Introduction

Pneumonia is the most common respiratory disease in pediatrics and one of the leading causes of mortality in children under five years old worldwide. Severe pneumonia is a major contributor to pediatric acute respiratory distress syndrome (pARDS), a condition associated with high mortality and poor outcomes1. pARDS is an acute, progressive respiratory failure induced by pulmonary or systemic inflammatory responses, with a mortality rate as high as 17%2. Therefore, early identification of children with severe pneumonia who are at risk of developing pARDS is critical for formulating effective treatment strategies and improving clinical outcomes.

pARDS is caused by dual damage to epithelial and endothelial cells, leading to the release of biomarkers into the bloodstream. Theoretically, measuring the levels of these biomarkers in serum could help predict the onset of pARDS3. Krebs von den lungen-6 (KL-6) is a mucin-like glycoprotein expressed by alveolar epithelial cells and is closely associated with the degree of epithelial cell injury and the repair process4. Surfactant protein D (SP-D), primarily secreted by type II alveolar epithelial cells, serves as an early indicator of damage to the alveolar-capillary barrier5. Von willebrand factor (vWF) is a multimeric glycoprotein primarily released by endothelial cells and reflects endothelial cell integrity6. Interleukin-8 (IL-8), a pro-inflammatory cytokine, mediates neutrophil chemotaxis and activation. Given the cellular damage mechanisms underlying lung injury, selecting biomarkers that reflect epithelial cell damage, alveolar-capillary barrier injury, endothelial cell dysfunction, inflammatory response, and lung tissue repair is critical for monitoring the occurrence and severity of lung injury7.

The lung injury prediction score (LIPS), a validated risk-stratification tool for lung injury in adult ICU populations, remains understudied in pediatric pneumonia due to developmental and pathophysiological disparities between children and adults8. Based on the different mechanisms of action of LIPS and serum biomarkers in pARDS, the combined application of both is expected to achieve complementary advantages in the early diagnosis of pARDS, thus optimizing diagnostic efficiency. This study is the first to evaluate the predictive value of LIPS and serum biomarkers in children with severe pneumonia at risk for pARDS.

Materials and methods

Study population

This prospective study included children hospitalized in the PICU of the Third Affiliated Hospital of Zhengzhou University due to severe pneumonia from October 2023 to December 2024. A total of 128 Han Chinese children with severe pneumonia were initially recruited. The inclusion criteria were: (1) age between 1 month and 14 years; (2) diagnosis consistent with the 2019 Guidelines for the Diagnosis and Treatment of Community-Acquired Pneumonia in Children9; (3) the ability to complete LIPS scoring, serum biomarker measurements, and clinical data collection at the specified time points after admission. The exclusion criteria were: (1) children diagnosed with pARDS prior to initial assessment or blood sampling (n = 3); (2) children who died within 24 h of admission (n = 1); (3) children who failed to complete sample collection or data acquisition at the specified time points (n = 11); (4) the hospitalization period is insufficient to determine whether the child will develop pARDS (n = 3); and (5) children with perinatal lung diseases, genetic metabolic disorders, immunodeficiency diseases, or congestive heart failure (n = 13). Ultimately, 90 children with severe pneumonia were included in the study, as shown in Fig. 1. According to the 2023 International Pediatric Acute Respiratory Distress Syndrome (pARDS) Diagnosis and Treatment Guidelines10, two physicians with PICU attending or higher qualifications categorized the children into the pARDS group (30 cases) and the non-pARDS group (67 cases) based on whether pARDS developed within 7 days after identifying the primary etiological insult. Additionally, 30 healthy children undergoing routine physical examinations at the hospital were selected as the control group. The study was approved by the Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Approval No. 2023-326-01), and informed consent was obtained from the guardians of all participants.

Fig. 1
figure 1

Inclusion and exclusion criteria for study participants pARDS: pediatric acute respiratory distress syndrome; non-pARDS: non-pediatric acute respiratory distress syndrome.

Full size image

Sample size calculation

This prospective study estimated the sample size based on the primary outcome, which was the diagnostic performance of LIPS combined with four serum biomarkers in predicting pARDS. With reference to prior literature, we hypothesized an area under the receiver operating characteristic curve (AUC) of 0.75 for LIPS alone and an expected improvement to 0.88 when combined with biomarkers (α = 0.05, β = 0.20, 80% statistical power)8,11,12. Using PASS 23.0 software, a minimum sample size of 30 cases (pARDS group) and 60 controls (non-pARDS group) was calculated, yielding a total of 90 participants. Accounting for potential attrition (15%) and confounding factors, the final recruitment target was set at 128 children with severe pneumonia. The analysis included 97 participants (30 in the pARDS group and 67 in the non-pARDS group), which not only met the minimum sample size requirement but also demonstrated superior predictive performance (AUC = 0.906) compared to initial projections, with robust statistical power and clinical relevance.

