Peptidomics Characteristics of Pediatric Sepsis

Peptidomics Characteristics of Pediatric Sepsis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Peptidomics Characteristics of Pediatric Sepsis Haipeng Yan, Xun Li, Ting Luo, Xiaohui Zeng, Xiao Li, Longlong Xie, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4645827/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Mar, 2025 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract This study explores the significant differential expression of peptides in sepsis patients compared to healthy controls and those with common infections using plasma peptidomics analysis. Blood samples were collected from 10 pediatric sepsis patients admitted to Hunan Children's Hospital in 2021, along with 20 age- and sex-matched healthy controls and 5 children with common infections. Differential peptide precursor proteins underwent GO and KEGG pathway enrichment analyses and protein-protein interaction analysis using the STRING database. A total of 3149 endogenous peptides corresponding to 480 precursor proteins were identified. Compared to the healthy group, the sepsis group exhibited 1113 differential peptides, with 880 upregulated and 233 downregulated. Compared to the common infection group, the sepsis group showed 181 upregulated and 86 downregulated peptides. These differences were primarily in humoral immune response and complement and coagulation cascades. The peptide RSFFSFLGEA, associated with the precursor protein SAA1, had the highest LogFC values between sepsis and healthy groups, and sepsis and common infection groups, with values of 6.828 and 5.580, respectively. This study reveals specific changes in peptide expression in sepsis patients' plasma, particularly significant alterations in peptides related to SAA1, complement C3, HB, and HP. These peptides are involved in acute inflammatory response, complement system, and free hemoglobin pathways, indicating their crucial roles in sepsis pathology. These findings provide new insights into the mechanisms of sepsis and suggest potential applications of these peptides in sepsis diagnosis and treatment, aiming to improve early diagnosis and therapeutic outcomes. Health sciences/Biomarkers Health sciences/Diseases Sepsis Peptides Biomarker Figures Figure 1 Figure 2 Figure 3 Introduction Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection[ 1 ], with an in-hospital mortality rate of approximately 25%[ 2 , 3 ]. Children, particularly those under the age of five, are among the most susceptible to sepsis, accounting for about 40% of global sepsis cases in this age group[ 4 ]. Data from Germany indicate that sepsis is responsible for 11.5% of pediatric in-hospital deaths[ 5 ]. Research has shown that every hour of delay in administering medication negatively impacts the length of hospital stay, secondary organ damage, and mortality rate[ 6 ]. Therefore, early identification and timely treatment of sepsis are crucial for improving prognosis and reducing mortality. Due to their unique physiological characteristics, the symptoms and pathological features of sepsis in children differ from those in adults. Pediatric sepsis often presents with atypical symptoms such as poor appetite, lethargy, fever, or hypothermia, making early recognition more challenging. The immature immune system of children may respond differently to infections compared to adults, affecting disease progression and prognosis. Hence, identifying specific characteristics and early biomarkers of pediatric sepsis is vital for improving outcomes. In recent years, the significance of serum peptides as early biomarkers of diseases has become increasingly prominent. Endogenous peptides are widely distributed across various organs, tissues, cells, and body fluids, typically ranging from 3 to 50 amino acids in length and with a molecular weight of less than 10 kD. These peptides play key roles in physiological and pathological processes such as immune regulation, cell differentiation, neurotransmitter modulation, and tumorigenesis[ 7 , 8 ]. Studies have shown that changes in the types and quantities of proteins and peptides often occur before the appearance of obvious symptoms or pathological changes, thus presenting broad clinical diagnostic applications. For instance, numerous studies have confirmed that procalcitonin has significant clinical value in the diagnosis, monitoring, and guiding the use of antibiotics in infectious diseases[ 9 , 10 ]. The peptide model constructed by Meng et al. achieved accuracies and sensitivities of 82.20% and 82.50%, respectively, in diagnosing type 2 diabetes patients[ 11 ]. Other studies have found that the peptide ASRPS can inhibit angiogenesis in triple-negative breast cancer (TNBC), providing a new target for TNBC treatment[ 12 ]. The peptide COL-4A1 can disrupt endothelial cells through the TGF-β/PI3K/AKT pathway, increasing blood pressure in preeclampsia (PE) model rats, reducing the weight of the placenta and fetus, and exacerbating pathological changes in the kidneys and placenta, offering a new target for PE treatment[ 13 ]. These findings underscore the significant potential of peptidomics in the early diagnosis and treatment of diseases. The advantages of serum peptides as a focus of disease research are primarily reflected in the following aspects[ 7 , 14 , 15 ]: firstly, changes in the types and quantities of peptides can often be observed before the appearance of obvious symptoms or pathological changes; secondly, as ideal target molecules, peptides have strong specificity and low immunogenicity compared to chemical drugs or protein-based drugs. Therefore, this study aims to analyze the peptidomics of plasma in pediatric sepsis patients, exploring the peptidomic characteristics of pediatric sepsis to provide new insights and strategies for early diagnosis and treatment. Methods 1. Materials Blood samples were collected from 10 pediatric sepsis patients admitted to Hunan Children's Hospital in 2021. Additionally, blood samples from 20 age- and sex-matched healthy children undergoing routine check-ups were collected as the control group, along with samples from 5 children with common infections as the common infection group. Clinical data were extracted from electronic medical records. The diagnostic criteria for sepsis were based on the "International Consensus Criteria for Pediatric Sepsis and Septic Shock."[ 1 ] This study was conducted according to the principles of the Declaration of Helsinki. This study protocol was approved by the Medical Ethics Committee of the Hunan Children's Hospital (HCHLL-2020-93). All blood samples were collected after obtaining informed consent. 2. Peptide Detection Methods Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to detect and analyze the plasma peptides in each group. The sample analysis was performed by Biotree(Shanghai, CA). 3. Bioinformatics Analysis 3.1 Protein Annotation Methods The raw mass spectrometry files were analyzed using the Sequest HT search engine in the Proteome Discoverer software (version 2.4.0.305). Differentially expressed peptides were annotated using Gene Ontology (GO) analysis based on the Uniprot-SwissProt database (species Homo sapiens, 2021-03-18, reviewed entries 20396). 3.2 Protein Functional Enrichment Functional enrichment analysis was performed using the clusterProfiler, org.Hs.eg.db, and enrichplot packages in R. Protein functional enrichment was categorized into GO enrichment analysis and KEGG enrichment analysis. GO annotations were divided into Biological Process, Cellular Component, and Molecular Function. KEGG annotations were categorized into Organismal Systems, Human Diseases, Cellular Processes, Metabolism, and Environmental Information Processing. The InterPro database was used to analyze the enrichment of functional domains of differentially expressed proteins. 3.3 Protein-Protein Interaction Network Analysis Differential protein database identifiers or sequences from different comparison groups were compared against the STRING (version 12.0) protein interaction network database. Interactions were extracted with a confidence score > 0.7, and the interaction network was visualized using Cytoscape software (version 3.8+). 4. Statistical Analysis The comparison of peptide expression levels between groups was conducted using the rank-sum test, with group differences represented by logFC. Pearson correlation analysis was used for correlation analysis. The Benjamini-Hochberg method was applied to adjust the P-values for differences in peptide expression between groups, with an adjusted P-value < 0.05 considered significant. GO and KEGG pathway enrichment analyses were performed on the precursor proteins of the differentially expressed peptides, and a protein-protein interaction network was constructed. Results 1. General Information of Pediatric Sepsis Patients The study included 35 subjects aged from 1.8 months to 13.5 years. In the 0–1 year age group, there were 3 cases of sepsis, all male, and 6 healthy controls, all male. In the 1–5 year age group, there were 3 cases of sepsis (2 males and 1 female) and 6 healthy controls (4 males and 2 females). In the 5–14 year age group, there were 4 cases of sepsis (2 males and 2 females) and 8 healthy controls (4 males and 4 females). In the general infection group, there were 4 children aged 1–5 years (2 males and 2 females) and 1 female aged 5–14 years. Regarding the initial symptoms in the sepsis group, 2 cases presented with respiratory system symptoms, 4 with digestive system symptoms, and 4 with nervous system symptoms (see Table 1 ). Table 1 Clinical Characteristics of Children with Sepsis Record Number Age (years) Sex Onset System Diagnosis in the course of disease Discharge Outcome Respiratory System Circulatory/Cardiovascular System Digestive System Urinary System Central Nervous System Coagulation System Case 1 0.15 Male Nervous System CRF Septic Shock Purulent Meningitis Hematologic