#16,826
We've been following the rise of acute hepatitis in children around the world since early April, and while there are several plausible explanations under investigation, so far no definitive cause has been identified.
Yesterday the CDC's NCIRD (National Center for Immunization and Respiratory Diseases) published a preliminary technical report on what has been learned so far, along with avenues of investigation.
Due to its length I've only posted some excerpts, so you'll want to follow the link to read it in its entirety. I'll have a brief postscript after the break.
Technical Report: Acute Hepatitis of Unknown Cause
This is a technical report intended for scientific audiences. Additional information, including materials targeted to the general public, are available here.
Executive Summary
This report reviews what is currently known about acute hepatitis with unknown cause in children under the age of 11 years, and describes the investigations that CDC and state, local, tribal, and territorial partners are conducting.
As of June 15, 2022, 290 patients under investigation (PUIs) have been reported in 41 states and territories, with dates of onset on or after October 1, 2021. The median age of PUIs is 2 years. To date, 17 (6%) PUIs have required a liver transplant, and 11 (4%) have died; cause of death is under investigation. In the week prior to June 15, 16 additional PUIs were reported. However, only 9 PUIs experienced symptom onset between June 1-15, 2022.
The current PUI definition is:
Patient under investigation: Children <10 years of age with elevated (>500 U/L) aspartate aminotransferase (AST) or alanine aminotransferase (ALT) who have an unknown etiology for their hepatitis (with or without any adenovirus testing results, irrespective of the results) since October 1, 2021
CDC is investigating several etiological hypotheses, notably a possible association with any adenovirus infection, and specifically type-41 infection. Of the 236 PUIs for whom adenovirus testing was conducted on any specimen type (blood, respiratory specimens, stool), 45% were found to be positive for adenovirus. Additional hypotheses, including a possible association with current or previous SARS-CoV-2 infection, or other viruses, are also being evaluated. Details on the leading hypotheses, planned investigations, and what is known to date are available below.
Clinical providers caring for children with hepatitis of unknown etiology should refer to the latest guidance available. Guidance on adenovirus testing, typing, and testing submission is also available.
Disease Background
Hepatitis is inflammation of the liver. Its causes include viral infections, alcohol use, toxins, medications, and certain medical conditions. In the United States, the most common causes of viral hepatitis are hepatitis A, hepatitis B, and hepatitis C viruses [2]. Signs and symptoms of hepatitis include fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark urine, light-colored stools, joint pain, and jaundice [2]. Treatment of hepatitis depends on the underlying etiology.
Adenoviruses are doubled-stranded DNA viruses that spread by close personal contact, respiratory droplets, and fomites [3]. There are more than 50 types of immunologically distinct adenoviruses that can cause infections in humans. Adenoviruses most commonly cause respiratory illness, but some adenovirus types can cause other illnesses such as gastroenteritis, conjunctivitis, cystitis, and, less commonly, neurological disease [3]. There is no specific treatment for adenovirus infections.
Adenovirus type 41 commonly causes acute gastroenteritis in children, which typically presents as diarrhea, vomiting, and fever; it is often accompanied by respiratory symptoms [4]. While there have been case reports of hepatitis in immunocompromised children associated with adenovirus type 41 infection, adenovirus type 41 is not known to be a cause of hepatitis in otherwise healthy children [5, 6].
(SNIP)
Hypotheses under Investigation
CDC is investigating several etiologic hypotheses, notably a possible association with adenovirus infection, and specifically type-41 infection. Of the 236 patients under investigation for whom adenovirus testing was conducted on any specimen type (blood, respiratory, stool), 45% are positive for adenovirus. Ongoing and planned investigations include adenovirus testing, including typing and genome sequencing, for all PUIs with adequate specimens. This will facilitate understanding of the range of adenoviruses associated with acute hepatitis and if adenovirus is a previously unrecognized cause of pediatric hepatitis in non-immunocompromised children.
Selected additional etiologic possibilities include:
- Do some children, due to age or other factors, exhibit an atypical response to their first adenovirus (or other viral) infection which results in hepatitis? Pandemic mitigation measures have likely resulted in a large cohort of young children with minimal exposure to viral illnesses usually experienced in the first several years of life. Return to regular activities may have resulted in a larger than usual number of first infections, and at an older age than expected.
- Are multiple factors contributing to the illnesses seen among reported PUIs, as opposed to one primary driver? 30-50% [7-9] of liver failure in children is idiopathic; there are multiple known and unknown pathways to acute liver failure in children.
- Is acute hepatitis in children due to a combination of persistent or prior infection with SARS-CoV-2 (or other viruses) and adenovirus, causing an autoimmune phenomenon or superantigen reaction? Prevalence of an active SARS-CoV-2 infection is ~10% among PUIs for whom data is available, and up to 1/3 report history of prior COVID-19 infection. Testing for SARS-CoV-2 antibodies to confirm prior infections, as well as testing for viruses is ongoing.
- Is acute hepatitis in children a manifestation of Multisystem Inflammatory Syndrome in Children (MIS-C), an inflammatory condition that develops in a small proportion of children after infection with SARS-CoV- 2? MIS-C associated with COVID-19 most often presents with cardiac or renal organ involvement, but occasionally signs of hepatitis. Among over 8,000 US patients with MIS-C, <1% developed liver failure and nearly all were secondary to shock.
- Is pediatric acute hepatitis caused by an environmental trigger or ingested toxin? Although epidemiological investigations are still underway for the majority of PUIs, no associations have been found with pets, food, medication, toxins, or other exposures evaluated. However, this is analysis is preliminary and may change as additional information becomes available.
Risk Assessment (based on time of publication)
At this time, the incidence of acute hepatitis in children is not higher than pre-pandemic baseline levels, and severe outcomes are infrequent. Investigations are ongoing to better understand cases of acute hepatitis of unknown etiology in children. CDC encourages parents and caregivers to be aware of the symptoms of hepatitis – particularly jaundice, which is a yellowing of the skin or eyes – and to contact their child’s healthcare provider if present.
Social media is rife with speculation - often presented as `fact' - about the cause of these cases, and while some of these theories are plausible, many are not.
Unlike on the internet - where the best meme wins - real science requires credible evidence of causation.
Last week the UKHSA announced that their preliminary investigation into the cause of these hepatitis infections would be published this week.
The investigation continues to suggest a strong association with adenovirus. Adenovirus is the most frequently detected virus in samples tested and a formal epidemiological study is underway. Preliminary findings will be published on 16 June.
For whatever reason, that report has not yet appeared on the UKHSA website. Good science takes time, but hopefully we'll see that report in the next few days.
