Soluble CD25 as a Prognostic Biomarker for Pediatric Septic Shock and Its Comparison with Hemophagocytic Lymphohistiocytosis

Soluble CD25 as a Prognostic Biomarker for Pediatric Septic Shock and Its Comparison with Hemophagocytic Lymphohistiocytosis | 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 Short Report Soluble CD25 as a Prognostic Biomarker for Pediatric Septic Shock and Its Comparison with Hemophagocytic Lymphohistiocytosis TB Garcia, V Knight, HF Scott This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8641402/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 8 You are reading this latest preprint version Abstract Objectives: Identifying children at highest risk for deterioration during evaluation for septic shock in emergency department (ED) settings remains challenging. Soluble CD25 (sCD25), a hemophagocytic lymphohistiocytosis (HLH) diagnostic criterion, has been associated with sepsis mortality in ICU settings. This study aimed to determine whether sCD25 is associated with adverse outcomes in children undergoing initial septic shock evaluation in a pediatric ED. We also sought to compare sCD25 in patients with septic shock, infection without sepsis, and HLH. Results: Children with HLH demonstrated significantly higher sCD25 levels [25,800 pg/mL (IQR: 1,620–42,300)] compared with those with septic shock [5,200 pg/mL (IQR: 2,500–20,600)] or infection [5,500 pg/mL (IQR: 2,200–12,500)]. No statistical differences were observed between septic shock and infection groups; however, a subset of septic shock patients exhibited sCD25 elevations comparable to HLH patients. These patients experienced severe outcomes, including 100% PICU admission, 50% vasoactive support requirement, and prolonged hospitalization (16 days). Bloodstream infections were associated with the highest sCD25 levels. These findings suggest sCD25 elevation may be associated with adverse outcomes in children with septic shock. Larger studies are warranted to validate sCD25 as a prognostic marker for children with septic shock. hemophagocytic lymphohistiocytosis pediatrics sepsis septic shock soluble CD25 Figures Figure 1 Figure 2 Figure 3 Introduction Pediatric septic shock represents a significant cause of morbidity and mortality worldwide ( 1 , 2 ). Identifying patients at risk for adverse outcomes during early sepsis evaluation remains a challenge. Biomarkers that are detectable at initial emergency department (ED) evaluation and are associated with severe outcomes including fluid-refractory shock, requirement for positive pressure ventilation (PPV), and prolonged hospitalization are needed for more effective prognostication and identification of patients that may benefit from novel, targeted therapies. Patients with sepsis who develop concurrent hemophagocytic lymphohistiocytosis (HLH) have poor outcomes including increased mortality, suggesting markers of HLH may have prognostic utility in sepsis( 3 ). Up to one third of children who die of sepsis have evidence of concurrent HLH ( 4 , 5 ). Surrogate markers of macrophage activation in HLH including ferritin and soluble CD163 have been associated with mortality in children with sepsis. However, it is unclear whether markers associated with abnormal T cell activation, a key component of HLH pathogenesis, may be useful in early sepsis prognostication. Soluble CD25 (sCD25) is a surrogate marker of T cell activity and HLH diagnostic criterion ( 6 ). sCD25 has high sensitivity and specificity for HLH diagnosis, and elevation is associated with disease severity, response to therapy, and mortality ( 6 – 8 ). In adult sepsis, sCD25 has shown promise in distinguishing patients with bacterial infections and high risk of mortality ( 9 – 11 ). Likewise, sCD25 elevation has been associated with increased mortality in children with sepsis admitted to an ICU ( 12 ). However, the prognostic value of sCD25 in early sepsis evaluation in children remains unexplored. This study sought to describe sCD25 levels in pediatric patients with suspected septic shock and to determine whether higher levels were associated with illness severity. Additionally, we compared sCD25 between patients with suspected septic shock, those with infection without sepsis, and those with HLH. Methods Participants This was a prospective cohort study conducted at Children’s Hospital Colorado, an academic pediatric referral center that treats 75,000 patients yearly in the ED, over the period from March 2024 to April 2025. Children who presented to the ED were eligible for enrollment in the suspected septic shock cohort if they were ≥ 12 months to < 18 years old, had clinical concern for sepsis defined as use of a sepsis order set, had at least one hypotensive systolic blood pressure for age defined as less than 70 + 2(age in years), and required an IV for clinical care ( 13 ). Patients less than 12 months old were excluded due to age-related variability in sCD25 levels in this group ( 14 ). Patients were eligible for enrollment in the infectious control population if they were ≥ 12 months to 38.0°C in the emergency department or within 24 hours preceding the encounter), required intravenous access for clinical care, and had no clinical concern for sepsis. Age matching with the sepsis population was performed using the following brackets: 1–5 years, 6–10 years, and 11–17 years. Patients with immunodeficiencies, cancer not in remission, history of a solid organ transplant, or were receiving immunomodulatory medications including systemic corticosteroids within one week of ED presentation were excluded to minimize heterogeneity of the study population. This study was approved by the Colorado Multiple Institutions Review Board. To identify patients with a diagnosis of HLH, all patients throughout the hospital system (including inpatients and ED patients) who had a sCD25 level ordered for clinical care between January 1, 2022 and April 30, 2024 underwent retrospective chart review. Patients who met HLH-2004 diagnostic criteria as determined by the primary team, hematology, or rheumatology were included in this cohort. Patients with concerns for concurrent sepsis were excluded from this group. Outcome The primary outcome was to determine the association between sCD25 levels and a clinical diagnosis of sepsis in patients undergoing evaluation for septic shock in the ED. Secondary outcomes were comparison of sCD25 levels between patients with sepsis, HLH, and infection without sepsis and association of sCD25 with key outcomes (PICU admission, PPV requirement, vasoactive medication use, pediatric logistic organ dysfunction-2 (PELOD-2) score, infection source, and positive bacterial culture) in patients with sepsis. Data collection The study team identified potential subjects who had use of an ED sepsis order set (septic shock cohort) or had fever within the past 24 hours without use of a sepsis order set (infection cohort). Treating physicians