Sex-Based Differences in Long-Term Lipid Metabolism, Inflammation and Stress Regulation After Non-Severe Paediatric Burns

Sex-Based Differences in Long-Term Lipid Metabolism, Inflammation and Stress Regulation After Non-Severe Paediatric Burns | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var 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Jacqueline Davis , View ORCID Profile Nina D’Vaz , View ORCID Profile Lucy W Barrett , View ORCID Profile Nicola Gray , View ORCID Profile Fiona M Wood , View ORCID Profile Elaine Holmes , View ORCID Profile Mark W Fear , View ORCID Profile Luke Whiley doi: https://doi.org/10.1101/2025.09.23.25336456 Monique J Ryan 1 Centre for Computational Systems Medicine, Health Futures Institute, Murdoch University, Harry Perkins Institute , Murdoch, WA 6150, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Monique J Ryan Eva Kierath 1 Centre for Computational Systems Medicine, Health Futures Institute, Murdoch University, Harry Perkins Institute , Murdoch, WA 6150, Australia 2 Fiona Wood Foundation, Fiona Stanley Hospital , Murdoch, WA 6150, Australia 3 Burn Injury Research Unit, School of Biomedical Sciences, University of Western Australia , Perth, WA 6009, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Eva Kierath Samantha Lodge 1 Centre for Computational Systems Medicine, Health Futures Institute, Murdoch University, Harry Perkins Institute , Murdoch, WA 6150, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Samantha Lodge Reika Masuda 1 Centre for Computational Systems Medicine, Health Futures Institute, Murdoch University, Harry Perkins Institute , Murdoch, WA 6150, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Reika Masuda Jacqueline Davis 4 The Kids Research Institute Australia, Perth Children’s Hospital , Perth, WA 6009, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jacqueline Davis Nina D’Vaz 4 The Kids Research Institute Australia, Perth Children’s Hospital , Perth, WA 6009, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Nina D’Vaz Lucy W Barrett 2 Fiona Wood Foundation, Fiona Stanley Hospital , Murdoch, WA 6150, Australia 3 Burn Injury Research Unit, School of Biomedical Sciences, University of Western Australia , Perth, WA 6009, Australia 4 The Kids Research Institute Australia, Perth Children’s Hospital , Perth, WA 6009, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Lucy W Barrett Nicola Gray 1 Centre for Computational Systems Medicine, Health Futures Institute, Murdoch University, Harry Perkins Institute , Murdoch, WA 6150, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Nicola Gray Fiona M Wood 2 Fiona Wood Foundation, Fiona Stanley Hospital , Murdoch, WA 6150, Australia 3 Burn Injury Research Unit, School of Biomedical Sciences, University of Western Australia , Perth, WA 6009, Australia 5 Burns Service of Western Australia, WA Department of Health , Nedlands, WA 6009, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Fiona M Wood Elaine Holmes 1 Centre for Computational Systems Medicine, Health Futures Institute, Murdoch University, Harry Perkins Institute , Murdoch, WA 6150, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Elaine Holmes Mark W Fear 2 Fiona Wood Foundation, Fiona Stanley Hospital , Murdoch, WA 6150, Australia 3 Burn Injury Research Unit, School of Biomedical Sciences, University of Western Australia , Perth, WA 6009, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Mark W Fear Luke Whiley 1 Centre for Computational Systems Medicine, Health Futures Institute, Murdoch University, Harry Perkins Institute , Murdoch, WA 6150, Australia 6 Curtin Medical School, Curtin University , Bentley, WA 6102, Australia 7 Curtin Medical Research Institute, Curtin University , Bentley, WA 6102, Australia 8 Dementia Centre of Excellence, enAble Institute, Curtin University , Bentley, WA 6102, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Luke Whiley For correspondence: luke.whiley{at}murdoch.edu.au Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Paediatric burn injuries are a global health concern with long-term health consequences, such as psychological, immune, and cardiovascular complications, that can persist even after non-severe injuries. Emerging evidence suggests that biological sex may influence post-burn outcomes in children, as female burn survivors have been shown to experience higher mortality, scarring, anxiety, depression, and poorer quality of life compared to males. This study addresses a critical research gap by examining sex-specific lipidomic and inflammatory responses following paediatric non-severe burn injury. Children under five years were recruited as a part of the Childhood Burn Injury Biobank at hospital admission with longitudinal follow-ups and non-burn controls aged 1 and 3 were collected from the ORIGINS cohort. Plasma lipid profiling and acute-phase glycoprotein systemic inflammatory markers (GlycA and GlycB) were quantified using metabolic phenotyping with hair cortisol provided as a longitudinal measure of stress. Lipidomic analysis revealed acute-phase disruptions in fatty acids and lysophospholipids in both sexes but only females demonstrated a persistent increase of arachidonic acid (FA 20:4) and depletion of monoacylglycerols more than a year post-injury. Females also had significantly higher acute-phase GlycA/GlycB levels around the time of injury and exhibited increasing variability in hair cortisol over time, while male burn survivors did not. These findings highlight a sex-specific response between lipid