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Eurosurveillance: Investigation into Cases of Hepatitis of Unknown Aetiology Among Young Children, Scotland
#16,695
A little over a week ago the UK HSA announced they were Investigating An Unusual Increase In Hepatitis In Children, which as not linked to any of the common (A-E) hepatitis viruses, and whose cause was unknown.
Since then we've learned that over 70 children - mostly under the age of 5 - in England, Scotland, and Wales have been hospitalized and several have either undergone or are being evaluated for liver transplants.
While the cause remains unclear, a viral cause - possibly an adenovirus - is suspected.
Adenoviruses - which are a common cause of (generally mild) respiratory and gastrointestinal illnesses in both adults and children - have been linked to acute hepatitis, although it is usually seen seen in immunocompromised patients.
Today the Journal Eurosurveillance provides us with the first detailed report on a subset (n=13) of these cases, and where the investigation currently stands. We also learn that the CDC appears be investigating similar cases here in the United States.
I've only post excerpts from a much longer report, so you'll probably want to follow the link to read it in its entirety. I'll have a brief postscript when you return.
Rapid communication Open Access
Although a viral cause has not been identified, it is clearly at the top of these investigator's list. While this could be due to something new, it is also possible that an old virus has simply learned a new trick.
Eight years ago we saw the emergence of a previously known, but relatively uncommon EV-D68 non-polio enterovirus that sparked a late summer respiratory outbreak, mostly in children and adolescents (see CDC HAN Advisory On EV-D68) across North America.
Along with the usual respiratory symptoms, a small percentage also developed AFM; a polio-like paralysis called Acute Flaccid Myelitis.
This outbreak was followed by two more, one in 2016 and the biggest, in 2018 (see chart below). While it was expected to return in 2020, global pandemic mitigation appears to have disrupted this bi-yearly pattern. Whether (or when) it will return remains unknown.
Since that 2014 outbreak, research has suggested the EV-D68 had mutated slightly, and had gained the ability to infect neuronal cells (see mBio: Contemporary EV-D68 Strains Have Acquired The Ability To Infect Human Neuronal Cells).
It is admittedly far to early to begin to assign a cause to this outbreak, but similar cases on this side of the pond would favor a viral - rather than environmental - cause.
Hopefully we'll be getting some details on the CDC's investigation in the days ahead as well.
#16,695
A little over a week ago the UK HSA announced they were Investigating An Unusual Increase In Hepatitis In Children, which as not linked to any of the common (A-E) hepatitis viruses, and whose cause was unknown.
Since then we've learned that over 70 children - mostly under the age of 5 - in England, Scotland, and Wales have been hospitalized and several have either undergone or are being evaluated for liver transplants.
While the cause remains unclear, a viral cause - possibly an adenovirus - is suspected.
Adenoviruses - which are a common cause of (generally mild) respiratory and gastrointestinal illnesses in both adults and children - have been linked to acute hepatitis, although it is usually seen seen in immunocompromised patients.
Today the Journal Eurosurveillance provides us with the first detailed report on a subset (n=13) of these cases, and where the investigation currently stands. We also learn that the CDC appears be investigating similar cases here in the United States.
I've only post excerpts from a much longer report, so you'll probably want to follow the link to read it in its entirety. I'll have a brief postscript when you return.
Rapid communication Open Access
Investigation into cases of hepatitis of unknown aetiology among young children, Scotland, 1 January 2022 to 12 April 2022 
Kimberly Marsh1,* , Rachel Tayler2,* , Louisa Pollock3 , Kirsty Roy1 , Fatim Lakha1 , Antonia Ho4 , David Henderson1 , Titus Divala1 , Sandra Currie1 , David Yirrell1 , Michael Lockhart1 , Maria K. Rossi1 , Nick Phin1
On 31 March 2022, the Scottish National Health Service (NHS) Greater Glasgow and Clyde (GGC) Health Board alerted Public Health Scotland (PHS) to five children aged 3–5 years presenting to the Royal Hospital for Children, Glasgow with severe hepatitis of unknown aetiology within a 3-week period. The typical number of cases of hepatitis of unknown aetiology across Scotland would be fewer than four per year [1].
This paper describes the initial investigation into the first Scottish cases and aims to raise awareness of this severe illness of unknown aetiology among young children.
Early signal detection
Following the alert, PHS convened a multi-disciplinary team of experts from across Scotland to review clinical and epidemiological data from the first five children presenting to hospital with acute severe hepatitis of unknown origin. Clinical case review revealed vomiting in preceding weeks, jaundice, and exceptionally high levels of alanine aminotransferase (ALT) among children of a similar age. Most children presented with transaminases greater than 2,000 international units per litre (IU/L) where the normal range is 10 to 40 IU/L [2]. Initial screening for hepatitis viruses A, B, C, and E was negative, with one hepatitis E result pending. One child had insufficient sample material to test for hepatitis B. As an indicator of disease severity, three children were transferred to quaternary paediatric liver units in England to be evaluated for liver transplant, with one receiving a transplant.