System Survived Case 2 0.21 Male Digestive System Cholangitis Survived Case 3 0.49 Male Respiratory System Severe Pneumonia Coagulation Dysfunction Survived Case 4 2.30 Male Digestive System Respiratory Failure Septic Shock Strangulated Intestinal Obstruction with Intestinal Necrosis, Liver Failure AKI(Stage III) DIC Death Case 5 2.36 Male Digestive System Respiratory Failure Septic Shock, Myocardial Injury Meckel's Diverticulum, Diffuse Peritonitis, Strangulated Intestinal Septic Encephalopathy DIC Survived Case 6 3.24 Female Nervous System CRF Septic Shock, Myocardial Injury Obstruction Purulent Encephalitis Coagulation Dysfunction Survived Case 7 8.13 Female Nervous System Respiratory Failure, Pulmonary Hemorrhage Myocardial Injury Upper Gastrointestinal Bleeding AKI(Stage III) Status Epilepticus DIC Death Case 8 9.76 Male Respiratory System ARDS Liver Failure Coagulation Dysfunction Survived Case 9 12.58 Male Digestive System Septic Shock, Myocardial Injury, Successful Resuscitation after Cardiac Arrest Stress Ulcer AKI(Stage III) Hypoxic-Ischemic Encephalopathy DIC Survived Case 10 13.50 Female Nervous System CRF Septic Shock, Myocardial Injury Intestinal Obstruction, Diffuse Peritonitis Epidemic Japanese Encephalitis Coagulation Dysfunction Survived AKI: Acute Kidney Injury; DIC: Disseminated Intravascular Coagulation ; CRF: Central Respiratory Failure; ARDS: Acute Respiratory Distress Syndrome 2. Analysis of Differential Plasma Peptides in Pediatric Sepsis Patients A total of 3149 endogenous peptide segments and 480 related precursor proteins were identified. Comparing the sepsis group to the healthy control group, 1113 differential peptides and 157 precursor proteins were identified. Among these, 880 peptides (121 precursor proteins) were upregulated, and 233 peptides (64 precursor proteins) were downregulated (see Fig. 1 ). When comparing the sepsis group to the general infection group, 181 peptides (44 precursor proteins) were upregulated, and 86 peptides (37 precursor proteins) were downregulated. According to the LogFC ranking between groups, the peptide segment of the precursor protein SAA1 had the highest differential fold change in both the sepsis vs. healthy group and the sepsis vs. general infection group, with LogFC values of 9.434 and 5.580, respectively (see Table 2 ). Table 2 The Top Ten Upregulated and Downregulated Proteins with the Highest logFC Health vs Sepsis CI vs Sepsis Precursor protein LogFC adj. P* Precursor protein LogFC adj. P a Upregulated Upregulated SAA1 9.434 < 0.001 SAA1 5.580 0.036 SAA2 9.103 < 0.001 HP 3.813 0.046 ALB 8.626 < 0.001 FGA 3.658 0.047 HBA1 8.438 < 0.001 SAA2 3.266 0.047 C3 8.370 0.002 CFB 3.264 0.040 FGA 8.248 < 0.001 HBG2 3.078 0.046 A2M 7.944 < 0.001 HBB 3.033 0.049 ALDOA 7.871 0.005 SERPINA1 3.017 0.049 APOC2 7.466 < 0.001 FGG 2.948 0.047 HBB 7.192 < 0.001 MGP 2.678 0.046 Downregulated Downregulated SFTPD -8.433 < 0.001 HRG -4.492 0.047 COL1A1 -8.143 < 0.001 ALB -4.130 0.046 SERPINA1 -6.820 0.004 IGKV4-1 -4.097 0.040 APOA1 -6.181 0.014 HPX -3.998 0.047 BCL11B -5.094 < 0.001 IGKV3D-11 -3.915 0.046 C4B -5.025 0.001 IGKV3-20 -3.706 0.047 FGA -4.743 < 0.001 CLU -3.610 0.047 SFRP4 -4.553 < 0.019 AHSG -3.604 0.046 BGLAP -4.380 < 0.001 APOL1 -3.552 0.049 COL2A1 -4.231 < 0.001 APOA1 -3.527 0.049 a adj. P -values adjusted using the Benjamini-Hochberg method.CI: common infection control 3. GO Functional Enrichment Analysis of Differentially Expressed Peptide-Related Precursor Proteins GO functional enrichment analysis was conducted on the precursor proteins of the differentially expressed peptides. In the sepsis vs. healthy group, the biological process classification revealed that these precursor proteins were mainly involved in processes such as the humoral immune response, negative regulation of catalytic activity, and wound healing. In the cellular component classification, these precursor proteins were mainly located in the blood microparticle, collagen-containing extracellular matrix, and endoplasmic reticulum lumen. For the molecular function classification, these precursor proteins exhibited enzyme inhibitor activity, peptidase regulator activity, and peptidase inhibitor activity(see Fig. 2 A). In the sepsis vs. general infection group, the biological process classification showed that these precursor proteins were mainly involved in processes such as the humoral immune response, negative regulation of catalytic activity, and wound healing. In the cellular component classification, these precursor proteins were mainly located in the blood microparticle, collagen-containing extracellular matrix, and vesicle lumen. For the molecular function classification, these precursor proteins exhibited enzyme inhibitor activity, peptidase regulator activity, and endopeptidase regulator activity (see Fig. 2 B). 4. KEGG Pathway Enrichment Analysis of Differentially Expressed Peptide-Related Precursor Proteins The KEGG pathway enrichment analysis of the sepsis group versus the healthy group revealed that the precursor proteins of the differential peptides were primarily involved in several key pathways. In the Organismal Systems category, they participated in the complement and coagulation cascades, neutrophil extracellular trap formation, and platelet activation pathways. In the Human Diseases category, they were involved in pathways related to COVID-19, Staphylococcus aureus infection, and pertussis. In the Cellular Processes category, the phagosome pathway was prominently featured. In the Metabolism category, they were involved in glycolysis/gluconeogenesis pathways. Finally, in the Environmental Information Processing category, they participated in the ECM-receptor interaction pathway(see Fig. 2 C). The KEGG pathway enrichment analysis comparing the sepsis group to the general infection group showed that the precursor proteins of the differential peptides were primarily involved in the complement and coagulation cascades, neutrophil extracellular trap formation, and platelet activation pathways in the Organismal Systems category. In the Human Diseases category, they were mainly involved in pathways related to COVID-19 and Staphylococcus aureus infection(see Fig. 2 D). 5. Protein-Protein Interaction Network of Differentially Expressed Precursor Proteins The protein-protein interaction analysis of the differentially expressed proteins between the sepsis and healthy groups identified the top five nodes with the highest degrees as ALB (36), AHSG (28), APOA1 (28), APOB (27), and A2M (25) (see Fig. 2 E). Similarly, the analysis between the sepsis and general infection groups identified the top five nodes as APOA1 (23), ALB (22), AHSG (19), A2M (18), and APOE (15) (see Fig. 2 F). 6. Comparative Analysis of Differentially Expressed Peptides Between Groups An analysis of peptides with a logFC > 2 or logFC < -2 revealed 705 peptides meeting the criteria in the comparison between the sepsis and healthy groups, and 128 peptides in the comparison between the sepsis and general infection groups. A total of 66 overlapping peptides were identified between the two comparisons (see Fig. 3 ). The comparative expression of these overlapping peptides, ranked by LogFC in the sepsis vs. general infection group, is shown in Fig. 3 B. Among these, the SAA1-related peptide RSFFSFLGEA exhibited the highest LogFC values of 6.828 and 5.580 in the sepsis vs. healthy group and the sepsis vs. general infection group, respectively (see Table 3 ). Table 3 Precursor Proteins of Peptides and LogFC of Expression Levels Between Different Groups Precursor protein Polypeptide sequence Health vs Sepsis CI vs Sepsis LogFC adj. P* LogFC adj. P a SAA1 RSFFSFLGEA 6.828 < 0.001 5.580 0.036 HP YVGKKQLVE 4.947 0.008 3.813 0.046 CFB IEGVDAEDGHGPGEQQ 3.706 < 0.001 3.264 0.040 HBG2 GHFTEEDKATITSL 4.476 < 0.001 2.945 0.047 FGG PSDKFFTSHNGMQF 6.022 < 0.001 2.835 0.049 FGA FLAEGGGVR 3.803 < 0.001 2.812 0.047 SERPINA1 LEAIPMSIPPEVKFNKPFVF 3.254 < 0.001 2.735 0.047 SPP1 RISHELDSASSEVN 3.801 < 0.001 2.669 0.049 HBB WGKVNVDEVGGEALGRLL 5.543 0.001 2.618 0.047 C3 IITPNILRLESEE 4.287 0.001 2.568 0.047 a adj. P -values adjusted using the Benjamini-Hochberg method. CI: common infection control Discussion In this study, we identified significant differential expression of peptides between sepsis patients, healthy individuals, and individuals with general infections through plasma peptidomics analysis. These differences were primarily observed in processes such as humoral immune response, complement, and coagulation cascades. Among these, peptides related to Serum Amyloid A1 (SAA1) exhibited the most notable changes. The Serum Amyloid A (SAA) gene family comprises four distinct loci: SAA1 and SAA2 encode acute-phase SAAs (A-SAAs), while SAA3 and SAA4 encode other types of SAA proteins. A-SAA is a crucial acute-phase reactant that plays a significant role in the immune response, including the induction of cytokine production, promotion of leukocyte migration and adhesion, and activation of the complement system[ 16 , 17 ]. A-SAA can activate the nuclear factor-kappa B (NF-κB) signaling pathway by binding to Toll-like receptors (TLR) 2 and TLR4, thereby inducing cytokine production and participating in the inflammatory response[ 18 ]. Studies have shown that combining SAA1 with other inflammatory markers can enhance the diagnostic accuracy for sepsis. For example, a predictive model combining SAA1, C-reactive protein (CRP), and procalcitonin (PCT) achieved an area under the receiver operating characteristic (ROC) curve (AUC) of 0.89 [95% CI 0.82–0.95] for diagnosing sepsis, significantly outperforming the individual predictive values of CRP, PCT, and interleukin-6 (IL-6) [ 19 ]. In neonatal sepsis, SAA has also demonstrated good diagnostic and monitoring value[ 20 ]. Moreover, SAA1 can directly bind to pathogens, such as Gram-negative bacteria, thereby enhancing the phagocytic and bactericidal activities of macrophages and neutrophils[ 