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Outbreak of hepatitis in children: clinical course of children with acute liver failure admitted to the intensive care unit

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A recent outbreak of acute non-A-E hepatitis with serum transaminases greater than 500 IU/L identified in children aged under 16 years reported in United Kingdom (UK) has become a serious cause for concern for public health authorities and paediatric liver and critical care services [1]. From 1 January to 16 May 2022, UK public health authorities have reported 197 cases with median age 3 years, male (50%), from all regions of UK with 11 children requiring liver transplantation (LT).

Paediatric liver services are centralised to 3 centres in the UK with King’s College Hospital (KCH), London being the largest paediatric LT centre. Eight children were admitted to paediatric intensive care unit (PICU) at KCH from February to May 2022. In this report, we describe the ICU course of these patients (Table 1). All but one were < 5 years old; all were from White ethnic background. All children presented with abdominal symptoms (diarrhoea and vomiting) followed by jaundice and raised transaminases (alanine aminotransferase (AST) and aspartate aminotransferase (AST) > 2500 IU/L) with adenovirus DNA positivity from whole blood. All patients were screened for an extended viral panel from blood, urine, stool and respiratory samples according to UK Health Security Agency (UKHSA) recommendations [1]. Two patients had history of SARS-CoV-2 in the preceding 8 weeks. 6 out of these 8 patients had antibodies positive for SARS-CoV-2, but all were tested via polymerase chain reaction (PCR) and resulted negative for SARS-CoV-2 and none had COVID vaccine. It must be noted that according to the technical briefing of the UKHSA 25 April 2022, population cumulative seropositivity of SARS-CoV-2 was 47% in 1–4 year olds and 67% in 5–11 years old in January–February 2022 (unpublished UKHSA seroprevalence data) [2]. Official recent update on the seroprevalence in this age group is awaited.

Table 1 Intensive care course of children admitted with acute liver failure due to hepatitis outbreak

The main reason for PICU admission was neurologic deterioration (hepatic encephalopathy) with rising ammonia, lactate and international normalized ratio (INR) (peak values—Table 1). Patients were neuro-monitored with transcranial Dopplers (TCD) and reversed jugular venous saturations. Four patients had abnormal pulsatility index on TCD and 6 showed low reversed jugular venous saturations (lowest being 25.9%) requiring intervention. They were neuro-protected with early initiation of high-volume continuous kidney replacement therapy (CKRT) (minimum CKRT dose-60 mL/kg/h initiated within 24 h of PICU admission), plasma exchange, use of hypertonic saline, noradrenaline to maintain cerebral perfusion pressure, temperature control and thiopentone infusion. All received N-acetylcysteine and those positive for adenovirus received at least 2 doses of cidofovir.

We used INR > 4 as the LT listing criteria. All eight children survived with six requiring LT (one was re-transplanted) and two survived without LT with one of them delisted after 6 days on the super-urgent list as his clinical and biochemical condition improved. One patient received methylprednisolone for anti-nuclear antibody positivity. Five patients received LT from donors deceased after brain death diagnosis including one auxiliary graft and one received a liver graft from living donor. Median waiting time to LT from listing was 3 days (range 1–6 days). Median length of stay in PICU was 12 days (4–22 days). Longer length of stay as associated with the use of neuroprotective measures especially deep sedation pre- and post-transplant. All six explants were negative for adenovirus by immunostaining. Details of histopathology of liver explants is shown in Table 1.

Investigations as to causation in the UK-wide cases found a high occurrence of positivity for adenovirus (68% of those tested, primarily from blood), most commonly 41F type.

However, histopathology studies on the explant liver and in a few who have had biopsies have not demonstrated evidence of adenovirus in hepatocytes, though all of them revealed hepatocyte necrosis and parenchymal collapse. The lack of adenovirus demonstration in hepatocytes, but severe liver injury leading to acute liver failure may be related to an aberrant immune response from the host’s immune system of liver. Detailed characterisation of immune infiltrates in the liver of children who progress to liver failure may identify a subgroup that respond to immunosuppression including steroids and avoid liver transplantation. Media speculations relating this outbreak to SARS-CoV-2 or vaccine are not yet substantiated. The presence of adenovirus in these children raises a hypothesis of SARS-CoV-2 superantigen mediated disease potentiated by a second virus [3]. The hypothesis of an aberrant immune response in those (< 10%) who required urgent transplantation is being investigated.

With a limited number of donor organs and stretched paediatric critical care capacity (at one stage, four of our patients were receiving CRRT), it is important to identify patients who should be listed for LT and others who are likely to recover with supportive therapy. The majority of children who develop hepatitis can be managed locally with expert advice from tertiary liver centres. However, good outcomes both with and without transplant can be achieved in those who progress to acute liver failure (ALF) by dedicated liver intensive care including early referral to liver transplant centres, early recognition of neurologic deterioration, early institution of high-volume extracorporeal therapies, close neuro-monitoring and neuroprotection and working in close collaboration with hepatology and transplant colleagues to decide medical treatments and timing of listing of these patients [4, 5]. As our understanding of the mechanism underpinning these cases (especially if immune-mediated) become clear, it might be possible to manage these children with intensive care therapies in conjunction with steroids and other immunomodulatory drugs.

References

  1. United Kingdom Health Security Agency (UKHSA) (2022) Increase in acute hepatitis cases of unknown aetiology in children. UKHSA, London; 8 Apr. https://www.gov.uk/government/publications/hepatitis-increase-in-acute-cases-of-unknown-aetiology-in-children/increase-in-acute-hepatitis-cases-of-unknown-aetiology-in-children. Accessed 11 May

  2. United Kingdom Health Security Agency (UKHSA) (2022) Increase in acute hepatitis cases of unknown aetiology in children. UKHSA, London; 25 Apr. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1071198/acute-hepatitis-technical-briefing-1_4_.pdf. Accessed 11 May

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Acknowledgements

We would like to thank the hepatology, surgical transplant and intensive care services at King’s College Hospital who went above and beyond to deal with this surge of patients with acute hepatitis.

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Correspondence to Akash Deep or Anil Dhawan.

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Conflicts of interest

AkD is the Chair of Scientific Affairs of the European Society of Pediatric and Neonatal Intensive Care (ESPNIC). AnD is a recipient of a National Institute for Health Research (NIHR) i4i grant to develop treatment for ALF with alginate microbead embedded hepatocytes and a Medical Research Council (MRC) grant for a first in human clinical trial of alginate embedded human hepatocytes as treatment for ALF (MRC MR/V038583/1), has been paid by Ambys and J and J for consultation, has a patent pending approval for alginate microbead manufacturing. TG is a consultant for Albireo. None of the other authors declare any conflict of interest.

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Deep, A., Grammatikopoulos, T., Heaton, N. et al. Outbreak of hepatitis in children: clinical course of children with acute liver failure admitted to the intensive care unit. Intensive Care Med 48, 958–962 (2022). https://doi.org/10.1007/s00134-022-06765-3

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