Outbreak at a glance
Six hundred and fifty probable cases of acute hepatitis of unknown etiology have been reported to children in 33 countries in five WHO regions between April 5 and May 26, 2022. etiology of this severe acute hepatitis remains unknown and is being investigated; the cases are clinically more severe and a higher proportion develop acute liver failure compared to previous reports of acute hepatitis of unknown etiology in children. It remains to be seen if and where the cases detected are above reference levels. The WHO values global risk as moderate.
Outbreak description:
Following the news of WHO outbreaks of multinational diseases on acute hepatitis of unknown etiology published on April 23, 2022, there have been continued reports of cases of acute hepatitis of unknown cause among young children.
As of 26 May 2022, the WHO has reported 650 probable cases that fit the WHO case definition1 of 33 countries in five WHO regions, with an additional 99 cases pending classification. The majority of reported cases (n = 374; 58%) came from the WHO European region (22 countries), with 222 (34%) cases only from the United Kingdom of Great Britain and Northern Ireland. Probable cases and cases pending classification have also been reported in the Region of the Americas (n = 240, including 216 cases in the United States of America), the Western Pacific Region (n = 34), the South American Region. East Asia (n = 14) and the Eastern Mediterranean Region (n = 5) (Figure 1, Table 1).
1 WHO case study definition:
Confirmed: N / A currently
Likely: a person with acute hepatitis (non-hep AE *) with serum transaminase> 500 IU / L (AST or ALT), aged 16 years or less, as of October 1, 2021
Epi-linked: a person with acute hepatitis (not hep AE *) of any age who is in close contact with a probable case, as of October 1, 2021
* If the results of hepatitis AE serology are expected, but other criteria are met, these can be reported and will be classified as “pending classification”. Cases are discarded with other explanations for their clinical presentation.
** Delta testing is not necessary, as it is only performed in people with HBsAg positive to establish the presence of coinfection.
Figure 1. Distribution of probable cases of severe acute hepatitis of unknown etiology in children by country, as of May 26, 2022 (n = 650).
Table 1. Classification of probable cases reported by country as of October 1, 2021, as of May 26, 2022.
Of the 650 probable cases, at least 38 (6%) children required transplants and nine (1%) deaths were reported to the WHO.
According to the latest Joint Monitoring Report of the WHO Regional Office for Europe (EURO) and the European Center for Disease Prevention and Control (ECDC) on cases in EU / EEA countries have been notified through the European Surveillance System (TESSy), as of May 20, 2022:
- Three-quarters (75.4%) of cases are under 5 years old.
- Of the 156 cases with hospital admission information, 22 (14.1%) were admitted to an intensive care unit. Of the 117 cases for which this information was available, 14 (12%) received a liver transplant.
- In total, 181 cases were tested for adenovirus by any type of specimen, of which 110 (60.8%) tested positive. The positivity rate was the highest in whole blood samples (69.5%).
- Of the 188 PCR cases tested for SARS-CoV-2, 23 (12.2%) tested positive. SARS-CoV-2 serology results were only available for 26 cases, of which 19 (73.1%) had a positive finding.
- Of the 63 cases with vaccination data against COVID-19, 53 (84.1%) were not vaccinated.
Most of the reported cases appear unrelated and extensive epidemiological research is being conducted to identify common exposures, risk factors, or links between cases. Two pairs of epidemiologically related cases have been reported in Scotland and related cases have also been reported in the Netherlands.
Based on the definition of work cases for probable cases, laboratory tests have ruled out hepatitis AE viruses in these children. SARS-CoV-2 and / or adenovirus have been detected in some cases, although the data reported to the WHO are incomplete. The United Kingdom has recently seen an increase in the activity of adenoviruses, which co-circulates with SARS-CoV-2, although the role of these viruses in pathogenesis is not yet clear.
Various national authorities, research networks and different WHO working groups and partners are conducting more detailed epidemiological, clinical, laboratory, histopathological and toxicological research into the possible causes of these cases. Additional investigations are also planned to determine if and where the cases detected are above reference levels.