18 ]. Research has also found that SAA has a protective role in lipopolysaccharide (LPS)-induced inflammation and tissue damage by binding to LPS and promoting its clearance[ 21 ]. SAA1 is an important inflammatory marker that reflects the degree and activity of inflammation. SAA1 levels rise rapidly upon infection or injury and decrease quickly after antigen clearance, making it valuable for early diagnosis, risk assessment, treatment monitoring, and prognostic evaluation in clinical practice. Our study found that SAA1-related peptides were significantly elevated in children with sepsis, distinguishing them from healthy and generally infected patients, with the peptide RSFFSFLGEA showing the most significant difference. This finding further supports the diagnostic value of SAA1 in pediatric sepsis. The complement system is a part of the immune system that initiates inflammatory responses by recognizing pathogens and damaged cells. Activation of the complement system can lead to cell lysis, release of inflammatory mediators, and recruitment of immune cells. Complement component 3 (C3) is a key protein in the complement system, involved in pathogen marking and clearance, as well as in regulating the inflammatory response[ 22 ]. In this study, we found that peptides related to C3 and Complement Factor B (CFB) were significantly elevated in children with sepsis, with the peptides IITPNILRLESEE and IEGVDAEDGHGPGEQQ showing the most notable differences. The activation of the complement system not only enhances the immune response but may also exacerbate inflammation, leading to more severe pathological states. Research has revealed that the Carboxypeptidase B1 (Cpb1)-C3-C3a receptor (C3aR) pathway significantly impacts the severity of endotoxemia. Deficiency of C3aR or the use of C3aR inhibitors can reduce the expression of inflammatory mediators and weight loss in mice with endotoxemia, thereby improving their survival rates. C3aR plays an important role in primary human macrophages by enhancing the inflammatory response, and its expression is associated with increased caspase-5 expression in peripheral blood mononuclear cells of sepsis patients. The complement pathway amplifies caspase-11-dependent cell death through the Cpb1-C3-C3aR signaling pathway, which is crucial for the severity of Gram-negative bacterial infections and endotoxemia. Thus, C3aR may serve as an early therapeutic target for sepsis, and C3aR and caspase-5 transcripts could be potential biomarkers for diagnosing sepsis[ 23 ]. In addition, this study found that hemoglobin (Hb)-related peptides, specifically those related to hemoglobin subunit beta (HBB) and hemoglobin subunit gamma-2 (HBG2), were significantly elevated in pediatric sepsis patients. Among these, the peptides WGKVNVDEVGGEALGRLL and GHFTEEDKATITSL exhibited the most notable differences. The destruction of erythrocytes induced by infection may be an important early marker event in sepsis. Erythrocyte destruction leads to elevated levels of free hemoglobin (free-Hb). Verma et al. found through Raman spectroscopy that free-Hb was observed in a lipopolysaccharide (LPS)-induced endotoxin shock model, but not in a thioglycolate-induced sterile peritonitis model. This study suggests that hemolysis is a marker of systemic inflammation rather than local inflammation[ 24 ]. The onset of systemic inflammatory response is an early event in sepsis; hence, hemolysis-related markers induced by infection have potential value for the early diagnosis of sepsis. Additionally, free-Hb plays an important role in the progression of sepsis. Elevated levels of free-Hb increase mortality and lung injury in septic shock animals. The mechanism of action of free-Hb may be related to the generation of a cytokine storm and its nutritional role for bacteria. Free-Hb can significantly elevate the levels of cytokines and chemokines, promoting the occurrence of a cytokine storm. Free-Hb may also provide iron that promotes bacterial growth, further exacerbating the condition[ 25 , 26 ]. Notably, our previous research identified haptoglobin (HP), another important protein involved in hemolysis-related injury, as an independent risk factor for mortality in pediatric sepsis[ 27 ]. HP can specifically bind to free-Hb, facilitating its transfer to the liver for catabolism, thus mitigating the toxic effects of free-Hb and inhibiting bacterial growth[ 26 , 28 ]. HP also binds to high mobility group box 1 protein (HMGB1) and mediates the production of interleukin-10 (IL-10) and heme oxygenase-1 (HO-1) through the CD163 signaling pathway, thereby reducing inflammation and oxidative stress[ 29 ]. Consequently, HP is known as a natural scavenger of hemolytic toxic effects within the body. In this study, we found that HP-related peptides were significantly elevated in sepsis, with the peptide YVGKKQLVE showing the most significant difference. This finding further supports the evaluative value of HP in sepsis severity. Conclusion In summary, this study revealed specific changes in peptide expression in the plasma of sepsis patients through peptidomics analysis, particularly significant changes in peptides related to SAA1, complement component 3 (C3), Hb, and HP. These peptides are associated with acute inflammatory response processes, the complement system, free-Hb, and other pathways, suggesting their important roles in the pathology of sepsis. These findings provide new insights into the pathological mechanisms of sepsis. Future research can further explore the potential applications of these peptides in the diagnosis and treatment of sepsis, aiming to improve the early diagnosis rate and treatment outcomes of sepsis. This study is the first to describe the peptidomic characteristics of pediatric sepsis, but the sample size is relatively small. Further large-sample validation is needed to determine the clinical application value of the identified candidate biomarkers. Declarations CONFLICT OF INTEREST STATEMENT The authors declare no conflict of interest. ETHICS STATEMENT The study protocol was reviewed and approved by the Medical Ethics Committee of the Hunan Children's Hospital (HCHLL-2020-93). Informed consent was waved because of the retrospective design. The authors had no access to information that could identify individual participants during and after data collection. Funding (Acknowledgements) Author Contribution HY contributed to the study’s conception, analysed and interpreted the data, and wrote the manuscript. ZX and XLu contributed to the study design, interpreted the data, and revised the manuscript. XLi, XHZ, TL, LX, XW, YY, XZ, JH, PL, LL, JC, and HZ performed chart reviews, interpreted the data, and revised the manuscript. ZX and XLu designed the study, interpreted the data, and revised the manuscript. All authors read and approved the final manuscript. Data Availability The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. References Schlapbach, L. J., Watson, R. S., Sorce, L. R., Argent, A. C., et al. , International Consensus Criteria for Pediatric Sepsis and Septic Shock. Jama 2024, 331 . Xiao, C., Wang, S., Fang, F., Xu, F., et al. , Epidemiology of Pediatric Severe Sepsis in Main PICU Centers in Southwest China*. Pediatric Critical Care Medicine 2019, 20 , 1118–1125. Humoodi, M. O., Aldabbagh, M. A., Salem, M. M., Al Talhi, Y. M., et al. , Epidemiology of pediatric sepsis in the pediatric intensive care unit of king Abdulaziz Medical City, Jeddah, Saudi Arabia. BMC Pediatrics 2021, 21 . World Health Organization. "Sepsis." World Health Organization, 3 May 2024, . Born, S., Dame, C., Matthäus-Krämer, C., Schlapbach, L. 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Cite Share Download PDF Status: Published Journal Publication published 19 Mar, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 23 Oct, 2024 Reviews received at journal 28 Aug, 2024 Reviews received at journal 19 Aug, 2024 Reviewers agreed at journal 07 Aug, 2024 Reviewers agreed at journal 06 Aug, 2024 Reviewers invited by journal 06 Aug, 2024 Editor assigned by journal 29 Jul, 2024 Editor invited by journal 02 Jul, 2024 Submission checks completed at journal 01 Jul, 2024 First submitted to journal 26 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4645827","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":330465822,"identity":"707e357d-d3b4-416c-92ef-86052c2c37e0","order_by":0,"name":"Haipeng Yan","email":"","orcid":"","institution":"Central South University (Hunan Children’s Hospital)","correspondingAuthor":false,"prefix":"","firstName":"Haipeng","middleName":"","lastName":"Yan","suffix":""},{"id":330465823,"identity":"f444f931-58f7-498a-b5ff-7c2415890322","order_by":1,"name":"Xun Li","email":"","orcid":"","institution":"Central South University (Hunan Children’s Hospital)","correspondingAuthor":false,"prefix":"","firstName":"Xun","middleName":"","lastName":"Li","suffix":""},{"id":330465824,"identity":"764e39ea-5e4d-4be5-bc86-6df41a392189","order_by":2,"name":"Ting Luo","email":"","orcid":"","institution":"Central South University (Hunan Children’s Hospital)","correspondingAuthor":false,"prefix":"","firstName":"Ting","middleName":"","lastName":"Luo","suffix":""},{"id":330465825,"identity":"3d3eb765-401a-4042-a0a3-808515b3eafa","order_by":3,"name":"Xiaohui Zeng","email":"","orcid":"","institution":"Central South University (Hunan Children’s Hospital)","correspondingAuthor":false,"prefix":"","firstName":"Xiaohui","middleName":"","lastName":"Zeng","suffix":""},{"id":330465826,"identity":"81ae8e9e-eb99-40aa-836e-fd14071fee03","order_by":4,"name":"Xiao Li","email":"","orcid":"","institution":"Central South University (Hunan Children’s Hospital)","correspondingAuthor":false,"prefix":"","firstName":"Xiao","middleName":"","lastName":"Li","suffix":""},{"id":330465827,"identity":"0520edf7-12a3-4899-9168-8fb277c69fc1","order_by":5,"name":"Longlong Xie","email":"","orcid":"","institution":"Central South University (Hunan