Sepsis remains a major cause of morbidity and mortality worldwide, with rising incidence and high in-hospital mortality1, 2. Rapid detection of sepsis facilitates timely intervention, which is critical for improving patient outcomes3. However, the diagnosis can be challenging due to the heterogeneity of the clinical manifestations of sepsis4. Consequently, in this context, there is a great need for reliable diagnostic biomarkers to aid in the diagnosis of sepsis.

Actin is an abundant structural protein that makes up the cytoskeleton in most eukaryotic cells5. When cells are damaged or die due to injury or inflammation, actin is released into the extracellular space6. Free extracellular actin then undergoes polymerization to form long, insoluble filamentous actin (F-actin)6, 7. These actin filaments can have detrimental effects systemically, including exacerbating vascular leakage, activating platelets, perturbing blood coagulation, and obstructing pulmonary microcirculation to impair gas exchange8, 9, 10, 11. Moreover, circulating F-actin aggregates can trigger further inflammatory signaling when interacting with immune cells12, 13. Together, these effects of extracellular F-actin propagate cellular damage and contribute to multiple organ dysfunction14. Plasma gelsolin (pGSN) plays a crucial role in mitigating these adverse effects of released actin15. As an actin-scavenging protein, pGSN binds and effectively removes circulating F-actin15. Thus, pGSN helps limit inflammatory and thrombotic complications of extensive cell injury and death.

During past two decades, pGSN has been an important and promising diagnostic markers for sepsis detection16. Previous studies have reported significantly decreased pGSN levels in patients with sepsis compared to non-septic patients or healthy controls15, 17, 18, 19. The reductions appear to correlate with sepsis severity and development of multi-organ failure20, 21. Furthermore, pGSN levels show diagnostic ability in distinguishing sepsis from non-infectious systemic inflammation15, 18, 20, 22. Taken together, these findings indicate the potential usefulness of pGSN as a diagnostic biomarker for sepsis screening and as an indicator of sepsis severity. This mini review summarizes evidence on the diagnostic performance of pGSN specifically in sepsis and discuss its utility as a biomarker.

Gelsolin was first described as an intracellular actin-binding protein that regulates cytoskeletal dynamics23. Its secreted isoform, pGSN, was later found to circulate in blood plasma at high levels and to serve a critical actin-scavenging function extracellularly15. The diagnostic potential of pGSN was recognized in the 1990s, when major tissue injury was shown to cause a rapid, profound drop in its levels24. A 1999 trauma study established decreased pGSN as an early prognostic biomarker that strongly predicts adverse outcomes like mortality25. Extensive research since has solidified the utility of pGSN as a biomarker reflecting the severity of cellular damage in various inflammation-driven conditions like sepsis, surgery, trauma, and critical illness15, 16, 25, 26. The rapid decline in pGSN levels indicates overwhelmed actin-scavenging capacity and reflects a need for gelsolin repletion therapy, thereby making it a useful indicator of prognosis and a guide for potential therapeutic intervention.

Several studies have evaluated pGSN levels in patients with sepsis. A study by Lee et al.27 assessed plasma gelsolin levels in 21 non-surgical septic patients and found significantly decreased levels compared to healthy controls. Actin was detected in the plasma of 17/21 sepsis patients, suggesting that tissue injury and actin release occur early in sepsis. Septic non-survivors had significantly lower pGSN levels upon admission than survivors. The degree of pGSN depletion correlated with mortality risk, with every quartile reduction in pGSN associated with a 3.4-fold increase in the odds of death. Levels of pGSN were more predictive of the outcome than were APACHE III scores.

Another study by Wang et al. 20 measured pGSN levels in 91 surgical ICU patients with severe sepsis. Levels were significantly decreased compared to both non-septic ICU patients and healthy controls. An inverse correlation was found between pGSN levels upon admission and APACHE II scores. Although pGSN levels upon admission did not differ between sepsis survivors and non-survivors, only survivors exhibited recovery of depleted pGSN levels over time.

Huang et al. 28 evaluated 102 burn patients, 43 of whom developed sepsis. Levels of pGSN decreased with increasing burn size and were significantly lower in septic than non-septic patients at multiple timepoints. Sepsis non-survivors had lower pGSN levels than survivors. Logistic regression found that pGSN levels were inversely associated with sepsis occurrence and sepsis mortality.

A pilot study by Halis et al. also measured pGSN levels in 40 preterm infants with neonatal sepsis18. Gelsolin levels were significantly lower during sepsis compared to after recovery and in healthy controls. Gelsolin levels also were inversely correlated with clinical sepsis scores. The authors proposed that gelsolin may be a valuable biomarker for neonatal sepsis.

A few studies have examined the potential diagnostic accuracy of using pGSN levels to identify sepsis patients. Lee et al. 27 performed receiver operating characteristic (ROC) analysis, which showed moderate predictive ability of pGSN levels for 28-day mortality in sepsis patients, with an area under the curve (AUC) of 0.86. Using a cutoff of 113.6 mg/l, pGSN had 66.7% sensitivity and 93.3% specificity for mortality prediction. The AUC was slightly higher compared to that of APACHE III scores. This indicates that pGSN levels have reasonable accuracy for distinguishing sepsis survivors from non-survivors.