metabolism, systemic inflammation and stress in paediatric recovery from non-severe burns. Understanding these differences may guide the development of targeted psychological and physiological strategies to improve long-term outcomes for young burn survivors. Introduction Paediatric burn injuries are a significant global health burden. In Western Australia alone, children under the age of 15 account for approximately 35% of all burn-related hospital admissions, which is a trend that is reflected across both high- and lower-middle-income countries 1 . The consequences of burn trauma in children extend well beyond the initial injury. Paediatric burn traumas can lead to long-term cardiovascular, immune, musculoskeletal and nervous system complications, which can persist for decades post-injury even in non-severe cases 2 – 7 . These long-term complications are often combined with chronic pain, reduced exercise capacity, muscle weakness, scarring, and psychosocial challenges, significantly impacting the quality of life of childhood burn survivors and their families 7 . Despite improvements in acute burn care, recent research has identified biological sex as an additional risk factor for some of the long-term complications associated with burn injury. In adult cohorts, females have been reported to have twice the mortality rate compared to males when adjusted for total body surface area percentage (TBSA%) and age 8 – 12 . In paediatric cases, this is reflected with female children experiencing higher rates of mortality following severe burn injuries 13 , higher rates of pathologic scarring 14 , 15 and poorer long-term psychological outcomes, including greater incidence of anxiety, depression, with female burn survivors reporting a lower overall quality of life 16 , 17 . However, there are discrepancies in the literature, with some studies finding that being female was protective of adverse burn outcomes, and others reporting no significant sex differences in terms of patient outcomes 18 – 21 . These inconsistencies, coupled with limited research, highlight the need for further studies to better understand the impact of sex on paediatric burn injury recovery and long-term outcomes. A potential mechanistic area for sex-differences in outcomes after paediatric burn injury may lie between stress, inflammation and metabolism, particularly lipid-mediated inflammation. Inflammation and lipid metabolism are two correlated biological systems that are known to influence each other 22 and contribute to the pathophysiology of various diseases, including cancer 23 , cardiovascular disease 24 , diabetes 25 and even burn trauma 26 . Studies in other chronic inflammatory conditions, such as asthma, cystic fibrosis and sickle cell anaemia, have shown that females under ten exhibit a stronger increase in inflammatory markers compared to males 27 , 28 . These studies identified higher neutrophil counts and C-reactive protein levels with more frequent or severe clinical symptoms in females 27 , 28 , which may also be relevant in the context of recovery after paediatric burn injuries. Psychological stress is another factor known to modulate inflammation through steroid hormones such as cortisol 29 , 30 and has recently been associated with lipid metabolic changes in children 29 . Research into childhood pain responses has found that young females are more vulnerable to long-term anxiety and stress compared to males 31 , with adult females who experienced childhood burn trauma reporting significantly higher rates of psychological adversity 16 . Furthermore, studies on childhood trauma and stress have identified a higher risk of developing metabolic diseases, such as obesity and cardiovascular conditions, in women later in life. These outcomes are partly attributed to elevated cortisol levels and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis 32 , 33 . Together, this evidence points to a potentially underexplored, systemically linked triad of stress, inflammation, and metabolism that may influence sex-based differences in responses to paediatric burn injury, both in the short and long term. Recent research has identified sex differences in the lipidome in both healthy adults and children 34 – 37 . In addition to this sex-difference in the lipidome, lipid-related inflammatory pathways may provide insights into sex-specific responses during burn injury and recovery. While our previous pilot study identified lipidomic alterations up to three years post-injury in paediatric burn survivors 38 , sex differences in these lipidomic responses have not yet been explored. The current study seeks to address this gap by conducting a detailed metabolic phenotyping analysis in children under the age of five, to characterise lipid-related inflammatory and cortisol differences between male and female children following non-severe burn trauma. Understanding these sex-specific molecular pathways may help inform more targeted and effective interventions to improve long-term outcomes for all paediatric burn survivors. Methods Study design The Childhood Burn Injury Biobank recruited children (n=237) from Perth Children’s Hospital who were treated for a burn injury of any severity and were less than 16 years old, with informed consent granted through a parent or guardian. For this study, only those patients that were ≤5 years of age at time of injury were included (n=118). Ethics for this biobank and subsequent research was approved by The Child and Adolescent Health Service Ethics Committee (Ethics No. RGS0000001403) and by Murdoch University Human Research Ethics Committee (Ethics No. 2021/160) in Western Australia. For non-burn controls, samples from children aged 1 and 3 (n=299) were provided by ORIGINS Biobank 39 , 40 . ORIGINS is a population cohort in Western Australia that follows 10 000 children from birth until the age of 10. Ethics for use of these samples was approved by the Ramsay Health Care WA / SA Human Research Ethics Committee (Reference: 2146W). Plasma collection Plasma was collected in lithium heparin collection tubes using matched protocols by both the Childhood Injury Biobank and ORIGINS for each child 40 . Non-burn controls had one sample taken at ages 1 and 3. For the paediatric burn cohort, blood was drawn on admission to the Burns Unit when receiving treatment for a burn injury. Follow-up samples were collected on re-visit to hospital, which fell into the following time categories: ‘Acute phase’ which was <14 days from the initial injury, ‘Recovering phase’ between 14 days to 1-year post-admission and once deemed ‘Recovered’, over a year post-admission. Ethics approval for the analysis of these samples was obtained from Murdoch University Human Research Ethics Committee (Ethics No. 2021/160). Hair cortisol measurements Hair strands with ∼5mm diameter were collected from the posterior vertex region of the scalp. The hair tip was placed into a 2mL cryotube and cut near the scalp to ensure cortisol measurements closest to time since injury. Only 3 cm from the scalp (roughly 3 months of growth) was used for analysis. Hair strands were collected up to 1 week post-admission to hospital (to mimic a pre-burn injury baseline), between 1 week to 1 month, 3 to 6 months, 6 to 12 months and over 1 year since injury. Cortisol extraction from the hair and subsequent analysis was performed by Stratech Scientific (Mona Vale, Australia) according to their validated protocol. In brief, hair strands were weighed prior to extraction for correction post-analysis, then mechanically crushed and extracted using 100% methanol. Samples were dried down to remove the solvent before reconstitution in phosphate-buffered saline. Cortisol was analysed using a salivary cortisol enzyme-linked immunosorbent assay kit (Salimetrics, Pennsylvania, USA) with a calibration range of 0.012 - 3 µg/dL. Comprehensive lipid profiling Lipid profiling on the plasma samples was performed in accordance with an established protocol that has previously been published and validated 41 . In brief, 20 µL of plasma was extracted with 180 µL of isopropanol (Thermo Fisher Scientific, Malaga, Western Australia, Australia) containing Ultimate SPLASH™ ONE, SphingoSPLASH™ I, 17:1 Lyso PS and 18:1-d7 MG from Avanti Polar Lipids (Sigma-Aldrich, North Ryde, New South Wales, Australia), and Arachidonic acid-d5, Linoleic acid-d11, Oleic acid-d9, Palmitic acid-d5 and Stearic acid-d4 from Cayman Chemical (Sapphire Bioscience, Redfern, New South Wales, Australia). Samples were vortexed, chilled at −20 °C and centrifuged before supernatant extraction (50 µL) into 96-well plates for liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. For detection of lipids from hair strands, 20 µL of the leftover methanol extraction for the cortisol measurements underwent the same procedure as in the described plasma protocol. A list of internal standards and their concentrations are available in Supplementary Table S1. LC-MS/MS was performed using a SCIEX ExionLC and QTRAP 6500+ mass spectrometer to detect 1163 lipid species and pooled quality control (QC) samples created from combining all cohort samples were run intermittently to assess instrument performance. Raw spectra were imported into Skyline v24.1 (MacCoss, WA, USA) for peak integration, while data pre-processing and filtering were carried out in R (v4.4.3, R Foundation, Vienna, Austria) using RStudio IDE (build 2024.12.1+563, RStudio, Boston, MA, USA) 42 . Lipid species and samples with >50% missing values were excluded. For those with 30% in pooled QC samples were also removed. To correct for signal drift, each lipid concentration was adjusted using the Random Forest method within the statTarget R package (available from github.com/statTarget ) using pooled QCs as reference. 1H NMR spectroscopy Plasma was prepared for 1 H NMR spectroscopy using an established validated protocol 43 – 45 . In summary, a 600 MHz Bruker Avance III HD spectrometer coupled with a BBI probe and SampleJet robot (Bruker BioSpin, Massachusetts, USA) was employed to analyse plasma samples maintained at 5 °C in the system. Plasma was diluted 1:1 with a phosphate buffer (75 mM Na 2 HPO 4 , 2 mM NaN 3 , and 4.6 mM sodium trimethylsilyl propionate-[2,2,3,3-2H 4 ] (TSP) in D 2 O, pH 7.4 ± 0.1) before 180 µL of the mixture was added into 3 mm SampleJet NMR tubes. 1 H NMR spectroscopy was performed per Bruker in vitro Diagnostics research (IVDr) methods for 1 H 1D and PGPE experiments 44 , 46 . 