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2022 hepatitis of unknown origin in children

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2022 hepatitis of unknown origin in children
Map
DiseaseAcute 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]

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

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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

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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

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Cases by country and territory
Country/Territory Cases Deaths Last Update
 Argentina 8 10 May 2022[8]
 Austria 3 17 June 2022[2]
 Belgium 14 17 June 2022[2]
 Brazil 88 7 13 June 2022[28]
 Bulgaria 1 17 June 2022[2]
 Canada 7 10 May 2022[8]
 Costa Rica 2 10 May 2022[8]
 Cyprus 2 17 June 2022[2]
 Denmark 7 17 June 2022[2]
 France 7 17 June 2022[2]
 Germany 1 5 May 2022[29]
 Greece 9 17 June 2022[2]
 Indonesia 5 10 May 2022[8]
 Ireland 14 17 June 2022[2]
 Israel 5 17 June 2022[2]
 Italy 33 17 June 2022[2]
 Japan 162 1 22 August 2023[30]
 Latvia 1 17 June 2022[2]
 Moldova 1 17 June 2022[2]
 Netherlands 15 17 June 2022[2]
 Norway 5 17 June 2022[2]
 Palestine 1 10 May 2022[8]
 Panama 1 10 May 2022[8]
 Poland 8 17 June 2022[2]
 Portugal 15 17 June 2022[2]
 Romania 8 5 May 2022[29]
 Serbia 1 17 June 2022[2]
 Singapore 1 10 May 2022[8]
 South Korea 1 10 May 2022[8]
 Spain 37 17 June 2022[2]
 Sweden 9 17 June 2022[2]
 United Kingdom 258 21 June 2022[31]
 United States 296 11 24 June 2022[32]

Symptoms

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

Possible causes

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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

