Sepsis remains one of the leading causes of death in children worldwide, arising when an infection triggers a dysregulated immune response that damages the body’s own organs. In adults, clinicians have long recognized that the liver is both a victim and a signal in this process. Hepatic dysfunction in adult sepsis is considered an independent predictor of mortality, meaning that even after accounting for other factors, a failing liver marks a patient at elevated risk. Whether the same holds true for children, however, had never been systematically examined. Individual pediatric studies had reported varying rates of liver injury and conflicting associations with death, but no one had pooled the data. The Indonesian team registered their review prospectively with PROSPERO under the identifier CRD420261387360 and searched five major databases, including PubMed, Scopus, MEDLINE via EBSCO, the Cochrane Library, and ClinicalTrials.gov, from their inception through 21 May 2026, without language restrictions. Notably, Embase was not searched, a limitation the authors acknowledge.

The eligibility criteria were strict. Studies had to enroll children aged one month to 18 years, define sepsis according to consensus criteria, and report outcomes stratified by the presence or absence of liver injury. Two reviewers independently screened records and extracted data, a standard safeguard against individual error. Risk of bias was evaluated using two prespecified instruments: the Newcastle-Ottawa Scale for the observational studies included in the mortality analysis and the Quality in Prognosis Studies tool, known as QUIPS, which is specifically designed for prognostic research. Statistical pooling employed a Mantel-Haenszel random effects model for mortality odds ratios, while the proportion of children developing liver injury was estimated with a logistic-normal generalized linear mixed model, an approach better suited to proportions than naive averaging. Certainty of the evidence was graded using GRADE, the framework that rates confidence in findings from high to very low.

After screening, ten studies made the final cut. The headline result came from five of these studies, encompassing 1,717 children, that reported mortality according to liver injury status. Pooling their unadjusted data, the researchers found that children with SALI had nearly four times the odds of dying compared with those without it, with an odds ratio of 3.88 and a 95 percent confidence interval of 2.21 to 6.80. Three of the studies measured death during hospital admission, one measured death in the pediatric intensive care unit, and one did not specify the timing. On the surface, this is a striking signal: a liver under assault during sepsis appears to mark a child in grave danger.

But the statistical fine print tells a more cautious story. The prediction interval, which estimates the range of true effects one might expect in future studies, stretched from 0.63 to 23.80, crossing the value of 1.0 that would indicate no association at all. In other words, some future pediatric population might show no link between liver injury and death, while another might show an enormous one. The Hartung-Knapp adjusted confidence interval, a more conservative calculation that accounts for uncertainty in the between-study variance, widened further to 1.65 to 9.12. Combined with a GRADE rating of very low certainty, these numbers mean clinicians should treat the fourfold figure as a hypothesis-generating signal rather than a settled fact. The heterogeneity across studies, likely driven by different definitions of liver injury, different patient populations, and different measurement schedules, is substantial enough to temper any confident clinical claim.

The deeper problem is confounding by severity. Children whose livers fail during sepsis are, almost by definition, sicker than children whose livers hold out. Two of the included studies attempted to address this statistically. Saini and colleagues reported that SALI remained associated with mortality after adjustment for selected clinical covariates, but their mortality model did not include pSOFA, the pediatric Sequential Organ Failure Assessment score, or any other validated global severity measure. Without such a score, it is impossible to know whether the liver adds information beyond what general illness severity already captures. Only Koca and colleagues adjusted hepatic markers for validated pediatric severity scores, namely PRISM III, the Pediatric Risk of Mortality Score, and PELOD-2, the Pediatric Logistic Organ Dysfunction Score. In that analysis, neither alanine aminotransferase, the enzyme ALT commonly used to detect liver cell damage, nor total bilirubin, the pigment that accumulates when the liver fails to clear it, remained independently associated with death. Once a child’s overall severity was accounted for, the liver’s apparent prognostic power evaporated.

Beyond mortality, the review also estimated how often liver injury occurs in pediatric sepsis at all. Across seven studies covering 1,876 children, the pooled proportion was 29 percent, with a wide 95 percent confidence interval of 17 to 46 percent. That range is itself informative: it reveals how inconsistently SALI is defined and detected across the pediatric literature. Some studies may rely on a single elevated transaminase value, others on bilirubin thresholds, and still others on composite criteria, and the timing of measurement during the septic episode varies just as widely. The authors argue that this heterogeneity makes a strong case for standardized pediatric definitions of sepsis-associated liver injury and for agreed ascertainment schedules, so that future studies measure the same thing at the same moments. The Pediatric Organ Dysfunction Information Update Mandate, or PODIUM, represents one ongoing effort to bring consistency to organ dysfunction definitions in pediatric critical care.