1 H 1D experiments with solvent pre-saturation ran for an experiment time of 14 min 53 s acquiring 128 scans, 98 K data points with a spectral width of 30 ppm, followed by the PGPE experiment run for 16 min and 47 s obtaining 256 scans, 98 K data points and a spectral width of 30 ppm. The PGPE experiment was run with a secondary irradiation field for solvent suppression (set at the water frequency) to ensure the capture of N -glycan inflammatory markers GlycA (arising from N -acetylneuraminic acid moieties) and GlycB (originating from N -acetylglucosamine moieties) within the spectra. Data pre-processing was performed in R (v4.4.3) using in-house and open-source packages nmr-parser (available from github.com/phenological/nmr-parser ) and nmr-spectra-processing (available from github.com/phenological/nmr-spectra-processing ). Spectra obtained from the PGPE experiment was corrected for instrument variability using the ERECTIC factor and baseline corrected with an asymmetric least-squares routine. Signals from acetylated glycoproteins known to be associated with inflammation 47 , 48 , GlycA and GlycB, were integrated by summing fixed spectral regions at δ 2.05−2.09 (GlycA) and δ 2.09−2.12 (GlycB). Statistical analysis and data visualisation Statistical analysis and visualisation of the data was conducted using R (v4.4.3) and the RStudio IDE (build 2024.12.1+563). Mann-Whitney U tests were applied for univariate statistical analysis with significance set at p -value < 0.05. Multivariate analysis including orthogonal projections to latent structures-discriminate analysis (OPLS-DA) was performed using the mva.plots R package (v0.0.8) (available from github.com/phenological/mva-plots )and eruption plots were generated for each of the models. Eruption plots, the multivariate equivalent of a volcano plot 49 , enable the visualisation of the univariate effect size through Cliff’s delta (x-axis) combined with the multivariate OPLS-DA predictive loadings (y-axis). Lipid subclasses were calculated by summing all the lipid species within each subclass. There is an exception with triacylglycerols (TGs) where after summing the subclass is divided by three due to the limitation in the LC-MS/MS analysing the same TG species three times for each sidechain 50 . All visualisations utilising data from other packages were produced through ggplot2 from github.com/tidyverse/ggplot2 . Results Clinical outcomes of sex in paediatric patients For the overall paediatric cohort, there were no statistically significant differences between females and males in terms of age, Fitzpatrick skin type, burn depth, burn source, wound and scar management, or surgical requirements ( Table 1 ). Females had a significantly longer hospital stay ( p -value = 0.043) and a higher incidence of face, neck and forearm burns ( p -value <0.01) compared to males. For the overall cohort, both males and females had <10% TBSA which is classified as a non-severe burn. View this table: View inline View popup Table 1. Demographics of the total paediatric burn cohort split by sex and corresponding p -values. Significant p -values (<0.05) are bolded. Burn healing trajectories are different for males and females after non-severe burn injury when compared to non-burn controls Both male and female paediatric burn patients displayed distinct lipidomic signatures during the acute phase (<14 days post-injury) of the non-severe burn injury compared to non-burn controls at 1 year of age, which is a similar age to the burn cohort at the time of injury ( Figure 1A-B ). The OPLS-DA models revealed strong and significant lipidomic differences for males ( Figure 1A : R 2 X(cum) = 0.474, R 2 Y(cum) = 0.846, Q 2 (cum) = 0.676) and females ( Figure 1B : R 2 X(cum) = 0.575, R 2 Y(cum) = 0.908, Q 2 (cum) = 0.712). Due to the large number of TG lipid species detected (50% of the total lipid species: n=444, total lipid species n = 888), eruption plots ( Figure 2 ) were generated with the lipid subclasses instead to highlight the lipidomic changes that may be otherwise be overshadowed by TGs. The results showed that the lipidomic signatures in males and females were similar compared to non-burn controls in the acute phase ( Figure 2A-B ). Burn lipidomic signatures were characterised by increases in the concentration of the plasma fatty acid (FA) subclass and decreases in the lysophosphatidylglycerol (LPG) subclass. For males, the increases in FA were a more significant contributor to the model than for females during the acute phase of burn injury. Download figure Open in new tab Figure 1. Lipidomic differences between males and females post-non-severe burn injury compared to non-burn controls. OPLS-DA classed by injury are separated in columns by sex (Left: female burn injury = green, female non-burn = purple; Right: male burn injury = orange, male non-burn = burgundy) A) Non-burn controls at the age of one compared to the burn acute phase (<14 day from injury) for females, B) Non-burn controls at the age of one compared to the burn acute phase ( 1 year from injury) for females, and D) Non-burn controls at the age of three compared to burn cohort when considered ‘recovered’ (> 1 year from injury) for males. Note: Metadata provided for the non-burn controls stipulated ages 1 or 3, resulting in a standard deviation of 0 in the plot subtitles. Download figure Open in new tab Figure 2. Changes in lipid subclasses over time in females and males within the paediatric burn cohort. Visualised by an eruption plot depicting Cliff’s delta (x-axis) and OPLS-DA predictive loadings (y-axis) of lipid classes subclass coloured by significance (Mann-Whitney U p -value < 0.05 and Cliff’s delta ± 0.5 effect size). Plots organised by OPLS-DA modelling of females A) acute phase compared to non-burn controls (age 1) and C) ‘recovered’ compared to non-burn controls (age 3), with plots replicated for males in B) and D) . Grey lines show cut-off values for Cliff’s delta ± 0.5. After recovery from the burn (>1 year post-injury), the lipidome of the burn injury cohort began to diverge when compared to non-burn controls at age 3. In