Letter to the editor

Severe acute hepatitis in children of unspecified etiology and what is known, May 2022

Belsy Acosta-Herrera^{1  *} 

¹Viceministerio de Higiene, Epidemiología y Microbiología. Ministerio de Salud Pública de la República de Cuba.

Acute hepatitis is the term used to describe a wide variety of pathological conditions characterized by acute inflammation of the liver parenchyma that progresses to normalization of liver function tests in a period of less than six months. The severity can range from mild and self-limited to severe disease requiring liver transplantation. Etiologically, it can be caused by toxic agents, drugs, environmental factors, autoimmune processes or infectious agents (bacteria, fungi, parasites and viruses). Viruses are considered the most common etiologic agents of acute hepatitis. Hepatitis A (HAV), B, C, D, and E viruses are recognized as the cause of viral hepatitis and differ among themselves in modes of transmission, disease severity, geographic distribution, and prevention methods. Other viral agents can cause acute hepatitis: Epstein-Barr virus, cytomegalovirus, herpes simplex virus, coxsackievirus, dengue virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).¹

On 5 April 2022, the International Health Regulations National Focal Point for Central Scotland notified the United Kingdom a significant and unexpected increase in cases (10) of severe acute hepatitis in previously healthy young children (under 10 years of age) in which no known association with travel was identified. In nine of the cases, the onset of symptoms was in March 2022 and in one, in January 2022. The 10 cases were hospitalized. As a result of a nationwide investigation, April 8, 2022, a total of 74 cases had been identified in the United Kingdom based on a definition of confirmed case considering any person presenting with acute hepatitis (testing negative for viruses from hepatitis A to E) with serum transaminases >500 IU/L (Aspartate Transaminase-AST or Alanine Transaminase-ALT), who is 10 years old or younger, since January 1, 2022.²

A technical report of 81 cases identified in England describes cases of acute hepatitis with very high transaminases (>500 IU/L), frequently with jaundice in more than 74% of cases followed by vomiting (72.8 %), pale stools (58.0%), common gastrointestinal symptoms including diarrhea (49.4%) and nausea (39.5%), lethargy (55.6%), fever (29.6%) and less frequently, respiratory symptoms (19.8%). Some cases required transfer to specialized pediatric units and six children required liver transplantation. No died were reported.³

Following notification from the United Kingdom, in Alabama, United States, nine pediatric patients with severe acute hepatitis and one adenovirus infection (detected by real-time PCR in whole blood samples) were identified on admission, between October 2021 and February 2022. These patients came from geographically different parts and there were no epidemiological links between them. The median age at admission was 2 years, 11 months. All patients were immunocompetent with no significant medical comorbidities. On admission, 88% of the patients had scleral jaundice, 77% had hepatomegaly, and one had encephalopathy. Three patients developed acute liver failure and two of them required liver transplantation. Nucleotide sequencing of the hypervariable region of the adenovirus hexon gene was performed on samples from five patients, adenovirus type 41 was detected in all them. In all nine cases, the laboratory results showed a negative result for hepatitis A to E viruses and no other known cause of hepatitis was detected.⁴

Several countries have reported cases compatible with the established definition through the mechanisms of the WHO and the European Center for Disease Control and Prevention. On April 23, the WHO published a document that recommends Member States to identify, investigate and report cases of severe acute hepatitis in children and reinforces the need for research to elucidate the etiology.⁵

An analysis carried out up to May 20 shows that 75.4% of cases are <5 years of age. Of 156 cases with available information on hospital admission, 22 (14.1%) required care in intensive care units and 14 (12%) of 117, received a liver transplant. Among all the cases, 181 samples were taken for adenovirus diagnosis in different types of samples (nasopharyngeal swab, serum, whole blood, urine, feces) and 110 (60.8%) were positive for this agent. Positivity was higher in whole blood samples. For SARS-CoV-2 of 188 samples processed by PCR, 23 (12.2%) were positive. The information on vaccination history for COVID-19 available in 63 cases showed that in 53 (84.1%) there was no history of it.⁶

