2022 hepatitis of unknown origin in children

Last updated
2022 hepatitis of unknown origin in children
Map of 2022 hepatitis of unknown origin in children.svg
Map
Disease Acute hepatitis
DateOctober 2021 – September 2022
Confirmed cases895
Deaths
18

In 2022, cases of severe sudden hepatitis of unknown origin in children were reported to the World Health Organization (WHO) from several countries. [1] [2] The outbreak led to a significant interest in adenoviruses, though as of 2023 no definite explanation has been agreed on the cause of the hepatitis. [3]

Contents

In October 2021, a cluster of cases of severe hepatitis of unknown origin were identified at a children's hospital in the U.S. state of Alabama. [4] Between 5 April and 8 July 2022, 35 countries had reported 1,010 probable cases of acute hepatitis of unknown cause in children. [1] WHO guidance has since recommended the testing of several other viruses in children aged 16 years or younger presenting with an acute hepatitis not caused by hepatitis viruses A–E, where serum aminotransferase levels are higher than 500 IU/L, and other local causes of hepatitis have been excluded. [5]

It is not uncommon for the cause of some hepatitis cases in children to remain unknown. [6] As of September 2022, the cause of the rise in cases remains unknown, although it has been suggested by some UK-studies that a co-infection with adeno-associated virus 2 (AAV2) and adenovirus or less likely herpesvirus might have caused some. [5] [7]

Case definition

A probable case as defined by the ECDC and WHO, is a person 16 years old or younger since 1 October 2021, who presents with an acute hepatitis that tests negative for hepatitis viruses A, B, C, D and E, and has a higher than 500 IU/L of the liver enzyme aspartate transaminase. [8] Hepatitis due to drug toxicity, and inherited metabolic disorders, or autoimmune disorders are not included. [8] Worldwide, not all countries may have used the same criteria. [8]

History

From October 2021 to February 2022, nine children, all at the Children's of Alabama hospital, were identified with severe hepatitis of unknown origin. [4] [9] All were previously healthy and the CDC was notified in November. [10]

On 31 March 2022, Public Health Scotland (PHS) were notified of five children aged three-to-five-years that were diagnosed with severe hepatitis of unknown origin at the Royal Hospital for Children. [11] On 5 April, the International Health Regulations (IHR) National Focal Point (NFP) for the UK informed the WHO of 10 cases of sudden severe hepatitis of unknown origin in children across Scotland, one whose symptoms began in January while the others first became unwell in March. [12] They were previously healthy. [13] By 8 April 2022, 74 cases had been identified in the UK, with six requiring a liver transplantation. [12] [14] Subsequently, a few cases were reported in Ireland and Spain. [12] By 21 April, there were 114 cases in the UK. [15]

By 23 April 2022, 11 European countries and the US had reported at least 169 cases of sudden onset hepatitis in children under the age of 16-years, with most cases in the UK. [16] The common hepatitis causing viruses, A, B, C, D and E, were excluded in all 169 cases. [16] Most did not have a fever, and many presented with diarrhoea, vomiting and abdominal pain, before finding raised levels of liver enzymes in their blood and jaundice. [16] According to the WHO, "It is not yet clear if there has been an increase in hepatitis cases, or an increase in awareness of hepatitis cases that occur at the expected rate but go undetected." [16] The WHO confirmed one child death, 17 liver transplantations and that the youngest child affected was one month old. [16] At least 74 tested positive for adenovirus, 20 that were tested were positive for SARS-CoV-2, and of those tested 19 were detected with both a SARS-CoV-2 and adenovirus co-infection. [16] Most affected children had not received a COVID-19 vaccine. [16] The WHO's report of 23 April confirmed that 114 have been reported in the UK and Northern Ireland, 13 in Spain, 12 in Israel, nine in the US, six in Denmark, less than five in Ireland, four in the Netherlands, four in Italy, two in Norway, two in France, one in Romania, and one in Belgium. [16] The WHO initiated an investigation into the outbreaks. [17]

By 25 April 2022 most cases were confirmed as under the age of five-years and 10 had required a liver transplantation. [14] There were no deaths in the UK. [14] On 26 April 2022, the Public Health Agency of Canada announced it was investigating reports of the disease affecting children in the country. The Guardian also reported that cases have been reported from countries in Asia; specifically in Japan, where a child was flagged for the disease on April 21, and in Singapore, on April 30. [18] [19] [20] On 30 April 2022, Singapore's Ministry of Health reported that a 10-month old infant with acute hepatitis of unknown cause was hospitalised on 25 April. [21]