the case of males, the OPLS-DA model initially failed to generate a significant orthogonal component and resulted in a lower Q 2 Y (cum) value of 0.108 when generation of an orthogonal component was forced (Table S2). Comparatively, the OPLS-DA model for the males at admission generated 3 orthogonal components while the models for females generated up to 5 orthogonal components (Table S2), which highlights the increased variation between female children post-injury compared to non-burn controls. This suggests that the lipidome of ‘recovered’ males was like that of non-burn controls, although some significant differences remained, particularly in the lysophosphatidylcholine (LPC) subclass. In contrast, females exhibited a distinct lipidomic signature at the ‘recovered’ stage, similar to our observations at the acute phase, with a robust model (R 2 X(cum) = 0.575, R 2 Y(cum) = 0.976, Q 2 Y(cum) = 0.527) and a clearer separation from non-burn controls. Of particular interest was the role of the monoacylglycerol (MG) subclass which emerged as a key driver of separation in female paediatric burn patients at the ‘recovered’ stage. Over time, there was a marked decrease in MG species in females from the acute phase (adj. p -value < 0.001) to the ‘recovered’ stage, whereas this trend was not observed in males ( Figure 2C-D , Figure S1). To investigate why the MG subclass had decreased in females, analysis shifted focus to the lipid species instead. Within the MG subclass, lipid species MG(18:1)(adj. p -value < 0.0001), MG(18:2) (adj. p -value < 0.0001) and MG(18:3) (adj. p -value < 0.01) showed the most significant decline over time for females, with levels lower than that of non-burn controls when ‘recovered’ (Figure S1). While males exhibited a similar pattern to females in the acute phase for the same MG species (adj. p -value 0.05). Systemic inflammation is greater in females after a non-severe burn injury As FAs were among the lipid subclasses significantly elevated in paediatric burn patients across both sexes during the acute phase and remained higher into recovery ( Figure 2 ), we explored the specific species within this subclass given their roles in inflammation 52 . All 20 FA lipid species contributed substantially to group separation in the OPLS-DA models (Table S2), but of particular interest was arachidonic acid (FA(20:4)), which is a central precursor to an array of pro-inflammatory mediators 52 . Longitudinal visualisation of FA(20:4) levels revealed sex-specific patterns ( Figure 3A ). In the acute phase, male and female burn patients exhibited significantly higher plasma concentrations of FA(20:4) compared to non-burn controls (adj. p -value < 0.0001). However, trajectories over time diverged for the sexes. In males, although FA(20:4) remained significantly elevated compared to non-burn male patients at age 3, we observed a gradual decline that appeared to be approaching the levels seen in non-burn controls. In contrast, females showed a persistent increase in FA(20:4) levels more than a year post-injury (‘recovered’), which is in contrast to the natural age-related decline of this FA that is observed in non-burn controls. This is indicative of a sex-specific disruption in lipid species following burn injury. Download figure Open in new tab Figure 3. Sex differences in systemic inflammatory markers for paediatric burn injury in females and males compared to non-burn controls. Changes in females (green) compared to non-burn controls, replicated in males (orange) across the burn stages using a linear regression in A) FA(20:4), B) GlycA and C) GlycB. Univariate statistics using Mann-Whitney U (adjusted with Benjamin-Hochberg) show significance: ns = not significant, * = p -value < 0.05; ** = p -value < 0.01; *** = p -value < 0.001; **** = p -value < 0.0001. Building on these findings, we assessed systemic inflammation through quantification of GlycA and GlycB, which are composite markers derived from N -glycan moieties that reflect circulating acute-phase glycoproteins during inflammation 53 – 55 . In the acute phase following burn injury, females showed significantly higher levels of both GlycA and GlycB (adj. p -value < 0.001) compared to female non-burn controls of a similar age ( Figure 3B-C ). GlycA and GlycB levels decreased over time in the recovering and recovered stages for females, eventually aligning with the levels in non-burn children. In contrast, male burn survivors showed no significant change in trajectory over time, with no significant increase in GlycA and GlycB in the acute phase and levels appearing to follow the typical developmental progression observed in non-burn male children aged between 1 and 3 years old. It has been demonstrated in healthy adults that there is no significant difference of the glycoproteins in relation to sex 56 . Long-term stress levels and lipid influence in response to paediatric burn injury Cortisol measurements from hair samples were used as a non-invasive method to monitor long-term stress levels and to capture pre-injury baseline levels. Average cortisol levels in females and males were comparable from pre-injury (hair sample taken up to 1 week after injury) and remained so up to 3-6 months post-injury. Although the difference between males and females was not statistically significant, females demonstrated increasing variability over time in cortisol concentration as seen in the broader spread of their data up to 12+ months. This is reflected in the increasing fold changes from 1 week