Acute Hepatitis Cases in Children 2022

Authored by
Staff
Last reviewed
May 16, 2022

Acute Hepatitis Cases In Children During 2022

The World Health Organization (WHO), the U.K, Europe, the U.S. CDC, and other countries have recently reported about 450 acute hepatitis/adenovirus infections of unknown etiology among children in about thirty countries. There is no known association between hepatitis viruses (A to E) with serum transaminases greater than 500 IU/l in these children. And some of these children had been, and about 11% were recently infected with the SARS-CoV-2 coronavirus.

Since the initial report in September 2021, positive adenovirus tests in children have been higher than in the previous five years. However, according to the European CDC, most researchers involved in these acute liver investigations have not formulated a hypostasis and continue to question causality vs. coincidence.

On May 11, 2022, the U.S. CDC confirmed 109 pediatric liver cases of an unknown cause, seven liver transplants, and five related fatalities in twenty-four states and Puerto Rico since October 2021. About 50% of these cases indicate adenovirus (hAd41-F) infections. Separately, the National Adenovirus Type Reporting System (NATRS) confirms the total number of adenovirus tests performed and positive results found in the USA. The NATRS's updated report is as of May 7, 2022.

And in the U.K., the Heath Security Agency (UKHSA) confirmed on May 12, 2022, the total number of cases in the UK was 176 as of May 10, 2022. Of the confirmed cases, 128 are resident in England, 26 are in Scotland, 13 are in Wales, and 9 are in Northern Ireland. No children have died. As part of the investigation, a small number of adolescents over the age of ten are also being investigated.

The UKHSA also published Technical Briefing #2: Investigation into acute hepatitis of unknown etiology in children in England, which includes a post-infectious SARS-CoV-2 syndrome.

As of May 13, 2022, the European CDC and the WHO reported about 194 cases of acute hepatitis of unknown etiology in children aged 16 years or below had been reported, by 12 countries: Belgium (12), Cyprus (2), Denmark (6), Greece (2), Italy (24), the Netherlands (6), Norway (5), Poland (1), Serbia (1), Slovenia (1), Spain (26), and Sweden (9). Of the 173 cases PCR tested for SARS-CoV-2, 20 (11.6%) tested positive. Serology results for the SARS-CoV-2 virus were only available for 19 cases, of which 14 (73.7%) had a positive finding. Of the 56 cases with data on COVID-19 vaccination, 47 (83.9%) were unvaccinated.

EU/EEA Acute Hepatitis Case Definitions

Probable: A person presenting with acute hepatitis (non-hepatitis viruses A, B, C, D, and E) with aspartate transaminase or alanine transaminase over 500 IU/L, who is 16 years old or younger, since 1 October 2021. Epi-linked: A person presenting with acute hepatitis (non-hepatitis viruses A, B, C, D, and E) of any age who is a close contact with a probable case since 1 October 2021.

Acute Hepatitis - Adenovirus News For 2022

May 16, 2022 - NanoViricides, Inc. has initiated a program to screen its library of broad-spectrum antiviral nanoviricides against human Adenovirus 41 Type F (hAd41-F), believed to be strongly associated with the occurrence of severe hepatitis syndrome in some children, causing liver transplants as well as fatalities in large percentages of cases.

May 16, 2022 - Isabella Eckerle, co-Head of the Centre for Emerging Viral Diseases at the Geneva University Hospitals, said the possibility of acute hepatitis in children following COVID-19 infection cannot be ruled out.

May 15, 2022 - The BBC reported an investigation is underway after a spike in the number of newborn baby deaths in Scotland. At least 18 babies under four weeks old died in March 2022, a rate of 4.6 per 1,000 births. It comes after at least 21 babies under four weeks old died in September 2021. Public Health Scotland reported on May 12, 2022, that it is continuing to investigate 26 cases of sudden onset hepatitis in children. 

May 13, 2022 - Bloomberg reported four additional children have died of acute hepatitis in Indonesia, bringing the country's total fatalities to seven.

May 13, 2022 - The Lancet published: Severe acute hepatitis in children: investigate SARS-CoV-2 superantigens. 'We suggest that children with acute hepatitis be investigated for SARS-CoV-2 persistence in stool, T-cell receptor skewing, and IFN-γ upregulation because this could provide evidence of a SARS-CoV-2 superantigen mechanism in an adenovirus-41F-sensitised host. If evidence of superantigen-mediated immune activation is found, immunomodulatory therapies should be considered in children with severe acute hepatitis.'

