Hepatitis of unknown cause in children - what do we know about this ?

Afra Shamnath


The recent weeks have seen a significant number of reports of hepatitis (inflammation of the liver) in children with no apparent cause deciphered. Many of these children, typically under the age of 10 have gastrointestinal symptoms to start with , progressions to jaundice with elevated liver enzymes and in some cases quickly progressing to liver failure and typically negative for the common hepatitis viruses. Over 300 such cases have been reported globally from over 20 countries from Europe, America's and Asia and have been puzzling clinicians and researchers.

Hepatitis refers to the inflammation or swelling of the liver thereby damaging the liver and affecting its functions[1]. A number of well known causes of hepatitis has been well studied in the past. This includes viruses which cause infection and inflammation of the liver like the hepatitis viruses (hepatitis virus types A, B, C, D, or E). Generally, Hepatitis A and E are spread by contact with contaminated food or water from an infected person's faeces. Hepatitis E can also be contracted by eating raw and undercooked shellfish, deer or pork. Hepatitis B, C, and D are transmitted by coming into touch with the blood of someone who has the illness. Hepatitis B and D can also be transmitted by bodily fluids[2]

Additionally a number of toxins and chemicals including alcohol could also cause hepatitis[3]. Autoimmunity, a condition where the body's immune system attacks itself could also cause hepatitis[3,4.]


A number of clinicians and researchers have been following up cases of hepatitis in children as they continue to be reported across the world. It should be noted that in a significant number of the cases tested, lab results has ruled out hepatitis A, B, C, and E viruses (as well as D when relevant) although Severe Acute Respiratory Syndrome coronavirus type 2 (SARS-CoV-2) and/or adenovirus have been found in some. Toxicology reports have shed little light and has not provided much information.[5]


The World Health Organisation (WHO) is also keeping a careful eye on the issue, having detected 348 cases of severe hepatitis in children with no known cause in at least 20 nations (as of 10th May 2022) including United Kingdom, Northern Ireland ,Spain, Israel, the United States of America, Canada, Denmark, Ireland , The Netherlands , Italy , Norway , France , Romania , and Belgium as well as in Asia like Japan[6] . The cases reported may be significantly underestimated due to gaps in disease reporting and surveillance in many countries.

Several possibilities

Several possibilities as the cause of hepatitis are currently being worked out closely. This includes a variety of infections including COVID-19 in isolation as well as with other infections, novel pathogens, as well as drug toxins including environmental exposure. Another active possibility being explored is autoimmunity being activated by infections including COVID-19.[5]. While the exact cause of the phenomenon may take considerable effort and collaboration between countries to solve, it is significant to note that some early insights provide clues into the phenomenon and potential leads to explore further.


Many of the current insights have come from the UKHSA cohorts The UK Health Security Agency (UKHSA) is working with the National Health Service (NHS) and the public health agencies of the 4 nations of the UK to investigate the potential cause of the unusually high number of acute hepatitis cases being seen in children in the past few weeks[5].


According to the data released by the UKHSA(UK Health Security Agency), as of May 3rd 2022 there have been no deaths, and eleven cases of liver transplant. It also states that since January 1, 2022, there have been 163 occurrences of acute non-A-E hepatitis in children under the age of 16 in the United Kingdom, with serum transaminases more than 500 IU/l. From the 163 cases, adeno virus was detected in 72% of cases and SARS-CoV-2 was detected in 18% cases. There are also two pairs of epidemiologically connected cases, according to Public Health Scotland[5].


A recent commentary in The Lancet suggests superantigen formation from a preexisting COVID-19 viral reservoir due to a prior infection in the gut with superimposed adenovirus infection could be a possible factor in development of hepatitsis[11]. To elaborate, a prior COVID-19 infection can result in the formation of a viral reservoir[12]. The persistence of the virus in the gut (gastrointestinal )tract can result in a constant release of viral proteins leading to an immune activation[13]. A superantigen motif inside the SARS-CoV-2 spike protein that resembles Staphylococcal enterotoxin B6 might stimulate broad and non-specific T-cell activation, resulting in recurrent immunological activation.[13] This recurrent immune activation is seen as the pathway or mechanism for multisystem inflammatory syndrome in children (MIS-C).[14]

Is Adenovirus the culprit ?

A number of children affected with hepatitis in the current cohort from across the world have been tested positive for Adenovirus. Adenovirus infections are more likely to cause serious illness in those who have weaker immune systems or who already have respiratory or heart disorders. Known symptoms associated with the virus are acute gastroenteritis (inflammation of the stomach and intestines), fever, common cold, pneumonia (infection of the lungs), and conjunctivitis. Over a hundred antigenic types have been identified that infect mammals and birds. There are forty seven types of Adenovirus that infect humans [7] Infection is often spread by respiratory or ocular secretions (secretions of the eye). Generally adenovirus infections are common in children and no particular treatment is available to treat adenovirus infections. There are however vaccines available for Type 4 and Type 7 adenovirus.[8]


Adenovirus F 41 was the type which was identified in a majority of patients. Adenovirus type F41, which is more likely to cause serious gastrointestinal disease in children. Despite prior reports of viral infection causing hepatitis in immunocompromised children[9] , adenovirus type 41 is not a common reason for hepatitis in otherwise healthy children. Although the pathogenesis is not yet known, the nation has lately seen an upsurge in adenovirus activity, which is co-circulating with SARS-CoV-2.