were then asked to complete a screening form to assess inclusion and exclusion criteria. Per US law and IRB regulations, consent from a parent or legal guardian is required for all children < 18 years old. Written informed consent was obtained from parents or guardians of all subjects, and written assent was obtained from children ≥ 7 years old. After consenting patients were enrolled, a single venous sample was collected for sCD25 measurement. sCD25 levels were measured by the Children’s Hospital Immunopathology and Hematopathology Laboratory using a commercial enzyme linked immunosorbent assay (ELISA) kit (Human sIL-2R Instant ELISA, Invitrogen). Institutional cutoffs were used to determine sCD25 elevation (Supplemental Table 1).Clinical data were collected for all patients including age, gender, chronic medical conditions, history of sepsis within the past year, vital signs at presentation and daily for the first 2 days of hospitalization, admitting service, discharge date, vasoactive medication requirement, respiratory support requirement, clinical diagnosis, and microbial culture results. Missing data was assumed to be normal. On days where multiple data points were available, the most abnormal value was recorded. For patients in the HLH cohort, day 0 was considered the day that the first sCD25 level of admission was obtained in order to compare data between patients with septic shock and HLH at the time the sCD25 was measured. Statistical Analysis Demographic and clinical characteristics were described using counts and percentages for categorical variables, and medians with interquartile ranges for continuous variables with non-normal distributions. Normality was assessed with the Shapiro-Wilk test. For normally distributed data, t-tests or one-way analysis of variance (ANOVA) were used, as appropriate. Mann-Whitney U tests and Kruskal-Wallis tests were used for nonparametric data. We planned a subgroup analysis of all sepsis patients with a sCD25 level above the diagnostic criteria for HLH based on our institutional age-specific reference ranges (Supplemental Table 1). All analyses were conducted using GraphPad Prism 10 (GraphPad Software, La Jolla, CA). Results Study Population Between March 2024 and April 2025, 7 children with suspected septic shock, 7 with infection without sepsis, and 28 with HLH were enrolled (Table 1 ). There was no statistical difference in age between the cohorts (p 0.40). PICU admission rates were the same for septic shock and HLH groups (43% each; p > 0.99) with no PICU admissions in the infection without sepsis group. HLH patients had longer hospitalizations (median 9 days [IQR: 4–50]) compared to septic shock patients (4 days [IQR: 0–20] p < 0.01). Although higher percentages of septic shock patients required vasoactive medications (29% vs 18%, p 0.40) and positive pressure ventilation (43% vs 29%, p 0.22) than HLH patients, these differences were not statistically significant. Regarding infectious etiology, patients with septic shock demonstrated higher rates of positive bacterial cultures compared to other groups, though this difference was not statistically significant (sepsis 29% vs. infection 0% vs. HLH 7%, p 0.24). Conversely, patients with HLH showed higher rates of viral infections, but this difference also did not reach statistical significance (HLH 43% vs. sepsis 0% vs. infection 14%, p = 0.06). The most common etiology of HLH was an underlying rheumatologic condition (46%) followed by unknown cause (21%), infection (11%), CAR T-cell therapy (11%), genetic (7%), and malignancy (4%). Table 1 Study Population Sepsis (n = 7) No Sepsis (n = 7) HLH (n = 28) p Age 12 ( 8 – 14 ) 11 ( 8 – 16 ) 9 ( 2 – 15 ) 0.40 % Female 6 (86) 3 (43) 14 (50) 0.18 Chronic medical condition 6 (86) 1 ( 14 ) 21 (75) 0.99 GI/liver 2 (29) 0 1 ( 4 ) 0.13 Renal 1 ( 14 ) 0 1 ( 4 ) 0.56 Hematologic 1 ( 14 ) 0 5 ( 18 ) 0.81 Cardiac 5 (71) 0 1 ( 4 ) < 0.01 Rheumatologic 0 0 13 (46) 0.99 Non-PICU admission 2 (29) 3 (42.9) 16 (57.1) 0.44 Length of stay (d) 4 (0–20) 0 (0–1) 9 (4–50) < 0.01 Positive pressure ventilation 3 (43) 0 8 (29) 0.22 Vasoactive agent 2 (29) 0 5 ( 18 ) 0.40 Primary infection source Blood 1 ( 14 ) 0 8 (29) 0.30 Pneumonia 2 (29) 2 (29) 5 ( 18 ) 0.62 Meningitis 0 0 0 Urinary tract 1 ( 14 ) 0 0 Skin/soft tissue/musculoskeletal 0 0 0 Other 2 (29) 4 (57) 2 ( 7 ) < 0.01 Unknown 2 (29) 1 ( 14 ) 1 ( 4 ) 0.10 Pathogen identified Bacteria 2 (29) 0 2 ( 7 ) 0.24 Virus 0 1 ( 14 ) 12 (43) 0.06 Fungus 0 0 0 None 5 (71) 6 (86) 15 (54) 0.32 a Categorical values are displayed as counts and percentages. Continuous variables are shown as median and interquartile (IQR) range values. Comparison of sCD25 Levels Between Groups HLH patients demonstrated significantly higher sCD25 levels (25,800 pg/mL [IQR: 1,620 − 42,300]) compared to both septic shock (5,200 pg/mL [IQR: 2,500 − 20,600]) and infection (5,500 pg/mL [IQR: 2,200 − 12,500] p < 0.001) groups (Fig. 1 ). While no statistical differences were detected between septic shock and infection cohorts, a subset of septic shock patients exhibited elevated sCD25 levels comparable to those observed in HLH patients (Fig. 1 a). When sCD25 levels were compared in patients evaluated for suspected septic shock based on a discharge diagnosis of sepsis or not, patients with clinically confirmed sepsis demonstrated a wider range of sCD25 [10,300 pg/mL (IQR: 3,600 − 18,875)] than those with an alternate diagnosis [4,200 pg/mL (IQR: 4,000–5,200)] (Fig. 1 b). Notably, a subset of patients with a clinical diagnosis of sepsis had markedly elevated sCD25 levels while all patients with an alternative diagnosis had normal levels. Clinical Outcomes We examined associations between sCD25 levels and clinical outcomes in sepsis patients. Those with elevated sCD25 demonstrated elevated PELOD-2 scores across all time points (Day 0: 5 vs 2, Day 1: 4 vs 2, Day 2: 3 vs 1), increased PICU admission rates (100% vs 20%), longer hospitalizations (16 days vs 4 days), and greater need for vasoactive support (50% vs 20%), though these differences did not reach statistical significance (Table 2 ). Table 2 Clinical outcomes in suspected septic shock patients with normal vs elevated sCD25. Outcome sCD25 Normal sCD25 Elevated P value PELOD-2 score Day 0 2.0 5.0 0.95 Day 1 2.0 4.0 > 0.99 Day 2 1.0 3.0 > 0.99 PICU admission, n (%) 1 (20) 2 (100) 0.14 Length of stay, days 4 16 0.38 Vasopressor use, n (%) 1 (20) 1 (50) > 0.99 a Categorical values are displayed as counts and percentages. Continuous variables are shown as medians. Analysis by infection site revealed that bloodstream infections were associated with the highest sCD25 levels (20,600 pg/mL, n = 1), followed by pneumonia (10,300 pg/mL, IQR: 6,900 − 13,700) (Fig. 2 ). Patients requiring PICU admission, positive pressure ventilation, or vasoactive medications and nonsignificant trends towards sCD25 compared with those who did not (Fig. 3 a-c). Patients with