Browsing by Author "Wong, Hector R."

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    Cerebrospinal fluid levels of extracellular heat shock protein 72: A potential biomarker for bacterial meningitis in children
    (Thieme, 2014-03) Standage, Stephen W.; Lahni, Patrick M.; Ma, William; Kernie, Steven G.; Wong, Hector R.; Wheeler, Derek S.; Pediatrics, School of Medicine
    Extracellular heat shock protein 72 (Hsp72) is an endogenous danger signal and potential biomarker for critical illness in children. We hypothesized that elevated levels of extracellular Hsp72 in the cerebrospinal fluid (CSF) of children with suspected meningitis could predict bacterial meningitis. We measured extracellular Hsp72 levels in the CSF of 31 critically ill children with suspected meningitis via a commercially available enzyme-linked immunosorbent assay. Fourteen had bacterial meningitis based on CSF pleocytosis and bacterial growth in either blood or CSF culture. Seventeen children with negative cultures comprised the control group. CSF Hsp72 was significantly elevated in children with bacterial meningitis compared to controls. Importantly, CSF Hsp72 levels did not correlate with the CSF white blood cell count. On receiver operator characteristic analysis, using a cut-off of 8.1 ng/mL, CSF Hsp72 has a sensitivity of 79% and a specificity of 94% for predicting bacterial meningitis. We therefore conclude that CSF extracellular Hsp72 levels are elevated in critically ill children with bacterial meningitis versus controls. Hsp72 potentially offers clinicians improved diagnostic information in distinguishing bacterial meningitis from other processes.
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    Electrolyte derangements in critically ill children receiving balanced versus unbalanced crystalloid fluid resuscitation
    (Springer Nature, 2022-12-06) Stanski, Natalja L.; Gist, Katja M.; Pickett, Kaci; Brinton, John T.; Sadlowski, Jennifer; Wong, Hector R.; Mourani, Peter; Soranno, Danielle E.; Kendrick, Jessica; Stenson, Erin K.; Pediatrics, School of Medicine
    Background: Adult studies have demonstrated potential harm from resuscitation with 0.9% sodium chloride (0.9%NaCl), resulting in increased utilization of balanced crystalloids like lactated ringers (LR). The sodium and potassium content of LR has resulted in theoretical safety concerns, although limited data exists in pediatrics. We hypothesized that use of LR for resuscitation would not be associated with increased electrolyte derangements compared to 0.9%NaCl. Methods: A prospective, observational cohort study of critically ill children who received ≥ 20 ml/kg of fluid resuscitation and were admitted to two pediatric intensive care units from November 2017 to February 2020. Fluid groups included patients who received > 75% of fluids from 0.9%NaCl, > 75% of fluids from LR, and a mixed group. The primary outcome was incidence of electrolyte derangements (sodium, chloride, potassium) and acidosis. Results: Among 559 patients, 297 (53%) received predominantly 0.9%NaCl, 74 (13%) received predominantly LR, and 188 (34%) received a mixture. Extreme hyperkalemia (potassium ≥ 6 mmol/L) was more common in 0.9%NaCl group (5.8%) compared to LR group (0%), p 0.05. Extreme acidosis (pH > 7.1) was more common in 0.9%NaCl group (11%) compared to LR group (1.6%), p 0.016. Conclusions: LR is associated with fewer electrolyte derangements compared to 0.9%NaCl. Prospective interventional trials are needed to validate these findings.
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    Integrated PERSEVERE and endothelial biomarker risk model predicts death and persistent MODS in pediatric septic shock: a secondary analysis of a prospective observational study
    (BMC, 2022-07-11) 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; Allen, Geoffrey L.; Thomas, Neal J.; Grunwell, Jocelyn R.; Baines, Torrey; Quasney, Michael; Haileselassie, Bereketeab; Lindsell, Christopher J.; Alder, Matthew N.; Wong, Hector R.; Pediatrics, School of Medicine
    Background: Multiple organ dysfunction syndrome (MODS) is a critical driver of sepsis morbidity and mortality in children. Early identification of those at risk of death and persistent organ dysfunctions is necessary to enrich patients for future trials of sepsis therapeutics. Here, we sought to integrate endothelial and PERSEVERE biomarkers to estimate the composite risk of death or organ dysfunctions on day 7 of septic shock. Methods: We measured endothelial dysfunction markers from day 1 serum among those with existing PERSEVERE data. TreeNet® classification model was derived incorporating 22 clinical and biological variables to estimate risk. Based on relative variable importance, a simplified 6-biomarker model was developed thereafter. Results: Among 502 patients, 49 patients died before day 7 and 124 patients had persistence of MODS on day 7 of septic shock. Area under the receiver operator characteristic curve (AUROC) for the newly derived PERSEVEREnce model to predict death or day 7 MODS was 0.93 (0.91-0.95) with a summary AUROC of 0.80 (0.76-0.84) upon tenfold cross-validation. The simplified model, based on IL-8, HSP70, ICAM-1, Angpt2/Tie2, Angpt2/Angpt1, and Thrombomodulin, performed similarly. Interaction between variables-ICAM-1 with IL-8 and Thrombomodulin with Angpt2/Angpt1-contributed to the models' predictive capabilities. Model performance varied when estimating risk of individual organ dysfunctions with AUROCS ranging from 0.91 to 0.97 and 0.68 to 0.89 in training and test sets, respectively. Conclusions: The newly derived PERSEVEREnce biomarker model reliably estimates risk of death or persistent organ dysfunctions on day 7 of septic shock. If validated, this tool can be used for prognostic enrichment in future pediatric trials of sepsis therapeutics.
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    Prospective clinical testing and experimental validation of the Pediatric Sepsis Biomarker Risk Model
    (American Association for the Advancement of Science, 2019-11-13) Wong, Hector R.; Caldwell, J. Timothy; Cvijanovich, Natalie Z.; Weiss, Scott L.; Fitzgerald, Julie C.; Bigham, Michael T.; Jain, Parag N.; Schwarz, Adam; Lutfi, Riad; Nowak, Jeffrey; Allen, Geoffrey L.; Thomas, Neal J.; Grunwell, Jocelyn R.; Baines, Torrey; Quasney, Michael; Haileselassie, Bereketeab; Lindsell, Christopher J.; Pediatrics, School of Medicine
    Sepsis remains a major public health problem with no major therapeutic advances over the last several decades. The clinical and biological heterogeneity of sepsis have limited success of potential new therapies. Accordingly, there is considerable interest in developing a precision medicine approach to inform more rational development, testing, and targeting of new therapies. We previously developed the Pediatric Sepsis Biomarker Risk Model (PERSEVERE) to estimate mortality risk and proposed its use as a prognostic enrichment tool in sepsis clinical trials; prognostic enrichment selects patients based on mortality risk independent of treatment. Here, we show that PERSEVERE has excellent performance in a diverse cohort of children with septic shock with potential for use as a predictive enrichment strategy; predictive enrichment selects patients based on likely response to treatment. We demonstrate that the PERSEVERE biomarkers are reliably associated with mortality in mice challenged with experimental sepsis, thus providing an opportunity to test precision medicine strategies in the preclinical setting. Using this model, we tested two clinically feasible therapeutic strategies, guided by the PERSEVERE-based enrichment, and found that mice identified as high risk for mortality had a greater bacterial burden and could be rescued by higher doses of antibiotics. The association between higher pathogen burden and higher mortality risk was corroborated among critically ill children with septic shock. This bedside to bench to bedside approach provides proof of principle for PERSEVERE-guided application of precision medicine in sepsis.