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References

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  1. ^ a b Elsheikh, Randa; Tien, Hoang Thuy; Makram, Abdelrahman M.; Van, Nguyen Thanh; Le, Trang Thi Bich; Vasanthakumaran, Tamilarasy; Huy, Nguyen Tien (1 June 2023). "Acute hepatitis of unknown origin in children: Behind the statistics". Hepatology. 77 (6): 2118–2127. doi:10.1002/hep.32682. ISSN 1527-3350. PMID 35862247. S2CID 250732438.
  2. ^ a b c d e f g h i j k l m n o p q r s t "Joint ECDC-WHO Regional Office for Europe Hepatitis of Unknown Origin in Children Surveillance Bulletin". cdn.ecdc.europa.eu. 17 June 2022. Archived from the original on 22 June 2022. Retrieved 24 June 2022.
  3. ^ Grand, Roger J. (December 2023). "Pathogenicity and virulence of human adenovirus F41: Possible links to severe hepatitis in children". Virulence. 14 (1): 2242544. doi:10.1080/21505594.2023.2242544. ISSN 2150-5608. PMC 10405776. PMID 37543996. S2CID 260679964.
  4. ^ a b Baker, Julia M. (29 April 2022). "Acute Hepatitis and Adenovirus Infection Among Children — Alabama, October 2021–February 2022". MMWR. Morbidity and Mortality Weekly Report. 71 (18): 638–640. doi:10.15585/mmwr.mm7118e1. PMC 9098244. PMID 35511732. S2CID 248463283. Archived from the original on 3 May 2022. Retrieved 3 May 2022.
  5. ^ a b Venkatesan, Priya (1 September 2022). "New guidance for researching acute hepatitis in children". The Lancet Microbe. 3 (9): e651. doi:10.1016/S2666-5247(22)00229-4. ISSN 2666-5247. PMID 36058232. S2CID 252023562.
  6. ^ "Overview: Children with Hepatitis of Unknown Cause". www.cdc.gov. 7 June 2022. Retrieved 9 June 2022.
  7. ^ "Acute hepatitis: technical briefing". GOV.UK. Retrieved 11 September 2022.
  8. ^ a b c d e f g h i j k l "Epidemiological update: Hepatitis of unknown aetiology in children". European Centre for Disease Prevention and Control. 11 May 2022. Retrieved 13 May 2022.
  9. ^ "CDC Alerts Providers to Hepatitis Cases of Unknown Origin". Centers for Disease Control and Prevention. 21 April 2022. Archived from the original on 25 April 2022. Retrieved 25 April 2022.
  10. ^ "Health Alert Network (HAN): Recommendations for Adenovirus Testing and Reporting of Children with Acute Hepatitis of Unknown Etiology". emergency.cdc.gov. Centers for Disease Control and Prevention. 21 April 2022. Archived from the original on 25 April 2022. Retrieved 25 April 2022.
  11. ^ Marsh, Kimberly; Tayler, Rachel; Pollock, Louisa; Roy, Kirsty; Lakha, Fatim; Ho, Antonia; Henderson, David; Divala, Titus; Currie, Sandra; Yirrell, David; Lockhart, Michael; Rossi, Maria K.; Phin, Nick (14 April 2022). "Investigation into cases of hepatitis of unknown aetiology among young children, Scotland, 1 January 2022 to 12 April 2022". Eurosurveillance. 27 (15): 2200318. doi:10.2807/1560-7917.ES.2022.27.15.2200318. PMC 9012090. PMID 35426362. S2CID 248180709.
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  13. ^ "Update: Hepatitis of unknown origin in children". European Centre for Disease Prevention and Control. 19 April 2022. Retrieved 24 April 2022.
  14. ^ a b c "Increase in hepatitis (liver inflammation) cases in children under investigation". GOV.UK. Retrieved 13 May 2022.
  15. ^ "Investigation into acute hepatitis of unknown aetiology in children in England: Technical briefing". UK Health Security Agency. 25 April 2022. p. 3
  16. ^ a b c d e f g h i "Multi-Country – Acute, severe hepatitis of unknown origin in children". www.who.int. Archived from the original on 24 April 2022. Retrieved 24 April 2022.
  17. ^ Mitropoulos, Arielle (2022-04-28). "Concerning clusters of severe hepatitis cases in children being investigated". ABC News. Retrieved 2022-04-29.
  18. ^ "Global mystery hepatitis outbreak spreads to Asia and Canada". The Guardian. April 27, 2022. Retrieved April 27, 2022.
  19. ^ Pelley, Lauren (April 26, 2022). "Severe hepatitis of 'unknown origin' in children being investigated in Canada". CBC News. Retrieved April 27, 2022.
  20. ^ "Infant with acute hepatitis of unknown cause hospitalised at KKH; MOH investigating". The Straits Times. April 30, 2022. Retrieved April 30, 2022.
  21. ^ 卢慧菁 (2022-04-30). "本地一10月大男婴 罹患原因不明急性肝炎" (in Chinese (Singapore)). 联合早报. Archived from the original on 2022-04-30. Retrieved 2022-04-30.
