Pediatric Acute Liver Failure Study Research Articles

CHALF Score: A Novel Tool to Rapidly Risk Stratify Children in Need of Liver Transplant Evaluation During Acute Liver Failure.

Pediatric acute liver failure (PALF) can require emergent liver transplantation (LT, >25%) or lead to death (~15%). Existing models cannot predict clinical trajectory or survival with native liver (SNL). We aimed to create a predictive model for PALF clinical outcomes based on admission variables. A retrospective, single-center PALF cohort (April 2003 to January 2022) was identified using International Classification of Disease codes, selected using National Institutes of Health PALF Study Group (PALFSG) criteria, and grouped by clinical outcome (SNL, LT, or death). Significant admission variables were advanced for feature selection using least absolute shrinkage and selection operator regression with bootstrapping (5000×). A predictive model of SNL versus LT or death was created using logistic regression and validated using PALFSG data. Our single-center cohort included 147 patients (58% SNL, 32% LT, 10% expired), while the PALFSG validation cohort included 492 patients (50% SNL, 35% LT, 15% expired). Admission variables associated with SNL included albumin (odds ratio [OR], 16; P < 0.01), ammonia (OR, 2.37; P < 0.01), and total bilirubin (OR, 2.25; P < 0.001). A model using these variables predicted SNL versus LT or death with high accuracy (accuracy [0.75 training, 0.70 validation], area under the curve [0.83 training, 0.78 validation]). A scaled score (CHLA-acute liver failure score) was created that predicted SNL versus LT or death with greater accuracy (C statistic 0.83) than Pediatric End-Stage Liver Disease (C statistic 0.76) and admission liver injury unit (C statistic 0.76) scores. The CHLA-acute liver failure score predicts SNL versus LT or mortality in PALF using admission laboratories with high accuracy. This novel, externally validated model offers an objective guide for urgent referral to a pediatric LT center.

Prognostic Markers in Pediatric Acute Liver Failure

Introduction: Acute liver failure (ALF), although rare in children, is a complex progressive pathology, with multisystem involvement and high mortality. Isolated variables or those included in prognostic scores have been studied, to optimize organ allocation. However, its validation is challenging. This study aimed to assess the accuracy of several biomarkers and scores as predictors of prognosis in pediatric ALF (PALF). Methods: An observational study with retrospective data collection, including all cases of ALF, was defined according to the criteria of the Pediatric Acute Liver Failure Study Group, admitted to a pediatric intensive care unit (PICU) for 28 years. Two groups were defined: spontaneous recovery (SR) and non-SR (NSR) – submitted to liver transplantation (LT) or death at PICU discharge. Results: Fifty-nine patients were included, with a median age of 24 months, and 54% were female. The most frequent etiologies were metabolic (25.4%) and infectious (18.6%); 32.2% were undetermined. SR occurred in 21 patients (35.6%). In NSR group (N = 38, 64.4%), 25 required LT (42.4%) and 19 died (32.2%), 6 (15.7%) of whom after LT. The accuracy to predict NSR was acceptable for lactate at admission (AUC 0.72; 95% CI: 0.57–0.86; p = 0.006), ammonia peak (AUC 0.72; 95% CI: 0.58–0.86; p = 0.006), and INR peak (AUC 0.70; 95% CI: 0.56–0.85; p = 0.01). The cut-off value for lactate at admission was 1.95 mmol/L (sensitivity 78.4% and specificity 61.9%), ammonia peak was 64 μmol/L (sensitivity 100% and specificity 38.1%), and INR peak was 4.8 (sensitivity 61.1% and specificity 76.2%). Lactate on admission was shown to be an independent predictor of NSR on logistic regression model. Two prognostic scores had acceptable discrimination for NSR, LIU (AUC 0.73; 95% CI: 0.59–0.87; p = 0.004) and PRISM (AUC 0.71; 95% CI: 0.56–0.86; p = 0.03). In our study, the PALF delta score (PALF-ds) had lower discrimination capacity (AUC 0.63; 95% CI: 0.47–0.78; p = 0.11). Conclusions: The lactate at admission, an easily obtained parameter, had a similar capacity than the more complex scores, LIU and PRISM, to predict NSR. The prognostic value in our population of the promising dynamic score, PALF-ds, was lower than expected.