Children’s Hospital)","correspondingAuthor":false,"prefix":"","firstName":"Longlong","middleName":"","lastName":"Xie","suffix":""},{"id":330465828,"identity":"a1348469-b470-4db5-8989-8dc4bd4698c5","order_by":6,"name":"Xiangyu Wang","email":"","orcid":"","institution":"Central South University (Hunan Children’s Hospital)","correspondingAuthor":false,"prefix":"","firstName":"Xiangyu","middleName":"","lastName":"Wang","suffix":""},{"id":330465829,"identity":"ca8ad8b7-c4ee-4774-9dcb-893b21083d83","order_by":7,"name":"Yufan Yang","email":"","orcid":"","institution":"Central South University (Hunan Children’s Hospital)","correspondingAuthor":false,"prefix":"","firstName":"Yufan","middleName":"","lastName":"Yang","suffix":""},{"id":330465830,"identity":"48cb25d3-641d-48f5-873b-e831544fb9dc","order_by":8,"name":"Xinping Zhang","email":"","orcid":"","institution":"Central South University (Hunan Children’s Hospital)","correspondingAuthor":false,"prefix":"","firstName":"Xinping","middleName":"","lastName":"Zhang","suffix":""},{"id":330465831,"identity":"cf8d805b-9c13-4a92-a20a-51bcf64dd0e1","order_by":9,"name":"Jiaotian Huang","email":"","orcid":"","institution":"Central South University (Hunan Children’s Hospital)","correspondingAuthor":false,"prefix":"","firstName":"Jiaotian","middleName":"","lastName":"Huang","suffix":""},{"id":330465832,"identity":"35db68f4-1159-4b40-a280-f4fb322ca035","order_by":10,"name":"Pingping Liu","email":"","orcid":"","institution":"Central South University (Hunan Children’s Hospital)","correspondingAuthor":false,"prefix":"","firstName":"Pingping","middleName":"","lastName":"Liu","suffix":""},{"id":330465833,"identity":"4cd49d63-59f7-45ec-baba-b22d6aea630e","order_by":11,"name":"Lan Luo","email":"","orcid":"","institution":"Central South University (Hunan Children’s Hospital)","correspondingAuthor":false,"prefix":"","firstName":"Lan","middleName":"","lastName":"Luo","suffix":""},{"id":330465834,"identity":"3397b79b-e8da-4011-8f30-e6beccd60ff8","order_by":12,"name":"Jianshe Cao","email":"","orcid":"","institution":"Central South University (Hunan Children’s Hospital)","correspondingAuthor":false,"prefix":"","firstName":"Jianshe","middleName":"","lastName":"Cao","suffix":""},{"id":330465835,"identity":"9165673a-c241-4c5d-ae65-5d14824e4465","order_by":13,"name":"Haiyin Zhou","email":"","orcid":"","institution":"Central South University (Hunan Children’s Hospital)","correspondingAuthor":false,"prefix":"","firstName":"Haiyin","middleName":"","lastName":"Zhou","suffix":""},{"id":330465836,"identity":"653bd634-4f93-48fe-a24f-9d4052e0961a","order_by":14,"name":"Xiulan Lu","email":"","orcid":"","institution":"Central South University (Hunan Children’s Hospital)","correspondingAuthor":false,"prefix":"","firstName":"Xiulan","middleName":"","lastName":"Lu","suffix":""},{"id":330465837,"identity":"e7c74359-7fee-40a6-bf59-4d20efb57508","order_by":15,"name":"Zhenghui Xiao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyklEQVRIiWNgGAWjYDACZiBmbLCR42dvbHzwgQQtacaSPYebDWcQbRNjw+HEDTfS26Q5iFFtcJz54cOfO4C2zHzYIM3AYCen20BAi2Qzm7GB5BmgX6QTG4wLGJKNzQ4Q0MLPzGAmYdgGtGV2YkPyDIYDidsIaWFjZv8mkdgG9MvNgw2HeYjRws/MYyZxEKTlBmNjM1FaJJt5ig0bQQ7rSWxmnGFAhF8Mzh/f+PBnGygqjz//8aHCTo6gFnQTSFM+CkbBKBgFowAHAACKqkNoL4p8ggAAAABJRU5ErkJggg==","orcid":"","institution":"Central South University (Hunan Children’s Hospital)","correspondingAuthor":true,"prefix":"","firstName":"Zhenghui","middleName":"","lastName":"Xiao","suffix":""}],"badges":[],"createdAt":"2024-06-27 03:54:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4645827/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4645827/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-92101-w","type":"published","date":"2025-03-19T15:57:59+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":61107246,"identity":"58ca256b-6ca8-4b18-9f21-e1087aa02806","added_by":"auto","created_at":"2024-07-25 16:26:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":885117,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eVolcano Plot of Peptides in Sepsis Group versus Healthy Group.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-4645827/v1/4d893cff19febaeca1141e07.png"},{"id":61107248,"identity":"6c863b72-965a-4e22-81e9-9a4697147405","added_by":"auto","created_at":"2024-07-25 16:26:21","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":6486563,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGO, KEGG, and Protein-Protein Interaction Network Analysis of Precursor Proteins of Differential Peptides Between Sepsis Group and Healthy Group, and Between Sepsis Group and Common Infection Group.\u003c/strong\u003e A. GO analysis of precursor proteins of differential peptides between the sepsis and healthy groups. B. GO analysis of precursor proteins of differential peptides between the sepsis and common infection groups. C. KEGG analysis of precursor proteins of differential peptides between the sepsis and healthy groups. D. KEGG analysis of precursor proteins of differential peptides between the sepsis and common infection groups. E. Protein-protein interaction network analysis of precursor proteins of differential peptides between the sepsis and healthy groups. F. Protein-protein interaction network analysis of precursor proteins of differential peptides between the sepsis and common infection groups.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-4645827/v1/6a5229db48aa6e4b75a4afa5.png"},{"id":61107245,"identity":"55a06ca5-29b2-4524-8380-a19b43a2dca9","added_by":"auto","created_at":"2024-07-25 16:26:20","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1737365,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparison of Differential Peptides Between Sepsis Group and Healthy Group, and Between Sepsis Group and Common Infection Group. \u003c/strong\u003eA. Venn diagram of differential peptides between the sepsis and healthy groups, and between the sepsis and common infection groups. B. Heatmap of normalized expression of overlapping differential peptides between the sepsis and healthy groups, and between the sepsis and common infection groups. C. Comparison of peptide expression levels between the groups.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-4645827/v1/2666ef78ab80b92817caaf26.png"},{"id":79120475,"identity":"f8b6cc75-fea9-4cd0-b1ae-4214775ddf78","added_by":"auto","created_at":"2025-03-24 16:08:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":9308001,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4645827/v1/595279a1-6876-4591-a957-18aa8918f4c0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Peptidomics Characteristics of Pediatric Sepsis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], with an in-hospital mortality rate of approximately 25%[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Children, particularly those under the age of five, are among the most susceptible to sepsis, accounting for about 40% of global sepsis cases in this age group[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Data from Germany indicate that sepsis is responsible for 11.5% of pediatric in-hospital deaths[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Research has shown that every hour of delay in administering medication negatively impacts the length of hospital stay, secondary organ damage, and mortality rate[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Therefore, early identification and timely treatment of sepsis are crucial for improving prognosis and reducing mortality. Due to their unique physiological characteristics, the symptoms and pathological features of sepsis in children differ from those in adults. Pediatric sepsis often presents with atypical symptoms such as poor appetite, lethargy, fever, or hypothermia, making early recognition more challenging. The immature immune system of children may respond differently to infections compared to adults, affecting disease progression and prognosis. Hence, identifying specific characteristics and early biomarkers of pediatric sepsis is vital for improving outcomes.\u003c/p\u003e \u003cp\u003eIn recent years, the significance of serum peptides as early biomarkers of diseases has become increasingly prominent. Endogenous peptides are widely distributed across various organs, tissues, cells, and body fluids, typically ranging from 3 to 50 amino acids in length and with a molecular weight of less than 10 kD. These peptides play key roles in physiological and pathological processes such as immune regulation, cell differentiation, neurotransmitter modulation, and tumorigenesis[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Studies have shown that changes in the types and quantities of proteins and peptides often occur before the appearance of obvious symptoms or pathological changes, thus presenting broad clinical diagnostic applications.\u003c/p\u003e \u003cp\u003eFor instance, numerous studies have confirmed that procalcitonin has significant clinical value in the diagnosis, monitoring, and guiding the use of antibiotics in infectious diseases[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The peptide model constructed by Meng et al. achieved accuracies and sensitivities of 82.20% and 82.50%, respectively, in diagnosing type 2 diabetes patients[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Other studies have found that the peptide ASRPS can inhibit angiogenesis in triple-negative breast cancer (TNBC), providing a new target for TNBC treatment[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The peptide COL-4A1 can disrupt endothelial cells through the TGF-β/PI3K/AKT pathway, increasing blood pressure in preeclampsia (PE) model rats, reducing the weight of the placenta and fetus, and exacerbating pathological changes in the kidneys and placenta, offering a new target for PE treatment[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. These findings underscore the significant potential of peptidomics in the early diagnosis and treatment of diseases.