Browsing by Author "Faustino, E. Vincent S."

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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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    Pediatric Organ Dysfunction Information Update Mandate (PODIUM) Contemporary Organ Dysfunction Criteria: Executive Summary
    (American Academy of Pediatrics, 2022) Bembea, Melania M.; Agus, Michael; Akcan-Arikan, Ayse; Alexander, Peta; Basu, Rajit; Bennett, Tellen D.; Bohn, Desmond; Brandão, Leonardo R.; Brown, Ann-Marie; Carcillo, Joseph A.; Checchia, Paul; Cholette, Jill; Cheifetz, Ira M.; Cornell, Timothy; Doctor, Allan; Eckerle, Michelle; Erickson, Simon; Farris, Reid W.D.; Faustino, E. Vincent S.; Fitzgerald, Julie C.; Fuhrman, Dana Y.; Giuliano, John S.; Guilliams, Kristin; Gaies, Michael; Gorga, Stephen M.; Hall, Mark; Hanson, Sheila J.; Hartman, Mary; Hassinger, Amanda B.; Irving, Sharon Y.; Jeffries, Howard; Jouvet, Philippe; Kannan, Sujatha; Karam, Oliver; Khemani, Robinder G.; Kissoon, Niranjan; Lacroix, Jacques; Laussen, Peter; Leclerc, Francis; Lee, Jan Hau; Leteurtre, Stephane; Lobner, Katie; McKiernan, Patrick J.; Menon, Kusum; Monagle, Paul; Muszynski, Jennifer A.; Odetola, Folafoluwa; Parker, Robert; Pathan, Nazima; Pierce, Richard W.; Pineda, Jose; Prince, Jose M.; Robinson, Karen A.; Rowan, Courtney M.; Ryerson, Lindsay M.; Sanchez-Pinto, L. Nelson; Schlapbach, Luregn J.; Selewski, David T.; Shekerdemian, Lara S.; Simon, Dennis; Smith, Lincoln S.; Squires, James E.; Squires, Robert H.; Sutherland, Scott M.; Ouellette, Yves; Spaeder, Michael C.; Srinivasan, Vijay; Steiner, Marie E.; Tasker, Robert C.; Thiagarajan, Ravi; Thomas, Neal; Tissieres, Pierre; Traube, Chani; Tucci, Marisa; Typpo, Katri V.; Wainwright, Mark S.; Ward, Shan L.; Watson, R. Scott; Weiss, Scott; Whitney, Jane; Willson, Doug; Wynn, James L.; Yehya, Nadir; Zimmerman, Jerry J.; Pediatrics, School of Medicine
    Prior criteria for organ dysfunction in critically ill children were based mainly on expert opinion. We convened the Pediatric Organ Dysfunction Information Update Mandate (PODIUM) expert panel to summarize data characterizing single and multiple organ dysfunction and to derive contemporary criteria for pediatric organ dysfunction. The panel was composed of 88 members representing 47 institutions and 7 countries. We conducted systematic reviews of the literature to derive evidence-based criteria for single organ dysfunction for neurologic, cardiovascular, respiratory, gastrointestinal, acute liver, renal, hematologic, coagulation, endocrine, endothelial, and immune system dysfunction. We searched PubMed and Embase from January 1992 to January 2020. Study identification was accomplished using a combination of medical subject headings terms and keywords related to concepts of pediatric organ dysfunction. Electronic searches were performed by medical librarians. Studies were eligible for inclusion if the authors reported original data collected in critically ill children; evaluated performance characteristics of scoring tools or clinical assessments for organ dysfunction; and assessed a patient-centered, clinically meaningful outcome. Data were abstracted from each included study into an electronic data extraction form. Risk of bias was assessed using the Quality in Prognosis Studies tool. Consensus was achieved for a final set of 43 criteria for pediatric organ dysfunction through iterative voting and discussion. Although the PODIUM criteria for organ dysfunction were limited by available evidence and will require validation, they provide a contemporary foundation for researchers to identify and study single and multiple organ dysfunction in critically ill children.
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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.