Pediatric acute liver failure in Saudi Arabia: prognostic indicators, outcomes and the role of genetic testing.

The objective of this study was to determine the etiologies, outcomes, prognostic indicators and the role of genetic testing in children with acute liver failure (ALF). This retrospective study included 46 patients with pediatric acute liver failure (PALF) according to the PALF study group definition, admitted to King Fahad Specialist Hospital-Dammam, Saudi Arabia, between January 2014 and December 2021. Patients who survived with supportive therapy were designated as the recovery group, whereas those who died or underwent liver transplantation were designated as the death/transplant group. There were 26 (56.5%) patients in the recovery group and 20 (43.5%) patients in the death/transplant group. Four patients (8.7%) underwent liver transplantation. After indeterminate causes (45.6%), genetic-metabolic diseases and drug-induced liver injury (DILI) were the most common cause with 15.2 and 13%, respectively. Genetic testing had a high yield of (6/31) in identifying monogenic disease associated with ALF. Younger age, lower Glasgow Coma Scale and higher international normalized ratio (INR) on admission were predictors for poor prognosis. The death/transplant group had longer intensive care unit stay ( P < 0.001), and on admission they had more advanced hepatic encephalopathy ( P < 0.005), more prolonged prothrombin time ( P < 0.001), higher lactate ( P < 0.006), higher total and direct bilirubin ( P < 0.008) and ( P < 0.001), respectively. Genetic, metabolic and DILI causes constituted the most common cause of PALF after indeterminate causes. The use of genetic testing can improve diagnostic rates in special cases, but we could not assess the effect of genetic testing on prognosis. The overall survival rate in our study was 65.2%. Younger age, higher admission INR and lower Glasgow coma scale were indicators of poor prognosis.

Four Biomarkers Linked to Activation of Cluster of Differentiation 8-Positive Lymphocytes Predict Clinical Outcomes in Pediatric Acute Liver Failure.

Immune dysregulation contributes to the pathogenesis of pediatric acute liver failure (PALF). Our aim was to identify immune activation markers (IAMs) in PALF that are associated with a distinct clinical phenotype and outcome. Among 47 PALF study participants, 12 IAMs collected ≤6days after enrollment were measured by flow cytometry and IMMULITE assay on blood natural killer and cluster of differentiation 8-positive (CD8+ ) lymphocytes and subjected to unsupervised hierarchical analyses. A derivation cohort using 4 of 12 IAMs which were available in all participants (percent perforin-positive and percent granzyme-positive CD8 cells, absolute number of CD8 cells, soluble interleukin-2 receptor level) were sufficient to define high (n=10), medium (n=15), and low IAM (n=22) cohorts. High IAM was more frequent among those with indeterminate etiology than those with defined diagnoses (80% versus 20%, P<0.001). High IAM was associated with higher peak serum total bilirubin levels than low IAM (median peak 21.7 versus 4.8mg/dL, P<0.001) and peak coma grades. The 21-day outcomes differed between groups, with liver transplantation more frequent in high IAM participants (62.5%) than those with medium (28.2%) or low IAM (4.8%) (P=0.002); no deaths were reported. In an independent validation cohort (n=71) enrolled in a prior study, segregation of IAM groups by etiology, initial biochemistries, and short-term outcomes was similar, although not statistically significant. High serum aminotransferases, total bilirubin levels, and leukopenia at study entry predicted a high immune activation profile. Four circulating T-lymphocyte activation markers identify a subgroup of PALF participants with evidence of immune activation associated with a distinct clinical phenotype and liver transplantation; these biomarkers may identify PALF participants eligible for future clinical trials of early targeted immunosuppression.

Activated CD8 T-cell Hepatitis in Children With Indeterminate Acute Liver Failure: Results From a Multicenter Cohort.

