This document summarizes a case series of 44 children in the UK who presented with acute hepatitis of unknown cause between January and April 2022. The majority (86%) spontaneously improved, while 6 children (14%) experienced acute liver failure requiring transplantation. Human adenovirus was detected via molecular testing in 90% of cases tested. While the exact cause remains unclear, a working hypothesis is an abnormal immune response to a common virus like adenovirus in the context of reduced exposure during pandemic lockdowns. Ongoing investigation is needed to better understand the natural history and immune mechanisms involved.

1. 2
KELOMPOK
DIGESTIVE

2. Ketua : dr. Renno Firaldy (Ilmu Penyakit Dalam)
Anggota :
dr. Ailen Oktaviana Hambalie (Patologi Anatomi)
dr. Annisa Safira Nurdila (Radiologi)
dr. Fatimah Rizky Fitriani (Patologi Klinik)
dr. Fendy Ferdian (Patologi Klinik)
dr. Fildzah Febriana Iskandar (Mikrobiologi Klinik)

3. Since January 2022: ↑ acute hepatitis
of unknown cause in children (mainly in UK) 
ongoing investigations
Retrospective study: MRs of children ≤ 10 years old
referred to a pediatric liver transplant center in the
UK, had hepatitis that met UKHSA case definition
(January 1st – April 11th, 2022)
Case definition (UKHSA):
Acute hepatitis (not A-E); no metabolic,
inherited/genetic, congenital, mechanical cause;
serum aminotransferase > 500 IU/L

4. Introduction

5. 10 cases of acute hepatitis of
unknown cause in Scotland (January-
March 2022)  WHO: disease
outbreak notification (April 15th, 2022)
U.K. Health
Security Agency
(UKHSA)
May 19, 2022
UK :
197 confirmed &
possible cases
January 1 - May 16
− Jaundice (68.8%)
− Vomiting (57.6%)
− Pale stools (42.7%)
− GI symptoms
Diarrhea (43.1%)
Nausea (25.7%)
Abdominal pain (36.1%)
All children: negative
tests for common
infective causes
Hepatitis A - E, CMV,
and EBV
11 children (5.6%) underwent liver transplantation
179 underwent molecular
testing for human adenovirus
116 (64.8%)
positive

6. Methods

7. PATIENTS
Inclusion: ≤ 10 years old with acute hepatitis consistent with confirmed
case definition of the UKHSA (not hep. A – E, no metabolic,
inherited/genetic, congenital, or mechanical cause, serum
aminotransferase level >500 IU / L that were referred to the unit (January
1 - April 11, 2022)
TESTING AND DEFINITIONS
• Demographic, biochemical, and radiologic data  from NORSe records and inpatient notes.
• CBC, liver biochemical tests, coagulation screening, viral serologic tests for hep. A - E, molecular
tests were recorded for CMV, EBV, SARS-CoV-2, parvovirus, and adenovirus.
• Interval of onset of jaundice - peak serum bilirubin and ALT levels were recorded.

8. TESTING AND DEFINITIONS
• Some had additional testing due to ↑ liver aminotransferase levels.
• All had abdominal USG  liver histologic findings included if biopsy
sample available / if the liver was explanted for transplant.
TESTING AND DEFINITIONS
Acute liver failure : coagulopathy (not corrected with vit. K) with PT > 15 s and
INR > 1.5 in patients with encephalopathy, or PT > 20 s and INR > 2 in patients
with or without encephalopathy.

9. TREATMENT
• Acute liver failure protocol  IV broad-spectrum antibiotics, antifungal, PPI, vit. K, fluid restriction to
70% maintenance level + dextrose to maintain normoglycemia.
• Children with no liver failure  supportive (vit. K, A, D, E and ursodeoxycholic acid) and monitored
closely (blood tests) to detect clinical deterioration.
• Children with acute liver failure  super-urgent category 6 for liver transplant  prioritized over other
indications.
• Cidofovir after transplant  only if whole blood PCR for human adenovirus viral load > 500 copies/mL.

10. 3. Death
1. Improving condition (resolving liver
dysfunction: consistent decrease of bilirubin
& aminotransferase + normal coagulation)
Clinical outcome categories:
2. Liver transplant
STATISTICAL ANALYSIS
Number of days from initial presentation to listing for liver
transplant time, from jaundice to encephalopathy, from listing
for transplant to transplant, and human adenovirus viral load on
PCR after transplant were reported as medians with a range.

