Association of bronchoalveolar lavage fluid caspase-4 with inflammatory responses in pediatric acute respiratory distress syndrome

Introduction

Acute respiratory distress syndrome (ARDS) is a heterogeneous clinical syndrome characterized by diffuse inflammatory lung injury and severe hypoxemia and remains associated with substantial mortality and long-term morbidity (1-3). In pediatric intensive care settings, ARDS is a life-threatening condition associated with reported mortality rates ranging from 17% to 33.7% (4,5). Pediatric ARDS (PARDS) can result from both intrapulmonary and extrapulmonary insults, with pneumonia being the leading cause, accounting for approximately 55.2–82.8% of cases. Current diagnosis and management are guided by the Pediatric Acute Lung Injury Consensus Conference (PALICC) recommendations, which were updated in 2023 to refine diagnostic definitions and risk stratification in children (6,7).

Pyroptosis is a pro-inflammatory form of programmed cell death distinct from apoptosis and has been increasingly recognized in the pathogenesis of lung injury in ARDS. It is triggered by inflammasome activation in response to pathogen-associated molecular patterns, leading to the release of inflammatory mediators and amplification of immune responses (8-10). While canonical inflammasome-mediated pyroptosis has been extensively studied, recent work has highlighted the role of the non-canonical inflammasome pathway mediated by caspase-4 in humans (8,11,12).

Caspase-4 can be directly activated by cytosolic lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria. Activation of caspase-4 leads to cleavage of gasdermin D, membrane pore formation, and inflammatory cell death (8-10). This process promotes cytokine release, disrupts alveolar–capillary barrier integrity, and contributes to lung injury (10,13). Experimental and clinical studies suggest that caspase-4-mediated inflammatory signaling plays an important role in host responses to Gram-negative infections (14).

Despite these advances, the role of caspase-4-mediated pyroptosis in PARDS remains poorly defined. In particular, data on caspase-4 expression and its association with inflammatory mediators in the pulmonary microenvironment of children are limited. Bronchoalveolar lavage fluid (BALF) reflects local airway and alveolar inflammation and provides a useful tool for investigating these mechanisms in vivo (15).

Therefore, the present study aimed to evaluate BALF levels of caspase-4 and related inflammatory cytokines in children with ARDS. By analyzing caspase-4, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), we sought to examine their association with disease severity and to assess their potential as biomarkers of inflammatory lung injury in PARDS. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0379/rc).

Methods

Study design and participants

This retrospective observational study was conducted at Chengdu Women and Children’s Central Hospital, a tertiary pediatric medical center in Chengdu, China. We screened children aged 1 month to 14 years who were diagnosed with ARDS and admitted to the respiratory department or pediatric intensive care unit (PICU) between September 2023 and December 2025. This age range corresponds to the routine admission criteria of the pediatric departments at our institution, and all eligible patients who underwent clinically indicated bronchoscopy with bronchoalveolar lavage during the study period were within this age range.

ARDS was diagnosed according to the PALICC-2 recommendations (6). Patients were categorized into three groups: Gram-negative bacterial infection-associated ARDS, virus-associated ARDS, and a non-infectious control group. Gram-negative bacterial infection was confirmed by conventional culture and/or metagenomic next-generation sequencing (mNGS), while viral infections were identified using a combination of mNGS and pathogen-specific nucleic acid testing. Given the established role of caspase-4 as a cytosolic receptor for LPS derived from Gram-negative bacteria, the study was specifically designed to compare Gram-negative bacterial ARDS with viral ARDS. Gram-positive bacterial infections were outside the scope of the present investigation and were therefore not included as a separate study group.

The non-infectious control group consisted of 17 children who underwent bronchoscopy with bronchoalveolar lavage for non-infectious respiratory conditions, including airway foreign body aspiration (n=5), chronic cough (n=4), recurrent wheeze (n=3), congenital airway anomalies (n=3), and airway malacia (n=2). None of the control subjects had clinical symptoms of acute respiratory infection or laboratory and microbiological evidence of active infection.

