Dataset Information

Dynamics of Systemic Inflammation as a Function of Developmental Stage in Pediatric Acute Liver Failure.

ABSTRACT: The Pediatric Acute Liver Failure (PALF) study is a multicenter, observational cohort study of infants and children diagnosed with this complex clinical syndrome. Outcomes in PALF reflect interactions among the child's clinical condition, response to supportive care, disease severity, potential for recovery, and, if needed, availability of a suitable organ for liver transplantation (LTx). Previously, we used computational analyses of immune/inflammatory mediators that identified three distinct dynamic network patterns of systemic inflammation in PALF associated with spontaneous survivors, non-survivors (NS), and LTx recipients. To date, there are no data exploring age-specific immune/inflammatory responses in PALF. Accordingly, we measured a number of clinical characteristics and PALF-associated systemic inflammatory mediators in daily serum samples collected over the first 7 days following enrollment from five distinct PALF cohorts (all spontaneous survivors without LTx): infants (INF, <1 year), toddlers (TOD, 1-2 years.), young children (YCH, 2-4 years), older children (OCH, 4-13 years) and adolescents (ADO, 13-18 years). Among those groups, we observed significant (P<0.05) differences in ALT, creatinine, Eotaxin, IFN-?, IL-1RA, IL-1?, IL-2, sIL-2R?, IL-4, IL-6, IL-12p40, IL-12p70, IL-13, IL-15, MCP-1, MIP-1?, MIP-1?, TNF-?, and NO2-/NO3- . Dynamic Bayesian Network inference identified a common network motif with HMGB1 as a central node in all sub-groups, with MIG/CXCL9 being a central node in all groups except INF. Dynamic Network Analysis (DyNA) inferred different dynamic patterns and overall dynamic inflammatory network complexity as follows: OCH>INF>TOD>ADO>YCH. Hypothesizing that systemically elevated but sparsely connected inflammatory mediators represent pathological inflammation, we calculated the AuCon score (area under the curve derived from multiple measures over time divided by DyNA connectivity) for each mediator, and identified HMGB1, MIG, IP-10/CXCl10, sIL-2R?, and MCP-1/CCL2 as potential correlates of PALF pathophysiology, largely in agreement with the results of Partial Least Squares Discriminant Analysis. Since NS were in the INF age group, we compared NS to INF and found greater inflammatory coordination and dynamic network connectivity in NS vs. INF. HMGB1 was the sole central node in both INF and NS, though NS had more downstream nodes. Thus, multiple machine learning approaches were used to gain both basic and potentially translational insights into a complex inflammatory disease.

SUBMITTER: Vodovotz Y

PROVIDER: S-EPMC7844097 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Dynamics of Systemic Inflammation as a Function of Developmental Stage in Pediatric Acute Liver Failure.

Vodovotz Yoram Y Barclay Derek D Yin Jinling J Squires Robert H RH Zamora Ruben R

Frontiers in immunology 20210115

The Pediatric Acute Liver Failure (PALF) study is a multicenter, observational cohort study of infants and children diagnosed with this complex clinical syndrome. Outcomes in PALF reflect interactions among the child's clinical condition, response to supportive care, disease severity, potential for recovery, and, if needed, availability of a suitable organ for liver transplantation (LTx). Previously, we used computational analyses of immune/inflammatory mediators that identified three distinct d ...[more]

PMID: 33519820

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Project description:BackgroundAlthough human studies have shown that inflammation plays a role in the development of congestive heart failure, scarce information exists on white blood cell count (WBC) and differential cell counts in various stages of heart failure in man and dogs. A few studies demonstrated increased concentrations of C-reactive protein (CRP), a major acute-phase protein, in cardiac diseases in dogs. Our research aimed to investigate whether CRP concentration, WBC and neutrophil count (NEUT), as markers of systemic inflammation, are elevated in canine cardiovascular patients. We also aimed to find out whether there is an association between CRP concentration and WBC and NEUT, as well as associations between these inflammatory markers and selected echocardiographic parameters. Sixty-two client-owned canine cardiac patients and 12 healthy dogs were included in the study. The patients were classified into International Small Animal Cardiac Health Council classes (ISACHC I-III). The serum CRP concentration was determined using a canine CRP test kit. WBC and NEUT were determined using an automated hematology analyzer.ResultsSignificantly higher serum CRP concentration, WBC and NEUT were found in the decompensated stage of heart failure (ISACHC III) compared with healthy dogs and with patients in ISACHC group II and ISACHC group I. Serum CRP concentration significantly positively correlated with WBC (r = 0.65, P < 0.001) and NEUT (r = 0.58, P = 0.002) in the ISACHC III group, while no significant correlations were found in the ISACHC I and II groups. A significant negative correlation between serum CRP concentration and the left ventricular ejection fraction (r = - 0.49, P = 0.046) and a significant positive correlation between CRP and the E wave velocity of the mitral valve inflow (r = 0.52, P = 0.046) were found in the ISACHC III group.ConclusionsThe CRP concentration, WBC and NEUT were significantly increased in advanced-stage heart failure patients in comparison with compensated patients and healthy dogs, which indicate the presence of systemic inflammation. However, normal CRP concentration and normal WBC and NEUT can also be present in heart failure.

