Publications by authors named "Natalie Z Cvijanovich"

37 Publications

Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome.

JAMA Neurol 2021 Mar 5. Epub 2021 Mar 5.

Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama at Birmingham.

Importance: Coronavirus disease 2019 (COVID-19) affects the nervous system in adult patients. The spectrum of neurologic involvement in children and adolescents is unclear.

Objective: To understand the range and severity of neurologic involvement among children and adolescents associated with COVID-19.

Setting, Design, And Participants: Case series of patients (age <21 years) hospitalized between March 15, 2020, and December 15, 2020, with positive severe acute respiratory syndrome coronavirus 2 test result (reverse transcriptase-polymerase chain reaction and/or antibody) at 61 US hospitals in the Overcoming COVID-19 public health registry, including 616 (36%) meeting criteria for multisystem inflammatory syndrome in children. Patients with neurologic involvement had acute neurologic signs, symptoms, or diseases on presentation or during hospitalization. Life-threatening involvement was adjudicated by experts based on clinical and/or neuroradiologic features.

Exposures: Severe acute respiratory syndrome coronavirus 2.

Main Outcomes And Measures: Type and severity of neurologic involvement, laboratory and imaging data, and outcomes (death or survival with new neurologic deficits) at hospital discharge.

Results: Of 1695 patients (909 [54%] male; median [interquartile range] age, 9.1 [2.4-15.3] years), 365 (22%) from 52 sites had documented neurologic involvement. Patients with neurologic involvement were more likely to have underlying neurologic disorders (81 of 365 [22%]) compared with those without (113 of 1330 [8%]), but a similar number were previously healthy (195 [53%] vs 723 [54%]) and met criteria for multisystem inflammatory syndrome in children (126 [35%] vs 490 [37%]). Among those with neurologic involvement, 322 (88%) had transient symptoms and survived, and 43 (12%) developed life-threatening conditions clinically adjudicated to be associated with COVID-19, including severe encephalopathy (n = 15; 5 with splenial lesions), stroke (n = 12), central nervous system infection/demyelination (n = 8), Guillain-Barré syndrome/variants (n = 4), and acute fulminant cerebral edema (n = 4). Compared with those without life-threatening conditions (n = 322), those with life-threatening neurologic conditions had higher neutrophil-to-lymphocyte ratios (median, 12.2 vs 4.4) and higher reported frequency of D-dimer greater than 3 μg/mL fibrinogen equivalent units (21 [49%] vs 72 [22%]). Of 43 patients who developed COVID-19-related life-threatening neurologic involvement, 17 survivors (40%) had new neurologic deficits at hospital discharge, and 11 patients (26%) died.

Conclusions And Relevance: In this study, many children and adolescents hospitalized for COVID-19 or multisystem inflammatory syndrome in children had neurologic involvement, mostly transient symptoms. A range of life-threatening and fatal neurologic conditions associated with COVID-19 infrequently occurred. Effects on long-term neurodevelopmental outcomes are unknown.
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http://dx.doi.org/10.1001/jamaneurol.2021.0504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936352PMC
March 2021

Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19.

JAMA 2021 03;325(11):1074-1087

Division of Hospital Medicine, Department of Pediatrics, Hackensack University Medical Center, Hackensack, New Jersey.

Importance: Refinement of criteria for multisystem inflammatory syndrome in children (MIS-C) may inform efforts to improve health outcomes.

Objective: To compare clinical characteristics and outcomes of children and adolescents with MIS-C vs those with severe coronavirus disease 2019 (COVID-19).

Setting, Design, And Participants: Case series of 1116 patients aged younger than 21 years hospitalized between March 15 and October 31, 2020, at 66 US hospitals in 31 states. Final date of follow-up was January 5, 2021. Patients with MIS-C had fever, inflammation, multisystem involvement, and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase-polymerase chain reaction (RT-PCR) or antibody test results or recent exposure with no alternate diagnosis. Patients with COVID-19 had positive RT-PCR test results and severe organ system involvement.

Exposure: SARS-CoV-2.

Main Outcomes And Measures: Presenting symptoms, organ system complications, laboratory biomarkers, interventions, and clinical outcomes. Multivariable regression was used to compute adjusted risk ratios (aRRs) of factors associated with MIS-C vs COVID-19.

Results: Of 1116 patients (median age, 9.7 years; 45% female), 539 (48%) were diagnosed with MIS-C and 577 (52%) with COVID-19. Compared with patients with COVID-19, patients with MIS-C were more likely to be 6 to 12 years old (40.8% vs 19.4%; absolute risk difference [RD], 21.4% [95% CI, 16.1%-26.7%]; aRR, 1.51 [95% CI, 1.33-1.72] vs 0-5 years) and non-Hispanic Black (32.3% vs 21.5%; RD, 10.8% [95% CI, 5.6%-16.0%]; aRR, 1.43 [95% CI, 1.17-1.76] vs White). Compared with patients with COVID-19, patients with MIS-C were more likely to have cardiorespiratory involvement (56.0% vs 8.8%; RD, 47.2% [95% CI, 42.4%-52.0%]; aRR, 2.99 [95% CI, 2.55-3.50] vs respiratory involvement), cardiovascular without respiratory involvement (10.6% vs 2.9%; RD, 7.7% [95% CI, 4.7%-10.6%]; aRR, 2.49 [95% CI, 2.05-3.02] vs respiratory involvement), and mucocutaneous without cardiorespiratory involvement (7.1% vs 2.3%; RD, 4.8% [95% CI, 2.3%-7.3%]; aRR, 2.29 [95% CI, 1.84-2.85] vs respiratory involvement). Patients with MIS-C had higher neutrophil to lymphocyte ratio (median, 6.4 vs 2.7, P < .001), higher C-reactive protein level (median, 152 mg/L vs 33 mg/L; P < .001), and lower platelet count (<150 ×103 cells/μL [212/523 {41%} vs 84/486 {17%}, P < .001]). A total of 398 patients (73.8%) with MIS-C and 253 (43.8%) with COVID-19 were admitted to the intensive care unit, and 10 (1.9%) with MIS-C and 8 (1.4%) with COVID-19 died during hospitalization. Among patients with MIS-C with reduced left ventricular systolic function (172/503, 34.2%) and coronary artery aneurysm (57/424, 13.4%), an estimated 91.0% (95% CI, 86.0%-94.7%) and 79.1% (95% CI, 67.1%-89.1%), respectively, normalized within 30 days.

Conclusions And Relevance: This case series of patients with MIS-C and with COVID-19 identified patterns of clinical presentation and organ system involvement. These patterns may help differentiate between MIS-C and COVID-19.
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http://dx.doi.org/10.1001/jama.2021.2091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905703PMC
March 2021

Proprotein Convertase Subtilisin/Kexin Type 9 Loss-of-Function Is Detrimental to the Juvenile Host With Septic Shock.

Crit Care Med 2020 Oct;48(10):1513-1520

Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH.

Objectives: Proprotein convertase subtilisin/kexin type 9 is a central regulator of lipid metabolism and has been implicated in regulating the host response to sepsis. Proprotein convertase subtilisin/kexin type 9 loss-of-function is associated with improved sepsis outcomes in the adult host through increased hepatic bacterial clearance. Thus, there is interest in leveraging proprotein convertase subtilisin/kexin type 9 inhibitors as a therapeutic strategy in adults with sepsis. We sought to validate this association in children with septic shock and in a juvenile murine model of sepsis.

Design: Prospectively enrolled cohort of children with septic shock; experimental mice.

Setting: Seventeen participating institutions; research laboratory.