Clinical data collection

(1) Basic information on the participants was collected, including age, sex, weight, history of underlying diseases, length of hospital stay, complications, vital signs, laboratory findings, and imaging data.(2) Systematic scoring: The LIPS scoring system evaluates lung injury risk based on four components-susceptibility factors, high-risk surgeries, trauma, and risk factors-with a maximum score of 33.5. Higher scores indicate a greater risk of lung injury. LIPS were assessed at PICU admission (T1) and at the time of pARDS diagnosis (T2). Scoring was performed by two PICU physicians blinded to the specific biomarker data being measured.

Sample collection and analysis

At PICU admission (T1) and at pARDS diagnosis (T2), 3 mL of venous blood was collected from each participant. For the healthy control group, 3 mL of venous blood was collected on the day of their routine physical examination. The blood samples were allowed to stand at room temperature for 30 min, then centrifuged at 2000 r/min for 10 min to separate the serum, which was stored at -80 °C for later analysis. Serum levels of KL-6, SP-D, vWF, and IL-8 were measured using enzyme-linked immunosorbent assay. The assay kits were purchased from JONLNBIO in Shanghai, and all procedures were conducted according to the manufacturer’s instructions. Laboratory personnel involved in the analysis were blinded to the specific details of the clinical study.

Statistical methods

Statistical analyses were performed using SPSS 27.0 software. Normally distributed continuous variables were expressed as mean ± standard deviation (SD), and group comparisons were conducted using the independent samples t-test. Non-normally distributed data were presented as median (interquartile range, IQR), and group comparisons were performed using the Mann-Whitney U test. Categorical variables were expressed as frequency (%), and group comparisons were conducted using the Chi-squared test. The primary outcome of this study was the predictive performance of the combined model (LIPS with four serum biomarkers), measured by the area under the receiver operating characteristic curve (AUC). Secondary outcomes included the individual predictive capacity of each biomarker (KL-6, SP-D, vWF, IL-8) assessed through AUC, sensitivity, specificity, and their roles as independent risk factors identified by logistic regression analysis. A P-value of < 0.05 was considered indicative of statistical significance.

Results

Comparison of general clinical characteristics

A total of 128 children with severe pneumonia were recruited for this study, and 97 cases were included in the final analysis. Among these, 30 children developed pARDS (27 cases classified as mild/moderate and 3 as severe), while 67 did not develop pARDS. An additional 30 healthy children undergoing routine physical examinations were selected as the control group. As shown in Table 1, there were no statistically significant differences in age, weight, sex, or ethnicity among the pARDS group, non-pARDS group, and control group (P > 0.05). As presented in Table 2, no significant differences were observed between the pARDS group and the non-pARDS group regarding white blood cell count(WBC), platelet count, creatinine, D-dimer, total protein, or albumin levels (P > 0.05). Additionally, the pARDS group exhibited significantly lower pediatric critical illness score (PCIS) and longer hospital length of stay compared to the non-pARDS group (P < 0.05).

Table 1 Comparison of general clinical data among the three groups.
Full size table
Table 2 Comparison of general clinical characteristics between the pARDS and non-pARDS groups.
Full size table

Comparison of LIPS and serum biomarkers

At T1, the LIPS, KL-6, SP-D, vWF, and IL-8 levels in the pARDS group were significantly higher compared to both the non-pARDS group and the control group (P < 0.05). At T2, the LIPS and the levels of the four serum biomarkers in the pARDS group were higher than those at T1 (P < 0.01), as shown in Table 3; Fig. 2.

Table 3 Comparison of LIPS and serum biomarker levels at different time points among the groups.
Full size table
Fig. 2
figure 2

Comparison of LIPS and serum biomarker levels across groups at different time points pARDS: pediatric acute respiratory distress syndrome; non-pARDS: non-pediatric acute respiratory distress syndrome; LIPS: lung injury prediction score; KL-6: krebs von den lungen-6; SP-D: surfactant protein D; vWF: von willebrand factor; IL-8: interleukin-8.