In addition to the clinical case review, the number of children presenting acutely with abnormal liver function tests in March 2022 to the Royal Hospital for Children, Glasgow were compared with those in March 2019 as well as March 2020 and 2021. These data confirmed higher-than-expected numbers in 2022 among children under 5 years of age, but not older children. As noted above, the number presenting in March 2022 at the Royal Hospital for Children also exceeded the total number expected for the whole of Scotland over 1 year [1].
On the basis of these reviews, PHS established a National Incident Management Team (IMT) to manage the ongoing public health investigation and response in Scotland. The National IMT developed a working case definition and active case finding was initiated, including a retrospective review of admissions to Scottish referral hospitals since 1 January 2022.
Working case definition
A confirmed case includes anyone presenting since 1 January 2022 with aspartate transaminase (AST) or ALT greater than 500 IU/L of unknown cause who is either aged 10 years and under or who was a contact of any age of a possible or confirmed case. A possible case is defined as a person presenting since 1 January 2022 with jaundice without any known cause, either aged 10 years and under or who was a contact of any age of a possible or confirmed case.
(SNIP)
Discussion
We report here on a cluster of cases of severe hepatitis of unknown origin in Scotland, mainly affecting children between the ages of 3–5 years. Approximately 60 cases have now been reported in England, Wales and Northern Ireland since 1 January 2022 [7]. PHS is also aware of a cluster of hepatitis and adenovirus cases among children being investigated by the US Centers for Disease Control and Prevention (personal communication: Hannah L. Kirking, 12 March 2022).
In addition to the temporal clustering of these cases, the severity of disease upon presentation to hospital is unfortunately remarkable. At the time of publication, all 13 children had been hospitalised and three children required liver transplant evaluation in quaternary care centres in England, where specialist services are available. One child went on to receive a successful transplant. Five of the 13 cases are still being treated in hospital. To date, there have not been any fatalities.
Initial hypotheses about the aetiological nature of the severe hepatitis included either an infectious pathogen or a toxic exposure to food, drinks or toys favoured by younger children. Toxicology analyses are ongoing among cases from across the UK, although responses to the enhanced investigation questionnaire about food, drink and personal care habits have not yet identified any common exposures.
An infectious aetiology is now considered more likely given the epidemiological and clinical features, and taking into account the additional cases from across the UK and the US cluster. At the time of publication, the leading hypotheses centre around adenovirus—either a new variant with a distinct clinical syndrome or a routinely circulating variant that is more severely impacting younger children who are immunologically naïve. The latter scenario may be the result of restricted social mixing during the COVID-19 pandemic. Adenovirus infection as a cause of severe hepatitis is rare in immunocompetent children but has been reported in case reports and series [9-11].
Other infectious causes still being explored include increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland) or infection by an as yet uncharacterised SARS-CoV-2 variant. Of note, none of the children were vaccinated for SARS-CoV-2. A novel or yet undetected virus also cannot be ruled out at this time.
Conclusion
We describe a clear and first signal in Scotland of the number of young children presenting to hospital with severe hepatitis of unknown origin. Rapid epidemiological analysis and laboratory testing is underway to identify the source. Public health specialists, paediatricians and other clinicians should be aware of children presenting acutely with gastrointestinal symptoms and jaundice or elevated serum transaminases > 500 UI/L (AST or ALT) and have a higher index of suspicion and a lower threshold for referral for specialist care. Cases should be reported to national and international public health bodies for appropriate follow-up investigation and management as well as the WHO for situational awareness. Until the cause of these cases of severe illness is found, standard public health guidance emphasising the importance of hand hygiene should be provided in settings where unexplained hepatitis is detected.
Kimberly Marsh1,* , Rachel Tayler2,* , Louisa Pollock3 , Kirsty Roy1 , Fatim Lakha1 , Antonia Ho4 , David Henderson1 , Titus Divala1 , Sandra Currie1 , David Yirrell1 , Michael Lockhart1 , Maria K. Rossi1 , Nick Phin1
On 31 March 2022, the Scottish National Health Service (NHS) Greater Glasgow and Clyde (GGC) Health Board alerted Public Health Scotland (PHS) to five children aged 3–5 years presenting to the Royal Hospital for Children, Glasgow with severe hepatitis of unknown aetiology within a 3-week period. The typical number of cases of hepatitis of unknown aetiology across Scotland would be fewer than four per year [1].
This paper describes the initial investigation into the first Scottish cases and aims to raise awareness of this severe illness of unknown aetiology among young children.
Early signal detection
Following the alert, PHS convened a multi-disciplinary team of experts from across Scotland to review clinical and epidemiological data from the first five children presenting to hospital with acute severe hepatitis of unknown origin. Clinical case review revealed vomiting in preceding weeks, jaundice, and exceptionally high levels of alanine aminotransferase (ALT) among children of a similar age. Most children presented with transaminases greater than 2,000 international units per litre (IU/L) where the normal range is 10 to 40 IU/L [2]. Initial screening for hepatitis viruses A, B, C, and E was negative, with one hepatitis E result pending. One child had insufficient sample material to test for hepatitis B. As an indicator of disease severity, three children were transferred to quaternary paediatric liver units in England to be evaluated for liver transplant, with one receiving a transplant.