In addition, the study of Halis et al.18 had also assessed the diagnostic value of gelsolin through ROC curve analysis which showed strong predictive ability, with an AUC of 0.96 when using pGSN levels to diagnose sepsis. Sensitivity was 90.3% and specificity 95% using a cutoff of 44.97 μg/ml.

The utility of serum gelsolin for differentiating sepsis from non-infectious systemic inflammation was evaluated by Horváth-Szalai et al.22 as well. Gelsolin demonstrated an AUC of 0.77 for distinguishing sepsis from SIRS patients (p < 0.05). The optimal cut-off value was determined to be 21.04 mg/L, resulting in a sensitivity of 83.3% and a specificity of 68.7% for diagnosing sepsis. Furthermore, for predicting 7-day mortality in the sepsis cohort, gelsolin had an AUC of 0.74 (p < 0.05). A gelsolin level below 11.38 mg/L predicted mortality with 76.2% sensitivity and 72.7% specificity. Their findings suggested that gelsolin demonstrated diagnostic and prognostic utility in this sepsis study, distinguishing it from non-infectious SIRS and predicting short-term mortality with moderate accuracy comparable to established biomarkers like procalcitonin22.

Multiple studies have shown an association between decreased pGSN levels and poor outcomes in critically ill patients. In a study of 91 patients with severe sepsis, non-survivors failed to recover their depleted gelsolin levels over time, whereas survivors showed substantial recovery of gelsolin levels starting around day 1120. Another study of burn patients found significantly lower gelsolin levels in those who developed and died from sepsis compared to those without sepsis and survivors of sepsis29. Lower gelsolin levels upon admission have also been correlated with increased mortality after major trauma and in surgical ICU patients18, 25, 26, 27. The mechanism likely involves extensive actin exposure from cellular injury that consumes circulating gelsolin. Loss of gelsolin’s ability to clear actin and bind inflammatory mediators then leads to exacerbation of inflammation and tissue damage. The correlation of gelsolin recovery with clinical improvement supports its pathogenetic role.

While existing evidence consistently links low pGSN levels with worse outcomes, most studies to date have been small pilot investigations. Larger, multicenter trials are needed to definitively establish gelsolin as a prognostic biomarker for critical illness. There has also been heterogeneity in study populations and gelsolin measurement methodology among studies. Establishing standard reference ranges and optimal methods for determining gelsolin levels will help facilitate broader clinical adoption. More research is also needed to clarify the mechanisms connecting gelsolin depletion to organ injury in sepsis and related inflammatory states. Finally, though animal studies showing a mortality benefit of gelsolin replacement are promising, further investigation of therapeutic potential in human sepsis is needed.

If substantiated as an early prognostic indicator of severity and mortality risk of sepsis, pGSN testing could aid in risk stratification and decision making for critically ill patients. Low gelsolin upon admission may warrant more aggressive resuscitation, while failure to recover pGSN levels could indicate poor prognosis. In a research setting, pGSN levels may aid in patient selection and serve as a surrogate endpoint for clinical trials investigating new sepsis treatments. Demonstrating the efficacy of gelsolin repletion therapy in human sepsis could also spur development of gelsolin-based drugs to improve outcomes. Research efforts focused on illuminating gelsolin’s protective mechanisms against organ dysfunction may uncover novel therapeutic targets. Thus, pGSN has promise both as a clinical prognostic tool and as a facilitator of further research to enhance our approach for managing sepsis.

In conclusion, existing evidence suggests that pGSN, as an actin-scavenging protein that helps mitigate cellular injury from inflammation, has potential utility as both a diagnostic and prognostic biomarker for sepsis. Multiple studies have shown significant reductions in pGSN levels during sepsis compared to a healthy state. The degree of depletion correlates with sepsis severity and development of organ dysfunction, while failure of gelsolin levels to recover portends worse outcomes. Though larger studies are needed to confirm these findings and establish standard reference values, current data indicate that pGSN testing could aid in clinical decision-making for sepsis patients. Low or falling levels may prompt earlier intervention or predict mortality risk. If gelsolin’s protective role is further validated, repletion therapy could also emerge as a novel sepsis treatment. Thus, continued research on pGSN in sepsis is warranted and may ultimately help transform management of this deadly syndrome. Understanding the mechanisms linking gelsolin to inflammation and tissue damage could uncover new therapeutic targets, as well. In summary, as a window into systemic inflammatory burden and tissue injury, pGSN shows promise both for guiding clinical care and facilitating translational research to improve sepsis outcomes.

pGSN: plasma gelsolin, SIRS: systemic inflammatory response syndrome

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H.A.A conceived the concept. H.A.A and A.J wrote the manuscript. H.K.A-T critically revised the manuscript. All authors have read and approved the final manuscript.

None.

Data and materials used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Not applicable.

Not applicable.

The authors declare that they have no competing interests.