positive bacterial cultures had higher sCD25 levels than culture-negative patients [13,750 pg/mL (IQR: 6,900 − 26,000) vs 4,200 pg/mL (IQR: 3,250-9,450)] (Fig. 3 d). Discussion In this study, we demonstrate that a subset of patients undergoing ED evaluation for septic shock have sCD25 levels comparable to HLH patients. Patients with sepsis and sCD25 elevation had trends toward worse clinical outcomes, including higher disease severity scores, increased need for intensive care, greater requirement for advanced supportive therapies (i.e., vasoactive medications and positive pressure ventilation), and longer lengths of stay. Among patients undergoing sepsis evaluation, those with a clinical diagnosis of sepsis had higher sCD25 levels than those with alternative diagnoses suggesting possible diagnostic utility for sCD25. The broad range in sCD25 levels in the suspected septic shock group is representative of the well-recognized clinical and pathophysiologic heterogeneity in this population. Our findings are consistent with prior reports that have interrogated HLH diagnostic criteria in the setting of sepsis. One-third of children who died of sepsis fulfilled 5/6 HLH diagnostic criteria ( 5 ). Hyperferritinemia was present in up to 66% of patients admitted to a PICU with sepsis and organ failure ( 15 , 16 ). With the known variability of immune responses in sepsis, elevated sCD25 levels would be expected in only a subset of patients, as observed in our study. The severity of illness in the few sepsis patients who had an elevation in sCD25 levels suggests that this marker may be a helpful prognostic indicator in sepsis. Correlations between sCD25 and mortality have been observed in adults and children with sepsis in ICU settings ( 9 , 15 , 17 , 18 ) Our study suggests sCD25 may be useful earlier in sepsis evaluation and associated with adverse outcomes beyond mortality. There are several limitations to this study. First, the limited sample size restricts our power and precludes firm conclusions about the potential role of sCD25 as a prognostic biomarker in pediatric sepsis. Our study is single-centered and may not be generalizable to other pediatric EDs with different patient populations or clinical practices. The patients in the suspected septic shock cohort were relatively mild in illness severity (some failed to meet clinical criteria for sepsis after initial diagnostic workup) as compared to studies in ICU settings where patients are generally more critically ill. In fact, none of our patients in suspected septic shock met the Phoenix sepsis criteria, which may limit generalizability of these results to more severely ill patients. Finally, we excluded patients younger than 12 months old and those with malignancy or immune deficiencies. While this may have decreased sCD25 heterogeneity in this study, it limits generalizability to these high-risk populations. In conclusion, sCD25 may be a potential prognostic marker in children undergoing ED evaluation for septic shock. Our findings warrant validation in larger, multicenter studies but suggest sCD25 may be a useful tool for risk stratification and clinical management of pediatric patients with sepsis. Prospective studies are warranted to further investigate the clinical utility of sCD25 in pediatric sepsis evaluation. Abbreviations HLH (hemophagocytic lymphophistiocytosis), sCD25 (soluble CD25), ED (emergency department), PPV (positive pressure ventilation), PICU (pediatric intensive care unit), PELOD-2 (pediatric logistic organ dysfunction-2), ELISA (enzyme linked immunosorbent assay) Declarations Ethical Approval : Ethics review and approval was given by the Colorado Multiple Institutions Review Board (23–0948). Under US law and IRB regulations, patients < 18 years old are considered minors and cannot participate in research without parental consent, which we obtained. Additionally, all patients ≥ 7 were present for the consent process and were required to give written voluntary informed assent to participate in the study, which was obtained in all participants. Consent for publication : written informed consent was obtained from the parents or guardians of all patients, and when appropriate, assent was obtained from the children themselves. Conflict of Interest : No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article. Funding Declaration: This work was funded by the Elevate Grant Fund, Section of Emergency Medicine, Children’s Hospital Colorado 23 − 03 (Garcia). Author Contribution TBG: conceptualization, data curation, data analysis, writing- original draft. VK: conceptualization, methodology, supervision, data- generation and analysis, writing- review and editing. HFS: conceptualization, methodology, supervision, data analysis, writing- review and editing. Acknowledgements: not applicable Data Availability The data generated during the current study are available from the corresponding author on reasonable request. References Tan B, Wong JJ, Sultana R, Koh J, Jit M, Mok YH, et al. Global Case-Fatality Rates in Pediatric Severe Sepsis and Septic Shock: A Systematic Review and Meta-analysis. JAMA Pediatr. 2019;173(4):352–62. Cruz AT, Lane RD, Balamuth F, Aronson PL, Ashby DW, Neuman MI, et al. Updates on pediatric sepsis. J Am Coll Emerg Physicians Open. 2020;1(5):981–93. Carcillo JA, Shakoory B. Cytokine Storm and Sepsis-Induced Multiple Organ Dysfunction Syndrome. Adv Exp Med Biol. 2024;1448:441–57. Castillo L, Carcillo J. 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J Clin Med. 2022;11(6). American Academy of Pediatrics AHA. Pediatric Advanced Life Support Provider Manual. Dallas, TX: AHA; 2020. Sack U, Burkhardt U, Borte M, Schädlich H, Berg K, Emmrich F. Age-dependent levels of select immunological mediators in sera of healthy children. Clin Diagn Lab Immunol. 1998;5(1):28–32. Fan Z, Kernan KF, Qin Y, Canna S, Berg RA, Wessel D, et al. Hyperferritinemic sepsis, macrophage activation syndrome, and mortality in a pediatric research network: a causal inference analysis. Crit Care. 2023;27(1):347. Horvat CM, Fabio A, Nagin DS, Banks RK, Qin Y, Park HJ, et al. Mortality Risk in Pediatric Sepsis Based on C-reactive Protein and Ferritin Levels. Pediatr Crit Care Med. 2022;23(12):968–79. Matera G, Puccio R, Giancotti A, Quirino A, Pulicari MC, Zicca E, et al. Impact of interleukin-10, soluble CD25 and interferon-γ on the prognosis and early diagnosis of bacteremic systemic inflammatory response syndrome: a prospective observational study. Crit Care. 2013;17(2):R64. Kyriazopoulou E, Leventogiannis K, Norrby-Teglund A, Dimopoulos G, Pantazi A, Orfanos SE, et al. Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis. BMC Med. 2017;15(1):172. Additional Declarations No competing interests reported. Supplementary Files SupplementalTable1.docx Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 05 May, 2026 Reviews received at journal 04 May, 2026 Reviewers agreed at journal 15 Apr, 2026 Reviewers invited by journal 19 Feb, 2026 Editor assigned by journal 19 Feb, 2026 Editor invited by journal 03 Feb, 2026 Submission checks completed at journal 02 Feb, 2026 First submitted to journal 02 Feb, 2026 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. 