As of 1 May 2022, the WHO had received reports of at least 228 probable cases from 20 countries, with over 50 cases under investigation. [22] On 2 May 2022, Indonesia's Ministry of Health reported that 3 children died of acute hepatitis in April 2022. [23] [24] On 6 May 2022, Malaysia reported a case of hepatitis of unknown origin in a 4-year-old boy who sought treatment in March 2022 and subsequently underwent liver transplantation. [25] Also on 6 May, the CDC said that it is investigating 109 children with hepatitis of unknown origin, including five recorded deaths. More than 90% of the children were hospitalized and 14% received a liver transplant due to liver failure. The majority of children have recovered. [26] As of 11 May, the EDCP estimated around 450 reported cases worldwide. [8] [27]

Statistics

Cases by country and territory
Country/TerritoryCasesDeathsLast Update
Flag of Argentina.svg  Argentina 810 May 2022 [8]
Flag of Austria.svg  Austria 317 June 2022 [2]
Flag of Belgium (civil).svg  Belgium 1417 June 2022 [2]
Flag of Brazil.svg  Brazil 88713 June 2022 [28]
Flag of Bulgaria.svg  Bulgaria 117 June 2022 [2]
Flag of Canada (Pantone).svg  Canada 710 May 2022 [8]
Flag of Costa Rica.svg  Costa Rica 210 May 2022 [8]
Flag of Cyprus.svg  Cyprus 217 June 2022 [2]
Flag of Denmark.svg  Denmark 717 June 2022 [2]
Flag of France.svg  France 717 June 2022 [2]
Flag of Germany.svg  Germany 15 May 2022 [29]
Flag of Greece.svg  Greece 917 June 2022 [2]
Flag of Indonesia.svg  Indonesia 510 May 2022 [8]
Flag of Ireland.svg  Ireland 1417 June 2022 [2]
Flag of Israel.svg  Israel 517 June 2022 [2]
Flag of Italy.svg  Italy 3317 June 2022 [2]
Flag of Japan.svg  Japan 162122 August 2023 [30]
Flag of Latvia.svg  Latvia 117 June 2022 [2]
Flag of Moldova.svg  Moldova 117 June 2022 [2]
Flag of the Netherlands.svg  Netherlands 1517 June 2022 [2]
Flag of Norway.svg  Norway 517 June 2022 [2]
Flag of Palestine.svg  Palestine 110 May 2022 [8]
Flag of Panama.svg  Panama 110 May 2022 [8]
Flag of Poland.svg  Poland 817 June 2022 [2]
Flag of Portugal.svg  Portugal 1517 June 2022 [2]
Flag of Romania.svg  Romania 85 May 2022 [29]
Flag of Serbia.svg  Serbia 117 June 2022 [2]
Flag of Singapore.svg  Singapore 110 May 2022 [8]
Flag of South Korea.svg  South Korea 110 May 2022 [8]
Flag of Spain.svg  Spain 3717 June 2022 [2]
Flag of Sweden.svg  Sweden 917 June 2022 [2]
Flag of the United Kingdom.svg  United Kingdom 25821 June 2022 [31]
Flag of the United States.svg  United States 2961124 June 2022 [32]

Symptoms

Those affected by the disease experience the following symptoms: [26] [33]

Possible causes

Transmission electron micrograph of two adenovirus particles Adenovirus 4.jpg
Transmission electron micrograph of two adenovirus particles

The cause of the outbreak remains unknown. The leading hypothesis is a link to human adenovirus infection, [34] particularly serotype F41. [35] As of May 2022, laboratory testing showed infection with human adenovirus in about three quarters of cases. [36] This serotype has previously been associated with gastrointestinal symptoms, but not hepatitis. This suggests there is an additional co-factor at play. [37] In August 2022, 9 children in a U.S. case series of hepatitis of unknown cause [38] and 27 of 30 children in a U.K. case series with hepatitis of unknown cause who underwent molecular testing [39] tested positive for human adenovirus 41 in a sample. It remained unclear, however, whether human adenovirus 41 was the cause.