post-injury for females (3-6 months = 0.62 FC, 6-12 months = 2.27 FC and >12 months = 5.64 FC) compared to males who exhibited smaller fold changes in cortisol concentrations (3-6 months = 0.27 FC, 6-12 months = 0.83 FC and >12 months = 1.46 FC). Correlation analysis of cortisol with 545 lipid species detected in their hair samples revealed sex-specific differences. In males, no significant associations were observed with only weak negative correlations across all lipid species ( Figure 4B , Table S3), a trend also evident at the subclass level (Table S4). However, in females 101 lipid species were significantly correlated with cortisol after adjustment and 96% of which belonged to the TG subclass (Table S3, Table S4). The strongest association was observed for TG(56:2_FA20:0) (Pearson’s r = 0.72, adj. p -value = 1.77×10 −10 ). The summed TG class also correlated significantly with cortisol (r = 0.38, adj. p -value = 0.015). Outside the TG subclass, only cholesteryl ester CE(18:2) showed a moderate association (r = 0.40, adj. p -value = 0.005). Download figure Open in new tab Figure 4. Cortisol trends and lipid subclass correlations split by sex in hair collected from the paediatric burn cohort. A) Females (green, n = 28) and males (orange, n = 35) cortisol measurements from 3 cm strands categorised into five timepoints (up to 1 week: n = 47; 1 week-1 month: n = 10; 3-6 months: n = 12; 6-12 months: n = 39; 12+ months: n = 42). Individual measurements for both sexes are indicated by the jittered dot points. B) Correlation matrix of lipid subclasses detected and cortisol levels in hair split by male and female children after burn injury. Pearson’s correlation scale ranging from positive (orange) to negative (blue) correlation with ‘*’ denoting a significant correlation after p -value adjustment for each lipid subclass. Discussion This study highlights sex-specific trajectories of inflammation and lipid metabolism in paediatric burn patients. Consistent with prior research, we observed a disruption in the lipidome in both male and female children in the acute phase (<14 days) following burn injury, which was characterised by increased FA subclasses and a decrease in lysophospholipids (LPGs, LPCs and lysophosphatidylethanolamines (LPEs)) and phosphatidylglycerols (PGs). The shift in FAs is similar to lipidomic changes previously reported in adult 57 and paediatric 58 burn cohorts, which could indicate that perturbations in lipid metabolism, particularly increases in circulating FAs, are a hallmark of the early post-burn response regardless of age. However, our data also revealed distinct sex differences in the paediatric burn plasma lipidome. Although both sexes showed lipidomic disruptions, males demonstrated a more pronounced increase in FA subclasses while females exhibited higher levels of the inflammatory glycoproteins GlycA and GlycB during the acute phase of the burn injury compared to non-burn controls. The elevated GlycA and GlycB levels in females that returned to non-burn control levels during recovery are consistent with a transient, systemic inflammatory response typically observed after a burn. These markers have been previously found by our research team to be increased post-burn in adults 59 and children 6 . To our knowledge, no other studies have examined GlycA and GlycB responses specifically in paediatric burn trauma. Beyond burn injury, GlycA and GlycB have been reported to be elevated in adolescents with inflammatory conditions such as pre-diabetes 60 , obesity 61 and cystic fibrosis 62 . Within these conditions, sex differences have also been observed in other traditional inflammatory markers, including C-reactive protein (CRP). In both adults and children, females consistently exhibited higher CRP levels than males during inflammatory responses which supports the sex-specific patterns observed in our study 27 , 63 . In contrast, males did not exhibit any spike in GlycA and GlycB during the acute phase or up to the ‘recovered’ stage. The implication of this muted systemic response is unknown, and it is unclear whether it predisposes males to a long-term recovery advantage or instead reflects an impeded activation of specific inflammatory pathways. Evidence for such observations is limited but findings from a study of post-operative systemic inflammation following major abdominal surgery showed that higher systemic inflammation (measured by CRP) was associated with poorer quality of recovery for adults 64 . This raises the possibility that the minimal systemic response observed in male children may be more protective in the context of burn recovery, but more research is needed in this area. The increases in FA lipid species observed in children with burn injury may also indicate a shift to a pro-inflammatory state. Within the FA subclasses, there was a lack of elevation in some omega-3 fatty acids, particularly eicosapentaenoic acid (FA(20:5)) and (FA(22:6)), during both the acute and recovery stages. These long-chain polyunsaturated fatty acids are known precursors of anti-inflammatory mediators, such as resolvins and protectins, that modulate inflammation 65 . This is coupled with an increase in FA(20:4), also known as arachidonic acid, which is a precursor to numerous pro-inflammatory molecules in the eicosanoid pathway, including prostaglandins, thromboxanes, and leukotrienes 65 . The skewed ratio with more pro-inflammatory FA(20:4) to anti-inflammatory FA(20:5) or FA(22:6) suggests that the paediatric burn lipidome remains in a