Plasma acid sphingomyelinase activity in sepsis: diagnostic utility and association with disease severity

Plasma acid sphingomyelinase (ASM) is a key enzyme generating ceramide, a lipid mediator implicated in inflammation, endothelial injury, and microvascular dysfunction [1, 2]. Although increased ASM activity has been described in sepsis [3, 4], its clinical relevance in relation to disease severity remains insufficiently characterized. We evaluated plasma ASM activity in patients with sepsis, including those with or without septic shock and examined its association with demographic factors and clinical severity indicators.

Plasma samples were obtained from 185 individuals, including 147 patients with sepsis (105 without shock and 42 with septic shock) and 38 healthy controls (Table S1). Samples from sepsis patients were collected in the emergency department immediately upon arrival, before any therapeutic intervention, whereas healthy controls were recruited from individuals undergoing routine medical check-ups who were clinically healthy, free of acute or chronic illness, and without infections requiring systemic antibiotics within the past month. To investigate whether plasma ASM activity changes according to disease severity, sepsis patients were stratified according to Sepsis-3 criteria into those without shock and those with septic shock, the most severe form of sepsis. ASM activity was quantified by an ultra-performance liquid chromatography–based enzymatic assay. Clinical data including APACHE II and SOFA scores, lactate and procalcitonin (PCT) concentrations, and routine laboratory indices were collected at emergency department presentation for sepsis patients, and from check-up records for healthy controls. Plasma ASM activity was markedly higher in sepsis without shock than in healthy controls (P < 0.001) and further increased in septic shock (P = 0.004 vs. sepsis without shock) (Fig. S1A). ASM activity tended to be higher in non-survivors than in survivors, although not significantly (Fig. S1B), suggesting that increased ASM may reflect overall physiological stress rather than functioning as a categorical mortality discriminator. Demographic influences were also observed. ASM activity was generally higher in males than in females (Fig. S1C), a pattern consistent with known sex-related differences in susceptibility to severe sepsis [5]. Age-related effects were noted in sepsis, with significantly elevated ASM levels with age in sepsis without shock (Fig. S1D). In contrast, septic shock patients exhibited uniformly high ASM activity across all age groups, suggesting that age effects may be overshadowed by severe physiological stress in advanced disease.

Multivariable logistic regression demonstrated that ASM was independently associated with sepsis diagnosis compared with healthy controls (OR 2.18, 95% CI 1.31–3.62; P = 0.003), and similarly showed an independent association with septic shock (OR 3.22, 95% CI 1.72–6.05; P < 0.001) (Table S2). Within the sepsis cohort, higher ASM activity was associated with progression to septic shock (OR 1.18, 95% CI 1.05–1.32; P = 0.004). These findings suggest that ASM may function as an independent indicator of both sepsis diagnosis and disease severity.

We further evaluated ASM activity in relation to clinical severity indices across the entire sepsis cohort, including patients with and without septic shock. ASM levels were elevated in both APACHE II score < 20 and ≥ 20 groups versus controls, with a mild upward trend in the ≥ 20 group (Fig. 1A). A similar pattern was observed for qSOFA score < 2 and ≥ 2 (Fig. 1B). In contrast, stratification by serum lactate concentration demonstrated a clear divergence: patients with lactate concentration ≥ 2 mmol/L exhibited markedly higher ASM activity than those with < 2 mmol/L (P < 0.001) (Fig. 1C). When qSOFA score and lactate concentration were combined, ASM remained significantly elevated across all subgroups and reached the highest levels in patients with lactate concentration ≥ 2 mmol/L regardless of qSOFA score (Fig. 1D), emphasizing the strong link between ASM and metabolic stress associated with tissue hypoperfusion. Correlation analyses reinforced these observations. Plasma ASM activity showed significant positive correlations with APACHE II (r = 0.16, P = 0.048) and SOFA scores (r = 0.2, P = 0.016) and lactate (r = 0.31, P < 0.001) and PCT concentrations (r = 0.29, P < 0.001) (Fig. 1E and Fig. S2). Among these, lactate concentration demonstrated the strongest relationship with ASM, supporting the concept that ASM activation parallels metabolic derangement, impaired oxygen utilization, and endothelial injury across the sepsis spectrum, including septic shock.