Patients And Subjects: Five-hundred twenty-two children with septic shock; juvenile (14 d old) and adult (10-14 wk) mice with constitutive proprotein convertase subtilisin/kexin type 9 null and wildtype control mice (C57BL/6).

Interventions: Proprotein convertase subtilisin/kexin type 9 single-nucleotide polymorphisms, serum proprotein convertase subtilisin/kexin type 9, and lipid profiles in patients. Cecal slurry murine model of sepsis; survival studies in juvenile and adult mice, assessment of lipoprotein fractions, bacterial burden, and inflammation in juvenile mice.

Measurements And Main Results: PCSK9 loss-of-function genetic variants were independently associated with increased odds of complicated course and mortality in children with septic shock. PCSK9, low-density lipoprotein, and high-density lipoprotein concentrations were lower among patients with complicated course relative to those without. PCSK9 concentrations negatively correlated with proinflammatory cytokine interleukin-8. Proprotein convertase subtilisin/kexin type 9 loss-of-function decreased survival in juvenile mice, but increased survival in adult mice with sepsis. PCSK9 loss-of-function resulted in low lipoproteins and decreased hepatic bacterial burden in juvenile mice.

Conclusions: In contrast to the adult host, proprotein convertase subtilisin/kexin type 9 loss-of-function is detrimental to the juvenile host with septic shock. PCSK9 loss-of-function, in the context of low lipoproteins, may result in reduced hepatic bacterial clearance in the juvenile host with septic shock. Our data indicate that children should be excluded in sepsis clinical trials involving proprotein convertase subtilisin/kexin type 9 inhibitors.
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http://dx.doi.org/10.1097/CCM.0000000000004487DOI Listing
October 2020

Severe acute kidney injury is independently associated with mortality in children with septic shock.

Intensive Care Med 2020 05 11;46(5):1050-1051. Epub 2020 Feb 11.

Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 2005, Cincinnati, OH, 45229, USA.

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http://dx.doi.org/10.1007/s00134-020-05940-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677896PMC
May 2020

PERSEVERE Biomarkers Predict Severe Acute Kidney Injury and Renal Recovery in Pediatric Septic Shock.

Am J Respir Crit Care Med 2020 04;201(7):848-855

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Acute kidney injury (AKI), a common complication of sepsis, is associated with substantial morbidity and mortality and lacks definitive disease-modifying therapy. Early, reliable identification of at-risk patients is important for targeted implementation of renal protective measures. The updated Pediatric Sepsis Biomarker Risk Model (PERSEVERE-II) is a validated, multibiomarker prognostic enrichment strategy to estimate baseline mortality risk in pediatric septic shock. To assess the association between PERSEVERE-II mortality probability and the development of severe, sepsis-associated AKI on Day 3 (D SA-AKI) in pediatric septic shock. We performed secondary analysis of a prospective observational study of children with septic shock in whom the PERSEVERE biomarkers were measured to assign a PERSEVERE-II baseline mortality risk. Among 379 patients, 65 (17%) developed severe D SA-AKI. The proportion of patients developing severe D SA-AKI increased directly with increasing PERSEVERE-II risk category, and increasing PERSEVERE-II mortality probability was independently associated with increased odds of severe D SA-AKI after adjustment for age and illness severity (odds ratio, 1.4; 95% confidence interval, 1.2-1.7;  < 0.001). Similar associations were found between increasing PERSEVERE-II mortality probability and the need for renal replacement therapy. Lower PERSEVERE-II mortality probability was independently associated with increased odds of renal recovery among patients with early AKI. A newly derived model incorporating the PERSEVERE biomarkers and Day 1 AKI status predicted severe D SA-AKI with an area under the received operating characteristic curve of 0.95 (95% confidence interval, 0.92-0.98). Among children with septic shock, the PERSEVERE biomarkers predict severe D SA-AKI and identify patients with early AKI who are likely to recover.
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http://dx.doi.org/10.1164/rccm.201911-2187OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7124707PMC
April 2020

Prospective clinical testing and experimental validation of the Pediatric Sepsis Biomarker Risk Model.

Sci Transl Med 2019 11;11(518)

Vanderbilt University Medical Center, Nashville, TN 37212, USA.

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.
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http://dx.doi.org/10.1126/scitranslmed.aax9000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720682PMC
November 2019

Early Enteral Nutrition Is Associated With Improved Clinical Outcomes in Critically Ill Children: A Secondary Analysis of Nutrition Support in the Heart and Lung Failure-Pediatric Insulin Titration Trial.

Pediatr Crit Care Med 2020 03;21(3):213-221

Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA.

Objectives: The impact of early enteral nutrition on clinical outcomes in critically ill children has not been adequately described. We hypothesized that early enteral nutrition is associated with improved clinical outcomes in critically ill children.

Design: Secondary analysis of the Heart and Lung Failure-Pediatric Insulin Titration randomized controlled trial.

Setting: Thirty-five PICUs.

Patients: Critically ill children with hyperglycemia requiring inotropic support and/or invasive mechanical ventilation who were enrolled for at least 48 hours with complete nutrition data.

Interventions: Subjects received nutrition via guidelines that emphasized enteral nutrition and were classified into early enteral nutrition (enteral nutrition within 48 hr of study randomization) and no early enteral nutrition (enteral nutrition after 48 hr of study randomization, or no enteral nutrition at any time).

Measurements And Main Results: Of 608 eligible subjects, 331 (54%) received early enteral nutrition. Both early enteral nutrition and no early enteral nutrition groups had similar daily caloric intake over the first 8 study days (median, 36 vs 36 kcal/kg/d; p = 0.93). After controlling for age, body mass index z scores, primary reason for ICU admission, severity of illness, and mean Vasopressor-Inotrope Score at the time of randomization, and adjusting for site, early enteral nutrition was associated with lower 90-day hospital mortality (8% vs 17%; p = 0.007), more ICU-free days (median, 20 vs 17 d; p = 0.02), more hospital-free days (median, 8 vs 0 d; p = 0.003), more ventilator-free days (median, 21 vs 19 d; p = 0.003), and less organ dysfunction (median maximum Pediatric Logistic Organ Dysfunction, 11 vs 12; p < 0.001).

Conclusions: In critically ill children with hyperglycemia requiring inotropic support and/or mechanical ventilation, early enteral nutrition was independently associated with better clinical outcomes.
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http://dx.doi.org/10.1097/PCC.0000000000002135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060827PMC
March 2020

Hyperchloremia Is Associated With Complicated Course and Mortality in Pediatric Patients With Septic Shock.

Pediatr Crit Care Med 2018 02;19(2):155-160

Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH.

Objective: Hyperchloremia is associated with poor outcome among critically ill adults, but it is unknown if a similar association exists among critically ill children. We determined if hyperchloremia is associated with poor outcomes in children with septic shock.

Design: Retrospective analysis of a pediatric septic shock database.

Setting: Twenty-nine PICUs in the United States.

Patients: Eight hundred ninety children 10 years and younger with septic shock.

Interventions: None.