In addition to the clinical case review, the number of children presenting acutely with abnormal liver function tests in March 2022 to the Royal Hospital for Children, Glasgow were compared with those in March 2019 as well as March 2020 and 2021. These data confirmed higher-than-expected numbers in 2022 among children under 5 years of age, but not older children. As noted above, the number presenting in March 2022 at the Royal Hospital for Children also exceeded the total number expected for the whole of Scotland over 1 year [1].
On the basis of these reviews, PHS established a National Incident Management Team (IMT) to manage the ongoing public health investigation and response in Scotland. The National IMT developed a working case definition and active case finding was initiated, including a retrospective review of admissions to Scottish referral hospitals since 1 January 2022.
Working case definition
A confirmed case includes anyone presenting since 1 January 2022 with aspartate transaminase (AST) or ALT greater than 500 IU/L of unknown cause who is either aged 10 years and under or who was a contact of any age of a possible or confirmed case. A possible case is defined as a person presenting since 1 January 2022 with jaundice without any known cause, either aged 10 years and under or who was a contact of any age of a possible or confirmed case.
(SNIP)
Discussion
We report here on a cluster of cases of severe hepatitis of unknown origin in Scotland, mainly affecting children between the ages of 3–5 years. Approximately 60 cases have now been reported in England, Wales and Northern Ireland since 1 January 2022 [7]. PHS is also aware of a cluster of hepatitis and adenovirus cases among children being investigated by the US Centers for Disease Control and Prevention (personal communication: Hannah L. Kirking, 12 March 2022).
In addition to the temporal clustering of these cases, the severity of disease upon presentation to hospital is unfortunately remarkable. At the time of publication, all 13 children had been hospitalised and three children required liver transplant evaluation in quaternary care centres in England, where specialist services are available. One child went on to receive a successful transplant. Five of the 13 cases are still being treated in hospital. To date, there have not been any fatalities.
Initial hypotheses about the aetiological nature of the severe hepatitis included either an infectious pathogen or a toxic exposure to food, drinks or toys favoured by younger children. Toxicology analyses are ongoing among cases from across the UK, although responses to the enhanced investigation questionnaire about food, drink and personal care habits have not yet identified any common exposures.
An infectious aetiology is now considered more likely given the epidemiological and clinical features, and taking into account the additional cases from across the UK and the US cluster. At the time of publication, the leading hypotheses centre around adenovirus—either a new variant with a distinct clinical syndrome or a routinely circulating variant that is more severely impacting younger children who are immunologically naïve. The latter scenario may be the result of restricted social mixing during the COVID-19 pandemic. Adenovirus infection as a cause of severe hepatitis is rare in immunocompetent children but has been reported in case reports and series [9-11].
Other infectious causes still being explored include increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland) or infection by an as yet uncharacterised SARS-CoV-2 variant. Of note, none of the children were vaccinated for SARS-CoV-2. A novel or yet undetected virus also cannot be ruled out at this time.
Conclusion
We describe a clear and first signal in Scotland of the number of young children presenting to hospital with severe hepatitis of unknown origin. Rapid epidemiological analysis and laboratory testing is underway to identify the source. Public health specialists, paediatricians and other clinicians should be aware of children presenting acutely with gastrointestinal symptoms and jaundice or elevated serum transaminases > 500 UI/L (AST or ALT) and have a higher index of suspicion and a lower threshold for referral for specialist care. Cases should be reported to national and international public health bodies for appropriate follow-up investigation and management as well as the WHO for situational awareness. Until the cause of these cases of severe illness is found, standard public health guidance emphasising the importance of hand hygiene should be provided in settings where unexplained hepatitis is detected.
Although a viral cause has not been identified, it is clearly at the top of these investigator's list. While this could be due to something new, it is also possible that an old virus has simply learned a new trick.
Eight years ago we saw the emergence of a previously known, but relatively uncommon EV-D68 non-polio enterovirus that sparked a late summer respiratory outbreak, mostly in children and adolescents (see CDC HAN Advisory On EV-D68) across North America.
Along with the usual respiratory symptoms, a small percentage also developed AFM; a polio-like paralysis called Acute Flaccid Myelitis.
This outbreak was followed by two more, one in 2016 and the biggest, in 2018 (see chart below). While it was expected to return in 2020, global pandemic mitigation appears to have disrupted this bi-yearly pattern. Whether (or when) it will return remains unknown.
Since that 2014 outbreak, research has suggested the EV-D68 had mutated slightly, and had gained the ability to infect neuronal cells (see mBio: Contemporary EV-D68 Strains Have Acquired The Ability To Infect Human Neuronal Cells).
It is admittedly far to early to begin to assign a cause to this outbreak, but similar cases on this side of the pond would favor a viral - rather than environmental - cause.
Hopefully we'll be getting some details on the CDC's investigation in the days ahead as well.