The review also examined candidate biomarkers that might identify liver injury or predict outcomes earlier than conventional tests. The most promising was APRI, the AST-to-platelet ratio index, a simple calculation combining aspartate aminotransferase levels with platelet counts. In two cohorts, APRI showed areas under the receiver operating characteristic curve, or AUROCs, of 0.83 to 0.89, values generally considered good discriminative ability. Yet the authors urge caution on two fronts. First, the diagnostic thresholds differed substantially between the two cohorts, meaning a child classified as having liver injury by one study’s cutoff might be classified as normal by another’s. Second, the APRI is built on AST, while the outcome definitions in these studies were based on ALT, creating an overlap problem that limits how the biomarker’s performance can be interpreted. Other markers examined in the underlying studies, including lactate dehydrogenase, apolipoprotein A-V, and the albumin-corrected anion gap, remain at even earlier stages of evaluation. The authors conclude that no candidate biomarker is ready for clinical use without prospective multicenter validation.

What does this mean for the pediatric intensivist at the bedside? The practical takeaway is nuanced. An elevated ALT or bilirubin in a septic child should certainly prompt attention, and the unadjusted association suggests these children warrant heightened vigilance. But the evidence does not yet support treating liver injury as an independent prognostic marker that adds value beyond established severity scores such as PRISM III, PELOD-2, or pSOFA. The honest answer to whether hepatic dysfunction carries prognostic information of its own is that nobody currently knows, and the review makes that uncertainty explicit rather than papering over it. This kind of transparency is increasingly valued in evidence-based medicine, where overconfident meta-analytic estimates can mislead practice as surely as absent evidence can.

The study, published open access on 7 October 2026 and available under a Creative Commons license, received no external funding and its authors declare no competing interests. Its limitations are clearly stated: only ten studies were available, Embase was not searched, adjusted analyses were rare, and the underlying literature is dominated by observational designs vulnerable to confounding. The research team, which also included Ade Gautama and Khanyfah Syagita, notes with gratitude that Dr. Abdulkerim Elmas provided unpublished subgroup data through personal correspondence, strengthening the primary mortality analysis. For now, the review stands as both a warning and a roadmap: liver injury during pediatric sepsis is common, appears dangerous, and demands rigorous, standardized study before it can be woven into the scoring systems that guide care for the world’s sickest children.

Subject of Research: Sepsis-associated liver injury and mortality outcomes in children

Article Title: Sepsis-associated liver injury and clinical outcomes in children: a systematic review and meta-analysis

Article References: Wiriadinata, N. E. R., Gautama, A., Syagita, K., & Oswari, H. (2026). Sepsis-associated liver injury and clinical outcomes in children: a systematic review and meta-analysis. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07775-6

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07775-6

Keywords: sepsis, liver injury, pediatrics, meta-analysis, mortality, PICU, biomarkers, APRI, PRISM III, PELOD-2, pSOFA, systematic review

The research team, led by investigators at Children’s Hospital, Zhejiang University School of Medicine, together with collaborators spanning thirteen pediatric intensive care units across China, assembled a retrospective cohort of 2,374 children under eighteen years of age who were admitted to intensive care with suspected infections between 2023 and 2025. Rather than treating this population as a single undifferentiated group, the investigators prespecified two clinically distinct sub-cohorts for focused analysis: a neonatal group of 576 infants aged twenty-eight days or younger, and a hematology group of 494 children, a population in which underlying malignancies, immunosuppression, and hematologic abnormalities complicate both the diagnosis of sepsis and the interpretation of laboratory-based severity scores. This design choice reflects a growing recognition in the field that a scoring system validated in a general pediatric intensive care population may not transfer cleanly to the extremes of age or to immunocompromised patients.

Methodologically, the study followed a disciplined approach to score calculation. For each child, both the Phoenix sepsis score and the pSOFA score were computed using the worst available physiological and laboratory values recorded within the first twenty-four hours of intensive care unit admission. This window matters: early severity assessment is precisely what clinicians need when deciding how aggressively to resuscitate, monitor, and escalate care. The primary outcome was in-hospital mortality, and the principal metric of prognostic accuracy was the adjusted area under the receiver operating characteristic curve, or AUROC, a statistic that captures how well a score discriminates between children who died and those who survived, with 0.5 representing chance-level performance and 1.0 representing perfect discrimination. By adjusting the AUROC, the researchers accounted for confounding structure in the data, strengthening the comparability of the two scores.

The headline finding is statistically clear. Across the full cohort of 2,374 critically ill children, the Phoenix sepsis score achieved an adjusted AUROC of 0.840, significantly outperforming the pSOFA score’s 0.817, with a P value below 0.001. In absolute terms the difference may appear modest, but in the world of mortality prediction models, where incremental gains in discrimination can translate into earlier recognition and redirected resources for the sickest patients, such a difference across a cohort of this size carries weight. The result provides external validation, on a scale and in a healthcare context distinct from the original derivation studies, that the Phoenix framework’s emphasis on four organ systems, respiratory, cardiovascular, coagulation, and neurologic, captures lethal trajectories in infected children at least as well as, and slightly better than, the older pSOFA construct.