In many pediatric acute liver failure (PALF) cases, a diagnosis is not identified, and the etiology is indeterminate (IND-PALF). Our pilot study found dense CD8 T-cell infiltrates and increased T-cell clonality in liver specimens from IND-PALF patients. We aimed to validate these findings in a multicenter cohort with investigators blinded to diagnosis. PALF Study Group registry subjects with IND-PALF (n = 37) and known diagnoses (DX-PALF) (n = 18), ages 1 to 17 years, with archived liver tissue were included. Liver tissue slides were stained for T cells (CD8 and CD4), B cells (CD20), macrophages (CD163), perforin, and tissue resident-memory T cells (Trm, CD103), and scored as minimal, moderate, or dense. Lymphocytes were isolated from frozen liver tissue for T-cell receptor beta (TCRβ) sequencing. Dense hepatic CD8 staining was found in significantly more IND-PALF (n = 29, 78%) compared with DX-PALF subjects (n = 5, 28%) (P = 0.001). IND-PALF subjects were more likely to have dense or moderate perforin (88% vs 50%, P = 0.03) and CD103 (82% vs 40%, P = 0.02) staining compared with DX-PALF subjects. TCRβ sequencing of 15 IND-PALF cases demonstrated increased clonal overlap compared with 6 DX-PALF cases (P = 0.002). Dense infiltration of effector Trm CD8 T cells characterizes liver tissue from IND-PALF subjects. Increased clonality suggests the T-cell expansion is antigen(s)-driven as opposed to a nonspecific inflammatory response. These findings support CD8 staining as a new biomarker of the activated CD8 T-cell PALF phenotype. Future studies are needed to characterize potential antigens, host risk factors, and inflammatory pathways with the goal of developing targeted therapies.

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Etiology, clinical presentation, and outcome of children with fulminant hepatic failure: Experience from a tertiary center in Pakistan

Objectives:To determine etiologies, clinical presentations and outcomes of children with fulminant hepatic failure in the first liver transplant center of Pakistan.Methods:It was a retrospective, observational study, conducted in Paediatric Gastroenterology Department of Shifa International Hospital. Patients between one month to 16 years were included who fulfilled the Pediatric Acute Liver Failure study group (PALFSG) definition of acute liver failure as biochemical evidence of liver injury with no known co-existing chronic liver disease, coagulopathy not corrected by vitamin K, an International Normalized Ratio (INR) greater than 1.5 if the patient has encephalopathy, or greater than 2.0 if the patient does not have encephalopathy. The data collected was recorded on a self-constructed proforma after IRB approval.Results:There were 28 patients in the study which ncluded 17 males and 11 females with a mean age of 72.86±52.50 months. The most common etiologies were Hepatitis A (29%) in isolation or co-infection with Wilson Disease, typhoid fever. It was followed by seronegative hepatitis (29%). Majority (64%) had acute presentation (7 to 28 days), jaundice (82%) being the most common symptom. Severity of encephalopathy was significantly associated with outcome (p=0.02). There were 6 (21%) patients who succumbed to death.Conclusions:The study highlights infective diseases as the predominant etiology causing fulminant liver failure in children. Our study highlights lower mortality in children

Hepatic Encephalopathy in Children With Acute Liver Failure: Utility of Serum Neuromarkers.

Pediatric acute liver failure (PALF) is a public heath burden, often requiring prolonged hospitalization and liver transplantation. Hepatic encephalopathy (HE) is a complication of PALF with limited diagnostic tools to predict outcomes. Serum neurological markers (neuron-specific enolase, S100β, and myelin basic protein) can be elevated in traumatic or ischemic brain injury. We hypothesized that these neuromarkers would be associated with the development of HE in PALF. PALF study participants enrolled between May 2012 and December 2014 by 12 participating centers were the subjects of this analysis. Daily HE assessments were determined by study investigators. Neurological and inflammatory markers were measured using enzyme-linked immunosorbent assay and MILLIPLEX techniques, respectively. To model encephalopathy, these markers were log2 transformed and individually examined for association with HE using a generalized linear mixed model with a logit link and random intercept. Eighty-two children had neurological and inflammatory marker levels and HE assessments recorded, with the majority having assessments for 3 days during their illness. An indeterminate diagnosis (29%) was most common and the median age was 2.9 years. Significant associations were observed for HE with S100β (odds ratio 1.16, 95% confidence interval [1.03-1.29], P = 0.04) and IL-6 (odds ratio 1.24 [1.11-1.38], P = 0.006). Serum S100β and IL-6 are associated with HE in children with PALF. Measuring these markers may assist in assessing neurological injury in PALF, impacting clinical decisions.