Measurements And Main Results: We considered the minimum, maximum, and mean chloride values during the initial 7 days of septic shock for each study subject as separate hyperchloremia variables. Within each category, we considered hyperchloremia as a dichotomous variable defined as a serum concentration greater than or equal to 110 mmol/L. We used multivariable logistic regression to determine the association between the hyperchloremia variables and outcome, adjusted for illness severity. We considered all cause 28-day mortality and complicated course as the primary outcome variables. Complicated course was defined as mortality by 28 days or persistence of greater than or equal to two organ failures at day 7 of septic shock. Secondarily, we conducted a stratified analysis using a biomarker-based mortality risk stratification tool. There were 226 patients (25%) with a complicated course and 93 mortalities (10%). Seventy patients had a minimum chloride greater than or equal to 110 mmol/L, 179 had a mean chloride greater than or equal to 110 mmol/L, and 514 had a maximum chloride greater than or equal to 110 mmol/L. A minimum chloride greater than or equal to 110 mmol/L was associated with increased odds of complicated course (odds ratio, 1.9; 95% CI, 1.1-3.2; p = 0.023) and mortality (odds ratio, 3.7; 95% CI, 2.0-6.8; p < 0.001). A mean chloride greater than or equal to 110 mmol/L was also associated with increased odds of mortality (odds ratio, 2.1; 95% CI, 1.3-3.5; p = 0.002). The secondary analysis yielded similar results.

Conclusion: Hyperchloremia is independently associated with poor outcomes among children with septic shock.
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http://dx.doi.org/10.1097/PCC.0000000000001401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798001PMC
February 2018

Endotype Transitions During the Acute Phase of Pediatric Septic Shock Reflect Changing Risk and Treatment Response.

Crit Care Med 2018 03;46(3):e242-e249

Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.

Objective: We previously identified septic shock endotypes A and B based on 100 genes reflecting adaptive immunity and glucocorticoid receptor signaling. The endotypes differ with respect to outcome and corticosteroid responsiveness. We determined whether endotypes change during the initial 3 days of illness, and whether changes are associated with outcomes.

Design: Observational cohort study including existing and newly enrolled participants.

Setting: Multiple PICUs.

Patients: Children with septic shock.

Interventions: None.

Measurements And Main Results: We measured the 100 endotyping genes at day 1 and day 3 of illness in 375 patients. We determined if endotype assignment changes over time, and whether changing endotype is associated with corticosteroid response and outcomes. We used multivariable logistic regression to adjust for illness severity, age, and comorbidity burden. Among the 132 subjects assigned to endotype A on day 1, 56 (42%) transitioned to endotype B by day 3. Among 243 subjects assigned to endotype B on day 1, 77 (32%) transitioned to endotype A by day 3. Assignment to endotype A on day 1 was associated with increased odds of mortality. This risk was modified by the subsequent day 3 endotype assignment. Corticosteroids were associated with increased risk of mortality among subjects who persisted as endotype A.

Conclusions: A substantial proportion of children with septic shock transition endotypes during the acute phase of illness. The risk of poor outcome and the response to corticosteroids change with changes in endotype assignment. Patients persisting as endotype A are at highest risk of poor outcomes.
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http://dx.doi.org/10.1097/CCM.0000000000002932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5825261PMC
March 2018

Evaluation of IFITM3 rs12252 Association With Severe Pediatric Influenza Infection.

J Infect Dis 2017 07;216(1):14-21

Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee.

Background: Interferon-induced transmembrane protein 3 (IFITM3) restricts endocytic fusion of influenza virus. IFITM3 rs12252_C, a putative alternate splice site, has been associated with influenza severity in adults. IFITM3 has not been evaluated in pediatric influenza.

Methods: The Pediatric Influenza (PICFLU) study enrolled children with suspected influenza infection across 38 pediatric intensive care units during November 2008 to April 2016. IFITM3 was sequenced in patients and parents were genotyped for specific variants for family-based association testing. rs12252 was genotyped in 54 African-American pediatric outpatients with influenza (FLU09), included in the population-based comparisons with 1000 genomes. Splice site analysis of rs12252_C was performed using PICFLU and FLU09 patient RNA.

Results: In PICFLU, 358 children had influenza infection. We identified 22 rs12252_C homozygotes in 185 white non-Hispanic children. rs12252_C was not associated with influenza infection in population or family-based analyses. We did not identify the Δ21 IFITM3 isoform in RNAseq data. The rs12252 genotype was not associated with IFITM3 expression levels, nor with critical illness severity. No novel rare IFITM3 functional variants were identified.

Conclusions: rs12252 was not associated with susceptibility to influenza-related critical illness in children or with critical illness severity. Our data also do not support it being a splice site.
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http://dx.doi.org/10.1093/infdis/jix242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853450PMC
July 2017

Improved Risk Stratification in Pediatric Septic Shock Using Both Protein and mRNA Biomarkers. PERSEVERE-XP.

Am J Respir Crit Care Med 2017 08;196(4):494-501

19 Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Rationale: We previously derived and validated the Pediatric Sepsis Biomarker Risk Model (PERSEVERE) to estimate baseline mortality risk in children with septic shock. The PERSEVERE biomarkers are serum proteins selected from among the proteins directly related to 80 mortality risk assessment genes. The initial approach to selecting the PERSEVERE biomarkers left 68 genes unconsidered.

Objectives: To determine if the 68 previously unconsidered genes can improve upon the performance of PERSEVERE and to provide biological information regarding the pathophysiology of septic shock.

Methods: We reduced the number of variables by determining the biological linkage of the 68 previously unconsidered genes. The genes identified through variable reduction were combined with the PERSEVERE-based mortality probability to derive a risk stratification model for 28-day mortality using classification and regression tree methodology (n = 307). The derived tree, PERSEVERE-XP, was then tested in a separate cohort (n = 77).

Measurements And Main Results: Variable reduction revealed a network consisting of 18 mortality risk assessment genes related to tumor protein 53 (TP53). In the derivation cohort, PERSEVERE-XP had an area under the receiver operating characteristic curve (AUC) of 0.90 (95% confidence interval, 0.85-0.95) for differentiating between survivors and nonsurvivors. In the test cohort, the AUC was 0.96 (95% confidence interval, 0.91-1.0). The AUC of PERSEVERE-XP was superior to that of PERSEVERE.

Conclusions: PERSEVERE-XP combines protein and mRNA biomarkers to provide mortality risk stratification with possible clinical utility. PERSEVERE-XP significantly improves on PERSEVERE and suggests a role for TP53-related cellular division, repair, and metabolism in the pathophysiology of septic shock.
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http://dx.doi.org/10.1164/rccm.201701-0066OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564676PMC
August 2017

Glucocorticoid Receptor Polymorphisms and Outcomes in Pediatric Septic Shock.

Pediatr Crit Care Med 2017 Apr;18(4):299-303

1Department of Pediatrics, UCSF Benioff Children's Hospital Oakland, Oakland, CA. 2Department of Pediatrics, Children's Hospital of Orange County, Orange, CA. 3Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO. 4Department of Pediatrics, Penn State Hershey Children's Hospital, Hershey, PA. 5Department of Pediatrics, Akron Children's Hospital, Akron, OH. 6Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA. 7Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX. 8Department of Pediatrics, Miami Children's Hospital, Miami, FL. 9Department of Pediatrics, C.S. Mott Children's Hospital at the University of Michigan, Ann Arbor, MI. 10Department of Pediatrics, Children's Hospital of Wisconsin, Milwaukee, WI. 11Department of Pediatrics, Children's National Health System, Washington, DC. 12Department of Pediatrics, Children's Hospital and Clinics of Minnesota, Minneapolis, MN. 13Department of Pediatrics, Riley Hospital for Children, Indianapolis, IN. 14Department of Pediatrics, Hackensack University Medical Center, Joseph M. Sanzari Children's Hospital, Hackensack, NJ. 15Department of Pediatrics, Children's Healthcare of Atlanta at Egleston, Atlanta, GA. 16Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH. 17Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.