Full size image

Logistic regression analysis of factors influencing the development of pARDS in children with severe pneumonia

In the univariate analysis using the presence of pARDS as the dependent variable for the relevant indicators at T1 in children with severe pneumonia in the PICU, it was found that LIPS, KL-6, SP-D, vWF, IL-8, and PCIS were closely associated with the prediction of pARDS occurrence in these children. However, the multivariate analysis revealed that only the LIPS, KL-6, SP-D, and vWF levels were independent risk factors for predicting the occurrence of pARDS in children with severe pneumonia (P < 0.05), while IL-8, PCIS, and length of hospital stay did not demonstrate independent predictive ability (P > 0.05), as shown in Table 4.

Table 4 Univariate and multivariate logistic regression analysis of various indicators.
Full size table

Evaluation of the predictive performance of LIPS and serum biomarkers for early detection of pARDS in children with severe pneumonia

In 97 children with severe pneumonia in the PICU, ROC analysis was performed at T1 to evaluate the AUC for LIPS and serum biomarkers in predicting the occurrence of pARDS in children with severe pneumonia, as well as the diagnostic cutoff points, sensitivity, and specificity, as shown in Table 5; Fig. 3. The primary outcome demonstrated that the combination of the LIPS with four serum biomarkers yielded the highest predictive performance, achieving an AUC of 0.906 (sensitivity: 83.3%, specificity: 91.0%). Among secondary outcomes, the LIPS + KL-6 combination exhibited the most robust predictive capacity compared to other pairwise biomarker integrations. Furthermore, the standalone predictive efficacy of individual biomarkers followed a descending hierarchy: LIPS > KL-6 > SP-D > vWF > IL-8.

Table 5 Evaluation of the predictive efficacy of LIPS and serum biomarkers for pARDS.
Full size table
Fig. 3
figure 3

ROC curves for LIPS and serum biomarkers in predicting pARDS in children with severe pneumonia. IL-8: interleukin-8; vWF: von willebrand factor; SP-D: surfactant protein D; KL-6: krebs von den lungen-6; LIPS: lung injury prediction score.

Full size image

Discussion

LIPS was initially proposed by Trillo-Alvarez et al. in 2011 and later refined by Gajic et al. through a large multicenter study, confirming its utility in early identification of high-risk ALI/ARDS patients8. In this study, children in the pARDS group had significantly higher LIPS at PICU admission compared to the non-pARDS group, with further increases at the time of pARDS diagnosis. Logistic regression analysis identified LIPS as an independent predictor of pARDS in children with severe pneumonia, with an AUC of 0.786. By comparison, a study conducted in South Korea involving 548 patients reported that LIPS had an AUC of 0.82 for predicting ARDS12.The slightly lower performance in our study may be attributed to the restriction of the study population to pediatric patients with pneumonia.

KL-6, secreted by activated type II alveolar epithelial cells, rises significantly during epithelial injury and repair, serving as a key marker of alveolar epithelial damage13. A meta-analysis involving 3753 participants demonstrated that KL-6 is the most relevant serum biomarker for diagnosing ARDS, with a pooled OR of 6.1 (95% CI: 3.0,12.1)14. In this study, KL-6 levels were significantly higher in the pARDS group and was an independent predictor of pARDS in children with severe pneumonia(AUC: 0.757). In conclusion, KL-6 demonstrates favorable diagnostic performance in both pediatric and adult acute respiratory distress syndrome (pARDS and ARDS) patients.

SP-D is a key surfactant protein, and its serum levels rise significantly when alveolar-capillary permeability increases due to lung injury15. In this study, the level of SP-D in the pARDS group was significantly higher than in both the non-pARDS group and the control group, and further elevated at diagnosis, indicating that SP-D levels may show an increasing trend early in the disease course. This suggests that SP-D is an independent risk factor for predicting pARDS in children with severe pneumonia, with an AUC of 0.722. Similar findings from large U.S. and South Korean cohorts reported SP-D as a potential ARDS biomarker within 48 h of ICU admission (AUC: 0.71)16. The conclusions of this study are consistent with these previous findings, further supporting the potential application value of SP-D as an early diagnostic biomarker for pARDS.

vWF is stored in Weibel-Palade bodies of endothelial cells and released upon injury or activation, leading to elevated serum levels17. In this study, vWF levels were significantly higher in the pARDS group and identified as an independent risk factor for predicting pARDS. However, its diagnostic performance for predicting pARDS was relatively low, with an AUC of only 0.681. A multicenter randomized controlled trial conducted by Majid et al. demonstrated that vWF could more effectively identify the risk of ARDS in burn patients, with the model achieving an AUC of 0.9018. The results of this study are significantly lower than those reported by Majid et al., likely attributable to more profound endothelial injury and systemic inflammation in burn cohorts.