May 13, 2022 - The ECDC and the WHO reported today: Of 143 cases with information, 22 (15.4%) were admitted to an intensive care unit. Of the 98 cases for which this information was available, six (6.1%) have received a liver transplant. And there had been (1) fatality associated with this disease. Overall, 151 cases were tested for adenovirus by any specimen type, of which 90 (59.6%) tested positive. The positivity rate was the highest in whole blood specimens (68.9%).

May 12, 2022 - The UK announced investigations have identified a further 13 confirmed cases since the last update on May 6, 2022, bringing the total number of cases in the UK to 176. 'We are working closely with the NHS and academic partners to actively investigate the role of other contributors, including prior SARS-CoV-2 and other infections.'

May 12, 2022 - In Argentina, local media reported 9 cases with the new suspicion of San Juan.

May 12, 2022 - The Lancet published: Explaining the unexplained hepatitis in children.

May 11, 2022 - The U.S. CDC issued Health Alert Network Health Update CDCHAN-00465 with information about an epidemiologic investigation of pediatric cases of hepatitis of unknown etiology in the U.S. Where possible, clinical specimens should be tested locally to ensure timely results for patient care. Nucleic acid amplification testing, such as polymerase chain reaction, is preferred for adenovirus detection (currently not available for FFPE liver biopsy or native liver explant). Testing whole blood by PCR is more sensitive to and is preferred over testing plasma by PCR.

May 11, 2022 - The ECDC reported about 450 global cases, with 106 from the EU and 181 from other countries, and (11) related fatalities have been reported in Indonesia, Palestine, and the United States.

May 10, 2022 - In Pittsburgh, local media reported that UPMC Children’s Hospital has had a “handful of children that meet reporting requirements but none of these cases have been confirmed as of this time." The infections began in October 2021, and there are no current hospitalizations. 

May 10, 2022 - Phillipa Easterbrook, M.D., MPH, senior scientist with the WHO, said during a telebriefing (at 31 min.) from Geneva, Switzerland, 'that 70 more (liver failure/hepatitis/adenovirus) cases in children are pending confirmation from 13 countries.' The PAHO issued a similar statement.

May 9, 2022 - Indonesia identified 15 cases of acute hepatitis of unknown origin after reporting three pediatric fatalities.

May 9, 2022 - The UK Health Security Agency published a blog post, that included 'The viruses that normally cause hepatitis (hepatitis viruses A to E) have not been found in the children affected'. And 'Some of the children with acute hepatitis have recently had a COVID-19 infection, but there has been a high number of COVID-19 infections in this age group so this is not unexpected. There is no link between these hepatitis cases and the COVID-19 vaccine.'

May 6, 2022 - The UK Heath Security Agency published its second detailed technical briefing on the UK-wide investigations into a rise in cases of sudden onset hepatitis in children. Since the April 29th update, active case-finding investigations have identified 18 new confirmed cases, bringing the total number of UK cases to 163 as of May 3rd.

May 6, 2022 - Staff from the U.S. CDC conducted a telebriefing where Dr. Jay Butler, the deputy director of infectious diseases, commented 'these pediatric cases have been reported since October 2021, with initial cases confirmed in Alabama. Of the 109 diagnosed children, 90% were hospitalized, 14% required liver transplants, five children have died, with some children are still hospitalized.

May 6, 2022 - The European Centre for Disease Prevention and Control (ECDC) weekly communicable diseases report stated approximately 95 cases of acute hepatitis among children aged 16 and under have been reported from 15 EU/EEA countries (Austria [2], Belgium [3], Cyprus [2], Denmark [6], France [2], Germany [1], Ireland [<5], Italy [35], the Netherlands [6], Norway [2], Poland [1], Portugal [4], Romania [4], Slovenia [1] and Spain [22]). Among these cases, at least 13 have tested positive for adenovirus, at least three tested positive for SARS-CoV-2, and five cases have required a liver transplant.

May 6, 2022 - MedpageToday reported Markus Buchfellner, M.D., a fellow in pediatric infectious diseases at the University of Alabama at Birmingham, stated, "They looked like a jaundiced newborn, and that is really concerning for liver disease."

May 3, 2022 - Three children in Indonesia have been reported to have died from liver disease.

May 3, 2022 - AFP reported WHO spokesman Tarik Jasarevic told reporters in Geneva, "As of May 1, at least 228 probable cases were reported to WHO from 20 countries, with over 50 additional cases under investigation."

April 30, 2022 - The AP reported the Minnesota Department of Health said it’s investigating two severe cases of hepatitis, which included a liver transplant, among children.

April 29, 2022 - The UKHSA reported the total number of cases under investigation is 145. Of these cases, ten children have received a liver transplant. No children have died. Findings suggest that the rise in sudden onset hepatitis in children may be linked to adenovirus infection, but other causes are still being actively investigated. The UK published briefing document #1.