Continued case reporting has reached 650 cases notified to WHO from 33 countries in 5 WHO regions between April 5 and May 26, 2022. Most cases continue to be reported as sporadic unrelated cases. The most affected region is Europe with 374 cases (58%) and 22 countries, followed by the United Kingdom with 222 cases (34%). The Region of the Americas reported 240 cases (216 from the USA); the Western Pacific Region, 34 cases; Southeast Asia, 14 and the Eastern Mediterranean Region, five. Although adenoviruses have been detected in 75% of cases in the United Kingdom, information from other countries is incomplete. Most of these samples have been typed as adenovirus 41F. Adenovirus-associated virus 2 has also been identified in the United Kingdom by metagenomics studies on whole blood and liver samples.⁷

Adenoviruses are double-stranded DNA viruses belonging to the Adenoviridae family that includes four genera and more than 100 serotypes. More than 50 adenovirus serotypes are known to infect humans and belong to species A to G. In species F are serotypes 40 and 41 that produce viral gastroenteritis. They usually cause acute respiratory infections, but depending on the type of adenovirus, they can also cause other diseases such as conjunctivitis, cystitis, pneumonia, croup, myocarditis and encephalitis. Infections in immunocompetent patients are generally mild and self-limiting, but in immunocompromised patients they can develop serious infections.³ To date, the pattern of acute hepatitis is not known to be typical of adenovirus infection in immunocompetent children.

The etiology of severe acute hepatitis in children to date, remains unknown. Several hypotheses have been proposed; the most recent publication on this aspect points to adenoviruses as the leading agent in the etiology of severe acute hepatitis in children. Six hypotheses are proposed, regarding this aspect, it is pointed out that the increase in cases with acute hepatitis and negative results for hepatitis A to E viruses occurs due to:

1. 1. A normal adenovirus infection due to one of the following: abnormal host susceptibility or response causing mild adenovirus infection to progress to hepatitis (direct or immunopathologic damage) that may be related to decreased exposure to adenoviruses due to prolonged isolation measures during the pandemic, a prolonged epidemic wave of common adenovirus infections that may exceptionally cause rare or unrecognized complications, susceptibility or abnormal host response to a previous infection with SARS-CoV-2 (Omicron variant) or other infection, susceptibility or abnormal host response to adenovirus infection due to co-infection with SARS-CoV-2 or other agent, abnormal host susceptibility or response to adenovirus infection due to toxin, drug or environmental exposure.

2. 2. A new variant of adenovirus, with or without the contribution of a cofactor.

3. 3. A post-SARS-CoV-2 infection syndrome.

4. 4. A drug, toxin, or environmental exposure.

5. 5. A new pathogen acting alone or as a co-infection.

6. 6. A new variant of SARS-CoV-2⁸

Regarding the possible role of SARS-CoV-2, a published hypothesis is that the clinical presentation of severe acute hepatitis in children may be a consequence of infection by adenovirus with intestinal tropism (41F) in children previously infected with SARS-CoV-2. The viral persistence of SARS-CoV-2 in the gastrointestinal tract can lead to the repeated release of viral proteins that behave as superantigens and that produce sustained activation of the immune system (T cells), and this response generates multisystem inflammatory syndrome in children.⁹

Initially, the possible association between cases of severe acute hepatitis in children negative for hepatitis A to E viruses and the effects attributable to vaccination against COVID-19 was considered among the hypotheses. This hypothesis seems remote and can be rejected when considering that most of the cases occurred in children who do not have a history of this vaccination.^3,4 Most publications describe the predominance of cases of severe acute hepatitis of unknown cause in young children, with children aged 5 years and younger who were not part of the groups vaccinated globally for vaccination against COVID-19. For this reason, the possibility of an aetiological role of vaccination against COVID-19 in this disease could be excluded.^3,4,5

