According to the latest data from the World Health Organization (WHO), 34 countries around the world have reported about 700 cases of unexplained childhood hepatitis, and 112 cases are under investigation, of which at least 38 have undergone liver transplantation and 10 have died. Currently, the cause of these cases is still under investigation, and patients who progress to liver failure and require transplantation have become the key to clinical treatment.
On June 10, local time, researchers from the Paediatric Intensive Care Unit of King's College Hospital (KCH) in London, UK, published an article in the journal "INTENSIVE CARE MEDICINE" titled "Hepatitis Outbreaks in Children: Acute Liver Failure in Intensive Care Unit Admissions." Outbreak of hepatitis in children: clinical course of children with acute liver failure admitted to the intensive care unit.
Eight children with liver failure in the Paediatric Intensive Care Unit at King's College Hospital (KCH), six received liver transplants. Adenovirus was detected in the whole blood of 8 children, but not in the livers of 6 children (recipients of liver transplants) who had liver biopsies. Six of the eight children were infected with the new coronavirus (positive for SARS-CoV-2 antibodies), accounting for 75%. The researchers also pointed out that it must be noted that according to the technical briefing issued by the UK Health Security Agency on April 25, in January-February 2022, the SARS-CoV-2 seroprevalence rate of 1-4 year olds was 47%, SARS-CoV-2 seroprevalence was 67% in people aged 5-11. The latest official information on seroprevalence in this age group is currently awaited.
The UK was the first country to report this high-profile outbreak of unexplained childhood hepatitis. On 5 April 2022, WHO was notified of 10 cases of severe acute hepatitis of unknown etiology in children under 10 years of age in central Scotland. Three days later, on April 8, the UK reported 74 cases. It is worth mentioning that one of the reasons why the UK was the first to report and quickly count more cases was that the UK paediatric liver service was concentrated in three centres.
Among them, King's College Hospital (KCH), where the article was published, is the largest pediatric liver transplant center in the world, and is also recognized by the industry as the origin of pediatric hepatology.
Outbreaks of acute non-AE hepatitis with serum transaminases greater than 500 IU/L found in children under 16 years of age have become a major concern for public health authorities, pediatric liver and critical care services, the researchers noted. From 1 January to 16 May 2022, Public Health England reported 197 cases, with a median age of 3 years, 50/50 boys and girls, from all regions of the UK, and 11 children undergoing liver transplants ( LT).
Of these, eight children were admitted to the Paediatric Intensive Care Unit (PICU) at King's College Hospital (KCH) from February to May 2022. All but one patient were younger than 5 years old; all children were white. All children presented with abdominal symptoms (diarrhea and vomiting) followed by jaundice and elevated transaminases (ALT and AST > 2500 IU/L). In addition, the whole blood of these cases was positive for adenovirus DNA.
Based on UK Health Safety Agency (UKHSA) recommendations, the researchers performed extensive virus screening of blood, urine, stool and respiratory samples from all patients. Two of the patients had a history of SARS-CoV-2 8 weeks before onset. Six of the eight patients were positive for SARS-CoV-2 antibodies. However, none of these pediatric intensive care unit patients tested negative for SARS-CoV-2 by polymerase chain reaction (PCR) and were not vaccinated against COVID-19.
The researchers also pointed out that it must be noted that according to the technical briefing issued by the UK Health Security Agency on April 25, in January-February 2022, the SARS-CoV-2 seroprevalence rate of 1-4 year olds was 47%, SARS-CoV-2 seroprevalence was 67% in people aged 5-11. The latest official information on seroprevalence in this age group is currently awaited.
The main reason for the transfer of these children to the pediatric intensive care unit was neurological deterioration (hepatic encephalopathy) with elevated transaminases, elevated lactate levels, and elevated international normalized ratios (INRs). The so-called hepatic encephalopathy is a kind of neuropsychiatric syndrome of varying severity, which is based on metabolic disorders, caused by severe acute and chronic liver dysfunction or various abnormal portal-systemic shunting.
The researchers used transcranial Doppler (using the Doppler effect of ultrasound to detect intracranial and extracranial vascular hemodynamics, TCD), jugular vein saturation for neurological monitoring in patients. Four patients had abnormal TCD pulsatility index and six patients had low jugular vein saturation (the lowest was 25.9%), requiring intervention.
To protect the nervous system, interventions included early (within 24 hours of PICU admission) initiation of continuous renal replacement therapy (minimum dose 60 ml/kg/h), plasma exchange, hypertonic saline, norepinephrine Cerebral perfusion pressure was maintained, body temperature was controlled, and thiopental sodium was injected.
All patients received N-acetylcysteine, and adenovirus-positive patients received at least 2 doses of cidofovir.