pro-inflammatory state even when considered ‘recovered’. Notably, although still elevated, FA(20:4) levels in males appear to trend toward non-burn control levels one year post-injury. In contrast, females had a persistent, unchanged increase in FA(20:4) even during the ‘recovered’ stage. Additionally, females had a unique lipidomic change compared to non-burn controls that males did not exhibit when considered ‘recovered’. One-year post-burn, we observed a significant depletion of the MG subclasses in female burn survivors, which was not observed in males. In contrast, our team has previously identified MG lipid species in adult burn patients to increase after injury 59 which demonstrates an opposing response in paediatric female burn survivors. This decrease in the MG subclass and increased FAs, particularly 1-MG species (MG(18:1), MG(18:2) and MG(18:3)), may suggest a sex-specific disruption in the de novo synthesis of MGs, potentially via impaired esterification of FAs to glycerol 66 and could reflect a maladaptive lipidomic response during burn recovery. In this study, we have identified sex-specific lipidomic changes in paediatric burns that may be influenced inherently by sex hormones 13 . Sex differences in burn recovery outcomes have been attributed to the role of oestrogen and related hormones as potent modulators of inflammation 67 – 69 . However, limited studies conducted mainly in murine models implies the biological mechanisms of these sex-based disparities are not well understood, particularly in pre-pubescent children where the role of oestrogen and other sex hormones is less clear. We propose that hormones are not the sole drivers of sex differences in paediatric burn outcomes, as sex-dependent hormonal activity is unlikely to play a major role in children at such a young age. Blood oestradiol and testosterone levels typically rise significantly only around age 8 in females and age 9 in males, respectively 70 . Thus, other factors may substantially contribute to these sex-specific differences. One important consideration is stress which represents a major long-term health issue following both severe and non-severe burn injuries in both adults and children 71 – 73 . When comparing cortisol hair levels over time in the paediatric burn cohort, females displayed a trend of increased cortisol levels and greater inter-individual variability from 6-12 months to over a year post-injury. Females who experienced a burn in their childhood have been reported to be twice as likely than males to develop a psychological disorder, such as an anxiety disorder, post-traumatic stress disorder or depression 16 , 74 . This trend may indicate a prolonged stress response in females which aligns with prior findings that female paediatric burn survivors report lower quality of life 75 . Moreover, this trend may be linked to persistent elevations in arachidonic acid (FA 20:4), a precursor to eicosanoids, which can mediate stress and inflammation 76 . On the contrary, hair cortisol levels did not increase in males from pre-injury (hair sampled up to a week post-injury) to a year post-burn. There are some discrepancies in the literature where studies have identified higher levels of urinary cortisol in males after a burn than females 77 , 78 . It is noted that hair cortisol levels do not associate with urinary cortisol but are more closely aligned to salivary cortisol, which may explain the differing results in the literature regarding cortisol measurements from hair, saliva or urine post-injury 79 . Interestingly, we identified a potential correlation between hair lipids and cortisol measurements only in female children post-burn injury. TG species showed the most significant and strongest correlations in this group that potentially aligns with limited evidence in other inflammatory conditions such as paediatric obesity, where circulating triglycerides positively associate with cortisol levels 80 . In adults, stressors can stimulate the HPA axis and lead to elevated cortisol levels that in turn raise circulating triglycerides 81 . These findings suggest a possible link between circulating TGs and cortisol that can be detected in hair which can offer a novel approach for monitoring stress and systemic lipid changes. Moreover, the observed associations highlight a sex-specific relationship between stress and inflammation that warrants further investigation, as males showed no significant correlations between cortisol and lipids that is likely reflected by their relatively stable cortisol levels. Importantly, our findings contribute to a broader and sometimes contradictory discussion on sex-specific outcomes in burn recovery. Some studies have reported that females fare worse post-burn in terms of physical and mental health, psychological distress, and burn-specific quality of life metrics 82 – 84 . Other studies suggest that females exhibit a less profound hypermetabolic response compared to males through reduced catecholamines, energy expenditure, and protein catabolism which could be protective 78 . The dichotomy of these perspectives is complex and underpins the necessity for validating these findings in population-based paediatric burn cohorts to fully elucidate the potential differences between sexes in response to injury. The role of demographic and injury-related factors must also be considered. Previous studies have linked female sex, young age, and specific burn sites (e.g., face, neck and upper limbs) with increased risk of poor long-term outcomes, including