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    Researching COVID to enhance recovery (RECOVER) pediatric study protocol: Rationale, objectives and design
    (Public Library of Science, 2023-06-23) Gross, Rachel; Thaweethai, Tanayott; Rosenzweig, Erika B.; Chan, James; Chibnik, Lori B.; Cicek, Mine S.; Elliott, Amy J.; Flaherman, Valerie J.; Foulkes, Andrea S.; Witvliet, Margot Gage; Gallagher, Richard; Gennaro, Maria Laura; Jernigan, Terry L.; Karlson, Elizabeth W.; Katz, Stuart D.; Kinser, Patricia A.; Kleinman, Lawrence C.; Lamendola-Essel, Michelle F.; Milner, Joshua D.; Mohandas, Sindhu; Mudumbi, Praveen C.; Newburger, Jane W.; Rhee, Kyung E.; Salisbury, Amy L.; Snowden, Jessica N.; Stein, Cheryl R.; Stockwell, Melissa S.; Tantisira, Kelan G.; Thomason, Moriah E.; Truong, Dongngan T.; Warburton, David; Wood, John C.; Ahmed, Shifa; Akerlundh, Almary; Alshawabkeh, Akram N.; Anderson, Brett R.; Aschner, Judy L.; Atz, Andrew M.; Aupperle, Robin L.; Baker, Fiona C.; Balaraman, Venkataraman; Banerjee, Dithi; Barch, Deanna M.; Baskin-Sommers, Arielle; Bhuiyan, Sultana; Bind, Marie-Abele C.; Bogie, Amanda L.; Buchbinder, Natalie C.; Bueler, Elliott; Bükülmez, Hülya; Casey, B. J.; Chang, Linda; Clark, Duncan B.; Clifton, Rebecca G.; Clouser, Katharine N.; Cottrell, Lesley; Cowan, Kelly; D'Sa, Viren; Dapretto, Mirella; Dasgupta, Soham; Dehority, Walter; Dummer, Kirsten B.; Elias, Matthew D.; Esquenazi-Karonika, Shari; Evans, Danielle N.; Faustino, E. Vincent S.; Fiks, Alexander G.; Forsha, Daniel; Foxe, John J.; Friedman, Naomi P.; Fry, Greta; Gaur, Sunanda; Gee, Dylan G.; Gray, Kevin M.; Harahsheh, Ashraf S.; Heath, Andrew C.; Heitzeg, Mary M.; Hester, Christina M.; Hill, Sophia; Hobart-Porter, Laura; Hong, Travis K. F.; Horowitz, Carol R.; Hsia, Daniel S.; Huentelman, Matthew; Hummel, Kathy D.; Iacono, William G.; Irby, Katherine; Jacobus, Joanna; Jacoby, Vanessa L.; Jone, Pei-Ni; Kaelber, David C.; Kasmarcak, Tyler J.; Kluko, Matthew J.; Kosut, Jessica S.; Laird, Angela R.; Landeo-Gutierrez, Jeremy; Lang, Sean M.; Larson, Christine L.; Lim, Peter Paul C.; Lisdahl, Krista M.; McCrindle, Brian W.; McCulloh, Russell J.; Mendelsohn, Alan L.; Metz, Torri D.; Morgan, Lerraughn M.; Müller-Oehring, Eva M.; Nahin, Erica R.; Neale, Michael C.; Ness-Cochinwala, Manette; Nolan, Sheila M.; Oliveira, Carlos R.; Oster, Matthew E.; Payne, R. Mark; Raissy, Hengameh; Randall, Isabelle G.; Rao, Suchitra; Reeder, Harrison T.; Rosas, Johana M.; Russell, Mark W.; Sabati, Arash A.; Sanil, Yamuna; Sato, Alice I.; Schechter, Michael S.; Selvarangan, Rangaraj; Shakti, Divya; Sharma, Kavita; Squeglia, Lindsay M.; Stevenson, Michelle D.; Szmuszkovicz, Jacqueline; Talavera-Barber, Maria M.; Teufel, Ronald J., II; Thacker, Deepika; Udosen, Mmekom M.; Warner, Megan R.; Watson, Sara E.; Werzberger, Alan; Weyer, Jordan C.; Wood, Marion J.; Yin, H. Shonna; Zempsky, William T.; Zimmerman, Emily; Dreyer, Benard P.; Pediatrics, School of Medicine
    Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. Methods: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms. Discussion: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.