\u003c/p\u003e \u003cp\u003eThe advantages of serum peptides as a focus of disease research are primarily reflected in the following aspects[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]: firstly, changes in the types and quantities of peptides can often be observed before the appearance of obvious symptoms or pathological changes; secondly, as ideal target molecules, peptides have strong specificity and low immunogenicity compared to chemical drugs or protein-based drugs. Therefore, this study aims to analyze the peptidomics of plasma in pediatric sepsis patients, exploring the peptidomic characteristics of pediatric sepsis to provide new insights and strategies for early diagnosis and treatment.\u003c/p\u003e "},{"header":"Methods","content":"\u003ch2\u003e1. Materials\u003c/h2\u003e\u003cp\u003eBlood samples were collected from 10 pediatric sepsis patients admitted to Hunan Children's Hospital in 2021. Additionally, blood samples from 20 age- and sex-matched healthy children undergoing routine check-ups were collected as the control group, along with samples from 5 children with common infections as the common infection group. Clinical data were extracted from electronic medical records. The diagnostic criteria for sepsis were based on the \"International Consensus Criteria for Pediatric Sepsis and Septic Shock.\"[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] This study was conducted according to the principles of the Declaration of Helsinki. This study protocol was approved by the Medical Ethics Committee of the Hunan Children's Hospital (HCHLL-2020-93). All blood samples were collected after obtaining informed consent.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2. Peptide Detection Methods\u003c/h2\u003e \u003cp\u003eLiquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to detect and analyze the plasma peptides in each group. The sample analysis was performed by Biotree(Shanghai, CA).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e3. Bioinformatics Analysis\u003c/h2\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003e3.1 Protein Annotation Methods\u003c/h2\u003e \u003cp\u003eThe raw mass spectrometry files were analyzed using the Sequest HT search engine in the Proteome Discoverer software (version 2.4.0.305). Differentially expressed peptides were annotated using Gene Ontology (GO) analysis based on the Uniprot-SwissProt database (species Homo sapiens, 2021-03-18, reviewed entries 20396).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Protein Functional Enrichment\u003c/h2\u003e \u003cp\u003eFunctional enrichment analysis was performed using the clusterProfiler, org.Hs.eg.db, and enrichplot packages in R. Protein functional enrichment was categorized into GO enrichment analysis and KEGG enrichment analysis. GO annotations were divided into Biological Process, Cellular Component, and Molecular Function. KEGG annotations were categorized into Organismal Systems, Human Diseases, Cellular Processes, Metabolism, and Environmental Information Processing. The InterPro database was used to analyze the enrichment of functional domains of differentially expressed proteins.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Protein-Protein Interaction Network Analysis\u003c/h2\u003e \u003cp\u003eDifferential protein database identifiers or sequences from different comparison groups were compared against the STRING (version 12.0) protein interaction network database. Interactions were extracted with a confidence score\u0026thinsp;\u0026gt;\u0026thinsp;0.7, and the interaction network was visualized using Cytoscape software (version 3.8+).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e4. Statistical Analysis\u003c/h2\u003e \u003cp\u003eThe comparison of peptide expression levels between groups was conducted using the rank-sum test, with group differences represented by logFC. Pearson correlation analysis was used for correlation analysis. The Benjamini-Hochberg method was applied to adjust the P-values for differences in peptide expression between groups, with an adjusted P-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 considered significant. GO and KEGG pathway enrichment analyses were performed on the precursor proteins of the differentially expressed peptides, and a protein-protein interaction network was constructed.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e1. General Information of Pediatric Sepsis Patients\u003c/h2\u003e \u003cp\u003eThe study included 35 subjects aged from 1.8 months to 13.5 years. In the 0\u0026ndash;1 year age group, there were 3 cases of sepsis, all male, and 6 healthy controls, all male. In the 1\u0026ndash;5 year age group, there were 3 cases of sepsis (2 males and 1 female) and 6 healthy controls (4 males and 2 females). In the 5\u0026ndash;14 year age group, there were 4 cases of sepsis (2 males and 2 females) and 8 healthy controls (4 males and 4 females). In the general infection group, there were 4 children aged 1\u0026ndash;5 years (2 males and 2 females) and 1 female aged 5\u0026ndash;14 years.\u003c/p\u003e \u003cp\u003eRegarding the initial symptoms in the sepsis group, 2 cases presented with respiratory system symptoms, 4 with digestive system symptoms, and 4 with nervous system symptoms (see Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical Characteristics of Children with Sepsis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRecord Number\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003cp\u003e(years)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOnset System\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c10\" namest=\"c5\"\u003e \u003cp\u003eDiagnosis in the course of disease\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eDischarge Outcome\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRespiratory System\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCirculatory/Cardiovascular System\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDigestive System\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eUrinary System\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCentral Nervous System\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eCoagulation System\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCase 1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNervous System\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCRF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSeptic Shock\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePurulent Meningitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eHematologic System\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eSurvived\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCase 2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDigestive System\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCholangitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eSurvived\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCase 3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRespiratory System\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSevere Pneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eCoagulation Dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eSurvived\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCase 4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDigestive System\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRespiratory Failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSeptic Shock\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eStrangulated Intestinal Obstruction with Intestinal Necrosis, Liver Failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAKI(Stage III)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eDeath\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCase 5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDigestive System\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRespiratory Failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSeptic Shock, Myocardial Injury\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMeckel's Diverticulum, Diffuse Peritonitis, Strangulated Intestinal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSeptic Encephalopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eSurvived\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCase 6\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNervous System\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCRF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSeptic Shock, Myocardial Injury\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eObstruction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePurulent Encephalitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eCoagulation Dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eSurvived\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCase 7\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNervous System\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRespiratory Failure, Pulmonary Hemorrhage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMyocardial Injury\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUpper Gastrointestinal Bleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAKI(Stage III)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eStatus Epilepticus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eDeath\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCase 8\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRespiratory System\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eARDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLiver Failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eCoagulation Dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eSurvived\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCase 9\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDigestive System\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSeptic Shock, Myocardial Injury, Successful Resuscitation after Cardiac Arrest\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eStress Ulcer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAKI(Stage III)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eHypoxic-Ischemic Encephalopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDIC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eSurvived\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCase 10\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNervous System\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCRF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSeptic Shock, Myocardial Injury\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIntestinal Obstruction, Diffuse Peritonitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eEpidemic Japanese Encephalitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eCoagulation Dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eSurvived\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"11\"\u003eAKI: Acute Kidney Injury; DIC: Disseminated Intravascular Coagulation ; CRF: Central Respiratory Failure; ARDS: Acute Respiratory Distress Syndrome\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e2. Analysis of Differential Plasma Peptides in Pediatric Sepsis Patients\u003c/h2\u003e \u003cp\u003eA total of 3149 endogenous peptide segments and 480 related precursor proteins were identified. Comparing the sepsis group to the healthy control group, 1113 differential peptides and 157 precursor proteins were identified. Among these, 880 peptides (121 precursor proteins) were upregulated, and 233 peptides (64 precursor proteins) were downregulated (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). When comparing the sepsis group to the general infection group, 181 peptides (44 precursor proteins) were upregulated, and 86 peptides (37 precursor proteins) were downregulated. According to the LogFC ranking between groups, the peptide segment of the precursor protein SAA1 had the highest differential fold change in both the sepsis vs. healthy group and the sepsis vs. general infection group, with LogFC values of 9.434 and 5.580, respectively (see Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe Top Ten Upregulated and Downregulated Proteins with the Highest logFC\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eHealth vs Sepsis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eCI vs Sepsis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrecursor protein\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLogFC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eadj. \u003cem\u003eP*\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePrecursor protein\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLogFC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eadj. \u003cem\u003eP\u003c/em\u003e\u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUpregulated\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eUpregulated\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSAA1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9.434\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSAA1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5.580\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSAA2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9.103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.813\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.626\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.658\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHBA1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.438\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSAA2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.266\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.370\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCFB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.264\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.040\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.248\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHBG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.078\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA2M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.944\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHBB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.049\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALDOA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.871\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSERPINA1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.049\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPOC2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.466\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.948\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHBB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.192\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMGP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.678\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDownregulated\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eDownregulated\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSFTPD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-8.433\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHRG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-4.492\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOL1A1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-8.143\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eALB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-4.130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSERPINA1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-6.820\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIGKV4-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-4.097\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.040\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPOA1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-6.181\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHPX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-3.998\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBCL11B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-5.094\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIGKV3D-11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-3.915\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC4B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-5.025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIGKV3-20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-3.706\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-4.743\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCLU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-3.610\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSFRP4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-4.553\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAHSG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-3.604\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBGLAP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-4.380\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAPOL1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-3.552\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.049\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOL2A1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-4.231\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAPOA1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-3.527\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.049\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e adj. \u003cem\u003eP\u003c/em\u003e-values adjusted using the Benjamini-Hochberg method.CI: common infection control\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3. GO Functional Enrichment Analysis of Differentially Expressed Peptide-Related Precursor Proteins\u003c/h2\u003e \u003cp\u003eGO functional enrichment analysis was conducted on the precursor proteins of the differentially expressed peptides. In the sepsis vs. healthy group, the biological process classification revealed that these precursor proteins were mainly involved in processes such as the humoral immune response, negative regulation of catalytic activity, and wound healing. In the cellular component classification, these precursor proteins were mainly located in the blood microparticle, collagen-containing extracellular matrix, and endoplasmic reticulum lumen. For the molecular function classification, these precursor proteins exhibited enzyme inhibitor activity, peptidase regulator activity, and peptidase inhibitor activity(see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn the sepsis vs. general infection group, the biological process classification showed that these precursor proteins were mainly involved in processes such as the humoral immune response, negative regulation of catalytic activity, and wound healing. In the cellular component classification, these precursor proteins were mainly located in the blood microparticle, collagen-containing extracellular matrix, and vesicle lumen. For the molecular function classification, these precursor proteins exhibited enzyme inhibitor activity, peptidase regulator activity, and endopeptidase regulator activity (see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e4. KEGG Pathway Enrichment Analysis of Differentially Expressed Peptide-Related Precursor Proteins\u003c/h2\u003e \u003cp\u003eThe KEGG pathway enrichment analysis of the sepsis group versus the healthy group revealed that the precursor proteins of the differential peptides were primarily involved in several key pathways. In the Organismal Systems category, they participated in the complement and coagulation cascades, neutrophil extracellular trap formation, and platelet activation pathways. In the Human Diseases category, they were involved in pathways related