April 29, 2022 - The CDC reported: The Alabama cluster review: cases began Oct. 1, 2021, no geographical or epidemiological links between the children who were <= age 5; adenovirus was detected in all children, with type 41 detected in five specimens; three patients developed acute liver failure, two of whom were treated with cidofovir (off-label use) and steroids, and underwent liver transplantation; at admission, eight patients had scleral icterus, seven had hepatomegaly, six had jaundice, and one had encephalopathy.

April 29, 2022 - Garcetin Madrid reported that in Spain, between January 2022 and April 29, 2022, twenty-two acute hepatitis-like cases have been detected with no epidemiological link. A total of 8 have been in the Community of Madrid. In one case, it has been possible to determine through genomic sequencing that the Adenovirus is type 2.

April 28, 2022 - The ECDC reported that 'the current leading hypothesis is that a cofactor affecting young children having an adenovirus infection, which would be mild in normal circumstances, triggers a more severe infection or immune-mediated liver damage. The cases tested positive for adenovirus in England (75%) and Scotland (50%). Subtyping of 11 patients from the UK investigation found that these were all type 41F. Other aetiologies (infectious or toxic agents) are still under investigation.

April 28, 2022 - The California Department of Public Health investigates seven children for possible liver damage from hepatitis.

April 27, 2022 - The  Wisconsin Department of Health Services is investigating at least four cases among children. This includes two children who had severe outcomes, one liver transplant, and one fatality.

Apr 27, 2022 - JPGN Reports published: Pediatric Acute Liver Failure Due to Type 2 Autoimmune Hepatitis Associated With SARS-CoV-2 Infection: A Case Report.

April 26, 2022 - CBC reported Canada’s Public Health Agency is investigating reports of severe acute hepatitis of unknown origin in young children. It did not reveal the number of cases or their location.

April 26, 2022 - The Romanian Ministry of Health announced a 5-year-old child from the Bucharest-Ilfov area was admitted to a specialized hospital on April 4, 2022, for severe acute hepatitis.

April 25, 2022 - The UK Heath Security Agency published a detailed technical briefing on the investigations into a rise in cases of sudden onset hepatitis (liver inflammation) in children, with data and findings on cases resident in England, up to 20 April 2022. Of these cases, ten children have received a liver transplant. No UK cases have died. The UKHSA said it believed cofactors affecting young children are rendering normal adenovirus infections more severe or causing them to trigger immunopathology.

April 25, 2022 - The Illinois Department of Public Health announced that it has learned of three suspected cases of severe hepatitis in children under ten years of age, potentially linked to a strain of adenovirus.

April 25, 2022 -  Jiji Press reported that Japan's health ministry said a child had been hospitalized as a possible acute child hepatitis case of unknown origin.

April 24, 2022 - A case of an acute variant of hepatitis in children has now also been discovered in Belgium. Virologist Steven Van Gucht of Sciensano commented: "I think there will be new possible cases in days or weeks."

April 22, 2022 - Reuters reported that health authorities worldwide are investigating a mysterious increase in severe cases of hepatitis in children.

April 21, 2022 - Department of Health and Human Services confirmed two cases of hepatitis in young children.

April 21, 2022 - The UK Health Security Agency's ongoing investigation into higher than usual rates of liver inflammation (hepatitis) in children across the UK has confirmed an additional 34 cases since the previous update, bringing the total number of cases to 108. Of the confirmed cases, 79 are in England, 14 are in Scotland, and the remaining (15) are located in Wales and Northern Ireland.

April 21, 2022 - The U.S. CDC published Health Advisory #CDCHAN-00462 - Recommendations for Adenovirus Testing and Reporting of Children with Acute Hepatitis of Unknown Etiology. A possible association between pediatric hepatitis and adenovirus 41 infection is currently under investigation.

April 21, 2022 - Science Media Centre - Prof Will Irving, Professor of Virology, University of Nottingham, expert reaction to update from UKHSA on hepatitis (41) cases in children under investigation.

April 19, 2022 - The Israel Health Ministry confirmed 12 cases of liver disease (hepatitis) in children in recent months at Shaare Zedek and Schneider hospitals. Scientists are considering other sources of the disease. According to the Jerusalem Post, the children are from various parts of Israel and not from any specific ethnic or religious group.