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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-8641402","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":594036344,"identity":"24524d14-e01c-464a-a34e-2b610b1ca022","order_by":0,"name":"TB Garcia","email":"data:image/png;base64,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","orcid":"","institution":"University of Colorado Anschutz Medical Campus","correspondingAuthor":true,"prefix":"","firstName":"TB","middleName":"","lastName":"Garcia","suffix":""},{"id":594036345,"identity":"b922412f-eb04-4938-b9a7-fe514694154a","order_by":1,"name":"V Knight","email":"","orcid":"","institution":"University of Colorado Anschutz Medical Campus","correspondingAuthor":false,"prefix":"","firstName":"V","middleName":"","lastName":"Knight","suffix":""},{"id":594036346,"identity":"6801f98d-ad2f-4bb9-baa9-960128120dbc","order_by":2,"name":"HF Scott","email":"","orcid":"","institution":"University of Colorado Anschutz Medical Campus","correspondingAuthor":false,"prefix":"","firstName":"HF","middleName":"","lastName":"Scott","suffix":""}],"badges":[],"createdAt":"2026-01-19 16:23:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8641402/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8641402/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103349207,"identity":"fbbe9489-42d9-4c4a-843d-087059d2d7a4","added_by":"auto","created_at":"2026-02-24 16:41:25","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":74833,"visible":true,"origin":"","legend":"\u003cp\u003eSoluble CD25 Levels Across Clinical Groups (a) Log transformed sCD25 values in patients with clinical concern for septic shock, infection without sepsis, and HLH. (B) Log transformed sCD25 values in patients evaluated for septic shock based on whether they received a clinical diagnosis of sepsis during admission. Data are displayed as mean ± standard deviation. *** \u0026lt;0.001.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8641402/v1/921b1b96905da1c1049c1291.jpeg"},{"id":103349204,"identity":"a0333bfe-946f-4c14-a9b0-9c7e091d32a2","added_by":"auto","created_at":"2026-02-24 16:41:25","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":52791,"visible":true,"origin":"","legend":"\u003cp\u003esCD25 levels (pg/mL) displayed by primary source of infection in patients undergoing evaluation for suspected septic shock. Data are displayed as mean ± standard deviation.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8641402/v1/9347e12f486df74b5a169631.jpeg"},{"id":103349235,"identity":"666076c4-c02f-44d7-a4ac-b07703c51020","added_by":"auto","created_at":"2026-02-24 16:41:28","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":101224,"visible":true,"origin":"","legend":"\u003cp\u003esCD25 Levels by Clinical Outcomes. sCD25 levels in patients undergoing evaluation for septic shock based on the requirement for (a) PICU admission, (b) vasoactive medication use, (c) PPV use, and (d) a positive bacterial culture. Data are displayed as median with 95% CI.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8641402/v1/10d25cfd197041af4831fedc.jpeg"},{"id":103349247,"identity":"ca703fcb-426f-4468-b133-2a3165879b0f","added_by":"auto","created_at":"2026-02-24 16:41:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":782821,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8641402/v1/35a2537a-e9ac-4d40-bcf4-46ecd67800e8.pdf"},{"id":103349164,"identity":"d461800e-69ce-4ce9-9f11-50f458034ff3","added_by":"auto","created_at":"2026-02-24 16:41:18","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14425,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8641402/v1/e1590c7489c5e242e38c5b0e.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Soluble CD25 as a Prognostic Biomarker for Pediatric Septic Shock and Its Comparison with Hemophagocytic Lymphohistiocytosis","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePediatric septic shock represents a significant cause of morbidity and mortality worldwide (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Identifying patients at risk for adverse outcomes during early sepsis evaluation remains a challenge. Biomarkers that are detectable at initial emergency department (ED) evaluation and are associated with severe outcomes including fluid-refractory shock, requirement for positive pressure ventilation (PPV), and prolonged hospitalization are needed for more effective prognostication and identification of patients that may benefit from novel, targeted therapies.\u003c/p\u003e \u003cp\u003ePatients with sepsis who develop concurrent hemophagocytic lymphohistiocytosis (HLH) have poor outcomes including increased mortality, suggesting markers of HLH may have prognostic utility in sepsis(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Up to one third of children who die of sepsis have evidence of concurrent HLH (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Surrogate markers of macrophage activation in HLH including ferritin and soluble CD163 have been associated with mortality in children with sepsis. However, it is unclear whether markers associated with abnormal T cell activation, a key component of HLH pathogenesis, may be useful in early sepsis prognostication.\u003c/p\u003e \u003cp\u003eSoluble CD25 (sCD25) is a surrogate marker of T cell activity and HLH diagnostic criterion (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). sCD25 has high sensitivity and specificity for HLH diagnosis, and elevation is associated with disease severity, response to therapy, and mortality (\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). In adult sepsis, sCD25 has shown promise in distinguishing patients with bacterial infections and high risk of mortality (\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Likewise, sCD25 elevation has been associated with increased mortality in children with sepsis admitted to an ICU (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). However, the prognostic value of sCD25 in early sepsis evaluation in children remains unexplored.\u003c/p\u003e \u003cp\u003eThis study sought to describe sCD25 levels in pediatric patients with suspected septic shock and to determine whether higher levels were associated with illness severity. Additionally, we compared sCD25 between patients with suspected septic shock, those with infection without sepsis, and those with HLH.