to COVID-19, Staphylococcus aureus infection, and pertussis. In the Cellular Processes category, the phagosome pathway was prominently featured. In the Metabolism category, they were involved in glycolysis/gluconeogenesis pathways. Finally, in the Environmental Information Processing category, they participated in the ECM-receptor interaction pathway(see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003eThe KEGG pathway enrichment analysis comparing the sepsis group to the general infection group showed that the precursor proteins of the differential peptides were primarily involved in the complement and coagulation cascades, neutrophil extracellular trap formation, and platelet activation pathways in the Organismal Systems category. In the Human Diseases category, they were mainly involved in pathways related to COVID-19 and Staphylococcus aureus infection(see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e5. Protein-Protein Interaction Network of Differentially Expressed Precursor Proteins\u003c/h2\u003e \u003cp\u003eThe protein-protein interaction analysis of the differentially expressed proteins between the sepsis and healthy groups identified the top five nodes with the highest degrees as ALB (36), AHSG (28), APOA1 (28), APOB (27), and A2M (25) (see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE). Similarly, the analysis between the sepsis and general infection groups identified the top five nodes as APOA1 (23), ALB (22), AHSG (19), A2M (18), and APOE (15) (see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eF).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e6. Comparative Analysis of Differentially Expressed Peptides Between Groups\u003c/h2\u003e \u003cp\u003eAn analysis of peptides with a logFC\u0026thinsp;\u0026gt;\u0026thinsp;2 or logFC \u0026lt; -2 revealed 705 peptides meeting the criteria in the comparison between the sepsis and healthy groups, and 128 peptides in the comparison between the sepsis and general infection groups. A total of 66 overlapping peptides were identified between the two comparisons (see Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The comparative expression of these overlapping peptides, ranked by LogFC in the sepsis vs. general infection group, is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB. Among these, the SAA1-related peptide RSFFSFLGEA exhibited the highest LogFC values of 6.828 and 5.580 in the sepsis vs. healthy group and the sepsis vs. general infection group, respectively (see Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrecursor Proteins of Peptides and LogFC of Expression Levels Between Different Groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePrecursor protein\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePolypeptide sequence\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eHealth vs Sepsis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eCI vs Sepsis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLogFC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eadj. \u003cem\u003eP*\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLogFC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eadj. \u003cem\u003eP\u003c/em\u003e\u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSAA1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRSFFSFLGEA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.828\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5.580\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYVGKKQLVE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.947\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.813\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCFB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIEGVDAEDGHGPGEQQ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.706\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.264\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.040\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHBG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGHFTEEDKATITSL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.476\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.945\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePSDKFFTSHNGMQF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.835\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.049\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFGA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFLAEGGGVR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.803\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.812\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSERPINA1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLEAIPMSIPPEVKFNKPFVF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.254\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.735\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSPP1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRISHELDSASSEVN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.801\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.669\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.049\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHBB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWGKVNVDEVGGEALGRLL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.543\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.618\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIITPNILRLESEE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.287\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.568\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e adj. \u003cem\u003eP\u003c/em\u003e-values adjusted using the Benjamini-Hochberg method. CI: common infection control\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we identified significant differential expression of peptides between sepsis patients, healthy individuals, and individuals with general infections through plasma peptidomics analysis. These differences were primarily observed in processes such as humoral immune response, complement, and coagulation cascades. Among these, peptides related to Serum Amyloid A1 (SAA1) exhibited the most notable changes.\u003c/p\u003e \u003cp\u003eThe Serum Amyloid A (SAA) gene family comprises four distinct loci: SAA1 and SAA2 encode acute-phase SAAs (A-SAAs), while SAA3 and SAA4 encode other types of SAA proteins. A-SAA is a crucial acute-phase reactant that plays a significant role in the immune response, including the induction of cytokine production, promotion of leukocyte migration and adhesion, and activation of the complement system[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. A-SAA can activate the nuclear factor-kappa B (NF-κB) signaling pathway by binding to Toll-like receptors (TLR) 2 and TLR4, thereby inducing cytokine production and participating in the inflammatory response[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eStudies have shown that combining SAA1 with other inflammatory markers can enhance the diagnostic accuracy for sepsis. For example, a predictive model combining SAA1, C-reactive protein (CRP), and procalcitonin (PCT) achieved an area under the receiver operating characteristic (ROC) curve (AUC) of 0.89 [95% CI 0.82\u0026ndash;0.95] for diagnosing sepsis, significantly outperforming the individual predictive values of CRP, PCT, and interleukin-6 (IL-6) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In neonatal sepsis, SAA has also demonstrated good diagnostic and monitoring value[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Moreover, SAA1 can directly bind to pathogens, such as Gram-negative bacteria, thereby enhancing the phagocytic and bactericidal activities of macrophages and neutrophils[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Research has also found that SAA has a protective role in lipopolysaccharide (LPS)-induced inflammation and tissue damage by binding to LPS and promoting its clearance[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSAA1 is an important inflammatory marker that reflects the degree and activity of inflammation. SAA1 levels rise rapidly upon infection or injury and decrease quickly after antigen clearance, making it valuable for early diagnosis, risk assessment, treatment monitoring, and prognostic evaluation in clinical practice. Our study found that SAA1-related peptides were significantly elevated in children with sepsis, distinguishing them from healthy and generally infected patients, with the peptide RSFFSFLGEA showing the most significant difference. This finding further supports the diagnostic value of SAA1 in pediatric sepsis.\u003c/p\u003e \u003cp\u003eThe complement system is a part of the immune system that initiates inflammatory responses by recognizing pathogens and damaged cells. Activation of the complement system can lead to cell lysis, release of inflammatory mediators, and recruitment of immune cells. Complement component 3 (C3) is a key protein in the complement system, involved in pathogen marking and clearance, as well as in regulating the inflammatory response[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In this study, we found that peptides related to C3 and Complement Factor B (CFB) were significantly elevated in children with sepsis, with the peptides IITPNILRLESEE and IEGVDAEDGHGPGEQQ showing the most notable differences. The activation of the complement system not only enhances the immune response but may also exacerbate inflammation, leading to more severe pathological states.