Exclusion criteria were congenital heart disease with significant hemodynamic abnormalities, chronic lung disease requiring long-term respiratory support, primary immunodeficiency, and incomplete clinical data.

To reduce confounding related to disease severity and to ensure procedural safety, only patients with mild ARDS were included, as bronchoalveolar lavage in moderate-to-severe ARDS may transiently impair oxygenation and introduce additional variability. Given the focus on BALF biomarkers, only patients with available BALF samples obtained during clinically indicated bronchoscopy were included in the analysis.

The study size was determined by the number of consecutive eligible patients admitted during the study period. No formal sample size calculation was performed due to the retrospective design.

To reduce potential sources of bias, consecutive patients meeting the inclusion criteria were enrolled to minimize selection bias. BALF sampling and laboratory measurements were performed according to standardized clinical protocols to reduce measurement bias. Furthermore, relevant clinical and laboratory variables were systematically collected, and predefined inclusion and exclusion criteria were applied to limit potential confounding.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was approved by the Ethics Committee of Chengdu Women and Children’s Central Hospital [approval No. 2024(31)-2]. Written informed consent was obtained from the guardians of all participants.

Clinical data collection

Clinical data were retrospectively extracted from the electronic medical records of all enrolled patients admitted to the respiratory department and PICU. Demographic characteristics, including age and sex, were recorded. Clinical information included presenting symptoms, underlying conditions, presumed etiologies of ARDS, as well as relevant laboratory and radiological findings. Laboratory parameters included routine blood tests (white blood cell count and differential), inflammatory markers [C-reactive protein (CRP) and procalcitonin (PCT)], coagulation indices, liver and renal function tests, and cardiac injury biomarkers.

Data related to respiratory support and disease severity were also collected, including the mode and duration of ventilatory support and oxygenation parameters. For patients receiving invasive mechanical ventilation, the oxygenation index (OI) was calculated as [mean airway pressure × fraction of inspired oxygen (FiO₂) × 100]/partial pressure of arterial oxygen (PaO₂), and the oxygen saturation index (OSI) was calculated as (mean airway pressure × FiO₂ × 100)/oxygen saturation (SpO₂) to assess the severity of hypoxemia. Oxygenation status was further evaluated using the PaO₂/FiO₂ (P/F) ratio. For patients who had not yet undergone invasive mechanical ventilation, the P/F ratio was derived from arterial blood gas measurements obtained prior to intubation under conventional oxygen therapy.

ARDS was diagnosed according to the PALICC-2 recommendations. For descriptive purposes, oxygenation status was assessed using P/F values. As pre-intubation P/F values were used in some cases, these measurements were interpreted primarily as indicators of baseline oxygenation rather than for formal severity classification.

BALF collection

Bronchoscopy with bronchoalveolar lavage was performed based on clinical indications and only in hemodynamically stable patients. Because of the underlying respiratory compromise in children with ARDS, a reduced lavage volume and shorter procedure duration were applied to minimize procedure-related deterioration. BALF was therefore not performed according to a fully standardized research protocol, and lavage volume was adjusted according to individual clinical tolerance.

In patients with ARDS, BALF was collected at the time of initiation of invasive mechanical ventilation (immediately after endotracheal intubation) to minimize variability related to disease progression and treatment. In the virus-associated ARDS and non-infectious control groups, one BALF sample was obtained from each patient, and no repeated sampling was performed.

The recovered BALF volume was recorded for each procedure, with a recovery rate of approximately 40–50% of the instilled volume. For biomarker analysis, a fixed volume of 3 mL of BALF supernatant was aliquoted and stored at −80 °C until assay.

Measurement of BALF biomarkers

The concentrations of caspase-4, IL-1β, IL-6, and TNF-α in BALF were measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits (Shanghai Xitang Biotechnology Co., Ltd., Shanghai, China; Cat. No. FP67398, F01220, F01310, and F02810, respectively) according to the manufacturers’ instructions. Optical density was measured at 450 nm using a microplate reader, and analyte concentrations were calculated from standard curves. All samples were assayed in duplicate, and the mean values were used for statistical analysis. The lower limits of detection were <0.1 ng/mL for caspase-4, <1.5 pg/mL for IL-1β, <8 pg/mL for IL-6, and <8 pg/mL for TNF-α.