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eParticipants\u003c/p\u003e\n\u003cp\u003eThis was a prospective cohort study conducted at Children\u0026rsquo;s Hospital Colorado, an academic pediatric referral center that treats 75,000 patients yearly in the ED, over the period from March 2024 to April 2025. Children who presented to the ED were eligible for enrollment in the suspected septic shock cohort if they were \u003cspan class=\"Underline\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;12 months to \u0026lt;\u0026thinsp;18 years old, had clinical concern for sepsis defined as use of a sepsis order set, had at least one hypotensive systolic blood pressure for age defined as less than 70\u0026thinsp;+\u0026thinsp;2(age in years), and required an IV for clinical care (\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e). Patients less than 12 months old were excluded due to age-related variability in sCD25 levels in this group (\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e). Patients were eligible for enrollment in the infectious control population if they were \u003cspan class=\"Underline\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;12 months to \u0026lt;\u0026thinsp;18 years of age, had evidence of infection (defined as documented fever\u0026thinsp;\u0026gt;\u0026thinsp;38.0\u0026deg;C in the emergency department or within 24 hours preceding the encounter), required intravenous access for clinical care, and had no clinical concern for sepsis. Age matching with the sepsis population was performed using the following brackets: 1\u0026ndash;5 years, 6\u0026ndash;10 years, and 11\u0026ndash;17 years. Patients with immunodeficiencies, cancer not in remission, history of a solid organ transplant, or were receiving immunomodulatory medications including systemic corticosteroids within one week of ED presentation were excluded to minimize heterogeneity of the study population. This study was approved by the Colorado Multiple Institutions Review Board.\u003c/p\u003e\n\u003cp\u003eTo identify patients with a diagnosis of HLH, all patients throughout the hospital system (including inpatients and ED patients) who had a sCD25 level ordered for clinical care between January 1, 2022 and April 30, 2024 underwent retrospective chart review. Patients who met HLH-2004 diagnostic criteria as determined by the primary team, hematology, or rheumatology were included in this cohort. Patients with concerns for concurrent sepsis were excluded from this group.\u003c/p\u003e\n\u003cp\u003eOutcome\u003c/p\u003e\n\u003cp\u003eThe primary outcome was to determine the association between sCD25 levels and a clinical diagnosis of sepsis in patients undergoing evaluation for septic shock in the ED. Secondary outcomes were comparison of sCD25 levels between patients with sepsis, HLH, and infection without sepsis and association of sCD25 with key outcomes (PICU admission, PPV requirement, vasoactive medication use, pediatric logistic organ dysfunction-2 (PELOD-2) score, infection source, and positive bacterial culture) in patients with sepsis.\u003c/p\u003e\n\u003cp\u003eData collection\u003c/p\u003e\n\u003cp\u003eThe study team identified potential subjects who had use of an ED sepsis order set (septic shock cohort) or had fever within the past 24 hours without use of a sepsis order set (infection cohort). Treating physicians were then asked to complete a screening form to assess inclusion and exclusion criteria. Per US law and IRB regulations, consent from a parent or legal guardian is required for all children\u0026thinsp;\u0026lt;\u0026thinsp;18 years old. Written informed consent was obtained from parents or guardians of all subjects, and written assent was obtained from children\u0026thinsp;\u003cspan class=\"Underline\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;7 years old. After consenting patients were enrolled, a single venous sample was collected for sCD25 measurement. sCD25 levels were measured by the Children\u0026rsquo;s Hospital Immunopathology and Hematopathology Laboratory using a commercial enzyme linked immunosorbent assay (ELISA) kit (Human sIL-2R Instant ELISA, Invitrogen). Institutional cutoffs were used to determine sCD25 elevation (Supplemental Table\u0026nbsp;1).Clinical data were collected for all patients including age, gender, chronic medical conditions, history of sepsis within the past year, vital signs at presentation and daily for the first 2 days of hospitalization, admitting service, discharge date, vasoactive medication requirement, respiratory support requirement, clinical diagnosis, and microbial culture results. Missing data was assumed to be normal. On days where multiple data points were available, the most abnormal value was recorded. For patients in the HLH cohort, day 0 was considered the day that the first sCD25 level of admission was obtained in order to compare data between patients with septic shock and HLH at the time the sCD25 was measured.\u003c/p\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\n\u003cp\u003eDemographic and clinical characteristics were described using counts and percentages for categorical variables, and medians with interquartile ranges for continuous variables with non-normal distributions. Normality was assessed with the Shapiro-Wilk test. For normally distributed data, t-tests or one-way analysis of variance (ANOVA) were used, as appropriate. Mann-Whitney U tests and Kruskal-Wallis tests were used for nonparametric data. We planned a subgroup analysis of all sepsis patients with a sCD25 level above the diagnostic criteria for HLH based on our institutional age-specific reference ranges (Supplemental Table\u0026nbsp;1). All analyses were conducted using GraphPad Prism 10 (GraphPad Software, La Jolla, CA).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eStudy Population\u003c/p\u003e \u003cp\u003eBetween March 2024 and April 2025, 7 children with suspected septic shock, 7 with infection without sepsis, and 28 with HLH were enrolled (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). There was no statistical difference in age between the cohorts (p 0.40). PICU admission rates were the same for septic shock and HLH groups (43% each; p\u0026thinsp;\u0026gt;\u0026thinsp;0.99) with no PICU admissions in the infection without sepsis group. HLH patients had longer hospitalizations (median 9 days [IQR: 4\u0026ndash;50]) compared to septic shock patients (4 days [IQR: 0\u0026ndash;20] p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Although higher percentages of septic shock patients required vasoactive medications (29% vs 18%, p 0.40) and positive pressure ventilation (43% vs 29%, p 0.22) than HLH patients, these differences were not statistically significant. Regarding infectious etiology, patients with septic shock demonstrated higher rates of positive bacterial cultures compared to other groups, though this difference was not statistically significant (sepsis 29% vs. infection 0% vs. HLH 7%, p 0.24). Conversely, patients with HLH showed higher rates of viral infections, but this difference also did not reach statistical significance (HLH 43% vs. sepsis 0% vs. infection 14%, p\u0026thinsp;=\u0026thinsp;0.06). The most common etiology of HLH was an underlying rheumatologic condition (46%) followed by unknown cause (21%), infection (11%), CAR T-cell therapy (11%), genetic (7%), and malignancy (4%).