Fig. 1.

Correlation of plasma ASM activity and disease severity parameters. A-C. Plasma ASM activity was analyzed among APACHE II score (A, HC, n = 38; < 20, n = 129; ≥20 n = 18), qSOFA score (B, HC, n = 38; < 2, n = 107; ≥2 n = 40), and lactate concentration (C, HC, n = 38; < 2, n = 72; ≥2 n = 75) in across the entire sepsis cohort, including sepsis with or without septic shock. D. Plasma ASM activity was analyzed combined with qSOFA score and lactate concentration. E. Depicted are scatter plots and linear regression models of the correlation analyzes of plasma ASM activity with APACHE II score, SOFA score, lactate concentration, and PCT concentration. HC: healthy control. A-D, One-way analysis of variance, Tukey’s post hoc test. E, Pearson’s correlation test. P-value < 0.05 was considered statistically significant

Given these correlations, we evaluated the diagnostic performance of ASM using ROC curve analysis. ASM demonstrated an AUC of 0.83 for differentiating sepsis without shock from healthy controls, with a sensitivity of 76.2% and specificity of 81.6% at the optimal cutoff (> 0.016 nmol/ml/hr) (Fig. 2A and Table S3). ASM also showed strong discriminative ability for septic shock (AUC 0.93), with sensitivity of 83.3% and specificity of 92.1% at the optimal cutoff (> 0.025 nmol/ml/hr) (Fig. 2B and Table S3). These values were comparable to or exceeded those of conventional biomarkers, including concentrations of lactate (AUC 0.66 for sepsis; 0.96 for septic shock), PCT, and CRP.

Fig. 2.

The ROC curves of the plasma ASM and clinical biomarkers to predict the diagnostic value of sepsis. A and B. ROC curves of sepsis without (A) or with septic shock (B). AUC: Area under curve, PCT: procalcitonin, CRP: c-reactive protein

The parallel elevation of ASM with lactate-a critical indicator of circulatory dysfunction-suggests that ASM may reflect both metabolic and endothelial dimensions of sepsis pathophysiology. Unlike CRP concentration, which primarily capture inflammatory activation, ASM appears to represent downstream consequences of cellular stress, vascular permeability, and microcirculatory impairment. Integrating ASM measurement with lactate concentration or SOFA score may therefore provide a more comprehensive assessment of physiological deterioration in sepsis.

Previous studies linked ASM activity to organ failure or mortality in heterogeneous ICU cohorts [3, 4], but these investigations focused primarily on prognostic outcomes. Our findings expand the clinical context by demonstrating diagnostic relevance, severity stratification, demographic influences, and strong metabolic associations in clearly defined groups of sepsis with or without septic shock. These results underscore the potential value of ASM as an adjunctive biomarker that integrates endothelial and metabolic dimensions of sepsis and may aid in the early identification of patients at risk for physiological decline.

Abbreviations

APACHE II

Acute Physiology and Chronic Health Evaluation II

ASM

Acid sphingomyelinase

AUC

Area under the curve

CIs

Confidence intervals

CRP

C-reactive protein

IQRs

Interquartile ranges

OR

Odds ratios

PCT

Procalcitonin

ROC

Receiver operating characteristic

SOFA

Sequential Organ Failure Assessment

Author contributions

M.H.P., H.K.J., and B.J.C. designed and performed experiments and wrote the paper. H.J.Y., D.H.C., and S.J. performed experiments and analyzed data. C.K. and J.S.B. designed the study and wrote the paper. All authors discussed results and commented on the manuscript.

Funding

This research was supported by Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare (RS-2025-02213034, Republic of Korea).

Data availability

Data will be available upon reasonable request to corresponding author.

Declarations

Ethics approval and consent to participate

The study was approved by the Institutional Review Board of Kyungpook National University Chilgok Hospital (IRB No. 2020-12-025). All participants and/or their legal representatives provided written informed consent prior to enrollment, in accordance with the ethical principles of the Declaration of Helsinki.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Conflict of interest

The authors declare no conflict of interests.