Project description:Background and Aims: Many patients with indeterminate pediatric acute liver failure (PALF) have evidence of T-cell driven immune injury, however the precise inflammatory pathways have not been well defined. We have thus characterized the hepatic cytokine and transcriptional signatures of PALF patients. Approach and Results: Retrospective review was performed on 22 children presenting with indeterminate (IND-PALF; n=17) or other diagnoses (DX-PALF; n=6) with available archived liver tissue. Specimens were stained for CD8 T-cells and scored as dense, moderate, or minimal. Measurement of immune analytes and RNA-sequencing (RNA-seq) were performed on whole liver tissue. Immune analyte data was analyzed by principal component analysis, and RNA-seq was analyzed by unsupervised hierarchical clustering, differential gene expression, and gene set enrichment analysis. Most IND-PALF patients (94%) had dense/moderate CD8 staining and were characterized by Th1 immune analytes including TNFα, IFNγ, IL-1β, IL-12, CXCL9, and CXCL12. Transcriptional analyses identified 2 transcriptional PALF phenotypes. Most patients in Group 1 (91%) had IND-PALF and dense/moderate CD8 staining. This group was characterized by increased expression of genes and cell-subset specific signatures related to innate inflammation, T-cell activation, and antigen stimulation. Group 1 also expressed significantly higher levels of gene signatures for T-regulatory cells, macrophages, Th1 cells, T effector memory cells, cytotoxic T-cells, and activated dendritic cells (p-adj <0.05). In contrast, patients in Group 2 exhibited increased expression for genes involved in metabolic processes. Conclusions: IND-PALF patients have evidence of a Th1 mediated inflammatory response driven by IFNγ. Transcriptional analyses suggest a complex immune network may regulate an immune-driven PALF phenotype with less evidence of metabolic processes. These findings provide novel insight into mechanisms of hepatic injury in PALF, areas for future research, and potential therapeutic targets.

Project description:Many patients with indeterminate pediatric acute liver failure (PALF) have evidence of T-cell driven immune injury; however, the precise inflammatory pathways are not well defined. We have characterized the hepatic cytokine and transcriptional signatures of patients with PALF. A retrospective review was performed on 22 children presenting with indeterminate (IND-PALF; n = 17) or other known diagnoses (DX-PALF; n = 6) with available archived liver tissue. Specimens were stained for clusters of differentiation 8 (CD8) T cells and scored as dense, moderate, or minimal. Measurement of immune analytes and RNA sequencing (RNA-seq) was performed on whole-liver tissue. Immune analyte data were analyzed by principal component analysis, and RNA-seq was analyzed by unsupervised hierarchical clustering, differential gene expression, and gene-set enrichment analysis. Most patients with IND-PALF (94%) had dense/moderate CD8 staining and were characterized by Th1 immune analytes including tumor necrosis factor α, interferon γ (IFN-γ), interleukin (IL) 1β, IL-12, C-X-C motif chemokine ligand (CXCL) 9, and CXCL12. Transcriptional analyses identified two transcriptional PALF phenotypes. Most patients in group 1 (91%) had IND-PALF and dense/moderate CD8 staining. This group was characterized by increased expression of genes and cell subset-specific signatures related to innate inflammation, T-cell activation, and antigen stimulation. Group 1 expressed significantly higher levels of gene signatures for regulatory T cells, macrophages, Th1 cells, T effector memory cells, cytotoxic T cells, and activated dendritic cells (adjusted P < 0.05). In contrast, patients in group 2 exhibited increased expression for genes involved in metabolic processes. Conclusion: Patients with IND-PALF have evidence of a Th1-mediated inflammatory response driven by IFN-γ. Transcriptional analyses suggest that a complex immune network may regulate an immune-driven PALF phenotype with less evidence of metabolic processes. These findings provide insight into mechanisms of hepatic injury in PALF, areas for future research, and potential therapeutic targets.

Dataset Information

Dynamics of Systemic Inflammation as a Function of Developmental Stage in Pediatric Acute Liver Failure.

Publications

Dynamics of Systemic Inflammation as a Function of Developmental Stage in Pediatric Acute Liver Failure.

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