April 19, 2022 - The European CDC reported the cases in the United Kingdom presented clinically with severe acute hepatitis, with increased levels of liver enzymes (aspartate transaminase) or Alanine aminotransaminase greater than 500 IU/L), and many cases were jaundiced. In addition, some patients reported gastrointestinal symptoms, including abdominal pain, diarrhea, and vomiting in the preceding weeks. Laboratory investigations excluded viral hepatitis types A, B, C, D, and E in all cases. Of the 13 cases reported by Scotland for which detailed information is available, 11 had results for adenovirus testing, and five tested positive. 

April 18, 2022 - The Alabama Department of Public Health recently announced it is investigating an increase in hepatitis in nine young children in Alabama, with a potential association with Adenovirus 41.

April 15, 2022 - The WHO was notified of ten cases of severe acute hepatitis of unknown etiology in children across central Scotland. By April 8, 2022, 74 patients had been identified in the United Kingdom. Hepatitis viruses (A, B, C, E, and D, where applicable) have been excluded after laboratory testing while further investigations are ongoing to understand the etiology of these cases. 

April 14, 2022 - Euroscience published a Rapid Communication - Investigation of hepatitis of unknown etiology among young children in Scotland during 2022.

April 8, 2022 - The UKHSA, NHS, and public health colleagues have been investigating the cause of acute hepatitis cases in children from England, Scotland, and Wales in the past few weeks. There is no known association with travel, and hepatitis viruses (A to E) have not been detected in these children.

Abnormal Liver Tests

On May 9, 2022, additional guidance from AAP: Red Book Online Outbreaks: Hepatitis Cases Possibly Associated with Adenoviral Infection. The following summary recommends adenovirus testing in children with acute hepatitis of unknown etiology.

On May 6, 2022, the U.S. CDC stated 'a possible association between pediatric hepatitis and adenovirus infection is currently under investigation after subsequent laboratory testing identified adenovirus type 41 infection in several cases.' Please consider the collection and submission of the following specimen types (if available) for adenovirus detection.

Elevated liver enzymes are a common scenario encountered by physicians in clinical practice. The term "liver function tests" (LFTs) is used commonly to check the overall health of a person's liver. LFTs have been found to be imprecise and potentially misleading since many of the tests are not direct measures of their function. Furthermore, the commonly used liver biochemical tests may be abnormal even in patients with a healthy liver. As an example, a population-based survey in the U.S. conducted between 1999 and 2002 estimated that abnormal alanine aminotransferase was present in 8.9% of respondents.

Email [email protected] with additional questions. 

Adenovirus Overview

Adenoviruses are common respiratory viruses that cause various illnesses at any age. However, according to the U.S. CDC on April 29, 2022, people (children) with weakened immune systems or existing respiratory or cardiac disease are more likely than others to get very sick from an adenovirus (Adenovirus41.com) infection. In general, respiratory adenoviruses do not typically demonstrate discernible seasonal circulation patterns

Adenoviruses are medium-sized (90-100 nm), non-enveloped icosohedral viruses with double-stranded DNA. More than 50 types of immunologically distinct adenoviruses can cause infections in humans. While there have been case reports of hepatitis in immunocompromised children infected with Adenovirus type 41f (TAK, Ad41), an unknown cause of hepatitis in healthy children, stated the CDC on April 21, 2022. In addition, Dr. Leandro Soares Sereno, Advisor for Viral Hepatitis Prevention and Control at the Pan American Health Organization, posted a FAQ on May 3, 2022.

Adenovirus Vaccines For 2022 (Non-COVID-19)

There is an adenovector vaccine available for most U.S. military personnel. In addition, the U.S. Department of Defense recommends it for military recruits entering basic training. It may also be recommended for other military personnel at high risk for adenovirus infection. Initially approved by the U.S. FDA in 2011, the Johnson & Johnson (Barr Labs, Inc.) adenovirus vaccine contains live adenovirus Type 4 and Type 7. The vaccine (BL 125296) comes as two tablets, taken orally, and should be swallowed whole, not chewed or crushed. The safety and effectiveness of Adenovirus Type 4 and Type 7 Vaccine in immunocompromised individuals have not been evaluated. In Canada, the Adenovirus Vaccine (W6369-19A009/A) was approved in 2018.

Adenovirus Treatments

Treatment of adenovirus infection is supportive. Unfortunately, current antiviral therapy options for adenovirus infections are limited. While evidence from controlled trials is lacking, there are reports of the successful intravenous use of cidofovir in immunocompromised patients with severe adenoviral disease. In addition, intravenous immunoglobulins are also used as adjunctive treatment in immunocompromised patients as they contain high titers of neutralizing antibodies for adenovirus.