Public health response
- Responses to clinical and public health incidents in the affected regions have been activated to coordinate case research with the investigation of the cause of the disease in these children.
- Additional investigations by various national authorities are ongoing to include more detailed exposure histories, toxicology tests, and additional virological / microbiological testing.
- In addition, a case-control study is being conducted in the UK to determine the frequency of adenovirus screening in hospitalized cases of acute hepatitis compared to those hospitalized for other reasons. Research is also being coordinated between WHO regions and with partners.
- The WHO continues to support the exchange of information with professional networks and specialized liver units.
- Guidelines are being developed to support Member States in diagnosing, investigating and reporting cases, clinical characterization and clinical management of acute hepatic impairment in children.
- The initial survey of pediatric and hepatic centers conducted mainly in Europe has been expanded to establish whether the number of current cases of severe acute hepatitis of unknown etiology in children is above the background rates in several countries or only in certain countries.
WHO risk assessment
The WHO rates global risk as moderate given that:
- The etiology of this severe acute hepatitis remains unknown and is being investigated; cases are clinically more severe and a higher proportion develop acute liver failure compared to previous reports of acute hepatitis of unknown etiology in children;
- The WHO currently has limited epidemiological, laboratory, histopathological and clinical information;
- The actual number of cases may be underestimated in some settings, in part due to the existing limited surveillance capability;
- The source and mode of transmission of potential etiological agents have not yet been determined, so the likelihood of further spread cannot be fully assessed;
- Although no reports of healthcare associated infections are available, human-to-human transmission cannot be ruled out, as there have been some reports of epidemiologically related cases.
Adenovirus has been found in 75% of cases tested in the UK, but data from other countries are incomplete. Of the small number of samples that have been typed so far, most have been confirmed for adenovirus type 41 (in the UK, in 27 of the 35 cases with one result available). Adenovirus 2-associated virus (AAV-2) has also been detected in a small number of cases in the UK by metagenomics in liver and blood samples. However, in many of the remaining cases, adequate samples were not taken, which highlights the importance of proper sampling (whole blood) to further characterize the type of adenovirus detected. In addition, adenovirus type 41 infection has not been previously associated with this clinical presentation in healthy children.
Although adenovirus is a plausible hypothesis as part of the pathogenesis mechanism, further research is underway for the causative agent; Adenovirus infection (which usually causes self-limiting mild gastrointestinal or respiratory infections in young children) does not fully explain the more serious clinical picture observed with these cases. Factors such as increased susceptibility among young children after a lower level of adenovirus circulation during the COVID-19 pandemic, the potential emergence of a new adenovirus, co-infection with SARS-CoV-2 or a complication of a previous SARS-CoV-2 infection. , which leads to superantigen-mediated immune cell activation, proposed a causal mechanism of multisystem inflammatory syndrome in children that needs further investigation. Hypotheses related to the side effects of COVID-19 vaccines are currently not supported, as most affected children did not receive these vaccines. Other infectious and non-infectious explanations should be excluded as independent or contributing factors to fully assess and manage risk. It is important to note that the current apparent association identified with adenovirus could be an incidental finding due to improved laboratory testing in association with increased levels of adenovirus community transmission. This will be further clarified by the expansion of adenovirus testing to other cases beyond Europe and the United States, and the report of the findings of the ongoing UKHSA case and control study. doing.
The absence of a confirmed etiology poses additional challenges in some countries, including the implementation of the WHO case definition and greater diagnostic exclusion, due to limited testing capacity, including hepatitis AE viruses. and adenovirus. The presence of cases of acute hepatitis in children in countries where no cases have yet been detected or reported cannot be ruled out, but it is unlikely that symptomatic and severe patients in need of hospitalization will not be detected.
WHO Council
Member States are encouraged to identify, investigate and report potential cases that fit the previous case definition. Epidemiological and basic risk factor …