One possibility is that restrictions imposed during the COVID-19 pandemic led to young children being exposed to adenovirus at a later point than normal in their lives, leading to a stronger immune response. [40] The increased susceptibility to a gut-tropic adenovirus amongst young children could be a consequence of a lower level of respiratory adenovirus circulation in the last 2 years. [37]

Another co-factor might be prior or concurrent infection with COVID-19 [37] [41] [34] or to another virus or environmental agent. [36] No notable exposures relating to travel, parental occupation, diet, exposure to animals or to toxicants have been recorded in association with cases to date. [37] Another suggestion is that there has been a change in the genetic make-up of adenovirus, so that it causes liver inflammation more readily, [40] although data is lacking to support this. [37]

According to the WHO, these theories require further investigation. [16]

No link to COVID-19 or other vaccinations, which use adenovirus as a vaccine vector has been seen, [37] particularly since the majority of cases occurred in an age group of children which were not vaccinated against COVID-19. [42] This observation almost excludes the possibility of COVID-19 vaccination playing a role in the outbreak. [43] [44]

See also

Related Research Articles

<span class="mw-page-title-main">Hepatitis</span> Inflammation of the liver

Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), poor appetite, vomiting, tiredness, abdominal pain, and diarrhea. Hepatitis is acute if it resolves within six months, and chronic if it lasts longer than six months. Acute hepatitis can resolve on its own, progress to chronic hepatitis, or (rarely) result in acute liver failure. Chronic hepatitis may progress to scarring of the liver (cirrhosis), liver failure, and liver cancer.

<span class="mw-page-title-main">Hepatitis C</span> Human viral infection

Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection period, people often have mild or no symptoms. Early symptoms can include fever, dark urine, abdominal pain, and yellow tinged skin. The virus persists in the liver, becoming chronic, in about 70% of those initially infected. Early on, chronic infection typically has no symptoms. Over many years however, it often leads to liver disease and occasionally cirrhosis. In some cases, those with cirrhosis will develop serious complications such as liver failure, liver cancer, or dilated blood vessels in the esophagus and stomach.

<span class="mw-page-title-main">Infectious mononucleosis</span> Common viral infectious disease

Infectious mononucleosis, also known as glandular fever, is an infection usually caused by the Epstein–Barr virus (EBV). Most people are infected by the virus as children, when the disease produces few or no symptoms. In young adults, the disease often results in fever, sore throat, enlarged lymph nodes in the neck, and fatigue. Most people recover in two to four weeks; however, feeling tired may last for months. The liver or spleen may also become swollen, and in less than one percent of cases splenic rupture may occur.

<span class="mw-page-title-main">SARS</span> Disease caused by severe acute respiratory syndrome coronavirus

Severe acute respiratory syndrome (SARS) is a viral respiratory disease of zoonotic origin caused by the virus SARS-CoV-1, the first identified strain of the SARS-related coronavirus. The first known cases occurred in November 2002, and the syndrome caused the 2002–2004 SARS outbreak. In the 2010s, Chinese scientists traced the virus through the intermediary of Asian palm civets to cave-dwelling horseshoe bats in Xiyang Yi Ethnic Township, Yunnan.

Hepatitis D is a type of viral hepatitis caused by the hepatitis delta virus (HDV). HDV is one of five known hepatitis viruses: A, B, C, D, and E. HDV is considered to be a satellite because it can propagate only in the presence of the hepatitis B virus (HBV). Transmission of HDV can occur either via simultaneous infection with HBV (coinfection) or superimposed on chronic hepatitis B or hepatitis B carrier state (superinfection).

<span class="mw-page-title-main">Hepatitis A</span> Acute infectious disease of the liver

Hepatitis A is an infectious disease of the liver caused by Hepatovirus A (HAV); it is a type of viral hepatitis. Many cases have few or no symptoms, especially in the young. The time between infection and symptoms, in those who develop them, is two–six weeks. When symptoms occur, they typically last eight weeks and may include nausea, vomiting, diarrhea, jaundice, fever, and abdominal pain. Around 10–15% of people experience a recurrence of symptoms during the 6 months after the initial infection. Acute liver failure may rarely occur, with this being more common in the elderly.

<span class="mw-page-title-main">Hepatitis E</span> Human disease caused by Orthohepevirus A

Hepatitis E is inflammation of the liver caused by infection with the hepatitis E virus (HEV); it is a type of viral hepatitis. Hepatitis E has mainly a fecal-oral transmission route that is similar to hepatitis A, although the viruses are unrelated. HEV is a positive-sense, single-stranded, nonenveloped, RNA icosahedral virus and one of five known human hepatitis viruses: A, B, C, D, and E.