Autoimmune Hepatitis

Autoimmune hepatitis (AIH) can occur in individuals where environmental factors trigger an immune-mediated reaction against hepatocytes. Vaccines are a very rare cause of AIH. There are two clinically relevant types of AIH, including type 1and type 2. Type 1 AIH, also referred to as the classic type, is typically diagnosed in adulthood, whereas type 2 is diagnosed during childhood. Both types are treated similarly; however, type 2 AIH can be more severe and difficult to control. 

Nonalcoholic Steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is a condition in which fat builds up in your liver. The more severe form of NAFLD is called nonalcoholic steatohepatitis (NASH). NASH causes the liver to swell and become damaged. NAFLD is one of the most common forms of chronic liver disease in children and adolescents, which may be related to environmental and genetic reasons.

Hepatitis B Vaccination For Children

The U.S. Advisory Committee on Immunization Practices recommends universal hepatitis B vaccination within 24 hours of birth, followed by completion of the vaccine series and vaccination of children and adolescents aged <19 years who have not been vaccinated previously.

Hepatitis Vaccines

The U.S. CDC published the updated pediatric vaccination schedule, including hepatitis, in February 2022In addition, breaking hepatitis vaccine news is posted at this link.

COVID-19 Vaccination Investigation

COVID-19 vaccinations are not recommended for most children aged under five, who comprise about 75% of these acute hepatitis/liver cases. In the UK, a few older children are recorded as having had a COVID-19 vaccination before illness onset. As of May 6, 2022, there is no evidence of a link between COVID-19 vaccination and acute liver failure.

Adenovirus Hepatitis Research 2017 - 2022

April 20, 2022 - The Journal of Virology published: SARS-CoV-2 vaccination can elicit a CD8 T-cell dominant hepatitis. In this case report, we show that highly activated T cells accumulate and are evenly distributed in the different areas of the liver in a patient with liver inflammation following SARS-CoV-2 vaccination. Moreover, within these liver infiltrating T cells, we observed an enrichment of T cells reactive to SARS-CoV-2, suggesting that these vaccine-induced cells can contribute to liver inflammation. Autoimmune-hepatitis-like disease after vaccination against SARS-CoV-2 is now recognized as a rare adverse event not identified in early trials. The widespread use of the vaccine with the administration of hundreds of million doses worldwide also raises questions of causality vs. coincidence.

February 28, 2022 - The U.S. NIH posted: Adenovirus (41) Hepatitis in Immunocompetent Adults. Case Report.

August 11, 2021 - The U.S. NIH stated: Acute hepatitis is a term used to describe a wide variety of conditions characterized by acute inflammation of the hepatic parenchyma or injury to hepatocytes resulting in elevated liver function indices. In general, hepatitis is classified as acute or chronic based on the duration of the inflammation and insult to the hepatic parenchyma.

April 13, 2021 - Case Report: Autoimmune hepatitis developing after COVID-19 vaccine: Causality or casualty? 'To our knowledge, this is the first reported episode of autoimmune hepatitis developing post-COVID-19 vaccination, raising concern regarding the possibility of vaccine-induced autoimmunity.'

March 12, 2019 - Adenovirus in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of PracticeProspective randomized clinical trials do not support the use of antiviral therapy. However, most transplant centers consider intravenous cidofovir the standard practice for treating severe, progressive, or disseminated adenovirus disease. In addition, intravenous immunoglobulin may be beneficial, primarily in a select group of patients with hypogammaglobulinemia.

October 6, 2017 - U.S. CDC MMWR: Human Adenovirus (41) Surveillance — the United States, 2003–2016.

August 4, 2017 - Epidemic Keratoconjunctivitis Outbreak Associated with Human Adenovirus Type 8 — U.S. Virgin Islands, June–November 2016.

June 2017 - The American Journal of Surgical Pathology: Adenovirus Hepatitis - Clinicopathologic Analysis of 12 Consecutive Cases From a Single Institution. 

January 2007 - Treatment of Adenovirus Disease in Stem Cell Transplant Recipients with Cidofovir. In conclusion, early treatment of AdV disease with cidofovir inhibits viral replication in vivo and reduces mortality in allogeneic SCT recipients compared with historical data.

August 1996 - U.S. NIH - Adenovirus 41 replication: cell-related differences in viral gene transcription.

August 1994 - This paper used various approaches to characterize the two proteins and determine whether both fibers were expressed in infected cells and viral particles. DNA sequencing of the subgroup F human adenovirus serotype 41 (TAK, Ad41) fiber gene revealed the presence of two adjacent open reading frames encoding information for proteins with molecular weights of 60.6 kDa and 41.4 kDa (Pieniazek et al.; Nucleic Acids Res. 18: p. 1901, 1990).

 

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