Objective: Polymorphisms of the glucocorticoid receptor gene are associated with outcome and corticosteroid responsiveness among patients with inflammatory disorders. We conducted a candidate gene association study to test the hypothesis that these polymorphisms are associated with outcome and corticosteroid responsiveness among children with septic shock.

Design: We genotyped 482 children with septic shock for the presence of two glucocorticoid receptor polymorphisms (rs56149945 and rs41423247) associated with increased sensitivity and one glucocorticoid receptor polymorphism (rs6198) associated with decreased sensitivity to corticosteroids. The primary outcome variable was complicated course, defined as 28-day mortality or the persistence of two or more organ failures 7 days after a septic shock diagnosis. We used logistic regression to test for an association between corticosteroid exposure and outcome, within genotype group, and adjusted for illness severity.

Setting: Multiple PICUs in the United States.

Interventions: Standard care.

Measurements And Main Results: There were no differences in outcome when comparing the various genotype groups. Among patients homozygous for the wild-type glucocorticoid receptor allele, corticosteroids were independently associated with increased odds of complicated course (odds ratio, 2.30; 95% CI, 1.01-5.21; p = 0.047).

Conclusions: Based on these glucocorticoid receptor polymorphisms, we could not detect a beneficial effect of corticosteroids among any genotype group. Among children homozygous for the wild-type allele, corticosteroids were independently associated with increased odds of poor outcome.
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http://dx.doi.org/10.1097/PCC.0000000000001058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380529PMC
April 2017

Pediatric Sepsis Biomarker Risk Model-II: Redefining the Pediatric Sepsis Biomarker Risk Model With Septic Shock Phenotype.

Crit Care Med 2016 Nov;44(11):2010-2017

1Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH. 2Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH. 3UCSF Benioff Children's Hospital Oakland, Oakland, CA. 4Children's Hospital of Orange County, Orange, CA. 5Children's Mercy Hospital, Kansas City, MO. 6Penn State Hershey Children's Hospital, Hershey, PA. 7Akron Children's Hospital, Akron, OH. 8The Children's Hospital of Philadelphia, Philadelphia, PA. 9Texas Children's Hospital and Baylor College of Medicine, Houston, TX. 10Miami Children's Hospital, Miami, FL. 11CS Mott Children's Hospital at the University of Michigan, Ann Arbor, MI. 12Nationwide Children's Hospital, Columbus, OH. 13Children's Hospital of Wisconsin, Milwaukee, WI. 14Children's National Medical Center, Washington, DC. 15Children's Hospital and Clinics of Minnesota, Minneapolis, MN. 16Riley Hospital for Children, Indianapolis, IN. 17Hackensack University Medical Center, Joseph M. Sanzari Children's Hospital, Hackensack, NJ. 18Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.

Objective: The Pediatric Sepsis Biomarker Risk Model (PERSEVERE), a pediatric sepsis risk model, uses biomarkers to estimate baseline mortality risk for pediatric septic shock. It is unknown how PERSEVERE performs within distinct septic shock phenotypes. We tested PERSEVERE in children with septic shock and thrombocytopenia-associated multiple organ failure (TAMOF), and in those without new onset thrombocytopenia but with multiple organ failure (MOF).

Design: PERSEVERE-based mortality risk was generated for each study subject (n = 660). A priori, we determined that if PERSEVERE did not perform well in both the TAMOF and the MOF cohorts, we would revise PERSEVERE to incorporate admission platelet counts.

Setting: Multiple PICUs in the United States.

Interventions: Standard care.

Measurements And Main Results: PERSEVERE performed well in the TAMOF cohort (areas under the receiver operating characteristic curves [AUC], 0.84 [95% CI, 0.77-0.90]), but less well in the MOF cohort (AUC, 0.71 [0.61-0.80]). PERSEVERE was revised using 424 subjects previously reported in the derivation phase. PERSEVERE-II had an AUC of 0.89 (0.85-0.93) and performed equally well across TAMOF and MOF cohorts. PERSEVERE-II performed well when tested in 236 newly enrolled subjects. Sample size calculations for a clinical trial testing the efficacy of plasma exchange for children with septic shock and TAMOF indicated PERSEVERE-II-based stratification could substantially reduce the number of patients necessary, when compared with no stratification.

Conclusions: Testing PERSEVERE in the context of septic shock phenotypes prompted a revision incorporating platelet count. PERSEVERE-II performs well upon testing, independent of TAMOF or MOF status. PERSEVERE-II could potentially serve as a prognostic enrichment tool.
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http://dx.doi.org/10.1097/CCM.0000000000001852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5201138PMC
November 2016

Combining Prognostic and Predictive Enrichment Strategies to Identify Children With Septic Shock Responsive to Corticosteroids.

Crit Care Med 2016 10;44(10):e1000-3

1Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH.2Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.3Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH.4UCSF Benioff Children's Hospital Oakland, Oakland, CA.5Children's Hospital of Orange County, Orange, CA.6Children's Mercy Hospital, Kansas City, MO.7Penn State Hershey Children's Hospital, Hershey, PA.8Akron Children's Hospital, Akron, OH.9The Children's Hospital of Philadelphia, Philadelphia, PA.10Texas Children's Hospital and Baylor College of Medicine, Houston, TX.11Miami Children's Hospital, Miami, FL.12CS Mott Children's Hospital at the University of Michigan, Ann Arbor, MI.13Nationwide Children's Hospital, Columbus, OH.14Children's Hospital of Wisconsin, Milwaukee, WI.15Children's National Medical Center, Washington, DC.16Children's Hospital and Clinics of Minnesota, Minneapolis, MN.17Riley Hospital for Children, Indianapolis, IN.18Hackensack University Medical Center, Joseph M. Sanzari Children's Hospital, Hackensack, NJ.19Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.

Objectives: Prognostic and predictive enrichment strategies are fundamental tools of precision medicine. Identifying children with septic shock who may benefit from corticosteroids remains a challenge. We combined prognostic and predictive strategies to identify a pediatric septic shock subgroup responsive to corticosteroids.

Design: We conducted a secondary analysis of 288 previously published pediatric subjects with septic shock. For prognostic enrichment, each study subject was assigned a baseline mortality probability using the pediatric sepsis biomarker risk model. For predictive enrichment, each study subject was allocated to one of two septic shock endotypes, based on a 100-gene signature reflecting adaptive immunity and glucocorticoid receptor signaling. The primary study endpoint was complicated course, defined as the persistence of two or more organ failures at day 7 of septic shock or 28-day mortality. We used logistic regression to test for an association between corticosteroids and complicated course within endotype.

Measurements And Main Results: Among endotype B subjects at intermediate to high pediatric sepsis biomarker risk model-based risk of mortality, corticosteroids were independently associated with more than a 10-fold reduction in the risk of a complicated course (relative risk, 0.09; 95% CI, 0.01-0.54; p = 0.007).

Conclusions: A combination of prognostic and predictive strategies based on serum protein and messenger RNA biomarkers can identify a subgroup of children with septic shock who may be more likely to benefit from corticosteroids. Prospective validation of these strategies and the existence of this subgroup are warranted.
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http://dx.doi.org/10.1097/CCM.0000000000001833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026540PMC
October 2016

Changes in Pediatric-Sized Endotracheal Tube Cuff Pressure With Elevation Gain: Observations in Ex Vivo Simulations and In Vivo Air Medical Transport.

Pediatr Emerg Care 2018 Aug;34(8):570-573

C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, MI.

Objectives: Prolonged excessive endotracheal cuff pressure greater than 30 cmH2O is thought to cause ischemic airway injury. Excessive cuff pressure with altitude gain during air medical transport has been previously described in adult patients. It is poorly understood how pediatric-sized endotracheal tube (ETT) cuffs behave with atmospheric pressure change during flight.