\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\u003eStudy Population\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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=\"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=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSepsis (n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo Sepsis (n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHLH (n\u0026thinsp;=\u0026thinsp;28)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eAge\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12 CR13\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12 CR13 CR14 CR15\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003e% Female\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eChronic medical condition\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeuromuscular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePulmonary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndocrine/metabolic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGI/liver\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematologic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRheumatologic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eHistory of sepsis within the past year\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eClinical Outcomes\u003c/em\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\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePICU admission\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (42.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (42.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-PICU admission\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (42.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (57.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of stay (d)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (0\u0026ndash;20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0\u0026ndash;1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (4\u0026ndash;50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive pressure ventilation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVasoactive agent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePrimary infection source\u003c/em\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\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMeningitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrinary tract\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin/soft tissue/musculoskeletal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePathogen identified\u003c/em\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\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBacteria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVirus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFungus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003csup\u003ea\u003c/sup\u003eCategorical values are displayed as counts and percentages. Continuous variables are shown as median and interquartile (IQR) range values.\u003c/p\u003e \u003cp\u003eComparison of sCD25 Levels Between Groups\u003c/p\u003e \u003cp\u003eHLH patients demonstrated significantly higher sCD25 levels (25,800 pg/mL [IQR: 1,620\u0026thinsp;\u0026minus;\u0026thinsp;42,300]) compared to both septic shock (5,200 pg/mL [IQR: 2,500\u0026thinsp;\u0026minus;\u0026thinsp;20,600]) and infection (5,500 pg/mL [IQR: 2,200\u0026thinsp;\u0026minus;\u0026thinsp;12,500] p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). While no statistical differences were detected between septic shock and infection cohorts, a subset of septic shock patients exhibited elevated sCD25 levels comparable to those observed in HLH patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). When sCD25 levels were compared in patients evaluated for suspected septic shock based on a discharge diagnosis of sepsis or not, patients with clinically confirmed sepsis demonstrated a wider range of sCD25 [10,300 pg/mL (IQR: 3,600\u0026thinsp;\u0026minus;\u0026thinsp;18,875)] than those with an alternate diagnosis [4,200 pg/mL (IQR: 4,000\u0026ndash;5,200)] (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). Notably, a subset of patients with a clinical diagnosis of sepsis had markedly elevated sCD25 levels while all patients with an alternative diagnosis had normal levels.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eClinical Outcomes\u003c/p\u003e \u003cp\u003eWe examined associations between sCD25 levels and clinical outcomes in sepsis patients. Those with elevated sCD25 demonstrated elevated PELOD-2 scores across all time points (Day 0: 5 vs 2, Day 1: 4 vs 2, Day 2: 3 vs 1), increased PICU admission rates (100% vs 20%), longer hospitalizations (16 days vs 4 days), and greater need for vasoactive support (50% vs 20%), though these differences did not reach statistical significance (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\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\u003eClinical outcomes in suspected septic shock patients with normal vs elevated sCD25.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003esCD25 Normal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003esCD25 Elevated\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePELOD-2 score\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 \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay 0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePICU admission, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of stay, days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVasopressor use, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003csup\u003ea\u003c/sup\u003eCategorical values are displayed as counts and percentages. Continuous variables are shown as medians.\u003c/p\u003e \u003cp\u003eAnalysis by infection site revealed that bloodstream infections were associated with the highest sCD25 levels (20,600 pg/mL, n\u0026thinsp;=\u0026thinsp;1), followed by pneumonia (10,300 pg/mL, IQR: 6,900\u0026thinsp;\u0026minus;\u0026thinsp;13,700) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePatients requiring PICU admission, positive pressure ventilation, or vasoactive medications and nonsignificant trends towards sCD25 compared with those who did not (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea-c). Patients with positive bacterial cultures had higher sCD25 levels than culture-negative patients [13,750 pg/mL (IQR: 6,900\u0026thinsp;\u0026minus;\u0026thinsp;26,000) vs 4,200 pg/mL (IQR: 3,250-9,450)] (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we demonstrate that a subset of patients undergoing ED evaluation for septic shock have sCD25 levels comparable to HLH patients. Patients with sepsis and sCD25 elevation had trends toward worse clinical outcomes, including higher disease severity scores, increased need for intensive care, greater requirement for advanced supportive therapies (i.e., vasoactive medications and positive pressure ventilation), and longer lengths of stay. Among patients undergoing sepsis evaluation, those with a clinical diagnosis of sepsis had higher sCD25 levels than those with alternative diagnoses suggesting possible diagnostic utility for sCD25.