A Learning Collaborative Approach Increases Specificity of Diagnosis of Acute Liver Failure in Pediatric Patients

doi:10.1016/j.cgh.2018.04.050

Clinical Gastroenterology and Hepatology

Volume 16, Issue 11, November 2018, Pages 1801-1810.e3

https://doi.org/10.1016/j.cgh.2018.04.050 Get rights and content

Background & Aims

Many pediatric patients with acute liver failure (PALF) do not receive a specific diagnosis (such as herpes simplex virus or Wilson disease or fatty acid oxidation defects)—they are left with an indeterminate diagnosis and are more likely to undergo liver transplantation, which is contraindicated for some disorders. Strategies to facilitate complete diagnostic testing should increase identification of specific liver diseases and might reduce liver transplantation. We investigated whether performing recommended age-specific diagnostic tests (AS-DTs) at the time of hospital admission reduces the percentage PALFs with an indeterminate diagnosis.

Methods

We performed a multinational observational cohort study of 658 PALF participants in the United States and Canada, enrolled at 10 medical centers, during 3 study phases from December 1999 through December 2014. A learning collaborative approach was used to implement AS-DT using an electronic medical record admission order set at hospital admission in phase 3 of the study. Data from 10 study sites participating in all 3 phases were compared before (phases 1 and 2) and after (phase 3) diagnostic test recommendations were inserted into electronic medical record order sets.

Results

The percentage of subjects with an indeterminate diagnosis decreased significantly between phases 1–2 (48.0%) and phase 3 (to 30.8%) (P = .0003). The 21-day cumulative incidence rates for liver transplantation were significantly different among phase 1 (34.6%), phase 2 (31.9%), and phase 3 (20.2%) (P = .030). The 21-day cumulative incidence rates for death did not differ significantly among phase 1 (17.9%), phase 2 (11.9%), and phase 3 (11.3%) (P = .20).

Conclusions

In a multinational study of children with acute liver failure, we found that incorporating diagnostic test recommendations into electronic medical record order sets accessed at time of admission reduced the percentage with an indeterminate diagnosis that may have reduced liver transplants without increasing mortality. Widespread use of this approach could significantly enhance care of acute liver failure in children.

Section snippets

Materials and Methods

This observational cohort study was conducted by the PALF study group funded by the National Institute of Diabetes and Digestive and Kidney Diseases (UO1-DK072146). Patients <18 years of age were eligible for enrollment if they met the following criteria: (1) no prior evidence of chronic liver disease, (2) biochemical evidence of acute liver injury, and (3) hepatic insufficiency characterized by prothrombin time ≥20 seconds or international normalized ratio ≥2.0 (not correctable with vitamin K)

Results

Twenty-four sites in the PALF consortium enrolled participants in at least 1 phase and 10 participated in all 3 phases (Supplementary Table 2). Demographic, diagnostic, and laboratory data in the overall PALF cohort (n = 1144) and the 10-site subcohort (n = 658; P1 + P2 [n = 515] and P3 [n = 143]) are reported (Table 1). P3 participants were younger, more likely to be male, and had similar total bilirubin and alanine aminotransferase levels as those in combined P1 and P2. Differences in

Discussion

Using principles of collaborative learning, PALF investigators implemented recommendations that impacted diagnostic testing, final diagnosis, and outcome.7, 8 Following integration of AS-DT into admission EMR-based order sets, diagnostic testing increased and percentage of participants with specified diagnosis increased, whereas percentage of both indeterminate diagnosis and LT decreased. LT use was reduced without increasing mortality. These efforts affirm the report from the Institute of

Acknowledgments

Key individuals who have actively participated in the PALF studies by site are listed next. Current Sites, Principal Investigators and Coordinators: Robert H. Squires, MD, Kathryn Bukauskas, RN, CCRC, Madeline Schulte, RN, BSN, Clinical Research Coordinator (Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania); Michael R. Narkewicz, MD, Michelle Hite, MA, CCRC (Children's Hospital Colorado, Aurora, Colorado); Kathleen M. Loomes, MD, Elizabeth B. Rand, MD, David Piccoli, MD,