In conclusion, the etiology of severe acute hepatitis in children, of which cases have been identified in more than 30 countries, remains unknown. The main hypothesis involves an adenovirus infection that is usually mild and self-limiting in immunocompetent children, but it is proposed that a cofactor is decisive for the infection to be serious and cause liver damage directly or mediated by the immune response. The pathogenesis and transmission routes are also unknown to date. There is no clear evidence of person-to-person transmission. The evolution of some cases to acute liver failure, requiring liver transplantation, and a non-negligible number of dead children determines that the impact for the affected pediatric population is considered high. Other etiologies related to different infectious agents, drugs, toxins, environmental factors remain under investigation without definitive results, but those obtained are considered of little estimation. Although the future evolution of the event associated with cases of severe acute hepatitis in children is unpredictable and numerous investigations to clarify its etiology are ongoing, it is currently a public health event of concern.

Referencias/References

1.  Schaefer TJ, John S. Acute Hepatitis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 20221.

2.  World Health Organization (WHO). Disease Outbreak News: Acute hepatitis of unknown aetiology - the United Kingdom of Great Britain and Northern Ireland 15 April 2022. Geneva: WHO; 2022. Available at: https://www.who.int/emergencies/disease-outbreaknews/item/acute-hepatitis-of-unknown-aetiology---the-united-kingdom-of-greatbritain-and-northern-ireland2.  . (Consultado en línea: 1 mayo 2022).

3.  UK Health Security Agency (UKHSA). Investigation into acute hepatitis of unknown aetiology in children in England: technical briefing, Version 1.0 25 April 2022 GOV-12076. London: UKHSA; 2022. Available at: https://www.gov.uk/government/publications/acute-hepatitis-technicalbriefing3.  . (Consultado en línea: 17 mayo 2022).

4.  Baker JM, Buchfellner M, Britt W, Sanchez V, Potter JL, Ingram LA, et al. Acute Hepatitis and Adenovirus Infection Among Children - Alabama, October 2021-February 2022. MMWR Morb Mortal Wkly Rep.2022; 71(18): 638-40. doi: https://10.15585/mmwr.mm7118e1.

5.  World Health Organization (WHO). Disease Outbreak News: Multi-Country - Acute, severe hepatitis of unknown origin in children 23 April 2022. Geneva: WHO; 2022. Available at: https://www.who.int/emergencies/disease-outbreak-news/item/multi-country-acutesevere-hepatitis-of-unknown-origin-in-children5.  .(Consultado en línea: 25 abril 2022).

6.  European Centre for Disease Prevention and Control (ECDC). Joint ECDC-WHO Regional Office for Europe Hepatitis of Unknown Origin in Children Surveillance Bulletin. Estocolmo: ECDC; 2022. Available at https://www.ecdc.europa.eu/en/hepatitis/joint-weekly-hepatitis-unknown-origin-children-surveillance-bulletin6.  . (Consultado en línea: 30 mayo 2022).

7.  World Health Organization (WHO). Disease Outbreak News: Acute hepatitis of unknown aetiology in children - Multi-country 27 May 2022. Geneva: WHO; 2022. Available at: https://www.who.int/emergencies/disease-outbreak-news/item/DON-389. (Consultado en línea: 30 mayo 2022).

8.  UK Health Security Agency (UKHSA). Investigation into acute hepatitis of unknown aetiology in children in England: technical briefing, Version 3.0 19 may 2022 GOV-12076. 2022. Available at: https://www.gov.uk/government/publications/acute-hepatitis-technical briefing8.  . (Consultado en línea: 30 mayo 2022).

9.  Brodin P, Arditi M. Severe acute hepatitis in children: investigate SARS-CoV-2 superantigens. Lancet Gastroenterol Hepatol. 2022; 7(7):594-5.doi: https:/10.1016/ S2468-1253(22)00166-2.

Received: June 03, 2022; Accepted: June 20, 2022

Autor para correspondencia: [e-mail]

⁽Médico Especialista II Grado en Microbiología, DrC Médicas, Investigador y Profesor titular. Médico Especialista Superior para la Microbiología. Viceministerio de Higiene, Epidemiología y Microbiología. Ministerio de Salud Pública de la República de Cuba