\u003c/p\u003e \u003cp\u003eThe broad range in sCD25 levels in the suspected septic shock group is representative of the well-recognized clinical and pathophysiologic heterogeneity in this population. Our findings are consistent with prior reports that have interrogated HLH diagnostic criteria in the setting of sepsis. One-third of children who died of sepsis fulfilled 5/6 HLH diagnostic criteria (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Hyperferritinemia was present in up to 66% of patients admitted to a PICU with sepsis and organ failure (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). With the known variability of immune responses in sepsis, elevated sCD25 levels would be expected in only a subset of patients, as observed in our study.\u003c/p\u003e \u003cp\u003eThe severity of illness in the few sepsis patients who had an elevation in sCD25 levels suggests that this marker may be a helpful prognostic indicator in sepsis. Correlations between sCD25 and mortality have been observed in adults and children with sepsis in ICU settings (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) Our study suggests sCD25 may be useful earlier in sepsis evaluation and associated with adverse outcomes beyond mortality.\u003c/p\u003e \u003cp\u003eThere are several limitations to this study. First, the limited sample size restricts our power and precludes firm conclusions about the potential role of sCD25 as a prognostic biomarker in pediatric sepsis. Our study is single-centered and may not be generalizable to other pediatric EDs with different patient populations or clinical practices. The patients in the suspected septic shock cohort were relatively mild in illness severity (some failed to meet clinical criteria for sepsis after initial diagnostic workup) as compared to studies in ICU settings where patients are generally more critically ill. In fact, none of our patients in suspected septic shock met the Phoenix sepsis criteria, which may limit generalizability of these results to more severely ill patients. Finally, we excluded patients younger than 12 months old and those with malignancy or immune deficiencies. While this may have decreased sCD25 heterogeneity in this study, it limits generalizability to these high-risk populations.\u003c/p\u003e \u003cp\u003eIn conclusion, sCD25 may be a potential prognostic marker in children undergoing ED evaluation for septic shock. Our findings warrant validation in larger, multicenter studies but suggest sCD25 may be a useful tool for risk stratification and clinical management of pediatric patients with sepsis. Prospective studies are warranted to further investigate the clinical utility of sCD25 in pediatric sepsis evaluation.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eHLH (hemophagocytic lymphophistiocytosis), sCD25 (soluble CD25), ED (emergency department), PPV (positive pressure ventilation), PICU (pediatric intensive care unit), PELOD-2 (pediatric logistic organ dysfunction-2), ELISA (enzyme linked immunosorbent assay)\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e:\u003c/h2\u003e\n\u003cp\u003eEthics review and approval was given by the Colorado Multiple Institutions Review Board (23\u0026ndash;0948). Under US law and IRB regulations, patients\u0026thinsp;\u0026lt;\u0026thinsp;18 years old are considered minors and cannot participate in research without parental consent, which we obtained. Additionally, all patients\u0026thinsp;\u003cspan class=\"Underline\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;7 were present for the consent process and were required to give written voluntary informed assent to participate in the study, which was obtained in all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ewritten informed consent was obtained from the parents or guardians of all patients, and when appropriate, assent was obtained from the children themselves.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e \u003cstrong\u003eConflict of Interest\u003c/strong\u003e:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;Declaration:\u003c/strong\u003e This work was funded by the Elevate Grant Fund, Section of Emergency Medicine, Children\u0026rsquo;s Hospital Colorado 23\u0026thinsp;\u0026minus;\u0026thinsp;03 (Garcia).\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eTBG: conceptualization, data curation, data analysis, writing- original draft. VK: conceptualization, methodology, supervision, data- generation and analysis, writing- review and editing. HFS: conceptualization, methodology, supervision, data analysis, writing- review and editing.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements:\u003c/h2\u003e\n\u003cp\u003enot applicable\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe data generated during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTan B, Wong JJ, Sultana R, Koh J, Jit M, Mok YH, et al. Global Case-Fatality Rates in Pediatric Severe Sepsis and Septic Shock: A Systematic Review and Meta-analysis. JAMA Pediatr. 2019;173(4):352\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCruz AT, Lane RD, Balamuth F, Aronson PL, Ashby DW, Neuman MI, et al. Updates on pediatric sepsis. J Am Coll Emerg Physicians Open. 2020;1(5):981\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarcillo JA, Shakoory B. Cytokine Storm and Sepsis-Induced Multiple Organ Dysfunction Syndrome. Adv Exp Med Biol. 2024;1448:441\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCastillo L, Carcillo J. Secondary hemophagocytic lymphohistiocytosis and severe sepsis/ systemic inflammatory response syndrome/multiorgan dysfunction syndrome/macrophage activation syndrome share common intermediate phenotypes on a spectrum of inflammation. Pediatr Crit Care Med. 2009;10(3):387\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEl-Sayed ZA, El-Owaidy RH, Khamis MA, Rezk AR. Screening of hemophagocytic lymphohistiocytosis in children with severe sepsis in pediatric intensive care. Sci Prog. 2021;104(3):368504211044042.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLin M, Park S, Hayden A, Giustini D, Trinkaus M, Pudek M, et al. Clinical utility of soluble interleukin-2 receptor in hemophagocytic syndromes: a systematic scoping review. Ann Hematol. 2017;96(8):1241\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBleesing J, Prada A, Siegel DM, Villanueva J, Olson J, Ilowite NT, et al. The diagnostic significance of soluble CD163 and soluble interleukin-2 receptor alpha-chain in macrophage activation syndrome and untreated new-onset systemic juvenile idiopathic arthritis. Arthritis Rheum. 