How can these children be assessed for the need for liver transplantation? The research team used INR>4 as inclusion criteria. All 8 children admitted to the King's College Hospital (KCH) Paediatric Intensive Care Unit (PICU) survived, 6 of whom required liver transplantation (1 retransplantation); 2 ultimately survived without liver transplantation, 1 of whom was 6 days later Removed from the super urgent list due to improved clinical and biochemical status, and another patient received methylprednisolone for positive antinuclear antibodies.
The median wait time for transplant children from being listed to needing a liver transplant was 3 days (range, 1-6 days), and the median length of stay in the pediatric intensive care unit was 12 days (4-22 days) . The researchers mentioned that longer hospital stays were associated with the use of neuroprotective measures, especially deep sedation before and after transplantation. The immunohistochemical results of the livers of the 6 transplanted children were all negative for adenovirus.
The researchers mentioned that the etiological investigation of cases in the UK found a high incidence of adenovirus positive, with current data showing that 68% of those tested were positive, with the main samples coming from blood, the most common being type 41F. However, the article pointed out that histopathological studies of the livers and few biopsies of the six transplanted children mentioned above did not demonstrate the presence of adenovirus in hepatocytes, although all showed hepatocyte necrosis and parenchymal atrophy.
Adenovirus is lacking in hepatocytes, but severe liver injury leading to acute liver failure may be related to an abnormal immune response of the host's liver immune system, the article said. Detailed characterization of liver immune infiltration in children who progress to liver failure may identify a subgroup that responds to immunosuppression, including steroids, to avoid liver transplantation.
The researchers also pointed out that speculation that the outbreak of hepatitis in children is related to SARS-CoV-2 or a vaccine has not been confirmed. Adenoviruses are present in these children, and one hypothesis is being mediated by a second virus-enhanced SARS-CoV-2 superantigen. At the same time, the hypothesis of abnormal immune response (<10%) in patients requiring urgent liver transplantation is also under investigation.
The researchers concluded by exploring the strained pediatric critical care capacity due to the limited number of donor organs. Therefore, it is particularly important to determine which patients should be listed for liver transplantation and which patients are likely to recover with supportive care.
They believe that most children with hepatitis can receive specialist consultation at a tertiary liver center locally. However, those who progress to acute liver failure require specialized liver intensive care. Factors such as early referral to a liver transplant center, early detection of neurological deterioration, early interventional therapy, and close neurological monitoring and protection, and working closely with colleagues in liver and transplantation to determine treatment and timing of transplantation in these patients Can bring relatively good clinical outcomes.
The team at King's College Hospital (KCH) concludes that as our understanding of the mechanisms underpinning these cases (especially if immune-mediated) becomes clear, we may be able to manage with intensive care therapy in combination with steroids and other immunomodulatory drugs these children.
Paper link: https://link.springer.com/article/10.1007/s00134-022-06765-3
On June 10, local time, researchers from the Paediatric Intensive Care Unit of King's College Hospital (KCH) in London, UK, published an article in the journal "INTENSIVE CARE MEDICINE" titled "Hepatitis Outbreaks in Children: Acute Liver Failure in Intensive Care Unit Admissions." Outbreak of hepatitis in children: clinical course of children with acute liver failure admitted to the intensive care unit.
Eight children with liver failure in the Paediatric Intensive Care Unit at King's College Hospital (KCH), six received liver transplants. Adenovirus was detected in the whole blood of 8 children, but not in the livers of 6 children (recipients of liver transplants) who had liver biopsies. Six of the eight children were infected with the new coronavirus (positive for SARS-CoV-2 antibodies), accounting for 75%. The researchers also pointed out that it must be noted that according to the technical briefing issued by the UK Health Security Agency on April 25, in January-February 2022, the SARS-CoV-2 seroprevalence rate of 1-4 year olds was 47%, SARS-CoV-2 seroprevalence was 67% in people aged 5-11. The latest official information on seroprevalence in this age group is currently awaited.The UK was the first country to report this high-profile outbreak of unexplained childhood hepatitis. On 5 April 2022, WHO was notified of 10 cases of severe acute hepatitis of unknown etiology in children under 10 years of age in central Scotland. Three days later, on April 8, the UK reported 74 cases. It is worth mentioning that one of the reasons why the UK was the first to report and quickly count more cases was that the UK paediatric liver service was concentrated in three centres.
Among them, King's College Hospital (KCH), where the article was published, is the largest pediatric liver transplant center in the world, and is also recognized by the industry as the origin of pediatric hepatology.
Outbreaks of acute non-AE hepatitis with serum transaminases greater than 500 IU/L found in children under 16 years of age have become a major concern for public health authorities, pediatric liver and critical care services, the researchers noted. From 1 January to 16 May 2022, Public Health England reported 197 cases, with a median age of 3 years, 50/50 boys and girls, from all regions of the UK, and 11 children undergoing liver transplants ( LT).
Of these, eight children were admitted to the Paediatric Intensive Care Unit (PICU) at King's College Hospital (KCH) from February to May 2022. All but one patient were younger than 5 years old; all children were white. All children presented with abdominal symptoms (diarrhea and vomiting) followed by jaundice and elevated transaminases (ALT and AST > 2500 IU/L). In addition, the whole blood of these cases was positive for adenovirus DNA.