<span class="mw-page-title-main">Viral hepatitis</span> Liver inflammation from a viral infection

Viral hepatitis is liver inflammation due to a viral infection. It may present in acute form as a recent infection with relatively rapid onset, or in chronic form, typically progressing from a long-lasting asymptomatic condition up to a decompensated hepatic disease and hepatocellular carcinoma (HCC).

<span class="mw-page-title-main">Liver disease</span> Medical condition

Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.

<span class="mw-page-title-main">Adenovirus infection</span> Medical condition

Adenovirus infection is a contagious viral disease, caused by adenoviruses, commonly resulting in a respiratory tract infection. Typical symptoms range from those of a common cold, such as nasal congestion, coryza and cough, to difficulty breathing as in pneumonia. Other general symptoms include fever, fatigue, muscle aches, headache, abdominal pain and swollen neck glands. Onset is usually two to fourteen days after exposure to the virus. A mild eye infection may occur on its own, combined with a sore throat and fever, or as a more severe adenoviral keratoconjunctivitis with a painful red eye, intolerance to light and discharge. Very young children may just have an earache. Adenovirus infection can present as a gastroenteritis with vomiting, diarrhoea and abdominal pain, with or without respiratory symptoms. However, some people have no symptoms.

A breakthrough infection is a case of illness in which a vaccinated individual becomes infected with the illness, because the vaccine has failed to provide complete immunity against the pathogen. Breakthrough infections have been identified in individuals immunized against a variety of diseases including mumps, varicella (Chickenpox), influenza, and COVID-19. The characteristics of the breakthrough infection are dependent on the virus itself. Often, infection of the vaccinated individual results in milder symptoms and shorter duration than if the infection were contracted naturally.

Adenovirus serotype 14 (Ad14) is a serovar of adenovirus which, unlike other adenovirus serovars, is known to cause potentially fatal adenovirus infections. According to the United States Centers for Disease Control and Prevention (CDC), as of September 2007, outbreaks have been identified in four states in the U.S., with ten identified deaths since May 2006.

<span class="mw-page-title-main">Hepatitis B</span> Human viral infection

Hepatitis B is an infectious disease caused by the hepatitis B virus (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection.

<span class="mw-page-title-main">2009 Gujarat hepatitis outbreak</span> Disease outbreak in India

The 2009 Gujarat hepatitis B outbreak was a cluster of hepatitis B cases that appeared in Modasa, northern Gujarat, India in 2009. Over 125 people were infected and up to 49 people died. Several doctors were investigated and arrested after the outbreaks.

<span class="mw-page-title-main">Pandemic H1N1/09 virus</span> Virus responsible for the 2009 swine flu pandemic

The pandemic H1N1/09 virus is a swine origin influenza A virus subtype H1N1 strain that was responsible for the 2009 swine flu pandemic. This strain is often called swine flu by the public media due to the prevailing belief that it originated in pigs. The virus is believed to have originated around September 2008 in central Mexico.

<span class="mw-page-title-main">MERS</span> Viral respiratory infection

Middle East respiratory syndrome (MERS) is a viral respiratory infection caused by Middle East respiratory syndrome–related coronavirus (MERS-CoV). Symptoms may range from none, to mild, to severe depending on age and risk level. Typical symptoms include fever, cough, diarrhea, and shortness of breath. The disease is typically more severe in those with other health problems.

<span class="mw-page-title-main">Acute flaccid myelitis</span> Condition of the spinal cord with symptoms of rapid onset of arm or leg weakness

Acute flaccid myelitis (AFM) is a serious condition of the spinal cord. Symptoms include rapid onset of arm or leg weakness and decreased reflexes. Difficulty moving the eyes, speaking, or swallowing may also occur. Occasionally, numbness or pain may be present. Complications can include trouble breathing.

DTaP-IPV-HepB vaccine is a combination vaccine whose generic name is diphtheria and tetanus toxoids and acellular pertussis adsorbed, hepatitis B (recombinant) and inactivated polio vaccine or DTaP-IPV-Hep B. It protects against the infectious diseases diphtheria, tetanus, pertussis, poliomyelitis, and hepatitis B.

<span class="mw-page-title-main">Andrea Ammon</span> German physician

Andrea Ammon is a German physician and the former director of the European Centre for Disease Prevention and Control (ECDC), a European Union (EU) agency strengthening Europe's defence against infectious disease. She advised the German government on the SARS and Influenza A virus subtype H2N2 outbreaks.

Human adenovirus 41(HAdV-F41), is an enteric Adenovirus, a nonenveloped virus with an icosahedral nucleocapsid containing a double-stranded DNA genome.

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