On April 15, 2022, the World Health Organization issued an alert regarding the emergence of an outbreak of acute hepatitis of unknown etiology in the United Kingdom of Great Britain and Northern Ireland in previously generally healthy young children. Since then the number of hepatitis cases has increased and as of April 21, 2022, at least 169 cases of acute hepatitis of unknown origin had been reported in 12 countries [United Kingdom (114), Spain (13), Israel (12 ), United States (9), Denmark (6), Ireland (5), Netherlands (4), Italy (4), Norway (2), France (2), Romania (1) and Belgium (1)]. So far, 17 people, between 1 month old and 16 years old, have required a liver transplant and at least one death has been recorded.
The syndrome has been described as severe acute hepatitis with marked elevation of liver enzymes and jaundice, accompanied in most cases by previous gastrointestinal symptoms that include abdominal pain, diarrhea and vomiting. Most cases did not have fever. The common viruses that cause acute viral hepatitis (hepatitis A, B, C, D, and E viruses) were not detected in any of these cases. International travel or links to other countries have not been identified as factors based on the information currently available.
The common viruses that cause acute viral hepatitis (hepatitis A, B, C, D, and E viruses) have not been detected in any of the cases, but adenoviruses have been detected in at least 74 patients. Adenovirus F 41 has been identified in 18 cases. SARS-CoV-2 has been detected in 20 cases. And in 19 cases coinfection with SARS-CoV-2 and adenovirus has been detected.
Adenovirus F 41 could be the cause of acute hepatitis but the severity of the clinical picture has not yet been completely explained. Factors such as increased susceptibility among young children following a lower level of adenovirus circulation during the COVID-19 pandemic, the possible emergence of a new adenovirus, as well as co-infection with SARS-CoV-2, should be further investigated. background. Hypotheses related to the side effects of COVID-19 vaccines are currently not supported, since the vast majority of affected children did not receive the COVID-19 vaccine, therefore they are not related to the application of vaccines against COVID-19. Exclusion of other infectious and non-infectious explanations is necessary to fully assess and manage risk.
Case definition presented by WHO (April 23, 2022):
• Confirmed case: not currently available
• Probable case: A person presenting with acute hepatitis (non-hep AE*) with serum transaminase >500 IU/L (AST or ALT), who is 16 years of age or younger, since October 1, 2021
• Epi-linked case: Person who presents with acute hepatitis (non-hep AE*) of any age who is a close contact of a probable case, since October 1, 2021.
*If hepatitis AE serology results are awaited, but other criteria are met, these may be reported and will be classified as “classification pending.” Cases with other explanations for their clinical presentation are discarded.
The CDC recommends considering adenovirus testing in pediatric patients with hepatitis of unknown origin. NAAT (e.g., PCR) is preferred and can be performed on respiratory specimens, stool, rectal swab, or blood.
Adenoviruses are common human pathogens and have the capacity to cause diseases in the respiratory tract, eyes, intestine, liver, and urinary tract. They are non-enveloped, icosahedral viruses with a linear double-stranded DNA genome. They are divided into seven species (A–G). Human adenoviruses are classified into more than 100 subtypes, including serotypes 1–52 (which were identified by seroneutralization and hemagglutination inhibition assays) and genotypes 53–103 (which were classified by bioinformatic analyses). Different serotypes are associated with different diseases.
Adenovirus 40/41 gastroenteritis characterized by fever, vomiting, and diarrhea can cause severe illness and is a common cause of hospitalization. Adenovirus F41 infection is not seasonal, it can occur at any time of the year. The most susceptible are children under two years of age. In general, adenovirus infection is contracted through contact with secretions from an infected person or with a contaminated object. The infection can be transmitted through the air or water.
Diagnostic evaluation
When evaluating a patient with suspected hepatitis of unknown cause, diagnostic studies must be in-depth to identify possible infectious, toxic or metabolic etiologies. Part of the studies must include assessment of acute viral hepatitis (serology hepatitis A, B, C, D - where applicable -, and E), in addition to EBV, CMV and HIV. In the current epidemiological context, respiratory viruses (Influenza A and B, Adenovirus, SARS-CoV-2) and specific gastrointestinal pathogens (stool culture, identification of Adenovirus and rotavirus in fecal matter) should be considered. In addition, a history should be taken aimed at identifying different hepatotoxics.
Surveillance of viral hepatitis in Argentina
Viral hepatitis in Argentina constitute Mandatory Notification Events according to National Law 15,465/60, which obliges medical and laboratory personnel to notify cases throughout the country in effectors of any subsector (public, social security or private). Its specific objectives include:
• Detect new infections.
