Browsing by Author "Geva, Alon"

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    Data-driven clustering identifies features distinguishing multisystem inflammatory syndrome from acute COVID-19 in children and adolescents
    (Elsevier, 2021-08-31) Geva, Alon; Patel, Manish M.; Geva, Alon; Patel, Manish M.; Newhams, Margaret M.; Young, Cameron C.; Son, Mary Beth F.; Kong, Michele; Maddux, Aline B.; Hall, Mark W.; Riggs, Becky J.; Singh, Aalok R.; Giuliano, John S.; Hobbs, Charlotte V.; Loftis, Laura L.; McLaughlin, Gwenn E.; Schwartz, Stephanie P.; Schuster, Jennifer E.; Babbitt, Christopher J.; Halasa, Natasha B.; Gertz, Shira J.; Doymaz, Sule; Hume, Janet R.; Bradford, Tamara T.; Irby, Katherine; Carroll, Christopher L.; McGuire, John K.; Tarquinio, Keiko M.; Rowan, Courtney M.; Mack, Elizabeth H.; Cvijanovich, Natalie Z.; Fitzgerald, Julie C.; Spinella, Philip C.; Staat, Mary A.; Clouser, Katharine N.; Soma, Vijaya L.; Dapul, Heda; Maamari, Mia; Bowens, Cindy; Havlin, Kevin M.; Mourani, Peter M.; Heidemann, Sabrina M.; Horwitz, Steven M.; Feldstein, Leora R.; Tenforde, Mark W.; Newburger, Jane W.; Mandl, Kenneth D.; Randolph, Adrienne G.; Overcoming COVID-19 Investigators; Pediatrics, School of Medicine
    Background Multisystem inflammatory syndrome in children (MIS-C) consensus criteria were designed for maximal sensitivity and therefore capture patients with acute COVID-19 pneumonia. Methods We performed unsupervised clustering on data from 1,526 patients (684 labeled MIS-C by clinicians) <21 years old hospitalized with COVID-19-related illness admitted between 15 March 2020 and 31 December 2020. We compared prevalence of assigned MIS-C labels and clinical features among clusters, followed by recursive feature elimination to identify characteristics of potentially misclassified MIS-C-labeled patients. Findings Of 94 clinical features tested, 46 were retained for clustering. Cluster 1 patients (N = 498; 92% labeled MIS-C) were mostly previously healthy (71%), with mean age 7·2 ± 0·4 years, predominant cardiovascular (77%) and/or mucocutaneous (82%) involvement, high inflammatory biomarkers, and mostly SARS-CoV-2 PCR negative (60%). Cluster 2 patients (N = 445; 27% labeled MIS-C) frequently had pre-existing conditions (79%, with 39% respiratory), were similarly 7·4 ± 2·1 years old, and commonly had chest radiograph infiltrates (79%) and positive PCR testing (90%). Cluster 3 patients (N = 583; 19% labeled MIS-C) were younger (2·8 ± 2·0 y), PCR positive (86%), with less inflammation. Radiographic findings of pulmonary infiltrates and positive SARS-CoV-2 PCR accurately distinguished cluster 2 MIS-C labeled patients from cluster 1 patients. Interpretation Using a data driven, unsupervised approach, we identified features that cluster patients into a group with high likelihood of having MIS-C. Other features identified a cluster of patients more likely to have acute severe COVID-19 pulmonary disease, and patients in this cluster labeled by clinicians as MIS-C may be misclassified. These data driven phenotypes may help refine the diagnosis of MIS-C.
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    Derivation, Validation, and Clinical Relevance of a Pediatric Sepsis Phenotype With Persistent Hypoxemia, Encephalopathy, and Shock
    (Wolters Kluwer, 2023) Sanchez-Pinto, L. Nelson; Bennett, Tellen D.; Stroup, Emily K.; Luo, Yuan; Atreya, Mihir; Bubeck Wardenburg, Juliane; Chong, Grace; Geva, Alon; Faustino, E. Vincent S.; Farris, Reid W.; Hall, Mark W.; Rogerson, Colin; Shah, Sareen S.; Weiss, Scott L.; Khemani, Robinder G.; Pediatrics, School of Medicine
    Objectives: Untangling the heterogeneity of sepsis in children and identifying clinically relevant phenotypes could lead to the development of targeted therapies. Our aim was to analyze the organ dysfunction trajectories of children with sepsis-associated multiple organ dysfunction syndrome (MODS) to identify reproducible and clinically relevant sepsis phenotypes and determine if they are associated with heterogeneity of treatment effect (HTE) to common therapies. Design: Multicenter observational cohort study. Setting: Thirteen PICUs in the United States. Patients: Patients admitted with suspected infections to the PICU between 2012 and 2018. Interventions: None. Measurements and main results: We used subgraph-augmented nonnegative matrix factorization to identify candidate trajectory-based phenotypes based on the type, severity, and progression of organ dysfunction in the first 72 hours. We analyzed the candidate phenotypes to determine reproducibility as well as prognostic, therapeutic, and biological relevance. Overall, 38,732 children had suspected infection, of which 15,246 (39.4%) had sepsis-associated MODS with an in-hospital mortality of 10.1%. We identified an organ dysfunction trajectory-based phenotype (which we termed persistent hypoxemia, encephalopathy, and shock) that was highly reproducible, had features of systemic inflammation and coagulopathy, and was independently associated with higher mortality. In a propensity score-matched analysis, patients with persistent hypoxemia, encephalopathy, and shock phenotype appeared to have HTE and benefit from adjuvant therapy with hydrocortisone and albumin. When compared with other high-risk clinical syndromes, the persistent hypoxemia, encephalopathy, and shock phenotype only overlapped with 50%-60% of patients with septic shock, moderate-to-severe pediatric acute respiratory distress syndrome, or those in the top tier of organ dysfunction burden, suggesting that it represents a nonsynonymous clinical phenotype of sepsis-associated MODS. Conclusions: We derived and validated the persistent hypoxemia, encephalopathy, and shock phenotype, which is highly reproducible, clinically relevant, and associated with HTE to common adjuvant therapies in children with sepsis.