\u003c/p\u003e \u003cp\u003eResearch has revealed that the Carboxypeptidase B1 (Cpb1)-C3-C3a receptor (C3aR) pathway significantly impacts the severity of endotoxemia. Deficiency of C3aR or the use of C3aR inhibitors can reduce the expression of inflammatory mediators and weight loss in mice with endotoxemia, thereby improving their survival rates. C3aR plays an important role in primary human macrophages by enhancing the inflammatory response, and its expression is associated with increased caspase-5 expression in peripheral blood mononuclear cells of sepsis patients. The complement pathway amplifies caspase-11-dependent cell death through the Cpb1-C3-C3aR signaling pathway, which is crucial for the severity of Gram-negative bacterial infections and endotoxemia. Thus, C3aR may serve as an early therapeutic target for sepsis, and C3aR and caspase-5 transcripts could be potential biomarkers for diagnosing sepsis[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn addition, this study found that hemoglobin (Hb)-related peptides, specifically those related to hemoglobin subunit beta (HBB) and hemoglobin subunit gamma-2 (HBG2), were significantly elevated in pediatric sepsis patients. Among these, the peptides WGKVNVDEVGGEALGRLL and GHFTEEDKATITSL exhibited the most notable differences. The destruction of erythrocytes induced by infection may be an important early marker event in sepsis.\u003c/p\u003e \u003cp\u003eErythrocyte destruction leads to elevated levels of free hemoglobin (free-Hb). Verma et al. found through Raman spectroscopy that free-Hb was observed in a lipopolysaccharide (LPS)-induced endotoxin shock model, but not in a thioglycolate-induced sterile peritonitis model. This study suggests that hemolysis is a marker of systemic inflammation rather than local inflammation[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The onset of systemic inflammatory response is an early event in sepsis; hence, hemolysis-related markers induced by infection have potential value for the early diagnosis of sepsis. Additionally, free-Hb plays an important role in the progression of sepsis. Elevated levels of free-Hb increase mortality and lung injury in septic shock animals. The mechanism of action of free-Hb may be related to the generation of a cytokine storm and its nutritional role for bacteria. Free-Hb can significantly elevate the levels of cytokines and chemokines, promoting the occurrence of a cytokine storm. Free-Hb may also provide iron that promotes bacterial growth, further exacerbating the condition[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNotably, our previous research identified haptoglobin (HP), another important protein involved in hemolysis-related injury, as an independent risk factor for mortality in pediatric sepsis[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. HP can specifically bind to free-Hb, facilitating its transfer to the liver for catabolism, thus mitigating the toxic effects of free-Hb and inhibiting bacterial growth[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. HP also binds to high mobility group box 1 protein (HMGB1) and mediates the production of interleukin-10 (IL-10) and heme oxygenase-1 (HO-1) through the CD163 signaling pathway, thereby reducing inflammation and oxidative stress[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Consequently, HP is known as a natural scavenger of hemolytic toxic effects within the body. In this study, we found that HP-related peptides were significantly elevated in sepsis, with the peptide YVGKKQLVE showing the most significant difference. This finding further supports the evaluative value of HP in sepsis severity.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, this study revealed specific changes in peptide expression in the plasma of sepsis patients through peptidomics analysis, particularly significant changes in peptides related to SAA1, complement component 3 (C3), Hb, and HP. These peptides are associated with acute inflammatory response processes, the complement system, free-Hb, and other pathways, suggesting their important roles in the pathology of sepsis. These findings provide new insights into the pathological mechanisms of sepsis. Future research can further explore the potential applications of these peptides in the diagnosis and treatment of sepsis, aiming to improve the early diagnosis rate and treatment outcomes of sepsis. This study is the first to describe the peptidomic characteristics of pediatric sepsis, but the sample size is relatively small. Further large-sample validation is needed to determine the clinical application value of the identified candidate biomarkers.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCONFLICT OF INTEREST STATEMENT\u003c/h2\u003e \u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eETHICS STATEMENT\u003c/h2\u003e \u003cp\u003e The study protocol was reviewed and approved by the Medical Ethics Committee of the Hunan Children's Hospital (HCHLL-2020-93). Informed consent was waved because of the retrospective design. The authors had no access to information that could identify individual participants during and after data collection.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003e(Acknowledgements)\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eHY contributed to the study\u0026rsquo;s conception, analysed and interpreted the data, and wrote the manuscript. ZX and XLu contributed to the study design, interpreted the data, and revised the manuscript. XLi, XHZ, TL, LX, XW, YY, XZ, JH, PL, LL, JC, and HZ performed chart reviews, interpreted the data, and revised the manuscript. ZX and XLu designed the study, interpreted the data, and revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and/or analysed during the current study available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSchlapbach, L. J., Watson, R. S., Sorce, L. R., Argent, A. C., \u003cem\u003eet al.\u003c/em\u003e, International Consensus Criteria for Pediatric Sepsis and Septic Shock. \u003cem\u003eJama\u003c/em\u003e 2024, \u003cem\u003e331\u003c/em\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXiao, C., Wang, S., Fang, F., Xu, F., \u003cem\u003eet al.\u003c/em\u003e, Epidemiology of Pediatric Severe Sepsis in Main PICU Centers in Southwest China*. Pediatric Critical Care Medicine 2019, \u003cem\u003e20\u003c/em\u003e, 1118\u0026ndash;1125.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHumoodi, M. O., Aldabbagh, M. 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Blood 2013, \u003cem\u003e121\u003c/em\u003e, 1276\u0026ndash;1284.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Sepsis, Peptides, Biomarker","lastPublishedDoi":"10.21203/rs.3.rs-4645827/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4645827/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis study explores the significant differential expression of peptides in sepsis patients compared to healthy controls and those with common infections using plasma peptidomics analysis. Blood samples were collected from 10 pediatric sepsis patients admitted to Hunan Children's Hospital in 2021, along with 20 age- and sex-matched healthy controls and 5 children with common infections. Differential peptide precursor proteins underwent GO and KEGG pathway enrichment analyses and protein-protein interaction analysis using the STRING database. A total of 3149 endogenous peptides corresponding to 480 precursor proteins were identified. Compared to the healthy group, the sepsis group exhibited 1113 differential peptides, with 880 upregulated and 233 downregulated. Compared to the common infection group, the sepsis group showed 181 upregulated and 86 downregulated peptides. These differences were primarily in humoral immune response and complement and coagulation cascades. The peptide RSFFSFLGEA, associated with the precursor protein SAA1, had the highest LogFC values between sepsis and healthy groups, and sepsis and common infection groups, with values of 6.828 and 5.580, respectively. This study reveals specific changes in peptide expression in sepsis patients' plasma, particularly significant alterations in peptides related to SAA1, complement C3, HB, and HP. These peptides are involved in acute inflammatory response, complement system, and free hemoglobin pathways, indicating their crucial roles in sepsis pathology. These findings provide new insights into the mechanisms of sepsis and suggest potential applications of these peptides in sepsis diagnosis and treatment, aiming to improve early diagnosis and therapeutic outcomes.\u003c/p\u003e","manuscriptTitle":"Peptidomics Characteristics of Pediatric Sepsis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-25 16:26:15","doi":"10.21203/rs.3.rs-4645827/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-10-23T04:25:46+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-29T03:02:29+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-19T08:46:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"328923252557202777623929061671288408443","date":"2024-08-07T12:34:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"323580152779308430056263985324573949041","date":"2024-08-06T08:43:43+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-06T08:39:20+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-29T08:10:14+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-07-02T16:35:47+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-01T09:14:01+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-06-27T03:53:09+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"da6b4b24-5fca-4538-93fc-1d478d68f1a7","owner":[],"postedDate":"July 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":34982089,"name":"Health sciences/Biomarkers"},{"id":34982090,"name":"Health sciences/Diseases"}],"tags":[],"updatedAt":"2025-03-24T16:02:44+00:00","versionOfRecord":{"articleIdentity":"rs-4645827","link":"https://doi.org/10.1038/s41598-025-92101-w","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-03-19 15:57:59","publishedOnDateReadable":"March 19th, 2025"},"versionCreatedAt":"2024-07-25 16:26:15","video":"","vorDoi":"10.1038/s41598-025-92101-w","vorDoiUrl":"https://doi.org/10.1038/s41598-025-92101-w","workflowStages":[]},"version":"v1","identity":"rs-4645827","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4645827","identity":"rs-4645827","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}