Statistical analysis

Statistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA). Data distribution was assessed using the Shapiro-Wilk test. As the continuous variables were not normally distributed, data are presented as median [interquartile range (IQR)]. Between-group comparisons were performed using the Mann-Whitney U test or Kruskal-Wallis test, as appropriate. Categorical variables are expressed as counts (percentages) and compared using the χ² test or Fisher’s exact test, as appropriate. Correlations between BALF biomarkers and clinical parameters were assessed using Spearman rank correlation analysis.

Correlation analyses were performed using pooled data from all ARDS patients (Gram-negative bacterial ARDS and virus-associated ARDS combined, n=28). The non-infectious control group was not included because disease severity indicators, including D-dimer levels, OI, and duration of ventilatory support, were not applicable to this group.

Continuous variables were analyzed in their original form without arbitrary categorization, and comparisons were performed across pathogen-defined groups. All tests were two-tailed, and a P value <0.05 was considered statistically significant. Given the exploratory nature of the study and the limited sample size, all analyses were unadjusted, and no multivariable adjustment for potential confounders was performed. No missing data were identified among the variables included in the final analyses. No additional analyses, including subgroup, interaction, or sensitivity analyses, were performed beyond the predefined pathogen-based group comparisons.

Results

Baseline characteristics of the study population

A total of 68 children with ARDS were screened, of whom 40 were excluded based on predefined criteria. The remaining 28 ARDS patients were included and classified as Gram-negative bacterial infection-associated ARDS (n=14) or virus-associated ARDS (n=14). In addition, a separate non-infectious control group (n=17) was enrolled (Figure 1).

Figure 1 Flow diagram of patient selection and grouping. ARDS, acute respiratory distress syndrome.

Baseline demographic and clinical characteristics are summarized in Table 1. Age differed significantly among groups, with younger patients in the virus-associated ARDS group, whereas sex distribution was comparable.

Neutrophil proportion, CRP, and PCT levels were higher in the Gram-negative ARDS group than in the other groups, whereas white blood cell counts did not differ significantly. Pathogen distributions are summarized in Table 1. Haemophilus influenzae was the most frequently detected organism in the Gram-negative ARDS group, followed by Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii complex, and Klebsiella pneumoniae. In the virus-associated ARDS group, respiratory syncytial virus was most common, with additional detections of adenovirus, influenza virus, rhinovirus, and bocavirus.

BALF biomarker levels

BALF concentrations of caspase-4 and inflammatory cytokines (IL-1β, IL-6, and TNF-α) were compared among the three groups (Table 2, Figure 2). No significant differences in caspase-4 levels were observed, with median values of 0.741 (IQR, 0.309–1.625) ng/mL in the Gram-negative ARDS group, 0.937 (IQR, 0.528–1.634) ng/mL in the virus-associated ARDS group, and 1.460 (IQR, 0.810–1.740) ng/mL in controls (P=0.67). Similarly, BALF cytokine levels were comparable across groups. Median IL-1β levels were 12.552 (IQR, 7.818–18.654), 21.279 (IQR, 10.509–43.160), and 15.131 (IQR, 10.023–52.564) pg/mL, respectively (P=0.62), while IL-6 levels were 101.345 (IQR, 72.556–188.026), 113.413 (IQR, 76.471–178.291), and 82.613 (IQR, 60.119–215.059) pg/mL (P=0.95). TNF-α levels did not differ significantly among groups, although numerically higher values were observed in the virus-associated ARDS group (P=0.11).

