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Analysis of viral testing in nonacetaminophen pediatric acute liver failure.

ABSTRACT: Viral infections are often suspected to cause pediatric acute liver failure (PALF), but large-scale studies have not been performed. We analyzed the results of viral testing among nonacetaminophen PALF study participants.Participants were enrolled in the PALF registry. Diagnostic evaluation and final diagnosis were determined by the site investigator and methods for viral testing by local standard of care. Viruses were classified as either causative viruses (CVs) or associated viruses (AVs). Supplemental testing for CV was performed if not done clinically and serum was available. Final diagnoses included "viral," "indeterminate," and "other."Of 860 participants, 820 had at least 1 test result for a CV or AV. A positive viral test was found in 166/820 (20.2%) participants and distributed among "viral" (66/80 [82.5%]), "indeterminate" (52/420 [12.4%]), and "other" (48/320 [15.0%]) diagnoses. CVs accounted for 81/166 (48.8%) positive tests. Herpes simplex virus (HSV) was positive in 39/335 (11.6%) who were tested 26/103 (25.2%) and 13/232 (5.6%) among infants 0 to 6 and >6 months, respectively. HSV was not tested in 61.0% and 53% of the overall cohort and those 0 to 6 months, respectively. Supplemental testing yielded 17 positive, including 5 HSV.Viral testing in PALF occurs frequently but is often incomplete. The evidence for acute viral infection was found in 20.2% of those tested for viruses. HSV is an important viral cause for PALF in all age groups. The etiopathogenic role of CV and AV in PALF requires further investigation.

SUBMITTER: Schwarz KB

PROVIDER: S-EPMC4305349 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Analysis of viral testing in nonacetaminophen pediatric acute liver failure.

Schwarz Kathleen B KB Dell Olio Dominic D Lobritto Steven J SJ Lopez M James MJ Rodriguez-Baez Norberto N Yazigi Nada A NA Belle Steven H SH Zhang Song S Squires Robert H RH

Journal of pediatric gastroenterology and nutrition 20141101 5

<h4>Objective</h4>Viral infections are often suspected to cause pediatric acute liver failure (PALF), but large-scale studies have not been performed. We analyzed the results of viral testing among nonacetaminophen PALF study participants.<h4>Methods</h4>Participants were enrolled in the PALF registry. Diagnostic evaluation and final diagnosis were determined by the site investigator and methods for viral testing by local standard of care. Viruses were classified as either causative viruses (CVs ...[more]

PMID: 25340974

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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.

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:IntroductionPediatric acute liver failure is a rare and serious disease. Though liver transplantation is considered as the established treatment option for patients who are unlikely to recover with medical management, however, with the advancement of medical care there has been an increase in spontaneous regeneration of liver, obviating the need for liver transplantation. We identified the etiologies, outcome and prognostic factors of acute liver failure and the validity of the existing liver transplantation criteria to predict the outcome of pediatric acute liver failure.Materials and methodsThis was a retrospective study done from January 2014 to December 2019 in a tertiary pediatric critical care unit in South India. All children aged between 1 month to 18 years admitted with acute liver failure were enrolled.ResultsOf 125 children with acute liver failure, the main etiologies were infections (32%), indeterminate (23%), paracetamol toxicity (21%), metabolic (13%) and others (11%). Dengue was the most common infection (55%). The median pediatric logistic organ dysfunction score at admission was 12 (4-27). Of 125 patients, 63.2% (n = 79) had spontaneous regeneration which was higher in paracetamol induced (92.3%) compared to non-paracetamol induced acute liver failure (55.5%). Only two patients underwent liver transplantation and 35% died. Peak alanine transaminase and use of inotropes significantly predicted the outcome of disease. Of 38 children meeting King's College Hospital criteria for liver transplantation, 57.9% had spontaneous regeneration and 36.8% died. Of 74 children meeting INR > 4 criteria, 54% (n = 40) had spontaneous regeneration and 43.2% died. INR >4 criteria was more sensitive than King's College Hospital criteria for predicting the need for liver transplantation.ConclusionPediatric acute liver failure is caused by varied etiologies and infections were the commonest cause. Despite having a seriously ill cohort of patients, medical management resulted in spontaneous regeneration in the majority of children with acute liver failure. The use of inotropes, advanced hepatic encephalopathy, and peak alanine transaminase were predictors of poor outcome in children with acute liver failure and these patients could be considered for liver transplantation as available. Therefore, we may need to develop better predictors of pediatric acute liver failure in resource limited settings.

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Analysis of viral testing in nonacetaminophen pediatric acute liver failure.

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Analysis of viral testing in nonacetaminophen pediatric acute liver failure.

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