• Provide early warning of cases that require community prevention and control actions (cases and outbreaks of hepatitis A related to the consumption of contaminated water or food; outbreaks of hepatitis B or C from a possible common source such as those associated with health care). , aesthetic treatments or blood transfusions and blood products).
• Monitor the temporal and spatial distribution of cases
• Characterize affected populations by age, gender, risk factors; opportunity in access to diagnosis and treatment, among others.
• Contribute to improving the quality of care at all levels, including appropriate care of HCV and HBV positive donors.
• Contribute to eliminating mother-to-child transmission of hepatitis B.
• Evaluate the impact of the interventions, mainly the implemented prevention strategies with vaccines for hepatitis A and B, the detection of cases and implementation of hepatitis C treatments, the control of outbreaks and access to care for positive donors.
• Contribute to the estimation of prevalence in different populations.
• Contribute to estimating the burden of disease through the registry of the sequelae of viral hepatitis (fulminant hepatitis, hepatocellular carcinoma and cirrhosis associated with viral hepatitis).
Immunopreventable viral hepatitis
It is recalled that among the most frequent causes of serious viral hepatitis in pediatrics are hepatitis A and hepatitis B, which are two vaccine-preventable diseases. Both vaccines are included in the National Vaccination Calendar with the following schedules:
Hepatitis A: one dose given at 12 months of age (in people born after 2004).
Hepatitis B: three doses at 0, 1 and 6 months (the indication for this vaccine is universal).
The negative impact that the SARS-CoV-2 pandemic has had on both the supply and demand of vaccination services throughout the world should not be minimized and constitutes an urgent public health problem. The global decline recorded in vaccination coverage during the year 2020 is worrying in Argentina and the rest of the Region of the Americas.
Vaccination coverage with Pentavalent (3 doses): Coqueluche-Diphtheria-Tetanus-Hib-Hepatitis B
• 160,000 boys and girls under 1 year of age did not receive the complete primary scheme
• Last neonatal tetanus: 2007
• Last case of diphtheria: 2006. Cases are still recorded in countries in the Americas.
• Accumulation of susceptibles favors the appearance of outbreaks, especially in children under 1 year of age, with a greater risk of suffering from serious illnesses and higher mortality.
• 1 in 4 children did not complete their primary regimen with quintuple and inactivated polio vaccines.
DPT3 and IPV3 coverage by region of the country
• No inequalities were observed in access according to conditions of vulnerability.
• The coverage was heterogeneous in the different jurisdictions, registering up to 20 points of difference between the extremes.
• Heterogeneity of vaccination coverage.
• Low coverage in the Central region (with high population density).
National vaccination coverage at one year of age. Argentina, 2019-2020
• Hepatitis A vaccine coverage: A decrease of 6.2 points was observed in vaccination coverage between 2019 and 2020. This implied a drop of 7% compared to the coverage achieved in 2019.
Final considerations and recommendations for pediatricians:
• Although an increase in cases of acute hepatitis has not been observed in the country or in the region in relation to other years, we must raise awareness of the suspicion of hepatitis in the event of compatible cases according to definitions and carry out notification through the National System. of Health Surveillance (SNVS) or its epidemiological reference.
• It is important for the pediatrician to recognize the symptoms of hepatitis: asthenia, vomiting, abdominal pain, jaundice, hypocolia, choluria, fever, epistaxis and quickly request a laboratory test that includes blood count, hepatogram, proteinogram, blood glucose, coagulogram, urea and creatinine; and perform abdominal ultrasound. The patient must be referred to a Pediatric Hepatology center to continue with diagnostic studies.
• Many respiratory and gastrointestinal viruses can cause hepatitis, but their true incidence is not established, since not all of these viruses are routinely studied. Since the SARS-CoV-2 pandemic, the study of other respiratory viruses in hospitalized patients is more frequent, so the reported association with adenovirus could be related to the increase in records of infections due to these. virus.
• Most of the traditionally diagnosed acute hepatitis is indeterminate, that is, without a proven cause, after the most common causes have been ruled out: Hepatitis ABCE virus, Epstein-Barr virus (EBV), Cytomegalovirus (CMV), toxicity, autoimmunity. However, due to the reported association with adenovirus 41, the inclusion of the study of these viruses in all patients with severe acute hepatitis should be considered.
• Vaccination against hepatitis A and B has significantly reduced the circulation of these viruses in our population. However, a reduction in coverage is observed since the SARS-CoV-2 pandemic. It is recommended to start or complete vaccination schedules according to the National Immunization Calendar
• Hepatitis treatment is supportive, monitoring the development of liver failure, which is rare in the evolution of these patients.
• It is important to be cautious and provide serenity and adequate information to families, emphasizing vaccination for hepatitis A and B, maintaining ventilation conditions, hand and surface hygiene.