Methods: In ex vivo models 4.0, 6.0, and 8.0, ETTs restricted within scaled syringe tubing were inflated to 20 cmH2O. Pressure was measured against 1500 ft elevation gain in ground and flight models. In an in vivo observation of pediatric patient transport, change in cuff pressure was measured between takeoff and helicopter peak flight altitudes.

Results: In the ex vivo ground model, endotracheal cuff pressure increased linearly with altitude and exceeded 40 cmH2O in all tube sizes. Comparable pressure change was demonstrated in the flight model. No difference was demonstrated in the degree of pressure change between ETT sizes. In the in vivo observations during patient transport, pressure increase was consistent with that seen in the ex vivo models.

Conclusions: Children who are intubated with cuffed ETTs for air medical transport are subject to excessive endotracheal cuff pressure at even low flight altitudes. Endotracheal tube size did not affect the degree of cuff pressure change, contrary to previous study. These findings need to be validated and correlated to patient clinical outcomes. The implications of these data need to be considered clinically particularly for prolonged transport of intubated pediatric patients at elevation.
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http://dx.doi.org/10.1097/PEC.0000000000000755DOI Listing
August 2018

Prospective Testing and Redesign of a Temporal Biomarker Based Risk Model for Patients With Septic Shock: Implications for Septic Shock Biology.

EBioMedicine 2015 Dec 22;2(12):2087-93. Epub 2015 Nov 22.

Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States.

The temporal version of the pediatric sepsis biomarker risk model (tPERSEVERE) estimates the risk of a complicated course in children with septic shock based on biomarker changes from days 1 to 3 of septic shock. We validated tPERSEVERE performance in a prospective cohort, with an a priori plan to redesign tPERSEVERE if it did not perform well. Biomarkers were measured in the validation cohort (n = 168) and study subjects were classified according to tPERSEVERE. To redesign tPERSEVERE, the validation cohort and the original derivation cohort (n = 299) were combined and randomly allocated to training (n = 374) and test (n = 93) sets. tPERSEVERE was redesigned using the training set and CART methodology. tPERSEVERE performed poorly in the validation cohort, with an area under the curve (AUC) of 0.67 (95% CI: 0.58-0.75). Failure analysis revealed potential confounders related to clinical characteristics. The redesigned tPERSEVERE model had an AUC of 0.83 (0.79-0.87) and a sensitivity of 93% (68-97) for estimating the risk of a complicated course. Similar performance was seen in the test set. The classification tree segregated patients into two broad endotypes of septic shock characterized by either excessive inflammation or immune suppression.
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http://dx.doi.org/10.1016/j.ebiom.2015.11.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703723PMC
December 2015

Differential expression of the Nrf2-linked genes in pediatric septic shock.

Crit Care 2015 Sep 17;19:327. Epub 2015 Sep 17.

Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, 3333 Burnet Avenue, MLC 2005, Cincinnati, OH, 45229, USA.

Introduction: Experimental data from animal models of sepsis support a role for a transcription factor, nuclear erythroid-related factor 2 p45-related factor 2 (Nrf2), as a master regulator of antioxidant and detoxifying genes and intermediary metabolism during stress. Prior analysis of a pediatric septic shock transcriptomic database showed that the Nrf2 response is a top 5 upregulated signaling pathway in early pediatric septic shock.

Methods: We conducted a focused analysis of 267 Nrf2-linked genes using a multicenter, genome-wide expression database of 180 children with septic shock 10 years of age or younger and 53 healthy controls. The analysis involved RNA isolated from whole blood within 24 h of pediatric intensive care unit admission for septic shock and a false discovery rate of 5 %. We compared differentially expressed genes from (1) patients with septic shock and healthy controls and (2) across validated gene expression-based subclasses of pediatric septic shock (endotypes A and B) using several bioinformatic methods.

Results: We found upregulation of 123 Nrf2-linked genes in children with septic shock. The top gene network represented by these genes contained primarily enzymes with oxidoreductase activity involved in cellular lipid metabolism that were highly connected to the peroxisome proliferator activated receptor and the retinoic acid receptor families. Endotype A, which had higher organ failure burden and mortality, exhibited a greater downregulation of Nrf2-linked genes than endotype B, with 92 genes differentially regulated between endotypes.

Conclusions: Our findings indicate that Nrf2-linked genes may contribute to alterations in oxidative signaling and intermediary metabolism in pediatric septic shock.
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http://dx.doi.org/10.1186/s13054-015-1052-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574004PMC
September 2015

A Multibiomarker-Based Model for Estimating the Risk of Septic Acute Kidney Injury.

Crit Care Med 2015 Aug;43(8):1646-53

1Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH. 2Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH. 3Division of Critical Care Medicine, UCSF Benioff Children's Hospital Oakland, Oakland, CA. 4Division of Critical Care Medicine, Children's Hospital of Orange County, Orange, CA. 5Division of Critical Care Medicine, Children's Mercy Hospital, Kansas City, MO. 6Division of Critical Care Medicine, Penn State Hershey Children's Hospital, Hershey, PA. 7Division of Critical Care Medicine, Akron Children's Hospital, Akron, OH. 8Division of Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA. 9Division of Critical Care Medicine, Texas Children's Hospital, Houston, TX. 10Division of Critical Care Medicine, Miami Children's Hospital, Miami, FL. 11Division of Critical Care Medicine, CS Mott Children's Hospital at the University of Michigan, Ann Arbor, MI. 12Division of Critical Care Medicine, Nationwide Children's Hospital, Columbus, OH. 13Division of Critical Care Medicine, Children's Hospital of Wisconsin, Milwaukee, WI. 14Division of Critical Care Medicine, Children's National Medical Center, Washington, DC. 15Division of Critical Care Medicine, Children's Hospital and Clinics of Minnesota, Minneapolis, MN. 16Division of Critical Care Medicine, Riley Hospital for Children, Indianapolis, IN. 17Division of Critical Care Medicine, Hackensack University Medical Center, Joseph M. Sanzari Children's Hospital, Hackensack, NJ. 18Division of Critical Care Medicine, The University of Chicago Comer Children's Hospital, Chicago, IL. 19Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.

Objective: The development of acute kidney injury in patients with sepsis is associated with worse outcomes. Identifying those at risk for septic acute kidney injury could help to inform clinical decision making. We derived and tested a multibiomarker-based model to estimate the risk of septic acute kidney injury in children with septic shock.

Design: Candidate serum protein septic acute kidney injury biomarkers were identified from previous transcriptomic studies. Model derivation involved measuring these biomarkers in serum samples from 241 subjects with septic shock obtained during the first 24 hours of admission and then using a Classification and Regression Tree approach to estimate the probability of septic acute kidney injury 3 days after the onset of septic shock, defined as at least two-fold increase from baseline serum creatinine. The model was then tested in a separate cohort of 200 subjects.

Setting: Multiple PICUs in the United States.

Interventions: None other than standard care.

Measurements And Main Results: The decision tree included a first-level decision node based on day 1 septic acute kidney injury status and five subsequent biomarker-based decision nodes. The area under the curve for the tree was 0.95 (CI95, 0.91-0.99), with a sensitivity of 93% and a specificity of 88%. The tree was superior to day 1 septic acute kidney injury status alone for estimating day 3 septic acute kidney injury risk. In the test cohort, the tree had an area under the curve of 0.83 (0.72-0.95), with a sensitivity of 85% and a specificity of 77% and was also superior to day 1 septic acute kidney injury status alone for estimating day 3 septic acute kidney injury risk.