Figure 2 BALF levels of caspase-4 and inflammatory cytokines among study groups. Box-and-whisker plots showing BALF concentrations of caspase-4 (A), TNF-α (B), IL-6 (C), and IL-1β (D) in children with GN-ARDS, Viral-ARDS, and non-infectious controls. Each dot represents an individual patient. Boxes indicate the IQR, the center line represents the median, and whiskers indicate the minimum and maximum values. Overall comparisons among groups were performed using the Kruskal-Wallis test. ARDS, acute respiratory distress syndrome; BALF, bronchoalveolar lavage fluid; GN-ARDS, Gram-negative bacterial infection-associated ARDS; IL-1β, interleukin-1β; IL-6, interleukin-6; IQR, interquartile range; TNF-α, tumor necrosis factor-α; Viral-ARDS, virus-associated ARDS.

Clinical outcomes and correlation analysis

Clinical outcomes, including duration of ventilatory support and indicators of disease severity, are summarized in Table 3. Correlation analyses were performed using pooled data from all ARDS patients (Gram-negative bacterial ARDS and virus-associated ARDS combined, n=28). BALF caspase-4 levels showed significant positive correlations with IL-1β (r=0.641, P<0.001), IL-6 (r=0.668, P<0.001), TNF-α (r=0.375, P=0.04), and D-dimer levels (r=0.433, P=0.03) (Table 3). Scatter plots illustrating these associations are shown in Figure 3. A modest association was observed between caspase-4 and OI (r=0.376, P=0.053). In contrast, caspase-4 levels showed a weak inverse correlation with the duration of ventilatory support (r=−0.388, P=0.045) (Table 3, Figure 4). An overview of the correlations among biomarkers and clinical variables is presented in Figure 4. Owing to the limited sample size, multivariable regression analysis was not performed.

Figure 3 Correlations between BALF caspase-4 levels and inflammatory cytokines in children with ARDS. Scatter plots show the correlations between BALF caspase-4 levels and TNF-α (A), IL-6 (B), and IL-1β (C). Each dot represents an individual patient. Correlations were assessed using Spearman rank correlation analysis. Correlation coefficients (r) and corresponding P values are shown in each panel. ARDS, acute respiratory distress syndrome; BALF, bronchoalveolar lavage fluid; IL-1β, interleukin-1β; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α.

Figure 4 Correlation heatmap of BALF caspase-4, inflammatory cytokines, and clinical parameters in PARDS. Spearman correlation coefficients (r) are shown for associations between BALF caspase-4, inflammatory cytokines (IL-1β, IL-6, and TNF-α), and clinical parameters, including D-dimer levels, OI, and duration of ventilatory support. Positive correlations are indicated in red and negative correlations in blue, with color intensity reflecting the strength of the correlation. Statistically significant correlations are indicated by asterisks (*, P<0.05; ***, P<0.001). ARDS, acute respiratory distress syndrome; BALF, bronchoalveolar lavage fluid; IL-1β, interleukin-1β; IL-6, interleukin-6; OI, oxygenation index; PARDS, pediatric ARDS; TNF-α, tumor necrosis factor-α.

Discussion

In this study, BALF levels of caspase-4 and inflammatory cytokines did not differ significantly among groups. However, caspase-4 levels were consistently associated with local inflammatory activity and clinical indicators of disease severity. Caspase-4 showed positive correlations with IL-1β, IL-6, TNF-α, and D-dimer, as well as a modest association with oxygenation impairment. These findings suggest that caspase-4–related inflammatory activation may reflect ongoing pulmonary inflammation rather than pathogen-specific responses in PARDS.

Caspase-4 is a central mediator of the non-canonical inflammasome pathway and can be directly activated by cytosolic LPS, leading to gasdermin D cleavage, membrane pore formation, and pyroptotic cell death (8-10). This form of regulated cell death, particularly in alveolar macrophages, has been implicated in amplification of inflammatory responses and lung injury (14). Experimental studies have demonstrated that activation of caspase-4-dependent signaling promotes cytokine release and contributes to tissue damage in severe infections and sepsis (12,16,17). Our findings are consistent with these observations and suggest that similar mechanisms may operate in the pulmonary microenvironment of children with ARDS.

