Browsing by Author "Zingarelli, Basilia"

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    Derivation, validation, and transcriptomic assessment of pediatric septic shock phenotypes identified through latent profile analyses: Results from a prospective multi-center observational cohort
    (Research Square, 2023-12-06) Atreya, Mihir R.; Huang, Min; Moore, Andrew R.; Zheng, Hong; Hasin-Brumshtein, Yehudit; Fitzgerald, Julie C.; Weiss, Scott L.; Cvijanovich, Natalie Z.; Bigham, Michael T.; Jain, Parag N.; Schwarz, Adam J.; Lutfi, Riad; Nowak, Jeffrey; Thomas, Neal J.; Quasney, Michael; Dahmer, Mary K.; Baines, Torrey; Haileselassie, Bereketeab; Lautz, Andrew J.; Stanski, Natalja L.; Standage, Stephen W.; Kaplan, Jennifer M.; Zingarelli, Basilia; Sweeney, Timothy E.; Khatri, Purvesh; Sanchez-Pinto, L. Nelson; Kamaleswaran, Rishikesan; Pediatrics, School of Medicine
    Background: Sepsis poses a grave threat, especially among children, but treatments are limited due to clinical and biological heterogeneity among patients. Thus, there is an urgent need for precise subclassification of patients to guide therapeutic interventions. Methods: We used clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock cohort to derive phenotypes using latent profile analyses. Thereafter, we trained a support vector machine model to assign phenotypes in a hold-out validation set. We tested interactions between phenotypes and common sepsis therapies on clinical outcomes and conducted transcriptomic analyses to better understand the phenotype-specific biology. Finally, we compared whether newly identified phenotypes overlapped with established gene-expression endotypes and tested the utility of an integrated subclassification scheme. Findings: Among 1,071 patients included, we identified two phenotypes which we named 'inflamed' (19.5%) and an 'uninflamed' phenotype (80.5%). The 'inflamed' phenotype had an over 4-fold risk of 28-day mortality relative to those 'uninflamed'. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and suggested an overabundance of developing neutrophils, pro-T/NK cells, and NK cells among those 'inflamed'. There was no significant overlap between endotypes and phenotypes. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing endophenotypes. Interpretation: Our research underscores the reproducibility of latent profile analyses to identify clinical and biologically informative pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill.
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    External validation of the modified sepsis renal angina index for prediction of severe acute kidney injury in children with septic shock
    (Springer Nature, 2023-11-28) Stanski, Natalja L.; Basu, Rajit K.; Cvijanovich, Natalie Z.; Fitzgerald, Julie C.; Bigham, Michael T.; Jain, Parag N.; Schwarz, Adam J.; Lutfi, Riad; Thomas, Neal J.; Baines, Torrey; Haileselassie, Bereketeab; Weiss, Scott L.; Atreya, Mihir R.; Lautz, Andrew J.; Zingarelli, Basilia; Standage, Stephen W.; Kaplan, Jennifer; Chawla, Lakhmir S.; Goldstein, Stuart L.; Pediatrics, School of Medicine
    Background: Acute kidney injury (AKI) occurs commonly in pediatric septic shock and increases morbidity and mortality. Early identification of high-risk patients can facilitate targeted intervention to improve outcomes. We previously modified the renal angina index (RAI), a validated AKI prediction tool, to improve specificity in this population (sRAI). Here, we prospectively assess sRAI performance in a separate cohort. Methods: A secondary analysis of a prospective, multicenter, observational study of children with septic shock admitted to the pediatric intensive care unit from 1/2019 to 12/2022. The primary outcome was severe AKI (≥ KDIGO Stage 2) on Day 3 (D3 severe AKI), and we compared predictive performance of the sRAI (calculated on Day 1) to the original RAI and serum creatinine elevation above baseline (D1 SCr > Baseline +). Original renal angina fulfillment (RAI +) was defined as RAI ≥ 8; sepsis renal angina fulfillment (sRAI +) was defined as RAI ≥ 20 or RAI 8 to < 20 with platelets < 150 × 103/µL. Results: Among 363 patients, 79 (22%) developed D3 severe AKI. One hundred forty (39%) were sRAI + , 195 (54%) RAI + , and 253 (70%) D1 SCr > Baseline + . Compared to sRAI-, sRAI + had higher risk of D3 severe AKI (RR 8.9, 95%CI 5-16, p < 0.001), kidney replacement therapy (KRT) (RR 18, 95%CI 6.6-49, p < 0.001), and mortality (RR 2.5, 95%CI 1.2-5.5, p = 0.013). sRAI predicted D3 severe AKI with an AUROC of 0.86 (95%CI 0.82-0.90), with greater specificity (74%) than D1 SCr > Baseline (36%) and RAI + (58%). On multivariable regression, sRAI + retained associations with D3 severe AKI (aOR 4.5, 95%CI 2.0-10.2, p < 0.001) and need for KRT (aOR 5.6, 95%CI 1.5-21.5, p = 0.01). Conclusions: Prediction of severe AKI in pediatric septic shock is important to improve outcomes, allocate resources, and inform enrollment in clinical trials examining potential disease-modifying therapies. The sRAI affords more accurate and specific prediction than context-free SCr elevation or the original RAI in this population.