11. Results

12. Patients Included in the Case Series : 50 children with acute hepatitis referred to our
center (January 1 - April 11, 2022)  44 met the definition of a confirmed case

15. • 38 children with acute hepatitis (86%) -> spontaneous improvement
• 6 (14%) -> worsened liver function and got liver transplant -> 5 of them
had rapidly progressive encephalopathy within 1 week
• 5 of 6 patients tested positive of adenovirus infection
• 4 of 5 patients with (+) adenovirus infection received
Cidofovir. Viral load decreased within 8 days
• 1 patient got no antivirus and had adenovirus viremia
until 26 days

16. Liver Findings
Microscopic (3 biopsy)
• Bile duct : normal size, mild to diffuse
inflammation  lymphocyte, plasma
cell, and eosinophils.
• Severe parenchymal disarray with
hepatocyte ballooning, canalicular
cholestasis, scattered apoptotic bodies
Gross (6 explanted)
•Small
•Smooth
•Gray with bile staining on the
cut surface
Children who recovered showed
panacinar necrosis, while explanted
ones showed parenchyma replaced
with a sheet of macrophages.
In summary: 44 confirmed (median age : 4): jaundice (93%),
vomiting (54%), diarrhea (32%). Human adenovirus molecular
test  27 of 30 (90%) (+). Acute fulminant liver failure  6
(14%)  all had a liver transplant. None died.
All of them showed improvement and were discharged home

17. Discussions

18. EPIDEMIOLOGY
INCIDENCE
A case series of 44 children with acute hepatitis
of unknown cause was referred to a pediatric
hepatology tertiary referral unit in UK, 2022.
Most of these young children were previously well.
The high incidence of progression to hepatic failure
warranting transplantation (in 14% of the patients)
underscores the severity of the illness.

19. Investigation for causative agent  ongoing
Results of biochemical tests in prodromal phase
suggested acute hepatitis
USG findings : gall bladder wall thickening +
pericholecystic fluid, abdominal lymph nodes, mild
hepatosplenomegaly  possible viral cause.
Extensive viral testing  adenovirus (most
common); other viruses identified infrequently.
UKHSA3 : human adenovirus subtype 41F (primarily
known to cause gastroenteritis and differs in tissue
tropism from respiratory & ocular infections subtypes).
Positive adenovirus tests on routine clinical
evaluations are recorded in second-generation
surveillance system in UK
INVESTIGATION

20. Reports of positive human adenovirus tests from any
sampling site
Blood, stool, or respiratory secretions — in children 1 - 4
years old  more common in November 2021 - April 2022 than
previous 5 years.
The comparison warrants caution because the testing and reporting
procedures are variable and influenced by clinical presentation.
Adenovirus infections: typically self-limiting in immunocompetent
children  may cause serious disseminated infection in
immunocompromised.
British Pediatric Surveillance Unit: a 13-month prospective study from
January 1, 2014: adenovirus caused acute infectious hepatitis in
hospitalized children in 6% of cases (5 of 81).
INVESTIGATION

21. The current cause of acute hepatitis in children is unclear  liver
histologic findings negative for viral inclusion bodies and immunostains
.
Working hypothesis  abnormal host response  possibly because of :
SARS-CoV-2 pandemic lockdown  lack of exposure
The epidemic of normal human adenovirus causing complications more frequently
Increased susceptibility to human adenovirus because of drugs, environment, or
concomitant virus coinfections (e.g. SARS- CoV-2).
With the exception of 1 patient with positive SARS-CoV-2 test 6 – 8 weeks before
presentation of acute hepatitis, there was no clear SARS-CoV-2 infection history.
It is difficultto be sure due to no symptoms or previous tests documentations.
Example: molecular testing for SARS-CoV-2 was positive in 11 of 39 children
(28%) tested at admission with acute hepatitis. Of the 13 children who underwent a
serologic test for SARS-CoV-2, 5 (38%) were positive.
INVESTIGATION

22. Pooled data in UKHSA technical briefing include 125 children
from England tested for SARS-CoV-2 (PCR / lateral flow test).
16 with positive tests  13 were positive on admission and 3
were positive 8 weeks before presentation.
UKHSA is undertaking retrospective serologic testing for
SARS-CoV-2 to explore its role in acute hepatitis pathogenesis
INVESTIGATION

23. October 2021 - February 2022: 9
children in Alabama, US  acute
hepatitis + human adenovirus viremia
Similar
pattern to this
cohort
.
Median age at presentation: 2 y 11 mo
(all previously healthy and presented
with GI illness before jaundice onset)
3 children had acute
liver failure
1 child recovered with
supportive measures
Other 2 children received cidofovir,
IVIG, and glucocorticoids, but did not
improve  liver transplantation.

24. No very high ferritin levels / other
diagnostic features that implicate
secondary hemophagocytic
lymphohistiocytosis as
contributing factor.
The presenting and peak
bilirubin and ALT, PTT,
and adenovirus loads on
PCR were higher in
children who got transplant
Small size of cohort
precludes meaningful
statistical comparisons.

25. Antivirus for human
adenovirus in
immunocompetent children
 not supported by RCT.
Cidofovir  standard in
immunocompromised solid organs &
bone marrow recipients  less clear
role for disseminated disease in
immunocompetent children  there are
reports of successful use.
↓ adenoviral loads after transplant with or
without cidofovir (4 and 1 child,
respectively). Time to reach viral load
<500/mm  longer in “no cidofovir” (26
days) than in “cidofovir” (2 - 16 days).
Lack of data on recommended
treatment duration
Case reports  treat until viral load
is undetectable  discontinue if
side effects seen.
A consensus clinical
framework is now available
in the UK for these children.
Human adenovirus possibly has
immunopathogenic mechanism of
injury  glucocorticoids + cidofovir
is being explored.