The picture grows more complicated in the predefined sub-cohorts. In the hematology group, the Phoenix score again outperformed pSOFA, with adjusted AUROCs of 0.718 versus 0.682, a difference that reached statistical significance at P equal to 0.006. Yet the investigators were careful to characterize discriminative ability in this subgroup as limited for both tools. Children with hematologic disease present a notoriously difficult prediction problem: baseline cytopenias, chemotherapy-related organ toxicity, and altered inflammatory responses can all inflate or deflate organ dysfunction scores independent of sepsis severity. A score of 0.718, while better than chance, leaves substantial room for misclassification, and the authors’ framing suggests that neither score should be treated as a reliable standalone prognostic instrument in this vulnerable population.

In neonates, the story changes again. Among the 576 infants aged twenty-eight days or younger, the Phoenix score posted a strikingly high adjusted AUROC of 0.915 compared with 0.850 for pSOFA, but the difference did not reach statistical significance, with P equal to 0.222. The absence of a significant gap does not mean either score performed poorly; indeed, both achieved excellent discrimination in this low-event-rate setting. Rather, the finding suggests that in newborns the two instruments are statistically interchangeable for mortality prediction, an important practical conclusion given that the Phoenix criteria were designed to span pediatric and neonatal populations and that neonatal sepsis has long posed unique challenges, from nonspecific clinical presentation to the scarcity of neonate-specific validation data for adult-derived scoring frameworks.

Beyond discrimination, the study examined how the scores behave at their operational threshold, the cutoff clinicians actually use to flag sepsis. At the standard threshold of two or more points, both the Phoenix score and pSOFA maintained high sensitivity, exceeding 80 percent across all cohorts, meaning they rarely missed a child who went on to die. The trade-off came in specificity: positive predictive values were low, at or below 50 percent everywhere, and in the neonatal sub-cohort they fell below 8 percent. This asymmetry is not a flaw unique to these scores but a mathematical consequence of applying screening thresholds in settings where deaths are, thankfully, uncommon. A highly sensitive tool catches nearly everyone at risk, but in a population where most children survive, most flagged children will nonetheless survive, producing many false alarms.

The trade-off between sensitivity and positive predictive value took on a different character in the hematology sub-cohort, where the event rate was high enough to make predictive values more meaningful. There, the Phoenix score traded approximately five percentage points of sensitivity for a meaningfully higher positive predictive value than pSOFA. In practical terms, the Phoenix score was somewhat more likely to miss a child who died, but when it flagged a child, that flag was more often correct. Which trade-off a clinician or unit should prefer depends on context: in settings where missing a death is the dominant concern, sensitivity may reign; where flagged patients trigger resource-intensive interventions, a higher positive predictive value reduces unnecessary escalations. The study does not prescribe a choice but equips decision-makers with the quantitative texture needed to make one.

The findings land amid an active international debate about the Phoenix criteria, which were developed and validated by a global consensus effort published in JAMA in 2024 and have since undergone external validation in cohorts from the United States, Bolivia, Australia, and beyond, with mixed results in low-resource settings and emergency departments. The new Chinese multicenter analysis adds a critical piece: evidence from a large, geographically diverse, non-Western cohort, with dedicated attention to neonates and hematology patients, two groups underrepresented in earlier validation work. It also complements the research group’s own prior multicenter study of the Phoenix score, pSOFA, and SIRS criteria in non-intensive care settings, extending the comparison to the sickest children in intensive care.

For the field, the message is one of calibrated confidence. The Phoenix sepsis score can now claim superior discrimination for in-hospital mortality in the general population of critically ill children with suspected infection, supporting its adoption in pediatric intensive care contexts. But the study simultaneously cautions against universal enthusiasm: in neonates, the older pSOFA remains an equally defensible choice, and in children with hematologic disease, both scores fall short of what clinicians would want from a decision-support tool, underscoring the need for population-specific approaches, whether through recalibration, integration of novel biomarkers, or entirely new models tailored to immunocompromised hosts. As sepsis mortality prediction moves from one-size-fits-all scores toward precision risk stratification, this study provides both a benchmark and a reminder that the sickest children often defy the averages on which general scores are built.

Subject of Research: External validation comparing the Phoenix sepsis score and pSOFA for predicting in-hospital mortality in critically ill children with suspected infection.

Article Title: Discrimination performance of the Phoenix sepsis score versus pediatric sequential organ failure assessment for predicting in-hospital mortality in critically ill children: a multicenter external validation study

Article References: Ru, X.-W., Liu, R.-Y., Yang, Z.-H., Huang, C.-Z., Zhang, C., Li, T.-W., Yang, J.-M., Liu, Y., Cui, X.-Y., Chen, H.-B., Zhou, X., Tang, F., Gong, X.-Y., Ling, P., Lv, X., Zeng, Q., Ma, Z., Yuan, B.-Y., Zhu, H., … Ye, Q. (2026). Discrimination performance of the Phoenix sepsis score versus pediatric sequential organ failure assessment for predicting in-hospital mortality in critically ill children: a multicenter external validation study. World Journal of Pediatrics. https://doi.org/10.1007/s12519-026-01073-y

Image Credits: AI Generated

DOI: 10.1007/s12519-026-01073-y

Keywords: Phoenix sepsis score, pSOFA, pediatric sepsis, in-hospital mortality, critical care, neonatal sepsis, hematology, AUROC, external validation, organ dysfunction, predictive scoring, intensive care unit