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    Identification and transcriptomic assessment of latent profile pediatric septic shock phenotypes
    (Springer Nature, 2024-07-17) Atreya, Mihir R.; Huang, Min; Moore, Andrew R.; Zheng, Hong; Hasin-Brumshtein, Yehudit; Fitzgerald, Julie C.; Weiss, Scott L.; Cvijanovich, Natalie Z.; Bigham, Michael T.; Jain, Parag N.; Schwarz, Adam J.; Lutfi, Riad; Nowak, Jeffrey; Thomas, Neal J.; Quasney, Michael; Dahmer, Mary K.; Baines, Torrey; Haileselassie, Bereketeab; Lautz, Andrew J.; Stanski, Natalja L.; Standage, Stephen W.; Kaplan, Jennifer M.; Zingarelli, Basilia; Sahay, Rashmi; Zhang, Bin; Sweeney, Timothy E.; Khatri, Purvesh; Sanchez-Pinto, L. Nelson; Kamaleswaran, Rishikesan; Pediatrics, School of Medicine
    Background: Sepsis poses a grave threat, especially among children, but treatments are limited owing to heterogeneity among patients. We sought to test the clinical and biological relevance of pediatric septic shock subclasses identified using reproducible approaches. Methods: We performed latent profile analyses using clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock observational cohort to derive phenotypes and trained a support vector machine model to assign phenotypes in an internal validation set. We established the clinical relevance of phenotypes and tested for their interaction with common sepsis treatments on patient outcomes. We conducted transcriptomic analyses to delineate phenotype-specific biology and inferred underlying cell subpopulations. Finally, we compared whether latent profile phenotypes overlapped with established gene-expression endotypes and compared survival among patients based on an integrated subclassification scheme. Results: Among 1071 pediatric septic shock patients requiring vasoactive support on day 1 included, we identified two phenotypes which we designated as Phenotype 1 (19.5%) and Phenotype 2 (80.5%). Membership in Phenotype 1 was associated with ~ fourfold adjusted odds of complicated course relative to Phenotype 2. Patients belonging to Phenotype 1 were characterized by relatively higher Angiopoietin-2/Tie-2 ratio, Angiopoietin-2, soluble thrombomodulin (sTM), interleukin 8 (IL-8), and intercellular adhesion molecule 1 (ICAM-1) and lower Tie-2 and Angiopoietin-1 concentrations compared to Phenotype 2. We did not identify significant interactions between phenotypes, common treatments, and clinical outcomes. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and driven primarily by developing neutrophils among patients designated as Phenotype 1. There was no statistically significant overlap between established gene-expression endotypes, reflective of the host adaptive response, and the newly derived phenotypes, reflective of the host innate response including microvascular endothelial dysfunction. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing patient endophenotypes. Conclusions: Our research underscores the reproducibility of latent profile analyses to identify pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill.
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    Serum Soluble Endoglin in Pediatric Septic Shock Associated Multiple Organ Dysfunction Syndrome
    (Wolters Kluwer, 2023) Atreya, Mihir R.; Cvijanovich, Natalie Z.; Fitzgerald, Julie C.; Weiss, Scott L.; Bigham, Michael T.; Jain, Parag N.; Schwarz, Adam J.; Lutfi, Riad; Nowak, Jeffrey; Thomas, Neal J.; Quasney, Michael; Haileselassie, Bereketeab; Baines, Torrey D.; Zingarelli, Basilia; Genomics of Pediatric Septic Shock Investigators; Pediatrics, School of Medicine
    Background: Endothelial activation is a key driver of multiple organ dysfunction syndrome (MODS). Soluble endoglin (sENG) is expressed by mature and progenitor endothelial cells and thought to have angiogenic properties. We sought to determine the association between sENG and pediatric sepsis associated MODS. Methods: Prospective observational study of pediatric septic shock. Primary outcome of interest was complicated course -a composite of death by (or) MODS on day 7 of illness. Secondary outcomes included individual organ dysfunctions. Endothelial biomarkers including sENG were measured using multiplex Luminex assays among patients with existing data on pediatric sepsis biomarker risk model data (PERSEVERE-II). Multivariable regression was used to test the independent association between sENG and clinical outcomes. Serum sENG concentrations across PERSEVERE-II mortality risk strata and correlations with established markers of endothelial dysfunction. Results: 306 critically ill children with septic shock were included. Serum sENG concentrations were higher among those with primary and secondary outcomes of interest, with the exception of acute neurological dysfunction. sENG was independently associated with increased odds of complicated course [adj OR 1.53 (95% CI: 1.02–2.27), p=0.038] and acute renal dysfunction [adj OR 1.84 (95%CI: 1.18–2.876), p=0.006]. sENG demonstrated graded responses across PERSEVERE-II risk strata and was positively correlated with endothelial biomarkers, except Angiopoietin-1. Conclusions: Serum soluble endoglin is independently associated with complicated course and acute renal dysfunction in pediatric septic shock. Future studies are required to validate our observational data and mechanistic studies are necessary to elucidate whether endoglin plays a organ-specific role in development or resolution of acute renal dysfunction in sepsis.