Conclusions: We have derived and tested a model to estimate the risk of septic acute kidney injury on day 3 of septic shock using a novel panel of biomarkers. The model had very good performance in a test cohort and has test characteristics supporting clinical utility and further prospective evaluation.
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http://dx.doi.org/10.1097/CCM.0000000000001079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667777PMC
August 2015

Safety and Dose Escalation Study of Intravenous Zinc Supplementation in Pediatric Critical Illness.

JPEN J Parenter Enteral Nutr 2016 08 19;40(6):860-8. Epub 2015 Feb 19.

Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA Division of Critical Care, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Background: Critically ill children have low plasma zinc (pZn), correlating with organ failure. Since Zn influences inflammation, immune function, and glucose control, Zn supplementation is a plausible therapeutic modality. We sought to determine a safe dose of intravenous (IV) Zn to restore pZn in critically ill children.

Methods: Stepwise dose escalation study of IV Zn supplementation at a tertiary children's hospital. All children (<10 years) admitted to the pediatric intensive care unit with a Pediatric Risk of Mortality III score >5, or ≥1 new organ failure were eligible. After consent, patients were sequentially enrolled into 4 dosing groups: (1) no zinc, (2) Zn250: 250 mcg/kg/d ZnSO4, (3) Zn500: 500 mcg/kg/d ZnSO4, or (4) Zn750: 750 mcg/kg/d ZnSO4 ZnSO4 was administered 3 times daily for 7 days. pZn was measured at baseline, end of first ZnSO4 infusion, 1 hour postinfusion, and 7 hours postinfusion on day 1, then daily through days 2-7. Interleukin-6 (IL-6), C-reactive protein (CRP), and lymphocyte subsets were measured on days 1 and 3. Glucose was measured 3 times daily for 7 days.

Results: Twenty-four patients were enrolled. Baseline demographics were similar among groups. Baseline pZn was low in all patients (mean [SD], 41.8 [16.0] mcg/dL). pZn increased over the study period in supplemented groups; however, mean pZn in the Zn750 group exceeded the 50th percentile. pZn was not associated with IL-6, CRP, or lymphocyte subsets among groups. Degree of hyperglycemia did not differ among groups. No patient had a study-related adverse event.

Conclusions: IV zinc supplementation at 500 mcg/kg/d restores pZn to near the 50th percentile and is well tolerated.
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http://dx.doi.org/10.1177/0148607115572193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609528PMC
August 2016

Developing a clinically feasible personalized medicine approach to pediatric septic shock.

Am J Respir Crit Care Med 2015 Feb;191(3):309-15

1 Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, Ohio.

Rationale: Using microarray data, we previously identified gene expression-based subclasses of septic shock with important phenotypic differences. The subclass-defining genes correspond to adaptive immunity and glucocorticoid receptor signaling. Identifying the subclasses in real time has theranostic implications, given the potential for immune-enhancing therapies and controversies surrounding adjunctive corticosteroids for septic shock.

Objectives: To develop and validate a real-time subclassification method for septic shock.

Methods: Gene expression data for the 100 subclass-defining genes were generated using a multiplex messenger RNA quantification platform (NanoString nCounter) and visualized using gene expression mosaics. Study subjects (n = 168) were allocated to the subclasses using computer-assisted image analysis and microarray-based reference mosaics. A gene expression score was calculated to reduce the gene expression patterns to a single metric. The method was tested prospectively in a separate cohort (n = 132).

Measurements And Main Results: The NanoString-based data reproduced two septic shock subclasses. As previously, one subclass had decreased expression of the subclass-defining genes. The gene expression score identified this subclass with an area under the curve of 0.98 (95% confidence interval [CI95] = 0.96-0.99). Prospective testing of the subclassification method corroborated these findings. Allocation to this subclass was independently associated with mortality (odds ratio = 2.7; CI95 = 1.2-6.0; P = 0.016), and adjunctive corticosteroids prescribed at physician discretion were independently associated with mortality in this subclass (odds ratio = 4.1; CI95 = 1.4-12.0; P = 0.011).

Conclusions: We developed and tested a gene expression-based classification method for pediatric septic shock that meets the time constraints of the critical care environment, and can potentially inform therapeutic decisions.
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http://dx.doi.org/10.1164/rccm.201410-1864OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351580PMC
February 2015

Differential expression of the nuclear-encoded mitochondrial transcriptome in pediatric septic shock.

Crit Care 2014 Nov 19;18(6):623. Epub 2014 Nov 19.

Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, 3333 Burnet Avenue, MLC 2005, Cincinnati, OH, 45229, USA.

Introduction: Increasing evidence supports a role for mitochondrial dysfunction in organ injury and immune dysregulation in sepsis. Although differential expression of mitochondrial genes in blood cells has been reported for several diseases in which bioenergetic failure is a postulated mechanism, there are no data about the blood cell mitochondrial transcriptome in pediatric sepsis.

Methods: We conducted a focused analysis using a multicenter genome-wide expression database of 180 children ≤ 10 years of age with septic shock and 53 healthy controls. Using total RNA isolated from whole blood within 24 hours of PICU admission for septic shock, we evaluated 296 nuclear-encoded mitochondrial genes using a false discovery rate of 1%. A series of bioinformatic approaches were applied to compare differentially expressed genes across previously validated gene expression-based subclasses (groups A, B, and C) of pediatric septic shock.

Results: In total, 118 genes were differentially regulated in subjects with septic shock compared to healthy controls, including 48 genes that were upregulated and 70 that were downregulated. The top scoring canonical pathway was oxidative phosphorylation, with general downregulation of the 51 genes corresponding to the electron transport system (ETS). The top two gene networks were composed primarily of mitochondrial ribosomal proteins highly connected to ETS complex I, and genes encoding for ETS complexes I, II, and IV that were highly connected to the peroxisome proliferator activated receptor (PPAR) family. There were 162 mitochondrial genes differentially regulated between groups A, B, and C. Group A, which had the highest maximum number of organ failures and mortality, exhibited a greater downregulation of mitochondrial genes compared to groups B and C.

Conclusions: Based on a focused analysis of a pediatric septic shock transcriptomic database, nuclear-encoded mitochondrial genes were differentially regulated early in pediatric septic shock compared to healthy controls, as well as across genotypic and phenotypic distinct pediatric septic shock subclasses. The nuclear genome may be an important mechanism contributing to alterations in mitochondrial bioenergetic function and outcomes in pediatric sepsis.
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http://dx.doi.org/10.1186/s13054-014-0623-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4247726PMC
November 2014

Corticosteroids and pediatric septic shock outcomes: a risk stratified analysis.

PLoS One 2014 11;9(11):e112702. Epub 2014 Nov 11.

Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH, United States of America; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America.

Background: The potential benefits of corticosteroids for septic shock may depend on initial mortality risk.

Objective: We determined associations between corticosteroids and outcomes in children with septic shock who were stratified by initial mortality risk.

Methods: We conducted a retrospective analysis of an ongoing, multi-center pediatric septic shock clinical and biological database. Using a validated biomarker-based stratification tool (PERSEVERE), 496 subjects were stratified into three initial mortality risk strata (low, intermediate, and high). Subjects receiving corticosteroids during the initial 7 days of admission (n = 252) were compared to subjects who did not receive corticosteroids (n = 244). Logistic regression was used to model the effects of corticosteroids on 28-day mortality and complicated course, defined as death within 28 days or persistence of two or more organ failures at 7 days.