HMGB1 is a Central Driver of Dynamic Pro-inflammatory Networks in Pediatric Acute Liver Failure induced by Acetaminophen

Acetaminophen (APAP) overdose (APAPo) is predominant in the NIH Pediatric Acute Liver Failure (PALF) Study. We assayed multiple inflammatory mediators in serial serum samples from 13 PALF survivors with APAPo + N-acetylcysteine (NAC, the frontline therapy for APAPo), 8 non-APAPo + NAC, 40 non-APAPo non-NAC, and 12 non-survivors. High Mobility Group Box 1 (HMGB1) was a dominant mediator in dynamic inflammation networks in all sub-groups, associated with a threshold network complexity event at d1–2 following enrollment that was exceeded in non-survivors vs. survivors. We thus hypothesized that differential HMGB1 network connectivity after day 2 is related to the putative threshold event in non-survivors. DyNA showed that HMGB1 is most connected in non-survivors on day 2–3, while no connections were observed in APAPo + NAC and non-APAPo + NAC survivors. Inflammatory dynamic networks, and in particular HMGB1 connectivity, were associated with the use of NAC in the context of APAPo. To recapitulate hepatocyte (HC) damage in vitro, primary C57BL/6 HC and HC-specific HMGB1-null HC were treated with APAP + NAC. Network phenotypes of survivors were recapitulated in C57BL/6 mouse HC and were greatly altered in HMGB1-null HC. HC HMGB1 may thus coordinate a pro-inflammatory program in PALF non-survivors (which is antagonized by NAC), while driving an anti-inflammatory/repair program in survivors.

Liver Transplant Listing in Pediatric Acute Liver Failure: Practices and Participant Characteristics.

Liver transplant (LT) decisions in pediatric acute liver failure (PALF) are complex. Three phases of the PALF registry, containing data on 1,144 participants over 15 years, were interrogated to characterize clinical features associated with listing status. A decrease in the cumulative incidence of listing (P < 0.005) and receiving (P < 0.05) LT occurred without an increase in the cumulative incidence of death (P = 0.67). Time to listing was constant and early (1 day; quartiles 1-3 = 0-2; P = 0.88). The most frequent reasons for not listing were "not sick enough" and "medically unsuitable." Participants listed for LT were more likely male, with coma grade scores >0; had higher international normalized ratio, bilirubin, lactate, and venous ammonia; and had lower peripheral lymphocytes and transaminase levels compared to those deemed "not sick enough." Participants listed versus those deemed "medically unsuitable" were older; had higher serum aminotransferase levels, bilirubin, platelets, and albumin; and had lower lactate, venous ammonia, and lymphocyte count. An indeterminate diagnosis was more prevalent in listed participants. Ventilator (23.8%) and vasopressor (9.2%) support occurred in a significant portion of listed participants but less frequently than in those who were not "medically suitable." Removal from the LT list was a rare event. Conclusion: The cumulative incidence of listing for and receiving LT decreased throughout the PALF study without an increase in the cumulative incidence of death. While all participants fulfilled entry criteria for PALF, significant differences were noted between participants listed for LT and those deemed "not sick enough" as well as those who were "medically unsuitable." Having an indeterminate diagnosis and a requirement for cardiopulmonary support appeared to influence decisions toward listing; optimizing listing decisions in PALF may reduce the frequency of LT without increasing the frequency of death.