pathological scarring 14 . In this cohort, females experienced significantly higher face and neck burns than males. These factors could influence the lipidomic and inflammatory alterations we observed, potentially related to the psychological stress of having visible burns but this topic remains a subject of debate in the literature 73 , 85 . Our findings also emphasise that mental health should not be overlooked in young children post-burn, as psychological and physiological stress responses may shape recovery in ways that are not immediately evident in clinical assessments. Notably, we observed sex-specific differences in lipidomic profiles and cortisol levels in response to relatively minor (non-severe) burns, as the children had an average of 2% TBSA. This suggests that even non-severe burn injuries can trigger systemic responses in children as previously seen with potential long-term psychological and physiological consequences 6 , 7 , 38 , 73 , 86 , 87 . These findings warrant greater attention to childhood non-severe burn injury in both research and clinical settings. We have identified unique, sex-specific lipidomic and inflammatory trajectories, along with stress-related trends that may deepen our understanding of the metabolic consequences of post-paediatric non-severe burn injury. Further studies should link these changes to long-term outcomes and clarify how sex, stress, and inflammation connect during paediatric burn recovery. Conclusion This study identified sex-specific differences in lipidomic and inflammatory responses following non-severe burn injury in paediatric patients. While both males and females showed disruptions in lipid metabolism during the acute phase, only females exhibited persistent alterations with elevated FA(20:4) (arachidonic acid) and depleted MG lipid species over one year post-injury, despite their burn being fully healed. These changes were accompanied by higher levels of systemic inflammatory markers GlycA and GlycB during the acute phase in females and a potential trend toward elevated long-term stress through hair cortisol levels that significantly correlation with TG species. In contrast, males showed a more transient inflammatory profile, with lipid levels becoming similar to those of non-burn controls in the ‘recovered’ stage, with the exception of change in plasma FA concentrations, which was trending downward. Although clinical characteristics between sexes were similar, the observed biological differences suggest that sex may play a role in shaping long-term recovery trajectories at the molecular level. Burn trauma and the impact of factors like stress and injury location on recovery is complex and our findings underscore the need for population-based, longitudinal studies to validate these sex-specific patterns and explore their implications for outcomes and therapeutic strategies in paediatric care with non-severe burns. Data Availability The data presented in this study are not publicly available. Data are available from ORIGINS via an application process, including Scientific Committee and ORIGINS Director approval, Ramsay Human Research Ethics approval, and payment of an access fee. This application process is in place as the data collected are sensitive health data related to pregnancy, birth and children. Acknowledgements and Funding We dedicate this work to the memory of our co-author and mentor, Dr. Mark W Fear. His guidance, dedication and commitment to pushing the boundaries of research and science for the betterment of children’s health has left an imprint on all who worked with him. His passion for improving the lives of children and families continues to inspire us and his legacy will forever guide our work. We are grateful to all the ORIGINS families who support the project. We would also like to acknowledge and thank the following teams and individuals who have made ORIGINS possible: ORIGINS project team; Joondalup Health Campus (JHC); members of ORIGINS Community Reference and Participant Reference Groups; Research Interest Groups and the ORIGINS Scientific Committee; The Kids Research Institute Australia; City of Wanneroo; City of Joondalup; and Professor Fiona Stanley. This study is a sub-project of ORIGINS. This unique long-term study, a collaboration between The Kids Research Institute Australia and Joondalup Health Campus, is one of the most comprehensive studies of pregnant women and their families in Australia to date, recruiting 10,000 families over a decade from the Joondalup and Wanneroo communities of Western Australia. ORIGINS has received core funding support from the Telethon Perth Children’s Hospital Research Fund, Joondalup Health Campus, the Paul Ramsay Foundation and the Commonwealth Government of Australia through the Channel 7 Telethon Trust. Substantial in-kind support has been provided by The Kids Research Institute Australia and Joondalup Health Campus. Additionally, the Children’s Burn Injury Biobank has received core funding support from the Fiona Wood Foundation and the Stan Perron Charitable Foundation. Sample preparation and mass spectrometry analyses conducted at the Australian National Phenome Centre were supported by the Western Australian State Government and the Medical Research Future Fund. Author Holmes acknowledges support from the Department of Jobs, Tourism, Science and Innovation through the Western Australian Premier’s Fellowship, as well as the Australian Research Council Laureate Fellowship. 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