Results: Subjects who received corticosteroids had greater organ failure burden, higher illness severity, higher mortality, and a greater requirement for vasoactive medications, compared to subjects who did not receive corticosteroids. PERSEVERE-based mortality risk did not differ between the two groups. For the entire cohort, corticosteroids were associated with increased risk of mortality (OR 2.3, 95% CI 1.3-4.0, p = 0.004) and a complicated course (OR 1.7, 95% CI 1.1-2.5, p = 0.012). Within each PERSEVERE-based stratum, corticosteroid administration was not associated with improved outcomes. Similarly, corticosteroid administration was not associated with improved outcomes among patients with no comorbidities, nor in groups of patients stratified by PRISM.

Conclusions: Risk stratified analysis failed to demonstrate any benefit from corticosteroids in this pediatric septic shock cohort.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0112702PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227847PMC
March 2016

Corticosteroids are associated with repression of adaptive immunity gene programs in pediatric septic shock.

Am J Respir Crit Care Med 2014 Apr;189(8):940-6

1 Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Rationale: Corticosteroids are prescribed commonly for patients with septic shock, but their use remains controversial and concerns remain regarding side effects.

Objectives: To determine the effect of adjunctive corticosteroids on the genomic response of pediatric septic shock.

Methods: We retrospectively analyzed an existing transcriptomic database of pediatric septic shock. Subjects receiving any formulation of systemic corticosteroids at the time of blood draw for microarray analysis were classified in the septic shock corticosteroid group. We compared normal control subjects (n = 52), a septic shock no corticosteroid group (n = 110), and a septic shock corticosteroid group (n = 70) using analysis of variance. Genes differentially regulated between the no corticosteroid group and the corticosteroid group were analyzed using Ingenuity Pathway Analysis.

Measurements And Main Results: The two study groups did not differ with respect to illness severity, organ failure burden, mortality, or mortality risk. There were 319 gene probes differentially regulated between the no corticosteroid group and the corticosteroid group. These genes corresponded predominately to adaptive immunity-related signaling pathways, and were down-regulated relative to control subjects. Notably, the degree of down-regulation was significantly greater in the corticosteroid group, compared with the no corticosteroid group. A similar pattern was observed for genes corresponding to the glucocorticoid receptor signaling pathway.

Conclusions: Administration of corticosteroids in pediatric septic shock is associated with additional repression of genes corresponding to adaptive immunity. These data should be taken into account when considering the benefit to risk ratio of adjunctive corticosteroids for septic shock.
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http://dx.doi.org/10.1164/rccm.201401-0171OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098101PMC
April 2014

The temporal version of the pediatric sepsis biomarker risk model.

PLoS One 2014 13;9(3):e92121. Epub 2014 Mar 13.

Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.

Background: PERSEVERE is a risk model for estimating mortality probability in pediatric septic shock, using five biomarkers measured within 24 hours of clinical presentation.

Objective: Here, we derive and test a temporal version of PERSEVERE (tPERSEVERE) that considers biomarker values at the first and third day following presentation to estimate the probability of a "complicated course", defined as persistence of ≥2 organ failures at seven days after meeting criteria for septic shock, or death within 28 days.

Methods: Biomarkers were measured in the derivation cohort (n = 225) using serum samples obtained during days 1 and 3 of septic shock. Classification and Regression Tree (CART) analysis was used to derive a model to estimate the risk of a complicated course. The derived model was validated in the test cohort (n = 74), and subsequently updated using the combined derivation and test cohorts.

Results: A complicated course occurred in 23% of the derivation cohort subjects. The derived model had a sensitivity for a complicated course of 90% (95% CI 78-96), specificity was 70% (62-77), positive predictive value was 47% (37-58), and negative predictive value was 96% (91-99). The area under the receiver operating characteristic curve was 0.85 (0.79-0.90). Similar test characteristics were observed in the test cohort. The updated model had a sensitivity of 91% (81-96), a specificity of 70% (64-76), a positive predictive value of 47% (39-56), and a negative predictive value of 96% (92-99).

Conclusions: tPERSEVERE reasonably estimates the probability of a complicated course in children with septic shock. tPERSEVERE could potentially serve as an adjunct to physiological assessments for monitoring how risk for poor outcomes changes during early interventions in pediatric septic shock.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0092121PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3953585PMC
December 2015

Testing the prognostic accuracy of the updated pediatric sepsis biomarker risk model.

PLoS One 2014 29;9(1):e86242. Epub 2014 Jan 29.

Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.

Background: We previously derived and validated a risk model to estimate mortality probability in children with septic shock (PERSEVERE; PEdiatRic SEpsis biomarkEr Risk modEl). PERSEVERE uses five biomarkers and age to estimate mortality probability. After the initial derivation and validation of PERSEVERE, we combined the derivation and validation cohorts (n = 355) and updated PERSEVERE. An important step in the development of updated risk models is to test their accuracy using an independent test cohort.

Objective: To test the prognostic accuracy of the updated version PERSEVERE in an independent test cohort.

Methods: Study subjects were recruited from multiple pediatric intensive care units in the United States. Biomarkers were measured in 182 pediatric subjects with septic shock using serum samples obtained during the first 24 hours of presentation. The accuracy of PERSEVERE 28-day mortality risk estimate was tested using diagnostic test statistics, and the net reclassification improvement (NRI) was used to test whether PERSEVERE adds information to a physiology-based scoring system.

Results: Mortality in the test cohort was 13.2%. Using a risk cut-off of 2.5%, the sensitivity of PERSEVERE for mortality was 83% (95% CI 62-95), specificity was 75% (68-82), positive predictive value was 34% (22-47), and negative predictive value was 97% (91-99). The area under the receiver operating characteristic curve was 0.81 (0.70-0.92). The false positive subjects had a greater degree of organ failure burden and longer intensive care unit length of stay, compared to the true negative subjects. When adding PERSEVERE to a physiology-based scoring system, the net reclassification improvement was 0.91 (0.47-1.35; p<0.001).

Conclusions: The updated version of PERSEVERE estimates mortality probability reliably in a heterogeneous test cohort of children with septic shock and provides information over and above a physiology-based scoring system.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0086242PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906040PMC
September 2014

Biomarkers and genetics of brain injury risk in diabetic ketoacidosis: A pilot study.

J Pediatr Intensive Care 2014;3(2)

Department of Pediatric Critical Care Medicine, Children's Hospital and Research Center Oakland, Oakland, CA, USA.

Diabetic ketoacidosis (DKA) is the primary cause of death for children with diabetes, especially when complicated by cerebral edema. Central nervous system (CNS) involvement is common, however the mechanism of, and predictors of CNS dysfunction/injury are largely unknown. In this observational pilot study, blood was collected from pediatric DKA patients at three time points (consent, 12 hr and 24 hr after beginning treatment), to test genetic markers, ribonucleic acid expression and plasma biomarkers reflecting inflammation (tumor necrosis factor-alpha [TNF-α], interleukin-6 [IL-6]) and cerebral dysfunction and/or possible injury (S100β, glial fibrillary acidic protein [GFAP]). Thirty patients were enrolled in the study. The average age was 11.3 yr, 73% were new onset diabetes and 53% were female. Forty percent exhibited abnormal mentation (Glasgow Coma Scale <15), consistent with CNS dysfunction. IL-6 and TNF-α were elevated in plasma, suggesting systemic inflammation. GFAP was measurable in 45% of patients and correlated positively with GCS. Only two patients had detectable levels of S100β. In conclusion, children with DKA often present with evidence of acute neurologic dysfunction or injury. We have demonstrated the feasibility of exploring genetic and biochemical markers of potential importance in the pathophysiology of CNS dysfunction and/or possible injury in DKA. We have identified IL-6, TNF-α and GFAP as potentially important markers for further exploration. A larger, follow-up study will help to better understand the extent and type of CNS injury in DKA as well as the mechanism underlying this dysfunction/injury.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472439PMC
http://dx.doi.org/10.3233/PIC-14091DOI Listing
January 2014

Post-ICU admission fluid balance and pediatric septic shock outcomes: a risk-stratified analysis.