From a clinical perspective, the observed association between elevated BALF caspase-4 levels and worse OIs, as well as prolonged PICU stay, indicates that caspase-4-related inflammatory activity may reflect disease severity. Previous studies have demonstrated that dysregulated inflammatory responses are closely linked to the progression of lung injury and adverse outcomes in ARDS (18-23). In pediatric populations, most investigations have focused on systemic or cytokine-based markers, whereas data on upstream inflammatory signaling pathways remain limited (24-26). Recent studies have highlighted the substantial clinical and biological heterogeneity of PARDS and emphasized the need for biomarker-driven approaches to improve risk stratification and precision medicine strategies. In this context, identification of novel inflammatory biomarkers may facilitate characterization of distinct disease endotypes and provide additional prognostic information (1). By assessing caspase-4 in BALF, our study provides additional insight into local inflammatory processes within the lung and their relationship with clinical severity.

BALF analysis offers a direct assessment of the alveolar microenvironment and has been associated with disease severity and inflammatory burden in children with severe pneumonia and ARDS (15,19,20). In this context, the combined assessment of caspase-4 and downstream cytokines may provide a more comprehensive evaluation of inflammatory activity than conventional biomarkers alone.

Limitations

Several limitations should be acknowledged. First, this was a single-center study with a relatively small sample size, which may limit statistical power and generalizability. Second, the retrospective design may introduce selection bias, and bronchoalveolar lavage was performed based on clinical indications rather than a standardized protocol. Third, although lavage procedures were conducted using a reduced volume to ensure safety in ARDS patients, variability in recovery volume may have influenced biomarker concentrations. Fourth, BALF samples were collected at a single early time point, precluding assessment of dynamic changes over the disease course. Fifth, the cross-sectional nature of the analysis limits causal inference between caspase-4 activation and disease severity. In addition, only patients with mild ARDS were included, which restricts extrapolation to more severe cases. Finally, residual confounding cannot be excluded, particularly with regard to prior treatments and potential co-infections.

Interpretation

Taken together, these findings indicate that BALF caspase-4 is linked to inflammatory activation in PARDS. However, its association with clinical severity appears modest, suggesting that caspase-4 reflects inflammatory activity rather than overall disease burden. These results should be interpreted cautiously given the study design, sample size, and lack of multivariable adjustment. In addition, multiple comparisons were performed without formal correction, which may increase the risk of type I error. Further prospective studies are required to confirm these findings and clarify their clinical significance.

Generalizability

The generalizability of these findings is limited. This was a single-center study conducted in a tertiary pediatric hospital, and the study population may not fully represent broader ARDS populations. Moreover, inclusion was restricted to patients with mild ARDS undergoing clinically indicated bronchoscopy, which may limit applicability to other clinical settings. Nonetheless, the observed associations are biologically plausible and may be relevant in similar contexts. Further validation in larger, multicenter cohorts is needed.

Conclusions

In conclusion, BALF caspase-4 levels are closely associated with local inflammatory activity in PARDS. Although no significant differences were observed between etiological groups, the correlations between caspase-4 and inflammatory cytokines suggest that caspase-4 may reflect the intensity of pulmonary inflammation rather than pathogen-specific mechanisms. These findings provide preliminary evidence supporting caspase-4 as a potential biomarker of disease activity. Larger prospective studies with longitudinal sampling are needed to further define its clinical relevance and mechanistic role.

Acknowledgments

The authors thank all the children and their families for participating in this study. We also acknowledge the medical and laboratory staff of the Department of Pediatric Respiratory Medicine, Chengdu Women and Children’s Central Hospital, for their support in data collection and sample processing.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0379/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0379/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0379/prf

Funding: This study was supported by the Chengdu Municipal Health Commission (Health Commission of Chengdu) Medical Research Project (No. 2023107).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0379/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was approved by the Ethics Committee of Chengdu Women and Children’s Central Hospital [approval No. 2024(31)-2]. Written informed consent was obtained from the guardians of all participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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