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    External validation and biomarker assessment of a high-risk, data-driven pediatric sepsis phenotype characterized by persistent hypoxemia, encephalopathy, and shock
    (Research Square, 2023-08-02) Atreya, Mihir R.; Bennett, Tellen D.; Geva, Alon; Faustino, E. Vincent S.; Rogerson, Colin M.; Lutfi, Riad; Cvijanovich, Natalie Z.; Bigham, Michael T.; Nowak, Jeffrey; Schwarz, Adam J.; Baines, Torrey; Haileselassie, Bereketeab; Thomas, Neal J.; Luo, Yuan; Sanchez-Pinto, L. Nelson; Novel Data-Driven Sepsis Phenotypes in Children Study and the Genomics of Pediatric Septic Shock Investigators; Pediatrics, School of Medicine
    Objective: Identification of children with sepsis-associated multiple organ dysfunction syndrome (MODS) at risk for poor outcomes remains a challenge. Data-driven phenotyping approaches that leverage electronic health record (EHR) data hold promise given the widespread availability of EHRs. We sought to externally validate the data-driven 'persistent hypoxemia, encephalopathy, and shock' (PHES) phenotype and determine its association with inflammatory and endothelial biomarkers, as well as biomarker-based pediatric risk-strata. Design: We trained and validated a random forest classifier using organ dysfunction subscores in the EHR dataset used to derive the PHES phenotype. We used the classifier to assign phenotype membership in a test set consisting of prospectively enrolled pediatric septic shock patients. We compared biomarker profiles of those with and without the PHES phenotype and determined the association with established biomarker-based mortality and MODS risk-strata. Setting: 25 pediatric intensive care units (PICU) across the U.S. Patients: EHR data from 15,246 critically ill patients sepsis-associated MODS and 1,270 pediatric septic shock patients in the test cohort of whom 615 had biomarker data. Interventions: None. Measurements and main results: The area under the receiver operator characteristic curve (AUROC) of the new classifier to predict PHES phenotype membership was 0.91(95%CI, 0.90-0.92) in the EHR validation set. In the test set, patients with the PHES phenotype were independently associated with both increased odds of complicated course (adjusted odds ratio [aOR] of 4.1, 95%CI: 3.2-5.4) and 28-day mortality (aOR of 4.8, 95%CI: 3.11-7.25) after controlling for age, severity of illness, and immuno-compromised status. Patients belonging to the PHES phenotype were characterized by greater degree of systemic inflammation and endothelial activation, and overlapped with high risk-strata based on PERSEVERE biomarkers predictive of death and persistent MODS. Conclusions: The PHES trajectory-based phenotype is reproducible, independently associated with poor clinical outcomes, and overlap with higher risk-strata based on validated biomarker approaches.
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    Phoenix Sepsis Criteria in Critically Ill Children: Retrospective Validation Using a United States Nine-Center Dataset, 2012–2018
    (Wolters Kluwer, 2025) Sanchez-Pinto, L. Nelson; Daniels, Latasha A.; Atreya, Mihir; Faustino, E. Vincent S.; Farris, Reid W. D.; Geva, Alon; Khemani, Robinder G.; Rogerson, Colin; Shah, Sareen S.; Weiss, Scott L.; Bennett, Tellen D.; Pediatrics, School of Medicine
    Objectives: To perform: 1) external validation of the Phoenix Sepsis Score and Phoenix sepsis criteria in a multicenter cohort of critically ill children with infection and a comparison with the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) criteria; 2) a study of Phoenix sepsis criteria performance in patient subgroups based on age and comorbidities; 3) an assessment of microbiological profile of children with Phoenix sepsis; and 4) a study of the performance of the Phoenix-8 score. Design: Secondary, retrospective analysis of a multicenter cohort study from 2012 to 2018. Setting: Nine PICUs in the United States. Patients: PICU admissions with suspected infection. Interventions: None. Measurements and main results: Among 25,680 encounters of children with suspected or confirmed infection on PICU admission (4.6% in-hospital mortality), 11,168 (43%) met Phoenix criteria for sepsis or septic shock (9% in-hospital mortality). The Phoenix criteria generally outperformed the IPSCC criteria at discriminating mortality in all critically ill children with infections and across all subgroup analyses, including age group, malignancy, or technology dependence. Of 11,168 patients who met Phoenix criteria, 28% were negative for IPSCC criteria for sepsis and these had higher in-hospital mortality than those who met IPSCC sepsis criteria but not Phoenix criteria (4.7% vs.1.7%; p < 0.001), which was similar to the mortality of patients without sepsis (1.3%). Sepsis was associated with respiratory or bloodstream infection, most commonly Pseudomonas aeruginosa or Staphylococcus aureus. The Phoenix-8 score had good discrimination of mortality in children with infections, comparable to or better than validated and widely used severity of illness and organ dysfunction scores. Conclusions: In 2012-2018, among U.S. patients with suspected or confirmed infection admitted to nine PICUs, those with the highest risk of mortality can be identified using the Phoenix sepsis criteria, including in children of different age groups and those with major comorbidities.