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Surveillance identified 377 patients from 45 US jurisdictions with hepatitis of unknown aetiology with onset from Oct 1, 2021, to Sept 30, 2022. The median age of patients was 2·8 years (IQR 1·2–5·0) and 192 (51%) were male, 184 (49%) were female, and one patient had sex unknown. Only 22 (6%) patients had a notable predisposing underlying condition. 347 patients (92%) were admitted to hospital, 21 (6%) subsequently received a liver transplant, and nine (2%) died. Among the 318 patients without notable underlying conditions, 275 were tested for adenovirus. Of these 116 (42%) had at least one positive specimen, and species F type 41 was the most frequent type identified (19 [73%] of 26 typed specimens were HAdV-41). Proportions of patients who had acute liver failure, received a liver transplant, and died were similar between those who tested positive for adenovirus compared with those who tested negative. Adenovirus species F was detected by polymerase chain reaction in nine pathology liver evaluations, but not by immunohistochemistry in seven of the nine with adequate liver tissue available. Interviews with caregivers yielded no common exposures.
Adenovirus, alone or in combination with other factors, might play a potential role in acute hepatitis among immunocompetent children identified in this investigation, but the pathophysiologic mechanism of liver injury is unclear. To inform both prevention and intervention measures, more research is warranted to determine if and how adenovirus might contribute to hepatitis risk and the potential roles of other pathogens and host factors.
None.
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To describe the usefulness of rapid whole genome sequencing (rWGS) in a cohort of children presenting with acute liver dysfunction.
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In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency.
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Citation Excerpt :
The present analysis was strictly limited to genuine iPALF in infancy for which other conditions affecting the liver have been excluded. Timely selection of appropriate liver transplantation candidates with PALF has always been challenging, but it has been suggested that better delineation and refinement of possible etiologies could significantly reduce the number of unnecessary transplantation.30,31 This could be because a rapidly identified cause could be managed medically or, perhaps more importantly, because transplantation could be avoided in those who would not benefit owing to their underlying irreversible pathology.
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We retrospectively analyzed 78 children with PALF aged <24 months referred over almost 2 decades. The studied patients with a phenotype of HLH syndrome had a comprehensive immunologic workup, including additional genetic analysis for primary immunologic causes.
Thirty of the 78 children had the HLH phenotype and underwent genetic assessment, which demonstrated positive findings in 19 (63.3%), including 9 (30%) with biallelic primary HLH mutations and 10 (33.3%) with heterozygous mutations and/or polymorphisms. The most common form of primary HLH was familial hemophagocytic lymphohistiocytosis (FHL)-2, diagnosed in 6 children, 4 of whom had a c.50delT (p.Leu17ArgfsTer34) mutation in the PRF1 gene. Three patients with primary HLH received genetic diagnoses of FHL-3, Griscelli syndrome, and LRBA (lipopolysaccharide-responsive vesicle trafficking, beach- and anchor-containing) protein deficiency. Overall mortality in the series was 52.6% (10 of 19), and mortality in children with a documented biallelic pathogenic HLH mutation (ie, primary HLH) was 66.6% (6 of 9). Two children underwent liver transplantation, and 4 children underwent emergency hematopoietic stem cell transplantation; all but 1 child survived medium term.
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: Conflicts of interest These authors disclose the following: Phil Rosenthal has consulted for Gilead, Abbvie, Roche/Genentech, Intercept, Alexion, Retrophin, Albireo, and Audentes; received research grants from Gilead, Abbvie, BMS, and Roche/Genentech; and served on the speakers’ bureau for Retrophin. Rene Romero has consulted for Gilead. Robert H. Squires received royalties from Up-To-Date. The remaining authors disclose no conflicts.

: Funding Supported by the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases, U01 DK072146).

View full text

Original articlePancreas, biliary tract, and liverA Learning Collaborative Approach Increases Specificity of Diagnosis of Acute Liver Failure in Pediatric Patients

Background & Aims

Methods

Results

Conclusions

Section snippets

Materials and Methods

Results

Discussion

Acknowledgments

J Hepatol

Am Heart J

Hepatology

Gastroenterol Clin North Am

J Hepatol

Clin Radiol

Gastroenterology

Clin Ther

J Pediatr

Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group

J Pediatr

Clinical course among cases of acute liver failure of indeterminate diagnosis

J Pediatr

Evaluation of the liver injury unit scoring system to predict survival in a multinational study of pediatric acute liver failure

J Pediatr

Pattern of diagnostic evaluation for the causes of pediatric acute liver failure: an opportunity for quality improvement

J Pediatr

An update of N-acetylcysteine treatment for acute acetaminophen toxicity in children

Curr Opin Pediatr

Utilizing a collaborative learning model to promote early extubation following infant heart surgery

Pediatr Crit Care Med

A collaborative approach reduces the learning curve and improves outcomes in laparoscopic nephrectomy

Surg Endosc

Fulminant hepatitis and acute liver failure

Analysis of viral testing in nonacetaminophen pediatric acute liver failure

J Pediatr Gastroenterol Nutr

Characterization and outcomes of young infants with acute liver failure

J Pediatr

Improving diagnosis in health care–the next imperative for patient safety

N Engl J Med

Original article
Pancreas, biliary tract, and liver
A Learning Collaborative Approach Increases Specificity of Diagnosis of Acute Liver Failure in Pediatric Patients