2007;56(3):965\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGao ZY, Li XY, Bhandari V, Li LD, Lan D. Pre-B-cell colony-enhancing factor is markedly elevated in childhood hemophagocytic lymphohistiocytosis. Genet Mol Res. 2015;14(2):5287\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang CM, Xu XJ, Qi WQ, Ge QM. Prognostic significance of soluble CD25 in patients with sepsis: a prospective observational study. Clin Chem Lab Med. 2022;60(6):952\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaito K, Wagatsuma T, Toyama H, Ejima Y, Hoshi K, Shibusawa M, et al. Sepsis is characterized by the increases in percentages of circulating CD4\u0026thinsp;+\u0026thinsp;CD25+ regulatory T cells and plasma levels of soluble CD25. Tohoku J Exp Med. 2008;216(1):61\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarc\u0026iacute;a de Guadiana-Romualdo L, Berger M, Jim\u0026eacute;nez-Santos E, Rebollo-Acebes S, Jim\u0026eacute;nez-S\u0026aacute;nchez R, Esteban-Torrella P, et al. Pancreatic stone protein and soluble CD25 for infection and sepsis in an emergency department. Eur J Clin Invest. 2017;47(4):297\u0026ndash;304.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePilar-Orive FJ, Astigarraga I, Azkargorta M, Elortza F, Garcia-Obregon S. A Three-Protein Panel to Support the Diagnosis of Sepsis in Children. J Clin Med. 2022;11(6).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmerican Academy of Pediatrics AHA. Pediatric Advanced Life Support Provider Manual. Dallas, TX: AHA; 2020.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSack U, Burkhardt U, Borte M, Sch\u0026auml;dlich H, Berg K, Emmrich F. Age-dependent levels of select immunological mediators in sera of healthy children. Clin Diagn Lab Immunol. 1998;5(1):28\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFan Z, Kernan KF, Qin Y, Canna S, Berg RA, Wessel D, et al. Hyperferritinemic sepsis, macrophage activation syndrome, and mortality in a pediatric research network: a causal inference analysis. Crit Care. 2023;27(1):347.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHorvat CM, Fabio A, Nagin DS, Banks RK, Qin Y, Park HJ, et al. Mortality Risk in Pediatric Sepsis Based on C-reactive Protein and Ferritin Levels. Pediatr Crit Care Med. 2022;23(12):968\u0026ndash;79.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatera G, Puccio R, Giancotti A, Quirino A, Pulicari MC, Zicca E, et al. Impact of interleukin-10, soluble CD25 and interferon-γ on the prognosis and early diagnosis of bacteremic systemic inflammatory response syndrome: a prospective observational study. Crit Care. 2013;17(2):R64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKyriazopoulou E, Leventogiannis K, Norrby-Teglund A, Dimopoulos G, Pantazi A, Orfanos SE, et al. Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis. BMC Med. 2017;15(1):172.\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":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-research-notes","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"resn","sideBox":"Learn more about [BMC Research Notes](http://bmcresnotes.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/resn/default.aspx","title":"BMC Research Notes","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"hemophagocytic lymphohistiocytosis, pediatrics, sepsis, septic shock, soluble CD25","lastPublishedDoi":"10.21203/rs.3.rs-8641402/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8641402/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjectives:\u003c/h2\u003e \u003cp\u003eIdentifying children at highest risk for deterioration during evaluation for septic shock in emergency department (ED) settings remains challenging. Soluble CD25 (sCD25), a hemophagocytic lymphohistiocytosis (HLH) diagnostic criterion, has been associated with sepsis mortality in ICU settings. This study aimed to determine whether sCD25 is associated with adverse outcomes in children undergoing initial septic shock evaluation in a pediatric ED. We also sought to compare sCD25 in patients with septic shock, infection without sepsis, and HLH.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eChildren with HLH demonstrated significantly higher sCD25 levels [25,800 pg/mL (IQR: 1,620\u0026ndash;42,300)] compared with those with septic shock [5,200 pg/mL (IQR: 2,500\u0026ndash;20,600)] or infection [5,500 pg/mL (IQR: 2,200\u0026ndash;12,500)]. No statistical differences were observed between septic shock and infection groups; however, a subset of septic shock patients exhibited sCD25 elevations comparable to HLH patients. These patients experienced severe outcomes, including 100% PICU admission, 50% vasoactive support requirement, and prolonged hospitalization (16 days). Bloodstream infections were associated with the highest sCD25 levels. These findings suggest sCD25 elevation may be associated with adverse outcomes in children with septic shock. Larger studies are warranted to validate sCD25 as a prognostic marker for children with septic shock.\u003c/p\u003e","manuscriptTitle":"Soluble CD25 as a Prognostic Biomarker for Pediatric Septic Shock and Its Comparison with Hemophagocytic Lymphohistiocytosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-24 16:41:01","doi":"10.21203/rs.3.rs-8641402/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-05T13:19:08+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-04T22:16:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"328977629428457504770055092838946550708","date":"2026-04-15T20:16:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-19T16:40:41+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-19T16:38:34+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-03T10:10:19+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-02T18:18:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Research Notes","date":"2026-02-02T18:08:06+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-research-notes","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"resn","sideBox":"Learn more about [BMC Research Notes](http://bmcresnotes.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/resn/default.aspx","title":"BMC Research Notes","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1f4154a9-8423-4dc8-8352-acfe007b8d7c","owner":[],"postedDate":"February 24th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-05T13:19:08+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-04T22:16:07+00:00","index":33,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-15T12:25:13+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-24 16:41:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8641402","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8641402","identity":"rs-8641402","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}