BACKGROUND

Acute hepatitis severely attacks previously healthy young children (age range: 11 months to five-year-old) across central Scotland.

It was on 5 April 2022, the International Health Regulations (IHR) National Focal Point (NFP) for the United Kingdom notified WHO of 10 cases of severe of this unknown aetiology.

Of these 10 cases, nine had onset of symptoms in March 2022 while one case had an onset of symptoms in January 2022. Symptoms included jaundice, diarrhoea, vomiting and abdominal pain. All 10 cases were detected when hospitalised. As of 8 April 2022, further investigations across the United Kingdom have identified a total of 74 cases (including the 10 cases) fulfilling the case definition.

The clinical syndrome in identified cases is of acute hepatitis with markedly elevated liver enzymes, often with jaundice, sometimes preceded by gastrointestinal symptoms, in children principally up to 10 years old. Some cases have required transfer to specialist children’s liver units and six children have undergone liver transplantation. As of 11 April, no death has been reported among these cases and one epidemiologically linked case has been detected.

Laboratory testing has excluded hepatitis type A, B, C, and E viruses (and D where applicable) in these cases while Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and/or adenovirus have been detected in several cases. The United Kingdom has recently observed an increase in adenovirus activity, which is co-circulating with SARS-CoV-2, though the role of these viruses in the pathogenesis (mechanism by which disease develops) is not yet clear. No other epidemiological risk factors have been identified to date, including recent international travel. Overall, the aetiology of the current hepatitis cases is still considered unknown and remains under active investigation.

Laboratory testing for additional infections, chemicals and toxins is underway for the identified cases. Following the notification from the UK, less than five cases (confirmed or possible) have been reported in Ireland, further investigations into these are ongoing. Additionally, three confirmed cases of acute hepatitis of unknown aetiology have been reported in children (age range 22-month-old to 13-year-old) in Spain. The national authorities are currently investigating these cases.

WHO RISK ASSESSMENT

The United Kingdom has reported a recent unexpected significant increase in cases of severe acute hepatitis of unknown aetiology in young children. Although the potential role of adenovirus and/or SARS-CoV-2 in the pathogenesis of these cases is one hypothesis, other infectious and non-infectious factors need to be fully investigated to properly assess and manage the risk.

As there is an on-going increasing trend in cases in the United Kingdom over the past month together with more extensive case searching, it is very likely that more cases will be detected before the aetiology has been found (either biological, chemical or other agent(s)) and corresponding appropriate control and prevention measures have been taken.

EXPLANATION ON ACUTE HEPATITIS

Acute hepatitis is a term used to describe a wide variety of conditions characterized by acute inflammation of the hepatic parenchyma or injury to hepatocytes resulting in elevated liver function indices. In general, hepatitis is classified as acute or chronic based on the duration of the inflammation and insult to the hepatic parenchyma. If the period of inflammation or hepatocellular injury lasts for less than six months, characterized by normalization of the liver function tests, it is called acute hepatitis.

In contrast, if the inflammation or hepatocellular injury persists beyond six months, it is termed chronic hepatitis. The most common infectious cause of acute hepatitis is due to a viral infection(acute viral hepatitis). Nevertheless, acute hepatitis can result from a wide variety of non-infectious causes as well that include but not limited to are drugs (drug-induced hepatitis), alcohol (alcoholic hepatitis), immunologic (autoimmune hepatitis, primary biliary cholangitis) or as a result of indirect insult secondary to biliary tract dysfunction (cholestatic hepatitis), pregnancy-related liver dysfunction, shock or metastatic disease.

TREATMENT/MANAGEMENT ON ACUTE HEPATITIS

The management of acute hepatitis depends on the specific etiological factor implicated in the acute injury to the hepatocytes. Hepatitis A and E are the most common infectious causes of acute hepatitis and usually have a self-limited clinical course, resolving in 2 to 4 weeks with supportive treatment that includes IV fluids, antiemetics, and symptomatic treatment. Patients should avoid the use of alcohol and other potentially hepatotoxic medications and over the counter supplements but otherwise.

They should also receive education about reducing the risk of transmission of infection to others. Acute acetaminophen ingestion is a common non- infectious cause of acute hepatitis leading to acute liver failure and needs to be considered in all patients presenting with signs and symptoms of acute liver failure. Prompt treatment with N-acetylcysteine should be initiated as early as possible after obtaining an initial history and acetaminophen testing. N-acetylcysteine can be administered orally or IV based on the clinical scenario as mentioned below.

• 72-hour oral protocol–  N-acetylcysteine oral: 140 mg/kg orally as a loading dose, followed by 70 mg/kg every 4 hours for a total of 17 doses
• 20 hour IV protocol– N-acetylcysteine IV: 150 mg/kg intravenously over 60 minutes as a loading dose, followed by 50 mg/kg over 4 hours (12.5 mg/k/ per hour for 4 hrs), then 100 mg/kg over 16 hours (6.25 mg/kg per hour for 16 hours)

Treatment with N-acetylcysteine is also recommended for all patients with acute liver failure except ischemic hepatitis, with or without evidence of acetaminophen overdose. The majority of the patient’s with minimal symptoms and abnormal liver function tests and normal liver synthetic function can be evaluated as an outpatient or referred to hepatology. In patients with persistently elevated liver function with no clear identification of a specific etiology, further evaluation with a liver biopsy is warranted.

Infrequently, patients with acute hepatitis associated with acute liver failure characterized by hepatic encephalopathy and coagulopathy (INR greater than 1.5) should be discussed with and evaluated by the hepatology team for possible transfer to the nearest liver transplant centre. There are several criteria scoring tools (e.g., King’s College Criteria) to help determine the need for referral for liver transplantation.

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WHO ADVICE

Further work is required to identify cases both inside the United Kingdom and internationally. The priority is to determine the aetiology of these cases to guide further clinical and public health actions. Any epidemiological links between or among the cases might provide indications for tracking the source of illness. Temporal and geographical information of the cases, as well as their contacts should be reviewed for potential risk factors. While some cases tested positive for SARS-CoV-2 and/or adenovirus, genetic characterization of viruses should be undertaken to determine any potential associations between cases. Member States are strongly encouraged to identify, investigate and report potential cases fitting the case definition.