6. Prognostic markers in pediatric acute liver failure with advanced hepatic encephalopathy

Background and Aims: Pediatric acute liver failure (PALF) with advanced hepatic encephalopathy (HE) has been seen as a group with relatively poor prognosis. Early detection of patients with poor prognosis can improve the outcome of the PALF in this subgroup. This study was undertaken to identify the prognostic markers in PALF with advanced HE. Methods: All cases of PALF presenting to this centre during January 2012 to January 2018, with HE grade III and IV were included in the study. PALF was defined as per the PALF study group. HE was classified as per the age appropriate West Haven Classification. Results: In the study period 156 children with PALF were admitted to this centre, of which 78 had HE grade III and IV. Median age of the children was 9.05 years (IQR 4.2–13). Forty –four (56.4%) had a viral etiology. Of the 78 PALF with HE grade III & IV, 26 survived with native liver, 10 were transplanted and 42 died. Overall survival and survival with native liver were 46.15% and 33.33% respectively. On logistic regression analysis (LRA), poor prognosis (death or need for liver transplant) was associated with a higher Pediatric End Stage Liver Disease (PELD) score at 72 h (Poor prognosis: 39.72 ± 10.5 vs. Survivors: 17.42 ± 9.2, OR1.24; 95%CI: 1.08 to 1.44; p-value 0.003), and longer jaundice to encephalopathy interval (JEI) (Poor prognosis: 20 ± 14.5 vs. Survivors: 2.88 ± 1.81 days, OR 1.43; 95%CI:1.02 to 2.01; p-value 0.038). Viral etiology was protective (OR 0.055; 95%CI: 0.003 to 0.857; p-value 0.038). The model predicted 86% of the variation in the outcome (R square 0.858) and correctly classified it in 93.2%. The ROC analysis revealed PELD score at 72 h ≥28 (Sensititvity 93.9% and Specificity 84.6%), and JEI of >6 days (Sensititvity 75.8% and Specificity 100%), to be the best discriminators with an AUROC of 94% and 84% respectively (Fig. 1). Conclusions: Outcome in a case of PALF with advanced HE can be predicted correctly in 93.2% cases by a PELD score at 72 h of ≥28, JEI of >6 days and viral etiology. The authors have none to declare.

Presenting Features and Prognosis of Ischemic and Nonischemic Neonatal Liver Failure.

To describe the epidemiological features, clinical characteristics and outcomes of neonates diagnosed with liver failure, as well as determine prognostic factors. Cohort study conducted at a single tertiary referral and university-affiliated pediatric center. Hospital records of all neonates diagnosed with liver failure between January 2003 and December 2015 were retrospectively reviewed, and data on clinical and laboratory findings, treatment, and outcomes were collected. Survival analysis (Kaplan-Meier) and Cox regression were performed to identify prognostic factors at diagnosis. Liver failure diagnosis was established using the pediatric acute liver failure study group's diagnostic criteria for every patient with coagulopathy and biochemical pattern of liver disease. Forty-five patients were included. In our series, most cases were secondary to ischemia (28.9%). Other causes were neonatal hemochromatosis (17.8%), viral infections (13.3%), and inborn errors of metabolism (13.3%). A total 55.6% (25/45) of the patients died (median age: 16 days; range 1-235 days). Alanine aminotransferase (ALT) at diagnosis was associated with higher mortality or the need for liver transplantation on day 21 after diagnosis (P = .006). For every 500 IU/L increase in ALT serum levels, the mortality/liver transplantation rate increased 1.3 times (hazard ratio 95% confidence interval: 1.1-1.6). Although ischemic neonatal acute liver failure presents with higher ALT levels, these cases appear to have better outcomes. Higher international normalized ratio tended to increase mortality/transplantation (hazard ratio 1.02; 95% confidence interval 0.91-1.2). Neonatal liver failure should perhaps be considered in the differential diagnoses of any coagulopathy. ALT and international normalized ratio levels at diagnosis could predict prognosis in the short term. Ischemic liver failure appears to have a better prognosis.

Prevalence and Significance of Autoantibodies in Children With Acute Liver Failure.