In 1890, Robert Koch put forward a set of four postulates for assessing if a certain organism is the cause of a particular illness, popularly known as Koch's Postulates[10] , while may not be fully applicable for many viral diseases, provides the guide to assess causality of pathogens.

Hepatitis cases in India following COVID-19

There have been sporadic cases of hepatitis in children being reported from various parts of India in the last two years. However, recently Bundelkhand Medical College (BMC), Sagar, Madhya Pradesh and the Post Graduate Institute of Medical Research, Chandigarh put together a report of 475 children from April to July 2021[15]. From the cohort of 475 children tested positive for COVID-19, 37 (about 8%) having Covid Acquired Hepatitis (CAH). Even though rare, 10 children had presented themselves with Multisystem Inflammatory Syndrome in Children (MIS-C) which results in severe inflammation of multiple organsThe children had symptoms of nausea, loss of apetite and mild fever. The report stated that the 37 children had an uneventful recovery which means that routine treatment and medication was sufficient for the recovery.

COVID-19 immunisation and Hepatitis in children

The Joint Committee on Vaccination and Immunisation does not recommend COVID-19 immunizations for children under the age of five[16]. In children under the age of 5, which accounts for more than 75 percent of hepatitis cases, no COVID-19 immunizations were recorded. There are just about 5 elderly case-patients who got a COVID-19 vaccination before developing hepatitis[6]. Therefore a correlation between COVID-19 immunisation and acute hepatic syndrome has not been established.

Should we be worried? What can we do?

Even though theoretically a hepatitis infection may be rare in healthy children, parents should keep a close watch and not ignore any symptoms of gastroenteritis like illness such as vomiting, diarrhoea and nausea. Signs of jaundice should also not be ignored (yellow colour in eyes and skin). Many common illnesses, including adenovirus, may be prevented with simple hygienic practices including complete handwashing and proper respiratory hygiene. However there are no recommendations that suggest travel or trade restrictions.

References

1. Friedman, S. L. Mechanisms of hepatic fibrogenesis. Gastroenterology 134, 1655–1669 (2008).
2. Hepatitis (Viral). National Institute of Diabetes and Digestive and Kidney Diseases https://www.niddk.nih.gov/health-information/liver-disease/viral-hepatitis.
3. Lucey, M. R., Mathurin, P. & Morgan, T. R. Alcoholic hepatitis. N. Engl. J. Med. 360, 2758–2769 (2009).
4. Krawitt, E. L. Autoimmune hepatitis. N. Engl. J. Med. 354, 54–66 (2006).
5. UK Health Security Agency. Acute hepatitis: technical briefing. GOV.UK https://www.gov.uk/government/publications/acute-hepatitis-technical-briefing (2022).
6. Multi-Country – Acute, severe hepatitis of unknown origin in children. https://www.who.int/emergencies/disease-outbreak-news/item/2022-DON376.
7. Doerfler, W. Adenoviruses. in Medical Microbiology. 4th edition (University of Texas Medical Branch at Galveston, 1996).
8. Collins, N. D. et al. Live Oral Adenovirus Type 4 and Type 7 Vaccine Induces Durable Antibody Response. Vaccines (Basel) 8, (2020).
9. Munoz, R. E., Piedra, P. A. & Demmler, G. J. Disseminated Adenovirus Disease in Immunocompromised and Immunocompetent Children. Clin. Infect. Dis. 27, 1194–1200 (1998).
10. Changing how we think about infectious diseases. 321–365 (Academic Press, 2019).
11. Severe acute hepatitis in children: investigate SARS-CoV-2 superantigens. The Lancet Gastroenterology & Hepatology (2022) doi:10.1016/S2468-1253(22)00166-2.
12. Brodin, P. SARS-CoV-2 infections in children: Understanding diverse outcomes. Immunity 55, 201–209 (2022).
13. Yonker, L. M. et al. Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier. J. Clin. Invest. 131, (2021).
14. Porritt, R. A. et al. HLA class I-associated expansion of TRBV11-2 T cells in multisystem inflammatory syndrome in children. J. Clin. Invest. 131, (2021).
15. Ratho, R. K., Asati, A. A., Mishra, N., Jain, A. & Rawat, S. K. COVID-19 Associated Hepatitis in Children (CAH-C) during the second wave of SARS-CoV-2 infections in Central India: Is it a complication or transient phenomenon. medRxiv 2021.07.23.21260716 (2022).
16. JCVI statement on vaccination of children aged 5 to 11 years old. GOV.UK https://www.gov.uk/government/publications/jcvi-update-on-advice-for-covid-19-vaccination-of-children-aged-5-to-11/jcvi-statement-on-vaccination-of-children-aged-5-to-11-years-old.

About the author

Afra Shamnath is a researcher at the CSIR Institute of Genomics and Integrative Biology with interests in genomics of viral infections and genetic diseases . All opinion expressed is personal. She can be reached on twitter