IL-8, a key pro-inflammatory cytokine in acute lung injury, promotes neutrophil activation, leading to barrier damage and impaired gas exchange19,20. A multicenter trial on pARDS showed IL-8 levels were elevated and associated with prognosis, but not with pARDS development20.In this study, IL-8 was significantly higher in the pARDS group than in the non-pARDS group. However, its ability to independently predict the occurrence of pARDS in children with severe pneumonia was poor, indicating that while IL-8 may serve as an inflammation marker, its predictive ability for the development of pARDS on its own may be limited.

In this study, the predictive performance ranking for pARDS was demonstrated as LIPS > KL-6 > SP-D > vWF > IL-8, a finding that aligns closely with the distinct pathophysiological roles of these biomarkers in pARDS development. The LIPS, which integrates multiple clinical risk factors, demonstrates superior predictive capacity by enabling early identification of comprehensive lung injury risk11,21. KL-6, as a specific biomarker of alveolar epithelial injury, exhibits marked elevation during initial disease phases13. Although SP-D also originates from type II alveolar epithelial cells, it primarily reflects alterations in barrier permeability, resulting in comparatively lower predictive capability than KL-622. While vWF indicates vascular endothelial damage, its predictive sensitivity is limited by the typically delayed manifestation of such injury during disease progression6. IL-8, as an inflammatory cytokine, demonstrates reduced specificity due to its involvement in multiple inflammatory cascades19. These observed disparities in predictive efficacy reflect the stage-specific expression patterns of different biomarkers throughout the pathological continuum, underscoring the clinical superiority of multi-parameter biomarker panels for comprehensive risk assessment.

Building on these mechanistic insights, we further evaluated whether combining LIPS with these biomarkers could enhance predictive performancey23,24. The ROC curve analysis demonstrated that the predictive performance of the LIPS combined with serum biomarkers was superior to that of the LIPS alone, with the LIPS + KL-6 combination showing the best performance. The AUC of LIPS combined with four serum biomarkers reached 0.906, indicating a favorable clinical value in predicting the development of pARDS in children with severe pneumonia. This combined strategy may assist clinicians in the early identification of high-risk children with severe pneumonia who are likely to progress to pARDS, allowing for timely escalation of care and implementation of preventive interventions. However, practical challenges in measuring all four biomarkers simultaneously, including procedural complexity and increased financial burden, underscore the need to streamline the testing process. This study advocates for the combined use of LIPS and KL-6 as a clinically practical solution that ensures diagnostic accuracy while improving feasibility.

Although KL-6, SP-D, and vWF are primarily derived from alveolar epithelial cells and vascular endothelial cells, respectively, and are theoretically reflective of localized lung injury, their measurement from peripheral blood samples does not exclude the possibility of non-specific elevations driven by systemic inflammatory responses, such as sepsis25,26. Particularly, IL-8, as a central mediator in the inflammatory cascade, may be elevated due to both pulmonary and extrapulmonary inflammatory stimuli19. In this study, we attempted to minimize this confounding effect by strictly enrolling patients with pneumonia-induced pARDS and excluding cases of extrapulmonary ARDS. Nevertheless, it should be acknowledged that the serum levels of these biomarkers may still be influenced by both localized and systemic inflammatory processes.

Limitations and future directions

This study has certain limitations. First, as a single-center prospective observational study with a relatively small sample size, the generalizability of the findings may be limited. Second, heterogeneity in the etiologies and inflammatory backgrounds among pediatric patients may influence serum biomarker expression and introduce confounding effects. To comprehensively evaluate the clinical utility of LIPS combined with serum biomarkers in predicting pARDS, future studies should consider incorporating more lung-specific samples, such as exhaled breath condensate (EBC), bronchoalveolar lavage fluid, or lung tissue specimens to further clarify the organ specificity and diagnostic accuracy of these biomarkers. Moreover, large-scale, multicenter prospective studies involving pARDS patients with diverse inflammatory conditions are recommended to validate the robustness and broad applicability of the current findings.

Conclusion

By studying LIPS and serum biomarkers (KL-6, SP-D, vWF, IL-8) in children with severe pneumonia in the PICU, this study found that both LIPS and serum biomarker levels were significantly higher in pARDS patients compared to non-pARDS patients. The combination of LIPS with serum biomarkers such as KL-6, SP-D, vWF, and IL-8 improved the accuracy of early prediction of pARDS in children with severe pneumonia. This approach can help healthcare providers assess the severity of the patient’s condition promptly and initiate early interventions, thereby offering practical significance in reducing mortality.