsis Syndrome: Connecting Cellular Dysfunction to Clinical Manifestations
At a Glance
Category Detail
Condition Post-Sepsis Syndrome (PSS) Key Mechanisms Persistent neutrophil extracellular traps (NETs), mitochondrial dysfunction, oxidative and nitrosative stress, damage-associated molecular patterns (DAMPs) activation of TLR4 and NLRP3 inflammasome, persistent NF-κB, MAPK, and JAK/STAT pathway signaling Target Population Sepsis survivors experiencing long-term symptoms including chronic fatigue, immunosuppression, neuromuscular impairment, and cognitive decline Care Setting Post-acute care and long-term follow-up of sepsis survivors in hospital and outpatient settings
Key Highlights
Persistent NETs and mitochondrial DNA contribute to chronic inflammation and immunothrombosis after sepsis. Mitochondrial dysfunction leads to energy failure and perpetuates oxidative damage, underpinning multiple PSS phenotypes. Long-term immune dysregulation involves epigenetic reprogramming and sustained activation of inflammatory signaling pathways. Guideline-Based Recommendations
Diagnosis
Recognize symptom constellation of PSS including fatigue, immunosuppression, neuromuscular and cognitive impairments. Consider molecular markers related to NETs, mitochondrial dysfunction, and inflammatory signaling pathways as potential diagnostic tools. Acknowledge overlap between PSS and Persistent Inflammation, Immunosuppression, and Catabolism syndrome (PICS). Management
Focus on early identification of sepsis survivors at risk for PSS to guide monitoring and intervention. Target mitochondrial function and oxidative stress pathways as potential therapeutic strategies. Address immunosuppression and vulnerability to secondary infections through tailored immunomodulatory approaches. Monitoring & Follow-up
Longitudinal assessment of inflammatory markers, mitochondrial function, and immune status in sepsis survivors. Monitor for clinical manifestations such as chronic fatigue, neuromuscular weakness, and cognitive decline. Evaluate for persistent coagulopathy and immunothrombosis markers linked to NETs. Risks
Increased susceptibility to secondary infections and viral reactivations due to prolonged immunosuppression. Chronic organ dysfunction related to sustained mitochondrial and metabolic disturbances. Potential for persistent prothrombotic states contributing to morbidity. Patient & Prescribing Data
Sepsis survivors exhibiting post-sepsis syndrome symptoms
Current evidence is preliminary; therapeutic focus is on mitigating mitochondrial dysfunction, controlling inflammation, and preventing immunosuppression-related complications. No established pharmacologic treatments specifically approved for PSS.
Clinical Best Practices
Integrate multidisciplinary follow-up care for sepsis survivors to identify and manage PSS manifestations. Employ biomarker-guided approaches to stratify risk and personalize interventions. Promote research into mitochondrial-targeted therapies and immunomodulation in post-sepsis care. Educate healthcare providers on the overlapping phenotypes and molecular underpinnings of PSS and PICS. Recognize the importance of long-term monitoring beyond acute sepsis resolution. References