The purpose of the present study is to estimate autoantibody (auto-AB) frequency, clinical characteristics, and 21-day outcome of participants in the Pediatric Acute Liver Failure Study Group (PALFSG) by antinuclear antibody, smooth muscle antibody, and liver-kidney microsomal (LKM) antibody status. Auto-ABs were determined at local and/or central laboratories. Subjects were assigned to autoimmune hepatitis (AIH), indeterminate, and other diagnoses groups. Between 1999 and 2010, 986 subjects were enrolled in the PALFSG. At least 1 auto-AB result was available for 722 (73.2%). At least 1 auto-AB was positive for 202 (28.0%). Diagnoses for auto-AB+ subjects were AIH (63), indeterminate (75), and other (64). Auto-ABs were more common in Wilson disease (12/32, 37.5%) compared with other known diagnoses (52/253, 20.6%, P = 0.03). LKM+ subjects were younger (median 2.4 vs 9.1 years, P < 0.001) and more likely to undergo liver transplantation (53.3% vs 31.4% P = 0.02) than other auto-AB+/LKM- subjects. Steroid treatment of subjects who were auto-AB+ was not significantly associated with survival and the subgroup with known diagnoses other than AIH had a higher risk of death. Auto-ABs are common in children with acute liver failure, occurring in 28%. Auto-AB+ subjects have similar outcomes to auto-AB negative subjects. LKM+ children are younger and more likely to undergo liver transplantation compared with other auto-AB+ subjects. Although auto-AB may indicate a treatable condition, positivity does not eliminate the need for a complete diagnostic evaluation because auto-ABs are present in other conditions. The significance of auto-AB in pediatric acute liver failure remains uncertain, but LKM+ appears to identify a unique population of children who merit further study.

Lactate and Lactate: Pyruvate Ratio in the Diagnosis and Outcomes of Pediatric Acute Liver Failure

To assess the accuracy of blood lactate and lactate: pyruvate molar ratio (L:P) as a screen for mitochondrial, respiratory chain, or fatty acid oxidation disorders in children with pediatric acute liver failure (PALF); to determine whether serum lactate ≥ 2.5 mmol/L or L:P ≥ 25 correlated with biochemical variables of clinical severity; and to determine whether lactate or L:P is associated with clinical outcome at 21 days. Retrospective review of demographic, clinical, laboratory, and outcome data for PALF study group participants who had lactate and pyruvate levels collected on the same day. Of 986 participants, 110 had lactate and pyruvate levels collected on the same day. Of the 110, the etiology of PALF was a mitochondrial disorder in 8 (7%), indeterminate in 65 (59%), and an alternative diagnosis in 37 (34%). Lactate, pyruvate, and L:P were similar among the 3 etiologic groups. There was no significant association between the initial lactate or L:P and biochemical variables of clinical severity or clinical outcome at 21 days. A serum lactate ≥ 2.5 mmol/L and/or elevated L:P was common in all causes of PALF, not limited to those with a mitochondrial etiology, and did not predict 21-day clinical outcome. ClinicalTrials.gov: NCT00986648.

Outcomes of Children With and Without Hepatic Encephalopathy From the Pediatric Acute Liver Failure Study Group

Hepatic encephalopathy (HE) is challenging to identify in children with acute liver failure and was not a requirement for enrollment into the Pediatric Acute Liver Failure Study Group (PALFSG). The outcomes of PALFSG participants presenting with and without HE are presented. PALFSG participants were classified based on daily assessment of HE during the first 7 days following study enrollment: group 1-never developed HE; group 2-no HE at enrollment with subsequent HE development; and group 3-HE at study enrollment. Clinical and biochemical parameters and outcomes of death, spontaneous recovery, or liver transplantation were compared between groups. Data from 769 PALFSG (54% boys; median age 4.2 years; range 0-17.9 years) participants were analyzed, with 277 in group 1 (36%), 83 in group 2 (11%), and 409 in group 3 (53%). Mortality occurred in 11% of all participants and was highest among group 3 participants who demonstrated persistent grade III-IV HE (55%) or showed progression of HE (26%). Eleven (4%) group 1 participants died within 21 days of enrollment. Spontaneous recovery was highest in group 1 (79%) and lowest in group 2 (25%; P < 0.001). Mortality 21 days after enrollment was highest in participants enrolled with severe HE (grades III or IV) or demonstrating HE progression. Four percent of participants without recorded clinical HE in the 7 days after enrollment, however, died within 21 days. Improved assessment of neurological injury and pediatric acute liver failure prognostication schema are needed.

Data-Driven Modeling for Precision Medicine in Pediatric Acute Liver Failure.