Crit Care Med 2014 Feb;42(2):397-403

1Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH. 2Children's Hospital and Research Center Oakland, Oakland, CA. 3Penn State Hershey Children's Hospital, Hershey, PA. 4Children's Mercy Hospital, Kansas City, MO. 5Children's Hospital of Orange County, Orange, CA. 6Akron Children's Hospital, Akron, OH. 7Nationwide Children's Hospital, Columbus, OH. 8Children's National Medical Center, Washington, DC. 9Morgan Stanley Children's Hospital, Columbia University Medical Center, New York, NY. 10Miami Children's Hospital, Miami, FL. 11Texas Children's Hospital, Houston, TX. 12CS Mott Children's Hospital at the University of Michigan, Ann Arbor, MI. 13Children's Hospital and Clinics of Minnesota, Minneapolis, MN. 14The Children's Hospital of Philadelphia, Philadelphia, PA. 15St. Christopher's Hospital for Children, Philadelphia, PA. 16Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH. 17Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.

Objective: Observed associations between fluid balance and septic shock outcomes are likely confounded by initial mortality risk. We conducted a risk-stratified analysis of the association between post-ICU admission fluid balance and pediatric septic shock outcomes.

Design: Retrospective analysis of an ongoing multicenter pediatric septic shock clinical and biological database.

Setting: Seventeen PICUs in the United States.

Patients: Three hundred and seventeen children with septic shock.

Interventions: None.

Measurements And Main Results: We stratified subjects into three mortality risk categories (low, intermediate, and high) using a validated biomarker-based stratification tool. Within each category, we assessed three fluid balance variables: total fluid intake/kg/d during the first 24 hours, percent positive fluid balance during the first 24 hours, and cumulative percent positive fluid balance up to 7 days. We used logistic regression to estimate the effect of fluid balance on the odds of 28-day mortality, and on complicated course, which we defined as either death within 28 days or persistence of two or more organ failures at 7 days. There were 40 deaths, and 91 subjects had a complicated course. Increased cumulative percent positive fluid balance was associated with mortality in the low-risk cohort (n = 204; odds ratio, 1.035; 95% CI, 1.004-1.066) but not in the intermediate- and high-risk cohorts. No other associations with mortality were observed. Fluid intake, percent positive fluid balance in the first 24 hours, and cumulative percent positive fluid balance were all associated with increased odds of a complicated course in the low-risk cohort but not in the intermediate- and high-risk cohorts.

Conclusions: When stratified for mortality risk, increased fluid intake and positive fluid balance after ICU admission are associated with worse outcomes in pediatric septic shock patients with a low initial mortality risk but not in patients at moderate or high mortality risk.
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http://dx.doi.org/10.1097/CCM.0b013e3182a64607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3947064PMC
February 2014

Interleukin-27 is a novel candidate diagnostic biomarker for bacterial infection in critically ill children.

Crit Care 2012 Oct 29;16(5):R213. Epub 2012 Oct 29.

Introduction: Differentiating between sterile inflammation and bacterial infection in critically ill patients with fever and other signs of the systemic inflammatory response syndrome (SIRS) remains a clinical challenge. The objective of our study was to mine an existing genome-wide expression database for the discovery of candidate diagnostic biomarkers to predict the presence of bacterial infection in critically ill children.

Methods: Genome-wide expression data were compared between patients with SIRS having negative bacterial cultures (n = 21) and patients with sepsis having positive bacterial cultures (n = 60). Differentially expressed genes were subjected to a leave-one-out cross-validation (LOOCV) procedure to predict SIRS or sepsis classes. Serum concentrations of interleukin-27 (IL-27) and procalcitonin (PCT) were compared between 101 patients with SIRS and 130 patients with sepsis. All data represent the first 24 hours of meeting criteria for either SIRS or sepsis.

Results: Two hundred twenty one gene probes were differentially regulated between patients with SIRS and patients with sepsis. The LOOCV procedure correctly predicted 86% of the SIRS and sepsis classes, and Epstein-Barr virus-induced gene 3 (EBI3) had the highest predictive strength. Computer-assisted image analyses of gene-expression mosaics were able to predict infection with a specificity of 90% and a positive predictive value of 94%. Because EBI3 is a subunit of the heterodimeric cytokine, IL-27, we tested the ability of serum IL-27 protein concentrations to predict infection. At a cut-point value of ≥5 ng/ml, serum IL-27 protein concentrations predicted infection with a specificity and a positive predictive value of >90%, and the overall performance of IL-27 was generally better than that of PCT. A decision tree combining IL-27 and PCT improved overall predictive capacity compared with that of either biomarker alone.

Conclusions: Genome-wide expression analysis has provided the foundation for the identification of IL-27 as a novel candidate diagnostic biomarker for predicting bacterial infection in critically ill children. Additional studies will be required to test further the diagnostic performance of IL-27. The microarray data reported in this article have been deposited in the Gene Expression Omnibus under accession number GSE4607.
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http://dx.doi.org/10.1186/cc11847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682317PMC
October 2012

The pediatric sepsis biomarker risk model.

Crit Care 2012 Oct 1;16(5):R174. Epub 2012 Oct 1.

Introduction: The intrinsic heterogeneity of clinical septic shock is a major challenge. For clinical trials, individual patient management, and quality improvement efforts, it is unclear which patients are least likely to survive and thus benefit from alternative treatment approaches. A robust risk stratification tool would greatly aid decision-making. The objective of our study was to derive and test a multi-biomarker-based risk model to predict outcome in pediatric septic shock.

Methods: Twelve candidate serum protein stratification biomarkers were identified from previous genome-wide expression profiling. To derive the risk stratification tool, biomarkers were measured in serum samples from 220 unselected children with septic shock, obtained during the first 24 hours of admission to the intensive care unit. Classification and Regression Tree (CART) analysis was used to generate a decision tree to predict 28-day all-cause mortality based on both biomarkers and clinical variables. The derived tree was subsequently tested in an independent cohort of 135 children with septic shock.

Results: The derived decision tree included five biomarkers. In the derivation cohort, sensitivity for mortality was 91% (95% CI 70 - 98), specificity was 86% (80 - 90), positive predictive value was 43% (29 - 58), and negative predictive value was 99% (95 - 100). When applied to the test cohort, sensitivity was 89% (64 - 98) and specificity was 64% (55 - 73). In an updated model including all 355 subjects in the combined derivation and test cohorts, sensitivity for mortality was 93% (79 - 98), specificity was 74% (69 - 79), positive predictive value was 32% (24 - 41), and negative predictive value was 99% (96 - 100). False positive subjects in the updated model had greater illness severity compared to the true negative subjects, as measured by persistence of organ failure, length of stay, and intensive care unit free days.

Conclusions: The pediatric sepsis biomarker risk model (PERSEVERE; PEdiatRic SEpsis biomarkEr Risk modEl) reliably identifies children at risk of death and greater illness severity from pediatric septic shock. PERSEVERE has the potential to substantially enhance clinical decision making, to adjust for risk in clinical trials, and to serve as a septic shock-specific quality metric.
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http://dx.doi.org/10.1186/cc11652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682273PMC
October 2012