26. Not all follow-up results were
available  only 11 patients; 7
had normalization of liver
biochemical at 4 – 8 weeks
No deaths in this series
Children who recovered
without transplant
underwent follow-up blood
tests in regional hospitals.
All have been advised to have
ongoing monitoring for
aplastic anemia

27. Limitations:
• All cohorts of
patients evaluated
retrospectively
• Some data missing
If more data is
available  ↑
understanding
natural history and
immunopathogenesis
of the illness
Helpful in
planning
interventions
Further studies with
metagenomics and
immunologic
investigations of
hosts needed
Ongoing in UK 
understanding
hepatotropism

28. Diagnostic tests: molecular test of
whole blood for viruses, etc.
1.
The current increase of incidence of acute hepatitis
in young children. 14% of them in this cohort
underwent a liver transplant
Though new cases continue to be identified in the UK,
there is an overall decline, similar to the declining
prevalence of human adenovirus infection in 1-4 y.o.
2.
3. We should be vigilant in identifying children
with prodromal illness followed by jaundice
44 children with acute hepatitis of
uncertain cause  human adenovirus
were isolated in most of them (role not
established)

29. Critical Appraisal (JBI)
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30. √
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31. √
Pasien yang dimasukkan ke dalam penelitian adalah satu kelompok anak-anak yang memenuhi
kriteria hepatitis akut UKHSA pada usia dan jangka waktu tertentu di suatu fasilitas kesehatan
berdasarkan studi retrospektif, tidak ada kelompok lain.

32. √
Pasien yang dimasukkan ke dalam penelitian adalah satu kelompok anak-anak yang memenuhi
kriteria hepatitis akut UKHSA pada usia dan jangka waktu tertentu di suatu fasilitas kesehatan
berdasarkan studi retrospektif, tidak ada kelompok lain, jadi hanya diteliti satu kelompok itu saja

33. √
Pasien yang dimasukkan ke dalam penelitian adalah satu kelompok anak-anak yang memenuhi
kriteria hepatitis akut UKHSA pada usia dan jangka waktu tertentu di suatu fasilitas kesehatan
berdasarkan studi retrospektif. Pada pemeriksaan baru ditemukan ada yang memiliki human
adenovirus, ada yang tidak

34. √
Ya , di sini confounding yang bisa muncul adalah secondary hemophagocytic lymphohistiocytosis yang
bisa merancukan outcome

35. √
Ya , di sini confounding yang bisa muncul adalah secondary hemophagocytic lymphohistiocytosis yang
bisa merancukan outcome. Hal ini sudah diatasi sejak awal studi dengan cara membuat kriteria inklusi yang
jelas dan ketat

36. √
Ya , pada kriteria inklusi jelas disebutkan pasien seperti apa yang bisa masuk, dan dijelaskan lebih
jauh di bagian yang berbeda bahwa pasien kebanyakan dalam kondisi sehat sebelum masuk

37. √
Ya , 3 outcome klinis yang dilihat diukur dengan kriteria yang jelas (sehat, kebutuhan transplan hati,
meninggal). Kriteria transplan hati jelas

38. √
Ya , follow up dilakukan cukup lama, sejak pasien masuk RS (melalui rekam medis) hingga pasien
pulang dan di follow up di rumah sakit daerah masing-masing

39. √
Sebagian (11) pasien dilakukan follow up lengkap, sisanya data tidak ditemukan dan tidak terjangkau

40. √
Tidak, pasien loss of follow up dibiarkan saja, tidak dimasukkan studi

41. √
Ya , analisis statistic sudah tepat dan baik

42. Komentar
Menurut kelompok kami, jurnal ini sudah cukup baik, tetapi masih belum dapat dijadikan dasar
rekomendasi tatalaksana, tetapi bisa menjadi dasar dan memberi sedikit gambaran untuk apa yang
bisa dilakukan di masa depan. Beberapa poin yang kami tekankan:
1. Desain penelitian ini sedikit rancu antara retrospective cohort dan retrospective case series. Tidak
dijelaskan di jurnal secara tersurat desain yang digunakan apa
2. Penelitian ini memiliki loss of follow up yang cukup banyak dan tidak ada strategi khusus untuk
mencegah.
3. Ukuran sampel di sini masih terbilang kecil, bisa jadi karena memang ini penyakit baru
4. Perlu dilakukan penelitian lebih jauh, bisa berupa penelitian eksperimental atau RCT untuk
penyakit ini, terutama di daerah lain
5. Analisis data tidak tertulis secara tersurat menggunakan metode apa
6. Perlu dipertimbangkan beberapa bias yang bisa terjadi, misalnya kesalahan tulisan pada rekam
medis

43. Thank You