Absence of early outcome biomarkers for Pediatric Acute Liver Failure (PALF) hinders medical and liver transplant decisions. We sought to define dynamic interactions among circulating inflammatory mediators to gain insights into PALF outcome sub-groups. Serum samples from 101 participants in the PALF study, collected over the first 7 days following enrollment, were assayed for 27 inflammatory mediators. Outcomes (Spontaneous survivors [S, n=61], Non-survivors [NS, n=12], and liver transplant patients [LTx, n=28]) were assessed at 21 days post-enrollment. Dynamic interrelations among mediators were defined using data-driven algorithms. Dynamic Bayesian Network inference identified a common network motif with HMGB1 as a central node in all patient sub-groups. The networks in S and LTx were similar, and differed from NS. Dynamic Network Analysis suggested similar dynamic connectivity in S and LTx, but a more highly-interconnected network in NS that increased with time. A Dynamic Robustness Index calculated to quantify how inflammatory network connectivity changes as a function of correlation stringency differentiated all three patient sub-groups. Our results suggest that increasing inflammatory network connectivity is associated with non-survival in PALF, and may ultimately lead to better patient outcome stratification.

Acetaminophen Adducts Detected in Serum of Pediatric Patients With Acute Liver Failure.

Previous studies in patients with acute liver failure identified acetaminophen (APAP) protein adducts in the serum of 12% and 19% of children and adults, respectively, with acute liver failure of indeterminate etiology. This article details the testing of APAP adducts in a subset (n = 393) of patients with varied diagnoses in the Pediatric Acute Liver Failure Study Group (PALFSG). Serum samples were available from 393 participants included in the PALFSG registry. Adduct measurement was performed using validated methods. Participants were grouped by diagnostic category as known APAP overdose, known other diagnosis, and indeterminate etiology. Demographic and clinical characteristics and participant outcomes were compared by adduct status (positive or negative) within each group. APAP adduct testing was positive in 86% of participants with known APAP overdose, 6% with other known diagnoses, and 11% with an indeterminate cause of liver failure. Adduct-positive participants were noted to have marked elevation of serum alanine aminotransferase and aspartate aminotransferase coupled with total serum bilirubin that was significantly lower than adduct-negative patients. In the indeterminate group, adduct-positive patients had different outcomes than adduct-negative patients (P = 0.03); spontaneous survival was 16 of 21 (76%) in adduct-positive patients versus 75 of 169 (44%) in adduct-negative patients. Prognosis did not vary by adduct status in patients with known diagnoses. Furthermore, study is needed to understand the relation of APAP exposure, as determined by the presence of APAP adducts, to the clinical phenotype and outcomes of children with acute liver failure.

Neuropsychological functioning and health-related quality of life: pediatric acute liver failure study group results.

Pediatric acute liver failure (PALF) is a rare but serious event, with poorly understood functional outcomes. The goal was to determine the prevalence of reduced neuropsychological functioning and health-related quality of life (HRQOL) following PALF. This multicenter study examined neuropsychological functioning and HRQOL 1 to 6 (median 3.8) years after PALF. Participants ages 6 to 16 (median 9.9) years were recruited from the PALF registry and administered measures of intelligence, visual spatial/visual motor coordination, attention, executive function, depression, and adaptive skills. HRQOL and fatigue were assessed using the Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL 4.0) and PedsQL Multidimensional Fatigue Scale. A total of 36 patients participated; 50% were boys and 67% were white. Median age at PALF was 5.6 years. A history of grade 3 or 4 hepatic encephalopathy was reported in 5/36 (14%) participants and 23/36 (64%) received a liver transplant. Visual spatial ability was significantly better than norms (P = 0.009), but motor coordination was worse (P = 0.04). Teachers (P = 0.04 to P < 0.0001) and parents (P = 0.005) reported more executive deficits versus norms, and participants had worse attention (P = 0.02). Participants did not differ significantly from norms on IQ, depression, or adaptive functioning. All of the child self-report PedsQL Generic Core and fatigue scales were significantly lower than a matched healthy sample (P = 0.001 to P < 0.0001) and parent proxy report was lower on the fatigue scales (P = 0.001 to P < 0.0001). Long-term PALF survivors demonstrate average IQ and visual spatial ability, but greater than expected impairments in motor skills, attention, executive function, HRQOL, and fatigue.

Validity of pediatric index of mortality 2 (PIM2) score in pediatric acute liver failure.

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Analysis of viral testing in nonacetaminophen pediatric acute liver failure.

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.