Based on UK Health Safety Agency (UKHSA) recommendations, the researchers performed extensive virus screening of blood, urine, stool and respiratory samples from all patients. Two of the patients had a history of SARS-CoV-2 8 weeks before onset. Six of the eight patients were positive for SARS-CoV-2 antibodies. However, none of these pediatric intensive care unit patients tested negative for SARS-CoV-2 by polymerase chain reaction (PCR) and were not vaccinated against COVID-19.
The researchers also pointed out that it must be noted that according to the technical briefing issued by the UK Health Security Agency on April 25, in January-February 2022, the SARS-CoV-2 seroprevalence rate of 1-4 year olds was 47%, SARS-CoV-2 seroprevalence was 67% in people aged 5-11. The latest official information on seroprevalence in this age group is currently awaited.
The main reason for the transfer of these children to the pediatric intensive care unit was neurological deterioration (hepatic encephalopathy) with elevated transaminases, elevated lactate levels, and elevated international normalized ratios (INRs). The so-called hepatic encephalopathy is a kind of neuropsychiatric syndrome of varying severity, which is based on metabolic disorders, caused by severe acute and chronic liver dysfunction or various abnormal portal-systemic shunting.
The researchers used transcranial Doppler (using the Doppler effect of ultrasound to detect intracranial and extracranial vascular hemodynamics, TCD), jugular vein saturation for neurological monitoring in patients. Four patients had abnormal TCD pulsatility index and six patients had low jugular vein saturation (the lowest was 25.9%), requiring intervention.
To protect the nervous system, interventions included early (within 24 hours of PICU admission) initiation of continuous renal replacement therapy (minimum dose 60 ml/kg/h), plasma exchange, hypertonic saline, norepinephrine Cerebral perfusion pressure was maintained, body temperature was controlled, and thiopental sodium was injected.
All patients received N-acetylcysteine, and adenovirus-positive patients received at least 2 doses of cidofovir.
How can these children be assessed for the need for liver transplantation? The research team used INR>4 as inclusion criteria. All 8 children admitted to the King's College Hospital (KCH) Paediatric Intensive Care Unit (PICU) survived, 6 of whom required liver transplantation (1 retransplantation); 2 ultimately survived without liver transplantation, 1 of whom was 6 days later Removed from the super urgent list due to improved clinical and biochemical status, and another patient received methylprednisolone for positive antinuclear antibodies.
The median wait time for transplant children from being listed to needing a liver transplant was 3 days (range, 1-6 days), and the median length of stay in the pediatric intensive care unit was 12 days (4-22 days) . The researchers mentioned that longer hospital stays were associated with the use of neuroprotective measures, especially deep sedation before and after transplantation. The immunohistochemical results of the livers of the 6 transplanted children were all negative for adenovirus.The researchers mentioned that the etiological investigation of cases in the UK found a high incidence of adenovirus positive, with current data showing that 68% of those tested were positive, with the main samples coming from blood, the most common being type 41F. However, the article pointed out that histopathological studies of the livers and few biopsies of the six transplanted children mentioned above did not demonstrate the presence of adenovirus in hepatocytes, although all showed hepatocyte necrosis and parenchymal atrophy.
Adenovirus is lacking in hepatocytes, but severe liver injury leading to acute liver failure may be related to an abnormal immune response of the host's liver immune system, the article said. Detailed characterization of liver immune infiltration in children who progress to liver failure may identify a subgroup that responds to immunosuppression, including steroids, to avoid liver transplantation.
The researchers also pointed out that speculation that the outbreak of hepatitis in children is related to SARS-CoV-2 or a vaccine has not been confirmed. Adenoviruses are present in these children, and one hypothesis is being mediated by a second virus-enhanced SARS-CoV-2 superantigen. At the same time, the hypothesis of abnormal immune response (<10%) in patients requiring urgent liver transplantation is also under investigation.
The researchers concluded by exploring the strained pediatric critical care capacity due to the limited number of donor organs. Therefore, it is particularly important to determine which patients should be listed for liver transplantation and which patients are likely to recover with supportive care.
They believe that most children with hepatitis can receive specialist consultation at a tertiary liver center locally. However, those who progress to acute liver failure require specialized liver intensive care. Factors such as early referral to a liver transplant center, early detection of neurological deterioration, early interventional therapy, and close neurological monitoring and protection, and working closely with colleagues in liver and transplantation to determine treatment and timing of transplantation in these patients Can bring relatively good clinical outcomes.
The team at King's College Hospital (KCH) concludes that as our understanding of the mechanisms underpinning these cases (especially if immune-mediated) becomes clear, we may be able to manage with intensive care therapy in combination with steroids and other immunomodulatory drugs these children.
Paper link: https://link.springer.com/article/10.1007/s00134-022-06765-3
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