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  23. ^ "Masyarakat Agar Waspada Setelah 3 Pasien Anak Dengan Hepatitis Akut Meninggal Dunia". Sehat Negeriku (in Indonesian). Indonesian Ministry of Health. 2022-05-01. Retrieved 2022-05-24.
  24. ^ "Three Children Died of Acute Hepatitis in Indonesia Last Month". Bloomberg.com. 2022-05-02. Retrieved 2022-05-02.
  25. ^ "Malaysia Suspects Hepatitis Case Of Unknown Origin In Sabah Child". CodeBlue. 2022-05-06. Retrieved 2022-05-06.
  26. ^ a b Mahr, Krista (2022-05-06). "CDC investigating more than 100 children with hepatitis of unknown cause". Politico. Retrieved 2022-05-07.
  27. ^ Crist, Carolyn (12 May 2022). "CDC Updates Guidelines for Hepatitis Outbreak Among Children". Medscape. Archived from the original on 13 May 2022. Retrieved 13 May 2022.
  28. ^ "Hepatite misteriosa: Ministério da Saúde investiga 88 casos e sete mortes no Brasil". O Globo (in Brazilian Portuguese). 2022-06-13. Retrieved 2022-06-24.
  29. ^ a b Holmgaard Mersh, Amalie (6 April 2022). "ECDC: Around 95 cases of mysterious child hepatitis in 15 EU countries". Eeuractiv. Retrieved 9 May 2022.
  30. ^ "Japan confirms first death from mysterious form of child hepatitis". Asahi Shimbun. Retrieved 22 August 2023.
  31. ^ "Increase in hepatitis (liver inflammation) cases in children under investigation". UK Health Security Agency. Retrieved 24 June 2022.
  32. ^ Ledford, Heidi (24 June 2022). "Mysterious child hepatitis continues to vex researchers". Nature. 607 (7917): 20–21. Bibcode:2022Natur.607...20L. doi:10.1038/d41586-022-01706-y. PMID 35750922. S2CID 250022494.
  33. ^ Rettner, Rachael (2022-04-28). "Mysterious hepatitis outbreak in children: What we know". Live Science. Retrieved 2022-04-29.
  34. ^ a b Gurdasani D, Trent M, Ziauddeen H, Mnatzaganian E, Turville S, Chen X, Kunasekaran MP, Chughtai AA, Moa A, McEniery J, Greenhalgh T, MacIntyre CR. Acute hepatitis of unknown aetiology in children: evidence for and against causal relationships with SARS-CoV-2, HAdv and AAV2. BMJ Paediatr Open. 2024 Dec 9;8(1):e002410. doi:10.1136/bmjpo-2023-002410
  35. ^ Ilic, Irena; Ilic, Milena (2023). "Multi-country outbreak of severe acute hepatitis of unknown origin in children, 2022". Acta Paediatrica. 112 (6): 1148–1156. doi:10.1111/apa.16685. PMID 36705335. S2CID 256303849.
  36. ^ a b Sallam, Malik; Mahafzah, Azmi; Şahin, Gülşen Özkaya (2022). "Hepatitis of Unknown Origin and Etiology (Acute non HepA-E Hepatitis) among Children in 2021/2022: Review of the Current Findings". Healthcare. 10 (6): 973. doi:10.3390/healthcare10060973. PMC 9222544. PMID 35742029.
  37. ^ a b c d e f Mücke, Marcus Maximilian; Zeuzem, Stefan (2022). "The recent outbreak of acute severe hepatitis in children of unknown origin – what is known so far". Journal of Hepatology. 77 (1): 237–242. doi:10.1016/j.jhep.2022.05.001. PMID 35533802. S2CID 248613117.
  38. ^ Gutierrez Sanchez, L. Helena; Shiau, Henry; Baker, Julia M.; Saaybi, Stephanie; Buchfellner, Markus; Britt, William; et al. (2022-07-13). "A Case Series of Children with Acute Hepatitis and Human Adenovirus Infection". New England Journal of Medicine. 387 (7): 620–630. doi:10.1056/NEJMoa2206294. ISSN 0028-4793. PMC 9808750. PMID 35830653. S2CID 250529116.
  39. ^ Kelgeri, Chayarani; Couper, Michael; Gupte, Girish L.; Brant, Alexandra; Patel, Mitul; Johansen, Lauren; et al. (2022-07-13). "Clinical Spectrum of Children with Acute Hepatitis of Unknown Cause". New England Journal of Medicine. 387 (7): 611–619. doi:10.1056/NEJMoa2206704. ISSN 0028-4793. PMID 35830627. S2CID 250528150.
  40. ^ a b Adenovirus probable cause of mysterious child hepatitis. BBC News, 25 April 2022. Retrieved 25 April 2022.
  41. ^ Elbeltagi, Reem; Al-Beltagi, Mohammed; Saeed, Nermin Kamal; Bediwy, Adel Salah; Toema, Osama (2023). "May 2022 acute hepatitis outbreak, is there a role for COVID-19 and other viruses?". World Journal of Hepatology. 15 (3): 364–376. doi:10.4254/wjh.v15.i3.364. PMC 10075009. PMID 37034240.
  42. ^ "Multi-Country – Acute, severe hepatitis of unknown origin in children". www.who.int. Retrieved 2022-05-06.
  43. ^ "Coronavirus disease (COVID-19): Vaccines". www.who.int. Retrieved 2022-05-06.
  44. ^ Sallam, Malik; Mahafzah, Azmi; Şahin, Gülşen Özkaya (2022). "Hepatitis of Unknown Origin and Etiology (Acute non HepA-E Hepatitis) among Children in 2021/2022: Review of the Current Findings". Healthcare. 10 (6): 973. doi:10.3390/healthcare10060973. PMC 9222544. PMID 35742029.
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